{"gname":"University of Sydney","grp_id":"50","rels":[{"rel_title":"Sociodemographic and health correlates of reimbursement authorizations for cannabis for medical purposes in Canadian veterans: A cross-sectional study linking the Life After Services Studies 2019 and Health Administrative Databases","rel_doi":"10.64898\/2026.06.10.26355368","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355368","rel_abs":"Background Evidence on factors associated with cannabis for medical purposes (CMP) authorizations among Veterans Affairs Canada (VAC) clients remains limited and inconsistent, particularly concerning mental health and posttraumatic stress disorder (PTSD), a leading indication for use. We investigated demographic, clinical and service characteristics associated with VAC authorizations for CMP reimbursement. Method We linked VAC administrative CMP program data with responses from the 2019 Life After Services Studies cross-sectional survey of Regular Force veterans released between 1998 and 2018. Multivariable logistic regressions examined associations between CMP reimbursement (yes\/no) and demographic, clinical and well-being factors, with analyses stratified by PTSD status. Results Among 1,289 respondents (weighted n=33,131), 18.4% were authorized for CMP reimbursement. Younger age (<40 vs. [&ge;]60 years: OR 4.78, 95% CI: 2.24-10.21), unemployment with inability to work vs. employed (OR 3.10, 95% CI: 1.78-5.40), land service vs. air (OR 2.07, 95% CI: 1.22-3.50), PTSD (OR 2.81, 95% CI: 1.69-4.66), anxiety (OR 2.32, 95% CI: 1.45-3.70), and severe pain vs. no pain (OR 3.61, 95% CI: 1.97-6.60) were independently associated with authorization. Unemployment and severe pain were consistent correlates across PTSD strata. Among those without PTSD, younger age, multiple physical conditions, and frequent mental health visits were significant; among those with PTSD, shorter service, witnessing destruction, and suicidal ideation were additional factors. Conclusions CMP authorization patterns among Canadian veterans reflect the intersection of mental health, pain, and functional impairment, with variation by PTSD status. These findings underscore the need for longitudinal research on CMP mechanisms, effectiveness and safety.","rel_num_authors":12,"rel_authors":[{"author_name":"Tetyana Kendzerska","author_inst":"University of Ottawa"},{"author_name":"Juli\u00e1n Reyes","author_inst":"Veterans Affairs Canada"},{"author_name":"Noah Poirier","author_inst":"Veterans Affairs Canada"},{"author_name":"Alain Poirier","author_inst":"Veterans Affairs Canada"},{"author_name":"Alex Cull","author_inst":"Veterans Affairs Canada"},{"author_name":"Anthony Murkar","author_inst":"University of Ottawa"},{"author_name":"Mouaz Saymeh","author_inst":"Ottawa Hospital Research Institute"},{"author_name":"Stephanie Belanger","author_inst":"College Militaire Royal du Canada: Royal Military College of Canada"},{"author_name":"Monnica Williams","author_inst":"University of Ottawa"},{"author_name":"Jakov Shlik","author_inst":"University of Ottawa Faculty of Graduate and Postdoctoral Studies: University of Ottawa"},{"author_name":"Rakesh Jetly","author_inst":"University of Ottawa"},{"author_name":"Rebecca Robillard","author_inst":"University of Ottawa"}],"rel_date":"2026-06-12","rel_site":"medrxiv"},{"rel_title":"Sociodemographic and health correlates of reimbursement authorizations for cannabis for medical purposes in Canadian veterans: A cross-sectional study linking the Life After Services Studies 2019 and Health Administrative Databases","rel_doi":"10.64898\/2026.06.10.26355368","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355368","rel_abs":"Background Evidence on factors associated with cannabis for medical purposes (CMP) authorizations among Veterans Affairs Canada (VAC) clients remains limited and inconsistent, particularly concerning mental health and posttraumatic stress disorder (PTSD), a leading indication for use. We investigated demographic, clinical and service characteristics associated with VAC authorizations for CMP reimbursement. Method We linked VAC administrative CMP program data with responses from the 2019 Life After Services Studies cross-sectional survey of Regular Force veterans released between 1998 and 2018. Multivariable logistic regressions examined associations between CMP reimbursement (yes\/no) and demographic, clinical and well-being factors, with analyses stratified by PTSD status. Results Among 1,289 respondents (weighted n=33,131), 18.4% were authorized for CMP reimbursement. Younger age (<40 vs. [&ge;]60 years: OR 4.78, 95% CI: 2.24-10.21), unemployment with inability to work vs. employed (OR 3.10, 95% CI: 1.78-5.40), land service vs. air (OR 2.07, 95% CI: 1.22-3.50), PTSD (OR 2.81, 95% CI: 1.69-4.66), anxiety (OR 2.32, 95% CI: 1.45-3.70), and severe pain vs. no pain (OR 3.61, 95% CI: 1.97-6.60) were independently associated with authorization. Unemployment and severe pain were consistent correlates across PTSD strata. Among those without PTSD, younger age, multiple physical conditions, and frequent mental health visits were significant; among those with PTSD, shorter service, witnessing destruction, and suicidal ideation were additional factors. Conclusions CMP authorization patterns among Canadian veterans reflect the intersection of mental health, pain, and functional impairment, with variation by PTSD status. These findings underscore the need for longitudinal research on CMP mechanisms, effectiveness and safety.","rel_num_authors":12,"rel_authors":[{"author_name":"Tetyana Kendzerska","author_inst":"University of Ottawa"},{"author_name":"Juli\u00e1n Reyes","author_inst":"Veterans Affairs Canada"},{"author_name":"Noah Poirier","author_inst":"Veterans Affairs Canada"},{"author_name":"Alain Poirier","author_inst":"Veterans Affairs Canada"},{"author_name":"Alex Cull","author_inst":"Veterans Affairs Canada"},{"author_name":"Anthony Murkar","author_inst":"University of Ottawa"},{"author_name":"Mouaz Saymeh","author_inst":"Ottawa Hospital Research Institute"},{"author_name":"Stephanie Belanger","author_inst":"College Militaire Royal du Canada: Royal Military College of Canada"},{"author_name":"Monnica Williams","author_inst":"University of Ottawa"},{"author_name":"Jakov Shlik","author_inst":"University of Ottawa Faculty of Graduate and Postdoctoral Studies: University of Ottawa"},{"author_name":"Rakesh Jetly","author_inst":"University of Ottawa"},{"author_name":"Rebecca Robillard","author_inst":"University of Ottawa"}],"rel_date":"2026-06-12","rel_site":"medrxiv"},{"rel_title":"Heterogeneity of Treatment Effect of Aspirin and Clinically Significant Bleeding in Older Adults","rel_doi":"10.64898\/2026.06.10.26355385","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355385","rel_abs":"Aim: The global population of older adults is growing, and older age is linked to higher bleeding risk. Although guidelines discourage aspirin for primary prevention in healthy older adults due to bleeding harms outweighing benefits, many continue taking it without a clear indication. It remains unclear whether all older adults face uniform aspirin-related bleeding risk or if certain subgroups are more vulnerable. Methods: We analyzed data from 19,114 ASPREE trial participants to develop machine learning models using 116 baseline variables. Random forest (RF) and random survival forest (RSF) models predicted 5-year bleeding risk, and participants were stratified into low, intermediate, and high-risk groups based on the 20th and 80th percentiles of predicted risk. We assessed heterogeneity of treatment effect (HTE) by testing treatment-by-risk group interactions on the relative scale using Fine-Gray models, and on the absolute scale using observed 5-year cumulative incidence rates. Results: Over a median follow-up of 4.7 years, 626 major bleeding events occurred. The RF model had moderate discrimination (AUC = 0.65, 95% CI: 0.63-0.67) and good calibration (Brier = 0.032, 95% CI: 0.029-0.034). Statistically significant HTE was observed on the relative scale, with the greatest relative increase in bleeding risk seen in the low-risk group (subdistribution hazard ratio = 2.26, 95% CI: 1.27-4.01). On the absolute scale, low-risk participants experienced higher bleeding with aspirin (absolute risk difference (ARD) = 1.17%, 95% CI: 0.37-1.95), but heterogeneity in ARDs was not statistically significant (Cochran's Q p > 0.45). Similar findings were observed when using the RSF model. Conclusion: Participants at lowest baseline bleeding risk experienced the greatest relative increase in bleeding risk with aspirin therapy. We found statistically significant heterogeneity in treatment effects on the relative but not absolute scale. These findings support an individualized, risk-based approach to aspirin therapy decision-making in older adults.","rel_num_authors":12,"rel_authors":[{"author_name":"Giorgos Tzimas","author_inst":"DePaul University"},{"author_name":"Roselyne B. Tchoua","author_inst":"DePaul University"},{"author_name":"Joseph C Vanghelof","author_inst":"Rush University"},{"author_name":"Rory C Wolfe","author_inst":"Monash University"},{"author_name":"Geoffrey Cloud","author_inst":"Monash University"},{"author_name":"Suzanne Mahady","author_inst":"Monash University"},{"author_name":"Lianlian Du","author_inst":"Rush University Medical Center"},{"author_name":"Michael E. Ernst","author_inst":"The University of Iowa"},{"author_name":"Erica M Wood","author_inst":"Monash University"},{"author_name":"Daniela S Raicu","author_inst":"DePaul University"},{"author_name":"Shara Ket","author_inst":"Monash University"},{"author_name":"Raj C. Shah","author_inst":"Rush University Medical Center"}],"rel_date":"2026-06-12","rel_site":"medrxiv"},{"rel_title":"Home-based binocular serious games in virtual reality to treat visual acuity and stereovision in residual amblyopia: AMBER study","rel_doi":"10.64898\/2026.06.12.26355255","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.12.26355255","rel_abs":"Objectives: Amblyopia is a pediatric visual disorder traditionally treated by patching the fellow eye, though many patients retain residual amblyopia post-treatment. Increasing evidence suggests that visual plasticity allows treat-ment beyond the classical therapeutic window. AMBER evaluated the efficacy of binocular serious games in virtual reality (VR) in residual amblyopia. Methods and Analysis: The monocentric, prospective, randomized, crossover trial (reported as case series) includ-ed 14 anisometropic, strabismic, or mixed residual amblyopia patients (6-35 years; 5 children, 9 adults). Participants underwent two 2-month intervention phases: optical correction (standard care) and standard care plus VR games (2.5 h\/week), each with a 2-month follow-up. Best-corrected visual acuity (BCVA), stereoacuity, and reading speed were assessed (5 timepoints) using the Sloan and Landolt charts, the Titmus, TNO, Lang II, Asteroid, and Mnread tests. Compliance and adverse events (AE) were recorded. Results: VR training improved BCVA in 10 amblyopic eyes (Landolt and Sloan), with more pronounced effects in anisometropic patients. Six patients showed improved stereoacuity (Titmus; 4x mixed, 1x anisometropic, 1x stra-bismic amblyopia), persistent only in children (1x strabismic, 1x mixed amblyopia). Four improvements were ob-served with TNO (1x), Lang II (1x), Asteroid (0x), and MNread (1x). Despite positive trends, when comparing re-sults of individual patients, between both eyes, and with standard treatment, consistency of improvements cannot be conclusively demonstrated. One non-severe AE (dizziness) was reported. Conclusions: Following individual cases, VR training improved BCVA and stereoacuity, particularly in children and patients with high compliance. However, considering the cohort as a whole, consistency of effects has to be confirmed in larger groups. Thus, the methodologically sophisticated AMBER study revealed differences in VR treatment efficacy between amblyopia types, children\/adults, endpoints and tests, offering precious data for the design of meaningful future studies. It shows that neurovisual plasticity gauged by VR-games offers safe, engaging treatment options for residual amblyopia.","rel_num_authors":15,"rel_authors":[{"author_name":"Aurelia Aurilia","author_inst":"Department of Ophthalmology, University Hospitals of Geneva, Geneva, Switzerland"},{"author_name":"Nour-Louise Martin","author_inst":"Department of Ophthalmology, University Hospitals of Geneva, Geneva, Switzerland"},{"author_name":"Cristina Simon-Martinez","author_inst":"Institute of Informatics, School of Management, University of Applied Sciences Western Switzerland Valais-Wallis, Sierre, Switzerland"},{"author_name":"Maria-Paraskevi Antoniou","author_inst":"Institute of Informatics, School of Management, University of Applied Sciences Western Switzerland Valais-Wallis, Sierre, Switzerland"},{"author_name":"Walid Bouthour","author_inst":"Department of Ophthalmology, University Hospitals of Geneva, Geneva, Switzerland"},{"author_name":"Daphne Bavelier","author_inst":"Faculty of Psychology and Education Sciences, University of Geneva, Geneva, Switzerland"},{"author_name":"Benjamin T. Backus","author_inst":"Vivid Vision, Inc, 424 Treat Ave., Ste B, San Francisco, CA 94110, USA"},{"author_name":"Brian Dornbos","author_inst":"Vivid Vision, Inc, 424 Treat Ave., Ste B, San Francisco, CA 94110, USA"},{"author_name":"James J. Blaha","author_inst":"Vivid Vision, Inc, 424 Treat Ave., Ste B, San Francisco, CA 94110, USA"},{"author_name":"Martina Kropp","author_inst":"Department of Ophthalmology, University Hospitals of Geneva, Geneva, Switzerland"},{"author_name":"Henning Muller","author_inst":"Institute of Informatics, School of Management, University of Applied Sciences Western Switzerland Valais-Wallis, Sierre, Switzerland"},{"author_name":"Micah M. Murray","author_inst":"Department of Radiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland"},{"author_name":"Gabriele Thumann","author_inst":"Department of Ophthalmology, University Hospitals of Geneva, Geneva, Switzerland"},{"author_name":"Heimo Steffen","author_inst":"Department of Ophthalmology, University Hospitals of Geneva, Geneva, Switzerland"},{"author_name":"Pawel J. Matusz","author_inst":"Institute of Health Sciences, School of Health Sciences, HES-SO Valais-Wallis, Sion, Switzerland"}],"rel_date":"2026-06-12","rel_site":"medrxiv"},{"rel_title":"Genomic wastewater surveillance of seasonal and zoonotic influenza A viruses in California during the 2024-2025 flu season","rel_doi":"10.64898\/2026.06.10.26355323","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355323","rel_abs":"Wastewater genomic surveillance provides an opportunity to detect human and animal influenza A virus (IAV). We aimed to implement an IAV genomic surveillance framework agnostic to subtype, which enables recovery of IAV from multiple hosts and estimation of proportions across subtypes. We conducted IAV genomic surveillance in wastewater during the 2024-2025 flu season at multiple sites in California and compared these data with available human clinical IAV sequences and test positivity. We applied a custom whole-genome, multi-host IAV probe enrichment panel and adapted our custom expectation-maximization (EM) algorithm to deconvolute IAV mixtures in wastewater and infer subtype relative abundances. Absolute IAV concentrations were quantified using RT-PCR-based assays. H5N1 wastewater and clinical sequences were further characterized by constructing a whole-genome maximum-likelihood phylogenetic tree. Finally, we performed variant analysis to examine amino acid substitutions detected in wastewater. Our IAV probe enrichment method and EM algorithm successfully enriched all eight segments of three circulating IAV subtypes and accurately estimated subclade relative abundances for mixed IAV samples. Seasonal human H1N1pdm09 and H3N2 were detected throughout the study period from both wastewater and clinical sequencing data, with H1N1 subclades 6B.1A.5a.2a.1 and 6B.1A.5a.2a co-circulating, and H3N2 dominated by subclade 3C.2a1b.2a.2a.3a.1. Wastewater surveillance consistently detected H5N1 clade 2.3.4.4b across three monitored wastewater sites, while clinical H5N1 detections, from anywhere in CA, were sporadic and rare. Whole-genome phylogenetic analysis revealed that wastewater H5N1 sequences clustered with reference sequences associated with dairy cow and avian infections, while all human clinical H5N1 sequences clustered exclusively with reference sequences associated with dairy cow infections. Amino acid substitutions were identified across viral segments, and no mutations associated with mammalian adaptation were observed from wastewater samples.","rel_num_authors":10,"rel_authors":[{"author_name":"Audrey Li-Wen Wang","author_inst":"University of California, Berkeley"},{"author_name":"Alexandra Lamtyugina","author_inst":"University of Hawaii at Manoa"},{"author_name":"Minxi Jiang","author_inst":"University of California, Berkeley"},{"author_name":"Alexander T. Yu","author_inst":"California Department of Public Health"},{"author_name":"Chunye Lu","author_inst":"California Department of Public Health"},{"author_name":"Debra Wadford","author_inst":"California Department of Public Health"},{"author_name":"Elisabeth Burnor","author_inst":"California Department of Public Health"},{"author_name":"Lenore Pipes","author_inst":"University of Hawaii at Manoa"},{"author_name":"Rose Kantor","author_inst":"Lawrence Livermore National Laboratory"},{"author_name":"Kara L Nelson","author_inst":"University of California, Berkeley"}],"rel_date":"2026-06-12","rel_site":"medrxiv"},{"rel_title":"Disentangling Confounders from Pathology in Long-COVID Trajectory Prediction for Women: An Interpretable Large-Language-Model Approach","rel_doi":"10.64898\/2026.06.10.26355420","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355420","rel_abs":"Objective. Post-acute sequelae of SARS-CoV-2 infection (PASC, \"Long COVID\") dispropor- tionately affects women, in whom hallmark symptoms--insomnia, fatigue, palpitations, cogni- tive difficulty--overlap with comorbidities and hormonal transitions such as menopause. This diagnostic overlap is a confounding problem: models that forecast future symptom severity risk attributing baseline physiological noise to viral pathology. We ask whether an interpretable, causally disentangled language model can separate true pathological signal from such con- founders while remaining competitive with strong predictors of future PASC severity","rel_num_authors":9,"rel_authors":[{"author_name":"Jing Wang","author_inst":"NIH: National Institutes of Health"},{"author_name":"Zorina Galis","author_inst":"National Institute of Health Sciences"},{"author_name":"Tong Zhang","author_inst":"University of Illinois Urbana-Champaign"},{"author_name":"Yiming Luo","author_inst":"Columbia University"},{"author_name":"Amar Sra","author_inst":"George Washington University Medical Center"},{"author_name":"Xing Niu","author_inst":"Amazon.com Dedc LLC"},{"author_name":"Jie Shen","author_inst":"Stevens Institute of Technology"},{"author_name":"Qiaomin Xie","author_inst":"UW Madison: University of Wisconsin Madison"},{"author_name":"Jeremy  C Weiss","author_inst":"National Institute of Health Sciences"}],"rel_date":"2026-06-12","rel_site":"medrxiv"},{"rel_title":"Genome-wide association and multi-omics functional screens reveal the genetic architecture of foveal development","rel_doi":"10.64898\/2026.06.11.26355452","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355452","rel_abs":"Foveal hypoplasia causes visual impairment across congenital eye disorders, yet the genetic programmes governing foveal development remain poorly characterised and no tractable model exists for foveal disease. In the first genome-wide association study of foveal hypoplasia, we identified 42 sentinel variants mapping to 54 effector genes supported by >= 2 criteria from a variant-to-gene framework incorporating developmental multi-omics. Disruption of six effector genes using mutant lines and CRISPR knockouts in the zebrafish high acuity zone recapitulates structural, functional, and ultrastructural hallmarks of foveal hypoplasia, establishing the first vertebrate disease model. Integration with human foetal single-cell and spatial transcriptomics reveals two temporal waves of effector gene expression and identifies Muller glia as critical mediators of foveal patterning. Phenome-wide analyses reveal foveal variants are pleiotropic with refractive, lenticular, and metabolic traits, connecting foveal development to anterior segment and systemic disease biology. These findings should inform mechanistic studies of macular disease.","rel_num_authors":44,"rel_authors":[{"author_name":"Callum Hunt","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester,"},{"author_name":"Manjiri Patil","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester"},{"author_name":"Hammad Syed","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Ha-Jun Yoon","author_inst":"Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"},{"author_name":"Tingting Yang","author_inst":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Vanessa Rodwell","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Zhanhan Tu","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Gail DE Maconachie","author_inst":"The School of AHPPNM, Faculty of Health, Division of Ophthalmology and Orthoptics, The University of Sheffield, Sheffield, United Kingdom"},{"author_name":"Kayesha Coley","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"Alvin Lirio","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Nick Shrine","author_inst":"University of Leicester"},{"author_name":"Richard Packer","author_inst":"University of Leicester"},{"author_name":"Mahmoud Fassad","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"RIDDHI SHENOY","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Natalie Allcock","author_inst":"Electron Microscopy Facility Core Biotechnology Services, College of Life Sciences, University of Leicester, Leicester, UK."},{"author_name":"Brandon Lim","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"Helen J Kuht","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Girish Varma","author_inst":"International Institute of Information Technology Hyderabad, Gachibowli, Telangana, India"},{"author_name":"Irem Karaer","author_inst":"University of Leicester"},{"author_name":"Ranjit Injety","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"William Jakins","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Reenette Savant","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Rishi Sekhri","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Michael Hisaund","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Jinu Han","author_inst":"Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Korea (the Republic of)"},{"author_name":"Seema Teli","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Jun Wang","author_inst":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Zhen Zuo","author_inst":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Josh Whittingham","author_inst":"Electron Microscopy Facility Core Biotechnology Services, College of Life Sciences, University of Leicester, Leicester, UK."},{"author_name":"Gareth Douglas","author_inst":"School of Engineering, University of Leicester, Leicester, UK"},{"author_name":"Nicolas Sylvius","author_inst":"NUCLEUS Genomics, Core Biotechnology Services, University of Leicester, Leicester, UK"},{"author_name":"Pradeep C Vasudevan","author_inst":"University Hospitals of Leicester NHS Trust, Leicester, UK"},{"author_name":"Ala Moshiri","author_inst":"Department of Ophthalmology & Vision Science, University of California Davis School of Medicine, Sacramento, California, United States"},{"author_name":"Jonathan Zippin","author_inst":"Department of Dermatology, Weill Cornell Medical College of Cornell University, New York, New York, United States"},{"author_name":"Brian  P Brooks","author_inst":"National Institute of Health"},{"author_name":"Lluis Montoliu","author_inst":"Department of Molecular and Cellular Biology, National Centre for Biotechnology (CNB-CSIC), Madrid, Spain"},{"author_name":"Irene Gottlob","author_inst":"Neurology, Cooper University Health Care, Camden, New Jersey, United States"},{"author_name":"Ko-Fan Chen","author_inst":"Division of Genetics and Genome Biology, University of Leicester, Leicester, UK"},{"author_name":"Takeshi Yoshimatsu","author_inst":"Department of Ophthalmology and Visual Sciences, Washington University in St Louis School of Medicine, St. Louis, USA"},{"author_name":"Martin D Tobin","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"William HJ Norton","author_inst":"The University of Leicester, Division of Biosciences Education"},{"author_name":"Rui Chen","author_inst":"Brunson Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology and Visual Sciences, University of California, Irvine"},{"author_name":"Chiara Batini","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"Mervyn G Thomas","author_inst":"University of Leicester"}],"rel_date":"2026-06-12","rel_site":"medrxiv"},{"rel_title":"Genome-wide association and multi-omics functional screens reveal the genetic architecture of foveal development","rel_doi":"10.64898\/2026.06.11.26355452","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355452","rel_abs":"Foveal hypoplasia causes visual impairment across congenital eye disorders, yet the genetic programmes governing foveal development remain poorly characterised and no tractable model exists for foveal disease. In the first genome-wide association study of foveal hypoplasia, we identified 42 sentinel variants mapping to 54 effector genes supported by >= 2 criteria from a variant-to-gene framework incorporating developmental multi-omics. Disruption of six effector genes using mutant lines and CRISPR knockouts in the zebrafish high acuity zone recapitulates structural, functional, and ultrastructural hallmarks of foveal hypoplasia, establishing the first vertebrate disease model. Integration with human foetal single-cell and spatial transcriptomics reveals two temporal waves of effector gene expression and identifies Muller glia as critical mediators of foveal patterning. Phenome-wide analyses reveal foveal variants are pleiotropic with refractive, lenticular, and metabolic traits, connecting foveal development to anterior segment and systemic disease biology. These findings should inform mechanistic studies of macular disease.","rel_num_authors":44,"rel_authors":[{"author_name":"Callum Hunt","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester,"},{"author_name":"Manjiri Patil","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester"},{"author_name":"Hammad Syed","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Ha-Jun Yoon","author_inst":"Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA"},{"author_name":"Tingting Yang","author_inst":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Vanessa Rodwell","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Zhanhan Tu","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Gail DE Maconachie","author_inst":"The School of AHPPNM, Faculty of Health, Division of Ophthalmology and Orthoptics, The University of Sheffield, Sheffield, United Kingdom"},{"author_name":"Kayesha Coley","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"Alvin Lirio","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Nick Shrine","author_inst":"University of Leicester"},{"author_name":"Richard Packer","author_inst":"University of Leicester"},{"author_name":"Mahmoud Fassad","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"RIDDHI SHENOY","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Natalie Allcock","author_inst":"Electron Microscopy Facility Core Biotechnology Services, College of Life Sciences, University of Leicester, Leicester, UK."},{"author_name":"Brandon Lim","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"Helen J Kuht","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Girish Varma","author_inst":"International Institute of Information Technology Hyderabad, Gachibowli, Telangana, India"},{"author_name":"Irem Karaer","author_inst":"University of Leicester"},{"author_name":"Ranjit Injety","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"William Jakins","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Reenette Savant","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Rishi Sekhri","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Michael Hisaund","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Jinu Han","author_inst":"Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seodaemun-gu, Seoul, Korea (the Republic of)"},{"author_name":"Seema Teli","author_inst":"Ulverscroft Eye Unit, School of Psychology and Vision Sciences, University of Leicester, Leicester, UK"},{"author_name":"Jun Wang","author_inst":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Zhen Zuo","author_inst":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Josh Whittingham","author_inst":"Electron Microscopy Facility Core Biotechnology Services, College of Life Sciences, University of Leicester, Leicester, UK."},{"author_name":"Gareth Douglas","author_inst":"School of Engineering, University of Leicester, Leicester, UK"},{"author_name":"Nicolas Sylvius","author_inst":"NUCLEUS Genomics, Core Biotechnology Services, University of Leicester, Leicester, UK"},{"author_name":"Pradeep C Vasudevan","author_inst":"University Hospitals of Leicester NHS Trust, Leicester, UK"},{"author_name":"Ala Moshiri","author_inst":"Department of Ophthalmology & Vision Science, University of California Davis School of Medicine, Sacramento, California, United States"},{"author_name":"Jonathan Zippin","author_inst":"Department of Dermatology, Weill Cornell Medical College of Cornell University, New York, New York, United States"},{"author_name":"Brian  P Brooks","author_inst":"National Institute of Health"},{"author_name":"Lluis Montoliu","author_inst":"Department of Molecular and Cellular Biology, National Centre for Biotechnology (CNB-CSIC), Madrid, Spain"},{"author_name":"Irene Gottlob","author_inst":"Neurology, Cooper University Health Care, Camden, New Jersey, United States"},{"author_name":"Ko-Fan Chen","author_inst":"Division of Genetics and Genome Biology, University of Leicester, Leicester, UK"},{"author_name":"Takeshi Yoshimatsu","author_inst":"Department of Ophthalmology and Visual Sciences, Washington University in St Louis School of Medicine, St. Louis, USA"},{"author_name":"Martin D Tobin","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"William HJ Norton","author_inst":"The University of Leicester, Division of Biosciences Education"},{"author_name":"Rui Chen","author_inst":"Brunson Center for Translational Vision Research, Gavin Herbert Eye Institute, Department of Ophthalmology and Visual Sciences, University of California, Irvine"},{"author_name":"Chiara Batini","author_inst":"Division of Public Health and Epidemiology, University of Leicester, Leicester, UK"},{"author_name":"Mervyn G Thomas","author_inst":"University of Leicester"}],"rel_date":"2026-06-12","rel_site":"medrxiv"},{"rel_title":"Deconvolution-based cell-type specific DNA methylation-wide and transcriptome-wide association studies identify risk CpG sites and genes associated with colorectal cancer risk","rel_doi":"10.64898\/2026.06.11.26355460","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355460","rel_abs":"Bulk tissue-based DNA methylation-wide (MWAS) and transcriptome-wide association studies (TWAS) have identified CpG sites and genes associated with colorectal cancer (CRC) risk, but do not account for cellular heterogeneity. To address this, we developed a deconvolution-informed framework to infer cell-type specific DNA methylation and gene expression profiles from bulk normal colon tissues using reference single-cell epigenomic and transcriptomic datasets. We performed cell-type specific MWAS (ctMWAS) using deconvoluted DNA methylation data from 293 normal colon samples and conducted cell-type specific TWAS (ctTWAS) using deconvoluted gene expression data from 707 normal colon samples. Genetically predicted methylation and expression models were integrated with CRC GWAS summary statistics (78,473 cases and 107,143 controls) to identify risk-associated CpG sites and genes. Through ctMWAS, ctTWAS, and colocalization analyses, we identified 178 significant cell-type-specific CpG sites in 106 loci and 68 risk genes in 40 loci, including 26 previously unreported loci. Through additional integrative methylation-gene analysis, we prioritized 132 candidate risk genes, the majority of which were supported by multi-omics evidence and stage-specific dysregulation across the adenoma-carcinoma and serrated-carcinoma progression pathways. Pathway enrichment analyses implicated pathways involved in DNA double-strand break repair, TP53 regulation, TGF-{beta} signaling, and innate immune responses. Among prioritized genes, 14 were identified as putative druggable targets linked to 90 FDA-approved or clinical-stage drugs. Experimental validation supports an oncogenic role for SF3A3. These findings demonstrate that deconvolution-informed integrative analyses enable cell-type-resolved identification of epigenetic and transcriptional mechanisms underlying CRC susceptibility and provide insights into disease biology, prevention, and therapeutic target discovery.","rel_num_authors":18,"rel_authors":[{"author_name":"Qing Li","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Lili Xu","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Jifeng Wang","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Chao Li","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Wanqing Wen","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Xiang Shu","author_inst":"Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Yaohua Yang","author_inst":"Department of Genome Sciences, UVA Comprehensive Cancer Center, School of Medicine, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Xiao-ou Shu","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Qiuyin Cai","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Jirong Long","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Bhuminder Singh","author_inst":"Epithelial Biology Center and Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Ken S Lau","author_inst":"Epithelial Biology Center and Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA."},{"author_name":"Zhijun Yin","author_inst":"Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Graham Casey","author_inst":"Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA."},{"author_name":"Mingyang Song","author_inst":"Departments of Epidemiology and Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA"},{"author_name":"Ulrike Peters","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA."},{"author_name":"Wei Zheng","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Xingyi Guo","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"}],"rel_date":"2026-06-12","rel_site":"medrxiv"},{"rel_title":"Deconvolution-based cell-type specific DNA methylation-wide and transcriptome-wide association studies identify risk CpG sites and genes associated with colorectal cancer risk","rel_doi":"10.64898\/2026.06.11.26355460","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.11.26355460","rel_abs":"Bulk tissue-based DNA methylation-wide (MWAS) and transcriptome-wide association studies (TWAS) have identified CpG sites and genes associated with colorectal cancer (CRC) risk, but do not account for cellular heterogeneity. To address this, we developed a deconvolution-informed framework to infer cell-type specific DNA methylation and gene expression profiles from bulk normal colon tissues using reference single-cell epigenomic and transcriptomic datasets. We performed cell-type specific MWAS (ctMWAS) using deconvoluted DNA methylation data from 293 normal colon samples and conducted cell-type specific TWAS (ctTWAS) using deconvoluted gene expression data from 707 normal colon samples. Genetically predicted methylation and expression models were integrated with CRC GWAS summary statistics (78,473 cases and 107,143 controls) to identify risk-associated CpG sites and genes. Through ctMWAS, ctTWAS, and colocalization analyses, we identified 178 significant cell-type-specific CpG sites in 106 loci and 68 risk genes in 40 loci, including 26 previously unreported loci. Through additional integrative methylation-gene analysis, we prioritized 132 candidate risk genes, the majority of which were supported by multi-omics evidence and stage-specific dysregulation across the adenoma-carcinoma and serrated-carcinoma progression pathways. Pathway enrichment analyses implicated pathways involved in DNA double-strand break repair, TP53 regulation, TGF-{beta} signaling, and innate immune responses. Among prioritized genes, 14 were identified as putative druggable targets linked to 90 FDA-approved or clinical-stage drugs. Experimental validation supports an oncogenic role for SF3A3. These findings demonstrate that deconvolution-informed integrative analyses enable cell-type-resolved identification of epigenetic and transcriptional mechanisms underlying CRC susceptibility and provide insights into disease biology, prevention, and therapeutic target discovery.","rel_num_authors":18,"rel_authors":[{"author_name":"Qing Li","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Lili Xu","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Jifeng Wang","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Chao Li","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Wanqing Wen","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Xiang Shu","author_inst":"Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Yaohua Yang","author_inst":"Department of Genome Sciences, UVA Comprehensive Cancer Center, School of Medicine, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Xiao-ou Shu","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Qiuyin Cai","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Jirong Long","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Bhuminder Singh","author_inst":"Epithelial Biology Center and Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Ken S Lau","author_inst":"Epithelial Biology Center and Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA."},{"author_name":"Zhijun Yin","author_inst":"Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Graham Casey","author_inst":"Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA."},{"author_name":"Mingyang Song","author_inst":"Departments of Epidemiology and Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA"},{"author_name":"Ulrike Peters","author_inst":"Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA."