{"gname":"University of Massachusetts Chan Medical School ","grp_id":"44","rels":[{"rel_title":"Evidence of Epistatic Interactive Effects of HK1 and GCK Genes on Circulating Hemoglobin A1c Levels","rel_doi":"10.64898\/2026.05.01.26352221","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.01.26352221","rel_abs":"Abstract Background Hemoglobin A1c (HbA1c), an important diagnostic biomarker for type 2 diabetes (T2D), is also associated with aging, cognitive performance, and mortality. To identify epistatic interactions, we assessed 133 known gene variants associated with HbA1c among 3,778 non-diabetic subjects of European ancestry in the Long Life Family Study (LLFS). Methods We applied Bayesian Imputation Based Association Mapping (BIMBAM) to identify significant pairwise epistatic interactions among genetic variants that were previously shown to be associated with levels of HbA1c. To take into account confounding effects, we adjusted age, sex, field centers, body mass index (BMI), and genetic principal components (PCs). Results This analysis yielded seven pairs with log10(BF)>10; of those, six pairs were confirmed using a full-term mixed regression model. Specifically, these included significant interactions of HK1-rs17476364 with variants in GCK (rs2971670, rs4607517) or G6PC2 (rs560887), as well as between HK1-rs16926246 and the same variants (P values for each term [&le;] 7.14e-3). All epistatic interactions between HK1 and GCK, and between HK1 and G6PC2 were replicated in two large independent studies (namely, Framingham Offspring Study, P < 0.05; Health and Retirement Study, P < 0.05). Conclusion The present study revealed that HK1 and GCK interact to contribute to regulating levels of HbA1c and are likely to be involved in molecular mechanisms underlying healthy aging processes.","rel_num_authors":10,"rel_authors":[{"author_name":"Lihua Wang","author_inst":"Washu"},{"author_name":"Joseph H Lee","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Bharat Thyagarajan","author_inst":"University of Minnesota Medical School Twin Cities Campus: University of Minnesota Twin Cities School of Medicine"},{"author_name":"Anatoliy I. Yashin","author_inst":"Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, North Carolina, USA"},{"author_name":"Thomas T. Perls","author_inst":"Department of Medicine, Geriatrics Section, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts, USA"},{"author_name":"Kaare Christensen","author_inst":"University of Southern Denmark"},{"author_name":"Warwick DAW","author_inst":"Department of Genetics and Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Joseph M. Zmuda","author_inst":"Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"},{"author_name":"Michael Province","author_inst":"Department of Genetics and Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Ping An","author_inst":"Department of Genetics and Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA"}],"rel_date":"2026-05-03","rel_site":"medrxiv"},{"rel_title":"Evidence of Epistatic Interactive Effects of HK1 and GCK Genes on Circulating Hemoglobin A1c Levels","rel_doi":"10.64898\/2026.05.01.26352221","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.01.26352221","rel_abs":"Abstract Background Hemoglobin A1c (HbA1c), an important diagnostic biomarker for type 2 diabetes (T2D), is also associated with aging, cognitive performance, and mortality. To identify epistatic interactions, we assessed 133 known gene variants associated with HbA1c among 3,778 non-diabetic subjects of European ancestry in the Long Life Family Study (LLFS). Methods We applied Bayesian Imputation Based Association Mapping (BIMBAM) to identify significant pairwise epistatic interactions among genetic variants that were previously shown to be associated with levels of HbA1c. To take into account confounding effects, we adjusted age, sex, field centers, body mass index (BMI), and genetic principal components (PCs). Results This analysis yielded seven pairs with log10(BF)>10; of those, six pairs were confirmed using a full-term mixed regression model. Specifically, these included significant interactions of HK1-rs17476364 with variants in GCK (rs2971670, rs4607517) or G6PC2 (rs560887), as well as between HK1-rs16926246 and the same variants (P values for each term [&le;] 7.14e-3). All epistatic interactions between HK1 and GCK, and between HK1 and G6PC2 were replicated in two large independent studies (namely, Framingham Offspring Study, P < 0.05; Health and Retirement Study, P < 0.05). Conclusion The present study revealed that HK1 and GCK interact to contribute to regulating levels of HbA1c and are likely to be involved in molecular mechanisms underlying healthy aging processes.","rel_num_authors":10,"rel_authors":[{"author_name":"Lihua Wang","author_inst":"Washu"},{"author_name":"Joseph H Lee","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Bharat Thyagarajan","author_inst":"University of Minnesota Medical School Twin Cities Campus: University of Minnesota Twin Cities School of Medicine"},{"author_name":"Anatoliy I. Yashin","author_inst":"Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, North Carolina, USA"},{"author_name":"Thomas T. Perls","author_inst":"Department of Medicine, Geriatrics Section, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts, USA"},{"author_name":"Kaare Christensen","author_inst":"University of Southern Denmark"},{"author_name":"Warwick DAW","author_inst":"Department of Genetics and Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Joseph M. Zmuda","author_inst":"Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"},{"author_name":"Michael Province","author_inst":"Department of Genetics and Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA"},{"author_name":"Ping An","author_inst":"Department of Genetics and Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA"}],"rel_date":"2026-05-03","rel_site":"medrxiv"},{"rel_title":"A Clinical Prediction Model for Sudden Cardiac Arrest Presenting as Pulseless Electrical Activity","rel_doi":"10.64898\/2026.04.30.26352187","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.30.26352187","rel_abs":"Background: The incidence of sudden cardiac arrest (SCA) manifesting as pulseless electrical activity (PEA) has increased, and survival remains extremely low. Methods for early identification and management of high-risk individuals are needed, but no clinical risk scores currently exist to predict PEA-SCA. Our objective was to develop and validate a clinical prediction model for PEA-SCA. Methods: From an ongoing prospective, population-based study of SCA in Portland, Oregon (catchment pop. ?1 M, 2002-2020), we identified PEA-SCA adults. Lifetime clinical records were compared with those of a control group with >50% prevalence of significant coronary disease. Prediction models were constructed using backwards stepwise logistic regression in a training dataset (67%) and evaluated in a validation dataset (33%). Model discrimination was assessed using receiver operating characteristic curves (C statistic). External validation was performed in a geographically distinct population in Ventura County, California (population ?850,000, 2015-2022). Results: The final clinical algorithm (PEA-Risk) incorporating 12 clinical, electrocardiogram and medication variables demonstrated strong discrimination in the training dataset (C statistic = 0.860 [95% CI: 0.838-0.881]) and remained robust in internal (C statistic = 0.832 [95% CI: 0.800-0.865]) and external validation datasets (C statistic = 0.704 [95% CI: 0.665-0.743]). Conclusions: We developed and externally validated a clinical algorithm for predicting PEA-SCA. Given the low rates of successful resuscitation after PEA arrest, this risk prediction tool may enable earlier identification and prevention of PEA-SCA.","rel_num_authors":8,"rel_authors":[{"author_name":"Harpriya Chugh","author_inst":"Cedars-Sinai Medical Center Smidt Heart Institute"},{"author_name":"Kyndaron Reinier","author_inst":"Cedars-Sinai Medical Center Department of Cardiology"},{"author_name":"Audrey Uy-Evanado","author_inst":"Cedars-Sinai Medical Center Smidt Heart Institute"},{"author_name":"Kotoka Nakamura","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Ali A Sovari","author_inst":"St John?s Regional Medical Center, Dignity Health"},{"author_name":"Angelo Salvucci","author_inst":"Ventura County"},{"author_name":"Jonathan Jui","author_inst":"Oregon Health and Science University"},{"author_name":"Sumeet S. Chugh","author_inst":"Cedars-Sinai"}],"rel_date":"2026-05-03","rel_site":"medrxiv"},{"rel_title":"Disease Burden and Direct Health-Care Spending on Brain Conditions in Switzerland: Findings from the Global Burden of Disease 2023 Study for the Implementation of the Swiss Brain Health Plan","rel_doi":"10.64898\/2026.05.01.26352201","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.01.26352201","rel_abs":"Background Brain disorders are leading contributors to increasing disability and spending worldwide. In 2022 the Swiss Brain Health Plan (SBHP) was launched to promote brain health and prevent brain disorders. To guide the implementation of the SBHP, we performed a detailed analysis of the health and economic burden of brain disorders in Switzerland. Methods We analyzed Global Burden of Disease 2023 disability-adjusted life years (DALYs) and Institute for Health Metrics and Evaluation (IHME) cause-specific health-care spending estimates for Switzerland. DALYs were quantified for 1990 - 2023. Spending was analyzed for 2000 - 2019 across six types of care. We examined age and sex patterns, spending distribution, and international comparisons with six other countries (Germany, France, Denmark, Norway, Italy, Singapore). To assess short- and longer-term association between burden and spending estimates, we fitted panel regression models with disorder and year fixed effects under one-year and five-year lag specifications. Findings Both disease burden and spending were highly concentrated in a small number of conditions in Switzerland. In 2023, ten brain disorders accounted for 82.9% of Switzerland's total DALY burden. In 2019, ten brain disorders accounted for 86.0% of all direct brain-health spending, with dementia alone comprising 29.5% of total expenditures. Among seven analyzed comparator countries, Switzerland had the highest per-capita brain-health spending and the highest spending per DALY. In fixed-effects panel models that accounted for spending persistence, lagged DALYs were not statistically associated with subsequent spending. Suicide prevention and addiction showed significant lower-than-expected health-sector spending (self-harm: beta = -0.23; drug use disorders: beta = -0.08 to -0.18 across lag models). Interpretation Brain disorders generate a large burden in Switzerland. Within the IHME estimates, the burden-spending relationship over time appears limited. The implementation of the SBHP will refer to the current data and call for a burden-informed financing to guide strategic cross-sectorial allocation and prevention investments.","rel_num_authors":7,"rel_authors":[{"author_name":"Indrit Begue","author_inst":"University of Geneva, Switzerland"},{"author_name":"Lorina Sinanaj","author_inst":"University of Geneva, Switzerland"},{"author_name":"Xaviera Steele","author_inst":"University of Washington, United States"},{"author_name":"Raphael Guzman","author_inst":"University Hospital Basel, Department of Neurosurgery, Switzerland"},{"author_name":"Luca Crivelli","author_inst":"University of Applied Sciences and Arts of Southern Switzerland; (SUPSI) Scuola universitaria professionale della Svizzera Italiana"},{"author_name":"Alexandre N Datta","author_inst":"University Children's Hospital Basel, Switzerland"},{"author_name":"Claudio L.A. Bassetti","author_inst":"University of Bern, Switzerland"}],"rel_date":"2026-05-03","rel_site":"medrxiv"},{"rel_title":"Predicting first-onset depression in adolescents: Do general population models generalize to youth with ADHD?","rel_doi":"10.64898\/2026.04.30.26351304","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.30.26351304","rel_abs":"Background: Most studies seeking to identify youth at increased risk for depression have developed prediction models using a limited set of risk factors in general population samples. It is unclear whether these models generalize to high-risk youth. Here, we developed machine learning algorithms to predict first-onset depression in youth from the general population and high-risk youth with attention-deficit\/hyperactivity disorder (ADHD). Methods: Participants were 4803 unrelated children from the ABCD study with no prior mood disorder and complete data at baseline (age 9-10 years) and 2-year follow-up. Support Vector Machine, Random Forest, and Elastic Net models were used to predict first-onsets from clinically-relevant risk factors spanning mental and physical health, cognitive, dispositional, interpersonal, and socio-environmental domains. Predictive performance was evaluated in the full sample and separately in participants with ADHD (N=584, 12.16%). Results: Models trained on the full sample achieved good discriminative predictive power (area under the curve [AUC]=0.70 and accuracy=0.70-0.82). Predictors that replicated across models included earlier pubertal development, higher behavioral inhibition and aggression, and more time spent passively watching media content. In the ADHD subsample, model performance declined (AUC=0.46-0.61) and predictors only partly overlapped with those identified in the full sample. Conclusions: Models effectively predicted depression in the general population but showed poor generalization to high-risk youth with ADHD, suggesting different risk factors in this group. These findings highlight that models trained in general population samples may not generalize to high-risk groups, pointing to the need for more tailored efforts to predict depression in youth at increased risk.","rel_num_authors":5,"rel_authors":[{"author_name":"Shiqi Lu","author_inst":"Centre for Brain & Behaviour, Department of Psychology, School of Biological and Behavioural Sciences, Queen Mary University of London, London, UK"},{"author_name":"Toby Wise","author_inst":"Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK"},{"author_name":"Deanna M Barch","author_inst":"Departments of Psychological & Brain Sciences, Psychiatry, and Radiology, Washington University, St. Louis, MO, USA"},{"author_name":"Georgina M Hosang","author_inst":"Departments of Psychological & Brain Sciences, Psychiatry, and Radiology, Washington University, St. Louis, MO, USA"},{"author_name":"Giorgia Michelini","author_inst":"Centre for Brain & Behaviour, Department of Psychology, School of Biological and Behavioural Sciences, Queen Mary University of London, London, UK; Departments "}],"rel_date":"2026-05-03","rel_site":"medrxiv"},{"rel_title":"Znf804a is a regulator of circadian behaviors in zebrafish","rel_doi":"10.64898\/2026.04.29.721668","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.29.721668","rel_abs":"Sleep disturbances are common among individuals with schizophrenia and can exacerbate disruptions in cognitive processes like learning and memory. Elucidating pharmacologically targetable molecular pathways perturbed by schizophrenia genes may uncover new treatment avenues. Here, we investigated the relationship of the schizophrenia-associated gene znf804a with sleep and circadian pathways. Using multi-day behavior tracking, we showed that znf804a zebrafish mutants displayed changes in sleep and circadian behaviors when light cues were removed. Through bulk RNA sequencing of fish raised under normal light cycling and dark-only conditions, we identified altered gene expression in the core and auxiliary pathways controlling circadian rhythms. Expression of fbxl3a, which encodes a modulator of the core negative feedback regulator of the clock, decreased in a dose-dependent manner as znf804a mutant copy number increased. Further analysis also revealed shifts in the relative abundance of specific transcripts, including idh1, suggesting znf804a could influence transcript processing or stability. Together, these findings link a ZNF804A ortholog to sleep and circadian behaviors and identify the regulation of fbxl3a and transcript processing as candidate mechanisms through which this schizophrenia risk gene may influence circadian biology.","rel_num_authors":4,"rel_authors":[{"author_name":"Brandon L. Bastien","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Eric H. Li","author_inst":"Harvard University"},{"author_name":"Mary E.S. Capps","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Summer Thyme","author_inst":"University of Massachusetts Chan Medical School"}],"rel_date":"2026-05-03","rel_site":"biorxiv"},{"rel_title":"SPP1hi macrophages in fibrin niches promote hyperplastic tissue remodeling in rheumatoid arthritis synovium","rel_doi":"10.64898\/2026.04.29.721703","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.29.721703","rel_abs":"In chronic inflammatory diseases, maladaptive tissue remodelling is driven by a complex interplay of resident cells, immune infiltrates and the extracellular matrix. In the autoimmune disorder rheumatoid arthritis (RA), synovial tissue undergoes massive expansion to form an invasive pannus that drives the erosion of cartilage and bone. The mechanisms mediating this aggressive growth are incompletely defined. Using spatial transcriptomics profiling of patient tissue, we detected an abundance of proliferating fibroblasts near the synovial tissue lining surface and adjacent to SPP1hi macrophages. Notably, these synovial lining regions were also distinctly marked by deposits of the clot-forming protein fibrin. While the SPP1hi macrophages phenotypically resemble pro-fibrotic macrophages that drive lung and liver fibrosis, these niches were devoid of the dense highly ordered collagen that marks fibrosis. Functionally, we found that SPP1hi macrophages degrade and phagocytose fibrin matrices and promote fibroblast proliferation. As fibrin provides transient matrices for de novo tissue generation in the context of wound healing, these data support a model of hyperplastic tissue outgrowth involving SPP1hi macrophages, fibroblasts and fibrin matrices adhered to the exterior synovial tissue surface. While current RA therapies primarily aim to dampen pro-inflammatory responses, our findings provide rationale for targeting pro-generative pathways and SPP1hi macrophages.","rel_num_authors":21,"rel_authors":[{"author_name":"Ian Mantel","author_inst":"Weill Cornell Medicine; Hospital for Special Surgery"},{"author_name":"Haoxuan Zhang","author_inst":"Weill Cornell Medicine; Memorial Sloan Kettering Cancer Center"},{"author_name":"Juan Vargas","author_inst":"Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus; MPH Biostatistics, University of Colorado Anschutz Medical Campus"},{"author_name":"Ce Gao","author_inst":"Brigham and Women's Hospital; Harvard Medical School"},{"author_name":"Hope Townsend","author_inst":"University of Colorado Boulder"},{"author_name":"Richard Bell","author_inst":"Hospital for Special Surgery"},{"author_name":"Amit Lakhanpal","author_inst":"Hospital for Special Surgery"},{"author_name":"Miriam R. Fein","author_inst":"Hospital for Special Surgery"},{"author_name":"- Accelerating Medicines Partnership: RA\/SLE Network","author_inst":"Accelerating Medicines Partnership: RA\/SLE Network"},{"author_name":"Thomas Norman","author_inst":"Weill Cornell Medicine; Memorial Sloan Kettering Cancer Center"},{"author_name":"Dana Orange","author_inst":"The Rockefeller University; Hospital for Special Surgery"},{"author_name":"Daniel Ramirez","author_inst":"Hospital for Special Surgery"},{"author_name":"Edward F. DiCarlo","author_inst":"Hospital for Special Surgery"},{"author_name":"Susan M. Goodman","author_inst":"Hospital for Special Surgery"},{"author_name":"Melanie H. Smith","author_inst":"Weill Cornell Medicine; Hospital for Special Surgery"},{"author_name":"Fan Zhang","author_inst":"Division of Rheumatology, Department of Medicine, Center for Health Artificial Intelligence, University of Colorado School Anschutz Medical Campus"},{"author_name":"Kevin Wei","author_inst":"Brigham and Women's Hospital"},{"author_name":"Kushal K. Dey","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Alexander Rudensky","author_inst":"Weill Cornell Medicine; Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center; Louis V. Gerstner Jr. Graduate School of Biomedic"},{"author_name":"Christina S. Leslie","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Laura T. Donlin","author_inst":"Weill Cornell Medicine; Hospital for Special Surgery"}],"rel_date":"2026-05-03","rel_site":"biorxiv"},{"rel_title":"Metabolic Reprogramming Induced by Mitochondrial Citrate Carrier Deletion Mitigates Antibiotics-Induced Acute Tubular Injury","rel_doi":"10.64898\/2026.04.29.721583","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.29.721583","rel_abs":"Introduction The mitochondrial citrate carrier (CiC), which mediates the transport of citrate across mitochondria, has been implicated in various diseases, but its role in kidney tubules is unclear. Here, we unraveled a novel role of CiC in tubular metabolism in the context of antibiotics-induced acute tubular injury (ATI). Methods ATI was induced by administration of vancomycin and gentamycin for 48 hours in mice (V+G-ATI). Tubular-specific CiC knockout (KO) was induced by adeno-associated virus (AAV) serotype 9 encoding Cre recombinase driven by KSP promoter (AAV9-Ksp-Cre) injection. Unbiased proteomic and metabolomic analyses were performed in CiC KO mouse kidneys. We performed in vivo 13C metabolic flux analysis to elucidate metabolic alterations in ATI and the effect of CiC KO. Results In this study, V+G-induced ferroptosis, oxidative damage, and extensive ATI in mice were alleviated by CiC KO. Metabolic reprogramming induced by CiC KO increased mitochondrial TCA cycle intermediates, including alpha ketoglutarate (AKG), and elevated levels of the endogenous antioxidant glutathione (GSH). Supplementation with AKG or GSH attenuated V+G-ATI in mice. Tracking of the 13C pyruvate \/ lactate revealed an increased flux of glucose oxidation pathway in V+G-ATI. Interestingly, tubular-specific CiC KO expands the effective TCA cycle pool reserve space, which may contribute to mitigation of ROS. The beneficial metabolic alteration in CiC KO requires AKG and glutamate, as simultaneous inhibition of mitochondrial transporters of AKG and glutamate attenuated the cytoprotective effects of CiC KO against antibiotic-induced oxidative damage. Conclusions This is the first study to demonstrate the role of mitochondrial CiC in kidney tubular epithelial cells, showing that it induces metabolic alterations that protect against antibiotic-induced ATI.","rel_num_authors":9,"rel_authors":[{"author_name":"Ming-Hung Hu","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Kai-Hao Wang","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Peir-Ing Liang","author_inst":"Kaohsiung Medical University"},{"author_name":"Elaine Y Dai","author_inst":"UCSD"},{"author_name":"Adam Rauckhorst","author_inst":"Florida International University"},{"author_name":"Renny S Lan","author_inst":"UAMS"},{"author_name":"Hailemariam Assress","author_inst":"UAMS"},{"author_name":"Eric B Taylor","author_inst":"U Iowa"},{"author_name":"Dao-Fu Dai","author_inst":"Johns Hopkins University School of Medicine"}],"rel_date":"2026-05-03","rel_site":"biorxiv"},{"rel_title":"Metabolic Reprogramming Induced by Mitochondrial Citrate Carrier Deletion Mitigates Antibiotics-Induced Acute Tubular Injury","rel_doi":"10.64898\/2026.04.29.721583","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.29.721583","rel_abs":"Introduction The mitochondrial citrate carrier (CiC), which mediates the transport of citrate across mitochondria, has been implicated in various diseases, but its role in kidney tubules is unclear. Here, we unraveled a novel role of CiC in tubular metabolism in the context of antibiotics-induced acute tubular injury (ATI). Methods ATI was induced by administration of vancomycin and gentamycin for 48 hours in mice (V+G-ATI). Tubular-specific CiC knockout (KO) was induced by adeno-associated virus (AAV) serotype 9 encoding Cre recombinase driven by KSP promoter (AAV9-Ksp-Cre) injection. Unbiased proteomic and metabolomic analyses were performed in CiC KO mouse kidneys. We performed in vivo 13C metabolic flux analysis to elucidate metabolic alterations in ATI and the effect of CiC KO. Results In this study, V+G-induced ferroptosis, oxidative damage, and extensive ATI in mice were alleviated by CiC KO. Metabolic reprogramming induced by CiC KO increased mitochondrial TCA cycle intermediates, including alpha ketoglutarate (AKG), and elevated levels of the endogenous antioxidant glutathione (GSH). Supplementation with AKG or GSH attenuated V+G-ATI in mice. Tracking of the 13C pyruvate \/ lactate revealed an increased flux of glucose oxidation pathway in V+G-ATI. Interestingly, tubular-specific CiC KO expands the effective TCA cycle pool reserve space, which may contribute to mitigation of ROS. The beneficial metabolic alteration in CiC KO requires AKG and glutamate, as simultaneous inhibition of mitochondrial transporters of AKG and glutamate attenuated the cytoprotective effects of CiC KO against antibiotic-induced oxidative damage. Conclusions This is the first study to demonstrate the role of mitochondrial CiC in kidney tubular epithelial cells, showing that it induces metabolic alterations that protect against antibiotic-induced ATI.","rel_num_authors":9,"rel_authors":[{"author_name":"Ming-Hung Hu","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Kai-Hao Wang","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Peir-Ing Liang","author_inst":"Kaohsiung Medical University"},{"author_name":"Elaine Y Dai","author_inst":"UCSD"},{"author_name":"Adam Rauckhorst","author_inst":"Florida International University"},{"author_name":"Renny S Lan","author_inst":"UAMS"},{"author_name":"Hailemariam Assress","author_inst":"UAMS"},{"author_name":"Eric B Taylor","author_inst":"U Iowa"},{"author_name":"Dao-Fu Dai","author_inst":"Johns Hopkins University School of Medicine"}],"rel_date":"2026-05-03","rel_site":"biorxiv"},{"rel_title":"Metabolic Reprogramming Induced by Mitochondrial Citrate Carrier Deletion Mitigates Antibiotics-Induced Acute Tubular Injury","rel_doi":"10.64898\/2026.04.29.721583","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.29.721583","rel_abs":"Introduction The mitochondrial citrate carrier (CiC), which mediates the transport of citrate across mitochondria, has been implicated in various diseases, but its role in kidney tubules is unclear. Here, we unraveled a novel role of CiC in tubular metabolism in the context of antibiotics-induced acute tubular injury (ATI). Methods ATI was induced by administration of vancomycin and gentamycin for 48 hours in mice (V+G-ATI). Tubular-specific CiC knockout (KO) was induced by adeno-associated virus (AAV) serotype 9 encoding Cre recombinase driven by KSP promoter (AAV9-Ksp-Cre) injection. Unbiased proteomic and metabolomic analyses were performed in CiC KO mouse kidneys. We performed in vivo 13C metabolic flux analysis to elucidate metabolic alterations in ATI and the effect of CiC KO. Results In this study, V+G-induced ferroptosis, oxidative damage, and extensive ATI in mice were alleviated by CiC KO. Metabolic reprogramming induced by CiC KO increased mitochondrial TCA cycle intermediates, including alpha ketoglutarate (AKG), and elevated levels of the endogenous antioxidant glutathione (GSH). Supplementation with AKG or GSH attenuated V+G-ATI in mice. Tracking of the 13C pyruvate \/ lactate revealed an increased flux of glucose oxidation pathway in V+G-ATI. Interestingly, tubular-specific CiC KO expands the effective TCA cycle pool reserve space, which may contribute to mitigation of ROS. The beneficial metabolic alteration in CiC KO requires AKG and glutamate, as simultaneous inhibition of mitochondrial transporters of AKG and glutamate attenuated the cytoprotective effects of CiC KO against antibiotic-induced oxidative damage. Conclusions This is the first study to demonstrate the role of mitochondrial CiC in kidney tubular epithelial cells, showing that it induces metabolic alterations that protect against antibiotic-induced ATI.","rel_num_authors":9,"rel_authors":[{"author_name":"Ming-Hung Hu","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Kai-Hao Wang","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Peir-Ing Liang","author_inst":"Kaohsiung Medical University"},{"author_name":"Elaine Y Dai","author_inst":"UCSD"},{"author_name":"Adam Rauckhorst","author_inst":"Florida International University"},{"author_name":"Renny S Lan","author_inst":"UAMS"},{"author_name":"Hailemariam Assress","author_inst":"UAMS"},{"author_name":"Eric B Taylor","author_inst":"U Iowa"},{"author_name":"Dao-Fu Dai","author_inst":"Johns Hopkins University School of Medicine"}],"rel_date":"2026-05-03","rel_site":"biorxiv"},{"rel_title":"Translational Opportunity of Engineered IFN\u03b3-eEVs Through Targeted Inhibition of JAK\/STAT1 Signaling, Mimicking IVIg Therapy","rel_doi":"10.64898\/2026.04.29.721601","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.29.721601","rel_abs":"Immunoglobulin (Ig) replacement therapies (IgRT) including intravenous (IVIg) and subcutaneous (SCIg), are pooled IgG preparations widely used to restore humoral immunity and to suppress pathological inflammation in autoimmune and inflammatory disorders. Despite broad clinical use, the mechanisms underlying their immunomodulatory effects remain incompletely defined. Here, we identify extracellular vesicle (EV)-associated cytokines as mediators of IVIg activity. Multiplex bead-based flow cytometry revealed that EVs isolated by size exclusion followed by ultracentrifugation from IVIg were CD63 positive but depleted of platelet-derived and HLA markers relative to EVs from unprocessed human plasma. Luminex profiling demonstrated substantial reduction of pro-inflammatory cytokines in IVIg EVs. Notably, although IVIg EVs contained abundant IFN{gamma}, they failed to activate IFNGR\/JAK\/STAT1 signaling. Instead, prolonged exposure to IVIg EVs suppressed subsequent IFN{gamma}-induced STAT1 activation. Engineered IFN{gamma}-coated EVs (IFN{gamma}-eEVs) recapitulated both activating and inhibitory effects indicating context-dependent signaling bias. Critically, cold ethanol precipitation, a key step in IVIg manufacturing, selectively abrogated the activating function of IFN{gamma}-eEVs while preserving their inhibitory capacity. These findings define a previously unrecognized mechanism where IVIg processing generates EVs that bias IFN{gamma} signaling toward suppression. EV-associated cytokines therefore represent a generalizable pathway through which IVIg exerts anti-inflammatory effects across immune-mediated diseases.","rel_num_authors":17,"rel_authors":[{"author_name":"Kylie E Preihs","author_inst":"Thomas Jefferson University"},{"author_name":"Kubra Karagoz","author_inst":"Thomas Jefferson University"},{"author_name":"Claire R Shuey","author_inst":"Thomas Jefferson University"},{"author_name":"Amritha Achuthkumar","author_inst":"Thomas Jefferson University"},{"author_name":"Ana M Pivovarnik","author_inst":"Thomas Jefferson University"},{"author_name":"Sophia M Crocker","author_inst":"Thomas Jefferson University"},{"author_name":"Michelle L Pleet","author_inst":"National Institutes of Health"},{"author_name":"Jubin George","author_inst":"National Institutes of Health"},{"author_name":"Robert D Carlson","author_inst":"Thomas Jefferson University"},{"author_name":"Adam E Snook","author_inst":"Thomas Jefferson University"},{"author_name":"Adam J Luginbuhl","author_inst":"Thomas Jefferson University"},{"author_name":"Peter J Wermuth","author_inst":"Thomas Jefferson University"},{"author_name":"Andreas Moeller","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Jennifer C Jones","author_inst":"National Institutes of Health"},{"author_name":"Larry A Harshyne","author_inst":"Thomas Jefferson University"},{"author_name":"Alice P Pentland","author_inst":"University of Rochester"},{"author_name":"My G Mahoney","author_inst":"Thomas Jefferson University"}],"rel_date":"2026-05-03","rel_site":"biorxiv"},{"rel_title":"Water beneath the pavement: assessing the benefits of passive irrigation for urban Lophostemon confertus trees in western Sydney","rel_doi":"10.64898\/2026.04.29.721794","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.29.721794","rel_abs":"Urban environments typically experience higher temperatures than surrounding natural landscapes, making urban vegetation crucial for cooling local areas and improving the health of city residents. Impervious urban surfaces limit the absorption and retention of precipitation, potentially limiting tree water access and threatening long-term survival. Here, we measured tree physiology and growth of Lophostemon confertus (Queensland brush box) trees to investigate how a passive irrigation system that stores stormwater affected the performance of young, establishing trees in a hot and dry suburb of western Sydney, Australia. During the 2024-2025 austral summer, three years after planting, the local climate was periodically hot and dry, with a total of 16 days above 35 C. Irrigated L. confertus trees had higher water availability (i.e., higher predawn leaf water potential, {Psi}pre), lower water stress (i.e., higher midday leaf water potential, {Psi}mid, more frequently above turgor loss point), greater stomatal conductance (gs) on hot and dry summer days, and reduced leaf temperatures (Tleaf), compared to control trees. No significant differences in growth rates were observed between irrigated and control trees during the first three establishment years, but irrigated trees had greater crown survival during the hot, dry summer. Our results suggest passive irrigation may mitigate periods of short-term heat and drought stress in urban trees by increasing water access to support transpiration that prevents leaves from overheating, improving tree health. Higher tree transpiration may lead to greater ecosystem services by increasing cooling benefits, contributing to mitigation of urban heat island effects.","rel_num_authors":6,"rel_authors":[{"author_name":"Davide Siclari","author_inst":"Hawkesbury Institute for the Environment, Western Sydney University, Penrith, NSW 2751, Australia"},{"author_name":"Mark G Tjoelker","author_inst":"Hawkesbury Institute for the Environment, Western Sydney University, Penrith, NSW 2751, Australia"},{"author_name":"Chathurika Perera","author_inst":"Blacktown City Council, 62 Flushcombe Rd, Blacktown NSW 2148"},{"author_name":"Sebastian Pfautsch","author_inst":"Hawkesbury Institute for the Environment, Western Sydney University, Penrith, NSW 2751, Australia"},{"author_name":"Paul D Rymer","author_inst":"Hawkesbury Institute for the Environment, Western Sydney University, Penrith, NSW 2751, Australia"},{"author_name":"Renee M Marchin","author_inst":"Hawkesbury Institute for the Environment, Western Sydney University, Penrith, NSW 2751, Australia"}],"rel_date":"2026-05-03","rel_site":"biorxiv"},{"rel_title":"Subnuclear cofactor partitioning underlies auxin-dependent transcriptional regulation","rel_doi":"10.64898\/2026.04.29.721720","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.29.721720","rel_abs":"Cellular and organismal function relies on the precise activation and repression of gene expression by DNA-binding transcription factors (TFs). Many TFs occur in large gene families, and a key question in biology is how divergent functions emerge in TF families during evolution. Here we discover the biochemical mechanism for transcriptional activation by the Marchantia polymorpha AUXIN RESPONSE FACTOR1 (MpARF1) TF, which relies on direct recruitment of the Mediator complex into subnuclear MpARF1 clusters. We find that the Mediator recruitment region was the evolutionary innovation that converted ARF repressors into activators, switching binding specificity from co-repressor to co-activator. We demonstrate that this evolutionary innovation can be recreated, thereby revealing a deeply conserved mechanism based on competition between ARF clusters at the heart of the transcriptional auxin response.","rel_num_authors":12,"rel_authors":[{"author_name":"Jorge Hernandez-Garcia","author_inst":"Universidad Politecnica de Madrid"},{"author_name":"Melissa Dipp Alvarez","author_inst":"Wageningen University"},{"author_name":"Martijn de Roij","author_inst":"Wageningen University"},{"author_name":"Maria Guillem-Bernal","author_inst":"Universidad Politecnica de Madrid"},{"author_name":"Mark Roosjen","author_inst":"Wageningen University"},{"author_name":"Zeynep Baltaci","author_inst":"University of Toronto"},{"author_name":"Harrison W. Smith","author_inst":"University of Toronto"},{"author_name":"Danilo Pereira","author_inst":"Wageningen University"},{"author_name":"Jan Willem Borst","author_inst":"Wageningen University"},{"author_name":"Alex S Holehouse","author_inst":"Washington School of Medicine"},{"author_name":"Hyun O. Lee","author_inst":"University of Toronto"},{"author_name":"Dolf Weijers","author_inst":"Wageningen University"}],"rel_date":"2026-05-03","rel_site":"biorxiv"},{"rel_title":"Multi-point convective delivery overcomes mass transport barriers for myocardial therapeutics","rel_doi":"10.64898\/2026.04.29.721610","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.29.721610","rel_abs":"Angiogenesis-promoting macromolecules reduce adverse remodeling and preserve cardiac function in rodents following myocardial infarctions, yet repeatedly fail to translate across length scales in humans. Through mass transport studies in human and swine myocardium, we found that dense, anisotropic myocardial fibers limit therapeutic diffusion and convection to millimeter scales for existing approaches including bolus intramyocardial injections, shear-thinning hydrogels, and epicardial patches. Furthermore, distributions are confined to one dimension along fibers. To increase myocardial drug distribution to centimeter length scales in vivo in swine, we engineered a three-dimensional multi-injection drug delivery array. Our device performs up to 40 simultaneous 120 L injections of functional macromolecules, hydrogels, or mRNA lipid nanoparticles. Injections are precisely placed in relation to fiber alignment, achieving near-complete coverage of the left ventricular myocardium.","rel_num_authors":16,"rel_authors":[{"author_name":"Jihoon Park","author_inst":"Georgia Institute of Technology"},{"author_name":"Adwik Rahematpura","author_inst":"Georgia Institute of Technology"},{"author_name":"Eva Beresin","author_inst":"Georgia Institute of Technology"},{"author_name":"Aaditya Majumdar","author_inst":"Georgia Institute of Technology"},{"author_name":"Yusra Azeem","author_inst":"Georgia Institute of Technology"},{"author_name":"Haruto Mizukai","author_inst":"Georgia Institute of Technology"},{"author_name":"Ramy Ghanim","author_inst":"Georgia Institute of Technology"},{"author_name":"Joy Jackson","author_inst":"Georgia Institute of Technology"},{"author_name":"Sean Healy","author_inst":"Georgia Institute of Technology"},{"author_name":"Julia Z. Ding","author_inst":"Georgia Institute of Technology"},{"author_name":"McKenna Clinch","author_inst":"Georgia Institute of Technology"},{"author_name":"Abdulraouf M. Abbas","author_inst":"Georgia Institute of Technology"},{"author_name":"Megan Belanger","author_inst":"Emory University"},{"author_name":"James E. Dahlman","author_inst":"Emory University"},{"author_name":"Joshua L. Chan","author_inst":"Emory University"},{"author_name":"Alex Abramson","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-05-02","rel_site":"biorxiv"},{"rel_title":"One-pot parallel Sidewinder construction from oligo pools","rel_doi":"10.64898\/2026.05.01.722326","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.01.722326","rel_abs":"Reliable and cost effective de novo DNA production has become central to studying and engineering biology. Short synthetic single-stranded DNA oligo pools offer substantially reduced costs at the sacrifice of yield and individual oligo isolation. Efficiently constructing longer synthetic double-stranded DNA molecules from oligo pools as the input has remained an engineering challenge with the potential to drastically reduce costs, labor, and experimental turn-around time. Here we show one-pot, parallel assembly of hundreds of DNA fragments simultaneously into dozens of defined constructs with high fidelity using Sidewinder. We designed a novel string-based bespoke barcode design algorithm which rapidly generates Sidewinder barcodes at unprecedented scale. We apply the new algorithm to Sidewinder using oligo pools, demonstrating construct-specific amplification from pooled assemblies with misconnection rates as low as 1 in 10,000,000. Further, we demonstrate universal amplification of pooled assemblies to generate a library of specific target sequences that we combine with in vitro hierarchical assembly to 12.5 kilobases.","rel_num_authors":9,"rel_authors":[{"author_name":"Noah Evan Robinson","author_inst":"California Institute of Technology"},{"author_name":"Jean-Sebastien Paul","author_inst":"California Institute of Technology"},{"author_name":"Weilin Zhang","author_inst":"California Institute of Technology"},{"author_name":"Hanqiao Zhang","author_inst":"California Institute of Technology"},{"author_name":"Sixiang Wang","author_inst":"California Institute of Technology"},{"author_name":"Tianhua Zhao","author_inst":"California Institute of Technology"},{"author_name":"Ezri Abraham","author_inst":"California Institute of Technology"},{"author_name":"Benjamin Simpson","author_inst":"California Institute of Technology"},{"author_name":"Kaihang Wang","author_inst":"California Institute of Technology"}],"rel_date":"2026-05-02","rel_site":"biorxiv"},{"rel_title":"Structural Insights into the Coupling Mechanism of Vectorial CO2 Uptake by DAB1","rel_doi":"10.64898\/2026.05.01.722082","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.01.722082","rel_abs":"CO2 transporters enable bacterial carbon-concentrating mechanisms by catalyzing directional hydration of CO2, yet the basis of this vectorial carbonic anhydrase (CA) activity remains an open question. We used cryo-EM to determine the structure of the DAB1 complex from Thermocrinis albus to 2.13 [A], revealing a heterotrimer in which a deeply buried {beta}-CA active site in DabA is structurally coupled to the proton-translocating subunit DabB. Two conformational states define distinct solvent channels for substrate entry and