{"gname":"University of Massachusetts Chan Medical School ","grp_id":"44","rels":[{"rel_title":"Multimodal Immune Profile Score (IPS) as a Pan-Cancer Biomarker for Stratifying Outcomes of Immune Checkpoint Inhibitor Benefit in Microsatellite Stable Colorectal Cancer and Rare Solid Tumors","rel_doi":"10.64898\/2026.10.07.26364989","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364989","rel_abs":"Background Immune checkpoint inhibitor (ICI) therapies have revolutionized oncology, but identifying patients who benefit remains a challenge, particularly in populations where ICIs are not the standard of care, including microsatellite stable colorectal cancer (MSS CRC) and rare solid cancers. We evaluated real-world performance of the Immune Profile Score (IPS), a validated DNA- and RNA-based molecular signature, in these cohorts. Methods In an exploratory analysis, we analyzed two real-world cohorts: 1) MSS CRC; and 2) MSS, tumor mutational burden-low rare solid cancers treated with off-label ICI. IPS-High and IPS-Low were calculated using a previously validated threshold. Cox proportional hazards models were fit to demonstrate prognostic utility for real-world overall survival (rwOS). In MSS CRC, time-to-next-treatment (TTNT) on prior non-ICI therapy was compared to rwOS on subsequent ICI therapy. Results In MSS CRC (n=46), IPS-High patients (13%) demonstrated clinically meaningful improvement in rwOS versus IPS-Low (Median OS: not reached vs 7.3 months; HR = 0.22, 90% CI 0.04-1.16). While IPS was not associated with TTNT on the preceding non-ICI line (HR = 1.07, 90% CI 0.60-1.91), it was associated with OS in patients receiving later line ICI (HR 0.21, 90% CI 0.04-1.22). In the rare cancers cohort (n=90; 26 unique malignancies), IPS-High (17.8%) was associated with longer OS to ICI therapy (HR = 0.26, 90% CI 0.11-0.61), even when restricted to histologies represented in both IPS groups (HR = 0.18, 90%, CI 0.05-0.62). Conclusions Preliminary evidence suggests that IPS may serve as a generalizable, pan-cancer biomarker capable of stratifying outcomes for ICI treatment in populations traditionally excluded from immunotherapy benefit.","rel_num_authors":26,"rel_authors":[{"author_name":"Michelle A. Ting-Lin","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Emmanuel S. Antonarakis","author_inst":"University of Minnesota, Minneapolis, MN"},{"author_name":"Xifeng Wang","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Rossin Erbe","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Alia D. Zander","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Yan Liu","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Ailin Jin","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Gregory A. Vidal","author_inst":"Clinical Research and Breast Oncology Program, Lee S Schwartzberg Research Center, West Cancer Center and Research Institute, Memphis, TN"},{"author_name":"Scott M. Haake","author_inst":"Vanderbilt Health, Nashville, TN, USA; Nashville VA Hospital, Nashville, TN"},{"author_name":"Michelle M. Stein","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Dana F. DeSantis","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Kyle A. Beauchamp","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Matthew E. Campbell","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Ezra E.W. Cohen","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Seung Won Hyun","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Ronan J. Kelly","author_inst":"Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas"},{"author_name":"Aparna Kalyan","author_inst":"Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL"},{"author_name":"Babar Bashir","author_inst":"Thomas Jefferson University, Philadelphia, PA"},{"author_name":"B.J. Rimel","author_inst":"University of Washington and Fred Hutch Cancer Center, Seattle, WA"},{"author_name":"Thomas J. Herzog","author_inst":"University of Cincinnati Cancer Center; University of Cincinnati, Cincinnati, OH"},{"author_name":"Victoria L. Chiou","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Chithra Sangli","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Halla Nimeiri","author_inst":"Tempus AI, Inc., Chicago, IL"},{"author_name":"Jay Carlson","author_inst":"Mercy Health, St. Louis, MO"},{"author_name":"Diane M. Simeone","author_inst":"UCSD Moores Cancer Center, San Diego, CA"},{"author_name":"John H. Strickler","author_inst":"Mayo Clinic, Jacksonville, FL"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"The transition to retirement and dementia risk: An application of sequence analysis","rel_doi":"10.64898\/2026.10.07.26364998","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364998","rel_abs":"Background: Retirement is a major life transition that may influence cognitive aging. Retirement pathways are becoming increasingly diversified, yet evidence on how heterogeneous retirement trajectories relate to dementia risk remains limited. This study used sequence and cluster analysis to characterize thousands of transition-to-retirement trajectories, including retirement timing and work intensity, to estimate associations with dementia risk. Methods: We used data from 13,879 participants in the U.S. Health and Retirement Study. Our exposure was transition-to-retirement trajectories between ages 51 and 75 identified using sequence and cluster analysis. Our outcome was a validated algorithmically derived dementia probability measure. We estimated associations between trajectory clusters and dementia risk beginning at age 76 using generalized estimating equations, adjusting for sociodemographic characteristics. Inverse probability weights were used to account for attrition. Results: We identified ten distinct transition-to-retirement trajectories characterized by differences in timing of retirement, part-time work, disability, and labor force attachment. Compared with individuals retiring after full-time work in their early-to-mid 60s, dementia risk was similar among those retiring earlier or later from full-time work. In contrast, individuals with sustained part-time employment between ages 51 and 75 had lower odds of dementia (OR: 0.62, 95% CI: 0.48, 0.80), while trajectories characterized by prolonged disability were associated with higher odds of dementia (OR: 1.53, 95% CI: 1.22, 1.91). Conclusions: Retirement timing alone showed limited association with later-life dementia risk, whereas sustained part-time employment and disability-related trajectories were more strongly associated with dementia risk. These findings suggest that employment intensity and health-related exit from the labor force may be more relevant for dementia risk than retirement timing, and that gradual and flexible work-to-retirement transitions may benefit brain health. Background: Retirement is a major life transition that may influence cognitive aging. Retirement pathways are becoming increasingly diversified, yet evidence on how heterogeneous retirement trajectories relate to dementia risk remains limited. This study used sequence and cluster analysis to characterize thousands of transition-to-retirement trajectories, including retirement timing and work intensity, to estimate associations with dementia risk. Methods: We used data from 13,879 participants in the U.S. Health and Retirement Study. Our exposure was transition-to-retirement trajectories between ages 51 and 75 identified using sequence and cluster analysis. Our outcome was a validated algorithmically derived dementia probability measure. We estimated associations between trajectory clusters and dementia risk beginning at age 76 using generalized estimating equations, adjusting for sociodemographic characteristics. Inverse probability weights were used to account for attrition. Results: We identified ten distinct transition-to-retirement trajectories characterized by differences in timing of retirement, part-time work, disability, and labor force attachment. Compared with individuals retiring after full-time work in their early-to-mid 60s, dementia risk was similar among those retiring earlier or later from full-time work. In contrast, individuals with sustained part-time employment between ages 51 and 75 had lower odds of dementia (OR: 0.62, 95% CI: 0.48, 0.80), while trajectories characterized by prolonged disability were associated with higher odds of dementia (OR: 1.53, 95% CI: 1.22, 1.91). Conclusions: Retirement timing alone showed limited association with later-life dementia risk, whereas sustained part-time employment and disability-related trajectories were more strongly associated with dementia risk. These findings suggest that employment intensity and health-related exit from the labor force may be more relevant for dementia risk than retirement timing, and that gradual and flexible work-to-retirement transitions may benefit brain health.","rel_num_authors":7,"rel_authors":[{"author_name":"Lucia Pacca","author_inst":"Washington University in Saint Louis"},{"author_name":"Jillian Hebert","author_inst":"Washington University in St. Louis"},{"author_name":"Dawn C Carr","author_inst":"Claude Pepper Center and Department of Sociology, Florida State University"},{"author_name":"Willa D. Brenowitz","author_inst":"Kaiser Permanente Center for Health Research, Portland, Oregon, USA"},{"author_name":"M. Maria Glymour","author_inst":"Boston University School of Public Health"},{"author_name":"Amal Harrati","author_inst":"Community and Social Health, Kaiser Permanente, USA"},{"author_name":"Anusha M Vable","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"Protocol and Statistical Analysis Plan for the Waveform Capnography versus Colorimetric Carbon Dioxide Detection During Tracheal Intubation of Critically Ill Adults (WAVE) Study","rel_doi":"10.64898\/2026.10.07.26364973","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364973","rel_abs":"Background: During emergency tracheal intubation, clinicians use waveform capnography or colorimetric carbon dioxide (CO2) detection to confirm exhaled CO2 from the endotracheal tube to determine its location. Both devices reliably yield a negative result when the tube is in the esophagus. However, in most emergency intubations the tube is correctly located in the trachea, and in this circumstance the relative diagnostic accuracy of the two devices is uncertain. If one device more often fails to detect exhaled CO2 despite correct tube placement (a false negative result), this could lead to unnecessary tube removal, repeated intubation attempts, and an increased risk of serious complications. Research Question: Among critically ill adults undergoing emergency tracheal intubation, is waveform capnography or colorimetric CO2 detection more sensitive for identifying an endotracheal tube correctly placed in the trachea? Study Design and Methods: The WAVE study is a pragmatic, prospective, paired diagnostic accuracy study conducted in emergency departments and intensive care units in the United States. The study compares waveform capnography and colorimetric CO2 detection (index tests) against a non-CO2-based reference standard for endotracheal tube location among 2,092 critically ill adults undergoing tracheal intubation. The primary outcome is the sensitivity of each index test for identifying a tube located in the trachea. The secondary outcome is specificity for identifying a tube located outside the trachea. Results: Enrollment began on April 21, 2025 and is ongoing, with completion anticipated in 2026. Interpretation: The WAVE study will provide prospective evidence comparing waveform capnography with colorimetric CO2 detection for determination of endotracheal tube location in critically ill adults. These findings may inform clinical practice and guideline recommendations regarding the optimal test of exhaled CO2 for use in the ED and ICU. Prespecifying the protocol and statistical analysis plan before completion of enrollment enhances the rigor, reproducibility, and transparency of the study.","rel_num_authors":32,"rel_authors":[{"author_name":"Aaron E Robinson","author_inst":"Hennepin County Medical Center"},{"author_name":"Matthew E Prekker","author_inst":"Hennepin County Medical Center"},{"author_name":"Avignat S Patel","author_inst":"Lahey Hospital & Medical Center"},{"author_name":"Michael Waxman","author_inst":"Albany Medical College"},{"author_name":"John P Gaillard","author_inst":"Wake Forest School of Medicine"},{"author_name":"Shilpa Sridhar","author_inst":"Ohio State University School of Medicine"},{"author_name":"Bjorn C Westgard","author_inst":"Regions Hospital"},{"author_name":"Akram Khan","author_inst":"Oregon Health & Science University"},{"author_name":"J Taylor Herbert","author_inst":"Duke University School of Medicine"},{"author_name":"Alexandra L Schick","author_inst":"Regions Hospital"},{"author_name":"Kevin G Buell","author_inst":"Rush University Medical Center"},{"author_name":"Michael Gottlieb","author_inst":"Rush University Medical Center"},{"author_name":"Alec Bunting","author_inst":"Hennepin County Medical Center"},{"author_name":"Fraser Mackay","author_inst":"Lahey Hospital & Medical Center"},{"author_name":"Alexander Bracey","author_inst":"Albany Medical College"},{"author_name":"Jordan E Nogle","author_inst":"Wake Forest School of Medicine"},{"author_name":"Matthew C Exline","author_inst":"Ohio State University School of Medicine"},{"author_name":"Matthew Dillon","author_inst":"Oregon Health & Science University"},{"author_name":"Vijay Krishnamoorthy","author_inst":"Duke University School of Medicine"},{"author_name":"Karen E Jackson","author_inst":"Rush University Medical Center"},{"author_name":"Thomas Alcorn","author_inst":"Rush University Medical Center"},{"author_name":"Taya Haas","author_inst":"Hennepin County Medical Center"},{"author_name":"Ian Ward A. Maia","author_inst":"Universidade de Sao Paulo"},{"author_name":"Wesley H. Self","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Todd W Rice","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Matthew W Semler","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jonathan D Casey","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Lianne Siegel","author_inst":"University of Minnesota School of Public Health"},{"author_name":"Joseph S Koopmeiners","author_inst":"University of Minnesota School of Public Health"},{"author_name":"Joanna Kuo","author_inst":"Hennepin County Medical Center"},{"author_name":"Michael A Puskarich","author_inst":"Hennepin County Medical Center"},{"author_name":"Brian E Driver","author_inst":"Hennepin County Medical Center"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"Protocol and Statistical Analysis Plan for the Waveform Capnography versus Colorimetric Carbon Dioxide Detection During Tracheal Intubation of Critically Ill Adults (WAVE) Study","rel_doi":"10.64898\/2026.10.07.26364973","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364973","rel_abs":"Background: During emergency tracheal intubation, clinicians use waveform capnography or colorimetric carbon dioxide (CO2) detection to confirm exhaled CO2 from the endotracheal tube to determine its location. Both devices reliably yield a negative result when the tube is in the esophagus. However, in most emergency intubations the tube is correctly located in the trachea, and in this circumstance the relative diagnostic accuracy of the two devices is uncertain. If one device more often fails to detect exhaled CO2 despite correct tube placement (a false negative result), this could lead to unnecessary tube removal, repeated intubation attempts, and an increased risk of serious complications. Research Question: Among critically ill adults undergoing emergency tracheal intubation, is waveform capnography or colorimetric CO2 detection more sensitive for identifying an endotracheal tube correctly placed in the trachea? Study Design and Methods: The WAVE study is a pragmatic, prospective, paired diagnostic accuracy study conducted in emergency departments and intensive care units in the United States. The study compares waveform capnography and colorimetric CO2 detection (index tests) against a non-CO2-based reference standard for endotracheal tube location among 2,092 critically ill adults undergoing tracheal intubation. The primary outcome is the sensitivity of each index test for identifying a tube located in the trachea. The secondary outcome is specificity for identifying a tube located outside the trachea. Results: Enrollment began on April 21, 2025 and is ongoing, with completion anticipated in 2026. Interpretation: The WAVE study will provide prospective evidence comparing waveform capnography with colorimetric CO2 detection for determination of endotracheal tube location in critically ill adults. These findings may inform clinical practice and guideline recommendations regarding the optimal test of exhaled CO2 for use in the ED and ICU. Prespecifying the protocol and statistical analysis plan before completion of enrollment enhances the rigor, reproducibility, and transparency of the study.","rel_num_authors":32,"rel_authors":[{"author_name":"Aaron E Robinson","author_inst":"Hennepin County Medical Center"},{"author_name":"Matthew E Prekker","author_inst":"Hennepin County Medical Center"},{"author_name":"Avignat S Patel","author_inst":"Lahey Hospital & Medical Center"},{"author_name":"Michael Waxman","author_inst":"Albany Medical College"},{"author_name":"John P Gaillard","author_inst":"Wake Forest School of Medicine"},{"author_name":"Shilpa Sridhar","author_inst":"Ohio State University School of Medicine"},{"author_name":"Bjorn C Westgard","author_inst":"Regions Hospital"},{"author_name":"Akram Khan","author_inst":"Oregon Health & Science University"},{"author_name":"J Taylor Herbert","author_inst":"Duke University School of Medicine"},{"author_name":"Alexandra L Schick","author_inst":"Regions Hospital"},{"author_name":"Kevin G Buell","author_inst":"Rush University Medical Center"},{"author_name":"Michael Gottlieb","author_inst":"Rush University Medical Center"},{"author_name":"Alec Bunting","author_inst":"Hennepin County Medical Center"},{"author_name":"Fraser Mackay","author_inst":"Lahey Hospital & Medical Center"},{"author_name":"Alexander Bracey","author_inst":"Albany Medical College"},{"author_name":"Jordan E Nogle","author_inst":"Wake Forest School of Medicine"},{"author_name":"Matthew C Exline","author_inst":"Ohio State University School of Medicine"},{"author_name":"Matthew Dillon","author_inst":"Oregon Health & Science University"},{"author_name":"Vijay Krishnamoorthy","author_inst":"Duke University School of Medicine"},{"author_name":"Karen E Jackson","author_inst":"Rush University Medical Center"},{"author_name":"Thomas Alcorn","author_inst":"Rush University Medical Center"},{"author_name":"Taya Haas","author_inst":"Hennepin County Medical Center"},{"author_name":"Ian Ward A. Maia","author_inst":"Universidade de Sao Paulo"},{"author_name":"Wesley H. Self","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Todd W Rice","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Matthew W Semler","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jonathan D Casey","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Lianne Siegel","author_inst":"University of Minnesota School of Public Health"},{"author_name":"Joseph S Koopmeiners","author_inst":"University of Minnesota School of Public Health"},{"author_name":"Joanna Kuo","author_inst":"Hennepin County Medical Center"},{"author_name":"Michael A Puskarich","author_inst":"Hennepin County Medical Center"},{"author_name":"Brian E Driver","author_inst":"Hennepin County Medical Center"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"Advancing genetic pathogenicity prediction with three-dimensional proteoform-phenotype analysis","rel_doi":"10.64898\/2026.10.07.26364649","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364649","rel_abs":"Ascertaining the pathogenicity and clinical relevance of genetic mutations is a longstanding challenge across human disease. This is particularly relevant for genes with many variants of unknown significance (VUS), such as PRPH2-retinopathy, where complex variable phenotype patterns and limited genotype correlations hinder application of precision-medicine therapies. Recent AI-based pathogenicity tools, while powerful, may be limited by insufficient mechanistic or phenotypic training data. We established a three-dimensional proteoform-phenotype analysis framework by combining AI-generated protein structural models with clinical genomics data, in which expert consensus adjudicates model outputs through a human-in-the-loop AI approach, to evaluate 46 curated pathogenic missense variants against a background VUS pool. The framework was prospectively validated using an independently evaluated clinical patient cohort. This analysis resolved spatial biophysical signatures corresponding to distinct clinical phenotypes (i.e., retinitis pigmentosa, macular dystrophy, and pattern dystrophy) as well as complex blended presentations. Leveraging these confirmed structural signatures, we prioritized high-risk VUS. This mechanism-resolved framework can be extended to other therapeutically actionable genes to identify novel causal variants and improve diagnosis, prognosis, and better select rare, eligible patients for emerging molecular gene therapy trials.","rel_num_authors":13,"rel_authors":[{"author_name":"Young Joo Sun","author_inst":"Stanford University"},{"author_name":"Gabriel Velez","author_inst":"Stanford University"},{"author_name":"Angela S. Li","author_inst":"Stanford University"},{"author_name":"Aarushi Kumar","author_inst":"Stanford University"},{"author_name":"Jennifer T. Vu","author_inst":"Stanford University"},{"author_name":"Claudia J. Phillips","author_inst":"Stanford University"},{"author_name":"Ditte K. Rasmussen","author_inst":"Stanford University"},{"author_name":"Jin Kyun Oh","author_inst":"Columbia University"},{"author_name":"Mauricio G.S. Costa","author_inst":"Fundacao Oswaldo Cruz"},{"author_name":"Stephen H. Tsang","author_inst":"Columbia University"},{"author_name":"Yang Sun","author_inst":"Stanford University"},{"author_name":"Alexander G. Bassuk","author_inst":"University of Iowa"},{"author_name":"Vinit B. Mahajan","author_inst":"Stanford University"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"Advancing genetic pathogenicity prediction with three-dimensional proteoform-phenotype analysis","rel_doi":"10.64898\/2026.10.07.26364649","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364649","rel_abs":"Ascertaining the pathogenicity and clinical relevance of genetic mutations is a longstanding challenge across human disease. This is particularly relevant for genes with many variants of unknown significance (VUS), such as PRPH2-retinopathy, where complex variable phenotype patterns and limited genotype correlations hinder application of precision-medicine therapies. Recent AI-based pathogenicity tools, while powerful, may be limited by insufficient mechanistic or phenotypic training data. We established a three-dimensional proteoform-phenotype analysis framework by combining AI-generated protein structural models with clinical genomics data, in which expert consensus adjudicates model outputs through a human-in-the-loop AI approach, to evaluate 46 curated pathogenic missense variants against a background VUS pool. The framework was prospectively validated using an independently evaluated clinical patient cohort. This analysis resolved spatial biophysical signatures corresponding to distinct clinical phenotypes (i.e., retinitis pigmentosa, macular dystrophy, and pattern dystrophy) as well as complex blended presentations. Leveraging these confirmed structural signatures, we prioritized high-risk VUS. This mechanism-resolved framework can be extended to other therapeutically actionable genes to identify novel causal variants and improve diagnosis, prognosis, and better select rare, eligible patients for emerging molecular gene therapy trials.","rel_num_authors":13,"rel_authors":[{"author_name":"Young Joo Sun","author_inst":"Stanford University"},{"author_name":"Gabriel Velez","author_inst":"Stanford University"},{"author_name":"Angela S. Li","author_inst":"Stanford University"},{"author_name":"Aarushi Kumar","author_inst":"Stanford University"},{"author_name":"Jennifer T. Vu","author_inst":"Stanford University"},{"author_name":"Claudia J. Phillips","author_inst":"Stanford University"},{"author_name":"Ditte K. Rasmussen","author_inst":"Stanford University"},{"author_name":"Jin Kyun Oh","author_inst":"Columbia University"},{"author_name":"Mauricio G.S. Costa","author_inst":"Fundacao Oswaldo Cruz"},{"author_name":"Stephen H. Tsang","author_inst":"Columbia University"},{"author_name":"Yang Sun","author_inst":"Stanford University"},{"author_name":"Alexander G. Bassuk","author_inst":"University of Iowa"},{"author_name":"Vinit B. Mahajan","author_inst":"Stanford University"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"Locus coeruleus intensity as a marker of early-stage Alzheimers disease: associations with plasma pTau217 and memory","rel_doi":"10.64898\/2026.10.07.26364896","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364896","rel_abs":"INTRODUCTION: The locus coeruleus (LC) is one of the earliest sites of Alzheimers disease (AD) pathophysiological changes. LC magnetic resonance imaging (MRI) intensity may reflect effects of AD pathophysiology on the LC, providing a biomarker of early-stage AD. This study examined relationships among MRI-derived LC intensity, plasma phosphorylated tau 217 (pTau217), and memory in older adults without dementia. METHODS: Independently living adults aged 59-89 years (N = 163) underwent neuropsychological assessment and T1-weighted fast spin-echo MRI. We quantified a bilateral LC contrast ratio relative to a pontine reference region, averaged across axial slices. Plasma pTau217 was measured using the Quanterix ALZpath p-Tau217 Advantage PLUS assay. For a subset (n = 127), a memory composite score was calculated. RESULTS: After adjustment for age, sex, and APOE4 carrier status, lower LC intensity was associated with higher plasma pTau217 concentrations (B = 0.17, P = .02). Each 1-SD decrease in LC intensity was associated with 53% higher odds of pTau217 positivity (P = .03). In models additionally adjusted for education, a significant LC x pTau217 interaction for memory (B = 0.18, P = .009) indicated that lower LC intensity was associated with worse memory at low (P = .01), but not high (P = .64) pTau217 levels. DISCUSSION: These findings support MRI-derived LC intensity as a marker of early AD-related processes and suggest that LC intensity may provide complementary information not captured by plasma pTau217 alone. Longitudinal studies are warranted to determine how these relationships change across the early stages of AD.","rel_num_authors":23,"rel_authors":[{"author_name":"Melanie Quiring","author_inst":"University of Southern California"},{"author_name":"Yuhan Shuai","author_inst":"University of California, San Francisco"},{"author_name":"Wenhui Zhao","author_inst":"University of Southern California"},{"author_name":"John Paul Alitin","author_inst":"University of Southern California"},{"author_name":"Arunima Kapoor","author_inst":"University Of California, Irvine"},{"author_name":"Allison C Engstrom","author_inst":"University of California, Irvine"},{"author_name":"Jillian L Joyce","author_inst":"University of Southern California,"},{"author_name":"Preeti Iyengar","author_inst":"University of Southern California,"},{"author_name":"Trevor Lohman","author_inst":"University of Southern California"},{"author_name":"Basant Lashin","author_inst":"University of Southern California,"},{"author_name":"Aimee Gaubert","author_inst":"University of Southern California"},{"author_name":"Fatemah Shenasa","author_inst":"University of California Irvine"},{"author_name":"Lorena Contreras","author_inst":"University of Southern California,"},{"author_name":"Kevin W Law","author_inst":"University of Southern California,"},{"author_name":"Farrah Ferrer","author_inst":"University of Southern California,"},{"author_name":"Danny JJ Wang","author_inst":"University of Southern California,"},{"author_name":"Elizabeth Head","author_inst":"University of California, Irvine"},{"author_name":"Rond Malhas","author_inst":"University of California, Irvine"},{"author_name":"Kathleen Rodgers","author_inst":"University of Arizona"},{"author_name":"S. Duke Han","author_inst":"University of Southern California"},{"author_name":"Julian F. Thayer","author_inst":"The University of California Irvine"},{"author_name":"Mark W Bondi","author_inst":"University of California, San Diego"},{"author_name":"Daniel A. Nation","author_inst":"University of Southern California"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"A Blood-Based Synaptic Biomarker in Neuronally-Enriched Extracellular Vesicles Predicts Disability Progression in Progressive Multiple Sclerosis","rel_doi":"10.64898\/2026.10.07.26364982","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364982","rel_abs":"Progressive multiple sclerosis (PMS) lacks blood-based biomarkers of the neurodegenerative processes driving disability. We measured synaptopodin, a postsynaptic protein, in neuronal-enriched extracellular vesicles (NEVs) across two independent cohorts: the SPRINT-MS trial (n=184) and a real-world validation cohort (n=268). A one SD increase in baseline synaptopodin was associated with ~32% lower risk of confirmed disability progression in PMS (p=0.011), with the strongest effect in secondary PMS (SPMS) (~57% lower odds, p=0.019). This SPMS association was replicated in the validation cohort (~60% lower odds, p=0.009). Higher baseline synaptopodin was associated with future slower whole-brain atrophy and preserved microstructural integrity across MRI metrics (p=0.007-0.013). Longitudinal changes in NEV synaptopodin were associated with disability worsening (p=0.007) and paralleled MRI microstructural changes. NEV synaptopodin, but not NfL, was associated with confirmed disability progression in PMS participants with both biomarkers measured (HR 0.71 vs 1.12, p=0.007 vs 0.22 for NEV synaptopodin and NfL, respectively) and SPMS (HR 0.58 vs 1.10, p=0.003 vs 0.50). Adding synaptopodin, but not NfL, to a base model improved discrimination for disability progression in SPMS in both cohorts (e.g. validation AUC 0.755 to 0.838, p=0.005). These findings identify NEV synaptopodin as a prognostic and longitudinal, blood biomarker of synaptic integrity in PMS, particularly SPMS, complementing NfL.","rel_num_authors":19,"rel_authors":[{"author_name":"Larissa Jank","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA; Institute of Clinical Ne"},{"author_name":"Madathiparambil K.S. Kumar","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Deepika Joshi","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Veronica Minney","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Rahel Eskinder","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Rohit Thapa","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"John G. Heller","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Angeliki G. Filippatou","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Fatemeh Siavoshi","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Matthew D. Smith","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Christopher Harp","author_inst":"Genentech, South San Francisco, CA, USA"},{"author_name":"Ibraheem Abioye","author_inst":"Genentech, South San Francisco, CA, USA"},{"author_name":"Elias S. Sotirchos","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Blake E. Dewey","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Shiv Saidha","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Kathryn C. Fitzgerald","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Peter A. Calabresi","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Ellen M. Mowry","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Pavan Bhargava","author_inst":"Division of Neuroimmunology and Neurological Infections, Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"When Is Maltreatment 'Acceptable'? Cross-Cultural Patterns in Child Maltreatment Exposure and its Perceived Social Acceptability Across 13 Countries and Regions","rel_doi":"10.64898\/2026.10.07.26364967","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364967","rel_abs":"Child maltreatment (CM) is a global phenomenon, yet its prevalence, acceptability, and psychosocial consequences vary across cultures. This study examined self-reported CM, its perceived acceptability, and associations with psychosocial outcomes among 1,617 adults (Mage = 25.21, SD = 6.74) across 13 countries and regions. Participants completed an online survey assessing physical neglect, physical abuse, emotional maltreatment, sexual abuse, and witnessing domestic violence, alongside perceived acceptability, post-traumatic growth, resilience, perceived social support, post-traumatic symptoms, and psychological distress. Country\/region differences were tested via mixed-effects; whether CM-outcome associations varied by country\/region was tested via fixed-effects interaction models. Significant cross-country\/region variability emerged for most CM subtypes, especially for emotional maltreatment. Witnessing domestic violence rates did not differ significantly, though its acceptability still varied significantly, as did all other types. Greater CM exposure was linked to poorer mental health for several subtypes and to greater acceptability of maltreatment, raising concerns about intergenerational normalisation. CM-outcome associations were largely consistent across countries\/regions, with only isolated, exploratory exceptions. Findings show that while CM's adverse psychosocial impact shows little cross-national variation, its prevalence and normative framing are culturally shaped, underscoring the need for culturally sensitive assessment and intervention.","rel_num_authors":28,"rel_authors":[{"author_name":"Dan Jenkins","author_inst":"Department of Psychology, University of Fribourg, Switzerland; Department of Psychiatry, Stellenbosch University, South Africa"},{"author_name":"Rachel Langevin","author_inst":"Department of Educational and Counselling Psychology, McGill University, Canada"},{"author_name":"Stefanie Rita Balle","author_inst":"Department of Psychology, LMU Munich, Germany"},{"author_name":"Jiaqing O","author_inst":"Department of Psychology, University of Macau, Macau"},{"author_name":"Shir Porat-Butman","author_inst":"Faculty of Education, Bar-Ilan University, Israel."},{"author_name":"Einat Levy-Gigi","author_inst":"Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Israel."