},{"author_name":"Wei Zheng","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"},{"author_name":"Xingyi Guo","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashvil"}],"rel_date":"2026-06-12","rel_site":"medrxiv"},{"rel_title":"Reduced nighttime smartphone use among cohabiting partners: a longitudinal study under the lens of social control of health behaviors theory","rel_doi":"10.64898\/2026.06.09.26355243","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355243","rel_abs":"Objective: We examined the link between cohabitation with a partner and nighttime smartphone use through the social control of health behavior theory. Background: Nighttime smartphone use is a behavioral risk factor for sleep problems. While previous research has predominantly focused on individual-level risks of sleep disturbances, the role of social context remains underexplored. Theoretical frameworks, specifically the Social Control of Health Behavior, suggest that social relationships regulate health-related behaviors; however, it is unclear how far this regulation extends to modern digital behaviors among couples. Method: We analyzed survey data from three waves of the SmartSleep Study (2018, 2020, and 2023; total N = 25,028), including a longitudinal follow-up subset (N = 1,003). We tested multivariate associations between living with a partner, changes in cohabitation status and frequent nighttime smartphone use by fitting generalized linear mixed-effects models. Additionally, we mapped the complex interplay between indicators of social integration, social support, smartphone use, and sleep quality using hierarchical clustering of non-linear correlations. Results: Cohabiting participants had lower odds of frequent nighttime smartphone use compared to those living alone (OR = 0.66; 95% CI: 0.61, 0.72). This lower risk was driven primarily by cohabitation with a partner (OR = 0.49; 95% CI: 0.36, 0.66). Longitudinal analysis supported these findings, showing that sustained cohabitation was associated with less frequent nighttime use (OR = 0.56; 95% CI: 0.38, 0.82). Clustering analysis revealed that indicators of social integration and support clustered with favorable sleep quality. Conclusion: Our findings suggest that the health-protective effects of cohabitation with a partner extend to digital behaviors. Consistent with social control of health behavior theory, the presence of a partner appears to reduce frequent nighttime smartphone use, highlighting the critical importance of considering social context when addressing digital health hygiene and promoting sleep.","rel_num_authors":3,"rel_authors":[{"author_name":"Tove Alma Klasson","author_inst":"Copenhagen Health Complexity Center, Department of Public Health, University of Copenhagen"},{"author_name":"Naja Hulvej Rod","author_inst":"Copenhagen Health Complexity Center, Department of Public Health, University of Copenhagen"},{"author_name":"Adrian Gabriel Zucco","author_inst":"Copenhagen Health Complexity Center, Department of Public Health, University of Copenhagen"}],"rel_date":"2026-06-12","rel_site":"medrxiv"},{"rel_title":"Molecular and ecological determinants of effective reassortment in orthohantaviruses","rel_doi":"10.64898\/2026.06.10.731004","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731004","rel_abs":"A central unsolved problem in RNA virus evolution is understanding why some viral reassortants establish and persist while others do not. To answer this question, we reconstructed reassortant histories across 553 viral genomes from seven orthohantavirus species between 1983 and 2024 using phylogenetic reconciliation and molecular dating. We found that the frequency of retained reassortants varied among orthohantaviruses. For example, reassortment ranged from absent in Andes virus to frequent in Dobrava-Belgrade, Sin Nombre, Seoul, Puumala, and Tula viruses, showing that effective reassortment is not a genus-wide constant. Our Bayesian hierarchical models identified local host overlap as the strongest ecological factor associated with viral reassortment, while cross-segment linkage and terminal RNA structure serve as a molecular filter. We found that the probability of reassortment establishment is highest when ecological opportunity is paired with molecular permissiveness, with their interaction term inferred as the strongest signal in our establishment models (posterior probability = 0.97). These results suggest that reassortment in orthohantaviruses is a sequentially filtered evolutionary process in which divergent lineages must first meet in a host through ecological overlap, exchange segments that are molecularly compatible, and do so within a lineage background permissive to establishment in the host population.","rel_num_authors":10,"rel_authors":[{"author_name":"Ricardo Rivero","author_inst":"Washington State University"},{"author_name":"David Simons","author_inst":"Pennsylvania State University"},{"author_name":"Lambodhar Damodaran","author_inst":"Emory University"},{"author_name":"Irene Karegi","author_inst":"Washington State University"},{"author_name":"Sarah Gurev","author_inst":"Harvard Medical School"},{"author_name":"Daniel J Becker","author_inst":"University of Oklahoma"},{"author_name":"Dan L Warren","author_inst":"Charles Sturt University"},{"author_name":"Nicola F Mueller","author_inst":"University of California San Francisco"},{"author_name":"David A Rasmussen","author_inst":"North Carolina State University"},{"author_name":"Stephanie N Seifert","author_inst":"Washington State University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Molecular and ecological determinants of effective reassortment in orthohantaviruses","rel_doi":"10.64898\/2026.06.10.731004","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731004","rel_abs":"A central unsolved problem in RNA virus evolution is understanding why some viral reassortants establish and persist while others do not. To answer this question, we reconstructed reassortant histories across 553 viral genomes from seven orthohantavirus species between 1983 and 2024 using phylogenetic reconciliation and molecular dating. We found that the frequency of retained reassortants varied among orthohantaviruses. For example, reassortment ranged from absent in Andes virus to frequent in Dobrava-Belgrade, Sin Nombre, Seoul, Puumala, and Tula viruses, showing that effective reassortment is not a genus-wide constant. Our Bayesian hierarchical models identified local host overlap as the strongest ecological factor associated with viral reassortment, while cross-segment linkage and terminal RNA structure serve as a molecular filter. We found that the probability of reassortment establishment is highest when ecological opportunity is paired with molecular permissiveness, with their interaction term inferred as the strongest signal in our establishment models (posterior probability = 0.97). These results suggest that reassortment in orthohantaviruses is a sequentially filtered evolutionary process in which divergent lineages must first meet in a host through ecological overlap, exchange segments that are molecularly compatible, and do so within a lineage background permissive to establishment in the host population.","rel_num_authors":10,"rel_authors":[{"author_name":"Ricardo Rivero","author_inst":"Washington State University"},{"author_name":"David Simons","author_inst":"Pennsylvania State University"},{"author_name":"Lambodhar Damodaran","author_inst":"Emory University"},{"author_name":"Irene Karegi","author_inst":"Washington State University"},{"author_name":"Sarah Gurev","author_inst":"Harvard Medical School"},{"author_name":"Daniel J Becker","author_inst":"University of Oklahoma"},{"author_name":"Dan L Warren","author_inst":"Charles Sturt University"},{"author_name":"Nicola F Mueller","author_inst":"University of California San Francisco"},{"author_name":"David A Rasmussen","author_inst":"North Carolina State University"},{"author_name":"Stephanie N Seifert","author_inst":"Washington State University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"The missing part of the DMSP cycle in coral holobionts: Endozoicomonas exports acetate derived from DMSP degradation","rel_doi":"10.64898\/2026.06.12.731890","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.12.731890","rel_abs":"Endozoicomonas, a dominant symbiotic bacterium in coral holobionts, is noted for its ability to degrade dimethylsulfoniopropionate (DMSP) so as to generate acetate. While acetate is a well-known short-chain fatty acid in metabolic cross-feeding relationships, it remains unclear whether acetate derived from bacterial DMSP degradation is available to corals and their other symbionts. In this study, we employed Endozoicomonas ruthgatesiae strain 8E (herein referred as 8E) as a model to examine availability of DMSP-derived acetate for other symbionts. Using gas chromatography-mass spectrometry (GC-MS), we observed a significant increase in acetate excretion in 8E upon exposure to DMSP. Stable isotope labeling further confirmed that this elevated acetate efflux originated directly from DMSP, suggesting a complete cycle of DMSP-derived carbon among coral symbionts. Transcriptomic analysis revealed that DMSP exposure upregulated dddD expression and triggered a systemic reconfiguration of metabolism, characterized by down-regulation of the TCA cycle and the Pta-AckA pathway, with carbon flux redirected to the glyoxylate shunt. These findings suggest that upon exposure to DMSP, metabolism of 8E shifts from biomass production to DMSP catabolism, resulting in acetate efflux. Notably, we found that elevated temperature diminishes DMSP cleavage activity of 8E, indicating thermal sensitivity of this bacterial metabolic activity.","rel_num_authors":9,"rel_authors":[{"author_name":"Ying-Chieh Chen","author_inst":"Academia Sinica"},{"author_name":"Jui-Hung Yen","author_inst":"Academia Sinica"},{"author_name":"Ting-Chang Hsu","author_inst":"Academia Sinica"},{"author_name":"Wan-Ting Liao","author_inst":"Academia Sinica"},{"author_name":"Hsin-Feng Chang","author_inst":"Academia Sinica"},{"author_name":"Chih-Ying Lu","author_inst":"Academia Sinica"},{"author_name":"Li-Rong Lin","author_inst":"Academia Sinica"},{"author_name":"Sen-Lin Tang","author_inst":"Academia Sinica"},{"author_name":"Po-Shun Chuang","author_inst":"Biodiversity Research Center Academia Sinica"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Comparative genomics of Dolichospermum circinale strains with differential paralytic shellfish toxin profiles","rel_doi":"10.64898\/2026.06.11.731795","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731795","rel_abs":"The cyanobacterium Dolichospermum circinale is a known producer of the neurotoxin saxitoxin and its analogues, collectively known as the paralytic shellfish toxins (PSTs). PSTs vary in potency, and the reported toxin profiles of D. circinale blooms vary in the quantities of individual PSTs, with the regulation of these profiles being poorly understood. In this study, we present the genomes of four D. circinale strains (ACBU01, ACMB03, ACMB13 and FSS-124) with unique PST profiles and perform genome-wide comparisons and specific analysis of the PST-producing biosynthetic gene cluster (sxt) to understand the variability in PST quotas. A reassessment of the previously published D. circinale AWQC131C genome was also performed to collate genomic variation between all strains. Analysis at the nucleotide and amino acid sequence level revealed that toxic strains maintain high genome-wide similarities, corroborated by the analysis of the pan- and variable genomes of each strain. Specifically, the sxt gene sequences were 99-100% identical across all strains. Novel tailoring (sxtSUL, sxtDIOX) and transport (sxtM4) genes were identified within the sxt cluster that were not reported previously in D. circinale. Taken together, these results indicate that the genetic machinery involved in PST production is conserved in this species, suggesting that the regulation of PST biosynthesis in D. circinale does not occur at the genomic level.","rel_num_authors":5,"rel_authors":[{"author_name":"Joao P.A. Pereyra","author_inst":"University of New South Wales"},{"author_name":"Paul D'Agostino","author_inst":"Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)"},{"author_name":"Verlaine J. Timms","author_inst":"University of Newcastle Australia"},{"author_name":"Torsten Thomas","author_inst":"University of New South Wales"},{"author_name":"Brett A Neilan","author_inst":"University of Newcastle"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Mechanistic simulation identifies predictive dose-dependent biomarkers of propofol anesthesia","rel_doi":"10.64898\/2026.06.10.731411","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731411","rel_abs":"Understanding how receptor-level pharmacological modulation reorganizes large-scale brain circuits remains a central challenge in neuropharmacology. We introduce a multiscale mechanistic model with explicit core-matrix thalamocortical architecture, driven solely by GABA-A modulation without parameter fitting to any anesthesia data, to examine how propofol reorganizes brainwide activity from individual receptors to systems-level circuits. The model exhibits anesthetic effects spanning individual synaptic conductances to widespread changes in spiking, field potentials, and coherence. Without training on any task-specific data, our simulation of sensory processing in a standard auditory oddball paradigm matches independent macaque datasets. The same simulation, unmodified, also reproduces changes to functional connectivity in anesthetized humans, exhibiting selective attenuation of matrix thalamocortical loops relative to core loops. Most importantly, the simulation identified a dose-dependent biomarker of propofol concentration - elevated residual inter-stimulus cortical activity - that was subsequently confirmed in empirical macaque data where it had previously gone unnoticed. This simulation-first discovery, arising from mechanistic circuit dynamics rather than statistical comparison of clinical populations, illustrates a generative framework for translating receptor-level modulation into circuit-scale biomarkers with potential applications across predictive neuropharmacology.","rel_num_authors":10,"rel_authors":[{"author_name":"Anand Pathak","author_inst":"Dartmouth"},{"author_name":"Scott L Brincat","author_inst":"MIT"},{"author_name":"Yihan Xiong","author_inst":"Vanderbilt University"},{"author_name":"Haris Organtzidis","author_inst":"Stony Brook University"},{"author_name":"Mason Protter","author_inst":"Stony Brook University"},{"author_name":"Vincent Du","author_inst":"Stony Brook University"},{"author_name":"Helmut H Strey","author_inst":"Stony Brook University"},{"author_name":"Lilianne Rivka Mujica-Parodi","author_inst":"Stony Brook University"},{"author_name":"Earl K Miller","author_inst":"MIT"},{"author_name":"Richard Granger","author_inst":"Dartmouth"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Scaling Across Environments: Temperature and nutrition independently shape the genetics of size plasticity and morphological scaling","rel_doi":"10.64898\/2026.06.10.731218","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731218","rel_abs":"Across animals, variation in adult body size is accompanied by coordinated variation in the size of individual morphological traits. However, the same morphological trait can scale differently with body size depending on what drives the size variation. In Drosophila melanogaster, for example, wing size scales differently with body size when size varies because of developmental nutrition versus developmental temperature. Whether the genetic basis of size plasticity and scaling is shared across different environmental regulators of size remains unclear, but is central to predicting how selection acts on the developmental mechanisms that regulate trait size, plasticity, and morphological scaling. Using ~200 isogenic D. melanogaster lineages, we measured wing and leg size across nutritional and thermal treatments. For each lineage, we estimated nutritional and thermal plasticity for both traits, as well as the wing-leg individual-level scaling relationship, or ILSR, generated by each environmental source of size variation. We found extensive genetic variation in both thermal and nutritional plasticity for wings and legs, and in the slope of the ILSR between them. However, a lineage's thermal plasticity was genetically uncorrelated with its nutritional plasticity for either trait, and we detected no genetic correlation between the slopes of thermal and nutritional wing-leg ILSRs. We also found no genetic correlation in the slope of nutritional wing-leg ILSRs across temperatures. Thus, the slope of a lineage's nutritional ILSR at one temperature was not predictive of its slope at another temperature. Nevertheless, the overall pattern of nutritional ILSRs was conserved across temperatures. These results suggest that the genetic architecture of size plasticity and scaling depends on the environmental source of size variation. Consequently, the evolutionary response of scaling to selection in heterogeneous environments may not be predictable from genetic variation measured in any single environment.","rel_num_authors":5,"rel_authors":[{"author_name":"Shampa M Ghosh","author_inst":"Kalinga Institute of Industrial Technology (KIIT),"},{"author_name":"Isabelle M Vea","author_inst":"University of Illinois Chicago"},{"author_name":"Austin S Wilcox","author_inst":"University of Illinois Chicago"},{"author_name":"W.Anthony Frankino","author_inst":"University of Houston"},{"author_name":"Alexander W Shingleton","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Genetic Modeling of Dyadic Behavioral Traits: Implications for Estimation and Interpretation of Variance Components","rel_doi":"10.64898\/2026.06.10.731434","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731434","rel_abs":"Studying the genomic control of dyadic social interactions is gaining traction in animal genetics. However, genetic modeling of social interactions poses several challenges, one of which is whether social interactions should be treated as dyadic traits or as aggregated traits at the individual level. In this study, we systematically compared two approaches: dyadic models using dyadic traits and marginal models using marginally aggregated traits and we derived the algebraic relationships between their variance components. In the application, we used a published dataset on post-mixing aggression in pigs, including both directed and undirected aggression records collected during the 9-hour period after mixing among 797 finishing pigs in 59 social groups, as an example to show how model choice can affect variance estimation. Results showed that dyadic models can estimate genetic effects and permanent environmental effects by exploiting repeated dyadic interaction records, thereby enabling a more complete understanding of the sources of variation underlying social interactions. In contrast, marginal models can bias the estimation and interpretation of genetic components, as the aggregated genetic variance may be confounded with other variance components due to the aggregation of dyadic traits. Marginal models may also lead to overestimation of social group and residual variance. These results can provide useful guidance for choosing appropriate modeling strategies for social interaction traits.","rel_num_authors":3,"rel_authors":[{"author_name":"Xiaohan Jiang","author_inst":"Iowa State University"},{"author_name":"Janice Siegford","author_inst":"Michigan State University"},{"author_name":"Juan Pedro Steibel","author_inst":"Iowa State University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Genetic Modeling of Dyadic Behavioral Traits: Implications for Estimation and Interpretation of Variance Components","rel_doi":"10.64898\/2026.06.10.731434","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731434","rel_abs":"Studying the genomic control of dyadic social interactions is gaining traction in animal genetics. However, genetic modeling of social interactions poses several challenges, one of which is whether social interactions should be treated as dyadic traits or as aggregated traits at the individual level. In this study, we systematically compared two approaches: dyadic models using dyadic traits and marginal models using marginally aggregated traits and we derived the algebraic relationships between their variance components. In the application, we used a published dataset on post-mixing aggression in pigs, including both directed and undirected aggression records collected during the 9-hour period after mixing among 797 finishing pigs in 59 social groups, as an example to show how model choice can affect variance estimation. Results showed that dyadic models can estimate genetic effects and permanent environmental effects by exploiting repeated dyadic interaction records, thereby enabling a more complete understanding of the sources of variation underlying social interactions. In contrast, marginal models can bias the estimation and interpretation of genetic components, as the aggregated genetic variance may be confounded with other variance components due to the aggregation of dyadic traits. Marginal models may also lead to overestimation of social group and residual variance. These results can provide useful guidance for choosing appropriate modeling strategies for social interaction traits.","rel_num_authors":3,"rel_authors":[{"author_name":"Xiaohan Jiang","author_inst":"Iowa State University"},{"author_name":"Janice Siegford","author_inst":"Michigan State University"},{"author_name":"Juan Pedro Steibel","author_inst":"Iowa State University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Antigen Stimulation Reactivates HIV-1 Proviruses Despite Integration in Repressive Chromatin","rel_doi":"10.64898\/2026.06.11.731680","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731680","rel_abs":"Intact HIV-1 proviruses become progressively enriched in transcriptionally repressive genomic regions during long-term antiretroviral therapy (ART) and in elite controllers, raising questions about their capacity for reactivation in vivo. We used an antigen-restricted quantitative viral outgrowth assay (ag qVOA) to test whether cognate antigen stimulation can reverse latency of proviruses integrated within repressive chromatin. Using cells from two people with HIV (PWH) on ART, one on long-term treatment and one an elite controller, we show that antigen-specific stimulation induces viral outgrowth from intact proviruses integrated into a pericentromeric transition region and a zinc finger gene, respectively. These findings demonstrate that antigen recognition can overcome epigenetic constraints to reactivate proviruses with low inducibility and suggest that proviruses in so-called 'deeper latency' may contribute to residual viremia and viral rebound following treatment interruption.","rel_num_authors":14,"rel_authors":[{"author_name":"Angelica Camilo-Contreras","author_inst":"Johns Hopkins University"},{"author_name":"Filippo Dragoni","author_inst":"Johns Hopkins University"},{"author_name":"Hao Zhang","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Junlin Zhuo","author_inst":"Johns Hopkins University"},{"author_name":"Daniel F Smith","author_inst":"Johns Hopkins School of Public Health"},{"author_name":"Arturo Casadevall","author_inst":"Johns Hopkins School of Public Health"},{"author_name":"Jun Lai","author_inst":"Johns Hopkins School of Medicine: The Johns Hopkins University School of Medicine"},{"author_name":"Pablo Tebas","author_inst":"University of Pennsylvania"},{"author_name":"Janet D Siliciano","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Robert F Siliciano","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Stuart Ray","author_inst":"Johns Hopkins University"},{"author_name":"Luis J. Montaner","author_inst":"The Wistar Institute"},{"author_name":"Joel N. Blankson","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Francesco Roberto Simonetti","author_inst":"Johns Hopkins University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Type I interferon primes the alveolar epithelium to receive reparative signals from tissue-resident macrophages","rel_doi":"10.64898\/2026.06.10.731366","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731366","rel_abs":"Lung repair in response to viral infection requires integrated communication between epithelial and immune compartments, yet the impact of antiviral mediators on epithelial regenerative capacity remains poorly defined. Here, we demonstrate that type I interferon (IFN-I) signaling primes the lung for alveolar renewal following viral challenge. IFN-I contributes to the induction of an interferon-stimulated gene (ISG)hi Sca-1Pos population of alveolar type II (ATII) epithelial cells. Sca-1Pos ATIIs exhibit enhanced proliferative capacity and increased organoid-forming efficiency compared with their Sca-1Neg counterparts. Viral challenge concurrently drives phenotypic reprogramming of tissue-resident alveolar macrophages (trAMs). Sca-1Pos ATIIs display heightened responsiveness to oncostatin M (OSM) and, following viral challenge, require trAM-derived OSM for their proliferation. Together, these findings reveal that viral stimuli induce coordinated IFN-I-dependent epithelial and macrophage states that poise the lung for regeneration, positioning IFN-I not only as a central antiviral defense mechanism but as a priming signal that prepares lung tissue for renewal.","rel_num_authors":18,"rel_authors":[{"author_name":"Alan Y Baez Vazquez","author_inst":"Harvard University, Harvard Medical School"},{"author_name":"Daisy A Hoagland","author_inst":"Harvard Medical School"},{"author_name":"Alexander O Mann","author_inst":"Harvard Medical School"},{"author_name":"Yunkang Lin","author_inst":"Harvard Medical School"},{"author_name":"Susanna M Dang","author_inst":"Boston Children's Hospital"},{"author_name":"Max Hauptschein","author_inst":"Harvard Medical School"},{"author_name":"Louison Thorens","author_inst":"Northeastern University"},{"author_name":"Shahinoor Begum","author_inst":"Harvard Medical School"},{"author_name":"Martha A Castro","author_inst":"Harvard Medical School"},{"author_name":"Patricia Rodriguez-Morales","author_inst":"Harvard Medical School"},{"author_name":"Alicia Lai","author_inst":"Harvard Medical School"},{"author_name":"Irving Barrera","author_inst":"Broad Institute"},{"author_name":"Dawei Sun","author_inst":"Broad Institute"},{"author_name":"Andrea Shehaj","author_inst":"Boston Children's Hospital"},{"author_name":"Fei Chen","author_inst":"Broad Institute"},{"author_name":"Christophe Benoist","author_inst":"Harvard Medical School"},{"author_name":"Carla F Kim","author_inst":"Boston Children's Hospital"},{"author_name":"Ruth A Franklin","author_inst":"Harvard University, Harvard Medical School"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Type I interferon primes the alveolar epithelium to receive reparative signals from tissue-resident macrophages","rel_doi":"10.64898\/2026.06.10.731366","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731366","rel_abs":"Lung repair in response to viral infection requires integrated communication between epithelial and immune compartments, yet the impact of antiviral mediators on epithelial regenerative capacity remains poorly defined. Here, we demonstrate that type I interferon (IFN-I) signaling primes the lung for alveolar renewal following viral challenge. IFN-I contributes to the induction of an interferon-stimulated gene (ISG)hi Sca-1Pos population of alveolar type II (ATII) epithelial cells. Sca-1Pos ATIIs exhibit enhanced proliferative capacity and increased organoid-forming efficiency compared with their Sca-1Neg counterparts. Viral challenge concurrently drives phenotypic reprogramming of tissue-resident alveolar macrophages (trAMs). Sca-1Pos ATIIs display heightened responsiveness to oncostatin M (OSM) and, following viral challenge, require trAM-derived OSM for their proliferation. Together, these findings reveal that viral stimuli induce coordinated IFN-I-dependent epithelial and macrophage states that poise the lung for regeneration, positioning IFN-I not only as a central antiviral defense mechanism but as a priming signal that prepares lung tissue for renewal.","rel_num_authors":18,"rel_authors":[{"author_name":"Alan Y Baez Vazquez","author_inst":"Harvard University, Harvard Medical School"},{"author_name":"Daisy A Hoagland","author_inst":"Harvard Medical School"},{"author_name":"Alexander O Mann","author_inst":"Harvard Medical School"},{"author_name":"Yunkang Lin","author_inst":"Harvard Medical School"},{"author_name":"Susanna M Dang","author_inst":"Boston Children's Hospital"},{"author_name":"Max Hauptschein","author_inst":"Harvard Medical School"},{"author_name":"Louison Thorens","author_inst":"Northeastern University"},{"author_name":"Shahinoor Begum","author_inst":"Harvard Medical School"},{"author_name":"Martha A Castro","author_inst":"Harvard Medical School"},{"author_name":"Patricia Rodriguez-Morales","author_inst":"Harvard Medical School"},{"author_name":"Alicia Lai","author_inst":"Harvard Medical School"},{"author_name":"Irving Barrera","author_inst":"Broad Institute"},{"author_name":"Dawei Sun","author_inst":"Broad Institute"},{"author_name":"Andrea Shehaj","author_inst":"Boston Children's Hospital"},{"author_name":"Fei Chen","author_inst":"Broad Institute"},{"author_name":"Christophe Benoist","author_inst":"Harvard Medical School"},{"author_name":"Carla F Kim","author_inst":"Boston Children's Hospital"},{"author_name":"Ruth A Franklin","author_inst":"Harvard University, Harvard Medical School"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Gonadal regulation of sex-specific immunity in tuberculosis: enhanced lymphocyte function in females and dysfunctional myeloid responses in males","rel_doi":"10.64898\/2026.06.11.731661","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731661","rel_abs":"Tuberculosis (TB), the worlds deadliest infection, shows higher prevalence and mortality in males than in females (M\/F ratio >1.7). Using Four Core Genotype (FCG) mice to decouple gonadal from chromosomal sex (XX, XY gonadal males and XX, XY gonadal females), we show that gonadal males develop accelerated disease driven by dysfunctional myeloid responses rather than impaired bacterial recognition. Both XX and XY males exhibited increased mortality, higher Mycobacterium tuberculosis (Mtb) burden, and severe lung pathology. Mechanistically, gonadal male susceptibility involved early myeloid priming, excessive neutrophil recruitment, CCR2+ monocyte accumulation, and hyperinflammation, with enhanced neutrophil extracellular trap (NET) formation and disorganized granulomas, implicating testes and androgens as key drivers of male susceptibility. While XY gonadal females were less susceptible, XX gonadal females showed the greatest resistance, associated with coordinated T- and B-cell responses and enhanced B-cell follicle formation. Together, these findings identify gonad-driven myeloid dysregulation as a central mechanism underlying male TB susceptibility.","rel_num_authors":13,"rel_authors":[{"author_name":"Manish Gupta","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Nishtha Nayyar","author_inst":"ICAR-NBAIR, Bengaluru, India"},{"author_name":"Jessica Shen","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Shichun Lun","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Sabal Chaulagain","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Nikita Mangla","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Oscar Nino Meza","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Stefanie Krug","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Geetha Srikrishna","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Joseph P. Hoffmann","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Eileen Scully","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Sabra L. Klein","author_inst":"Johns Hopkins Bloomberg School of Public Health; Johns Hopkins University School of Medicine"},{"author_name":"William Bishai","author_inst":"Johns Hopkins School of Medicine"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Monoclonal nephritic factors reveal insights into C3 convertase dynamics and dysregulation","rel_doi":"10.64898\/2026.06.11.731599","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731599","rel_abs":"C3- and C5-nephritic factors are potent but poorly understood autoantibodies that dysregulate complement convertases. To date, their underlying mechanisms of action, epitopes, and sequences remain unknown. To address this knowledge gap, we immune profiled B cells from a nephritic factor-positive C3 glomerulopathy patient and identified the first monoclonal C3- and C5-nephritic factors. We present the structure of a C3-nephritic factor bound to a C3 convertase with the convertase protease domain unexpectedly rotated and inhibited. This rotation advances our understanding of complement convertase progression and decay, explains disease-associated convertase variants, and reveals the molecular mechanism by which nephritic factors can either activate or inhibit convertase activity. We also detail heterogeneity within and between C3- and C5-nephritic factors in terms of convertase binding, stabilizing capacity, regulator inhibition, fluid-phase activation, and disease contribution. These findings improve stratification of patients with C3 glomerulopathy, redefine basic C3 convertase dynamics, and provide insights into antibody-mediated modulation of the complement system.","rel_num_authors":26,"rel_authors":[{"author_name":"Seth J Welsh","author_inst":"University of Iowa"},{"author_name":"Christopher T Culek","author_inst":"University of Iowa"},{"author_name":"Zhen Xu","author_inst":"University of Iowa"},{"author_name":"Hector Martin Merinero","author_inst":"University of Iowa"},{"author_name":"Jannik Sichau","author_inst":"University of Ulm Medical Centre"},{"author_name":"Daniel Walls","author_inst":"University of Iowa"},{"author_name":"Renee Goodfellow","author_inst":"University of Iowa"},{"author_name":"Dingwu Shao","author_inst":"University of Iowa"},{"author_name":"Cobey Donelson","author_inst":"University of Iowa"},{"author_name":"Kameron Kruger","author_inst":"University of Iowa"},{"author_name":"Sarah Roberts","author_inst":"University of Iowa"},{"author_name":"Nicole C Meyer","author_inst":"University of Iowa"},{"author_name":"Angela F.M. Nelson","author_inst":"University of Iowa"},{"author_name":"Anna R Carmen","author_inst":"University of Iowa"},{"author_name":"Sydney S Jellison","author_inst":"University of Iowa"},{"author_name":"Stephanie N Cook","author_inst":"University of Iowa"},{"author_name":"Monica D Hall","author_inst":"University of Iowa"},{"author_name":"Rebecca Franklin","author_inst":"University of Iowa"},{"author_name":"Tina Liu","author_inst":"University of Iowa"},{"author_name":"Jill Hall","author_inst":"University of Iowa"},{"author_name":"Lauren O Fergus","author_inst":"University of Iowa"},{"author_name":"Nicholas J Schnicker","author_inst":"University of Iowa"},{"author_name":"Christoph Q Schmidt","author_inst":"University of Ulm Medical Centre"},{"author_name":"Yuzhou Zhang","author_inst":"University of Iowa"},{"author_name":"Carla M Nester","author_inst":"University of Iowa"},{"author_name":"Richard J.H. Smith","author_inst":"University of Iowa"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Effects of Left Atrial Wall Thickness on Myocardial Mechanics and Blood Dynamics using Multiscale Modeling","rel_doi":"10.64898\/2026.06.09.731221","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731221","rel_abs":"Purpose: Patient-specific models of left atrial (LA) mechanics often assume uniform left atrial wall thickness (LAWT), but the effect of LAWT on the mechanics and hemodynamics remains less quantified. Methods: Four LA myocardium models were built from gated CTA images: a baseline variable thickness (VT#0), two reduced-dilation variants, and a 2 mm uniform thickness model. Multiscale mechanics and blood flow simulations were performed across all the thickness variants using model parameters personalized on the baseline model. Predicted displacements, wall stresses and strains, and hemodynamics were compared. Results: Across all LAWT variants, myocardial volume spanned 14.4--19.9 mL (38%), while cavity volume remained mostly within 5% of image data throughout the cardiac cycle. Circulatory system output, myocardial displacements, and strains varied by 5--6% relative to the baseline model. Instantaneous stresses increased by up to 19% in the thinner variable thickness models and decreased by up to 16% in the uniformly thick case. Globally, the area under low time-averaged wall shear stress (TAWSS) varied between 23% and 30% across all thickness variants, while LA exposed to elevated oscillatory shear index (OSI) increased from nearly 6% to 19%. Over 90% of LAA was exposed to low shear, but the high-OSI area increased from 7% in VT#0 to over 30% in Uniform. Conclusion: A personalized multiscale modeling framework was leveraged to demonstrate that the left atrial myocardial stresses and oscillatory shear had a greater sensitivity to local wall thickness representation compared to cavity volumes, tissue displacements, strains, and mean blood shear.","rel_num_authors":4,"rel_authors":[{"author_name":"Boyang Gan","author_inst":"Columbia University"},{"author_name":"Lei Shi","author_inst":"Kennesaw State University"},{"author_name":"Ian Y. Chen","author_inst":"Stanford University School of Medicine"},{"author_name":"Vijay Vedula","author_inst":"Columbia University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Co-Expressed MicroRNAs Identify Potential Mechanisms Underlying Risk for Multimorbid Depression and Type 2 Diabetes in Midlife Women","rel_doi":"10.64898\/2026.06.10.731370","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731370","rel_abs":"Background Women are disproportionately affected by multimorbid depression and type 2 diabetes (T2D), with prevalence peaking during midlife (40-64 years), a biologically dynamic timeframe due to changes associated with reproductive aging. Yet, phenotypic and mechanistic factors contributing to midlife women's disproportionate risk for co-occurrence remain poorly defined. We previously identified co-expressed microRNAs (miRs) in midlife women with prediabetes that increased odds of assignment to a high psychometabolic risk phenotype. Here, we extend these findings by characterizing putative mRNA targets of these co-expressed miRs and pathways overrepresented among mRNAs, providing insights into potential mechanisms underlying psychometabolic risk in midlife women. Methods This study included baseline data from midlife women (ages 40-64 years) with prediabetes who participated in the Diabetes Prevention Program (DPP) (n = 603). In silico analyses were performed using miRTarBase to identify mRNAs regulated by 3 or more of the miRs that most prominently loaded a principal component previously identified to increase odds of assignment to a high psychometabolic risk phenotype defined in this sample. Pathway enrichment analysis was conducted to assess for overrepresentation of KEGG pathways among predicted mRNA targets. To enhance interpretability, pathways were thematically clustered based on their evidenced role in human physiology. Results We identified a total of 13 mRNAs targeted by co-expressed miRs associated with increased odds of assignment to a high psychometabolic risk phenotype in midlife women with prediabetes. Pathway enrichment analysis revealed a total of 71 KEGG pathways with overrepresentation of identified mRNA targets. Four overarching biological themes emerged, reflecting involvement of metabolic, inflammatory, endocrine, and stress\/biological weathering-related processes. Conclusions Experimentally validated mRNA targets related biological pathways were identified, providing multisystem insights into potential mechanisms underlying risk for multimorbid depression and T2D in midlife women. Findings offer mechanistic targets for experimental validation and future precision health research focused on this high-risk population. Overall, this work positions the utility of miRs as context-sensitive biomarkers in the characterization of risk for complex, multimorbid conditions in women during biologically dynamic timeframes. Keywords: biomarkers, depression, type 2 diabetes, multimorbidity risk, women's health","rel_num_authors":7,"rel_authors":[{"author_name":"Kayla  D. D. Longoria","author_inst":"The University of Texas Health Science Center at Houston"},{"author_name":"Benjamin Stroebel","author_inst":"University of California, San Francisco"},{"author_name":"Meghana Gadgil","author_inst":"University of California, San Francisco"},{"author_name":"Sandra Weiss","author_inst":"University of California, San Francisco"},{"author_name":"Kimberly A. Lewis","author_inst":"UCLA Health"},{"author_name":"Nicole Perez","author_inst":"New York University"},{"author_name":"Elena Flowers","author_inst":"University of California, San Francisco"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"LizardLens: A Two-Stage Deep Learning Pipeline for Detecting and Classifying Similar Species in Visually Complex Environments","rel_doi":"10.64898\/2026.06.10.731342","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731342","rel_abs":"Community science platforms like iNaturalist generate unprecedented volumes of biodiversity data, but their scientific utility depends critically on accurate species identification; a persistent challenge when contributors often lack taxonomic expertise. We developed LizardLens, a two-stage machine learning pipeline that decouples object detection from species classification to enable fine-grained identification of morphologically similar organisms in visually complex field photographs. Using 10,000 verified iNaturalist images of five Anolis lizard species in Florida, we trained specialized YOLO-based detection and Swin Transformer classification models and compared performance against state-of-the-art single-stage architectures. Our two-stage pipeline achieved 83.0% Top-1 accuracy and a macro-averaged F1-score of 89.0%, indicating strong precision-recall performance across species and outperforming single-stage YOLOv8 and YOLOv12 models across all evaluation metrics for all species, with relative improvements ranging from 10.5% to 13.2%. Gradient-weighted Class Activation Mapping (Grad-CAM) indicated that the models predictions were consistently associated with regions corresponding to diagnostic morphological (e.g., head shape, feet, and limb lengths) and pattern features (e.g., ocular rings and body patterning), providing evidence that LizardLens leverages biologically relevant visual cues consistent with those used by expert taxonomists. Error analysis identified partial occlusion and multiple proximate individuals as primary sources of missed detections, while spurious detections of lizard-like environmental features (e.g., sticks, bark) represented the dominant false positive error mode. We deployed LizardLens as an accessible web application featuring interactive bounding box correction, ranked species predictions with confidence scores, directly supporting the Lizards on the Loose middle school community science initiative. By combining technical advances in fine-grained visual classification with user-centered design, LizardLens demonstrates how machine learning can simultaneously enhance data quality for biodiversity monitoring and provide authentic scientific experiences for student participants. Our approach is generalizable to other small-bodied organisms in complex habitats and provides a framework for translating computer vision advances into practical tools for community science and conservation.","rel_num_authors":8,"rel_authors":[{"author_name":"Wen Han Chia","author_inst":"Georgia Institute of Technology"},{"author_name":"Ilia Jahanshahi","author_inst":"Iowa State University"},{"author_name":"Le Yang Loh","author_inst":"Georgia Institute of Technology"},{"author_name":"Anqi Zheng","author_inst":"Georgia Institute of Technology"},{"author_name":"Niral Verma","author_inst":"Georgia Institute of Technology"},{"author_name":"Stephen Mussman","author_inst":"Georgia Institute of Technology"},{"author_name":"Breanna Shi","author_inst":"Georgia Institute of Technology"},{"author_name":"James T. Stroud","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"LizardLens: A Two-Stage Deep Learning Pipeline for Detecting and Classifying Similar Species in Visually Complex Environments","rel_doi":"10.64898\/2026.06.10.731342","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731342","rel_abs":"Community science platforms like iNaturalist generate unprecedented volumes of biodiversity data, but their scientific utility depends critically on accurate species identification; a persistent challenge when contributors often lack taxonomic expertise. We developed LizardLens, a two-stage machine learning pipeline that decouples object detection from species classification to enable fine-grained identification of morphologically similar organisms in visually complex field photographs. Using 10,000 verified iNaturalist images of five Anolis lizard species in Florida, we trained specialized YOLO-based detection and Swin Transformer classification models and compared performance against state-of-the-art single-stage architectures. Our two-stage pipeline achieved 83.0% Top-1 accuracy and a macro-averaged F1-score of 89.0%, indicating strong precision-recall performance across species and outperforming single-stage YOLOv8 and YOLOv12 