{"gname":"The Rockefeller University","grp_id":"2","rels":[{"rel_title":"Exploratory Assessment of Pulsed-Wave Doppler Representations of Lung Sounds Using Deep Learning: An In-Vitro Phantom Study","rel_doi":"10.64898\/2026.06.09.26353787","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26353787","rel_abs":"The increasing availability of portable ultrasound systems motivates exploration of novel approaches to respiratory signal assessment. In this in-vitro study, we investigate whether pulsed-wave (PW) Doppler ultrasound can capture structured spectral patterns from replayed lung sound recordings. Digitized respiratory sounds were replayed through a tissue-mimicking ultrasound phantom, generating 1,478 PW Doppler spectral images from recordings associated with healthy subjects and several externally labeled disease categories. Exploratory classification experiments using a ResNet-18 architecture demonstrated that these Doppler representations contain learnable differences under controlled conditions. These findings motivate further investigation into PW Doppler as a potential representation of respiratory acoustics.","rel_num_authors":5,"rel_authors":[{"author_name":"Ali A Saad","author_inst":"Alumnus of Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"Sarah B Murthi","author_inst":"University of Maryland School of Medicine, R Adams Cowley Shock Trauma Center, Baltimore, MD, USA"},{"author_name":"Emad M Boctor","author_inst":"Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA"},{"author_name":"William A Teeter","author_inst":"University of Maryland School of Medicine, R Adams Cowley Shock Trauma Center, Baltimore, MD, USA"},{"author_name":"Nitin Seam","author_inst":"Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, MD, USA"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Developmental Associations Linking Childhood Trauma and Early Cannabis Use to Adolescent DNA Methylation and Psychotic-Like Experiences","rel_doi":"10.64898\/2026.06.09.26355257","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355257","rel_abs":"Background. Psychotic-like experiences (PLEs) index early risk for psychotic disorders and are consistently associated with childhood trauma, yet underlying biological mechanisms remain poorly understood. DNA methylation (DNAm) may capture the biological embedding of early adversity, while adolescent exposures such as cannabis use may modify these processes. We examined epigenome-wide associations of childhood trauma and PLEs, tested the moderating role of early cannabis use, and evaluated DNAm as a potential mediator. Methods. We analysed data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK population-based birth cohort. Childhood trauma was assessed prospectively and retrospectively. Epigenome-wide DNAm was measured in peripheral blood at ~17 years using the Illumina 450K array, and PLEs were assessed at 18 using a structured interview. Epigenome-wide association studies were conducted for trauma-DNAm and DNAm-PLEs associations in the final sample (n = 1,457), adjusting for demographic, biological, and technical covariates. Differentially methylated regions (DMRs) were identified using DMRff, followed by functional enrichment analyses. Cannabis use at 15.5 was modelled as a moderator with multiple imputation for missing data. Mediation was tested using the Divide-Aggregate Composite-null Test (DACT). Results. Childhood trauma was associated with widespread DNAm differences, primarily at the regional level, with enrichment in pathways related to cellular stress responses. In contrast, DNAm associated with PLEs was more limited and implicated loci involved in epigenetic regulatory processes. These signatures were largely distinct, and there was no evidence supporting mediation after multiple testing correction. Incorporating cannabis use altered the pattern and extent of DNAm associations, with stronger and more significant signals observed at both CpG and regional levels, although these did not translate into evidence of mediation. Conclusion. Childhood trauma and PLEs show distinct DNAm signatures in adolescence, with trauma-related DNAm reflecting broad stress-related processes and PLE-associated DNAm implicating regulatory mechanisms. We found little evidence that DNAm mediates the trauma-PLE association. Instead, adolescent exposures, particularly cannabis use, may distinctly influence trauma-related epigenetic variation with limited detectable downstream effects on PLEs. These findings support a context-dependent model of epigenetic risk and highlight the need for larger longitudinal studies to clarify causal pathways linking early adversity to psychosis.","rel_num_authors":20,"rel_authors":[{"author_name":"Giulia Trotta","author_inst":"King's College London"},{"author_name":"Zhonghua Liu","author_inst":"Columbia University"},{"author_name":"Isabelle Austin-Zimmerman","author_inst":"King's College London"},{"author_name":"Edoardo Spinazzola","author_inst":"King's College London"},{"author_name":"Lucia Sideli","author_inst":"Lumsa"},{"author_name":"Monica Aas","author_inst":"King's College London"},{"author_name":"Victoria Rodriguez","author_inst":"King's College London"},{"author_name":"Zhikun Li","author_inst":"King's College London"},{"author_name":"Bok Man Leung","author_inst":"King's College London"},{"author_name":"Qiang Li","author_inst":"King's College London"},{"author_name":"Shengmin Zhang","author_inst":"King's College London"},{"author_name":"Pak C Sham","author_inst":"The University of Hong Kong"},{"author_name":"Evangelos Vassos","author_inst":"King's College London"},{"author_name":"Richard Bentall","author_inst":"University of Sheffield"},{"author_name":"Emma M Walker","author_inst":"University of Exeter"},{"author_name":"Emma Dempster","author_inst":"University of Exeter"},{"author_name":"Robin Murray","author_inst":"King's College London"},{"author_name":"Marta Di Forti","author_inst":"King's College London"},{"author_name":"Luis Alameda","author_inst":"King's College London"},{"author_name":"Chloe C.Y Wong","author_inst":"King's College London"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Developmental Associations Linking Childhood Trauma and Early Cannabis Use to Adolescent DNA Methylation and Psychotic-Like Experiences","rel_doi":"10.64898\/2026.06.09.26355257","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355257","rel_abs":"Background. Psychotic-like experiences (PLEs) index early risk for psychotic disorders and are consistently associated with childhood trauma, yet underlying biological mechanisms remain poorly understood. DNA methylation (DNAm) may capture the biological embedding of early adversity, while adolescent exposures such as cannabis use may modify these processes. We examined epigenome-wide associations of childhood trauma and PLEs, tested the moderating role of early cannabis use, and evaluated DNAm as a potential mediator. Methods. We analysed data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK population-based birth cohort. Childhood trauma was assessed prospectively and retrospectively. Epigenome-wide DNAm was measured in peripheral blood at ~17 years using the Illumina 450K array, and PLEs were assessed at 18 using a structured interview. Epigenome-wide association studies were conducted for trauma-DNAm and DNAm-PLEs associations in the final sample (n = 1,457), adjusting for demographic, biological, and technical covariates. Differentially methylated regions (DMRs) were identified using DMRff, followed by functional enrichment analyses. Cannabis use at 15.5 was modelled as a moderator with multiple imputation for missing data. Mediation was tested using the Divide-Aggregate Composite-null Test (DACT). Results. Childhood trauma was associated with widespread DNAm differences, primarily at the regional level, with enrichment in pathways related to cellular stress responses. In contrast, DNAm associated with PLEs was more limited and implicated loci involved in epigenetic regulatory processes. These signatures were largely distinct, and there was no evidence supporting mediation after multiple testing correction. Incorporating cannabis use altered the pattern and extent of DNAm associations, with stronger and more significant signals observed at both CpG and regional levels, although these did not translate into evidence of mediation. Conclusion. Childhood trauma and PLEs show distinct DNAm signatures in adolescence, with trauma-related DNAm reflecting broad stress-related processes and PLE-associated DNAm implicating regulatory mechanisms. We found little evidence that DNAm mediates the trauma-PLE association. Instead, adolescent exposures, particularly cannabis use, may distinctly influence trauma-related epigenetic variation with limited detectable downstream effects on PLEs. These findings support a context-dependent model of epigenetic risk and highlight the need for larger longitudinal studies to clarify causal pathways linking early adversity to psychosis.","rel_num_authors":20,"rel_authors":[{"author_name":"Giulia Trotta","author_inst":"King's College London"},{"author_name":"Zhonghua Liu","author_inst":"Columbia University"},{"author_name":"Isabelle Austin-Zimmerman","author_inst":"King's College London"},{"author_name":"Edoardo Spinazzola","author_inst":"King's College London"},{"author_name":"Lucia Sideli","author_inst":"Lumsa"},{"author_name":"Monica Aas","author_inst":"King's College London"},{"author_name":"Victoria Rodriguez","author_inst":"King's College London"},{"author_name":"Zhikun Li","author_inst":"King's College London"},{"author_name":"Bok Man Leung","author_inst":"King's College London"},{"author_name":"Qiang Li","author_inst":"King's College London"},{"author_name":"Shengmin Zhang","author_inst":"King's College London"},{"author_name":"Pak C Sham","author_inst":"The University of Hong Kong"},{"author_name":"Evangelos Vassos","author_inst":"King's College London"},{"author_name":"Richard Bentall","author_inst":"University of Sheffield"},{"author_name":"Emma M Walker","author_inst":"University of Exeter"},{"author_name":"Emma Dempster","author_inst":"University of Exeter"},{"author_name":"Robin Murray","author_inst":"King's College London"},{"author_name":"Marta Di Forti","author_inst":"King's College London"},{"author_name":"Luis Alameda","author_inst":"King's College London"},{"author_name":"Chloe C.Y Wong","author_inst":"King's College London"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Estimating COVID-19 Cumulative Incidence from Seroprevalence Surveys accounting for Time-Varying Seroreversion: A Fully Bayesian Methodology","rel_doi":"10.64898\/2026.06.09.26355264","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26355264","rel_abs":"Seroprevalence surveys reveal the extent of humoral immunity against pathogens such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and under some circumstances represent cumulative incidence of prior infection. However, antibody waning - or seroreversion - biases these estimates by reducing assay sensitivity in a time-varying manner. Because assay sensitivity decays over time, naively using serosurveys can substantially bias estimates of SARS-CoV-2 cumulative incidence and fatality rates. The Bayesian assay-specific, time-varying sensitivity adjustment developed in this paper can reliably correct for this bias and account for the delay between infection and serosurvey. In seroprevalence studies conducted in the United States in 2020, adjusting for time-varying sensitivity increased cumulative incidence by up to 1.4-fold, with an adjustment of 1.08 for a national study. Our estimates contrast with a previously published 2-fold adjustment that did not account for assay design. This suggests that previous analyses overestimated cumulative incidence by applying seroreversion corrections that did not account for assay-specific effects, or underestimated cumulative incidence by not applying seroreversion corrections. These biases imply fatality rate underestimation and overestimation, respectively. Our model provides a framework for design-specific time-varying sensitivity corrections in seroprevalence surveys for other pathogens.","rel_num_authors":8,"rel_authors":[{"author_name":"Nana Owusu-Boaitey","author_inst":"Fischell Department of Bioengineering, University of Maryland, College Park, Maryland, USA"},{"author_name":"Mark J. Meyer","author_inst":"Department of Mathematics and Statistics, Georgetown University, Washington, DC, USA"},{"author_name":"Daniel Herrera-Esposito","author_inst":"Computational Neuroscience Initiative, University of Pennsylvania, Philadelphia, Pennsylvania, USA"},{"author_name":"Lucas Bottcher","author_inst":"Department of Computational Science and Philosophy, Frankfurt School of Finance and Management, Frankfurt, Germany"},{"author_name":"Maria Lukz","author_inst":"School of Public Health, University of Maryland, College Park, Maryland, USA"},{"author_name":"Sydney Cook","author_inst":"Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA"},{"author_name":"Michael A. Stoto","author_inst":"Department of Health Management and Policy, Georgetown University, Washington, DC, USA"},{"author_name":"John D. Kraemer","author_inst":"Department of Health Management and Policy, Georgetown University, Washington, DC, USA"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Resolving Diagnostic Discordance in Group 2 Pulmonary Hypertension Through Staged Physiologic Testing: Insights From PVDOMICS","rel_doi":"10.64898\/2026.06.04.26354961","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354961","rel_abs":"Background World Symposium on Pulmonary Hypertension (WSPH) Group 2 pulmonary hypertension (PH) is a clinically integrated phenotype attributed to left heart disease, whereas pre- versus post-capillary classification is operationalized primarily by pulmonary capillary wedge pressure (PCWP). Although current recommendations emphasize contextual interpretation and provocative testing for intermediate PCWP values, the relationship between PCWP-based classification and underlying phenotype has not been systematically evaluated. We aim to quantify phenotype-hemodynamic discordance across the PCWP spectrum and evaluate a staged physiology-guided framework incorporating inhaled nitric oxide (iNO), ventricular geometry, and provocative testing. Methods We studied 1,032 participants from the NHLBI-sponsored PVDOMICS cohort with multidisciplinary adjudicated phenotypes integrating clinical, imaging, physiologic, and hemodynamic data. Stage-specific PCWP thresholds classified pre- versus post-capillary physiology at rest, during iNO, and during provocation (fluid challenge or invasive cardiopulmonary exercise testing [iCPET]). Echocardiographic right ventricular-to-left ventricular (RV\/LV) ratio was evaluated as a marker of ventricular interdependence. Restricted cubic spline and staged concordance analyses defined certainty-based PCWP ranges and incremental diagnostic yield. Results Adjudicated Group 2 phenotype was present in 37.0% of participants. Resting PCWP demonstrated good discrimination (AUC 0.86), but substantial bidirectional phenotype-hemodynamic discordance persisted across intermediate PCWP ranges. At a resting PCWP of 12 mmHg, 25% of participants classified as pre-capillary had adjudicated Group 2 PH, whereas at 18 mmHg, 35% classified as post-capillary remained discordant non-Group 2. Concordance did not approach 90% until PCWP values were <9 mmHg or >24 mmHg. Dynamic testing incrementally improved concordance within these overlap zones. Nearly half of adjudicated Group 2 PH participants (46.5%) were not identified by resting PCWP alone; incorporation of iNO and provocative testing increased cumulative Group 2 identification by 63.4% and improved sensitivity from 79.9% to 83.7%. Model discrimination improved from an AUC of 0.863 to 0.908 (likelihood-ratio P<0.001). iNO increased PCWP in discordant Pre\/G2 participants, unmasking latent left-sided limitation, while lowering PCWP in discordant Post\/NonG2 participants, consistent with ventricular interdependence. RV\/LV ratio [&ge;]0.94 reduced discordant Post\/NonG2 classification by 70.5%, and incorporation of PCWP\/cardiac output slope improved physiologic specificity during exercise. Conclusions Group 2 PH is a dynamic, load-dependent phenotype inadequately characterized by resting PCWP alone. Intermediate PCWP values represent continuous probabilities of bidirectional discordance rather than discrete diagnostic states. A staged physiology-guided approach integrating iNO, ventricular geometry, and provocative testing improves concordance between hemodynamic classification and clinically integrated phenotype assignment.","rel_num_authors":21,"rel_authors":[{"author_name":"Franz Rischard","author_inst":"The University of Arizona College of Medicine Tucson"},{"author_name":"PVCOMICS Study Group","author_inst":""},{"author_name":"Mateo Mendoza","author_inst":"Cedars-Sinai Health System"},{"author_name":"Michael Insel","author_inst":"University of Arizona"},{"author_name":"Gerald Beck","author_inst":"Cleveland Clinic Foundation"},{"author_name":"Serpil Erzurum","author_inst":"Cleveland Clinic"},{"author_name":"Robert P Frantz","author_inst":"Mayo Clinic"},{"author_name":"J. Emanuel Finet","author_inst":"Cleveland Clinic"},{"author_name":"Paul Hassoun","author_inst":"Johns Hopkins University"},{"author_name":"Anna R. Hemnes","author_inst":"Vanderbilt University"},{"author_name":"Nicholas S. Hill","author_inst":"Tufts University School of Dental Medicine"},{"author_name":"Evelyn M Horn","author_inst":"Weill Cornell Medical College"},{"author_name":"Jane A. Leopold","author_inst":"Brigham and Women's Hospital"},{"author_name":"Stephen C Mathai","author_inst":"Johns Hopkins Medical Institutions, Baltimore, MD"},{"author_name":"Reena Mehra","author_inst":"University of Washington"},{"author_name":"Yogesh N. V. Reddy","author_inst":"Division of Cardiology, Mayo Clinic"},{"author_name":"Erika B. Rosenzweig","author_inst":"Westchester Medical Center"},{"author_name":"David M Systrom","author_inst":"Brigham & Women's Hospital"},{"author_name":"W. H. Wilson Tang","author_inst":"Cleveland Clinic"},{"author_name":"Aaron Waxman","author_inst":"Brigham and Women's Hospital Department of Medicine"},{"author_name":"Barry A Borlaug","author_inst":"Division of Cardiology, Mayo Clinic"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Resolving Diagnostic Discordance in Group 2 Pulmonary Hypertension Through Staged Physiologic Testing: Insights From PVDOMICS","rel_doi":"10.64898\/2026.06.04.26354961","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354961","rel_abs":"Background World Symposium on Pulmonary Hypertension (WSPH) Group 2 pulmonary hypertension (PH) is a clinically integrated phenotype attributed to left heart disease, whereas pre- versus post-capillary classification is operationalized primarily by pulmonary capillary wedge pressure (PCWP). Although current recommendations emphasize contextual interpretation and provocative testing for intermediate PCWP values, the relationship between PCWP-based classification and underlying phenotype has not been systematically evaluated. We aim to quantify phenotype-hemodynamic discordance across the PCWP spectrum and evaluate a staged physiology-guided framework incorporating inhaled nitric oxide (iNO), ventricular geometry, and provocative testing. Methods We studied 1,032 participants from the NHLBI-sponsored PVDOMICS cohort with multidisciplinary adjudicated phenotypes integrating clinical, imaging, physiologic, and hemodynamic data. Stage-specific PCWP thresholds classified pre- versus post-capillary physiology at rest, during iNO, and during provocation (fluid challenge or invasive cardiopulmonary exercise testing [iCPET]). Echocardiographic right ventricular-to-left ventricular (RV\/LV) ratio was evaluated as a marker of ventricular interdependence. Restricted cubic spline and staged concordance analyses defined certainty-based PCWP ranges and incremental diagnostic yield. Results Adjudicated Group 2 phenotype was present in 37.0% of participants. Resting PCWP demonstrated good discrimination (AUC 0.86), but substantial bidirectional phenotype-hemodynamic discordance persisted across intermediate PCWP ranges. At a resting PCWP of 12 mmHg, 25% of participants classified as pre-capillary had adjudicated Group 2 PH, whereas at 18 mmHg, 35% classified as post-capillary remained discordant non-Group 2. Concordance did not approach 90% until PCWP values were <9 mmHg or >24 mmHg. Dynamic testing incrementally improved concordance within these overlap zones. Nearly half of adjudicated Group 2 PH participants (46.5%) were not identified by resting PCWP alone; incorporation of iNO and provocative testing increased cumulative Group 2 identification by 63.4% and improved sensitivity from 79.9% to 83.7%. Model discrimination improved from an AUC of 0.863 to 0.908 (likelihood-ratio P<0.001). iNO increased PCWP in discordant Pre\/G2 participants, unmasking latent left-sided limitation, while lowering PCWP in discordant Post\/NonG2 participants, consistent with ventricular interdependence. RV\/LV ratio [&ge;]0.94 reduced discordant Post\/NonG2 classification by 70.5%, and incorporation of PCWP\/cardiac output slope improved physiologic specificity during exercise. Conclusions Group 2 PH is a dynamic, load-dependent phenotype inadequately characterized by resting PCWP alone. Intermediate PCWP values represent continuous probabilities of bidirectional discordance rather than discrete diagnostic states. A staged physiology-guided approach integrating iNO, ventricular geometry, and provocative testing improves concordance between hemodynamic classification and clinically integrated phenotype assignment.","rel_num_authors":21,"rel_authors":[{"author_name":"Franz Rischard","author_inst":"The University of Arizona College of Medicine Tucson"},{"author_name":"PVCOMICS Study Group","author_inst":""},{"author_name":"Mateo Mendoza","author_inst":"Cedars-Sinai Health System"},{"author_name":"Michael Insel","author_inst":"University of Arizona"},{"author_name":"Gerald Beck","author_inst":"Cleveland Clinic Foundation"},{"author_name":"Serpil Erzurum","author_inst":"Cleveland Clinic"},{"author_name":"Robert P Frantz","author_inst":"Mayo Clinic"},{"author_name":"J. Emanuel Finet","author_inst":"Cleveland Clinic"},{"author_name":"Paul Hassoun","author_inst":"Johns Hopkins University"},{"author_name":"Anna R. Hemnes","author_inst":"Vanderbilt University"},{"author_name":"Nicholas S. Hill","author_inst":"Tufts University School of Dental Medicine"},{"author_name":"Evelyn M Horn","author_inst":"Weill Cornell Medical College"},{"author_name":"Jane A. Leopold","author_inst":"Brigham and Women's Hospital"},{"author_name":"Stephen C Mathai","author_inst":"Johns Hopkins Medical Institutions, Baltimore, MD"},{"author_name":"Reena Mehra","author_inst":"University of Washington"},{"author_name":"Yogesh N. V. Reddy","author_inst":"Division of Cardiology, Mayo Clinic"},{"author_name":"Erika B. Rosenzweig","author_inst":"Westchester Medical Center"},{"author_name":"David M Systrom","author_inst":"Brigham & Women's Hospital"},{"author_name":"W. H. Wilson Tang","author_inst":"Cleveland Clinic"},{"author_name":"Aaron Waxman","author_inst":"Brigham and Women's Hospital Department of Medicine"},{"author_name":"Barry A Borlaug","author_inst":"Division of Cardiology, Mayo Clinic"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Prediction of immunotherapy response using live tumor fragments from routine clinical biopsies","rel_doi":"10.64898\/2026.06.05.26354635","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354635","rel_abs":"Functional ex vivo assays using live tumor tissues have demonstrated strong predictive accuracy for response to immune checkpoint inhibitors (ICIs) but are not scalable, requiring manual processing of large resections collected at academic centers. Here, an ex vivo live tumor fragment (LTF) platform was developed using standard-of-care biopsies from 228 patients with suspected malignancy collected across prospective, multicenter observational trials and biobanks. Hierarchical clustering of ICI-mediated changes in cytokine production identified two groups: responders and nonresponders. A binary classifier (elive index) using 8 cytokines achieved an AUC of 0.99 for cluster prediction. elive index correctly predicted clinical benefit in 93% (26\/28) of patients (P = 3.2x10-5) and accurately identified 83% (10\/12) of objective responders. Critically, elive responders were identified among biomarker-negative patients, highlighting the platform as a scalable approach that complements existing companion diagnostics and expands the population of patients identified to benefit from ICI therapy.","rel_num_authors":46,"rel_authors":[{"author_name":"David Braun","author_inst":"Yale School of Medicine, New Haven, CT"},{"author_name":"Nicholas Dana","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Hilary R. Hernan","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Shalini Sahni","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Christina Scribano","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Christin Johnson","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Lindsey Vedder","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Erika von Euw","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Julie Zweng","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Ellen Wargowski","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Aishwarya Sunil","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Deepa Sharma","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Josh Routh","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Katherine Rexroad","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Payton McDonnell","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Victor Jergens","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Catarina Costa","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Richard Zuniga","author_inst":"New York Cancer & Blood Specialists, New York, NY"},{"author_name":"Giuseppe V. Toia","author_inst":"University of Wisconsin School of Medicine and Public Health, Madison, WI"},{"author_name":"Paras M. Patel","author_inst":"JPS Health Network, Fort Worth, TX"},{"author_name":"Robert C.G. Martin II","author_inst":"University of Louisville School of Medicine, Louisville, KY"},{"author_name":"Umair Majeed","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Debabrata Mukhopadhyay","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Yanyan Lou","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Nima Kokabi","author_inst":"University of North Carolina, Chapel Hill, NC"},{"author_name":"James W. Jakub","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"David Hays","author_inst":"CARTI, Little Rock, AR"},{"author_name":"Andrew K. Godwin","author_inst":"University of Kansas Medical Center, Kansas City, KS"},{"author_name":"Victoria Giffi","author_inst":"Meritus Health, Hagerstown, MD"},{"author_name":"Alexander Gelbard","author_inst":"Vanderbilt, Nashville, TN"},{"author_name":"Andreas Friedl","author_inst":"University of Wisconsin School of Medicine and Public Health, Madison, WI"},{"author_name":"Emma Kate Duimstra","author_inst":"EmpiriQA LLC, Long Grove, IL"},{"author_name":"Roxana S. Dronca","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Ruqin Chen","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Heather Chalfin","author_inst":"Frederick Health, Frederick, MD"},{"author_name":"Barbara Broome","author_inst":"Orlando Health, Orlando, FL"},{"author_name":"Hani M. Babiker","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Tarun Chandra","author_inst":"EmpiriQA LLC, Long Grove, IL"},{"author_name":"Sean Caenepeel","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Laura C. F. Hrycyniak","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Chetan Sood","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Hilario Ramos","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Premal Patel","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Pooja Advani","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Hinco