},{"author_name":"Nino Makhasvili","author_inst":"Mental Health Centre, Ilia State University, Tbilisi, Georgia"},{"author_name":"Ulrich Schnyder","author_inst":"University of Zurich, Switzerland"},{"author_name":"Mayron Piccolo","author_inst":"Department of Psychology, Harvard University, USA; Department of Psychiatry, Harvard Medical School, USA"},{"author_name":"Saman Kamari Songhorabadi","author_inst":"Faculty of Educational Sciences and Psychology, Shiraz University, Shiraz, Iran; Department of Psychology and Cognitive Science, University of Trento, Rovereto,"},{"author_name":"Farhad Khormaei","author_inst":"Faculty of Educational Sciences and Psychology, Shiraz University, Shiraz, Iran"},{"author_name":"Ghasem Khayati","author_inst":"Institute for Cognitive Neuroscience, Faculty of Social Sciences, Higher School of Economics, Moscow, Russian Federation"},{"author_name":"Gorkem Ayas","author_inst":"Koc University Graduate School of Health Sciences, Istanbul, Turkiye"},{"author_name":"Tugba Turk Kurtca","author_inst":"Department of Psychological Counseling and Guidance, Faculty of Education, Trakya Universty, Edirne, Turkiye"},{"author_name":"Deniz Ceylan","author_inst":"Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA; Department of Psychiatry, School of Medicine, Koc University, Istanbul, Turkiye"},{"author_name":"Vedat Sar","author_inst":"Koc University School of Medicine Department of Psychiatry, Istanbul"},{"author_name":"Fares-Otero Natalia E.","author_inst":"Department of Psychiatry and Psychotherapy, Technical University of Munich (TUM), Munich, Germany"},{"author_name":"Halligan Sarah L","author_inst":"Department of Psychology, University of Bath, Bath, UK"},{"author_name":"Monique Pfaltz","author_inst":"Department of Education, Psychology and Social Work, Mid Sweden University, Sweden"},{"author_name":"Billy Jansson","author_inst":"Department of Education, Psychology and Social Work, Mid Sweden University, Sweden"},{"author_name":"Tanya Tandon","author_inst":"Department of Psychology, University of Fribourg, Switzerland"},{"author_name":"Monica Fernandez-Boente","author_inst":"Department of Psychology, University of Fribourg, Switzerland"},{"author_name":"Chantal Martin-Soelch","author_inst":"Department of Psychology, University of Fribourg, Switzerland"},{"author_name":"Eleonora Bartoli","author_inst":"Department of Psychology, Goethe University, Frankfurt am Main, Germany"},{"author_name":"Georgina Spies","author_inst":"Department of Psychology, University of Cape Town, South Africa"},{"author_name":"Naved Iqbal","author_inst":"Jamia Millia Islamia, Delhi, India"},{"author_name":"Misari Oe","author_inst":"Department of Neuropsychiatry, Kurume University School of Medicine, Japan"},{"author_name":"- GCTS Child Trauma Network","author_inst":"-"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"Factors Associated with Predischarge Morbidity and Mortality in Small for Gestational Age Infants: A Single-Center Retrospective Cohort Study","rel_doi":"10.64898\/2026.10.07.26364995","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364995","rel_abs":"Objective: To identify factors associated with predischarge morbidity and mortality among small for gestational age infants. Study Design: We conducted a retrospective single-center cohort study of small for gestational age infants admitted to a level IV neonatal intensive care unit. We determined the association of clinical characteristics, congenital anomalies, and genetic disorders with the primary outcome of predischarge morbidity or mortality and characterized morbidity and mortality across congenital anomaly subgroups. Results: Among 293 small for gestational age infants, 18 (6.1%) had a genetic disorder and 103 (35.2%) had a major congenital anomaly, with congenital heart disease (CHD) representing the largest subgroup. The primary outcome of morbidity or mortality occurred in 93 infants (31.7%); 74 infants (25.3%) experienced morbidity and 19 (6.5%) died. CHD (adjusted odds ratio [aOR]: 16.5, 95% CI 6.44-45.7) and multiple congenital anomalies (aOR: 17.8, 95% CI 4.64-71.1) were found to be strongly associated with morbidity or mortality, after accounting for sex, maternal race, and intubation > 7 days. Statistically significant associations were also found with the presence of musculoskeletal anomalies as well as genetic disorders in infants without congenital anomalies, though in limited sample sizes. CHD was the largest contributor to morbidity, whereas multiple congenital anomalies accounted for the greatest proportion of mortality. Infants with abdominal wall defects and central nervous system anomalies experienced no morbidity or mortality. Conclusion: Congenital heart disease and multiple congenital anomalies were strongly associated with morbidity and mortality among SGA infants, whereas the degree of SGA alone was not. These findings suggest that risk is not explained by the degree of SGA alone and may be more strongly associated with congenital disease and other underlying factors.","rel_num_authors":6,"rel_authors":[{"author_name":"Christopher Cinkus-Rios","author_inst":"Columbia University Irving Medical Center, Department of Pediatrics"},{"author_name":"Samantha Pickell","author_inst":"Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons"},{"author_name":"Charlotte Thompson","author_inst":"Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons"},{"author_name":"Miles Bomback","author_inst":"Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons"},{"author_name":"Alex Lyford","author_inst":"Middlebury College, Department of Statistics"},{"author_name":"Thomas Hays","author_inst":"Columbia University Irving Medical Center, Department of Pediatrics"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"Burden of Non-Communicable Diseases Attributable to Polygenic Risk and Its Association with Healthcare Utilization in Taiwan","rel_doi":"10.64898\/2026.10.07.26365010","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26365010","rel_abs":"Background Non-communicable diseases (NCDs) impose substantial population burden. Their polygenic architecture informs early risk stratification through polygenic risk scores (PRS). Previous studies reported elevated-PRS burden comparable to some modifiable risk factors (MRFs), yet evidence remains confined to European populations. We quantified the PRS-attributable NCD burden in Taiwan. Methods Linking Taiwan Biobank and National Health Insurance Research Database (N = 140K), we analyzed 42 high-burden NCDs. Elevated genetic risk (PRSe; top 10%) was assessed using Cox models. We estimated population attributable fractions (PAFs) and disability-adjusted life years (DALYs) using Taiwan-specific estimates from Global Burden of Disease 2023, and examined associations between an integrated PRS (iPRS) and healthcare utilization. Findings Strongest PRSe associations occurred for atrial fibrillation (AFib; HR = 3.56 [95% CI: 3.23-3.92]) and gout (2.41 [2.33-2.49]), yielding PAFs of 20% and 12%, respectively, while population-level attributable DALYs were largest for type 2 diabetes (T2D), intracranial hemorrhage (ICH), and lung cancer. At the individual level, PRS_e corresponded to 1.50 [1.42-1.57] healthy life-years lost for T2D and 0.57 [0.40-0.76] for ICH, approaching 2.4 years for the top 1% PRS. Polygenic attributable burden was overall greater in men. For several diseases, PRS_e-associated PAF and DALYs exceeded those of individual MRFs (e.g., smoking, alcohol use). Top-decile iPRS was linked to 23.9% (15.0-33.6%) more hospital days, 19.1% (13.2-25.3%) more inpatient visits, and 9.6% (6.9-12.4%) more outpatient visits. Interpretation Polygenic risk accounts for a measurable--and for several diseases, MRF-comparable--share of NCD burden in Taiwan, providing a quantitative foundation for integrating genetic liability into preventive care and health planning.","rel_num_authors":5,"rel_authors":[{"author_name":"Mu-Yi Shih","author_inst":"Institute of Health Data Analytics and Statistics, College of Public Health, National Taiwan University"},{"author_name":"Yi-Syuan Ke","author_inst":"Institute of Health Data Analytics and Statistics, College of Public Health, National Taiwan University"},{"author_name":"Xue-Yong Chang","author_inst":"Institute of Health Data Analytics and Statistics, College of Public Health, National Taiwan University"},{"author_name":"Ling-Hua Wang","author_inst":"Institute of Health Data Analytics and Statistics, College of Public Health, National Taiwan University"},{"author_name":"Yen-Chen Anne Feng","author_inst":"Institute of Health Data Analytics and Statistics, College of Public Health, National Taiwan University"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"Seasonally Normalized Vitamin D Status and Long-Term Mortality and Multisystem Disease Risk in the UK Biobank","rel_doi":"10.64898\/2026.10.07.26364983","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364983","rel_abs":"Background: Vitamin D deficiency has been associated with mortality and chronic disease. In a recent study of Israeli Leumit Health Services (LHS) and US TriNetX populations, severe deficiency was reproducibly associated with mortality and multisystem morbidity, while longitudinal supplementation reconstructed from pharmacy dispensing was associated with lower risk. Methods: We sought to reproduce these associations and address a wide range of potential confounders in the deeply phenotyped UK Biobank. Baseline circulating 25-hydroxyvitamin D [25(OH)D] was standardized to a common late-winter nadir using an eight-harmonic model, and participants were categorized according to nadir-equivalent 25(OH)D as <5, 5-10, 10-15, 15-20, or [&ge;]20 ng\/mL. Primary survival analyses used one-year delayed entry and complete-case multivariable adjustment. Results: Analyses included 412,020 participants and 31,197 deaths. Mortality hazard ratios were 2.03 (95% CI 1.90-2.18), 1.34 (1.29-1.39), 1.08 (1.04-1.11), respectively, for <5, 5-10 and 10-15, versus [&ge;]20 ng\/mL. Associations previously observed in LHS and TriNetX were reproduced, notably for diabetes, myocardial infarction, cerebrovascular disease, dementia, diabetic retinopathy, and end-stage renal disease, whereas skin malignancies showed the opposite gradient, consistent with greater ultraviolet exposure. DAG-informed causal analyses using generalized overlap weighting achieved acceptable balance across measured covariates; weighted 10-year mortality was 9.7% with very severe deficiency versus 4.8% with [&ge;]20 ng\/mL, supporting a causal interpretation. Estimates remained stable with landmark lags extending to 5 years after measurement. Conclusions: Seasonally normalized 25(OH)D identifies a reproducible state of systemic vulnerability while reducing exposure misclassification caused by calendar timing of measurement. An interactive implementation of the normalization model is available: https:\/\/vitamind.medil.ai.","rel_num_authors":7,"rel_authors":[{"author_name":"Ariel Israel","author_inst":"Leumit Health Services"},{"author_name":"Abraham Weizman","author_inst":"Gray Faculty of Medicine and Health Sciences, Tel Aviv University"},{"author_name":"Shai Ashkenazi","author_inst":"Ariel University, Ariel, Israel"},{"author_name":"Eli Magen","author_inst":"Ariel University, Ariel, Israel"},{"author_name":"Eugene Merzon","author_inst":"Ariel University, Ariel, Israel"},{"author_name":"Shlomo Vinker","author_inst":"Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Nadav Rappoport","author_inst":"Ben-Gurion University of the Negev"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"Investigating the Causal Impact of COVID-19 on Acute Myocardial Infarction: A Multi-ancestry Mendelian Randomization Study","rel_doi":"10.64898\/2026.10.07.26364920","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364920","rel_abs":"Observational studies suggest an association between COVID-19 and acute myocardial infarction (AMI), however, whether this relationship is causal remains unclear. We conducted a multi-ancestry Mendelian randomization (MR) study across European, East Asian, South Asian, and African populations, evaluating three COVID-19 phenotypes: very severe COVID-19, hospitalized COVID-19, and general infection association with AMI. GWAS summary statistics were obtained from the COVID-19 Host Genetics Initiative Round 7 and UK Biobank\/Biobank Japan for AMI. Inverse-variance weighted (IVW) MR was the primary method, with fixed- or random-effects models selected according to heterogeneity test. MR-Egger, weighted median and weighted mode were conducted as sensitivity analyses. In European ancestry, genetic liability to very severe COVID-19 and hospitalized COVID-19 was slightly inversely associated with AMI risk, but without statistical significances across sensitivity analyses. Hospitalized COVID-19 showed a suggestive but non-significant inverse association in South Asian ancestry. No significant associations were identified in East Asian or African ancestries. Our findings did not support a robust causal association between COVID-19 susceptibility or severity and AMI risk across ancestries, suggesting that the observed cardiovascular burden may be driven more by acute pathophysiological mechanisms than shared genetic architecture.","rel_num_authors":2,"rel_authors":[{"author_name":"Katherine Zhou","author_inst":"Choate Rosemary Hall"},{"author_name":"Ying Ma","author_inst":"Brown University"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"Temporal and Phylodynamic analyses of the 2026 Bundibugyo virus disease outbreak in the Democratic Republic of the Congo","rel_doi":"10.64898\/2026.10.07.26365001","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26365001","rel_abs":"The Democratic Republic of the Congo is experiencing a major outbreak of Ebola disease caused by Orthoebolavirus bundibugyoense (Bundibugyo virus), which was declared on May 15, 2026. To investigate the timing of emergence and early transmission, we generated near full length Bundibugyo virus genomes from 686 PCR-confirmed individuals across 22 health zones. We estimated the time of emergence as late February 2026 (95% highest posterior density interval [HPDI]: January 21 and March 25, 2026) and an evolutionary rate of 8.7X10-4 substitutions per site per year (95% HPDI: 7.6 and 9.9X10-4), with no evidence of mutations associated with rapidly growing lineages.","rel_num_authors":67,"rel_authors":[{"author_name":"Tony Wawina-Bokalanga","author_inst":"Institut National de Recherche Biomedicale"},{"author_name":"Pierre Akilimali","author_inst":"Institut National de Sante Publique (INSP), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Jonathan Pekar","author_inst":"Institute of Ecology and Evolution, University of Edinburgh, Edinburgh, UK"},{"author_name":"Pascal Adroba","author_inst":"Centre de Recherche en Maladies Tropicales"},{"author_name":"Adrienne Amuri-Aziza","author_inst":"Institut National de Recherche Biomedicale (INRB), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Eddy Kinganda Lusamaki","author_inst":"Institut National de Recherche Biomedicale (INRB), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Daan Jansen","author_inst":"Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium"},{"author_name":"Bernardo Gutierrez","author_inst":"Oxford University: University of Oxford"},{"author_name":"Ciara Judge","author_inst":"Pandemic Sciences Institute, University of Oxford, United Kingdom"},{"author_name":"Olga Ntumba-Tshitenge","author_inst":"World Health Organization Country Office, Kinshasa, Democratic Republic of the Congo"},{"author_name":"Joshua Quick","author_inst":"University of Birmingham"},{"author_name":"Diallo Amadou Mouctar","author_inst":"World Health Organization Country Office, Kinshasa, Democratic Republic of the Congo"},{"author_name":"Sam AJ Wilkinson","author_inst":"University of Birmingham"},{"author_name":"Jean-Claude Makangara-Cigolo","author_inst":"Institut National de Recherche Biomedicale (INRB), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Marcel Lola-Loway","author_inst":"Division Provinciale de la Sante, Ituri, Democratic Republic of the Congo"},{"author_name":"John O OTSHUDIEMA","author_inst":"World Health Organization (WHO)"},{"author_name":"Nicksy Gumede","author_inst":"World Health Organization Regional Office for Africa, Brazzaville, Republic of Congo"},{"author_name":"Felix Mulangu","author_inst":"Direction Surveillance Epidemiologique, Ministry of Public Health, Hygiene and Social Welfare, Kinshasa, Democratic Republic of the Congo"},{"author_name":"Justus Nsio","author_inst":"Africa Centres for Disease Control and Prevention, Addis Ababa, Ethiopia"},{"author_name":"Prince Akil-Bandali","author_inst":"Institut National de Recherche Biomedicale (INRB), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Jepsy Yango","author_inst":"Institut National de Recherche Biomedicale (INRB), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Dav M. Ebengo","author_inst":"Institut National de Recherche Biomedicale (INRB), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Tania Bishola Tshitenge","author_inst":"Institut National de Recherche Biomedicale (INRB), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Cris Kacita","author_inst":"Ministry of Health"},{"author_name":"Joelle Ngalula-Mudiayi","author_inst":"Institut National de Sante Publique (INSP), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Mathias Mossoko","author_inst":"Institut National de Sante Publique (INSP), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Pauline-Chloe Musuamba-Kayembe","author_inst":"Institut National de Recherche Biomedicale (INRB), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Lievin Tibasima-Dhesa","author_inst":"Laboratoire Provincial de Sante Publique, Ituri, Democratic Republic of the Congo"},{"author_name":"Princesse Paku-Tshambu","author_inst":"Institut National de Recherche Biomedicale (INRB), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Sabue Mulangu","author_inst":"Institut National de Recherche Biomedicale (INRB), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Pius  Zakayi KABUTU","author_inst":"University of Kinshasa Faculty of Medicine: Universite de Kinshasa Faculte de Medecine"},{"author_name":"Olivier Tshiani-Mbaya","author_inst":"Institut National de Recherche Biomedicale (INRB), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Dieudonne Mvumbi Makaba","author_inst":"University of Kinshasa"},{"author_name":"Marie-Roseline Belizaire","author_inst":"World Health Organization Regional Office for Africa, Brazzaville, Republic of Congo"},{"author_name":"Anne  W. Rimoin","author_inst":"UCLA: University of California Los Angeles"},{"author_name":"Lorenzo Subissi","author_inst":"WHO"},{"author_name":"Martine Peeters","author_inst":"Institut de recherche pour le developpement"},{"author_name":"Ahidjo Ayouba","author_inst":"Institut de recherche pour le developpement"},{"author_name":"Mosoka  Papa Fallah","author_inst":"Africa Centres for Disease Control and Prevention"},{"author_name":"Kevin K. Arien","author_inst":"Institute of Tropical Medicine Antwerp"},{"author_name":"Sofonias K. Tessema","author_inst":"Gates Foundation, Seattle, USA"},{"author_name":"David Blazes","author_inst":"Gates Foundation, Seattle, USA"},{"author_name":"Nicholas James Loman","author_inst":"University of Birmingham"},{"author_name":"Caroline James Colijn","author_inst":"Simon Fraser University"},{"author_name":"Olivier le Polain de Waroux","author_inst":"London School of Hygiene and Tropical Medicine"},{"author_name":"Joseph L.H Tsui","author_inst":"Pandemic Sciences Institute, University of Oxford, United Kingdom"},{"author_name":"Cathal Mills","author_inst":"Pandemic Sciences Institute, University of Oxford, United Kingdom"},{"author_name":"Ellie Bourgikos","author_inst":"Pandemic Sciences Institute, University of Oxford, United Kingdom"},{"author_name":"Samuel V. Scarpino","author_inst":"Institute for Experiential AI, Northeastern University, Boston, MA, USA"},{"author_name":"Aine O'Toole","author_inst":"Institute of Evolutionary Biology, University of Edinburgh"},{"author_name":"Renny Doig","author_inst":"Simon Fraser University, British Columbia, Canada"},{"author_name":"Guy Baele","author_inst":"KU Leuven"},{"author_name":"Nohelia Navarrete","author_inst":"Culmen International, Alexandria, VA, USA"},{"author_name":"Laurens Liesenborghs","author_inst":"Institute for Tropical Medicine"},{"author_name":"Miles W Carroll","author_inst":"University of Oxford"},{"author_name":"Georges  Mvumbi Lelo","author_inst":"University of Kinshasa Faculty of Medicine: Universite de Kinshasa Faculte de Medecine"},{"author_name":"Daniel Mukadi-Bamuleka","author_inst":"Rodolphe Merieux Institut National de Recherche Biomedicale Laboratory"},{"author_name":"Piet Maes","author_inst":"European Plotkin Institute for Vaccinology, Universite Libre de Bruxelles (ULB), Brussels, Belgium"},{"author_name":"Christian Ngandu","author_inst":"Institut National de Sante Publique (INSP), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Jason Kindrachuk","author_inst":"University of Manitoba"},{"author_name":"Dieudonne Mwamba","author_inst":"Institut National de Sante Publique (INSP), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Jean-Jacques  Tamfum Muyembe","author_inst":"INRB: Institut National de Recherche Biomedicale"},{"author_name":"Steve Ahuka-Mundeke","author_inst":"Institut National de Recherche Biomedicale (INRB), Kinshasa, Democratic Republic of the Congo"},{"author_name":"Koen Vercauteren","author_inst":"Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp, Belgium"},{"author_name":"Moritz  U. G. Kraemer","author_inst":"University of Oxford"},{"author_name":"Andrew Rambaut","author_inst":"University of Edinburgh"},{"author_name":"Mbala Placide","author_inst":"INRB: Institut National de Recherche Biomedicale"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"Cognitive and Motor Impairment Patterns among HIV+ Adults with and without Stroke in Botswana: Implications for Neurorehabilitation","rel_doi":"10.64898\/2026.10.07.26364959","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364959","rel_abs":"Background: HIV and stroke are major contributors to disability in sub-Saharan Africa, yet their combined impact on cognitive and motor functioning remains poorly understood. Botswana has a high prevalence of HIV and rising stroke incidence, underscoring the need to characterize impairment to inform neurorehabilitation. Objective: To examine differences in cognitive performance, motor function, and activities of daily living between adults living with HIV only and those living with both HIV and stroke in Botswana. Methods: Thirty-three adults (19 HIV only; 14 HIV\/ stroke) completed standardized cognitive (e.g. MoCA and Digit Symbol Coding [DSC]), and motor assessments (such as Box and Block Test [BBT], Grooved Pegboard [GPB], Grip Strength [GS], 10-Meter Walk Test [10MWT], Timed Up and Go [TUG]), and ADL measures (such as Barthel Index, Lawton IADL). Group comparisons used Wilcoxon rank-sum tests. Impairment was determined using both international z-score norms and Botswana-specific cutoffs from a prior cohort study. Results: Cognitive impairment was evident in both groups, but DSC z-scores were worse in the HIV\/stroke vs HIV only group (median= -2.71 vs -1.34, p=0.015). Gross motor function showed deficits in the HIV\/stroke group, including lower dominant-hand BBT performance (median z-score -2.79 vs. -1.75; p=0.008). Fine motor dexterity was markedly reduced in the HIV\/stroke group, with GPB dominant-hand median z-scores of -4.26 vs. -1.40 (p=0.038) and non-dominant-hand impairment rates of 100% vs. 63.2% (p=0.043). Non-dominant GS was weaker in the HIV\/stroke group (100% impaired vs. 47.4%; p=0.0014). Lower-limb performance was substantially worse, including TUG (median z-score -3.63 vs. 0.10; p=0.0001) and 10MWT (median z-score -5.36 vs. -2.47; p=0.0025). ADL scores were also lower in the HIV\/stroke group compared to both Barthel and Lawton (p=0.002). Conclusions: HIV alone is associated with cognitive and motor impairment, with the addition of stroke producing significantly greater deficits across all motor domains. These findings demonstrate the need to integrate structured neurorehabilitation into HIV clinical care in Botswana.","rel_num_authors":11,"rel_authors":[{"author_name":"Michelle J Johnson","author_inst":"Department of Physical Medicine and Rehabilitation, University of Pennsylvania"},{"author_name":"Rochelle J Mendonca","author_inst":"Department of Occupational Therapy, Columbia University"},{"author_name":"Frances S Shofer","author_inst":"Emergency Medicine, University of Pennsylvania"},{"author_name":"Nstatsi Mogorosi","author_inst":"Rehab Robotics Lab, Botswana UPenn Partnership"},{"author_name":"Ngadzi Goitsemang","author_inst":"Rehab Robotics Lab, Botswana UPenn Partnership"},{"author_name":"Lefika Bothomilwe","author_inst":"Rehab Robotics Lab, Botswana UPenn Partnership"},{"author_name":"Cassandra C Ocampo-Ilagan","author_inst":"Department of Neurology, University of Botswana"},{"author_name":"Billy Tsima","author_inst":"Family Medicine and Public Health, University of Botswana"},{"author_name":"Justus M Nthitu","author_inst":"Department of Occupational Therapy, Mahalapye District Hospital (former) and Boitekanelo College"},{"author_name":"Lingani Mbakile-Mahlanza","author_inst":"Psychology Department, University of Botswana"},{"author_name":"Maikutlo B Kebaetse","author_inst":"Biomedical Sciences Department, University of Botswana"}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"Navigating Life After Dementia Diagnosis: Questions, Challenges, and Support Needs Among Dementia Dyads","rel_doi":"10.64898\/2026.10.07.26364992","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364992","rel_abs":"Background: Older adults living with mild cognitive impairment (MCI) or Alzheimer's disease and related dementias (AD\/ADRD) and their care partners face substantial daily challenges that evolve with disease progression and extend far beyond the clinical setting, including symptom management, care coordination, healthcare navigation, and planning for future care needs. Understanding these challenges is essential for developing innovative solutions to provide ongoing and targeted support. In this study, we explored questions, challenges, and support needs experienced by dementia dyads following diagnosis to inform the development of an artificial intelligence (AI)-based chatbot designed to provide ongoing support for dementia dyads. Methods: We recruited 11 community-dwelling dyads comprising persons living with MCI or mild AD\/ADRD and their care partners, one additional care partner, and 12 dementia care experts from academic medical centers, clinics, and aging organizations in the U.S. We conducted semi-structured interviews and analyzed them using conventional content analysis. Results: Participants described interconnected questions, challenges, and support needs that evolved while navigating life with MCI or AD\/ADRD. Questions centered around day-to-day care management, medical concerns, behavioral symptom management, diagnosis and prognosis, safety, and resources and services. Challenges included care partner overwhelm, limited dementia knowledge, condition-related uncertainty, healthcare system navigation difficulties, financial constraints, and technology-related barriers. Participants identified needs for ongoing education, personalized care planning, resource navigation, logistical support and follow-up, culturally responsive care, and social and emotional support. Conclusions: Dementia dyads experience substantial informational, emotional, and practical support needs in the early stages of MCI and AD\/ADRD. Findings suggest that post-diagnostic support should extend beyond information provision alone to provide ongoing, personalized, and practical guidance that helps dyads navigate changing needs, resources, and everyday dementia care. These findings are informing the development of an AI-based chatbot intended to complement existing dementia care by extending access to education, practical guidance, and resource navigation between clinical encounters.","rel_num_authors":7,"rel_authors":[{"author_name":"Katherine Britt","author_inst":"The University of Iowa"},{"author_name":"Alaa Harb","author_inst":"University of Iowa"},{"author_name":"Brianna Bailey","author_inst":"BrainCheck, Inc."},{"author_name":"Bridget Saffold","author_inst":"University of Iowa"},{"author_name":"Xiao Luo","author_inst":"Southern Methodist University"},{"author_name":"Rebecca T Brown","author_inst":"University of Pennsylvania"},{"author_name":"Bin Huang","author_inst":"BrainCheck, Inc."}],"rel_date":"2026-10-09","rel_site":"medrxiv"},{"rel_title":"The chemosensory system of the clonal raider ant larva","rel_doi":"10.64898\/2026.10.06.757048","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.06.757048","rel_abs":"Ant larvae are blind and immobile, depending heavily on the adults for care in the form of feeding, grooming, and transport. However, they are not inactive colony members but play a central role in the organization of ant societies by modulating adult behavior and physiology. While adult ants have been studied extensively, we still know little about what sensory modalities larvae use to perceive their environment. Here, we provide a molecular and circuit-level characterization of the chemosensory system of the clonal raider ant larva. Combining scanning electron microscopy and confocal imaging, we show that dome sensilla in the maxillary and labial palps are innervated by odorant receptor (OR) neurons. A larger population of ionotropic receptor (IR) neurons innervate papilla sensilla across various regions of the larval head: the antennae, the labrum, the maxillary palps and galeae, as well as the labial palps and the ventral labium. This suggests that IRs, which can have various functions, from taste and olfaction to temperature and humidity sensing, constitute the predominant chemosensory modality in ant larvae. To investigate projections into the central brain, we imaged transgenic lines that fluorescently label OR- and IR-expressing neurons. We found that OR- and IR-expressing neurons in the labium and maxilla project along the labial and maxillary nerves through the subesophageal ganglion to the deutocerebrum, whereas IR-expressing neurons from the labrum project to the tritocerebrum and those from the antenna project to the posterior deutocerebrum. Together, our findings establish a structural and molecular framework to study larval chemosensation in ants.","rel_num_authors":7,"rel_authors":[{"author_name":"Daniel H. Pastor","author_inst":"The Rockefeller University"},{"author_name":"Leonora Olivos-Cisneros","author_inst":"The Rockefeller University"},{"author_name":"Alejandra Hurtado-Giraldo","author_inst":"The Rockefeller University"},{"author_name":"Anurag Sharma","author_inst":"The Rockefeller University"},{"author_name":"Patrick K. Piekarski","author_inst":"The Rockefeller University"},{"author_name":"Giacomo L. Glotzer","author_inst":"The Rockefeller University"},{"author_name":"Daniel Kronauer","author_inst":"The Rockefeller University"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"The fusion gene occurrence spectrum predicts the spatial structure of chromosomes","rel_doi":"10.64898\/2026.10.07.757465","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.07.757465","rel_abs":"Chromosome was \"self-assembled\" into a complex three-dimensional topology in the nucleus, which provided the structural basis for important biological processes such as gene expression regulation and cell differentiation. The current understanding of the three-dimensional organization of the genome is based on high-throughput sequencing and imaging technologies to visualize the conformation of chromatin in its native environment. This study proposes a new research perspective and technical means to use fusion genes to determine the interaction information and three-dimensional structure of chromosomes. This three-dimensional information provided by the fusion gene spectrum not only shows the universality of the spatial layout of chromosomes, but also increases the interpretability of the occurrence of fusion genes. The chromatin conformation capture data of multiple tissues and periods is significantly correlated with the strength of fusion genes. For example, the frequency of trans-interaction between chromosomes 11 and 17 was the highest, and the frequency of fusion gene occurrence corresponding to KMT2A on chromosome 11 was the highest. Therefore, we infer that this structural universality is a common feature of the human genome, which provides a theoretical basis and data for predicting chromosome fusion events.","rel_num_authors":10,"rel_authors":[{"author_name":"Xianzhen Ren","author_inst":"Jiangnan University"},{"author_name":"Yueqiy Cao","author_inst":"Jiangnan University"},{"author_name":"Yongliang Dai","author_inst":"College of Life Sciences, University of Chinese Academy of Sciences"},{"author_name":"Zhiyuan Huang","author_inst":"Jiangnan University"},{"author_name":"Junan Yu","author_inst":"Jiangnan University"},{"author_name":"Shousshou Feng","author_inst":"Jiangnan University"},{"author_name":"Lingfeng Long","author_inst":"Jiangnan University"},{"author_name":"Chentao Yang","author_inst":"BGI"},{"author_name":"Qiong Wang","author_inst":"Department of Blood Transfusion, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medic"},{"author_name":"Hailin Yang","author_inst":"Jiangnan University"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"NECTIN4 defines a subtype-dependent tumor state coupling enfortumab vedotin targetability to antitumor immunity in bladder cancer","rel_doi":"10.64898\/2026.10.07.757381","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.07.757381","rel_abs":"NECTIN4 is the target of enfortumab vedotin (EV), but its biological role in bladder cancer (BC) and its relationship to EV plus PD-1 blockade remain unclear. Integrating clinical multi-omics, spatial and single-cell immune profiling, and experimental models, we identify NECTIN4 as a subtype-dependent determinant of tumor state and antitumor immunity. In basal BC cells, NECTIN4 suppressed inflammatory and mesenchymal programs. Consistently, NECTIN4-high basal\/squamous muscle-invasive BCs showed favorable survival, higher checkpoint inhibitor response rates, and a coordinated CD8+ T cell-inflamed microenvironment with no comparable associations in luminal papillary tumors. In orthotopic models, murine Nectin4 promoted CD8+ T cell-dependent tumor control, whereas human NECTIN4 conferred EV sensitivity. EV also attenuated NECTIN4-dependent TIGIT binding. Conversely, NECTIN4-low models were preferentially sensitive to HDAC inhibition. NECTIN4 therefore couples antibody-drug conjugate targetability to a subtype-specific tumor-immune state permissive for checkpoint blockade, whereas the NECTIN4-low state defines a distinct inflammatory-mesenchymal state with an alternative therapeutic vulnerability.","rel_num_authors":32,"rel_authors":[{"author_name":"Kazuki Nishimura","author_inst":"Division of Cancer RNA Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Department of Urology, Osaka Medical and Pharmaceutical Unive"},{"author_name":"Ryoichi Maenosono","author_inst":"Division of Cancer RNA Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Department of Urology, Osaka Medical and Pharmaceutical Unive"},{"author_name":"Takuya Owari","author_inst":"Division of Cancer Immunology, Research Institute\/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Chiba 277-8577, Japan"},{"author_name":"Moritoshi Sakamoto","author_inst":"Division of Cancer RNA Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Department of Urology, Osaka Medical and Pharmaceutical Unive"},{"author_name":"Takahiro Nishino","author_inst":"Division of Cancer RNA Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan"},{"author_name":"Kensuke Hirosuna","author_inst":"Division of Cancer RNA Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Department of Urology, Osaka Medical and Pharmaceutical Unive"},{"author_name":"Takuya Tsujino","author_inst":"Division of Cancer RNA Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Department of Urology, Osaka Medical and Pharmaceutical Unive"},{"author_name":"Takuya Izumi-Tamura","author_inst":"Division of Cancer RNA Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan"},{"author_name":"Yuki Yoshikawa","author_inst":"Department of Urology, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan"},{"author_name":"Miyu Azuma","author_inst":"Division of Cancer RNA Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan"},{"author_name":"Sakura Inoue","author_inst":"Division of Cancer RNA Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan"},{"author_name":"Asuka Kawachi","author_inst":"Division of Cancer RNA Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan"},{"author_name":"Atsuya Ishida","author_inst":"Division of Cancer RNA Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan"},{"author_name":"Kei Nishimori","author_inst":"Division of Cancer RNA Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan"},{"author_name":"Junko Mukohyama","author_inst":"Division of Cancer RNA Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Department of Surgery, The Institute of Medical Science, The "},{"author_name":"Natsuko Shinohara","author_inst":"Division of Cancer RNA Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan"},{"author_name":"Marimu Sakumoto","author_inst":"Division of Cancer RNA Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan"},{"author_name":"Masataka Amisaki","author_inst":"Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba 277-8577, Japan; Global Center of Research Excellence on Advanced Medicine "},{"author_name":"Kazuki Okuyama","author_inst":"Division of Cancer RNA Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan"},{"author_name":"Mitsuaki Ishida","author_inst":"Department of Pathology, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan"},{"author_name":"Masahiko Ajiro","author_inst":"Division of Cancer RNA Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan"},{"author_name":"Yoshinobu Hirose","author_inst":"Department of Pathology, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan"},{"author_name":"Yutaka Suzuki","author_inst":"Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba 277-8561, Japan"},{"author_name":"Hiroyoshi Nishikawa","author_inst":"Division of Cancer Immunology, Research Institute\/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Chiba 277-8577, Japan; D"},{"author_name":"Haruhito Azuma","author_inst":"Department of Urology, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan"},{"author_name":"Filipe L.F. Carvalho","author_inst":"Department of Urology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA"},{"author_name":"Adam S. Kibel","author_inst":"Department of Urology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA"},{"author_name":"Li Jia","author_inst":"Department of Urology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA"},{"author_name":"Shohei Koyama","author_inst":"Division of Cancer Immunology, Research Institute\/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Chiba 277-8577, Japan; D"},{"author_name":"Takayuki Yoshino","author_inst":"Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba 277-8577, Japan; Global Center of Research Excellence on Advanced Medicine "},{"author_name":"Kazumasa Komura","author_inst":"Department of Urology, Kawasaki Medical School, Okayama 701-0192, Japan"},{"author_name":"Akihide Yoshimi","author_inst":"Division of Cancer RNA Research, National Cancer Center Research Institute, Tokyo 104-0045, Japan"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Autoregulation of RNase E synthesis: Predominant impact of a branched RNA stem-loop to which the nuclease binds","rel_doi":"10.64898\/2026.10.07.757400","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.07.757400","rel_abs":"Due to its crucial role in proteobacterial RNA processing and degradation, the synthesis of the endonuclease RNase E is tightly controlled by a post-transcriptional autoregulatory mechanism governed by the 5' untranslated region of rne mRNA, the transcript that encodes it. Previous studies have identified one structural component of the rne 5' untranslated region (hp2) that helps to mediate this process in Escherichia coli by binding to RNase E. Here, we show that another component (hp3), a branched stem-loop, makes an even greater contribution to feedback regulation of RNase E synthesis and that the effects of hp2 and hp3 are additive, suggesting independent function. Despite the structural complexity of hp3, a single constituent branch appears to be the principal source of its regulatory activity. This branch also enables hp3 to bind RNase E with high affinity. The secondary structure of this branch, including the presence of two internal loops essential for its impact, is conserved in diverse Enterobacterales species, whereas the sequence of the internal loops is not. We propose that hp2 and hp3 mediate autoregulation by recruiting RNase E to the rne transcript.","rel_num_authors":3,"rel_authors":[{"author_name":"Salah Eldein Elkattawy","author_inst":"New York University School of Medicine"},{"author_name":"Tithi Banerjee","author_inst":"New York University School of Medicine"},{"author_name":"Joel G. Belasco","author_inst":"New York University School of Medicine"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Learning Interpretable Switching Dynamics in Shared Neural-Behavioral Latent Space","rel_doi":"10.64898\/2026.10.02.756323","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.02.756323","rel_abs":"Modern recording technologies enable simultaneous measurement of high-dimensional neural activity and rich behavioral variables, creating both an opportunity and a modeling challenge: identifying the shared latent structure that mediates the brain-behavior relationship and the underlying dynamics through which it evolves across behavioral states. Existing approaches focus on different parts of this challenge: shared representation learning methods identify neural-behavioral subspaces but typically do not model dynamical structure, while dynamical models capture temporal variation and discrete state transitions in neural activity, but do not explicitly disentangle shared neural-behavioral structure from modality-specific variability. We introduce Switching Shared Latent Dynamics (SSLD), a unified framework that learns a latent representation shared between neural activity and behavior and endows this shared space with nonlinear switching recurrent dynamics to reflect the hypothesis that behaviorally relevant neural representations exhibit structured dynamical changes across behavioral states. Complementary private latent variables capture modality-specific variability, providing a window into neural activity that does not directly interact with behavior. We evaluate SSLD on a simulated dataset and four diverse experimental datasets spanning species, brain regions, and recording modalities: monkey motor and premotor cortex during reaching, somatosensory cortex during a bump task, widefield calcium imaging across mouse dorsal cortex during (a) self-initiated decision-making and (b) spontaneous movements. Across all four datasets, SSLD accurately reconstructs neural and behavioral signals, recovers discrete states in the dynamics that align with experimentally defined behavioral epochs, and isolates behaviorally-relevant neural information in the shared latent while preserving private neural variability. Ablations confirm that shared representation learning, behavioral supervision, and switching dynamics each contribute to performance. SSLD offers an interpretable approach to modeling shared neural-behavioral dynamics that complements ongoing efforts toward foundation models for neuroscience.","rel_num_authors":7,"rel_authors":[{"author_name":"Yongxu Zhang","author_inst":"Yale University"},{"author_name":"Josue Ortega Caro","author_inst":"Yale University"},{"author_name":"Rachel Oren","author_inst":"Yale University"},{"author_name":"Michael James Higley","author_inst":"Yale University"},{"author_name":"Jessica Cardin","author_inst":"Yale University"},{"author_name":"Anne Churchland","author_inst":"University of California, Los Angeles"},{"author_name":"Shreya Saxena","author_inst":"Yale University"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Engaging the host adaptive response to nutrient limitation delays cancer cachexia","rel_doi":"10.64898\/2026.10.08.757672","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.757672","rel_abs":"Cancer cachexia is a debilitating wasting syndrome associated with involuntary weight loss, reduced appetite and food intake, adipose and muscle atrophy, and systemic inflammation with induction of a myriad of candidate cachexia factors. Using a multi-omic approach in a genetically engineered mouse model of lung cancer cachexia, we found that early circulating metabolic alterations preceded overt weight loss. Although both cachexia and fasting are characterized by a reduction in food intake, we show that the systemic metabolic changes in cachexia are distinct, indicating a lack of induction in the normal protective response to negative energy balance during cachexia. Cancer cachexia causes profound hepatic reprogramming, and activation of inflammatory programs, alongside muscle atrophy and elevation of circulating cytokines. However, targeting individual candidate cachectic factors such as IL-6, TNF-, GDF15, CCL2, LIF, and IL17A failed to rescue weight loss or prolong survival. In contrast, caloric restriction initiated prior to tumor induction elicited a program of protection during tumor progression that attenuated multi-tissue inflammatory and catabolic transcriptional responses, preserved lean mass, and prolonged survival. Together, these findings suggest that metabolic preconditioning broadly dampens systemic inflammation and delays the onset and progression of cancer cachexia.","rel_num_authors":27,"rel_authors":[{"author_name":"Maria Gomez-Jenkins","author_inst":"Rutgers Cancer Institute"},{"author_name":"Trishna Das","author_inst":"Rutgers Cancer