models across all evaluation metrics for all species, with relative improvements ranging from 10.5% to 13.2%. Gradient-weighted Class Activation Mapping (Grad-CAM) indicated that the models predictions were consistently associated with regions corresponding to diagnostic morphological (e.g., head shape, feet, and limb lengths) and pattern features (e.g., ocular rings and body patterning), providing evidence that LizardLens leverages biologically relevant visual cues consistent with those used by expert taxonomists. Error analysis identified partial occlusion and multiple proximate individuals as primary sources of missed detections, while spurious detections of lizard-like environmental features (e.g., sticks, bark) represented the dominant false positive error mode. We deployed LizardLens as an accessible web application featuring interactive bounding box correction, ranked species predictions with confidence scores, directly supporting the Lizards on the Loose middle school community science initiative. By combining technical advances in fine-grained visual classification with user-centered design, LizardLens demonstrates how machine learning can simultaneously enhance data quality for biodiversity monitoring and provide authentic scientific experiences for student participants. Our approach is generalizable to other small-bodied organisms in complex habitats and provides a framework for translating computer vision advances into practical tools for community science and conservation.","rel_num_authors":8,"rel_authors":[{"author_name":"Wen Han Chia","author_inst":"Georgia Institute of Technology"},{"author_name":"Ilia Jahanshahi","author_inst":"Iowa State University"},{"author_name":"Le Yang Loh","author_inst":"Georgia Institute of Technology"},{"author_name":"Anqi Zheng","author_inst":"Georgia Institute of Technology"},{"author_name":"Niral Verma","author_inst":"Georgia Institute of Technology"},{"author_name":"Stephen Mussman","author_inst":"Georgia Institute of Technology"},{"author_name":"Breanna Shi","author_inst":"Georgia Institute of Technology"},{"author_name":"James T. Stroud","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Citrate Compartmentalization Controls Calcium-Dependent Cytokine Production in Effector T Cells","rel_doi":"10.64898\/2026.06.11.731694","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731694","rel_abs":"Cytokine production is a core function of effector T cells, yet the mechanisms that regulate cytokine output during an immune response remain incompletely understood. Here, we identify citrate compartmentalization as a cellular mechanism by which CD8+ T cells couple cytokine production to glucose availability. Under glucose-replete conditions, citrate transport from the mitochondria to the cytosol by the citrate carrier SLC25A1 suppresses calcium-dependent transcription factor activity in effector T cells. Either reducing glucose availability or blocking the exchange of citrate across the mitochondrial membrane raises free cytosolic calcium, thereby driving nuclear localization of Nuclear Factor of Activated T cells (NFAT)-family transcription factors and sustaining cytokine production. As a calcium-chelating metabolite, we show that citrate buffers free cytosolic calcium, thereby linking calcium-dependent signaling to mitochondrial fuel oxidation. We also identify signatures of this regulatory mechanism across hundreds of human cancer cell lines, where there are negative associations between citrate-derived metabolites and calcium-dependent transcriptional programs, and within the spatial organization of human tumors. These findings identify cytosolic citrate as a broadly conserved metabolic rheostat coupling glucose availability to calcium signaling. By adding calcium signaling to the known functions regulated by SLC25A1, our work reveals a mechanism by which mitochondria adaptively tune cytokine expression and other calcium-dependent programs in response to local metabolic conditions, such as nutrients that are available within a tissue or tumor.","rel_num_authors":7,"rel_authors":[{"author_name":"Andrea L. Cote","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Claire L. McIntyre","author_inst":"Ragon Institute of Mass General Brigham, MIT, and Harvard"},{"author_name":"Joshua A. Acklin","author_inst":"Ragon Institute of Mass General Brigham, MIT, and Harvard"},{"author_name":"Lillian R. Delacruz","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Yunping Qiu","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Irwin J. Kurland","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Alison E. Ringel","author_inst":"Ragon Institute of Mass General Brigham, MIT, and Harvard"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"PN6047 Demonstrates Broad Preclinical Efficacy in Headache Models as a Novel Delta-Opioid Receptor Agonist","rel_doi":"10.64898\/2026.06.09.729278","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.729278","rel_abs":"Background: The Delta-opioid receptor (DOR) has gained attention as a promising target for the treatment of migraine and headache disorders. This is largely attributed to its unique pharmacological profile, which suggests that DOR-targeting treatment offers effective therapeutic effect with a lower risk of medication overuse headache (MOH), reduced abuse liability, and minimal potential for physical dependence. These advantages have driven the development of a novel DOR agonist PN6047 (3-[[4-(dimethylcarbamoyl) phenyl]-[1-(thiazol-5-ylmethyl)-4-piperidylidene] methyl]benzamide), which has completed Phase I clinical trial and showed a favorable safety and tolerability profile. Although PN6047 has shown promising effects in neuropathic pain models, its efficacy in preclinical models of headache-associated pain remains to be evaluated. Here, we investigated the effects of PN6047 in models of migraine-associated pain and aura as well as post-traumatic headache (PTH) and MOH. Methods: C57BL6\/J mice were used to examine the effects of PN6047 in the following migraine models: chronic intermittent nitroglycerin (NTG)-induced migraine-associated pain, PTH, KCl-induced cortical spreading depression (CSD), and optogenetic evoked CSD in a freely behaving transgenic mice expressing ChR2-eYFP. In addition, we tested whether chronic PN6047 induced MOH and whether it could prevent the development of MOH induced by sumatriptan. Results: A single injection of PN6047 blocked chronic cephalic allodynia established by chronic intermittent NTG and PTH. Moreover, chronic PN6047 treatment prevented the development of MOH induced by sumatriptan, without causing MOH itself. In addition, PN6047 significantly reduced the number of CSD events in the KCl-induced CSD model, and delayed CSD onset triggered in freely behaving mice along with subsequent CSD-evoked allodynia. Conclusion: PN6047, a novel DOR agonist, strikingly blocks headache-associated mechanism and symptoms in preclinical models of chronic migraine, migraine aura, PTH, and MOH. Importantly, prolonged PN6047 treatment did not induce MOH or analgesic tolerance. Together, these data demonstrate that despite the distinct mechanisms underlying migraine and headache disorder models, PN6047 exhibits robust efficacy without inducing MOH, and displays a favorable safety and tolerability profile.","rel_num_authors":11,"rel_authors":[{"author_name":"Yaseen Awad-Igbaria","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Yanping Zhang","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Mattin Aframian","author_inst":"University of California Los Angeles"},{"author_name":"Guido  C. Faas","author_inst":"UCLA: University of California Los Angeles"},{"author_name":"Andrew Charles","author_inst":"University of California Los Angeles"},{"author_name":"Serapio M Baca","author_inst":"University of Virginia"},{"author_name":"Emily Jutkiewicz","author_inst":"University of Michigan"},{"author_name":"Bengt von Mentzer","author_inst":"Pharmnovo"},{"author_name":"John Traynor","author_inst":"University of Michigan"},{"author_name":"David Kendall","author_inst":"Pharmnovo"},{"author_name":"Amynah A Pradhan","author_inst":"Washington University School of Medicine in St. Louis"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Evaluating cell type annotations in single-cell omics in the absence of ground truth","rel_doi":"10.64898\/2026.06.10.731285","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731285","rel_abs":"Accurate cell type annotation is essential for single-cell transcriptomics, directly shaping downstream analyses and biological interpretations. Yet, objective evaluation of annotation quality remains a major challenge. Here, we argue that a cell type or cell state label has practical utility only if it captures a molecular pattern that is reproducible across biological replicates. Based on this principle, we introduce inter-sample consistency (ISC), a quantitative framework to assess annotation quality in single-cell RNA-seq datasets. Unlike existing cluster validation approaches, ISC distinguishes annotations that generalize across samples and individuals from those driven by technical or unwanted variation, thereby providing principled criteria for annotation quality and transferability. When applied to published single-cell atlases, ISC reveals widespread reproducibility gaps and provides actionable guidance for repairing inconsistent annotations. Notably, ISC enables benchmarking of automated cell type annotation tools even when ground-truth labels are unavailable, providing interpretable metrics to guide their development and evaluation. Implemented as the scTypeEval Bioconductor package, this framework offers a broadly applicable resource for evaluating and improving cell type annotations in single-cell RNA-seq experiments.","rel_num_authors":3,"rel_authors":[{"author_name":"Josep Garnica","author_inst":"University of Geneva"},{"author_name":"Massimo Andreatta","author_inst":"University of Geneva"},{"author_name":"Santiago J Carmona","author_inst":"University of Geneva"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"LizardMorph: A generalizable machine learning framework for automated anatomical landmark detection in digital images","rel_doi":"10.64898\/2026.06.10.731351","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731351","rel_abs":"Morphological measurements underpin a wide range of ecological and evolutionary research, yet the manual landmarking workflows on which most morphometric studies depend remain a persistent bottleneck that limits both the pace and scale of biological research. Machine learning offers compelling solutions, but most automated landmarking tools require substantial computational expertise, creating a gap between technical capability and practical adoption by biologists. Here, we present LizardMorph, an integrated machine learning pipeline and web-based interface for semi-automated anatomical landmark detection on biological images. LizardMorph couples a fine-tuned ML-Morph shape predictor with an accessible, browser-based interface that enables researchers to upload images, review automated landmark predictions, interactively correct outliers through point-and-click editing, and export results in standard morphometric formats; all without programming expertise or local software installation. Using dorsal X-ray radiographs of Anolis lizards with 34 anatomical landmarks as a proof-of-concept, we show that the ML-Morph model achieves high predictive accuracy, with landmarks on well-defined skeletal structures predicted with 100% accuracy within a 1 mm tolerance threshold. A controlled user study comparing LizardMorph against traditional manual landmarking (TpsDig2) demonstrated significant efficiency gains: experienced annotators completed LizardMorph landmark verification 37.5% faster than manual annotation. Extrapolated to batch processing 1,000 lizards, LizardMorph saves experienced researchers approximately 6.5 hours of manual processing time. Critically, LizardMorph implements a human-in-the-loop design in which automated predictions serve as editable starting points, preserving researcher oversight and enabling correction of the occasional large-error outliers that would be unacceptable in fully automated workflows. LizardMorph is freely available as an open-source tool and provides a replicable framework for developing ML-assisted annotation tools that can democratize access to high-quality morphometric analysis across diverse biological research communities.","rel_num_authors":8,"rel_authors":[{"author_name":"Mercedes Quintana","author_inst":"Georgia Institute of Technology"},{"author_name":"Le Yang Loh","author_inst":"Georgia Institute of Technology"},{"author_name":"Ayush Parikh","author_inst":"Georgia Institute of Technology"},{"author_name":"Jonathan J. Suh","author_inst":"Georgia Institute of Technology"},{"author_name":"Victoria Chavez","author_inst":"Northwestern University"},{"author_name":"Arthur Porto","author_inst":"University of Florida"},{"author_name":"Breanna Shi","author_inst":"Georgia Institute of Technology"},{"author_name":"James T. Stroud","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Connectome wiring shapes population-level neural geometry in the Drosophila visual system","rel_doi":"10.64898\/2026.06.10.731214","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731214","rel_abs":"What does biological wiring actually contribute to neural computation? Behavioral experiments can test whether a model produces the right outputs, but they cannot determine whether its internal representations are biologically faithful. Brunton et al. (2026) made this concrete: a C. elegans worm connectome trained with deep reinforcement learning produces realistic Drosophila fly walking -- yet the model is biologically meaningless, because behavioral fidelity is achievable without biological fidelity. We need a population-level metric that discriminates real biological wiring from arbitrary wiring, without requiring a behavioral decoder. We propose representational geometry as that metric. Representational geometry -- the structure of pairwise distances between population responses to different stimuli -- captures how a neural circuit organizes its representational space, independently of what behavior it drives. We apply representational similarity analysis (RSA) and centered kernel alignment (CKA) to the Flyvis pretrained Drosophila melanogaster visual system ensemble (Lappalainen et al. 2024): 50 networks whose architecture is fixed to the FlyWire connectome, compared against stability-constrained random baselines (sign-preserving weight shuffles, rejection-sampled for dynamic stability, n = 50). Connectome-constrained networks produce a smooth circular direction geometry that random networks cannot replicate: RSA Spearman r = 0.686 (p < 0.0001) for ON edge stimuli and r = 0.846 (p < 0.0001) for ON+OFF edge stimuli, corroborated by CKA (p < 0.05 in both experiments). The geometry also tracks biological T4\/T5 direction tuning recorded in living flies (Maisak et al. 2013): connectome-constrained geometry matches biology substantially better than random geometry (r = 0.930 vs. r = 0.603, gap {Delta}r = 0.327, p < 0.0001). Within each stimulus polarity, the ON pathway encodes direction with stronger geometric separation than the OFF pathway ({Delta}r = 0.138, 95% CI [0.091, 0.236]), consistent with known T4\/T5 asymmetries in direction selectivity strength. These results establish representational geometry as a candidate fidelity metric that discriminates biological from arbitrary wiring at the population level. The framework requires no behavioral decoder and no single-unit recordings -- only population responses to a structured stimulus set -- suggesting a practical path toward verifiable fidelity metrics for connectome-scale emulations as they scale toward mammalian cortex.","rel_num_authors":2,"rel_authors":[{"author_name":"Michael George Zhou","author_inst":"Georgia Institute of Technology"},{"author_name":"Jennifer Olson Hasler","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"The Geometry of Allostery: A Laplacian Minor Hierarchy for Many-Body Protein Communication","rel_doi":"10.64898\/2026.06.10.731266","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731266","rel_abs":"Quantifying how cooperative, many-body relationships drive allostery in protein networks remains a major challenge. To address this, we develop the Laplacian minor hierarchy, a mathematical framework that characterizes the geometric invariants of a protein network. Lower-order minors yield standard metrics including the partition function and effective distances, whereas higher-order minors define novel topological measures: cooperation indices, each bounded between zero and one, that characterize pathway correlations at increasing levels of complexity, the third-order minor determines whether allosteric pathways are correlated or uncorrelated, and the fourth-order minor quantifies how distinct pathways communicate through intermediary residues. We apply this framework to analyze the evolutionary adaptation of the PSD95pdz3 domain from Class I to Class II ligand specificity via mutations G330T and H372A. The cooperation index demonstrates a distinct evolutionary hierarchy: the G330T mutation establishes distributed pathway couplings that the H372A mutation subsequently exploits, whereas H372A alone produces minimal global changes. Furthermore, the fourth-order analysis identifies His317 as a critical intermediary node bridging the class-switching (330-372) and class-bridging (330-400) allosteric pathways. These results demonstrate that allosteric dependencies emerge only when mutations accumulate in specific combinations, with a hierarchical organization of pathways structured around position 330 and intermediary nodes His317 and Phe400. Rather than predicting allosteric mechanisms, this framework provides a mechanistic explanation for why and how allostery emerges during protein evolution.","rel_num_authors":2,"rel_authors":[{"author_name":"Fatma Senguler Ciftci","author_inst":"Koc University"},{"author_name":"Burak Erman","author_inst":"Koc University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Generalisable tissue-wide molecular reconstruction from histology","rel_doi":"10.64898\/2026.06.09.731252","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731252","rel_abs":"Spatial transcriptomics technologies measure gene expression within intact tissues but remain difficult to scale across large tissue sections and patient cohorts. Consequently, many studies rely on tissue microarrays (TMAs) or sparse spatial profiling designs, where molecular measurements are available for only limited tissue regions and are often generated using heterogeneous gene panels. Existing H&E to spatial gene expression prediction methods remain challenged by sparse molecular measurements, partially overlapping gene panels and tissue-wide reconstruction across heterogeneous spatial datasets. Here, we present GHIST+, a framework for tissue-wide reconstruction of single-cell molecular states from H&E histology. GHIST+ integrates cellular morphology, local tissue context and shared tissue representations to extend sparse molecular measurements into tissue-wide molecular maps across heterogeneous spatial datasets. Across multiple cancer types and GTEx breast tissues, GHIST+ reconstructs biologically meaningful tissue-wide molecular organisation from sparse TMA-derived measurements while preserving spatial tissue structure, cell-type organisation and age-associated tissue states across cancer and non-cancer settings. GHIST+ establishes a scalable framework for transforming sparse spatial profiling experiments into tissue-wide molecular maps, enabling cohort-scale molecular reconstruction from routine histology under heterogeneous spatial transcriptomic settings.","rel_num_authors":13,"rel_authors":[{"author_name":"Andrew Zhang","author_inst":"University of Sydney"},{"author_name":"Lijia Yu","author_inst":"The University of Sydney"},{"author_name":"Beilei Bian","author_inst":"University of Sydney"},{"author_name":"Yue Cao","author_inst":"The University of Sydney"},{"author_name":"Shuchang Ye","author_inst":"University of Sydney"},{"author_name":"Ethan Han","author_inst":"University of Sydney"},{"author_name":"Harry Robertson","author_inst":"University of Sydney"},{"author_name":"Yuhao Dong","author_inst":"National University of Singapore"},{"author_name":"Yixiao Mao","author_inst":"National University of Singapore"},{"author_name":"Boxiang Liu","author_inst":"National University of Singapore"},{"author_name":"Ellis Patrick","author_inst":"University of Sydney"},{"author_name":"Jinman Kim","author_inst":"University of Sydney"},{"author_name":"Jean Yee Hwa Yang","author_inst":"University of Sydney"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Nutrient currencies and P resorption greatly amplify the perceived costs of reproductive allocation in perennial heath shrubs","rel_doi":"10.64898\/2026.06.10.731282","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731282","rel_abs":"-In woody perennials, reproductive allocation considered as a fraction of NPP (RA) has been rarely quantified, especially tracked across plant lifetimes, measured in biologically meaningful currencies, and separated from standing biomass. -We addressed this gap by measuring dry mass, nitrogen, and phosphorus for every aboveground tissue type for 14 iteroparous perennial shrubs tracked across their full lifetimes, calculating RA using four accounting schemes and three currencies. -RA was substantially higher by mid-life than typical estimates from ecosystem-scale studies. Distinguishing standing biomass from yearly production further revised RA upwards. Using a nutrient currency (especially P) increased the perceived costs of reproduction. Propagules were highly nutrient-enriched and reproductive accessory costs consumed more nutrients than did the propagules themselves. Considering N and P resorption from senescing leaves and wood shrank the effective vegetative nutrient budget, further concentrating net annual nutrient demand in reproductive tissues. -Our results highlight high investment in RA for woody perennials, especially using nutrient currencies. Broadly similar allocation patterns were observed across species with different functional traits and lifespans, suggesting generality that may apply across biomes. Widespread underestimation of RA in forest growth models likely overestimates the proportion of NPP available for vegetative growth, leading to substantial errors in predictions.","rel_num_authors":4,"rel_authors":[{"author_name":"Elizabeth Wenk","author_inst":"University of New South Wales"},{"author_name":"Daniel S Falster","author_inst":"University of New South Wales"},{"author_name":"Ian J Wright","author_inst":"Western Sydney University"},{"author_name":"Mark Westoby","author_inst":"Macquarie University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Nutrient currencies and P resorption greatly amplify the perceived costs of reproductive allocation in perennial heath shrubs","rel_doi":"10.64898\/2026.06.10.731282","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731282","rel_abs":"-In woody perennials, reproductive allocation considered as a fraction of NPP (RA) has been rarely quantified, especially tracked across plant lifetimes, measured in biologically meaningful currencies, and separated from standing biomass. -We addressed this gap by measuring dry mass, nitrogen, and phosphorus for every aboveground tissue type for 14 iteroparous perennial shrubs tracked across their full lifetimes, calculating RA using four accounting schemes and three currencies. -RA was substantially higher by mid-life than typical estimates from ecosystem-scale studies. Distinguishing standing biomass from yearly production further revised RA upwards. Using a nutrient currency (especially P) increased the perceived costs of reproduction. Propagules were highly nutrient-enriched and reproductive accessory costs consumed more nutrients than did the propagules themselves. Considering N and P resorption from senescing leaves and wood shrank the effective vegetative nutrient budget, further concentrating net annual nutrient demand in reproductive tissues. -Our results highlight high investment in RA for woody perennials, especially using nutrient currencies. Broadly similar allocation patterns were observed across species with different functional traits and lifespans, suggesting generality that may apply across biomes. Widespread underestimation of RA in forest growth models likely overestimates the proportion of NPP available for vegetative growth, leading to substantial errors in predictions.","rel_num_authors":4,"rel_authors":[{"author_name":"Elizabeth Wenk","author_inst":"University of New South Wales"},{"author_name":"Daniel S Falster","author_inst":"University of New South Wales"},{"author_name":"Ian J Wright","author_inst":"Western Sydney University"},{"author_name":"Mark Westoby","author_inst":"Macquarie University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Why do we seek information about the future? On the origins of subjective value without instrumental value","rel_doi":"10.64898\/2026.06.09.731206","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731206","rel_abs":"Why do we want to know the future? Humans and many animals pay for information to predict uncertain rewards, even when they cannot control them. The reason for this conserved yet seemingly paradoxical preference - \"subjective value without instrumental value\" - remains unknown. Here we develop a normative framework to explain the origins of such preferences, their persistence across species, and their contributions to survival. We formalize and evaluate theories that explain subjective value as originating from an adaptive estimate of advantage for solving core computational problems in naturalistic environments. We show that human and animal subjective values are remarkably well suited to solve these problems, accomplishing the goals of multiple theories simultaneously. We derive novel forms of information to enable existing theories to be dissociated, and show that pooling their subjective values improves performance across diverse environments. Thus, organisms may value information because it pays diverse dividends in nature.","rel_num_authors":3,"rel_authors":[{"author_name":"Ethan S Bromberg-Martin","author_inst":"Johns Hopkins University"},{"author_name":"Josh Merel","author_inst":"Fauna Robotics"},{"author_name":"Ilya E Monosov","author_inst":"Johns Hopkins University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Automated Segmentation of Brainstem and Subcortical White Matter: Mapping the Deep Tegmental Core with BundleParc","rel_doi":"10.64898\/2026.06.09.731210","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731210","rel_abs":"Diffusion MRI enables noninvasive mapping of human white matter pathways, but automated segmentation methods have largely focused on large association, projection, and commissural bundles. Yet compact brainstem and subcortical pathways supporting basal ganglia, cerebellar, limbic\/reward, sensory, and homeostatic functions remain underrepresented in large-scale connectomic analyses. To address this gap, we adapted BundleParc, a recently introduced bundle-parcellation architecture, into an automated pipeline for direct segmentation and along-tract parcellation of 97 subcortical and brainstem white matter pathways. The model was trained on a curated reference dataset derived from Human Connectome Project diffusion MRI using anatomy-guided tractography, explicit inclusion and exclusion criteria, automated outlier filtering, and manual quality assurance. Operating directly on native-space fiber orientation distributions, the algorithm successfully recovers these intricate anatomical trajectories and ordered parcellations. We show the model generalizes to diverse external datasets spanning development, aging, and neurodegenerative disease cohorts, maintaining robust performance across variations in spatial resolution and angular sampling. The released container, trained model, population atlas, reference streamlines, and quality assurance outputs provide a resource for studying deep brainstem and subcortical pathways in development, aging, disease, and neuromodulation-relevant anatomy.","rel_num_authors":19,"rel_authors":[{"author_name":"Kurt G. Schilling","author_inst":"Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, United States; Department of Radiology and Radiological"},{"author_name":"Gaurav Rudravaram","author_inst":"Department of Electrical Engineering, Vanderbilt University, Nashville, TN, United States"},{"author_name":"Antoine Theberge","author_inst":"Sherbrooke Connectivity Imaging Lab (SCIL), Universite de Sherbrooke, Quebec, Canada."},{"author_name":"Matthew Amandola","author_inst":"Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, United States; Department of Radiology and Radiological"},{"author_name":"Michael E. Kim","author_inst":"Department of Computer Science, Vanderbilt University, Nashville, TN, United States"},{"author_name":"Kathryn L. Humphreys","author_inst":"Vanderbilt University, Department of Psychology and Human Development, Nashville, TN, USA"},{"author_name":"Laurie Cutting","author_inst":"Vanderbilt University, Vanderbilt Brain Institute, Nashville, TN, USA; Peabody College of Education and Human Development, Department of Special Education, Nash"},{"author_name":"Derek Archer","author_inst":"Vanderbilt University, Vanderbilt Brain Institute, Nashville, TN, USA; Vanderbilt Memory and Alzheimer's Center, Vanderbilt University School of Medicine, Nashv"},{"author_name":"Timothy J. Hohman","author_inst":"Vanderbilt Memory and Alzheimers Center, Vanderbilt University School of Medicine, Nashville, TN, United States; Vanderbilt University Medical Center, Vanderbil"},{"author_name":"Angela L. Jefferson","author_inst":"Vanderbilt Memory and Alzheimers Center, Vanderbilt University School of Medicine, Nashville, TN, United States; Vanderbilt University Medical Center, Departmen"},{"author_name":"Lori L. Beason Held","author_inst":"Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA"},{"author_name":"Murat Bilgel","author_inst":"Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA"},{"author_name":"- Alzheimers Disease Neuroimaging Initiative","author_inst":"Alzheimers Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu)"},{"author_name":"- The BIOCARD Study Team","author_inst":"BIOCARD study, supported by grant U19AG033655 from the National Institute on Aging"},{"author_name":"Maxime Chamberland","author_inst":"Department of Mathematics and Computer Science, Eindhoven University of Technology, The Netherlands"},{"author_name":"Maxime Descoteaux","author_inst":"Sherbrooke Connectivity Imaging Lab (SCIL), Universite de Sherbrooke, Quebec, Canada."},{"author_name":"Laurent Petit","author_inst":"IRP\/LIA OpTeam, CNRS Biologie et Universite de Bordeaux, France - Universite de Sherbrooke, Sherbrooke, Canada; Universite Bordeaux, CNRS, CEA, IMN, GIN, UMR 52"},{"author_name":"Francois Rheault","author_inst":"Sherbrooke Connectivity Imaging Lab (SCIL), Universite de Sherbrooke, Quebec, Canada."},{"author_name":"Bennett A. Landman","author_inst":"Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, United States; Department of Radiology and Radiological"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Unified comparison of spinal locomotion control architectures in neuromechanical simulations","rel_doi":"10.64898\/2026.06.09.731213","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731213","rel_abs":"Neuromechanical simulations provide a powerful framework for investigating how neural control architectures generate and regulate human locomotion. Numerous biologically inspired locomotion controllers have been proposed, including reflex-based, central pattern generator (CPG)-based, and muscle synergy-based models. However, direct comparison across studies remains difficult because of differences in musculoskeletal models, optimization methods, and evaluation protocols. Here, we implemented four representative locomotion control architectures, reflex-based, CPG-reflex-based, muscle synergy-based, and CPG-reflex-synergy-based controllers, within a unified neuromechanical simulation framework to enable controlled comparisons under shared biomechanical and computational conditions. Performance was assessed in terms of (1) agreement with experimentally observed gait characteristics, including kinematics, kinetics, muscle activations, and biomechanical trends across speeds and slopes, and (2) locomotor versatility across speed-slope conditions. The reflex-based and CPG-reflex-synergy-based controllers most closely reproduced experimentally observed gait characteristics, while the CPG-reflex-synergy controller achieved the broadest range of stable walking behaviors across speeds and slopes, followed closely by the reflex-based controller. These findings should be interpreted as comparisons of specific model implementations rather than definitive evaluations of the underlying biological hypotheses. Moreover, because the investigated controllers primarily focused on spinal-level mechanisms for nominal steady-state locomotion, the limited versatility observed in some of the models across broader speed and slope conditions suggests the importance of integrating spinal locomotor mechanisms with supraspinal modulation when modeling locomotion beyond nominal steady gait. To facilitate further investigation, we publicly share the simulation framework and controller implementations.","rel_num_authors":2,"rel_authors":[{"author_name":"Vincent Ton","author_inst":"Northeastern University"},{"author_name":"Seungmoon Song","author_inst":"Northeastern University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Biological Aging of the Cardiopulmonary System","rel_doi":"10.64898\/2026.06.09.731192","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731192","rel_abs":"Age-related stiffening of large arteries is a predictor of cardiovascular morbidity and mortality, yet how pulmonary vascular stiffening integrates with right ventricular (RV) and lung functional decline and how best to quantify biological cardiopulmonary aging remains unclear. Here we map cardiopulmonary aging across the adult murine lifespan by integrating RV, proximal pulmonary artery (PA), and lung biomechanics with single-cell transcriptomics. Using ex vivo biaxial testing of the proximal PA, in vivo echocardiography, and lung mechanics, we find that cardiopulmonary aging is phase-dependent: PA circumferential stiffening and reduced distensibility progress largely linearly with age; whereas, RV remodeling and lung mechanical changes exhibit non-linear trajectories. This is consistent with early intrinsic functional decline of cells and organs followed by later, extrinsic load-dependent structural adaptation. To quantify organ-level biological aging, we apply principal component analysis to PA, RV, and lung feature sets to derive physiology-based aging scores that summarize coordinated variance within and across organs. Anchoring differential gene expression in PA single-cell RNA-seq to these continuous biological aging scores rather than chronological age reveals extensive, cell type-specific remodeling programs (13,636 genes) that are sparse or non-informative when modeled by chronologic age. Biological aging associates across endothelia, smooth muscle cells, fibroblasts, and perivascular macrophages with increased oxidative phosphorylation signatures alongside suppression of adaptive\/regulatory pathways, including impaired endothelial mechanotransduction, reduced smooth muscle Wnt signaling, altered extracellular matrix remodeling programs, and erosion of macrophage innate immune and TGF{beta}\/NF-{kappa}B signaling nodes. These findings support a model in which pulmonary arterial stiffening is not merely a marker but an active contributor to cardiopulmonary aging via a biomechanical-metabolic-inflammatory uncoupling that diminishes vasoactive and mechano-adaptive reserve and promotes a positive feedback loop. Together, our work establishes physiology-derived biological aging as a powerful framework for interpreting vascular single-cell aging trajectories and identifies mechanistic pathways to target pulmonary vascular stiffening and preserve cardiopulmonary function with age.","rel_num_authors":15,"rel_authors":[{"author_name":"Dongnan Liu","author_inst":"Yale School of Medicine"},{"author_name":"Pramath Doddaballapur","author_inst":"University of California, Santa Barbara"},{"author_name":"Zhongyu Cai","author_inst":"Yale School of Medicine"},{"author_name":"Rira Choi","author_inst":"Yale School of Medicine"},{"author_name":"Jack Di Palo","author_inst":"Yale School of Medicine"},{"author_name":"Nicole Guerrera","author_inst":"Yale School of Medicine"},{"author_name":"Nebal Abu Hussein","author_inst":"Yale School of Medicine"},{"author_name":"Meredith S. Gwin","author_inst":"Yale School of Medicine"},{"author_name":"Liqin Lin","author_inst":"Yale School of Medicine"},{"author_name":"Siming Zheng","author_inst":"Yale School of Medicine"},{"author_name":"Yuening Zhang","author_inst":"Yale School of Medicine"},{"author_name":"Aurelien Justet","author_inst":"Yale University School of Medicine"},{"author_name":"Abhay B. Ramachandra","author_inst":"Iowa State University"},{"author_name":"Xiting Yan","author_inst":"Yale University School of Medicine"},{"author_name":"Edward P. Manning","author_inst":"VA, Yale"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Biological Aging of the Cardiopulmonary System","rel_doi":"10.64898\/2026.06.09.731192","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731192","rel_abs":"Age-related stiffening of large arteries is a predictor of cardiovascular morbidity and mortality, yet how pulmonary vascular stiffening integrates with right ventricular (RV) and lung functional decline and how best to quantify biological cardiopulmonary aging remains unclear. Here we map cardiopulmonary aging across the adult murine lifespan by integrating RV, proximal pulmonary artery (PA), and lung biomechanics with single-cell transcriptomics. Using ex vivo biaxial testing of the proximal PA, in vivo echocardiography, and lung mechanics, we find that cardiopulmonary aging is phase-dependent: PA circumferential stiffening and reduced distensibility progress largely linearly with age; whereas, RV remodeling and lung mechanical changes exhibit non-linear trajectories. This is consistent with early intrinsic functional decline of cells and organs followed by later, extrinsic load-dependent structural adaptation. To quantify organ-level biological aging, we apply principal component analysis to PA, RV, and lung feature sets to derive physiology-based aging scores that summarize coordinated variance within and across organs. Anchoring differential gene expression in PA single-cell RNA-seq to these continuous biological aging scores rather than chronological age reveals extensive, cell type-specific remodeling programs (13,636 genes) that are sparse or non-informative when modeled by chronologic age. Biological aging associates across endothelia, smooth muscle cells, fibroblasts, and perivascular macrophages with increased oxidative phosphorylation signatures alongside suppression of adaptive\/regulatory pathways, including impaired endothelial mechanotransduction, reduced smooth muscle Wnt signaling, altered extracellular matrix remodeling programs, and erosion of macrophage innate immune and TGF{beta}\/NF-{kappa}B signaling nodes. These findings support a model in which pulmonary arterial stiffening is not merely a marker but an active contributor to cardiopulmonary aging via a biomechanical-metabolic-inflammatory uncoupling that diminishes vasoactive and mechano-adaptive reserve and promotes a positive feedback loop. Together, our work establishes physiology-derived biological aging as a powerful framework for interpreting vascular single-cell aging trajectories and identifies mechanistic pathways to target pulmonary vascular stiffening and preserve cardiopulmonary function with age.","rel_num_authors":15,"rel_authors":[{"author_name":"Dongnan Liu","author_inst":"Yale School of Medicine"},{"author_name":"Pramath Doddaballapur","author_inst":"University of California, Santa Barbara"},{"author_name":"Zhongyu Cai","author_inst":"Yale School of Medicine"},{"author_name":"Rira Choi","author_inst":"Yale School of Medicine"},{"author_name":"Jack Di Palo","author_inst":"Yale School of Medicine"},{"author_name":"Nicole Guerrera","author_inst":"Yale School of Medicine"},{"author_name":"Nebal Abu Hussein","author_inst":"Yale School of Medicine"},{"author_name":"Meredith S. Gwin","author_inst":"Yale School of Medicine"},{"author_name":"Liqin Lin","author_inst":"Yale School of Medicine"},{"author_name":"Siming Zheng","author_inst":"Yale School of Medicine"},{"author_name":"Yuening Zhang","author_inst":"Yale School of Medicine"},{"author_name":"Aurelien Justet","author_inst":"Yale University School of Medicine"},{"author_name":"Abhay B. Ramachandra","author_inst":"Iowa State University"},{"author_name":"Xiting Yan","author_inst":"Yale University School of Medicine"},{"author_name":"Edward P. Manning","author_inst":"VA, Yale"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"A multi-omics map of diabetic nephropathy links c-Jun activation to tubular injury and metabolic stress","rel_doi":"10.64898\/2026.06.09.731164","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731164","rel_abs":"Diabetic nephropathy (DN) is a major cause of end-stage renal disease, yet the molecular mechanisms driving tubular injury and fibrosis remain poorly defined. Here, we integrated single-cell multiplexed protein imaging, spatial transcriptomics, single-nucleus and single-cell RNA sequencing and chromatin accessibility profiling to comprehensively characterize human DN pathology. Our multi-modal analysis precisely maps kidney cell types and their spatial distributions, immune-fibrotic interactions, and key transcriptional regulators. We identified eight distinct cellular neighborhoods defining the immune-fibrotic microenvironment and uncovered molecular networks driving tubular injury and