product exit. A suppressor screen identifies mutations that disrupt coupling while retaining CA activity, underlying the importance of conserved residues that link proton translocation to active-site remodeling. These results support a model in which proton-driven conformational changes regulate substrate access to the active site, enabling vectorial CO2 hydration.","rel_num_authors":4,"rel_authors":[{"author_name":"Naiya R Phillips","author_inst":"University of California, Berkeley"},{"author_name":"Luke M Oltrogge","author_inst":"University of California, Berkeley"},{"author_name":"Jonathan P Remis","author_inst":"University of California, Berkeley"},{"author_name":"David F Savage","author_inst":"University of California, Berkeley"}],"rel_date":"2026-05-02","rel_site":"biorxiv"},{"rel_title":"A chimeric human-mouse lung vascular model using induced pluripotent stem cells reveals insights into the pathogenesis of BMPR2-related pulmonary hypertension","rel_doi":"10.64898\/2026.04.29.721664","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.29.721664","rel_abs":"Advances in tissue biology have revealed remarkable transcriptomic heterogeneity of endothelial cells between and within organ systems. This necessitates more precise models of organ-specific endothelium to understand the pathogenesis of genetic vascular disorders, such as pulmonary hypertension (PH), where gene-disease associations have implicated endothelial cell dysfunction as a key driver of disease pathogenesis. Towards this end, human induced pluripotent stem cells (hiPSCs) hold immense promise for PH disease modeling where hiPSCs are generated from an affected individual and undergo gene correction to generate syngeneic controls that can be differentiated to endothelial cells (hiEndos), providing a limitless source of material for downstream studies; however, the ability to generate lung-specific hiEndos to model pulmonary vascular disease has been limited. To overcome this challenge, we developed a chimeric human-mouse lung vascular model wherein hiEndos are first patterned via BMP9-induced signaling towards a lung-like molecular phenotype in vitro and are then intravenously transplanted into the mouse lung vasculature in vivo to generate orthotopic lung-specific endothelium for downstream studies. Transplanted pre-patterned hiEndos form functional connections to the native mouse lung vasculature and upregulate differentiated lung-specific molecular cell subtype profiles that include capillary- and arterial-like cell populations. To apply this approach for disease modeling, we generated new hiPSC lines by reprogramming fibroblasts from individuals of the 2001 landmark cohort of BMPR2 gene variant-associated PH and developed a novel in vivo competitive lung endothelial reconstitution assay to quantify functional and molecular differences between human BMPR2-variant vs syngeneic gene-corrected\/edited hiEndos. Our approach revealed novel insights into PH disease pathogenesis, not previously evident with prior models, including BMPR2 variant-induced in vivo defects in human lung capillary gene expression, elevated lncRNA H19 expression, increased AHR signaling, and diminished functional capacity to repopulate the pulmonary vascular endothelium.","rel_num_authors":8,"rel_authors":[{"author_name":"Alexander M. Holtz","author_inst":"Boston Children's Hospital"},{"author_name":"Marcus Vorpahl","author_inst":"Boston Children's Hospital"},{"author_name":"Mohamed J. Ahmed","author_inst":"Hamdan Bin Mohammed College of Dental Medicine"},{"author_name":"Eric D. Austin","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Pushpinder S. Bawa","author_inst":"Boston University and Boston Medical Center"},{"author_name":"Carlos Villacorta-Martin","author_inst":"Boston University and Boston Medical Center"},{"author_name":"Mervin C. Yoder","author_inst":"University of Pittsburgh"},{"author_name":"Darrell N. Kotton","author_inst":"Boston University and Boston Medical Center"}],"rel_date":"2026-05-02","rel_site":"biorxiv"},{"rel_title":"The Unified Human Virome Database: A toolkit for expanded human virome analysis","rel_doi":"10.64898\/2026.05.01.722327","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.01.722327","rel_abs":"Current approaches for computationally analyzing viruses within human microbiomes often rely on databases largely composed of fragmented viral genomes from gastrointestinal samples, limiting identification of viruses exclusively found outside the gastrointestinal tract and analyses requiring high-quality genomes. To address these issues, we created the Unified Human Virome Database (UHVDB), comprising 575,497 high-quality, annotated viral genomes from human gastrointestinal, airway, skin, and urogenital sample metagenomes. We developed an associated toolkit that uses UHVDB to characterize viruses and their potential activity from metagenomes, then applied this toolkit to 1,983 airway sample metagenomes from people with cystic fibrosis. Over half of detected viruses lacked evidence of potential activity and were detected transiently. UHVDB is nearly three times larger than prior viral databases and its ability to identify likely active viruses enables rigorous analysis of viruses from diverse human sample types, expanding the capacity to define virus contributions to health and disease.","rel_num_authors":9,"rel_authors":[{"author_name":"Carson J Miller","author_inst":"University of Washington School of Medicine"},{"author_name":"Christopher E Pope","author_inst":"University of Washington School of Medicine"},{"author_name":"Margot L Lavitt","author_inst":"University of California Berkeley"},{"author_name":"Lindsay J Caverly","author_inst":"University of Michigan Medical School"},{"author_name":"John J. LiPuma","author_inst":"University of Michigan Medical School"},{"author_name":"Kelsi Penewit","author_inst":"University of Washington School of Medicine"},{"author_name":"Janessa D Lewis","author_inst":"University of Washington School of Medicine"},{"author_name":"Stephen J Salipante","author_inst":"University of Washington School of Medicine"},{"author_name":"Lucas R Hoffman","author_inst":"University of Washington School of Medicine"}],"rel_date":"2026-05-02","rel_site":"biorxiv"},{"rel_title":"Dietary and gut microbial variation among urban and rural populations of house mice (Mus musculus domesticus)","rel_doi":"10.64898\/2026.04.30.721966","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.30.721966","rel_abs":"Urbanization can result in shifts in abiotic and biotic factors, including temperature, pollution, habitat type, pathogens, and diet, among others. These shifts can, in turn, shape the ecological and evolutionary trajectory of urban wildlife. The gut microbiota has the potential to mediate host-environment interactions, especially in the context of diet and disease, and thus may be a useful lens for understanding the impacts of urbanization. House mice (Mus musculus domesticus) are a cosmopolitan human commensal with a wealth of genomic and metagenomic resources. Here, we investigate patterns of variation in diet and gut microbial diversity, community composition, and function using a paired urban-rural sampling design in house mice from three metro regions in the eastern United States. First, using stable isotope analysis, we found that habitat, urban versus rural, was a major driver of variation in {delta}15N, suggesting a diet richer in animal proteins in cities. Next, using short-read sequencing of the 16S rRNA gene, we found that urban mice have lower gut microbial taxonomic diversity than their rural counterparts. We also found that community composition varied among urban and rural habitats, with differences largely reflecting shifts among closely related taxa. In particular, Prevotellaceae, a family known to be responsive to dietary quality, was differentially abundant, with lower abundance in urban habitats. Finally, we found differentiation in a few predicted microbial functions across habitat, primarily related to metabolism. Together, data across three independent sampling regions provide strong evidence that urbanization has the potential to shape the diet and the microbiome of house mice.","rel_num_authors":9,"rel_authors":[{"author_name":"Samantha M. Giancarli","author_inst":"Drexel University"},{"author_name":"Adrienne E. Kasprowicz","author_inst":"Drexel University"},{"author_name":"Madeline Balman","author_inst":"Northeastern University"},{"author_name":"Ren\u00e9 D. Clark","author_inst":"Drexel University"},{"author_name":"Stephen C. Kupchella","author_inst":"Drexel University"},{"author_name":"Logan J. Lacy","author_inst":"Drexel University"},{"author_name":"Andrew Moeller","author_inst":"Cornell University"},{"author_name":"Taichi Suzuki","author_inst":"Arizona State University"},{"author_name":"Megan Phifer-Rixey","author_inst":"Drexel University College of Arts and Sciences"}],"rel_date":"2026-05-02","rel_site":"biorxiv"},{"rel_title":"Decoding the BRCA2 reversion principles underlying PARP inhibitor resistance","rel_doi":"10.64898\/2026.04.29.721733","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.29.721733","rel_abs":"Reversion mutations that restore BRCA2 function represent a major mechanism of resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) in BRCA2-mutant cancers. Understanding and predicting these events could inform treatment strategies, identify patients at increased risk of acquiring PARPi resistance, and improve the clinical interpretation of secondary BRCA2 variants detected in resistant tumors. Here, we evaluated reversions in an isogenic cell system using CRISPR editing and long-read transcript analysis to define the principles governing BRCA2 reversion systematically. We find that local sequence context dictates the spectrum of reversions, whereas BRCA2 domain architecture determines which of these events confer PARPi resistance. Moreover, we characterize the two routes of BRCA2 reversion: DNA-level restoration of the reading frame and transcript-level rescue through altered splicing. Both mechanisms were frequently used to restore BRCA2 expression across exon boundaries. The detection of such events at multiple loci suggests that inter-exonic reversion may be more widespread than previously appreciated. Lastly, we identify a unique set of mechanisms that underlie exon 11 reversions. In this region, reversions arose through both large genomic deletions and recurrent splicing events, including isoforms predicted to remove all eight BRC repeats. These splicing-mediated reversions engaged cryptic donors and were conserved across distinct genotypes, including the founder mutation c.5946delT. These findings define a predictive reversion code that governs the paths to BRCA2 functional rescue, enabling anticipation of reversion-mediated PARPi resistance and interpretation of secondary BRCA2 variants in resistant tumors.","rel_num_authors":7,"rel_authors":[{"author_name":"Anna G Horacek","author_inst":"Department of Molecular and Cell Biology, University of California, Berkeley"},{"author_name":"Frances L Kueper","author_inst":"Department of Molecular and Cell Biology, University of California, Berkeley"},{"author_name":"Robert Lu","author_inst":"Department of Molecular and Cell Biology, University of California, Berkeley"},{"author_name":"Isabella P Lamont","author_inst":"Department of Molecular and Cell Biology, University of California, Berkeley"},{"author_name":"Stella Tran","author_inst":"Department of Molecular and Cell Biology, University of California, Berkeley"},{"author_name":"Hanqin Li","author_inst":"Innovative Genomic Institute, University of California, Berkeley"},{"author_name":"Dirk Hockemeyer","author_inst":"Department of Molecular and Cell Biology, University of California, Berkeley"}],"rel_date":"2026-05-02","rel_site":"biorxiv"},{"rel_title":"Integrin-independent Tie2 activation using de novo designed proteins","rel_doi":"10.64898\/2026.05.01.718274","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.01.718274","rel_abs":"The Angiopoietin-Tie2 pathway is a key regulator of vascular stability, but therapeutic exploitation has been limited by the poor developability of Angiopoietin-1 (Ang1), and there are key unresolved mechanistic questions. Ang1 binds both Tie2 and 5{beta}1 integrin, and the role of the 5{beta}1 interaction in signaling has been unclear. We used RFdiffusion to design a stable, high-affinity Tie2 minibinder that has no affinity for 5{beta}1. The binder is a selective antagonist in monomeric form, and a potent agonist when assembled into an octavalent architecture (H8mb) which drives Tie2 clustering. H8mb signals as potently as Ang1, indicating that integrin engagement is not required for Tie2 activation. However, the duration of signaling is reduced, and internalization of H8mb-Tie2 complexes is more rapid, suggesting that integrin may function as a co-receptor for Ang1 that prolongs signaling by extending the lifetime of the receptor ligand complex on the cell surface. In a mouse model of acute respiratory distress syndrome (ARDS), H8mb markedly improved survival. These results demonstrate that de novo designed receptor binders can enable dissection of co-receptor control of signaling dynamics, and the more stable and manufacturable H8mb provides routes to more developable therapeutic candidates.","rel_num_authors":19,"rel_authors":[{"author_name":"Clara McCurdy","author_inst":"University of Washington"},{"author_name":"Yan Ting Zhao","author_inst":"University of Washington"},{"author_name":"Saurav Kumar","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Brian Coventry","author_inst":"University of Washington"},{"author_name":"Anne Pink","author_inst":"Translational Cancer Medicine Program, University of Helsinki"},{"author_name":"Yaoyao Fu","author_inst":"Institute for Basic Science"},{"author_name":"Phil Bohn","author_inst":"University of Washington"},{"author_name":"Siyu Zhu","author_inst":"University of Washington"},{"author_name":"Inna Goreshnik","author_inst":"University of Washington"},{"author_name":"Xinru Wang","author_inst":"University of Washington"},{"author_name":"Garrett Ruth","author_inst":"University of Washington"},{"author_name":"Rashmi Ravichandran","author_inst":"University of Washington"},{"author_name":"Julie Mathieu","author_inst":"University of Washington"},{"author_name":"Jonathan A Cooper","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Deborah   Heydenburg Fuller","author_inst":"University of Washington"},{"author_name":"Ho Min Kim","author_inst":"Korea Advanced Institute of Science and Technology"},{"author_name":"Pipsa Saharinen","author_inst":"University of Helsinki"},{"author_name":"David Baker","author_inst":"University of Washington"},{"author_name":"Hannele Ruohola-Baker","author_inst":"University of Washington"}],"rel_date":"2026-05-02","rel_site":"biorxiv"},{"rel_title":"Impact of histone N-terminal domains and linker DNA on H2A.Z deposition by yeast SWR1C","rel_doi":"10.64898\/2026.05.01.722189","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.01.722189","rel_abs":"ATP-dependent chromatin remodeling enzymes play a central role in governing the essential functions of the genome, and deficiencies in their catalytic function often lead to developmental disorders or disease. While most remodelers use the energy of ATP hydrolysis to either mobilize nucleosomes or evict histone octamers, yeast SWR1C catalyzes the ATP-dependent replacement of nucleosomal H2A\/H2B dimers with variant H2A.Z\/H2B dimers. The H2A.Z histone variant is conserved in all eukaryotes where it plays key roles in regulating gene transcription, DNA repair, and heterochromatin function. Consequently, the regulation of H2A.Z deposition by SWR1C is central to numerous genomic functions. Here, we use both quantitative fluorescence-based assays and gel-based, electrophoretic methods to dissect the roles of histone tails, histone acetylation, and linker DNA in SWR1C-mediated H2A.Z deposition in vitro. Unlike many other remodeling enzymes, we find that histone tails are largely dispensable for the catalytic activity of SWR1C, and histone acetylation by the NuA4 acetyltransferase has only a minor stimulatory impact on SWR1C activity. In contrast, we confirm previous studies that nucleosome-free, linker DNA stimulates SWR1C activity even under saturating enzyme levels. These insights provide a clearer understanding of the structural and regulatory determinants that guide H2A.Z deposition by SWR1C, offering potential new avenues to investigate its role in chromatin dynamics and genome stability.","rel_num_authors":2,"rel_authors":[{"author_name":"Yonca B Karadeniz","author_inst":"UMass Chan Medical School"},{"author_name":"Craig Peterson","author_inst":"U Mass Chan Medical School"}],"rel_date":"2026-05-02","rel_site":"biorxiv"},{"rel_title":"Combinatorial effects of gene dosage, polygenic background and environment on complex traits","rel_doi":"10.64898\/2026.04.30.26352063","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.30.26352063","rel_abs":"Complex traits arise from the combined effects of rare and common genetic variation, development and environment, but resolving their joint contributions has been limited by statistical power. Here, we meta-analyze effects of recurrent copy number variants (CNVs), polygenic scores, sex, age and medications on height and body mass index in 1,447,001 individuals across 6 biobanks and clinical cohorts. CNVs show largely mirror dose-dependent effects of deletions and duplications on both traits, but a subset of loci exhibit asymmetric dose-responses on adult height, consistent with buffering of one allele but not the other. Polygenic background and medications combine with CNVs in ways broadly consistent with additivity. However, detailed analyses of loci at 16p11.2 and 22q11.2 reveal context-dependent effects that vary across development, physiology and sex. At 22q11.2, the net effect of a CNV reflects opposing and reinforcing contributions of multiple genes, providing a potential mechanism for buffering of dosage effects. These results indicate that genetic effects follow additive patterns in aggregate, while context-dependent deviations are widespread for specific loci.","rel_num_authors":55,"rel_authors":[{"author_name":"Molly F. Sacks","author_inst":"University of California San Diego"},{"author_name":"Marieke Klein","author_inst":"Radboud University Medical Center"},{"author_name":"Tim Bigdeli","author_inst":"SUNY Downstate Health Sciences University"},{"author_name":"Mart Kals","author_inst":"University of Tartu"},{"author_name":"Matthew Oetjens","author_inst":"Geisinger College of Health Sciences"},{"author_name":"Florian Benetiere","author_inst":"Universite de Montreal"},{"author_name":"Jacquelyn Johnson","author_inst":"University of California San Diego"},{"author_name":"Adam Maihofer","author_inst":"University of California San Diego"},{"author_name":"Margit Noukas","author_inst":"University of Tartu"},{"author_name":"Michael Francis","author_inst":"VA Boston Healthcare System"},{"author_name":"Bryan Gorman","author_inst":"VA Boston Healthcare System"},{"author_name":"Iskander Said","author_inst":"VA Boston Healthcare System"},{"author_name":"Giulio Genovese","author_inst":"Broad Institute of Harvard and MIT"},{"author_name":"Georgios Voloudakis","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Kyriacos Markianos","author_inst":"VA Boston Healthcare System"},{"author_name":"Murray Stein","author_inst":"University of California San Diego"},{"author_name":"Joel Gelernter","author_inst":"University of California San Diego"},{"author_name":"David H. Ledbetter","author_inst":"Florida State University College of Medicine"},{"author_name":"Caroline M. Nievergelt","author_inst":"University of California San Diego"},{"author_name":"Christa Lese Martin","author_inst":"Geisinger College of Health Sciences"},{"author_name":"Vincent-Raphael Bourque","author_inst":"Universite de Montreal"},{"author_name":"Omar Shanta","author_inst":"University of California San Diego"},{"author_name":"Jeffrey R. MacDonald","author_inst":"The Hospital for Sick Children"},{"author_name":"Bhooma Thiruvahindrapuram","author_inst":"The Hospital for Sick Children"},{"author_name":"Mamad Ahangari","author_inst":"University of California San Diego"},{"author_name":"Anjali Srinivasan","author_inst":"University of California San Diego"},{"author_name":"James Guevara","author_inst":"University of California San Diego"},{"author_name":"Jessica H. Hall","author_inst":"Cardiff University"},{"author_name":"Josephine E. Haddon","author_inst":"Cardiff University"},{"author_name":"Claudia Vingerhoets","author_inst":"Maastricht University"},{"author_name":"David Linden","author_inst":"Maastricht University"},{"author_name":"Mieke M. van Haelst","author_inst":"University of Amsterdam"},{"author_name":"Marianne B. M. van den Bree","author_inst":"Cardiff University"},{"author_name":"Carrie E. Bearden","author_inst":"University of California Los Angeles"},{"author_name":"Raquel E. Gur","author_inst":"University of Pennsylvania"},{"author_name":"T. Blaine Crowley","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Daniel E. McGinn","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Beverly S. Emanuel","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Elaine H. Zackai","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Ann Swillen","author_inst":"KU Leuven"},{"author_name":"Therese van Amelsvoort","author_inst":"Maastrict University"},{"author_name":"Jacob Vorstman","author_inst":"The Hospital for Sick Children"},{"author_name":"Anne S. Bassett","author_inst":"University of Toronto"},{"author_name":"Donna M. MacDonald-McGinn","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Panos Roussos","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Mihaela Aslan","author_inst":"Veterans Affairs Connecticut Healthcare System"},{"author_name":"Philip D. Harvey","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"- Million Veteran Program","author_inst":"-"},{"author_name":"- Estonian Biobank Research Team","author_inst":"-"},{"author_name":"- Genes to Mental Health Consortium","author_inst":"-"},{"author_name":"Sebastien Jacquemont","author_inst":"Centre Hospitalier Universitaire Sainte-Justine Research Center"},{"author_name":"Saiju Pyarajan","author_inst":"VA Boston Healthcare System"},{"author_name":"Kelli Lehto","author_inst":"University of Tartu"},{"author_name":"Peter M. Visscher","author_inst":"University of Oxford"},{"author_name":"Jonathan Sebat","author_inst":"University of California San Diego"}],"rel_date":"2026-05-01","rel_site":"medrxiv"},{"rel_title":"Machine Learning-Assisted Feature Selection Identifies the Joint Association of Body Mass Index and Periaortic Adipose Tissue as a Risk Factor for Aortic Dissection: A Multicenter Retrospective Study","rel_doi":"10.64898\/2026.04.29.26352087","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.29.26352087","rel_abs":"BACKGROUND: Aortic dissection (AD) is a life-threatening emergency with high mortality. Although elevated body mass index (BMI) is associated with both AD incidence and mortality, the underlying mechanisms remain unclear. Periaortic adipose tissue (PAAT) increases with BMI, and the PAAT of AD shows marked inflammatory infiltration, suggesting PAAT-driven inflammation may contribute to the development of AD. However, no direct evidence links BMI and PAAT to AD. To further elucidate the obesity-inflammation-AD relationship, we aim to quantify the contributions of BMI, PAAT, and their derived indices to the risk of AD. METHODS: This retrospective multicenter study (June-November 2025) quantified PAAT around the descending thoracic aorta with CT angiography (CTA). Logistic regression analyses were performed to identify AD risk factors. Based on the Boruta algorithm (a machine learning feature selection method) and ROC curve analysis, the variable importance for AD risk was assessed. The dose?response relationship between BMI?Volume-derived metric (BMV) and AD risk was further characterized by quartile stratification and restricted cubic spline (RCS). RESULTS: This study enrolled 376 consecutive participants. After adjusting for potential confounders, BMI, smoking, systolic blood pressure (SBP), diabetes mellitus (DM), TC\/HDLC, ApoE, PAAT volume (Volume), PAAT fat attenuation index (FAI), and BMV were identified as independent predictors of AD. Volume was the strongest AD predictor with the highest Z-score. Compared with BMI [AUC 0.627, 95% confidence interval (CI): 0.569?0.687] and Volume (AUC 0.716, 95% CI: 0.662?0.772), BMV showed better discriminatory performance (AUC 0.726, 95% CI: 0.673?0.778). RCS showed an approximately linear positive association between BMV and AD risk (P-overall < 0.001, P-non-linear = 0.09). CONCLUSIONS: In this retrospective multicenter study, BMV, a composite measure integrating systemic and periaortic adipose tissue factor, showed a positive association with AD risk, and improved predictive performance beyond BMI, indicating incremental predictive value, pending external validation.","rel_num_authors":16,"rel_authors":[{"author_name":"Shuangjing Wang","author_inst":"Department of Vascular Surgery, Zhongshan Hospital, Fudan University"},{"author_name":"Heyue Jia","author_inst":"Chinese PLA General Hospital"},{"author_name":"Pengfei Yuan","author_inst":"Chinese PLA General Hospital"},{"author_name":"Luxia Ren","author_inst":"Chinese PLA General Hospital"},{"author_name":"Mingwei Wu","author_inst":"Changhai Hospital"},{"author_name":"HaoNan Zhang","author_inst":"Boea Wisdom (Hangzhou) Network Technology Co., Ltd"},{"author_name":"Peidong Qian","author_inst":"Department of Simulation Science and Technology, Boea Wisdom (Hangzhou) Network Technology Co., Ltd"},{"author_name":"Huan Luo","author_inst":"Boea Wisdom (Hangzhou) Network Technology Co., Ltd."},{"author_name":"Yuanming Luo","author_inst":"The University of Iowa, Department of Mechanical Engineering"},{"author_name":"ZeChen Guan","author_inst":"Zhongshan Hospital, Fudan University"},{"author_name":"Kai Hou","author_inst":"Department of Radiology, Zhongshan Hospital Fudan University"},{"author_name":"Min Zhou","author_inst":"Department of Vascular Surgery, Zhongshan Hospital, Fudan University"},{"author_name":"Chengkai Hu","author_inst":"Zhongshan Hospital Fudan University"},{"author_name":"Jiang Xiong","author_inst":"Chinese PLA General Hospital"},{"author_name":"Lixin Wang","author_inst":"Zhongshan Hospital Fudan University"},{"author_name":"Weiguo Fu","author_inst":"Zhongshan Hospital, Fudan University"}],"rel_date":"2026-05-01","rel_site":"medrxiv"},{"rel_title":"In-Context Learning with Large Language Models for Scalable Glycemic Index Assignment to Food Composition Databases: Development, Validation, and Reproducibility","rel_doi":"10.64898\/2026.04.23.26351292","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.23.26351292","rel_abs":"Assigning glycemic index (GI) values to food composition databases is a critical bottleneck in nutritional epidemiology. We developed an in-context learning approach using large language models (LLMs), in which a structured knowledge system (termed a skill) loads GI reference databases (~11,000 entries), expert decision rules, and error-correction heuristics into the model's context window (~300,000 tokens). The LLM performs GI assignments without scripted logic, functioning simultaneously as a semantic matching engine, numerical reasoning system, and expert curator. We validated this approach in two experiments. In Validation Study 1, the skill predicted the expert-curated US National GI Database (9,428 foods) using only European reference data, achieving within +\/- 10 agreement of 73.7% without manual review - compared with 31.3% retention of previously published cosine-similarity approach. In Validation Study 2, the skill was augmented with US GIDB and applied to 1,157 European food descriptions classified using the EFSA FoodEx2 system, achieving ICC = 0.79 with the expert (weighted k = 0.65; triplicate ICC = 0.88). We then applied the skill prospectively to extend US dietary GI and GL surveillance to two additional NHANES cycles (2019-2023), identifying a continued decline in energy-adjusted glycemic load. Reproducibility was assessed through triplicate runs (temperature = 0, pinned model version). The skill architecture is described in sufficient detail to inform future applications of in-context learning for nutritional database construction.","rel_num_authors":5,"rel_authors":[{"author_name":"Karen A. Della Corte","author_inst":"Brigham Young University"},{"author_name":"Joshua L. Ebbert","author_inst":"Brigham Young University"},{"author_name":"Jennie Brand-Miller","author_inst":"School of Life and Environmental Sciences and Charles Perkins Centre, University of Sydney, Sydney, Australia"},{"author_name":"Fiona Atkinson","author_inst":"School of Life and Environmental Sciences and Charles Perkins Centre, University of Sydney, Sydney, Australia"},{"author_name":"Dennis Della Corte","author_inst":"Brigham Young University, Provo, Utah"}],"rel_date":"2026-05-01","rel_site":"medrxiv"},{"rel_title":"PREDIGT Trial: Piloting an Unsupervised, Home-Based Toolkit to Screen for Parkinson Disease","rel_doi":"10.64898\/2026.04.30.26352172","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.30.26352172","rel_abs":"Background: Effective screening for Parkinson disease (PD) is important for both symptomatic treatment and recruitment into intervention trials. We recently developed a toolkit to quantify PD risk. Here, we examined the PREDIGT model's diagnostic performance when deployed at home. Methods: We contacted 613 subjects following outpatient clinic encounters. Between 2022-2024, 305 participants (range, 40-85 years) were recruited: 93 with typical PD; 66 had other neurological diseases (OND); 146 were neurologically healthy. Two versions of the toolkit were completed: First, an original, 69-item-long questionnaire paired with a 40-scent smell test; thereafter, a simplified, 11-item-long questionnaire and a newly developed, 8-scent smell test. PREDIGT summary scores were calculated for each subject to examine diagnostic classifications. Area-under-the-ROC-curve, sensitivity, specificity, and likelihood ratios were used to evaluate performances and to determine clinically relevant thresholds. Results: In both versions, PD patients had higher questionnaire scores and lower smell test scores than neurologically healthy controls (p<0.001); scores for OND subjects ranked at intermediate levels. The simplified questionnaire outperformed the original version in diagnostic accuracy. The abbreviated smell test performed as well as the 40-item version in identifying hyposmia. At a value of 22.94 (range 0-100) for the threshold that separates PD subjects from other participants, the simplified PREDIGT summary score showed a sensitivity of 0.98, a specificity of 0.83, and revealed positive and negative likelihood ratios of 5.88 and 0.02, respectively. Interpretation: Our study reveals that unsupervised screening for typical PD can be effectively carried out at home using an 11-item questionnaire and 8-scent smell test.","rel_num_authors":10,"rel_authors":[{"author_name":"Juan Li","author_inst":"Ottawa Hospital Research Institute"},{"author_name":"Kelsey Grimes","author_inst":"Ottawa Hospital Research Institute"},{"author_name":"Joseph Saade","author_inst":"Ottawa Hospital Research Institute"},{"author_name":"David Lewis","author_inst":"Parkinson Research Consortium"},{"author_name":"Julianna J Tomlinson","author_inst":"Ottawa Hospital Research Institute"},{"author_name":"Andrew Frank","author_inst":"Bruyere Research Institute"},{"author_name":"Timothy Ramsay","author_inst":"University of Ottawa"},{"author_name":"Natalina Salmaso","author_inst":"Carleton University"},{"author_name":"Douglas Manuel","author_inst":"Ottawa Hospital Research Institute"},{"author_name":"Michael G Schlossmacher","author_inst":"Ottawa Hospital Research Institute"}],"rel_date":"2026-05-01","rel_site":"medrxiv"},{"rel_title":"PREDIGT Trial: Piloting an Unsupervised, Home-Based Toolkit to Screen for Parkinson Disease","rel_doi":"10.64898\/2026.04.30.26352172","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.30.26352172","rel_abs":"Background: Effective screening for Parkinson disease (PD) is important for both symptomatic treatment and recruitment into intervention trials. We recently developed a toolkit to quantify PD risk. Here, we examined the PREDIGT model's diagnostic performance when deployed at home. Methods: We contacted 613 subjects following outpatient clinic encounters. Between 2022-2024, 305 participants (range, 40-85 years) were recruited: 93 with typical PD; 66 had other neurological diseases (OND); 146 were neurologically healthy. Two versions of the toolkit were completed: First, an original, 69-item-long questionnaire paired with a 40-scent smell test; thereafter, a simplified, 11-item-long questionnaire and a newly developed, 8-scent smell test. PREDIGT summary scores were calculated for each subject to examine diagnostic classifications. Area-under-the-ROC-curve, sensitivity, specificity, and likelihood ratios were used to evaluate performances and to determine clinically relevant thresholds. Results: In both versions, PD patients had higher questionnaire scores and lower smell test scores than neurologically healthy controls (p<0.001); scores for OND subjects ranked at intermediate levels. The simplified questionnaire outperformed the original version in diagnostic accuracy. The abbreviated smell test performed as well as the 40-item version in identifying hyposmia. At a value of 22.94 (range 0-100) for the threshold that separates PD subjects from other participants, the simplified PREDIGT summary score showed a sensitivity of 0.98, a specificity of 0.83, and revealed positive and negative likelihood ratios of 5.88 and 0.02, respectively. Interpretation: Our study reveals that unsupervised screening for typical PD can be effectively carried out at home using an 11-item questionnaire and 8-scent smell test.","rel_num_authors":10,"rel_authors":[{"author_name":"Juan Li","author_inst":"Ottawa Hospital Research Institute"},{"author_name":"Kelsey Grimes","author_inst":"Ottawa Hospital Research Institute"},{"author_name":"Joseph Saade","author_inst":"Ottawa Hospital Research Institute"},{"author_name":"David Lewis","author_inst":"Parkinson Research Consortium"},{"author_name":"Julianna J Tomlinson","author_inst":"Ottawa Hospital Research Institute"},{"author_name":"Andrew Frank","author_inst":"Bruyere Research Institute"},{"author_name":"Timothy Ramsay","author_inst":"University of Ottawa"},{"author_name":"Natalina Salmaso","author_inst":"Carleton University"},{"author_name":"Douglas Manuel","author_inst":"Ottawa Hospital Research Institute"},{"author_name":"Michael G Schlossmacher","author_inst":"Ottawa Hospital Research Institute"}],"rel_date":"2026-05-01","rel_site":"medrxiv"},{"rel_title":"Effects of a social network modification of a community-based family planning intervention on contraceptive use among adolescent wives in Niger: a cluster randomized controlled trial","rel_doi":"10.64898\/2026.04.29.26352112","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.29.26352112","rel_abs":"Niger has the world's highest adolescent fertility rate. Social network (SN) approaches to family planning may improve intervention impact through diffusion beyond direct beneficiaries. We tested a social network modification of a community-based family planning intervention to increase contraceptive use compared to standard implementation and control.Three-arm cluster-randomized trial in 56 rural villages in Maradi, Niger. Eligible participants were adolescent wives (AW) aged 15-19 with 0-1 children and their husbands. Villages were randomized using covariate-constrained randomization (Minirand): standard Kulawa (100% coverage), SN modification (50% coverage pairing AW-mother-in-law dyads with adopt-a-friend diffusion), or control. Interventions were delivered over 12 months. Blinding of participants and implementers was infeasible; analysts were blinded. Primary outcome was current contraceptive use assessed at endline and analyzed using intention-to-treat difference-in-differences logistic regression adjusting for clustering; no missing data were imputed. ClinicalTrials.gov NCT05777473; trial closed to enrollment.From May 1 to September 30, 2022, 1,538 female AW were enrolled (517 control, 532 Kulawa, 489 Kulawa SN); 1,396 (90.8%) completed endline (May-August 2024). Compared to control, the SN arm significantly increased contraceptive use (AOR 2.36, 95% CI 1.27-4.44); the standard arm showed no significant effect (AOR 1.36, 95% CI 0.76-2.41). Within SN villages, both non-participants (AOR 2.66, 95% CI 1.25-5.70) and direct participants (AOR 2.10, 95% CI 0.99-4.44) showed increased use versus control, demonstrating behavioral diffusion. No intervention-related adverse events were observed in any arm. An SN approach targeting AWs, husbands, mothers-in-law, and adopted friends achieved greater effects than standard implementation despite 50% lower coverage, with evidence of diffusion to non-participants. Leveraging social networks may improve impact of family planning programs in high-fertility settings.","rel_num_authors":6,"rel_authors":[{"author_name":"Holly Baker","author_inst":"University of California San Diego"},{"author_name":"Shweta Tomar","author_inst":"University of California San Diego"},{"author_name":"Amani Hachimou","author_inst":"Grade Africa"},{"author_name":"Kadidiatou Boubacar Moussa","author_inst":"consultant"},{"author_name":"Jennifer Gayles","author_inst":"consultant"},{"author_name":"Rebecka Lundgren","author_inst":"University of California San Diego"}],"rel_date":"2026-05-01","rel_site":"medrxiv"},{"rel_title":"Day-to-Day Circadian Phase Fluctuations Shape Sleep and Behavior in Adolescents with ADHD","rel_doi":"10.64898\/2026.04.30.26352043","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.30.26352043","rel_abs":"Sleep-wake regulation arises from the interaction between homeostatic sleep pressure and circadian timing, yet current assessments evaluate these processes independently and fail to capture their dynamic modulation by environmental pressures. This limitation is particularly relevant in adolescents with attention-deficit\/hyperactivity disorder (ADHD), who are at increased risk of circadian delay and sleep disruption. Here, we combined month-long wearable-based physiological monitoring with ecological behavioral assessments in adolescents with ADHD to characterize circadian and homeostatic processes dynamically in real-world settings. Using continuous skin temperature recordings, we derived individualized and day-specific estimates of circadian phase through hierarchical modelling, and integrated these measures with actigraphy-based sleep estimates and daily assessments of neurocognitive functioning and functional impairment. Temperature-derived circadian phase correlated with questionnaire-based chronotype but more accurately predicted sleep patterns. Delayed circadian phase was associated with later sleep onset and greater weekday-weekend variability. Importantly, circadian phase exhibited significant day-to-day fluctuations, particularly in individuals with delayed phase, reflecting interactions with environmental constraints. Sleep latency was jointly determined by homeostatic sleep pressure and day-specific circadian phase, with combined models outperforming either process alone. Crucially, both sleep deprivation and day-specific circadian misalignment independently predicted fluctuations in ADHD symptom severity, perceived stress, and neurocognitive impulsivity. In contrast, mean circadian phase alone did not explain behavioral variability. These findings demonstrate that circadian regulation is a dynamic, environmentally sensitive process rather than a fixed trait. Wearable-based estimation of circadian phase provides a scalable approach to capture these dynamics and may enable personalized interventions targeting sleep and circadian dysregulation.","rel_num_authors":6,"rel_authors":[{"author_name":"Natacha Reich","author_inst":"Developmental Imaging and Psychopathology Laboratory, University of Geneva School of medicine, Geneva, Switzerland"},{"author_name":"Andrea Imparato","author_inst":"Developmental Imaging and Psychopathology Laboratory, University of Geneva School of medicine, Geneva, Switzerland"},{"author_name":"Maude Schneider","author_inst":"Clinical Psychology Unit for Intellectual and Developmental Disabilities, Faculty of Psychology and Educational Sciences, University of Geneva, Geneva, Switzerl"},{"author_name":"Stephan Eliez","author_inst":"Developmental Imaging and Psychopathology Laboratory, University of Geneva School of medicine, Geneva, Switzerland ; Fondation P\u00f4le Autisme, Geneva, Switzerland"},{"author_name":"Christopher Graser","author_inst":"Dana-Farber Cancer Institute, Harvard University, Boston, Massachusetts, United States of America."