J. Gierman","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Janis Taube","author_inst":"Johns Hopkins University School of Medicine, Baltimore, MD"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Prediction of immunotherapy response using live tumor fragments from routine clinical biopsies","rel_doi":"10.64898\/2026.06.05.26354635","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354635","rel_abs":"Functional ex vivo assays using live tumor tissues have demonstrated strong predictive accuracy for response to immune checkpoint inhibitors (ICIs) but are not scalable, requiring manual processing of large resections collected at academic centers. Here, an ex vivo live tumor fragment (LTF) platform was developed using standard-of-care biopsies from 228 patients with suspected malignancy collected across prospective, multicenter observational trials and biobanks. Hierarchical clustering of ICI-mediated changes in cytokine production identified two groups: responders and nonresponders. A binary classifier (elive index) using 8 cytokines achieved an AUC of 0.99 for cluster prediction. elive index correctly predicted clinical benefit in 93% (26\/28) of patients (P = 3.2x10-5) and accurately identified 83% (10\/12) of objective responders. Critically, elive responders were identified among biomarker-negative patients, highlighting the platform as a scalable approach that complements existing companion diagnostics and expands the population of patients identified to benefit from ICI therapy.","rel_num_authors":46,"rel_authors":[{"author_name":"David Braun","author_inst":"Yale School of Medicine, New Haven, CT"},{"author_name":"Nicholas Dana","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Hilary R. Hernan","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Shalini Sahni","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Christina Scribano","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Christin Johnson","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Lindsey Vedder","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Erika von Euw","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Julie Zweng","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Ellen Wargowski","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Aishwarya Sunil","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Deepa Sharma","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Josh Routh","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Katherine Rexroad","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Payton McDonnell","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Victor Jergens","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Catarina Costa","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Richard Zuniga","author_inst":"New York Cancer & Blood Specialists, New York, NY"},{"author_name":"Giuseppe V. Toia","author_inst":"University of Wisconsin School of Medicine and Public Health, Madison, WI"},{"author_name":"Paras M. Patel","author_inst":"JPS Health Network, Fort Worth, TX"},{"author_name":"Robert C.G. Martin II","author_inst":"University of Louisville School of Medicine, Louisville, KY"},{"author_name":"Umair Majeed","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Debabrata Mukhopadhyay","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Yanyan Lou","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Nima Kokabi","author_inst":"University of North Carolina, Chapel Hill, NC"},{"author_name":"James W. Jakub","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"David Hays","author_inst":"CARTI, Little Rock, AR"},{"author_name":"Andrew K. Godwin","author_inst":"University of Kansas Medical Center, Kansas City, KS"},{"author_name":"Victoria Giffi","author_inst":"Meritus Health, Hagerstown, MD"},{"author_name":"Alexander Gelbard","author_inst":"Vanderbilt, Nashville, TN"},{"author_name":"Andreas Friedl","author_inst":"University of Wisconsin School of Medicine and Public Health, Madison, WI"},{"author_name":"Emma Kate Duimstra","author_inst":"EmpiriQA LLC, Long Grove, IL"},{"author_name":"Roxana S. Dronca","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Ruqin Chen","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Heather Chalfin","author_inst":"Frederick Health, Frederick, MD"},{"author_name":"Barbara Broome","author_inst":"Orlando Health, Orlando, FL"},{"author_name":"Hani M. Babiker","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Tarun Chandra","author_inst":"EmpiriQA LLC, Long Grove, IL"},{"author_name":"Sean Caenepeel","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Laura C. F. Hrycyniak","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Chetan Sood","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Hilario Ramos","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Premal Patel","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Pooja Advani","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Hinco J. Gierman","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Janis Taube","author_inst":"Johns Hopkins University School of Medicine, Baltimore, MD"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Prediction of immunotherapy response using live tumor fragments from routine clinical biopsies","rel_doi":"10.64898\/2026.06.05.26354635","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354635","rel_abs":"Functional ex vivo assays using live tumor tissues have demonstrated strong predictive accuracy for response to immune checkpoint inhibitors (ICIs) but are not scalable, requiring manual processing of large resections collected at academic centers. Here, an ex vivo live tumor fragment (LTF) platform was developed using standard-of-care biopsies from 228 patients with suspected malignancy collected across prospective, multicenter observational trials and biobanks. Hierarchical clustering of ICI-mediated changes in cytokine production identified two groups: responders and nonresponders. A binary classifier (elive index) using 8 cytokines achieved an AUC of 0.99 for cluster prediction. elive index correctly predicted clinical benefit in 93% (26\/28) of patients (P = 3.2x10-5) and accurately identified 83% (10\/12) of objective responders. Critically, elive responders were identified among biomarker-negative patients, highlighting the platform as a scalable approach that complements existing companion diagnostics and expands the population of patients identified to benefit from ICI therapy.","rel_num_authors":46,"rel_authors":[{"author_name":"David Braun","author_inst":"Yale School of Medicine, New Haven, CT"},{"author_name":"Nicholas Dana","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Hilary R. Hernan","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Shalini Sahni","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Christina Scribano","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Christin Johnson","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Lindsey Vedder","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Erika von Euw","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Julie Zweng","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Ellen Wargowski","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Aishwarya Sunil","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Deepa Sharma","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Josh Routh","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Katherine Rexroad","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Payton McDonnell","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Victor Jergens","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Catarina Costa","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Richard Zuniga","author_inst":"New York Cancer & Blood Specialists, New York, NY"},{"author_name":"Giuseppe V. Toia","author_inst":"University of Wisconsin School of Medicine and Public Health, Madison, WI"},{"author_name":"Paras M. Patel","author_inst":"JPS Health Network, Fort Worth, TX"},{"author_name":"Robert C.G. Martin II","author_inst":"University of Louisville School of Medicine, Louisville, KY"},{"author_name":"Umair Majeed","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Debabrata Mukhopadhyay","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Yanyan Lou","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Nima Kokabi","author_inst":"University of North Carolina, Chapel Hill, NC"},{"author_name":"James W. Jakub","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"David Hays","author_inst":"CARTI, Little Rock, AR"},{"author_name":"Andrew K. Godwin","author_inst":"University of Kansas Medical Center, Kansas City, KS"},{"author_name":"Victoria Giffi","author_inst":"Meritus Health, Hagerstown, MD"},{"author_name":"Alexander Gelbard","author_inst":"Vanderbilt, Nashville, TN"},{"author_name":"Andreas Friedl","author_inst":"University of Wisconsin School of Medicine and Public Health, Madison, WI"},{"author_name":"Emma Kate Duimstra","author_inst":"EmpiriQA LLC, Long Grove, IL"},{"author_name":"Roxana S. Dronca","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Ruqin Chen","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Heather Chalfin","author_inst":"Frederick Health, Frederick, MD"},{"author_name":"Barbara Broome","author_inst":"Orlando Health, Orlando, FL"},{"author_name":"Hani M. Babiker","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Tarun Chandra","author_inst":"EmpiriQA LLC, Long Grove, IL"},{"author_name":"Sean Caenepeel","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Laura C. F. Hrycyniak","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Chetan Sood","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Hilario Ramos","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Premal Patel","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Pooja Advani","author_inst":"Mayo Clinic Jacksonville, Jacksonville, FL"},{"author_name":"Hinco J. Gierman","author_inst":"Elephas Biosciences, Madison, WI"},{"author_name":"Janis Taube","author_inst":"Johns Hopkins University School of Medicine, Baltimore, MD"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Trajectories of brain structure and function in young adult carriers of genetic frontotemporal dementia variants","rel_doi":"10.64898\/2026.06.08.26355165","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355165","rel_abs":"Background and Objectives: Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods: This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results: Variant carriers (n=147) and familial non-carriers (n=113) did not differ in age (mean{+\/-}SD, 25.9{+\/-}3.2 years), sex (53% female), or number of visits (2.1{+\/-}1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years (b=-982.8mm3, SE=317.0, p=0.0046, f2=0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines (b=64.4mm3, SE=29.9, p=0.035, f2=0.07). For MAPT and GRN, there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion: C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.","rel_num_authors":79,"rel_authors":[{"author_name":"Isis So","author_inst":"Western University"},{"author_name":"Jolina Lombardi","author_inst":"University of California, San Francisco, CA, USA"},{"author_name":"Adam M Staffaroni","author_inst":"University of California, San Francisco"},{"author_name":"Kristy Coleman","author_inst":"Western University"},{"author_name":"Arabella Bouzigues","author_inst":"University College London"},{"author_name":"Eve Ferry-Bolder","author_inst":"University College London"},{"author_name":"Eva Cullen","author_inst":"University College London"},{"author_name":"Lucy Russell","author_inst":"University College London"},{"author_name":"Phoebe Foster","author_inst":"University College London"},{"author_name":"Sophie Farley","author_inst":"University College London"},{"author_name":"Rhian Convery","author_inst":"University College London"},{"author_name":"John C van Swieten","author_inst":"Erasmus MC University Medical Center"},{"author_name":"Lize C. Jiskoot","author_inst":"Erasmus MC University Medical Center"},{"author_name":"Harro Seelaar","author_inst":"Erasmus MC University Medical Centre"},{"author_name":"Daniela Galimberti","author_inst":"University of Milan"},{"author_name":"Rik Vandenberghe","author_inst":"KU Leuven"},{"author_name":"Robert Laforce Jr.","author_inst":"Laval University"},{"author_name":"Rose Bruffaerts","author_inst":"University of Antwerp"},{"author_name":"Maxime Bertoux","author_inst":"University of Lille"},{"author_name":"Thibaud Lebouvier","author_inst":"University of Lille"},{"author_name":"Eino Solje","author_inst":"University of Eastern Finland"},{"author_name":"Johannes Levin","author_inst":"Ludwig-Maximilians-Universitat Munchen"},{"author_name":"Giuseppe di Fede","author_inst":"Fondazione IRCCS Istituto Neurologico Carlo Besta"},{"author_name":"Alexander Thompson","author_inst":"University of Oxford"},{"author_name":"Isabelle Le Ber","author_inst":"Institut du Cerveau"},{"author_name":"Raffaella Lara Migliaccio","author_inst":"Institut du Cerveau"},{"author_name":"Peter Kortvelyessy","author_inst":"Charite Universitatsmedizin Berlin"},{"author_name":"Matthias L. Schroeter","author_inst":"Max Planck Institute for Human Cognitive and Brain Sciences"},{"author_name":"Giancarlo Logroscino","author_inst":"University of Bari"},{"author_name":"Markus Otto","author_inst":"Martin Luther University Halle-Wittenberg, University clinic"},{"author_name":"Zeljko Uzelac","author_inst":"University of Ulm"},{"author_name":"Ignacio Illan-Gala","author_inst":"Hospital de la Santa Creu i Sant Pau"},{"author_name":"Johanna Kruger","author_inst":"University of Oulu"},{"author_name":"Benedetta Nacmias","author_inst":"University of Florence"},{"author_name":"Alexander Gerhard","author_inst":"University of Manchester"},{"author_name":"Tobias Langheinrich","author_inst":"University of Manchester"},{"author_name":"Simon Ducharme","author_inst":"McGill University"},{"author_name":"Isabel J Santana","author_inst":"University of Coimbra"},{"author_name":"Carmela Tartaglia","author_inst":"University of Toronto"},{"author_name":"Mario Masellis","author_inst":"University of Toronto"},{"author_name":"Alexandre de Mendonca","author_inst":"University of Lisbon"},{"author_name":"James Rowe","author_inst":"University of Cambridge"},{"author_name":"Caroline Graff","author_inst":"Karolinska Institutet"},{"author_name":"Fermin Morenoizco","author_inst":"Hospital Universitario Donostia, San Sebastian"},{"author_name":"Matthis Synofzik","author_inst":"University of Tubingen"},{"author_name":"Barbara Borroni","author_inst":"Universita degli Studi di BRESCIA"},{"author_name":"Raquel Sanchez-Valle","author_inst":"University of Barcelona"},{"author_name":"Danielle Brushaber","author_inst":"Mayo Clinic"},{"author_name":"Ciaran Considine","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Kelley Faber","author_inst":"Indiana University"},{"author_name":"Julie Fields","author_inst":"Mayo Clinic"},{"author_name":"Tatiana Foroud","author_inst":"Mayo Clinic"},{"author_name":"Leah K. Forsberg","author_inst":"Mayo Clinic"},{"author_name":"Tania Gendron","author_inst":"Mayo Clinic"},{"author_name":"Daniel Geschwind","author_inst":"UCLA"},{"author_name":"Hilary Heuer","author_inst":"University of California, San Francisco"},{"author_name":"Eric Huang","author_inst":"University of California, San Francisco"},{"author_name":"Kejal Kantarci","author_inst":"Mayo Clinic in Rochester"},{"author_name":"Tyler Kolander","author_inst":"Mayo Clinic"},{"author_name":"Argentina Lario Lago","author_inst":"University of California, San Francisco"},{"author_name":"Shannon B. Lavigne","author_inst":"Mayo Clinic"},{"author_name":"Carly Mester","author_inst":"Mayo Clinic"},{"author_name":"Joie Molden","author_inst":"Indiana University"},{"author_name":"Leonard Petrucelli","author_inst":"Mayo Clinic"},{"author_name":"Rosa Rademakers","author_inst":"University of Antwerp"},{"author_name":"Eliana Marisa Ramos","author_inst":"University of California, Los Angeles"},{"author_name":"Katherine P. Rankin","author_inst":"University of California, San Francisco"},{"author_name":"Katya Rascovsky","author_inst":"University of Pennsylvania"},{"author_name":"Kristoffer W. Rhoads","author_inst":"University of Pennsylvania"},{"author_name":"Marijne Vandebergh","author_inst":"VIB-UAntwerp Center for Molecular Neurology"},{"author_name":"Sandra Weintraub","author_inst":"Northwestern University"},{"author_name":"Bonnie Wong","author_inst":"Harvard University"},{"author_name":"Bradley Boeve","author_inst":"Mayo Clinic"},{"author_name":"Adam L. Boxer","author_inst":"University of California, San Francisco"},{"author_name":"Howard J. Rosen","author_inst":"University of California, San Francisco"},{"author_name":"Suzee E. Lee","author_inst":"University of California, San Francisco"},{"author_name":"Jonathan D. Rohrer","author_inst":"University College London"},{"author_name":"Elizabeth C. Finger","author_inst":"Western University"},{"author_name":"- Frontotemporal Dementia Prevention Initiative (FPI) Investigators","author_inst":""}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Trajectories of brain structure and function in young adult carriers of genetic frontotemporal dementia variants","rel_doi":"10.64898\/2026.06.08.26355165","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355165","rel_abs":"Background and Objectives: Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods: This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results: Variant carriers (n=147) and familial non-carriers (n=113) did not differ in age (mean{+\/-}SD, 25.9{+\/-}3.2 years), sex (53% female), or number of visits (2.1{+\/-}1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years (b=-982.8mm3, SE=317.0, p=0.0046, f2=0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines (b=64.4mm3, SE=29.9, p=0.035, f2=0.07). For MAPT and GRN, there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion: C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.","rel_num_authors":79,"rel_authors":[{"author_name":"Isis So","author_inst":"Western University"},{"author_name":"Jolina Lombardi","author_inst":"University of California, San Francisco, CA, USA"},{"author_name":"Adam M Staffaroni","author_inst":"University of California, San Francisco"},{"author_name":"Kristy Coleman","author_inst":"Western University"},{"author_name":"Arabella Bouzigues","author_inst":"University College London"},{"author_name":"Eve Ferry-Bolder","author_inst":"University College London"},{"author_name":"Eva Cullen","author_inst":"University College London"},{"author_name":"Lucy Russell","author_inst":"University College London"},{"author_name":"Phoebe Foster","author_inst":"University College London"},{"author_name":"Sophie Farley","author_inst":"University College London"},{"author_name":"Rhian Convery","author_inst":"University College London"},{"author_name":"John C van Swieten","author_inst":"Erasmus MC University Medical Center"},{"author_name":"Lize C. Jiskoot","author_inst":"Erasmus MC University Medical Center"},{"author_name":"Harro Seelaar","author_inst":"Erasmus MC University Medical Centre"},{"author_name":"Daniela Galimberti","author_inst":"University of Milan"},{"author_name":"Rik Vandenberghe","author_inst":"KU Leuven"},{"author_name":"Robert Laforce Jr.","author_inst":"Laval University"},{"author_name":"Rose Bruffaerts","author_inst":"University of Antwerp"},{"author_name":"Maxime Bertoux","author_inst":"University of Lille"},{"author_name":"Thibaud Lebouvier","author_inst":"University of Lille"},{"author_name":"Eino Solje","author_inst":"University of Eastern Finland"},{"author_name":"Johannes Levin","author_inst":"Ludwig-Maximilians-Universitat Munchen"},{"author_name":"Giuseppe di Fede","author_inst":"Fondazione IRCCS Istituto Neurologico Carlo Besta"},{"author_name":"Alexander Thompson","author_inst":"University of Oxford"},{"author_name":"Isabelle Le Ber","author_inst":"Institut du Cerveau"},{"author_name":"Raffaella Lara Migliaccio","author_inst":"Institut du Cerveau"},{"author_name":"Peter Kortvelyessy","author_inst":"Charite Universitatsmedizin Berlin"},{"author_name":"Matthias L. Schroeter","author_inst":"Max Planck Institute for Human Cognitive and Brain Sciences"},{"author_name":"Giancarlo Logroscino","author_inst":"University of Bari"},{"author_name":"Markus Otto","author_inst":"Martin Luther University Halle-Wittenberg, University clinic"},{"author_name":"Zeljko Uzelac","author_inst":"University of Ulm"},{"author_name":"Ignacio Illan-Gala","author_inst":"Hospital de la Santa Creu i Sant Pau"},{"author_name":"Johanna Kruger","author_inst":"University of Oulu"},{"author_name":"Benedetta Nacmias","author_inst":"University of Florence"},{"author_name":"Alexander Gerhard","author_inst":"University of Manchester"},{"author_name":"Tobias Langheinrich","author_inst":"University of Manchester"},{"author_name":"Simon Ducharme","author_inst":"McGill University"},{"author_name":"Isabel J Santana","author_inst":"University of Coimbra"},{"author_name":"Carmela Tartaglia","author_inst":"University of Toronto"},{"author_name":"Mario Masellis","author_inst":"University of Toronto"},{"author_name":"Alexandre de Mendonca","author_inst":"University of Lisbon"},{"author_name":"James Rowe","author_inst":"University of Cambridge"},{"author_name":"Caroline Graff","author_inst":"Karolinska Institutet"},{"author_name":"Fermin Morenoizco","author_inst":"Hospital Universitario Donostia, San Sebastian"},{"author_name":"Matthis Synofzik","author_inst":"University of Tubingen"},{"author_name":"Barbara Borroni","author_inst":"Universita degli Studi di BRESCIA"},{"author_name":"Raquel Sanchez-Valle","author_inst":"University of Barcelona"},{"author_name":"Danielle Brushaber","author_inst":"Mayo Clinic"},{"author_name":"Ciaran Considine","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Kelley Faber","author_inst":"Indiana University"},{"author_name":"Julie Fields","author_inst":"Mayo Clinic"},{"author_name":"Tatiana Foroud","author_inst":"Mayo Clinic"},{"author_name":"Leah K. Forsberg","author_inst":"Mayo Clinic"},{"author_name":"Tania Gendron","author_inst":"Mayo Clinic"},{"author_name":"Daniel Geschwind","author_inst":"UCLA"},{"author_name":"Hilary Heuer","author_inst":"University of California, San Francisco"},{"author_name":"Eric Huang","author_inst":"University of California, San Francisco"},{"author_name":"Kejal Kantarci","author_inst":"Mayo Clinic in Rochester"},{"author_name":"Tyler Kolander","author_inst":"Mayo Clinic"},{"author_name":"Argentina Lario Lago","author_inst":"University of California, San Francisco"},{"author_name":"Shannon B. Lavigne","author_inst":"Mayo Clinic"},{"author_name":"Carly Mester","author_inst":"Mayo Clinic"},{"author_name":"Joie Molden","author_inst":"Indiana University"},{"author_name":"Leonard Petrucelli","author_inst":"Mayo Clinic"},{"author_name":"Rosa Rademakers","author_inst":"University of Antwerp"},{"author_name":"Eliana Marisa Ramos","author_inst":"University of California, Los Angeles"},{"author_name":"Katherine P. Rankin","author_inst":"University of California, San Francisco"},{"author_name":"Katya Rascovsky","author_inst":"University of Pennsylvania"},{"author_name":"Kristoffer W. Rhoads","author_inst":"University of Pennsylvania"},{"author_name":"Marijne Vandebergh","author_inst":"VIB-UAntwerp Center for Molecular Neurology"},{"author_name":"Sandra Weintraub","author_inst":"Northwestern University"},{"author_name":"Bonnie Wong","author_inst":"Harvard University"},{"author_name":"Bradley Boeve","author_inst":"Mayo Clinic"},{"author_name":"Adam L. Boxer","author_inst":"University of California, San Francisco"},{"author_name":"Howard J. Rosen","author_inst":"University of California, San Francisco"},{"author_name":"Suzee E. Lee","author_inst":"University of California, San Francisco"},{"author_name":"Jonathan D. Rohrer","author_inst":"University College London"},{"author_name":"Elizabeth C. Finger","author_inst":"Western University"},{"author_name":"- Frontotemporal Dementia Prevention Initiative (FPI) Investigators","author_inst":""}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Development of an Open-Access Action Observation Video Library for Upper Limb Motor Rehabilitation","rel_doi":"10.64898\/2026.06.10.26355108","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.10.26355108","rel_abs":"Background: Occupational therapists can improve stroke survivors hand and arm movement and participation in daily activities through action observation (AO). AO involves watching another persons hand or arm complete a movement or task. While research generally supports the use of AO with stroke survivors, there are limited AO videos are available to occupational therapists which makes applying AO challenging. Objective: The purpose of this work is to develop structured and widely accessible tool to support access to AO for stroke survivors, occupational therapists, and researchers. Methods: To develop an AO video library for stroke rehabilitation, functional and non-functional upper limb task deficits were first identified through clinical observations and clinician interviews to establish a prioritized list of daily activities. In collaboration with media production specialists, healthy adult volunteers were recruited and filmed performing these tasks from both first- and third-person perspectives. The recorded videos were then systematically edited, enhanced with instructional title slides, and distributed via a public YouTube channel for clinical application and a categorized digital repository for research purposes. Results: Initial assessments revealed a complete lack of familiarity, awareness, and utilization of AO resources among local occupational therapists, despite high perceived clinical utility. To address this gap, a final library of 150 tasks was established, resulting in the production of 419 finalized, standardized videos featuring six healthy volunteers. For clinical application, these videos were hosted on a free, public YouTube channel organized into 18 functional playlists, while a parallel set was structured into distinct movement categories for research repository storage. Conclusion: By providing a structured and highly accessible tool, this repository enables clinicians, researchers, and caregivers to readily implement evidence-based action observation interventions in both clinical and home settings.","rel_num_authors":3,"rel_authors":[{"author_name":"Medina Madison","author_inst":"Department of Occupational Therapy, Byrdine F. Lewis College of Nursing and Health Professions, Georgia State University"},{"author_name":"Lewis A Wheaton","author_inst":"Georgia Tech"},{"author_name":"Veronica Rowe","author_inst":"Department of Occupational Therapy, Byrdine F. Lewis College of Nursing and Health Professions, Georgia State University"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Longitudinal brain structural changes during clozapine treatment: associations with neuroreceptor architecture and clinical response","rel_doi":"10.64898\/2026.06.06.26354980","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.06.26354980","rel_abs":"In treatment-resistant schizophrenia, clozapine treatment has been associated with longitudinal reductions in subcortical volumes, ventricular enlargement, and widespread cortical thinning. However, it is unknown how these structural changes relate to clozapines pharmacological profile and clinical efficacy. We combined five longitudinal datasets with MRI acquired before and on average 5 months after clozapine initiation in 143 individuals to quantify brain structural changes and their association with normative maps relating to neuroreceptor architecture and physiological systems, and improvement in symptom severity. Clozapine treatment was associated with grey matter volume reductions across multiple subcortical regions (including the amygdala, hippocampus, thalamus, caudate, putamen and nucleus accumbens), increases in pallidal volume, ventricular enlargement, and widespread cortical thinning. Cortical regions showing the greatest magnitude of thinning corresponded to areas with higher normative densities of serotonergic 5-HT1A, 5-HT2A and 5-HT4 receptors. Changes in subcortical volume or cortical thickness during clozapine treatment were not associated with changes in total or positive symptom severity. In addition, baseline subcortical volume, cortical thickness, or gyrification prior to starting clozapine did not predict subsequent symptom improvement. Cortical thinning may partly reflect clozapines activity at serotonergic receptors, which have been implicated in cortical network stabilisation and neuroplasticity, however structural remodelling during clozapine treatment may reflect a process independent from its clinical efficacy in improving core symptoms of psychosis.","rel_num_authors":21,"rel_authors":[{"author_name":"Bridget King","author_inst":"King's College London"},{"author_name":"Dara Cannon","author_inst":"Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway"},{"author_name":"Nicolas A Crossley","author_inst":"Pontificia Universidad Catolica de Chile"},{"author_name":"Alfonso Gonzalez Valderrama","author_inst":"School of Medicine, Finis Terrae University, Santiago, Chile; Dr Jose Horwitz Barack Psychiatric Institute, Santiago Chile"},{"author_name":"Brian Hallahan","author_inst":"Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway"},{"author_name":"Wi Hoon Jung","author_inst":"Department of Psychology, Gachon University, Gyeonggi-do, Republic of Korea"},{"author_name":"Matthew J. Kempton","author_inst":"Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom"},{"author_name":"Seoyoung Kim","author_inst":"Department of Psychiatry, Seoul National University Bundang Hospital, Gyeonggi-do, Seoul, Republic of Korea."