fibrosis. JUN (encoding c-Jun) emerged as a central regulator of transcriptional reprogramming during tubular injury and fibrogenic remodeling. In a diabetic mouse model, c-Jun is activated in injured proximal tubules. Using an inducible c-Jun mouse model, we demonstrated that tubular-specific c-Jun activation alone is sufficient to induce tubular injury, chronic inflammation, progressive fibrosis, and systemic metabolic alterations, including impaired glucose homeostasis. We also observed reduced expression of SLC4A4, a bicarbonate transporter essential for proximal tubular function, in injured tubules. Together, our findings establish a spatially resolved framework for understanding DN pathogenesis and identify c-Jun as a key mediator of tubular injury and fibrosis in diabetic kidney disease.","rel_num_authors":11,"rel_authors":[{"author_name":"Qiwen Deng","author_inst":"Department of Pathology, Stanford School of Medicine"},{"author_name":"Yu Liu","author_inst":"Cardiovascular Institute, Stanford School of Medicine"},{"author_name":"Nathan Bracey","author_inst":"Stanford Institute for Immunology, Transplantation and Infection, Stanford University"},{"author_name":"Yi-Chuan Wang","author_inst":"Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan"},{"author_name":"Paul Wadsworth","author_inst":"Department of Pathology, Stanford School of Medicine"},{"author_name":"Marjia Afrin","author_inst":"Department of Pathology, Stanford School of Medicine"},{"author_name":"Matteo Santoro","author_inst":"Department of Pathology, Stanford School of Medicine"},{"author_name":"Shih-Yu Chen","author_inst":"Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan"},{"author_name":"Joseph Wu","author_inst":"Cardiovascular Institute, Stanford School of Medicine"},{"author_name":"Vivek Charu","author_inst":"Department of Pathology, Stanford School of Medicine"},{"author_name":"Gerlinde Wernig","author_inst":"Department of Pathology, Stanford School of Medicine"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"3D-Printed Scaffolds for Local Chemotherapeutic Delivery in Resected Spine Metastases","rel_doi":"10.64898\/2026.06.09.731191","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731191","rel_abs":"Spinal metastases often occur secondary to breast, lung and prostate cancer and lead to instability, pain and poor quality of life. Standard care for spine metastases includes a multidisciplinary approach with surgery playing a major role in tumor resection, stabilization and decompression. Surgical resection with adjuvant is an effective treatment, yet it is often accompanied by tumor recurrence from residual disease. Furthermore, acrylic cements applied to defect sites provide stability, but they do not promote bone repair and can become destabilized during recurrence events. Developing new tools to stabilize defect sites, promote bone repair and locally deliver therapeutics may circumvent these limitations. We have previously developed mechanically competent 3D printed lactide\/mineral scaffolds conducive to bone repair in vivo. We have also developed 3D printed nanoporous scaffolds conducive to both bone repair and chemotherapeutic delivery. Here, we set out to assess doxorubicin and cisplatin uptake and release rates and efficacy of drug delivery in 2D and custom physiological 3D cultures of two human cancer cell lines associated with metastases, MDA-MB-231 (human breast) and C42B (human prostate). Composite scaffolds had a compressive modulus close to trabecular bone, and could sustainably and effectively release doxorubicin and cisplatin as measured against both breast and prostate cell lines in 2D and 3D custom physiological metastases models. As a proof-of-concept, doxorubicin loaded composite scaffolds were implanted into rat caudal vertebrae following MDA-MB-231 xenograft resection. Following 6 weeks of implantation, no adverse events were noted and microCT analysis revealed boney integration of the construct. Taken together, these data indicate that our composite scaffolds may be an appropriate alternate therapy to stabilize bone defects, promote bone repair and effectively inhibit cancer recurrence post-tumor resection. Future work will test composite scaffolds using in vivo bone metastases models.","rel_num_authors":10,"rel_authors":[{"author_name":"Audrey A Pitaru","author_inst":"McGill University"},{"author_name":"Ateeque Siddique","author_inst":"McGill University"},{"author_name":"Mansoureh Mohseni-Garakani","author_inst":"Polytechnique Montreal"},{"author_name":"Branda N Boakye","author_inst":"McGill University"},{"author_name":"Michael H Weber","author_inst":"University of Connecticut"},{"author_name":"Abdellah Ajji","author_inst":"Polytechnique Montreal"},{"author_name":"Michael Wertheimer","author_inst":"Polytechnique Montreal"},{"author_name":"Isabelle Villemure","author_inst":"Polytechnique Montreal"},{"author_name":"Lisbet Haglund","author_inst":"McGill University"},{"author_name":"Derek Rosenzweig","author_inst":"McGill University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Structural and Mechanistic Basis of F227C-Mediated Hypersusceptibility to Islatravir in HIV-1 Reverse Transcriptase","rel_doi":"10.64898\/2026.06.08.730881","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730881","rel_abs":"Islatravir (ISL; 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA)), a first-in-class nucleoside reverse transcriptase (RT) translocation inhibitor (NRTTI), was recently approved by the FDA for the treatment of HIV-1 infection in combination with the non-nucleoside RT inhibitor (NNRTI), doravirine (DOR). Notably, the RT mutation F227C, which confers clinical resistance to multiple NNRTIs, including DOR, unexpectedly increases susceptibility to ISL. To elucidate the mechanistic basis of this hypersusceptibility, we determined a 1.8 angstrom crystal structure of F227C RT in complex with a ddGMP-terminated primer\/template and ISL-triphosphate. The structure reveals conformational rearrangements that propagate into an adjacent cleft, thereby affecting ATP-mediated unblocking of chain-terminating antivirals. Complementary biochemical assays showed that although F227C does not significantly affect ISL incorporation, it alters RT translocation and impairs ATP-dependent phosphorolytic excision of ISL-terminated primers, thereby enhancing ISL susceptibility. These findings establish direct structural and mechanistic links between NNRTI resistance and ISL hypersusceptibility, providing a structural foundation for rationally designed, resistance-informed combination regimens that exploit this unique collateral sensitivity.","rel_num_authors":7,"rel_authors":[{"author_name":"Alexa A Snyder","author_inst":"Emory University"},{"author_name":"Isabella L Kaufman","author_inst":"Emory University"},{"author_name":"Jack MacQuillan","author_inst":"Emory University"},{"author_name":"Ryan L Slack","author_inst":"Emory University"},{"author_name":"Karen A Kirby","author_inst":"Emory University"},{"author_name":"Eleftherios Michailidis","author_inst":"Emory University"},{"author_name":"Stefan G Sarafianos","author_inst":"Emory University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Ecosystem disservices are underrepresented in literature on annual crop agroecosystems","rel_doi":"10.64898\/2026.06.09.730574","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.730574","rel_abs":"Maximising ecosystem service (ES) benefits while minimising ecosystem disservices (EDS) is essential for ecological intensification in annual crop systems. Yet ecosystem disservices are often underreported in the scientific literature, potentially biasing how agroecosystem functioning is understood. To test this, we built a predicted network of plausible links between ecosystem service providers (taxa or functional groups that can deliver ecosystem services or disservices), and the ES or EDS they may provide. We then compared this with a realised network based on systematic Scopus searches of annual crop literature. The predicted network contained 47 nodes and 103 links, whereas the realised network contained 33 nodes and 58 links, representing declines of 29.8% in nodes and 43.7% in links. Overall connectivity declined, especially for highly connected nodes, and four of the nine predicted disservice nodes were absent from the literature. ES links were more likely to be documented than EDS links, and EDS links were three times more likely to be absent. Across all links, ES were reported in 6.6 times more papers than EDS. Projected networks, which map indirect connections by linking ES directly to EDS if they share common providers, showed that these bundled interactions were strongly reduced, obscuring multifunctionality and trade-offs. This systematic underrepresentation of EDS, reflecting a cognitive bias, can inflate perceived benefits, distort the evaluation of key taxa and interactions, and create unrealistic expectations about intervention outcomes in biological crop protection. Addressing EDS alongside ES is therefore essential for more balanced assessments of crop-system management and better-informed decisions.","rel_num_authors":25,"rel_authors":[{"author_name":"Gabor Pozsgai","author_inst":"Centre for Applied Economics of the Atlantic, University of Azores, Angra do Heroismo, Portugal"},{"author_name":"Kris Wyckhuys","author_inst":"Chrysalis Consulting, Danang, Vietnam"},{"author_name":"Ibtissem Ben Fekih","author_inst":"Functional and Evolutionary Entomology, Terra, Gembloux Agro-Bio Tech, University of Liege, Passage des Deportes 2, 5030 Gembloux, Belgium."},{"author_name":"Liette Vasseur","author_inst":"UNESCO Chair on Community Sustainability: From Local to Global, Dept. Biol. Sci., Brock University, Canada"},{"author_name":"Geoff Gurr","author_inst":"Gulbali Institute, School of Agriculture, Environment and Veterinary Sciences, Charles Sturt University, Orange NSW 2800, Australia"},{"author_name":"Mark Goettel","author_inst":"Agriculture and Agri-Food Canada, Lethbridge Research Centre, Lethbridge, AB, Canada"},{"author_name":"Heather VanVolkenburg","author_inst":"Brock University, Canada"},{"author_name":"Sunita Pandey","author_inst":"Ministry of Agriculture and Livestock Development, Singhadurbar, Nepal"},{"author_name":"Jamile Queiroz-Sousa","author_inst":"Instituto de Biociencias de Botucatu (IBB), Universidade Estadual Paulista Julio de Mesquita Filho (UNESP), Botucatu, Sao Paulo, Brazil"},{"author_name":"Pingyang Zhu","author_inst":"College of Life Sciences, Zhejiang Normal University, Jinhua 321004, China"},{"author_name":"Mohammed Abul Monjur Khan","author_inst":"Department of Entomology, Faculty of Agriculture, Bangladesh Agricultural University, Mymensingh-2202, Bangladesh"},{"author_name":"Titus Imboma","author_inst":"Ornithology Section of the Zoology Department, National Museums of Kenya, PO Box 40658- 00100, GPO. Nairobi, Kenya"},{"author_name":"Margaret M. Hughes","author_inst":"Department of Biological Sciences, University of Calgary, Calgary, AB, Canada"},{"author_name":"Jian Liu","author_inst":"Artificial Intelligence and Cyber Futures Centre, Charles Sturt University, Orange NSW 2800, Australia"},{"author_name":"Syed Rizvi","author_inst":"Applied Biosciences, Macquarie University, Sydney, Australia"},{"author_name":"Olivia Reynolds","author_inst":"Gulbali Institute, School of Agriculture, Environment and Veterinary Sciences, Charles Sturt University, Orange NSW 2800, Australia"},{"author_name":"Hafiz Sohaib Ahmed Saqib","author_inst":"Yunnan Key Laboratory of Forest Ecosystem Stability and Global Change, Xishuangbanna Tropical Botanical Garden, Chinese Academy of Sciences, Menglun, Mengla, Yu"},{"author_name":"Stephen Wratten","author_inst":"Bio-Protection Research Centre, Lincoln University, New Zealand"},{"author_name":"Jie Zhang","author_inst":"Fujian Key Laboratory for Monitoring and Integrated Management of Crop Pests, Fujian Engineering Research Center for Green Pest Management, Institute of Plant P"},{"author_name":"Wenwu Zhou","author_inst":"State Key Laboratory of Rice Biology, Key Laboratory of Molecular Biology of Crop Pathogens and Insects, Ministry of Agriculture, Zhejiang University, Hangzhou,"},{"author_name":"Francisco Javier Garcia","author_inst":"Independent Researcher, Murcia, Spain"},{"author_name":"Lucas Alexander Shuttleworth","author_inst":"National Institute of Agricultural Botany (NIAB), Department of Pest & Pathogen Ecology, East Malling, Kent ME19 6BJ United Kingdom"},{"author_name":"Li-Lin Chen","author_inst":"State Key Laboratory of Agriculture and Forestry Biosecurity, Institute of Applied Ecology, Fujian Agriculture and Forestry University, Fuzhou 350002, China"},{"author_name":"Gabor L. Lovei","author_inst":"Department of Agroecology, Flakkebjerg Research Centre, Aarhus University, 4200 Slagelse, Denmark"},{"author_name":"Minsheng You","author_inst":"State Key Laboratory of Agriculture and Forestry Biosecurity, Institute of Applied Ecology, Fujian Agriculture and Forestry University, Fuzhou 350002, China"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Passive Physiological Responses Fail to Predict Context-Dependent Action Selection in Bats","rel_doi":"10.64898\/2026.06.09.731189","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731189","rel_abs":"How social animals encode vocalizations, assign them value, and formulate behavioral responses remains largely unknown. We asked whether physiological signatures of social-call perception predict behavioral responses across contexts, using the Egyptian Fruit Bat (Rousettus aegyptiacus), an auditory specialist with a rich repertoire of social calls. Using heart rate monitoring during playback of conspecific vocalizations, we found that females showed larger heart rate responses than males to social calls (aggression and distress), whereas non-social echolocation calls evoked no sex difference. In vivo recordings from primary auditory cortex (A1) revealed call-selective units whose selectivity was independent of frequency tuning, with the largest selective fraction for distress calls. In a behavioral assay, female bats approached a distress-call playback only when a live conspecific was coupled with it. However, in isolation, the same calls elicited interest (grooming, pointing) but no approach. Together, the neural and autonomic signatures of social-call perception are present across contexts, whereas the behavioral response is not. Social context, therefore, does not modulate the behavioral readout of social calls; rather, it gates it.","rel_num_authors":4,"rel_authors":[{"author_name":"Zaria J George","author_inst":"University of Illinois Chicago"},{"author_name":"Inaky Marin","author_inst":"University of Illinois Chicago"},{"author_name":"Anna C Sanderson","author_inst":"University of Iowa"},{"author_name":"Angeles Salles","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Passive Physiological Responses Fail to Predict Context-Dependent Action Selection in Bats","rel_doi":"10.64898\/2026.06.09.731189","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731189","rel_abs":"How social animals encode vocalizations, assign them value, and formulate behavioral responses remains largely unknown. We asked whether physiological signatures of social-call perception predict behavioral responses across contexts, using the Egyptian Fruit Bat (Rousettus aegyptiacus), an auditory specialist with a rich repertoire of social calls. Using heart rate monitoring during playback of conspecific vocalizations, we found that females showed larger heart rate responses than males to social calls (aggression and distress), whereas non-social echolocation calls evoked no sex difference. In vivo recordings from primary auditory cortex (A1) revealed call-selective units whose selectivity was independent of frequency tuning, with the largest selective fraction for distress calls. In a behavioral assay, female bats approached a distress-call playback only when a live conspecific was coupled with it. However, in isolation, the same calls elicited interest (grooming, pointing) but no approach. Together, the neural and autonomic signatures of social-call perception are present across contexts, whereas the behavioral response is not. Social context, therefore, does not modulate the behavioral readout of social calls; rather, it gates it.","rel_num_authors":4,"rel_authors":[{"author_name":"Zaria J George","author_inst":"University of Illinois Chicago"},{"author_name":"Inaky Marin","author_inst":"University of Illinois Chicago"},{"author_name":"Anna C Sanderson","author_inst":"University of Iowa"},{"author_name":"Angeles Salles","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Using HD-DOT in precision accuracy microgenetic research designs to measure change over time in speech, language, and hearing clinical populations","rel_doi":"10.64898\/2026.06.09.725667","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.725667","rel_abs":"Documenting change is fundamental to understanding the process of intervention among individuals with communication disorders. This technical report demonstrates the clinical applicability of wearable fNIRS systems and the NeuroDOT processing pipelines for examining within-person cortical dynamics of learning. Using a microgenetic research design and a dense sampling approach, we examined changes in the prefrontal cortical hemodynamic response in an adult female participant who completed the same spoken sentence repetition and auditory fixation tasks across eight sessions. In addition to behavioral accuracy, hemodynamic data were collected with a continuous-wave, multi-channel fNIRS system (NIRSport2) using a prefrontal 20-channel optode montage. Data were processed using NeuroDOT (https:\/\/www.nitrc.org\/projects\/neurodot) (Eggebrecht & Culver, 2019) to: (i) standardize signal quality across the sessions to quantify motion levels and to ensure standardized brain map specificity, (ii) to examine both channel space fluctuations in the hemodynamic response and map changes in cortical activation patterns over the sessions. The signal quality met the predefined criteria for only the first five sessions. Participant's repetition accuracy did not improve over the five sessions. Channel-wise analysis revealed that HbO concentration differs significantly over right and left hemisphere channels over the course of the five sessions for the Sentence Repetition task, but not for the Auditory Fixation condition. Brain maps revealed qualitative differences in the pattern of prefrontal cortical activation across the five sessions. Behavioral assessments do not fully capture what occurs during speech repetition tasks, and leveraging neuroimaging can help identify and discriminate between disordered and neurotypical populations.","rel_num_authors":6,"rel_authors":[{"author_name":"Sarah Crow","author_inst":"The University of Texas at Dallas"},{"author_name":"Ari Segel","author_inst":"Washington University in St. Louis"},{"author_name":"Emma Speh","author_inst":"Washington University in St. Louis"},{"author_name":"Adam T Eggebrecht","author_inst":"Washington University in St. Louis"},{"author_name":"Paulina Skolasinska","author_inst":"McGill University"},{"author_name":"Julia Evans","author_inst":"The University of Texas at Dallas"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Spatial Organization of Lipids Drives GPCR Conformational Equilibria","rel_doi":"10.64898\/2026.06.11.731710","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731710","rel_abs":"Despite the widespread use of lipid nanodiscs for structure-function studies of membrane proteins, little is known about how lipids are spatially organized within nanodiscs and how this organization influences embedded proteins. The activity and conformational equilibria of the human A2A adenosine receptor, a class A G protein-coupled receptor, are highly sensitive to anionic lipids that directly interact with the receptor. We leverage this lipid-dependent sensitivity to probe the accessibility of anionic lipids across nanodiscs of varying sizes. We identify a threshold concentration of anionic lipids required to fully populate active receptor conformations that is higher for POPS than for POPG. Computational simulations reveal that POPS and POPG each form lipid clusters reducing the effective availability of anionic lipids to interact with the receptor. This effect is stronger for POPS and scales with increasing nanodisc size, correlating with experimental biophysical and biochemical measurements. Simulations further identify positively charged residues within the membrane scaffold protein that coordinate anionic lipid headgroups. Targeted protein engineering reduces the threshold concentration of anionic lipids required for receptor activation, supporting strategies to control lipid accessibility within nanodiscs. Because membrane scaffold proteins are derived from apolipoprotein AI, similar lipid-protein interactions may also influence lipid organization within biological systems such as HDL particles.","rel_num_authors":10,"rel_authors":[{"author_name":"Anuradha Viraj Wijesekara","author_inst":"University of Florida"},{"author_name":"Jingjing Ji","author_inst":"University of Delaware"},{"author_name":"Nessa Pesaran Afsharian","author_inst":"University of Florida"},{"author_name":"Keen Zhang","author_inst":"University of Florida"},{"author_name":"Naveen Thakur","author_inst":"University of Florida"},{"author_name":"Arka P. Ray","author_inst":"University of Florida"},{"author_name":"Bar Elmaleh","author_inst":"University of Florida"},{"author_name":"Niloofar Gopal Pour","author_inst":"University of Florida"},{"author_name":"Edward Lyman","author_inst":"Univ. of Delaware"},{"author_name":"Matthew Eddy","author_inst":"University of Florida"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Isolation of postnatal human neural stem cells","rel_doi":"10.64898\/2026.06.11.731596","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.11.731596","rel_abs":"While it was once thought that neurogenesis is complete by birth, it is now apparent that the human brain continues to generate new neurons postnatally, at least into childhood. While much attention has been focused on postnatally-born neurons, their presumed progenitor -- the postnatal neural stem cell (NSC) -- remains poorly characterized. Using index sorting, we identify and prospectively isolate two subsets of NSCs from the postnatal human brain, and describe their differentiation dynamics using clonal barcoding and in vivo xenotransplantation. We demonstrate an A2B5+EGFR+ population biased towards interneuron and oligodendrocyte fates (NINO), and an A2B5-EGFRhi population biased towards an astrocyte fate (NAC). Profiling of human brains across lifespan shows that the frequency of NSCs declined exponentially across the first two decades of life, but stabilized thereafter, still present in the brains of donors as old as 90 years. Our study provides a framework for the functional study of postnatal human NSCs and their potential roles in development, aging, and disease.","rel_num_authors":24,"rel_authors":[{"author_name":"Daniel D Liu","author_inst":"Stanford University"},{"author_name":"Anna E Eastman","author_inst":"Stanford University"},{"author_name":"Nicole L Womack-Gambrel","author_inst":"Stanford University"},{"author_name":"Chang N Kim","author_inst":"University of California San Francisco"},{"author_name":"Joy Q He","author_inst":"Stanford University"},{"author_name":"Suyash Raj","author_inst":"Stanford University"},{"author_name":"Emily Reilly","author_inst":"Stanford University"},{"author_name":"Rahul Sinha","author_inst":"Stanford University"},{"author_name":"Nobuko Uchida","author_inst":"Stanford University"},{"author_name":"Kelly Chau","author_inst":"Stanford University"},{"author_name":"Benjamin F Ohene-Gambill","author_inst":"Stanford University"},{"author_name":"Samrat Thapa","author_inst":"Stanford University"},{"author_name":"Emon Nasajpour","author_inst":"Stanford University"},{"author_name":"Julia A Belk","author_inst":"Stanford University"},{"author_name":"Norma F Neff","author_inst":"Stanford University"},{"author_name":"Siddhartha Jaiswal","author_inst":"Stanford University"},{"author_name":"H Westley Phillips","author_inst":"Stanford University"},{"author_name":"Meagan Chambers","author_inst":"Stanford University"},{"author_name":"Claudia K Petritsch","author_inst":"Stanford Univeristy"},{"author_name":"Gerald A Grant","author_inst":"Duke University"},{"author_name":"Laura M Prolo","author_inst":"Stanford University"},{"author_name":"Jody E Hooper","author_inst":"Stanford University"},{"author_name":"Tomasz J. Nowakowski","author_inst":"University of California San Francisco"},{"author_name":"Irving L Weissman","author_inst":"Stanford University"}],"rel_date":"2026-06-12","rel_site":"biorxiv"},{"rel_title":"Malaria Risk among Internally Mobile Individuals and Heterogeneous Mobility Patterns in Two Hypoendemic Communities: Implications for Malaria Elimination in the Peruvian Amazon.","rel_doi":"10.64898\/2026.06.10.26355294","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355294","rel_abs":"Background: Human mobility is increasingly recognized as a key factor influencing malaria transmission dynamics, particularly in low-transmission settings approaching elimination. This study aimed to assess mobility patterns and their association with malaria risk in two hypoendemic communities in the Peruvian Amazon. Method: A longitudinal study was conducted in the communities of Libertad and Urcomirano (Mazan River basin). Monthly population screenings were combined with weekly active and passive case detection. A total of 678 individuals were enrolled. Mobility patterns were assessed through structured questionnaires, and social network analysis was used to characterize travel connections. Log-binomial regression analysis was applied to identify risk factors associated with malaria infection. Result: Internally, mobile individuals in Libertad showed a higher malaria incidence (>32.47 cases per 1,000 person-months) than those in Urcomirano (<10.15 cases per 1,000 person-months). Travel networks were mainly connected to Mazan district and Iquitos city, followed by local streams such as Armas and Arahuana. Mobility was primarily driven by family, administrative and occupational activities. Male sex (PR = 2.15, 95% CI: 1.37 - 3.37) and age [&ge;]15 years (PR = 1.98, 95% CI: 1.24 - 3.19) were significantly associated with malaria infection (p-value < 0.05). Conclusion: Internally mobile populations represent a key high-risk group sustaining malaria transmission in hypoendemic settings. Targeted interventions focusing on mobile individuals should be integrated into malaria elimination strategies in the Peruvian Amazon and similar endemic regions.","rel_num_authors":8,"rel_authors":[{"author_name":"Roberson Ramirez Saavedra","author_inst":"Unidad Especializada de Biotecnologia, Centro de Investigacion de Recursos Naturales de la Amazonia, Universidad Nacional de la Amazonia Peruana, Iquitos, Peru"},{"author_name":"Carlos Acosta","author_inst":"Laboratorio ICEMR-Enfermedades Emergentes, Laboratorios de Investigacion y Desarrollo, Facultad de Ciencias e Ingenieria, Universidad Peruana Cayetano Heredia, "},{"author_name":"Pamela Rodriguez","author_inst":"Laboratorio de Malaria: Parasitos y Vectores, Laboratorios de Investigacion y Desarrollo, Facultad de Ciencias e Ingenieria, Universidad Peruana Cayetano Heredi"},{"author_name":"Luis Cabrera-Sosa","author_inst":"Laboratorio de Malaria: Parasitos y Vectores, Laboratorios de Investigacion y Desarrollo, Facultad de Ciencias e Ingenieria, Universidad Peruana Cayetano Heredi"},{"author_name":"Ananias A. Escalente","author_inst":"Institute for Genomics and Evolutionary Medicine (IGEM), Temple University, Philadelphia, Pennsylvania, USA."},{"author_name":"Joseph M. Vinetz","author_inst":"Section of Infectious Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA."},{"author_name":"Katherine Torres","author_inst":"Departamento de Ciencias Celulares y Moleculares, Facultad de Ciencias e Ingenieria, Universidad Peruana Cayetano Heredia, Lima, Peru."},{"author_name":"Dionicia Gamboa","author_inst":"Departamento de Ciencias Celulares y Moleculares, Facultad de Ciencias e Ingenieria, Universidad Peruana Cayetano Heredia, Lima, Peru."}],"rel_date":"2026-06-11","rel_site":"medrxiv"},{"rel_title":"Incremental costs of transitioning from four to eight WHO-recommended antenatal care visits in Uganda: A costing analysis from a societal perspective","rel_doi":"10.64898\/2026.06.10.26355347","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355347","rel_abs":"Background In 2016, the World Health Organization revised its antenatal care (ANC) recommendation from four to eight visits. For low- and middle-income countries like Uganda, where achieving even four visits remains a challenge, this transition has significant cost implications for both the health system and households. This study estimated the incremental costs of adopting the eight-visit model from a societal perspective. Methods The study was conducted in six government health facilities in southwestern Uganda. A micro-costing approach estimated health facility costs (personnel, equipment, consumables, and overhead). Costs incurred at patients end (transport, ultrasound, medical expenses, and time) were collected from 785 women using a questionnaire, with all costs in 2025 USD. Results For an average of 4.3 visits, total cost per woman was $100.1: facility costs $43.7 (43.7%), and patient costs $56.4 (56.3%). Transitioning to eight visits would increase total cost by $57.8 (57.8%), of which $36.4 (63.0%) would fall on households, equivalent to 68.8% of average monthly household income. Total costs would rise by 55.4% ($115.5 to $179.5) at Health Center IVs and 64.3% ($102.3 to $168.1) at Health Center IIIs, with facility costs up 43.4% and 62.9% and patient costs up 61.2% and 65.7%, respectively. Conclusion Transitioning to eight ANC visits would impose a large financial burden on households, with the incremental patient cost equivalent to more than two-thirds of average monthly household income. Equitable implementation requires improving availability of medicines and diagnostics, subsidizing transport, exploring telemedicine or community-based models, and improving efficiency at lower-tier health centers.","rel_num_authors":10,"rel_authors":[{"author_name":"Elly  B Atuhumuza","author_inst":"Mbarara University of Science and Technology, Mbarara, Uganda"},{"author_name":"Esther C Atukunda","author_inst":"Mbarara University of Science and Technology, Mbarara, Uganda"},{"author_name":"Angella Musiimenta","author_inst":"Mbarara University of Science and Technology, Mbarara, Uganda"},{"author_name":"Godfrey R Mugyenyi","author_inst":"Mbarara University of Science and Technology, Mbarara, Uganda"},{"author_name":"Jessica Haberer","author_inst":"Department of Medicine and Center for Global Health, Massachusetts General Hospital, Boston, Massachusetts, United States of America"},{"author_name":"Celestino Obua","author_inst":"Mbarara University of Science and Technology, Mbarara, Uganda"},{"author_name":"Mark J Siedner","author_inst":"Department of Medicine and Center for Global Health, Massachusetts General Hospital, Boston, Massachusetts, United States of America"},{"author_name":"Lynn T Matthews","author_inst":"Yale School of Medicine, Yale University, New Haven, Connecticut"},{"author_name":"Vincent Batwala","author_inst":"Mbarara University of Science and Technology, Mbarara, Uganda"},{"author_name":"Van T Nghiem","author_inst":"University of Alabama at Birmingham, School of Public Health, Department of Health Policy and Organization, AL, USA"}],"rel_date":"2026-06-11","rel_site":"medrxiv"},{"rel_title":"Decoding the Genetic Architecture of Autistic Traits in the Aging Population","rel_doi":"10.64898\/2026.06.10.26355340","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355340","rel_abs":"Autism research has mostly focused on diagnostic frameworks in childhood. However, autistic traits including social skills, communication, attention switching, attention to detail, and imagination may also vary in many undiagnosed individuals beyond childhood, and the genetic architecture of autistic traits in undiagnosed aging adults remains poorly understood. Here, we performed an exome-wide association study of autistic traits in adults aged >=40 from the UK Biobank (n = 161,269) and independently validated key findings in the SPARK cohort (n = 142,357). We identified exome-wide significance at 17q21.31, represented by a lead variant associated with social skills (rs199533, beta = 0.081, P = 2.04e-11). In addition, we identified an independent signal for communication (rs12632110, beta = 0.042, P = 3.07e-12) and two independent signals for attention switching (rs690733, beta = 0.046, P = 4.26e-12; rs2164272, beta = -0.047, P = 1.73e-12). Gene-based analyses further implicated loss-of-function variation in ZSCAN2 (beta = 1.00, P = 2.44e-6), which was associated with communication differences. Enrichment analyses revealed preferential expression of implicated genes in the cerebral cortex, while phenotypic and neuroimaging analyses linked those variants to cortical brain structure and regional volume. Taken together, these findings delineate the genetic architecture of autistic traits in the aging population and link genetic variation to downstream molecular and neuroanatomical mechanisms.","rel_num_authors":7,"rel_authors":[{"author_name":"Panhui Tian","author_inst":"Peking university"},{"author_name":"Xiaoli Rao","author_inst":"Peking university"},{"author_name":"Yang Sui","author_inst":"University of Washington School of Medicine, Seattle"},{"author_name":"Shilin Gao","author_inst":"Peking University"},{"author_name":"YingYing Meng","author_inst":"Peking university"},{"author_name":"Xu Han","author_inst":"Peking university"},{"author_name":"Tianyun Wang","author_inst":"Peking University"}],"rel_date":"2026-06-11","rel_site":"medrxiv"},{"rel_title":"Vascular Phenotyping in Parkinson's Disease: Diabetes Mellitus Operationalizes a Microvascular Metabolic Syndrome Cluster Across PPMI Diagnostic Cohorts","rel_doi":"10.64898\/2026.06.09.26355285","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355285","rel_abs":"Background: Diabetes mellitus elevates Parkinson's disease (PD) risk, via hypothesized cerebrovascular mediation. Whether the diabetes\/prediabetes vascular-risk phenotype concentrates in cardiometabolic risk or macrovascular events across prodromal and clinically diagnosed PD remains unresolved. Objectives: To quantify the vascular-risk burden associated with diabetes\/prediabetes across the PPMI diagnostic cohorts to test whether this association differs by cohort. Methods: Cross-sectional analysis of 413 PPMI participants (76 healthy controls, 145 prodromal PD, 192 clinically diagnosed PD) examined diabetes\/prediabetes (n = 73) and seven vascular risk factors. The Vascular Burden Score (0 to 7) was a priori partitioned into microvascular and macrovascular sub-scores. Modified Poisson regression estimated adjusted prevalence ratios (aPR), adjusted for age, sex, and body mass index. A cohort-by-diabetes interaction tested cross-cohort consistency. Sensitivity analyses incorporated nigral diffusion tensor imaging (PD-risk biomarker) and FreeSurfer white matter hypointensity volume (cerebrovascular marker). Results: Diabetes\/prediabetes elevated Vascular Burden Score ({beta} = 0.53, 95% CI 0.29 to 0.77, p < 0.001) versus non-diabetic participants, with a non-significant cohort-by-diabetes interaction (F = 0.29, p = 0.747). Three microvascular factors survived false discovery rate correction: obesity (aPR 2.28), hypertension (aPR 1.60), and hyperlipidemia (aPR 1.45). Macrovascular events showed no diabetic amplification ({beta} = -0.06, p = 0.25). In the imaging-phenotyped subset, Vascular Burden Score components contributed classifier variance distinct from nigral microstructure. Conclusions: Diabetes\/prediabetes operationalize a microvascular cluster stable across prodromal and idiopathic PD. Cardiometabolic phenotyping may complement established PD-risk biomarkers (dopamine transporter SPECT, nigral diffusion), pending longitudinal validation linking vascular phenotype to dopaminergic markers.","rel_num_authors":5,"rel_authors":[{"author_name":"Alexander Belnavis","author_inst":"Arizona State University"},{"author_name":"Shannon Chiu","author_inst":"Mayo Clinic"},{"author_name":"Kewei Chen","author_inst":"Arizona State University"},{"author_name":"Roland Thorpe","author_inst":"John Hopkins University"},{"author_name":"Edward Ofori","author_inst":"Arizona State University"}],"rel_date":"2026-06-11","rel_site":"medrxiv"},{"rel_title":"Foundation model-based tool for automated ulcerative colitis histology scoring demonstrates non-inferiority to pathologists across multiple scoring indices","rel_doi":"10.64898\/2026.06.09.26355212","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355212","rel_abs":"In clinical trials for ulcerative colitis (UC), pathologists assess disease severity through standardized histological indices, including the Geboes Score, Robarts Histopathology Index (RHI), and Nancy Histologic Index (NHI). Despite strong associations with clinical outcomes, histologic scoring suffers from inter- and intra-reader variability, and consensus criteria for histologic remission remain uncertain. Through a consortium approach, we developed an artificial intelligence-based measurement (AIM) tool for scoring histology in UC mucosal biopsies (AIM-HI UC). This model, trained on a large dataset of UC biopsies (N=10,230), utilizes additive multiple instance learning models leveraging PLUTO, a pathology foundation model, that predict each of the Geboes subgrades, from which the Geboes grade-level score, RHI, and NHI can be calculated. Evaluation of this model on a standalone verification set including clinical trial specimens established algorithm non-inferiority and\/or superiority relative to standard qualified pathologists through comparison of algorithm-consensus and pathologist-consensus agreement metrics (non-inferior if difference >-0.1, superior if difference >0, inclusive of confidence intervals). AIM-HI UC was determined to be non-inferior to pathologists (N=3) for the prediction of all seven Geboes subgrades, grade-level Geboes, RHI, NHI, histologic improvement (GS<3.1), 2A histologic remission (GS<2A.0), and 2B histologic remission (GS<2B.0). AIM-HI UC was superior to pathologists for several Geboes subgrades (GS 0, GS 1, GS 2B, and GS 5), as well as grade-level Geboes, RHI, and positive percent agreement of 2A histologic remission. The model was shown to be greater than 99% repeatable for all histologic scoring metrics examined. Model-derived scores were shown to strongly correlate with canonical histologic features of inflammation, including the proportion of total epithelium that is inflamed (Spearman r=0.83; p<0.01), the proportion of neutrophils localized within crypt epithelium (Spearman r=0.83, p<0.01), and the amount of mucosal area classified as erosion or ulceration (Spearman r=0.80, p<0.01). Overall, these results suggest that AIM-HI UC has the potential to improve consistency of UC histology interpretation, providing a path toward standardization of UC histology scoring in clinical trials.","rel_num_authors":38,"rel_authors":[{"author_name":"Waleed Tahir","author_inst":"PathAI, Inc."},{"author_name":"John Shamshoian","author_inst":"PathAI, Inc."},{"author_name":"John Tauber","author_inst":"PathAI, Inc."},{"author_name":"Lani K Clinton","author_inst":"PathAI, Inc."},{"author_name":"Michael Griffin","author_inst":"PathAI, Inc."},{"author_name":"Chintan Shah","author_inst":"PathAI, Inc."},{"author_name":"Geetika Singh","author_inst":"PathAI, Inc."},{"author_name":"Darren Fahy","author_inst":"PathAI, Inc."},{"author_name":"Kathleen Sucipto","author_inst":"PathAI, Inc."},{"author_name":"Jacqueline Brosnan-Cashman","author_inst":"PathAI, Inc."},{"author_name":"Tara A Altepeter","author_inst":"US Food and Drug Administration"},{"author_name":"Sabyasachi Bhattacharya","author_inst":"AbbVie Bay Area"},{"author_name":"Wallace Crandall","author_inst":"Eli Lilly and Company"},{"author_name":"Chong Duan","author_inst":"Pfizer Research Technology Center"},{"author_name":"Jeremy D Gale","author_inst":"Pfizer Research Technology Center"},{"author_name":"Vandana Gupta","author_inst":"Takeda Pharmaceuticals America Inc"},{"author_name":"Helene Haarmann","author_inst":"Takeda Pharmaceuticals International"},{"author_name":"Noam Harpaz","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Andrea T Hooper","author_inst":"Regeneron Pharmaceuticals, Inc."},{"author_name":"Julie Horowitz","author_inst":"Regeneron Pharmaceuticals Inc."},{"author_name":"Andres Hurtado-Lorenzo","author_inst":"Crohn's and Colitis Foundation"},{"author_name":"Bader E Hussaini","author_inst":"Takeda Pharmaceuticals America Inc"},{"author_name":"Vipul Jairath","author_inst":"Western University Faculty of Health Sciences"},{"author_name":"Autumn Jones","author_inst":"Foundation for the National Institutes of Health"},{"author_name":"Ben Kostiuk","author_inst":"Crohn's and Colitis Foundation"},{"author_name":"Anjli Kukreja","author_inst":"Boehringer Ingelheim Corp USA"},{"author_name":"F. Stephen Laroux","author_inst":"AbbVie Bioresearch Center"},{"author_name":"Trevor Lissoos","author_inst":"Eli Lilly and Company"},{"author_name":"Russell B McBride","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Fedaa Najdawi","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Anil Nayyar","author_inst":"US Food and Drug Administration"},{"author_name":"Mark T Osterman","author_inst":"Bristol Myers Squibb"},{"author_name":"Pratik Panchal","author_inst":"Takeda Pharmaceuticals America Inc"},{"author_name":"Darren Ruane","author_inst":"Janssen Research & Development"},{"author_name":"Simon Travis","author_inst":"University of Oxford Nuffield Department of Medicine"},{"author_name":"Sudha Visvanathan","author_inst":"Boehringer Ingelheim Corp USA"},{"author_name":"Laura Wilson","author_inst":"Kenneth Rainin Foundation"},{"author_name":"Christina Jayson","author_inst":"PathAI, Inc."