},{"author_name":"Corrado Sandini","author_inst":"Developmental Imaging and Psychopathology Laboratory, University of Geneva School of medicine, Geneva, Switzerland ; Fondation P\u00f4le Autisme, Geneva, Switzerland"}],"rel_date":"2026-05-01","rel_site":"medrxiv"},{"rel_title":"Early-life dentine based elemental biodynamics and cord blood telomere length","rel_doi":"10.64898\/2026.04.30.26351974","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.30.26351974","rel_abs":"Background: Leukocyte telomere length (LTL) from cord blood is a marker of biological aging and long-term systemic health. Exposure to essential and toxic metals has been shown to influence LTL in a sexually dimorphic manner. However, little is known about the interplay between early-life longitudinal biodynamic patterns of these elements and cord blood LTL, as well as potential sex differences. Methods: From an ongoing longitudinal birth cohort study in Mexico City, we used available tooth samples from 231 children (129 males and 102 females) to generate 16 elemental weekly time series of direct fetal intensities from the second trimester through four to five months after birth. We analyzed the dentine growth rings using Inductively Coupled Plasma Mass Spectrometry to generate time-resolved elemental intensities. The elements included were Li, Mg, Ca, Mn, Co, Ni, Cu, Zn, As, Sr, Mo, Cd, Sn, Ba, Pb, and Bi. LTL was measured in cord blood using qPCR. We used cross-recurrence quantification analysis and entropy-complexity-based measures to generate time-resolved features that quantify the synchronization of elemental biodynamics. A stability-selection approach using five-fold cross-validation of regularized ridge regression was used for feature selection, and covariate-adjusted linear models were used to estimate associations with LTL. Findings: The biodynamic interaction of Mg-Co and Mn-Sn was identified as the most stable feature among male and female children, respectively. In males, higher vertical entropy (i.e., a measure of higher variability) of Mg-Co temporal biodynamics was associated with shorter LTL ({beta}[95%CI]: -0.9[-0.14,-0.03]; p-value<0.01), but not in females ({beta}[95%CI]:-0.02[-0.10,0.06]; p-value=0.60); whereas higher recurrence rate (i.e., a measure of higher synchronicity) of Mn-Sn temporal biodynamics was associated with longer LTL ({beta}[95%CI]: 0.09[0.02,0.16]; p-value=0.01), in females but not in males ({beta}[95%CI], 0.03[-0.04, 0.09]; p-value=0.39). Interpretation: We demonstrate that time-varying multi-elemental synchronization of early-life elemental biodynamics, a potential marker of homeostatic balance, may be associated with cord blood-based telomere length in a sexual dimorphic manner. Keywords: Metals, Telomere Aging, Elemental Biodynamics, Machine Learning, Child Health","rel_num_authors":22,"rel_authors":[{"author_name":"Bhargavi Srinath","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Rohitha Ravisekar","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Kshitij Sachdev","author_inst":"University of Iowa College of Public Health"},{"author_name":"Joseph Eggers","author_inst":"University of Iowa College of Public Health"},{"author_name":"Libni Avib Torres Olascoaga","author_inst":"National Institute of Public Health"},{"author_name":"Nia McRae","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Inessa Lopez","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Chelsea A. DeBolt","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Aderonke Akinkugbe","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Romana Ranchadiya","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Martha M Tellez-Rojo","author_inst":"National Institute of Public Health"},{"author_name":"Chris Gennings","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Robert B. Wallace","author_inst":"University of Iowa College of Public Health"},{"author_name":"Robert Wright","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Rosalind J. Wright","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Manish Arora","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Cecilia S. Alcala","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Manasi Agrawal","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Jamil M. Lane","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Maria J. Rosa","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Shoshannah I. Eggers","author_inst":"University of Iowa College of Public Health"},{"author_name":"Vishal Midya","author_inst":"Icahn School of Medicine at Mount Sinai"}],"rel_date":"2026-05-01","rel_site":"medrxiv"},{"rel_title":"Disease Risk Prediction Using Structured EHR Data: Can Generalist Large Language Models Match Specialized Clinical Foundation Models? A Comparative Evaluation with Fine-Tuning","rel_doi":"10.64898\/2026.04.24.26351503","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.24.26351503","rel_abs":"Background: Electronic health records (EHRs) with clinical decision support tools are now ubiquitous in healthcare organizations. Clinical foundation models (CFMs) pretrained on large-scale, heterogeneous structured EHR data have emerged as a powerful approach to improve predictive performance and generalizability. Meanwhile, large language models (LLMs) pretrained on broad data sources are being applied to an expanding range of healthcare tasks. However, it remains unclear whether generalist LLMs can match specialized CFMs for disease risk prediction using structured clinical data. Methods: We compared CFMs (Med-BERT, CLMBR) against fine-tuned generalist LLMs (Mistral, LLaMA-2\/3\/3.1), a clinical LLM (Me-LLaMA), and LLM-generated embeddings paired with simple classifiers (using DeepSeek, Qwen3, and GPT-OSS) on two disease risk prediction tasks: heart failure risk among diabetic patients (DHF) and pancreatic cancer diagnosis (PaCa). Evaluations spanned multi-site EHR data, claims data, and an open-source single-institution benchmark (EHRSHOT). Performance was assessed using the area under the receiver operating characteristic curve (AUROC) and the area under the precision-recall curve (AUPRC). Results: On larger EHR and claims cohorts (>30,000 patients), fine-tuned CFMs outperformed fine-tuned LLMs by a small but statistically significant margin (<1% AUROC). The clinical LLM performed comparably to generalist LLMs despite being smaller. On the open-source PaCa cohort (3,810 patients, 199 cases), LLMs achieved slightly higher AUROCs that were not statistically significant (LLaMA-3.1-70B 86.1% vs. Med-BERT 85.3%, p=0.27), but CFMs achieved significantly higher AUPRC (Med-BERT 55.9% vs. LLaMA-3.1-70B 41.1%, p=0.001). Notably, LLM-generated trajectory embeddings paired with logistic regression or a simple MLP, without any LLM fine-tuning, achieved the best overall performance, with AUROC exceeding 90% (Qwen3) and AUPRC reaching 66% (GPT-OSS 20B). Conclusion: LLM-generated embeddings with lightweight classifiers outperformed both fine-tuned CFMs and fine-tuned LLMs on AUROC and AUPRC. While these results demonstrate the potential of generalist models to match or surpass specialized CFMs, their substantially greater computational cost and variable AUPRC performance in the fine-tuning setting warrant caution. We provide a reproducible evaluation framework and codebase to support continued benchmarking.","rel_num_authors":8,"rel_authors":[{"author_name":"Bingyu Mao","author_inst":"The University of Texas Health Science Center at Houston"},{"author_name":"Made K. Prasadha","author_inst":"The University of Texas Health Science Center at Houston"},{"author_name":"Ziqian Xie","author_inst":"The University of Texas Health Science Center at Houston"},{"author_name":"Jianping He","author_inst":"The University of Texas Health Science Center at Houston"},{"author_name":"Michael Ghebranious","author_inst":"The University of Texas Health Science Center at Houston"},{"author_name":"Hua Xu","author_inst":"Yale University"},{"author_name":"Degui Zhi","author_inst":"The University of Texas Health Science Center at Houston"},{"author_name":"Laila Rasmy","author_inst":"The University of Texas Health Science Center at Houston"}],"rel_date":"2026-05-01","rel_site":"medrxiv"},{"rel_title":"The Alzheimer's disease Burden in China (ABC) study: protocol for a nationwide multicentre cross-sectional and prospective cohort study","rel_doi":"10.64898\/2026.04.30.26352138","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.30.26352138","rel_abs":"Introduction: Alzheimer's disease (AD) is imposing an increasing public health and socioeconomic burden. In China, rapid population ageing is sharply increasing disease burden. Previous studies have shown that AD-related costs are mainly driven by long-term informal care. However, evidence in China remains limited by an incomplete cost framework, and insufficient consideration of caregivers' burden and indirect costs. Notably, the National Dementia Action Plan (2024-2030), issued by the Chinese government, marks a major shift to early detection and comprehensive care of AD, highlighting the urgent need for nationally representative economic evidence to support policy implementation. This study aims to evaluate the economic burden and quality of life of AD patients and their caregivers in mainland China, and is the first nationwide study to include individuals with amnestic mild cognitive impairment (aMCI), providing foundational data for future health technology assessment (HTA) of early AD interventions. Methods and analysis: Baseline characteristics will be presented and compared using t-tests or chi-square tests. Economic burden will be estimated by calculating the per capita cost and weighted national total based on provincial numbers of AD patients. Indirect costs will be assessed using locally adapted replacement cost approach and forgone wages approach. The analysis will be stratified by disease severity and age. Future burden will be projected by linking data from China Statistical Yearbook 2025 and the United Nations World Population Prospects 2024. Unmet care needs, AD-related catastrophic health expenditure (CHE), and AD dependency ratio (ADDR) will also be assessed. Ethics and dissemination: Ethics approval was obtained from the Ethics Committee of Xuanwu Hospital, Capital Medical University. The study has been registered at ClinicalTrials.gov and the Chinese Clinical Trial Registry (ChiCTR). The results from this study will be actively disseminated through research articles and conference presentations. Trial registration number: NCT05995418; ChiCTR2300074723.","rel_num_authors":9,"rel_authors":[{"author_name":"Yixuan Wang","author_inst":"Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Department of Neurology & Innovation Center for Neurological Disorders,"},{"author_name":"Qi Qin","author_inst":"Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Department of Neurology & Innovation Center for Neurological Disorders,"},{"author_name":"Kun Yang","author_inst":"Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing, CN"},{"author_name":"Mingzhi Yu","author_inst":"Peking University Health Science Center, School of Public Health, Beijing, CN"},{"author_name":"Yao Yao","author_inst":"Peking University, School of Public Health, Beijing, CN"},{"author_name":"Chao Gong","author_inst":"Peking University School of Public Health, Beijing, 100191, CN"},{"author_name":"Jing Guo","author_inst":"Peking University Health Science Center, School of Public Health, Beijing, CN"},{"author_name":"Li Yang","author_inst":"Peking University School of Public Health, Department of Health Policy and Management, Beijing, Beijing, CN"},{"author_name":"Yi Tang","author_inst":"National Center for Neurological Disorders, Department of Neurology & Innovation Center for Neurological Disorders, Beijing, CN"}],"rel_date":"2026-05-01","rel_site":"medrxiv"},{"rel_title":"Effects of Controlled Diets High in and Free of Ultraprocessed Food on the Brain of Emerging Adults","rel_doi":"10.64898\/2026.04.30.26352056","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.30.26352056","rel_abs":"Objective: The average American consumes 55% of their daily energy from ultraprocessed foods (UPF) created through industrial processes and additives not used at home. We investigated if a high-UPF diet alters brain response to milkshake compared with a diet free-from UPF (NonUPF) in emerging adults, who are in a critical period for brain development and typically consume high amounts of UPF. Methods: In a randomized controlled crossover trial participants aged 18-25 completed two, 2-week controlled feeding periods including a UPF (81% UPF) and nonUPF (0% UPF) diet. Before and after each diet intervention participants consumed milkshake concomitant with functional magnetic resonance imaging. Results: In the entire cohort, there were no differences between diet conditions in brain response. An exploratory analysis revealed orbitofrontal cortex (OFC) response to milkshake decreased after the UPF diet and increased following the NonUPF diet in adolescents (18-21 years) but not young adults (22-25 years). Habitual UPF intake (gs) was positively associated with OFC response to milkshake independent of diet intervention in all participants. Conclusions: An acute UPF dietary intervention may only alter brain response in adolescents. Further work is needed to determine potential vulnerability of adolescents to changes in dietary UPF on brain response to rewards.","rel_num_authors":15,"rel_authors":[{"author_name":"Emma Leslie","author_inst":"Fralin Biomedical Research Institute, Virginia Tech Carilion, Virginia Tech"},{"author_name":"Maria Rego","author_inst":"Department of Human Nutrition, Foods, and Exercise, Virginia Tech"},{"author_name":"Monica L Ahrens","author_inst":"Department of Internal Medicine, Division of Medical Informatics, University of Kansas Medical Center"},{"author_name":"Wenjing Yu","author_inst":"Department of Human Nutrition, Foods, and Exercise, Virginia Tech"},{"author_name":"Mary Elizabeth Baugh","author_inst":"Fralin Biomedical Research Institute, Virginia Tech Carilion, Virginia Tech"},{"author_name":"Anastasia Groccia","author_inst":"School of Neuroscience, Virginia Tech"},{"author_name":"Rhianna Sullivan","author_inst":"School of Neuroscience, Virginia Tech"},{"author_name":"Han Lee","author_inst":"Fralin Biomedical Research Institute, Virginia Tech Carilion, Virginia Tech"},{"author_name":"Ryann Kolb","author_inst":"Fralin Biomedical Research Institute, Virginia Tech Carilion, Virginia Tech"},{"author_name":"Delbert L Herald III","author_inst":"Fralin Biomedical Research Institute, Virginia Tech Carilion, Virginia Tech"},{"author_name":"Valisa E Hedrick","author_inst":"Department of Human Nutrition, Foods, and Exercise, Virginia Tech"},{"author_name":"Kevin P Davy","author_inst":"Department of Human Nutrition, Foods, and Exercise, Virginia Tech"},{"author_name":"Benjamin Katz","author_inst":"Department of Human Development and Family Science, Virginia Tech"},{"author_name":"Brenda M Davy","author_inst":"Department of Human Nutrition, Foods, and Exercise, Virginia Tech"},{"author_name":"Alexandra Gold DiFeliceantonio","author_inst":"Fralin Biomedical Research Institute, Virginia Tech Carilion, Virginia Tech"}],"rel_date":"2026-05-01","rel_site":"medrxiv"},{"rel_title":"Global Socioeconomic Context and Brain Ageing in Epilepsy: an ENIGMA-Epilepsy study","rel_doi":"10.64898\/2026.04.30.26352177","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.30.26352177","rel_abs":"Introduction: Brain structural differences consistent with an older-appearing brain have been reported in people with epilepsy, but the extent to which these differences reflect clinical characteristics vs broader socioeconomic context is unclear. We investigated whether country-level socioeconomic factors are associated with neuroanatomical differences in adults with epilepsy using MRI-based age prediction, along with epilepsy subtype, sex, and clinical factors. Methods: Structural MRI and clinical data were collected from 26 epilepsy centres across 12 countries in the Americas, Australia, Europe, Asia and Africa. MRI-based age estimates were estimated using a previously developed prediction model trained on 29,175 healthy subjects. Brain predicted age difference (BrainPAD) was calculated as the difference between MRI-predicted brain age and chronological age. National gross domestic product (GDP) per capita and income inequality (Gini index) were obtained from the World Bank. Associations between BrainPAD and epilepsy subtype (temporal lobe epilepsy, extratemporal epilepsy, and genetic generalised epilepsy), national socioeconomic context (GDP per capita and Gini index), age and sex were assessed using regression models. Results: We analyzed 2,109 individuals with epilepsy and 1,041 healthy non-epilepsy controls (57% female; median age = 35; range 17-83). BrainPAD was higher in epilepsy than controls (4.2 years, SE 0.4; t=10.6), with increases ranging from 2.5 to 6 years across subtypes. Male sex was associated with 1 year higher BrainPAD relative to females (SE 0.33, t=3.12). There were no main effects of GDP or Gini index; however, significant interactions between were observed. The effect of epilepsy on BrainPAD was greater in countries with lower GDP per capita (t=-2.74) and higher income inequality (t=2.72). Conclusions: Clinical factors and socioeconomic context both influence brain structural ageing in epilepsy. These findings highlight the importance of geographic and economic diversity in neuroimaging research and underscore the relevance of global socioeconomic context when interpreting brain health measures.","rel_num_authors":95,"rel_authors":[{"author_name":"Heath R Pardoe","author_inst":"Florey Institute of Neuroscience and Mental Health"},{"author_name":"Orrin Devinsky","author_inst":"Department of Neurology, NYU Grossman School of Medicine"},{"author_name":"Jemima Robson","author_inst":"Florey Institute of Neuroscience and Mental Health"},{"author_name":"Molly Ireland","author_inst":"Florey Institute of Neuroscience and Mental Health"},{"author_name":"Julie Absil","author_inst":"HUB Hopital Erasme - Radiology - MRI Unit"},{"author_name":"Andre Altmann","author_inst":"UCL Hawkes Insititute, Department of Medical Physics and Biomedical Engineering, UCL"},{"author_name":"Marina KM Alvim","author_inst":"Neuroimaging Laboratory, Department of Neurology, University of Campinas-UNICAMP"},{"author_name":"Donatello Arienzo","author_inst":"Department of Radiation Medicine and Applied Sciences and Psychiatry, UCSD"},{"author_name":"Alice Ballerini","author_inst":"Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia"},{"author_name":"Elisa Barbi","author_inst":"Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS"},{"author_name":"Emanuele Bartolini","author_inst":"Department of Developmental Neurosciences, IRCCS Foundation Stella Maris"},{"author_name":"Tobias Bauer","author_inst":"Department of Neuroradiology, University Hospital Bonn"},{"author_name":"Andrea Bernasconi","author_inst":"Department of Neurology and Neurosurgery, McGill University"},{"author_name":"Neda Bernasconi","author_inst":"Department of Neurology and Neurosurgery, McGill University"},{"author_name":"Boris Bernhardt","author_inst":"Department of Neurology and Neurosurgery, McGill University"},{"author_name":"Karen Blackmon","author_inst":"Department of Psychiatry, Geisel School of Medicine at Dartmouth"},{"author_name":"Paolo Bonanni","author_inst":"Scientific Institute IRCCS E.Medea, Epilepsy and Clinical Neurophysiology Unit"},{"author_name":"Leonardo Bonilha","author_inst":"Department of Neurology, University of South Carolina School of Medicine"},{"author_name":"Paolo Bosco","author_inst":"IRCCS Stella Maris Foundation"},{"author_name":"Jacob Bunyamin","author_inst":"Department of Neuroscience, The School of Translational Medicine, Alfred Health, Monash University"},{"author_name":"Maria Eugenia Caligiuri","author_inst":"Institute of Neurology, Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro"},{"author_name":"Fernando Cendes","author_inst":"Neuroimaging Laboratory, Department of Neurology, University of Campinas-UNICAMP"},{"author_name":"Raphael Christin","author_inst":"Department of Neurology, University California San Francisco"},{"author_name":"Luis Concha","author_inst":"Institute of Neurobiology, Universidad Nacional Autonoma de Mexico"},{"author_name":"Merran R Courtney","author_inst":"Department of Neuroscience, The School of Translational Medicine, Alfred Health, Monash University"},{"author_name":"Raul R Cruces","author_inst":"McConnel Brain Imaging Center, Montreal Neurological Institute"},{"author_name":"Alberto Danieli","author_inst":"Epilepsy and Clinical Neuropshysiology Unit, Scientific Institute IRCCS E. Medea"},{"author_name":"Kathryn A Davis","author_inst":"Department of Neurology, Perelman School of Medicine, University of Pennsylvania"},{"author_name":"Chantal Depondt","author_inst":"Department of Neurology, Erasme Hospital, Hopital Universitaire de Bruxelles, Universite Libre de Bruxelles"},{"author_name":"Patricia Dugan","author_inst":"Department of Neurology, NYU Grossman School of Medicine"},{"author_name":"Gian Marco Duma","author_inst":"Scientific Institute IRCCS E.Medea, Epilepsy and Clinical Neurophysiology Unit"},{"author_name":"John S Duncan","author_inst":"Research Department of Epilepsy, UCL Queen Square Institute of Neurology, UCL"},{"author_name":"Jerome Engel","author_inst":"Department of Neurology, David Geffen School of Medicine at UCLA"},{"author_name":"Carolina Ferreira Atuesta","author_inst":"Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich"},{"author_name":"Niels KN Focke","author_inst":"Department of Neurology, Medical University Center Gottingen"},{"author_name":"Francesco Fortunato","author_inst":"Institute of Neurology, Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro"},{"author_name":"Cesare Gagliardo","author_inst":"Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), University of Palermo"},{"author_name":"Marian Galovic","author_inst":"Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich"},{"author_name":"Antonio Gambardella","author_inst":"Institute of Neurology, Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro"},{"author_name":"Taha Gholipour","author_inst":"Department of Neurosciences, University of California San Diego"},{"author_name":"Ezequiel Gleichgerrcht","author_inst":"Department of Neurology, Emory University"},{"author_name":"Renzo Guerrini","author_inst":"Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS"},{"author_name":"MV Gule","author_inst":"Neuroscience Institute, Department of Psychiatry and Mental Health, University of Cape Town"},{"author_name":"Ev-Christin Heide","author_inst":"Department of Neurology, Medical University Center Gottingen"},{"author_name":"Sara Inati","author_inst":"National Institute of Neurological Disorders and Stroke Intramural Research Program"},{"author_name":"Victoria Ives-Deliperi","author_inst":"Neuroscience Institute, Department of Psychiatry and Mental Health, University of Cape Town"},{"author_name":"Graeme D Jackson","author_inst":"Florey Institute of Neuroscience and Mental Health, The Univeristy of Melbourne"},{"author_name":"Sarah Jacobs","author_inst":"Neuroscience Institute, Department of Psychiatry and Mental Health, University of Cape Town"},{"author_name":"Neda Jahanshad","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California"},{"author_name":"Jonathan K Kleen","author_inst":"Department of Neurology, University of California San Francisco"},{"author_name":"Raviteja Kotikalapudi","author_inst":"Department of Clinical Neurophysiology, University Hospital Gottingen"},{"author_name":"Mohamad Zakaria Koubeissi","author_inst":"Department of Neurology and Rehabilitation Medicine, George Washington University"},{"author_name":"Angelo Labate","author_inst":"Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), University of Palermo"},{"author_name":"Sara Larivere","author_inst":"Department of medical imaging and radiation sciences, Universite de Sherbrooke"},{"author_name":"Matteo Lenge","author_inst":"Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS"},{"author_name":"Helena Martins","author_inst":"University College London Queen Square Institute of Neurology"},{"author_name":"Mario Mascalchi","author_inst":"Department of Clinical and Experimental Medical Sciences, University of Florence"},{"author_name":"Stefano Meletti","author_inst":"Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia"},{"author_name":"Patrick B Moloney","author_inst":"Research Department of Epilepsy, UCL Queen Square Institute of Neurology, UCL"},{"author_name":"Terence J O'Brien","author_inst":"Department of Neuroscience, The School of Translational Medicine, Alfred Health, Monash University"},{"author_name":"Conor Owens-Walton","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California"},{"author_name":"Costanza Parodi","author_inst":"Neuroradiology Unit, IRCCS Istituto Giannina Gaslini"},{"author_name":"Ev-Christin Poelstra","author_inst":"Department of Neurology, Medical University Center Gottingen"},{"author_name":"Antonella Riva","author_inst":"Department of Neurosciences Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa"},{"author_name":"Rebecca W Roth","author_inst":"Department of Neurology, Emory University"},{"author_name":"Jessica Royer","author_inst":"McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University"},{"author_name":"Theodor BD Ruber","author_inst":"Department of Neuroradiology, University Hospital Bonn"},{"author_name":"Luca Saba","author_inst":"Department of Radiology, University of Cagliari"},{"author_name":"Ilaria Sammarra","author_inst":"Institute of Neurology, Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro"},{"author_name":"Lucas Scardua-Silva","author_inst":"Neuroimaging Laboratory, Department of Neurology, University of Campinas-UNICAMP"},{"author_name":"Kai Michael Schubert","author_inst":"Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich"},{"author_name":"Leigh Sepeta","author_inst":"Department of Neuropsychology, Children's National Hospital, The George Washington University School of Medicine"},{"author_name":"Mariasavina Severino","author_inst":"Neuroradiology Unit, IRCCS Istituto Giannina Gaslini"},{"author_name":"Ben Sinclair","author_inst":"Department of Neuroscience, The School of Translational Medicine, Alfred Health, Monash University"},{"author_name":"Nishant Sinha","author_inst":"Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania"},{"author_name":"Richard J Staba","author_inst":"Department of Neurology, David Geffen School of Medicine at UCLA"},{"author_name":"Dan J Stein","author_inst":"SAMRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry & Neuroscience Institute, University of Cape Town"},{"author_name":"Joel M Stein","author_inst":"Department of Radiology, University of Pennsylvania"},{"author_name":"Travis R Stoub","author_inst":"Department of Neurological Sciences, Rush University Medical Center"},{"author_name":"Pasquale Striano","author_inst":"IRCCS Istituto Giannina Gaslini, full member of ERN EpiCARE"},{"author_name":"Rainer Surges","author_inst":"Department of Epileptology, University Hospital Bonn"},{"author_name":"Robert Terziev","author_inst":"Charite - Universitaetsmedizin Berlin"},{"author_name":"Sophia I Thomopoulos","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California"},{"author_name":"Manuela Tondelli","author_inst":"Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia"},{"author_name":"Domenico Tortora","author_inst":"Neuroradiology Unit IRCCS Istituto Giannina Gaslini"},{"author_name":"Sebastiano Vacca","author_inst":"Center for Neurosciences, The Feinstein Institutes for Medical Research"},{"author_name":"Anna Elisabetta Vaudano","author_inst":"Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia"},{"author_name":"Lucy Vivash","author_inst":"Department of Neuroscience, The School of Translational Medicine, Alfred Health, Monash University"},{"author_name":"Kimberley C Williams","author_inst":"Neuroscience Institute, Department of Psychiatry and Mental Health, University of Cape Town"},{"author_name":"Clarissa L Yasuda","author_inst":"State University of Campinas"},{"author_name":"Zhiqiang Zhang","author_inst":"Jinling Hospital, Nanjing University School of Medicine"},{"author_name":"Erik Kaestner","author_inst":"Department of Radiation Medicine and Applied Sciences and Psychiatry, UCSD"},{"author_name":"Paul M Thompson","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California"},{"author_name":"Sanjay M Sisodiya","author_inst":"Research Department of Epilepsy, UCL Queen Square Institute of Neurology, UCL"},{"author_name":"Carrie R McDonald","author_inst":"Department of Radiation Medicine and Applied Sciences and Psychiatry, UCSD"}],"rel_date":"2026-05-01","rel_site":"medrxiv"},{"rel_title":"Global Socioeconomic Context and Brain Ageing in Epilepsy: an ENIGMA-Epilepsy study","rel_doi":"10.64898\/2026.04.30.26352177","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.30.26352177","rel_abs":"Introduction: Brain structural differences consistent with an older-appearing brain have been reported in people with epilepsy, but the extent to which these differences reflect clinical characteristics vs broader socioeconomic context is unclear. We investigated whether country-level socioeconomic factors are associated with neuroanatomical differences in adults with epilepsy using MRI-based age prediction, along with epilepsy subtype, sex, and clinical factors. Methods: Structural MRI and clinical data were collected from 26 epilepsy centres across 12 countries in the Americas, Australia, Europe, Asia and Africa. MRI-based age estimates were estimated using a previously developed prediction model trained on 29,175 healthy subjects. Brain predicted age difference (BrainPAD) was calculated as the difference between MRI-predicted brain age and chronological age. National gross domestic product (GDP) per capita and income inequality (Gini index) were obtained from the World Bank. Associations between BrainPAD and epilepsy subtype (temporal lobe epilepsy, extratemporal epilepsy, and genetic generalised epilepsy), national socioeconomic context (GDP per capita and Gini index), age and sex were assessed using regression models. Results: We analyzed 2,109 individuals with epilepsy and 1,041 healthy non-epilepsy controls (57% female; median age = 35; range 17-83). BrainPAD was higher in epilepsy than controls (4.2 years, SE 0.4; t=10.6), with increases ranging from 2.5 to 6 years across subtypes. Male sex was associated with 1 year higher BrainPAD relative to females (SE 0.33, t=3.12). There were no main effects of GDP or Gini index; however, significant interactions between were observed. The effect of epilepsy on BrainPAD was greater in countries with lower GDP per capita (t=-2.74) and higher income inequality (t=2.72). Conclusions: Clinical factors and socioeconomic context both influence brain structural ageing in epilepsy. These findings highlight the importance of geographic and economic diversity in neuroimaging research and underscore the relevance of global socioeconomic context when interpreting brain health measures.","rel_num_authors":95,"rel_authors":[{"author_name":"Heath R Pardoe","author_inst":"Florey Institute of Neuroscience and Mental Health"},{"author_name":"Orrin Devinsky","author_inst":"Department of Neurology, NYU Grossman School of Medicine"},{"author_name":"Jemima Robson","author_inst":"Florey Institute of Neuroscience and Mental Health"},{"author_name":"Molly Ireland","author_inst":"Florey Institute of Neuroscience and Mental Health"},{"author_name":"Julie Absil","author_inst":"HUB Hopital Erasme - Radiology - MRI Unit"},{"author_name":"Andre Altmann","author_inst":"UCL Hawkes Insititute, Department of Medical Physics and Biomedical Engineering, UCL"},{"author_name":"Marina KM Alvim","author_inst":"Neuroimaging Laboratory, Department of Neurology, University of Campinas-UNICAMP"},{"author_name":"Donatello Arienzo","author_inst":"Department of Radiation Medicine and Applied Sciences and Psychiatry, UCSD"},{"author_name":"Alice Ballerini","author_inst":"Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia"},{"author_name":"Elisa Barbi","author_inst":"Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS"},{"author_name":"Emanuele Bartolini","author_inst":"Department of Developmental Neurosciences, IRCCS Foundation Stella Maris"},{"author_name":"Tobias Bauer","author_inst":"Department of Neuroradiology, University Hospital Bonn"},{"author_name":"Andrea Bernasconi","author_inst":"Department of Neurology and Neurosurgery, McGill University"},{"author_name":"Neda Bernasconi","author_inst":"Department of Neurology and Neurosurgery, McGill University"},{"author_name":"Boris Bernhardt","author_inst":"Department of Neurology and Neurosurgery, McGill University"},{"author_name":"Karen Blackmon","author_inst":"Department of Psychiatry, Geisel School of Medicine at Dartmouth"},{"author_name":"Paolo Bonanni","author_inst":"Scientific Institute IRCCS E.Medea, Epilepsy and Clinical Neurophysiology Unit"},{"author_name":"Leonardo Bonilha","author_inst":"Department of Neurology, University of South Carolina School of Medicine"},{"author_name":"Paolo Bosco","author_inst":"IRCCS Stella Maris Foundation"},{"author_name":"Jacob Bunyamin","author_inst":"Department of Neuroscience, The School of Translational Medicine, Alfred Health, Monash University"},{"author_name":"Maria Eugenia Caligiuri","author_inst":"Institute of Neurology, Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro"},{"author_name":"Fernando Cendes","author_inst":"Neuroimaging Laboratory, Department of Neurology, University of Campinas-UNICAMP"},{"author_name":"Raphael Christin","author_inst":"Department of Neurology, University California San Francisco"},{"author_name":"Luis Concha","author_inst":"Institute of Neurobiology, Universidad Nacional Autonoma de Mexico"},{"author_name":"Merran R Courtney","author_inst":"Department of Neuroscience, The School of Translational Medicine, Alfred Health, Monash University"},{"author_name":"Raul R Cruces","author_inst":"McConnel Brain Imaging Center, Montreal Neurological Institute"},{"author_name":"Alberto Danieli","author_inst":"Epilepsy and Clinical Neuropshysiology Unit, Scientific Institute IRCCS E. Medea"},{"author_name":"Kathryn A Davis","author_inst":"Department of Neurology, Perelman School of Medicine, University of Pennsylvania"},{"author_name":"Chantal Depondt","author_inst":"Department of Neurology, Erasme Hospital, Hopital Universitaire de Bruxelles, Universite Libre de Bruxelles"},{"author_name":"Patricia Dugan","author_inst":"Department of Neurology, NYU Grossman School of Medicine"},{"author_name":"Gian Marco Duma","author_inst":"Scientific Institute IRCCS E.Medea, Epilepsy and Clinical Neurophysiology Unit"},{"author_name":"John S Duncan","author_inst":"Research Department of Epilepsy, UCL Queen Square Institute of Neurology, UCL"},{"author_name":"Jerome Engel","author_inst":"Department of Neurology, David Geffen School of Medicine at UCLA"},{"author_name":"Carolina Ferreira Atuesta","author_inst":"Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich"},{"author_name":"Niels KN Focke","author_inst":"Department of Neurology, Medical University Center Gottingen"},{"author_name":"Francesco Fortunato","author_inst":"Institute of Neurology, Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro"},{"author_name":"Cesare Gagliardo","author_inst":"Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), University of Palermo"},{"author_name":"Marian Galovic","author_inst":"Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich"},{"author_name":"Antonio Gambardella","author_inst":"Institute of Neurology, Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro"},{"author_name":"Taha Gholipour","author_inst":"Department of Neurosciences, University of California San Diego"},{"author_name":"Ezequiel Gleichgerrcht","author_inst":"Department of Neurology, Emory University"},{"author_name":"Renzo Guerrini","author_inst":"Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS"},{"author_name":"MV Gule","author_inst":"Neuroscience Institute, Department of Psychiatry and Mental Health, University of Cape Town"},{"author_name":"Ev-Christin Heide","author_inst":"Department of Neurology, Medical University Center Gottingen"},{"author_name":"Sara Inati","author_inst":"National Institute of Neurological Disorders and Stroke Intramural Research Program"},{"author_name":"Victoria Ives-Deliperi","author_inst":"Neuroscience Institute, Department of Psychiatry and Mental Health, University of Cape Town"},{"author_name":"Graeme D Jackson","author_inst":"Florey Institute of Neuroscience and Mental Health, The Univeristy of Melbourne"},{"author_name":"Sarah Jacobs","author_inst":"Neuroscience Institute, Department of Psychiatry and Mental Health, University of Cape Town"},{"author_name":"Neda Jahanshad","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California"},{"author_name":"Jonathan K Kleen","author_inst":"Department of Neurology, University of California San Francisco"},{"author_name":"Raviteja Kotikalapudi","author_inst":"Department of Clinical Neurophysiology, University Hospital Gottingen"},{"author_name":"Mohamad Zakaria Koubeissi","author_inst":"Department of Neurology and Rehabilitation Medicine, George Washington University"},{"author_name":"Angelo Labate","author_inst":"Department of Biomedicine, Neurosciences and Advanced Diagnostics (BIND), University of Palermo"},{"author_name":"Sara Larivere","author_inst":"Department of medical imaging and radiation sciences, Universite de Sherbrooke"},{"author_name":"Matteo Lenge","author_inst":"Neuroscience and Human Genetics Department, Meyer Children's Hospital IRCCS"},{"author_name":"Helena Martins","author_inst":"University College London Queen Square Institute of Neurology"},{"author_name":"Mario Mascalchi","author_inst":"Department of Clinical and Experimental Medical Sciences, University of Florence"},{"author_name":"Stefano Meletti","author_inst":"Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia"},{"author_name":"Patrick B Moloney","author_inst":"Research Department of Epilepsy, UCL Queen Square Institute of Neurology, UCL"},{"author_name":"Terence J O'Brien","author_inst":"Department of Neuroscience, The School of Translational Medicine, Alfred Health, Monash University"},{"author_name":"Conor Owens-Walton","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California"},{"author_name":"Costanza Parodi","author_inst":"Neuroradiology Unit, IRCCS Istituto Giannina Gaslini"},{"author_name":"Ev-Christin Poelstra","author_inst":"Department of Neurology, Medical University Center Gottingen"},{"author_name":"Antonella Riva","author_inst":"Department of Neurosciences Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa"},{"author_name":"Rebecca W Roth","author_inst":"Department of Neurology, Emory University"},{"author_name":"Jessica Royer","author_inst":"McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University"},{"author_name":"Theodor BD Ruber","author_inst":"Department of Neuroradiology, University Hospital Bonn"},{"author_name":"Luca Saba","author_inst":"Department of Radiology, University of Cagliari"},{"author_name":"Ilaria Sammarra","author_inst":"Institute of Neurology, Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro"},{"author_name":"Lucas Scardua-Silva","author_inst":"Neuroimaging Laboratory, Department of Neurology, University of Campinas-UNICAMP"},{"author_name":"Kai Michael Schubert","author_inst":"Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich"},{"author_name":"Leigh Sepeta","author_inst":"Department of Neuropsychology, Children's National Hospital, The George Washington University School of Medicine"},{"author_name":"Mariasavina Severino","author_inst":"Neuroradiology Unit, IRCCS Istituto Giannina Gaslini"},{"author_name":"Ben Sinclair","author_inst":"Department of Neuroscience, The School of Translational Medicine, Alfred Health, Monash University"},{"author_name":"Nishant Sinha","author_inst":"Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania"},{"author_name":"Richard J Staba","author_inst":"Department of Neurology, David Geffen School of Medicine at UCLA"},{"author_name":"Dan J Stein","author_inst":"SAMRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry & Neuroscience Institute, University of Cape Town"},{"author_name":"Joel M Stein","author_inst":"Department of Radiology, University of Pennsylvania"},{"author_name":"Travis R Stoub","author_inst":"Department of Neurological Sciences, Rush University Medical Center"},{"author_name":"Pasquale Striano","author_inst":"IRCCS Istituto Giannina Gaslini, full member of ERN EpiCARE"},{"author_name":"Rainer Surges","author_inst":"Department of Epileptology, University Hospital Bonn"},{"author_name":"Robert Terziev","author_inst":"Charite - Universitaetsmedizin Berlin"},{"author_name":"Sophia I Thomopoulos","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California"},{"author_name":"Manuela Tondelli","author_inst":"Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia"},{"author_name":"Domenico Tortora","author_inst":"Neuroradiology Unit IRCCS Istituto Giannina Gaslini"},{"author_name":"Sebastiano Vacca","author_inst":"Center for Neurosciences, The Feinstein Institutes for Medical Research"},{"author_name":"Anna Elisabetta Vaudano","author_inst":"Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia"},{"author_name":"Lucy Vivash","author_inst":"Department of Neuroscience, The School of Translational Medicine, Alfred Health, Monash University"},{"author_name":"Kimberley C Williams","author_inst":"Neuroscience Institute, Department of Psychiatry and Mental Health, University of Cape Town"},{"author_name":"Clarissa L Yasuda","author_inst":"State University of Campinas"},{"author_name":"Zhiqiang Zhang","author_inst":"Jinling Hospital, Nanjing University School of Medicine"},{"author_name":"Erik Kaestner","author_inst":"Department of Radiation Medicine and Applied Sciences and Psychiatry, UCSD"},{"author_name":"Paul M Thompson","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California"},{"author_name":"Sanjay M Sisodiya","author_inst":"Research Department of Epilepsy, UCL Queen Square Institute of Neurology, UCL"},{"author_name":"Carrie R McDonald","author_inst":"Department of Radiation Medicine and Applied Sciences and Psychiatry, UCSD"}],"rel_date":"2026-05-01","rel_site":"medrxiv"},{"rel_title":"Patient Perceptions of a Seizure Service Dog in the Epilepsy Monitoring Unit","rel_doi":"10.64898\/2026.04.30.26352073","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.30.26352073","rel_abs":"Objective: Seizure dogs are service animals trained to respond supportively to seizures in people with epilepsy; some are also trained to detect seizure-specific scents, particularly ictal volatile organic compounds (VOCs). This survey study examines feasibility and safety of incorporating a seizure service dog (SSD) into an inpatient setting, as well as patient perceptions of having an SSD in the Epilepsy Monitoring Unit (EMU). Methods: Our SSD underwent specialized training for seizure response and seizure recognition based on seizure-specific VOCs, and accompanied his epileptologist owner in the EMU on rounds for over four years prior to the study. We administered surveys to patients hospitalized in the EMU before and after interactions with a trained seizure dog. The surveys assessed patient comfort with the dog, perceived usefulness of service dogs, safety, and tolerability. Select cases in which seizure dog spontaneously alerted to epileptic seizures in the EMU are also reported with EEG confirmation. Results: Patient responses underscored overall high enthusiasm for seizure dog therapy, with 93% of participants reporting feeling \"very comfortable\" or \"extremely comfortable\" with a seizure dog present. No adverse concerns or negative experiences were reported by participants. 91% reported personally experiencing benefits of working with the seizure dog, citing emotional and comfort benefits during their hospitalization. 