Institute"},{"author_name":"Maria Ibrahim","author_inst":"Rutgers Cancer Institute"},{"author_name":"Damon Fard","author_inst":"Rutgers Cancer Institute"},{"author_name":"Sereno Lopez-Darwin","author_inst":"Princeton University"},{"author_name":"Justine Raeber","author_inst":"Princeton"},{"author_name":"Jesse Powers","author_inst":"Rutgers Cancer Institute"},{"author_name":"Zhixian Hu","author_inst":"Rutgers Cancer Institute"},{"author_name":"Hirak Sarkar","author_inst":"Princeton"},{"author_name":"Eduardo CararoLopes","author_inst":"Rutgers Cancer Institute"},{"author_name":"Akshada Sawant","author_inst":"Rutgers Cancer Institute"},{"author_name":"Gabriela Reyes-Castellanos","author_inst":"Rutgers Cancer Institute"},{"author_name":"Wenyun Lu","author_inst":"Princeton University"},{"author_name":"Hantao Qiang","author_inst":"Princeton University"},{"author_name":"Aslihan Sen","author_inst":"Rutgers Cancer Institute"},{"author_name":"Young-Yon Kwon","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Selina Wadhera","author_inst":"Rutgers Cancer Institute"},{"author_name":"Honiyah Armughan","author_inst":"Rutgers Cancer Institute"},{"author_name":"Shang Shi","author_inst":"Rutgers Cancer Institute"},{"author_name":"Joshua D Rabinowitz","author_inst":"Princeton University"},{"author_name":"Sheng Hui","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Tracy G Anthony","author_inst":"Rutgers University"},{"author_name":"Michael Skinnider","author_inst":"Princeton University"},{"author_name":"Benjamin Raphael","author_inst":"Princeton University"},{"author_name":"Marcus D Goncalves","author_inst":"NYU Langone Health"},{"author_name":"Tobias Janowitz","author_inst":"Cold Spring Harbor Laboratory"},{"author_name":"Eileen White","author_inst":"Rutgers Cancer Institute"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Engaging the host adaptive response to nutrient limitation delays cancer cachexia","rel_doi":"10.64898\/2026.10.08.757672","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.757672","rel_abs":"Cancer cachexia is a debilitating wasting syndrome associated with involuntary weight loss, reduced appetite and food intake, adipose and muscle atrophy, and systemic inflammation with induction of a myriad of candidate cachexia factors. Using a multi-omic approach in a genetically engineered mouse model of lung cancer cachexia, we found that early circulating metabolic alterations preceded overt weight loss. Although both cachexia and fasting are characterized by a reduction in food intake, we show that the systemic metabolic changes in cachexia are distinct, indicating a lack of induction in the normal protective response to negative energy balance during cachexia. Cancer cachexia causes profound hepatic reprogramming, and activation of inflammatory programs, alongside muscle atrophy and elevation of circulating cytokines. However, targeting individual candidate cachectic factors such as IL-6, TNF-, GDF15, CCL2, LIF, and IL17A failed to rescue weight loss or prolong survival. In contrast, caloric restriction initiated prior to tumor induction elicited a program of protection during tumor progression that attenuated multi-tissue inflammatory and catabolic transcriptional responses, preserved lean mass, and prolonged survival. Together, these findings suggest that metabolic preconditioning broadly dampens systemic inflammation and delays the onset and progression of cancer cachexia.","rel_num_authors":27,"rel_authors":[{"author_name":"Maria Gomez-Jenkins","author_inst":"Rutgers Cancer Institute"},{"author_name":"Trishna Das","author_inst":"Rutgers Cancer Institute"},{"author_name":"Maria Ibrahim","author_inst":"Rutgers Cancer Institute"},{"author_name":"Damon Fard","author_inst":"Rutgers Cancer Institute"},{"author_name":"Sereno Lopez-Darwin","author_inst":"Princeton University"},{"author_name":"Justine Raeber","author_inst":"Princeton"},{"author_name":"Jesse Powers","author_inst":"Rutgers Cancer Institute"},{"author_name":"Zhixian Hu","author_inst":"Rutgers Cancer Institute"},{"author_name":"Hirak Sarkar","author_inst":"Princeton"},{"author_name":"Eduardo CararoLopes","author_inst":"Rutgers Cancer Institute"},{"author_name":"Akshada Sawant","author_inst":"Rutgers Cancer Institute"},{"author_name":"Gabriela Reyes-Castellanos","author_inst":"Rutgers Cancer Institute"},{"author_name":"Wenyun Lu","author_inst":"Princeton University"},{"author_name":"Hantao Qiang","author_inst":"Princeton University"},{"author_name":"Aslihan Sen","author_inst":"Rutgers Cancer Institute"},{"author_name":"Young-Yon Kwon","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Selina Wadhera","author_inst":"Rutgers Cancer Institute"},{"author_name":"Honiyah Armughan","author_inst":"Rutgers Cancer Institute"},{"author_name":"Shang Shi","author_inst":"Rutgers Cancer Institute"},{"author_name":"Joshua D Rabinowitz","author_inst":"Princeton University"},{"author_name":"Sheng Hui","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Tracy G Anthony","author_inst":"Rutgers University"},{"author_name":"Michael Skinnider","author_inst":"Princeton University"},{"author_name":"Benjamin Raphael","author_inst":"Princeton University"},{"author_name":"Marcus D Goncalves","author_inst":"NYU Langone Health"},{"author_name":"Tobias Janowitz","author_inst":"Cold Spring Harbor Laboratory"},{"author_name":"Eileen White","author_inst":"Rutgers Cancer Institute"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"De novo protein design in an expanded chemical space","rel_doi":"10.64898\/2026.10.08.757794","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.757794","rel_abs":"Generative protein design has made sequence and structure programmable, yet its chemical alphabet remains largely confined to the canonical twenty. Here, we establish CheMoDesign, an experimentally validated generative framework for designing proteins de novo around user-specified chemistry. CheMoDesign weakens pair-representation conditioning in a pretrained all-atom structure-prediction model while preserving chemical anchors, then refines generated backbones through sequence-conditioned denoising. By treating post-translational modifications, synthetic residues, and chemical modifications as user-defined building blocks, the framework generated proteins with chemistry-dependent recognition and reactivity in single-round experimental campaigns. Sulfotyrosine and nitrotyrosine enabled modification-dependent recognition of thrombin and HER2, respectively. Genetically encoded noncanonical residues enabled bioorthogonal affinity switching and light- or proximity-triggered covalent target capture. Post-expression chemical modifications yielded a light-activated covalent PD-L1 binder and an isoform-selective CA IX inhibitor (KD = 45 nM) designed to engage catalytic Zn2+;. CheMoDesign makes chemical mechanism a programmable dimension of de novo protein design.","rel_num_authors":6,"rel_authors":[{"author_name":"Yuxuan Li","author_inst":"Peking University"},{"author_name":"Yanbo Jing","author_inst":"Peking University"},{"author_name":"Yeyu Su","author_inst":"Peking University"},{"author_name":"Wei Ren","author_inst":"Peking University"},{"author_name":"Jiayi Zhang","author_inst":"Peking University"},{"author_name":"Tao Liu","author_inst":"Peking University"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"TorPause: Efficient Static Organ Preservation for Transplants","rel_doi":"10.64898\/2026.10.08.755167","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.755167","rel_abs":"Transplantation is limited by how long organs survive outside the body. Existing preservation methods slow metabolism or sustain physiological support, but neither eliminates ischemia-reperfusion injury (IRI), which shortens storage and drives organ discard. Embryonic diapause and hibernation show that mammalian cells retain a latent capacity for reversible metabolic arrest. Screening the PI3K-mTOR axis, we identified a dual inhibitor that pauses embryonic stem cells reversibly at ambient oxygen and holds intact mouse embryos in arrest for 11 days. Combined with a mitochondria-targeted hydrogen sulfide donor, this yields TorPause: a two-component flush pairing metabolic pausing with mitochondrial protection, compatible with existing preservation protocols. In a rat liver transplantation model, TorPause reduced structural injury and improved recipient survival after severe warm ischemic storage, potentially expanding the usable donor pool.","rel_num_authors":10,"rel_authors":[{"author_name":"Joydeep Bhadury","author_inst":"ISCBRM, Stanford University School of Medicine"},{"author_name":"Tetsuya Tajima","author_inst":"Department of Surgery, Division of Abdominal Transplantation, Stanford University School of Medicine"},{"author_name":"Fabian P Suchy","author_inst":"ISCBRM, Stanford University School of Medicine"},{"author_name":"Hideki Masaki","author_inst":"Stem Cell Therapy Division, Advanced Research Initiative, Institute of Integrated Research, Institute of Science Tokyo, Tokyo, Japan"},{"author_name":"Jinyu Zhang","author_inst":"ISCBRM, Stanford University School of Medicine"},{"author_name":"Moises Rivera","author_inst":"ISCBRM, Stanford University School of Medicine"},{"author_name":"Toshiya Nishimura","author_inst":"ISCBRM, Stanford University School of Medicine"},{"author_name":"Carsten T. Charlesworth","author_inst":"ISCBRM, Stanford University School of Medicine"},{"author_name":"Carlos O. Esquivel","author_inst":"Department of Surgery, Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA, USA"},{"author_name":"Hiromitsu Nakauchi","author_inst":"Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"In situ architecture of the basal body reveals regionalized assembly and central pair microtubules nucleation","rel_doi":"10.64898\/2026.10.08.757802","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.757802","rel_abs":"The basal body (BB) is essential for axoneme assembly and ciliary function, and its defects are associated with ciliogenesis disorders and ciliopathies (1,2). However, the molecular basis of the BB's region-specific transitions along the proximal-distal axis, and the mechanism by which ciliary central pair (CP) microtubules are nucleated during ciliogenesis, have remained largely unknown. Here, we resolve the subnanometer architecture of native BBs in mammalian multiciliated cells using cryo-electron tomography and subtomogram averaging, and identify 11 ciliary-base microtubule-associated proteins (CMAPs), including 5 previously uncharacterized core components. These CMAPs localize specifically along ciliary base that facilitate the triplet-to-doublet microtubule transition. We further identify luminal gamma-tubulin ring complexes (gamma-TuRCs) anchored to the microtubule wall via the augmin complex, and propose that they may serve as candidate nucleation sites for CP microtubules biogenesis. Together, these findings define a molecular blueprint of the BB and provide a structural framework for understanding how regional architectural specialization and luminal nucleation collectively drive ciliary assembly and how their dysfunction causes ciliopathies.","rel_num_authors":6,"rel_authors":[{"author_name":"Ziyan Wang","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Huan Yang","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Hao Lang","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Xueliang Zhu","author_inst":"Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences"},{"author_name":"Yun Zhu","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Fei Sun","author_inst":"Chinese Academy of Sciences"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"One Scaffold, Many Targets: Fully Modified RNA Nanostructures for Multi-Gene Silencing Beyond the Liver","rel_doi":"10.64898\/2026.10.08.757482","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.757482","rel_abs":"Therapeutic siRNAs are a major clinical modality for hepatic gene silencing, but efficient extrahepatic delivery and multi-gene modulation remain significant barriers. Nucleic acid nanotechnology offers programmable assembly, but conventional structures suffer from enzymatic instability in vivo . Here we report fully chemically modified RNA nanostructures (FMRNs): a vehicle-free platform entirely composed of stabilized therapeutic nucleic acids that integrate structural precision with metabolic durability. Following systemic administration, FMRNs exhibit enhanced pharmacokinetics and extrahepatic accumulation, with in vivo behavior influenced greatly by hydrodynamic size rather than molecular weight. Using triangular and square geometries, we demonstrate programmable control over siRNA stoichiometry to achieve sustained, simultaneous silencing of up to four genes from a single entity. Nanostructure assembly alone drives productive delivery, especially to heart and muscle, matching lipophilic conjugation. Furthermore, cerebrospinal fluid administration reveals that larger FMRNs improve central nervous system distribution and retention revealing physicochemical parameters that impact brain exposure. FMRNs establish a modular and effective platform combining improved pharmacokinetics, extrahepatic delivery, and multi-gene silencing for complex diseases.","rel_num_authors":11,"rel_authors":[{"author_name":"Hassan H. Fakih","author_inst":"UMass Chan Medical School - RNA Therapeutics Institute"},{"author_name":"Ashley Summers","author_inst":"UMass Chan Medical School - RNA Therapeutics Institute"},{"author_name":"Qi Tang","author_inst":"UMass Chan Medical School - RNA Therapeutics Institute and Department of Dermatology"},{"author_name":"Rosemary Gagnon","author_inst":"UMass Chan Medical School - RNA Therapeutics Institute"},{"author_name":"Brianna M Bramato","author_inst":"UMass Chan Medical School - RNA Therapeutics Institute"},{"author_name":"Raymond Furgal","author_inst":"UMass Chan Medical School - RNA Therapeutics Institute"},{"author_name":"Katherine Y Gross","author_inst":"UMass Chan Medical School - RNA Therapeutics Institute"},{"author_name":"Jana H. Fakih","author_inst":"UMass Chan Medical School - RNA Therapeutics Institute; current affiliation American University of Beirut"},{"author_name":"Dimas Echeverria","author_inst":"UMass Chan Medical School - RNA Therapeutics Institute"},{"author_name":"Hanadi F Sleiman","author_inst":"McGill University"},{"author_name":"Anastasia Khvorova","author_inst":"UMass Chan Medical School - RNA Therapeutics Institute"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Microstructural heterogeneity of white-matter aging and its age-dependent coupling to cognition","rel_doi":"10.64898\/2026.10.09.757817","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.09.757817","rel_abs":"Brain white matter (WM) microstructure undergoes extensive changes with age, yet the regional and cellular heterogeneity of age-related WM alterations and their impact on cognition remain unclear. Leveraging Neurite Orientation Dispersion and Density Imaging (NODDI), an advanced microstructural modelling to capture specific WM cellular properties, we investigated age-dependent relationships between advanced microstructural markers and cognitive performance, indexed by six cognitive domains derived from principal component analysis. Using a suite of standard diffusion tensor imaging (DTI) and NODDI techniques in eighty-six cognitively normal adults (Young: n=33, Older: n=53), we show that age group differences are widespread across whole brain white matter, with converging region-based and voxel-level evidence implicating commissural, association, and limbic pathways. Older adults exhibited significant and widespread reductions in global fractional anisotropy (FA) and neurite density index (NDI), concomitant with increases in mean diffusivity (MD), orientation density index (ODI), and free water fraction (FWF). Critically, age moderated WM-cognition associations in a domain- and tract-specific manner: younger adults exhibited stronger coupling between commissural and association tract microstructure and language and visual memory, whereas older adults showed greater dependence on projection and limbic tracts for executive and language function. The observed age-dependent coupling between specific microstructural metrics and cognition underscores the value of advanced diffusion models for capturing heterogeneity in brain aging, reveals age-specific biomarkers of cognitive health. These patterns align with phylogenetic and ontogenetic patterns of white matter vulnerability in callosal, long-range association, and limbic pathways, and suggest cellular specificity in white matter changes associated with cognitive decline.","rel_num_authors":5,"rel_authors":[{"author_name":"Rowena Chin","author_inst":"Brown University"},{"author_name":"Xiaoyang Hu","author_inst":"Brown University"},{"author_name":"Jasine Ranieri","author_inst":"Brown University"},{"author_name":"Ji-Hyun Kim","author_inst":"Brown University"},{"author_name":"Hwamee Oh","author_inst":"Brown University"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"GRASS-MIL: graph-based representation and discovery of phenotype-associated spatial structures with multiple instance learning","rel_doi":"10.64898\/2026.10.08.757722","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.757722","rel_abs":"Tissue function is shaped by both cellular composition and the spatial organization of cells. Spatial single-cell technologies capture this organization across tissue sections, enabling tissue architecture to be linked to disease phenotypes, prognosis and treatment response. However, many current graph-based predictive models depend on assay-specific molecular features, limiting joint analysis of cohorts profiled with incompatible panels, and either aggregate local predictions uniformly or rely on post hoc importance scores that do not directly decompose the basis of a sample-level prediction. Here we introduce GRASS-MIL, a graph multiple-instance learning framework that learns the relative relevance and class-specific evidence of individual cellular neighborhoods, predicts phenotypes across platforms, and decomposes each sample-level prediction exactly into signed contribution from each local neighborhood. These contributions are terms of the prediction itself rather than a post hoc approximation and sum exactly to the predicted logit. In simulations, GRASS-MIL distinguished phenotypes with identical global cell-type composition but different spatial organization, whereas composition-based classifiers performed no better than chance. A single model trained jointly on CosMx spatial molecular imaging, Xenium and MERFISH datasets, harmonized only through a shared cell-type vocabulary, predicted treatment status in high-grade serous ovarian carcinoma with an area under the receiver operating characteristic curve of 0.74 and associated this prediction with two stromal architectures: an immune-rich niche admixed with malignant cells and a desmoplastic niche characterized by malignant-cell exclusion. Applied to spatial proteomics data from non-small-cell lung cancer, GRASS-MIL identified distinct niches associated with relapse (area under the receiver operating characteristic curve, 0.57), including myeloid-rich niches in relapsing tumors and adaptive immune niches in non-relapsing tumors. In a separate lung adenocarcinoma cohort, a similar lymphoid-myeloid polarity was observed when predicting 3-year mortality (area under the receiver operating characteristic curve, 0.62), with a B-cell and CD4+ T-cell niche associated with favorable outcome and a neutrophil and macrophage niche associated with adverse outcome. GRASS-MIL thus combines cross-platform phenotype prediction with an exact, signed decomposition of each prediction into the cellular neighborhoods on which it depends, providing a direct route from sample-level prediction to testable hypotheses linking tissue architecture with patient phenotypes.","rel_num_authors":4,"rel_authors":[{"author_name":"Lovro Rabuzin","author_inst":"ETH Zurich"},{"author_name":"Josephine Yates","author_inst":"The Broad Institute of MIT and Harvard"},{"author_name":"Mina L Xu","author_inst":"Yale University"},{"author_name":"Valentina Boeva","author_inst":"ETH Zurich"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"The adaptive architecture of tRNA dependencies across physiological tumor environments","rel_doi":"10.64898\/2026.10.08.757597","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.757597","rel_abs":"The genetic code is decoded by a highly redundant transfer RNA (tRNA) repertoire, yet whether this apparent redundancy serves a functional role beyond ensuring robust translation remains unclear. Here, we establish an atlas of tRNA dependencies through large-scale CRISPRi perturbation mapping across matched in vivo tumor growth and in vitro cell culture for 16 cancer cell lines spanning seven tissue types. During in vivo tumor growth, tRNA dependencies exhibited tissue organization at isodecoder resolution and were associated with codon demand at the isoacceptor level. Strikingly, these relationships were reorganized when cells were cultured in vitro, establishing environmental sensitivity of tRNA dependency--in contrast to protein components of the decoding machinery such as aminoacyl-tRNA synthetases (aaRSs), whose dependencies were largely preserved across environments. Despite pronounced context specificity, environmental alterations in tRNA dependency were dominated by a shared response across cancer cell lines, organized across isoacceptor and isodecoder levels. By disentangling stable cellular identity from environment-associated dependency states, we resolved a shared axis of isoacceptor dependency remodeling and identified specific tRNA isoacceptors associated with promoting or restraining adaptation to the tumor environment. We further connect this functional architecture to differential translation of codon-usage-biased programs associated with proliferation and tumor-microenvironmental stress. Together, our study reveals that tRNA redundancy does not imply functional equivalence, but instead forms a structured and environmentally plastic control layer linking coding information to translational output.","rel_num_authors":9,"rel_authors":[{"author_name":"Siyu Chen","author_inst":"Arc Institute"},{"author_name":"Trey Charbonneau","author_inst":"Arc Institute"},{"author_name":"Kian Yousefi","author_inst":"UCSF"},{"author_name":"Bahar Zirak","author_inst":"UCSF"},{"author_name":"Sean Lee","author_inst":"UCSF"},{"author_name":"Tanvi Joshi","author_inst":"UCSF"},{"author_name":"April Pawluk","author_inst":"Arc Institute"},{"author_name":"Vijay Ramani","author_inst":"Gladstone Institutes"},{"author_name":"Hani Goodarzi","author_inst":"Arc Institute"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Fine-tuning genomic models on rare splicing events identifies a novel biomarker of TDP-43 pathology","rel_doi":"10.64898\/2026.10.07.757366","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.07.757366","rel_abs":"Genomic foundation models (GFMs) are pretrained on large genomic datasets, but their ability to predict rare disease-associated events after fine-tuning remains unclear. We tested this using TDP-43 cryptic exons, well characterized splicing events linked to neurodegenerative disease that are poorly represented in standard annotations. We compared the state-of-the-art GFM AlphaGenome with OpenSpliceAI, a specialized splice site prediction model. Fine-tuned OpenSpliceAI detected held-out cryptic exons in human and mouse and captured allele-specific splicing effects at the disease-associated UNC13A locus. In contrast, a splicing prediction head trained on AlphaGenome's frozen pretrained backbone failed to predict cryptic exons. Unfreezing and fine-tuning all model weights, however, enabled AlphaGenome to generalize to held-out data. To investigate cryptic splicing in cell types that are difficult to study experimentally, we applied fine-tuned OpenSpliceAI across the genome to study cell type-specific genes. This led to the identification of new cryptic splicing events in CLDN11 and ARHGAP23, which were subsequently validated in FTLD-TDP brain tissue. Notably, the cryptic exon in CLDN11 is predicted to generate a neoepitope that could serve as an oligodendrocyte-specific biomarker of TDP-43 pathology. Our results show that even a state-of-the-art GFM can fail to generalize to rare splicing events, even with substantial pretraining. However, both foundation and specialized models that learn to generalize to rare biological events can have broad applications in biological discovery and medicine.","rel_num_authors":7,"rel_authors":[{"author_name":"Cristina P. Martin-Linares","author_inst":"Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA; Center for Computational Biology, Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"Aswathy Peethambaran Mallika","author_inst":"Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Parker S. Sandal","author_inst":"Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Tyler W. Martin","author_inst":"Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Meaghan Morris","author_inst":"Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA; Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"Philip C. Wong","author_inst":"Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA; Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Jonathan P. Ling","author_inst":"Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Reduced skeletal density and mechanical resistance in mangrove-associated Pocillopora sp. corals","rel_doi":"10.64898\/2026.10.07.757461","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.07.757461","rel_abs":"Coral skeletal integrity underpins reef habitat complexity and coastal protection, yet it remains unclear whether corals persisting in chemically variable marginal habitats, such as mangrove-associated reefs, maintain sufficient mechanical resistance to withstand physical disturbance. We combined micro-computed tomography (micro-CT) morphometric analysis with compression testing to quantify skeletal microarchitecture and compressive mechanical performance of Pocillopora sp. skeletons collected across a habitat gradient at Low Isles, Great Barrier Reef, from mangrove-associated sites to exposed reef sites. Baseline skeletal properties varied among sites, with the Proximal Reef site having the densest and least porous skeletons, while mangrove-associated sites had the most porous skeletons. Similarly, Proximal Reef skeletons exhibited two-to-three-fold greater compressive stiffness and peak force than mangrove-associated skeletons. Percentage object volume was a stronger predictor of compressive stiffness than surface area-to-volume (S\/V) ratio, indicating that bulk skeletal density better captured load-bearing capacity than surface architectural complexity. Structural failure mode also differed markedly among habitats: mangrove-associated skeletons underwent catastrophic fragmentation of their open, porous framework, whereas Distal and Proximal Reef skeletons failed through discrete crack-plane propagation while largely maintaining overall structural coherence. These results indicate that the physiological stress tolerance associated with mangrove habitats occurs alongside reduced mechanical resistance and more destructive failure modes, suggesting a potential trade-off between chemical stress tolerance and structural investment. Assessments of resilience in marginal coral populations should therefore consider skeletal mechanical performance alongside physiological tolerance, particularly as climate change intensifies storms and alters hydrodynamic disturbance regimes.","rel_num_authors":4,"rel_authors":[{"author_name":"Adi Zweifler (Zvifler)","author_inst":"School of Life and Environmental Sciences, The University of Sydney"},{"author_name":"Dayana Chadda-Harmer","author_inst":"School of Life and Environmental Sciences, The University of Sydney"},{"author_name":"Matthew Foley","author_inst":"Sydney Microscopy and Microanalysis, The University of Sydney"},{"author_name":"Shawna A. Foo","author_inst":"School of Life and Environmental Sciences, The University of Sydney"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"The dark transcriptome mouse organogenesis cell atlas","rel_doi":"10.64898\/2026.10.06.756869","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.06.756869","rel_abs":"Single-cell atlases have transformed our understanding of mammalian tissue biology, yet the diverse noncoding \"dark transcriptome\" remains largely uncharted. Here, we present the Dark Transcriptome Mouse Organogenesis Cell Atlas (DT-MOCA), comprising 276,455 cells across embryonic days 11 to 18 and jointly capturing protein-coding transcripts and five major classes of noncoding RNAs through single-nucleus total RNA sequencing, establishing the first comprehensive catalog of noncoding RNAs across major cell types and developmental lineages. We found that long noncoding RNA and microRNA profiles distinguished major cell types and developmental lineages with resolution comparable to messenger RNA, whereas transfer RNA, small nuclear RNA, and small nucleolar RNA programs were less cell type-discriminative and more broadly shared. We further resolve noncoding RNA expression patterns as lineage-specific, temporally modulated, or coordinately regulated by cell identity and developmental stage. We observed that temporally regulated long noncoding RNAs were evolutionarily younger than those associated with cell identity. We further generate a catalog of the change of noncoding RNAs cross all 11 major developmental trajectories. It revealed lineage-specific coordination between transfer RNA supply and codon demand during musculoskeletal organogenesis as well as dynamic microRNA and small nucleolar RNA programs during the central nervous system development. We observed microRNAs converge on regulators of proliferation and gliogenesis and shared induction of Snord116 defining a developmental window relevant to Prader Willi syndrome. Together, this atlas provides a comprehensive catalog of the developmental dark transcriptome and reveals how noncoding RNA programs are organized across cell identity, developmental time, and lineage progression.","rel_num_authors":8,"rel_authors":[{"author_name":"Miao Liu","author_inst":"Yale University"},{"author_name":"Dingyao Zhang","author_inst":"Yale University"},{"author_name":"Keyi Li","author_inst":"Yale University"},{"author_name":"Yuval Kluger","author_inst":"Yale University"},{"author_name":"Jun Lu","author_inst":"Yale University"},{"author_name":"Mark B. Gerstein","author_inst":"Yale university"},{"author_name":"Haikuo Li","author_inst":"Yale University"},{"author_name":"Rong Fan","author_inst":"Yale University"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Lateral recurrence dynamically refines visual representations for task performance","rel_doi":"10.64898\/2026.10.02.756219","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.02.756219","rel_abs":"Recurrent connections are pervasive in visual cortex, and visual representations evolve as recurrent processing unfolds. Yet the mechanism underlying this temporal transformation remains poorly understood. To address this question, we trained recurrent convolutional networks on face and object recognition and tested them on a parametric stimulus set in which category, identity, and pose were systematically varied. This design isolates how lateral recurrence reshapes neural-population representational geometry and single-unit tuning across recurrent timesteps. Within the trained domain, recurrence increased the separability between identities in deeper layers, while leaving the non-trained domain representations largely unchanged. Gating lateral weights abolished the across-timestep gain in trained-domain identity decoding, demonstrating that lateral recurrence drives this refinement. At the single-unit level, recurrence strengthened the correlation between each unit's category preference and its within-domain identity sensitivity, providing a unit-level mechanism for the population-level changes. These results identify lateral recurrence as a dynamic mechanism for refining learned representational structure within a fixed neural population, yielding testable predictions for time-resolved recordings in domain-selective cortex.","rel_num_authors":5,"rel_authors":[{"author_name":"Amirhossein Farzmahdi","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Hossein Adeli","author_inst":"Columbia University"},{"author_name":"Wang Boran","author_inst":"Columbia University"},{"author_name":"Chase King","author_inst":"Columbia University"},{"author_name":"Nikolaus Kriegeskorte","author_inst":"Columbia University"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Lateral recurrence dynamically refines visual representations for task performance","rel_doi":"10.64898\/2026.10.02.756219","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.02.756219","rel_abs":"Recurrent connections are pervasive in visual cortex, and visual representations evolve as recurrent processing unfolds. Yet the mechanism underlying this temporal transformation remains poorly understood. To address this question, we trained recurrent convolutional networks on face and object recognition and tested them on a parametric stimulus set in which category, identity, and pose were systematically varied. This design isolates how lateral recurrence reshapes neural-population representational geometry and single-unit tuning across recurrent timesteps. Within the trained domain, recurrence increased the separability between identities in deeper layers, while leaving the non-trained domain representations largely unchanged. Gating lateral weights abolished the across-timestep gain in trained-domain identity decoding, demonstrating that lateral recurrence drives this refinement. At the single-unit level, recurrence strengthened the correlation between each unit's category preference and its within-domain identity sensitivity, providing a unit-level mechanism for the population-level changes. These results identify lateral recurrence as a dynamic mechanism for refining learned representational structure within a fixed neural population, yielding testable predictions for time-resolved recordings in domain-selective cortex.","rel_num_authors":5,"rel_authors":[{"author_name":"Amirhossein Farzmahdi","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Hossein Adeli","author_inst":"Columbia University"},{"author_name":"Wang Boran","author_inst":"Columbia University"},{"author_name":"Chase King","author_inst":"Columbia University"},{"author_name":"Nikolaus Kriegeskorte","author_inst":"Columbia University"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Heritable variation in root bacterial microbiomes alters natural selection on host plants","rel_doi":"10.64898\/2026.10.07.757180","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.07.757180","rel_abs":"Heritable variation in microbiome composition could theoretically evolve in response to selection acting on hosts, but empirical evidence of this is scarce. We tested for effects of allelic variation in Boechera stricta on microbiome composition and downstream consequences for host fitness. In the greenhouse, near-isogenic lines with contrasting phytochemistry alleles differentially conditioned soil microbiota in ways that changed the relative fecundity of host genotypes. In the field, root microbiome differences mediated allelic effects on host fitness. Selection gradients on individual taxa and multivariate axes of root microbiome composition suggest that independent components of the bacterial community favor each allele, especially under drought. These results show that microbiota contribute to natural selection on a major-effect phytochemistry gene, empirically closing the loop between microbiome heritability and host trait evolution.","rel_num_authors":5,"rel_authors":[{"author_name":"Lauren N. Carley","author_inst":"University of Chicago"},{"author_name":"Anita Simha","author_inst":"Louisiana State University"},{"author_name":"Ethan Bass","author_inst":"University of Chicago"},{"author_name":"Amanda Carmichael","author_inst":"University of Kansas"},{"author_name":"Maggie R Wagner","author_inst":"University of Kansas"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Heritable variation in root bacterial microbiomes alters natural selection on host plants","rel_doi":"10.64898\/2026.10.07.757180","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.07.757180","rel_abs":"Heritable variation in microbiome composition could theoretically evolve in response to selection acting on hosts, but empirical evidence of this is scarce. We tested for effects of allelic variation in Boechera stricta on microbiome composition and downstream consequences for host fitness. In the greenhouse, near-isogenic lines with contrasting phytochemistry alleles differentially conditioned soil microbiota in ways that changed the relative fecundity of host genotypes. In the field, root microbiome differences mediated allelic effects on host fitness. Selection gradients on individual taxa and multivariate axes of root microbiome composition suggest that independent components of the bacterial community favor each allele, especially under drought. These results show that microbiota contribute to natural selection on a major-effect phytochemistry gene, empirically closing the loop between microbiome heritability and host trait evolution.","rel_num_authors":5,"rel_authors":[{"author_name":"Lauren N. Carley","author_inst":"University of Chicago"},{"author_name":"Anita Simha","author_inst":"Louisiana State University"},{"author_name":"Ethan Bass","author_inst":"University of Chicago"},{"author_name":"Amanda Carmichael","author_inst":"University of Kansas"},{"author_name":"Maggie R Wagner","author_inst":"University of Kansas"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Land use and climate warming interact to reshape global avian biodiversity through ecological filtering and homogenisation","rel_doi":"10.64898\/2026.10.08.757631","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.757631","rel_abs":"Land-use and climate change are dominant drivers of terrestrial biodiversity change, yet are usually analysed separately although they co-occur and may interact. We integrated global bird assemblage records from PREDICTS with temperature anomalies and species' ecological characteristics to test how land use modifies biodiversity responses to climate warming across three dimensions: local abundance and richness, compositional dissimilarity among assemblages, and species occurrence across ecological groups. Land use modified warming associations for both abundance and richness. Relative to primary vegetation, warming associations were more positive in low-intensity agriculture for both responses, but more negative for richness in high-intensity agriculture and urban land. Predicted richness remained below the reference, defined as primary vegetation at temperature anomaly 0, across all modified land uses, with the largest declines in high-intensity agriculture (-17.9%) and urban land (-21.8%). Within land-use classes, greater warming exposure was generally associated with higher compositional similarity, consistent with warming associated biotic homogenisation. Occurrence models revealed ecological filtering: broad-niched generalists were favoured in warmer modified habitats, whereas range-restricted habitat specialists were filtered out under intensive land use and warming. Conservation assessments should therefore integrate land-use-warming interactions with changes in assemblage composition and ecological strategies, particularly in agricultural and urban landscapes where warming further disadvantaged range-restricted specialists.","rel_num_authors":9,"rel_authors":[{"author_name":"Chenchen Ding","author_inst":"Institute of Ecology and State Key Laboratory for Vegetation Structure, Function and Construction (VegLab), College of Urban and Environmental Sciences, Peking "},{"author_name":"Tim Newbold","author_inst":"Centre for Biodiversity and Environment Research, Department of Genetics, Evolution and Environment, University College London"},{"author_name":"Adrienne Etard","author_inst":"International Institute for Applied Systems Analysis"},{"author_name":"Richard Cornford","author_inst":"International Institute for Applied Systems Analysis"},{"author_name":"Martin Jung","author_inst":"International Institute for Applied