}],"rel_date":"2026-06-11","rel_site":"medrxiv"},{"rel_title":"Long-term exposure to PM2.5 components and lipid profiles in WTC Health Program general responders","rel_doi":"10.64898\/2026.06.10.26355272","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355272","rel_abs":"Fine particulate matter (PM2.5) was found to be associated with elevated blood lipids, but fewer studies have examined the associations with specific constituents of PM2.5. We studied the associations between exposure to annual PM2.5 and its 14 constituents, and repeated blood lipid measurements among general responders enrolled in the World Trade Center Health Program between 2003 and 2019 (n = 44,876). We used generalized additive mixed effect models to investigate the single-pollutant associations with repeated measures of blood total cholesterol (TC), high and low-density lipoprotein (HDL-C and LDL-C) levels. We then used linear generalized weighted quantile sum regression with a random intercept for participant ID to account for the clustering of repeated measures and evaluate the combined associations with the component mixture. A decile increase in the mixture of 14 PM2.5 chemical components was associated with 0.375 mg\/dL increase in TC levels (95% confidence Interval (CI): 0.174-0.577) and 0.302 mg\/dL increase in LDL-C (95% CI: 0.063, 0.540). Lead, organic carbon, and iron were major drivers of both associations. Component-specific models also show higher TC and LDL levels associated with interquartile range increases in organic carbon (0.472, 95% CI [0.027, 0.918] and 0.648 95% CI [0.136, 1.160]) and iron exposure (1.081, 95% CI [0.630, 1.532] and 0.748, 95% CI [0.318, 1.178]). In conclusion, we found PM2.5 exposure to be associated with elevated lipid levels. The associations differed by PM2.5 composition, highlighting organic carbon, lead, and iron and major drivers. These findings are highly significant for a population exposed to extreme air pollution event and susceptible to lipid alterations that might trigger cardiovascular events.","rel_num_authors":8,"rel_authors":[{"author_name":"Helena Krasnov","author_inst":"Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY"},{"author_name":"pablo knobel","author_inst":"Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY"},{"author_name":"Leon Hsiao-Hsien Hsu","author_inst":"Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY"},{"author_name":"Susan Teitelbaum","author_inst":"Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY"},{"author_name":"Maryann Mclaughlin","author_inst":"Department of Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY"},{"author_name":"Allan C. Just","author_inst":"Department of Epidemiology, Brown University School of Public Health, Providence, Rhode Island"},{"author_name":"Itai Kloog","author_inst":"Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY"},{"author_name":"Maayan Yitshak Sade","author_inst":"Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY"}],"rel_date":"2026-06-11","rel_site":"medrxiv"},{"rel_title":"Large-scale proteomics and timing of hypertensive disorders of pregnancy","rel_doi":"10.64898\/2026.06.09.26355317","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355317","rel_abs":"Background: Hypertensive disorders of pregnancy (HDP) may first be diagnosed antepartum, during labor, or postpartum. We utilized untargeted large-scale proteomics to identify pathways associated with HDP based on timing of onset. Methods: We performed a nested case-control study comparing differential protein expression, from the SomaScan 7K platform, based on timing of onset of HDP versus controls (referent) using first-trimester samples from the NuMoM2b-Heart Health Study, a multi-site cohort that followed nulliparous individuals from the first trimester. Associations of proteins with timing of onset of HDP, adjusted for co-variates, were assessed using logistic regression q value-based false discovery rates and pathway enrichment and differential expression analysis were conducted. Results: Of 1628 individuals included, 678 had HDP, of which 67% manifested antepartum (AP), 29% intrapartum (IP), and 3% postpartum (PP). After adjusting for co-variates, compared to controls, 698 proteins, 39 proteins, and 144 proteins were differentially expressed in those with HDP according to AP, IP, PP onset, respectively. There was little overlap in individual protein expression based on timing of HDP. Pathway enrichment and graphical summary analyses suggested distinct processes. Specifically, there was downregulation of angiogenic proteins in AP HDP, downregulation of immune-related proteins in IP HDP, and upregulation of complement activation promoting fibrotic changes leading to cardiac dysfunction in PP HDP. Conclusion: There are differences in first-trimester protein expression based on whether HDP first manifests AP, IP or PP. This raises the possibility that there may be distinct mechanistic phenotypes that could uniquely inform diagnostic and therapeutic targets for HDP.","rel_num_authors":17,"rel_authors":[{"author_name":"Alisse Hauspurg","author_inst":"Alpert Medical School at Brown University"},{"author_name":"Xiaoning Huang","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Philip Greenland","author_inst":"Northwestern University Feinberg School of Medicine, Chicago, IL"},{"author_name":"Victoria Pemberton","author_inst":"NHLBI"},{"author_name":"C. Noel Bairey Merz","author_inst":"Cedars-Sinai Smidt Heart Institute"},{"author_name":"George R. Saade","author_inst":"Eastern Virginia Medical School (EVMS)"},{"author_name":"Lynn M Yee","author_inst":"Northwestern University, Feinberg School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Lisa D. Levine","author_inst":"Hospital of the University of Pennsylvania Helen O Dickens Center for Women's Health"},{"author_name":"Angela Ranzini","author_inst":"The MetroHealth System"},{"author_name":"David M Haas","author_inst":"Indiana University School of Medicine"},{"author_name":"Matthew Hoffman","author_inst":"Columbia University"},{"author_name":"Emily Lau","author_inst":"MassGeneral Brigham \/ Harvard Medical School"},{"author_name":"Sadiya S. Khan","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Brian Kleiboeker","author_inst":"University of Pittsburgh School of Medicine"},{"author_name":"Uma M. Reddy","author_inst":"Yale School of Medicine"},{"author_name":"Janet M. Catov","author_inst":"University of Pittsburgh"},{"author_name":"William Grobman","author_inst":"Brown Unviversity"}],"rel_date":"2026-06-11","rel_site":"medrxiv"},{"rel_title":"Large-scale proteomics and timing of hypertensive disorders of pregnancy","rel_doi":"10.64898\/2026.06.09.26355317","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355317","rel_abs":"Background: Hypertensive disorders of pregnancy (HDP) may first be diagnosed antepartum, during labor, or postpartum. We utilized untargeted large-scale proteomics to identify pathways associated with HDP based on timing of onset. Methods: We performed a nested case-control study comparing differential protein expression, from the SomaScan 7K platform, based on timing of onset of HDP versus controls (referent) using first-trimester samples from the NuMoM2b-Heart Health Study, a multi-site cohort that followed nulliparous individuals from the first trimester. Associations of proteins with timing of onset of HDP, adjusted for co-variates, were assessed using logistic regression q value-based false discovery rates and pathway enrichment and differential expression analysis were conducted. Results: Of 1628 individuals included, 678 had HDP, of which 67% manifested antepartum (AP), 29% intrapartum (IP), and 3% postpartum (PP). After adjusting for co-variates, compared to controls, 698 proteins, 39 proteins, and 144 proteins were differentially expressed in those with HDP according to AP, IP, PP onset, respectively. There was little overlap in individual protein expression based on timing of HDP. Pathway enrichment and graphical summary analyses suggested distinct processes. Specifically, there was downregulation of angiogenic proteins in AP HDP, downregulation of immune-related proteins in IP HDP, and upregulation of complement activation promoting fibrotic changes leading to cardiac dysfunction in PP HDP. Conclusion: There are differences in first-trimester protein expression based on whether HDP first manifests AP, IP or PP. This raises the possibility that there may be distinct mechanistic phenotypes that could uniquely inform diagnostic and therapeutic targets for HDP.","rel_num_authors":17,"rel_authors":[{"author_name":"Alisse Hauspurg","author_inst":"Alpert Medical School at Brown University"},{"author_name":"Xiaoning Huang","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Philip Greenland","author_inst":"Northwestern University Feinberg School of Medicine, Chicago, IL"},{"author_name":"Victoria Pemberton","author_inst":"NHLBI"},{"author_name":"C. Noel Bairey Merz","author_inst":"Cedars-Sinai Smidt Heart Institute"},{"author_name":"George R. Saade","author_inst":"Eastern Virginia Medical School (EVMS)"},{"author_name":"Lynn M Yee","author_inst":"Northwestern University, Feinberg School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Lisa D. Levine","author_inst":"Hospital of the University of Pennsylvania Helen O Dickens Center for Women's Health"},{"author_name":"Angela Ranzini","author_inst":"The MetroHealth System"},{"author_name":"David M Haas","author_inst":"Indiana University School of Medicine"},{"author_name":"Matthew Hoffman","author_inst":"Columbia University"},{"author_name":"Emily Lau","author_inst":"MassGeneral Brigham \/ Harvard Medical School"},{"author_name":"Sadiya S. Khan","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Brian Kleiboeker","author_inst":"University of Pittsburgh School of Medicine"},{"author_name":"Uma M. Reddy","author_inst":"Yale School of Medicine"},{"author_name":"Janet M. Catov","author_inst":"University of Pittsburgh"},{"author_name":"William Grobman","author_inst":"Brown Unviversity"}],"rel_date":"2026-06-11","rel_site":"medrxiv"},{"rel_title":"Large-scale proteomics and timing of hypertensive disorders of pregnancy","rel_doi":"10.64898\/2026.06.09.26355317","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355317","rel_abs":"Background: Hypertensive disorders of pregnancy (HDP) may first be diagnosed antepartum, during labor, or postpartum. We utilized untargeted large-scale proteomics to identify pathways associated with HDP based on timing of onset. Methods: We performed a nested case-control study comparing differential protein expression, from the SomaScan 7K platform, based on timing of onset of HDP versus controls (referent) using first-trimester samples from the NuMoM2b-Heart Health Study, a multi-site cohort that followed nulliparous individuals from the first trimester. Associations of proteins with timing of onset of HDP, adjusted for co-variates, were assessed using logistic regression q value-based false discovery rates and pathway enrichment and differential expression analysis were conducted. Results: Of 1628 individuals included, 678 had HDP, of which 67% manifested antepartum (AP), 29% intrapartum (IP), and 3% postpartum (PP). After adjusting for co-variates, compared to controls, 698 proteins, 39 proteins, and 144 proteins were differentially expressed in those with HDP according to AP, IP, PP onset, respectively. There was little overlap in individual protein expression based on timing of HDP. Pathway enrichment and graphical summary analyses suggested distinct processes. Specifically, there was downregulation of angiogenic proteins in AP HDP, downregulation of immune-related proteins in IP HDP, and upregulation of complement activation promoting fibrotic changes leading to cardiac dysfunction in PP HDP. Conclusion: There are differences in first-trimester protein expression based on whether HDP first manifests AP, IP or PP. This raises the possibility that there may be distinct mechanistic phenotypes that could uniquely inform diagnostic and therapeutic targets for HDP.","rel_num_authors":17,"rel_authors":[{"author_name":"Alisse Hauspurg","author_inst":"Alpert Medical School at Brown University"},{"author_name":"Xiaoning Huang","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Philip Greenland","author_inst":"Northwestern University Feinberg School of Medicine, Chicago, IL"},{"author_name":"Victoria Pemberton","author_inst":"NHLBI"},{"author_name":"C. Noel Bairey Merz","author_inst":"Cedars-Sinai Smidt Heart Institute"},{"author_name":"George R. Saade","author_inst":"Eastern Virginia Medical School (EVMS)"},{"author_name":"Lynn M Yee","author_inst":"Northwestern University, Feinberg School of Medicine, Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine"},{"author_name":"Lisa D. Levine","author_inst":"Hospital of the University of Pennsylvania Helen O Dickens Center for Women's Health"},{"author_name":"Angela Ranzini","author_inst":"The MetroHealth System"},{"author_name":"David M Haas","author_inst":"Indiana University School of Medicine"},{"author_name":"Matthew Hoffman","author_inst":"Columbia University"},{"author_name":"Emily Lau","author_inst":"MassGeneral Brigham \/ Harvard Medical School"},{"author_name":"Sadiya S. Khan","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Brian Kleiboeker","author_inst":"University of Pittsburgh School of Medicine"},{"author_name":"Uma M. Reddy","author_inst":"Yale School of Medicine"},{"author_name":"Janet M. Catov","author_inst":"University of Pittsburgh"},{"author_name":"William Grobman","author_inst":"Brown Unviversity"}],"rel_date":"2026-06-11","rel_site":"medrxiv"},{"rel_title":"Corticospinal tract risk modifies motor recovery after minimally invasive surgery for intracerebral hemorrhage: a secondary analysis of MISTIE-III","rel_doi":"10.64898\/2026.06.10.26354920","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26354920","rel_abs":"Objective: Outcome after surgical hematoma evacuation for intracerebral hemorrhage (ICH) depends on hematoma location. As corticospinal tract (CST) integrity affects motor recovery after stroke, we hypothesized that CST integrity drives heterogeneity in surgical outcomes and investigated this in a secondary analysis of MISTIE-III participants. Methods: Risk of CST injury was categorized into four levels, based on the interaction between the CST, the hematoma, and perihematomal edema (PHE) on automatically segmented stability CT: no risk, PHE infiltration, hematoma infiltration, and complete interruption of the CST. Associations with outcome were tested using multivariable linear regression for motor National Institutes of Health Stroke Scale (NIHSS) at day 180 and ordinal regression for modified Rankin Scale (mRS) at day 365, introducing an interaction term between CST risk and treatment group. Results: Day 180 motor NIHSS was significantly lower for 'no risk' ({beta}:-3.77, [95% confidence interval [CI]: -5.8 to -1.70], p=0.0003) and 'PHE infiltration' ({beta}:-2.3, [95%CI: -3.5 to -1.1]; p=0.0002) vs. 'complete interruption'. Surgery was associated with lower Day 180 motor NIHSS in participants with hematoma infiltration ({beta}:-2.07, [95%CI: -3.8 to -0.4], p=0.016). Compared to complete interruption, 'no risk' (adjusted odds ratio [aOR]:0.27, [95%CI: 0.10 to 0.74], p=0.01) and 'PHE infiltration' (aOR:0.41, [95%CI: 0.23 to 0.74]; p=0.003) were associated with lower odds of unfavorable day 365 mRS. Surgery was associated with lower mRS in participants with no risk (aOR:0.23, [95%CI: 0.05 to 0.97, p=0.045). Interpretation: Increasing CST risk is associated with worse motor recovery (day 180) and disability (day 365). CST risk modifies the effect of the MISTIE-III procedure on motor recovery and disability.","rel_num_authors":11,"rel_authors":[{"author_name":"Olivia N Murray","author_inst":"The University of Manchester"},{"author_name":"David Jenkins","author_inst":"The University of Manchester"},{"author_name":"Nathan Walborn","author_inst":"John Hopkins Medical Institutions"},{"author_name":"Hiren C Patel","author_inst":"Salford Royal NHS Foundation Trust"},{"author_name":"George WJ Harston","author_inst":"Oxford University Hospitals NHS Foundation Trust"},{"author_name":"Timothy F Cootes","author_inst":"University of Manchetser"},{"author_name":"Catharina J.M. Klijn","author_inst":"Radboud University Medical Center"},{"author_name":"Wendy C Ziai","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Daniel F Hanley","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Ulrike Hammerbeck","author_inst":"Kings College London"},{"author_name":"Adrian R Parry-Jones","author_inst":"University of Manchester"}],"rel_date":"2026-06-11","rel_site":"medrxiv"},{"rel_title":"Sequence-encoded H2A.Z nucleosome dynamics control DNA unwrapping and SUV420H1 recognition","rel_doi":"10.64898\/2026.06.10.731474","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731474","rel_abs":"H2A.Z and canonical H2A adopt nearly identical nucleosomal folds, yet their distinct chromatin functions are not captured by static structural analysis. Using fast magic-angle spinning 1H-detected solid-state NMR, we show that H2A.Z possesses enhanced backbone flexibility in the L1 loop and the 2-L2 region (M2) relative to H2A. Chimeric segment-swapping demonstrates that these dynamic signatures are locally sequence-encoded and functionally transplantable. The inherent mobility of the M2 region promotes nucleosomal DNA-end unwrapping and persists when DNA ends are stabilized by linker histone H1 or opened by SUV420H1, indicating that this mobility is intrinsic rather than a passive consequence of DNA detachment. Chemical shift perturbation mapping and catalytic assays further show that SUV420H1 reads this H2A.Z-specific conformational landscape: the M2 region, together with the H2A.Z DS motif, supports variant-selective methyltransferase activity. These findings establish an axis of sequence-dynamics-accessibility-recognition along which local backbone fluctuations serve as physical determinants of epigenetic enzyme specificity.","rel_num_authors":9,"rel_authors":[{"author_name":"Tong Zhang","author_inst":"MOE Key Laboratory for Cellular Dynamics, School of Life Sciences, University of Science and Technology of China."},{"author_name":"Li Huang","author_inst":"Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences."},{"author_name":"Xuanfeng Li","author_inst":"MOE Key Laboratory for Cellular Dynamics, School of Life Sciences, University of Science and Technology of China."},{"author_name":"Bingyan Liu","author_inst":"MOE Key Laboratory for Cellular Dynamics, School of Life Sciences, University of Science and Technology of China."},{"author_name":"Juan Li","author_inst":"MOE Key Laboratory for Cellular Dynamics, School of Life Sciences, University of Science and Technology of China."},{"author_name":"Chaowei Shi","author_inst":"MOE Key Laboratory for Cellular Dynamics, School of Life Sciences, University of Science and Technology of China."},{"author_name":"Shusheng Fu","author_inst":"Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences."},{"author_name":"Zheng Zhou","author_inst":"Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences;University of Chinese Academy of Sciences."},{"author_name":"ShengQi Xiang","author_inst":"MOE Key Laboratory for Cellular Dynamics, School of Life Sciences, University of Science and Technology of China."}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Laboratory adaptation and complete genome assembly of a Beposo, Ghana strain of the human hookworm Necator americanus","rel_doi":"10.64898\/2026.06.10.728644","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.728644","rel_abs":"Laboratory models are invaluable tools for studying parasite biology and pathogenesis, especially for helminth infections. However, the complex life cycles and frequently narrow host specificity of helminths present challenges to maintaining access to critical parasite material in a laboratory setting. This is especially true of Necator americanus, the most common species of hookworm that infects humans globally. Here we report the successful laboratory adaptation of an African strain of N. americanus, originally isolated from infected individuals in Beposo, Ghana. The Beposo strain has been successfully passaged across 9 generations in Golden Syrian hamsters maintained on oral dexamethasone. Differential susceptibility to mebendazole and albendazole was evaluated using an egg hatch assay, and DNA sequencing of the beta-tubulin isotype 1 gene did not identify known resistance-associated mutations in the endemic strain. Sequencing of the mitochondrial COX1 gene revealed that specimens of N. americanus from Ghana, along with reported sequences from Togo, are distinct from those from South America and Asia. Complementary microsatellite-based population analysis revealed substantial genetic variation in the founding parasite population. To further characterize the novel Beposo strain, a draft hybrid genome assembly was generated from genomic DNA extracted from a single adult male worm via an optimized Oxford Nanopore Technologies MinION library preparation approach tailored to low-input sample types. This high-quality assembly, including a complete mitogenome, is 202.8Mb in 950 contigs with an N50 >449 kb. It contains >95% of conserved nematode orthologs in complete single copy and is estimated by homology-based gene prediction to contain 12,804 genes. This study represents the first comprehensive characterization of a strain of N. americanus originating in Africa that has been successfully adapted to a laboratory animal model.","rel_num_authors":14,"rel_authors":[{"author_name":"Lisa M. Harrison","author_inst":"Yale School of Medicine"},{"author_name":"Kaylee  S. Herzog","author_inst":"University of New Mexico - Albuquerque"},{"author_name":"Dickson Osabutey","author_inst":"University of Ghana Noguchi Memorial Institute for Medical Research"},{"author_name":"Mavis Konoma","author_inst":"University of Ghana Noguchi Memorial Institute for Medical Research"},{"author_name":"Emma Allen","author_inst":"Yale University School of Public Health"},{"author_name":"Kelly Hagadorn","author_inst":"Yale University School of Public Health"},{"author_name":"Santosh George","author_inst":"Yale School of Medicine"},{"author_name":"Richard D. Bungiro","author_inst":"Yale University School of Public Health"},{"author_name":"Claudia Gaither","author_inst":"Yale University Department of Ecology and Evolutionary Biology"},{"author_name":"Carol Mariani","author_inst":"Yale University Department of Ecology and Evolutionary Biology"},{"author_name":"Margaret K. Corley","author_inst":"Yale University Department of Ecology and Evolutionary Biology"},{"author_name":"Adalgisa Caccone","author_inst":"Yale University Department of Ecology and Evolutionary Biology"},{"author_name":"Joseph R. Fauver","author_inst":"University of Nebraska Medical Center College of Public Health"},{"author_name":"Michael Cappello","author_inst":"Yale School of Public Health"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Ultralow frequency vaso-oscillations in human cerebral arteries are independent from Mayer waves","rel_doi":"10.64898\/2026.06.09.731141","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731141","rel_abs":"This study tests the hypothesis that vasomotion, an ~ 0.1 Hz oscillation in arteriole diameter, is generated by intrinsic oscillations within the arterioles that perfuse the brain, and not by external drive from systemic blood pressure oscillations (Mayer waves). During cardio-pulmonary bypass that transiently eliminated systemic blood pressure oscillations in 14 patients, we observed that vasomotor oscillations persist with normal amplitudes and frequencies over the one- to three-hour time course of surgery. In contrast, ~ 0.1 Hz oscillations in peripheral blood pressure were predominantly absent. This implies that cerebral arterioles generate their own rhythmic vaso-dynamics, although we cannot discount that vasomotion can phase-lock with ~ 0.1 Hz systemic physiological rhythms in the awake, healthy state. We discuss the impact of this finding on the role of vasomotion in modulating the perfusion of blood and the transport of interstitial fluid in the brain.","rel_num_authors":6,"rel_authors":[{"author_name":"Aiman Alzetani","author_inst":"Department of Thoracic Surgery, Faculty of Medicine, University Hospital Southampton NHS Foundation Trust, SO16 6YD Southampton, UK"},{"author_name":"Jacob Duckworth","author_inst":"Department of Physics, University of California San Diego, La Jolla, CA 92093 USA"},{"author_name":"Anthony A Birch","author_inst":"Department of Medical Physics and Bioengineering, University Hospital Southampton NHS Foundation Trust, Southampton, SO16 6YD, UK"},{"author_name":"David M Simpson","author_inst":"Institute of Sound and Vibration Research, University of Southampton, Southampton, UK"},{"author_name":"David Kleinfeld","author_inst":"University of California San Diego"},{"author_name":"Roxana O Carare","author_inst":"Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"A systematic imputation framework for sparse, multimodal space biology datasets: application to retinal imaging and omics from the RR9 mission","rel_doi":"10.64898\/2026.06.09.730965","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.730965","rel_abs":"Space biology experiments are expensive, logistically complex, and inherently limited in sample size, resulting in datasets that are frequently incomplete and highly heterogeneous (2). Missing data is a fundamental barrier to building reliable computational models of how the human body responds to spaceflight. This work introduces a systematic framework for addressing missing data through imputation. We developed a validated four-stage framework for imputation specifically designed to preserve biological signal needed for digital twin development, while quantifying trade-offs in downstream analyses. Using retinal imaging and omics data from the NASA RR9 mission as a case study (9), we demonstrate how to diagnose why data is missing(10), select and optimize appropriate imputation strategies (5,10), and rigorously evaluate whether imputed data remains biologically meaningful. A key finding of this work is that while imputation substantially improves the performance of predictive models, it can simultaneously obscure subtle biological patterns; a critical trade-off that researchers must understand before applying these methods (11). This framework provides practical, actionable guidance for space biologists and data scientists working with sparse, multimodal datasets in space biology, and represents a foundational step toward more complete and reliable data-driven models of human physiology in extreme environments.","rel_num_authors":12,"rel_authors":[{"author_name":"Vaishnavi Nagesh","author_inst":"Open Science Data Repository AI\/ML Analysis Working Group volunteer, NASA Citizen Science Project"},{"author_name":"Lauren Sanders","author_inst":"Colossal Biosciences, Computational Biology, Dallas, Texas, USA"},{"author_name":"Sylvain V. Costes","author_inst":"Trivedi Institute for Space and Global Biomedicine, University of Pittsburgh, PA, USA"},{"author_name":"Pinar Avci","author_inst":"Open Science Data Repository AI\/ML Analysis Working Group volunteer, NASA Citizen Science Project"},{"author_name":"Ayse Sigit","author_inst":"Open Science Data Repository AI\/ML Analysis Working Group volunteer, NASA Citizen Science Project"},{"author_name":"Amey Agarwal","author_inst":"Open Science Data Repository AI\/ML Analysis Working Group volunteer, NASA Citizen Science Project"},{"author_name":"Alireza Haghighi","author_inst":"Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Alavia Batool","author_inst":"Open Science Data Repository AI\/ML Analysis Working Group volunteer, NASA Citizen Science Project"},{"author_name":"Fathi Karouia","author_inst":"Blue Marble Space Institute of Science, Seattle, Washington, USA"},{"author_name":"Atul M. Chander","author_inst":"Department of Biology, University of Mississippi, Oxford, Mississippi, USA"},{"author_name":"Caleb M. Schmidt","author_inst":"Open Science Data Repository AI\/ML Analysis Working Group volunteer, NASA Citizen Science Project"},{"author_name":"Jian Gong","author_inst":"School of Computing, University of Wyoming, Laramie, Wyoming, USA"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Mutant SOD1 expressed by oligodendrocytes aggregates in myelinic nanochannels and accelerates disease progression in familial ALS mice","rel_doi":"10.64898\/2026.06.09.731100","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731100","rel_abs":"Amyotrophic lateral sclerosis (ALS) is a highly debilitating and fatal disease characterized by the progressive loss of motor neurons. Reduced oligodendroglial support has been implicated in ALS progression but remains mechanistically unexplained. Here, using a mutant superoxide dismutase 1 (SOD1-G37R) mouse model of familial ALS, Cre-mediated excision of the mutant SOD1 gene within the oligodendrocyte lineage prior to myelin compaction is shown to slow disease onset, improve motor performance, and prolong survival. In contrast, silencing mutant SOD1 expression within oligodendrocytes after myelin compaction failed to ameliorate disease phenotype. Electron microscopy is used to identify aggregation of mutant SOD1 within paranodal loops and the inner periaxonal tongue of myelinic nanochannels, narrow cytosolic compartments for the diffusion of metabolites and motor-driven transport processes. In a second mouse model (SOD1-G93A) of familial, SOD1 mutant-mediated ALS, we show that induction of excessive myelin compaction and myelinic channel collapse (by depletion of CNP from myelin) accelerates disease and diminishes survival. Our data support loss of myelinic channel integrity as a contributor to familial ALS disease initiation and progression, findings likely relevant to neurodegenerative disease involving other aggregation prone proteins that are expressed in myelinating oligodendrocytes.","rel_num_authors":14,"rel_authors":[{"author_name":"Alexandra I Mot","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Ying Li","author_inst":"Brain Science Institute, Departments of Neurology and Neuroscience, Johns Hopkins University, Baltimore MD, USA"},{"author_name":"Payam Dibaj","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Iva D Tzvetanova","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Ulrike C Gerwig","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Tizibt A Bogale","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Sandra Goebbels","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Wiebke M\u00f6bius","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Dwight E Bergles","author_inst":"Brain Science Institute, Departments of Neurology and Neuroscience, Johns Hopkins University, Baltimore MD, USA"},{"author_name":"Brett M Morrison","author_inst":"Brain Science Institute, Departments of Neurology and Neuroscience, Johns Hopkins University, Baltimore MD, USA"},{"author_name":"Jeffrey D Rothstein","author_inst":"Brain Science Institute, Departments of Neurology and Neuroscience, Johns Hopkins University, Baltimore MD, USA"},{"author_name":"Don W Cleveland","author_inst":"Department of Molecular and Cellular Medicine, University of California at San Diego, La Jolla, CA 92093 USA"},{"author_name":"Julia M Edgar","author_inst":"School of Infection and Immunity, College of Medical, Veterinary and Life Sciences University of Glasgow, UK"},{"author_name":"Klaus-Armin Nave","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Mutant SOD1 expressed by oligodendrocytes aggregates in myelinic nanochannels and accelerates disease progression in familial ALS mice","rel_doi":"10.64898\/2026.06.09.731100","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731100","rel_abs":"Amyotrophic lateral sclerosis (ALS) is a highly debilitating and fatal disease characterized by the progressive loss of motor neurons. Reduced oligodendroglial support has been implicated in ALS progression but remains mechanistically unexplained. Here, using a mutant superoxide dismutase 1 (SOD1-G37R) mouse model of familial ALS, Cre-mediated excision of the mutant SOD1 gene within the oligodendrocyte lineage prior to myelin compaction is shown to slow disease onset, improve motor performance, and prolong survival. In contrast, silencing mutant SOD1 expression within oligodendrocytes after myelin compaction failed to ameliorate disease phenotype. Electron microscopy is used to identify aggregation of mutant SOD1 within paranodal loops and the inner periaxonal tongue of myelinic nanochannels, narrow cytosolic compartments for the diffusion of metabolites and motor-driven transport processes. In a second mouse model (SOD1-G93A) of familial, SOD1 mutant-mediated ALS, we show that induction of excessive myelin compaction and myelinic channel collapse (by depletion of CNP from myelin) accelerates disease and diminishes survival. Our data support loss of myelinic channel integrity as a contributor to familial ALS disease initiation and progression, findings likely relevant to neurodegenerative disease involving other aggregation prone proteins that are expressed in myelinating oligodendrocytes.","rel_num_authors":14,"rel_authors":[{"author_name":"Alexandra I Mot","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Ying Li","author_inst":"Brain Science Institute, Departments of Neurology and Neuroscience, Johns Hopkins University, Baltimore MD, USA"},{"author_name":"Payam Dibaj","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Iva D Tzvetanova","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Ulrike C Gerwig","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Tizibt A Bogale","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Sandra Goebbels","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Wiebke M\u00f6bius","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"},{"author_name":"Dwight E Bergles","author_inst":"Brain Science Institute, Departments of Neurology and Neuroscience, Johns Hopkins University, Baltimore MD, USA"},{"author_name":"Brett M Morrison","author_inst":"Brain Science Institute, Departments of Neurology and Neuroscience, Johns Hopkins University, Baltimore MD, USA"},{"author_name":"Jeffrey D Rothstein","author_inst":"Brain Science Institute, Departments of Neurology and Neuroscience, Johns Hopkins University, Baltimore MD, USA"},{"author_name":"Don W Cleveland","author_inst":"Department of Molecular and Cellular Medicine, University of California at San Diego, La Jolla, CA 92093 USA"},{"author_name":"Julia M Edgar","author_inst":"School of Infection and Immunity, College of Medical, Veterinary and Life Sciences University of Glasgow, UK"},{"author_name":"Klaus-Armin Nave","author_inst":"Department of Neurogenetics, Max Planck Institute for Multidisciplinary Sciences, G\u00f6ttingen, Germany"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"A quantitative coordinate system for developmental dynamics","rel_doi":"10.64898\/2026.06.09.730858","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.730858","rel_abs":"Quantitative comparison of morphogenesis across individuals remains a fundamental challenge, as developing embryos vary in shape, orientation and developmental tempo. Moreover, real-time three-dimensional imaging generates large, heterogeneous four-dimensional datasets that are difficult to directly align. As a result, developmental variability is typically described qualitatively rather than measured. Here we introduce STERN, a quantitative framework that learns continuous spatiotemporal representations of morphogenesis directly from in vivo 4D imaging data. By embedding embryos into a shared spatiotemporal space, STERN defines a quantitative developmental coordinate system that enables direct comparison of developmental trajectories across individuals without requiring explicit registration or staging. Applied to mouse embryogenesis, STERN reveals that embryos follow conserved developmental trajectories while progressing at distinct temporal rates, providing a quantitative measure of developmental heterochrony. Extending this framework to zebrafish neural crest light-sheet timelapse imaging, we further show that developmental order is preserved across distinct imaging views even with altered anatomical coverage, supporting the generality of the learned representation across vertebrate imaging contexts. Finally, in developing mouse hearts, where morphogenesis proceeds through subtle and continuously evolving structural changes, STERN resolves fine-scale developmental dynamics at minute-scale temporal resolution that are difficult to localize reproducibly using human experts or general-purpose multimodal AI. Together, these results establish a shared quantitative coordinate system for morphogenesis, in which developmental trajectories become directly comparable across individuals and developmental variability becomes a measurable property.","rel_num_authors":7,"rel_authors":[{"author_name":"Jiawei Wang","author_inst":"European Bioinformatics Institute; University of Bath"},{"author_name":"Jinzheng Ren","author_inst":"European Bioinformatics Institute; University of Bath; Australian National University"},{"author_name":"Cora Moore","author_inst":"University of Bath"},{"author_name":"Robert N. Kelsh","author_inst":"University of Bath"},{"author_name":"Katie McDole","author_inst":"MRC Laboratory of Molecular Biology"},{"author_name":"Bianca Dumitrascu","author_inst":"Columbia University"},{"author_name":"John C. Marioni","author_inst":"European Bioinformatics Institute"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Apollo 3: Multi-Species Genome Curation","rel_doi":"10.64898\/2026.06.08.730970","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730970","rel_abs":"We present Apollo 3, a new manual genome annotation tool that integrates with the JBrowse 2 genome browser. Its functionality is inspired by existing manual genome annotation tools such as Apollo, Artemis, and Otter, but uses an updated and more scalable architecture and technology stack. It allows the simultaneous editing of multiple genomes, including the visualization of synteny to inform those annotations. Apollo 3 can be used as a standalone annotation editor, or it can be installed on a server and used collaboratively. We describe the application's design, features, and use cases.","rel_num_authors":24,"rel_authors":[{"author_name":"Garrett J Stevens","author_inst":"University of California, Berkeley"},{"author_name":"Ky\u00f6sti Sutinen","author_inst":"European Bioinformatics Institute"},{"author_name":"Dario Beraldi","author_inst":"University of Glasgow"},{"author_name":"Shashank Budhanuru Ramaraju","author_inst":"European Bioinformatics Institute"},{"author_name":"Colin M Diesh","author_inst":"University of California, Berkeley"},{"author_name":"William Haese-Hill","author_inst":"University of Glasgow"},{"author_name":"Peter Xie","author_inst":"University of California, Berkeley"},{"author_name":"Caroline Bridge","author_inst":"Ontario Institute for Cancer Research"},{"author_name":"Adrien Morison","author_inst":"University of Glasgow"},{"author_name":"Angel Leung","author_inst":"University of California, Berkeley"},{"author_name":"Ulrike B\u00f6hme","author_inst":"University of Liverpool"},{"author_name":"Scott Cain","author_inst":"Pennsylvania State University"},{"author_name":"Nathan Dunn","author_inst":"University of California, Berkeley"},{"author_name":"Toby Hunt","author_inst":"European Bioinformatics Institute"},{"author_name":"Jane E Loveland","author_inst":"European Bioinformatics Institute"},{"author_name":"Adam Frankish","author_inst":"European Bioinformatics Institute"},{"author_name":"Alexie Papanicolau","author_inst":"Western Sydney University"},{"author_name":"Stefano Giorgetti","author_inst":"European Bioinformatics Institute"},{"author_name":"Jon Keatley","author_inst":"European Bioinformatics Institute"},{"author_name":"Bethany Flint","author_inst":"European Bioinformatics Institute"},{"author_name":"Lincoln D Stein","author_inst":"Ontario Institute for Cancer Research"},{"author_name":"Robert Buels","author_inst":"University of California, Berkeley"},{"author_name":"Matt Berriman","author_inst":"University of Glasgow"},{"author_name":"Ian Holmes","author_inst":"University of California, Berkeley"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Improving splice site usage prediction with SPLAIRE","rel_doi":"10.64898\/2026.06.08.731019","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.731019","rel_abs":"Alternative splicing, the mechanism by which intronic sequences are excised from pre-mRNAs to produce mature mRNA, affects >95% of human protein-coding genes and is a major driver of human disease states. The spliceosome, a protein-RNA complex responsible for splicing pre-mRNA, identifies candidate splice sites partly through the recognition of characteristic sequence motifs at exon-intron junctions. Deep learning models that predict the presence of splice sites from pre-mRNA sequence have achieved breakthrough performance relative to previous machine-learning techniques, and these models have improved our ability to identify pathogenic genetic variants that alter splicing. We show that, while overall performance measures from these models suggest near-perfect performance, substantial gaps in prediction remain, including the identification of splice sites with low usage rates and tissue-specific splice sites. We leverage one of the largest paired RNA and genotyping datasets used to date to train a novel splicing model optimized for a specific cell type, human airway epithelial cells. We trained a dilated convolutional neural network on data from cultured airway epithelial cells from 100 donors, and showed that this model outperforms current state-of-the-art models on splice site identification and splice site usage quantification, including on multiple tissues not included in the model training data. We present the most comprehensive evaluation of state-of-the-art splicing models published to date, revealing reasonable performance across models for genetic variant effect prediction, along with important performance gaps and insights into directions for future model development.","rel_num_authors":11,"rel_authors":[{"author_name":"Matthew Runyan","author_inst":"The