94% of participants were comfortable with physical contact with the dog or had no proximity preference. Conclusion: These findings suggest that seizure service dogs can be safely integrated into the inpatient EMU setting and have potential to enhance patient care and emotional well-being during EMU monitoring.","rel_num_authors":5,"rel_authors":[{"author_name":"LIA D ERNST","author_inst":"Oregon Health & Sciences University"},{"author_name":"Bahar Madani","author_inst":"Oregon Health & Sciences University"},{"author_name":"Danny Zhu","author_inst":"Oregon Health & Sciences University"},{"author_name":"Matthew McCaskill","author_inst":"Oregon Health & Sciences University"},{"author_name":"Marissa A Kellogg","author_inst":"Portland VA HCS & Oregon Health & Science Univ (OHSU)"}],"rel_date":"2026-05-01","rel_site":"medrxiv"},{"rel_title":"Cortical Lesions Form Predominantly in Early Multiple Sclerosis","rel_doi":"10.64898\/2026.04.30.26352141","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.30.26352141","rel_abs":"Background and Objectives: Cortical lesions are common in multiple sclerosis (MS) and associated with disability, but their characterization in early MS has been limited. Here, we aimed to characterize cortical lesions in newly diagnosed MS with 7 tesla (T) brain MRI. Methods: Adults within 14 months of relapsing-remitting MS diagnosis underwent 7T brain MRI and clinical evaluation at Mount Sinai. Cortical lesions were identified using T1-weighted (w) (median of three acquisitions) and T2*w images (both at 0.5mm3). Non-cortical brain lesions were segmented on 0.7mm3 T1w images. Lesion burden in newly diagnosed MS was compared with a previously analyzed NIH cohort with longer time since diagnosis, imaged using a similar protocol. Results: 61 individuals were included in the newly diagnosed MS cohort (mean age 34 +\/- 4 years; 72% female; median time since diagnosis 5 months, interquartile range [IQR] 6). Cortical lesions were identified in 50\/61 (81%) individuals, and subpial cortical lesions were identified in 46 (75%). Median cortical lesion number was 5 (IQR 11), median volume 319 l (IQR 1049). Cortical lesions constituted a median of 14% of total brain lesion volume (IQR 43%), and in 21% of individuals, cortical lesions constituted >50% of total brain lesion volume. Cortical lesion number was associated with worse 9-hole peg test ({rho}=0.33, p=0.008) and Symbol Digit Modalities Test performance ({rho}=-0.29, p=0.02). When pooled with the NIH cohort (n=60, median time since diagnosis 12 years, IQR 17), non-cortical lesion volume was ~3.5 times higher in people with time since diagnosis >36 months (median 4.7 ml, IQR 8.7) vs [&le;]36 months (median 1.2 ml, IQR 2.4, p<0.001). In contrast, cortical lesion volume was only ~1.3 times higher in people with time since diagnosis >36 months (median 416 l, IQR 1013) vs [&le;]36 months (median 318 l, IQR 925, p=0.04). Non-cortical lesion volume was moderately associated with time since diagnosis ({rho}=0.54, p<0.001) vs {rho}=0.27 (p<0.001) for cortical lesions. Discussion: Cortical lesions are prevalent in newly diagnosed MS and constitute a substantial portion of total lesion burden. Cortical lesion volume is similar in early vs established MS, suggesting most cortical lesions form early in disease.","rel_num_authors":10,"rel_authors":[{"author_name":"Batuhan Ayci","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Emma Dereskewicz","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Jonadab Dos Santos Silva","author_inst":"Yale School of Medicine"},{"author_name":"Julia Galasso","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Phoebe Rust","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Francesco La Rosa","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Jiaen Liu","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Daniel S Reich","author_inst":"National Institute of Neurological Disorders and Stroke"},{"author_name":"James F Sumowski","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Erin S Beck","author_inst":"Icahn School of Medicine at Mount Sinai"}],"rel_date":"2026-05-01","rel_site":"medrxiv"},{"rel_title":"PATIENT PATHWAYS TO UGANDA'S FIRST SPECIALISED EARLY INTERVENTION IN PSYCHOSIS SERVICE AND RELATION TO THEIR CLINICAL OUTCOMES.","rel_doi":"10.64898\/2026.04.30.26352152","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.30.26352152","rel_abs":"Background: Early Intervention for Psychosis Services (EIPS) enhance outcomes for individuals experiencing their first episode of psychosis (FEP). However, in low resource settings, there is limited knowledge about i) the pathways patients take to access EIPS, ii) the proportion and factors associated with acceptance of referral to EIPS, and iii) if different pathways to EIPS services affect clinical outcomes. Uganda's first EIPS, the Specialised Treatment Early in Psychosis Service at Makerere University Hospital (STEPMaKH), presents a unique opportunity to explore these important questions. Aims: We aimed to examine the pathways to EIPS, the factors associated with referral to specialised psychosis care and the impact of initial treatment seeking behaviour on long-term symptom remission and quality of life. Methods: We conducted a multiple method study. Pathways to care were assessed retrospectively using the WHO Encounter Form among adults with FEP eligible for referral to STEPMaKH. Among those who completed referral and enrolled in STEPMaKH. Symptom severity and quality of life were followed prospectively for 12 months. Modified Poisson regression identified predictors of referral completion. Kaplan Meier methods and Cox proportional hazards models examined time to symptom remission and time to achieving a good quality of life. Results: Of the 187 adults with first-episode psychosis eligible for referral to STEPMaKH, Native\/religious healers (n = 86) were the predominant first point of contact. Only 56 (29.9%) accepted referral to STEPMaKH. Participants referred from Mulago National Referral Hospital more likely to enrol than those referred from Butabika (RR = 4.7; 95% CI: 2.907.87). Longer delays from first treatment contact were associated with reduced likelihood of reaching STEPMaKH (RR = 0.99 per month; p = 0.041). After enrolment, symptoms improved rapidly with 60% achieving PANSS remission by Month 1, and fewer than 10% remained non-remitted by Months 23. In adjusted Cox models, participants initially seen by mental health workers achieved remission more quickly than those initially seen by non-medical personnel (HR = 1.48; 95% CI: 1.052.10). Older age was associated with slower remission (HR = 0.94; p = 0.023). Quality of life improved over the follow-up period, with earlier attainment of good quality of life among those initially managed by mental health workers. Conclusions: Pathways to care for FEP in Uganda are complex and culturally mediated, with substantial attrition before specialised early psychosis care is reached. Referral completion is strongly shaped by referral site and by delays in the care pathway. Once in specialised care, clinical outcomes improve rapidly, and initial contact with mental health workers is associated with faster symptom remission and earlier gains in quality of life. Strengthening referral systems, reducing pathway delays, and developing collaborative detection-and-referral links with community and frontline providers are key priorities for optimising early psychosis outcomes in low-resource settings.","rel_num_authors":14,"rel_authors":[{"author_name":"Emmanuel Kiiza Mwesiga","author_inst":"Department of Psychiatry, College of Health Sciences, Makerere University"},{"author_name":"Wilber Ssembajjwe","author_inst":"MRC\/UVRI Uganda Research Unit On AIDS: MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Rossette I Ndigamanya","author_inst":"MRC\/ UVRI & LSHTM Uganda Research Unit, Entebbe, Uganda."},{"author_name":"Sophia Balinga","author_inst":"Butabika National Referral Mental Hospital"},{"author_name":"Blessed T Aujo","author_inst":"Soroti University"},{"author_name":"Mary Ampiire","author_inst":"Specialised Treatment Early in Psychosis Service at Makerere University Hospital."},{"author_name":"Andrea K Kaddu","author_inst":"Specialised Treatment Early in Psychosis Service at Makerere University Hospital."},{"author_name":"Andrew Sentoogo SSEMATA","author_inst":"Makerere University College of Health Sciences"},{"author_name":"Allan Kalungi","author_inst":"MRC\/UVRI Uganda Research Unit On AIDS: MRC\/UVRI and LSHTM Uganda Research Unit"},{"author_name":"Ronald Kiguba","author_inst":"Department of Pharmacy, College of Health Sciences, Makerere University"},{"author_name":"Josaphat Byamugisha","author_inst":"Makerere University College of Health Sciences"},{"author_name":"Mark  Kaddu Mukasa","author_inst":"Makerere University Faculty of Medicine: Makerere University College of Health Sciences"},{"author_name":"Martha Sajatovic","author_inst":"Neurological and Behavioural Outcomes Centre, University Hospital Case Medical Centre, Case Western Reserve University"},{"author_name":"Noeline Nakasujja","author_inst":"Makerere University College of Health Sciences"}],"rel_date":"2026-05-01","rel_site":"medrxiv"},{"rel_title":"An mHealth-based social support program to improve antenatal care engagement and facility-based births in Uganda: A type I hybrid effectiveness-implementation clinical trial","rel_doi":"10.64898\/2026.04.28.26351943","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.28.26351943","rel_abs":"Background Ugandan women and their children suffer from high maternal and perinatal mortality, often due to low antenatal care (ANC) and skilled birth usage. We partnered with community members, women and the Ugandan Ministry of Health to formatively develop an intervention (Support-Moms app) to improve health education, engage social support networks, and augment access to ANC and delivery by a formal health care provider (HCP) for pregnant women in rural Uganda. Methods We conducted a type 1 hybrid effectiveness-implementation trial to test the effectiveness of the Support-Moms intervention. We enrolled 824 pregnant women (<20 weeks gestation) living in Southwestern Uganda and randomized them (1:1) to standard of care or Support-Moms intervention. The primary effectiveness outcome was completion of a HCP-led skilled birth (discharge card) and was analyzed as intention-to-treat. Secondary outcomes included number of ANC visits, institution-based delivery, social support, quality-of-life, mode of infant delivery, pre-term birth, birth weight, obstetric complications and deaths (maternal, fetal, newborn). Results A total of 1,216 women were screened, and 824 pregnant women enrolled (mean age [~]28 years; gestation at enrolment [~]13 weeks). Complete outcomes were available for 818 (99%). The Support-Moms intervention increased HCP-led skilled births compared to standard of care (93% vs 84%; OR 2.51, 95% CI 1.57-4.03, p<0.001). Women in the intervention group were more likely to achieve [&ge;]4 ANC visits (84.1% vs 75.1%; OR 1.76, 95% CI 1.24-2.50, p=0.001) and less likely experience postpartum hemorrhage (9.1% vs 22.7%, OR 0.34, 95% CI 0.22-0.52, p<0.001) or for their neonates to require resuscitation (9.8% vs 13.7%, OR 0.69, 95% CI 0.45-0.99, p=0.001). Initiation of breastfeeding within an hour was higher (97.1% vs 71.7%, OR 1.76, 95% CI 1.15-3.44, p=0.001) and postnatal depression decreased (20.1% vs 27.1%, OR 0.68, 95% CI 0.49-0.94, p=0.019). More intervention participants reported adequate support, were birth-prepared and had a birth companion. There were no maternal deaths or differences in term births, birthweight, mode of delivery, perinatal mortality or other obstetric complications. Conclusions In rural Uganda, the Support-Moms mHealth-based, social-support intervention significantly increased HCP-led skilled births compared with routine care, while also improving ANC attendance, early breastfeeding initiation, birth preparedness, perceived social support and higher presence of companion at birth. Less women experienced PPH, neonatal resuscitation, and postnatal depression. Further evaluation should focus on the cost effectiveness and sustainability of this program.","rel_num_authors":11,"rel_authors":[{"author_name":"Esther  C. Atukunda","author_inst":"Mbarara University of Science and Technology"},{"author_name":"Godfrey  R Mugyenyi","author_inst":"Mbarara University of Science and Technology"},{"author_name":"Jessica Haberer","author_inst":"Massachusetts General Hospital"},{"author_name":"Van  T Nghiem","author_inst":"University of Alabama at Birmingham"},{"author_name":"Elly  B Atuhumuza","author_inst":"Mbarara University of Science and Technology"},{"author_name":"Peter Waiswa","author_inst":"Makerere University College of Health Sciences"},{"author_name":"Angella Musiimenta","author_inst":"Mbarara University of Science and Technology"},{"author_name":"Micheal Kanyesigye","author_inst":"Mbarara University of Science and Technology Faculty of Computing and Informatics"},{"author_name":"Celestino Obua","author_inst":"Mbarara University of Science and Technology"},{"author_name":"Mark  J Siedner","author_inst":"Massachusetts General Hospital"},{"author_name":"Lynn  T. Matthews","author_inst":"Yale University"}],"rel_date":"2026-05-01","rel_site":"medrxiv"},{"rel_title":"Rapid phylogenomic analysis for viral surveillance and metagenomic profiling with Omni2Tree","rel_doi":"10.64898\/2026.04.29.721707","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.29.721707","rel_abs":"Phylogenomic surveillance is limited not by sequencing throughput, but by the difficulty of converting heterogeneous raw data into reliable evolutionary inference, particularly for low-titer and contaminated viral field samples. Here we present Omni2Tree, an assembly-free framework that reconstructs viral phylogenies directly from raw sequencing reads and generates easily shareable interactive reports and genome-wide entropy profiles to identify diversification. In H5N1 benchmark analyses, Omni2Tree maintained accurate placement and topological stability even under low coverage, unlike assembly or reference based methods. Omni2Tree generated an annotated phylogeny for 64-sample H5N1 field surveillance dataset from the eastern USA in under 3 hours. Omni2Tree recovered known phylogenetic structure and key variability insights across 1,328 hepatitis C virus and 707 human cytomegalovirus datasets, and resolved co-infecting respiratory viruses in clinical metagenomic samples. By enabling direct analysis from raw reads, Omni2Tree supports faster, more portable, and more decentralized phylogenomic surveillance across outbreak, clinical, and resource-limited settings.","rel_num_authors":9,"rel_authors":[{"author_name":"Sina Majidian","author_inst":"Department of Computer Science, Johns Hopkins University, 3400 North Charles St., Baltimore, MD 21218, United States"},{"author_name":"Adrian Chalco","author_inst":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Xinchang Zheng","author_inst":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Richard J Webby","author_inst":"St Jude Children's Research Hospital, Memphis, TN, 38105"},{"author_name":"Andrew S Bowman","author_inst":"The Ohio State University, Columbus, OH 43210"},{"author_name":"Rebecca L Poulson","author_inst":"Southeastern Cooperative Wildlife Disease Study, Department of Population Health, College of Veterinary Medicine, The University of Georgia, Athens, GA, 30602"},{"author_name":"Nicole M Nemeth","author_inst":"Southeastern Cooperative Wildlife Disease Study, Department of Population Health, College of Veterinary Medicine, University of Georgia, Athens, GA, 30602"},{"author_name":"Fritz J Sedlazeck","author_inst":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Daniel P Agustinho","author_inst":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Characterization of Cellular Senescence in Primary Human Astrocytes","rel_doi":"10.64898\/2026.04.29.721581","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.29.721581","rel_abs":"Senescent astrocytes have been identified in the brains of patients with neurodegenerative disorders, including Alzheimer's disease, yet the molecular characteristics of replicative senescence in human astrocytes remain largely unexplored. Prior work has been hampered by the low proliferative capacity and limited telomere shortening of primary human astrocytes in culture. Here, we describe a culture system in which primary human astrocytes propagated under physiological (3%) oxygen reach canonical telomeric replicative senescence after extensive expansion (up to ~76 population doublings). Senescence was confirmed through multiple biomarkers, including reduced EdU incorporation, elevated senescence-associated beta-galactosidase (SA-{beta}-gal) activity, persistent DNA damage foci ({gamma}H2AX and 53BP1) predominantly localized to telomeres, and nuclear accumulation of p53. RNA sequencing across a 12-week time course revealed early upregulation of young LINE-1 (L1HS) retrotransposon transcripts, type-I interferon (IFN-I) and senescence-associated secretory phenotype (SASP) pathway genes, alongside downregulation of cell-cycle and DNA repair programs. To resolve L1HS expression at individual locus resolution, we performed Nanopore DNA sequencing to generate a custom reference genome incorporating non-reference LINE-1 insertions. Applying our TE-Seq pipeline, we identified two full-length intergenic L1HS elements consistently upregulated across the replicative senescence time course, one of which, L1HS_9q22.32_2, retained intact ORF1 and ORF2 open reading frames, indicating potential retrotransposition competence. To contextualize the astrocyte replicative senescence program, we compared it to three additional conditions. First, parallel astrocyte cultures maintained under normoxic (20%) oxygen entered senescence earlier and showed stronger SASP upregulation. Second, DNA damage-induced senescence (DDIS) triggered by etoposide treatment produced a stronger pro-inflammatory transcriptional signature than replicative senescence, including elevated IL6, IL1A, and IL1B expression. DDIS also upregulated L1HS_9q22.32_2 as well as a second intact element, L1HS_14q23.2_3, which we have previously identified among the small number of intact L1HS loci activated during replicative senescence in fibroblasts. The convergent activation of these intact elements across cell types and senescence modalities reinforces L1HS-driven IFN-I signaling as a conserved feature of the senescent program. Third, comparison with replicatively senescent fibroblasts revealed cell-type-specific SASP regulation: the pro-inflammatory cytokines IL6 and CCL2 were downregulated in senescent astrocytes relative to proliferating cells, opposite to their behavior in fibroblasts. Together, these data establish the first comprehensive transcriptomic profile of replicative senescence in human astrocytes, offering a resource for understanding brain aging and senescence-associated neurodegeneration.","rel_num_authors":3,"rel_authors":[{"author_name":"Trenton A Woodham","author_inst":"Brown University"},{"author_name":"Maxfield M G Kelsey","author_inst":"Brown University"},{"author_name":"John M Sedivy","author_inst":"Brown University"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Spanning-Tree Thermostatistics of Protein Allostery: An Exact Kirchhoff Framework with Application to Oncogenic KRAS","rel_doi":"10.64898\/2026.04.29.721570","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.29.721570","rel_abs":"This study introduces a statistical mechanical framework for allosteric communication in proteins based on the spanning-tree ensemble of residue contact networks. By representing protein structures as weighted graphs, we identify each spanning tree as a topological microstate. The canonical partition function is evaluated exactly via the determinant of the reduced weighted Kirchhoff (Laplacian) matrix, allowing for the derivation of global thermodynamic functions (including Helmholtz free energy, internal energy, entropy, and heat capacity) without approximation. Allosteric channels between specific residue pairs are defined as sub-ensembles containing unique simple paths. Using the Burton-Pemantle theorem and the Moore-Penrose pseudoinverse of the graph Laplacian, we compute exact path probabilities and channel-specific thermodynamics. This methodology enables a decomposition of channel heat capacity into energetic and topological components and quantifies residue-level allosteric importance through fractional contributions to the channel partition function. The framework was applied to the G12D mutation in KRAS, comparing wild-type (PDB: 6GOD) and mutant (PDB: 6GOF) proteins. Results show that while the mutation minimally affects mean internal energy and entropy, it reduces global heat capacity by 27.3%. This indicates a topological stiffening where the mutant occupies a significantly narrower landscape of spanning-tree configurations. At the channel level, the mutation maintains distributional stability across six functional routes but triggers a substantial internal redistribution of allosteric importance. Specific residues, such as Q61 and F156, shift occupancy by up to 35.5%. These findings suggest that the G12D mutation does not destroy communication pathways but reorganizes internal information traffic to favor a catalytically impaired state. This approach provides a rigorous, parameter-free metric for understanding how point mutations perturb distal protein signaling.","rel_num_authors":2,"rel_authors":[{"author_name":"Fatma Senguler Ciftci","author_inst":"Private Investigator"},{"author_name":"Burak Erman","author_inst":"Koc University"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Facilitating NMR Resonance Assignment with Metabolic Tampering","rel_doi":"10.64898\/2026.04.29.721603","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.29.721603","rel_abs":"The ability to assign amino acid resonances in multidimensional NMR spectra of biomolecules is necessary for detailed studies of protein structure and dynamics. Despite creative advances in isotopic labeling, unlabeling and multidimensional NMR experiments, resonance assignment remains a bottleneck in studies of large proteins. In this work, we show that the metabolic flux through biosynthetic pathways of amino acid production during protein expression can be modulated to aid in the identification of resonances in two-dimensional NMR spectra. This straightforward method involves doping 15N-enriched minimal media with small amounts of rich natural abundance media to generate unique peak intensity attenuation patterns, producing type-specific signatures of amino acids in two-dimensional 15N HSQC experiments. Using three model proteins, IGPS (51 kDa heterodimer), PTP1B (35 kDa), PHPT1 (14 kDa), we show that this method can disentangle several amino acid types, is robust to different expression conditions, and is a useful supplement for triple resonance experiments in protein backbone resonance assignments.","rel_num_authors":5,"rel_authors":[{"author_name":"Danica Cui","author_inst":"Yale University"},{"author_name":"Evan O Anderson","author_inst":"Yale University"},{"author_name":"Erik Zavala","author_inst":"Yale University"},{"author_name":"George P Lisi","author_inst":"Brown University"},{"author_name":"J. Patrick Loria","author_inst":"Yale University"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Facilitating NMR Resonance Assignment with Metabolic Tampering","rel_doi":"10.64898\/2026.04.29.721603","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.29.721603","rel_abs":"The ability to assign amino acid resonances in multidimensional NMR spectra of biomolecules is necessary for detailed studies of protein structure and dynamics. Despite creative advances in isotopic labeling, unlabeling and multidimensional NMR experiments, resonance assignment remains a bottleneck in studies of large proteins. In this work, we show that the metabolic flux through biosynthetic pathways of amino acid production during protein expression can be modulated to aid in the identification of resonances in two-dimensional NMR spectra. This straightforward method involves doping 15N-enriched minimal media with small amounts of rich natural abundance media to generate unique peak intensity attenuation patterns, producing type-specific signatures of amino acids in two-dimensional 15N HSQC experiments. Using three model proteins, IGPS (51 kDa heterodimer), PTP1B (35 kDa), PHPT1 (14 kDa), we show that this method can disentangle several amino acid types, is robust to different expression conditions, and is a useful supplement for triple resonance experiments in protein backbone resonance assignments.","rel_num_authors":5,"rel_authors":[{"author_name":"Danica Cui","author_inst":"Yale University"},{"author_name":"Evan O Anderson","author_inst":"Yale University"},{"author_name":"Erik Zavala","author_inst":"Yale University"},{"author_name":"George P Lisi","author_inst":"Brown University"},{"author_name":"J. Patrick Loria","author_inst":"Yale University"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Replication fork remodeling proteins, Smc5\/6 and Rtt107, promote palindrome-mediated genome instability","rel_doi":"10.64898\/2026.04.29.721645","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.29.721645","rel_abs":"Palindromic sequences are a potent source of genomic instability that can lead to cancer and hereditary diseases in humans. Molecular evidence shows that palindrome instability results from the formation of secondary structures, such as hairpins and cruciforms, which are cleaved by structure-specific nucleases. However, the mechanisms underlying cruciform formation and cleavage at palindromic sequences in eukaryotic cells remain incompletely understood. Here, we describe a pathway for secondary structure formation and chromosomal breakage at palindromes involving DNA helicase Mph1, Rad51 recombinase, Rad54 ATPase DNA strand remodeler, Rtt107 scaffold protein, and the multifunctional Smc5\/6 complex. Deletion or mutation of any of these components results in a similar reduction in double-strand breaks at an Alu palindrome and a significant decrease in chromosomal rearrangements. We propose that Mph1, Rad51, and Rad54 work together at stalled replication forks to generate cruciform structures via fork remodeling, while Smc5\/6 and Rtt107 mark the cruciforms, indicating an appropriate substrate for nuclease cleavage. As members of this pathway are conserved in humans, the uncovered mechanisms may underlie genomic instability at palindrome sites involved in disease etiology.","rel_num_authors":7,"rel_authors":[{"author_name":"Alex B Costa","author_inst":"Georgia Institute of Technology"},{"author_name":"Anissia Aid Saada","author_inst":"Georgia Institute of Technology"},{"author_name":"Thy Pham","author_inst":"Georgia Institute of Technology"},{"author_name":"Jiayi Fan","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Rebecca Lever","author_inst":"Memorial Sloan-Kettering Cancer Center"},{"author_name":"Xiaolan Zhao","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Kirill S Lobachev","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Eukaryotic domestication of a bacterial immune protein following horizontal transfer","rel_doi":"10.64898\/2026.04.30.722052","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.30.722052","rel_abs":"Many components of eukaryotic innate immunity originated from bacterial immune systems. However, it has been unclear how eukaryotes acquire these genes, why eukaryotes have sampled only certain families of bacterial proteins, and how these components become domesticated into eukaryotic physiology. Here, we discovered a recent instance of bacteria-eukaryote horizontal transfer and used it to characterize the genetic and biochemical changes that accompanied HGT. We focus on TIR domains, which are widespread yet potentially costly immune modules that are commonly associated with inflammation and\/or cell death. By generating an atlas of TIR diversity across the tree of life, we phylogenetically categorized the domains and uncovered highly diverged TIR families found in eukaryotes. This analysis also allowed us to identify the TirBCD protein family of amoeba, which has been horizontally acquired and is closely related to the bacterial immune protein TIR-STING. Across their short eukaryotic history, the amoeba genes have acquired introns, evolved distinct patterns of gene expression, and engaged in evolutionary patterns of duplication and divergence typical of eukaryotic immune genes. While the TIR domain was transferred into amoebae, the genomic locus did not contain other components of a bacterial operon nor were regulatory domains transferred into the TIR protein. Nevertheless, TirC retains biochemical and physiological similarities to TIR-STING. TirC is a highly potent NADase, capable of spontaneously oligomerizing into large complexes and depleting cellular NAD even at very low protein concentrations. When expressed in yeast or E. coli, TirC is spontaneously active and highly toxic, illustrating the dangers of autoimmunity following TIR protein movement into novel hosts. In contrast, amoebae tolerated high TirC expression with no disruption in cell size, growth, or behavior. Single, double, and triple knock out mutants of amoeba tirBCD are viable and display modest defects in their ability to phagocytose bacteria, implying that the co-opted bacterial TIR domain may regulate eukaryotic host-microbe interactions. Overall, this study uncovers an informative example of recent eukaryotic TIR evolution that captures features of both bacterial and eukaryotic immunity. In addition, we expect that the TIR domain atlas will be useful to researchers in many model systems as they explore the vast diversity of TIR molecular and cellular functions.","rel_num_authors":12,"rel_authors":[{"author_name":"Edward M Culbertson","author_inst":"University of Pittsburgh"},{"author_name":"Emily Cruz-Lorenzo","author_inst":"University of Pittsburgh"},{"author_name":"Jocelyn Leon Padilla","author_inst":"University of California Irvine"},{"author_name":"Megan Halfmann","author_inst":"Stowers Institute"},{"author_name":"James R Drurey","author_inst":"University of Pittsburgh"},{"author_name":"Jeffrey J Lange","author_inst":"Stowers Institute"},{"author_name":"Yao Li","author_inst":"Harvard Medical School"},{"author_name":"Neha Garlapati","author_inst":"University of Pittsburgh"},{"author_name":"Harshitha Gompa","author_inst":"University of Pittsburgh"},{"author_name":"Benjamin R Morehouse","author_inst":"University of California Irvine"},{"author_name":"Randal Halfmann","author_inst":"Stowers Institute"},{"author_name":"Tera C Levin","author_inst":"University of Pittsburgh"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Insights from sourdough redefine the domestication landscape of baker's yeast","rel_doi":"10.64898\/2026.04.29.721752","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.29.721752","rel_abs":"While the domestication of plants and animals is widely recognized for its role in the rise of human civilization, humans have also cultivated microbes over millennia to produce food and beverages. One microbe in particular, Saccharomyces cerevisiae, is associated with a wide variety of human-fermentation environments, including wine, beer, and notably bread, such that it is often referred to as ''baker's yeast.'' To better illuminate the domestication history of baking associated yeast, we isolated 38 Saccharomyces cerevisiae strains from sourdough starters donated by bakers throughout North America and compared them to thousands of S. cerevisiae isolates from a variety of wild and human-fermentation environments. We identified 6 major clades with two primary domestication hubs, Mediterranean liquid-state fermentation and Asian solid-state fermentation, diverging across Eurasia that gave rise to human-associated lineages. Population genomic analyses demonstrate that S. cerevisiae strains found in sourdough starters are genetically distinct from commercial baking strains and do not come from the surrounding wild environment. Our results show that sourdough yeast strains are closely related to each other and have shared ancestry with strains isolated from various Asian solid state grain fermentations such Japanese sake, Asian rice wines, Chinese distilled spirits (baijiu), and Chinese steamed bread (mantou). We found evidence of significant admixture throughout S. cerevisiae populations, including baking-associated lineages, likely facilitated by human activity. Pangenome gene content largely captures S. cerevisiae traditional genomic sequence-based population structure and reflects human cultural practices, with differences in gene content and copy number between baking associated strains and other groups. Overall, we show that many generalized hallmarks of domestication, such as genome contraction, loss of genetic diversity, and lack of niche expansion, are not universal features of S. cerevisiae domestication, and that baking-associated yeasts have a complex evolutionary history heavily shaped by human culture.","rel_num_authors":6,"rel_authors":[{"author_name":"Margot Ruffieux","author_inst":"North Carolina State University"},{"author_name":"Nathan Brandt","author_inst":"North Carolina State University"},{"author_name":"Alexxis Gutierrez","author_inst":"Saint Louis University School of Medicine"},{"author_name":"Benjamin E. Wolfe","author_inst":"Tufts University - Biology"},{"author_name":"Robert R. Dunn","author_inst":"North Carolina State University"},{"author_name":"Caiti Smukowski Heil","author_inst":"North Carolina State University"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Forecasting climate-driven distributional changes in the threatened Caribbean marine species Aliger gigas (Queen conch)","rel_doi":"10.64898\/2026.04.29.721193","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.29.721193","rel_abs":"The queen conch (Aliger gigas) is a key native species of the Caribbean Sea and a primary source of income for thousands of fishers. Historically, it has been a highly valuable resource for the fishing sectors of countries such as the Bahamas, Turks and Caicos, Honduras, and Nicaragua. However, due to its high economic value, the species has been extensively overfished across the region. Overfishing, combined with limited larval dispersal, low recruitment, and poor population connectivity, has led to a drastic decline in population numbers of the species, resulting in its current classification as Threatened. Despite this status, likely impacts of climate change on its populations remain poorly understood, posing significant challenges to conservation efforts. To address this gap, we integrated occurrence records, climate data, and satellite-derived marine habitat data to develop ecological niche models estimating the current and future distribution of the queen conch under different climate change scenarios. We found substantial losses of suitable areas for queen conch along the northern Atlantic coast of South America and Central America, part of the Greater Antilles and the Lesser Antilles. The entire Caribbean region is projected to lose suitability entirely within 20-30 years under the moderate and most extreme climate scenarios. Conversely, our models estimate some suitable areas to persist or expand along the southeastern coast of the United States at least until sometime between 2040 and 2060. Overall, our results suggest a northward shift in the range of this species, with the magnitude of this shift closely tied to the severity of climate change impacts. This work aims to build upon and enhance existing knowledge about survival of queen conch populations in the Caribbean over time. Anticipating future habitat availability will be key to protecting this economically and ecologically important species.","rel_num_authors":3,"rel_authors":[{"author_name":"Daniel Rojas-Ariza","author_inst":"Department of Ecology & Evolutionary Biology and Biodiversity Institute, The University of Kansas"},{"author_name":"Claudia Nunez-Penichet","author_inst":"Department of Ecology & Evolutionary Biology and Biodiversity Institute, The University of Kansas"},{"author_name":"Zenia P Ruiz-Utrilla","author_inst":"Department of Ecology & Evolutionary Biology and Biodiversity Institute, The University of Kansas"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Behavior-Driven Marine Larval Dispersal and Settlement with AI Agent-Based Modeling","rel_doi":"10.64898\/2026.04.29.721765","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.29.721765","rel_abs":"Larval dispersal models are central to mapping and predicting ichthyoplankton dynamics in the ocean, yet despite decades of refinement they remain fundamentally limited by their ability to represent adaptive behaviors, relying instead on static trait parameterizations. This deficiency constrains our capacity to design effective restoration and mitigation strategies in an increasingly stressed ocean. SWARM (Simulating Waterborne Agent Routes for Marine connectivity) overcomes this barrier by integrating Large Language Model (LLM)-based behavioral agents with a standard biophysical model to simulate active decision making during the pelagic larval stage. In both idealized and realistic conditions focusing on Red Snapper larvae in the Gulf of Mexico, agents develop adaptive behaviors that improve settlement and generate explainable vertical distribution patterns. SWARM demonstrates that LLMs can overcome long standing limitations in dispersal modelling by explicitly representing behavioral drivers of movement, opening new pathways for predicting connectivity and designing effective marine-ecosystem restoration.","rel_num_authors":4,"rel_authors":[{"author_name":"Xing Zhou","author_inst":"School of Earth and Atmospheric Sciences, Georgia Institute of Technology, Atlanta, GA, USA"},{"author_name":"Guanghui Wang","author_inst":"College of Computing, Georgia Institute of Technology, Atlanta, GA, USA"},{"author_name":"Renzhi Wu","author_inst":"Meta Platforms, Inc., Menlo Park, CA, USA"},{"author_name":"Annalisa Bracco","author_inst":"Euro-Mediterranean Center on Climate Change, Milan, Italy"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"An expansive animal gut microbiome dataset elucidates major compositional shifts across bilaterian evolution","rel_doi":"10.64898\/2026.04.29.721755","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.29.721755","rel_abs":"Animal gut microbiomes provide key physiological functions and are critical for host health. They vary dramatically across the animal kingdom, and are shaped by factors including host diet, evolutionary history and environment. However, analyses of gut microbiomes spanning the entire metazoan clade are lacking, limiting our understanding of the fundamental principles governing gut microbiomes. Here we present the Gut Microbiome Tree of Life (GMToL), a curated 16S amplicon dataset of 17,366 samples from 1,553 host species across 26 host classes from 284 studies, enabling analysis of large-scale evolutionary trends. Using ancestral state reconstruction, we provide a critical baseline calculation of major compositional shifts in gut microbiomes throughout animal evolution. We show that the ancestral animal gut was likely dominated by Pseudomonadota. A major shift to Bacteroidota occurred during the evolution of tetrapods, followed by the emergence of Bacillota-dominated guts in mammals and birds. We identify conserved core gut microbes and demonstrate how GMToL can be leveraged to contextualize the evolutionary history of specific microbial taxa. Ultimately, this framework enables the predictive mapping of microbial symbionts across uncharacterized host lineages, and establishes a quantitative baseline for comparative microbiome research at scale.","rel_num_authors":15,"rel_authors":[{"author_name":"Samuel Degregori","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, California, USA"},{"author_name":"Lucas Patel","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, California, USA; Bioinformatics and Systems Biology Program, University of California Sa"},{"author_name":"Luis Xu","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, California, USA"},{"author_name":"Michael Iter","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, California, USA; Bioinformatics and Systems Biology Program, University of California Sa"},{"author_name":"Yuhan Weng","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, California, USA; Bioinformatics and Systems Biology Program, University of California Sa"},{"author_name":"Isabella Huang","author_inst":"Johns Hopkins University, Baltimore, Maryland, USA"},{"author_name":"Harrison J Martel","author_inst":"Johns Hopkins University, Baltimore, Maryland, USA"},{"author_name":"Dmitry Kisselev","author_inst":"Johns Hopkins University, Baltimore, Maryland, USA"},{"author_name":"Jianshu Zhou","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, California, USA"},{"author_name":"Celeste Allaband","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, California, USA"},{"author_name":"Gail Ackermann","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, California, USA"},{"author_name":"Antonio Gonzalez","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, California, USA"},{"author_name":"Daniel McDonald","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, California, USA"},{"author_name":"Katherine R Amato","author_inst":"Department of Anthropology, Northwestern University, Evanston, IL, USA"},{"author_name":"Rob Knight","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, California, USA"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"An expansive animal gut microbiome dataset elucidates major compositional shifts across bilaterian evolution","rel_doi":"10.64898\/2026.04.29.721755","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.29.721755","rel_abs":"Animal gut microbiomes provide key physiological functions and are critical for host health. They vary dramatically across the animal kingdom, and are shaped by factors including host diet, evolutionary history and environment. However, analyses of gut microbiomes spanning the entire metazoan clade are lacking, limiting our understanding of the fundamental principles governing gut microbiomes. Here we present the Gut Microbiome Tree of Life (GMToL), a curated 16S amplicon dataset of 17,366 samples from 1,553 host species across 26 host classes from 284 studies, enabling analysis of large-scale evolutionary trends. Using ancestral state reconstruction, we provide a critical baseline calculation of major compositional shifts in gut microbiomes throughout animal evolution. We show that the ancestral animal gut was likely dominated by Pseudomonadota. A major shift to Bacteroidota occurred during the evolution of tetrapods, followed by the emergence of Bacillota-dominated guts in mammals and birds. We identify conserved core gut microbes and demonstrate how GMToL can be leveraged to contextualize the evolutionary history of specific microbial taxa. Ultimately, this framework enables the predictive mapping of microbial symbionts across uncharacterized host lineages, and establishes a quantitative baseline for comparative microbiome research at scale.","rel_num_authors":15,"rel_authors":[{"author_name":"Samuel Degregori","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, California, USA"},{"author_name":"Lucas Patel","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, California, USA; Bioinformatics and Systems Biology Program, University of California Sa"},{"author_name":"Luis Xu","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, California, USA"},{"author_name":"Michael Iter","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, California, USA; Bioinformatics and Systems Biology Program, University of California Sa"},{"author_name":"Yuhan Weng","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, California, USA; Bioinformatics and Systems Biology Program, University of California Sa"},{"author_name":"Isabella Huang","author_inst":"Johns Hopkins University, Baltimore, Maryland, USA"},{"author_name":"Harrison J Martel","author_inst":"Johns Hopkins University, Baltimore, Maryland, USA"},{"author_name":"Dmitry Kisselev","author_inst":"Johns Hopkins University, Baltimore, Maryland, USA"},{"author_name":"Jianshu Zhou","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, California, USA"},{"author_name":"Celeste Allaband","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, California, USA"},{"author_name":"Gail Ackermann","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, California, USA"},{"author_name":"Antonio Gonzalez","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, California, USA"},{"author_name":"Daniel McDonald","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, California, USA"},{"author_name":"Katherine R Amato","author_inst":"Department of Anthropology, Northwestern University, Evanston, IL, USA"},{"author_name":"Rob Knight","author_inst":"Department of Pediatrics, University of California San Diego, La Jolla, California, USA"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Distinct phases of immune system programming during ART-suppressed immunodeficiency virus infection","rel_doi":"10.64898\/2026.04.29.721702","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.29.721702","rel_abs":"People living with HIV (PLWH) on suppressive antiretroviral therapy (ART) can face non-AIDS complications, partially driven by chronic immune activation. To define immune perturbations during ART-suppressed viral infection, we performed longitudinal single-cell transcriptomic and plasma proteomic analysis of rhesus macaques infected with SIVmac239M and ART-treated for 70 weeks. We identified broad, bi-phasic immune changes. Acute infection involves an interferon-driven signature, correlated with viral replication, that largely resolves with viral control. Cell-associated virus correlated with interferon-stimulated genes in most tissues; however, this was blunted in gut-associated lymph nodes, a feature that may contribute to reservoir persistence. Separate alterations manifest 54-66 weeks-post-infection, after 40 weeks of viral suppression, including broad TGF-{beta} and NF-{kappa}B signaling and discrete bursts of inflammatory monocytes, largely restricted to bone marrow. These data highlight the biphasic remodeling of long-term ART-suppressed HIV, identifying specific tissues and cell populations with dysregulation, with implications for the treatment of PLWH.","rel_num_authors":20,"rel_authors":[{"author_name":"Maanasa Kaza","author_inst":"Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, 97006, USA"},{"author_name":"Benjamin Varco-Merth","author_inst":"Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR, 97006, USA"},{"author_name":"GW McElfresh","author_inst":"Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, 97006, USA"},{"author_name":"Sebastian Benjamin","author_inst":"Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, 97006, USA"},{"author_name":"Gregory J. Boggy","author_inst":"Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, 97006, USA"},{"author_name":"Morgan Chaunzwa","author_inst":"Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, 97006, USA"},{"author_name":"Shana Feltham","author_inst":"Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR, 97006, USA"},{"author_name":"Sohita Ojha","author_inst":"Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR, 97006, USA"},{"author_name":"Karina Belica","author_inst":"Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR, 97006, USA"},{"author_name":"Andrea  N. Selseth","author_inst":"Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR, 97006, USA"},{"author_name":"Michael Nekorchuk","author_inst":"Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR, 97006, USA"},{"author_name":"Kathleen Busman-Sahay","author_inst":"Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR, 97006, USA"},{"author_name":"Brandon F Keele","author_inst":"AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA."},{"author_name":"Dan H. Barouch","author_inst":"Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA."},{"author_name":"Jeffrey  D. Lifson","author_inst":"AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA."},{"author_name":"Jacob  D. Estes","author_inst":"Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR, 97006, USA"},{"author_name":"Scott  G. Hansen","author_inst":"Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, 97006, USA"},{"author_name":"Afam Okoye","author_inst":"Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR, 97006, USA"},{"author_name":"Louis  J. Picker","author_inst":"Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, 97006, USA"},{"author_name":"Benjamin  N. Bimber","author_inst":"Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, 97006, USA"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Inhibition of oogenic JNK preserves fertility and ovarian hormones during DNA-damaging cancer therapy","rel_doi":"10.64898\/2026.04.28.721450","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.28.721450","rel_abs":"Primary ovarian insufficiency (POI) and related infertility, early menopause, and endocrine disorders due to hormonal deficiency are major side effects in young female cancer patients undergoing cancer therapy. Current strategies preserving the fertility and hormonal functions of the ovary remain imperfect due to concerns of feasibility, efficacy, or safety. Herein, we identified c-Jun N-terminal kinase (JNK) as a pivotal regulator of the DNA damage response (DDR) signaling in oocytes of primordial follicles in response to DNA-damaging cancer therapy. Using pharmacological JNK inhibition and a genetically modified mouse model with oocyte-specific JNK deletion, together with histological, bioinformatic, and molecular approaches, we demonstrated that JNK inhibition prevented chemotherapy-induced oocyte apoptosis and POI, and preserved long-term reproductive cycles and fertility. Mechanistically, JNK was activated in response to chemotherapy-induced DNA damage in oocytes of primordial follicles, causing activation of transcription factor TAp63 and subsequent oocyte apoptosis, ultimately resulting in diminished ovarian reserve and POI. A more clinically relevant breast cancer-bearing mouse model revealed that JNK inhibition preserved the ovarian reserve without compromising anti-cancer efficacy of chemotherapy. Together, our study identifies oocyte-intrinsic JNK as a promising target for developing ovarian protectants and safeguarding reproductive health and fertility in young female cancer survivors.","rel_num_authors":9,"rel_authors":[{"author_name":"Wenlong Zhao","author_inst":"Rutgers University"},{"author_name":"Jiyang Zhang","author_inst":"Rutgers University"},{"author_name":"Yingnan Bo","author_inst":"Rutgers University"},{"author_name":"Yingzheng Wang","author_inst":"Cornell University"},{"author_name":"Mi Ran Choi","author_inst":"Rutgers University"},{"author_name":"Shichao Liu","author_inst":"Rutgers University"},{"author_name":"Qiang Zhang","author_inst":"Emory University"},{"author_name":"So-Youn Kim","author_inst":"Rutgers University"},{"author_name":"Shuo Xiao","author_inst":"Rutgers University"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"OmniAge: a compendium of aging omic biomarkers links mitotic clocks to clonal hematopoiesis and causality","rel_doi":"10.64898\/2026.04.29.720033","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.29.720033","rel_abs":"Interest in aging 'omic' biomarkers has grown due to their ability to quantify biological age. Most of these biomarkers have been derived in blood and fall into many diverse categories, yet relatively little is known about their correlative patterns, especially between biomarkers from different categories. Here we present the OmniAge R and Python package, a collection of 413 aging omic biomarkers representing 12 different categories, including traditional epigenetic clocks, epigenetic mitotic clocks, DNA methylation-based proxies for clonal hematopoiesis and inflammaging, causal clocks, cell-type specific epigenetic clocks and single-cell transcriptomic clocks. By studying their inter-class correlations across large blood datasets, we reveal associations of mitotic age with clonal hematopoiesis subtypes and causal clocks, which are predictive of cancer risk. Using proxies of serum protein levels, we further dissect associations with mitotic clocks, clonal hematopoiesis and causal clocks into distinct biological processes mapping to key aging pathways. Applying OmniAge to multi-modal data of sorted immune cell-types reveals that age-acceleration derived from transcriptomic and epigenetic clocks correlate, but that this is driven by underlying cell-type heterogeneity. In summary, the OmniAge package is an exploratory tool for evaluating large numbers of aging omic biomarkers, and to aid discovery and generate new hypotheses.","rel_num_authors":5,"rel_authors":[{"author_name":"Zhaozhen Du","author_inst":"Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China."},{"author_name":"Yunchao Ling","author_inst":"Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China."},{"author_name":"Huige Tong","author_inst":"Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China."},{"author_name":"Xiaolong Guo","author_inst":"Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China."},{"author_name":"Andrew E. Teschendorff","author_inst":"Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China."}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Single-cell transcriptional landscape of muscle-derived stem\/progenitor cells reveals hallmarks of aging and rejuvenation","rel_doi":"10.64898\/2026.04.28.721405","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.28.721405","rel_abs":"Muscle-derived stem\/progenitor cells (MDSPCs) are an adult stem cell population with demonstrated regenerative and rejuvenative potential distinct from other muscle progenitor cells. However, their molecular identity and developmental status remain poorly defined. Using single-cell transcriptomics and proteomics, we comprehensively profiled murine MDSPCs across age groups. We show that MDSPCs exist along a transcriptional continuum of maturation--ranging from metabolically active, proliferative early-stage cells to late-stage, lineage-committed myogenic populations. While lacking canonical pluripotency markers, early-stage MDSPCs express gene programs associated with embryonic progenitor identity, suggesting a non-canonical, multipotent-like state. These features distinguish them from both satellite cells and committed myoblasts. Aging reshapes this continuum by reducing stemness-associated signatures while enhancing differentiation programs and oxidative stress. Our identification of distinct MDSPC states provide critical insights into mechanisms that underly tissue regeneration and aging. These findings offer a blueprint for development of future regenerative therapies to combat age-related functional decline.","rel_num_authors":8,"rel_authors":[{"author_name":"Kavitha Mukund","author_inst":"UCSD"},{"author_name":"Seth David Thompson","author_inst":"Shirley Ryan AbilityLab"},{"author_name":"Chelsea L Rugel","author_inst":"Shirley Ryan AbilityLab"},{"author_name":"Kamil K Gebis","author_inst":"Northwestern University"},{"author_name":"Richard Louis Lieber","author_inst":"Shirley Ryan AbilityLab"},{"author_name":"Jeffrey N Savas","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Shankar Subramaniam","author_inst":"UC San Diego"},{"author_name":"Mitra Lavasani","author_inst":"Shirley Ryan AbilityLab"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Lysophosphatidic Acid (LPA) Salivary Species Detection and Whole-mount LPA Receptor Localization in Mouse Salivary Gland","rel_doi":"10.64898\/2026.04.28.721492","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.28.721492","rel_abs":"This study builds on our previous findings on the role of salivary lysophosphatidic acid (LPA) species in humans to investigate their presence, together with salivary gland LPA receptor (LPAR) expression in a Porphyromonas gingivalis- infected murine (C57BL\/6J) model of periodontal disease (PD). Utilizing LC-MS\/MS for LPA analysis alongside confocal LPAR imaging and second harmonic (SHG) imaging for collagen visualization, we compared mouse salivary LPA levels and gland LPAR expression to previously established human and mouse data. The findings reveal that while healthy mouse saliva maintains low homeostatic LPA levels, PD triggers an ~ 10-fold increase, mirroring the elevation we observed in PD patients. Furthermore, the study confirmed the presence of LPA1, LPA3, and LPA4 within submandibular gland (SMG) tissue. Notably, LPA3 was identified as the most widely distributed subtype, while providing the first evidence of LPA4 expression in adult mouse salivary glands. The presence of multiple LPARs suggests that LPA signaling is a critical factor in salivary gland biology. The documented existence of multiple LPARs within salivary glands indicates that they must be taken into consideration in future research concerning autoimmune conditions, and in pharmacological studies involving drugs that impact salivary gland biology and secretory function.","rel_num_authors":7,"rel_authors":[{"author_name":"D. Roselyn Cerutis","author_inst":"Creighton University"},{"author_name":"Devendra Kumar","author_inst":"University of Nebraska Medical Center"},{"author_name":"Michael G. Nichols","author_inst":"Creighton University"},{"author_name":"Gabrielle Rae Roemer","author_inst":"Creighton University"},{"author_name":"Maxwell Emmett Fluent","author_inst":"Creighton University"},{"author_name":"Takanari Miyamoto","author_inst":"Creighton University"},{"author_name":"Yazen Alnouti","author_inst":"University of Nebraska Medical Center"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Xenium In Situ Profiling Uncovers HSPG-Dependent SULF1\/VEGFR2 Signaling Mediating Vascular Remodeling in Moyamoya Disease","rel_doi":"10.64898\/2026.04.28.721514","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.28.721514","rel_abs":"Background: Moyamoya disease (MMD) is characterized by progressive arterial stenosis and abnormal collateral formation, but the spatial organization of vessel-wall abnormalities remains incompletely understood. Methods: We combined Xenium in situ spatial transcriptomics and multiplex immunofluorescence in superficial temporal artery samples from patients with MMD and controls, and performed gain- and loss-of-function experiments in human brain microvascular endothelial cells (HBMECs). Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), tube-formation, Transwell migration, and cell scratch assays were used to assess signaling and endothelial phenotypes. Results: MMD vascular tissue showed intimal hyperplasia, altered spatial cellular architecture, and enrichment of extracellular matrix- and proteoglycan-related programs, with upregulation of sulfatase 1 (SULF1). In HBMECs, SULF1 knockdown reduced, whereas SULF1 overexpression enhanced, vascular endothelial growth factor A165 (VEGF-A165)-induced vascular endothelial growth factor receptor 2 (VEGFR2), extracellular signal-regulated kinase 1\/2 (ERK1\/2), and protein kinase B (AKT) phosphorylation, migration, tube formation, and angiogenesis- and adhesion-related gene expression. Heparinase III attenuated the signaling effects associated with SULF1 overexpression. Conclusion: These findings suggest that SULF1-associated extracellular matrix alterations may contribute to local vessel-wall remodeling and enhanced endothelial responsiveness in MMD.","rel_num_authors":6,"rel_authors":[{"author_name":"Yaoren Chang","author_inst":"Beijing Tiantan Hospital Department of Neurosurgery"},{"author_name":"Xiaofan Yu","author_inst":"Beijing Tiantan Hospital, Capital Medical University, Beijing, China"},{"author_name":"Talha Ahmed","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Yuanli Zhao","author_inst":"Peking Union Medical College Hospital Department of Neurosurgery"},{"author_name":"Shihao He","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Xun Ye","author_inst":"Beijing Tiantan Hospital Affiliated to Capital Medical University"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Interpretable sequence-based machine learning consolidates candidate H3N2 hemagglutinin antigenic sites","rel_doi":"10.64898\/2026.04.28.721429","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.28.721429","rel_abs":"Vaccine strain selection for seasonal influenza A(H3N2) depends on knowing which hemagglutinin (HA) substitutions are most likely to erode neutralizing antibody recognition, yet published antigenic site sets disagree substantially on which positions matter most. We applied interpretable gradient-boosted tree models with SHAP-based site attribution to two complementary hemagglutination inhibition (HI) datasets to produce a more consolidated ranking of candidate antigenic positions. Models trained on a Neher\/Bedford benchmark dataset recover the canonical cluster-transition sites established by prior analyses. Moreover, after filtering the WIC dataset for confounding factors, our models recover the majority of positions from four major prior reference sets (Koel, Neher\/Bedford, Harvey, and Shah) and improve concordance between rankings derived from the Neher\/Bedford and WIC datasets. Rankings from our models also agree more strongly with models trained to predict sampling time or passage identity than with standard evolutionary metrics used to detect diversifying selection. Our results show that interpretable sequence-based models can provide a more integrative ranking of candidate antigenic positions across different data sources and modeling approaches. This work should aid efforts to prioritize H3N2 substitutions for epidemic surveillance.","rel_num_authors":2,"rel_authors":[{"author_name":"Austin G Meyer","author_inst":"Baylor Scott and White Health"},{"author_name":"Mauricio Santillana","author_inst":"Northeastern University"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Defining a Midgestational Window for In Utero Genome Editing of the Fetal Murine Cortex","rel_doi":"10.64898\/2026.04.28.721509","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.28.721509","rel_abs":"Congenital disorders of cortical development arise from genetic lesions that disrupt neurogenesis and neuronal migration. Unfortunately, tools to model or correct these defects before birth are limited. Here we establish a platform for systemic in utero gene delivery and genome editing in the mouse cortex at midgestation. By microdissecting a uterine window over the vitelline vein at embryonic day 12.5 (E12.5), we achieve fetal circulation access, enabling robust AAV-mediated transduction of the central nervous system (CNS) while reducing off-target expression in peripheral organs. Barcoded capsid screens reveal that AAV9 exhibits developmental stage-dependent tropism, with higher CNS penetrance and lower liver transduction at E12.5 than at E15.5. Leveraging this window, we provide a proof-of-concept of efficient cortical editing, using Cre-lox and CRISPR\/Cas9 strategies to recapitulate prenatal reeler-like cortical misordering phenotypes following Reln knockout. We further use homology-directed repair to demonstrate precise genome modification, epitope-tagging the endogenous Reln and Actb loci, and installing a human-derived pathogenic allele of PDHA1. Importantly, we show that edited cells span neural progenitors and differentiated neurons across the cortex and hippocampus. These results define a permissive midgestational window for prenatal genome editing, providing a platform for functional modeling of congenital CNS disorders and exploration of early therapeutic interventions with minimized peripheral exposure.","rel_num_authors":6,"rel_authors":[{"author_name":"Cameron R Jackson","author_inst":"Caltech"},{"author_name":"M\u00e1t\u00e9 Borsos","author_inst":"Caltech"},{"author_name":"Nathan Appling","author_inst":"Caltech"},{"author_name":"Carrie R Jackson","author_inst":"Caltech"},{"author_name":"Gerard M Coughlin","author_inst":"Caltech"},{"author_name":"Viviana Gradinaru","author_inst":"Caltech"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"A low-dimensional transcriptional code enables decoding of BMP\/TGF\u03b2 signaling from single-cell transcriptomes","rel_doi":"10.64898\/2026.04.28.721387","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.28.721387","rel_abs":"Cells interpret complex extracellular environments through signaling pathways that compress diverse ligand inputs into a limited set of intracellular mediators. How this information is encoded in transcriptional responses, and whether it can be decoded to infer the original signaling environment, remains unclear. Here, we systematically map BMP\/TGF{beta} transcriptional responses using single-cell RNA sequencing across 48 ligand-concentration conditions, generating a multi-ligand dose-response atlas. We find that, for each ligand, transcriptional responses collapse onto a one-dimensional, highly coordinated program in which concentration modulates response amplitude without altering gene identity. Across ligands, we find a small number of distinct, ligand-dependent transcriptional programs. We leverage this structured encoding to define a quantitative perception score that captures pathway activity at single-cell resolution. Finally, we train a machine learning model to decode extracellular ligand concentrations from single-cell transcriptomes. The model further generalizes to in vivo intestinal epithelium, where it reconstructs the spatial BMP gradient profile. Together, these results reveal a low-dimensional transcriptional code in BMP\/TGF{beta} signaling that constrains cellular responses and enables quantitative inference of extracellular signaling environments from gene expression.","rel_num_authors":9,"rel_authors":[{"author_name":"Guy Ilan","author_inst":"Weizmann Institute of Science"},{"author_name":"Inbal Eizenberg-Magar","author_inst":"Weizmann Institute of Science"},{"author_name":"Adi Wider","author_inst":"Weizmann Institute of Science"},{"author_name":"Jialong Jiang","author_inst":"The Rockefeller University"},{"author_name":"Sisi Chen","author_inst":"Caltech"},{"author_name":"Jong H Park","author_inst":"Caltech"},{"author_name":"Tsviya Olender","author_inst":"Weizmann Institute of Science"},{"author_name":"Matt Thomson","author_inst":"Caltech"},{"author_name":"Yaron E Antebi","author_inst":"Weizmann Institute of Science"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"A low-dimensional transcriptional code enables decoding of BMP\/TGF\u03b2 signaling from single-cell transcriptomes","rel_doi":"10.64898\/2026.04.28.721387","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.28.721387","rel_abs":"Cells interpret complex extracellular environments through signaling pathways that compress diverse ligand inputs into a limited set of intracellular mediators. How this information is encoded in transcriptional responses, and whether it can be decoded to infer the original signaling environment, remains unclear. Here, we systematically map BMP\/TGF{beta} transcriptional responses using single-cell RNA sequencing across 48 ligand-concentration conditions, generating a multi-ligand dose-response atlas. We find that, for each ligand, transcriptional responses collapse onto a one-dimensional, highly coordinated program in which concentration modulates response amplitude without altering gene identity. Across ligands, we find a small number of distinct, ligand-dependent transcriptional programs. We leverage this structured encoding to define a quantitative perception score that captures pathway activity at single-cell resolution. Finally, we train a machine learning model to decode extracellular ligand concentrations from single-cell transcriptomes. The model further generalizes to in vivo intestinal epithelium, where it reconstructs the spatial BMP gradient profile. Together, these results reveal a low-dimensional transcriptional code in BMP\/TGF{beta} signaling that constrains cellular responses and enables quantitative inference of extracellular signaling environments from gene expression.","rel_num_authors":9,"rel_authors":[{"author_name":"Guy Ilan","author_inst":"Weizmann Institute of Science"},{"author_name":"Inbal Eizenberg-Magar","author_inst":"Weizmann Institute of Science"},{"author_name":"Adi Wider","author_inst":"Weizmann Institute of Science"},{"author_name":"Jialong Jiang","author_inst":"The Rockefeller University"},{"author_name":"Sisi Chen","author_inst":"Caltech"},{"author_name":"Jong H Park","author_inst":"Caltech"},{"author_name":"Tsviya Olender","author_inst":"Weizmann Institute of Science"},{"author_name":"Matt Thomson","author_inst":"Caltech"},{"author_name":"Yaron E Antebi","author_inst":"Weizmann Institute of Science"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Reconstructing True 3D Spatial Omics at Single-Cell Resolution","rel_doi":"10.64898\/2026.04.28.721395","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.28.721395","rel_abs":"Capturing the three-dimensional (3D) organization of cells is essential for deciphering complex biological processes, yet comprehensive 3D spatial omics is severely hindered by the destructive nature of physical sectioning and the depth limitations of intact tissue imaging. Current computational methods rely on 2.5D stacking of discrete slices, which inherently disrupts tissue topology and fails to resolve continuous depth-dependent molecular gradients. To bridge this gap, we introduce DeepSpatial, an Optimal Transport flow matching framework that models tissue evolution as a continuous dynamic vector field. By solving the underlying probability flow ODEs, DeepSpatial enables the direct extraction of uninterrupted, infinitely resolvable tissue states at arbitrary spatial depths. Using Deep STAR\/RIBOmap 3D technologies, we demonstrate that DeepSpatial achieves improved 3D reconstruction fidelity relative to 2.5D approaches, yielding structures that more closely recapitulate native tissue microenvironments in real-world datasets. Across diverse spatial omics modalities, including spatial proteomics using imaging mass cytometry in human breast cancer and spatial transcriptomics using openST in head and neck squamous cell carcinoma metastatic lymph nodes, DeepSpatial produces biologically interpretable and high-fidelity reconstructions across datasets. We evaluated the scalability and robustness of DeepSpatial on a large-scale mouse brain dataset, reconstructing a continuous 3D cellular atlas comprising 39 million cells within 41.6 hours. Systematic downstream characterization validated its ability to recapitulate consistent spatial architectures, cell-type distributions, transcriptomic patterns, and microenvironmental structures across brain regions. Collectively, these results demonstrate DeepSpatial as a generalizable and efficient solution for true 3D spatial reconstruction across scales and modalities.","rel_num_authors":11,"rel_authors":[{"author_name":"Yuhang Yang","author_inst":"State Key Laboratory of Cognitive Intelligence, University of Science and Technology of China, Hefei, China"},{"author_name":"Yiming Luo","author_inst":"Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital "},{"author_name":"Kai Zhang","author_inst":"State Key Laboratory of Cognitive Intelligence, University of Science and Technology of China, Hefei, China"},{"author_name":"Yonggan Bu","author_inst":"State Key Laboratory of Cognitive Intelligence, University of Science and Technology of China, Hefei, China"},{"author_name":"Zheng Xia","author_inst":"Biomedical Engineering Department Knight Cancer Institute, Oregon Health & Science University, Portland, USA"},{"author_name":"Haoxin Peng","author_inst":"Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital "},{"author_name":"Rui Yan","author_inst":"School of Biomedical Engineering, University of Science and Technology of China, Hefei, China"},{"author_name":"Qi Liu","author_inst":"State Key Laboratory of Cognitive Intelligence, University of Science and Technology of China, Hefei, China"},{"author_name":"Yang Chen","author_inst":"Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital "},{"author_name":"Lin Shen","author_inst":"Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital "},{"author_name":"Enhong Chen","author_inst":"State Key Laboratory of Cognitive Intelligence, University of Science and Technology of China, Hefei, China"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Reconstructing True 3D Spatial Omics at Single-Cell Resolution","rel_doi":"10.64898\/2026.04.28.721395","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.28.721395","rel_abs":"Capturing the three-dimensional (3D) organization of cells is essential for deciphering complex biological processes, yet comprehensive 3D spatial omics is severely hindered by the destructive nature of physical sectioning and the depth limitations of intact tissue imaging. Current computational methods rely on 2.5D stacking of discrete slices, which inherently disrupts tissue topology and fails to resolve continuous depth-dependent molecular gradients. To bridge this gap, we introduce DeepSpatial, an Optimal Transport flow matching framework that models tissue evolution as a continuous dynamic vector field. By solving the underlying probability flow ODEs, DeepSpatial enables the direct extraction of uninterrupted, infinitely resolvable tissue states at arbitrary spatial depths. Using Deep STAR\/RIBOmap 3D technologies, we demonstrate that DeepSpatial achieves improved 3D reconstruction fidelity relative to 2.5D approaches, yielding structures that more closely recapitulate native tissue microenvironments in real-world datasets. Across diverse spatial omics modalities, including spatial proteomics using imaging mass cytometry in human breast cancer and spatial transcriptomics using openST in head and neck squamous cell carcinoma metastatic lymph nodes, DeepSpatial produces biologically interpretable and high-fidelity reconstructions across datasets. We evaluated the scalability and robustness of DeepSpatial on a large-scale mouse brain dataset, reconstructing a continuous 3D cellular atlas comprising 39 million cells within 41.6 hours. Systematic downstream characterization validated its ability to recapitulate consistent spatial architectures, cell-type distributions, transcriptomic patterns, and microenvironmental structures across brain regions. Collectively, these results demonstrate DeepSpatial as a generalizable and efficient solution for true 3D spatial reconstruction across scales and modalities.","rel_num_authors":11,"rel_authors":[{"author_name":"Yuhang Yang","author_inst":"State Key Laboratory of Cognitive Intelligence, University of Science and Technology of China, Hefei, China"},{"author_name":"Yiming Luo","author_inst":"Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital "},{"author_name":"Kai Zhang","author_inst":"State Key Laboratory of Cognitive Intelligence, University of Science and Technology of China, Hefei, China"},{"author_name":"Yonggan Bu","author_inst":"State Key Laboratory of Cognitive Intelligence, University of Science and Technology of China, Hefei, China"},{"author_name":"Zheng Xia","author_inst":"Biomedical Engineering Department Knight Cancer Institute, Oregon Health & Science University, Portland, USA"},{"author_name":"Haoxin Peng","author_inst":"Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital "},{"author_name":"Rui Yan","author_inst":"School of Biomedical Engineering, University of Science and Technology of China, Hefei, China"},{"author_name":"Qi Liu","author_inst":"State Key Laboratory of Cognitive Intelligence, University of Science and Technology of China, Hefei, China"},{"author_name":"Yang Chen","author_inst":"Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital "},{"author_name":"Lin Shen","author_inst":"Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital "},{"author_name":"Enhong Chen","author_inst":"State Key Laboratory of Cognitive Intelligence, University of Science and Technology of China, Hefei, China"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Differential peripheral immune dynamics underlie therapeutic response to chemotherapy and chemo-immunotherapy in triple-negative breast cancer","rel_doi":"10.64898\/2026.04.28.721416","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.28.721416","rel_abs":"Triple-negative breast cancer (TNBC) remains the most aggressive breast cancer subtype, with limited treatment options and variable response to immune checkpoint inhibitors. While tumor-infiltrating lymphocytes have been extensively studied, the integration of system-level peripheral immune dynamics with mechanistic immune regulation underlying therapeutic response and resistance remain poorly defined. Here, we integrate systems-level immune state modeling with pathway-level mechanistic inference to analyze single-cell RNA sequencing of peripheral blood mononuclear cells from advanced TNBC patients treated with paclitaxel alone (chemotherapy) or in combination with anti-PD-L1 antibody atezolizumab (combination). This framework leverages treatment arm, longitudinal sampling, and clinical response to resolve coordinated immune programs across lymphoid and myeloid compartments. Using this approach, we identified distinct treatment- and response-specific immune states in pre- and post-treatment. Chemotherapy responders displayed pre-treatment adaptive immune priming, whereas combination therapy responders exhibited pre-existing effector T cell activity coupled with tumor tissue PD-L1 expression. In contrast, chemotherapy non-responders developed persistent post-treatment immune dysregulation in regulatory and terminal effector programs, while combination therapy non-responders demonstrated maladaptive remodeling of adaptive and innate lymphoid compartments, including dysfunctional NK and metabolically reprogrammed myeloid populations. Across both regimens, pathways involving protein translation, metabolic adaptation, and stress signaling emerged as critical modulators of response. These findings suggest that coordinated adaptive-innate immune dynamics underlie therapeutic efficacy, whereas systemic immune exhaustion and myeloid immunoregulation lead to resistance. Projection of these peripheral immune programs onto independent I-SPY2 showed concordant associations with tumor immune phenotypes and pathological complete response, supporting generalizability of the identified systemic immune states. Our study demonstrates the utility of an integrative systems-level approach for linking peripheral immune state organization with mechanistic insights, informing immune response and resistance in TNBC.","rel_num_authors":3,"rel_authors":[{"author_name":"zahra mesrizadeh","author_inst":"UC San Diego"},{"author_name":"Kavitha Mukund","author_inst":"UCSD"},{"author_name":"Shankar Subramaniam","author_inst":"UC San Diego"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Maternal senescence broadly reprograms gene expression in offspring","rel_doi":"10.64898\/2026.04.28.720237","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.28.720237","rel_abs":"Offspring of older parents have reduced fitness in many species1, but the mechanisms mediating this cross-generational dimension of ageing remain poorly understood. Senescence is associated with genome-wide epigenetic changes that alter transcription2, raising the possibility that older parents transmit dysregulated gene expression patterns3,4. Here we show that maternal senescence induces deleterious, transcriptome-wide reprogramming of gene expression in offspring. Gene ontology and pathway enrichment analyses reveal that broad changes in gene expression that characterise maternal senescence in the clonally reproducing arthropod Folsomia candida are also observed at a young age in the offspring of older mothers. These concordant fold-changes are apparent at the whole-transcriptome level, and encompass conserved sequalae of senescence, including reduced carbon and energy metabolism. However, senescent mothers and their offspring also exhibit some contrasting gene expression patterns, representing distinct transcriptomic signatures of senescence that are not reflected in its cross-generational effects. The broad reprogramming of gene expression in offspring of older mothers is associated with substantially reduced fitness. Our findings show that older females can transmit a senescence-like gene expression syndrome to their offspring, inducing deleterious phenotypes from a young age.","rel_num_authors":3,"rel_authors":[{"author_name":"Soleille Morelli Miller","author_inst":"University of New South Wales"},{"author_name":"Zachariah Wylde","author_inst":"University of New South Wales"},{"author_name":"Russell Bonduriansky","author_inst":"University of New South Whales"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Pseudouridylation landscape across 42 S. cerevisiae cytosolic tRNA isoacceptors via Nanopore direct RNA sequencing","rel_doi":"10.64898\/2026.04.28.721490","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.28.721490","rel_abs":"Pseudouridine is the most abundant RNA base modification due to its prevalence in tRNA and rRNA, where it serves as a key modulator of structure and function. Yet even in a widely used model organism, the budding yeast Saccharomyces cerevisiae, the positions of all pseudouridines in tRNA have not been completely annotated. Using Nanopore direct RNA sequencing (DRS), an established method for detecting RNA pseudouridylation positions, we sequenced cytosolic tRNA from eight pseudouridine synthase (PUS) knockout S. cerevisiae strains, including deletion strains of Pus1, Pus3, and Pus7. Analysis of these data verified thirty-four existing pseudouridine annotations and predicted eleven previously unannotated pseudouridine sites. Our analysis revealed DRS signal changes at several non-uridine sites with the loss of a PUS, including apparent changes in modification abundances at position 37 upon deletion of Pus3. LC-MS\/MS and primer extension assays, however, indicated no change in the abundance of these modifications with the loss of Pus3. Our analysis underscores the need for caution in interpreting DRS-based signal changes, particularly in modification-dense regions. Combining existing modification annotations for the thirty-one isoacceptors in the Modomics database with our dataset that added annotations for the remaining eleven isoacceptors, we created a map of all detected pseudouridines, and the enzymes responsible for their catalysis, across the forty-two S. cerevisiae cytosolic tRNA isoacceptors.","rel_num_authors":10,"rel_authors":[{"author_name":"Margaret L Barry","author_inst":"University of Oregon"},{"author_name":"Robin L Abu-Shumays","author_inst":"University of California Santa Cruz"},{"author_name":"Lauren E Barnes","author_inst":"University of Michigan"},{"author_name":"Ethan A Shaw","author_inst":"University of Oregon"},{"author_name":"Julia L Reinsch","author_inst":"University of Oregon"},{"author_name":"Abigail L Vaaler","author_inst":"University of Oregon"},{"author_name":"Zachary D Basham","author_inst":"University of Oregon"},{"author_name":"Miten Jain","author_inst":"Northeastern University"},{"author_name":"Kristin S Koutmou","author_inst":"University of Michigan"},{"author_name":"David M Garcia","author_inst":"University of Oregon, Institute of Molecular Biology"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Circulating inflammatory ILC2s as a biomarker of gastric cancer progression","rel_doi":"10.64898\/2026.04.28.721482","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.28.721482","rel_abs":"Gastric cancer is frequently diagnosed at an advanced stage, contributing to poor patient outcomes and highlighting the need for blood-based biomarkers that can detect disease earlier and track progression. We previously showed that a tuft cell-IL25-type 2 innate lymphoid cell (ILC2) circuit promotes gastric metaplasia and gastric tumour development, but whether this pathway gives rise to a circulating ILC2 population remained unknown. Here, we show that IL25-responsive inflammatory ILC2s (iILC2s) emerge in the blood across gastric disease progression and are selectively associated with gastric tumour contexts. Using multiple mouse models spanning SPEM, early gastric adenoma, and advanced gastric cancer, we found that circulating ILC2s increased progressively with disease severity, with the dominant increase occurring in the IL17RB+ iILC2 subset. This response was not observed in pancreatic or ovarian tumour models, indicating that circulating iILC2 mobilisation is not a general consequence of tumour burden. Instead, mobilisation was linked to gastric disease and accompanied by increased ILC2 accumulation in distal mucosal tissues. Genetic tuft cell ablation or therapeutic blockade of IL25 or IL13 significantly reduced circulating iILC2s, demonstrating that this response depends on the tuft cell-IL25 circuit. In vivo, mobilised iILC2s were associated with enhanced growth of distal tumour implants, supporting a functional contribution beyond the primary gastric site. Translationally, circulating ILC2s were elevated in patients with gastric inflammatory disease and gastric cancer, with the IL25-responsive subset predominating. Circulating ILC2s also showed strong discriminatory power between gastric cancer patients and healthy controls in ROC