},{"author_name":"Andrew J Lawrence","author_inst":"Institute of Psychiatry, Psychology and Neuroscience; King's College London"},{"author_name":"James H MacCabe","author_inst":"King's College London"},{"author_name":"Colm McDonald","author_inst":"Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway"},{"author_name":"Cristian Mena","author_inst":"Centro de Interes Nacional para Investigacion e Innovacion en Ninez, Adolescencia, Resiliencia y Adversidad (IINARA), Santiago, Chile; Dr Jose Horwitz Barack Ps"},{"author_name":"Shinichiro Nakajima","author_inst":"Department of Neuropsychiatry, Keio University School of Medicine, Tokyo."},{"author_name":"Andrew Papale","author_inst":"University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"},{"author_name":"Samira Raminfard","author_inst":"University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"},{"author_name":"Deepak Sarpal","author_inst":"University of Pittsburgh"},{"author_name":"Hyejin Sim","author_inst":"Department of Brain & Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea."},{"author_name":"Giulia Tronchin","author_inst":"Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway"},{"author_name":"Lauri Tuominen","author_inst":"University of Ottawa Institute of Mental Health Research, Ottawa, ON, Canada"},{"author_name":"Euitae Kim","author_inst":"Department of Psychiatry, Seoul National University Bundang Hospital, Gyeonggi-do, Seoul, Republic of Korea; Department of Brain & Cognitive Sciences, College o"},{"author_name":"Alice Egerton","author_inst":"Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Longitudinal brain structural changes during clozapine treatment: associations with neuroreceptor architecture and clinical response","rel_doi":"10.64898\/2026.06.06.26354980","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.06.26354980","rel_abs":"In treatment-resistant schizophrenia, clozapine treatment has been associated with longitudinal reductions in subcortical volumes, ventricular enlargement, and widespread cortical thinning. However, it is unknown how these structural changes relate to clozapines pharmacological profile and clinical efficacy. We combined five longitudinal datasets with MRI acquired before and on average 5 months after clozapine initiation in 143 individuals to quantify brain structural changes and their association with normative maps relating to neuroreceptor architecture and physiological systems, and improvement in symptom severity. Clozapine treatment was associated with grey matter volume reductions across multiple subcortical regions (including the amygdala, hippocampus, thalamus, caudate, putamen and nucleus accumbens), increases in pallidal volume, ventricular enlargement, and widespread cortical thinning. Cortical regions showing the greatest magnitude of thinning corresponded to areas with higher normative densities of serotonergic 5-HT1A, 5-HT2A and 5-HT4 receptors. Changes in subcortical volume or cortical thickness during clozapine treatment were not associated with changes in total or positive symptom severity. In addition, baseline subcortical volume, cortical thickness, or gyrification prior to starting clozapine did not predict subsequent symptom improvement. Cortical thinning may partly reflect clozapines activity at serotonergic receptors, which have been implicated in cortical network stabilisation and neuroplasticity, however structural remodelling during clozapine treatment may reflect a process independent from its clinical efficacy in improving core symptoms of psychosis.","rel_num_authors":21,"rel_authors":[{"author_name":"Bridget King","author_inst":"King's College London"},{"author_name":"Dara Cannon","author_inst":"Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway"},{"author_name":"Nicolas A Crossley","author_inst":"Pontificia Universidad Catolica de Chile"},{"author_name":"Alfonso Gonzalez Valderrama","author_inst":"School of Medicine, Finis Terrae University, Santiago, Chile; Dr Jose Horwitz Barack Psychiatric Institute, Santiago Chile"},{"author_name":"Brian Hallahan","author_inst":"Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway"},{"author_name":"Wi Hoon Jung","author_inst":"Department of Psychology, Gachon University, Gyeonggi-do, Republic of Korea"},{"author_name":"Matthew J. Kempton","author_inst":"Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom"},{"author_name":"Seoyoung Kim","author_inst":"Department of Psychiatry, Seoul National University Bundang Hospital, Gyeonggi-do, Seoul, Republic of Korea."},{"author_name":"Andrew J Lawrence","author_inst":"Institute of Psychiatry, Psychology and Neuroscience; King's College London"},{"author_name":"James H MacCabe","author_inst":"King's College London"},{"author_name":"Colm McDonald","author_inst":"Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway"},{"author_name":"Cristian Mena","author_inst":"Centro de Interes Nacional para Investigacion e Innovacion en Ninez, Adolescencia, Resiliencia y Adversidad (IINARA), Santiago, Chile; Dr Jose Horwitz Barack Ps"},{"author_name":"Shinichiro Nakajima","author_inst":"Department of Neuropsychiatry, Keio University School of Medicine, Tokyo."},{"author_name":"Andrew Papale","author_inst":"University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"},{"author_name":"Samira Raminfard","author_inst":"University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"},{"author_name":"Deepak Sarpal","author_inst":"University of Pittsburgh"},{"author_name":"Hyejin Sim","author_inst":"Department of Brain & Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea."},{"author_name":"Giulia Tronchin","author_inst":"Clinical Neuroimaging Laboratory, Centre for Neuroimaging, Cognition and Genomics (NICOG), Galway"},{"author_name":"Lauri Tuominen","author_inst":"University of Ottawa Institute of Mental Health Research, Ottawa, ON, Canada"},{"author_name":"Euitae Kim","author_inst":"Department of Psychiatry, Seoul National University Bundang Hospital, Gyeonggi-do, Seoul, Republic of Korea; Department of Brain & Cognitive Sciences, College o"},{"author_name":"Alice Egerton","author_inst":"Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Age-specific burden of medically attended respiratory virus disease in high-income countries: a scoping review and meta-analysis","rel_doi":"10.64898\/2026.06.09.26354660","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.09.26354660","rel_abs":"Introduction: Respiratory infections are a leading cause of morbidity. Newly available vaccines to prevent respiratory syncytial virus (RSV) disease and encouraging clinical progress on vaccines for human metapneumovirus (hMPV) and parainfluenza (PIV) could reduce the disease burden beyond existing influenza and SARS-CoV-2 immunisation programs. However, evidence on the contribution of these viruses to respiratory disease burden across the lifespan remains limited. Methods: We reviewed studies from 01\/2002-11\/2025 reporting age-stratified, medically attended cases of influenza, and at least one of RSV, hMPV, or PIV, in high-income countries, excluding periods substantially overlapping with the COVID-19 pandemic. Using only studies that tested for all four viruses, we estimated the age-specific proportion of cases that were non-influenza (total across RSV, hMPV and PIV) compared to influenza using a mixed-effects logistic regression model. Results: Following exclusions and screening, 61 studies were included in the primary analysis comprising >500,000 detections of the four viruses. We found that a substantial proportion of medically attended respiratory illness in infants and young children was due to PIV, hMPV and RSV, rather than influenza, with a non-influenza virus proportion of 90.2% (95% CI 85.9-93.2%) in young infants aged 0-6 months. The converse was true for school-aged children, with a non-influenza virus proportion of 34.8% (95% CI 26.5-44.2%) in children aged 5-18 years. In adults aged 65+ years, non-influenza causes of medically attended disease were common at 60.2% (95% CI 50.0-69.5%). Restricting to studies reporting hospitalised cases (n=19) produced broadly similar age-specific trends in relative virus burden contributions. Discussion: We highlight the significant burden of medically attended illness due to PIV, hMPV and RSV across ages, particularly in infant and preschool-aged children and older adults, supporting the need for effective vaccines targeting this burden.","rel_num_authors":7,"rel_authors":[{"author_name":"Muskaan Gupta","author_inst":"School of Population Health, UNSW Sydney"},{"author_name":"Hordur Zoega","author_inst":"School of Population Health, UNSW Sydney"},{"author_name":"Isaac J Stopard","author_inst":"School of Population Health, UNSW Sydney"},{"author_name":"Bette Liu","author_inst":"National Centre for Immunisation Research and Surveillance (NCIRS), Sydney, Australia"},{"author_name":"Kristine Macartney","author_inst":"National Centre for Immunisation Research and Surveillance (NCIRS), Sydney, Australia"},{"author_name":"James G Wood","author_inst":"School of Population Health, UNSW Sydney"},{"author_name":"Alexandra B Hogan","author_inst":"School of Population Health, UNSW Sydney"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Multi-ancestry genome-wide association study and meta-analysis of stimulant use disorder reveals biology and relationships to other psychiatric disorders","rel_doi":"10.64898\/2026.06.05.26354997","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354997","rel_abs":"Stimulant use disorder (StimUD) is a significant public health problem, but genetic studies have been limited by small sample sizes. We conducted genome-wide association studies (GWAS) of StimUD in the Million Veteran Program (MVP) and All of Us (AOU), followed by meta-analysis with FinnGen and 10 additional datasets, for a total of 709,369 individuals (Ncases=33,977, Ncontrols=675,392) in four broad ancestry groups: European (EUR) (Ncases=22,564, Ncontrols=624,672), African (AFR) (Ncases=7,574, Ncontrols=34,189), Admixed American (AMR) (Ncases=3,657, Ncontrols=15,698), and East Asian (EAS) (Ncases=182, Ncontrols=833). Population-specific SNP heritability was 6.1% in EUR and 2.4% in AFR. We discovered a total of 19 genome-wide-significant loci, six in EUR, including DRD2*rs5794864, P=7.32E-10, one in AFR, five in a multi-ancestry meta-analysis, including CHRNA5*rs55781567, P=3.27E-9, two in a male-only meta-analysis, including FTO*rs8057044, P=9.50E10-9, and five in a meta-analysis of sex-stratified results. In a hold-out AOU subsample (NEUR=18,841, NAFR=12,263, NAMR=9,739), ancestry-specific polygenic risk scores were significantly associated with StimUD in EUR (OR=3.28, 95% confidence interval (CI)=2.89-3.71) and AMR (OR=2.01, 95% CI=1.71-2.37). Transcriptome-wide association studies, fine-mapping, and colocalization analyses prioritized additional genes (e.g., GPX1, BSN). Genetic correlation, Mendelian randomization, and causal mixture analyses revealed relationships with other substance use and use disorder phenotypes, including cannabis use disorder (rg=0.94, P=5.43E-237) and opioid use disorder (rg=1.01, P=4.40E-107), and other psychiatric traits, including anxiety, depression, neuroticism, and attention-deficit\/hyperactivity disorder. This is the first well-powered GWAS of StimUD, and it offers significant insights into disease biology.","rel_num_authors":30,"rel_authors":[{"author_name":"Sarah E. Beck","author_inst":"Yale School of Medicine"},{"author_name":"Joseph D. Deak","author_inst":"Yale School of Medicine"},{"author_name":"Daniel F. Levey","author_inst":"Yale University; VA Connecticut Healthcare System"},{"author_name":"Tian Ge","author_inst":"Massachusetts General Hospital\/Harvard Medical School"},{"author_name":"Paul W. Jeffries","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Dongbing Lai","author_inst":"Indiana University School of Medicine"},{"author_name":"Travis T. Mallard","author_inst":"Massachusetts General Hospital"},{"author_name":"Louisa Degenhardt","author_inst":"University of New South Wales Sydney"},{"author_name":"Penelope A. Lind","author_inst":"QIMR Berghofer"},{"author_name":"Trine Tollerup Nielsen","author_inst":"Aarhus University"},{"author_name":"Justin D. Tubbs","author_inst":"Massachusetts General Hospital"},{"author_name":"Leah Wetherill","author_inst":"Indiana University School of Medicine"},{"author_name":"Emma C. Johnson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Alexander S. Hatoum","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"- The SUD Working Group of the Psychiatric Genomics Consortium","author_inst":""},{"author_name":"- COGA Collaborators","author_inst":""},{"author_name":"- Yale-Penn Collaboration","author_inst":""},{"author_name":"- The VA Million Veteran Program","author_inst":""},{"author_name":"Anders B\u00f8rglum","author_inst":"Aarhus University"},{"author_name":"Ditte Demontis","author_inst":"Aarhus University"},{"author_name":"Sarah E. Medland","author_inst":"QIMR Berghofer"},{"author_name":"Nicholas G. Martin","author_inst":"QIMR Berghofer"},{"author_name":"Elliot C. Nelson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Jordan W. Smoller","author_inst":"Massachusetts General Hospital\/Harvard Medical School"},{"author_name":"Henry R. Kranzler","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"J. Michael Gaziano","author_inst":"VA Boston Healthcare System"},{"author_name":"Murray B. Stein","author_inst":"University of California San Diego"},{"author_name":"Arpana Agrawal","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Howard J. Edenberg","author_inst":"Indiana University School of Medicine"},{"author_name":"Joel Gelernter","author_inst":"Yale School of Medicine"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Multi-ancestry genome-wide association study and meta-analysis of stimulant use disorder reveals biology and relationships to other psychiatric disorders","rel_doi":"10.64898\/2026.06.05.26354997","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354997","rel_abs":"Stimulant use disorder (StimUD) is a significant public health problem, but genetic studies have been limited by small sample sizes. We conducted genome-wide association studies (GWAS) of StimUD in the Million Veteran Program (MVP) and All of Us (AOU), followed by meta-analysis with FinnGen and 10 additional datasets, for a total of 709,369 individuals (Ncases=33,977, Ncontrols=675,392) in four broad ancestry groups: European (EUR) (Ncases=22,564, Ncontrols=624,672), African (AFR) (Ncases=7,574, Ncontrols=34,189), Admixed American (AMR) (Ncases=3,657, Ncontrols=15,698), and East Asian (EAS) (Ncases=182, Ncontrols=833). Population-specific SNP heritability was 6.1% in EUR and 2.4% in AFR. We discovered a total of 19 genome-wide-significant loci, six in EUR, including DRD2*rs5794864, P=7.32E-10, one in AFR, five in a multi-ancestry meta-analysis, including CHRNA5*rs55781567, P=3.27E-9, two in a male-only meta-analysis, including FTO*rs8057044, P=9.50E10-9, and five in a meta-analysis of sex-stratified results. In a hold-out AOU subsample (NEUR=18,841, NAFR=12,263, NAMR=9,739), ancestry-specific polygenic risk scores were significantly associated with StimUD in EUR (OR=3.28, 95% confidence interval (CI)=2.89-3.71) and AMR (OR=2.01, 95% CI=1.71-2.37). Transcriptome-wide association studies, fine-mapping, and colocalization analyses prioritized additional genes (e.g., GPX1, BSN). Genetic correlation, Mendelian randomization, and causal mixture analyses revealed relationships with other substance use and use disorder phenotypes, including cannabis use disorder (rg=0.94, P=5.43E-237) and opioid use disorder (rg=1.01, P=4.40E-107), and other psychiatric traits, including anxiety, depression, neuroticism, and attention-deficit\/hyperactivity disorder. This is the first well-powered GWAS of StimUD, and it offers significant insights into disease biology.","rel_num_authors":30,"rel_authors":[{"author_name":"Sarah E. Beck","author_inst":"Yale School of Medicine"},{"author_name":"Joseph D. Deak","author_inst":"Yale School of Medicine"},{"author_name":"Daniel F. Levey","author_inst":"Yale University; VA Connecticut Healthcare System"},{"author_name":"Tian Ge","author_inst":"Massachusetts General Hospital\/Harvard Medical School"},{"author_name":"Paul W. Jeffries","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Dongbing Lai","author_inst":"Indiana University School of Medicine"},{"author_name":"Travis T. Mallard","author_inst":"Massachusetts General Hospital"},{"author_name":"Louisa Degenhardt","author_inst":"University of New South Wales Sydney"},{"author_name":"Penelope A. Lind","author_inst":"QIMR Berghofer"},{"author_name":"Trine Tollerup Nielsen","author_inst":"Aarhus University"},{"author_name":"Justin D. Tubbs","author_inst":"Massachusetts General Hospital"},{"author_name":"Leah Wetherill","author_inst":"Indiana University School of Medicine"},{"author_name":"Emma C. Johnson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Alexander S. Hatoum","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"- The SUD Working Group of the Psychiatric Genomics Consortium","author_inst":""},{"author_name":"- COGA Collaborators","author_inst":""},{"author_name":"- Yale-Penn Collaboration","author_inst":""},{"author_name":"- The VA Million Veteran Program","author_inst":""},{"author_name":"Anders B\u00f8rglum","author_inst":"Aarhus University"},{"author_name":"Ditte Demontis","author_inst":"Aarhus University"},{"author_name":"Sarah E. Medland","author_inst":"QIMR Berghofer"},{"author_name":"Nicholas G. Martin","author_inst":"QIMR Berghofer"},{"author_name":"Elliot C. Nelson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Jordan W. Smoller","author_inst":"Massachusetts General Hospital\/Harvard Medical School"},{"author_name":"Henry R. Kranzler","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"J. Michael Gaziano","author_inst":"VA Boston Healthcare System"},{"author_name":"Murray B. Stein","author_inst":"University of California San Diego"},{"author_name":"Arpana Agrawal","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Howard J. Edenberg","author_inst":"Indiana University School of Medicine"},{"author_name":"Joel Gelernter","author_inst":"Yale School of Medicine"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Multi-ancestry genome-wide association study and meta-analysis of stimulant use disorder reveals biology and relationships to other psychiatric disorders","rel_doi":"10.64898\/2026.06.05.26354997","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354997","rel_abs":"Stimulant use disorder (StimUD) is a significant public health problem, but genetic studies have been limited by small sample sizes. We conducted genome-wide association studies (GWAS) of StimUD in the Million Veteran Program (MVP) and All of Us (AOU), followed by meta-analysis with FinnGen and 10 additional datasets, for a total of 709,369 individuals (Ncases=33,977, Ncontrols=675,392) in four broad ancestry groups: European (EUR) (Ncases=22,564, Ncontrols=624,672), African (AFR) (Ncases=7,574, Ncontrols=34,189), Admixed American (AMR) (Ncases=3,657, Ncontrols=15,698), and East Asian (EAS) (Ncases=182, Ncontrols=833). Population-specific SNP heritability was 6.1% in EUR and 2.4% in AFR. We discovered a total of 19 genome-wide-significant loci, six in EUR, including DRD2*rs5794864, P=7.32E-10, one in AFR, five in a multi-ancestry meta-analysis, including CHRNA5*rs55781567, P=3.27E-9, two in a male-only meta-analysis, including FTO*rs8057044, P=9.50E10-9, and five in a meta-analysis of sex-stratified results. In a hold-out AOU subsample (NEUR=18,841, NAFR=12,263, NAMR=9,739), ancestry-specific polygenic risk scores were significantly associated with StimUD in EUR (OR=3.28, 95% confidence interval (CI)=2.89-3.71) and AMR (OR=2.01, 95% CI=1.71-2.37). Transcriptome-wide association studies, fine-mapping, and colocalization analyses prioritized additional genes (e.g., GPX1, BSN). Genetic correlation, Mendelian randomization, and causal mixture analyses revealed relationships with other substance use and use disorder phenotypes, including cannabis use disorder (rg=0.94, P=5.43E-237) and opioid use disorder (rg=1.01, P=4.40E-107), and other psychiatric traits, including anxiety, depression, neuroticism, and attention-deficit\/hyperactivity disorder. This is the first well-powered GWAS of StimUD, and it offers significant insights into disease biology.","rel_num_authors":30,"rel_authors":[{"author_name":"Sarah E. Beck","author_inst":"Yale School of Medicine"},{"author_name":"Joseph D. Deak","author_inst":"Yale School of Medicine"},{"author_name":"Daniel F. Levey","author_inst":"Yale University; VA Connecticut Healthcare System"},{"author_name":"Tian Ge","author_inst":"Massachusetts General Hospital\/Harvard Medical School"},{"author_name":"Paul W. Jeffries","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Dongbing Lai","author_inst":"Indiana University School of Medicine"},{"author_name":"Travis T. Mallard","author_inst":"Massachusetts General Hospital"},{"author_name":"Louisa Degenhardt","author_inst":"University of New South Wales Sydney"},{"author_name":"Penelope A. Lind","author_inst":"QIMR Berghofer"},{"author_name":"Trine Tollerup Nielsen","author_inst":"Aarhus University"},{"author_name":"Justin D. Tubbs","author_inst":"Massachusetts General Hospital"},{"author_name":"Leah Wetherill","author_inst":"Indiana University School of Medicine"},{"author_name":"Emma C. Johnson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Alexander S. Hatoum","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"- The SUD Working Group of the Psychiatric Genomics Consortium","author_inst":""},{"author_name":"- COGA Collaborators","author_inst":""},{"author_name":"- Yale-Penn Collaboration","author_inst":""},{"author_name":"- The VA Million Veteran Program","author_inst":""},{"author_name":"Anders B\u00f8rglum","author_inst":"Aarhus University"},{"author_name":"Ditte Demontis","author_inst":"Aarhus University"},{"author_name":"Sarah E. Medland","author_inst":"QIMR Berghofer"},{"author_name":"Nicholas G. Martin","author_inst":"QIMR Berghofer"},{"author_name":"Elliot C. Nelson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Jordan W. Smoller","author_inst":"Massachusetts General Hospital\/Harvard Medical School"},{"author_name":"Henry R. Kranzler","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"J. Michael Gaziano","author_inst":"VA Boston Healthcare System"},{"author_name":"Murray B. Stein","author_inst":"University of California San Diego"},{"author_name":"Arpana Agrawal","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Howard J. Edenberg","author_inst":"Indiana University School of Medicine"},{"author_name":"Joel Gelernter","author_inst":"Yale School of Medicine"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Multi-ancestry genome-wide association study and meta-analysis of stimulant use disorder reveals biology and relationships to other psychiatric disorders","rel_doi":"10.64898\/2026.06.05.26354997","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354997","rel_abs":"Stimulant use disorder (StimUD) is a significant public health problem, but genetic studies have been limited by small sample sizes. We conducted genome-wide association studies (GWAS) of StimUD in the Million Veteran Program (MVP) and All of Us (AOU), followed by meta-analysis with FinnGen and 10 additional datasets, for a total of 709,369 individuals (Ncases=33,977, Ncontrols=675,392) in four broad ancestry groups: European (EUR) (Ncases=22,564, Ncontrols=624,672), African (AFR) (Ncases=7,574, Ncontrols=34,189), Admixed American (AMR) (Ncases=3,657, Ncontrols=15,698), and East Asian (EAS) (Ncases=182, Ncontrols=833). Population-specific SNP heritability was 6.1% in EUR and 2.4% in AFR. We discovered a total of 19 genome-wide-significant loci, six in EUR, including DRD2*rs5794864, P=7.32E-10, one in AFR, five in a multi-ancestry meta-analysis, including CHRNA5*rs55781567, P=3.27E-9, two in a male-only meta-analysis, including FTO*rs8057044, P=9.50E10-9, and five in a meta-analysis of sex-stratified results. In a hold-out AOU subsample (NEUR=18,841, NAFR=12,263, NAMR=9,739), ancestry-specific polygenic risk scores were significantly associated with StimUD in EUR (OR=3.28, 95% confidence interval (CI)=2.89-3.71) and AMR (OR=2.01, 95% CI=1.71-2.37). Transcriptome-wide association studies, fine-mapping, and colocalization analyses prioritized additional genes (e.g., GPX1, BSN). Genetic correlation, Mendelian randomization, and causal mixture analyses revealed relationships with other substance use and use disorder phenotypes, including cannabis use disorder (rg=0.94, P=5.43E-237) and opioid use disorder (rg=1.01, P=4.40E-107), and other psychiatric traits, including anxiety, depression, neuroticism, and attention-deficit\/hyperactivity disorder. This is the first well-powered GWAS of StimUD, and it offers significant insights into disease biology.","rel_num_authors":30,"rel_authors":[{"author_name":"Sarah E. Beck","author_inst":"Yale School of Medicine"},{"author_name":"Joseph D. Deak","author_inst":"Yale School of Medicine"},{"author_name":"Daniel F. Levey","author_inst":"Yale University; VA Connecticut Healthcare System"},{"author_name":"Tian Ge","author_inst":"Massachusetts General Hospital\/Harvard Medical School"},{"author_name":"Paul W. Jeffries","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Dongbing Lai","author_inst":"Indiana University School of Medicine"},{"author_name":"Travis T. Mallard","author_inst":"Massachusetts General Hospital"},{"author_name":"Louisa Degenhardt","author_inst":"University of New South Wales Sydney"},{"author_name":"Penelope A. Lind","author_inst":"QIMR Berghofer"},{"author_name":"Trine Tollerup Nielsen","author_inst":"Aarhus University"},{"author_name":"Justin D. Tubbs","author_inst":"Massachusetts General Hospital"},{"author_name":"Leah Wetherill","author_inst":"Indiana University School of Medicine"},{"author_name":"Emma C. Johnson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Alexander S. Hatoum","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"- The SUD Working Group of the Psychiatric Genomics Consortium","author_inst":""},{"author_name":"- COGA Collaborators","author_inst":""},{"author_name":"- Yale-Penn Collaboration","author_inst":""},{"author_name":"- The VA Million Veteran Program","author_inst":""},{"author_name":"Anders B\u00f8rglum","author_inst":"Aarhus University"},{"author_name":"Ditte Demontis","author_inst":"Aarhus University"},{"author_name":"Sarah E. Medland","author_inst":"QIMR Berghofer"},{"author_name":"Nicholas G. Martin","author_inst":"QIMR Berghofer"},{"author_name":"Elliot