Systems Analysis (IIASA)"},{"author_name":"Kyle Brumm","author_inst":"International Institute for Applied Systems Analysis"},{"author_name":"Zhigang Jiang","author_inst":"Institute of Zoology, Chinese Academy of Sciences"},{"author_name":"Piero Visconti","author_inst":"International Institute for Applied System Analysis"},{"author_name":"Zhiheng Wang","author_inst":"Institute of Ecology and State Key Laboratory for Vegetation Structure, Function and Construction (VegLab), College of Urban and Environmental Sciences, Peking "}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"User-friendly software for high-throughput processing of chlorophyll fluorescence images to assess plant stress responses: fvfmPy and fvfmR packages","rel_doi":"10.64898\/2026.10.06.757212","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.06.757212","rel_abs":"Chlorophyll fluorescence imaging is a powerful tool used to characterize abiotic and biotic stress response of photosynthesis in plants. However, extracting metrics such as Fv\/Fm (maximum quantum yield of photosystem II) from chlorophyll fluorescence images remains a substantial bottleneck in large measurement campaigns, often requiring significant manual effort. To resolve this issue, we developed fvfmPy, a user-friendly program which enables rapid analysis of chlorophyll fluorescence images of arrays of leaf discs. fvfmPy uses algorithmic image segmentation to identify regions of interest and extract fluorescence metrics from tens or hundreds of leaf samples per image with little to no manual input. fvfmPy is developed in Python and includes a graphical user interface enabling intuitive parameter adjustment and real-time quality control checking. We additionally developed fvfmR, an R wrapper package for fvfmPy. Fv\/Fm values extracted with fvfmPy were indistinguishable from those obtained using manual methods (r2 > 0.99) but required 94% less time to complete (13 s vs. 200 s per 100 measurements). fvfmPy and fvfmR were built to directly integrate with existing fluorescence software packages and can greatly increase throughput of fluorescence measurements to help address key challenges in agriculture and ecology.","rel_num_authors":3,"rel_authors":[{"author_name":"Josef C. Garen","author_inst":"Western Sydney University"},{"author_name":"Pieter A Arnold","author_inst":"Australian National University"},{"author_name":"Kristine Y Crous","author_inst":"Western Sydney University"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Genome-scale mapping of plant transcription factor effector domains reveals conserved regulatory principles across eukaryotes","rel_doi":"10.64898\/2026.10.08.757571","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.757571","rel_abs":"Eukaryotic life spans species that diverged over a billion years ago, yet our molecular view of gene regulation remains heavily skewed toward Opisthokonta model systems, particularly yeast and humans. The degree to which the protein features governing transcriptional regulation are conserved across eukaryotes or have diversified within individual eukaryotic supergroups remains unresolved. To provide a distinct evolutionary reference point, we used a massively parallel reporter assay in plant cells to identify transcriptional effector domains and define their sequence constraints, measuring ~26,000 protein fragments tiling nearly all Arabidopsis transcription factors (1,859 proteins). Comparison with the activity of the same peptide sequences in yeast revealed that activation is governed by a mixture of deeply conserved biochemical features and lineage-dependent functional differences across widely divergent eukaryotic lineages. Likewise, plant repression domains are governed by flexible sequence grammars that extend beyond conserved repression motifs. Together, these results reveal both broadly conserved and clade-specific principles governing eukaryotic transcriptional regulation.","rel_num_authors":11,"rel_authors":[{"author_name":"Simon Alamos","author_inst":"University of California, Berkeley"},{"author_name":"Anthony E Sarkiss","author_inst":"University of California, Berkeley"},{"author_name":"Jacob T Rapp","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Anya Lachwani","author_inst":"University of California, Berkeley"},{"author_name":"Izaiah J Ornelas","author_inst":"University of California, Berkeley"},{"author_name":"Maximo A Kesselhaut","author_inst":"University of California, Berkeley"},{"author_name":"Juan D Tibocha-Bonilla","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Amy Lanctot","author_inst":"University of California, Berkeley"},{"author_name":"James K Nu\u00f1ez","author_inst":"University of California, Berkeley"},{"author_name":"Hector Garcia Martin","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Patrick M Shih","author_inst":"University of California, Berkeley"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Behavioral dysfunction but not wasting in cancer cachexia is driven by altered tryptophan metabolism","rel_doi":"10.64898\/2026.10.08.757616","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.757616","rel_abs":"Cancer cachexia causes pathological weight loss, anorexia, and depressive symptoms, culminating in increased mortality. Using mouse models of pancreatic cancer cachexia, we identify tumor and hepatic inflammatory signaling, multi-organ energy charge depletion, and altered tryptophan metabolism. Metabolomic profiling and stable isotope tracing revealed altered tryptophan fates: serotonin depletion and kynurenine accumulation across tumor, liver, muscle and spleen. Kynurenine accumulation involved accelerated conversion of tryptophan to kynurenine with slowed downstream conversion to kynurenic acid. Restoring serotonin activity pharmacologically or metabolically normalized feeding, locomotion, and depression-like behavior, but wasting, tumor burden, and survival remained unchanged. Blocking kynurenine production or kynurenine-mediated AhR activation pharmacologically produced similar results. Thus, in cancer cachexia, the tryptophan pathway is subverted to deplete serotonin and accumulate kynurenine. This subversion contributes to cachexia-associated behavioral and feeding defects but not lethal systemic catabolism.","rel_num_authors":19,"rel_authors":[{"author_name":"Damon Fard","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA"},{"author_name":"Edisa Pirani","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA"},{"author_name":"Maria Gomez-Jenkins","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA"},{"author_name":"Sereno Lopez-Darwin","author_inst":"Ludwig Princeton Branch, Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ 08544, USA; Department of Computer Science, Princeton Univers"},{"author_name":"Maria Ibrahim","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA"},{"author_name":"Lilia Schell","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA"},{"author_name":"Charlotte Larkin","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA"},{"author_name":"Clara Gorgui","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA"},{"author_name":"Clara Berdasco","author_inst":"Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA"},{"author_name":"Zhixian Hu","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA"},{"author_name":"Trishna Das","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA"},{"author_name":"Jesse Powers","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA"},{"author_name":"Tracy G. Anthony","author_inst":"Department of Nutritional Sciences, Rutgers School of Environmental and Biological Sciences, Rutgers University, New Brunswick, NJ 08901, USA"},{"author_name":"Joshua D. Rabinowitz","author_inst":"Ludwig Princeton Branch, Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ 08544, USA"},{"author_name":"Benjamin J Raphael","author_inst":"Department of Computer Science, Princeton University, Princeton, NJ 08540, USA"},{"author_name":"Jessie Yanxiang Guo","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA; Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, N"},{"author_name":"Marcus D. Goncalves","author_inst":"Department of Medicine, NYU Langone Health, New York, NY 10016, USA"},{"author_name":"Tobias Janowitz","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Northwell Health Cancer Institute, Northwell Health, New Hyde Park, NY 11042, USA"},{"author_name":"Eileen White","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA; Ludwig Princeton Branch, Ludwig Institute for Cancer Research, Princeton University,"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Behavioral dysfunction but not wasting in cancer cachexia is driven by altered tryptophan metabolism","rel_doi":"10.64898\/2026.10.08.757616","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.757616","rel_abs":"Cancer cachexia causes pathological weight loss, anorexia, and depressive symptoms, culminating in increased mortality. Using mouse models of pancreatic cancer cachexia, we identify tumor and hepatic inflammatory signaling, multi-organ energy charge depletion, and altered tryptophan metabolism. Metabolomic profiling and stable isotope tracing revealed altered tryptophan fates: serotonin depletion and kynurenine accumulation across tumor, liver, muscle and spleen. Kynurenine accumulation involved accelerated conversion of tryptophan to kynurenine with slowed downstream conversion to kynurenic acid. Restoring serotonin activity pharmacologically or metabolically normalized feeding, locomotion, and depression-like behavior, but wasting, tumor burden, and survival remained unchanged. Blocking kynurenine production or kynurenine-mediated AhR activation pharmacologically produced similar results. Thus, in cancer cachexia, the tryptophan pathway is subverted to deplete serotonin and accumulate kynurenine. This subversion contributes to cachexia-associated behavioral and feeding defects but not lethal systemic catabolism.","rel_num_authors":19,"rel_authors":[{"author_name":"Damon Fard","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA"},{"author_name":"Edisa Pirani","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA"},{"author_name":"Maria Gomez-Jenkins","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA"},{"author_name":"Sereno Lopez-Darwin","author_inst":"Ludwig Princeton Branch, Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ 08544, USA; Department of Computer Science, Princeton Univers"},{"author_name":"Maria Ibrahim","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA"},{"author_name":"Lilia Schell","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA"},{"author_name":"Charlotte Larkin","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA"},{"author_name":"Clara Gorgui","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA"},{"author_name":"Clara Berdasco","author_inst":"Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, USA"},{"author_name":"Zhixian Hu","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA"},{"author_name":"Trishna Das","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA"},{"author_name":"Jesse Powers","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA"},{"author_name":"Tracy G. Anthony","author_inst":"Department of Nutritional Sciences, Rutgers School of Environmental and Biological Sciences, Rutgers University, New Brunswick, NJ 08901, USA"},{"author_name":"Joshua D. Rabinowitz","author_inst":"Ludwig Princeton Branch, Ludwig Institute for Cancer Research, Princeton University, Princeton, NJ 08544, USA"},{"author_name":"Benjamin J Raphael","author_inst":"Department of Computer Science, Princeton University, Princeton, NJ 08540, USA"},{"author_name":"Jessie Yanxiang Guo","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA; Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, N"},{"author_name":"Marcus D. Goncalves","author_inst":"Department of Medicine, NYU Langone Health, New York, NY 10016, USA"},{"author_name":"Tobias Janowitz","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Northwell Health Cancer Institute, Northwell Health, New Hyde Park, NY 11042, USA"},{"author_name":"Eileen White","author_inst":"Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ 08903, USA; Ludwig Princeton Branch, Ludwig Institute for Cancer Research, Princeton University,"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"MYC drives endothelial transformation and dedifferentiation in angiosarcoma","rel_doi":"10.64898\/2026.10.07.757149","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.07.757149","rel_abs":"MYC amplification is the most common genetic alteration in radiation-associated angiosarcoma and is also present in a subset of de novo primary angiosarcoma, yet its oncogenic role in this vascular malignancy remains unclear. Here, we report that inducible, endothelial-specific MYC overexpression alone was sufficient to drive angiosarcomagenesis in mice. The resulting pulmonary angiosarcoma tumors exhibited impaired endothelial differentiation, indicative of MYC-driven lineage plasticity. Notably, MYC inactivation in dedifferentiated allografts induced growth arrest and restored endothelial gene expression, demonstrating MYC-dependent reversible cellular plasticity. Integrative analyses of MYC ChIP-seq, ATAC-seq, and RNA-seq revealed that overexpressed MYC preferentially occupied highly accessible promoters and activated genes involved in cell growth. Consistent with the murine findings, MYC-amplified human angiosarcomas were enriched for MYC target and cell-cycle programs and depleted of endothelial lineage signatures. MYC overexpression in human endothelial and angiosarcoma cells recapitulated these transcriptional changes, enhanced proliferation, and impaired endothelial tube formation. Together, our results establish MYC as an oncoprotein that promotes endothelial lineage plasticity to drive angiosarcoma initiation and progression.","rel_num_authors":22,"rel_authors":[{"author_name":"Chen Khuan Wong","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Dan Li","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Tomer Itkin","author_inst":"Tel Aviv University"},{"author_name":"Cindy J. Lee","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Nicholas A. Teri","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Jiasheng Zhou","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Dana M. Schoeps","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Nikita R. Staniloae","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Mohini R. Pachai","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Makhzuna N. Khudoynazarova","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Priya Pancholi","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Woo Hyun Cho","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Gabriella Bayshtok","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Kae Kristoff","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Selina Fan","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Richard Lin","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Shahin Rafii","author_inst":"Weill Cornell Medicine"},{"author_name":"Benedikt Bosbach","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Scott W. Lowe","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Cristina R. Antonescu","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Ping Chi","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Yu Chen","author_inst":"Memorial Sloan Kettering Cancer Center"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Small-Molecule Inhibitors Allosterically Control Bruton's Tyrosine Kinase Assembly on the Membrane","rel_doi":"10.64898\/2026.10.08.757093","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.757093","rel_abs":"Bruton's tyrosine kinase (Btk) is the target of small-molecule, active site inhibitors for treatment of lymphomas and leukemias. Beyond its catalytic activity, Btk participates in signaling assemblies through scaffolding functions that can contribute to drug resistance. Here, we show that Btk forms micron-scale assemblies on membranes and that this behavior is allosterically controlled by ligand binding at the active site. Using supported lipid bilayers and total internal reflection fluorescence microscopy, we find that nucleotides and inhibitors including ibrutinib, acalabrutinib, and dasatinib promote assembly, whereas fenebrutinib and pirtobrutinib prevent assembly. Membrane organization is independent of catalysis but correlates with ligand-dependent changes in Btk conformational flexibility measured by hydrogen-deuterium exchange. These results reveal a previously unrecognized connection between active-site ligand binding and mesoscale membrane organization, demonstrating that kinase inhibitors can control Btk behavior beyond suppression of catalytic activity.","rel_num_authors":6,"rel_authors":[{"author_name":"Alexander D Fenton","author_inst":"Colorado State University"},{"author_name":"Kathryn Todd","author_inst":"Colorado State University"},{"author_name":"Shweta Shree","author_inst":"Colorado State University"},{"author_name":"David Yin-wei Lin","author_inst":"Iowa State University"},{"author_name":"Amy H Andreotti","author_inst":"Iowa State University"},{"author_name":"Jean K Chung","author_inst":"Colorado State University"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Active maintenance of accessible chromatin at poised meiotic promoters by the NFYA-NURF axis is required for meiotic entry in mice","rel_doi":"10.64898\/2026.10.07.757370","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.07.757370","rel_abs":"Developmental genes often acquire accessible chromatin prior to their activation, yet the mechanisms regulating this permissive state remain poorly understood. During spermatogenesis, many meiotic gene promoters display this poised state in spermatogonia, characterized by accessible promoters and paused RNA Pol II occupancy before their activation during meiosis. Here, we identify the NURF chromatin remodeling complex, comprised of SMARCA5 and its accessory subunit BPTF, as a key regulator of this process. We demonstrate that the transcription factor NFYA interacts with SMARCA5 and is required for its occupancy at poised meiotic gene promoters. Approximately one-third of poised meiotic gene promoters is co-occupied by NFYA, SMARCA5, and BPTF. Germline deletion of Smarca5 disrupts chromatin accessibility at poised meiotic promoters, impairs transcriptional program required for mitosis-to-meiosis transition, resulting in developmental arrest at meiotic entry. These findings identify NFYA-NURF as a key regulatory axis that regulates accessible chromatin at developmentally poised meiotic genes and primes them for activation later during meiosis.","rel_num_authors":7,"rel_authors":[{"author_name":"Atiyeh Eghbali","author_inst":"Stockholm University"},{"author_name":"Martin Saflund","author_inst":"Stockholms Universitet"},{"author_name":"Masomeh Askari","author_inst":"Stockholm University"},{"author_name":"Mukhtar Mohamed Abdi","author_inst":"Stockholm University"},{"author_name":"Ann-Kristin Ostlund Farrants","author_inst":"Stockholm University"},{"author_name":"Tianxiong Yu","author_inst":"University of Massachusetts Medical School"},{"author_name":"Deniz M. Ozata","author_inst":"Stockholm University"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Active maintenance of accessible chromatin at poised meiotic promoters by the NFYA-NURF axis is required for meiotic entry in mice","rel_doi":"10.64898\/2026.10.07.757370","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.07.757370","rel_abs":"Developmental genes often acquire accessible chromatin prior to their activation, yet the mechanisms regulating this permissive state remain poorly understood. During spermatogenesis, many meiotic gene promoters display this poised state in spermatogonia, characterized by accessible promoters and paused RNA Pol II occupancy before their activation during meiosis. Here, we identify the NURF chromatin remodeling complex, comprised of SMARCA5 and its accessory subunit BPTF, as a key regulator of this process. We demonstrate that the transcription factor NFYA interacts with SMARCA5 and is required for its occupancy at poised meiotic gene promoters. Approximately one-third of poised meiotic gene promoters is co-occupied by NFYA, SMARCA5, and BPTF. Germline deletion of Smarca5 disrupts chromatin accessibility at poised meiotic promoters, impairs transcriptional program required for mitosis-to-meiosis transition, resulting in developmental arrest at meiotic entry. These findings identify NFYA-NURF as a key regulatory axis that regulates accessible chromatin at developmentally poised meiotic genes and primes them for activation later during meiosis.","rel_num_authors":7,"rel_authors":[{"author_name":"Atiyeh Eghbali","author_inst":"Stockholm University"},{"author_name":"Martin Saflund","author_inst":"Stockholms Universitet"},{"author_name":"Masomeh Askari","author_inst":"Stockholm University"},{"author_name":"Mukhtar Mohamed Abdi","author_inst":"Stockholm University"},{"author_name":"Ann-Kristin Ostlund Farrants","author_inst":"Stockholm University"},{"author_name":"Tianxiong Yu","author_inst":"University of Massachusetts Medical School"},{"author_name":"Deniz M. Ozata","author_inst":"Stockholm University"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Carbonic anhydrase inhibition rescues heart function in the Tg2576 Alzheimer's mouse model by ameliorating cardiac amyloid-\u03b2 pathology and neurotrophic signaling impairment.","rel_doi":"10.64898\/2026.10.08.757731","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.757731","rel_abs":"FDA-approved carbonic anhydrase inhibitors (CAIs) have shown robust efficacy in reducing amyloid- beta pathology, neurodegeneration, and cerebrovascular dysfunction in Alzheimer disease (AD) and cerebral amyloid angiopathy (CAA) models, highlighting carbonic anhydrases (CAs) as a promising, previously untapped therapeutic target for AD and the vascular contribution to dementia. We have recently shown that amyloid- beta aggregates disrupt neuro-signaling and deplete neurotrophic factors (particularly BDNF) in the heart of AD mouse models and human subjects. In this study, we present the first in-depth examination of CAI therapy (acetazolamide, ATZ) in Tg2576 mice, a well-established model of AD and CAA. We confirm that progressive cardiac fibrosis and amyloid- beta deposition in 13-month-old mice severely impair the cardiac neuro-signaling system, marked by a drastic decrease in BDNF and reductions in adrenergic fibers and regenerating nerve endings (TH and GAP-43 markers), leading to significant declines in ejection fraction and fractional shortening compared to age-matched WT littermates. Critically, this study demonstrates that long-term ATZ treatment in Tg2576 mice significantly reduces cardiac amyloid- beta burden, prevents adverse neuro-signaling remodeling, and restores heart physiological function, as assessed via speckle tracking strain echocardiography. These in vivo findings were corroborated in human cardiomyocytes, in which CA inhibition reduced human amyloid- beta40 oligomer-dependent disruption of CREB signaling, thus preserving BDNF expression. Together, these results reveal a previously unrecognized cardio-neuroprotective role for CAIs in preventing amyloid- beta-induced cardiovascular remodeling and neuro-signaling disruption in the Tg2576-AD model. Given the established benefits of CAIs on cerebrovascular function and cognition, our findings further support advancing repurposing efforts into clinical trials. CAIs such as ATZ could offer a dual-action therapy approach, addressing both the central nervous system and cardiac pathologies associated with AD and, potentially, the systemic effects of amyloidosis.","rel_num_authors":7,"rel_authors":[{"author_name":"Andrea Elia","author_inst":"Lewis Katz School of Medicine, Temple University"},{"author_name":"Rafael Vazquez-Torres","author_inst":"Lewis Katz School of Medicine, Temple University"},{"author_name":"Ashley Carey","author_inst":"Lewis Katz School of Medicine, Temple University"},{"author_name":"Madison Wolf","author_inst":"Lewis Katz School of Medicine, Temple University"},{"author_name":"Varenya R Gade","author_inst":"Lewis Katz School of Medicine, Temple University"},{"author_name":"Micaelly Alves","author_inst":"Lewis Katz School of Medicine, Temple University"},{"author_name":"Silvia Fossati","author_inst":"Temple University Lewis Katz School of Medicine"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"tRNA-derived second messengers confer bacterial immunity","rel_doi":"10.64898\/2026.10.06.756102","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.06.756102","rel_abs":"Bacterial small-molecule messengers that function in diverse immune signaling pathways have been thought to derive strictly from biosynthesis using nucleotide and cofactor substrates. Here we report a nuclease-driven immune signaling pathway in which tRNA cleavage generates a specific small molecule that triggers cell death in response to RNA-guided transcript recognition in prokaryotes. We identify a class of type VI-B CRISPR systems in which the RNA-guided nuclease Cas13 and its accessory transmembrane protein, 2TM{beta}, are co-encoded in an operon and are jointly required for bacteriophage defense. Upon target RNA recognition, Cas13 activates 2TM{beta} by producing mono- and dinucleotide messengers bearing 2',3'-cyclic uridine phosphate ends by tRNA cleavage. Activated 2TM{beta} destroys infected cells by forming a multimeric complex that disrupts cell membranes to mediate cell death. These findings demonstrate RNA-programmed tRNA cleavage for second-messenger biogenesis, revealing a new logic for prokaryotic immune signaling.","rel_num_authors":20,"rel_authors":[{"author_name":"Luis E. Valentin-Alvarado","author_inst":"Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia; Innovative Genomics Institut"},{"author_name":"Peter H. Yoon","author_inst":"Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Department of Molecular and Cell Biology, University of California, Berkel"},{"author_name":"Santiago C. Lopez","author_inst":"Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Department of Molecular and Cell Biology, University of California, Berkel"},{"author_name":"Yekaterina Shulgina","author_inst":"Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Department of Molecular and Cell Biology, University of California, Berkel"},{"author_name":"Conner Langeberg","author_inst":"Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; California Institute for Quantitative Biosciences, University of Californi"},{"author_name":"Emily Armbruster","author_inst":"Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Department of Molecular and Cell Biology, University of California, Berkel"},{"author_name":"Muhammad Moez Ur-Rehman","author_inst":"Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA"},{"author_name":"Kenneth Loi","author_inst":"Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Department of Molecular and Cell Biology, University of California, Berkel"},{"author_name":"Cyntia Taveneau","author_inst":"Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia"},{"author_name":"Isabel Esain-Garcia","author_inst":"Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; California Institute for Quantitative Biosciences, University of Californi"},{"author_name":"Mert Koka","author_inst":"University of Rochester Medical Center, The Department of Biochemistry and Biophysics and Center for RNA Biology, Rochester, NY, USA"},{"author_name":"Zeyuan Terry Zhang","author_inst":"Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Biophysics Graduate Group, University of California, Berkeley, Berkeley, C"},{"author_name":"Dmitry Kashin","author_inst":"BIOLOG Life Science Institute, Bremen, 28071, Germany"},{"author_name":"Frank Schwede","author_inst":"BIOLOG Life Science Institute, Bremen, 28071, Germany"},{"author_name":"Gaetan Burgio","author_inst":"Division of Genome and Cancer, The John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia; The Shine-Dalgarno Cen"},{"author_name":"Mitchell R. OConnell","author_inst":"University of Rochester Medical Center, The Department of Biochemistry and Biophysics and Center for RNA Biology, Rochester, NY, USA"},{"author_name":"Erin E. Doherty","author_inst":"Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Department of Molecular and Cell Biology, University of California, Berkel"},{"author_name":"Jamie H. D. Cate","author_inst":"Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Department of Molecular and Cell Biology, University of California, Berkel"},{"author_name":"Gavin J. Knott","author_inst":"Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia"},{"author_name":"Jennifer A. Doudna","author_inst":"Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Department of Molecular and Cell Biology, University of California, Berkel"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"ATP synthase deficiency promotes prolonged hydrogenproduction in Chlamydomonas","rel_doi":"10.64898\/2026.10.08.757524","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.757524","rel_abs":"Photosynthetic electron transport is tightly regulated to balance ATP and NADPH production and prevent over-reduction of the photosynthetic machinery. How this balance is maintained under severe ATP limitation, particularly under anoxia, is not fully resolved. Here, we used several deletion mutants of chloroplast ATP synthase subunits from Chlamydomonas reinhardtii to examine how electron flow is reorganized under anoxic conditions through the interplay between linear electron flow, cyclic electron flow, and alternative electron sinks. Using a combination of optical spectroscopy methods and membrane inlet mass spectrometry, we characterized changes in photosynthetic electron transport, proton motive force relaxation and gas exchange. Under oxic conditions, the {Delta}atpH mutant (lacking the c-subunit) showed strong acceptor-side limitation at photosystem I (PSI), whereas atpC1-2 (lacking the {gamma}-subunit) resembled the wild type. Under anoxia, this limitation was partially relieved, coinciding with sustained electron transport and prolonged hydrogen production. In particular, the {Delta}atpH mutant exhibited increased cyclic electron flow under oxic conditions and maintained PSI activity under anoxia despite impaired ATP synthesis. Prolonged hydrogen production was also observed in atpC1-2, which did not share the increased respiration of {Delta}atpH. Hydrogenase activity under anoxia is consistent with a role as an electron sink that may help alleviate PSI acceptor-side limitation and rebalance the redox state of the electron transport chain. These findings show that ATP synthase deficiency reorganizes photosynthetic electron flow and promotes prolonged hydrogen production, and point to hydrogenase as a candidate electron sink under energy-constrained conditions.","rel_num_authors":4,"rel_authors":[{"author_name":"Jade Rachel Marcus","author_inst":"Tel Aviv University"},{"author_name":"Tamar Elman","author_inst":"Tel Aviv University"},{"author_name":"Felix Buchert","author_inst":"University of Muenster"},{"author_name":"Iftach Yacoby","author_inst":"Tel Aviv University"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Sample-efficient time-resolved X-ray crystallography with serial small wedges","rel_doi":"10.64898\/2026.10.04.756486","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.04.756486","rel_abs":"Time-resolved crystallography can be inaccessible for membrane proteins and other difficult-to-crystallize targets for which suitable crystals are scarce. Here we present an acquisition strategy that records consecutive diffraction images during a small crystal rotation synchronized to a single activation pulse. Matching image segments are merged across crystals to reconstruct successive time windows, enabling a single crystal ensemble to capture an extended structural trajectory. Using the Mesh&Collect workflow at a synchrotron, we obtained ten consecutive 7.5-ms time windows at 2 [A] resolution from 1,255 microcrystals of a bacteriorhodopsin triple mutant at room temperature. An additional 790 crystals extended the observation window to 500 ms. Rotation-based processing, retrospective time binning and dose control maximize information extracted from each crystal, while compatible measurements can be pooled across acquisitions. This approach makes millisecond time-resolved crystallography practical for crystal-limited targets at synchrotrons, with further development potentially extending the temporal resolution down to 1 ms.","rel_num_authors":14,"rel_authors":[{"author_name":"Sergei Bukhdruker","author_inst":"European Synchrotron Radiation Facility"},{"author_name":"Roman Astashkin","author_inst":"Eindhoven University of Technology"},{"author_name":"Dmitry Bratanov","author_inst":"Forschungszentrum Juelich GmbH"},{"author_name":"Nicolas Caramello","author_inst":"National Taiwan University"},{"author_name":"Sylvain Engilberge","author_inst":"Institut de Biologie Structurale"},{"author_name":"Christian Baeken","author_inst":"Forschungszentrum Juelich GmbH"},{"author_name":"Taras Balandin","author_inst":"Forschungszentrum Juelich GmbH"},{"author_name":"Alexander Popov","author_inst":"European Synchrotron Radiation Facility"},{"author_name":"Antoine Royant","author_inst":"Institut de Biologie Structurale"},{"author_name":"Christoph Mueller-Dieckmann","author_inst":"European Synchrotron Radiation Facility"},{"author_name":"Montserrat Soler-Lopez","author_inst":"European Synchrotron Radiation Facility"},{"author_name":"Ernst Bamberg","author_inst":"Max Planck Institute of Biophysics"},{"author_name":"Valentin Gordeliy","author_inst":"Institut de Biologie Structurale"},{"author_name":"Igor Melnikov","author_inst":"European Synchrotron Radiation Facility"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Single molecule Grb2 dynamics reveal spatiomechanical modulation of RTK signaling across length scales","rel_doi":"10.64898\/2026.10.06.757133","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.06.757133","rel_abs":"Extracellular matrix (ECM)-mediated cell adhesion and tension regulate development and disease through crosstalk with Receptor Tyrosine Kinases (RTKs). RTKs stimulate proliferation, survival, and metabolic reprogramming via Ras\/ERK and PI3K\/Akt signaling. Emerging evidence identify the biophysical and biochemical integration of integrin-mediated adhesions with RTK signaling, however, the molecular mechanisms regulating this phenotype remain poorly understood. Here, we demonstrate that ECM stiffness potentiates ligand-mediated epidermal growth factor receptor (EGFR) signaling at scales ranging from the single adaptor protein, Grb2 upward to multicellular spheroids and tissues. We show that ECM stiffness-driven RTK signaling is mediated by integrin adhesions that reshape the membrane to induce the formation of RTK signaling hotspots distributed globally across the cell membrane. A parsimonious computational model and biochemical membrane perturbations causally implicate membrane curvature and topography in tension-dependent integrin-EGFR crosstalk. The results demonstrate how the mechanical properties of the ECM direct molecular recruitment and confinement of signaling molecules to regulate growth factor-dependent RTK signaling. Given that many RTK-driven solid tumors develop a stiff stroma, the findings could explain why many therapeutic tyrosine kinase inhibitors develop clinical resistance. The findings suggest clarifying how tension regulates transmembrane receptor signaling could identify unique force-dependent molecular regulators towards which new antitumor therapies could be applied.","rel_num_authors":12,"rel_authors":[{"author_name":"Kashish Jain","author_inst":"UCSF"},{"author_name":"Dhruv Thakar","author_inst":"UCSF"},{"author_name":"Kshitiz Parihar","author_inst":"UPenn"},{"author_name":"Jenny JY Lin","author_inst":"UC Berkeley"},{"author_name":"Mary-Kate Hayward","author_inst":"UCSF"},{"author_name":"Moses Musiime","author_inst":"UCSF"},{"author_name":"Jonathan Lakins","author_inst":"UCSF"},{"author_name":"Scott D Hansen","author_inst":"University of Oregon"},{"author_name":"Ravi Radhakrishnan","author_inst":"Upenn"},{"author_name":"Jay T Groves","author_inst":"UC Berkeley"},{"author_name":"Valerie M Weaver","author_inst":"University of California, San Francisco"},{"author_name":"Shalini T Low-Nam","author_inst":"Purdue University"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"A cellular atlas of Astyanax mexicanus embryogenesis reveals principles of developmental microevolution","rel_doi":"10.64898\/2026.10.07.757402","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.07.757402","rel_abs":"The evolution of development is the primary mechanism by which morphological and functional diversity is generated. Comparing the developmental trajectories of single cells in entire embryos across species can reveal how gene expression is conserved and varies, as well as the molecular mechanisms underlying how cell- and tissue-specific changes in developmental regulation generate phenotypic differences. However, this perspective has not addressed the mechanisms of small-scale developmental microevolution, i.e, in closely-related species or even within a single species. The fish Astyanax mexicanus, which comes in two forms adapted to distinct environments - the eyed, river-dwelling morph and the eyeless, cave-adapted morph - is a remarkable model with which to investigate the evolution of gene regulation in a single species. Here, we generated and analyzed a single-nucleus RNA-seq atlas of the development of the two Astyanax morphs, from gastrula to swimming larva. Despite extensive changes in gene expression observed in the eight examined stages, for both ubiquitously-expressed and tissue-specific genes, and in both embryonic and extra-embryonic tissues, the temporal progression of cavefish and surface fish cells was similar in ordinal regression-based pseudotime models using 20-100 core genes. However, transcriptome-wide comparisons of gene expression waves revealed massive heterochronic shifts. In cavefish, some tissues had a majority of genes lagging behind in their transcriptional dynamics (e.g. the optic region), while in others, a majority of genes had accelerated dynamics (e.g. the mesoderm), or else, an equivalent number of genes were found in either category (e.g. the endoderm). Furthermore, cell fate acquisition and differentiation were variably affected in different cavefish lineages, with delays of ~6 hours in the retina, ~2 hours in the axial mesoderm and ~none in the extra-embryonic enveloping layer. Thus, cavefish embryos progress as a mosaic of different tissues, or modules, each following its own transcriptional tempo. Because gene expression differential regulation and time shifts were more prevalent in the early stages and gradually diminished throughout development, we propose that cavefish embryos initially undergo strong decanalisation before becoming re-canalized in line with the shared Astyanax developmental program.","rel_num_authors":8,"rel_authors":[{"author_name":"Sergi Roig Puiggros","author_inst":"University of Geneva"},{"author_name":"Goran Royer","author_inst":"Paris-Saclay Institute of Neuroscience, CNRS and University Paris-Saclay"},{"author_name":"Julien Prados","author_inst":"Department of Neurosciences, University of Geneva"},{"author_name":"Francois AGNES","author_inst":"Paris-Saclay Institute of Neuroscience, CNRS and University Paris-Saclay"},{"author_name":"Julien Leclercq","author_inst":"Paris-Saclay Institute of Neuroscience, CNRS and University Paris-Saclay"},{"author_name":"Denis Jabaudon","author_inst":"University of Geneva"},{"author_name":"Jorge Torres-Paz","author_inst":"Pars-Saclay Institute of Neuroscience, CNRS and University Paris-Saclay"},{"author_name":"Sylvie RETAUX","author_inst":"Paris-Saclay Institute of Neuroscience, CNRS and University Paris-Saclay"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"SatelliteQ: an open-source workflow for multidimensional, object-based quantification of centriolar satellites","rel_doi":"10.64898\/2026.10.07.756960","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.07.756960","rel_abs":"Centriolar satellites are membrane-less organelles that store, modify and traffic proteins, in particular those of the centrosome and the primary cilium, and their deregulation is linked to