Institute for Experiential AI, Northeastern University, Boston, MA, USA"},{"author_name":"Saumya Gupta","author_inst":"The Institute for Experiential AI, Northeastern University, Boston, MA, USA"},{"author_name":"Yul Leshaem","author_inst":"Channing Division of Network Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"David Geller-McGrath","author_inst":"Division of Pulmonary and Critical Care Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Congjian Liu","author_inst":"Division of Pulmonary and Critical Care Medicine, Brigham \\& Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Aabida Saferali","author_inst":"Channing Division of Network Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Jennifer Dy","author_inst":"Department of Electrical and Computer Engineering, Northeastern University, Boston, MA, USA"},{"author_name":"Predrag Radivojac","author_inst":"Khoury College of Computer Sciences, Northeastern University, Boston, MA, USA"},{"author_name":"Yohannes Tesfaigzi","author_inst":"Division of Pulmonary and Critical Care Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Peter Castaldi","author_inst":"Channing Division of Network Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Ayan Paul","author_inst":"The Institute for Experiential AI & Khoury College of Computer Sciences, Northeastern University, Boston, MA, USA"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Disparate introduction histories but similar climatic distribution patterns among congeneric invasive anurans","rel_doi":"10.64898\/2026.06.08.730926","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730926","rel_abs":"Commonly shared patterns of introduction and spread into new environmental conditions are often poorly understood, even though a better understanding of invasion history and niche dynamics among closely related invasive species could give practitioners valuable information to prevent and mitigate the impact of biological invasions. For this study, we investigate the invasion history and niche patterns among congeneric invasive species. We synthesize public occurrence data for five invasive alien anurans (Eleutherodactylus coqui, E. planirostris, E. johnstonei, E. antillensis, and E. martinicensis) to reconstruct their historic introductions and evaluate evidence for climatic niche shifts between their native and established non-native ranges. By pairing these data with current and future climate projections, we compare patterns of range shifts under future climate scenarios. Our results highlight different temporal and geographic introduction histories in invasive Eleutherodactylus, but a strong signal of colonizing broader invasive climatic niches, specifically into colder environmental conditions. Under future climate scenarios, suitable habitats for most of the non-native regions are likely to increase, although this increase is restricted under scenarios with high greenhouse gas emissions. Our results reveal that despite different invasion histories, the ability to spread into colder regions may be a conserved trait among the most widespread Eleutherodactylus anurans. This study ultimately shows that commonalities among closely related invasive species can provide clues about their ability to expand into areas with particular abiotic conditions, a pattern likely to be widespread, offering a potentially valuable opportunity to deploy targeted prevention strategies.","rel_num_authors":4,"rel_authors":[{"author_name":"Andrew J Mularo","author_inst":"W.K. Kellogg Biological Station - Michigan State University"},{"author_name":"Jong Yoon Jeon","author_inst":"Purdue University"},{"author_name":"Jackson T Kirkwood","author_inst":"Purdue University"},{"author_name":"Ximena E Bernal","author_inst":"Purdue University"}],"rel_date":"2026-06-11","rel_site":"biorxiv"},{"rel_title":"Exploratory Assessment of Pulsed-Wave Doppler Representations of Lung Sounds Using Deep Learning: An In-Vitro Phantom Study","rel_doi":"10.64898\/2026.06.09.26353787","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26353787","rel_abs":"The increasing availability of portable ultrasound systems motivates exploration of novel approaches to respiratory signal assessment. In this in-vitro study, we investigate whether pulsed-wave (PW) Doppler ultrasound can capture structured spectral patterns from replayed lung sound recordings. Digitized respiratory sounds were replayed through a tissue-mimicking ultrasound phantom, generating 1,478 PW Doppler spectral images from recordings associated with healthy subjects and several externally labeled disease categories. Exploratory classification experiments using a ResNet-18 architecture demonstrated that these Doppler representations contain learnable differences under controlled conditions. These findings motivate further investigation into PW Doppler as a potential representation of respiratory acoustics.","rel_num_authors":5,"rel_authors":[{"author_name":"Ali A Saad","author_inst":"Alumnus of Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"Sarah B Murthi","author_inst":"University of Maryland School of Medicine, R Adams Cowley Shock Trauma Center, Baltimore, MD, USA"},{"author_name":"Emad M Boctor","author_inst":"Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"William A Teeter","author_inst":"University of Maryland School of Medicine, R Adams Cowley Shock Trauma Center, Baltimore, MD, USA"},{"author_name":"Nitin Seam","author_inst":"Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, MD, USA"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Developmental Associations Linking Childhood Trauma and Early Cannabis Use to Adolescent DNA Methylation and Psychotic-Like Experiences","rel_doi":"10.64898\/2026.06.09.26355257","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355257","rel_abs":"Background. Psychotic-like experiences (PLEs) index early risk for psychotic disorders and are consistently associated with childhood trauma, yet underlying biological mechanisms remain poorly understood. DNA methylation (DNAm) may capture the biological embedding of early adversity, while adolescent exposures such as cannabis use may modify these processes. We examined epigenome-wide associations of childhood trauma and PLEs, tested the moderating role of early cannabis use, and evaluated DNAm as a potential mediator. Methods. We analysed data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK population-based birth cohort. Childhood trauma was assessed prospectively and retrospectively. Epigenome-wide DNAm was measured in peripheral blood at ~17 years using the Illumina 450K array, and PLEs were assessed at 18 using a structured interview. Epigenome-wide association studies were conducted for trauma-DNAm and DNAm-PLEs associations in the final sample (n = 1,457), adjusting for demographic, biological, and technical covariates. Differentially methylated regions (DMRs) were identified using DMRff, followed by functional enrichment analyses. Cannabis use at 15.5 was modelled as a moderator with multiple imputation for missing data. Mediation was tested using the Divide-Aggregate Composite-null Test (DACT). Results. Childhood trauma was associated with widespread DNAm differences, primarily at the regional level, with enrichment in pathways related to cellular stress responses. In contrast, DNAm associated with PLEs was more limited and implicated loci involved in epigenetic regulatory processes. These signatures were largely distinct, and there was no evidence supporting mediation after multiple testing correction. Incorporating cannabis use altered the pattern and extent of DNAm associations, with stronger and more significant signals observed at both CpG and regional levels, although these did not translate into evidence of mediation. Conclusion. Childhood trauma and PLEs show distinct DNAm signatures in adolescence, with trauma-related DNAm reflecting broad stress-related processes and PLE-associated DNAm implicating regulatory mechanisms. We found little evidence that DNAm mediates the trauma-PLE association. Instead, adolescent exposures, particularly cannabis use, may distinctly influence trauma-related epigenetic variation with limited detectable downstream effects on PLEs. These findings support a context-dependent model of epigenetic risk and highlight the need for larger longitudinal studies to clarify causal pathways linking early adversity to psychosis.","rel_num_authors":20,"rel_authors":[{"author_name":"Giulia Trotta","author_inst":"King's College London"},{"author_name":"Zhonghua Liu","author_inst":"Columbia University"},{"author_name":"Isabelle Austin-Zimmerman","author_inst":"King's College London"},{"author_name":"Edoardo Spinazzola","author_inst":"King's College London"},{"author_name":"Lucia Sideli","author_inst":"Lumsa"},{"author_name":"Monica Aas","author_inst":"King's College London"},{"author_name":"Victoria Rodriguez","author_inst":"King's College London"},{"author_name":"Zhikun Li","author_inst":"King's College London"},{"author_name":"Bok Man Leung","author_inst":"King's College London"},{"author_name":"Qiang Li","author_inst":"King's College London"},{"author_name":"Shengmin Zhang","author_inst":"King's College London"},{"author_name":"Pak C Sham","author_inst":"The University of Hong Kong"},{"author_name":"Evangelos Vassos","author_inst":"King's College London"},{"author_name":"Richard Bentall","author_inst":"University of Sheffield"},{"author_name":"Emma M Walker","author_inst":"University of Exeter"},{"author_name":"Emma Dempster","author_inst":"University of Exeter"},{"author_name":"Robin Murray","author_inst":"King's College London"},{"author_name":"Marta Di Forti","author_inst":"King's College London"},{"author_name":"Luis Alameda","author_inst":"King's College London"},{"author_name":"Chloe C.Y Wong","author_inst":"King's College London"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Developmental Associations Linking Childhood Trauma and Early Cannabis Use to Adolescent DNA Methylation and Psychotic-Like Experiences","rel_doi":"10.64898\/2026.06.09.26355257","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355257","rel_abs":"Background. Psychotic-like experiences (PLEs) index early risk for psychotic disorders and are consistently associated with childhood trauma, yet underlying biological mechanisms remain poorly understood. DNA methylation (DNAm) may capture the biological embedding of early adversity, while adolescent exposures such as cannabis use may modify these processes. We examined epigenome-wide associations of childhood trauma and PLEs, tested the moderating role of early cannabis use, and evaluated DNAm as a potential mediator. Methods. We analysed data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK population-based birth cohort. Childhood trauma was assessed prospectively and retrospectively. Epigenome-wide DNAm was measured in peripheral blood at ~17 years using the Illumina 450K array, and PLEs were assessed at 18 using a structured interview. Epigenome-wide association studies were conducted for trauma-DNAm and DNAm-PLEs associations in the final sample (n = 1,457), adjusting for demographic, biological, and technical covariates. Differentially methylated regions (DMRs) were identified using DMRff, followed by functional enrichment analyses. Cannabis use at 15.5 was modelled as a moderator with multiple imputation for missing data. Mediation was tested using the Divide-Aggregate Composite-null Test (DACT). Results. Childhood trauma was associated with widespread DNAm differences, primarily at the regional level, with enrichment in pathways related to cellular stress responses. In contrast, DNAm associated with PLEs was more limited and implicated loci involved in epigenetic regulatory processes. These signatures were largely distinct, and there was no evidence supporting mediation after multiple testing correction. Incorporating cannabis use altered the pattern and extent of DNAm associations, with stronger and more significant signals observed at both CpG and regional levels, although these did not translate into evidence of mediation. Conclusion. Childhood trauma and PLEs show distinct DNAm signatures in adolescence, with trauma-related DNAm reflecting broad stress-related processes and PLE-associated DNAm implicating regulatory mechanisms. We found little evidence that DNAm mediates the trauma-PLE association. Instead, adolescent exposures, particularly cannabis use, may distinctly influence trauma-related epigenetic variation with limited detectable downstream effects on PLEs. These findings support a context-dependent model of epigenetic risk and highlight the need for larger longitudinal studies to clarify causal pathways linking early adversity to psychosis.","rel_num_authors":20,"rel_authors":[{"author_name":"Giulia Trotta","author_inst":"King's College London"},{"author_name":"Zhonghua Liu","author_inst":"Columbia University"},{"author_name":"Isabelle Austin-Zimmerman","author_inst":"King's College London"},{"author_name":"Edoardo Spinazzola","author_inst":"King's College London"},{"author_name":"Lucia Sideli","author_inst":"Lumsa"},{"author_name":"Monica Aas","author_inst":"King's College London"},{"author_name":"Victoria Rodriguez","author_inst":"King's College London"},{"author_name":"Zhikun Li","author_inst":"King's College London"},{"author_name":"Bok Man Leung","author_inst":"King's College London"},{"author_name":"Qiang Li","author_inst":"King's College London"},{"author_name":"Shengmin Zhang","author_inst":"King's College London"},{"author_name":"Pak C Sham","author_inst":"The University of Hong Kong"},{"author_name":"Evangelos Vassos","author_inst":"King's College London"},{"author_name":"Richard Bentall","author_inst":"University of Sheffield"},{"author_name":"Emma M Walker","author_inst":"University of Exeter"},{"author_name":"Emma Dempster","author_inst":"University of Exeter"},{"author_name":"Robin Murray","author_inst":"King's College London"},{"author_name":"Marta Di Forti","author_inst":"King's College London"},{"author_name":"Luis Alameda","author_inst":"King's College London"},{"author_name":"Chloe C.Y Wong","author_inst":"King's College London"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Estimating COVID-19 Cumulative Incidence from Seroprevalence Surveys accounting for Time-Varying Seroreversion: A Fully Bayesian Methodology","rel_doi":"10.64898\/2026.06.09.26355264","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355264","rel_abs":"Seroprevalence surveys reveal the extent of humoral immunity against pathogens such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and under some circumstances represent cumulative incidence of prior infection. However, antibody waning-or seroreversion-biases these estimates by reducing assay sensitivity in a time-varying manner. Because assay sensitivity decays over time, naively using serosurveys can substantially bias estimates of SARS-CoV-2 cumulative incidence and fatality rates. The Bayesian assay-specific, time-varying sensitivity adjustment developed in this paper can reliably correct for this bias and account for the delay between infection and serosurvey. In seroprevalence studies conducted in the United States in 2020, adjusting for time-varying sensitivity increased cumulative incidence by up to 1.4-fold, with an adjustment of 1.08 for a national study. Our estimates contrast with a previously published 2-fold adjustment that did not account for assay design. This suggests that previous analyses overestimated cumulative incidence by applying seroreversion corrections that did not account for assay-specific effects, or underestimated cumulative incidence by not applying seroreversion corrections. These biases imply fatality rate underestimation and overestimation, respectively. Our model provides a framework for design-specific time-varying sensitivity corrections in seroprevalence surveys for other pathogens.","rel_num_authors":8,"rel_authors":[{"author_name":"Nana Owusu-Boaitey","author_inst":"Fischell Department of Bioengineering, University of Maryland, College Park, Maryland, USA"},{"author_name":"Mark J. Meyer","author_inst":"Department of Mathematics and Statistics, Georgetown University, Washington, DC, USA"},{"author_name":"Daniel Herrera-Esposito","author_inst":"Computational Neuroscience Initiative, University of Pennsylvania, Philadelphia, Pennsylvania, USA"},{"author_name":"Lucas Bottcher","author_inst":"Department of Computational Science and Philosophy, Frankfurt School of Finance and Management, Frankfurt, Germany"},{"author_name":"Maria Lukz","author_inst":"School of Public Health, University of Maryland, College Park, Maryland, USA"},{"author_name":"Sydney Cook","author_inst":"Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA"},{"author_name":"Michael A. Stoto","author_inst":"Department of Health Management and Policy, Georgetown University, Washington, DC, USA"},{"author_name":"John D. Kraemer","author_inst":"Department of Health Management and Policy, Georgetown University, Washington, DC, USA"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Resolving Diagnostic Discordance in Group 2 Pulmonary Hypertension Through Staged Physiologic Testing: Insights From PVDOMICS","rel_doi":"10.64898\/2026.06.04.26354961","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354961","rel_abs":"BackgroundWorld Symposium on Pulmonary Hypertension (WSPH) Group 2 pulmonary hypertension (PH) is a clinically integrated phenotype attributed to left heart disease, whereas pre- versus post-capillary classification is operationalized primarily by pulmonary capillary wedge pressure (PCWP). Although current recommendations emphasize contextual interpretation and provocative testing for intermediate PCWP values, the relationship between PCWP-based classification and underlying phenotype has not been systematically evaluated. We aim to quantify phenotype-hemodynamic discordance across the PCWP spectrum and evaluate a staged physiology-guided framework incorporating inhaled nitric oxide (iNO), ventricular geometry, and provocative testing.\n\nMethodsWe studied 1,032 participants from the NHLBI-sponsored PVDOMICS cohort with multidisciplinary adjudicated phenotypes integrating clinical, imaging, physiologic, and hemodynamic data. Stage-specific PCWP thresholds classified pre- versus post-capillary physiology at rest, during iNO, and during provocation (fluid challenge or invasive cardiopulmonary exercise testing [iCPET]). Echocardiographic right ventricular-to-left ventricular (RV\/LV) ratio was evaluated as a marker of ventricular interdependence. Restricted cubic spline and staged concordance analyses defined certainty-based PCWP ranges and incremental diagnostic yield.\n\nResultsAdjudicated Group 2 PH was present in 37.0% of participants. Resting PCWP demonstrated good discrimination (AUC 0.86), but substantial bidirectional phenotype-hemodynamic discordance persisted across intermediate PCWP ranges. At a resting PCWP of 12 mmHg, 25% of participants classified as pre-capillary had adjudicated Group 2 PH, whereas at 18 mmHg, 35% classified as post-capillary remained discordant non-Group 2. Concordance did not approach 90% until PCWP values were <9 mmHg or >24 mmHg. Dynamic testing incrementally improved concordance within these overlap zones. Nearly half of adjudicated Group 2 PH participants (46.5%) were not identified by resting PCWP alone; incorporation of iNO and provocative testing increased cumulative Group 2 identification by 63.4% and improved sensitivity from 79.9% to 83.7%. Model discrimination improved from an AUC of 0.863 to 0.908 (likelihood-ratio P<0.001). iNO increased PCWP in discordant Pre\/G2 participants, unmasking latent left-sided limitation, while lowering PCWP in discordant Post\/NonG2 participants, consistent with ventricular interdependence. RV\/LV ratio [&ge;]0.94 reduced discordant Post\/NonG2 classification by 70.5%, and incorporation of PCWP\/cardiac output slope improved physiologic specificity during exercise.\n\nConclusionsGroup 2 PH is a dynamic, load-dependent phenotype inadequately characterized by resting PCWP alone. Intermediate PCWP values represent continuous probabilities of bidirectional discordance rather than discrete diagnostic states. A staged physiology-guided approach integrating iNO, ventricular geometry, and provocative testing improves concordance between hemodynamic classification and clinically integrated phenotype assignment.\n\nClinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIIn the deeply phenotyped PVDOMICS cohort, resting pulmonary capillary wedge pressure demonstrated good overall discrimination for adjudicated Group 2 (left heart disease) pulmonary hypertension, yet intermediate values frequently either concealed latent left-heart disease or overclassified patients without intrinsic left-heart disease\nC_LIO_LIResting pulmonary capillary wedge pressure should be viewed as a continuous probability signal rather than a binary threshold, allowing additional physiologic testing to be targeted according to the degree of diagnostic uncertainty a clinician is willing to accept.\nC_LIO_LIA staged physiology-guided approach incorporating inhaled nitric oxide, ventricular geometry, and provocative testing improved concordance with adjudicated PH category and pre or post-capillary classification.\nC_LI\n\nWhat Are the Clinical Implications?O_LIPre- versus post-capillary classification should be interpreted within the broader clinical and physiologic context rather than relying on a single resting pulmonary capillary wedge pressure threshold.\nC_LIO_LIIntermediate pulmonary capillary wedge pressure values should prompt consideration of additional physiologic evaluation, with inhaled nitric oxide providing a practical intermediate step and provocative testing providing the greatest incremental diagnostic yield.\nC_LIO_LIExercise pulmonary capillary wedge pressure\/cardiac output slope and markers of ventricular interdependence may provide complementary information for resolving uncertainty when resting and dynamic hemodynamics are discordant.\nC_LI","rel_num_authors":21,"rel_authors":[{"author_name":"Franz Rischard","author_inst":"The University of Arizona College of Medicine Tucson"},{"author_name":"PVCOMICS Study Group","author_inst":""},{"author_name":"Mateo Mendoza","author_inst":"Cedars-Sinai Health System"},{"author_name":"Michael Insel","author_inst":"University of Arizona"},{"author_name":"Gerald Beck","author_inst":"Cleveland Clinic Foundation"},{"author_name":"Serpil Erzurum","author_inst":"Cleveland Clinic"},{"author_name":"Robert P Frantz","author_inst":"Mayo Clinic"},{"author_name":"J. Emanuel Finet","author_inst":"Cleveland Clinic"},{"author_name":"Paul Hassoun","author_inst":"Johns Hopkins University"},{"author_name":"Anna R. Hemnes","author_inst":"Vanderbilt University"},{"author_name":"Nicholas S. Hill","author_inst":"Tufts University School of Dental Medicine"},{"author_name":"Evelyn M Horn","author_inst":"Weill Cornell Medical College"},{"author_name":"Jane A. Leopold","author_inst":"Brigham and Women's Hospital"},{"author_name":"Stephen C Mathai","author_inst":"Johns Hopkins Medical Institutions, Baltimore, MD"},{"author_name":"Reena Mehra","author_inst":"University of Washington"},{"author_name":"Yogesh N. V. Reddy","author_inst":"Division of Cardiology, Mayo Clinic"},{"author_name":"Erika B. Rosenzweig","author_inst":"Westchester Medical Center"},{"author_name":"David M Systrom","author_inst":"Brigham & Women's Hospital"},{"author_name":"W. H. Wilson Tang","author_inst":"Cleveland Clinic"},{"author_name":"Aaron Waxman","author_inst":"Brigham and Women's Hospital Department of Medicine"},{"author_name":"Barry A Borlaug","author_inst":"Division of Cardiology, Mayo Clinic"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Resolving Diagnostic Discordance in Group 2 Pulmonary Hypertension Through Staged Physiologic Testing: Insights From PVDOMICS","rel_doi":"10.64898\/2026.06.04.26354961","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354961","rel_abs":"BackgroundWorld Symposium on Pulmonary Hypertension (WSPH) Group 2 pulmonary hypertension (PH) is a clinically integrated phenotype attributed to left heart disease, whereas pre- versus post-capillary classification is operationalized primarily by pulmonary capillary wedge pressure (PCWP). Although current recommendations emphasize contextual interpretation and provocative testing for intermediate PCWP values, the relationship between PCWP-based classification and underlying phenotype has not been systematically evaluated. We aim to quantify phenotype-hemodynamic discordance across the PCWP spectrum and evaluate a staged physiology-guided framework incorporating inhaled nitric oxide (iNO), ventricular geometry, and provocative testing.\n\nMethodsWe studied 1,032 participants from the NHLBI-sponsored PVDOMICS cohort with multidisciplinary adjudicated phenotypes integrating clinical, imaging, physiologic, and hemodynamic data. Stage-specific PCWP thresholds classified pre- versus post-capillary physiology at rest, during iNO, and during provocation (fluid challenge or invasive cardiopulmonary exercise testing [iCPET]). Echocardiographic right ventricular-to-left ventricular (RV\/LV) ratio was evaluated as a marker of ventricular interdependence. Restricted cubic spline and staged concordance analyses defined certainty-based PCWP ranges and incremental diagnostic yield.\n\nResultsAdjudicated Group 2 PH was present in 37.0% of participants. Resting PCWP demonstrated good discrimination (AUC 0.86), but substantial bidirectional phenotype-hemodynamic discordance persisted across intermediate PCWP ranges. At a resting PCWP of 12 mmHg, 25% of participants classified as pre-capillary had adjudicated Group 2 PH, whereas at 18 mmHg, 35% classified as post-capillary remained discordant non-Group 2. Concordance did not approach 90% until PCWP values were <9 mmHg or >24 mmHg. Dynamic testing incrementally improved concordance within these overlap zones. Nearly half of adjudicated Group 2 PH participants (46.5%) were not identified by resting PCWP alone; incorporation of iNO and provocative testing increased cumulative Group 2 identification by 63.4% and improved sensitivity from 79.9% to 83.7%. Model discrimination improved from an AUC of 0.863 to 0.908 (likelihood-ratio P<0.001). iNO increased PCWP in discordant Pre\/G2 participants, unmasking latent left-sided limitation, while lowering PCWP in discordant Post\/NonG2 participants, consistent with ventricular interdependence. RV\/LV ratio [&ge;]0.94 reduced discordant Post\/NonG2 classification by 70.5%, and incorporation of PCWP\/cardiac output slope improved physiologic specificity during exercise.\n\nConclusionsGroup 2 PH is a dynamic, load-dependent phenotype inadequately characterized by resting PCWP alone. Intermediate PCWP values represent continuous probabilities of bidirectional discordance rather than discrete diagnostic states. A staged physiology-guided approach integrating iNO, ventricular geometry, and provocative testing improves concordance between hemodynamic classification and clinically integrated phenotype assignment.\n\nClinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIIn the deeply phenotyped PVDOMICS cohort, resting pulmonary capillary wedge pressure demonstrated good overall discrimination for adjudicated Group 2 (left heart disease) pulmonary hypertension, yet intermediate values frequently either concealed latent left-heart disease or overclassified patients without intrinsic left-heart disease\nC_LIO_LIResting pulmonary capillary wedge pressure should be viewed as a continuous probability signal rather than a binary threshold, allowing additional physiologic testing to be targeted according to the degree of diagnostic uncertainty a clinician is willing to accept.\nC_LIO_LIA staged physiology-guided approach incorporating inhaled nitric oxide, ventricular geometry, and provocative testing improved concordance with adjudicated PH category and pre or post-capillary classification.\nC_LI\n\nWhat Are the Clinical Implications?O_LIPre- versus post-capillary classification should be interpreted within the broader clinical and physiologic context rather than relying on a single resting pulmonary capillary wedge pressure threshold.\nC_LIO_LIIntermediate pulmonary capillary wedge pressure values should prompt consideration of additional physiologic evaluation, with inhaled nitric oxide providing a practical intermediate step and provocative testing providing the greatest incremental diagnostic yield.\nC_LIO_LIExercise pulmonary capillary wedge pressure\/cardiac output slope and markers of ventricular interdependence may provide complementary information for resolving uncertainty when resting and dynamic hemodynamics are discordant.\nC_LI","rel_num_authors":21,"rel_authors":[{"author_name":"Franz Rischard","author_inst":"The University of Arizona College of Medicine Tucson"},{"author_name":"PVCOMICS Study Group","author_inst":""},{"author_name":"Mateo Mendoza","author_inst":"Cedars-Sinai Health System"},{"author_name":"Michael Insel","author_inst":"University of Arizona"},{"author_name":"Gerald Beck","author_inst":"Cleveland Clinic Foundation"},{"author_name":"Serpil Erzurum","author_inst":"Cleveland Clinic"},{"author_name":"Robert P Frantz","author_inst":"Mayo Clinic"},{"author_name":"J. Emanuel Finet","author_inst":"Cleveland Clinic"},{"author_name":"Paul Hassoun","author_inst":"Johns Hopkins University"},{"author_name":"Anna R. Hemnes","author_inst":"Vanderbilt University"},{"author_name":"Nicholas S. Hill","author_inst":"Tufts University School of Dental Medicine"},{"author_name":"Evelyn M Horn","author_inst":"Weill Cornell Medical College"},{"author_name":"Jane A. Leopold","author_inst":"Brigham and Women's Hospital"},{"author_name":"Stephen C Mathai","author_inst":"Johns Hopkins Medical Institutions, Baltimore, MD"},{"author_name":"Reena Mehra","author_inst":"University of Washington"},{"author_name":"Yogesh N. V. Reddy","author_inst":"Division of Cardiology, Mayo Clinic"},{"author_name":"Erika B. Rosenzweig","author_inst":"Westchester Medical Center"},{"author_name":"David M Systrom","author_inst":"Brigham & Women's Hospital"},{"author_name":"W. H. Wilson Tang","author_inst":"Cleveland Clinic"},{"author_name":"Aaron Waxman","author_inst":"Brigham and Women's Hospital Department of Medicine"},{"author_name":"Barry A Borlaug","author_inst":"Division of Cardiology, Mayo Clinic"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Prediction of immunotherapy response using live tumor fragments from routine clinical biopsies","rel_doi":"10.64898\/2026.06.05.26354635","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354635","rel_abs":"Functional ex vivo assays using live tumor tissues have demonstrated strong predictive accuracy for response to immune checkpoint inhibitors (ICIs) but are not scalable, requiring manual processing of large resections collected at academic centers. Here, an ex vivo live tumor fragment (LTF) platform was developed using standard-of-care biopsies from 228 patients with suspected malignancy collected across prospective, multicenter observational trials and biobanks. Hierarchical clustering of ICI-mediated changes in cytokine production identified two groups: responders and nonresponders. A binary classifier (elive index) using 8 cytokines achieved an AUC of 0.99 for cluster prediction. elive index correctly predicted clinical benefit in 93% (26\/28) of patients (P = 3.2x10-5) and accurately identified 83% (10\/12) of objective responders. Critically, elive responders were identified among biomarker-negative patients, highlighting the platform as a scalable approach that complements existing companion diagnostics and expands the population of patients identified to benefit from ICI therapy.","rel_num_authors":46,"rel_authors":[{"author_name":"David Braun","author_inst":"Yale School of Medicine, New Haven, CT"},{"author_name":"Nicholas Dana","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Hilary R. Hernan","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Shalini Sahni","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Christina Scribano","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Christin Johnson","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Lindsey Vedder","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Erika von Euw","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Julie Zweng","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Ellen Wargowski","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Aishwarya Sunil","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Deepa Sharma","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Josh Routh","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Katherine Rexroad","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Payton McDonnell","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Victor Jergens","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Catarina Costa","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Richard Zuniga","author_inst":"New York Cancer & Blood Specialists, New York, NY"},{"author_name":"Giuseppe V. Toia","author_inst":"University of Wisconsin School of Medicine and Public Health, Madison, WI"},{"author_name":"Paras M. Patel","author_inst":"JPS Health Network, Fort Worth, TX"},{"author_name":"Robert C.G. Martin II","author_inst":"University of Louisville School of Medicine, Louisville, KY"},{"author_name":"Umair Majeed","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Debabrata Mukhopadhyay","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Yanyan Lou","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Nima Kokabi","author_inst":"University of North Carolina, Chapel Hill, NC"},{"author_name":"James W. Jakub","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"David Hays","author_inst":"CARTI, Little Rock, AR"},{"author_name":"Andrew K. Godwin","author_inst":"University of Kansas Medical Center, Kansas City, KS"},{"author_name":"Victoria Giffi","author_inst":"Meritus Health, Hagerstown, MD"},{"author_name":"Alexander Gelbard","author_inst":"Vanderbilt, Nashville, TN"},{"author_name":"Andreas Friedl","author_inst":"University of Wisconsin School of Medicine and Public Health, Madison, WI"},{"author_name":"Emma Kate Duimstra","author_inst":"EmpiriQA LLC, Long Grove, IL"},{"author_name":"Roxana S. Dronca","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Ruqin Chen","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Heather Chalfin","author_inst":"Frederick Health, Frederick, MD"},{"author_name":"Barbara Broome","author_inst":"Orlando Health, Orlando, FL"},{"author_name":"Hani M. Babiker","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Tarun Chandra","author_inst":"EmpiriQA LLC, Long Grove, IL"},{"author_name":"Sean Caenepeel","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Laura C. F. Hrycyniak","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Chetan Sood","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Hilario Ramos","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Premal Patel","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Pooja Advani","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Hinco J. Gierman","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Janis Taube","author_inst":"Johns Hopkins University School of Medicine, Baltimore, MD"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Prediction of immunotherapy response using live tumor fragments from routine clinical biopsies","rel_doi":"10.64898\/2026.06.05.26354635","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354635","rel_abs":"Functional ex vivo assays using live tumor tissues have demonstrated strong predictive accuracy for response to immune checkpoint inhibitors (ICIs) but are not scalable, requiring manual processing of large resections collected at academic centers. Here, an ex vivo live tumor fragment (LTF) platform was developed using standard-of-care biopsies from 228 patients with suspected malignancy collected across prospective, multicenter observational trials and biobanks. Hierarchical clustering of ICI-mediated changes in cytokine production identified two groups: responders and nonresponders. A binary classifier (elive index) using 8 cytokines achieved an AUC of 0.99 for cluster prediction. elive index correctly predicted clinical benefit in 93% (26\/28) of patients (P = 3.2x10-5) and accurately identified 83% (10\/12) of objective responders. Critically, elive responders were identified among biomarker-negative patients, highlighting the platform as a scalable approach that complements existing companion diagnostics and expands the population of patients identified to benefit from ICI therapy.","rel_num_authors":46,"rel_authors":[{"author_name":"David Braun","author_inst":"Yale School of Medicine, New Haven, CT"},{"author_name":"Nicholas Dana","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Hilary R. Hernan","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Shalini Sahni","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Christina Scribano","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Christin Johnson","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Lindsey Vedder","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Erika von Euw","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Julie Zweng","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Ellen Wargowski","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Aishwarya Sunil","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Deepa Sharma","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Josh Routh","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Katherine Rexroad","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Payton McDonnell","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Victor Jergens","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Catarina Costa","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Richard Zuniga","author_inst":"New York Cancer & Blood Specialists, New York, NY"},{"author_name":"Giuseppe V. Toia","author_inst":"University of Wisconsin School of Medicine and Public Health, Madison, WI"},{"author_name":"Paras M. Patel","author_inst":"JPS Health Network, Fort Worth, TX"},{"author_name":"Robert C.G. Martin II","author_inst":"University of Louisville School of Medicine, Louisville, KY"},{"author_name":"Umair Majeed","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Debabrata Mukhopadhyay","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Yanyan Lou","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Nima Kokabi","author_inst":"University of North Carolina, Chapel Hill, NC"},{"author_name":"James W. Jakub","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"David Hays","author_inst":"CARTI, Little Rock, AR"},{"author_name":"Andrew K. Godwin","author_inst":"University of Kansas Medical Center, Kansas City, KS"},{"author_name":"Victoria Giffi","author_inst":"Meritus Health, Hagerstown, MD"},{"author_name":"Alexander Gelbard","author_inst":"Vanderbilt, Nashville, TN"},{"author_name":"Andreas Friedl","author_inst":"University of Wisconsin School of Medicine and Public Health, Madison, WI"},{"author_name":"Emma Kate Duimstra","author_inst":"EmpiriQA LLC, Long Grove, IL"},{"author_name":"Roxana S. Dronca","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Ruqin Chen","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Heather Chalfin","author_inst":"Frederick Health, Frederick, MD"},{"author_name":"Barbara Broome","author_inst":"Orlando Health, Orlando, FL"},{"author_name":"Hani M. Babiker","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Tarun Chandra","author_inst":"EmpiriQA LLC, Long Grove, IL"},{"author_name":"Sean Caenepeel","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Laura C. F. Hrycyniak","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Chetan Sood","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Hilario Ramos","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Premal Patel","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Pooja Advani","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Hinco J. Gierman","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Janis Taube","author_inst":"Johns Hopkins University School of Medicine, Baltimore, MD"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Prediction of immunotherapy response using live tumor fragments from routine clinical biopsies","rel_doi":"10.64898\/2026.06.05.26354635","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354635","rel_abs":"Functional ex vivo assays using live tumor tissues have demonstrated strong predictive accuracy for response to immune checkpoint inhibitors (ICIs) but are not scalable, requiring manual processing of large resections collected at academic centers. Here, an ex vivo live tumor fragment (LTF) platform was developed using standard-of-care biopsies from 228 patients with suspected malignancy collected across prospective, multicenter observational trials and biobanks. Hierarchical clustering of ICI-mediated changes in cytokine production identified two groups: responders and nonresponders. A binary classifier (elive index) using 8 cytokines achieved an AUC of 0.99 for cluster prediction. elive index correctly predicted clinical benefit in 93% (26\/28) of patients (P = 3.2x10-5) and accurately identified 83% (10\/12) of objective responders. Critically, elive responders were identified among biomarker-negative patients, highlighting the platform as a scalable approach that complements existing companion diagnostics and expands the population of patients identified to benefit from ICI therapy.","rel_num_authors":46,"rel_authors":[{"author_name":"David Braun","author_inst":"Yale School of Medicine, New Haven, CT"},{"author_name":"Nicholas Dana","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Hilary R. Hernan","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Shalini Sahni","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Christina Scribano","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Christin Johnson","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Lindsey Vedder","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Erika von Euw","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Julie Zweng","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Ellen