C. Nelson","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Jordan W. Smoller","author_inst":"Massachusetts General Hospital\/Harvard Medical School"},{"author_name":"Henry R. Kranzler","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"J. Michael Gaziano","author_inst":"VA Boston Healthcare System"},{"author_name":"Murray B. Stein","author_inst":"University of California San Diego"},{"author_name":"Arpana Agrawal","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Howard J. Edenberg","author_inst":"Indiana University School of Medicine"},{"author_name":"Joel Gelernter","author_inst":"Yale School of Medicine"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Host Genetic Regulation of NLRP3 Inflammasome Cytokines Reveals Immune and Vascular Pathways in HIV","rel_doi":"10.64898\/2026.06.08.26355202","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355202","rel_abs":"People with HIV exhibit elevated inflammation and cardiovascular risk despite antiretroviral therapy. To define the genetic architecture of inflammasome-associated inflammation, we performed whole-genome sequencing and quantified plasma IL-6, IL-1{beta}, and IL-18 in 1,000 ART-suppressed PWH from the U.S. Military HIV Natural History Study. Genome-wide analyses identified 14 loci implicating antiviral defense (DDX17, DDX41, EEA1, BCL11A), lipid metabolism (ABCA1, ABCA12, ABCC1, AGMO), and vascular remodeling (KLHL29, RNF213, ETV1). Transcriptome-wide analyses across cardiovascular and immune tissues identified regulatory programs linking interferon signaling, immune activation, and vascular biology to circulating cytokine levels. Mendelian randomization analyses supported causal relationships between inflammasome-associated cytokines and vascular events. Functional integration with genome-wide CRISPR perturbation datasets in primary CD4 T cells linked cytokine-associated loci to HIV antiviral pathways and cytokine regulatory networks. External validation in cohorts without HIV demonstrated pathway-level convergence despite limited variant-level overlap. These findings define genetic mechanisms linking inflammasome signaling, antiviral defense, and cardiovascular risk.","rel_num_authors":28,"rel_authors":[{"author_name":"Ryan Chung","author_inst":"University of California Berkeley, Berkeley, CA"},{"author_name":"Namratha Shivani Chalasani","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Alton S. Barbehenn","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Erik Lundgren","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Sonia Savur","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Sayane Shome","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Caroline H. Sheikhzadeh","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Sannidhi Sarvadhavabhatla","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Maria Sophia Donaire","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Vivian Pae","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Xiuping Chu","author_inst":"Uniformed Services University of the Health Sciences, Bethesda, MD"},{"author_name":"Daniel Winder","author_inst":"University of Utah, Salt Lake City, UT"},{"author_name":"Colin T Maguire","author_inst":"University of Utah, Salt Lake City, UT"},{"author_name":"Senay Topal","author_inst":"Uniformed Services University of the Health Sciences, Bethesda, MD"},{"author_name":"Anuradha Ganesan","author_inst":"Uniformed Services University of the Health Sciences,  Bethesda, MD"},{"author_name":"Joseph M. Yabes","author_inst":"Uniformed Services University of the Health Sciences,  Bethesda, MD"},{"author_name":"Derek T. Larson","author_inst":"Uniformed Services University of the Health Sciences,  Bethesda, MD"},{"author_name":"Tahaniyat Lalani","author_inst":"Uniformed Services University of the Health Sciences,  Bethesda, MD"},{"author_name":"Evan C. Ewers","author_inst":"Tripler Army Medical Center, Honolulu, HI"},{"author_name":"Rhonda E. Colombo","author_inst":"Uniformed Services University of the Health Sciences, Bethesda, MD"},{"author_name":"Eli Dugan","author_inst":"Gladstone Institutes, San Francisco, CA"},{"author_name":"Ujjwal Rathore","author_inst":"Gladstone Institutes, San Francisco, CA"},{"author_name":"Alexander Marson","author_inst":"Gladstone Institutes, San Francisco, CA"},{"author_name":"Brian K. Agan","author_inst":"Uniformed Services University of the Health Sciences, Bethesda, MD"},{"author_name":"Jeff Alan Tomalka","author_inst":"Emory School of Medicine, Atlanta, GA"},{"author_name":"Rafick-Pierre Sekaly","author_inst":"Emory School of Medicine, Atlanta, GA"},{"author_name":"Nilah M. Loannidis","author_inst":"University of California Berkeley, Berkeley, CA"},{"author_name":"Sulggi A. Lee","author_inst":"University of California San Francisco, San Francisco, CA"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Host Genetic Regulation of NLRP3 Inflammasome Cytokines Reveals Immune and Vascular Pathways in HIV","rel_doi":"10.64898\/2026.06.08.26355202","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355202","rel_abs":"People with HIV exhibit elevated inflammation and cardiovascular risk despite antiretroviral therapy. To define the genetic architecture of inflammasome-associated inflammation, we performed whole-genome sequencing and quantified plasma IL-6, IL-1{beta}, and IL-18 in 1,000 ART-suppressed PWH from the U.S. Military HIV Natural History Study. Genome-wide analyses identified 14 loci implicating antiviral defense (DDX17, DDX41, EEA1, BCL11A), lipid metabolism (ABCA1, ABCA12, ABCC1, AGMO), and vascular remodeling (KLHL29, RNF213, ETV1). Transcriptome-wide analyses across cardiovascular and immune tissues identified regulatory programs linking interferon signaling, immune activation, and vascular biology to circulating cytokine levels. Mendelian randomization analyses supported causal relationships between inflammasome-associated cytokines and vascular events. Functional integration with genome-wide CRISPR perturbation datasets in primary CD4 T cells linked cytokine-associated loci to HIV antiviral pathways and cytokine regulatory networks. External validation in cohorts without HIV demonstrated pathway-level convergence despite limited variant-level overlap. These findings define genetic mechanisms linking inflammasome signaling, antiviral defense, and cardiovascular risk.","rel_num_authors":28,"rel_authors":[{"author_name":"Ryan Chung","author_inst":"University of California Berkeley, Berkeley, CA"},{"author_name":"Namratha Shivani Chalasani","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Alton S. Barbehenn","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Erik Lundgren","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Sonia Savur","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Sayane Shome","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Caroline H. Sheikhzadeh","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Sannidhi Sarvadhavabhatla","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Maria Sophia Donaire","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Vivian Pae","author_inst":"University of California San Francisco, San Francisco, CA"},{"author_name":"Xiuping Chu","author_inst":"Uniformed Services University of the Health Sciences, Bethesda, MD"},{"author_name":"Daniel Winder","author_inst":"University of Utah, Salt Lake City, UT"},{"author_name":"Colin T Maguire","author_inst":"University of Utah, Salt Lake City, UT"},{"author_name":"Senay Topal","author_inst":"Uniformed Services University of the Health Sciences, Bethesda, MD"},{"author_name":"Anuradha Ganesan","author_inst":"Uniformed Services University of the Health Sciences,  Bethesda, MD"},{"author_name":"Joseph M. Yabes","author_inst":"Uniformed Services University of the Health Sciences,  Bethesda, MD"},{"author_name":"Derek T. Larson","author_inst":"Uniformed Services University of the Health Sciences,  Bethesda, MD"},{"author_name":"Tahaniyat Lalani","author_inst":"Uniformed Services University of the Health Sciences,  Bethesda, MD"},{"author_name":"Evan C. Ewers","author_inst":"Tripler Army Medical Center, Honolulu, HI"},{"author_name":"Rhonda E. Colombo","author_inst":"Uniformed Services University of the Health Sciences, Bethesda, MD"},{"author_name":"Eli Dugan","author_inst":"Gladstone Institutes, San Francisco, CA"},{"author_name":"Ujjwal Rathore","author_inst":"Gladstone Institutes, San Francisco, CA"},{"author_name":"Alexander Marson","author_inst":"Gladstone Institutes, San Francisco, CA"},{"author_name":"Brian K. Agan","author_inst":"Uniformed Services University of the Health Sciences, Bethesda, MD"},{"author_name":"Jeff Alan Tomalka","author_inst":"Emory School of Medicine, Atlanta, GA"},{"author_name":"Rafick-Pierre Sekaly","author_inst":"Emory School of Medicine, Atlanta, GA"},{"author_name":"Nilah M. Loannidis","author_inst":"University of California Berkeley, Berkeley, CA"},{"author_name":"Sulggi A. Lee","author_inst":"University of California San Francisco, San Francisco, CA"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Efficacy of the PragmaVAC Manual Negative Pressure Wound Therapy Device to Treat Acute Traumatic Wounds in a Conflict Setting: A Retrospective Cohort Study from Gaza","rel_doi":"10.64898\/2026.06.04.26354740","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354740","rel_abs":"Abstract: Background: Acute war-related traumatic wounds present significant challenges due to significant soft-tissue damage\/loss, risk of contamination, limited access to antimicrobial therapy, need for delayed closure, and limited access to surgical and wound care. Negative Pressure Wound Therapy (NPWT) has been used effectively to reduce the volume of soft-tissue defects, edema, and infection in traumatic wounds, and to promote growth of healthy granulation tissue. However, conventional NPWT devices are costly and electricity-dependent, limiting their utility in conflict settings. Methods: This retrospective cohort study evaluated the use of PragmaVAC, a manually operated, electricity-independent NPWT device, in patients across three hospitals in Gaza with conflict-related wounds that were deemed by the treating surgeon to be unsuitable for primary closure. Secondary analysis was performed of clinical records of patients treated with the PragmaVac NPWT device to assess ability to achieve a primary outcome of wound bed with healthy granulation tissue, time to primary outcome, and rates of adverse effects. Secondary outcome of wound closure and closure method was also assessed. Results: Treatment with PragmaVAC manual NPWT was prescribed to 88 patients. Of those, 27 (31%) had incomplete documentation of their wound healing or were lost to follow up. The remaining 61 (69%) had complete documentation of their wound healing, complications, and final outcome with 59 (67%) successful closure and 2(2%) failure. Conclusion: The use of the PragmaVAC NPWT device provided a safe, effective wound care option to achieve wound closure for large conflict-related traumatic wounds in resource-limited settings. Future studies may further evaluate such use through prospective trials, evalutions of patients' experiences with manual NPWT, and evaluating outcomes beyond primary wound closure to include medium- and long-term complications, cosmesis, and cost of therapy.","rel_num_authors":7,"rel_authors":[{"author_name":"Ibrahim Ramadan","author_inst":"Indonesian Hospital, Gaza, State of Palestine"},{"author_name":"Mahmoud Hariri","author_inst":"West Hertforshire NHS Trust"},{"author_name":"Omar Shalakhti","author_inst":"Rush University School of Medicine"},{"author_name":"Jude Alawa","author_inst":"Hospital for Special Surgery"},{"author_name":"Amandine Godier-Furnemont","author_inst":"University of California at San Francisco"},{"author_name":"Abd Al-Rahman Traboulsi","author_inst":"MassGeneral Brigham"},{"author_name":"HANI MOWAFI","author_inst":"Yale University"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Efficacy of the PragmaVAC Manual Negative Pressure Wound Therapy Device to Treat Acute Traumatic Wounds in a Conflict Setting: A Retrospective Cohort Study from Gaza","rel_doi":"10.64898\/2026.06.04.26354740","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354740","rel_abs":"Abstract: Background: Acute war-related traumatic wounds present significant challenges due to significant soft-tissue damage\/loss, risk of contamination, limited access to antimicrobial therapy, need for delayed closure, and limited access to surgical and wound care. Negative Pressure Wound Therapy (NPWT) has been used effectively to reduce the volume of soft-tissue defects, edema, and infection in traumatic wounds, and to promote growth of healthy granulation tissue. However, conventional NPWT devices are costly and electricity-dependent, limiting their utility in conflict settings. Methods: This retrospective cohort study evaluated the use of PragmaVAC, a manually operated, electricity-independent NPWT device, in patients across three hospitals in Gaza with conflict-related wounds that were deemed by the treating surgeon to be unsuitable for primary closure. Secondary analysis was performed of clinical records of patients treated with the PragmaVac NPWT device to assess ability to achieve a primary outcome of wound bed with healthy granulation tissue, time to primary outcome, and rates of adverse effects. Secondary outcome of wound closure and closure method was also assessed. Results: Treatment with PragmaVAC manual NPWT was prescribed to 88 patients. Of those, 27 (31%) had incomplete documentation of their wound healing or were lost to follow up. The remaining 61 (69%) had complete documentation of their wound healing, complications, and final outcome with 59 (67%) successful closure and 2(2%) failure. Conclusion: The use of the PragmaVAC NPWT device provided a safe, effective wound care option to achieve wound closure for large conflict-related traumatic wounds in resource-limited settings. Future studies may further evaluate such use through prospective trials, evalutions of patients' experiences with manual NPWT, and evaluating outcomes beyond primary wound closure to include medium- and long-term complications, cosmesis, and cost of therapy.","rel_num_authors":7,"rel_authors":[{"author_name":"Ibrahim Ramadan","author_inst":"Indonesian Hospital, Gaza, State of Palestine"},{"author_name":"Mahmoud Hariri","author_inst":"West Hertforshire NHS Trust"},{"author_name":"Omar Shalakhti","author_inst":"Rush University School of Medicine"},{"author_name":"Jude Alawa","author_inst":"Hospital for Special Surgery"},{"author_name":"Amandine Godier-Furnemont","author_inst":"University of California at San Francisco"},{"author_name":"Abd Al-Rahman Traboulsi","author_inst":"MassGeneral Brigham"},{"author_name":"HANI MOWAFI","author_inst":"Yale University"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Recognition and Treatment of Primary Aldosteronism in the Updated Guideline Era","rel_doi":"10.64898\/2026.06.08.26355219","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355219","rel_abs":"Background: Primary aldosteronism (PA) is increasingly recognized as a common cause of hypertension. The 2025 Endocrine Society guideline introduced a simplified diagnostic framework, but its real-world clinical implications remain unclear. Methods: We conducted a multicenter retrospective cohort study of hypertensive patients undergoing PA testing in Taiwan. PA was defined biochemically according to the 2025 Endocrine Society criteria. Multivariable logistic regression identified factors associated with PA diagnosis and aldosterone-targeted therapy. Among patients with suppressed renin (?1 ng\/mL\/h), restricted cubic splines evaluated the adjusted association between renin and PA probability. Results: Among 18,766 patients undergoing PA testing, 6,760 (36.0%) met diagnostic criteria for PA. PA was associated with older age, female sex, lower potassium, resistant hypertension, and a higher antihypertensive medication burden. Among patients with suppressed renin, lower renin remained significantly associated with higher adjusted PA probability. However, only 39.0% of patients with PA received aldosterone-targeted therapy, including 28.2% who received mineralocorticoid receptor antagonist therapy within 6 months and 9.4% who underwent adrenalectomy during follow-up. Lower renin, higher aldosterone, lower potassium, and resistant hypertension were associated with aldosterone-targeted therapy, while younger patients with fewer comorbidities were more likely to undergo adrenalectomy. Conclusions: Using the updated diagnostic framework, PA was highly prevalent among hypertensive patients undergoing PA testing. Nevertheless, many patients who met these biochemical criteria did not receive aldosterone-targeted therapy in routine care. These findings highlight the potential treatment implications of broader PA recognition and support the development of practical pathways to guide MRA therapy, adrenalectomy referral, and individualized management.","rel_num_authors":12,"rel_authors":[{"author_name":"Cheng-Hsuan Tsai","author_inst":"National Taiwan University Hospital Cardiovascular Center"},{"author_name":"Yu-Ching Chang","author_inst":"National Taiwan University Hospital"},{"author_name":"Chin-Chen Chang","author_inst":"National Taiwan University Hospital"},{"author_name":"Wan-Chen Wu","author_inst":"National Taiwan University Hospital"},{"author_name":"Yi-Yao Chang","author_inst":"Far Eastern Memorial Hospital Library"},{"author_name":"Uei-Lin Chen","author_inst":"National Taiwan University Hospital"},{"author_name":"Bo-Ching Lee","author_inst":"National Taiwan University"},{"author_name":"Chi-Sheng Hung","author_inst":"National Taiwan University Hospital and College of  Medicine"},{"author_name":"Kuo-How Huang","author_inst":"National Taiwan University Hospital Department of Urology"},{"author_name":"Jeff S. Chueh","author_inst":"National Taiwan University, College of Medicine"},{"author_name":"Vin-Cent Wu","author_inst":"College of Medicine, National Taiwan University"},{"author_name":"Yen-Hung Lin","author_inst":"National Taiwan University Hospital"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Identifying Clinical Diagnostic Trajectories Associated With Suicide Death Using Temporal Sequence Mining of Linked Claims and Mortality Data","rel_doi":"10.64898\/2026.06.08.26355231","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355231","rel_abs":"Background: Most approaches to suicide risk assessment consider clinical conditions as independent risk factors, potentially overlooking prognostic information in the order in which conditions accumulate. We applied temporal sequence mining to linked claims and mortality data to identify ordered clinical diagnostic trajectories associated with suicide death. Results: The cohort included 3 647 059 insured Maryland residents aged 10 years or older with available claims records in the Maryland Suicide Data Warehouse from January 1, 2016, to December 31, 2020, among whom 768 suicide deaths were ascertained through medical examiner linkage. Sequential pattern mining of ICD-10-CM diagnoses grouped into Clinical Classifications Software Refined categories identified 89 221 candidate sequences, of which 1 816 remained significantly associated with suicide death in time-varying Cox models. Adjusted hazard ratios (AHRs) ranged from 2.4 to 134.1. Two-thirds of significant trajectories ended in physical conditions, and approximately half crossed from psychiatric to physical endpoints. Among suicide decedents, 62% were exposed to at least 1 significant sequence (median, 16 per case); median sequence duration was 18.7 months, and median time from completion to death was 13.1 months. In landmark analyses, among patients with depression who later developed suicidal ideation (n = 26 356), the path through anxiety, then anemia, was associated with higher risk (AHR, 4.6; 95% CI, 2.2-9.5), whereas the anxiety-only path was not (AHR, 1.3; 95% CI, 0.8-2.1). Among patients with anxiety who later developed hypertension (n = 149 215), the path through history of self-harm was associated with higher risk (AHR, 32.0; 95% CI, 16.6-61.6). Associations were generally consistent across sex and age. Conclusions: Temporal ordering of clinical conditions may carry prognostic information for suicide death. Clinical trajectories incorporating physical illness within psychiatric sequences identified higher-risk groups. These findings suggest that opportunities for risk detection may extend beyond psychiatric settings and that suicide risk signals may be fragmented across care settings and not apparent within isolated encounters.","rel_num_authors":7,"rel_authors":[{"author_name":"Anas Belouali","author_inst":"Georgetown University"},{"author_name":"Christopher Kitchen","author_inst":"Department of Health Policy and Management, Center for Population Health Information Technology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD,"},{"author_name":"Emily Haroz","author_inst":"Center for Suicide Prevention, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Mental Health, Johns Hopkins Bloomberg School "},{"author_name":"Harold Lehmann","author_inst":"Biomedical Informatics and Data Science, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"author_name":"Paul S. Nestadt","author_inst":"Center for Suicide Prevention, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Mental Health, Johns Hopkins Bloomberg School "},{"author_name":"Holly C. Wilcox","author_inst":"Center for Suicide Prevention, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Mental Health, Johns Hopkins Bloomberg School "},{"author_name":"Hadi Kharrazi","author_inst":"Biomedical Informatics and Data Science, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Health Policy and Management, Center for Population"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Alzheimer's disease neuroimaging signature aids identification of cognitive impairment in older adults with early-onset epilepsy","rel_doi":"10.64898\/2026.06.05.26354952","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354952","rel_abs":"Background and Objectives: Older adults with epilepsy are at increased risk for Alzheimer's disease (AD), yet the mechanisms underlying this association remain poorly understood. We applied a validated AD neuroimaging signature to older adults with epilepsy to examine 1) whether older adults with epilepsy mirror AD-related changes, 2) associations with clinical, cognitive, and plasma biomarker outcomes, and 3) utility for identifying subgroups at heightened risk for cognitive decline. Our multicenter, prospectively enrolled cohort allowed for direct examination of differences in AD signatures between those with early-onset and late-onset unexplained epilepsy. Methods: Participants included 449 older adults: 87 with focal epilepsy from the multicenter Brain Aging and Cognition in Epilepsy (BrACE) cohort (age=66.10 [SD=6.86], including early-onset (<55 years at seizure onset) and late-onset ([&ge;]55 years at seizure onset) epilepsy); 362 from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU) healthy controls and individuals with mild cognitive impairment (MCI) or AD dementia. An AD signature was derived from regional cortical thickness and hippocampal volume weighted by their sensitivity to AD-related neurodegeneration in prior work. Associations between the AD signature, epilepsy characteristics, plasma biomarkers ({beta}-amyloid 42\/40, phosphorylated tau [pTau217, pTau181], neurofilament light chain [NfL]), and cognition were evaluated in BrACE. Results: Participants with epilepsy demonstrated more AD-like signatures compared to ADNI CU controls ({beta}= -0.43, p<0.001), reflecting reduced thickness\/volume in AD-vulnerable regions. This effect was stronger among early-onset ({beta}= -0.57) versus late-onset ({beta}= -0.26) epilepsy. In BrACE, the AD signature correlated with NfL ({beta}= -0.30, p=0.050), memory performance ({beta}= 0.30, p=0.006), and predicted greater odds of cognitive impairment specifically among those with early-onset, but not late-onset, epilepsy (interaction p=0.043). Further, among those with early-onset epilepsy, the AD signature significantly improved identification of cognitive impairment over and beyond the effects of plasma AD biomarkers (p=0.041). Findings were similar when examining the effects of epilepsy duration rather than epilepsy onset age. Discussion: AD neuroimaging signatures may help identify clinically meaningful subgroups among older adults with epilepsy, particularly when integrated with AD biomarkers. Findings support a multimodal framework for assessing AD-related risk in epilepsy and highlight interactive effects of epilepsy chronicity and AD-related processes that can influence cognitive outcomes.","rel_num_authors":22,"rel_authors":[{"author_name":"McKenna Williams","author_inst":"University of California San Diego"},{"author_name":"Kayela Arrotta","author_inst":"Cleveland Clinic"},{"author_name":"Katherine J. Bangen","author_inst":"University of California San Diego"},{"author_name":"Anny Reyes","author_inst":"Cleveland Clinic"},{"author_name":"Alena Stasenko","author_inst":"University of California San Diego"},{"author_name":"Ifrah Zawar","author_inst":"University of Virginia School of Medicine"},{"author_name":"Vineet Punia","author_inst":"Cleveland Clinic"},{"author_name":"Irene Wang","author_inst":"Cleveland Clinic"},{"author_name":"Wanyong Shin","author_inst":"Cleveland Clinic"},{"author_name":"Ting-Yu Su","author_inst":"Cleveland Clinic"},{"author_name":"Jerry J. Shih","author_inst":"University of California San Diego"},{"author_name":"Nikdokht Farid","author_inst":"University of California San Diego"},{"author_name":"Jaideep Kapur","author_inst":"University of Virginia School of Medicine"},{"author_name":"Aaron F. Struck","author_inst":"Washington University in St. Louis"},{"author_name":"Lynn M. Bekris","author_inst":"University of Washington"},{"author_name":"Lisa Ferguson","author_inst":"Cleveland Clinic"},{"author_name":"Dace N. Almane","author_inst":"Cleveland Clinic"},{"author_name":"Jana E. Jones","author_inst":"Cleveland Clinic"},{"author_name":"Bruce P. Hermann","author_inst":"University of Wisconsin Madison"},{"author_name":"Robyn M. Busch","author_inst":"Cleveland Clinic"},{"author_name":"Carrie R. McDonald","author_inst":"University of California San Diego"},{"author_name":"- for the Alzheimer's Disease Neuroimaging Initiative*","author_inst":""}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Alzheimer's disease neuroimaging signature aids identification of cognitive impairment in older adults with early-onset epilepsy","rel_doi":"10.64898\/2026.06.05.26354952","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354952","rel_abs":"Background and Objectives: Older adults with epilepsy are at increased risk for Alzheimer's disease (AD), yet the mechanisms underlying this association remain poorly understood. We applied a validated AD neuroimaging signature to older adults with epilepsy to examine 1) whether older adults with epilepsy mirror AD-related changes, 2) associations with clinical, cognitive, and plasma biomarker outcomes, and 3) utility for identifying subgroups at heightened risk for cognitive decline. Our multicenter, prospectively enrolled cohort allowed for direct examination of differences in AD signatures between those with early-onset and late-onset unexplained epilepsy. Methods: Participants included 449 older adults: 87 with focal epilepsy from the multicenter Brain Aging and Cognition in Epilepsy (BrACE) cohort (age=66.10 [SD=6.86], including early-onset (<55 years at seizure onset) and late-onset ([&ge;]55 years at seizure onset) epilepsy); 362 from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU) healthy controls and individuals with mild cognitive impairment (MCI) or AD dementia. An AD signature was derived from regional cortical thickness and hippocampal volume weighted by their sensitivity to AD-related neurodegeneration in prior work. Associations between the AD signature, epilepsy characteristics, plasma biomarkers ({beta}-amyloid 42\/40, phosphorylated tau [pTau217, pTau181], neurofilament light