ciliopathies, neurodevelopmental and neurodegenerative disorders. Satellite number, size, intensity and spatial distribution vary with cell type and cell state, yet satellites are usually quantified by a single readout, the pericentrosomal fluorescence intensity in maximum-projected images, which cannot distinguish changes in satellite number, size and position. Here we present SatelliteQ, an open-source Fiji and Python workflow for object-based quantification of satellites in 2D, 3D and time-lapse images. SatelliteQ segments satellites, detects centrosomes or primary cilia in the same cells, and reports satellite number, size, intensity, distance to the centrosome, shape and spatial distribution per satellite and per cell, with interactive graph and spatial viewers. Its measurements correlate closely with Imaris-based quantification; absolute values depend on segmentation settings and analysis mode, whereas the biological differences tested here were preserved across matched settings. Using SatelliteQ, we resolved distinct spatial signatures of satellite dispersal induced by microtubule depolymerization and by disruption of weak hydrophobic interactions, quantified differences between cell types and the scaling of satellite number with cell size, captured PCM1 granule dynamics in living cells, and compared satellite organization between ciliated and unciliated cells. Depletion of the ciliopathy-associated satellite protein CEP290 altered satellite abundance and pericentrosomal organization, while patient-derived cells carrying CEP290 mutations displayed divergent satellite phenotypes that were not explained by ciliation alone. SatelliteQ thus establishes satellite properties as a multidimensional cellular phenotype and provides an accessible framework for exploring satellites as an organelle-level readout in disease.","rel_num_authors":5,"rel_authors":[{"author_name":"Efe Begar","author_inst":"Koc University"},{"author_name":"Ezgi Odabasi","author_inst":"Koc University"},{"author_name":"Lucie Menguy","author_inst":"Universite Paris Cite"},{"author_name":"Sophie Saunier","author_inst":"Institut Imagine UMR1163"},{"author_name":"Elif Nur Firat-Karalar","author_inst":"Koc University"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Membrane Filtration Removes Lipids and Compromises the Acoustic Stability of Nanobubbles","rel_doi":"10.64898\/2026.10.04.756539","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.04.756539","rel_abs":"Nanobubbles (NBs) have been widely investigated as ultrasound contrast and therapeutic agents, yet whether submicron gas bubbles can directly generate measurable ultrasound signals remains controversial. Because acoustic scattering scales with bubble size, several studies have recently attributed nanobubble echogenicity primarily to larger bubbles. A recent Science Advances publication, attributed the loss of ultrasound signal after filtration to the removal of residual larger bubbles [1]. This interpretation assumes that filtration acts solely as a size-selection process. Here, we show that filtration also alters the shell properties and stability of lipid-coated NBs, independent of size. Filtered NBs (F-NBs) show significant lipid loss and accumulation on the filters themselves, resulting in decreased bubble stability and greater susceptibility to destruction under acoustic excitation. To decouple size from processing effects, we generated NB populations size-matched to filtered samples using increased centrifugation (IC-NBs), a comparatively gentler separation method. Despite comparable size distributions, IC-NBs retained sustained ultrasound scattering, whereas filtered NBs showed significantly reduced acoustic persistence. Filtration through 5 m pores, ~5-fold larger than the largest bubbles, preserved acoustic persistence but still reduced bubble concentration by ~30%, suggesting that membrane contact may contribute to bubble loss beyond size exclusion. Complementary lipid and gas-content assays provided further evidence of filtration-induced changes. The 0.45 m filtration removed substantially more total lipid than could be attributed to free-lipid removal alone, while the lipid associated with the larger bubbles removed during filtration accounted for only ~5% of the additional lipid loss. Encapsulated gas content remained comparable to that of size-matched centrifuged controls, suggesting that the reduced acoustic stability of filtered NBs is more closely associated with changes in lipid content than with loss of the gas core. These results indicate that membrane filtration is not a purely size-selective process: it removes substantially more lipid than size exclusion predicts and yields bubbles that are less stable under ultrasound, most likely through changes in shell lipid content or in the surrounding lipid reservoir, underscoring the importance of processing-induced effects in interpreting nanobubble echogenicity.","rel_num_authors":7,"rel_authors":[{"author_name":"Mahshid Yaali","author_inst":"Toronto Metropolitan University"},{"author_name":"Elizabeth Berndl","author_inst":"Toronto Metropolitan University"},{"author_name":"Aaqib Khan","author_inst":"Case Western Reserve University"},{"author_name":"Eric Strohm","author_inst":"Toronto Metropolitan university"},{"author_name":"Theresa Kosmides","author_inst":"Case Western Reserve University"},{"author_name":"Agata A Exner","author_inst":"Case Western Reserve University"},{"author_name":"Michael C Kolios","author_inst":"Toronto Metropolitan University"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Direct visualization of lysosome-mediated intracellular transport and membrane anchoring of TNF-\u03b1 in human T cells","rel_doi":"10.64898\/2026.10.07.757379","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.07.757379","rel_abs":"Tumor necrosis factor-alpha (TNF-) represents a major pro-inflammatory cytokine associated with chronic inflammation. Enhanced understanding of intracellular trafficking of TNF- enables the identification of drug targets that modulate TNF- secretion at the cellular source. However, conventional cytokine assays provide only bulk measurements of secreted TNF- or static measurements in fixed cells and therefore cannot provide mechanistic information. Here, we report a fluorescence imaging platform to visualize and quantify intracellular TNF- trafficking in human T cells. Using a Jurkat T cell line stably expressing TNF- fused to mStayGold as a model system, we revealed through single-particle tracking (SPT) that T cell activation increased the motility of TNF- vesicles and that microtubule perturbation disrupted this increased motility. 3D structured illumination microscopy uncovered spatial associations between TNF- vesicles and lysosomes, and SPT further demonstrated their coordinated transport. Using total internal reflection fluorescence microscopy, we captured the sub-second splitting of single TNF- vesicles into multiple puncta that subsequently separated, suggesting delivery of TNF- from the vesicle to the plasma membrane. Confocal-based super-resolution microscopy further resolved TNF- vesicles fusing with the plasma membrane and transmembrane TNF-. Together, these imaging capabilities for tracking and super-resolving the intracellular transport and membrane delivery of TNF- in live T cells enable mechanistic studies of TNF- trafficking and release.","rel_num_authors":4,"rel_authors":[{"author_name":"Alyssa Burgess","author_inst":"University of Illinois Chicago"},{"author_name":"Hirushi Gunasekara","author_inst":"University of Illinois Chicago"},{"author_name":"James Xie","author_inst":"University of Illinois Chicago"},{"author_name":"Ying Samuel Hu","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"A tissue-targeted auxin-inducible degradation toolkit for C. elegans embryogenesis","rel_doi":"10.64898\/2026.10.07.757239","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.07.757239","rel_abs":"Many proteins required for embryogenesis are expressed in multiple tissues and across developmental time, often with tissue- and stage-specific roles. To resolve where and when proteins function, we developed a tissue-targeted auxin-inducible degradation toolkit for C. elegans embryogenesis. We generated a plasmid set compatible with single-copy insertion or high-copy extrachromosomal array generation that employs tissue-specific promoters (active in the germline, intestine, muscle, pharynx, neuroblasts, neurons, sensory neurons, epidermis, and pan soma) to drive an operon expressing an optimized auxin-dependent plant F-box factor TIR1 and, in most cases, a fluorescent histone. Using a ubiquitous nuclear envelope marker as a test substrate, we identified single-copy insertions and arrays that exhibit efficient auxin-dependent, tissue-specific target degradation. We also establish a workflow that ensures all functionally important isoforms of a target are tagged and that degradation reproduces the loss-of-function phenotype prior to tissue-specific analysis. Applying the toolkit to the broadly expressed Rho kinase LET-502, we find that degradation in the epidermis, but not in other embryonic tissues, disrupts elongation. Unexpectedly, temporal analysis revealed that LET-502 is required for late as well as early elongation.","rel_num_authors":7,"rel_authors":[{"author_name":"Neha Varshney","author_inst":"University of California San Diego"},{"author_name":"Rebecca A Green","author_inst":"University of California San Diego"},{"author_name":"Ayla O Desai","author_inst":"University of California San Diego"},{"author_name":"Shabnam Moghareh","author_inst":"University of California Irvine"},{"author_name":"Dylan J Green","author_inst":"University of California San Diego"},{"author_name":"Arshad Desai","author_inst":"University of California San Diego"},{"author_name":"Karen Oegema","author_inst":"University of California San Diego"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Progressive Actomyosin Remodeling Defining a Structured Podocyte Injury Response in Nephrotic Syndrome","rel_doi":"10.64898\/2026.10.07.757076","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.07.757076","rel_abs":"Nephrotic syndrome, the leading cause of chronic kidney disease worldwide, is associated with injury and eventual loss of podocytes, the specialized epithelial cells that form the final layer of the kidney's filtration apparatus. The progression from injury to loss is largely irreversible. However, some forms of nephrotic syndrome undergo remission, suggesting that injured podocytes may retain a capacity for repair, the structural basis of which remains unknown. Podocytes respond to injury by the stereotypical morphological change known as foot process effacement (FPE), which can be visualized using transmission electron microscopy. Using modified ultrastructure expansion microscopy (U-ExM) protocol combined with super-resolution microscopy, we discovered that injured podocytes exhibit a three-stage progression of FPE maturation, with kinetics determined by the degree of actomyosin contractility. Through longitudinal study of adriamycin-induced nephropathy in mice, we identified three sequential stages of actomyosin reorganization within the sarcomere-like structures (SLSs) that define the injury response: focal infiltration of myosin IIA into synaptopodin-rich foot processes (Stage 1), disordered intermingling of synaptopodin\/myosin IIA (Stage 2), and the formation of highly organized periodic contractile arrays oriented perpendicular to the direction of capillary blood flow (Stage 3). Longitudinal quantification revealed predictable temporal dynamics, with mature Stage 3 predominating by day 7-9 post-injury. To determine whether this sequence is conserved in human disease, we analyzed kidney biopsies from patients with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and diabetic nephropathy. The same three stages were present across all four diseases, and their distribution tracked disease course: acute podocytopathies exhibited heterogeneous early-stage patterns, whereas chronic injuries converged on uniform, mature SLS organization. These findings demonstrate that podocyte injury is a graded, potentially reversible process rather than a binary switch. They identify structured actomyosin remodeling as a conserved wound response across mechanistically distinct kidney diseases and suggest that therapeutic strategies targeting specific stages of this progression could alter the trajectory of diverse glomerular diseases.","rel_num_authors":8,"rel_authors":[{"author_name":"Ewa Langner","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Karla Parra","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Shumeng Jiang","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Sanjay Jain","author_inst":"WashU Medicine"},{"author_name":"Moe R. Mahjoub","author_inst":"WashU Medicine"},{"author_name":"Guy M. Genin","author_inst":"Washington University in St. Louis"},{"author_name":"Jeffrey H. Miner","author_inst":"WashU Medicine"},{"author_name":"Hani Y. Suleiman","author_inst":"University of Texas Southwestern Medical Center"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"An AI-Enabled Translational Drug Discovery Framework for NALCN Channelopathy: From High-Throughput Screening to Therapeutic Candidate","rel_doi":"10.64898\/2026.10.08.757476","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.757476","rel_abs":"Background: More than 90% of rare diseases lack an approved therapy, partly reflecting economic barriers in developing treatments for small patient populations. A common bottleneck is costly and resource-intensive hit-to-lead prioritization. Congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD) is an ultra-rare neurodevelopmental disease often caused by de novo gain-of-function variants in the sodium leak channel NALCN, with no approved treatments. Methods: We developed a cost and resource-efficient, AI-enabled translational drug discovery framework integrating phenotypic high-throughput screening (HTS), structural biology foundation models for hit-to-lead prioritization, and orthogonal experimental validation. We applied this framework for drug repurposing to identify NALCN inhibitors as therapeutic candidates for CLIFAHDD. We screened ~1,200 approved drugs using a fluorescence-based membrane potential assay in doxycycline-inducible HEK293 cells stably expressing the NALCN channelosome. Boltz-2 modeling predicted binding affinity and mode to prioritize hits. Lead repurposing candidates were selected by a multidisciplinary expert review panel. Lead candidates were evaluated using patch-clamp electrophysiology in HEK293 cells expressing wild-type or CLIFAHDD-associated NALCN variants, primary mouse hippocampal neurons, and a C. elegans NALCN gain-of-function model. Results: HTS identified 11 candidate NALCN inhibitors. Boltz-2 prioritized candidates based on predicted binding affinity and predicted binding within the NALCN pore, consistent with a direct pore-blocking mechanism. Aprepitant emerged as the lead candidate after multidisciplinary evaluation based on its predicted mechanism, pharmacologic properties, blood-brain barrier penetration, established safety profile, and regulatory approval in children and adults. Patch-clamp electrophysiology confirmed partial inhibition of NALCN-mediated sodium leak currents in HEK293 cells (IC50;=2.22 M), with comparable potency against Cav3.1 (IC50=1.63 M). In primary mouse hippocampal neurons, aprepitant reduced sodium leak currents, hyperpolarized resting membrane potential, and decreased spontaneous firing. Aprepitant rescued hyperlocomotor and dystonic phenotypes in a C. elegans gain-of-function NALCN model. There was notable concordance between AI-predicted hits, phenotypic screening hits, and experimental validation. Conclusion: These findings identify aprepitant as a lead therapeutic candidate for CLIFAHDD, and establish an AI-enabled translational drug discovery framework integrating phenotypic screening, structural modeling, and experimental validation for NALCN channelopathies. This scalable and resource-conscious strategy may accelerate hit-to-lead prioritization and drug discovery for rare and ultra-rare diseases lacking effective therapies.","rel_num_authors":11,"rel_authors":[{"author_name":"Nattaya Thongsepee","author_inst":"Department of Preclinical Science, Faculty of Medicine, Thammasat University, Thailand"},{"author_name":"Jeremy A Tanner","author_inst":"Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, Department of Neurology, University of Texas Health Science Center at San Antonio, San Anton"},{"author_name":"Srikanth Polusani","author_inst":"Department of Biochemistry and Structural Biology and Center for Innovative Drug Discovery, University of Texas Health Science Center at San Antonio, Texas, USA"},{"author_name":"Alexandra Typou","author_inst":"IGF, Univ Montpellier, CNRS, Inserm, France"},{"author_name":"Nicholas A. Clanton","author_inst":"Voelcker Preclinical Pharmacology Core, Department of Chemistry, University of Texas San Antonio, San Antonio, TX, USA"},{"author_name":"Brandon B. Holmes","author_inst":"6.\tUCSF Weill Institute for Neurosciences, Department of Neurology, Edward and Pearl Fein Memory and Aging Center, University of California, San Francisco, San "},{"author_name":"Philippe Lory","author_inst":"IGF, Univ Montpellier, CNRS, Inserm, France"},{"author_name":"Donard S. Dwyer","author_inst":"Departments of Psychiatry and Behavioral Medicine and Pharmacology, Toxicology and Neuroscience, LSU Health Shreveport, Shreveport, LA, USA"},{"author_name":"Daohong Zhou","author_inst":"Department of Biochemistry and Structural Biology and Center for Innovative Drug Discovery, University of Texas Health Science Center at San Antonio, Texas, USA"},{"author_name":"Arnaud Monteil","author_inst":"IGF, Univ Montpellier, CNRS, Inserm, France; Department of Physiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Thailand"},{"author_name":"Yaxia Yuan","author_inst":"Department of Biochemistry and Structural Biology and Center for Innovative Drug Discovery, University of Texas Health Science Center at San Antonio, Texas, USA"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"A transient third metal ion shapes the catalytic cycle of a group I intron ribozyme","rel_doi":"10.64898\/2026.10.07.757386","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.07.757386","rel_abs":"The self-splicing group I intron ribozyme from Tetrahymena thermophillia (THr) is a prototypical example of how RNA overcomes its limited chemical repertoire to form complex, negatively charged junctions and catalyze chemical reactions. Despite over 30 years of biochemical and structural characterization, questions still remain regarding the requirements for THr catalysis that may inform structure based drug design against group I introns, as well as the use of THr as an RNA editing tool. Recent cryo-EM structures have provided an unprecedented window into the first and second steps of splicing, enabling detailed mechanistic investigation at the atomistic level. In this work, we leverage solvation theory, molecular dynamics, alchemical free energy simulations, and machine learning accelerated QM\/MM to probe outstanding questions related to 1) the role of a possible third Mg2+ binding in the active site, 2) differences in catalytic requirements between Gexo cofactors and between the first and second steps of splicing, 3) the potential role of an acid or base, and 4) restrictions on the identity of the 5' exon splice site nucleotide, U(-1). We propose that a transient, cofactor dependent, interaction with a third metal participates in the first step, while a higher affinity interaction with this third ion is required in the second step. We also propose that the presence of a phosphate on the Gexo in the first step, and analogously the G{omega} in the second step, forms a metal ion binding site not present when guanosine is bound. Finally, we propose and computationally test design modifications of G22 (isofunctional substitutions of 2,6-diaminopurine that tune the pKa at the N1 position) that we predict will enable the accommodation of C(-1) in a crucial wobble-like pair at physiological pH. This design would provide a potential strategy for expanding the sequence space accessible to programmable trans-splicing ribozymes in RNA editing applications.","rel_num_authors":8,"rel_authors":[{"author_name":"Erika McCarthy","author_inst":"Laboratory for Biomolecular Simulation Research, Institute for Quantitative Biomedicine and Department of Chemistry and Chemical Biology, Rutgers University, Pi"},{"author_name":"\u015e\u00f6len Ekesan","author_inst":"Laboratory for Biomolecular Simulation Research, Institute for Quantitative Biomedicine and Department of Chemistry and Chemical Biology, Rutgers University, Pi"},{"author_name":"Timothy J Giese","author_inst":"Laboratory for Biomolecular Simulation Research, Institute for Quantitative Biomedicine and Department of Chemistry and Chemical Biology, Rutgers University, Pi"},{"author_name":"Yanan Du","author_inst":"Laboratory for Biomolecular Simulation Research, Institute for Quantitative Biomedicine and Department of Chemistry and Chemical Biology, Rutgers University, Pi"},{"author_name":"German P Barletta","author_inst":"Laboratory for Biomolecular Simulation Research, Institute for Quantitative Biomedicine and Department of Chemistry and Chemical Biology, Rutgers University, Pi"},{"author_name":"Andreas W G\u00f6tz","author_inst":"San Diego Supercomputer Center, University of California San Diego, La Jolla, California 92093-0505, United States"},{"author_name":"Joseph A Piccirilli","author_inst":"Department of Chemistry and Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois 60637, United States"},{"author_name":"Darrin M York","author_inst":"Laboratory for Biomolecular Simulation Research, Institute for Quantitative Biomedicine and Department of Chemistry and Chemical Biology, Rutgers University, Pi"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"A transient third metal ion shapes the catalytic cycle of a group I intron ribozyme","rel_doi":"10.64898\/2026.10.07.757386","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.07.757386","rel_abs":"The self-splicing group I intron ribozyme from Tetrahymena thermophillia (THr) is a prototypical example of how RNA overcomes its limited chemical repertoire to form complex, negatively charged junctions and catalyze chemical reactions. Despite over 30 years of biochemical and structural characterization, questions still remain regarding the requirements for THr catalysis that may inform structure based drug design against group I introns, as well as the use of THr as an RNA editing tool. Recent cryo-EM structures have provided an unprecedented window into the first and second steps of splicing, enabling detailed mechanistic investigation at the atomistic level. In this work, we leverage solvation theory, molecular dynamics, alchemical free energy simulations, and machine learning accelerated QM\/MM to probe outstanding questions related to 1) the role of a possible third Mg2+ binding in the active site, 2) differences in catalytic requirements between Gexo cofactors and between the first and second steps of splicing, 3) the potential role of an acid or base, and 4) restrictions on the identity of the 5' exon splice site nucleotide, U(-1). We propose that a transient, cofactor dependent, interaction with a third metal participates in the first step, while a higher affinity interaction with this third ion is required in the second step. We also propose that the presence of a phosphate on the Gexo in the first step, and analogously the G{omega} in the second step, forms a metal ion binding site not present when guanosine is bound. Finally, we propose and computationally test design modifications of G22 (isofunctional substitutions of 2,6-diaminopurine that tune the pKa at the N1 position) that we predict will enable the accommodation of C(-1) in a crucial wobble-like pair at physiological pH. This design would provide a potential strategy for expanding the sequence space accessible to programmable trans-splicing ribozymes in RNA editing applications.","rel_num_authors":8,"rel_authors":[{"author_name":"Erika McCarthy","author_inst":"Laboratory for Biomolecular Simulation Research, Institute for Quantitative Biomedicine and Department of Chemistry and Chemical Biology, Rutgers University, Pi"},{"author_name":"\u015e\u00f6len Ekesan","author_inst":"Laboratory for Biomolecular Simulation Research, Institute for Quantitative Biomedicine and Department of Chemistry and Chemical Biology, Rutgers University, Pi"},{"author_name":"Timothy J Giese","author_inst":"Laboratory for Biomolecular Simulation Research, Institute for Quantitative Biomedicine and Department of Chemistry and Chemical Biology, Rutgers University, Pi"},{"author_name":"Yanan Du","author_inst":"Laboratory for Biomolecular Simulation Research, Institute for Quantitative Biomedicine and Department of Chemistry and Chemical Biology, Rutgers University, Pi"},{"author_name":"German P Barletta","author_inst":"Laboratory for Biomolecular Simulation Research, Institute for Quantitative Biomedicine and Department of Chemistry and Chemical Biology, Rutgers University, Pi"},{"author_name":"Andreas W G\u00f6tz","author_inst":"San Diego Supercomputer Center, University of California San Diego, La Jolla, California 92093-0505, United States"},{"author_name":"Joseph A Piccirilli","author_inst":"Department of Chemistry and Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois 60637, United States"},{"author_name":"Darrin M York","author_inst":"Laboratory for Biomolecular Simulation Research, Institute for Quantitative Biomedicine and Department of Chemistry and Chemical Biology, Rutgers University, Pi"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"A transient third metal ion shapes the catalytic cycle of a group I intron ribozyme","rel_doi":"10.64898\/2026.10.07.757386","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.07.757386","rel_abs":"The self-splicing group I intron ribozyme from Tetrahymena thermophillia (THr) is a prototypical example of how RNA overcomes its limited chemical repertoire to form complex, negatively charged junctions and catalyze chemical reactions. Despite over 30 years of biochemical and structural characterization, questions still remain regarding the requirements for THr catalysis that may inform structure based drug design against group I introns, as well as the use of THr as an RNA editing tool. Recent cryo-EM structures have provided an unprecedented window into the first and second steps of splicing, enabling detailed mechanistic investigation at the atomistic level. In this work, we leverage solvation theory, molecular dynamics, alchemical free energy simulations, and machine learning accelerated QM\/MM to probe outstanding questions related to 1) the role of a possible third Mg2+ binding in the active site, 2) differences in catalytic requirements between Gexo cofactors and between the first and second steps of splicing, 3) the potential role of an acid or base, and 4) restrictions on the identity of the 5' exon splice site nucleotide, U(-1). We propose that a transient, cofactor dependent, interaction with a third metal participates in the first step, while a higher affinity interaction with this third ion is required in the second step. We also propose that the presence of a phosphate on the Gexo in the first step, and analogously the G{omega} in the second step, forms a metal ion binding site not present when guanosine is bound. Finally, we propose and computationally test design modifications of G22 (isofunctional substitutions of 2,6-diaminopurine that tune the pKa at the N1 position) that we predict will enable the accommodation of C(-1) in a crucial wobble-like pair at physiological pH. This design would provide a potential strategy for expanding the sequence space accessible to programmable trans-splicing ribozymes in RNA editing applications.","rel_num_authors":8,"rel_authors":[{"author_name":"Erika McCarthy","author_inst":"Laboratory for Biomolecular Simulation Research, Institute for Quantitative Biomedicine and Department of Chemistry and Chemical Biology, Rutgers University, Pi"},{"author_name":"\u015e\u00f6len Ekesan","author_inst":"Laboratory for Biomolecular Simulation Research, Institute for Quantitative Biomedicine and Department of Chemistry and Chemical Biology, Rutgers University, Pi"},{"author_name":"Timothy J Giese","author_inst":"Laboratory for Biomolecular Simulation Research, Institute for Quantitative Biomedicine and Department of Chemistry and Chemical Biology, Rutgers University, Pi"},{"author_name":"Yanan Du","author_inst":"Laboratory for Biomolecular Simulation Research, Institute for Quantitative Biomedicine and Department of Chemistry and Chemical Biology, Rutgers University, Pi"},{"author_name":"German P Barletta","author_inst":"Laboratory for Biomolecular Simulation Research, Institute for Quantitative Biomedicine and Department of Chemistry and Chemical Biology, Rutgers University, Pi"},{"author_name":"Andreas W G\u00f6tz","author_inst":"San Diego Supercomputer Center, University of California San Diego, La Jolla, California 92093-0505, United States"},{"author_name":"Joseph A Piccirilli","author_inst":"Department of Chemistry and Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois 60637, United States"},{"author_name":"Darrin M York","author_inst":"Laboratory for Biomolecular Simulation Research, Institute for Quantitative Biomedicine and Department of Chemistry and Chemical Biology, Rutgers University, Pi"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"Molecular sterics guide tmRNA translocation on the ribosome","rel_doi":"10.64898\/2026.10.08.757657","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.757657","rel_abs":"Translation of defective mRNA transcripts can lead to the formation of stalled ``non-stop'' ribosome complexes. To rescue these ribosomes, bacteria have evolved a mechanism called trans-translation that is mediated by transfer-messenger RNA (tmRNA) and small protein B (SmpB). During the translocation step of trans-translation, the stalled mRNA is ejected and the reading frame found in the mRNA-like domain (MLD) of tmRNA is loaded into the mRNA channel. The ribosome then translates the new template, thereby tagging the nascent protein for degradation. While structures of tmRNA-SmpB on the ribosome have been available for years, little is known about the molecular factors that govern the dynamics of tmRNA translocation. Here, we use an energetically smooth model (i.e. SMOG) to simulate translocation of tmRNA-SmpB, which reveals that the structure of the ribosome gives rise to a preferred sequence of conformational substeps. Specifically, the tRNA-like domain (TLD) translocates, then the MLD loads, and finally the C-terminal tail of SmpB rearranges. These steps are interdependent and associated with a range of sterically-induced barriers that regulate the kinetics. This provides a structural and energetic framework for understanding, and ultimately controlling, the dynamics of trans-translation.","rel_num_authors":4,"rel_authors":[{"author_name":"George Wanes","author_inst":"Northeastern University"},{"author_name":"Kenneth C. Keiler","author_inst":"University of Texas at Austin"},{"author_name":"Christine M Dunham","author_inst":"Emory University"},{"author_name":"Paul Charles Whitford","author_inst":"Northeastern University"}],"rel_date":"2026-10-09","rel_site":"biorxiv"},{"rel_title":"REM sleep infraslow rhythms correlate with neuropsychiatric symptom severity","rel_doi":"10.64898\/2026.10.06.26364874","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.06.26364874","rel_abs":"Study objectives: Rapid eye movement (REM) sleep is commonly divided into phasic and tonic substates based on higher and lower oculomotor activity, respectively. Our previous study described an alternative framework in which REM temporal structure forms a continuum of infraslow rhythms (~0.01 Hz) across brain and body physiology. We now ask whether these infraslow rhythms vary with neuropsychiatric symptoms, given the long-standing but still inconsistent links between REM and mood- or trauma-related disorders. Methods: Using a cross-sectional polysomnographic dataset from male veterans, we examined 59 participants for correlations between REM infraslow rhythms and neuropsychiatric symptom scores, excluding participants with moderate\/severe apnea. Results: Oscillations in REM respiratory rate, but not cardiac rate or electroencephalogram beta power, showed higher infraslow frequencies in participants with multiple symptoms, including posttraumatic stress, pain, anxiety, depression, and cognitive difficulties. No significant correlations were found between these symptoms and conventional REM metrics (e.g., REM density, latency and duration). To further examine REM beyond phasic\/tonic binarization, we analyzed the timing between oculomotor activity and infraslow oscillations. Eye movements occurred preferentially during periods of high respiratory rate, low beta power and intermediate cardiac rate, with no changes in these temporal relationships across symptom severity. Conclusions: Neuropsychiatric associations with REM infraslow rhythms spanned multiple symptom domains but were physiologically specific, with respiratory rate oscillations representing the strongest readout of symptom burden. Furthermore, REM infraslow cycles across brain and body were differentially aligned with eye movements: a temporal pattern that may serve as a physiological target for neuropsychiatric and mechanistic research.","rel_num_authors":5,"rel_authors":[{"author_name":"Lezio S. Bueno-Junior","author_inst":"Department of Psychiatry, University of Michigan Medical School, Ann Arbor, MI 48109, USA"},{"author_name":"Peyton T. Wickham","author_inst":"Portland VA Research Foundation; Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA"},{"author_name":"Carolyn E. Jones-Tinsley","author_inst":"Portland VA Research Foundation; Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA"},{"author_name":"Miranda M. Lim","author_inst":"Portland VA Research Foundation; Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA"},{"author_name":"Brendon O. Watson","author_inst":"Department of Psychiatry, University of Michigan Medical School, Ann Arbor, MI 48109, USA"}],"rel_date":"2026-10-08","rel_site":"medrxiv"},{"rel_title":"Testing Bidirectional Genetic Links Between ADHD and the Big Five Personality Traits","rel_doi":"10.64898\/2026.10.05.26363336","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.05.26363336","rel_abs":"Attention Deficit Hyperactivity Disorder (ADHD) frequently co-occurs with distinct personality profiles, but whether ADHD shapes personality (scar model) or personality influences the development of ADHD (vulnerability model) remains unclear. Leveraging genome-wide association study (GWAS) data, we examined directional associations between ADHD and the Big Five personality traits (Neuroticism, Extraversion, Openness, Agreeableness, and Conscientiousness). We estimated genetic correlations and conducted bidirectional two-sample Mendelian Randomization (MR) analyses between ADHD and the Big Five. Robustness was evaluated using multiple sensitivity tests, including MR-CAUSE, which accounts for correlated and uncorrelated pleiotropy, and colocalization analyses on fine-mapped variants. Higher genetic liability to Neuroticism and Extraversion, alongside lower liability to Conscientiousness, increased ADHD risk, consistent with the vulnerability model. Conversely, ADHD genetic liability was associated with lower Agreeableness, supporting the scar model. Associations were generally robust across sensitivity analyses, with MR-CAUSE supporting the Neuroticism and Agreeableness associations and colocalization providing variant-level support for associations between ADHD and Neuroticism, Conscientiousness, and Agreeableness. These findings provide early, population-level insight into personality-related vulnerability to ADHD and motivate further work on the role of personality traits in ADHD risk.","rel_num_authors":8,"rel_authors":[{"author_name":"Hugo Peyre","author_inst":"Autism Reference Centre of Languedoc-Roussillon CRA-LR, Excellence Centre for Autism and Neurodevelopmental disorders CeAND, Montpellier University Hospital, MU"},{"author_name":"Nicolas Hoertel","author_inst":"Universite Paris Cite, Inserm U1266, Institut de Psychiatrie et Neuroscience de Paris, Paris, France; Service de Psychiatrie et Addictologie, DMU Psychiatrie et"},{"author_name":"Baptiste Pignon","author_inst":"Departement Medico Universitaire (DMU) - Innovation en sante Mentale, Psychiatrie et AddiCTologie, Hopitaux Universitaires \"H. Mondor\", Assistance Publique hopi"},{"author_name":"Sebastien Weibel","author_inst":"Psychiatry, Mental Health and Addictology Department, University Hospitals of Strasbourg, 1 place de l'Hopital, Strasbourg, 67000, France; INSERM UMR-S 1329, St"},{"author_name":"Mario Speranza","author_inst":"CESP Centre de recherche en Epidemiologie et Sante des Populations, INSERM U1178, Villejuif, France; Versailles Hospital Center, University Department of Child "},{"author_name":"Boris Chaumette","author_inst":"Department of Psychiatry, McGill University, Montreal, Canada; Universite Paris Cite, NeuroDiderot (INSERM U1141), Institut Pasteur (Human Genetics and Cognitiv"},{"author_name":"Ted Schwaba","author_inst":"Department of Psychology, Michigan State University, East Lansing, United States"},{"author_name":"Camille M. Williams","author_inst":"Laboratoire de Sciences Cognitives et Psycholinguistique (ENS, EHESS, CNRS), Ecole Normale Superieure, PSL University, Paris, France"}],"rel_date":"2026-10-08","rel_site":"medrxiv"},{"rel_title":"Delay in antiretroviral therapy initiation is associated with worse mood symptoms in adults with chronic HIV disease","rel_doi":"10.64898\/2026.10.07.26364968","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364968","rel_abs":"Background. In the era of successful antiretroviral therapy (ART), mood disturbance remains highly prevalent in people with HIV (PWH). In the present study, we investigated the long-term legacy effects of long delay in ART initiation and low nadir CD4 count on mood symptoms in adults with HIV. The impacts of demographic and other HIV clinical factors were also examined. Methods. A total of 109 PWH (disease duration: 24.6{+\/-}9.3 years) and 42 demographically matched healthy participants (people without HIV, or PWoH) participated in a cross-sectional study (41-70 years old (55.6{+\/-}6.8), 62.9% African Americans, 27.2% female, 14.3{+\/-}2.9 years of education). Mood symptoms were assessed with the Beck Depression Inventory-II (BDI-II) and the Profile of Mood States (POMS). A comprehensive neuropsychological test battery was administered to assess neurocognitive function. Results. Despite largely comparable neurocognitive performance between PWH and PWoH , PWH had worse mood symptoms than PWoH, including higher total BDI-II (p<.001) and total POMS scores (p=.002), as well as higher score in all POMS sub-scores (p<.007), except Vigor (p=.724). Within the PWH group, longer delays in ART initiation, lower nadir CD4 count, and lower educational attainment were associated with worse mood symptoms. By contrast, current plasma CD4+ cell count, plasma detectable viral load, and HIV disease duration were not associated with either BDI-II or POMS score. Conclusion. Mood disturbance is highly prevalent in PWH on ART. The long-term legacy effects of delay in ART initiation and low nadir CD4 count on mood management reinforce the necessity of early ART initiation in clinical practice.","rel_num_authors":8,"rel_authors":[{"author_name":"Hyunchan Lee","author_inst":"Georgetown University Medical Center"},{"author_name":"Claire O'Connor","author_inst":"Georgetown University Medical Center"},{"author_name":"Grace Hanly","author_inst":"Georgetown University Medical Center"},{"author_name":"Linxi Chen","author_inst":"Georgetown University Medical Center"},{"author_name":"Danial Mahmood","author_inst":"Georgetown University Medical Center"},{"author_name":"David J. Moore","author_inst":"University of California San Diego"},{"author_name":"Ronald J. Ellis","author_inst":"University of California, San Diego"},{"author_name":"Xiong Jiang","author_inst":"Georgetown University Medical Center"}],"rel_date":"2026-10-08","rel_site":"medrxiv"},{"rel_title":"Carrying