analysis, supporting their potential utility as a blood-based biomarker. Together, these findings identify circulating iILC2s as a systemic hallmark of gastric tuft cell-ILC2 signalling and establish their mechanistic and translational relevance in gastric cancer.","rel_num_authors":11,"rel_authors":[{"author_name":"Ryan N O'Keefe","author_inst":"Olivia Newton-John Cancer Research Institute"},{"author_name":"Kiruthiga Raghunathan","author_inst":"Olivia Newton-John Cancer Research Institute"},{"author_name":"Moritz F Eissmann","author_inst":"Olivia Newton-John Cancer Research Institute"},{"author_name":"David Baloyan","author_inst":"Olivia Newton-John Cancer Research Institute"},{"author_name":"Ashleigh R Poh","author_inst":"Olivia Newton-John Cancer Research Institute"},{"author_name":"Megan O'Brien","author_inst":"Olivia Newton-John Cancer Research Institute"},{"author_name":"Edgar Clapdorp","author_inst":"HOGENT University of Applied Sciences and Arts"},{"author_name":"Shoukat Afshar-Sterle","author_inst":"Olivia Newton-John Cancer Research Institute"},{"author_name":"Richard M Locksley","author_inst":"UCSF"},{"author_name":"Matthias Ernst","author_inst":"Olivia Newton John Cancer Research Institute"},{"author_name":"Michael Buchert","author_inst":"Olivia Newton-John Cancer Research Institute"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"G2-to-G0 cell cycle exit underlies sensitivity to ATR inhibition via the p53-p21-RB1 axis","rel_doi":"10.64898\/2026.04.28.721427","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.28.721427","rel_abs":"Ataxia-telangiectasia and Rad3-related (ATR) is an essential DNA damage response kinase that protects genome integrity by controlling cell cycle checkpoints, regulating origin firing, stabilizing replication forks, and signaling DNA repair. Due to hyper-proliferation, cancer cells depend on ATR for survival, implicating ATR inhibitors as promising therapeutics. However, variable tumor responses to ATR inhibitors highlights the need to uncover the determinants of cell fate. Here, we show breast cancer sensitivity to ATR inhibition correlates with the appearance of pan-nuclear DNA damage. The fate of these cells is driven by a p53-p21-RB1 axis that triggers a G2-to-G0-like cell cycle exit and is buffered by the p53 inhibitor MDM2. MDM2 inhibition lowers the DNA damage threshold for cell cycle exit and robustly targets ATR inhibitor-resistant cells. Our work reveals cell cycle plasticity as a mechanism determining cell fate during ATR inhibition and identifies MDM2 as a target for increasing ATR inhibitor efficacy.","rel_num_authors":4,"rel_authors":[{"author_name":"Celina Sanchez","author_inst":"Oregon Health and Science University"},{"author_name":"Carlos Origel Marmolejo","author_inst":"Oregon Health and Science University"},{"author_name":"Juyoung Lee","author_inst":"Oregon Health and Science University"},{"author_name":"Joshua C Saldivar","author_inst":"Oregon Health and Science University"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Arrestin-3 promotes locomotor sensitization to psychostimulants via JNK signaling in nucleus accumbens","rel_doi":"10.64898\/2026.04.28.719936","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.28.719936","rel_abs":"Arrestins play key role in desensitization of G protein-coupled receptors. Direct signaling role of arrestins has also been documented. Two ubiquitously expressed arrestin isoforms, arrestin-2 and -3 (Arr3), perform similarly in receptor desensitization and share many signaling functions, enabling them to substitute for one another. However, certain signaling roles are specific to each isoform. Mice lacking Arr3 (A3KO) show blunted acute responsiveness to the locomotor stimulatory effect of amphetamine (AMPH). Here we demonstrate that AMPH- and cocaine-induced locomotion of A3KO mice is significantly reduced. This loss-of-function phenotype suggests that Arr3-mediated signaling contributes to the effect. Virus-driven expression of Arr3 in caudate-putamen of A3KO and wild type mice suppressed AMPH-induced locomotion. In contrast, restoration of Arr3 in nucleus accumbens rescued locomotor response. Thus, in caudate-putamen Arr3 participates in the desensitization of dopamine receptors, whereas Arr3-dependent signaling in nucleus accumbens underlies the molecular mechanism of the locomotor response and sensitization. Using monofunctional Arr3-derived peptides, we showed that in the nucleus accumbens Arr3 promoted drug-induced locomotor responses via facilitation of JNK3 activation.","rel_num_authors":11,"rel_authors":[{"author_name":"Mohamed R Ahmed","author_inst":"Vanderbilt University"},{"author_name":"Jeffery L Dunning","author_inst":"Scripps Research"},{"author_name":"Chen Zheng","author_inst":"Vanderbilt University"},{"author_name":"Sonia Kim","author_inst":"Case Western Reserve University"},{"author_name":"Sebastian Milanes","author_inst":"Tulane University"},{"author_name":"Christopher Bozorgmehr","author_inst":"Washington University in Saint Louis"},{"author_name":"Jordan Janzen-Meza","author_inst":"Washington University in Saint Louis"},{"author_name":"Kathleen Yao","author_inst":"Vanderbilt University"},{"author_name":"Haoru Li","author_inst":"Vanderbilt University"},{"author_name":"Vsevolod V Gurevich","author_inst":"Vanderbilt University"},{"author_name":"Eugenia V Gurevich","author_inst":"Vanderbilt University"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Arrestin-3 promotes locomotor sensitization to psychostimulants via JNK signaling in nucleus accumbens","rel_doi":"10.64898\/2026.04.28.719936","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.28.719936","rel_abs":"Arrestins play key role in desensitization of G protein-coupled receptors. Direct signaling role of arrestins has also been documented. Two ubiquitously expressed arrestin isoforms, arrestin-2 and -3 (Arr3), perform similarly in receptor desensitization and share many signaling functions, enabling them to substitute for one another. However, certain signaling roles are specific to each isoform. Mice lacking Arr3 (A3KO) show blunted acute responsiveness to the locomotor stimulatory effect of amphetamine (AMPH). Here we demonstrate that AMPH- and cocaine-induced locomotion of A3KO mice is significantly reduced. This loss-of-function phenotype suggests that Arr3-mediated signaling contributes to the effect. Virus-driven expression of Arr3 in caudate-putamen of A3KO and wild type mice suppressed AMPH-induced locomotion. In contrast, restoration of Arr3 in nucleus accumbens rescued locomotor response. Thus, in caudate-putamen Arr3 participates in the desensitization of dopamine receptors, whereas Arr3-dependent signaling in nucleus accumbens underlies the molecular mechanism of the locomotor response and sensitization. Using monofunctional Arr3-derived peptides, we showed that in the nucleus accumbens Arr3 promoted drug-induced locomotor responses via facilitation of JNK3 activation.","rel_num_authors":11,"rel_authors":[{"author_name":"Mohamed R Ahmed","author_inst":"Vanderbilt University"},{"author_name":"Jeffery L Dunning","author_inst":"Scripps Research"},{"author_name":"Chen Zheng","author_inst":"Vanderbilt University"},{"author_name":"Sonia Kim","author_inst":"Case Western Reserve University"},{"author_name":"Sebastian Milanes","author_inst":"Tulane University"},{"author_name":"Christopher Bozorgmehr","author_inst":"Washington University in Saint Louis"},{"author_name":"Jordan Janzen-Meza","author_inst":"Washington University in Saint Louis"},{"author_name":"Kathleen Yao","author_inst":"Vanderbilt University"},{"author_name":"Haoru Li","author_inst":"Vanderbilt University"},{"author_name":"Vsevolod V Gurevich","author_inst":"Vanderbilt University"},{"author_name":"Eugenia V Gurevich","author_inst":"Vanderbilt University"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Arrestin-3 promotes locomotor sensitization to psychostimulants via JNK signaling in nucleus accumbens","rel_doi":"10.64898\/2026.04.28.719936","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.28.719936","rel_abs":"Arrestins play key role in desensitization of G protein-coupled receptors. Direct signaling role of arrestins has also been documented. Two ubiquitously expressed arrestin isoforms, arrestin-2 and -3 (Arr3), perform similarly in receptor desensitization and share many signaling functions, enabling them to substitute for one another. However, certain signaling roles are specific to each isoform. Mice lacking Arr3 (A3KO) show blunted acute responsiveness to the locomotor stimulatory effect of amphetamine (AMPH). Here we demonstrate that AMPH- and cocaine-induced locomotion of A3KO mice is significantly reduced. This loss-of-function phenotype suggests that Arr3-mediated signaling contributes to the effect. Virus-driven expression of Arr3 in caudate-putamen of A3KO and wild type mice suppressed AMPH-induced locomotion. In contrast, restoration of Arr3 in nucleus accumbens rescued locomotor response. Thus, in caudate-putamen Arr3 participates in the desensitization of dopamine receptors, whereas Arr3-dependent signaling in nucleus accumbens underlies the molecular mechanism of the locomotor response and sensitization. Using monofunctional Arr3-derived peptides, we showed that in the nucleus accumbens Arr3 promoted drug-induced locomotor responses via facilitation of JNK3 activation.","rel_num_authors":11,"rel_authors":[{"author_name":"Mohamed R Ahmed","author_inst":"Vanderbilt University"},{"author_name":"Jeffery L Dunning","author_inst":"Scripps Research"},{"author_name":"Chen Zheng","author_inst":"Vanderbilt University"},{"author_name":"Sonia Kim","author_inst":"Case Western Reserve University"},{"author_name":"Sebastian Milanes","author_inst":"Tulane University"},{"author_name":"Christopher Bozorgmehr","author_inst":"Washington University in Saint Louis"},{"author_name":"Jordan Janzen-Meza","author_inst":"Washington University in Saint Louis"},{"author_name":"Kathleen Yao","author_inst":"Vanderbilt University"},{"author_name":"Haoru Li","author_inst":"Vanderbilt University"},{"author_name":"Vsevolod V Gurevich","author_inst":"Vanderbilt University"},{"author_name":"Eugenia V Gurevich","author_inst":"Vanderbilt University"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"DIANNE: Segmentation-Free Localization of Histology Differential Attributes","rel_doi":"10.64898\/2026.04.28.721103","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.28.721103","rel_abs":"Pathologist-guided distinctions within histology and spatial omic images provide insights into health and disease, with digital pathology leveraging artificial intelligence to automate such assessments. To train computational models, current digital pathology methods rely on upfront manual annotations, which are time-consuming to generate. Pre-annotation is poorly suited to investigating novel spatial behaviors - a major need driven by advances in spatial profiling - for which annotation criteria and data needs will be uncertain. To address these challenges, we present DIANNE, a digital pathology approach for rapid training and inference of spatial differential attributes based on train-time Positive Class Mixup Augmentation. DIANNE can compute foundation model-derived segmentation-free localization of differential classifiers across whole slide H&E images within seconds on a workstation, enabling interactive investigation of spatial niches. Predictive models can be re-trained in real-time in response to patch or regional annotation changes, clarifying determinative biological attributes across slides from only a few dozen annotated patches. We demonstrate the effectiveness of DIANNE for tumor detection, artifact identification, and exploration of pancreatic, fetal membranes and kidney tissue structures. DIANNE also provides analogous capabilities for IHC, multiplex immunofluorescence, and registered spatial transcriptomic+H&E images. DIANNE is implemented in a Jupyter toolkit, enabling rapid development of high-resolution classifiers from weakly-supervised training. DIANNE provides a practical system to quantitatively understand known and novel spatial phenotypes.","rel_num_authors":13,"rel_authors":[{"author_name":"Sergii Domanskyi","author_inst":"The Jackson Laboratory for Genomic Medicine, Farmington, CT"},{"author_name":"Jill C. Rubinstein","author_inst":"The Jackson Laboratory for Genomic Medicine, Farmington, CT; Hartford HealthCare, Hartford, CT; Department of Genetics and Genome Sciences, UConn Health, Farmin"},{"author_name":"Todd B. Sheridan","author_inst":"The Jackson Laboratory for Genomic Medicine, Farmington, CT; Hartford HealthCare, Hartford, CT"},{"author_name":"Adam Thiesen","author_inst":"The Jackson Laboratory for Genomic Medicine, Farmington, CT"},{"author_name":"Javad Noorbakhsh","author_inst":"The Jackson Laboratory for Genomic Medicine, Farmington, CT"},{"author_name":"Juliana Alcoforado Diniz","author_inst":"The Jackson Laboratory for Genomic Medicine, Farmington, CT"},{"author_name":"Ramalakshmi Ramasamy","author_inst":"The Jackson Laboratory for Genomic Medicine, Farmington, CT"},{"author_name":"Dylan S. Baker","author_inst":"The Jackson Laboratory for Genomic Medicine, Farmington, CT"},{"author_name":"Riley Sheldon","author_inst":"The Jackson Laboratory for Genomic Medicine, Farmington, CT"},{"author_name":"Qian Wu","author_inst":"Department of Pathology and Laboratory Medicine, UConn Health, Farmington, CT"},{"author_name":"George Kuchel","author_inst":"UConn Center on Aging, UConn Health, Farmington, CT"},{"author_name":"Paul Robson","author_inst":"The Jackson Laboratory for Genomic Medicine, Farmington, CT; Department of Genetics and Genome Sciences, UConn Health, Farmington, CT"},{"author_name":"Jeffrey H. Chuang","author_inst":"The Jackson Laboratory for Genomic Medicine, Farmington, CT; Department of Genetics and Genome Sciences, UConn Health, Farmington, CT"}],"rel_date":"2026-05-01","rel_site":"biorxiv"},{"rel_title":"Performance of Human and Computer-aided Evaluation of Digital Chest Radiography for Community-based Screening of Asymptomatic Tuberculosis","rel_doi":"10.64898\/2026.04.29.26351560","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.29.26351560","rel_abs":"BackgroundThe World Health Organisation (WHO) recommends digital chest radiography (dCXR) with computer-aided detection (CAD) for tuberculosis (TB) screening of individuals >15 years of age.\n\nMethodologyAdults ([&ge;]18 years) were enrolled (March 2021-December 2022) in South Africa into a community-based Screening Cohort (household contacts) and a facility-based Triage Cohort (symptomatic clinic attendees). Microbiologically-confirmed pulmonary TB required positive sputum culture and\/or Xpert Ultra. Asymptomatic TB was diagnosed in participants without TB symptoms. dCXR were read by blinded human readers and qXR CAD (0.5 threshold; Qure.AI, India).\n\nResultsdCXR from 1,353 participants (886 Screening Cohort; 467 Triage Cohort) were analysed. Microbiologically-confirmed TB occurred in 48 (5.4%) Screening Cohort [9 symptomatic (19%) and 39 asymptomatic (81%)]; and 116 (24.8%) Triage Cohort (all symptomatic) participants. dCXR sensitivity (human readers) for asymptomatic TB in the Screening Cohort was 56.4%, vs. 72.4% for symptomatic TB in the Triage Cohort (difference -16%; 95%CI -2.9 to -29.1); with specificities 94.1% and 81.2%, respectively. Corresponding qXR CAD sensitivities were 69.2% vs. 83.6% (difference -14.4%; 95%CI -26 to -2.8), with specificities 89.3% and 73.5%, respectively. The difference in dCXR sensitivity and specificity for asymptomatic TB between qXR CAD and human readers was 12.8% (95%CI -0.48 to 26.1) and -4.8% (95%CI -12.4 to 28.2), respectively.\n\nConclusionSensitivity of community-based dCXR screening for microbiologically-confirmed asymptomatic TB among household contacts was lower than for facility-based triage of symptomatic TB, but approached 70% with CAD. Neither human reader nor qXR CAD evaluation met WHO targets for a TB screening test (90% sensitivity; 80% specificity).\n\nResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSThe World Health Organisation (WHO) recommends digital chest radiography (dCXR) with computer-aided detection (CAD) for tuberculosis (TB) screening of individuals >15 years of age, based on data from prevalence surveys and facility-based studies. Performance data for community-based screening of asymptomatic TB are lacking. We searched PubMed for literature published in English between January 1, 2000, and November 1, 2025, for community-based, active case-finding studies of adolescents and adults aged 15 years and older that used dCXR CAD for asymptomatic TB screening. We used the following search terms: \"Tuberculosis\" AND (\"asymptomatic\" OR \"subclinical\") AND (\"computer aided diagnosis\" OR \"artificial intelligence\") AND \"community-based screening\" AND \"chest radiography\" AND (\"diagnostic performance\" OR \"sensitivity\"). We identified five studies reporting on microbiologically-confirmed asymptomatic TB and dCXR CAD performance. Three of five studies tested sputum only in those who were symptomatic and\/or had abnormal CXR. One study did measure prevalence of asymptomatic TB by universal sputum testing of all participants, but did not report sensitivity and specificity for asymptomatic TB separately. One case-control study of CAD4TB (v7), which pooled data from five active case-finding cohorts, reported sensitivity of 61.4% and specificity of 86.7% for asymptomatic TB. However, the case-control design and inclusion of two cohorts using prevalence survey methodology and three cohorts enrolling high TB risk groups, two of which did not perform CXR on all participants, suggest potential for selection bias.\n\nAdded value of this studyWe evaluated discriminatory performance of dCXR screening for asymptomatic TB among adult household contacts of TB patients, using human readers and qXR CAD (QURE.AI, India), in three communities in South Africa (Screening Cohort). Performance was benchmarked against that for symptomatic TB among adult clinic attendees (Triage Cohort), to enable comparison with traditional published approaches. All participants underwent universal sputum testing, regardless of symptom status or dCXR results. Sensitivity of human readers for asymptomatic TB in the Screening Cohort was 56.4%, compared to 72.4% for symptomatic TB in the Triage Cohort, with specificity 94.1% and 81.2%, respectively. The corresponding sensitivity of qXR CAD for asymptomatic TB, using the manufacturers 0.5 threshold score, was 69.2%, compared to 83.6% for symptomatic TB, with specificity 89.3% and 73.5%, respectively. The difference in dCXR sensitivity and specificity for asymptomatic TB between qXR CAD and human readers was 12.8% and -4.8%, respectively. The adjusted qXR threshold score (0.007) required to achieve 90% sensitivity for asymptomatic TB reduced specificity to 18.9%; and did not meet the WHO Target Product Profile (TPP) for a high sensitivity (90%), high specificity (80%) TB screening test.\n\nImplications of all the available evidenceSensitivity of community-based dCXR screening of household contacts for asymptomatic TB was low, compared to facility-based triage of symptomatic TB. Neither human reader nor qXR CAD evaluation of dCXR met the minimal WHO TPP for a high sensitivity (90%), high specificity (80%) TB screening test. Although dCXR CAD community screening would detect more than two-thirds of all people with previously undiagnosed, microbiologically-confirmed asymptomatic TB, the significant proportion of people with TB that would remain undetected, and untreated, might allow ongoing Mycobacterium tuberculosis transmission and hinder elimination efforts.","rel_num_authors":25,"rel_authors":[{"author_name":"Sarah Nyangu","author_inst":"University of Cape Town"},{"author_name":"Humphrey Mulenga","author_inst":"University of Cape Town"},{"author_name":"Simon C Mendelsohn","author_inst":"University of Cape Town"},{"author_name":"Tahlia Perumal","author_inst":"University of Cape Town"},{"author_name":"Michele Tameris","author_inst":"University of Cape Town"},{"author_name":"Tumelo Moloantoa","author_inst":"University of Witwatersrand"},{"author_name":"Stephanus Theron Malherbe","author_inst":"Stellenbosch University"},{"author_name":"Firdows Noor","author_inst":"Stellenbosch University"},{"author_name":"Justin Shenje","author_inst":"University of Cape Town"},{"author_name":"Nicolette Tredoux","author_inst":"University of Cape Town"},{"author_name":"Angelique  K. Luabeya","author_inst":"University of Cape Town Faculty of Health Sciences"},{"author_name":"Fernanda Maruri","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Ravindre Panchia","author_inst":"Wits University: University of the Witwatersrand Johannesburg"},{"author_name":"Khuthadzo Hlongwane","author_inst":"University of Witwatersrand"},{"author_name":"Kim Stanley","author_inst":"Stellenbosch University"},{"author_name":"Yuri F van der Heijden","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Kate Hadley","author_inst":"University of Cape Town"},{"author_name":"Neil Martinson","author_inst":"University of Witwatersrand"},{"author_name":"Keertan Dheda","author_inst":"University of Cape Town Lung Institute"},{"author_name":"Alasdair Leslie","author_inst":"Africa Health Research Institute"},{"author_name":"Bernard Fourie","author_inst":"University of Pretoria"},{"author_name":"Gerhard Walzl","author_inst":"Stellenbosch University"},{"author_name":"Thomas Scriba","author_inst":"University of Cape Town"},{"author_name":"Timothy R Sterling","author_inst":"Vanderbilt University"},{"author_name":"Mark Hatherill","author_inst":"University of Cape Town"}],"rel_date":"2026-04-30","rel_site":"medrxiv"},{"rel_title":"Shortkit-ML: A Unified Multi-Perspective Framework for Detecting Shortcut Learning in Medical Imaging Embeddings","rel_doi":"10.64898\/2026.04.29.26352053","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.29.26352053","rel_abs":"Shortcut learning poses a significant challenge in clinical artificial intelligence, as models may rely on spurious signals rather than clinically relevant features, leading to biased predictions and poor generalization. Existing detection methods are fragmented and lack systematic evaluation across datasets and model architectures. To address this issue, we propose ShortKit-ML, an open-source Python framework for unified shortcut analysis in embedding spaces. The framework integrates over 20 detection methods and six mit- igation strategies within a modular pipeline, encompassing embedding analysis, fairness metrics, training dynamics, causal methods, explainability, and representation analysis. We evaluate the framework on chest X-ray datasets (CheXpert and MIMIC-CXR), syn- thetic benchmarks, and an out-of-domain dataset (CelebA). Experimental results demon- strate that multi-method auditing provides more stable and interpretable evidence than individual methods, while detector disagreement reveals meaningful representational differ- ences. The proposed framework offers automated reporting, interactive visualization, and is available as a pip-installable package. The source code and documentation are publicly available at https:\/\/github.com\/criticaldata\/ShortKit-ML and https:\/\/criticaldata. github.io\/ShortKit-ML\/.","rel_num_authors":11,"rel_authors":[{"author_name":"Sebastian Cajas","author_inst":"MIT Critical Data, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Aldo Marzullo","author_inst":"Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan,"},{"author_name":"Sahil Kapadia","author_inst":"MIT Critical Data, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Filipe Santos","author_inst":"IDMEC, Instituto Superior Tecnico, University of Lisbon, Lisbon, Portugal"},{"author_name":"Felipe Ocampo Osorio","author_inst":"Clinical Research Center, Artificial Intelligence Unit, Fundacion Valle del Lili, Cali, Valle del Cauca, Colombia"},{"author_name":"Qingpeng Kong","author_inst":"University of California, Berkeley, CA, USA"},{"author_name":"Alessandro Quarta","author_inst":"University of Calabria, Rende, Italy"},{"author_name":"Po-Chih Kuo","author_inst":"Department of Computer Science, National Tsing Hua University, Hsinchu, Taiwan"},{"author_name":"Milit Patel","author_inst":"MIT Critical Data, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Raul Ignacio Rojas Sillery","author_inst":"MIT Critical Data, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"author_name":"Leo Anthony Celi","author_inst":"MIT Critical Data, Massachusetts Institute of Technology, Cambridge, MA, USA"}],"rel_date":"2026-04-30","rel_site":"medrxiv"},{"rel_title":"Development and Validation of a Two-Stage NLP-LLM System for Automated Extraction of Deprescribing Recommendations from Discharge Summaries","rel_doi":"10.64898\/2026.04.29.26352010","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.29.26352010","rel_abs":"Introduction: Polypharmacy in older adults is associated with increased risks of adverse drug events and functional decline. Discharge summaries often contain deprescribing recommendations, but these are frequently overlooked due to documentation complexity. Objective: To develop and validate a two-stage hybrid system combining rule-based natural language processing (NLP) and large language model (LLM) for automated extraction of deprescribing recommendations from discharge summaries. Methods: This retrospective cohort study included 850 discharge summaries from patients aged [&ge;]65 years with hospitalisation [&ge;]48 hours across six public hospitals in New South Wales, Australia. Model 1 (rule-based NLP) extracted discharge medications and candidate sentences containing pre-defined deprescribing keywords. Model 2 (open-source LLM) classified candidate sentences into five categories. Data were split into training (80%) and test (20%) sets. Gold standard classifications were established by independent reviews, followed by adjudication of discrepancies. Results: Model 1 extracted 9,631 discharge medications (median 11 per patient) and 1,061 candidate sentences from 850 patients (median age 82.8 years). Model 2 achieved an F1 score of 0.91 and accuracy of 0.90 on the test set. Inter-rater reliability showed substantial agreement (Cohen's kappa = 0.70). The most frequently identified medications recommended for deprescribing were antibiotics and opioids. The most common misclassification was incorrectly identifying actions completed during hospitalisation as post-discharge recommendations. The combined processing time averaged 12.6 seconds per discharge summary. Conclusions: A two-stage hybrid approach combining rule-based NLP and open-source LLM can accurately extract deprescribing recommendations from discharge summaries, enabling cost-efficient, privacy-compliant local deployment.","rel_num_authors":4,"rel_authors":[{"author_name":"Kenji Fujita","author_inst":"Departments of Clinical Pharmacology and Aged Care, Kolling Institute, Faculty of Medicine and Health, The University of Sydney and the Northern Sydney Local He"},{"author_name":"Marion Matheson","author_inst":"Northern Beaches Hospital, Sydney NSW, Australia"},{"author_name":"Bhavya Valecha","author_inst":"Hornsby Ku-Ring-Gai Hospital, Sydney NSW, Australia"},{"author_name":"Sarah N Hilmer","author_inst":"Departments of Clinical Pharmacology and Aged Care, Kolling Institute, Faculty of Medicine and Health, The University of Sydney and the Northern Sydney Local He"}],"rel_date":"2026-04-30","rel_site":"medrxiv"},{"rel_title":"HIV Transmission in a Declining African Epidemic","rel_doi":"10.64898\/2026.04.29.26350859","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.29.26350859","rel_abs":"Background Novel HIV prevention interventions such as long-acting pre-exposure prophylaxis (PrEP) could substantially reduce HIV transmission in Africa. However, efficient implementation in high-prevalence settings where incidence has declined requires an understanding of the contemporary dynamics driving new infections. Methods We identified incident HIV cases from a longitudinal, population-based cohort in Uganda. We individually matched cases to HIV-negative controls; traced and enrolled reported sexual partners; and enrolled female sex workers (FSWs) from reported venues. Conditional logistic regression, transmission modeling, and phylogenetics were used to characterize transmission networks. Findings From 2021-2024, 38,899 HIV tests among 22,255 people identified 187 people with incident infections (47.6% male); 164 (88%) were enrolled and matched to 164 HIV-negative controls. Overall, 593 non-sex-worker partners (371 enrolled,62.6%), 146 FSW partners (21 enrolled,14.4%), and 28 venues (208 FSWs enrolled) were reported. Incident infection was most strongly predicted by partnership with a FSW (odds ratio:15.5; 95%CI:3.7-64.8), identified in 43.0% of male cases versus 6.3% of controls. Men with FSW partners had larger sexual networks than men without (median:6 vs 2 partners), and 91.2% of men with FSW partners also had non-sex-worker partners. Transmission modeling attributed 34.4% (95%CI:31.5-36.8%) of all male infections and 80.0% (95%CI:73.2-84.4%) of infections among male clients to sex with FSWs. Oral PrEP use among HIV-negative partners of incident cases was low (8.9% in women; 2.1% in men). Interpretation Men with FSW partners accounted for a substantial share of incident HIV infections and had markedly higher odds of infection than men without such partnerships. Together with the high potential for onward transmission within male client networks, these findings suggest that inclusion of male clients in long-acting HIV prevention strategies could be highly efficient and impactful.","rel_num_authors":29,"rel_authors":[{"author_name":"Griffin J Bell","author_inst":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"Mary Kathryn Grabowski","author_inst":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA; Division of Pathology, School of Medicine, Johns Ho"},{"author_name":"Josephine Mpagazi","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"Francesco Di Lauro","author_inst":"Nuffield Department of Medicine, University of Oxford, Oxford, UK"},{"author_name":"Aleya Khalifa","author_inst":"Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA"},{"author_name":"Anthony Ndyanabo","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"Hadijja Nakawooya","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"Joseph Kagaayi","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda; Department of Epidemiology and Biostatistics, School of Public Health, Makerere University, Kampala, Uganda"},{"author_name":"Godfrey Kigozi","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"Gertrude Nakigozi","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"Ronald M Galiwango","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"Grace Kigozi","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"Michael A Martin","author_inst":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"Luca Ferretti","author_inst":"Nuffield Department of Medicine, University of Oxford, Oxford, UK"},{"author_name":"Christophe Fraser","author_inst":"Nuffield Department of Medicine, University of Oxford, Oxford, UK"},{"author_name":"David Bonsall","author_inst":"Nuffield Department of Medicine, University of Oxford, Oxford, UK"},{"author_name":"Lucie Abeler-D\u00f6rner","author_inst":"Nuffield Department of Medicine, University of Oxford, Oxford, UK"},{"author_name":"Tanya Golubchik","author_inst":"Sydney Infectious Diseases Institute and School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, Australia"},{"author_name":"Aaron AR Tobian","author_inst":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA; Division of Pathology, School of Medicine, Johns Ho"},{"author_name":"Laura K Beres","author_inst":"Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"Caitlin Kennedy","author_inst":"Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"Justin Lessler","author_inst":"Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA; Carolina Population Center, University "},{"author_name":"Thomas C Quinn","author_inst":"Division of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Division of Infectious Diseases, School of Medicine, Johns Hopkins Univ"},{"author_name":"Steven J Reynolds","author_inst":"Division of Infectious Diseases, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Division of Intramural Research, National Institute of Allerg"},{"author_name":"Maria J Wawer","author_inst":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA; Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"Ronald H Gray","author_inst":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA; Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"David Serwadda","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda; Department of Epidemiology and Biostatistics, School of Public Health, Makerere University, Kampala, Uganda"},{"author_name":"Larry W Chang","author_inst":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA; Rakai Health Sciences Program, Kyotera, Uganda; Div"},{"author_name":"Robert Ssekubugu","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda; Department of Global Health, Karolinska Institutet, Stockholm, Sweden"}],"rel_date":"2026-04-30","rel_site":"medrxiv"},{"rel_title":"HIV Transmission in a Declining African Epidemic","rel_doi":"10.64898\/2026.04.29.26350859","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.29.26350859","rel_abs":"Background Novel HIV prevention interventions such as long-acting pre-exposure prophylaxis (PrEP) could substantially reduce HIV transmission in Africa. However, efficient implementation in high-prevalence settings where incidence has declined requires an understanding of the contemporary dynamics driving new infections. Methods We identified incident HIV cases from a longitudinal, population-based cohort in Uganda. We individually matched cases to HIV-negative controls; traced and enrolled reported sexual partners; and enrolled female sex workers (FSWs) from reported venues. Conditional logistic regression, transmission modeling, and phylogenetics were used to characterize transmission networks. Findings From 2021-2024, 38,899 HIV tests among 22,255 people identified 187 people with incident infections (47.6% male); 164 (88%) were enrolled and matched to 164 HIV-negative controls. Overall, 593 non-sex-worker partners (371 enrolled,62.6%), 146 FSW partners (21 enrolled,14.4%), and 28 venues (208 FSWs enrolled) were reported. Incident infection was most strongly predicted by partnership with a FSW (odds ratio:15.5; 95%CI:3.7-64.8), identified in 43.0% of male cases versus 6.3% of controls. Men with FSW partners had larger sexual networks than men without (median:6 vs 2 partners), and 91.2% of men with FSW partners also had non-sex-worker partners. Transmission modeling attributed 34.4% (95%CI:31.5-36.8%) of all male infections and 80.0% (95%CI:73.2-84.4%) of infections among male clients to sex with FSWs. Oral PrEP use among HIV-negative partners of incident cases was low (8.9% in women; 2.1% in men). Interpretation Men with FSW partners accounted for a substantial share of incident HIV infections and had markedly higher odds of infection than men without such partnerships. Together with the high potential for onward transmission within male client networks, these findings suggest that inclusion of male clients in long-acting HIV prevention strategies could be highly efficient and impactful.","rel_num_authors":29,"rel_authors":[{"author_name":"Griffin J Bell","author_inst":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"Mary Kathryn Grabowski","author_inst":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA; Division of Pathology, School of Medicine, Johns Ho"},{"author_name":"Josephine Mpagazi","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"Francesco Di Lauro","author_inst":"Nuffield Department of Medicine, University of Oxford, Oxford, UK"},{"author_name":"Aleya Khalifa","author_inst":"Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA"},{"author_name":"Anthony Ndyanabo","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"Hadijja Nakawooya","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"Joseph Kagaayi","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda; Department of Epidemiology and Biostatistics, School of Public Health, Makerere University, Kampala, Uganda"},{"author_name":"Godfrey Kigozi","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"Gertrude Nakigozi","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"Ronald M Galiwango","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"Grace Kigozi","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"Michael A Martin","author_inst":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"Luca Ferretti","author_inst":"Nuffield Department of Medicine, University of Oxford, Oxford, UK"},{"author_name":"Christophe Fraser","author_inst":"Nuffield Department of Medicine, University of Oxford, Oxford, UK"},{"author_name":"David Bonsall","author_inst":"Nuffield Department of Medicine, University of Oxford, Oxford, UK"},{"author_name":"Lucie Abeler-D\u00f6rner","author_inst":"Nuffield Department of Medicine, University of Oxford, Oxford, UK"},{"author_name":"Tanya Golubchik","author_inst":"Sydney Infectious Diseases Institute and School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, Australia"},{"author_name":"Aaron AR Tobian","author_inst":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA; Division of Pathology, School of Medicine, Johns Ho"},{"author_name":"Laura K Beres","author_inst":"Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"Caitlin Kennedy","author_inst":"Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"Justin Lessler","author_inst":"Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA; Carolina Population Center, University "},{"author_name":"Thomas C Quinn","author_inst":"Division of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Division of Infectious Diseases, School of Medicine, Johns Hopkins Univ"},{"author_name":"Steven J Reynolds","author_inst":"Division of Infectious Diseases, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Division of Intramural Research, National Institute of Allerg"},{"author_name":"Maria J Wawer","author_inst":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA; Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"Ronald H Gray","author_inst":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA; Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"David Serwadda","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda; Department of Epidemiology and Biostatistics, School of Public Health, Makerere University, Kampala, Uganda"},{"author_name":"Larry W Chang","author_inst":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA; Rakai Health Sciences Program, Kyotera, Uganda; Div"},{"author_name":"Robert Ssekubugu","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda; Department of Global Health, Karolinska Institutet, Stockholm, Sweden"}],"rel_date":"2026-04-30","rel_site":"medrxiv"},{"rel_title":"HIV Transmission in a Declining African Epidemic","rel_doi":"10.64898\/2026.04.29.26350859","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.29.26350859","rel_abs":"Background Novel HIV prevention interventions such as long-acting pre-exposure prophylaxis (PrEP) could substantially reduce HIV transmission in Africa. However, efficient implementation in high-prevalence settings where incidence has declined requires an understanding of the contemporary dynamics driving new infections. Methods We identified incident HIV cases from a longitudinal, population-based cohort in Uganda. We individually matched cases to HIV-negative controls; traced and enrolled reported sexual partners; and enrolled female sex workers (FSWs) from reported venues. Conditional logistic regression, transmission modeling, and phylogenetics were used to characterize transmission networks. Findings From 2021-2024, 38,899 HIV tests among 22,255 people identified 187 people with incident infections (47.6% male); 164 (88%) were enrolled and matched to 164 HIV-negative controls. Overall, 593 non-sex-worker partners (371 enrolled,62.6%), 146 FSW partners (21 enrolled,14.4%), and 28 venues (208 FSWs enrolled) were reported. Incident infection was most strongly predicted by partnership with a FSW (odds ratio:15.5; 95%CI:3.7-64.8), identified in 43.0% of male cases versus 6.3% of controls. Men with FSW partners had larger sexual networks than men without (median:6 vs 2 partners), and 91.2% of men with FSW partners also had non-sex-worker partners. Transmission modeling attributed 34.4% (95%CI:31.5-36.8%) of all male infections and 80.0% (95%CI:73.2-84.4%) of infections among male clients to sex with FSWs. Oral PrEP use among HIV-negative partners of incident cases was low (8.9% in women; 2.1% in men). Interpretation Men with FSW partners accounted for a substantial share of incident HIV infections and had markedly higher odds of infection than men without such partnerships. Together with the high potential for onward transmission within male client networks, these findings suggest that inclusion of male clients in long-acting HIV prevention strategies could be highly efficient and impactful.","rel_num_authors":29,"rel_authors":[{"author_name":"Griffin J Bell","author_inst":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"Mary Kathryn Grabowski","author_inst":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA; Division of Pathology, School of Medicine, Johns Ho"},{"author_name":"Josephine Mpagazi","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"Francesco Di Lauro","author_inst":"Nuffield Department of Medicine, University of Oxford, Oxford, UK"},{"author_name":"Aleya Khalifa","author_inst":"Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA"},{"author_name":"Anthony Ndyanabo","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"Hadijja Nakawooya","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"Joseph Kagaayi","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda; Department of Epidemiology and Biostatistics, School of Public Health, Makerere University, Kampala, Uganda"},{"author_name":"Godfrey Kigozi","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"Gertrude Nakigozi","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"Ronald M Galiwango","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"Grace Kigozi","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"Michael A Martin","author_inst":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"Luca Ferretti","author_inst":"Nuffield Department of Medicine, University of Oxford, Oxford, UK"},{"author_name":"Christophe