chain [NfL]), and cognition were evaluated in BrACE. Results: Participants with epilepsy demonstrated more AD-like signatures compared to ADNI CU controls ({beta}= -0.43, p<0.001), reflecting reduced thickness\/volume in AD-vulnerable regions. This effect was stronger among early-onset ({beta}= -0.57) versus late-onset ({beta}= -0.26) epilepsy. In BrACE, the AD signature correlated with NfL ({beta}= -0.30, p=0.050), memory performance ({beta}= 0.30, p=0.006), and predicted greater odds of cognitive impairment specifically among those with early-onset, but not late-onset, epilepsy (interaction p=0.043). Further, among those with early-onset epilepsy, the AD signature significantly improved identification of cognitive impairment over and beyond the effects of plasma AD biomarkers (p=0.041). Findings were similar when examining the effects of epilepsy duration rather than epilepsy onset age. Discussion: AD neuroimaging signatures may help identify clinically meaningful subgroups among older adults with epilepsy, particularly when integrated with AD biomarkers. Findings support a multimodal framework for assessing AD-related risk in epilepsy and highlight interactive effects of epilepsy chronicity and AD-related processes that can influence cognitive outcomes.","rel_num_authors":22,"rel_authors":[{"author_name":"McKenna Williams","author_inst":"University of California San Diego"},{"author_name":"Kayela Arrotta","author_inst":"Cleveland Clinic"},{"author_name":"Katherine J. Bangen","author_inst":"University of California San Diego"},{"author_name":"Anny Reyes","author_inst":"Cleveland Clinic"},{"author_name":"Alena Stasenko","author_inst":"University of California San Diego"},{"author_name":"Ifrah Zawar","author_inst":"University of Virginia School of Medicine"},{"author_name":"Vineet Punia","author_inst":"Cleveland Clinic"},{"author_name":"Irene Wang","author_inst":"Cleveland Clinic"},{"author_name":"Wanyong Shin","author_inst":"Cleveland Clinic"},{"author_name":"Ting-Yu Su","author_inst":"Cleveland Clinic"},{"author_name":"Jerry J. Shih","author_inst":"University of California San Diego"},{"author_name":"Nikdokht Farid","author_inst":"University of California San Diego"},{"author_name":"Jaideep Kapur","author_inst":"University of Virginia School of Medicine"},{"author_name":"Aaron F. Struck","author_inst":"Washington University in St. Louis"},{"author_name":"Lynn M. Bekris","author_inst":"University of Washington"},{"author_name":"Lisa Ferguson","author_inst":"Cleveland Clinic"},{"author_name":"Dace N. Almane","author_inst":"Cleveland Clinic"},{"author_name":"Jana E. Jones","author_inst":"Cleveland Clinic"},{"author_name":"Bruce P. Hermann","author_inst":"University of Wisconsin Madison"},{"author_name":"Robyn M. Busch","author_inst":"Cleveland Clinic"},{"author_name":"Carrie R. McDonald","author_inst":"University of California San Diego"},{"author_name":"- for the Alzheimer's Disease Neuroimaging Initiative*","author_inst":""}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Daily symptom monitoring is sustainable over months: retention, not compliance, is the primary barrier to long-duration digital tracking","rel_doi":"10.64898\/2026.06.08.26355180","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355180","rel_abs":"Ecological momentary assessment (EMA) enables real-time, longitudinal measurement of symptoms and behavior via smartphones, yet nearly all feasibility evidence comes from protocols lasting one to two weeks, far shorter than the timescales over which chronic diseases fluctuate and clinical decisions unfold. Whether daily compliance can be sustained over months, or whether it decays as short-protocol trends predict, is unknown. Here, 214 participants (173 with pain, 41 healthy controls) completed a 4-month (122-day) EMA protocol via the Soma smartphone app, generating 26,907 check-ins. Half the sample completed the full protocol without a two-week lapse. Aggregate compliance appeared moderate (50%), but this conflated two distinct phenomena: when recomputed over each participant's active period, compliance rose to 71%, with 91% achieving moderate-to-high adherence, and remained stable across all 17 study weeks. Pain status predicted earlier disengagement but not lower compliance among those who remained; after adjustment for differential retention, group differences disappeared. To our knowledge, this is the longest continuous daily EMA evaluation in a clinical population. It suggests the primary barrier to long-duration EMA is not declining motivation among active participants but concentrated early disengagement, with direct implications for the design of digital health protocols, decentralized trials, and remote symptom monitoring.","rel_num_authors":4,"rel_authors":[{"author_name":"Chloe Z Gunsilius","author_inst":"Brown University"},{"author_name":"Pangzhongyuan Pei","author_inst":"Brown University"},{"author_name":"Alexios Carayannopoulos","author_inst":"Brown University Health"},{"author_name":"Frederike H. Petzschner","author_inst":"Brown University"}],"rel_date":"2026-06-10","rel_site":"medrxiv"},{"rel_title":"Enhanced Target Binding by Leritrelvir Restores Dimerization of Mpro Mutants and Mitigates Drug Resistance","rel_doi":"10.64898\/2026.06.09.730104","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.730104","rel_abs":"The SARS-CoV-2 main protease (Mpro) has been a major target of antiviral drug development, leading to the development of inhibitors such as nirmatrelvir, the antiviral component of the COVID-19 drug Paxlovid. However, resistance-associated mutations that reduce the efficacy of current Mpro inhibitors, particularly nirmatrelvir, have emerged. Here, we evaluated the inhibitory activity of leritrelvir (RAY1216), an Mpro inhibitor approved in China for COVID-19 monotherapy, against a panel of Mpro variants carrying mutations at 12 resistance-associated residues distributed across four catalytic subsites. Using integrated biochemical, biophysical, structural, and cellular analyses, we demonstrate that leritrelvir retains stronger inhibitory activity against most tested resistant mutants compared with nirmatrelvir. Most of the tested mutations promote Mpro dimer dissociation, with E166V showing a particularly pronounced effect and markedly compromising nirmatrelvir binding. In contrast, thermal shift and size-exclusion chromatography assays demonstrate that leritrelvir binding restores dimerization of these Mpro mutants. Sixteen high-resolution crystal structures reveal that leritrelvir binding re-instates key dimer-interface interactions disrupted by resistance mutations. Mini-replicon assays further confirm leritrelvir to possess enhanced cellular antiviral efficacy compared with nirmatrelvir. Our findings indicate that tighter leritrelvir binding enables more effective inhibition of dissociation-prone Mpro mutants than nirmatrelvir, supporting its use as a more resilient antiviral agent for SARS-CoV-2 treatment.","rel_num_authors":21,"rel_authors":[{"author_name":"Xiaodong Huang","author_inst":"Guangzhou National Laboratory"},{"author_name":"Petr Kuzmic","author_inst":"BioKin Ltd."},{"author_name":"Sai Zhang","author_inst":"Guangzhou National Laboratory"},{"author_name":"Carlos A. Ramos Guzman","author_inst":"University of Bristol"},{"author_name":"Xiaoxin Chen","author_inst":"Guangdong Raynovent Biotech Co., Ltd"},{"author_name":"Jiacheng Gui","author_inst":"University of Chinese Academy of Sciences"},{"author_name":"Qianying Li","author_inst":"Guangzhou Medical University"},{"author_name":"Shujuan Yan","author_inst":"University of Chinese Academy of Sciences"},{"author_name":"Binqian Zou","author_inst":"Guangzhou Medical University"},{"author_name":"Chuanying Niu","author_inst":"University of Science and Technology of China"},{"author_name":"Yi Zhao","author_inst":"University of Chinese Academy of Sciences"},{"author_name":"Haopeng Lin","author_inst":"lin_haopeng@gibh.ac.cn"},{"author_name":"Nannan Wang","author_inst":"Guangzhou National Laboratory"},{"author_name":"Jiaheng Chen","author_inst":"Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences"},{"author_name":"Xinwen Chen","author_inst":"Guangzhou Laboratory"},{"author_name":"Jim Spencer","author_inst":"University of Bristol"},{"author_name":"Adrian J Mulholland","author_inst":"University of Bristol"},{"author_name":"Jizheng Chen","author_inst":"Guangzhou National Laboratory"},{"author_name":"Nanshan Zhong","author_inst":"State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University"},{"author_name":"Zifeng Yang","author_inst":"State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affilia"},{"author_name":"Xiaoli Xiong","author_inst":"Guangzhou National Laboratory"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"STAT transcription factors regulate host defences and vacuolar integrity during Mycobacterium marinum infection","rel_doi":"10.64898\/2026.06.09.729547","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.729547","rel_abs":"Signal transducers and activators of transcription (STAT) are central regulators of cytokine-mediated immunity in metazoans, yet their ancestral functions prior to the emergence of interferon signalling remain poorly understood. Dictyostelium discoideum expresses four STAT-like factors that impact the intracellular fate of Mycobacterium marinum (Mm). Using dst knockout strains, we identify DstA and DstB as susceptibility factors, whereas DstC acts as a resistance factor, revealing a regulatory axis controlling the integrity of the Mm-containing vacuole (MCV). Despite the absence of canonical cytokine receptors and JAK kinases, DstA rapidly translocates to the nucleus in a damage-dependent manner, whereas DstB and DstC exhibit delayed cytosolic redistribution. DstA associates with VacA, a membrane microdomain component, regulates its transcription and accumulation at the MCV, while VacA acts as a cytoplasmic anchor that limits DstA nuclear translocation. Our findings establish STAT-like proteins as evolutionarily ancient regulators of vacuole integrity and host defence, providing new insights into the origins of STAT-mediated immune responses during mycobacterial infection.","rel_num_authors":5,"rel_authors":[{"author_name":"Justine Toinon","author_inst":"University of Geneva"},{"author_name":"Nabil Hanna","author_inst":"University of Geneva"},{"author_name":"Ludovica Vanzan","author_inst":"University of Geneva"},{"author_name":"Lyudmil Raykov","author_inst":"University of Geneva"},{"author_name":"Thierry Soldati","author_inst":"University of Geneva"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Epithelial innate immune sensing of pneumococci is inherently restricted to a small cellular minority across species and infection niches","rel_doi":"10.64898\/2026.06.10.731054","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731054","rel_abs":"Streptococcus pneumoniae colonises the nasopharynx asymptomatically yet causes life-threatening invasive disease. How it navigates early epithelial immune surveillance to cause disease remains unclear. Conventional innate immune models predict coordinated, population-wide epithelial responses to bacterial infection. Using single-cell RNA sequencing, RNA fluorescence in situ hybridization and in vivo mouse and zebrafish models, pneumococcal infection is instead shown to activate innate immune genes including chemokine, NF-{kappa}B regulatory, and prostaglandin pathway genes, in only 1-4% of lung epithelial cells. This restriction is seemingly pneumococcal-specific as Escherichia coli triggers responses in over 40% of the same cells. Strikingly, nasopharyngeal epithelial cells show complete immune silence to pneumococci while responding robustly to E. coli and Staphylococcus aureus, suggesting niche-specific immune evasion. Additionally, pharmacological inhibition of COX-2 significantly increased mortality in a zebrafish meningitis model, identifying prostaglandin signalling as a protective host response during invasive disease. Competence-associated surface remodelling contributes modestly and incrementally to immune restriction, while the predominant dampening is competence-independent. These findings challenge canonical epithelial immunity models against bacterial infection and provide a cellular framework for understanding pneumococcal commensalism and pathogenesis.","rel_num_authors":10,"rel_authors":[{"author_name":"Vikrant Minhas","author_inst":"Department of Fundamental Microbiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland"},{"author_name":"Vincent de Bakker","author_inst":"Department of Fundamental Microbiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland"},{"author_name":"Kin Ki Jim","author_inst":"Department of Fundamental Microbiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland"},{"author_name":"Jun Kurushima","author_inst":"Department of Fundamental Microbiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland"},{"author_name":"Joern Pezoldt","author_inst":"Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland"},{"author_name":"Monica Rengifo-Gonzalez","author_inst":"Department of Fundamental Microbiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland"},{"author_name":"Camilla Ciolli Mattioli","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Roi Avraham","author_inst":"Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Bart Deplancke","author_inst":"Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland"},{"author_name":"Jan-Willem Veening","author_inst":"Department of Fundamental Microbiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Beta cell reactivity defines disease-relevant pancreatic CD8 T cells in type 1 diabetes","rel_doi":"10.64898\/2026.06.08.729940","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.729940","rel_abs":"Type 1 diabetes (T1D) is characterized by immune-mediated destruction of pancreatic beta cells, yet the properties that distinguish disease-associated CD8 T cells from other pancreatic resident T cells remain incompletely defined. In this study, we analyzed CD8 T cell receptor (TCR) clonotypes isolated from the pancreas of organ donors with and without T1D and assessed their reactivity to beta cells using stem cell-derived beta-like cells. We found that highly beta cell-reactive CD8 T cells were selectively present in the pancreas of T1D donors but were largely absent from donors without T1D. In contrast, virus-specific CD8 T cells were detected in pancreata of donors with and without T1D and showed no evidence of cross-reactivity to beta-like cells, indicating that pancreatic residency alone does not confer beta cell specificity. Among beta cell-reactive CD8 T cells in T1D, reactivity to native peptides from major islet proteins other than preproinsulin was rare. Thus, despite beta cell specificity as a hallmark of T1D, T cells reactive to native islet proteins other than preproinsulin do not infiltrate the islets. These results identify beta cell reactivity as a key functional feature separating T1D-associated CD8 T cells from other pancreatic T cells. This functional definition of pathogenic T cells offers a framework for understanding selective beta cell loss and for developing approaches to monitor and therapeutically target disease-relevant CD8 T cells.","rel_num_authors":14,"rel_authors":[{"author_name":"Amanda M. Anderson","author_inst":"Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine"},{"author_name":"Laurie G. Landry","author_inst":"Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine"},{"author_name":"Jessie M. Barra","author_inst":"University of Florida Diabetes Institute, University of Florida"},{"author_name":"Kristen L. Wells","author_inst":"Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine"},{"author_name":"Ali H. Shilleh","author_inst":"Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine"},{"author_name":"Roberto Castro-Gutierrez","author_inst":"Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine"},{"author_name":"Andrew M. Ladd","author_inst":"University of Florida Diabetes Institute, University of Florida"},{"author_name":"Megan DeNicola","author_inst":"Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Chan Medical School"},{"author_name":"Jenny Aurielle B. Babon","author_inst":"Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Chan Medical School"},{"author_name":"Roberto Mallone","author_inst":"Universite Paris Cite and INSERM U1016 Cochin Institute"},{"author_name":"Sally C. Kent","author_inst":"Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Chan Medical School"},{"author_name":"Aaron W. Michels","author_inst":"Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine"},{"author_name":"Holger A. Russ","author_inst":"University of Florida Diabetes Institute, University of Florida"},{"author_name":"Maki Nakayama","author_inst":"Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Beta cell reactivity defines disease-relevant pancreatic CD8 T cells in type 1 diabetes","rel_doi":"10.64898\/2026.06.08.729940","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.729940","rel_abs":"Type 1 diabetes (T1D) is characterized by immune-mediated destruction of pancreatic beta cells, yet the properties that distinguish disease-associated CD8 T cells from other pancreatic resident T cells remain incompletely defined. In this study, we analyzed CD8 T cell receptor (TCR) clonotypes isolated from the pancreas of organ donors with and without T1D and assessed their reactivity to beta cells using stem cell-derived beta-like cells. We found that highly beta cell-reactive CD8 T cells were selectively present in the pancreas of T1D donors but were largely absent from donors without T1D. In contrast, virus-specific CD8 T cells were detected in pancreata of donors with and without T1D and showed no evidence of cross-reactivity to beta-like cells, indicating that pancreatic residency alone does not confer beta cell specificity. Among beta cell-reactive CD8 T cells in T1D, reactivity to native peptides from major islet proteins other than preproinsulin was rare. Thus, despite beta cell specificity as a hallmark of T1D, T cells reactive to native islet proteins other than preproinsulin do not infiltrate the islets. These results identify beta cell reactivity as a key functional feature separating T1D-associated CD8 T cells from other pancreatic T cells. This functional definition of pathogenic T cells offers a framework for understanding selective beta cell loss and for developing approaches to monitor and therapeutically target disease-relevant CD8 T cells.","rel_num_authors":14,"rel_authors":[{"author_name":"Amanda M. Anderson","author_inst":"Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine"},{"author_name":"Laurie G. Landry","author_inst":"Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine"},{"author_name":"Jessie M. Barra","author_inst":"University of Florida Diabetes Institute, University of Florida"},{"author_name":"Kristen L. Wells","author_inst":"Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine"},{"author_name":"Ali H. Shilleh","author_inst":"Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine"},{"author_name":"Roberto Castro-Gutierrez","author_inst":"Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine"},{"author_name":"Andrew M. Ladd","author_inst":"University of Florida Diabetes Institute, University of Florida"},{"author_name":"Megan DeNicola","author_inst":"Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Chan Medical School"},{"author_name":"Jenny Aurielle B. Babon","author_inst":"Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Chan Medical School"},{"author_name":"Roberto Mallone","author_inst":"Universite Paris Cite and INSERM U1016 Cochin Institute"},{"author_name":"Sally C. Kent","author_inst":"Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Chan Medical School"},{"author_name":"Aaron W. Michels","author_inst":"Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine"},{"author_name":"Holger A. Russ","author_inst":"University of Florida Diabetes Institute, University of Florida"},{"author_name":"Maki Nakayama","author_inst":"Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"CXCL10-driven STAT3 signaling programs pathogenic CD4+ T cell responses and limits antiviral immunity during arthritogenic alphavirus infection","rel_doi":"10.64898\/2026.06.08.730944","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730944","rel_abs":"Arthritogenic alphaviruses, including onyong nyong (ONNV), chikungunya virus (CHIKV), and Mayaro (MAYV) viruses, cause acute and chronic inflammatory joint disease, with disease severity and resolution influenced by host age. The immunological mechanisms governing persistent inflammation remain incompletely defined. In an age-stratified murine model we show that ONNV infection induced elevated Cxcl10 expression and viral persistence in infected tissues, accompanied by preferential accumulation of CD4+ T cells and limited recruitment of CD8+ T cells. This was associated with skewed T cell differentiation, characterized by increased STAT3 phosphorylation and ROR{gamma}t expression. Infection with CHIKV and MAYV recapitulated these features, supporting a conserved CXCL10-driven pathogenic program across arthritogenic alphaviruses. Perturbation of this axis reduced CD4+ T cell accumulation, altered T cell differentiation states, and decreased tissue viral burden. Thus, we show that a CXCL10-biased immune response is highly proinflammatory but poorly effective in mediating viral clearance, thus setting the stage for chronic disease.","rel_num_authors":4,"rel_authors":[{"author_name":"Sainetra Sridhar","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Alexander Lemenze","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Aileen Chang","author_inst":"The George Washington University"},{"author_name":"Bobby Brooke Herrera","author_inst":"Rutgers Biomedical and Health Sciences"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Persistent stromal reprogramming defines incomplete mucosal healing and predicts therapeutic response in ulcerative colitis","rel_doi":"10.64898\/2026.06.09.730670","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.730670","rel_abs":"Mucosal healing (MH) is the primary therapeutic endpoint in ulcerative colitis (UC), yet frequent relapses suggest it does not reflect complete tissue recovery. To define the basis of this vulnerability, we generated a multimodal atlas of UC integrating single-cell and bulk transcriptomics, Visium HD spatial profiling, and multiplexed imaging across 89 patients. We show that MH represents a distinct biological state marked by persistent stromal remodeling along three axes: emergence of inflammatory fibroblasts, sustained loss of OGN niche-supporting fibroblasts, and expansion of pericytes with matrix-remodeling features and reduced vascular association. Spatial analyses revealed persistent reorganization of mucosal tissue domains despite apparent clinical remission. Across independent cohorts, baseline inflammatory fibroblast and pericyte signatures robustly predicted non-response to anti-TNF therapy. These findings suggest that patients in MH remain in a biologically altered state linked to relapse risk and identify stromal reprogramming as a determinant of disease persistence and therapeutic response in UC.","rel_num_authors":23,"rel_authors":[{"author_name":"Mor Hindi-Malowany","author_inst":"Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Yaniv Stein","author_inst":"Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Rachel Frieman-Sharabi","author_inst":"Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Oshrat Galibov-Levi","author_inst":"Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Neta Yanir","author_inst":"Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Merav Kedmi","author_inst":"Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Maor Pauker","author_inst":"IBD Center, Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel, Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, I"},{"author_name":"Manar matar","author_inst":"Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel  Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Childre"},{"author_name":"Yifat Snir","author_inst":"IBD Center, Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel  Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, I"},{"author_name":"Noa Tal","author_inst":"Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children Medical Center of Israel, Petah Tikva, Israel"},{"author_name":"Hagar Banai Eran","author_inst":"IBD Center, Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel  Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, I"},{"author_name":"Yael Weintraub","author_inst":"Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel  Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Childre"},{"author_name":"Sara Morgenstern","author_inst":"Institute of Pathology, Rabin Medical Center, Petah Tikva, Israel"},{"author_name":"Ofra Golani","author_inst":"Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Inna Goliand","author_inst":"Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Yosef Addadi","author_inst":"Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Hadas Keren-Shaul","author_inst":"Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Iris Dotan","author_inst":"IBD Center, Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel  Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, I"},{"author_name":"Raanan Shamir","author_inst":"Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel  Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Childre"},{"author_name":"Shalev Itzkovitz","author_inst":"Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Henit Yanai","author_inst":"IBD Center, Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Is"},{"author_name":"Dror S. Shouval","author_inst":"Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel  Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Childre"},{"author_name":"Ruth Scherz-Shouval","author_inst":"Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Persistent stromal reprogramming defines incomplete mucosal healing and predicts therapeutic response in ulcerative colitis","rel_doi":"10.64898\/2026.06.09.730670","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.730670","rel_abs":"Mucosal healing (MH) is the primary therapeutic endpoint in ulcerative colitis (UC), yet frequent relapses suggest it does not reflect complete tissue recovery. To define the basis of this vulnerability, we generated a multimodal atlas of UC integrating single-cell and bulk transcriptomics, Visium HD spatial profiling, and multiplexed imaging across 89 patients. We show that MH represents a distinct biological state marked by persistent stromal remodeling along three axes: emergence of inflammatory fibroblasts, sustained loss of OGN niche-supporting fibroblasts, and expansion of pericytes with matrix-remodeling features and reduced vascular association. Spatial analyses revealed persistent reorganization of mucosal tissue domains despite apparent clinical remission. Across independent cohorts, baseline inflammatory fibroblast and pericyte signatures robustly predicted non-response to anti-TNF therapy. These findings suggest that patients in MH remain in a biologically altered state linked to relapse risk and identify stromal reprogramming as a determinant of disease persistence and therapeutic response in UC.","rel_num_authors":23,"rel_authors":[{"author_name":"Mor Hindi-Malowany","author_inst":"Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Yaniv Stein","author_inst":"Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Rachel Frieman-Sharabi","author_inst":"Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Oshrat Galibov-Levi","author_inst":"Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Neta Yanir","author_inst":"Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Merav Kedmi","author_inst":"Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Maor Pauker","author_inst":"IBD Center, Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel, Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, I"},{"author_name":"Manar matar","author_inst":"Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel  Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Childre"},{"author_name":"Yifat Snir","author_inst":"IBD Center, Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel  Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, I"},{"author_name":"Noa Tal","author_inst":"Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children Medical Center of Israel, Petah Tikva, Israel"},{"author_name":"Hagar Banai Eran","author_inst":"IBD Center, Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel  Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, I"},{"author_name":"Yael Weintraub","author_inst":"Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel  Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Childre"},{"author_name":"Sara Morgenstern","author_inst":"Institute of Pathology, Rabin Medical Center, Petah Tikva, Israel"},{"author_name":"Ofra Golani","author_inst":"Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Inna Goliand","author_inst":"Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Yosef Addadi","author_inst":"Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Hadas Keren-Shaul","author_inst":"Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Iris Dotan","author_inst":"IBD Center, Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel  Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, I"},{"author_name":"Raanan Shamir","author_inst":"Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel  Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Childre"},{"author_name":"Shalev Itzkovitz","author_inst":"Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Henit Yanai","author_inst":"IBD Center, Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Is"},{"author_name":"Dror S. Shouval","author_inst":"Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel  Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Childre"},{"author_name":"Ruth Scherz-Shouval","author_inst":"Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Low-Energy Polishing Facilitates Breaking the Resolution Barrier of In Situ Cryo-EM","rel_doi":"10.64898\/2026.06.09.731061","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731061","rel_abs":"In situ structural analysis allows direct visualization of protein structures in their native cellular environments, but near-atomic resolution in cellular lamellae has been significantly limited to exceptionally large complexes such as ribosomes. A key factor underlying this limitation is the degradation of data quality of thin lamellae caused by substantial subsurface damage from cryo-focused ion beam (cryo-FIB). Here, we developed a cryogenic low-energy polishing in FIB approach, which reliably produces thin lamellae with low damage across different cell types. This advance, combined with in situ single particles analysis, has pushed down the molecular weight lower limit for in situ reconstruction at near-atomic resolution to 400 kDa. We demonstrate this by resolving photosynthetic complexes (3.4 [A] and 3.3 [A]), metabolic enzymes (3.3 [A]), chloroplast ribosome (4.0 [A]) and respiratory chain complexes (3.7 [A]) from Chlamydomonas reinhardtii. Furthermore, the efficient workflow enables rapid structural feedback upon changes in cellular states, offering a practical way to perform multi-condition in situ structural analysis.","rel_num_authors":5,"rel_authors":[{"author_name":"Chunling Wu","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Qi Yang","author_inst":"University of Chinese Academy of Sciences"},{"author_name":"Xiaodong Su","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Mei Li","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"},{"author_name":"Xinzheng Zhang","author_inst":"Institute of Biophysics, Chinese Academy of Sciences"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"MOFF2: A Transferable Coarse-Grained Protein Force Field for Predictive Condensate Simulations","rel_doi":"10.64898\/2026.06.10.731384","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.10.731384","rel_abs":"Coarse-grained protein force fields enable simulations of biomolecular systems at length and time scales that are difficult to access with atomistic models, but achieving transferability across folded, intrinsically disordered, and multidomain proteins remains challenging. A central difficulty is that one-bead-per-residue models must represent chemically specific residue interactions while also absorbing solvent-mediated and many-body effects into a simplified energy function. Here, we present MOFF2, a transferable coarse-grained protein force field that combines residue-pair-specific interactions with a density-dependent many-body potential. MOFF2 is optimized using a two-stage strategy: bottom-up parameter learning from heterogeneous reference ensembles followed by refinement against experimental conformational observables. The resulting model provides balanced performance across ordered proteins, intrinsically disordered proteins, and multidomain proteins, and predicts condensate saturation-concentration trends for A1-LCD variant systems. Analysis of the learned parameters reveals chemically interpretable interaction patterns and density-dependent effects that explain the model's improved transferability. These results demonstrate that combining a generalized coarse-grained energy function with data-driven optimization can produce a practical and interpretable force field for protein conformational and condensate simulations.","rel_num_authors":5,"rel_authors":[{"author_name":"Shuming Liu","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Yumeng Zhang","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Ivan Riveros","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Cong Wang","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Bin Zhang","author_inst":"Massachusetts Institute of Technology"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Uncovering Pseudotime-Varying Genetic Causal Effects Along Single-Cell Trajectories for Pulmonary Disease Trait","rel_doi":"10.64898\/2026.06.08.730759","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730759","rel_abs":"With the increasing accessibility of single-cell RNA sequencing (scRNA-seq) data, cell-type-specific gene expression can be linked to complex traits through pseudo-bulk method, which considered aggregated gene expression from multiple cells of the same annotated cell type per individual and clearly shows the limitation of ignoring intra-individual cell-to-cell variability. Concurrently, pseudotime trajectory inference has gained popularity for its ability to capture continuous biological processes such as cell differentiation and lineage development, instead of individual discrete stages. It is natural to consider whether genetic effects for complex traits, such as individual level disease status, show a dynamic pattern along the inferred trajectories. In this study, we introduce a novel framework that models gene expression as a function of pseudotime along the inferred trajectories. We mapped expression quantitative trait loci (eQTL) effects in the cis-region as functional parameters, which we called \"dynamic eQTLs\", showing regulatory effects exerted by genetic variants change continuously along the cellular trajectory. For eQTLs of constant effects across pseudotime we leveraged external bulk-eQTL information to enhance the power. Furthermore, we employed significant, variable dynamic eQTLs as instrumental variables to infer causal relationships between gene expression and complex traits. To address challenges inherent to scRNA-seq data - such as sparsity and high variability - we incorporate an empirical likelihood-based inference method, which is non-parametric and self-normalized. Besides, genes associated with trajectory branchpoints may bring confounding, and we also proposed a causal mediation analysis framework to determine whether a gene plays a causal role for the disease directly and indirectly through driving cell fates. Applying our method to scRNA-seq data from human lung tissue of 114 samples (66 pulmonary fibrosis cases and 48 controls), along with meta-analyzed GWAS summary statistics for IPF from 3 studies, we identified pseudotime-dependent causal effects for IPF from genes implicated in the trajectory AT2 -translational AT2 - AT1, which is crucial in lung tissue repair and regeneration. We also found that 30 genes have a mediated effect through cell fates.","rel_num_authors":5,"rel_authors":[{"author_name":"Siyuan Chen","author_inst":"Fred Hutchison Cancer Center"},{"author_name":"Ahila Moorthy","author_inst":"Penn State College of Medicine"},{"author_name":"Paul Kwong Yu","author_inst":"Penn State University"},{"author_name":"Jingshu Wang","author_inst":"The University of Chicago"},{"author_name":"Dajiang Liu","author_inst":"Penn State University"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Uncovering Pseudotime-Varying Genetic Causal Effects Along Single-Cell Trajectories for Pulmonary Disease Trait","rel_doi":"10.64898\/2026.06.08.730759","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730759","rel_abs":"With the increasing accessibility of single-cell RNA sequencing (scRNA-seq) data, cell-type-specific gene expression can be linked to complex traits through pseudo-bulk method, which considered aggregated gene expression from multiple cells of the same annotated cell type per individual and clearly shows the limitation of ignoring intra-individual cell-to-cell variability. Concurrently, pseudotime trajectory inference has gained popularity for its ability to capture continuous biological processes such as cell differentiation and lineage development, instead of individual discrete stages. It is natural to consider whether genetic effects for complex traits, such as individual level disease status, show a dynamic pattern along the inferred trajectories. In this study, we introduce a novel framework that models gene expression as a function of pseudotime along the inferred trajectories. We mapped expression quantitative trait loci (eQTL) effects in the cis-region as functional parameters, which we called \"dynamic eQTLs\", showing regulatory effects exerted by genetic variants change continuously along the cellular trajectory. For eQTLs of constant effects across pseudotime we leveraged external bulk-eQTL information to enhance the power. Furthermore, we employed significant, variable dynamic eQTLs as instrumental variables to infer causal relationships between gene expression and complex traits. To address challenges inherent to scRNA-seq data - such as sparsity and high variability - we incorporate an empirical likelihood-based inference method, which is non-parametric and self-normalized. Besides, genes associated with trajectory branchpoints may bring confounding, and we also proposed a causal mediation analysis framework to determine whether a gene plays a causal role for the disease directly and indirectly through driving cell fates. Applying our method to scRNA-seq data from human lung tissue of 114 samples (66 pulmonary fibrosis cases and 48 controls), along with meta-analyzed GWAS summary statistics for IPF from 3 studies, we identified pseudotime-dependent causal effects for IPF from genes implicated in the trajectory AT2 -translational AT2 - AT1, which is crucial in lung tissue repair and regeneration. We also found that 30 genes have a mediated effect through cell fates.","rel_num_authors":5,"rel_authors":[{"author_name":"Siyuan Chen","author_inst":"Fred Hutchison Cancer Center"},{"author_name":"Ahila Moorthy","author_inst":"Penn State College of Medicine"},{"author_name":"Paul Kwong Yu","author_inst":"Penn State University"},{"author_name":"Jingshu Wang","author_inst":"The University of Chicago"},{"author_name":"Dajiang Liu","author_inst":"Penn State University"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"TOMM40 '523' genotype induces sex- and tissue- specific differences in cholesterol and triglyceride levels in an APOE-TOMM40 humanized mouse model","rel_doi":"10.64898\/2026.06.09.731195","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731195","rel_abs":"Introduction: Genetic variants within the APOE-TOMM40 locus are associated with Alzheimer's disease (AD). A specific role for TOMM40 is indicated by the finding that '523' poly-T variants are associated with AD risk, but the mechanism for this effect has not been established. Our studies have shown that suppression of Tomm40 in mice increased brain cholesterol content, an AD risk factor, and thus the present study sought to assess whether major '523' poly-T variants (Short [S] and Very Long [VL]) are associated with altered lipid content of brain and other tissues. Methods: We utilized a mouse model containing the entire human APOE3-TOMM40 locus to quantify cholesterol and triglyceride levels in brain, liver, and white adipose tissue (WAT), as well as brain content of the AD biomarkers A{beta} 42 and tau, in mice carrying two homozygous TOMM40 '523' poly-T genotypes (S\/S and VL\/VL). Results: Male mice carrying the '523'-S\/S genotype, but not females, showed higher brain cholesterol and triglyceride levels than VL\/VL carriers, together with greater brain A{beta} 42 content. WAT showed similar lipid differences as in the brain, while hepatic lipid content was broadly similar between '523'-S\/S and -VL\/VL genotypes, though there was a trend for higher triglycerides in VL\/VL mice in a sex- and age- dependent manner. Discussion: These results demonstrate that TOMM40 '523' poly-T variants drive tissue-specific, sex-, and age-dependent lipid differences in humanized APOE3-TOMM40 mice, with the S\/S genotype linked to elevated brain cholesterol and A{beta} 42 levels, effects that link this locus to AD pathogenesis.","rel_num_authors":8,"rel_authors":[{"author_name":"Neil Victor Yang","author_inst":"University of California, San Francisco"},{"author_name":"Dellila Hodgson","author_inst":"Duke University Medical Center"},{"author_name":"Timothy M Jang","author_inst":"University of California, Berkeley"},{"author_name":"Justin J Kim","author_inst":"University of California, Berkeley"},{"author_name":"William K Gottschalk","author_inst":"Duke University Medical Center"},{"author_name":"Hussein N. Yassine","author_inst":"University of Southern California"},{"author_name":"Ornit Chiba-Falek","author_inst":"Duke University Medical Center"},{"author_name":"Ronald M Krauss","author_inst":"University of California, San Francisco"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"TOMM40 '523' genotype induces sex- and tissue- specific differences in cholesterol and triglyceride levels in an APOE-TOMM40 humanized mouse model","rel_doi":"10.64898\/2026.06.09.731195","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731195","rel_abs":"Introduction: Genetic variants within the APOE-TOMM40 locus are associated with Alzheimer's disease (AD). A specific role for TOMM40 is indicated by the finding that '523' poly-T variants are associated with AD risk, but the mechanism for this effect has not been established. Our studies have shown that suppression of Tomm40 in mice increased brain cholesterol content, an AD risk factor, and thus the present study sought to assess whether major '523' poly-T variants (Short [S] and Very Long [VL]) are associated with altered lipid content of brain and other tissues. Methods: We utilized a mouse model containing the entire human APOE3-TOMM40 locus to quantify cholesterol and triglyceride levels in brain, liver, and white adipose tissue (WAT), as well as brain content of the AD biomarkers A{beta} 42 and tau, in mice carrying two homozygous TOMM40 '523' poly-T genotypes (S\/S and VL\/VL). Results: Male mice carrying the '523'-S\/S genotype, but not females, showed higher brain cholesterol and triglyceride levels than VL\/VL carriers, together with greater brain A{beta} 42 content. WAT showed similar lipid differences as in the brain, while hepatic lipid content was broadly similar between '523'-S\/S and -VL\/VL genotypes, though there was a trend for higher triglycerides in VL\/VL mice in a sex- and age- dependent manner. Discussion: These results demonstrate that TOMM40 '523' poly-T variants drive tissue-specific, sex-, and age-dependent lipid differences in humanized APOE3-TOMM40 mice, with the S\/S genotype linked to elevated brain cholesterol and A{beta} 42 levels, effects that link this locus to AD pathogenesis.","rel_num_authors":8,"rel_authors":[{"author_name":"Neil Victor Yang","author_inst":"University of California, San Francisco"},{"author_name":"Dellila Hodgson","author_inst":"Duke University Medical Center"},{"author_name":"Timothy M Jang","author_inst":"University of California, Berkeley"},{"author_name":"Justin J Kim","author_inst":"University of California, Berkeley"},{"author_name":"William K Gottschalk","author_inst":"Duke University Medical Center"},{"author_name":"Hussein N. Yassine","author_inst":"University of Southern California"},{"author_name":"Ornit Chiba-Falek","author_inst":"Duke University Medical Center"},{"author_name":"Ronald M Krauss","author_inst":"University of California, San Francisco"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Inference of elevated mutation rates and variant effects using 700k exomes","rel_doi":"10.64898\/2026.06.09.730991","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.730991","rel_abs":"Genomic sequencing is now widely accessible for genetic diagnostics and is emerging as a component of newborn screening. This technological development generates the need to characterize incoming mutations, create comprehensive datasets of genes causing rare Mendelian disorders, and identify pathogenic variants. Large-scale exome sequencing datasets such as Genome Aggregation Database (gnomAD) have been assembled to help address these challenges. The recent release of gnomAD (v4; n = 730,947) uncovers millions of rare coding variants, many of which have arisen more than once by independent recurrent mutations in the rapidly growing recent human population. Here, we use newly developed theoretical understanding of sampling properties of rare variants to estimate key population genetics parameters of practical importance to human genetics such as demography history, mutation rate, and selection. Solely relying on population data, our method Population Inferred Estimates of Selection (PIES) identifies novel genes with loss-of-function mutational hotspots likely due to selection in spermatogonia. PIES efficiently estimates selection coefficients for heterozygous loss-of-function variants. Combining population genetics inference with variant effect predictors, PIES predicts pathogenic missense mutations and improves variant prioritization for genetic diagnostics and newborn screening.","rel_num_authors":11,"rel_authors":[{"author_name":"Prathitha Kar","author_inst":"Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA"},{"author_name":"Mikhail A. Moldovan","author_inst":"Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA"},{"author_name":"Jeremy Guez","author_inst":"Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Sumaiya Nazeen","author_inst":"Harvard Medical School"},{"author_name":"Julia K. Goodrich","author_inst":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Trisha Karani","author_inst":"Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Kaitlin E Samocha","author_inst":"Massachusetts General Hospital"},{"author_name":"Konrad Karczewski","author_inst":"Analytic and Translational Genetics Unit"},{"author_name":"Evan Koch","author_inst":"Department of Genetics, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Vladimir Seplyarskiy","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Shamil R. Sunyaev","author_inst":"Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Duplication of superoxide dismutase and a mutation in aquaglyceroporin mediates the sensitivity of Plasmodium falciparum to cryptosporin, a natural product derived from Acaromyces ingoldii","rel_doi":"10.64898\/2026.06.08.730986","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730986","rel_abs":"Cryptosporin, a fungal metabolite, exhibited potent antimalarial activity against both asexual blood stage Plasmodium falciparum and liver-stage Plasmodium berghei with minimal human HepG2 toxicity. Unlike atovaquone, the mechanism of cryptosporin is independent of mitochondrial electron transport. Minimum inoculum of resistance showed a low risk of resistance development. RNA-Seq analysis revealed the upregulation of genes associated with sexual development including many canonical markers such as Pfs25, and PfCCp3, suggesting a stress response that is also seen when parasites are treated with artemisinin. In vitro evolution and whole genome sequencing analysis identified a mutation (F138Y) in PfAQP (PF3D7_1132800) and duplications of the two superoxide dismutase genes, PfSOD-1 (PF3D7_0814900) and PfSOD-2 (PF3D7_0623500). CRISPR\/Cas9 editing confirmed that the F138Y mutation in PfAQP was sufficient to confer resistance to cryptosporin. Alignment of the P. falciparum structure with that of HsAQP3 suggests the mutation may impact transport of hydrogen peroxide and the transition between open and closed conformations. Indeed, studies with BY4742 yeast lacking fps1 but expressing PfAQP showed that the permeability of PfAQP was not affected by cryptosporin and that it is likely not a direct target. Taken together, this study highlights the role of PfAQP in the resistance development of cryptosporin. In addition, cryptosporin likely induces high levels of oxidative stress which results in the duplications of oxidative dismutase genes as part of the parasite defense response. These findings highlight the role of PfAQP in mediating drug resistance, the mechanism of which warrants further research.","rel_num_authors":22,"rel_authors":[{"author_name":"Tiantian Jiang","author_inst":"Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, United States."},{"author_name":"Jennifer E. Collins","author_inst":"Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, 12722 Research Parkway, Orlando, Florida 32826, United"},{"author_name":"Jin Woo Lee","author_inst":"College of Pharmacy, Duksung Women's University, Seoul, 01369, Republic of Korea."},{"author_name":"Sebastian Buss","author_inst":"Department of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Institute, Kiel University, Gutenbergstr. 76, 24118 Kiel, Germany."},{"author_name":"Basil T. Thommen","author_inst":"Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, United States."},{"author_name":"Rebecca C.S. Edgar","author_inst":"Faculty of Life Sciences, University of Dundee, Dundee, United Kingdom."},{"author_name":"Karen Wendt","author_inst":"Department of Medicinal Chemistry, School of Pharmacy, University of Michigan, 1007 East Huron Street, Ann Arbor, Michigan, 48104, United States."},{"author_name":"Daisy W. Chen","author_inst":"Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, United States."},{"author_name":"Carissa Li","author_inst":"Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, United States."},{"author_name":"Nimisha Mittal","author_inst":"Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, United States."},{"author_name":"Raphaella Paes","author_inst":"Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, 12722 Research Parkway, Orlando, Florida 32826, United"},{"author_name":"Natalia Mojica Santos","author_inst":"Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, 12722 Research Parkway, Orlando, Florida 32826, United"},{"author_name":"Leticia Tiburcio Ferreira","author_inst":"Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, 10032, United States. Center for Malaria Therapeutics and An"},{"author_name":"Jasveen Bhasin","author_inst":"Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, 12722 Research Parkway, Orlando, Florida 32826, United"},{"author_name":"Jeremiah D. Momper","author_inst":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, 92093, United States."},{"author_name":"David A. Fidock","author_inst":"Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, 10032, United States. Center for Malaria Therapeutics and An"},{"author_name":"Marcus Lee","author_inst":"Faculty of Life Sciences, University of Dundee, Dundee, United Kingdom."},{"author_name":"Manoj T. Duraisingh","author_inst":"Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, United States."},{"author_name":"Eric Beitz","author_inst":"Department of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Institute, Kiel University, Gutenbergstr. 76, 24118 Kiel, Germany."},{"author_name":"Robert H. Cichewicz","author_inst":"Department of Medicinal Chemistry, School of Pharmacy, University of Michigan, 1007 East Huron Street, Ann Arbor, Michigan, 48104, United States."},{"author_name":"Debopam Chakrabarti","author_inst":"Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, 12722 Research Parkway, Orlando, Florida 32826, United"},{"author_name":"Elizabeth A. Winzeler","author_inst":"Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, United States."}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Duplication of superoxide dismutase and a mutation in aquaglyceroporin mediates the sensitivity of Plasmodium falciparum to cryptosporin, a natural product derived from Acaromyces ingoldii","rel_doi":"10.64898\/2026.06.08.730986","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730986","rel_abs":"Cryptosporin, a fungal metabolite, exhibited potent antimalarial activity against both asexual blood stage Plasmodium falciparum and liver-stage Plasmodium berghei with minimal human HepG2 toxicity. Unlike atovaquone, the mechanism of cryptosporin is independent of mitochondrial electron transport. Minimum inoculum of resistance showed a low risk of resistance development. RNA-Seq analysis revealed the upregulation of genes associated with sexual development including many canonical markers such as Pfs25, and PfCCp3, suggesting a stress response that is also seen when parasites are treated with artemisinin. In vitro evolution and whole genome sequencing analysis identified a mutation (F138Y) in PfAQP (PF3D7_1132800) and duplications of the two superoxide dismutase genes, PfSOD-1 (PF3D7_0814900) and PfSOD-2 (PF3D7_0623500). CRISPR\/Cas9 editing confirmed that the F138Y mutation in PfAQP was sufficient to confer resistance to cryptosporin. Alignment of the P. falciparum structure with that of HsAQP3 suggests the mutation may impact transport of hydrogen peroxide and the transition between open and closed conformations. Indeed, studies with BY4742 yeast lacking fps1 but expressing PfAQP showed that the permeability of PfAQP was not affected by cryptosporin and that it is likely not a direct target. Taken together, this study highlights the role of PfAQP in the resistance development of cryptosporin. In addition, cryptosporin likely induces high levels of oxidative stress which results in the duplications of oxidative dismutase genes as part of the parasite defense response. These findings highlight the role of PfAQP in mediating drug resistance, the mechanism of which warrants further research.","rel_num_authors":22,"rel_authors":[{"author_name":"Tiantian Jiang","author_inst":"Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, United States."},{"author_name":"Jennifer E. Collins","author_inst":"Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, 12722 Research Parkway, Orlando, Florida 32826, United"},{"author_name":"Jin Woo Lee","author_inst":"College of Pharmacy, Duksung Women's University, Seoul, 01369, Republic of Korea."},{"author_name":"Sebastian Buss","author_inst":"Department of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Institute, Kiel University, Gutenbergstr. 76, 24118 Kiel, Germany."},{"author_name":"Basil T. Thommen","author_inst":"Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, United States."},{"author_name":"Rebecca C.S. Edgar","author_inst":"Faculty of Life Sciences, University of Dundee, Dundee, United Kingdom."},{"author_name":"Karen Wendt","author_inst":"Department of Medicinal Chemistry, School of Pharmacy, University of Michigan, 1007 East Huron Street, Ann Arbor, Michigan, 48104, United States."},{"author_name":"Daisy W. Chen","author_inst":"Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, United States."