Bangladesh with Them: How Pre-Migration Healthcare Norms Shape Bangladeshi Immigrants' Health-Seeking in the United States","rel_doi":"10.64898\/2026.10.07.26364503","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.07.26364503","rel_abs":"Bangladeshi immigrants are a rapidly growing U.S. immigrant population, yet little is known about how pre-migration healthcare experiences shape healthcare use after migration. This qualitative study explored how healthcare norms from Bangladesh influence the health-seeking behaviors of Bangladeshi immigrants in the U.S., the barriers and facilitators they encounter, and their perceptions of care quality. Semi-structured interviews were conducted with 29 Bangladeshi-born adults living in the U.S. from September 2020 to January 2021 and analyzed using the constant comparative method. Participants described healthcare expectations shaped by the healthcare system of Bangladesh, which is mostly out-of-pocket and resource-limited, including symptom-driven rather than preventive care, self-treatment, and family-based caregiving. In the U.S., they faced barriers such as insurance confusion, long waits, difficulty establishing care, coverage disruptions, financial concerns, and language challenges. While participants valued culturally and linguistically concordant care, preferences for Bangla-speaking or co-ethnic providers varied, especially when perceived quality was low. Community networks, online information, self-education, and self-advocacy helped facilitate care. Provider communication strongly shaped perceptions of U.S. healthcare: feeling heard, respected, and well-informed promoted trust, while dismissal or delayed diagnosis led to skepticism and avoidance. These findings suggest that healthcare engagement of Bangldeshi immigrants is shaped by both structural barriers and pre-migration norms. Improving access will require attention to subgroup-specific histories, insurance navigation, language access, and the relational quality of care.","rel_num_authors":2,"rel_authors":[{"author_name":"Aantaki Raisa","author_inst":"Washington University in St. Louis"},{"author_name":"Andrew H. Vu","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-10-08","rel_site":"medrxiv"},{"rel_title":"Dynamic near-term risk prediction of clinically significant immune-related adverse events using longitudinal electronic health records","rel_doi":"10.64898\/2026.10.06.26364907","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.06.26364907","rel_abs":"Objective: To develop and evaluate a dynamic model that repeatedly estimates the 30-day risk of a first grade [&ge;]2 immune-related adverse event (irAE) during immune checkpoint inhibitor (ICI) therapy. Materials and Methods: Adults initiating ICI therapy during 2015-2022 comprised the development cohort; 2023 initiators formed a nonoverlapping internal temporal evaluation cohort. Every 21 days during the first treatment year, models used available EHR information to predict a first structured phenotype-defined above Grade 2 irAE during the next 30 days. Evaluation included pooled and within-landmark discrimination, precision-recall performance, calibration, and patient-clustered bootstrap confidence intervals. Feature-state ablations and alternative update schedules examined the contribution of dynamic information. Results: Development included 1,522 patients and 18,744 evaluable landmarks; temporal evaluation included 526 patients and 6,263 landmarks, of which 184 were positive (2.94%). The multiscale XGBoost model achieved pooled AUROC 0.716 (95% CI, 0.676-0.755), AUPRC 0.067, within-landmark AUROC 0.672 (95% CI, 0.631-0.716), Brier score 0.0281, and log loss 0.1245. The time-aware baseline achieved AUROC 0.631 and within-landmark AUROC 0.536. Updated treatment exposure and laboratory trajectories accounted for most of the gain. A complete-state extension achieved AUROC 0.719 and AUPRC 0.073. The 21-day schedule had the highest discrimination among tested cadences. Conclusion: Longitudinal EHR updating improved near-term irAE prediction beyond pretreatment characteristics and treatment time. Phenotype adjudication and independent evaluation of calibration, transportability, and clinical utility are needed before implementation","rel_num_authors":5,"rel_authors":[{"author_name":"Liyuan Gong","author_inst":"Columbia University"},{"author_name":"Alice Agyekum","author_inst":"Columbia University"},{"author_name":"Nitish Aswani","author_inst":"Columbia University"},{"author_name":"Harry Reyes Nieva","author_inst":"Columbia University"},{"author_name":"Chin Hur","author_inst":"Columbia University"}],"rel_date":"2026-10-08","rel_site":"medrxiv"},{"rel_title":"National Prevalence and Determinants of Concurrent Wasting and Stunting among Under-Five Children in Yemen: Evidence from the 2022-2023 Multiple Indicator Cluster Survey","rel_doi":"10.64898\/2026.10.06.26364923","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.06.26364923","rel_abs":"Background Concurrent wasting and stunting (WaSt) is a severe form of child undernutrition, linked to higher mortality and long-term negative health outcomes. Malnutrition is a significant challenge in Yemen, where the country is experiencing a long-standing conflict, food insecurity, and socioeconomic deprivation. But there is still limited evidence on the burden and determinants of WaSt in Yemen on a national level. This study aimed to estimate the prevalence and identify factors associated with WaSt among children under 5 years in Yemen. Methods We conducted a cross-sectional analysis using nationally representative data from the 2022-2023 Yemen Multiple Indicator Cluster Survey (MICS). A significantly large dataset of 17,734 children aged 0-59 months from all the 22 governorates of Yemen was analyzed. Concurrent wasting and stunting (WaSt) was defined as the coexistence of a weight-for-height z-score (WHZ) below -2 standard deviations and a height-for-age z-score (HAZ) below -2 standard deviations from the WHO Child Growth Standards in the same child. Survey-weighted logistic regression was performed to analyze the factors associated with WaSt among the under 5 children in Yemen. Results The national prevalence of WaSt was 8.4% (95% CI: 7.6-9.2). The highest prevalence of WaSt was found in children aged 12-23 months (12.0%) and in the Western Coastal region (11.6%). After adjustment, male sex (AOR 1.52, 95% CI: 1.30-1.80), residence in the Western Coastal (AOR 2.00, 95% CI: 1.60-2.40), Eastern (AOR 2.00, 95% CI: 1.50-2.70), and Southern regions (AOR 1.60, 95% CI: 1.20-2.10), poorest household wealth (AOR 1.96, 95% CI: 1.30-2.90), moderate (AOR 1.51, 95% CI: 1.13-1.94) and severe food insecurity (AOR 1.94, 95% CI: 1.40-2.60), and recent diarrhoea (AOR 1.22, 95% CI: 1.02-1.44) were associated with higher odds of WaSt. Having a handwashing facility and improved sanitation were protective. Conclusion At least 1 in every 12 under-five children in Yemen was affected by WaSt, and there were significant socioeconomic, geographic, food-security and WASH-related factors influencing this devastating outcome. Instead of simple, one-dimensional approaches, multi-sectoral interventions are needed to address this adversity. And those efforts must be integrated into the system, interconnected with each other and specifically targeted to vulnerable children and households.","rel_num_authors":4,"rel_authors":[{"author_name":"Abdullah Salman","author_inst":"Ministry of Health & Family Welfare , Bangladesh"},{"author_name":"Rifa Sunzida","author_inst":"Chittagong Medical College"},{"author_name":"Bushra Kabir","author_inst":"Dhaka Medical College and Hospital"},{"author_name":"Rajat Das Gupta","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-10-08","rel_site":"medrxiv"},{"rel_title":"Evaluating Behavioral Parallelism and Cost Incentives in Voluntary Quarantine: A Randomized App-Based Epidemic Game at VinUniversity in Hanoi, Vietnam","rel_doi":"10.64898\/2026.10.06.26364443","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.06.26364443","rel_abs":"Background: Quantifying behavioral drivers of protective action during infectious disease outbreaks remains challenging. App-based experimental epidemic games (epigames) provide a framework for studying these decisions in naturalistic settings, but correspondence between in-game measures and real-life beliefs or behaviors requires evaluation. We examined whether an activity-based opportunity cost influenced voluntary quarantine decisions within an epigame and whether real-life health beliefs transferred into the game and predicted observed choices. Methods: We conducted a two-week randomized controlled trial from May 4 to May 17, 2026, at VinUniversity (VinUni) in Hanoi, Vietnam. Participants using the Epigames app installed in their smartphone were randomized to a low-barrier group, earning 1 point per qualifying contact with other participant when remaining active, or a high-barrier group, earning 2 points per contact. Of 439 enrolled participants, 283 were successfully randomized to one of the two groups, made at least one valid daily quarantine decision, and their data was used in the analysis. Real-life (S1) and in-game (S2) beliefs measured susceptibility, severity, quarantine self-efficacy, and perceived benefits. Belief correspondence was assessed using Holm-adjusted Spearman correlations and prospective cumulative-logit models. Quarantine choices were analyzed using participant-day binomial generalized estimating equations (GEE) and participant-level quasi-binomial models. Results: Participants made 1,823 valid daily decisions and chose quarantine on 458 participant-days (25.1%). Quarantine rates were 30.1% in the low-barrier group and 20.2% in the high-barrier group. The high barrier was associated with 41% lower population-averaged odds of quarantine (GEE odds ratio [OR] 0.59, 95% confidence interval [CI] 0.40-0.86,  = 0.0059); the quasibinomial estimate was identical (OR 0.59, 95% CI 0.40-0.86,  = 0.0055). Among 251 participants with matched S1-S2 data, all four corresponding beliefs were positively associated (Spearman's  = 0.259-0.418; all Holm-adjusted  < 0.001). Prospective ordinal models confirmed positive matched-domain associations (ORs 1.39-2.18 per one-point S1 increase). Beliefs showed little robust association with quarantine behavior, and neither S1 nor S2 beliefs jointly modified the randomized effect. Self-efficacy, network degree, and the preregistered gender main effect were also unsupported. Conclusion: A higher activity-based opportunity cost reduced voluntary quarantine within the VinUni epigame, while participants carried relative differences in stated health beliefs from real-life to in-game framing. These beliefs did not reliably predict observed quarantine choices within the game framing. Epigames can support controlled study of incentives and belief correspondence in naturalistic settings such as college campuses, but behavioral validity or real-world generalizability requires further work.","rel_num_authors":10,"rel_authors":[{"author_name":"Andres Colubri","author_inst":"UMass Chan Medical School, Worcester, Massachusetts, United States"},{"author_name":"Thu Le Anh","author_inst":"College of Health Sciences, VinUniversity, Hanoi, Vietnam"},{"author_name":"Ngoc Le Thi Minh","author_inst":"College of Health Sciences, VinUniversity, Hanoi, Vietnam"},{"author_name":"Huy Vu Nhat Ho","author_inst":"College of Health Sciences, VinUniversity, Hanoi, Vietnam"},{"author_name":"Anh Dang Ngoc Minh","author_inst":"College of Health Sciences, VinUniversity, Hanoi, Vietnam"},{"author_name":"Duong Le Huong","author_inst":"College of Health Sciences, VinUniversity, Hanoi, Vietnam"},{"author_name":"Minh Doan Hoang","author_inst":"College of Health Sciences, VinUniversity, Hanoi, Vietnam"},{"author_name":"Dale King","author_inst":"American University of Iraq-Baghdad, Baghdad, Iraq"},{"author_name":"Jasmina Panovska-Griffiths","author_inst":"Queen's College, University of Oxford, Oxford, United Kingdom"},{"author_name":"Pei Yee Woh","author_inst":"Innovations in Health Sciences, VinUniversity, Hanoi, Vietnam"}],"rel_date":"2026-10-08","rel_site":"medrxiv"},{"rel_title":"Plasma metabolomic profiling of frailty in older adults at risk of dementia","rel_doi":"10.64898\/2026.10.06.26364906","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.06.26364906","rel_abs":"Background: Frailty is a prominent risk factor for dementia. Early detection of at-risk individuals may enable intervention to prevent or slow dementia pathology. Blood-based biomarker discovery could offer a path for early detection of frailty and cognitive decline. Methods: Older adults at risk of dementia underwent comprehensive multi-disciplinary assessment at the Healthy Brain Ageing (HBA) clinic, including geriatric, neurophysiological and mood evaluations, in addition to providing a fasted blood sample. Clinical data were used to calculate a deficit accumulation frailty index (FI) score. Additional cohorts attended either one (n=118) or two (n=73) subsequent visits over an average period of 4 years. Untargeted metabolomics was performed on plasma samples, and metabolites were clustered by similarity. Linear regression was used to assess association of clusters with FI. Finally, change in plasma abundance over time was assessed. Results: At assessment, participants had a mean (SD) age of 68.10 (8.07) years; 72.2% were female. Hierarchical clustering identified 10 clusters of metabolites, of which 6 were significantly associated with FI (p<0.05) at baseline and contained similar classes of metabolite. Differential abundance analysis found unique temporal regulation of metabolite abundance in each cluster, but across clusters severity of frailty impacted direction of change in plasma abundance over time. Conclusions: Frailty index was associated with carboxylic acids and derivatives, fatty acyls and organooxygen compounds across multiple clusters, and a large number of lipids were linked to frailty score, potentially implicating dysregulation of energy metabolism in the pathophysiology of frailty and forming a panel of predictive biomarkers of at risk patients.","rel_num_authors":7,"rel_authors":[{"author_name":"Isabelle Alldritt","author_inst":"University of Technology Sydney"},{"author_name":"Johannes C Michaelian","author_inst":"The University of Sydney"},{"author_name":"Rachael Yu","author_inst":"The University of Sydney"},{"author_name":"Sarah E Deemer","author_inst":"University of North Texas"},{"author_name":"Richard J Mills","author_inst":"Murdoch Children's Research Institute"},{"author_name":"Sharon L Naismith","author_inst":"The University of Sydney"},{"author_name":"Andrew Philp","author_inst":"University of Technology Sydney"}],"rel_date":"2026-10-08","rel_site":"medrxiv"},{"rel_title":"The Dilated Cardiomyopathy E525K Mutation Stabilizes the Cardiac Myosin Interacting-Heads Motif While Activating the Isolated Motor Domain","rel_doi":"10.64898\/2026.10.02.756299","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.02.756299","rel_abs":"Mutations in {beta}-cardiac myosin are a common cause of inherited cardiomyopathies. The dilated cardiomyopathy E525K mutation alters both thick filament regulation and motor activity, yet the structural basis for these effects has remained unclear. Here, we combined cryo-EM and MD simulations to determine how E525K affects the conformational landscape of cardiac myosin in both its autoinhibited interacting-heads motif (IHM) and isolated myosin head states. E525K-mutated myosin exclusively adopted a single S2 conformation in IHM, in contrast to the conformational heterogeneity observed in wild-type myosin. Structural and electrostatic analyses revealed that the mutation increased positive charge density at the blocked-head (BH) - S2 (subfragment-2) interface, strengthening interactions with negatively charged residues within S2. 3D variability analysis and MD simulations of the E525K IHM demonstrated reduced S2 mobility, consistent with strengthened BH - S2 interactions, and decreased conformational flexibility, providing a structural mechanism for stabilization of the IHM state. To investigate the isolated myosin head, we determined cryo-EM structures of wild-type and E525K subfragment-1 (S1). The mutation induced local conformational rearrangements in the activation-loop and Loop 3 region, the SH3-like domain, and the essential light chain of S1, revealing structural changes that support the enhanced motor activity previously reported for isolated E525K myosin motors. These findings show that E525K stabilizes the autoinhibited IHM through electrostatic stabilization of the BH - S2 interface while inducing structural changes consistent with activation of the isolated motor domain, providing structural insights into how a single DCM mutation differentially regulates cardiac myosin S1 and IHM structure and function.","rel_num_authors":9,"rel_authors":[{"author_name":"Ruchi Gautam","author_inst":"University of Massachusetts Chan Medical School, Worcester, MA, USA"},{"author_name":"Arun Kumar Somavarapu","author_inst":"University of Massachusetts Chan Medical School, Worcester, MA, USA"},{"author_name":"Kalen Z. Robeson","author_inst":"University of Washington, Seattle, WA, USA"},{"author_name":"Matthew C. Childers","author_inst":"University of Washington, Seattle, WA, USA"},{"author_name":"Michael Regnier","author_inst":"University of Washington, Seattle, WA, USA"},{"author_name":"Jinghua Ge","author_inst":"Pennsylvania State University, College of Medicine; Hershey, PA, USA"},{"author_name":"Christopher M. Yengo","author_inst":"Pennsylvania State University, College of Medicine; Hershey, PA, USA"},{"author_name":"Roger Craig","author_inst":"University of Massachusetts Chan Medical School; Worcester, MA, USA"},{"author_name":"Raul Padron","author_inst":"University of Massachusetts Chan Medical School; Worcester, MA, USA"}],"rel_date":"2026-10-08","rel_site":"biorxiv"},{"rel_title":"mzQC: a versatile way to communicate quality information for biological mass spectrometry","rel_doi":"10.64898\/2026.10.02.756144","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.02.756144","rel_abs":"Reliable quality control (QC) is essential for reproducible biological mass spectrometry, yet QC information is still typically stored in tool-specific, poorly interoperable formats that hinder comparison, reuse, and transparent reporting. We present mzQC, a community-developed standard from the HUPO Proteomics Standards Initiative for the compact, machine-readable representation of QC metrics and their associated metadata across mass spectrometry workflows. mzQC is implemented in JSON, organized to support both individual mass spectrometry acquisitions and collections thereof, with formal QC metrics definitions supported by controlled vocabularies to ensure unambiguous metric interpretation and semantic consistency. The format is supported by validation tools and reference libraries in Python, R, and Java, facilitating integration into existing software ecosystems. We demonstrate the utility of mzQC across diverse analytical modalities and QC settings, spanning longitudinal instrument monitoring, acquisition-method evaluation, study-level quality assessment, repository-scale data characterization, and spatially resolved mass spectrometry imaging. Together, these use cases show that mzQC provides not merely a file format, but a shared foundation for interoperable QC reporting, large-scale data assessment, and more rigorous, reproducible, and reusable mass spectrometry-based research.","rel_num_authors":24,"rel_authors":[{"author_name":"Chris Bielow","author_inst":"Bioinformatics Solution Center, Institut fuer Informatik, Freie Universitaet Berlin, Takustr. 9, 14195 Berlin, Germany"},{"author_name":"Mathias Walzer","author_inst":"European Bioinformatics Institute, Wellcome Genome Campus, CB10 1SD, Cambridge, United Kingdom"},{"author_name":"Nils Hoffmann","author_inst":"Forschungszentrum Juelich GmbH, Institute for Bio- and Geosciences (IBG-5), Wilhelm-Johnen-Strasse 1, 52428 Juelich, Germany"},{"author_name":"Julian Uszkoreit","author_inst":"Ruhr University Bochum, Medical Faculty, Medical Bioinformatics, Universitaetsstr. 150, D-44801 Bochum, Germany"},{"author_name":"Fatemeh Mirzadeh Sarcheshmeh","author_inst":"University of Antwerp, Middelheimlaan 1, 2020 Antwerpen, Belgium"},{"author_name":"Franziska Nicolaus","author_inst":"Forschungszentrum Juelich GmbH, Institute for Bio- and Geosciences (IBG-5), Wilhelm-Johnen-Strasse 1, 52428 Juelich, Germany"},{"author_name":"Lars Andernach","author_inst":"Leibniz Institute of Plant Biochemistry, Program Center MetaCom, Halle, Germany"},{"author_name":"Patrick Boschmann","author_inst":"Applied Bioinformatics, Department of Computer Science, University of Tuebingen, Tuebingen, Germany"},{"author_name":"Bo Burla","author_inst":"Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, 28 Medical Dr, Singapore 117456"},{"author_name":"Eralp Dogu","author_inst":"Department of Statistics, Mugla Sitki Kocman University, 48000, Mu?la, Turkiye"},{"author_name":"Martin Eisenacher","author_inst":"Ruhr University Bochum, Medical Faculty, Medical Bioinformatics, Universitaetsstr. 150, D-44801 Bochum, Germany"},{"author_name":"Yasin El Abiead","author_inst":"BOKU University, Institute of Analytical Chemistry, Department of Natural Sciences and Sustainable Resources, 1190, Vienna, Austria"},{"author_name":"David Jimenez-Morales","author_inst":"Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA"},{"author_name":"Steffen Neumann","author_inst":"Leibniz Institute of Plant Biochemistry, Program Center MetaCom, Halle, Germany"},{"author_name":"Yasset Perez-Riverol","author_inst":"European Bioinformatics Institute, Wellcome Genome Campus, CB10 1SD, Cambridge, United Kingdom"},{"author_name":"Timo Sachsenberg","author_inst":"Applied Bioinformatics, Department of Computer Science, University of Tuebingen, Tuebingen, Germany"},{"author_name":"Reza M Salek","author_inst":"School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0SP, United Kingdom"},{"author_name":"Michael Strobel","author_inst":"Department of Computer Science and Engineering, University of California Riverside. 900 University Ave. Riverside, CA 92521"},{"author_name":"Stefan Tenzer","author_inst":"Institute of Immunology, University Medical Center of the Johannes-Gutenberg University, 55131, Mainz, Germany"},{"author_name":"Tim Van Den Bossche","author_inst":"VIB-UGent Center for Medical Biotechnology, VIB, 9000 Ghent, Belgium"},{"author_name":"Olga Vitek","author_inst":"Khoury College of Computer Science and Barnett Institute for Chemical and Biological Analysis, Northeastern University, Boston, MA 02115, USA"},{"author_name":"Mingxun Wang","author_inst":"Department of Computer Science and Engineering, University of California Riverside, Riverside, CA 92521, USA"},{"author_name":"David L. Tabb","author_inst":"Centre for Bioinformatics and Computational Biology, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch Uni"},{"author_name":"Wout Bittremieux","author_inst":"University of Antwerp, Middelheimlaan 1, 2020 Antwerpen, Belgium"}],"rel_date":"2026-10-08","rel_site":"biorxiv"},{"rel_title":"Distinct metabolic states of yeast and pseudohyphae differentially prime innate immune responsiveness","rel_doi":"10.64898\/2026.10.08.757614","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.08.757614","rel_abs":"Pseudohyphal growth in skin-associated fungi is often considered a morphological response to environmental stress, but whether it represents a coordinated metabolic state that influences host immunity remains unclear. Using Malassezia furfur, we combined synchronized morphogenesis, temporal metabolomics, stable-isotope tracing, targeted metabolite measurements, transcriptional profiling, and functional immune assays to compare yeast and pseudohyphal states. Yeast cells maintained an active tryptophan-aldehyde metabolic program that partitioned carbon between oxidative and reductive branches associated with redox balance and methylation potential. Pseudohyphal cells attenuated this program and instead underwent sequential metabolic remodeling, characterized by early changes in one-carbon and amino acid metabolism followed by sulfur-pathway remodeling and increased glutathione biosynthesis. These distinct fungal states generated extracellular environments that altered THP-1 innate immune responsiveness without directly inducing canonical macrophage polarization. Yeast-conditioned cells responded preferentially to tissue-repair signals, whereas pseudohypha-conditioned cells displayed enhanced responses to inflammatory stimuli. Individual metabolites did not reproduce these effects, suggesting that immune conditioning depends on the integrated extracellular milieu. Together, these findings identify pseudohyphal growth as an organized adaptive metabolic state and establish a framework linking fungal morphogenetic potential to context-dependent host immune responses.","rel_num_authors":9,"rel_authors":[{"author_name":"Hyuga Kato","author_inst":"Case Western Reserve University"},{"author_name":"Monali NandyMazumdar","author_inst":"Case Western Reserve University"},{"author_name":"Zhara Rahmani","author_inst":"Case Western Reserve University"},{"author_name":"Teagan Kukhta","author_inst":"Case Western Reserve University"},{"author_name":"Claire Wolford","author_inst":"Case Western Reserve University"},{"author_name":"Sahishnu Vallabhajoysul","author_inst":"Case Western Reserve University"},{"author_name":"Masaru Miyagi","author_inst":"Case Western Reserve University"},{"author_name":"Susumu Kajiwara","author_inst":"Tokyo Kogyo Daigaku"},{"author_name":"Mei Zhang","author_inst":"Case Western Reserve University"}],"rel_date":"2026-10-08","rel_site":"biorxiv"},{"rel_title":"Fu Ling (Wolfiporia cocos) Fungal \u03b2-Glucan in Combination with Bacillus coagulans Improve Colitis-Related Outcomes and Cecal Fermentation in DSS-Treated Mice","rel_doi":"10.64898\/2026.10.07.757334","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.07.757334","rel_abs":"Inflammatory bowel disease challenges modern gastroenterology due to high relapse rates. This study evaluated the effects of medicinal fungal sclerotium Fu Ling (Wolfiporia cocos), its derived {beta}-1,3-1,6-Glucan, Bacillus coagulans GBI-30, 6086, and their combinations in dextran sulfate sodium-induced colitis in male BALB\/c mice. The {beta}-glucan-B. coagulans combination significantly improved body weight, disease activity index, colon length and architecture, mucus secretion, and cecal fermentation over single ingredient. Consistently, this combination increased total short-chain fatty acids production, particularly acetate, improved gut tight-junction organization and reduced myeloperoxidase accumulation. Shotgun metagenomic sequencing indicated that this combination reshaped the gut microbiota, notably enriching Anaeromassilibacillus sp., which associated with improved clinical feature. These findings highlight the potential of fungal-derived {beta}-glucan and probiotic combinations as functional food ingredients for mitigating intestinal inflammation and supporting barrier repair.","rel_num_authors":5,"rel_authors":[{"author_name":"Ka Lee Ma","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Nelson Kei","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Sui Shan Chan","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Hoi Shan Kwan","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Peter C.K. Cheung","author_inst":"The Chinese University of Hong Kong"}],"rel_date":"2026-10-08","rel_site":"biorxiv"},{"rel_title":"Learning the electronic health record at the minute-scale","rel_doi":"10.64898\/2026.10.04.26364562","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.04.26364562","rel_abs":"Electronic health record foundation models are traditionally trained on the scale of years, days, or hours. These timescales, however, lack the minute-scale resolution required to directly guide clinical decisions at the bedside. We introduced minute-scale learning, a new paradigm for training and evaluating models, and developed MINT, a minute-scale foundation model for pediatric emergencies. MINT was pretrained and validated on 766,733 pediatric emergency department visits at five health systems, comprising 16 years of data from 10 hospitals. On minute-scale forecasting tasks, MINT outperformed and generalized to external health systems better than task-specific models (superior in 21 of 25 comparisons). MINT outperformed physicians in forecasting escalations of respiratory support. MINT demonstrated uniquely minute-scale capabilities including department-scale monitoring, dynamic risk explanations, individualized physiologic response forecasts, and hypothesis generation. Learning at the minute-scale improves performance, strengthens generalizability, and provides insights, actionability, and scientific capabilities that are not accessible at other timescales.","rel_num_authors":12,"rel_authors":[{"author_name":"Kush Narang","author_inst":"Stanford University"},{"author_name":"Newton Addo","author_inst":"University of California, San Francisco"},{"author_name":"Jaskaran Bains","author_inst":"University of California, San Francisco"},{"author_name":"Maytal Firnberg","author_inst":"University of California, San Francisco"},{"author_name":"Sonny Tat","author_inst":"University of California, San Francisco"},{"author_name":"Anneka Hooft","author_inst":"University of California, San Francisco"},{"author_name":"Daniela Chanci Arrubla","author_inst":"Duke University"},{"author_name":"Baraa Abed","author_inst":"Duke University"},{"author_name":"Chandan Singh","author_inst":"Microsoft Research"},{"author_name":"Rishikesan Kamaleswaran","author_inst":"Duke University"},{"author_name":"Jean Feng","author_inst":"University of California, San Francisco"},{"author_name":"Aaron E Kornblith","author_inst":"University of California San Francisco"}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"Memory and executive functioning show differential associations with scam susceptibility in middle to older adulthood","rel_doi":"10.64898\/2026.10.04.26364617","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.04.26364617","rel_abs":"Objectives: The rising prevalence of financial exploitation among older adults has prompted research on the cognitive mechanisms underlying financial decision making in later life. Prior work has demonstrated a link between cognitive impairment and financial vulnerability. The present study examined the unique contributions of composite measures of memory and executive functioning to scam susceptibility in middle-aged to older adults without dementia. Methods: One hundred and fifty-one participants (age= 68.2 {+\/-} 8.0 years, 72.2% female, years of education= 16.4 {+\/-} 2.2) completed standard neuropsychological measures from the Uniform Data Set (UDS), Version 3, and the California Verbal Learning Test, Second Edition, and a self-report scam susceptibility measure. Psychometrically robust composite scores, the UDS-M+ and UDS3-EF, were computed to represent memory and executive functioning domains. Linear regression models examined independent associations between UDS-M+ and UDS3-EF performance and scam susceptibility. Nested model comparisons evaluated unique contributions of the UDS-M+ and UDS3-EF when included in a joint model. Results: Lower UDS-M+ (b= -0.25, 95% CI [-0.45, -0.04], p= .018) and lower UDS3-EF (b= -0.33, 95% CI [-0.54, -0.12], p= .002) scores were independently associated with greater scam susceptibility after adjusting for age, sex, years of education, and income. However, only UDS3-EF remained significant in a joint model. Post hoc analyses revealed that only memory was associated with scam susceptibility in middle-aged adults whereas only executive functioning was significant in older adults. Conclusions: These findings highlight the importance of monitoring memory and executive functioning across middle to older adulthood when considering susceptibility to scams.","rel_num_authors":12,"rel_authors":[{"author_name":"Cassidy P. Molinare","author_inst":"University of Southern California"},{"author_name":"Belinda Y. Zhang","author_inst":"University of Southern California"},{"author_name":"Mark Sanderson-Cimino","author_inst":"UC San Francisco Memory and Aging Center"},{"author_name":"Melanie Leguizamon","author_inst":"University of Southern California"},{"author_name":"Emma Oyen","author_inst":"University of Southern California"},{"author_name":"Daisy T. Noriega-Makarskyy","author_inst":"University of Southern California"},{"author_name":"Jenna Axelrod","author_inst":"University of Southern California"},{"author_name":"Aaron C Lim","author_inst":"University of Southern California"},{"author_name":"Camdyn Wu","author_inst":"University of Southern California"},{"author_name":"Maanya Agarwal","author_inst":"University of Southern California"},{"author_name":"Laura Mosqueda","author_inst":"University of Southern California"},{"author_name":"S. Duke Han","author_inst":"University of Southern California"}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"Dietary sodium intake and kidney tubular protein abundance in urinary extracellular vesicles","rel_doi":"10.64898\/2026.10.04.26364680","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.04.26364680","rel_abs":"Background: Dietary sodium intake is a modifiable determinant of blood pressure, and impaired renal sodium handling is implicated in the pathogenesis of hypertension. Whether dietary sodium intake modulates renal tubular sodium transporter abundance among normotensive adults at risk for hypertension is unknown. Methods: Forty-six normotensive adults with normal kidney function at risk of developing hypertension were prospectively enrolled to complete a very low sodium (LS) diet followed by a high sodium (HS) diet. Urinary extracellular vesicle (uEV) proteins were quantified from a 24-hour urine collection at the end of each diet. We compared normalized uEV protein concentrations between diets and tested whether diet modified uEV protein associations with serum aldosterone, urinary aldosterone, and serum cortisol-cortisone ratio under either diet using Wilcoxon rank sums and linear mixed effects models, respectively. Results: Participants achieved median [IQR] urine sodium 13.2 [7.7-19.9] mEq\/24h on the LS diet and 244.0 [197.1-297.0] mEq\/24h on the HS diet. LS intake induced greater renin activity, greater plasma and urinary aldosterone, and lower urinary cortisol, when compared to HS intake. In parallel, NCC, ENaC, SGLT2, OXSR1, and Pendrin uEV concentrations were significantly higher during LS intake than HS intake (p<0.05 for all), whereas TRPV5 and AQP2 uEV concentrations were lower during LS intake than HS intake (p<0.001 for both). Conclusions: Controlled dietary sodium modulation induced nephron-segment specific changes in uEV protein abundance. These findings demonstrate the ability of uEVs to serve as a non-invasive tool to probe in vivo renal sodium, water, and electrolyte handling.","rel_num_authors":13,"rel_authors":[{"author_name":"Sophie E Claudel","author_inst":"Boston Medical Center"},{"author_name":"Sanan Mahrokhian","author_inst":"Brigham and Women's Hospital, Harvard Medical School"},{"author_name":"Isabelle Hanna","author_inst":"Brigham and Women's Hospital, Harvard Medical School"},{"author_name":"Andrew J Newman","author_inst":"Brigham and Women's Hospital, Harvard Medical School"},{"author_name":"Jenifer Brown","author_inst":"Brigham and Women's Hospital"},{"author_name":"Ashish Verma","author_inst":"Boston University School of Medicine, Boston, MA"},{"author_name":"Sushrut Waikar","author_inst":"Boston Medical Center"},{"author_name":"Richard J. Auchus","author_inst":"University of Michigan"},{"author_name":"Hayes McDonald","author_inst":"Vanderbilt University"},{"author_name":"Kevin Schey","author_inst":"Vanderbilt University"},{"author_name":"Dungeng Peng","author_inst":"Vanderbilt University"},{"author_name":"James M Luther","author_inst":"Vanderbilt University"},{"author_name":"Anand Vaidya","author_inst":"Brigham and Women's Hospital, Harvard Medical School"}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"A Modular Architecture for Dynamic Evaluation of Best-Practice Care","rel_doi":"10.64898\/2026.10.03.26364324","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.03.26364324","rel_abs":"ObjectiveRetrospective evaluation of clinical pathway adherence using electronic medical record (eMR) data is limited by heterogeneous data structures and statistical measures that do not account for patient-specific context, care sequence, or timing. We designed a modular event-based architecture to dynamically evaluate the New South Wales Adult Sepsis Pathway over time.\n\nMethodData from eMRs were collected from adult emergency department encounters across four hospitals between July 2022 and June 2024 and processed through three sequential layers: event-stream transformation, pathway-relevance filtering, and state-based pathway evaluation. Heterogeneous records were standardized and organized into a chronological timeline for each encounter. The framework then updated the pathways state as new clinical information became available and assessed whether recommended care was delivered within the relevant timeframe and sequence.\n\nResultThe architecture processed 451,124 encounters. This included 57,631,084 clinical events extracted and transformed into encounter-level event streams. After filtering for pathway relevance, 43,951,146 events remained (76.3%). A total of 129,907 (34.6%) encounters entered the sepsis pathway, 50,118 (38.6%) entered YELLOW state, indicating progression to suspected sepsis, and 3,349 (2.6%) encounters progressed to RED state from GREEN, indicating the initial shock. Of 50,118 encounters entering YELLOW state, 2,426 (4.8%) progressed to shock, 8,700 (17.4%) encounters were recognized with sepsis through a blood culture order, and 4,287 (8.6%) encounters were recognized with sepsis through an antibiotic order. This demonstrates the architectures ability to prioritize higher-acuity states during evaluation rather than going through an intermediate state.\n\nConclusionThe architecture developed shows the feasibility of transforming fragmented routine eMR data into a reusable longitudinal representation that supports context-dependent pathway evaluation. Separating data preparation from pathway rules improves transparency, maintainability, and adaptability and provides a foundation for future interoperable, near-real-time pathway monitoring","rel_num_authors":6,"rel_authors":[{"author_name":"Minh Trang Hoang","author_inst":"Faculty of Medicine and Health, The Univeristy of Sydney"},{"author_name":"Tim Shaw","author_inst":"Faculty of Medicine and Health, The Univeristy of Sydney"},{"author_name":"Christina Igasto","author_inst":"Digital Canberra"},{"author_name":"Candice Donnelly","author_inst":"Faculty of Medicine and Health, The Univeristy of Sydney"},{"author_name":"Amith Shetty","author_inst":"NSW Ministry of Heatlh"},{"author_name":"Malcolm Pradhan","author_inst":"Faculty of Medicine and Health, The Univeristy of Sydney"}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"Identifying Message \"Recipes\" for High Perceived Effectiveness: Cognitive, Social, and Emotional Profiles of Vaping Public Education Messages Among Young Adults Who Vape","rel_doi":"10.64898\/2026.10.04.26364669","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.04.26364669","rel_abs":"IntroductionVaping public education campaigns are a central prevention strategy for young adults (YAs), but message effectiveness varies widely and formative testing typically evaluates one message attribute at a time. This study examined how four perceptual dimensions--cognitive engagement, social relevance, emotional arousal, and emotional valence--relate to perceived message effectiveness (PME), and whether multiple combinations of these dimensions correspond to similarly high PME.\n\nMethodsIn a cross-sectional online message-testing study conducted from March to April 2025, 540 U.S. YAs who vape each evaluated 15 messages randomly sampled from a corpus of 229 text-image vaping public education messages, yielding 8,100 message evaluations. Cross-classified multilevel models estimated associations between each perceptual dimension and PME. An Explainable Boosting Machine probed nonlinear associations, and k-means clustering of high-predicted-PME perceptual configurations identified distinct profiles. Analyses were conducted in 2026.