Wargowski","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Aishwarya Sunil","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Deepa Sharma","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Josh Routh","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Katherine Rexroad","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Payton McDonnell","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Victor Jergens","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Catarina Costa","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Richard Zuniga","author_inst":"New York Cancer & Blood Specialists, New York, NY"},{"author_name":"Giuseppe V. Toia","author_inst":"University of Wisconsin School of Medicine and Public Health, Madison, WI"},{"author_name":"Paras M. Patel","author_inst":"JPS Health Network, Fort Worth, TX"},{"author_name":"Robert C.G. Martin II","author_inst":"University of Louisville School of Medicine, Louisville, KY"},{"author_name":"Umair Majeed","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Debabrata Mukhopadhyay","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Yanyan Lou","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Nima Kokabi","author_inst":"University of North Carolina, Chapel Hill, NC"},{"author_name":"James W. Jakub","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"David Hays","author_inst":"CARTI, Little Rock, AR"},{"author_name":"Andrew K. Godwin","author_inst":"University of Kansas Medical Center, Kansas City, KS"},{"author_name":"Victoria Giffi","author_inst":"Meritus Health, Hagerstown, MD"},{"author_name":"Alexander Gelbard","author_inst":"Vanderbilt, Nashville, TN"},{"author_name":"Andreas Friedl","author_inst":"University of Wisconsin School of Medicine and Public Health, Madison, WI"},{"author_name":"Emma Kate Duimstra","author_inst":"EmpiriQA LLC, Long Grove, IL"},{"author_name":"Roxana S. Dronca","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Ruqin Chen","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Heather Chalfin","author_inst":"Frederick Health, Frederick, MD"},{"author_name":"Barbara Broome","author_inst":"Orlando Health, Orlando, FL"},{"author_name":"Hani M. Babiker","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Tarun Chandra","author_inst":"EmpiriQA LLC, Long Grove, IL"},{"author_name":"Sean Caenepeel","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Laura C. F. Hrycyniak","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Chetan Sood","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Hilario Ramos","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Premal Patel","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Pooja Advani","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Hinco J. Gierman","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Janis Taube","author_inst":"Johns Hopkins University School of Medicine, Baltimore, MD"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Trajectories of brain structure and function in young adult carriers of genetic frontotemporal dementia variants","rel_doi":"10.64898\/2026.06.08.26355165","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355165","rel_abs":"Background and Objectives: Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods: This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results: Variant carriers (n=147) and familial non-carriers (n=113) did not differ in age (mean{+\/-}SD, 25.9{+\/-}3.2 years), sex (53% female), or number of visits (2.1{+\/-}1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years (b=-982.8mm3, SE=317.0, p=0.0046, f2=0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines (b=64.4mm3, SE=29.9, p=0.035, f2=0.07). For MAPT and GRN, there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion: C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.","rel_num_authors":79,"rel_authors":[{"author_name":"Isis So","author_inst":"Western University"},{"author_name":"Jolina Lombardi","author_inst":"University of California, San Francisco, CA, USA"},{"author_name":"Adam M Staffaroni","author_inst":"University of California, San Francisco"},{"author_name":"Kristy Coleman","author_inst":"Western University"},{"author_name":"Arabella Bouzigues","author_inst":"University College London"},{"author_name":"Eve Ferry-Bolder","author_inst":"University College London"},{"author_name":"Eva Cullen","author_inst":"University College London"},{"author_name":"Lucy Russell","author_inst":"University College London"},{"author_name":"Phoebe Foster","author_inst":"University College London"},{"author_name":"Sophie Farley","author_inst":"University College London"},{"author_name":"Rhian Convery","author_inst":"University College London"},{"author_name":"John C van Swieten","author_inst":"Erasmus MC University Medical Center"},{"author_name":"Lize C. Jiskoot","author_inst":"Erasmus MC University Medical Center"},{"author_name":"Harro Seelaar","author_inst":"Erasmus MC University Medical Centre"},{"author_name":"Daniela Galimberti","author_inst":"University of Milan"},{"author_name":"Rik Vandenberghe","author_inst":"KU Leuven"},{"author_name":"Robert Laforce Jr.","author_inst":"Laval University"},{"author_name":"Rose Bruffaerts","author_inst":"University of Antwerp"},{"author_name":"Maxime Bertoux","author_inst":"University of Lille"},{"author_name":"Thibaud Lebouvier","author_inst":"University of Lille"},{"author_name":"Eino Solje","author_inst":"University of Eastern Finland"},{"author_name":"Johannes Levin","author_inst":"Ludwig-Maximilians-Universitat Munchen"},{"author_name":"Giuseppe di Fede","author_inst":"Fondazione IRCCS Istituto Neurologico Carlo Besta"},{"author_name":"Alexander Thompson","author_inst":"University of Oxford"},{"author_name":"Isabelle Le Ber","author_inst":"Institut du Cerveau"},{"author_name":"Raffaella Lara Migliaccio","author_inst":"Institut du Cerveau"},{"author_name":"Peter Kortvelyessy","author_inst":"Charite Universitatsmedizin Berlin"},{"author_name":"Matthias L. Schroeter","author_inst":"Max Planck Institute for Human Cognitive and Brain Sciences"},{"author_name":"Giancarlo Logroscino","author_inst":"University of Bari"},{"author_name":"Markus Otto","author_inst":"Martin Luther University Halle-Wittenberg, University clinic"},{"author_name":"Zeljko Uzelac","author_inst":"University of Ulm"},{"author_name":"Ignacio Illan-Gala","author_inst":"Hospital de la Santa Creu i Sant Pau"},{"author_name":"Johanna Kruger","author_inst":"University of Oulu"},{"author_name":"Benedetta Nacmias","author_inst":"University of Florence"},{"author_name":"Alexander Gerhard","author_inst":"University of Manchester"},{"author_name":"Tobias Langheinrich","author_inst":"University of Manchester"},{"author_name":"Simon Ducharme","author_inst":"McGill University"},{"author_name":"Isabel J Santana","author_inst":"University of Coimbra"},{"author_name":"Carmela Tartaglia","author_inst":"University of Toronto"},{"author_name":"Mario Masellis","author_inst":"University of Toronto"},{"author_name":"Alexandre de Mendonca","author_inst":"University of Lisbon"},{"author_name":"James Rowe","author_inst":"University of Cambridge"},{"author_name":"Caroline Graff","author_inst":"Karolinska Institutet"},{"author_name":"Fermin Morenoizco","author_inst":"Hospital Universitario Donostia, San Sebastian"},{"author_name":"Matthis Synofzik","author_inst":"University of Tubingen"},{"author_name":"Barbara Borroni","author_inst":"Universita degli Studi di BRESCIA"},{"author_name":"Raquel Sanchez-Valle","author_inst":"University of Barcelona"},{"author_name":"Danielle Brushaber","author_inst":"Mayo Clinic"},{"author_name":"Ciaran Considine","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Kelley Faber","author_inst":"Indiana University"},{"author_name":"Julie Fields","author_inst":"Mayo Clinic"},{"author_name":"Tatiana Foroud","author_inst":"Mayo Clinic"},{"author_name":"Leah K. Forsberg","author_inst":"Mayo Clinic"},{"author_name":"Tania Gendron","author_inst":"Mayo Clinic"},{"author_name":"Daniel Geschwind","author_inst":"UCLA"},{"author_name":"Hilary Heuer","author_inst":"University of California, San Francisco"},{"author_name":"Eric Huang","author_inst":"University of California, San Francisco"},{"author_name":"Kejal Kantarci","author_inst":"Mayo Clinic in Rochester"},{"author_name":"Tyler Kolander","author_inst":"Mayo Clinic"},{"author_name":"Argentina Lario Lago","author_inst":"University of California, San Francisco"},{"author_name":"Shannon B. Lavigne","author_inst":"Mayo Clinic"},{"author_name":"Carly Mester","author_inst":"Mayo Clinic"},{"author_name":"Joie Molden","author_inst":"Indiana University"},{"author_name":"Leonard Petrucelli","author_inst":"Mayo Clinic"},{"author_name":"Rosa Rademakers","author_inst":"University of Antwerp"},{"author_name":"Eliana Marisa Ramos","author_inst":"University of California, Los Angeles"},{"author_name":"Katherine P. Rankin","author_inst":"University of California, San Francisco"},{"author_name":"Katya Rascovsky","author_inst":"University of Pennsylvania"},{"author_name":"Kristoffer W. Rhoads","author_inst":"University of Pennsylvania"},{"author_name":"Marijne Vandebergh","author_inst":"VIB-UAntwerp Center for Molecular Neurology"},{"author_name":"Sandra Weintraub","author_inst":"Northwestern University"},{"author_name":"Bonnie Wong","author_inst":"Harvard University"},{"author_name":"Bradley Boeve","author_inst":"Mayo Clinic"},{"author_name":"Adam L. Boxer","author_inst":"University of California, San Francisco"},{"author_name":"Howard J. Rosen","author_inst":"University of California, San Francisco"},{"author_name":"Suzee E. Lee","author_inst":"University of California, San Francisco"},{"author_name":"Jonathan D. Rohrer","author_inst":"University College London"},{"author_name":"Elizabeth C. Finger","author_inst":"Western University"},{"author_name":"- Frontotemporal Dementia Prevention Initiative (FPI) Investigators","author_inst":""}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Trajectories of brain structure and function in young adult carriers of genetic frontotemporal dementia variants","rel_doi":"10.64898\/2026.06.08.26355165","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355165","rel_abs":"Background and Objectives: Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods: This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results: Variant carriers (n=147) and familial non-carriers (n=113) did not differ in age (mean{+\/-}SD, 25.9{+\/-}3.2 years), sex (53% female), or number of visits (2.1{+\/-}1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years (b=-982.8mm3, SE=317.0, p=0.0046, f2=0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines (b=64.4mm3, SE=29.9, p=0.035, f2=0.07). For MAPT and GRN, there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion: C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.","rel_num_authors":79,"rel_authors":[{"author_name":"Isis So","author_inst":"Western University"},{"author_name":"Jolina Lombardi","author_inst":"University of California, San Francisco, CA, USA"},{"author_name":"Adam M Staffaroni","author_inst":"University of California, San Francisco"},{"author_name":"Kristy Coleman","author_inst":"Western University"},{"author_name":"Arabella Bouzigues","author_inst":"University College London"},{"author_name":"Eve Ferry-Bolder","author_inst":"University College London"},{"author_name":"Eva Cullen","author_inst":"University College London"},{"author_name":"Lucy Russell","author_inst":"University College London"},{"author_name":"Phoebe Foster","author_inst":"University College London"},{"author_name":"Sophie Farley","author_inst":"University College London"},{"author_name":"Rhian Convery","author_inst":"University College London"},{"author_name":"John C van Swieten","author_inst":"Erasmus MC University Medical Center"},{"author_name":"Lize C. Jiskoot","author_inst":"Erasmus MC University Medical Center"},{"author_name":"Harro Seelaar","author_inst":"Erasmus MC University Medical Centre"},{"author_name":"Daniela Galimberti","author_inst":"University of Milan"},{"author_name":"Rik Vandenberghe","author_inst":"KU Leuven"},{"author_name":"Robert Laforce Jr.","author_inst":"Laval University"},{"author_name":"Rose Bruffaerts","author_inst":"University of Antwerp"},{"author_name":"Maxime Bertoux","author_inst":"University of Lille"},{"author_name":"Thibaud Lebouvier","author_inst":"University of Lille"},{"author_name":"Eino Solje","author_inst":"University of Eastern Finland"},{"author_name":"Johannes Levin","author_inst":"Ludwig-Maximilians-Universitat Munchen"},{"author_name":"Giuseppe di Fede","author_inst":"Fondazione IRCCS Istituto Neurologico Carlo Besta"},{"author_name":"Alexander Thompson","author_inst":"University of Oxford"},{"author_name":"Isabelle Le Ber","author_inst":"Institut du Cerveau"},{"author_name":"Raffaella Lara Migliaccio","author_inst":"Institut du Cerveau"},{"author_name":"Peter Kortvelyessy","author_inst":"Charite Universitatsmedizin Berlin"},{"author_name":"Matthias L. Schroeter","author_inst":"Max Planck Institute for Human Cognitive and Brain Sciences"},{"author_name":"Giancarlo Logroscino","author_inst":"University of Bari"},{"author_name":"Markus Otto","author_inst":"Martin Luther University Halle-Wittenberg, University clinic"},{"author_name":"Zeljko Uzelac","author_inst":"University of Ulm"},{"author_name":"Ignacio Illan-Gala","author_inst":"Hospital de la Santa Creu i Sant Pau"},{"author_name":"Johanna Kruger","author_inst":"University of Oulu"},{"author_name":"Benedetta Nacmias","author_inst":"University of Florence"},{"author_name":"Alexander Gerhard","author_inst":"University of Manchester"},{"author_name":"Tobias Langheinrich","author_inst":"University of Manchester"},{"author_name":"Simon Ducharme","author_inst":"McGill University"},{"author_name":"Isabel J Santana","author_inst":"University of Coimbra"},{"author_name":"Carmela Tartaglia","author_inst":"University of Toronto"},{"author_name":"Mario Masellis","author_inst":"University of Toronto"},{"author_name":"Alexandre de Mendonca","author_inst":"University of Lisbon"},{"author_name":"James Rowe","author_inst":"University of Cambridge"},{"author_name":"Caroline Graff","author_inst":"Karolinska Institutet"},{"author_name":"Fermin Morenoizco","author_inst":"Hospital Universitario Donostia, San Sebastian"},{"author_name":"Matthis Synofzik","author_inst":"University of Tubingen"},{"author_name":"Barbara Borroni","author_inst":"Universita degli Studi di BRESCIA"},{"author_name":"Raquel Sanchez-Valle","author_inst":"University of Barcelona"},{"author_name":"Danielle Brushaber","author_inst":"Mayo Clinic"},{"author_name":"Ciaran Considine","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Kelley Faber","author_inst":"Indiana University"},{"author_name":"Julie Fields","author_inst":"Mayo Clinic"},{"author_name":"Tatiana Foroud","author_inst":"Mayo Clinic"},{"author_name":"Leah K. Forsberg","author_inst":"Mayo Clinic"},{"author_name":"Tania Gendron","author_inst":"Mayo Clinic"},{"author_name":"Daniel Geschwind","author_inst":"UCLA"},{"author_name":"Hilary Heuer","author_inst":"University of California, San Francisco"},{"author_name":"Eric Huang","author_inst":"University of California, San Francisco"},{"author_name":"Kejal Kantarci","author_inst":"Mayo Clinic in Rochester"},{"author_name":"Tyler Kolander","author_inst":"Mayo Clinic"},{"author_name":"Argentina Lario Lago","author_inst":"University of California, San Francisco"},{"author_name":"Shannon B. Lavigne","author_inst":"Mayo Clinic"},{"author_name":"Carly Mester","author_inst":"Mayo Clinic"},{"author_name":"Joie Molden","author_inst":"Indiana University"},{"author_name":"Leonard Petrucelli","author_inst":"Mayo Clinic"},{"author_name":"Rosa Rademakers","author_inst":"University of Antwerp"},{"author_name":"Eliana Marisa Ramos","author_inst":"University of California, Los Angeles"},{"author_name":"Katherine P. Rankin","author_inst":"University of California, San Francisco"},{"author_name":"Katya Rascovsky","author_inst":"University of Pennsylvania"},{"author_name":"Kristoffer W. Rhoads","author_inst":"University of Pennsylvania"},{"author_name":"Marijne Vandebergh","author_inst":"VIB-UAntwerp Center for Molecular Neurology"},{"author_name":"Sandra Weintraub","author_inst":"Northwestern University"},{"author_name":"Bonnie Wong","author_inst":"Harvard University"},{"author_name":"Bradley Boeve","author_inst":"Mayo Clinic"},{"author_name":"Adam L. Boxer","author_inst":"University of California, San Francisco"},{"author_name":"Howard J. Rosen","author_inst":"University of California, San Francisco"},{"author_name":"Suzee E. Lee","author_inst":"University of California, San Francisco"},{"author_name":"Jonathan D. Rohrer","author_inst":"University College London"},{"author_name":"Elizabeth C. Finger","author_inst":"Western University"},{"author_name":"- Frontotemporal Dementia Prevention Initiative (FPI) Investigators","author_inst":""}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Development of an Open-Access Action Observation Video Library for Upper Limb Motor Rehabilitation","rel_doi":"10.64898\/2026.06.10.26355108","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355108","rel_abs":"BackgroundOccupational therapists can improve stroke survivors hand and arm movement and participation in daily activities through action observation (AO). AO involves watching another persons hand or arm complete a movement or task. While research generally supports the use of AO with stroke survivors, there are limited AO videos are available to occupational therapists which makes applying AO challenging.\n\nObjectiveThe purpose of this work is to develop structured and widely accessible tool to support access to AO for stroke survivors, occupational therapists, and researchers.\n\nMethodsTo develop an AO video library for stroke rehabilitation, functional and non-functional upper limb task deficits were first identified through clinical observations and clinician interviews to establish a prioritized list of daily activities. In collaboration with media production specialists, healthy adult volunteers were recruited and filmed performing these tasks from both first-and third-person perspectives. The recorded videos were then systematically edited, enhanced with instructional title slides, and distributed via a public YouTube channel for clinical application and a categorized digital repository for research purposes.\n\nResultsInitial assessments revealed a complete lack of familiarity, awareness, and utilization of AO resources among local occupational therapists, despite high perceived clinical utility. To address this gap, a final library of 150 tasks was established, resulting in the production of 419 finalized, standardized videos featuring six healthy volunteers. For clinical application, these videos were hosted on a free, public YouTube channel organized into 18 functional playlists, while a parallel set was structured into distinct movement categories for research repository storage.\n\nConclusionBy providing a structured and highly accessible tool, this repository enables clinicians, researchers, and caregivers to readily implement evidence-based action observation interventions in both clinical and home settings.","rel_num_authors":3,"rel_authors":[{"author_name":"Medina Madison","author_inst":"Department of Occupational Therapy, Byrdine F. Lewis College of Nursing and Health Professions, Georgia State University"},{"author_name":"Lewis A Wheaton","author_inst":"Georgia Tech"},{"author_name":"Veronica Rowe","author_inst":"Department of Occupational Therapy, Byrdine F. Lewis College of Nursing and Health Professions, Georgia State University"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Longitudinal brain structural changes during clozapine treatment: associations with neuroreceptor architecture and clinical response","rel_doi":"10.64898\/2026.06.06.26354980","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.06.26354980","rel_abs":"In treatment-resistant schizophrenia, clozapine treatment has been associated with longitudinal reductions in subcortical volumes, ventricular enlargement, and widespread cortical thinning. However, it is unknown how these structural changes relate to clozapines pharmacological profile and clinical efficacy. We combined five longitudinal datasets with MRI acquired before and on average 5 months after clozapine initiation in 143 individuals to quantify brain structural changes and their association with normative maps relating to neuroreceptor architecture and physiological systems, and improvement in symptom severity. Clozapine treatment was associated with grey matter volume reductions across multiple subcortical regions (including the amygdala, hippocampus, thalamus, caudate, putamen and nucleus accumbens), increases in pallidal volume, ventricular enlargement, and widespread cortical thinning. Cortical regions showing the greatest magnitude of thinning corresponded to areas with higher normative densities of serotonergic 5-HT1A, 5-HT2A and 5-HT4 receptors. Changes in subcortical volume or cortical thickness during clozapine treatment were not associated with changes in total or positive symptom severity. In addition, baseline subcortical volume, cortical thickness, or gyrification prior to starting clozapine did not predict subsequent symptom improvement. Cortical thinning may partly reflect clozapines activity at serotonergic receptors, which have been implicated in cortical network stabilisation and neuroplasticity, however structural remodelling during clozapine treatment may reflect a process independent from its clinical efficacy in improving core symptoms of psychosis.","rel_num_authors":21,"rel_authors":[{"author_name":"Bridget King","author_inst":"King's College London"},{"author_name":"Dara Cannon","author_inst":"Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway"},{"author_name":"Nicolas A Crossley","author_inst":"Pontificia Universidad Catolica de Chile"},{"author_name":"Alfonso Gonzalez Valderrama","author_inst":"School of Medicine, Finis Terrae University, Santiago, Chile; Dr Jose Horwitz Barack Psychiatric Institute, Santiago Chile"},{"author_name":"Brian Hallahan","author_inst":"Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway"},{"author_name":"Wi Hoon Jung","author_inst":"Department of Psychology, Gachon University, Gyeonggi-do, Republic of Korea"},{"author_name":"Matthew J. Kempton","author_inst":"Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom"},{"author_name":"Seoyoung Kim","author_inst":"Department of Psychiatry, Seoul National University Bundang Hospital, Gyeonggi-do, Seoul, Republic of Korea."},{"author_name":"Andrew J Lawrence","author_inst":"Institute of Psychiatry, Psychology and Neuroscience; King's College London"},{"author_name":"James H MacCabe","author_inst":"King's College London"},{"author_name":"Colm McDonald","author_inst":"Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway"},{"author_name":"Cristian Mena","author_inst":"Centro de Interes Nacional para Investigacion e Innovacion en Ninez, Adolescencia, Resiliencia y Adversidad (IINARA), Santiago, Chile; Dr Jose Horwitz Barack Ps"},{"author_name":"Shinichiro Nakajima","author_inst":"Department of Neuropsychiatry, Keio University School of Medicine, Tokyo."},{"author_name":"Andrew Papale","author_inst":"University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"},{"author_name":"Samira Raminfard","author_inst":"University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"},{"author_name":"Deepak Sarpal","author_inst":"University of Pittsburgh"},{"author_name":"Hyejin Sim","author_inst":"Department of Brain & Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea."},{"author_name":"Giulia Tronchin","author_inst":"Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway"},{"author_name":"Lauri Tuominen","author_inst":"University of Ottawa Institute of Mental Health Research, Ottawa, ON, Canada"},{"author_name":"Euitae Kim","author_inst":"Department of Psychiatry, Seoul National University Bundang Hospital, Gyeonggi-do, Seoul, Republic of Korea; Department of Brain & Cognitive Sciences, College o"},{"author_name":"Alice Egerton","author_inst":"Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Longitudinal brain structural changes during clozapine treatment: associations with neuroreceptor architecture and clinical response","rel_doi":"10.64898\/2026.06.06.26354980","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.06.26354980","rel_abs":"In treatment-resistant schizophrenia, clozapine treatment has been associated with longitudinal reductions in subcortical volumes, ventricular enlargement, and widespread cortical thinning. However, it is unknown how these structural changes relate to clozapines pharmacological profile and clinical efficacy. We combined five longitudinal datasets with MRI acquired before and on average 5 months after clozapine initiation in 143 individuals to quantify brain structural changes and their association with normative maps relating to neuroreceptor architecture and physiological systems, and improvement in symptom severity. Clozapine treatment was associated with grey matter volume reductions across multiple subcortical regions (including the amygdala, hippocampus, thalamus, caudate, putamen and nucleus accumbens), increases in pallidal volume, ventricular enlargement, and widespread cortical thinning. Cortical regions showing the greatest magnitude of thinning corresponded to areas with higher normative densities of serotonergic 5-HT1A, 5-HT2A and 5-HT4 receptors. Changes in subcortical volume or cortical thickness during clozapine treatment were not associated with changes in total or positive symptom severity. In addition, baseline subcortical volume, cortical thickness, or gyrification prior to starting clozapine did not predict subsequent symptom improvement. Cortical thinning may partly reflect clozapines activity at serotonergic receptors, which have been implicated in cortical network stabilisation and neuroplasticity, however structural remodelling during clozapine treatment may reflect a process independent from its clinical efficacy in improving core symptoms of psychosis.","rel_num_authors":21,"rel_authors":[{"author_name":"Bridget King","author_inst":"King's College London"},{"author_name":"Dara Cannon","author_inst":"Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway"},{"author_name":"Nicolas A Crossley","author_inst":"Pontificia Universidad Catolica de Chile"},{"author_name":"Alfonso Gonzalez Valderrama","author_inst":"School of Medicine, Finis Terrae University, Santiago, Chile; Dr Jose Horwitz Barack Psychiatric Institute, Santiago Chile"},{"author_name":"Brian Hallahan","author_inst":"Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway"},{"author_name":"Wi Hoon Jung","author_inst":"Department of Psychology, Gachon University, Gyeonggi-do, Republic of Korea"},{"author_name":"Matthew J. Kempton","author_inst":"Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom"},{"author_name":"Seoyoung Kim","author_inst":"Department of Psychiatry, Seoul National University Bundang Hospital, Gyeonggi-do, Seoul, Republic of Korea."},{"author_name":"Andrew J Lawrence","author_inst":"Institute of Psychiatry, Psychology and Neuroscience; King's College London"},{"author_name":"James H MacCabe","author_inst":"King's College London"},{"author_name":"Colm McDonald","author_inst":"Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway"},{"author_name":"Cristian Mena","author_inst":"Centro de Interes Nacional para Investigacion e Innovacion en Ninez, Adolescencia, Resiliencia y Adversidad (IINARA), Santiago, Chile; Dr Jose Horwitz Barack Ps"},{"author_name":"Shinichiro Nakajima","author_inst":"Department of Neuropsychiatry, Keio University School of Medicine, Tokyo."},{"author_name":"Andrew Papale","author_inst":"University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"},{"author_name":"Samira Raminfard","author_inst":"University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"},{"author_name":"Deepak Sarpal","author_inst":"University of Pittsburgh"},{"author_name":"Hyejin Sim","author_inst":"Department of Brain & Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea."},{"author_name":"Giulia Tronchin","author_inst":"Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway"},{"author_name":"Lauri Tuominen","author_inst":"University of Ottawa Institute of Mental Health Research, Ottawa, ON, Canada"},{"author_name":"Euitae Kim","author_inst":"Department of Psychiatry, Seoul National University Bundang Hospital, Gyeonggi-do, Seoul, Republic of Korea; Department of Brain & Cognitive Sciences, College o"},{"author_name":"Alice Egerton","author_inst":"Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Age-specific burden of medically attended respiratory virus disease in high-income countries: a scoping review and meta-analysis","rel_doi":"10.64898\/2026.06.09.26354660","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26354660","rel_abs":"IntroductionRespiratory infections are a leading cause of morbidity. Newly available vaccines to prevent respiratory syncytial virus (RSV) disease and encouraging clinical progress on vaccines for human metapneumovirus (hMPV) and parainfluenza (PIV) could reduce the disease burden beyond existing influenza and SARS-CoV-2 immunisation programs. However, evidence on the contribution of these viruses to respiratory disease burden across the lifespan remains limited.\n\nMethodsWe reviewed studies from 01\/2002-11\/2025 reporting age-stratified, medically attended cases of influenza, and at least one of RSV, hMPV, or PIV, in high-income countries, excluding periods substantially overlapping with the COVID-19 pandemic. Using only studies that tested for all four viruses, we estimated the age-specific proportion of cases that were non-influenza (total across RSV, hMPV and PIV) compared to influenza using a mixed-effects logistic regression model.\n\nResultsFollowing exclusions and screening, 61 studies were included in the primary analysis comprising >500,000 detections of the four viruses. We found that a substantial proportion of medically attended respiratory illness in infants and young children was due to PIV, hMPV and RSV, rather than influenza, with a non-influenza virus proportion of 90.2% (95% CI 85.9-93.2%) in young infants aged 0-6 months. The converse was true for school-aged children, with a non-influenza virus proportion of 34.8% (95% CI 26.5-44.2%) in children aged 5-18 years. In adults aged 65+ years, non-influenza causes of medically attended disease were common at 60.2% (95% CI 50.0-69.5%). Restricting to studies reporting hospitalised cases (n=19) produced broadly similar age-specific trends in relative virus burden contributions.\n\nDiscussionWe highlight the significant burden of medically attended illness due to PIV, hMPV and RSV across ages, particularly in infant and preschool-aged children and older adults, supporting the need for effective vaccines targeting this burden.","rel_num_authors":7,"rel_authors":[{"author_name":"Muskaan Gupta","author_inst":"School of Population Health, UNSW Sydney"},{"author_name":"Hordur Zoega","author_inst":"School of Population Health, UNSW Sydney"},{"author_name":"Isaac J Stopard","author_inst":"School of Population Health, UNSW Sydney"},{"author_name":"Bette Liu","author_inst":"National Centre for Immunisation Research and Surveillance (NCIRS), Sydney, Australia"},{"author_name":"Kristine Macartney","author_inst":"National Centre for Immunisation Research and Surveillance (NCIRS), Sydney, Australia"},{"author_name":"James G Wood","author_inst":"School of Population Health, UNSW Sydney"},{"author_name":"Alexandra B Hogan","author_inst":"School of Population Health, UNSW Sydney"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Multi-ancestry genome-wide association study and meta-analysis of stimulant use disorder reveals biology and relationships to other psychiatric disorders","rel_doi":"10.64898\/2026.06.05.26354997","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354997","rel_abs":"Stimulant use disorder (StimUD) is a significant public health problem, but genetic studies have been limited by small sample sizes. We conducted genome-wide association studies (GWAS) of StimUD in the Million Veteran Program (MVP) and All of Us (AOU), followed by meta-analysis with FinnGen and 10 additional datasets, for a total of 709,369 individuals (Ncases=33,977, Ncontrols=675,392) in four broad ancestry groups: European (EUR) (Ncases=22,564, Ncontrols=624,672), African (AFR) (Ncases=7,574, Ncontrols=34,189), Admixed American (AMR) (Ncases=3,657, Ncontrols=15,698), and East Asian (EAS) (Ncases=182, Ncontrols=833). Population-specific SNP heritability was 6.1% in EUR and 2.4% in AFR. We discovered a total of 19 genome-wide-significant loci, six in EUR, including DRD2*rs5794864, P=7.32x10-10, one in AFR, five in a multi-ancestry meta-analysis, including CHRNA5*rs55781567, P=3.27x10-9, two in a male-only meta-analysis, including FTO*rs8057044, P=9.50x10-9, and five in a meta-analysis of sex-stratified results. In a hold-out AOU subsample (NEUR=18,841, NAFR=12,263, NAMR=9,739), ancestry-specific polygenic risk scores were significantly associated with StimUD in EUR (OR=3.28, 95% confidence interval (CI)=2.89-3.71) and AMR (OR=2.01, 95% CI=1.71-2.37). Transcriptome-wide association studies, fine-mapping, and colocalization analyses prioritized additional genes (e.g., GPX1, BSN). Genetic correlation, Mendelian randomization, and causal mixture analyses revealed relationships with other substance use and use disorder phenotypes, including cannabis use disorder (rg=0.94, P=5.43x10-237) and opioid use disorder (rg=1.01, P=4.40x10-107), and other psychiatric traits, including anxiety, depression, neuroticism, and attention-deficit\/hyperactivity disorder. This is the first well-powered GWAS of StimUD, and it offers significant insights into disease biology.","rel_num_authors":30,"rel_authors":[{"author_name":"Sarah E. Beck","author_inst":"Yale School of Medicine"},{"author_name":"Joseph D. Deak","author_inst":"Yale School of Medicine"},{"author_name":"Daniel F. Levey","author_inst":"Yale University; VA Connecticut Healthcare System"},{"author_name":"Tian Ge","author_inst":"Massachusetts General Hospital\/Harvard Medical School"},{"author_name":"Paul W. Jeffries","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Dongbing Lai","author_inst":"Indiana University School of Medicine"},{"author_name":"Travis T. Mallard","author_inst":"Massachusetts General Hospital"},{"author_name":"Louisa Degenhardt","author_inst":"University of New South Wales Sydney"},{"author_name":"Penelope A. Lind","author_inst":"QIMR Berghofer"},{"author_name":"Trine Tollerup Nielsen","author_inst":"Aarhus University"},{"author_name":"Justin D. Tubbs","author_inst":"Massachusetts General Hospital"},{"author_name":"Leah Wetherill","author_inst":"Indiana University School of Medicine"},{"author_name":"Emma C. Johnson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Alexander S. Hatoum","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"- The SUD Working Group of the Psychiatric Genomics Consortium","author_inst":""},{"author_name":"- COGA Collaborators","author_inst":""},{"author_name":"- Yale-Penn Collaboration","author_inst":""},{"author_name":"- The VA Million Veteran Program","author_inst":""},{"author_name":"Anders B\u00f8rglum","author_inst":"Aarhus University"},{"author_name":"Ditte Demontis","author_inst":"Aarhus University"},{"author_name":"Sarah E. Medland","author_inst":"QIMR Berghofer"},{"author_name":"Nicholas G. Martin","author_inst":"QIMR Berghofer"},{"author_name":"Elliot C. Nelson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Jordan W. Smoller","author_inst":"Massachusetts General Hospital\/Harvard Medical School"},{"author_name":"Henry R. Kranzler","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"J. Michael Gaziano","author_inst":"VA Boston Healthcare System"},{"author_name":"Murray B. Stein","author_inst":"University of California San Diego"},{"author_name":"Arpana Agrawal","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Howard J. Edenberg","author_inst":"Indiana University School of Medicine"},{"author_name":"Joel Gelernter","author_inst":"Yale School of Medicine"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Multi-ancestry genome-wide association study and meta-analysis of stimulant use disorder reveals biology and relationships to other psychiatric disorders","rel_doi":"10.64898\/2026.06.05.26354997","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354997","rel_abs":"Stimulant use disorder (StimUD) is a significant public health problem, but genetic studies have been limited by small sample sizes. We conducted genome-wide association studies (GWAS) of StimUD in the Million Veteran Program (MVP) and All of Us (AOU), followed by meta-analysis with FinnGen and 10 additional datasets, for a total of 709,369 individuals (Ncases=33,977, Ncontrols=675,392) in four broad ancestry groups: European (EUR) (Ncases=22,564, Ncontrols=624,672), African (AFR) (Ncases=7,574, Ncontrols=34,189), Admixed American (AMR) (Ncases=3,657, Ncontrols=15,698), and East Asian (EAS) (Ncases=182, Ncontrols=833). Population-specific SNP heritability was 6.1% in EUR and 2.4% in AFR. We discovered a total of 19 genome-wide-significant loci, six in EUR, including DRD2*rs5794864, P=7.32x10-10, one in AFR, five in a multi-ancestry meta-analysis, including CHRNA5*rs55781567, P=3.27x10-9, two in a male-only meta-analysis, including FTO*rs8057044, P=9.50x10-9, and five in a meta-analysis of sex-stratified results. In a hold-out AOU subsample (NEUR=18,841, NAFR=12,263, NAMR=9,739), ancestry-specific polygenic risk scores were significantly associated with StimUD in EUR (OR=3.28, 95% confidence interval (CI)=2.89-3.71) and AMR (OR=2.01, 95% CI=1.71-2.37). Transcriptome-wide association studies, fine-mapping, and colocalization analyses prioritized additional genes (e.g., GPX1, BSN). Genetic correlation, Mendelian randomization, and causal mixture analyses revealed relationships with other substance use and use disorder phenotypes, including cannabis use disorder (rg=0.94, P=5.43x10-237) and opioid use disorder (rg=1.01, P=4.40x10-107), and other psychiatric traits, including anxiety, depression, neuroticism, and attention-deficit\/hyperactivity disorder. This is the first well-powered GWAS of StimUD, and it offers significant insights into disease biology.","rel_num_authors":30,"rel_authors":[{"author_name":"Sarah E. Beck","author_inst":"Yale School of Medicine"},{"author_name":"Joseph D. Deak","author_inst":"Yale School of Medicine"},{"author_name":"Daniel F. Levey","author_inst":"Yale University; VA Connecticut Healthcare System"},{"author_name":"Tian Ge","author_inst":"Massachusetts General Hospital\/Harvard Medical School"},{"author_name":"Paul W. Jeffries","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Dongbing Lai","author_inst":"Indiana University School of Medicine"},{"author_name":"Travis T. Mallard","author_inst":"Massachusetts General Hospital"},{"author_name":"Louisa Degenhardt","author_inst":"University of New South Wales Sydney"},{"author_name":"Penelope A. Lind","author_inst":"QIMR Berghofer"},{"author_name":"Trine Tollerup Nielsen","author_inst":"Aarhus University"},{"author_name":"Justin D. Tubbs","author_inst":"Massachusetts General Hospital"},{"author_name":"Leah Wetherill","author_inst":"Indiana University School of Medicine"},{"author_name":"Emma C. Johnson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Alexander S. Hatoum","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"- The SUD Working Group of the Psychiatric Genomics Consortium","author_inst":""},{"author_name":"- COGA Collaborators","author_inst":""},{"author_name":"- Yale-Penn Collaboration","author_inst":""},{"author_name":"- The VA Million Veteran Program","author_inst":""},{"author_name":"Anders B\u00f8rglum","author_inst":"Aarhus University"},{"author_name":"Ditte Demontis","author_inst":"Aarhus University"},{"author_name":"Sarah E. Medland","author_inst":"QIMR Berghofer"},{"author_name":"Nicholas G. Martin","author_inst":"QIMR Berghofer"},{"author_name":"Elliot C. Nelson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Jordan W. Smoller","author_inst":"Massachusetts General Hospital\/Harvard Medical School"},{"author_name":"Henry R. Kranzler","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"J. Michael Gaziano","author_inst":"VA Boston Healthcare System"},{"author_name":"Murray B. Stein","author_inst":"University of California San Diego"},{"author_name":"Arpana Agrawal","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Howard J. Edenberg","author_inst":"Indiana University School of Medicine"},{"author_name":"Joel Gelernter","author_inst":"Yale School of Medicine"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Multi-ancestry genome-wide association study and meta-analysis of stimulant use disorder reveals biology and relationships to other psychiatric disorders","rel_doi":"10.64898\/2026.06.05.26354997","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354997","rel_abs":"Stimulant use disorder (StimUD) is a significant public health problem, but genetic studies have been limited by small sample sizes. We conducted genome-wide association studies (GWAS) of StimUD in the Million Veteran Program (MVP) and All of Us (AOU), followed by meta-analysis with FinnGen and 10 additional datasets, for a total of 709,369 individuals (Ncases=33,977, Ncontrols=675,392) in four broad ancestry groups: European (EUR) (Ncases=22,564, Ncontrols=624,672), African (AFR) (Ncases=7,574, Ncontrols=34,189), Admixed American (AMR) (Ncases=3,657, Ncontrols=15,698), and East Asian (EAS) (Ncases=182, Ncontrols=833). Population-specific SNP heritability was 6.1% in EUR and 2.4% in AFR. We discovered a total of 19 genome-wide-significant loci, six in EUR, including DRD2*rs5794864, P=7.32x10-10, one in AFR, five in a multi-ancestry meta-analysis, including CHRNA5*rs55781567, P=3.27x10-9, two in a male-only meta-analysis, including FTO*rs8057044, P=9.50x10-9, and five in a meta-analysis of sex-stratified results. In a hold-out AOU subsample (NEUR=18,841, NAFR=12,263, NAMR=9,739), ancestry-specific polygenic risk scores were significantly associated with StimUD in EUR (OR=3.28, 95% confidence