},{"author_name":"Carissa Li","author_inst":"Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, United States."},{"author_name":"Nimisha Mittal","author_inst":"Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, United States."},{"author_name":"Raphaella Paes","author_inst":"Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, 12722 Research Parkway, Orlando, Florida 32826, United"},{"author_name":"Natalia Mojica Santos","author_inst":"Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, 12722 Research Parkway, Orlando, Florida 32826, United"},{"author_name":"Leticia Tiburcio Ferreira","author_inst":"Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, 10032, United States. Center for Malaria Therapeutics and An"},{"author_name":"Jasveen Bhasin","author_inst":"Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, 12722 Research Parkway, Orlando, Florida 32826, United"},{"author_name":"Jeremiah D. Momper","author_inst":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, 92093, United States."},{"author_name":"David A. Fidock","author_inst":"Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY, 10032, United States. Center for Malaria Therapeutics and An"},{"author_name":"Marcus Lee","author_inst":"Faculty of Life Sciences, University of Dundee, Dundee, United Kingdom."},{"author_name":"Manoj T. Duraisingh","author_inst":"Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, United States."},{"author_name":"Eric Beitz","author_inst":"Department of Pharmaceutical and Medicinal Chemistry, Pharmaceutical Institute, Kiel University, Gutenbergstr. 76, 24118 Kiel, Germany."},{"author_name":"Robert H. Cichewicz","author_inst":"Department of Medicinal Chemistry, School of Pharmacy, University of Michigan, 1007 East Huron Street, Ann Arbor, Michigan, 48104, United States."},{"author_name":"Debopam Chakrabarti","author_inst":"Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, 12722 Research Parkway, Orlando, Florida 32826, United"},{"author_name":"Elizabeth A. Winzeler","author_inst":"Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, United States."}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Wnt\/\u03b2-catenin signaling regulates fibrotic atrophy of intra-articular adipose tissue in post-traumatic osteoarthritis","rel_doi":"10.64898\/2026.06.08.730865","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730865","rel_abs":"Synovial joints like the knee are home to adipose tissue depots whose anatomy and functions are closely intertwined with that of other intra-articular soft tissues such as synovium, underscoring the growing understanding that joints are multi-tissue organs. Traumatic joint injury and the onset of osteoarthritis (OA) dramatically remodel the intra-articular adipose niche, marked by infiltration of fibrotic tissue postulated to underpin OA-associated joint stiffness and pain, yet we know very little about the disease-associated dynamics of joint adipose remodeling nor the mechanisms driving these phenomena. Here, we employed 2D histomorphometry and spatial transcriptomics, alongside 3D osmium tetroxide-enhanced micro-computed tomography to comprehensively define the spatiotemporal, structural, and transcriptional rewiring of joint adipose tissue in a non-invasive mouse model of post-traumatic osteoarthritis (PTOA). These revealed marked loss of intra-articular adiposity accompanied by expansion of fibroblast-rich, collagen-dense tissue with pro-fibrotic hallmarks and Wnt\/{beta}-catenin-enriched gene programs. Joint adipose exhibited a distinct transcriptional signature compared to subcutaneous white adipose tissue, pointing to unique, depot-specific functions. Stromal cells isolated from PTOA joints had heightened baseline expression of fibrotic and Wnt pathway genes and exhibited impaired de novo adipogenesis, in contrast to cells derived from healthy joints. In accordance with the destabilized biomechanics of PTOA joints, in vitro modeling demonstrated that prolonged, injurious loading and perturbed Wnt\/{beta}-catenin signaling were convergent anti-adipogenic cues that suppressed lipid droplet formation and adipogenic gene induction, while promoting markers of fibrosis in joint-derived stromal cells. Complementary gain-of-function studies using ex vivo joint adipose explants and in vivo joint injections demonstrated that chronic Wnt\/{beta}-catenin activation, as seen in OA joints, is sufficient to diminish the intra-articular adipogenic program and shift adipose to a more fibrotic phenotype, independent of joint injury. Collectively, these findings establish a multi-modal framework for quantifying joint adipose atrophy and implicate aberrant Wnt\/{beta}-catenin signaling and pathological mechanical loading as key factors impairing de novo adipogenesis and driving fibrotic remodeling of intra-articular adipose tissue in PTOA.","rel_num_authors":17,"rel_authors":[{"author_name":"Alexander J Knights","author_inst":"Washington University"},{"author_name":"Danny M Nguyen","author_inst":"University of Michigan"},{"author_name":"Seth Kahan","author_inst":"University of Michigan"},{"author_name":"Michael D Newton","author_inst":"University of Michigan"},{"author_name":"Huong X Tran","author_inst":"ETH Zurich"},{"author_name":"Aanya Mohan","author_inst":"ETH Zurich"},{"author_name":"Isabelle J Smith","author_inst":"Washington University"},{"author_name":"Neil Bhate","author_inst":"University of Michigan"},{"author_name":"Lindsey Lammlin","author_inst":"ETH Zurich"},{"author_name":"Stephen J Redding","author_inst":"University of Michigan"},{"author_name":"Luke Stasikelis","author_inst":"Washington University"},{"author_name":"Tong Yang","author_inst":"Washington University"},{"author_name":"Rida Pervez","author_inst":"University of Michigan"},{"author_name":"Madison Buckles","author_inst":"University of Michigan"},{"author_name":"Erica L Scheller","author_inst":"Washington University"},{"author_name":"Kurt D Hankenson","author_inst":"University of Michigan"},{"author_name":"Tristan Maerz","author_inst":"ETH Zurich"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Gut bacterial Infection drives Parkinsonian pathology in LRRK2 G2019S Knock-in Mice","rel_doi":"10.64898\/2026.06.08.728789","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.728789","rel_abs":"The LRRK2 G2019S mutation is one of the most common genetic risk factors for Parkinson s disease (PD), yet LRRK2 G2019S knock in (KI) mice rarely develop robust neurodegeneration under basal conditions, suggesting that additional environmental triggers are required for disease progression. Here, we established a clinically relevant gene environment interaction mouse model of PD by subjecting LRRK2 G2019S KI mice to recurrent Citrobacter (C.) rodentium infection, a murine model of enteric bacterial inflammation. Repeated infection induced progressive PD like phenotypes selectively in KI mice, including motor impairment, reduced locomotor activity, impaired motor coordination, selective nigrostriatal dopaminergic neurodegeneration, enhanced neuroinflammation, and pathological phosphorylated alpha-synuclein (p alpha Syn) accumulation, whereas wild type (WT) mice remained largely resistant. Mechanistically, infected KI mice developed markedly exacerbated colonic inflammation, epithelial barrier dysfunction, increased intestinal permeability, and enhanced inflammasome activation despite normal bacterial clearance, indicating that pathogenic LRRK2 signaling amplifies inflammatory responses rather than impairing antimicrobial defense. In parallel, recurrent infection induced pronounced intestinal p alpha Syn accumulation and expansion of pathology beyond the epithelial layer in KI mice, supporting a gut brain axis mechanism linking intestinal inflammation to neurodegeneration. Collectively, these findings demonstrate that the LRRK2 G2019S mutation functions as a sensitizing factor that cooperates with recurrent enteric inflammation to drive PD related pathology. This study establishes a physiologically relevant LRRK2 G2019S gene environment interaction mouse model that recapitulates key behavioral, neuropathological, and inflammatory features of PD.","rel_num_authors":14,"rel_authors":[{"author_name":"Yuhang Wang","author_inst":"The university of Iowa"},{"author_name":"Matthew A Weber","author_inst":"The University of Iowa"},{"author_name":"Nick Stodden","author_inst":"University of Iowa"},{"author_name":"Lily Ziebarth","author_inst":"University of Iowa"},{"author_name":"Sivakumar Lingappa","author_inst":"The University of Iowa"},{"author_name":"Monserrath Borjabustamante","author_inst":"University of Iowa"},{"author_name":"Tharoon Balakrishnan","author_inst":"University of Iowa"},{"author_name":"Manab Jaily","author_inst":"University of Iowa"},{"author_name":"Taylor Sakaguchi","author_inst":"University of Iowa"},{"author_name":"Ramasamy Thangavel","author_inst":"University of Iowa"},{"author_name":"Wen Wen","author_inst":"University of Iowa"},{"author_name":"Jia Luo","author_inst":"The University of Iowa"},{"author_name":"Nandakumar Narayanan","author_inst":"University of Iowa"},{"author_name":"Zizhen Kang","author_inst":"The university of Iowa"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Sex-linked Lung Estrobolome May Contribute to Pulmonary Hypertension Penetrance of Bmpr2 R899X Mutation via an ET-1high Endoregulatory Macrophage Phenotype","rel_doi":"10.64898\/2026.06.08.729693","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.729693","rel_abs":"Mutations in the bone morphogenetic protein receptor 2 (BMPR2) are a major genetic driver of pulmonary arterial hypertension (PAH), yet their penetrance is strikingly sex-biased: females are disproportionately affected, while males experience poorer outcomes. While hormonal and chromosomal factors have been implicated, the biological basis for this disparity remains not fully understood. Here, we investigated the role of the lung microbiome in sex-linked PAH pathogenesis. We hypothesized that increased BMPR2 mutation penetrance in females is partly driven by the accumulation of potent vasoactive molecules, such as endothelin-1 (ET-1), in response to lung microbiome dysbiosis. Using humanized Bmpr2+\/R899X mice, we integrate lung metagenomics with basic functional immune profiling to show that females develop a distinct microbiome profile, characterized by increased microbial-derived lipopolysaccharide (LPS), potentially fueling the pathogenic effects of the estrogen metabolite 16-hydroxyestrone (16-OHE). These signals converge on macrophages, where co-exposure led to a hyperactivated state characterized by enhanced phagocytosis and ET-1 secretion. Tissue-level analyses confirmed immune cell infiltration and spatial association with elevated ET-1, providing evidence that these factors may contribute to the onset of sex-linked PAH. Taken together, these findings identify a previously unrecognized microbiome-estrogen-immune axis that amplifies BMPR2 dysfunction and provides a mechanistic basis for female-biased disease penetrance.","rel_num_authors":9,"rel_authors":[{"author_name":"Omar Loya","author_inst":"University of Illinois Chicago"},{"author_name":"Elizabeth Villarreal","author_inst":"University of Illinois Chicago"},{"author_name":"Alan Carneiro","author_inst":"University of Illinois Chicago"},{"author_name":"Stuti Agarwal","author_inst":"Stanford University"},{"author_name":"Dustin Fraidenburg","author_inst":"University of Illinois Chicago"},{"author_name":"Jun Sun","author_inst":"University of Illinois Chicago"},{"author_name":"Vinicio de Jesus Perez","author_inst":"Stanford University"},{"author_name":"Tim Lahm","author_inst":"National Jewish Health"},{"author_name":"Suellen Darc Oliveira","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Fluorescence correlation spectroscopy measurements of the chlamydia outer protein B (CopB) made by cell-free protein synthesis","rel_doi":"10.64898\/2026.06.07.728995","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.07.728995","rel_abs":"We demonstrate the use of fluorescence correlation spectroscopy (FCS) to characterize fluorescently-labeled protein production. We use cell-free protein synthesis to express the protein YFP-CopB, a fusion of Chlamydia Outer Protein (Cop) B and Yellow Fluorescent Protein (YFP). CopB is a ~50 kDa protein believed to have a critical role in chlamydial infection. After adding a plasmid encoding YFP-CopB to an E. coli cell-free lysate, protein expression begins. We track the cell-free reaction over several hours using the EI-FLEX, a commercial instrument with FCS capability. As protein is expressed over time, YFP-CopB increases in concentration, and the EI-FLEX detects an increase in fluorescent signal above the background of the cell-free lysate. The FCS data collected gives information about the size, aggregation tendencies, rates of production and fluorescent protein maturation, and concentration of the YFP-CopB produced. The use of FCS concurrent with cell-free synthesis presents a simple method to characterize proteins of interest as they are produced without the need for purification.","rel_num_authors":6,"rel_authors":[{"author_name":"Emma Laurence","author_inst":"Lawrence Livermore National Laboratory"},{"author_name":"Shakiba Nikfarjam","author_inst":"Lawrence Livermore National Laboratory"},{"author_name":"Steven Hoang-Phou","author_inst":"Lawrence Livermore National Laboratory"},{"author_name":"Ted Laurence","author_inst":"Lawrence Livermore National Laboratory"},{"author_name":"Matt Coleman","author_inst":"Lawrence Livermore National Laboratory"},{"author_name":"Chao Liu","author_inst":"Lawrence Livermore National Laboratory"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Anionic bacterial sphingolipids increase membrane stiffness","rel_doi":"10.64898\/2026.06.07.730480","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.07.730480","rel_abs":"Recent genetic and bioinformatic studies have led to the discovery that many bacterial species encode the genes required to produce sphingolipids. Shotgun lipidomic studies have identified numerous sphingolipid species with novel structures that do not exist in eukaryotic organisms. The impacts of these lipids on the biophysical properties of bacterial membranes have not yet been determined. In this study, we purify a novel anionic bacterial sphingolipid, ceramide phosphoglycerate (CPG), and investigate its effect on membrane zeta potential and bending stiffness. CPG and its precursor, ceramide 1-phosphate (C1P), are shown to increase the magnitude of the membrane zeta potential. These sphingolipids also increase the stiffness of these membranes, with CPG increasing rigidity more than C1P or ceramide. This work provides experimental and computational methods of lipid isolation and characterization that may be broadly applicable to a variety of uncharacterized bacterial sphingolipids.","rel_num_authors":6,"rel_authors":[{"author_name":"Joshua D Chamberlain","author_inst":"Rutgers University-Camden"},{"author_name":"Jesse Sandberg","author_inst":"Rutgers University"},{"author_name":"Ziqiang Guan","author_inst":"Duke University Medical School"},{"author_name":"Benjamin P Bratton","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Grace Brannigan","author_inst":"Rutgers University-Camden"},{"author_name":"Eric A Klein","author_inst":"Rutgers University"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Anionic bacterial sphingolipids increase membrane stiffness","rel_doi":"10.64898\/2026.06.07.730480","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.07.730480","rel_abs":"Recent genetic and bioinformatic studies have led to the discovery that many bacterial species encode the genes required to produce sphingolipids. Shotgun lipidomic studies have identified numerous sphingolipid species with novel structures that do not exist in eukaryotic organisms. The impacts of these lipids on the biophysical properties of bacterial membranes have not yet been determined. In this study, we purify a novel anionic bacterial sphingolipid, ceramide phosphoglycerate (CPG), and investigate its effect on membrane zeta potential and bending stiffness. CPG and its precursor, ceramide 1-phosphate (C1P), are shown to increase the magnitude of the membrane zeta potential. These sphingolipids also increase the stiffness of these membranes, with CPG increasing rigidity more than C1P or ceramide. This work provides experimental and computational methods of lipid isolation and characterization that may be broadly applicable to a variety of uncharacterized bacterial sphingolipids.","rel_num_authors":6,"rel_authors":[{"author_name":"Joshua D Chamberlain","author_inst":"Rutgers University-Camden"},{"author_name":"Jesse Sandberg","author_inst":"Rutgers University"},{"author_name":"Ziqiang Guan","author_inst":"Duke University Medical School"},{"author_name":"Benjamin P Bratton","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Grace Brannigan","author_inst":"Rutgers University-Camden"},{"author_name":"Eric A Klein","author_inst":"Rutgers University"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Architecture of a portal complex embedded in the poxvirus core","rel_doi":"10.64898\/2026.06.09.730874","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.730874","rel_abs":"Gene transcription within the viral core is a unique feature of poxvirus replication. Following entry into the cytoplasm, the poxvirus core dissociates from the lateral bodies and undergoes expansion, functioning as a compartment for early transcription. However, the mechanisms governing molecular exchange between the viral core and the host cytoplasm remain poorly understood. Here, we determine the structures of the portal complex and its pore on the poxvirus core at 7.1 [A] and 4.9 [A] resolution, respectively, using cryo-electron tomography and sub-tomogram averaging. The pore is assembled from three viral proteins, E8, E6, and L3, for which we constructed an atomic model. Structural and channel analyses reveal that the pore satisfies the geometric and electrostatic requirements for the transport of RNA and smaller negatively charged molecules, while excluding double-stranded DNA and cytosolic DNA sensors. Together, our findings establish a structural framework for understanding the assembly and function of the poxvirus portal complex and identify potential targets for antiviral intervention.","rel_num_authors":13,"rel_authors":[{"author_name":"Ye Hong","author_inst":"Tsinghua University"},{"author_name":"Shiyuan Liu","author_inst":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, NHC Key Laboratory of Biosafety, National Institute for Viral Disease C"},{"author_name":"Rui Liang","author_inst":"Tsinghua University School of Life Sciences"},{"author_name":"Keren wang","author_inst":"Tsinghua University School of Life Sciences"},{"author_name":"Junxia Zhang","author_inst":"Tsinghua University School of Life Sciences"},{"author_name":"Cheng Peng","author_inst":"Tsinghua University School of Life Sciences"},{"author_name":"Zefeng Zhu","author_inst":"Academy for Advanced Interdisciplinary Studies, Peking University"},{"author_name":"Zheyuan Zhang","author_inst":"Tsinghua University School of Life Sciences"},{"author_name":"Weiping Zhang","author_inst":"Tsinghua University School of Life Sciences"},{"author_name":"Baoying Huang","author_inst":"huangby@ivdc.chinacdc.cn"},{"author_name":"Chen Song","author_inst":"Peking University"},{"author_name":"Wenjie Tan","author_inst":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, NHC Key Laboratory of Biosafety, National Institute for Viral Disease C"},{"author_name":"Sai Li","author_inst":"School of Life Sciences, Tsinghua University"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Selenoprotein S plays role in translation and membrane protein biogenesis","rel_doi":"10.64898\/2026.06.08.725543","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.725543","rel_abs":"Human selenoprotein S (selenos) is part of the integrated cellular stress response and linked to protein quality control and signaling pathways. Consequently, genetic polymorphisms of selenos are associated with increased risk for diabetes, dyslipidemia, and cardiovascular diseases. Determining the specific roles of selenos in these cellular pathways and diseases has been challenging, as selenos associates with a wide range of protein complexes. Thus, to map the cellular functions of selenos and uncover their interconnections, we used affinity purification and in vivo crosslinking to stabilize transient protein interactions, followed by proteomics to record the resulting selenos interactome. Through mapping of selenos protein partners, we found evidence that selenos associates with complexes responsible for the insertion of membrane proteins into the ER bilayer and their connected quality control components. Furthermore, selenos is also part of metabolic, trafficking, and mitochondrial pathways. Notably, proteins involved in translation preferentially associate with selenos when its C-terminal intrinsically disordered segment containing the redox-active motif is accessible. Together, these results identify the C-terminal redox loop of selenos as a central interaction hub connecting translation with ER membrane protein biogenesis and quality control.","rel_num_authors":8,"rel_authors":[{"author_name":"Farid Ghelichkhani","author_inst":"University of Delaware"},{"author_name":"Mariia A. Kapitonova","author_inst":"University of Delaware"},{"author_name":"Atinuke Odunsi","author_inst":"University of Delaware"},{"author_name":"Erfan Rahmani","author_inst":"University of Delaware"},{"author_name":"Omar G. Rosas Bringas","author_inst":"The Rockefeller University"},{"author_name":"Mohammed Hanzala Kaniyar","author_inst":"The Rockefeller University"},{"author_name":"John LaCava","author_inst":"The Rockefeller University"},{"author_name":"Sharon Rozovsky","author_inst":"University of Delaware"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"eQTM (expression quantitative trait methylation) Atlas: a comprehensive resource of over 11 million DNA methylation-gene expression associations through across 11 tissues and 4 diseases","rel_doi":"10.64898\/2026.06.07.730721","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.07.730721","rel_abs":"Motivation: Epigenome-wide association studies (EWAS) have identified numerous DNA methylation (DNAm) CpG sites associated with complex traits and diseases, but interpretation of those CpG sites remains challenging because in EWAS, CpGs are mostly linked to nearby genes based only on genomic proximity. Expression quantitative trait methylation (eQTM) analyses connect DNAm CpGs with statistically associated gene expression levels. However, a comprehensive, searchable resource integrating eQTMs across diverse tissues and disease contexts has been lacking. Results: We developed the eQTM Atlas, a web-based resource that manually curates more than 11 million DNAm-gene expression associations from eight cohorts, covering 11 tissue types, four broad disease contexts, 173,886 unique CpG probes and 20,231 unique genes. The Atlas supports gene- or CpG- searches by tissue or disease type and finding associated CpG or genes, visualization of cis- and trans-eQTMs through genome browser, heatmap interfaces across various tissues, and cohort-level data downloads. By integrating eQTM results with EWAS resources, the eQTM Atlas enables users to connect disease- or trait-associated CpGs to statistically associated genes rather than relying solely on proximity-based gene annotation, supporting functional interpretation of EWAS findings and generation of disease-specific regulatory hypotheses. Availability and implementation: The eQTM Atlas is freely available at https:\/\/shiny.crc.pitt.edu\/eqtm_browser\/. The web interface is implemented in R Shiny and hosted through the University of Pittsburgh Center for Research Computing (CRC). Source code is available at https:\/\/github.com\/ads303\/eQTM-Atlas.","rel_num_authors":14,"rel_authors":[{"author_name":"Aditya Sriram","author_inst":"University of Pittsburgh"},{"author_name":"Soyeon Kim","author_inst":"University of Pittsburgh"},{"author_name":"Rebecca Caldino Bohn","author_inst":"University of Pittsburgh"},{"author_name":"Wei Chen","author_inst":"University of Pittsburgh"},{"author_name":"Tianhao Liu","author_inst":"University of Pittsburgh"},{"author_name":"Molin Yue","author_inst":"University of Pittsburgh"},{"author_name":"Niyati Jain","author_inst":"University of Chicago"},{"author_name":"Brandon Pierce","author_inst":"University of Chicago"},{"author_name":"Roby Joehanes","author_inst":"Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health"},{"author_name":"Daniel Levy","author_inst":"Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health"},{"author_name":"Etienne Patin","author_inst":"Institut Pasteur"},{"author_name":"Lluis Quintana-Murci","author_inst":"Institut Pasteur"},{"author_name":"Hyun Jung Park","author_inst":"University of Pittsburgh"},{"author_name":"Juan C Celedon","author_inst":"University of Pittsburgh"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Buried in two places: Lineages from elite Maya tombs also found in distant caves","rel_doi":"10.64898\/2026.06.07.724338","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.07.724338","rel_abs":"Classic Period Maya societies 250-900 CE carved out urban centers from the rainforest reaching population heights and political complexity previously unknown in the Mesoamerican tropics. Kinship was a central feature of the social fabric, and rulership was legitimized through claims of direct descent from mythical ancestors. Mortuary practices kept the dead close to the living, and ancestor veneration sometimes produced complex deposits of disarticulated remains that are difficult to identify and whose relationship to each other cannot be understood without genetic data. We screened 487 samples and successfully generated genome-wide data for 430 samples from at least 145 distinct individuals from an Early Classic Period kingdom 250-750 CE in the rugged Maya Mountains of Belize. Of these, 24 individuals have body parts in both an elite tomb, and in a ritual tooth cache in a distant cave on the other side of the Maya mountains. These results show elite lineages created ancestors from their deceased relatives in geographically expansive ways and highlights the importance of caves in the belief system of Classic Maya elites.","rel_num_authors":36,"rel_authors":[{"author_name":"Esther S. Brielle","author_inst":"Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA. ;Broad Institute of MIT and Harvard, Cambridge, MA, USA."},{"author_name":"Elizabeth Dorgay","author_inst":"Ya'axche Conservation Trust, Punta Gorda, Toledo District, Belize."},{"author_name":"Douglas J. Kennett","author_inst":"Department of Anthropology, University of California Santa Barbara, Santa Barbara, CA, USA."},{"author_name":"Jose Mes","author_inst":"Uchben'kaj Kin Ajaw Association, Santa Cruz, Toledo District, Belize."},{"author_name":"Emily Moes","author_inst":"Department of Anthropology, University of Texas at San Antonio, San Antonio, Texas, USA."},{"author_name":"Nadia C. Neff","author_inst":"Department of Anthropology, University of New Mexico, Albuquerque, NM, USA.;Center for Stable Isotopes, University of New Mexico, Albuquerque, NM, USA."},{"author_name":"Anna C. Novotny","author_inst":"Department of Sociology, Anthropology, and Social Work, Texas Tech University, Lubbock, TX, USA."},{"author_name":"Esteban Rangel","author_inst":"Department of Anthropology, University of New Mexico, Albuquerque, NM, USA.;Center for Stable Isotopes, University of New Mexico, Albuquerque, NM, USA."},{"author_name":"Erin E. Ray","author_inst":"Department of Anthropology, University of New Mexico, Albuquerque, NM, USA.;Center for Stable Isotopes, University of New Mexico, Albuquerque, NM, USA."},{"author_name":"Mark Robinson","author_inst":"Department of Archaeology and History, University of Exeter, Exeter, UK."},{"author_name":"Amy E. Thompson","author_inst":"Department of Geography and the Environment, The University of Texas at Austin, Austin, TX, USA."