Fraser","author_inst":"Nuffield Department of Medicine, University of Oxford, Oxford, UK"},{"author_name":"David Bonsall","author_inst":"Nuffield Department of Medicine, University of Oxford, Oxford, UK"},{"author_name":"Lucie Abeler-D\u00f6rner","author_inst":"Nuffield Department of Medicine, University of Oxford, Oxford, UK"},{"author_name":"Tanya Golubchik","author_inst":"Sydney Infectious Diseases Institute and School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, Australia"},{"author_name":"Aaron AR Tobian","author_inst":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA; Division of Pathology, School of Medicine, Johns Ho"},{"author_name":"Laura K Beres","author_inst":"Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"Caitlin Kennedy","author_inst":"Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"Justin Lessler","author_inst":"Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA; Carolina Population Center, University "},{"author_name":"Thomas C Quinn","author_inst":"Division of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Division of Infectious Diseases, School of Medicine, Johns Hopkins Univ"},{"author_name":"Steven J Reynolds","author_inst":"Division of Infectious Diseases, School of Medicine, Johns Hopkins University, Baltimore, MD, USA; Division of Intramural Research, National Institute of Allerg"},{"author_name":"Maria J Wawer","author_inst":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA; Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"Ronald H Gray","author_inst":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA; Rakai Health Sciences Program, Kyotera, Uganda"},{"author_name":"David Serwadda","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda; Department of Epidemiology and Biostatistics, School of Public Health, Makerere University, Kampala, Uganda"},{"author_name":"Larry W Chang","author_inst":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA; Rakai Health Sciences Program, Kyotera, Uganda; Div"},{"author_name":"Robert Ssekubugu","author_inst":"Rakai Health Sciences Program, Kyotera, Uganda; Department of Global Health, Karolinska Institutet, Stockholm, Sweden"}],"rel_date":"2026-04-30","rel_site":"medrxiv"},{"rel_title":"Is the messenger more important than the message? A theory of change for the IFRC Network s risk communication and community engagement intervention for vaccination in Nigeria and Ethiopia","rel_doi":"10.64898\/2026.04.29.26352040","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.29.26352040","rel_abs":"Introduction Community engagement is increasingly seen as essential within vaccination programming to improve uptake of vaccines, build trust and foster community ownership. Yet the goals and mechanisms of such interventions are often contested or not explicit. This article aims to address this by examining how those directly involved in implementing community engagement understand its intended aims and outcomes. We use as a case study a risk communication and community engagement (RCCE) intervention implemented by the Nigeria and Ethiopia Red Cross\/Red Crescent with support from the IFRC for COVID-19 vaccination. Methods We conducted 41 interviews, 12 participatory workshops and citizen ethnography in Dire Dawa, Ethiopia and Kano, Nigeria including with Red Cross\/Red Crescent and vaccination staff, vaccine users and community members. We explored how participants understood the RCCE intervention's theory of change, including how it was expected to work, for whom, under what circumstances, and why. Results Participants described RCCE activities as a mix of two-way (such as house-to-house visits) and mass approaches (such as media campaigns). These interventions were primarily seen as enhancing vaccine knowledge and countering misinformation. Key mechanisms included vaccine users willingness to act on the information provided, however this was heavily influenced by the credibility and trustworthiness of the bearers of vaccine information. While feedback mechanisms existed, communities were not involved in designing vaccination strategies. Efforts were shaped by a context with unpredictable vaccination campaigns, supply constraints and parallel RCCE efforts by community actors. Conclusions We show that in this theory of change messengers are more influential than the messages themselves. By developing a theory of change with our participants, we highlight the lack of clarity within the sector regarding the definition and expected impact of community engagement and reveal a gap between community engagement practice on the ground and normative goals such as co-production and dialogue.","rel_num_authors":12,"rel_authors":[{"author_name":"Rose Burns","author_inst":"London School of Hygiene and Tropical Medicine, United Kingdom"},{"author_name":"Yashua Alkali Hamza","author_inst":"Childcare and Wellness Clinics Abuja, Nigeria"},{"author_name":"Aminu M Dukku","author_inst":"Bayero University, Kano, Nigeria"},{"author_name":"Yohannes Mulugeta","author_inst":"Addis Ababa University, Addis Ababa, Ethiopia"},{"author_name":"Ombretta Baggio","author_inst":"International Federation of Red Cross and Red Crescent Societies, Geneva, Switzerland"},{"author_name":"Gefra Fulane","author_inst":"International Federation of Red Cross and Red Crescent Societies, Geneva, Switzerland"},{"author_name":"Monica Posada","author_inst":"International Federation of Red Cross and Red Crescent Societies, Geneva, Switzerland"},{"author_name":"Lilian Adeogba","author_inst":"International Federation of Red Cross and Red Crescent Societies Nigeria, Abuja, Nigeria"},{"author_name":"Abraham Tilahun","author_inst":"International Federation of Red Cross and Red Crescent Societies Ethiopia, Addis Ababa"},{"author_name":"Alex Odlum","author_inst":"University of Geneva, Geneva, Switzerland"},{"author_name":"Karl Blanchet","author_inst":"University of Geneva, Geneva, Switzerland"},{"author_name":"Luisa Enria","author_inst":"London School of Hygiene & Tropical Medicine, United Kingdom"}],"rel_date":"2026-04-30","rel_site":"medrxiv"},{"rel_title":"A Comparison of Diagnostic Models and Prognostic Scores of ACLF: Towards Global Harmonization","rel_doi":"10.64898\/2026.04.29.26352045","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.29.26352045","rel_abs":"Background and Aims: Acute-on-chronic liver failure (ACLF) is associated with high short-term mortality, but substantial heterogeneity among existing diagnostic and prognostic models results in inconsistent patient identification and risk assessment. We conducted a systematic head-to-head comparison of major ACLF diagnostic and prognostic models to evaluate concordance, short-term mortality prediction and clinical utility, with the goal of informing harmonization of ACLF assessment. Methods: We analysed 3,370 patients with acute decompensation of cirrhosis in the COSSH cohort, with external validation in an independent Ambi-Spective cohort from India (n=2,055). Five ACLF diagnostic models were evaluated for identification of patients at risk of 28-day mortality. Reclassification was assessed using net reclassification improvement. Prognostic scores were compared using concordance index, integrated discrimination improvement, calibration, and decision-curve analysis. Results: Diagnostic frameworks identified markedly different proportions of ACLF. A-TANGO and COSSH-ACLF classified the largest high-risk populations while maintaining substantial short-term mortality and balanced sensitivity-specificity profiles. Compared with COSSH-ACLF, A-TANGO improved net reclassification by 7.7%, with further gains versus EASL-CLIF (11.8%), APASL-ACLF (36.4%), and NACSELD-ACLF (45.9%). In the external cohort, A-TANGO and COSSH-ACLF showed similar discrimination and identified comparable proportions of patients. Combined application of the two models delineated three clinically meaningful strata, identifying a discordant intermediate-risk group with approximately 11% 28-day mortality. Among prognostic scores, COSSH-ACLF II and A-TANGO OF scores demonstrated strong and complementary performance across cohorts. Conclusions: Outcome-anchored ACLF definitions converge in identifying patients at highest short-term risk across diverse populations. Alignment between A-TANGO and COSSH-ACLF, together with identification of an intermediate-risk phenotype, supports a data-driven framework for improving consistency and advancing global harmonization of ACLF diagnosis and risk stratification.","rel_num_authors":37,"rel_authors":[{"author_name":"Meiqian Hu","author_inst":"University College London; Zhejiang University School of Medicine"},{"author_name":"Jinjin Luo","author_inst":"Zhejiang University School of Medicine"},{"author_name":"Nipun Verma","author_inst":"Department of Hepatology, Postgraduate Institute of Medical Education and Research"},{"author_name":"Pratibha Garg","author_inst":"Department of Hepatology, Postgraduate Institute of Medical Education and Research"},{"author_name":"Sunil Taneja","author_inst":"Department of Hepatology, Postgraduate Institute of Medical Education and Research"},{"author_name":"Juan Antonio Carbonell-Asins","author_inst":"INCLIVA Biomedical Research Institute"},{"author_name":"Maria Pilar Ballester","author_inst":"INCLIVA Biomedical Research Institute; Hospital Clinico Universitario de Valencia"},{"author_name":"Tingting Qi","author_inst":"University College London; Southern Medical University"},{"author_name":"Sina Jameie-Oskooei","author_inst":"University College London"},{"author_name":"Qun Cai","author_inst":"University College London; Ningbo Medical Center Lihuili Hospital"},{"author_name":"Xi Liang","author_inst":"Zhejiang University School of Medicine"},{"author_name":"Jiaqi Li","author_inst":"Zhejiang Provincial People's Hospital"},{"author_name":"Tianzhou Wu","author_inst":"Zhejiang University School of Medicine"},{"author_name":"Jiang Li","author_inst":"The First Affiliated Hospital of Anhui Medical University"},{"author_name":"Peng Li","author_inst":"Zhejiang University School of Medicine"},{"author_name":"Qian Zhou","author_inst":"Zhejiang University School of Medicine"},{"author_name":"Jiaojiao Xin","author_inst":"Zhejiang University School of Medicine"},{"author_name":"Dongyan Shi","author_inst":"Zhejiang University School of Medicine"},{"author_name":"Jing Jiang","author_inst":"Zhejiang University School of Medicine"},{"author_name":"Wei Qiang","author_inst":"Zhejiang University School of Medicine"},{"author_name":"Changze Hong","author_inst":"University College London; Southern Medical University"},{"author_name":"Xin Chen","author_inst":"Zhejiang University School of Medicine"},{"author_name":"Bing Zhu","author_inst":"Chinese PLA General Hospital"},{"author_name":"Tingting Feng","author_inst":"The First Affiliated Hospital of Suzhou University"},{"author_name":"Jianming Zheng","author_inst":"Huashan Hospital, Fudan University"},{"author_name":"Yuxian Huang","author_inst":"Huashan Hospital, Fudan University"},{"author_name":"Feng Ye","author_inst":"The First Affiliated Hospital of Xi'an Jiaotong University"},{"author_name":"Bingliang Lin","author_inst":"The Third Affiliated Hospital of Sun Yat-sen University"},{"author_name":"Jinjun Chen","author_inst":"Chongqing Medical University"},{"author_name":"Rajeshwar P Mookerjee","author_inst":"University College London"},{"author_name":"Yan Huang","author_inst":"Central South University"},{"author_name":"Shaoli You","author_inst":"Chinese PLA General Hospital"},{"author_name":"Cornelius Engelmann","author_inst":"Charite Universitatsmedizin Berlin"},{"author_name":"Yu Chen","author_inst":"Capital Medical University"},{"author_name":"Ajay Duseja","author_inst":"Department of Hepatology, Postgraduate Institute of Medical Education and Research"},{"author_name":"Jun Li","author_inst":"Zhejiang University School of Medicine"},{"author_name":"Rajiv Jalan","author_inst":"University College London"}],"rel_date":"2026-04-30","rel_site":"medrxiv"},{"rel_title":"Association between Weather Variables and Viral Gastroenteritis in the United States","rel_doi":"10.64898\/2026.04.29.26352095","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.29.26352095","rel_abs":"Abstract Infectious gastroenteritis (IGE) is a major cause of pediatric morbidity globally, with viral pathogens accounting for a substantial proportion of cases. While seasonal patterns of viral IGE are well recognized, the association between specific environmental exposures, such as ambient temperature, and viral IGE has not been fully quantified. First, we performed a secondary analysis of data from a prospective, multisite study of children presenting to emergency departments at five medical centers across the continental United States, linking individual level laboratory data to environmental exposures, including temperature, humidity, and air pollutants, measured during the 14 days preceding symptom onset. Mixed-effects logistic regression was applied to evaluate the association between viral IGE and environmental exposures, adjusting for site-level clustering and patient age. Among 868 children with IGE, higher ambient temperature was inversely associated with viral etiology (OR 0.50, 95% CI 0.36-0.68, p < 0.001). We did not find statistically significant associations between other environmental variables and viral IGE. Then, to contextualize these individual-level findings in children, we examined all-ages population-level surveillance data from GermWatch, a regional laboratory testing-based infectious disease surveillance system, which demonstrated concordant declines in viral pathogen detection with increasing temperature. These findings support the association of weather with viral transmission patterns. Incorporating environmental context into clinical decision-making may improve diagnostic stewardship and support more effective resource allocation during periods of increased viral IGE prevalence.","rel_num_authors":15,"rel_authors":[{"author_name":"Natalya Alekhina","author_inst":"University of Utah, Sat Lake City, UT"},{"author_name":"Paola Fonseca-Romero","author_inst":"University of Utah, Sat Lake City, UT"},{"author_name":"Per H. Gesteland","author_inst":"University of Utah, Sat Lake City, UT"},{"author_name":"Ben J Brintz","author_inst":"University of Utah, Sat Lake City, UT"},{"author_name":"Amy L. Leber","author_inst":"Nationwide Children's Hospital, Columbus, OH"},{"author_name":"Jami T. Jackson","author_inst":"Childrens Mercy Hospital, Kansas City, MO"},{"author_name":"Jennifer Dien Bard","author_inst":"University of Southern California, Los Angeles, CA"},{"author_name":"Neena Kanwar","author_inst":"Childrens Mercy Hospital, Kansas City, MO"},{"author_name":"Ara Festekjian","author_inst":"University of Southern California, Los Angeles"},{"author_name":"Chari Larsen","author_inst":"University of Utah, Salt Lake City, UT"},{"author_name":"Kimberle C. Chapin","author_inst":"Brown University, Providence, RI"},{"author_name":"Rangaraj Selvarangan","author_inst":"Childrens Mercy Hospital, Kansas City, MO"},{"author_name":"Sean Soisson","author_inst":"Intermountain Healthcare, Salt Lake City,  UT"},{"author_name":"Andrew T. Pavia","author_inst":"University of Utah, Salt Lake City, UT"},{"author_name":"Daniel T. Leung","author_inst":"University of Utah, Salt Lake City, UT"}],"rel_date":"2026-04-30","rel_site":"medrxiv"},{"rel_title":"Sequencing for a Lifetime: Value, Feasibility, and the Governance Gap in Lifelong Genomic Medicine","rel_doi":"10.64898\/2026.04.29.26352046","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.29.26352046","rel_abs":"Background. A vision of lifelong genomic medicine, in which stored genomic data can inform a lifetime of care, has long animated the field of genomic medicine. Component pieces of this vision are being researched or are already in clinical practice, including dozens of projects around the world sequencing healthy newborns, along with reanalysis of stored genomic data. Whether lifelong genomic medicine is desirable, and, if so, whether it is feasible, has not been explored in the literature. Methods. We conducted and thematically analyzed interviews with over 50 US-based healthcare professionals, including clinical geneticists, genetic counselors, primary care clinicians, laboratory personnel, and those who have implemented genomic screening in health systems. Results. We found broad endorsement of the value of lifelong genomic medicine across groups. Perceived clinical value stemmed from the existence of genomic information relevant at multiple stages of life, the ability to query the genome if an individual's medical circumstances change, and the ability to inform patients about relevant evolving scientific advances. Participants also articulated an efficiency argument for reanalyzing stored genomic data rather than retesting. The clinical value was contested by a few participants, who argued for more targeted testing for the clinical situation and disputed the efficiency argument. Many participants viewed the model as inevitable, with operational precedent already established for many component activities. The feasibility of lifelong genomic medicine was limited not by scientific barriers but by governance gaps spanning delivery models, consent, data stewardship, recontact, and the pediatric-to-adult transition. These gaps have equity implications that are cumulative and mutually reinforcing. Conclusions. The concept of lifelong genomic medicine was widely viewed as acceptable and desired. However, until the governance infrastructure is established, including accountability, funding, data stewardship, and recontact mechanisms, population-scale genomic sequencing risks proceeding faster than the frameworks needed to make it responsible.","rel_num_authors":7,"rel_authors":[{"author_name":"Anna C F Lewis","author_inst":"Mass General Brigham; Harvard Medical School; Broad Institute"},{"author_name":"Ingrid A. Holm","author_inst":"Harvard Medical School; Boston Children's Hospital"},{"author_name":"Adam H Buchanan","author_inst":"Geisinger"},{"author_name":"Aaron J Goldenberg","author_inst":"Case Western Reserve University"},{"author_name":"Bartha M Knoppers","author_inst":"McGill University"},{"author_name":"Amy L McGuire","author_inst":"Baylor College of Medicine"},{"author_name":"Robert C Green","author_inst":"Brigham and Women's Hospital, Broad Institute, Harvard Medical School"}],"rel_date":"2026-04-30","rel_site":"medrxiv"},{"rel_title":"Immune Subtypes and Survival in Patients with Primary Glioma","rel_doi":"10.64898\/2026.04.29.26351981","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.29.26351981","rel_abs":"Background: Gliomas are heterogeneous tumors with poor outcomes following current therapies, including immunotherapy. The tumor microenvironment (TME) is a critical determinant of therapeutic response in gliomas. We have classified the immune TME of gliomas by multiplex immunofluorescence (mIF). Methods: Tissue taken at initial resection from 354 patients with newly-diagnosed glioma grades 2-4 were analyzed using three mIF panels of markers for T, B, and myeloid cells. Tumor cores were characterized by the relative abundances of: (i) 15 primary immune phenotypes, (ii) 96 secondary immune phenotypes, and, (iii) 29 biologically meaningful multi-marker immune phenotypes. Results: Using unsupervised cluster analysis of WHO grade 4 gliomas we identified four subtypes , {beta}, {gamma}, and {delta} that were internally reproducible. Immune subtype  was characterized by high abundance of antigen-presenting cells (APCs) and low levels of MHC II- monocytes. Subtype {beta} was high in regulatory T cells and myeloid cells, but low in lymphocytes with effector functions. Subtype {gamma} displayed high abundance of immune cell phenotypes, particularly lymphocytes with effector or helper functions. Subtype {delta} was low in lymphoid and myeloid immune phenotypes and APCs, with poorer outcomes. Grade 3 tumors could also be classified into , {beta}, {gamma}, and {delta} subtypes, indicating generalizability of these immune TME subtypes across high grade gliomas. Conclusions: We have identified internally reproducible criteria for classifying gliomas according to the immune microenvironment, findings that could aid our understanding of the natural progression of low- and high-grade gliomas and inform the rational application of immune-oncologic therapeutic interventions.","rel_num_authors":14,"rel_authors":[{"author_name":"Yu Fang","author_inst":"Moffitt Cancer Center"},{"author_name":"Jiwoong Kim","author_inst":"University of South Florida, Tampa"},{"author_name":"Zachary J Thompson","author_inst":"Moffitt Cancer Center"},{"author_name":"Youngchul Kim","author_inst":"Moffitt Cancer Center"},{"author_name":"Harshan Ravi","author_inst":"Moffitt Cancer Center"},{"author_name":"Asim M Mazin","author_inst":"Moffitt Cancer Center"},{"author_name":"Carlos M Moran-Segura","author_inst":"Moffitt Cancer Center"},{"author_name":"Jonathan V Nguyen","author_inst":"Moffitt Cancer Center"},{"author_name":"Robert J Macaulay","author_inst":"Moffitt Cancer Center"},{"author_name":"Filippo Veglia","author_inst":"The Wistar Institute"},{"author_name":"Reid C Thompson","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Sajeel A Chowdhary","author_inst":"Tampa General Hospital Cancer Center"},{"author_name":"Kathleen M Egan","author_inst":"Moffitt Cancer Center"},{"author_name":"Natarajan Raghunand","author_inst":"Moffitt Cancer Center"}],"rel_date":"2026-04-30","rel_site":"medrxiv"},{"rel_title":"Polygenic predisposition modifies the associations of fish oil supplementation with circulating omega-3 fatty acids: a cross-sectional gene-diet interaction study in UK Biobank","rel_doi":"10.64898\/2026.04.29.26352078","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.29.26352078","rel_abs":"Background: Several genetic variants have been identified to modify the effects of fish oil supplementation (FOS) on increasing circulating omega-3 fatty acids, but it remains unexplored whether polygenic predisposition to low circulating omega-3 fatty acids modifies these effects. Objective: To test if polygenic scores (PGS) for circulating omega-3 fatty acids modify the associations of FOS with corresponding circulating concentrations. Methods: We developed PGS models for absolute circulating concentrations of total omega-3 fatty acids (Omega-3), docosahexaenoic acid (DHA), and their relative percentages in total fatty acids (Omega-3% and DHA%), using a multi-ethnic genome-wide association study (N=136,016). PGS models were validated in 437,803 UK Biobank participants of European (EUR), Central\/South Asian (CSA), African, and East Asian genetic ancestries. Linear models tested PGS-by-FOS interactions on corresponding observed circulating concentrations. Discovery analysis was performed separately in 237,380 EUR participants and each non-EUR group. Replication analyses were performed using oily fish intake and in another 178,935 EUR participants. Results: In EUR participants, PGS explained 5.3-11.1% of the phenotypic variance, and significant PGS-by-FOS interactions were detected across all four circulating omega-3 traits. Among participants in the bottom 5% of the PGS distribution, FOS was significantly associated with a 0.40 SD (95% CI: 0.39-0.44) increase in Omega-3. This association effect was 11.1% larger than the population average (beta = 0.36; 95% CI: 0.35-0.37; PInt = 0.016) and 42.8% larger than that in participants in the top 5% of the PGS distribution (beta = 0.28 SD; 95% CI: 0.25-0.32; PInt = 4.03e-10). These interaction patterns were consistently observed in CSA ancestry and confirmed in replication and sensitivity analyses. Conclusions: PGS modify the associations of FOS with circulating omega-3 fatty acids in EUR and CSA populations, with larger FOS effects in participants with lower PGS. These findings support the development of genome-informed precision nutrition.","rel_num_authors":9,"rel_authors":[{"author_name":"Huifang Xu","author_inst":"University of Georgia"},{"author_name":"Ge Yu","author_inst":"University of Georgia"},{"author_name":"Yueqi Lu","author_inst":"University of Georgia"},{"author_name":"Harriett Fuller","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Suhang Song","author_inst":"University of Georgia"},{"author_name":"Ye Shen","author_inst":"University of Georgia"},{"author_name":"Charleston W.K. Chiang","author_inst":"University of Southern California"},{"author_name":"Burcu F. Darst","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Kaixiong Ye","author_inst":"University of Georgia"}],"rel_date":"2026-04-30","rel_site":"medrxiv"},{"rel_title":"Acute Cardiovascular Effects of Psilocybin: A Pooled Analysis of 14 Studies with Safety Recommendations","rel_doi":"10.64898\/2026.04.28.26351625","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.28.26351625","rel_abs":"Background: Psilocybin is increasingly studied as a therapeutic for psychiatric and neurologic conditions, yet comprehensive cardiovascular safety data are limited. Current trials often exclude individuals with blood pressure >140\/90 mmHg, criteria established conservatively without robust empirical support. Objective: Characterize the blood pressure and heart rate response to typical therapeutic doses of psilocybin and provide an evidence base for cardiovascular eligibility criteria and monitoring protocols for future clinical trials and emerging therapeutic practice. Methods: We pooled data from 536 psilocybin sessions (oral doses 20-47 mg) among 368 participants across 14 studies at Johns Hopkins University since 1999. Blood pressure and heart rate were measured at baseline and at least hourly up to 360 minutes post-administration. We quantified peak changes, threshold excursions, and excursion duration. Results: Psilocybin produced modest, transient blood pressure elevations. Median peak systolic blood pressure (SBP) was 145 mmHg (IQR 134-156), representing a median increase of 22 mmHg from baseline. Blood pressure peaked at approximately 90 minutes and returned to near-baseline by 300 minutes. SBP exceeded 170 mmHg in 32 sessions (6.0%; median duration 8.5 minutes) and 180 mmHg in 17 sessions (3.2%; median duration 10 minutes). Antihypertensive medication was administered in only 1 session (0.2%). Higher baseline blood pressure was associated with smaller increases, suggesting a ceiling effect rather than exaggerated response. Conclusions: Psilocybin produces modest, transient blood pressure elevations comparable to moderate exercise. Current exclusion criteria of >140\/90 mmHg are not supported by these data. We propose broadening eligibility to <160\/100 mmHg while maintaining exclusions for established cardiovascular disease.","rel_num_authors":11,"rel_authors":[{"author_name":"Sandeep Manel Nayak","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Nathan D Sepeda","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Matthew Nielsen Dick","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Praachi Tiwari","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Zarmeen Zahid","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Ceyda Sayali","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Brandon M Weiss","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"David B Yaden","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Albert Garcia-Romeu","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Brian S Barnett","author_inst":"Cleveland Clinic"},{"author_name":"Frederick S Barrett","author_inst":"Johns Hopkins University School of Medicine"}],"rel_date":"2026-04-30","rel_site":"medrxiv"},{"rel_title":"Androgen Deprivation Therapy (ADT) and Radiotherapy (RT) with Imaging Evaluation Longitudinally (ARIEL) trial: protocol, early results, and implications of neoadjuvant ADT for focal RT boost in prostate cancer","rel_doi":"10.64898\/2026.04.22.26351215","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.22.26351215","rel_abs":"Background. Men with aggressive, localized prostate cancer (PC) undergo definitive radiotherapy (RT) with androgen deprivation therapy (ADT). The prospective, phase II ARIEL trial evaluates a quantitative MRI biomarker, Restriction Spectrum Imaging restriction score (RSIrs), at three time points (before treatment, after ADT and after RT) for treatment response assessment. RSIrs highlights intracellular restricted diffusion and is correlated with high-grade PC. Design. Participants are men with unfavorable-intermediate-risk or high-risk localized PC undergoing definitive RT with neoadjuvant and concurrent ADT, and MRI-RSI acquisitions at three time points: before therapy, after neoadjuvant ADT but before RT, and after RT. The primary aim is to evaluate performance of RSIrs for identifying patients who will experience early biochemical recurrence. Change in RSIrs within visible tumors after ADT and RT is the primary independent variable. Results. 97 patients met inclusion criteria and received [&ge;]1 MRI. On central review, visible PI-RADS lesions were identified in 88 patients: 80 patients had one lesion, and 8 patients had two lesions. After neoadjuvant ADT, 40% of lesions were not clearly visible. Those still visible had shrank by median 55.8% (IQR: 42.8-69.0%), much more than the prostate volume decrease of 21.5% (11.9-31.6%). RSIrs maximum within visible lesions decreased from mean 329 (SD:185) pre-ADT to 209 (SD:125) pre-RT (p<0.01), and to 107 (SD:61) post-RT (p<0.01). Conventional apparent diffusion coefficient (ADC) changes were less consistent. Follow-up is ongoing to assess whether imaging response is related to future recurrence risk. Conclusion. ARIEL has completed accrual and preliminary results demonstrate changes in RSIrs after treatment, which may indicate tumor response. Primary results will be presented when the primary endpoint is reached. With neoadjuvant ADT, both pre- and post-ADT MRI are likely necessary for accurate focal RT boost targeting. Concurrent commencement of ADT and RT simplifies workflows and facilitates accurate gross tumor volume delineation.","rel_num_authors":25,"rel_authors":[{"author_name":"Yuze Song","author_inst":"UCSD"},{"author_name":"Mariluz Rojo Domingo","author_inst":"UCSD"},{"author_name":"Lily Nguyen","author_inst":"UCSD"},{"author_name":"Christopher C Conlin","author_inst":"UCSD"},{"author_name":"Nitin Dhillon","author_inst":"UCSD"},{"author_name":"Son Do","author_inst":"UCSD"},{"author_name":"Anna Dornisch","author_inst":"UCSD"},{"author_name":"Michael E Hahn","author_inst":"UCSD"},{"author_name":"Roshan Karunamuni","author_inst":"UCSD"},{"author_name":"Josh Kim","author_inst":"UCSD"},{"author_name":"Kang-Lung Lee","author_inst":"Cambridge University"},{"author_name":"Jasmine Liu","author_inst":"UCSD"},{"author_name":"Rana R McKay","author_inst":"UCSD"},{"author_name":"Loren K Mell","author_inst":"UCSD"},{"author_name":"Arno Mundt","author_inst":"UCSD"},{"author_name":"Rakesh Patel","author_inst":"UCSD"},{"author_name":"Edmund M Qiao","author_inst":"UCSD"},{"author_name":"Brent S Rose","author_inst":"UCSD"},{"author_name":"Rhea Rupareliya","author_inst":"UCSD"},{"author_name":"Hadley Schaub","author_inst":"UCSD"},{"author_name":"Armin Schwartzman","author_inst":"UCSD"},{"author_name":"Tyler Stewart","author_inst":"UCSD"},{"author_name":"Anders M Dale","author_inst":"JCVI"},{"author_name":"Tyler M Seibert","author_inst":"UCSD"},{"author_name":"- ARIEL consortium","author_inst":"-"}],"rel_date":"2026-04-30","rel_site":"medrxiv"},{"rel_title":"Non-Invasive Arterial Blood Pressure Waveform Generation in Critically Ill Patients: A Sensor-Based Deep Learning Approach","rel_doi":"10.64898\/2026.04.28.26351954","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.28.26351954","rel_abs":"Continuous monitoring of Arterial Blood Pressure (ABP) in critically ill patients requires invasive arterial catheterization, which carries risks of thrombosis, vascular injury and infection. Here, we train and validate a computational model for continuous non-invasive ABP estimation in Intensive Care Unit (ICU) patients using a novel wearable sensor array. The sensor acquires continuous high frequency photoplethysmography (PPG) and electrocardiography (ECG) signals which are used as inputs in a deep learning algorithm for beat-to-beat reconstruction of ABP waveforms. We include 28 patients enrolled in four ICU units at Johns Hopkins Hospital, comprising 15,489 five-second ECG and PPG segments. A CNN\/LSTM hybrid architecture achieved an R2 of 0.812 and a sample-level mean absolute error (MAE) of 4.94 {+\/-} 4.96 mmHg, with systolic and diastolic blood pressure MAEs of 6.38 {+\/-} 6.62 and 3.99 {+\/-} 4.53 mmHg, respectively. This performance closely approached an upper-bound model trained on contemporaneously acquired ground truth ECG and PPG signals (R2 = 0.824, MAE = 4.81 mmHg), indicating that the sensors retain most hemodynamically relevant information. Split-conformal prediction provided calibrated uncertainty intervals with coverage meeting nominal targets, offering a principled framework for bedside confidence assessment. These findings demonstrate the feasibility of accurate, continuous, non-invasive ABP waveform estimation from wearable biosignals in critically ill patients, establishing a foundation for reducing dependence on invasive arterial monitoring while preserving the waveform-level information essential for hemodynamic management.","rel_num_authors":7,"rel_authors":[{"author_name":"Carl W Harris","author_inst":"Johns Hopkins University"},{"author_name":"Bright Nnadi","author_inst":"Johns Hopkins University"},{"author_name":"Sampath Rapuri","author_inst":"Johns Hopkins University"},{"author_name":"John Rattray","author_inst":"Johns Hopkins University"},{"author_name":"Francesco V Tenore","author_inst":"Johns Hopkins Applied Physics Laboratory"},{"author_name":"Ralph Etienne-Cummings","author_inst":"Johns Hopkins University"},{"author_name":"Robert D Stevens","author_inst":"Johns Hopkins University"}],"rel_date":"2026-04-29","rel_site":"medrxiv"},{"rel_title":"How Rare Is Rare? TNFAIP3 Variants and the High Collective Burden of Haploinsufficiency","rel_doi":"10.64898\/2026.04.20.26350987","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.20.26350987","rel_abs":"BackgroundMonogenic diseases are considered rare, yet many remain underdiagnosed when clinical manifestations are heterogeneous. A20 haploinsufficiency (HA20) is an early-onset inborn error of immunity (IEI) caused by heterozygous germline TNFAIP3 variants, resulting in dysregulated inflammatory signaling and diverse immune phenotypes.\n\nMethodsWe analyzed variants in all human haploinsufficiency disease genes in gnomAD v4, applying refined loss-of-function predictors to estimate population frequencies. We assessed rare TNFAIP3 variants (allele frequency <0.01%) in All of Us (AoU), UK Biobank (UKBB), and gnomAD. Variants were classified as predicted loss-of-function (pLOF) or high predicted pathogenic missense (HPPM). Clinical associations were tested through phenome-wide association studies (PheWAS) and validated in a University of Pittsburgh referral cohort.\n\nFindingsHigh-confidence deleterious variants in human haploinsufficiency disease genes, including IEI haploinsufficiency genes, occur frequently at the population level despite strong constraint. Across datasets, TNFAIP3 pLOF variants corresponded to estimated prevalences of [~]1:14,400 (U.S.) and [~]1:23,700 (global); combined pLOF + HPPM prevalences were [~]1:2,800 (U.S.) and [~]1:4,900 (global). PheWAS linked rare TNFAIP3 variants to immune phenotypes with large effect sizes. In a referral cohort (18 patients, 9 families), missense variants conferred hypomorphism with intermediate immunophenotypes.\n\nInterpretationDeleterious TNFAIP3 variants are over 100-fold more common than reported cases suggest and are associated with immune dysregulation spanning variable expressivity and severity. These findings establish proof-of-concept that haploinsufficiency diseases may be pervasively underrecognized. Patients with early-onset or treatment-refractory autoimmune disease should be considered for genetic testing, as precision therapies are available and commercial panels already incorporate TNFAIP3.\n\nFundingThis work was supported by NIAID (T32-AI074490, T32-GM144300), the Jeffrey Modell Foundation, Rheumatology Research Foundation, Samuel and Emma Winters Foundation, University of Pittsburgh Competitive Medicine Research Fund, Sobi, and Eli Lilly.\n\nResearch in Context\n\nEvidence before this studyPrior database analyses estimated that pathogenic variants in constrained haploinsufficiency genes may occur more frequently than case reports suggest, but these observations have not been validated clinically or for specific genetic diseases. Haploinsufficiency of A20 (HA20) is a monogenic immune disorder caused by deleterious variants in TNFAIP3, with fewer than 200 cases reported worldwide. Previous studies characterized clinical phenotypes and treatment responses but did not systematically assess population-level prevalence.\n\nAdded value of this studyThis is the first study to establish that a monogenic immune disease is substantially underrecognized at the population level. We first show that predicted deleterious variants in haploinsufficiency disease genes, including inborn errors of immunity, occur at unexpectedly high frequencies in population databases. We then demonstrate that predicted and functionally validated deleterious TNFAIP3 variants occur at over 100-fold higher frequencies than reported case numbers suggest. We further validate this through phenome-wide association studies showing that variant carriers have significantly elevated rates of immunologic disease, and through deep phenotyping of a referral cohort.\n\nImplications of all the available evidenceThese findings indicate that HA20, and likely other haploinsufficiency diseases, represent a substantial burden of undiagnosed monogenic disease. Clinicians evaluating patients with early-onset or treatment-refractory autoimmune and autoinflammatory conditions should consider genetic testing for inborn errors of immunity including HA20. The high prevalence of pathogenic variants, combined with the availability of targeted therapies, underscores the clinical urgency of improved recognition and diagnosis.","rel_num_authors":23,"rel_authors":[{"author_name":"Danica Lee","author_inst":"Departments of Medicine and Immunology, School of Medicine University of Pittsburgh, Pittsburgh, PA"},{"author_name":"Urekha Karri","author_inst":"Departments of Medicine and Public Health, University of Pittsburgh, Pittsburgh, PA"},{"author_name":"Priyamvada Guha Roy","author_inst":"Department of Immunology, Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA"},{"author_name":"Charlotte Vera Cuff","author_inst":"Departments of Medicine and Immunology, School of Medicine University of Pittsburgh, Pittsburgh, PA"},{"author_name":"Liva Pfuhler","author_inst":"Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA"},{"author_name":"Manuel Carpio Tumba","author_inst":"Departments of Medicine and Immunology, University of Pittsburgh, Pittsburgh, PA"},{"author_name":"Akuti Kethri","author_inst":"Departments of Medicine and Public Health, University of Pittsburgh, Pittsburgh, PA"},{"author_name":"Kyr Goyette","author_inst":"Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA"},{"author_name":"Kader Cetin Gedik","author_inst":"Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA"},{"author_name":"Sam Chiang","author_inst":"Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio"},{"author_name":"Li Yang","author_inst":"Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio"},{"author_name":"Erika Owsley","author_inst":"Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio"},{"author_name":"Josh Owens","author_inst":"Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA"},{"author_name":"Prabbal Chhibbar","author_inst":"Department of Immunology, Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA"},{"author_name":"Kyle Jones","author_inst":"National Institutes of Health, Bethesda, MD"},{"author_name":"Younglang Lee","author_inst":"Aventi"},{"author_name":"Michael Ero","author_inst":"Machaon Diagnostics"},{"author_name":"Connie Ng","author_inst":"Machaon Diagnostics"},{"author_name":"Camille Sambar","author_inst":"Machaon Diagnostics"},{"author_name":"Guido Hernan Falduto","author_inst":"Departments of Medicine and Immunology, University of Pittsburgh, Pittsburgh, PA"},{"author_name":"Jishnu Das","author_inst":"Department of Immunology, Center for Systems Immunology, University of Pittsburgh, Pittsburgh, PA"},{"author_name":"Yiming Luo","author_inst":"Department of Medicine, Columbia University Medical Center, New York, NY"},{"author_name":"Daniella Schwartz","author_inst":"Departments of Medicine and Immunology, University of Pittsburgh, Pittsburgh, PA"}],"rel_date":"2026-04-29","rel_site":"medrxiv"},{"rel_title":"Personalized Feature Statistics: Individual-Level Variant Inference under Genetic Ancestry Continuum","rel_doi":"10.64898\/2026.04.28.26351879","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.28.26351879","rel_abs":"Genome-wide association studies (GWAS) have successfully identified numerous genetic variants associated with complex diseases. However, the extent to which the effects of these variants vary across populations of diverse ancestries remains poorly understood. Furthermore, in these contexts genetic ancestry is treated as a categorical variable, thereby oversimplifying its continuous nature and the more nuanced ways in which it can influence genetic effects on disease. Here, we propose personalized feature statistics (PFstatistics), a statistical framework that quantifies the importance of genetic variants to a phenotype based on each individuals ancestry background, and profiles heterogeneous genetic effects across the genetic ancestry continuum. We demonstrate the utility of this framework through both simulations and real data analysis using sequencing data from ancestrally diverse cohorts in the Alzheimers Disease Sequencing Project (ADSP). We show that Alzheimers Disease (AD) risk variants span a spectrum from ancestry-homogeneous to ancestry-dependent effects, and that PFstatistics characterizes this spectrum at individual resolution across the ancestry continuum. PFstatistics also provides individual-level variant selection with FDR controlled at a target level, yielding distinct selection sets that vary across individuals according to their ancestry background. While demonstrated in the context of genetic ancestry, the proposed method is broadly applicable to other heterogeneity features such as environmental factors, offering a robust tool for understanding complex genetic contributions across diverse populations.","rel_num_authors":11,"rel_authors":[{"author_name":"Julie Fangran Wang","author_inst":"Stanford University"},{"author_name":"Rachel Yu","author_inst":"Stanford University"},{"author_name":"Jacob Edelson","author_inst":"Stanford University"},{"author_name":"Junyoung Park","author_inst":"Stanford University"},{"author_name":"Yann Le Guen","author_inst":"Stanford University"},{"author_name":"Xiaoxia Liu","author_inst":"Stanford University"},{"author_name":"Michael Belloy","author_inst":"Washington University School of Medicine"},{"author_name":"Iuliana Ionita-Laza","author_inst":"Columbia University"},{"author_name":"Michael Greicius","author_inst":"Stanford University"},{"author_name":"Hua Tang","author_inst":"Stanford University"},{"author_name":"Zihuai He","author_inst":"Stanford University"}],"rel_date":"2026-04-29","rel_site":"medrxiv"},{"rel_title":"Personalized Feature Statistics: Individual-Level Variant Inference under Genetic Ancestry Continuum","rel_doi":"10.64898\/2026.04.28.26351879","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.28.26351879","rel_abs":"Genome-wide association studies (GWAS) have successfully identified numerous genetic variants associated with complex diseases. However, the extent to which the effects of these variants vary across populations of diverse ancestries remains poorly understood. Furthermore, in these contexts genetic ancestry is treated as a categorical variable, thereby oversimplifying its continuous nature and the more nuanced ways in which it can influence genetic effects on disease. Here, we propose personalized feature statistics (PFstatistics), a statistical framework that quantifies the importance of genetic variants to a phenotype based on each individuals ancestry background, and profiles heterogeneous genetic effects across the genetic ancestry continuum. We demonstrate the utility of this framework through both simulations and real data analysis using sequencing data from ancestrally diverse cohorts in the Alzheimers Disease Sequencing Project (ADSP). We show that Alzheimers Disease (AD) risk variants span a spectrum from ancestry-homogeneous to ancestry-dependent effects, and that PFstatistics characterizes this spectrum at individual resolution across the ancestry continuum. PFstatistics also provides individual-level variant selection with FDR controlled at a target level, yielding distinct selection sets that vary across individuals according to their ancestry background. While demonstrated in the context of genetic ancestry, the proposed method is broadly applicable to other heterogeneity features such as environmental factors, offering a robust tool for understanding complex genetic contributions across diverse populations.","rel_num_authors":11,"rel_authors":[{"author_name":"Julie Fangran Wang","author_inst":"Stanford University"},{"author_name":"Rachel Yu","author_inst":"Stanford University"},{"author_name":"Jacob Edelson","author_inst":"Stanford University"},{"author_name":"Junyoung Park","author_inst":"Stanford University"},{"author_name":"Yann Le Guen","author_inst":"Stanford University"},{"author_name":"Xiaoxia Liu","author_inst":"Stanford University"},{"author_name":"Michael Belloy","author_inst":"Washington University School of Medicine"},{"author_name":"Iuliana Ionita-Laza","author_inst":"Columbia University"},{"author_name":"Michael Greicius","author_inst":"Stanford University"},{"author_name":"Hua Tang","author_inst":"Stanford University"},{"author_name":"Zihuai He","author_inst":"Stanford University"}],"rel_date":"2026-04-29","rel_site":"medrxiv"},{"rel_title":"A reliability-screened thalamocortical control-network phenotype tracks cocaine-use history in cocaine use disorder","rel_doi":"10.64898\/2026.04.28.26351962","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.28.26351962","rel_abs":"BackgroundA central goal in psychiatry is to move from symptom-defined diagnoses toward biologically interpretable and reliable phenotypes. In cocaine use disorder (CUD), many resting-state abnormalities have been reported, but few circuit-level findings have been explicitly screened for reliability. We tested whether prespecified thalamocortical features yield a reproducible phenotype in CUD and whether that phenotype reflects diagnosis, recent cocaine use, or longer-term illness history.