\n\nResultsCognitive engagement (b = 0.20, 95% CI [0.18, 0.22]) and social relevance (b = 0.15, 95% CI [0.13, 0.17]) showed the strongest associations with PME, followed by emotional arousal (b = 0.06, 95% CI [0.04, 0.08]); emotional valence showed no linear association (b = 0.00, 95% CI [-0.02, 0.02]). The Explainable Boosting Machine revealed a U-shaped valence pattern, with higher predicted PME at both the negative and positive ends of the scale. Clustering yielded five distinct perceptual profiles with similarly high predicted PME (4.10-4.25).\n\nConclusionsMultiple perceptual configurations correspond to similarly high PME, supporting a configurational approach to formative message testing rather than a single optimal message formula.","rel_num_authors":9,"rel_authors":[{"author_name":"Jiaying Liu","author_inst":"University of California, Santa Barbara"},{"author_name":"Qiyao Peng","author_inst":"University of California, Santa Barbara"},{"author_name":"Musa Malik","author_inst":"University of Oklahoma"},{"author_name":"Yidi Wang","author_inst":"University of California, San Diego"},{"author_name":"Emily Norton","author_inst":"University of Georgia"},{"author_name":"Tianlai Ye","author_inst":"University of California, Santa Barbara"},{"author_name":"Colleen Markey","author_inst":"University of Georgia"},{"author_name":"Allison Worsdale","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Lawrence H. Sweet","author_inst":"University of Georgia"}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"Rural-urban differences in gut microbiome among Vietnamese women","rel_doi":"10.64898\/2026.10.04.26364707","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.04.26364707","rel_abs":"Gut microbiome plays an important role in human health. Urbanization has been suggested to alter the gut microbiome. We comprehensively evaluated differences in gut microbiome profiles of 76 urban and 81 rural female residents of Vietnam using shotgun metagenomic data. We evaluated rural-urban differences in gut microbial diversity, individual microbial taxa, and metabolic pathways. Rural residents had higher alpha and beta diversities in age-adjusted models (p<0.05). Additionally, significant rural-urban differences were observed for 35 microbial taxa in age-adjusted models (FDR<0.1). Rural residents had higher relative abundance of classes, orders, and families of FGB2982 and FGB38642 and strain SGB15332 of the species Faecalibacterium prausnitzii, whereas urban residents had higher relative abundances of species Bacteroides thetaiotaomicron, Coprobacter fastidiosus, Bilophila wadsworthia, Enterobacter cloacae, Enterobacter hormaechei, Klebsiella aerogenes, Dielma fastidiosa, and Holdemania massiliensis. Notably, these associations were attenuated after further adjustment for socioeconomic characteristics, lifestyle, dietary factors, and comorbidity (FDR>0.1). In the fully adjusted model, significant rural-urban differences were observed in the abundance of 17 microbial taxa, including Ruminococcus sp AF13 28 and Prevotella pectinovora, as well as in three metabolic pathways (FDR<0.1). This study suggests that urbanization-related factors may contribute to differences in the gut microbiome between urban and rural Vietnamese women.","rel_num_authors":6,"rel_authors":[{"author_name":"Justin Y Guo","author_inst":"Montgomery Bell Academy"},{"author_name":"Huong T.T. Tran","author_inst":"Vietnam National Cancer Institute, National Cancer Hospital, Hanoi, Vietnam"},{"author_name":"Qiuyin Y Cai","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Minh  Van Hoang","author_inst":"Hanoi University of Public Health"},{"author_name":"Xiao-ou Shu","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Sang Minh Nguyen","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"Post-Initiation Care Patterns and Weight Loss With Semaglutide and Tirzepatide for Obesity in Clinical Practice","rel_doi":"10.64898\/2026.10.04.26364715","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.04.26364715","rel_abs":"BackgroundRandomized trials show substantial weight loss with semaglutide and tirzepatide under structured care, but little is known about whether patients in routine practice continue therapy, reach a maintenance dose, and have their weight measured.\n\nObjectivesTo describe the first year after initiation of semaglutide or tirzepatide for obesity, including care patterns, maintenance-dose attainment, weight documentation, and total body weight loss (TBWL).\n\nMethodsThis retrospective cohort study used Epic Cosmos, an electronic health record network of >350 US health systems, to identify adults with obesity and without diabetes who initiated injectable semaglutide or tirzepatide in 2024. Outcomes over 12 months included prescribing persistence, discontinuation, switching, add-on therapy, and reinitiation; attainment of Food and Drug Administration (FDA)-labeled maintenance doses; availability of follow-up weight; and TBWL across progressively restricted populations.\n\nResultsAmong 743,153 adults (60.1% semaglutide; mean age, 48.5 years; 72.5% female), 12-month prescribing persistence was 29.9% for semaglutide and 35.9% for tirzepatide. FDA-labeled maintenance-dose attainment was 28.3% and 55.0%, respectively, and only 8.8% and 16.4% remained prescribing persistent at a maintenance dose with a recorded weight at 12 months. About half of initiators lacked a 12-month weight. Among all initiators, [&ge;]5% TBWL was documented in 25.6% (semaglutide) and 30.4% (tirzepatide), rising to 51.9% and 61.9% among those with recorded weight, 66.1% and 79.5% among those also prescribing persistent, and 82.9% and 87.3% among those further at a maintenance dose.\n\nConclusionsIn routine practice, most patients initiating semaglutide or tirzepatide did not remain on therapy, reach a maintenance dose, and have weight documented through the first year. Documented weight loss was greatest among those completing each step of care, suggesting continuation, dose escalation, and monitoring as targets for improvement.\n\nCENTRAL ILLUSTRATIONCare Cascade and Weight-Loss Outcomes Among Semaglutide and Tirzepatide Initiators, Standardized to 100 Initiators.\n\nNumbers are per 100 initiators and were rounded so that categories at each step sum to the preceding step. At the 12-month dose step, prescribed dose was missing for 1 per 100 semaglutide initiators and <1 per 100 tirzepatide initiators.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC=\"FIGDIR\/small\/26364715v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (27K):\norg.highwire.dtl.DTLVardef@1c3233borg.highwire.dtl.DTLVardef@3e03b3org.highwire.dtl.DTLVardef@1650b0eorg.highwire.dtl.DTLVardef@b8d335_HPS_FORMAT_FIGEXP  M_FIG C_FIG","rel_num_authors":14,"rel_authors":[{"author_name":"Huanhuan Yang","author_inst":"Yale University"},{"author_name":"Chungsoo Kim","author_inst":"Yale School of Medicine"},{"author_name":"Joseph S. Ross","author_inst":"Yale University"},{"author_name":"Chenxi Huang","author_inst":"Yale University"},{"author_name":"Kyungseon Choi","author_inst":"Yale University"},{"author_name":"Bo Kang","author_inst":"Yale University"},{"author_name":"Adith Arun","author_inst":"Yale School of Medicine"},{"author_name":"Huilin Tang","author_inst":"The University of Pennsylvania"},{"author_name":"Yong Chen","author_inst":"The University of Pennsylvania"},{"author_name":"Hua Xu","author_inst":"Yale University"},{"author_name":"Mona Sharifi","author_inst":"Yale School of Medicine"},{"author_name":"Zhihui Li","author_inst":"Tsinghua University"},{"author_name":"Harlan Krumholz","author_inst":"Yale University"},{"author_name":"Yuan Lu","author_inst":"Yale University"}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"Emergency Department Utilization After 60-Day Peripheral Nerve Stimulation Versus Usual Care for Refractory Occipital Neuralgia: A Prospective Propensity-Matched Cohort, Difference-in-Differences Analysis","rel_doi":"10.64898\/2026.10.02.26364550","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.02.26364550","rel_abs":"BackgroundTemporary 60-day percutaneous peripheral nerve stimulation (PNS) can relieve pain in refractory occipital neuralgia (ON), but whether it alters acute healthcare utilization relative to the natural trajectory of the disease is unknown, because prior studies have lacked a concurrent comparator.\n\nMethodsWe performed a secondary analysis of prospectively collected data from a tertiary interventional pain center. Adults with medically refractory ON (primary diagnosis occipital neuralgia, ICD-10-CM M54.81) who underwent 60-day occipital PNS (n = 42) were compared with concurrent patients who were clinically eligible for PNS but were denied insurance authorization and continued optimized non-PNS management (usual care; n = 63). Headache-related emergency department (ED) encounters--index (occipital neuralgia) and non-index (other headache\/facial-pain diagnoses)--were ascertained over the 12 months before and after the treatment window via the electronic record and the statewide health information exchange. Patients were 1:1 propensity-matched on a priori confounders (age, sex, baseline total headache-related ED utilization, HIT-6, and baseline headache-medication use). The primary analysis was a difference-in-differences (DiD) comparison of the change in headache-related ED utilization, reported as the additive difference (Hodges- Lehmann estimate, distribution-free 95% CI) and, alongside, as a multiplicative rate ratio (RR).\n\nResultsThirty-six matched pairs were well balanced. Baseline headache-related ED utilization was nearly identical between matched groups (6.3 vs. 6.2 visits\/year). Over the following year, PNS patients utilization fell to 2.5 while usual-care patients rose to 6.9. The DiD was 5.0 fewer headache-related ED visits per patient (95% CI 3.0-6.0; p < 0.001), corresponding to a rate ratio of 0.36 (95% CI 0.27-0.48; p < 0.001). Results were consistent in the full sample, in covariate-adjusted models, and after excluding controls denied for incomplete conservative-therapy trials. The effect was driven by non-index headache visits.\n\nConclusionsRelative to a concurrent, matched usual-care cohort whose headache-related ED utilization rose over time, 60-day occipital PNS was associated with a substantial reduction in acute-care use, strengthening the case for a role of PNS on healthcare utilization in refractory ON.","rel_num_authors":6,"rel_authors":[{"author_name":"Cameron William Harris","author_inst":"Valley Health System GME"},{"author_name":"Eric T Nguyen","author_inst":"Department of Physical Medicine and Rehabilitation, Charles R. Drew University of Medicine and Science"},{"author_name":"Sergio Mosquera Limas","author_inst":"Department of Orthopaedics and Rehabilitation, Division of Physiatry, Yale New Haven Hospital"},{"author_name":"Samir J Sheth","author_inst":"Division of Pain Management, Sutter Health System"},{"author_name":"Robert William Chow","author_inst":"Department of Anesthesiology, Yale School of Medicine"},{"author_name":"Charles A. Odonkor","author_inst":"Division of Physiatry, Interventional Pain Medicine, Department of Orthopaedics and Rehabilitation, Yale School of Medicine"}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"Power Calculation for Noninferiority Stepped-Wedge Cluster Randomized Trials","rel_doi":"10.64898\/2026.10.04.26364705","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.04.26364705","rel_abs":"BackgroundStepped-wedge cluster randomized trials (SW-CRTs) are increasingly used when interventions need to be implemented sequentially across clusters. Despite extensive developments in the design and analysis of superiority SW-CRTs, methods for planning noninferiority SW-CRTs remain limited.\n\nMethodsWe propose swNIsim, a simulation-based framework for power calculation in noninferiority SW-CRTs using generalized linear mixed-effects models (GLMMs). The proposed approach accommodates both continuous and binary outcomes and supports practical design features, including unequal numbers of clusters across sequences, varying cluster-period sizes, delayed intervention effects, and analyses with or without adjustment for secular time effects. Noninferiority margins can be specified using several commonly applied strategies.\n\nResultsThrough extensive simulation studies, we examined the impact of key design parameters on statistical power, including the number of periods, the number of clusters per sequence, the number of individuals per cluster-period, and the degree of between-cluster variability. For a fixed total sample size, designs with more time periods consistently achieved higher power. Increasing the number of clusters per sequence produced modest gains in power, whereas greater between-cluster variability reduced power. Type I error rates were well controlled across the scenarios examined. Balanced allocation of clusters across sequences was more efficient than unbalanced allocation schemes. Two real-world SW-CRT examples were used to illustrate application of the method.\n\nConclusionsThe proposed swNIsim provides a flexible and practical approach for power calculation in noninferiority SW-CRTs. By accommodating a wide range of design configurations and outcome types, and through implementation as a freely available R package, swNIsim may facilitate the planning and design of noninferiority stepped-wedge trials.","rel_num_authors":3,"rel_authors":[{"author_name":"Justin Guo","author_inst":"Montgomery Bell Academy"},{"author_name":"Chih-Yuan Hsu","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Yu Shyr","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"Acquisition Speed versus Spatial Resolution in Ultra-High-Resolution Photon-Counting CT: Phantom Study to Guide Protocol Development","rel_doi":"10.64898\/2026.10.04.26363713","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.04.26363713","rel_abs":"BackgroundFaster ultrahigh-resolution (UHR) photon-counting CT acquisitions facilitate breath-hold imaging, but identical reconstruction settings may conceal differences in spatial resolution.\n\nPurposeTo assess spatial resolution and depiction of small airways and venous stents across helical UHR acquisition configurations.\n\nMaterials and MethodsStationary wire, airway, and venous-stent phantoms underwent one acquisition per configuration using five configurations on a dual-source scanner at 120 kVp. Reconstructions used 0.2- and 0.4-mm thicknesses, the same sharp kernel, and iterative reconstruction strength 1. We measured the full-width at half-maximum of the slice sensitivity profile (SSP) and spatial frequency at 20% of the modulation transfer function (MTF20). Rank-based F tests with Holm adjustment assessed configuration differences in resolution and variability across slices. Airway detection used a profile contrast-to-noise criterion; stent assessment was qualitative.\n\nResultsCalculated acquisition time for 400-mm coverage decreased from 9.80 to 1.30 seconds between the slowest and fastest configurations. At 0.2-mm reconstruction thickness, median SSP increased from 0.316 to 0.496 mm, and median MTF20 decreased from 2.870 to 2.059 lp\/mm (both P<.001). Interquartile ranges increased from 0.047 to 0.197 mm for SSP and from 0.256 to 0.654 lp\/mm for MTF20 (both variability P<.001). Increasing reconstruction thickness to 0.4 mm increased SSP by a median 0.221 mm across 2459 matched slice-wire measurements (P<.001). At 0.2-mm reconstruction thickness, 0.4- and 0.6-mm lumens with 0.2-mm walls were detected only in the slowest configuration. Faster configurations showed less distinct stent struts and greater adjacent-wall distortion.\n\nConclusionFaster helical UHR photon-counting CT configurations had poorer spatial resolution despite identical nominal slice thickness. Consistent acquisition and reconstruction settings are important for longitudinal comparisons.\n\nOriginal ResearchO_ST_ABSSummary StatementC_ST_ABSFaster helical ultrahigh-resolution photon-counting CT configurations had poorer spatial resolution and small-structure visibility despite identical reconstruction settings, supporting task-specific protocols and consistent techniques for longitudinal imaging.\n\nKey ResultsO_LIAt 0.2-mm reconstruction thickness in this phantom study, median slice sensitivity profile was 0.496 versus 0.316 mm for the fastest versus slowest configurations (calculated 400-mm scan times, 1.30 vs 9.80 seconds; P<.001).\nC_LIO_LIIn-plane spatial frequency at 20% modulation decreased from 2.870 to 2.059 lp\/mm (P<.001), with greater variability across slices.\nC_LIO_LIAt 0.2-mm reconstruction thickness, only the slowest configuration depicted 0.4- and 0.6-mm lumens with 0.2-mm walls.\nC_LI","rel_num_authors":3,"rel_authors":[{"author_name":"Navid Azimi","author_inst":"Emory University"},{"author_name":"Joao A.C. Lima","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Amir Pourmorteza","author_inst":"Emory University"}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"Overdose-related communication in Connecticut: reported receipt, perceived utility, and responses among overdose prevention and response professionals","rel_doi":"10.64898\/2026.10.01.26363949","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.01.26363949","rel_abs":"BackgroundTimely overdose response depends not only on surveillance systems that detect overdose clusters, but also on communication pathways that deliver actionable information to the professionals positioned to respond. Understanding which overdose-related communications are received, perceived as useful, and translated into action is essential for improving overdose prevention and response infrastructure.\n\nObjectiveWe assessed which overdose-related communication channels professionals reported receiving, which they perceived as most helpful, how organizations reported responding to overdoses or overdose clusters, and whether these patterns differed by professional role, county, and funding source.\n\nMethodsWe conducted an exploratory descriptive survey in 2024 using a convenience sample of professionals across Connecticut whose jobs involved overdose prevention or response (N=149). Using this survey data, we summarized reported receipt and perceived utility of overdose-related communication channels, organizational response actions, and internal receipt of Connecticut Department of Public Health overdose alerts. Results were stratified descriptively by professional role, county, and funding source. We interpreted findings using a public health communication-to-action cascade focused on signal detection, communication receipt, internal dissemination, perceived utility, and response action.\n\nResultsReported communication receipt and perceived utility differed most clearly by professional role. Peer information sharing was the most commonly reported communication source and was frequently perceived as helpful, but respondents who reported receiving formal channels such as state alerts, local alerts, or platform-based information often identified those channels as most helpful. Internal receipt of Connecticut Department of Public Health overdose alerts also varied by role. SSPs\/substance use treatment programs and first responders more often reported outreach to people who use drugs, whereas government and health district respondents reported a more even mix of public communication and outreach activities.\n\nConclusionsOverdose-related communication in Connecticut appears role-dependent and unevenly distributed. Informal peer networks are widely used and perceived as helpful, while formal alert systems may require improvements to reach and actionability. Practical improvements include opt-in communication pathways tailored to professional roles, clearer access points for state and local alerts, internal dissemination protocols that specify who should receive which alerts, and alert-to-action playbooks that connect specific alert types to recommended response steps.","rel_num_authors":2,"rel_authors":[{"author_name":"A Ram","author_inst":"Yale University"},{"author_name":"Frederick  L Altice","author_inst":"Yale University School of Medicine"}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"Diabetes Polygenic Scores Predict Glycemic Indices and Insulin Use in Individuals with Atypical Diabetes","rel_doi":"10.64898\/2026.10.01.26364299","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.01.26364299","rel_abs":"Aims\/HypothesisAtypical forms of diabetes often provide diagnostic challenges and are suboptimally treated. We sought to determine whether type 1 and 2 diabetes polygenic scores (PS) would help improve classification of islet autoantibody-negative (IAb-) atypical diabetes cases.\n\nMethodsWe implemented type 1 diabetes PS (T1D PS) and type 2 diabetes PS (T2D PS) in 309 IAb-individuals genome sequencing from the Rare and Atypical Diabetes Network (RADIANT), the largest and most comprehensively phenotyped collection of unsolved and atypical diabetes cases. We performed regression analyses to assess associations between PS, clinical characteristics, and glycemic measures.\n\nResultsBoth T1D and T2D PS were significantly higher in RADIANT than in ancestry-matched controls from UK Biobank. Both PS were associated with C-peptide measures throughout participant oral glucose tolerance tests (OGTT), although in opposite directions; T1D PS was associated with lower C-peptide measures, while T2D PS was associated with higher measures. Participants with T1D PS above a previously established optimal PS value for differentiating cases and controls (T1D PS GRS2>12.88) had 13-fold higher odds of both insulin deficiency on OGTT and use of both basal and bolus insulin therapy.\n\nConclusions\/InterpretationIndividuals in RADIANT with ambiguous diabetes subtypes displayed genetic enrichment for both type 1 and type 2 diabetes, despite ascertainment to remove standard type 1 and type 2 diabetes. T1D PS identified individuals with an unrecognized \"type 1 diabetes-like\" phenotype with insulin deficiency and need for intensive insulin in the absence of islet autoantibodies. PS may help identify individuals with atypical diabetes who will ultimately benefit from insulin therapy.","rel_num_authors":21,"rel_authors":[{"author_name":"Steven D. Gage","author_inst":"Center for Genomic Medicine and Diabetes Unit, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Mass General Brigham, Boston, MA, USA"},{"author_name":"Raymond J. Kreienkamp","author_inst":"Boston Children's Hospital"},{"author_name":"Aaron J. Deutsch","author_inst":"Center for Genomic Medicine and Diabetes Unit, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Mass General Brigham, Boston, MA, USA"},{"author_name":"Eric J. Richards","author_inst":"Diabetes Genetics Initiative and Programs in Metabolism and Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Boyce T"},{"author_name":"Liana K. Billings","author_inst":"Division of Endocrinology, Endeavor Health, Skokie, Illinois; Department of Medicine, University of Chicago Pritzker School of Medicine, Chicago, Illinois, USA"},{"author_name":"Sara J. Cromer","author_inst":"Center for Genomic Medicine and Diabetes Unit, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Mass General Brigham, Boston, MA, USA"},{"author_name":"Siri Atma W. Greeley","author_inst":"Department of Medicine and Pediatrics, Section of Endocrinology, Diabetes, and Metabolism, the Kovler Diabetes Center, University of Chicago, Chicago, IL, USA"},{"author_name":"Irl B. Hirsch","author_inst":"Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA"},{"author_name":"Alicia Huerta-Chagoya","author_inst":"Center for Genomic Medicine and Diabetes Unit, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Mass General Brigham, Boston, MA, USA"},{"author_name":"Steven E. Kahn","author_inst":"Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, WA, USA"},{"author_name":"Klara R. Klein","author_inst":"Division of Endocrinology and Metabolism, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA"},{"author_name":"Josep M. Mercader","author_inst":"Center for Genomic Medicine and Diabetes Unit, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Mass General Brigham, Boston, MA, USA"},{"author_name":"Neda Rasouli","author_inst":"Division of Endocrinology, Metabolism and Diabetes, University of Colorado, School of Medicine and VA Eastern Colorado Heath Care System, Aurora, CO, USA"},{"author_name":"Marjan Rezaei","author_inst":"Division of Endocrinology, Metabolism and Diabetes, University of Colorado, School of Medicine, Aurora, CO, USA"},{"author_name":"Maria J. Redondo","author_inst":"Department of Pediatrics, Diabetes and Endocrinology, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Ashok Balasubramanyam","author_inst":"Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Jose C. Florez","author_inst":"Center for Genomic Medicine and Diabetes Unit, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Mass General Brigham, Boston, MA, USA"},{"author_name":"Louis H. Philipson","author_inst":"Department of Medicine and Pediatrics, Section of Endocrinology, Diabetes, and Metabolism, the Kovler Diabetes Center, University of Chicago, Chicago, IL, USA"},{"author_name":"Jason Flannick","author_inst":"Diabetes Genetics Initiative and Programs in Metabolism and Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Divisio"},{"author_name":"Miriam S. Udler","author_inst":"Center for Genomic Medicine and Diabetes Unit, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Mass General Brigham, Boston, MA, USA"},{"author_name":"- RADIANT Study Group","author_inst":""}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"When Is Amyloid Really Cleared? Substantial Discordance Between Centiloid Quantification and Visual Reads of Amyloid PET after Amyloid-Targeting Therapy","rel_doi":"10.64898\/2026.10.03.26364642","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.03.26364642","rel_abs":"Amyloid-targeting therapies (ATTs) substantially reduce amyloid PET signal and slow clinical decline in early symptomatic Alzheimer disease. As ATTs enter clinical practice, PET may assess target engagement and guide treatment management, but there is no consensus on how to measure treatment-related amyloid clearance (TRAC). We compared Centiloid quantitation across pipelines and visual reads for interpreting pre- and post-ATT amyloid PET.\n\nMethodsWe analyzed 18F-florbetapir or 18F-florbetaben PET from 101 patients treated with lecanemab or donanemab: 88 pre-ATT and 54 post-ATT scans, including 41 paired scans. Centiloids were derived using FDA-cleared MIMneuro and two research pipelines (rPOP, CapAIBL) and compared using intraclass correlation coefficients (ICC). Clearance rates were estimated using linear mixed-effects models. Full TRAC was defined on post-ATT scans quantitatively (<11 Centiloids) or based on visual interpretation by 3 expert readers.\n\nResultsTreated patients were 74{+\/-}7 years old; 57% were female, 59% were apolipoprotein E {varepsilon}4 carriers, and 78% had mild cognitive impairment (22% mild dementia). Centiloid agreement between pipelines was equally high pre- and post-ATT (both ICCs=0.90). Among paired scans (mean treatment duration, 16.7{+\/-}4.6 months), clearance estimates were similar across pipelines and greater with donanemab (n=15 patients; between -62 and -60 Centiloids\/year depending on the pipeline) than lecanemab (n=26; -38 to -36 Centiloids\/year; all P<0.005). Among 54 post-ATT scans, between 44% and 57% were <11 Centiloids depending on pipeline, with 20 (37%) meeting this criterion across all 3 pipelines. In contrast, only 11%-19% were visually negative across readers, with 4 (7%) unanimously read as negative. Of the 20 post-ATT scans <11 Centiloids across all pipelines, 13 (65%) were considered positive by all readers, commonly with residual occipital binding.\n\nConclusionCentiloid quantitation was robust across pipelines before and after ATT initiation, yielding clearance rates consistent with clinical trials. However, quantitative and visual assessments were markedly discordant after ATT, with an unusually high proportion of scans <11 Centiloids remaining visually positive, warranting cautious interpretation of post-ATT Centiloid values. Larger studies should assess the clinical relevance of these findings and further develop robust approaches to establish full TRAC.","rel_num_authors":19,"rel_authors":[{"author_name":"Renaud La Joie","author_inst":"UCSF"},{"author_name":"Marlene Lin","author_inst":"UCSF"},{"author_name":"Yingbing Wang","author_inst":"UCSF"},{"author_name":"David N Soleimani-Meigooni","author_inst":"UCSF"},{"author_name":"Ganna Blazhenets","author_inst":"UCSF"},{"author_name":"Corrina S Fonseca","author_inst":"UCSF"},{"author_name":"Tara Ellingson","author_inst":"UCSF"},{"author_name":"Hong Nguyen","author_inst":"UCSF"},{"author_name":"Kambiz Nael","author_inst":"UCSF"},{"author_name":"Salil Soman","author_inst":"UCSF"},{"author_name":"Pierrick Bourgeat","author_inst":"CSIRO"},{"author_name":"Jake P Levy","author_inst":"UCSF"},{"author_name":"Gina Rhee","author_inst":"UCSF"},{"author_name":"Julio C Rojas","author_inst":"UCSF"},{"author_name":"Melanie Stephens","author_inst":"UCSF"},{"author_name":"Nhat Bui","author_inst":"UCSF"},{"author_name":"Peter A Ljubenkov","author_inst":"UCSF"},{"author_name":"Lawren VandeVrede","author_inst":"UCSF"},{"author_name":"Gil D Rabinovici","author_inst":"UCSF"}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"An adaptive technical and behavioral approach for biomarker acquisition in autism with intellectual disability","rel_doi":"10.64898\/2026.10.01.26364439","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.01.26364439","rel_abs":"Autistic individuals with intellectual disability (ASD+ID) and profound autism are rarely studied in neuroscience research due to barriers including communication challenges, sensory sensitivities, anxiety, and elevated behavioral support needs. Consequently, biomarker development in autism fails to include the portion of the autistic population with highest support needs and greatest potential to benefit from treatments derived from imminent advances in personalized medicine. Here we present a multimodal, participant-centered protocol for simultaneous electroencephalography (EEG) and eye-tracking (ET) acquisition to advance clinical trial readiness research in this underserved population. The protocol combines individualized behavioral supports and an adaptive EEG-ET acquisition platform. Pre-visit caregiver interviews informed participant-specific research plans, including customized visual supports, reinforcement strategies, and EEG net desensitization procedures. A gaze-contingent stimulus presentation system used participant-preferred videos to support attention to experimental stimuli and behavior consistent with data acquisition (e.g., refraining from movement) while dynamically adapting stimulus delivery based on visual engagement with the assay and real-time assessment of data quality. By quantifying attended trials in real time and prioritizing unattended stimulus classes, the paradigm maximizes acquisition efficiency to minimize participant burden. This approach was utilized to deploy candidate biomarkers with demonstrated replicability in the Autism Biomarkers Consortium for Clinical Trials (ABC-CT): the N170 event-related potential to faces, resting-state EEG, and visual attention to human faces (measured with ET). Feasibility was evaluated in 76 children with ASD+ID (M age = 8.76 years; IQ = 32.4) and a small comparison sample of 8 children with intellectual disability without autism (M age = 8.91 years; IQ = 45.9). Usable EEG data (>7 minutes) were acquired in 61% (ASD+ID) and 88% (ID) of participants, respectively. Sufficient ET data were obtained from 67% (ASD+ID) and 63% (ID) of participants, respectively. Findings demonstrate the feasibility of inclusive biomarker acquisition and provide a framework for expanding participation of individuals with ASD+ID and profound autism in neuroscience research. Ongoing research seeks to evaluate this approach in larger samples and to demonstrate feasibility in multisite research studies.","rel_num_authors":8,"rel_authors":[{"author_name":"Cassandra J Stevens","author_inst":"Schiefelbusch Institute for Life Span Studies, University of Kansas"},{"author_name":"Sara Eberle","author_inst":"Yale Child Study Center"},{"author_name":"Casey Carrow","author_inst":"Yale Child Study Center"},{"author_name":"Sherab Tsheringla","author_inst":"Yale Child Study Center"},{"author_name":"Christine Cukar-Capizzi","author_inst":"Yale Child Study Center"},{"author_name":"Julie  M. Wolf","author_inst":"Yale Child Study Center"},{"author_name":"Adam Naples","author_inst":"Yale Child Study Center"},{"author_name":"James McPartland","author_inst":"Yale Child Study Center"}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"An adaptive technical and behavioral approach for biomarker acquisition in autism with intellectual disability","rel_doi":"10.64898\/2026.10.01.26364439","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.01.26364439","rel_abs":"Autistic individuals with intellectual disability (ASD+ID) and profound autism are rarely studied in neuroscience research due to barriers including communication challenges, sensory sensitivities, anxiety, and elevated behavioral support needs. Consequently, biomarker development in autism fails to include the portion of the autistic population with highest support needs and greatest potential to benefit from treatments derived from imminent advances in personalized medicine. Here we present a multimodal, participant-centered protocol for simultaneous electroencephalography (EEG) and eye-tracking (ET) acquisition to advance clinical trial readiness research in this underserved population. The protocol combines individualized behavioral supports and an adaptive EEG-ET acquisition platform. Pre-visit caregiver interviews informed participant-specific research plans, including customized visual supports, reinforcement strategies, and EEG net desensitization procedures. A gaze-contingent stimulus presentation system used participant-preferred videos to support attention to experimental stimuli and behavior consistent with data acquisition (e.g., refraining from movement) while dynamically adapting stimulus delivery based on visual engagement with the assay and real-time assessment of data quality. By quantifying attended trials in real time and prioritizing unattended stimulus classes, the paradigm maximizes acquisition efficiency to minimize participant burden. This approach was utilized to deploy candidate biomarkers with demonstrated replicability in the Autism Biomarkers Consortium for Clinical Trials (ABC-CT): the N170 event-related potential to faces, resting-state EEG, and visual attention to human faces (measured with ET). Feasibility was evaluated in 76 children with ASD+ID (M age = 8.76 years; IQ = 32.4) and a small comparison sample of 8 children with intellectual disability without autism (M age = 8.91 years; IQ = 45.9). Usable EEG data (>7 minutes) were acquired in 61% (ASD+ID) and 88% (ID) of participants, respectively. Sufficient ET data were obtained from 67% (ASD+ID) and 63% (ID) of participants, respectively. Findings demonstrate the feasibility of inclusive biomarker acquisition and provide a framework for expanding participation of individuals with ASD+ID and profound autism in neuroscience research. Ongoing research seeks to evaluate this approach in larger samples and to demonstrate feasibility in multisite research studies.","rel_num_authors":8,"rel_authors":[{"author_name":"Cassandra J Stevens","author_inst":"Schiefelbusch Institute for Life Span Studies, University of Kansas"},{"author_name":"Sara Eberle","author_inst":"Yale Child Study Center"},{"author_name":"Casey Carrow","author_inst":"Yale Child Study Center"},{"author_name":"Sherab Tsheringla","author_inst":"Yale Child Study Center"},{"author_name":"Christine Cukar-Capizzi","author_inst":"Yale Child Study Center"},{"author_name":"Julie  M. Wolf","author_inst":"Yale Child Study Center"},{"author_name":"Adam Naples","author_inst":"Yale Child Study Center"},{"author_name":"James McPartland","author_inst":"Yale Child Study Center"}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"Social and behavioral risk factors are associated with age-related differences in sustained attention: A cross-sectional GradCPT analysis of the All of Us dataset","rel_doi":"10.64898\/2026.10.01.26364102","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.01.26364102","rel_abs":"BackgroundAttentional control declines with normal aging, yet the role of modifiable lifestyle factors in accelerating this decline remains incompletely characterised in large, diverse populations. We examined associations between four modifiable risk factors (smoking intensity, alcohol binge drinking, social satisfaction and blood pressure) and sustained attention performance in 13,866 adults drawn from the All of Us Research Program.\n\nMethodsCognitive performance was assessed using the Gradual-Onset Continuous Performance Task (GradCPT). A composite cognitive efficiency score was derived via principal component analysis of four GradCPT metrics: d' (perceptual sensitivity), response criterion, median reaction time and reaction time variability. Associations between cognitive efficiency and each risk factor were examined using multiple linear regression adjusted for age, sex and race\/ethnicity. Effect sizes were expressed as age-equivalent years of cognitive aging (age-equivalent years = regression coefficient for the risk factor divided by the regression coefficient for age) to aid clinical interpretation.\n\nResultsGradCPT performance declined progressively with age (p < 0.001). Social satisfaction emerged as the strongest lifestyle predictor: low social satisfaction was associated with approximately 5.8 additional age-equivalent years of cognitive aging relative to high social satisfaction. Smoking showed a dose-response pattern, with heavy smokers (> 20 cigarettes\/day) exhibiting an approximately 5-year age-equivalent deficit versus never-smokers. Stage 2 hypertension showed a modest, non-significant negative association. Binge drinking showed limited significant associations, likely complicated by survivor and abstainer biases. Bootstrapped analyses of combined exposures showed that combinations of risk factors, particularly those involving low social satisfaction, produced larger cognitive deficits than expected under an additive model.\n\nConclusionsThese findings support an interactive rather than a purely additive model of lifestyle-related cognitive vulnerability and highlight the GradCPT as a subclinical measure of attention-based cognitive risk in non-clinical populations.","rel_num_authors":4,"rel_authors":[{"author_name":"Natan M Coresh-Chiappori","author_inst":"Morgan State University"},{"author_name":"Theresa Boyer","author_inst":"Johns Hopkins University"},{"author_name":"A Richey Sharrett","author_inst":"Johns Hopkins University"},{"author_name":"Ingrid K Tulloch","author_inst":"Morgan State University"}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"Sex differences in genetic liability to modifiable Alzheimer's disease risk factors","rel_doi":"10.64898\/2026.10.01.26364536","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.01.26364536","rel_abs":"INTRODUCTIONAlzheimers disease (AD) shows sex differences in risk, clinical progression, and biomarker profiles, but whether inherited genetic liability to modifiable risk factors contributes differently to AD susceptibility in females and males remains unclear. We evaluated whether genetic relationships between several modifiable dementia risk factors and AD differ between females and males.\n\nMETHODSWe integrated polygenic risk scores (PRSs) for modifiable risk factors, genome-wide genetic correlation, and two-sample Mendelian randomization (MR) analyses. PRS associations with AD diagnosis were evaluated in the Alzheimers Disease Genetics Consortium (n=27,751) and with AD plasma biomarkers in the Health and Aging Brain Study-Health Disparities (n=2,307-2,737, depending on the biomarker). Primary analyses evaluated female- and male-specific associations and compared sex-specific estimates.