interval (CI)=2.89-3.71) and AMR (OR=2.01, 95% CI=1.71-2.37). Transcriptome-wide association studies, fine-mapping, and colocalization analyses prioritized additional genes (e.g., GPX1, BSN). Genetic correlation, Mendelian randomization, and causal mixture analyses revealed relationships with other substance use and use disorder phenotypes, including cannabis use disorder (rg=0.94, P=5.43x10-237) and opioid use disorder (rg=1.01, P=4.40x10-107), and other psychiatric traits, including anxiety, depression, neuroticism, and attention-deficit\/hyperactivity disorder. This is the first well-powered GWAS of StimUD, and it offers significant insights into disease biology.","rel_num_authors":30,"rel_authors":[{"author_name":"Sarah E. Beck","author_inst":"Yale School of Medicine"},{"author_name":"Joseph D. Deak","author_inst":"Yale School of Medicine"},{"author_name":"Daniel F. Levey","author_inst":"Yale University; VA Connecticut Healthcare System"},{"author_name":"Tian Ge","author_inst":"Massachusetts General Hospital\/Harvard Medical School"},{"author_name":"Paul W. Jeffries","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Dongbing Lai","author_inst":"Indiana University School of Medicine"},{"author_name":"Travis T. Mallard","author_inst":"Massachusetts General Hospital"},{"author_name":"Louisa Degenhardt","author_inst":"University of New South Wales Sydney"},{"author_name":"Penelope A. Lind","author_inst":"QIMR Berghofer"},{"author_name":"Trine Tollerup Nielsen","author_inst":"Aarhus University"},{"author_name":"Justin D. Tubbs","author_inst":"Massachusetts General Hospital"},{"author_name":"Leah Wetherill","author_inst":"Indiana University School of Medicine"},{"author_name":"Emma C. Johnson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Alexander S. Hatoum","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"- The SUD Working Group of the Psychiatric Genomics Consortium","author_inst":""},{"author_name":"- COGA Collaborators","author_inst":""},{"author_name":"- Yale-Penn Collaboration","author_inst":""},{"author_name":"- The VA Million Veteran Program","author_inst":""},{"author_name":"Anders B\u00f8rglum","author_inst":"Aarhus University"},{"author_name":"Ditte Demontis","author_inst":"Aarhus University"},{"author_name":"Sarah E. Medland","author_inst":"QIMR Berghofer"},{"author_name":"Nicholas G. Martin","author_inst":"QIMR Berghofer"},{"author_name":"Elliot C. Nelson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Jordan W. Smoller","author_inst":"Massachusetts General Hospital\/Harvard Medical School"},{"author_name":"Henry R. Kranzler","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"J. Michael Gaziano","author_inst":"VA Boston Healthcare System"},{"author_name":"Murray B. Stein","author_inst":"University of California San Diego"},{"author_name":"Arpana Agrawal","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Howard J. Edenberg","author_inst":"Indiana University School of Medicine"},{"author_name":"Joel Gelernter","author_inst":"Yale School of Medicine"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Multi-ancestry genome-wide association study and meta-analysis of stimulant use disorder reveals biology and relationships to other psychiatric disorders","rel_doi":"10.64898\/2026.06.05.26354997","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354997","rel_abs":"Stimulant use disorder (StimUD) is a significant public health problem, but genetic studies have been limited by small sample sizes. We conducted genome-wide association studies (GWAS) of StimUD in the Million Veteran Program (MVP) and All of Us (AOU), followed by meta-analysis with FinnGen and 10 additional datasets, for a total of 709,369 individuals (Ncases=33,977, Ncontrols=675,392) in four broad ancestry groups: European (EUR) (Ncases=22,564, Ncontrols=624,672), African (AFR) (Ncases=7,574, Ncontrols=34,189), Admixed American (AMR) (Ncases=3,657, Ncontrols=15,698), and East Asian (EAS) (Ncases=182, Ncontrols=833). Population-specific SNP heritability was 6.1% in EUR and 2.4% in AFR. We discovered a total of 19 genome-wide-significant loci, six in EUR, including DRD2*rs5794864, P=7.32x10-10, one in AFR, five in a multi-ancestry meta-analysis, including CHRNA5*rs55781567, P=3.27x10-9, two in a male-only meta-analysis, including FTO*rs8057044, P=9.50x10-9, and five in a meta-analysis of sex-stratified results. In a hold-out AOU subsample (NEUR=18,841, NAFR=12,263, NAMR=9,739), ancestry-specific polygenic risk scores were significantly associated with StimUD in EUR (OR=3.28, 95% confidence interval (CI)=2.89-3.71) and AMR (OR=2.01, 95% CI=1.71-2.37). Transcriptome-wide association studies, fine-mapping, and colocalization analyses prioritized additional genes (e.g., GPX1, BSN). Genetic correlation, Mendelian randomization, and causal mixture analyses revealed relationships with other substance use and use disorder phenotypes, including cannabis use disorder (rg=0.94, P=5.43x10-237) and opioid use disorder (rg=1.01, P=4.40x10-107), and other psychiatric traits, including anxiety, depression, neuroticism, and attention-deficit\/hyperactivity disorder. This is the first well-powered GWAS of StimUD, and it offers significant insights into disease biology.","rel_num_authors":30,"rel_authors":[{"author_name":"Sarah E. Beck","author_inst":"Yale School of Medicine"},{"author_name":"Joseph D. Deak","author_inst":"Yale School of Medicine"},{"author_name":"Daniel F. Levey","author_inst":"Yale University; VA Connecticut Healthcare System"},{"author_name":"Tian Ge","author_inst":"Massachusetts General Hospital\/Harvard Medical School"},{"author_name":"Paul W. Jeffries","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Dongbing Lai","author_inst":"Indiana University School of Medicine"},{"author_name":"Travis T. Mallard","author_inst":"Massachusetts General Hospital"},{"author_name":"Louisa Degenhardt","author_inst":"University of New South Wales Sydney"},{"author_name":"Penelope A. Lind","author_inst":"QIMR Berghofer"},{"author_name":"Trine Tollerup Nielsen","author_inst":"Aarhus University"},{"author_name":"Justin D. Tubbs","author_inst":"Massachusetts General Hospital"},{"author_name":"Leah Wetherill","author_inst":"Indiana University School of Medicine"},{"author_name":"Emma C. Johnson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Alexander S. Hatoum","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"- The SUD Working Group of the Psychiatric Genomics Consortium","author_inst":""},{"author_name":"- COGA Collaborators","author_inst":""},{"author_name":"- Yale-Penn Collaboration","author_inst":""},{"author_name":"- The VA Million Veteran Program","author_inst":""},{"author_name":"Anders B\u00f8rglum","author_inst":"Aarhus University"},{"author_name":"Ditte Demontis","author_inst":"Aarhus University"},{"author_name":"Sarah E. Medland","author_inst":"QIMR Berghofer"},{"author_name":"Nicholas G. Martin","author_inst":"QIMR Berghofer"},{"author_name":"Elliot C. Nelson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Jordan W. Smoller","author_inst":"Massachusetts General Hospital\/Harvard Medical School"},{"author_name":"Henry R. Kranzler","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"J. Michael Gaziano","author_inst":"VA Boston Healthcare System"},{"author_name":"Murray B. Stein","author_inst":"University of California San Diego"},{"author_name":"Arpana Agrawal","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Howard J. Edenberg","author_inst":"Indiana University School of Medicine"},{"author_name":"Joel Gelernter","author_inst":"Yale School of Medicine"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Host Genetic Regulation of NLRP3 Inflammasome Cytokines Reveals Immune and Vascular Pathways in HIV","rel_doi":"10.64898\/2026.06.08.26355202","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355202","rel_abs":"People with HIV exhibit elevated inflammation and cardiovascular risk despite antiretroviral therapy. To define the genetic architecture of inflammasome-associated inflammation, we performed whole-genome sequencing and quantified plasma IL-6, IL-1{beta}, and IL-18 in 1,000 ART-suppressed PWH from the U.S. Military HIV Natural History Study. Genome-wide analyses identified 14 loci implicating antiviral defense (DDX17, DDX41, EEA1, BCL11A), lipid metabolism (ABCA1, ABCA12, ABCC1, AGMO), and vascular remodeling (KLHL29, RNF213, ETV1). Transcriptome-wide analyses across cardiovascular and immune tissues identified regulatory programs linking interferon signaling, immune activation, and vascular biology to circulating cytokine levels. Mendelian randomization analyses supported causal relationships between inflammasome-associated cytokines and vascular events. Functional integration with genome-wide CRISPR perturbation datasets in primary CD4 T cells linked cytokine-associated loci to HIV antiviral pathways and cytokine regulatory networks. External validation in cohorts without HIV demonstrated pathway-level convergence despite limited variant-level overlap. These findings define genetic mechanisms linking inflammasome signaling, antiviral defense, and cardiovascular risk.","rel_num_authors":28,"rel_authors":[{"author_name":"Ryan Chung","author_inst":"University of California Berkeley, Berkeley, CA"},{"author_name":"Namratha Shivani Chalasani","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Alton S. Barbehenn","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Erik Lundgren","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Sonia Savur","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Sayane Shome","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Caroline H. Sheikhzadeh","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Sannidhi Sarvadhavabhatla","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Maria Sophia Donaire","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Vivian Pae","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Xiuping Chu","author_inst":"Uniformed Services University of the Health Sciences, Bethesda, MD"},{"author_name":"Daniel Winder","author_inst":"University of Utah, Salt Lake City, UT"},{"author_name":"Colin T Maguire","author_inst":"University of Utah, Salt Lake City, UT"},{"author_name":"Senay Topal","author_inst":"Uniformed Services University of the Health Sciences, Bethesda, MD"},{"author_name":"Anuradha Ganesan","author_inst":"Uniformed Services University of the Health Sciences,  Bethesda, MD"},{"author_name":"Joseph M. Yabes","author_inst":"Uniformed Services University of the Health Sciences,  Bethesda, MD"},{"author_name":"Derek T. Larson","author_inst":"Uniformed Services University of the Health Sciences,  Bethesda, MD"},{"author_name":"Tahaniyat Lalani","author_inst":"Uniformed Services University of the Health Sciences,  Bethesda, MD"},{"author_name":"Evan C. Ewers","author_inst":"Tripler Army Medical Center, Honolulu, HI"},{"author_name":"Rhonda E. Colombo","author_inst":"Uniformed Services University of the Health Sciences, Bethesda, MD"},{"author_name":"Eli Dugan","author_inst":"Gladstone Institutes, San Francisco, CA"},{"author_name":"Ujjwal Rathore","author_inst":"Gladstone Institutes, San Francisco, CA"},{"author_name":"Alexander Marson","author_inst":"Gladstone Institutes, San Francisco, CA"},{"author_name":"Brian K. Agan","author_inst":"Uniformed Services University of the Health Sciences, Bethesda, MD"},{"author_name":"Jeff Alan Tomalka","author_inst":"Emory School of Medicine, Atlanta, GA"},{"author_name":"Rafick-Pierre Sekaly","author_inst":"Emory School of Medicine, Atlanta, GA"},{"author_name":"Nilah M. Loannidis","author_inst":"University of California Berkeley, Berkeley, CA"},{"author_name":"Sulggi A. Lee","author_inst":"University of California San Francisco, San Francisco, CA"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Host Genetic Regulation of NLRP3 Inflammasome Cytokines Reveals Immune and Vascular Pathways in HIV","rel_doi":"10.64898\/2026.06.08.26355202","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355202","rel_abs":"People with HIV exhibit elevated inflammation and cardiovascular risk despite antiretroviral therapy. To define the genetic architecture of inflammasome-associated inflammation, we performed whole-genome sequencing and quantified plasma IL-6, IL-1{beta}, and IL-18 in 1,000 ART-suppressed PWH from the U.S. Military HIV Natural History Study. Genome-wide analyses identified 14 loci implicating antiviral defense (DDX17, DDX41, EEA1, BCL11A), lipid metabolism (ABCA1, ABCA12, ABCC1, AGMO), and vascular remodeling (KLHL29, RNF213, ETV1). Transcriptome-wide analyses across cardiovascular and immune tissues identified regulatory programs linking interferon signaling, immune activation, and vascular biology to circulating cytokine levels. Mendelian randomization analyses supported causal relationships between inflammasome-associated cytokines and vascular events. Functional integration with genome-wide CRISPR perturbation datasets in primary CD4 T cells linked cytokine-associated loci to HIV antiviral pathways and cytokine regulatory networks. External validation in cohorts without HIV demonstrated pathway-level convergence despite limited variant-level overlap. These findings define genetic mechanisms linking inflammasome signaling, antiviral defense, and cardiovascular risk.","rel_num_authors":28,"rel_authors":[{"author_name":"Ryan Chung","author_inst":"University of California Berkeley, Berkeley, CA"},{"author_name":"Namratha Shivani Chalasani","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Alton S. Barbehenn","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Erik Lundgren","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Sonia Savur","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Sayane Shome","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Caroline H. Sheikhzadeh","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Sannidhi Sarvadhavabhatla","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Maria Sophia Donaire","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Vivian Pae","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Xiuping Chu","author_inst":"Uniformed Services University of the Health Sciences, Bethesda, MD"},{"author_name":"Daniel Winder","author_inst":"University of Utah, Salt Lake City, UT"},{"author_name":"Colin T Maguire","author_inst":"University of Utah, Salt Lake City, UT"},{"author_name":"Senay Topal","author_inst":"Uniformed Services University of the Health Sciences, Bethesda, MD"},{"author_name":"Anuradha Ganesan","author_inst":"Uniformed Services University of the Health Sciences,  Bethesda, MD"},{"author_name":"Joseph M. Yabes","author_inst":"Uniformed Services University of the Health Sciences,  Bethesda, MD"},{"author_name":"Derek T. Larson","author_inst":"Uniformed Services University of the Health Sciences,  Bethesda, MD"},{"author_name":"Tahaniyat Lalani","author_inst":"Uniformed Services University of the Health Sciences,  Bethesda, MD"},{"author_name":"Evan C. Ewers","author_inst":"Tripler Army Medical Center, Honolulu, HI"},{"author_name":"Rhonda E. Colombo","author_inst":"Uniformed Services University of the Health Sciences, Bethesda, MD"},{"author_name":"Eli Dugan","author_inst":"Gladstone Institutes, San Francisco, CA"},{"author_name":"Ujjwal Rathore","author_inst":"Gladstone Institutes, San Francisco, CA"},{"author_name":"Alexander Marson","author_inst":"Gladstone Institutes, San Francisco, CA"},{"author_name":"Brian K. Agan","author_inst":"Uniformed Services University of the Health Sciences, Bethesda, MD"},{"author_name":"Jeff Alan Tomalka","author_inst":"Emory School of Medicine, Atlanta, GA"},{"author_name":"Rafick-Pierre Sekaly","author_inst":"Emory School of Medicine, Atlanta, GA"},{"author_name":"Nilah M. Loannidis","author_inst":"University of California Berkeley, Berkeley, CA"},{"author_name":"Sulggi A. Lee","author_inst":"University of California San Francisco, San Francisco, CA"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Efficacy of the PragmaVAC Manual Negative Pressure Wound Therapy Device to Treat Acute Traumatic Wounds in a Conflict Setting: A Retrospective Cohort Study from Gaza","rel_doi":"10.64898\/2026.06.04.26354740","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354740","rel_abs":"Abstract: Background: Acute war-related traumatic wounds present significant challenges due to significant soft-tissue damage\/loss, risk of contamination, limited access to antimicrobial therapy, need for delayed closure, and limited access to surgical and wound care. Negative Pressure Wound Therapy (NPWT) has been used effectively to reduce the volume of soft-tissue defects, edema, and infection in traumatic wounds, and to promote growth of healthy granulation tissue. However, conventional NPWT devices are costly and electricity-dependent, limiting their utility in conflict settings. Methods: This retrospective cohort study evaluated the use of PragmaVAC, a manually operated, electricity-independent NPWT device, in patients across three hospitals in Gaza with conflict-related wounds that were deemed by the treating surgeon to be unsuitable for primary closure. Secondary analysis was performed of clinical records of patients treated with the PragmaVac NPWT device to assess ability to achieve a primary outcome of wound bed with healthy granulation tissue, time to primary outcome, and rates of adverse effects. Secondary outcome of wound closure and closure method was also assessed. Results: Treatment with PragmaVAC manual NPWT was prescribed to 88 patients. Of those, 27 (31%) had incomplete documentation of their wound healing or were lost to follow up. The remaining 61 (69%) had complete documentation of their wound healing, complications, and final outcome with 59 (67%) successful closure and 2(2%) failure. Conclusion: The use of the PragmaVAC NPWT device provided a safe, effective wound care option to achieve wound closure for large conflict-related traumatic wounds in resource-limited settings. Future studies may further evaluate such use through prospective trials, evalutions of patients' experiences with manual NPWT, and evaluating outcomes beyond primary wound closure to include medium- and long-term complications, cosmesis, and cost of therapy.","rel_num_authors":7,"rel_authors":[{"author_name":"Ibrahim Ramadan","author_inst":"Indonesian Hospital, Gaza, State of Palestine"},{"author_name":"Mahmoud Hariri","author_inst":"West Hertforshire NHS Trust"},{"author_name":"Omar Shalakhti","author_inst":"Rush University School of Medicine"},{"author_name":"Jude Alawa","author_inst":"Hospital for Special Surgery"},{"author_name":"Amandine Godier-Furnemont","author_inst":"University of California at San Francisco"},{"author_name":"Abd Al-Rahman Traboulsi","author_inst":"MassGeneral Brigham"},{"author_name":"HANI MOWAFI","author_inst":"Yale University"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Efficacy of the PragmaVAC Manual Negative Pressure Wound Therapy Device to Treat Acute Traumatic Wounds in a Conflict Setting: A Retrospective Cohort Study from Gaza","rel_doi":"10.64898\/2026.06.04.26354740","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354740","rel_abs":"Abstract: Background: Acute war-related traumatic wounds present significant challenges due to significant soft-tissue damage\/loss, risk of contamination, limited access to antimicrobial therapy, need for delayed closure, and limited access to surgical and wound care. Negative Pressure Wound Therapy (NPWT) has been used effectively to reduce the volume of soft-tissue defects, edema, and infection in traumatic wounds, and to promote growth of healthy granulation tissue. However, conventional NPWT devices are costly and electricity-dependent, limiting their utility in conflict settings. Methods: This retrospective cohort study evaluated the use of PragmaVAC, a manually operated, electricity-independent NPWT device, in patients across three hospitals in Gaza with conflict-related wounds that were deemed by the treating surgeon to be unsuitable for primary closure. Secondary analysis was performed of clinical records of patients treated with the PragmaVac NPWT device to assess ability to achieve a primary outcome of wound bed with healthy granulation tissue, time to primary outcome, and rates of adverse effects. Secondary outcome of wound closure and closure method was also assessed. Results: Treatment with PragmaVAC manual NPWT was prescribed to 88 patients. Of those, 27 (31%) had incomplete documentation of their wound healing or were lost to follow up. The remaining 61 (69%) had complete documentation of their wound healing, complications, and final outcome with 59 (67%) successful closure and 2(2%) failure. Conclusion: The use of the PragmaVAC NPWT device provided a safe, effective wound care option to achieve wound closure for large conflict-related traumatic wounds in resource-limited settings. Future studies may further evaluate such use through prospective trials, evalutions of patients' experiences with manual NPWT, and evaluating outcomes beyond primary wound closure to include medium- and long-term complications, cosmesis, and cost of therapy.","rel_num_authors":7,"rel_authors":[{"author_name":"Ibrahim Ramadan","author_inst":"Indonesian Hospital, Gaza, State of Palestine"},{"author_name":"Mahmoud Hariri","author_inst":"West Hertforshire NHS Trust"},{"author_name":"Omar Shalakhti","author_inst":"Rush University School of Medicine"},{"author_name":"Jude Alawa","author_inst":"Hospital for Special Surgery"},{"author_name":"Amandine Godier-Furnemont","author_inst":"University of California at San Francisco"},{"author_name":"Abd Al-Rahman Traboulsi","author_inst":"MassGeneral Brigham"},{"author_name":"HANI MOWAFI","author_inst":"Yale University"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Recognition and Treatment of Primary Aldosteronism in the Updated Guideline Era","rel_doi":"10.64898\/2026.06.08.26355219","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355219","rel_abs":"BackgroundPrimary aldosteronism (PA) is increasingly recognized as a common cause of hypertension. The 2025 Endocrine Society guideline introduced a simplified diagnostic framework, but its real-world clinical implications remain unclear.\n\nMethodsWe conducted a multicenter retrospective cohort study of hypertensive patients undergoing PA testing in Taiwan. PA was defined biochemically according to the 2025 Endocrine Society criteria. Multivariable logistic regression identified factors associated with PA diagnosis and aldosterone-targeted therapy. Among patients with suppressed renin ([&le;]1 ng\/mL\/h), restricted cubic splines evaluated the adjusted association between renin and PA probability.\n\nResultsAmong 18,766 patients undergoing PA testing, 6,760 (36.0%) met diagnostic criteria for PA. PA was associated with older age, female sex, lower potassium, resistant hypertension, and a higher antihypertensive medication burden. Among patients with suppressed renin, lower renin remained significantly associated with higher adjusted PA probability. However, only 39.0% of patients with PA received aldosterone-targeted therapy, including 28.2% who received mineralocorticoid receptor antagonist therapy within 6 months and 9.4% who underwent adrenalectomy during follow-up. Lower renin, higher aldosterone, lower potassium, and resistant hypertension were associated with aldosterone-targeted therapy, while younger patients with fewer comorbidities were more likely to undergo adrenalectomy.\n\nConclusionsUsing the updated diagnostic framework, PA was highly prevalent among hypertensive patients undergoing PA testing. Nevertheless, many patients who met these biochemical criteria did not receive aldosterone-targeted therapy in routine care. These findings highlight the potential treatment implications of broader PA recognition and support the development of practical pathways to guide MRA therapy, adrenalectomy referral, and individualized management.","rel_num_authors":12,"rel_authors":[{"author_name":"Cheng-Hsuan Tsai","author_inst":"National Taiwan University Hospital Cardiovascular Center"},{"author_name":"Yu-Ching Chang","author_inst":"National Taiwan University Hospital"},{"author_name":"Chin-Chen Chang","author_inst":"National Taiwan University Hospital"},{"author_name":"Wan-Chen Wu","author_inst":"National Taiwan University Hospital"},{"author_name":"Yi-Yao Chang","author_inst":"Far Eastern Memorial Hospital Library"},{"author_name":"Uei-Lin Chen","author_inst":"National Taiwan University Hospital"},{"author_name":"Bo-Ching Lee","author_inst":"National Taiwan University"},{"author_name":"Chi-Sheng Hung","author_inst":"National Taiwan University Hospital and College of  Medicine"},{"author_name":"Kuo-How Huang","author_inst":"National Taiwan University Hospital Department of Urology"},{"author_name":"Jeff S. Chueh","author_inst":"National Taiwan University, College of Medicine"},{"author_name":"Vin-Cent Wu","author_inst":"College of Medicine, National Taiwan University"},{"author_name":"Yen-Hung Lin","author_inst":"National Taiwan University Hospital"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Identifying Clinical Diagnostic Trajectories Associated With Suicide Death Using Temporal Sequence Mining of Linked Claims and Mortality Data","rel_doi":"10.64898\/2026.06.08.26355231","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355231","rel_abs":"Background: Most approaches to suicide risk assessment consider clinical conditions as independent risk factors, potentially overlooking prognostic information in the order in which conditions accumulate. We applied temporal sequence mining to linked claims and mortality data to identify ordered clinical diagnostic trajectories associated with suicide death. Results: The cohort included 3 647 059 insured Maryland residents aged 10 years or older with available claims records in the Maryland Suicide Data Warehouse from January 1, 2016, to December 31, 2020, among whom 768 suicide deaths were ascertained through medical examiner linkage. Sequential pattern mining of ICD-10-CM diagnoses grouped into Clinical Classifications Software Refined categories identified 89 221 candidate sequences, of which 1 816 remained significantly associated with suicide death in time-varying Cox models. Adjusted hazard ratios (AHRs) ranged from 2.4 to 134.1. Two-thirds of significant trajectories ended in physical conditions, and approximately half crossed from psychiatric to physical endpoints. Among suicide decedents, 62% were exposed to at least 1 significant sequence (median, 16 per case); median sequence duration was 18.7 months, and median time from completion to death was 13.1 months. In landmark analyses, among patients with depression who later developed suicidal ideation (n = 26 356), the path through anxiety, then anemia, was associated with higher risk (AHR, 4.6; 95% CI, 2.2-9.5), whereas the anxiety-only path was not (AHR, 1.3; 95% CI, 0.8-2.1). Among patients with anxiety who later developed hypertension (n = 149 215), the path through history of self-harm was associated with higher risk (AHR, 32.0; 95% CI, 16.6-61.6). Associations were generally consistent across sex and age. Conclusions: Temporal ordering of clinical conditions may carry prognostic information for suicide death. Clinical trajectories incorporating physical illness within psychiatric sequences identified higher-risk groups. These findings suggest that opportunities for risk detection may extend beyond psychiatric settings and that suicide risk signals may be fragmented across care settings and not apparent within isolated encounters.","rel_num_authors":7,"rel_authors":[{"author_name":"Anas Belouali","author_inst":"Georgetown University"},{"author_name":"Christopher Kitchen","author_inst":"Department of Health Policy and Management, Center for Population Health Information Technology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD,"},{"author_name":"Emily Haroz","author_inst":"Center for Suicide Prevention, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Mental Health, Johns Hopkins Bloomberg School "},{"author_name":"Harold Lehmann","author_inst":"Biomedical Informatics and Data Science, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Paul S. Nestadt","author_inst":"Center for Suicide Prevention, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Mental Health, Johns Hopkins Bloomberg School "},{"author_name":"Holly C. Wilcox","author_inst":"Center for Suicide Prevention, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Mental Health, Johns Hopkins Bloomberg School "},{"author_name":"Hadi Kharrazi","author_inst":"Biomedical Informatics and Data Science, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Health Policy and Management, Center for Population"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Alzheimer's disease neuroimaging signature aids identification of cognitive impairment in older adults with early-onset epilepsy","rel_doi":"10.64898\/2026.06.05.26354952","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354952","rel_abs":"Background and ObjectivesOlder adults with epilepsy are at increased risk for Alzheimers disease (AD), yet the mechanisms underlying this association remain poorly understood. We applied a validated AD neuroimaging signature to older adults with epilepsy to examine 1) whether older adults with epilepsy mirror AD-related changes, 2) associations with clinical, cognitive, and plasma biomarker outcomes, and 3) utility for identifying subgroups at heightened risk for cognitive decline. Our multicenter, prospectively enrolled cohort allowed for direct examination of differences in AD signatures between those with early-onset and late-onset unexplained epilepsy.\n\nMethodsParticipants included 449 older adults: 87 with focal epilepsy from the multicenter Brain Aging and Cognition in Epilepsy (BrACE) cohort (age=66.10 [SD=6.86], including early-onset (<55 years at seizure onset) and late-onset ([&ge;]55 years at seizure onset) epilepsy); 362 from the Alzheimers Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU) healthy controls and individuals with mild cognitive impairment (MCI) or AD dementia. An AD signature was derived from regional cortical thickness and hippocampal volume weighted by their sensitivity to AD-related neurodegeneration in prior work. Associations between the AD signature, epilepsy characteristics, plasma biomarkers ({beta}-amyloid 42\/40, phosphorylated tau [pTau217, pTau181], neurofilament light chain [NfL]), and cognition were evaluated in BrACE.\n\nResultsParticipants with epilepsy demonstrated more AD-like signatures compared to ADNI CU controls ({beta}= -0.43, padj<0.001), reflecting reduced thickness\/volume in AD-vulnerable regions. This effect was stronger among early-onset ({beta}= -0.57) versus late-onset ({beta}= -0.26) epilepsy. In BrACE, the AD signature correlated with NfL ({beta}= -0.30, padj=0.050), memory performance ({beta}= 0.30, padj=0.006), and predicted greater odds of cognitive impairment specifically among those with early-onset, but not late-onset, epilepsy (interaction padj=0.043). Further, among those with early-onset epilepsy, the AD signature significantly improved identification of cognitive impairment over and beyond the effects of plasma AD biomarkers (p=0.041). Findings were similar when examining the effects of epilepsy duration rather than epilepsy onset age.\n\nDiscussionAD neuroimaging signatures may help identify clinically meaningful subgroups among older adults with epilepsy, particularly when integrated with AD biomarkers. Findings support a multimodal framework for assessing AD-related risk in epilepsy and highlight interactive effects of epilepsy chronicity and AD-related processes that can influence cognitive outcomes.","rel_num_authors":22,"rel_authors":[{"author_name":"McKenna Williams","author_inst":"University of California San Diego"},{"author_name":"Kayela Arrotta","author_inst":"Cleveland Clinic"},{"author_name":"Katherine J. Bangen","author_inst":"University of California San Diego"},{"author_name":"Anny Reyes","author_inst":"Cleveland Clinic"},{"author_name":"Alena Stasenko","author_inst":"University of California San Diego"},{"author_name":"Ifrah Zawar","author_inst":"University of Virginia School of Medicine"},{"author_name":"Vineet Punia","author_inst":"Cleveland Clinic"},{"author_name":"Irene Wang","author_inst":"Cleveland Clinic"},{"author_name":"Wanyong Shin","author_inst":"Cleveland Clinic"},{"author_name":"Ting-Yu Su","author_inst":"Cleveland Clinic"},{"author_name":"Jerry J. Shih","author_inst":"University of California San Diego"},{"author_name":"Nikdokht Farid","author_inst":"University of California San Diego"},{"author_name":"Jaideep Kapur","author_inst":"University of Virginia School of Medicine"},{"author_name":"Aaron F. Struck","author_inst":"Washington University in St. Louis"},{"author_name":"Lynn M. Bekris","author_inst":"University of Washington"},{"author_name":"Lisa Ferguson","author_inst":"Cleveland Clinic"},{"author_name":"Dace N. Almane","author_inst":"Cleveland Clinic"},{"author_name":"Jana E. Jones","author_inst":"Cleveland Clinic"},{"author_name":"Bruce P. Hermann","author_inst":"University of Wisconsin Madison"},{"author_name":"Robyn M. Busch","author_inst":"Cleveland Clinic"},{"author_name":"Carrie R. McDonald","author_inst":"University of California San Diego"},{"author_name":"- for the Alzheimer's Disease Neuroimaging Initiative*","author_inst":""}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Alzheimer's disease neuroimaging signature aids identification of cognitive impairment in older adults with early-onset epilepsy","rel_doi":"10.64898\/2026.06.05.26354952","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354952","rel_abs":"Background and ObjectivesOlder adults with epilepsy are at increased risk for Alzheimers disease (AD), yet the mechanisms underlying this association remain poorly understood. We applied a validated AD neuroimaging signature to older adults with epilepsy to examine 1) whether older adults with epilepsy mirror AD-related changes, 2) associations with clinical, cognitive, and plasma biomarker outcomes, and 3) utility for identifying subgroups at heightened risk for cognitive decline. Our multicenter, prospectively enrolled cohort allowed for direct examination of differences in AD signatures between those with early-onset and late-onset unexplained epilepsy.\n\nMethodsParticipants included 449 older adults: 87 with focal epilepsy from the multicenter Brain Aging and Cognition in Epilepsy (BrACE) cohort (age=66.10 [SD=6.86], including early-onset (<55 years at seizure onset) and late-onset ([&ge;]55 years at seizure onset) epilepsy); 362 from the Alzheimers Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU) healthy controls and individuals with mild cognitive impairment (MCI) or AD dementia. An AD signature was derived from regional cortical thickness and hippocampal volume weighted by their sensitivity to AD-related neurodegeneration in prior work. Associations between the AD signature, epilepsy characteristics, plasma biomarkers ({beta}-amyloid 42\/40, phosphorylated tau [pTau217, pTau181], neurofilament light chain [NfL]), and cognition were evaluated in BrACE.\n\nResultsParticipants with epilepsy demonstrated more AD-like signatures compared to ADNI CU controls ({beta}= -0.43, padj<0.001), reflecting reduced thickness\/volume in AD-vulnerable regions. This effect was stronger among early-onset ({beta}= -0.57) versus late-onset ({beta}= -0.26) epilepsy. In BrACE, the AD signature correlated with NfL ({beta}= -0.30, padj=0.050), memory performance ({beta}= 0.30, padj=0.006), and predicted greater odds of cognitive impairment specifically among those with early-onset, but not late-onset, epilepsy (interaction padj=0.043). Further, among those with early-onset epilepsy, the AD signature significantly improved identification of cognitive impairment over and beyond the effects of plasma AD biomarkers (p=0.041). Findings were similar when examining the effects of epilepsy duration rather than epilepsy onset age.\n\nDiscussionAD neuroimaging signatures may help identify clinically meaningful subgroups among older adults with epilepsy, particularly when integrated with AD biomarkers. Findings support a multimodal framework for assessing AD-related risk in epilepsy and highlight interactive effects of epilepsy chronicity and AD-related processes that can influence cognitive outcomes.","rel_num_authors":22,"rel_authors":[{"author_name":"McKenna Williams","author_inst":"University of California San Diego"},{"author_name":"Kayela Arrotta","author_inst":"Cleveland Clinic"},{"author_name":"Katherine J. Bangen","author_inst":"University of California San Diego"},{"author_name":"Anny Reyes","author_inst":"Cleveland Clinic"},{"author_name":"Alena Stasenko","author_inst":"University of California San Diego"},{"author_name":"Ifrah Zawar","author_inst":"University of Virginia School of Medicine"},{"author_name":"Vineet Punia","author_inst":"Cleveland Clinic"},{"author_name":"Irene Wang","author_inst":"Cleveland Clinic"},{"author_name":"Wanyong Shin","author_inst":"Cleveland Clinic"},{"author_name":"Ting-Yu Su","author_inst":"Cleveland Clinic"},{"author_name":"Jerry J. Shih","author_inst":"University of California San Diego"},{"author_name":"Nikdokht Farid","author_inst":"University of California San Diego"},{"author_name":"Jaideep Kapur","author_inst":"University of Virginia School of Medicine"},{"author_name":"Aaron F. Struck","author_inst":"Washington University in St. Louis"},{"author_name":"Lynn M. Bekris","author_inst":"University of Washington"},{"author_name":"Lisa Ferguson","author_inst":"Cleveland Clinic"},{"author_name":"Dace N. Almane","author_inst":"Cleveland Clinic"},{"author_name":"Jana E. Jones","author_inst":"Cleveland Clinic"},{"author_name":"Bruce P. Hermann","author_inst":"University of Wisconsin Madison"},{"author_name":"Robyn M. Busch","author_inst":"Cleveland Clinic"},{"author_name":"Carrie R. McDonald","author_inst":"University of California San Diego"},{"author_name":"- for the Alzheimer's Disease Neuroimaging Initiative*","author_inst":""}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Daily symptom monitoring is sustainable over months: retention, not compliance, is the primary barrier to long-duration digital tracking","rel_doi":"10.64898\/2026.06.08.26355180","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355180","rel_abs":"Ecological momentary assessment (EMA) enables real-time, longitudinal measurement of symptoms and behavior via smartphones, yet nearly all feasibility evidence comes from protocols lasting one to two weeks, far shorter than the timescales over which chronic diseases fluctuate and clinical decisions unfold. Whether daily compliance can be sustained over months, or whether it decays as short-protocol trends predict, is unknown. Here, 214 participants (173 with pain, 41 healthy controls) completed a 4-month (122-day) EMA protocol via the Soma smartphone app, generating 26,907 check-ins. Half the sample completed the full protocol without a two-week lapse. Aggregate compliance appeared moderate (50%), but this conflated two distinct phenomena: when recomputed over each participant's active period, compliance rose to 71%, with 91% achieving moderate-to-high adherence, and remained stable across all 17 study weeks. Pain status predicted earlier disengagement but not lower compliance among those who remained; after adjustment for differential retention, group differences disappeared. To our knowledge, this is the longest continuous daily EMA evaluation in a clinical population. It suggests the primary barrier to long-duration EMA is not declining motivation among active participants but concentrated early disengagement, with direct implications for the design of digital health protocols, decentralized trials, and remote symptom monitoring.","rel_num_authors":4,"rel_authors":[{"author_name":"Chloe Z Gunsilius","author_inst":"Brown University"},{"author_name":"Pangzhongyuan Pei","author_inst":"Brown University"},{"author_name":"Alexios Carayannopoulos","author_inst":"Brown University Health"},{"author_name":"Frederike H. Petzschner","author_inst":"Brown University"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Burden of Chronic Kidney Disease in China, 1990-2021: Findings from the 2021 Global Burden of Disease Study","rel_doi":"10.64898\/2026.06.06.26355056","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.06.26355056","rel_abs":"IntroductionTo investigate the epidemiological characteristics of chronic kidney diseases (CKD) in China in 2021 and its trends between 1990 and 2021, in the context of significant population growth and lifestyle changes over the past 30 years that have likely influenced the CKD spectrum.\n\nMethodsData on CKD prevalence, mortality, disability-adjusted life-years (DALY), and risk factors were obtained from the Global Burden of Disease Study 2021. The estimated decadal percentage changes were calculated to evaluate changes in trends in prevalence, mortality and disease burden.\n\nResultsIn 2021, an estimated 118.4 (95% UI 109.4 to 127.5) million people in China were affected by CKD, contributing to 204 230 (95% UI 164 736 to 246 372) deaths and 6.13 (95% UI 5.18 to 7.21) million DALY. Although CKD due to diabetes mellitus and hypertension accounted for less than a quarter of all cases, they were responsible for over 90% of CKD-related deaths. Over the past three decades, CKD mortality and DALY rates have steadily increased, although the prevalence has stabilized in the last decade. Diabetes mellitus type 2 and hypertension have emerged as key drivers of CKD burden in China.\n\nConclusionsThe CKD burden in China shows a dual pattern of rising incidence and high mortality from diabetes and hypertension-related chronic kidney disease, alongside persistently high years lived with disability from glomerulonephritis and other causes.","rel_num_authors":5,"rel_authors":[{"author_name":"Mengwei Wang","author_inst":"Shanxi Medical University"},{"author_name":"Taoran Zhao","author_inst":"Shanxi Medical University"},{"author_name":"Heng Wang","author_inst":"The University of Sydney"},{"author_name":"Shulin Hou","author_inst":"Shanxi Medical University"},{"author_name":"Yongqiang Fu","author_inst":"Shanxi Bethune Hospital"}],"rel_date":"2026-06-09","rel_site":"medrxiv"}]}