\n\nMethodsDiscovery analyses used resting-state data from 105 participants (46 healthy controls, 59 CUD). From a 13-region thalamocortical circuit, we derived an HC-trained LEiDA state model, generated 11 prespecified features, and advanced only those meeting split-half reliability criteria (ICC[3,1] [&ge;]0.40). A separate paired TMS sample (n=44) was used for extension analyses.\n\nResultsFive features survived reliability screening. Within CUD, longer duration since beginning cocaine use was associated with greater occupancy of a control-like state (standardized {beta}=0.37, q=0.005) and stronger whole-thalamus connectivity with control frontoparietal cortex (standardized {beta}=0.30, q=0.018). Neither days since last use nor CUD vs. healthy diagnosis were associated with any reliable feature after correction. Joint-history models indicated that the signal was better explained by longer-term use history than by recent use. Localization analyses indicated the connectivity effect was concentrated in dorsal thalamic regions. TMS-interaction and effective-connectivity follow-ups were null.\n\nConclusionsReliability screening identified a thalamocortical control-network phenotype in CUD that tracks longer cocaine-use history rather than diagnosis or recent use. More broadly, this workflow offers a practical framework for screening candidate circuit-level psychiatric phenotypes for reliability.","rel_num_authors":2,"rel_authors":[{"author_name":"Brice Bradley Edelman","author_inst":"Georgia Institute of Technology"},{"author_name":"Jeffrey Skolnick","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-04-29","rel_site":"medrxiv"},{"rel_title":"Sampling and host-strain interactions shape detection of Staphylococcus aureus transmission in hospitals","rel_doi":"10.64898\/2026.04.28.26351952","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.28.26351952","rel_abs":"In principle, whole-genome sequencing of Staphylococcus aureus in hospitals is most effective when used prospectively, but its practical limits are unclear. We performed large-scale genomic surveillance across two interconnected hospitals, sequencing 4,779 S. aureus isolates from admission screening and clinical cultures. Integration of genomic and epidemiologic data identified 361 transmission events undetected by standard surveillance. Despite dense sampling, most events (90%) were detected only at readmission, indicating that transmission escapes recognition during the index hospitalization. Serial or discharge screening is likely required to capture transmission. Detection depended on sampling: clinical isolates alone were insufficient, and nearly all events required screening and repeated sampling. Because such approaches are unlikely to scale if applied universally, surveillance must be targeted. Transmission concentrated in methicillin-resistant strains, and it increased when healthcare exposure aligned with hospital-associated strain lineage. These findings help define the limits of prospective genomic surveillance and provide a framework for targeted detection.\n\nMain pointThis work indicates that most MRSA transmission arises from asymptomatic carriers and is detected only after readmission, highlighting the need for targeted serial or discharge screening of high-risk patients to identify and interrupt hospital transmission.","rel_num_authors":16,"rel_authors":[{"author_name":"Kristine B. Rabii","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Courtney Takats","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Gregory Putzel","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Alice Tillman","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Magdalena Podkowik","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Julian McWilliams","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Nora Samhadaneh","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Julia Shenderovich","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Natalia Arguelles","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Anusha Srivastava","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Karl Drlica","author_inst":"Rutgers University"},{"author_name":"Victor J. Torres","author_inst":"St. Jude Children's Research Hospital"},{"author_name":"Alejandro Pironti","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Sarah E. Hochman","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Audrey Renson","author_inst":"NYU Grossman School of Medicine"},{"author_name":"Bo Shopsin","author_inst":"NYU Grossman School of Medicine"}],"rel_date":"2026-04-29","rel_site":"medrxiv"},{"rel_title":"A Sequential Multiple Assignment Randomized Trial Design with Response-Adaptive Tailoring Function","rel_doi":"10.64898\/2026.04.28.26351992","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.28.26351992","rel_abs":"We present a novel sequential multiple assignment randomized trial (SMART) design that integrates response-adaptive randomization with tailoring functions (RA-TF-SMART). We develop percentile-based and Z-score RA-TFs that incorporate both within-patient and between-patient adaptation to map continuous outcomes to randomization probabilities. We apply Q-learning, tree-based reinforcement learning, and G-estimation to estimate dynamic treatment regimens (DTRs). We compare our RA-TF-SMART designs to balanced randomized SMARTs (BR-SMARTs), tailoring function SMARTs (TF-SMARTs), and generalized outcome-adaptive SMARTs (GO-SMARTs). This study addresses limitations in SMART methodology by presenting designs where randomization probability does not require dichotomization of continuous outcomes and utilizes both individual patient outcomes and accumulated treatment efficacy data from prior participants. RA-TF-SMARTs offer a flexible framework that maximizes benefit for trial participants while maintaining statistical validity for post-trial DTR estimation.","rel_num_authors":2,"rel_authors":[{"author_name":"Zhengxi Chen","author_inst":"Case Western Reserve University"},{"author_name":"Holly Hartman","author_inst":"Case Western Reserve University"}],"rel_date":"2026-04-29","rel_site":"medrxiv"},{"rel_title":"Circles of Care: a geospatial analysis of computed tomography (CT) imaging access and socioeconomic vulnerability in Houston, Texas","rel_doi":"10.64898\/2026.04.28.26351996","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.28.26351996","rel_abs":"BackgroundComputed tomography (CT) is a cornerstone of timely diagnosis for stroke, trauma, and oncologic conditions, and delays in access are associated with worsened outcomes. Although Houston, Texas, is home to one of the worlds largest medical complexes, the geographic distribution of CT imaging infrastructure has not been systematically examined against neighborhood-level measures of socioeconomic vulnerability.\n\nMethodsWe conducted a cross-sectional geospatial analysis of CT imaging facilities across the Greater Houston metropolitan area. Facility locations -- including hospital-based scanners, independent imaging centers, and freestanding emergency facilities -- were compiled from publicly available imaging directories, Texas Department of State Health Services (DSHS) facility listings, Centers for Medicare & Medicaid Services (CMS) provider data, and CT location data contributed by MD Anderson Cancer Center. Census tract-level indicators (median household income, percent uninsured, poverty rate) were obtained from the U.S. Census Bureau American Community Survey. Facility locations were geocoded and overlaid on census-tract choropleths in ArcGIS Online and ArcGIS StoryMaps to identify tracts with elevated socioeconomic vulnerability and limited proximity to CT infrastructure.\n\nResultsCT imaging facilities were markedly clustered in the central urban core and in higher-income corridors, with hospital-based and independent scanners concentrated in census tracts with lower poverty rates, higher median household income (>$119,300), and higher insurance coverage. Conversely, peripheral and southeastern tracts with elevated poverty (>24%), median household income below $37,800, and uninsured rates exceeding 16% contained comparatively sparse CT infrastructure, generating spatial \"gaps\" in advanced diagnostic capacity. The pattern persisted across facility type: freestanding emergency and independent imaging centers did not meaningfully compensate for the undersupply of hospital-based scanners in vulnerable communities.\n\nConclusionsIn Houston, the spatial distribution of CT imaging resources mirrors rather than offsets underlying socioeconomic inequality. Neighborhoods with higher poverty and uninsured rates face compounded barriers of distance and coverage. Citywide spatial analysis renders these inequities visible in ways individual clinical encounters cannot, and supports equity-informed health-system planning, targeted investment in underserved catchments, and policies linking imaging-capacity expansion to measurable community need.","rel_num_authors":1,"rel_authors":[{"author_name":"Daniel Martinez","author_inst":"Brown University School of Public Health"}],"rel_date":"2026-04-29","rel_site":"medrxiv"},{"rel_title":"The Diurnal Rhythmicity of Untargeted Metabolomic Profiles in Humans","rel_doi":"10.64898\/2026.04.28.26347027","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.28.26347027","rel_abs":"It is well established that the circadian rhythm system plays a crucial role in metabolic regulation. Yet, the influence of time of sample collection in cross-sectional, untargeted metabolomics datasets remains underexplored. We therefore investigated the temporal oscillations of 853 serum metabolites from 5954 fasting samples in the Hispanic Community Health Study \/ Study of Latinos cohort, where blood samples were drawn within a short daytime window (7:45 am - 1:38 pm). In total, 84 serum metabolites were significantly associated (p<5.9e-05) with blood draw time. Time-varying metabolites exhibit enrichment in pathways of incretin hormones and light signaling, mechanistic connections to neurological and circadian control (dopamine response, melatonin activity), and implications for therapeutics (serotonergic drugs) and health disorder understanding (sleep, depression). Unsupervised analysis revealed latent, nonlinear patterns in five metabolite clusters according to their temporal profiles. Impact on false and missed discovery, and altered effect size estimates for metabolite-health disorder associations underscore the importance of accounting for time. Results fundamentally show that serum metabolites exhibit non-negligible temporal variation even in a restricted short daytime window. Accounting for this variance appears important for precise disease understanding from metabolomics data.","rel_num_authors":14,"rel_authors":[{"author_name":"Pavithra Nagarajan","author_inst":"Brigham and Women's Hospital"},{"author_name":"Tariq Faquih","author_inst":"Brigham and Women's Hospital; Harvard Medical School"},{"author_name":"Bing Yu","author_inst":"The University of Texas Health Science Center at Houston"},{"author_name":"Hassan S. Dashti","author_inst":"Massachusetts General Hospital and Harvard Medical School"},{"author_name":"Raymond Noordam","author_inst":"Leiden University Medical Center"},{"author_name":"Qian Xiao","author_inst":"The University of Texas Health Science Center at Houston"},{"author_name":"Robert Kaplan","author_inst":"Albert Einstein College of Medicine; Fred Hutchinson Cancer Research Center"},{"author_name":"Qibin Qi","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Carmen R. Isasi","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Richa Saxena","author_inst":"Massachusetts General Hospital; Harvard Medical School"},{"author_name":"Frank A.J.L. Scheer","author_inst":"Brigham and Women's Hospital; Harvard Medical School"},{"author_name":"Susan Redline","author_inst":"Brigham and Women's Hospital; Harvard Medical School"},{"author_name":"Tamar Sofer","author_inst":"Brigham and Women's Hospital; Beth Israel Deaconess Medical Center"},{"author_name":"Heming Wang","author_inst":"Brigham and Women's Hospital; Harvard Medical School"}],"rel_date":"2026-04-29","rel_site":"medrxiv"},{"rel_title":"Epigenetic inflammation signatures and lung cancer risk among never-smoking women: a nested case-control study","rel_doi":"10.64898\/2026.04.27.26351864","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.27.26351864","rel_abs":"IntroductionChronic inflammation has been implicated in lung carcinogenesis. Prospective studies have linked higher circulating C-reactive protein (CRP), an acute-phase inflammation marker, to higher lung cancer risk in predominantly smoking populations but lower risk in never smokers. We evaluated DNA methylation-based inflammation risk scores (DNAm-IRSs), which may capture longer-term immune-inflammatory and exposure-related biology, with lung cancer risk among never smokers.\n\nMethodsWe evaluated six DNAm-IRSs, including four CRP-based scores (IRSLigthart, IRSWielscher, IRSLinear_Hillary, IRSElnet_Hillary), in 683 risk-set-sampled case-control pairs nested in the Shanghai Womens Health Study (n=74,941). We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using conditional logistic regression. We examined DNAm-derived leukocyte composition and circulating immune-inflammatory proteins to characterize DNAm-IRS biology.\n\nResultsCirculating CRP correlated positively with IRSLigthart (r=0.19), IRSWielscher (r=0.13), and IRSElnet_Hillary (r=0.30), but inversely with IRSLinear_Hillary (r=-0.02). Per standard deviation increase, IRSLigthart was associated with lower lung cancer risk (HR=0.85, 95% CI: 0.76-0.95), and IRSWielscher with lower risks of lung cancer (HR=0.87, 95% CI: 0.77-0.97) and adenocarcinoma (HR=0.83, 95% CI: 0.71-0.97). Associations persisted after adjustment for leukocyte composition and strengthened after adjustment for DNAm pack-years, an epigenetic smoking index that may capture combustion-related exposures beyond active smoking. Inverse associations were more evident among women with lower DNAm pack-years, although formal interaction tests were not statistically significant. Both scores were positively associated with acute-phase inflammation, IFN-{gamma}\/effector trafficking, and higher CD8+ T-cell proportions.\n\nConclusionsAmong never smokers, selected CRP-related DNAm-IRSs were associated with lower lung cancer risk and were linked to immune features consistent with antitumor activity.","rel_num_authors":18,"rel_authors":[{"author_name":"Mohammad L. Rahman","author_inst":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA."},{"author_name":"Aishani Gargapati","author_inst":"University of Texas at Tyler School of Medicine, Tyler, TX"},{"author_name":"Lauren M. Hurwitz","author_inst":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA."},{"author_name":"Wei Hu","author_inst":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA."},{"author_name":"Alexander P. Keil","author_inst":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA."},{"author_name":"Charles E. Breeze","author_inst":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA."},{"author_name":"Anil Chaturvedi","author_inst":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA."},{"author_name":"Jianxin Shi","author_inst":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA."},{"author_name":"Qiuyin Cai","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA."},{"author_name":"Gong Yang","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA."},{"author_name":"Jirong Long","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA."},{"author_name":"Yu-tang Gao","author_inst":"Shanghai Cancer Institute, Shanghai, China"},{"author_name":"David C. Christiani","author_inst":"Departmemnt of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA."},{"author_name":"Nathaniel Rothman","author_inst":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA."},{"author_name":"Wei Zheng","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA."},{"author_name":"Xiao-Ou Shu","author_inst":"Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA."},{"author_name":"Jason Y.Y. Wong","author_inst":"Epidemiology and Community Health Branch, National Heart Lung and Blood Institute, Bethesda, MD, USA"},{"author_name":"Qing Lan","author_inst":"Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA."}],"rel_date":"2026-04-29","rel_site":"medrxiv"},{"rel_title":"Implementation of acute flaccid paralysis surveillance for polio eradication in Ethiopia: a qualitative study","rel_doi":"10.64898\/2026.04.27.26351901","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.27.26351901","rel_abs":"Ethiopia has implemented acute flaccid paralysis (AFP) surveillance for nearly three decades as a core polio eradication strategy, yet remains at risk of outbreaks, particularly in pastoralist and conflict-affected areas. As Global Polio Eradication Initiative support declines, understanding factors affecting AFP surveillance and sustainability is critical. This study assessed facilitators, barriers, and adaptive strategies influencing AFP surveillance implementation in Ethiopia. A qualitative study using semi-structured interviews was conducted with 43 participants who had been involved in AFP surveillance for at least 12 months between 1996 and 2018. Guided by the Consolidated Framework for Implementation Research, participants were purposively chosen from the Ministry of Health, regional health bureaus, zonal and district health offices, and included surveillance officers, program managers, and frontline health workers from governmental and partner organizations. Data were analyzed thematically using deductive and inductive approaches in NVivo version 12. AFP surveillance implementation in Ethiopia was influenced by multilevel facilitators and barriers. Strong leadership, organizational structures, and partnerships with global and community actors supported coordination and resource mobilization. Community-based networks, including local volunteers and motivated health workers enhanced case detection and reporting in hard-to-reach areas. However, performance was constrained by high staff turnover, logistical challenges, limited subnational resources, weak supervision, and socio-cultural. Geographic inaccessibility and insecurity further limited implementation. Frontline health workers and volunteers used various adaptive strategies such as community engagement, informal reporting, and context-specific logistical solutions, to sustain surveillance activities. Continued reliance on external support posed a concern for long-term sustainability. Strong organizational systems and community engagement can sustain AFP surveillance in resource-limited settings. However, declining external support is a concern for sustainability. Integrating AFP surveillance into broader health systems, increasing domestic investment, and strengthening community-based approaches are essential for long-term resilience.","rel_num_authors":6,"rel_authors":[{"author_name":"Wakgari Deressa","author_inst":"Addis Ababa University School of Public Health"},{"author_name":"Selamawit Hirpa","author_inst":"Addis Ababa University"},{"author_name":"Anna Kalbarczyk","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Svea Closser","author_inst":"Johns Hopkins Bloomberg School of Public Health: Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Assefa Seme","author_inst":"Addis Ababa University"},{"author_name":"Olakunle Alonge","author_inst":"The University of Alabama at Birmingham School of Public Health"}],"rel_date":"2026-04-29","rel_site":"medrxiv"},{"rel_title":"A class of deep intronic IGHMBP2 variants activate a shared cryptic splice donor, enabling correction of select variants with a single antisense oligonucleotide","rel_doi":"10.64898\/2026.04.20.26351111","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.20.26351111","rel_abs":"Biallelic disease-causing variants in IGHMBP2 cause spinal muscular atrophy with respiratory distress type I (SMARD1) and Charcot-Marie-Tooth type 2S (CMT2S). We present 12 unrelated patients with clinically suspected IGHMBP2-related-disease, each carrying a variant deep in intron 8 of IGHMBP2 (c.1235+1076G>A (n=6), c.1235+450G>A (n=5), and c.1235+894C>A (n=1)), along with a known deleterious variant in trans. To assess aberrant pathogenic splicing induced by these deep intronic variants in a relevant model, patient-derived induced pluripotent stem cells were differentiated into motor neurons (iMNs). Long-read RNA sequencing revealed introduction of different pseudoexons by each variant: c.1235+450G>A (626bp), c.1235+1076G>A (112bp and 77bp) and c.1235+894C>A (182bp). Although each variant utilizes a unique splice acceptor site, they all activate the same cryptic donor site, enabling a therapeutic approach to redirect aberrant splicing for all the variants using a single shared antisense oligonucleotide (ASO). Treatment of iMNs with this single ASO restored full-length IGHMBP2 protein in c.1235+894G>A and c.1235+1076G>A by decreasing the use of the novel acceptor site. In contrast, ASO treatment did not correct the splicing in c.1235+450G>A, suggesting that additional splice correction will be needed for this specific variant. A CRISPR interference screen of IGHMBP2 loss-of-function in iMNs identified ribonucleoprotein complex biogenesis (RNP), and rRNA and tRNA processing as top pathways implicated in motor neuron vulnerability. Proteomics and transcriptomics analysis of successfully treated patient iMNs revealed correction of RNP biogenesis and rRNA processing defects. This study highlights the importance of characterizing deep intronic variants in disease-relevant cells to assist the diagnostic process and inform therapeutics development.\n\nOne Sentence SummaryIntron 8 of IGHMBP2 is a hotspot for splice activating pathogenic variants causing SMARD1 and CMT2S, which can be targeted with a single antisense oligonucleotide to correct the aberrant splicing, increase protein and restore cellular function in patient derived motor neurons.","rel_num_authors":48,"rel_authors":[{"author_name":"Sarah Silverstein","author_inst":"Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda MD"},{"author_name":"Andrew D Nguyen","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"},{"author_name":"Rotem Orbach","author_inst":"Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda MD"},{"author_name":"Sandra Donkervoort","author_inst":"Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda MD"},{"author_name":"Thomas Cassini","author_inst":"Department of Pediatrics, Vanderbilt University Medical Center, Nashville TN"},{"author_name":"Mary Koziura","author_inst":"Department of Pediatrics, Vanderbilt University Medical Center, Nashville TN"},{"author_name":"Veronique Bolduc","author_inst":"Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda MD"},{"author_name":"Audrey M Winkelsas","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"},{"author_name":"Ester Masati","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"},{"author_name":"Shreya Nandi","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"},{"author_name":"George Harmison","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"},{"author_name":"Brian Johnson","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"},{"author_name":"Kory Johnson","author_inst":"Bioinformatics Core, NINDS, NIH Bethesda MD"},{"author_name":"Sarah E Kargbo-Hill","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"},{"author_name":"Jason J Bussgang","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"},{"author_name":"Jahan Misra","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"},{"author_name":"Ishaan Sharma","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"},{"author_name":"Jordan E Bontrager","author_inst":"University of Rochester Medical Center, Department of Neurology, NY"},{"author_name":"David N Herrmann","author_inst":"University of Rochester Medical Center, Department of Neurology, NY"},{"author_name":"Francesco Vetrini","author_inst":"Undiagnosed Rare Disease Clinic (URDC), Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA"},{"author_name":"Erin Conboy","author_inst":"Undiagnosed Rare Disease Clinic (URDC), Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA"},{"author_name":"Adam Comer","author_inst":"Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA"},{"author_name":"Kayla Treat","author_inst":"Undiagnosed Rare Disease Clinic (URDC), Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA."},{"author_name":"Katelyn Payne","author_inst":"Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA"},{"author_name":"Khurram Liaqat","author_inst":"Undiagnosed Rare Disease Clinic (URDC), Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA."},{"author_name":"Aneesh Patankar","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"},{"author_name":"Alayne P Meyer","author_inst":"Division of Genetic and Genomic Medicine, Nationwide Childrens Hospital, Columbus, OH"},{"author_name":"Daniel C. Koboldt","author_inst":"The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute, Nationwide Childrens Hospital, 700 Childrens Drive, Columbus, O"},{"author_name":"Anne M. Connolly","author_inst":"Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH"},{"author_name":"Richard Shell","author_inst":"15)\tDivision of Pulmonary, Sleep and CF, Nationwide Childrens Hospital, Columbus OH"},{"author_name":"Anthony R Miller","author_inst":"The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute, Nationwide Childrens Hospital, 700 Childrens Drive, Columbus, O"},{"author_name":"Pimchanok Kulsirichawaroj","author_inst":"Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand"},{"author_name":"Oranee Sanmaneechai","author_inst":"Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand"},{"author_name":"Kullasate Sakpichaisakul","author_inst":"Department of Pediatrics, Queen Sirikit National Institute of Child Health, Ministry of Public Health, Bangkok, Thailand"},{"author_name":"Kyeyoon Park","author_inst":"Stem Cell Unit, NINDS, NIH Bethesda MD"},{"author_name":"Yan Li","author_inst":"Proteomics Core Facility, NINDS, NIH Bethesda MD"},{"author_name":"Diana Bharucha-Goebel","author_inst":"Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda MD"},{"author_name":"William L Macken","author_inst":"Department of Neuromuscular diseases, UCL Queen Square Institute of Neurology, Queen Square House, London WC1N 3BG, UK"},{"author_name":"Anna Sarkozy","author_inst":"Dubowitz Neuromuscular Centre, Great Ormond Street Hospital, Institute of Child Health, University College London, London, UK"},{"author_name":"James Polke","author_inst":"National Hospital for Neurology and Neurosurgery and North Thames Genomics Laboratory Hub Rare Disease Laboratory, Queen Square, London, UK."},{"author_name":"Adnan Y Manzur","author_inst":"Dubowitz Neuromuscular Centre, Great Ormond Street Hospital, Institute of Child Health, University College London, London, UK"},{"author_name":"A. Reghan Foley","author_inst":"Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda MD"},{"author_name":"Katherine R Chao","author_inst":"Broad Institute of MIT\/Harvard, Boston MA"},{"author_name":"Sarah Neuhaus","author_inst":"Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda MD"},{"author_name":"David R Adams","author_inst":"Office of the clinical director, NHGRI, NIH Bethesda MD"},{"author_name":"Michael Ward","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"},{"author_name":"Carsten B\u00f6nnemann","author_inst":"Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda MD"},{"author_name":"Christopher Grunseich","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"}],"rel_date":"2026-04-29","rel_site":"medrxiv"},{"rel_title":"A class of deep intronic IGHMBP2 variants activate a shared cryptic splice donor, enabling correction of select variants with a single antisense oligonucleotide","rel_doi":"10.64898\/2026.04.20.26351111","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.20.26351111","rel_abs":"Biallelic disease-causing variants in IGHMBP2 cause spinal muscular atrophy with respiratory distress type I (SMARD1) and Charcot-Marie-Tooth type 2S (CMT2S). We present 12 unrelated patients with clinically suspected IGHMBP2-related-disease, each carrying a variant deep in intron 8 of IGHMBP2 (c.1235+1076G>A (n=6), c.1235+450G>A (n=5), and c.1235+894C>A (n=1)), along with a known deleterious variant in trans. To assess aberrant pathogenic splicing induced by these deep intronic variants in a relevant model, patient-derived induced pluripotent stem cells were differentiated into motor neurons (iMNs). Long-read RNA sequencing revealed introduction of different pseudoexons by each variant: c.1235+450G>A (626bp), c.1235+1076G>A (112bp and 77bp) and c.1235+894C>A (182bp). Although each variant utilizes a unique splice acceptor site, they all activate the same cryptic donor site, enabling a therapeutic approach to redirect aberrant splicing for all the variants using a single shared antisense oligonucleotide (ASO). Treatment of iMNs with this single ASO restored full-length IGHMBP2 protein in c.1235+894G>A and c.1235+1076G>A by decreasing the use of the novel acceptor site. In contrast, ASO treatment did not correct the splicing in c.1235+450G>A, suggesting that additional splice correction will be needed for this specific variant. A CRISPR interference screen of IGHMBP2 loss-of-function in iMNs identified ribonucleoprotein complex biogenesis (RNP), and rRNA and tRNA processing as top pathways implicated in motor neuron vulnerability. Proteomics and transcriptomics analysis of successfully treated patient iMNs revealed correction of RNP biogenesis and rRNA processing defects. This study highlights the importance of characterizing deep intronic variants in disease-relevant cells to assist the diagnostic process and inform therapeutics development.\n\nOne Sentence SummaryIntron 8 of IGHMBP2 is a hotspot for splice activating pathogenic variants causing SMARD1 and CMT2S, which can be targeted with a single antisense oligonucleotide to correct the aberrant splicing, increase protein and restore cellular function in patient derived motor neurons.","rel_num_authors":48,"rel_authors":[{"author_name":"Sarah Silverstein","author_inst":"Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda MD"},{"author_name":"Andrew D Nguyen","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"},{"author_name":"Rotem Orbach","author_inst":"Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda MD"},{"author_name":"Sandra Donkervoort","author_inst":"Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda MD"},{"author_name":"Thomas Cassini","author_inst":"Department of Pediatrics, Vanderbilt University Medical Center, Nashville TN"},{"author_name":"Mary Koziura","author_inst":"Department of Pediatrics, Vanderbilt University Medical Center, Nashville TN"},{"author_name":"Veronique Bolduc","author_inst":"Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda MD"},{"author_name":"Audrey M Winkelsas","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"},{"author_name":"Ester Masati","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"},{"author_name":"Shreya Nandi","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"},{"author_name":"George Harmison","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"},{"author_name":"Brian Johnson","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"},{"author_name":"Kory Johnson","author_inst":"Bioinformatics Core, NINDS, NIH Bethesda MD"},{"author_name":"Sarah E Kargbo-Hill","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"},{"author_name":"Jason J Bussgang","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"},{"author_name":"Jahan Misra","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"},{"author_name":"Ishaan Sharma","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"},{"author_name":"Jordan E Bontrager","author_inst":"University of Rochester Medical Center, Department of Neurology, NY"},{"author_name":"David N Herrmann","author_inst":"University of Rochester Medical Center, Department of Neurology, NY"},{"author_name":"Francesco Vetrini","author_inst":"Undiagnosed Rare Disease Clinic (URDC), Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA"},{"author_name":"Erin Conboy","author_inst":"Undiagnosed Rare Disease Clinic (URDC), Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA"},{"author_name":"Adam Comer","author_inst":"Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA"},{"author_name":"Kayla Treat","author_inst":"Undiagnosed Rare Disease Clinic (URDC), Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA."},{"author_name":"Katelyn Payne","author_inst":"Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA"},{"author_name":"Khurram Liaqat","author_inst":"Undiagnosed Rare Disease Clinic (URDC), Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA."},{"author_name":"Aneesh Patankar","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"},{"author_name":"Alayne P Meyer","author_inst":"Division of Genetic and Genomic Medicine, Nationwide Childrens Hospital, Columbus, OH"},{"author_name":"Daniel C. Koboldt","author_inst":"The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute, Nationwide Childrens Hospital, 700 Childrens Drive, Columbus, O"},{"author_name":"Anne M. Connolly","author_inst":"Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH"},{"author_name":"Richard Shell","author_inst":"15)\tDivision of Pulmonary, Sleep and CF, Nationwide Childrens Hospital, Columbus OH"},{"author_name":"Anthony R Miller","author_inst":"The Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute, Nationwide Childrens Hospital, 700 Childrens Drive, Columbus, O"},{"author_name":"Pimchanok Kulsirichawaroj","author_inst":"Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand"},{"author_name":"Oranee Sanmaneechai","author_inst":"Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand"},{"author_name":"Kullasate Sakpichaisakul","author_inst":"Department of Pediatrics, Queen Sirikit National Institute of Child Health, Ministry of Public Health, Bangkok, Thailand"},{"author_name":"Kyeyoon Park","author_inst":"Stem Cell Unit, NINDS, NIH Bethesda MD"},{"author_name":"Yan Li","author_inst":"Proteomics Core Facility, NINDS, NIH Bethesda MD"},{"author_name":"Diana Bharucha-Goebel","author_inst":"Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda MD"},{"author_name":"William L Macken","author_inst":"Department of Neuromuscular diseases, UCL Queen Square Institute of Neurology, Queen Square House, London WC1N 3BG, UK"},{"author_name":"Anna Sarkozy","author_inst":"Dubowitz Neuromuscular Centre, Great Ormond Street Hospital, Institute of Child Health, University College London, London, UK"},{"author_name":"James Polke","author_inst":"National Hospital for Neurology and Neurosurgery and North Thames Genomics Laboratory Hub Rare Disease Laboratory, Queen Square, London, UK."},{"author_name":"Adnan Y Manzur","author_inst":"Dubowitz Neuromuscular Centre, Great Ormond Street Hospital, Institute of Child Health, University College London, London, UK"},{"author_name":"A. Reghan Foley","author_inst":"Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda MD"},{"author_name":"Katherine R Chao","author_inst":"Broad Institute of MIT\/Harvard, Boston MA"},{"author_name":"Sarah Neuhaus","author_inst":"Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda MD"},{"author_name":"David R Adams","author_inst":"Office of the clinical director, NHGRI, NIH Bethesda MD"},{"author_name":"Michael Ward","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"},{"author_name":"Carsten B\u00f6nnemann","author_inst":"Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda MD"},{"author_name":"Christopher Grunseich","author_inst":"Inherited Neuromuscular Disease Unit, Neurogenetics Branch, NINDS, NIH Bethesda MD"}],"rel_date":"2026-04-29","rel_site":"medrxiv"},{"rel_title":"Blunted maturation of inhibitory control circuits in the NAC-shell underlies genetic vulnerability to early-life obesity and impulsivity","rel_doi":"10.64898\/2026.04.28.26351915","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.28.26351915","rel_abs":"Obesity and behavioral impulsivity are highly heritable traits that share overlapping genetic risk and often co-occur in childhood. This study investigates whether maturation of the nucleus accumbens shell (NAC-shell) inhibitory-control circuit mediates shared vulnerability to both traits. Using state-of-the-art dynamic fMRI, we mapped NAC-shell development across 460 longitudinal assessments from childhood to adulthood, in 136 healthy controls and 126 individuals with 22q11.2 deletion syndrome (22q11DS), a genetic model conferring high risk for obesity and impulsivity. Blunted NAC-shell maturation predicted steeper BMI increases and persistent neurocognitive impulsivity, consistently mediating their association in both HC and 22q11DS populations. NAC-shell development explained both impulsivity\/obesity genetic vulnerability linked to 22q11DS and familial correlations between affected\/unaffected siblings. These findings propose NAC-shell maturation as a transdiagnostic endophenotype underlying obesity and self-regulation, bridging neurodevelopment, genetics, and behavior. They could inform future early-screening and precision preventive strategies for youth at risk of obesity and other impulsivity-related phenotypes.","rel_num_authors":14,"rel_authors":[{"author_name":"Corrado Sandini","author_inst":"University of Geneva"},{"author_name":"Farnaz Delavari","author_inst":"University of Geneva"},{"author_name":"Natacha Reich","author_inst":"University of Geneva"},{"author_name":"Silas Forrer","author_inst":"University of Geneva"},{"author_name":"Andrea Imparato","author_inst":"University of Geneva"},{"author_name":"Nada Kojovic","author_inst":"University of Geneva"},{"author_name":"Caren Latreche","author_inst":"University of Geneva"},{"author_name":"Luigi Francesco Saccaro","author_inst":"University of Geneva"},{"author_name":"Valeria Parlatini","author_inst":"University of Southampton"},{"author_name":"Samuele Cortese","author_inst":"University of Southampton"},{"author_name":"Camille Piguet","author_inst":"University of Geneva"},{"author_name":"Maude Schneider","author_inst":"University of Geneva"},{"author_name":"Stephan Eliez","author_inst":"University of Geneva"},{"author_name":"Dimitri Van de Ville","author_inst":"University of Geneva"}],"rel_date":"2026-04-29","rel_site":"medrxiv"}]}