\n\nRESULTSEducational attainment and physical activity PRSs were associated with AD in both sexes. PRS sex differences were nominal for educational attainment, total cholesterol, and LDL cholesterol, but none remained significant after FDR correction. Genetic correlation showed FDR-significant sex differences for social isolation, physical activity, LDL cholesterol, and pulse pressure. MR identified FDR-significant associations within sex strata; higher HDL cholesterol was associated with lower AD risk in females, whereas higher total cholesterol and type 2 diabetes were associated with lower and higher AD risk, respectively, in males. Sensitivity analyses provided inconsistent support, and no sex difference in MR estimates remained significant after FDR correction. In HABS-HD, type 2 diabetes PRS was associated with higher NfL, BMI PRS with higher pTau181, and the composite PRS with higher NfL among males after FDR correction.\n\nDISCUSSIONEvidence that modifiable dementia risk factors relate differently to AD by sex was limited and depended on the genetic measure examined. Sex differences in genome-wide genetic overlap were not consistently reflected in PRS or MR, indicating that shared genetic architecture does not necessarily translate into sex-specific inherited liability or causal effects\n\nRESEARCH IN CONTEXTO_ST_ABSSystematic reviewC_ST_ABSWe reviewed the published literature on modifiable dementia risk factors, Alzheimers disease (AD) genetics, and sex differences using PubMed and relevant reference lists. Previous studies support genetic relationships between several modifiable risk factors and AD, but systematic comparisons of female- and male-specific relationships across complementary genetic approaches remain limited.\n\nInterpretatioThe strongest evidence of sex heterogeneity for modifiable risk factors and AD was observed in their shared genetic architectures, with FDR-significant female-male differences for social isolation, physical activity, LDL cholesterol, and pulse pressure. PRS and Mendelian randomization analyses provided less evidence of formal sex heterogeneity, suggesting that sex differences in shared genetic architecture do not necessarily imply sex-specific causal effects.\n\nFuture directionsLarger sex-stratified and ancestry-diverse GWAS integrated with longitudinal exposure and biomarker data are needed to determine whether these signals reflect sex-dependent biological mechanisms and whether they have implications for dementia prevention.\n\nHighlights- Sex differences in AD-related genetic architecture were concentrated in behavioral, lipid, and vascular traits.\n- Genetic correlations with AD differed between females and males for social isolation, physical activity, LDL cholesterol, and pulse pressure.\n- PRS analyses implicated educational attainment and physical activity in AD in both sexes, but no PRS sex difference survived FDR correction.\n- MR identified associations within sex strata but provided little robust evidence of sex-specific causal effects.","rel_num_authors":10,"rel_authors":[{"author_name":"Rakshya U Sharma","author_inst":"University of California, San Francisco"},{"author_name":"Paulina Tolosa-Tort","author_inst":"University of California, San Francisco"},{"author_name":"Meri Okorie","author_inst":"University of California, San Francisco"},{"author_name":"Aadrita Chatterjee","author_inst":"University of California, San Francisco"},{"author_name":"Caroline Jonson","author_inst":"DataTecnica LLC"},{"author_name":"Kristine Yaffe","author_inst":"University of California San Francisco"},{"author_name":"Michael E Belloy","author_inst":"Washington University in St. Louis"},{"author_name":"Shea J Andrews","author_inst":"University of California San Francisco"},{"author_name":"- ADGC","author_inst":""},{"author_name":"- HABS-HD Study team","author_inst":""}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"Sex differences in genetic liability to modifiable Alzheimer's disease risk factors","rel_doi":"10.64898\/2026.10.01.26364536","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.01.26364536","rel_abs":"INTRODUCTIONAlzheimers disease (AD) shows sex differences in risk, clinical progression, and biomarker profiles, but whether inherited genetic liability to modifiable risk factors contributes differently to AD susceptibility in females and males remains unclear. We evaluated whether genetic relationships between several modifiable dementia risk factors and AD differ between females and males.\n\nMETHODSWe integrated polygenic risk scores (PRSs) for modifiable risk factors, genome-wide genetic correlation, and two-sample Mendelian randomization (MR) analyses. PRS associations with AD diagnosis were evaluated in the Alzheimers Disease Genetics Consortium (n=27,751) and with AD plasma biomarkers in the Health and Aging Brain Study-Health Disparities (n=2,307-2,737, depending on the biomarker). Primary analyses evaluated female- and male-specific associations and compared sex-specific estimates.\n\nRESULTSEducational attainment and physical activity PRSs were associated with AD in both sexes. PRS sex differences were nominal for educational attainment, total cholesterol, and LDL cholesterol, but none remained significant after FDR correction. Genetic correlation showed FDR-significant sex differences for social isolation, physical activity, LDL cholesterol, and pulse pressure. MR identified FDR-significant associations within sex strata; higher HDL cholesterol was associated with lower AD risk in females, whereas higher total cholesterol and type 2 diabetes were associated with lower and higher AD risk, respectively, in males. Sensitivity analyses provided inconsistent support, and no sex difference in MR estimates remained significant after FDR correction. In HABS-HD, type 2 diabetes PRS was associated with higher NfL, BMI PRS with higher pTau181, and the composite PRS with higher NfL among males after FDR correction.\n\nDISCUSSIONEvidence that modifiable dementia risk factors relate differently to AD by sex was limited and depended on the genetic measure examined. Sex differences in genome-wide genetic overlap were not consistently reflected in PRS or MR, indicating that shared genetic architecture does not necessarily translate into sex-specific inherited liability or causal effects\n\nRESEARCH IN CONTEXTO_ST_ABSSystematic reviewC_ST_ABSWe reviewed the published literature on modifiable dementia risk factors, Alzheimers disease (AD) genetics, and sex differences using PubMed and relevant reference lists. Previous studies support genetic relationships between several modifiable risk factors and AD, but systematic comparisons of female- and male-specific relationships across complementary genetic approaches remain limited.\n\nInterpretatioThe strongest evidence of sex heterogeneity for modifiable risk factors and AD was observed in their shared genetic architectures, with FDR-significant female-male differences for social isolation, physical activity, LDL cholesterol, and pulse pressure. PRS and Mendelian randomization analyses provided less evidence of formal sex heterogeneity, suggesting that sex differences in shared genetic architecture do not necessarily imply sex-specific causal effects.\n\nFuture directionsLarger sex-stratified and ancestry-diverse GWAS integrated with longitudinal exposure and biomarker data are needed to determine whether these signals reflect sex-dependent biological mechanisms and whether they have implications for dementia prevention.\n\nHighlights- Sex differences in AD-related genetic architecture were concentrated in behavioral, lipid, and vascular traits.\n- Genetic correlations with AD differed between females and males for social isolation, physical activity, LDL cholesterol, and pulse pressure.\n- PRS analyses implicated educational attainment and physical activity in AD in both sexes, but no PRS sex difference survived FDR correction.\n- MR identified associations within sex strata but provided little robust evidence of sex-specific causal effects.","rel_num_authors":10,"rel_authors":[{"author_name":"Rakshya U Sharma","author_inst":"University of California, San Francisco"},{"author_name":"Paulina Tolosa-Tort","author_inst":"University of California, San Francisco"},{"author_name":"Meri Okorie","author_inst":"University of California, San Francisco"},{"author_name":"Aadrita Chatterjee","author_inst":"University of California, San Francisco"},{"author_name":"Caroline Jonson","author_inst":"DataTecnica LLC"},{"author_name":"Kristine Yaffe","author_inst":"University of California San Francisco"},{"author_name":"Michael E Belloy","author_inst":"Washington University in St. Louis"},{"author_name":"Shea J Andrews","author_inst":"University of California San Francisco"},{"author_name":"- ADGC","author_inst":""},{"author_name":"- HABS-HD Study team","author_inst":""}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"A Modality-Invariant Measure of Neural Health","rel_doi":"10.64898\/2026.10.02.26364203","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.02.26364203","rel_abs":"Quantifying neural health with a single measure remains a major unmet challenge. Here, we report a physiological marker based on the spatial distribution of signal-derived energy correlates in the resting brain. We hypothesize that energy organization in the healthy brain approaches an entropy-maximizing, homeostatically regulated state characterized by five properties: lognormal energy distributions, balanced spatial allocation, statistical independence between regions, low energy variance, and temporal stability. Together, these properties define an energetic profile that the Neural Health Index (NHI) summarizes as a single score, computable from (scalp\/intracranial) electroencephalography, magnetoencephalography, or functional magnetic resonance imaging. Across 808 participants spanning neurological, psychiatric, neurodevelopmental, and neurodegenerative disorders, NHI distinguished healthy from clinical populations with sensitivity and specificity exceeding 95% in internal and external validation, scaled with disease severity, tracked pharmacological treatment exposure, and generalized to unseen diagnoses. These findings support NHI as a disease-agnostic, modality-invariant candidate biomarker for disease stratification and treatment monitoring.","rel_num_authors":5,"rel_authors":[{"author_name":"Luis A Sanchez Colon","author_inst":"Johns Hopkins University"},{"author_name":"Ernst Niebur","author_inst":"Johns Hopkins University"},{"author_name":"Joon Kang","author_inst":"Johns Hopkins University"},{"author_name":"Chiadi Onyike","author_inst":"Johns Hopkins University"},{"author_name":"Sridevi Sarma","author_inst":"Johns Hopkins University"}],"rel_date":"2026-10-06","rel_site":"medrxiv"},{"rel_title":"Estimating Hepatitis C Virus Prevalence in US States and the District of Columbia, 2017-2020","rel_doi":"10.64898\/2026.09.29.26364309","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.29.26364309","rel_abs":"BackgroundState-level estimates of hepatitis C virus (HCV) prevalence are needed to guide resource allocation and to provide a baseline against which to measure progress toward elimination goals. Population prevalence is not directly observable, requiring estimation from indirect data sources.\n\nMethodsWe adapted a Bayesian spatial integrated abundance model to estimate state-level HCV prevalence during 2017-2020 across 48 states and the District of Columbia. The model integrated six HCV-related outcomes: acute and chronic surveillance cases, HCV-related deaths, observations of HCV in [MarketScan] administrative claims data, diagnoses of HCV in Medicaid recipients, and treatment with direct-acting antivirals in Medicaid recipients. Estimates were anchored to a national prevalence estimate, and the model accounted for data source-specific selection, heterogeneity in HCV risk factors across states, and geospatial correlation.\n\nResultsEstimated average prevalence was 1.32% (95% credible interval [CrI]: 0.94%-1.80%), corresponding to 3.33 million (95% CrI: 2.37-4.65 million) adults with HCV infection across 48 states and DC. State estimates ranged from 0.74% in North Dakota to 2.22% in Oklahoma (median state-specific prevalence, 1.27%), with higher prevalence concentrated in South Central states, Appalachia, and the West, and the lower prevalence in the upper Midwest, Southeast, and New England. Ten states accounted for 56% of estimated infections. Estimates were stable in sensitivity analyses (most differences <1 percentage point).\n\nConclusionsThese estimates quantify state-level HCV burden prior to the 2021 federal expansion of HCV surveillance funding, providing a baseline for monitoring elimination progress. Geographic variation indicates that resource needs will differ by jurisdiction.","rel_num_authors":6,"rel_authors":[{"author_name":"Heather Bradley","author_inst":"Emory University"},{"author_name":"Ya-Hui Yu","author_inst":"Emory University"},{"author_name":"Lanxin Li","author_inst":"University of Edinburgh"},{"author_name":"Shashi N Kapadia","author_inst":"Weill Cornell Medicine"},{"author_name":"Patrick S Sullivan","author_inst":"Emory University"},{"author_name":"Eric William Hall","author_inst":"Oregon Health & Science University"}],"rel_date":"2026-10-05","rel_site":"medrxiv"},{"rel_title":"Measuring enteric pathogen force of infection through antibody responses in children","rel_doi":"10.64898\/2026.09.29.26364344","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.29.26364344","rel_abs":"Enteric pathogens account for a substantial global disease burden, yet population-based surveillance remains limited by the transient nature of pathogen shedding, which constrains the sensitivity of stool-based molecular testing to a narrow detection window. Detection of IgG responses in serological surveys could enable new insights into enteric pathogen transmission, but benchmarking serological measures relative to stool-based measures of infection remains a critical evidence gap. We compared measures of disease transmission in longitudinal birth cohort samples using multiplex IgG (1,601 dried blood spots, 370 children) and PCR assays (2,231 stool samples, 370 children) that overlapped for nine pathogens (norovirus GI, GII, Shigella\/enteroinvasive Escherichia coli (EIEC), Campylobacter spp., enterotoxigenic Escherichia coli (LT-ETEC), Salmonella enterica, Giardia spp., Cryptosporidium spp., Entamoeba histolytica). LT-ETEC and Campylobacter ranked highest while E. histolytica and S. enterica ranked lowest by both IgG and PCR measures of infection. Measures of infection were less aligned for norovirus GI, norovirus GII, Cryptosporidium, Shigella\/EIEC, and Giardia. Despite this, for most pathogens, and across both measures, force of infection was lowest in the urban city of Esmeraldas and substantially higher in more rural populations, with relative risks in assay measures (seroconversion rate and PCR detected prevalence) over 2.0 for pathogens with the largest differences (Shigella\/EIEC and norovirus GI). Together, our results suggest that although absolute levels of infection differed between assays, IgG and PCR captured consistent relative risk of infection across geographic strata, suggesting either method can identify high-versus low-transmission settings.","rel_num_authors":25,"rel_authors":[{"author_name":"Nikolina Walas","author_inst":"Francis I. Proctor Foundation, University of California, San Francisco, CA, USA"},{"author_name":"Lesly Simba\u00f1a Vivanco","author_inst":"Institute of Microbiology, Colegio de Ciencias Biol\u00f3gicas y Ambientales, Universidad San Francisco de Quito, Quito, Ecuador"},{"author_name":"Stuart Torres Ayala","author_inst":"Institute of Microbiology, Colegio de Ciencias Biol\u00f3gicas y Ambientales, Universidad San Francisco de Quito, Quito, Ecuador"},{"author_name":"Chabier Coleman","author_inst":"Independent consultant"},{"author_name":"E. Brook Goodhew","author_inst":"Independent consultant"},{"author_name":"Kelsey J. Jesser","author_inst":"Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Nicolette A. Zhou","author_inst":"Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Christine S. Fagnant-Sperati","author_inst":"Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Jesse Contreras","author_inst":"Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Caitlin Hemlock","author_inst":"Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Jeffrey W. Priest","author_inst":"Retired"},{"author_name":"Richelle C. Charles","author_inst":"Massachusetts General Hospital, Harvard Medical School, Harvard T.H. Chan School of Public Health, Boston, MA, USA"},{"author_name":"Edward T. Ryan","author_inst":"Massachusetts General Hospital, Harvard Medical School, Harvard T.H. Chan School of Public Health, Boston, MA, USA"},{"author_name":"Claire Munroe","author_inst":"Massachusetts General Hospital, Harvard Medical School, Harvard T.H. Chan School of Public Health, Boston, MA, USA"},{"author_name":"Robert L. Atmar","author_inst":"Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Julianna Colado","author_inst":"Francis I. Proctor Foundation, University of California, San Francisco, CA, USA"},{"author_name":"Hadley Burroughs","author_inst":"Francis I. Proctor Foundation, University of California, San Francisco, CA, USA"},{"author_name":"Manuel Calvopi\u00f1a","author_inst":"Universidad de las Am\u00e9ricas, Facultad de Medicina, Carrera de Medicina, Quito, Ecuador"},{"author_name":"William Cevallos","author_inst":"Universidad Central del Ecuador, Instituto de Biomedicina, Quito, Ecuador"},{"author_name":"Josefina Coloma","author_inst":"School of Public Health, University of California, Berkeley, CA, USA"},{"author_name":"Gwenyth O. Lee","author_inst":"Rutgers Global Health Institute and Department of Biostatistics and Epidemiology, School of Public Health, Rutgers University, New Brunswick, NJ, USA"},{"author_name":"Gabriel Trueba","author_inst":"Institute of Microbiology, Colegio de Ciencias Biol\u00f3gicas y Ambientales, Universidad San Francisco de Quito, Quito, Ecuador"},{"author_name":"Joseph N.S. Eisenberg","author_inst":"Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Karen Levy","author_inst":"Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Benjamin F. Arnold","author_inst":"Francis I. Proctor Foundation, University of California, San Francisco, CA, USA"}],"rel_date":"2026-10-05","rel_site":"medrxiv"},{"rel_title":"Measuring enteric pathogen force of infection through antibody responses in children","rel_doi":"10.64898\/2026.09.29.26364344","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.29.26364344","rel_abs":"Enteric pathogens account for a substantial global disease burden, yet population-based surveillance remains limited by the transient nature of pathogen shedding, which constrains the sensitivity of stool-based molecular testing to a narrow detection window. Detection of IgG responses in serological surveys could enable new insights into enteric pathogen transmission, but benchmarking serological measures relative to stool-based measures of infection remains a critical evidence gap. We compared measures of disease transmission in longitudinal birth cohort samples using multiplex IgG (1,601 dried blood spots, 370 children) and PCR assays (2,231 stool samples, 370 children) that overlapped for nine pathogens (norovirus GI, GII, Shigella\/enteroinvasive Escherichia coli (EIEC), Campylobacter spp., enterotoxigenic Escherichia coli (LT-ETEC), Salmonella enterica, Giardia spp., Cryptosporidium spp., Entamoeba histolytica). LT-ETEC and Campylobacter ranked highest while E. histolytica and S. enterica ranked lowest by both IgG and PCR measures of infection. Measures of infection were less aligned for norovirus GI, norovirus GII, Cryptosporidium, Shigella\/EIEC, and Giardia. Despite this, for most pathogens, and across both measures, force of infection was lowest in the urban city of Esmeraldas and substantially higher in more rural populations, with relative risks in assay measures (seroconversion rate and PCR detected prevalence) over 2.0 for pathogens with the largest differences (Shigella\/EIEC and norovirus GI). Together, our results suggest that although absolute levels of infection differed between assays, IgG and PCR captured consistent relative risk of infection across geographic strata, suggesting either method can identify high-versus low-transmission settings.","rel_num_authors":25,"rel_authors":[{"author_name":"Nikolina Walas","author_inst":"Francis I. Proctor Foundation, University of California, San Francisco, CA, USA"},{"author_name":"Lesly Simba\u00f1a Vivanco","author_inst":"Institute of Microbiology, Colegio de Ciencias Biol\u00f3gicas y Ambientales, Universidad San Francisco de Quito, Quito, Ecuador"},{"author_name":"Stuart Torres Ayala","author_inst":"Institute of Microbiology, Colegio de Ciencias Biol\u00f3gicas y Ambientales, Universidad San Francisco de Quito, Quito, Ecuador"},{"author_name":"Chabier Coleman","author_inst":"Independent consultant"},{"author_name":"E. Brook Goodhew","author_inst":"Independent consultant"},{"author_name":"Kelsey J. Jesser","author_inst":"Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Nicolette A. Zhou","author_inst":"Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Christine S. Fagnant-Sperati","author_inst":"Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Jesse Contreras","author_inst":"Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Caitlin Hemlock","author_inst":"Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Jeffrey W. Priest","author_inst":"Retired"},{"author_name":"Richelle C. Charles","author_inst":"Massachusetts General Hospital, Harvard Medical School, Harvard T.H. Chan School of Public Health, Boston, MA, USA"},{"author_name":"Edward T. Ryan","author_inst":"Massachusetts General Hospital, Harvard Medical School, Harvard T.H. Chan School of Public Health, Boston, MA, USA"},{"author_name":"Claire Munroe","author_inst":"Massachusetts General Hospital, Harvard Medical School, Harvard T.H. Chan School of Public Health, Boston, MA, USA"},{"author_name":"Robert L. Atmar","author_inst":"Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Julianna Colado","author_inst":"Francis I. Proctor Foundation, University of California, San Francisco, CA, USA"},{"author_name":"Hadley Burroughs","author_inst":"Francis I. Proctor Foundation, University of California, San Francisco, CA, USA"},{"author_name":"Manuel Calvopi\u00f1a","author_inst":"Universidad de las Am\u00e9ricas, Facultad de Medicina, Carrera de Medicina, Quito, Ecuador"},{"author_name":"William Cevallos","author_inst":"Universidad Central del Ecuador, Instituto de Biomedicina, Quito, Ecuador"},{"author_name":"Josefina Coloma","author_inst":"School of Public Health, University of California, Berkeley, CA, USA"},{"author_name":"Gwenyth O. Lee","author_inst":"Rutgers Global Health Institute and Department of Biostatistics and Epidemiology, School of Public Health, Rutgers University, New Brunswick, NJ, USA"},{"author_name":"Gabriel Trueba","author_inst":"Institute of Microbiology, Colegio de Ciencias Biol\u00f3gicas y Ambientales, Universidad San Francisco de Quito, Quito, Ecuador"},{"author_name":"Joseph N.S. Eisenberg","author_inst":"Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Karen Levy","author_inst":"Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Benjamin F. Arnold","author_inst":"Francis I. Proctor Foundation, University of California, San Francisco, CA, USA"}],"rel_date":"2026-10-05","rel_site":"medrxiv"},{"rel_title":"Measuring enteric pathogen force of infection through antibody responses in children","rel_doi":"10.64898\/2026.09.29.26364344","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.29.26364344","rel_abs":"Enteric pathogens account for a substantial global disease burden, yet population-based surveillance remains limited by the transient nature of pathogen shedding, which constrains the sensitivity of stool-based molecular testing to a narrow detection window. Detection of IgG responses in serological surveys could enable new insights into enteric pathogen transmission, but benchmarking serological measures relative to stool-based measures of infection remains a critical evidence gap. We compared measures of disease transmission in longitudinal birth cohort samples using multiplex IgG (1,601 dried blood spots, 370 children) and PCR assays (2,231 stool samples, 370 children) that overlapped for nine pathogens (norovirus GI, GII, Shigella\/enteroinvasive Escherichia coli (EIEC), Campylobacter spp., enterotoxigenic Escherichia coli (LT-ETEC), Salmonella enterica, Giardia spp., Cryptosporidium spp., Entamoeba histolytica). LT-ETEC and Campylobacter ranked highest while E. histolytica and S. enterica ranked lowest by both IgG and PCR measures of infection. Measures of infection were less aligned for norovirus GI, norovirus GII, Cryptosporidium, Shigella\/EIEC, and Giardia. Despite this, for most pathogens, and across both measures, force of infection was lowest in the urban city of Esmeraldas and substantially higher in more rural populations, with relative risks in assay measures (seroconversion rate and PCR detected prevalence) over 2.0 for pathogens with the largest differences (Shigella\/EIEC and norovirus GI). Together, our results suggest that although absolute levels of infection differed between assays, IgG and PCR captured consistent relative risk of infection across geographic strata, suggesting either method can identify high-versus low-transmission settings.","rel_num_authors":25,"rel_authors":[{"author_name":"Nikolina Walas","author_inst":"Francis I. Proctor Foundation, University of California, San Francisco, CA, USA"},{"author_name":"Lesly Simba\u00f1a Vivanco","author_inst":"Institute of Microbiology, Colegio de Ciencias Biol\u00f3gicas y Ambientales, Universidad San Francisco de Quito, Quito, Ecuador"},{"author_name":"Stuart Torres Ayala","author_inst":"Institute of Microbiology, Colegio de Ciencias Biol\u00f3gicas y Ambientales, Universidad San Francisco de Quito, Quito, Ecuador"},{"author_name":"Chabier Coleman","author_inst":"Independent consultant"},{"author_name":"E. Brook Goodhew","author_inst":"Independent consultant"},{"author_name":"Kelsey J. Jesser","author_inst":"Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Nicolette A. Zhou","author_inst":"Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Christine S. Fagnant-Sperati","author_inst":"Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Jesse Contreras","author_inst":"Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Caitlin Hemlock","author_inst":"Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Jeffrey W. Priest","author_inst":"Retired"},{"author_name":"Richelle C. Charles","author_inst":"Massachusetts General Hospital, Harvard Medical School, Harvard T.H. Chan School of Public Health, Boston, MA, USA"},{"author_name":"Edward T. Ryan","author_inst":"Massachusetts General Hospital, Harvard Medical School, Harvard T.H. Chan School of Public Health, Boston, MA, USA"},{"author_name":"Claire Munroe","author_inst":"Massachusetts General Hospital, Harvard Medical School, Harvard T.H. Chan School of Public Health, Boston, MA, USA"},{"author_name":"Robert L. Atmar","author_inst":"Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Julianna Colado","author_inst":"Francis I. Proctor Foundation, University of California, San Francisco, CA, USA"},{"author_name":"Hadley Burroughs","author_inst":"Francis I. Proctor Foundation, University of California, San Francisco, CA, USA"},{"author_name":"Manuel Calvopi\u00f1a","author_inst":"Universidad de las Am\u00e9ricas, Facultad de Medicina, Carrera de Medicina, Quito, Ecuador"},{"author_name":"William Cevallos","author_inst":"Universidad Central del Ecuador, Instituto de Biomedicina, Quito, Ecuador"},{"author_name":"Josefina Coloma","author_inst":"School of Public Health, University of California, Berkeley, CA, USA"},{"author_name":"Gwenyth O. Lee","author_inst":"Rutgers Global Health Institute and Department of Biostatistics and Epidemiology, School of Public Health, Rutgers University, New Brunswick, NJ, USA"},{"author_name":"Gabriel Trueba","author_inst":"Institute of Microbiology, Colegio de Ciencias Biol\u00f3gicas y Ambientales, Universidad San Francisco de Quito, Quito, Ecuador"},{"author_name":"Joseph N.S. Eisenberg","author_inst":"Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Karen Levy","author_inst":"Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA"},{"author_name":"Benjamin F. Arnold","author_inst":"Francis I. Proctor Foundation, University of California, San Francisco, CA, USA"}],"rel_date":"2026-10-05","rel_site":"medrxiv"},{"rel_title":"Escaping the Negative Attentional Bias in Depression with Real-Time Neurofeedback","rel_doi":"10.64898\/2026.09.30.26363896","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.30.26363896","rel_abs":"Individuals with major depressive disorder (MDD) show an attentional bias toward negatively valenced stimuli and thoughts. In this study, we applied a closed-loop neurofeedback procedure designed to reduce this bias. Participants were shown composite negative faces and neutral scenes with variable opacity and were instructed to attend to the neutral scene while ignoring the negative face. Internal attentional states were decoded in real time from functional magnetic resonance imaging (fMRI) data. When a participants decoded attentional state indicated a failure to ignore the negative faces, the faces became more visible (higher opacity), thus externalizing the brains attentional lapse in that moment. Forty-eight individuals with MDD were randomly assigned to a real neurofeedback training group (N = 24) or a sham control group (N = 24); the control group received feedback yoked to a participant in the real group. All participants completed three fMRI neurofeedback sessions. The main outcome quantified the extent to which participants got \"stuck\" in the most negative attentional state of focusing strongly on the negative faces. We hypothesized that the real neurofeedback group would learn to escape that state by the end of training, relative to the sham control group. Consistent with our hypothesis, neurofeedback training reduced the probability of getting stuck in the most negative attentional state. In offline analyses, training reduced fMRI activity in the precuneus\/posterior cingulate and the medial prefrontal cortex when participants successfully attended to scenes and ignored faces. These results demonstrate the efficacy of remediating the negative attentional bias in depression with closed-loop neurofeedback from real-time fMRI.","rel_num_authors":9,"rel_authors":[{"author_name":"Nitzan Lubianiker","author_inst":"Department of Psychology, Yale University, New Haven, CT, USA"},{"author_name":"Brendan Woods","author_inst":"Center for Neuromodulation in Depression and Stress, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Frederick Nitchie","author_inst":"Center for Neuromodulation in Depression and Stress, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Alexandra Batzdorf","author_inst":"Center for Neuromodulation in Depression and Stress, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Anne Mennen","author_inst":"Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA"},{"author_name":"Qi Lin","author_inst":"Center for Neuroscience Imaging Research, Institute for Basic Science, Suwon, South Korea"},{"author_name":"Kenneth A. Norman","author_inst":"Princeton Neuroscience Institute, Princeton University, Princeton, NJ, USA"},{"author_name":"Nicholas B. Turk-Browne","author_inst":"Department of Psychology, Yale University, New Haven, CT, USA"},{"author_name":"Yvette I. Sheline","author_inst":"Center for Neuromodulation in Depression and Stress, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"rel_date":"2026-10-05","rel_site":"medrxiv"},{"rel_title":"Metabolic Signatures of Resistance to Mycobacterium Tuberculosis Infection: Insights from a Multi-Country Plasma Metabolomics Study","rel_doi":"10.64898\/2026.09.29.26364337","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.29.26364337","rel_abs":"BackgroundTuberculosis (TB) remains the leading infectious disease cause of mortality worldwide. A subset of individuals exposed to Mycobacterium tuberculosis (Mtb) remain TST\/IGRA-negative despite sustained exposure, termed \"TB resisters\". The biological mechanisms underlying this resistance remain poorly understood. We applied untargeted high-resolution metabolomics to determine whether systemic metabolic profiles differ between TB resisters and matched Mtb-infected close contacts.\n\nMethodsWe compared untargeted high-resolution plasma metabolomics using liquid chromatography mass spectrometry between 269 TB resisters and 269 matched Mtb-infected close contacts, enrolled across Brazil, India, and South Africa. TB resisters were defined as highly exposed close contacts who slept in the same room or spent at least 5 hours indoors per day with an infectious pulmonary TB index patient, but remained TST\/IGRA-negative. Mtb-infected close contacts were those who were TST\/IGRA positive. Metabolome-wide association studies (MWAS) were conducted using paired t-tests.\n\nResultsThere were 1,787 features with nominal differences between TB resisters and matched Mtb-infected contacts (p < 0.05). Pathway enrichment identified fructose and mannose metabolism and bile acid biosynthesis in the overall cohort, while lipid-related pathways were enriched in Brazil. Among metabolites with confirmed chemical identities, glyceric acid concentrations were higher in TB resisters by 0.53 {micro}M, whereas hydroxyproline was lower by 0.90 {micro}M, butyrobetaine was lower by 0.06 {micro}M, and homogentisate was lower by 0.0036 {micro}M at false discovery rate of 0.2.\n\nConclusionsPlasma metabolomic profiles differed between TB resisters and matched Mtb-infected close contacts. These findings indicate that systemic metabolic differences are associated with resistance to Mtb infection.","rel_num_authors":22,"rel_authors":[{"author_name":"Chang Liu","author_inst":"Emory University School of Public Health"},{"author_name":"Jeffrey  M. Collins","author_inst":"Emory University School of Medicine"},{"author_name":"Matheus Fernandes Gyorfy","author_inst":"Emory University"},{"author_name":"Mariana Araujo Pereira","author_inst":"Fundacao Oswaldo Cruz"},{"author_name":"Vidya Mave","author_inst":"Johns Hopkins University"},{"author_name":"Senbagavalli Prakash","author_inst":"Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India"},{"author_name":"Kamakshi Prudhula Devalraju","author_inst":"Bhagwan Mahavir Medical Research Centre, Hyderabad, India"},{"author_name":"Neil A. Martinson","author_inst":"Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa"},{"author_name":"Fay Willis","author_inst":"Emory University"},{"author_name":"Marina  C Figueiredo","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Marcelo Cordeiro-Santos","author_inst":"Universidade do Estado do Amazonas, Manaus, Brazil"},{"author_name":"Artur Trancoso Lopo de Queiroz","author_inst":"Laboratorio de Pesquisa Clinica e Translacional, Instituto Goncalo Moniz, Fundacao Oswaldo Cruz, Salvador, Brazil"},{"author_name":"Venkata Sanjeev Kumar Neela","author_inst":"Bhagwan Mahavir Medical Research Centre, Hyderabad, India"},{"author_name":"Rajesh Karyakarte","author_inst":"BJ Government Medical College, Pune"},{"author_name":"Timothy R Sterling","author_inst":"Vanderbilt University"},{"author_name":"Jerrold J. Ellner","author_inst":"Department of Medicine, Division of Infectious Diseases, Rutgers New Jersey Medical School, Rutgers Health, Newark, New Jersey, USA"},{"author_name":"James C.M. Brust","author_inst":"Division of General Internal Medicine, Albert Einstein College of Medicine, Bronx, NY, USA"},{"author_name":"Amita Gupta","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Bruno  B Andrade","author_inst":"FIOCRUZ Bahia: Instituto Goncalo Moniz"},{"author_name":"Yan V. Sun","author_inst":"Emory University"},{"author_name":"Neel  R. Gandhi","author_inst":"Emory University School of Public Health"},{"author_name":"- TB GWAS collaboration","author_inst":""}],"rel_date":"2026-10-05","rel_site":"medrxiv"},{"rel_title":"Metabolic Signatures of Resistance to Mycobacterium Tuberculosis Infection: Insights from a Multi-Country Plasma Metabolomics Study","rel_doi":"10.64898\/2026.09.29.26364337","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.29.26364337","rel_abs":"BackgroundTuberculosis (TB) remains the leading infectious disease cause of mortality worldwide. A subset of individuals exposed to Mycobacterium tuberculosis (Mtb) remain TST\/IGRA-negative despite sustained exposure, termed \"TB resisters\". The biological mechanisms underlying this resistance remain poorly understood. We applied untargeted high-resolution metabolomics to determine whether systemic metabolic profiles differ between TB resisters and matched Mtb-infected close contacts.\n\nMethodsWe compared untargeted high-resolution plasma metabolomics using liquid chromatography mass spectrometry between 269 TB resisters and 269 matched Mtb-infected close contacts, enrolled across Brazil, India, and South Africa. TB resisters were defined as highly exposed close contacts who slept in the same room or spent at least 5 hours indoors per day with an infectious pulmonary TB index patient, but remained TST\/IGRA-negative. Mtb-infected close contacts were those who were TST\/IGRA positive. Metabolome-wide association studies (MWAS) were conducted using paired t-tests.\n\nResultsThere were 1,787 features with nominal differences between TB resisters and matched Mtb-infected contacts (p < 0.05). Pathway enrichment identified fructose and mannose metabolism and bile acid biosynthesis in the overall cohort, while lipid-related pathways were enriched in Brazil. Among metabolites with confirmed chemical identities, glyceric acid concentrations were higher in TB resisters by 0.53 {micro}M, whereas hydroxyproline was lower by 0.90 {micro}M, butyrobetaine was lower by 0.06 {micro}M, and homogentisate was lower by 0.0036 {micro}M at false discovery rate of 0.2.\n\nConclusionsPlasma metabolomic profiles differed between TB resisters and matched Mtb-infected close contacts. These findings indicate that systemic metabolic differences are associated with resistance to Mtb infection.","rel_num_authors":22,"rel_authors":[{"author_name":"Chang Liu","author_inst":"Emory University School of Public Health"},{"author_name":"Jeffrey  M. Collins","author_inst":"Emory University School of Medicine"},{"author_name":"Matheus Fernandes Gyorfy","author_inst":"Emory University"},{"author_name":"Mariana Araujo Pereira","author_inst":"Fundacao Oswaldo Cruz"},{"author_name":"Vidya Mave","author_inst":"Johns Hopkins University"},{"author_name":"Senbagavalli Prakash","author_inst":"Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India"},{"author_name":"Kamakshi Prudhula Devalraju","author_inst":"Bhagwan Mahavir Medical Research Centre, Hyderabad, India"},{"author_name":"Neil A. Martinson","author_inst":"Perinatal HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa"},{"author_name":"Fay Willis","author_inst":"Emory University"},{"author_name":"Marina  C Figueiredo","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Marcelo Cordeiro-Santos","author_inst":"Universidade do Estado do Amazonas, Manaus, Brazil"},{"author_name":"Artur Trancoso Lopo de Queiroz","author_inst":"Laboratorio de Pesquisa Clinica e Translacional, Instituto Goncalo Moniz, Fundacao Oswaldo Cruz, Salvador, Brazil"},{"author_name":"Venkata Sanjeev Kumar Neela","author_inst":"Bhagwan Mahavir Medical Research Centre, Hyderabad, India"},{"author_name":"Rajesh Karyakarte","author_inst":"BJ Government Medical College, Pune"},{"author_name":"Timothy R Sterling","author_inst":"Vanderbilt University"},{"author_name":"Jerrold J. Ellner","author_inst":"Department of Medicine, Division of Infectious Diseases, Rutgers New Jersey Medical School, Rutgers Health, Newark, New Jersey, USA"},{"author_name":"James C.M. Brust","author_inst":"Division of General Internal Medicine, Albert Einstein College of Medicine, Bronx, NY, USA"},{"author_name":"Amita Gupta","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Bruno  B Andrade","author_inst":"FIOCRUZ Bahia: Instituto Goncalo Moniz"},{"author_name":"Yan V. Sun","author_inst":"Emory University"},{"author_name":"Neel  R. Gandhi","author_inst":"Emory University School of Public Health"},{"author_name":"- TB GWAS collaboration","author_inst":""}],"rel_date":"2026-10-05","rel_site":"medrxiv"}]}