},{"author_name":"Monica Warner","author_inst":"Department of Anthropology, University of New Mexico, Albuquerque, NM, USA.;Center for Stable Isotopes, University of New Mexico, Albuquerque, NM, USA."},{"author_name":"Ali Akbari","author_inst":"Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA.;Broad Institute of MIT and Harvard, Cambridge, MA, USA."},{"author_name":"Kim Callan","author_inst":"Department of Genetics, Harvard Medical School, Boston, MA, USA.;Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA."},{"author_name":"Ella Caughran","author_inst":"Department of Genetics, Harvard Medical School, Boston, MA, USA.;Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA."},{"author_name":"Romain Fournier","author_inst":"Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA."},{"author_name":"Trudi Frost","author_inst":"Department of Genetics, Harvard Medical School, Boston, MA, USA.;Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA."},{"author_name":"Lora Iliev","author_inst":"Department of Genetics, Harvard Medical School, Boston, MA, USA.;Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA."},{"author_name":"Aisling Kearns","author_inst":"Department of Genetics, Harvard Medical School, Boston, MA, USA."},{"author_name":"Jack Kellogg","author_inst":"Department of Genetics, Harvard Medical School, Boston, MA, USA.;Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA."},{"author_name":"Ann Marie Lawson","author_inst":"Department of Genetics, Harvard Medical School, Boston, MA, USA.;Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA."},{"author_name":"Iosif Lazaridis","author_inst":"Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA. ;Department of Genetics, Harvard Medical School, Boston, MA, USA."},{"author_name":"Matthew Mah","author_inst":"Department of Genetics, Harvard Medical School, Boston, MA, USA.;Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA.;Broad Institute of MI"},{"author_name":"Nihal Manjila","author_inst":"Department of Genetics, Harvard Medical School, Boston, MA, USA.;Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA."},{"author_name":"Mariam Nawaz","author_inst":"Department of Genetics, Harvard Medical School, Boston, MA, USA.;Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA."},{"author_name":"Inigo Olalde","author_inst":"Department of Zoology and Animal Cell Biology, University of the Basque Country EHU, Vitoria-Gasteiz, Spain.;Department of Human Evolutionary Biology, Harvard U"},{"author_name":"Jonas Oppenheimer","author_inst":"Department of Genetics, Harvard Medical School, Boston, MA, USA."},{"author_name":"Iris Patterson","author_inst":"Department of Genetics, Harvard Medical School, Boston, MA, USA.;Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA."},{"author_name":"Lijun Qiu","author_inst":"Department of Genetics, Harvard Medical School, Boston, MA, USA.;Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA."},{"author_name":"Kendra Sirak","author_inst":"Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA. ;Department of Genetics, Harvard Medical School, Boston, MA, USA."},{"author_name":"Gregory Soos","author_inst":"Department of Genetics, Harvard Medical School, Boston, MA, USA.;Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA."},{"author_name":"J. Noah Workman","author_inst":"Department of Genetics, Harvard Medical School, Boston, MA, USA.;Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA."},{"author_name":"Swapan Mallick","author_inst":"Department of Genetics, Harvard Medical School, Boston, MA, USA.;Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA.;Broad Institute of MI"},{"author_name":"Nadin Rohland","author_inst":"Department of Genetics, Harvard Medical School, Boston, MA, USA.;Broad Institute of MIT and Harvard, Cambridge, MA, USA."},{"author_name":"David Reich","author_inst":"Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA. ;Department of Genetics, Harvard Medical School, Boston, MA, USA.;Broad Instit"},{"author_name":"Keith M. Prufer","author_inst":"Department of Anthropology, University of New Mexico, Albuquerque, NM, USA.;Center for Stable Isotopes, University of New Mexico, Albuquerque, NM, USA."}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Tension TRAAKer: a chemigenetic fluorescent membrane tension reporter","rel_doi":"10.64898\/2026.06.08.730921","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730921","rel_abs":"Mechanical force transduction is essential to survival, underlying biological processes as fundamental as morphogenesis, somatosensation, audition, and interoception; and driving pathologies as diverse as hypertension and cancer metastasis. Exogenous forces are translated to intracellular signals through transient changes in membrane tension which are currently not possible to directly monitor in situ. To remedy this, we have designed and validated Tension TRAAKer, a chemigenetic fluorescent membrane tension reporter for the visualization of tension induction, propagation, and dissipation in living cells. Tension TRAAKer is derived from inserting a tension-sensitive nonconductive variant of the mechanosensitive potassium ion channel TRAAK into a self-labelling HaloTag. Increasing membrane tensions effect conformational changes in the TRAAK channel that are optically monitored by a HaloTag-conjugated fluorogenic (environment-sensitive) dye. EGFP incorporation C-terminal to the HaloTag enables unambiguous tension reporting in mobile membranes via dual-color ratiometric imaging that controls for variations in sensor density. Tension TRAAKer reports membrane tension changes rapidly, reversibly, and with spatiotemporal precision--its fluorescence scaling to both stimulus magnitude and area, with consistent effect sizes observed between diverse cell types. It better distinguishes among elevated membrane tensions than do available indirect chemical reporters, with the additional advantage of being readily genetically targetable. We thus expect Tension TRAAKer to be a powerful tool for the study of membrane tension across biological systems and disease states.","rel_num_authors":6,"rel_authors":[{"author_name":"Anna Elleman","author_inst":"University of California, Berkeley"},{"author_name":"Nels Gerstner","author_inst":"University of Iowa"},{"author_name":"Benjamin Smith","author_inst":"University of California, Berkeley"},{"author_name":"Evan Miller","author_inst":"University of California, Berkeley"},{"author_name":"Richard Kramer","author_inst":"University of California Berkeley"},{"author_name":"Stephen G Brohawn","author_inst":"University of California Berkeley"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Tension TRAAKer: a chemigenetic fluorescent membrane tension reporter","rel_doi":"10.64898\/2026.06.08.730921","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730921","rel_abs":"Mechanical force transduction is essential to survival, underlying biological processes as fundamental as morphogenesis, somatosensation, audition, and interoception; and driving pathologies as diverse as hypertension and cancer metastasis. Exogenous forces are translated to intracellular signals through transient changes in membrane tension which are currently not possible to directly monitor in situ. To remedy this, we have designed and validated Tension TRAAKer, a chemigenetic fluorescent membrane tension reporter for the visualization of tension induction, propagation, and dissipation in living cells. Tension TRAAKer is derived from inserting a tension-sensitive nonconductive variant of the mechanosensitive potassium ion channel TRAAK into a self-labelling HaloTag. Increasing membrane tensions effect conformational changes in the TRAAK channel that are optically monitored by a HaloTag-conjugated fluorogenic (environment-sensitive) dye. EGFP incorporation C-terminal to the HaloTag enables unambiguous tension reporting in mobile membranes via dual-color ratiometric imaging that controls for variations in sensor density. Tension TRAAKer reports membrane tension changes rapidly, reversibly, and with spatiotemporal precision--its fluorescence scaling to both stimulus magnitude and area, with consistent effect sizes observed between diverse cell types. It better distinguishes among elevated membrane tensions than do available indirect chemical reporters, with the additional advantage of being readily genetically targetable. We thus expect Tension TRAAKer to be a powerful tool for the study of membrane tension across biological systems and disease states.","rel_num_authors":6,"rel_authors":[{"author_name":"Anna Elleman","author_inst":"University of California, Berkeley"},{"author_name":"Nels Gerstner","author_inst":"University of Iowa"},{"author_name":"Benjamin Smith","author_inst":"University of California, Berkeley"},{"author_name":"Evan Miller","author_inst":"University of California, Berkeley"},{"author_name":"Richard Kramer","author_inst":"University of California Berkeley"},{"author_name":"Stephen G Brohawn","author_inst":"University of California Berkeley"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"A Reaction-Driven Condensate-to-Vesicle Transition Selects, Activates, and Spatially Organizes RNA","rel_doi":"10.64898\/2026.06.07.730732","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.07.730732","rel_abs":"Living systems depend on the selective concentration of informational polymers within membrane-bound compartments. Liquid-liquid phase-separated condensates efficiently concentrate biomolecules, whereas membrane-bound vesicles provide persistent compartment boundaries. However, direct chemical mechanisms that couple these organizational states remain largely unexplored. Here we report a reaction-driven pathway linking condensates to RNA-enriched lipid vesicles. Electrostatic interactions between cationic thioesters and RNA drive phase separation into reactive condensates. Reaction with cysteine generates membrane lipids and transforms the condensates into unilamellar bilayer vesicles with near-uniform size distribution. The vesicles encapsulate >90% of the RNA from the initial solution and concentrate it by more than two orders of magnitude to >100 M. Encapsulation is strongly dependent on RNA length, with short oligonucleotides excluded while longer RNAs are selectively retained. Under spatial gradients of the chemical trigger, sharply defined vesicle populations with distinct RNA compositions emerge. Reaction-driven compartmentalization raises local ribozyme and substrate concentrations above the threshold required for catalytic activity, enabling function from otherwise inactive dilute solutions. These findings establish a mechanism by which chemical reactions generate selective, functional, and spatially organized RNA-enriched membrane-bound compartments from heterogeneous molecular mixtures.","rel_num_authors":5,"rel_authors":[{"author_name":"Hong-Guen Lee","author_inst":"University of California, San Diego"},{"author_name":"Alessandro Fracassi","author_inst":"University of California San Diego"},{"author_name":"Alexander Harjung","author_inst":"University of California, San Diego"},{"author_name":"Taeyang An","author_inst":"University of California San Diego"},{"author_name":"Neal Devaraj","author_inst":"University of California, San Diego"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Not All Charges Are Equal: Side-Chain Chemistry Reshapes the Disordered Ensemble of \u03b1-synuclein","rel_doi":"10.64898\/2026.06.07.730657","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.07.730657","rel_abs":"The conformational ensembles of intrinsically disordered proteins (IDPs) are governed by the balance of electrostatic and hydrophobic interactions encoded in their primary sequences. Current polymer-physics models of IDPs frequently group amino acids by coarse-grained properties, such as net charge, often overlooking the distinct residues' side-chain chemistries. Analysis across the IDP database reveals that these sequences are sensitive to specific residue identities, where the substitution of aromatic, proline, or hydrophobic groups serves as a primary driver of chain dimensions. However, these data also highlight that even subtle chemical variations between similarly charged residues can consistently shift global compaction. Here, we explore the role of residue identity using small angle X-ray scattering (SAXS) of seven -synuclein variants with progressively increasing numbers of lysine-to-arginine substitutions, two positively charged amino acids with different side-chain chemistry. We show that increasing arginine content drives a systematic compaction of the conformational ensemble, although variants with identical number of substitutions but different positional arrangements suggest influence to the sequence context. Moreover, while increasing salt concentrations shift the structural ensemble from a Gaussian toward a self-avoiding-walk statistics, the arginine-dependent contraction trend remains robust across both regimes. Molecular-dynamics simulations combined with SAXS data reveal that arginine substitutions reduce ensemble heterogeneity by stabilizing transient long-range contacts. Finally, aggregation assays demonstrate that this arginine-driven compaction correlates with an accelerated transition to amyloid fibrils. Our findings demonstrate that chemically subtle substitutions between similarly charged residues can fundamentally reshape the conformational ensemble of IDPs, suggesting that side-chain identity is a critical, yet underappreciated, determinant of protein disorder and proteotoxicity.","rel_num_authors":9,"rel_authors":[{"author_name":"Gil Koren","author_inst":"Tel Aviv University"},{"author_name":"Nuno Fernandes","author_inst":"Structural Biology and NMR Laboratory, The Linderstr{\\o}m-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Asaf Sivan","author_inst":"Tel Aviv University, ISRAEL"},{"author_name":"Rawan Aodeh","author_inst":"Tel Aviv University, ISRAEL"},{"author_name":"Dean Yona","author_inst":"Tel Aviv University, Israel"},{"author_name":"Mathar Kravikass","author_inst":"Tel Aviv University, Israel"},{"author_name":"Yuval Keidar","author_inst":"Tel Aviv University , Israel"},{"author_name":"Kresten Lindorff-Larsen","author_inst":"University of Copenhagen"},{"author_name":"Roy Beck","author_inst":"Tel Aviv Univerisy"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Long-term small effective population size, inbreeding, and a recessive lethal haplotype drive premature death in the endangered Devils Hole pupfish (Cyprinodon diabolis)","rel_doi":"10.64898\/2026.06.06.730634","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.06.730634","rel_abs":"As anthropogenic habitat fragmentation and population decline accelerate globally, growing numbers of species face compounding demographic and genetic threats to long-term survival. Many populations are already forced to persist at chronically small sizes, yet the genomic and fitness consequences of this fate remain poorly understood. Here we leverage the demographic history of the Devils Hole pupfish to investigate how long-term small population size and recent bottlenecks have shaped genetic diversity, genetic load, inbreeding, and fitness through comparative population genomics, historical sequencing, and sampling embryos that died prematurely during development. We find that genetic diversity in Devils Hole pupfish is among the lowest recorded in the wild and that fixed load is high, consistent with thousands of generations of isolation at small population size. Even in the face of this low diversity and high fixed load, we show that inbreeding is still strongly associated with premature embryonic death, which affects up to 25% of offspring in the captive refuge and can be identified in advance based on a characteristic elongated heart tube and reduced heart rate. We discovered a recessive lethal haplotype segregating at ~20% frequency that accounts for 50% of embryonic deaths and contains mutations in MIB1 and MMP16, genes associated with cardiomyopathy and atrial fibrillation. Our findings link genotype, phenotype, and fitness in an iconic endangered species to provide a rare comprehensive view into the evolutionary dynamics and consequences of long-term small effective population size, demonstrating that endangered species remain vulnerable to inbreeding depression despite extremely low genetic diversity.","rel_num_authors":12,"rel_authors":[{"author_name":"David Tian","author_inst":"Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, CA, 90095, USA"},{"author_name":"Nicolas Alexandre","author_inst":"Department of Ecology and Evolutionary Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA"},{"author_name":"Naomi Siu","author_inst":"Museum of Vertebrate Zoology, University of California, Berkeley, Berkeley, CA, 94720, USA"},{"author_name":"Vanessa Muhl","author_inst":"Department of Biology, Texas A and M University, College Station, TX 77843, USA"},{"author_name":"Sean C. Lema","author_inst":"Biological Sciences Department, California Polytechnic State University, San Luis Obispo, San Luis Obispo, CA, 93407, USA"},{"author_name":"Bruce J. Turner","author_inst":"Department of Biological Sciences, Virginia Tech, Blacksburg, VA, 24061, USA"},{"author_name":"Olin Feuerbacher","author_inst":"Ash Meadows Fish Conservation Facility, US Fish and Wildlife Service, Amargosa Valley, NV, 89020, USA"},{"author_name":"Kevin Wilson","author_inst":"Death Valley National Park, National Park Service, Pahrump, NV, 89048, USA"},{"author_name":"Michael Schwemm","author_inst":"Southern Nevada Fish and Wildlife Office, US Fish and Wildlife Service, Las Vegas, NV, 89130, USA"},{"author_name":"Priya Moorjani","author_inst":"Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, 94720, USA"},{"author_name":"Jennifer Gumm","author_inst":"Fish and Aquatic Conservation Program, US Fish and Wildlife Service, Falls Church, VA, 22041, USA"},{"author_name":"Christopher Herbert Martin","author_inst":"Museum of Vertebrate Zoology, University of California, Berkeley, Berkeley, CA, 94720, USA"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Mannosidases IA, IB and IC are in segregated vesicular structures and involved in both glycoprotein quality control and maturation","rel_doi":"10.64898\/2026.06.07.730669","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.07.730669","rel_abs":"N-linked glycoprotein processing critically depends on the trimming of -1,2 mannose residues, a key step required both for glycoprotein maturation along the secretory pathway and for targeting defective glycoproteins to endoplasmic reticulum-associated degradation (ERAD). Mammalian cells express seven Class I -1,2 mannosidases, yet their individual roles remain poorly defined, particularly for ManIA, ManIB, and ManIC, which were originally considered Golgi-resident maturation enzymes. Here, we re-evaluated the subcellular localization and functional contributions of these three mannosidases to glycoprotein quality control and maturation. We found that ManIA, ManIB, and ManIC localize predominantly to quality control vesicles (QCVs), previously identified by our group, whereas only ManIC displays a substantial Golgi population. Surprisingly, each enzyme is confined to a different vesicular population. All three enzymes promote ERAD targeting of misfolded model glycoproteins, albeit with different substrate preferences. In addition, they redundantly support the maturation and cell-surface delivery of a model glycoprotein. Most strikingly, in vitro analyses revealed that ManIA, ManIB, and ManIC preferentially trim a properly folded model glycoprotein rather than its denatured form. This is the opposite of the substrate preference that we previously observed for ERManI, EDEM1, and EDEM2. These findings support a model in which ERManI and the EDEMs selectively process misfolded glycoproteins to promote their recognition by the proximal lectin OS-9 and subsequent ERAD. In contrast, ManIA, ManIB and ManIC can slowly process misfolded glycoproteins but act rapidly on properly folded glycoprotein molecules, releasing them from ER-Golgi lectin-mediated retention or retrieval pathways, thereby promoting forward trafficking and maturation in the Golgi.","rel_num_authors":5,"rel_authors":[{"author_name":"Haddas Saad","author_inst":"Tel Aviv University"},{"author_name":"Marina Shenkman","author_inst":"Tel Aviv University"},{"author_name":"Edward Avezov","author_inst":"University of Cambridge"},{"author_name":"Isam Khalaila","author_inst":"Ben-Gurion University"},{"author_name":"Gerardo Z Lederkremer","author_inst":"Tel Aviv University"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Reductive carboxylation via isocitrate dehydrogenase 1 supports cardiac metabolic adaptation during oncometabolic stress.","rel_doi":"10.64898\/2026.06.06.727699","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.06.727699","rel_abs":"Background: Cardiovascular disease and cancer are the two leading causes of morbidity and mortality worldwide. Metabolic dysregulation of cancer cells extends beyond the tumor microenvironment and increases the risk for cardiovascular diseases. One common somatic mutation in cancer cells affects isocitrate dehydrogenase (IDH) 1 and 2, which catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate in the cytosol and mitochondria, respectively. IDH1 and 2 mutations cause the production of the oncometabolite D-2-hydroxyglutarate (D2-HG), which allosterically inhibits alpha-ketoglutarate dehydrogenase (alpha-KGDH) and is associated with reduced cardiac contractile function. Methods: We combined stable isotope tracer studies with computational modeling to investigate the fundamental role of IDH isoforms in cardiac adaptation under oncometabolic stress. Results: We uncovered an unexpected cardiac phenotype that expands the role of IDH1 in the heart beyond oxidative metabolism. We quantified the stable isotopomer distributions from glucose and glutamine in perfused working rat hearts and isolated adult ventricular cardiomyocytes using mass spectrometry-based metabolomics. Our analysis revealed that defective mitochondrial metabolism causes the redirection of carbon flux from oxidative towards reductive pathways. Reductive carboxylation of alpha-KGDH increases glutamine uptake and glutamine-derived citrate formation in working rat heart perfusions and cultured adult mouse ventricular cardiomyocytes. To identify which IDH isoform is responsible for redirecting carbon flux, we developed knockout models of IDH1, IDH2, and IDH3 in adult mouse ventricular cardiomyocytes. Loss of IDH1 expression impaired the reductive formation of citrate and caused functional defects in cardiomyocytes. Lastly, epigenetic analyses of histone marks revealed that IDH1 induces widespread alterations in histone acetylation and tri-methylation. Conclusion: Our results highlight a novel role for IDH1 in cardiac metabolism and transcriptional control of metabolic adaptation to tumor-mediated stress, and provide evidence that reductive citrate formation may induce epigenetic modifications in the heart.","rel_num_authors":12,"rel_authors":[{"author_name":"Tanvi Shankar","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Yaqi Gao","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Zipporah Erebholo","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Nicole Nakama","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Kyoungmin Kim","author_inst":"Cedars Sinai Medical Center"},{"author_name":"Ian Williamson","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Nathaniel Snyder","author_inst":"Temple University"},{"author_name":"Evan Kransdorf","author_inst":"Cedars-Sinai Medical Center"},{"author_name":"Ralph DeBerardinis","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Heinrich Taegtmeyer","author_inst":"McGovern Medical School, The University of Texas at Houston"},{"author_name":"Brandon Faubert","author_inst":"University of Chicago"},{"author_name":"Anja Karlstaedt","author_inst":"Cedars-Sinai Medical Center"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Transformer-based framework uncovers state-dependent modular organization and conformational landscapes of the \u03b2-arrestin 1 C-terminal tail","rel_doi":"10.64898\/2026.06.06.730629","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.06.730629","rel_abs":"{beta}-arrestins ({beta}arr) regulate signaling and trafficking of G protein-coupled receptors (GPCRs) across diverse physiological and pathological processes. However, mechanistic understanding of how ligand-activated GPCRs engage and activate {beta}arr remains limited, with the conformation of the entire {beta}arr tail in the active state still unknown. Here, by comparatively analyzing temperature replica-exchange molecular dynamics simulation data of {beta}arr1 in basal and active states, we investigated the conformational landscape of the {beta}arr1 tail to elucidate its role in activation. To overcome limitation of conventional analyses in characterizing the vast conformational space sampled by the 62-residue tail, we developed a transformer-based autoencoder (TAE) framework that integrates attention-derived residue relationships and latent-space clustering to identify the tail's modular organization and conformational substates, providing an interpretable description of how local residue interactions couple to large-scale conformational rearrangements. Using the conformationally constrained basal state as a control, we validated the framework by showing that it recovers interpretable conformational features. In the active state, the framework revealed a reorganized modular architecture, recovered key interactions identified through manual analysis, and uncovered segment-specific dynamics inaccessible to conventional approaches. Our findings show that, in the active state, the {beta}arr1 tail preferentially engages the back side of the main body and forms substates in which the middle segment occupies the central crest crevice, suggesting that the released tail can self-engage functionally critical surfaces and influence the balance between tail-only and core-engaged receptor complexes. Together, this work establishes a TAE framework for analyzing large-scale conformational ensembles and advances our understanding of {beta}arr1 activation.","rel_num_authors":4,"rel_authors":[{"author_name":"Margaret Jane Robinson","author_inst":"National Institute on Drug Abuse"},{"author_name":"Van Ngo","author_inst":"Oak Ridge National Laboratory"},{"author_name":"Jonathan A Javitch","author_inst":"Columbia University"},{"author_name":"Lei Shi","author_inst":"National Institutes of Health"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"RERconverge Update: Runtime Reduction and Analysis Function Overhaul","rel_doi":"10.64898\/2026.06.06.730612","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.06.730612","rel_abs":"Motivation: Convergent evolution, or the independent acquisition of similar phenotypes in distinct lineages, provides a powerful framework for investigating genomic changes associated with a phenotype. This paper details an update to RERconverge, a powerful R package that tests for associations between gene relative evolutionary rates (RERs) and convergent phenotypes to infer genomic regions associated with traits or selective pressures. We introduce new customizable analysis choices and scalable and efficient algorithms that can process larger genomic datasets, a critical improvement as genomic data become available for more species. Results: Modifications to core functions in the RERconverge pipeline resulted in an immense speedup (by a factor of up to 28.6). The function that tests for associations between phenotypes and RERs has been expanded to include two new analytical methods for outlier control; we also provide here a summary of the statistical tests users can perform, along with their use cases. Availability and implementation: The code and walkthrough vignettes for the package are available at https:\/\/github.com\/nclark-lab\/RERconverge.","rel_num_authors":9,"rel_authors":[{"author_name":"Guillermo L. Hoffmann","author_inst":"University of Pittsburgh"},{"author_name":"Emily E. K. Kopania","author_inst":"University of Pittsburgh"},{"author_name":"Michael Tene","author_inst":"Lehigh University"},{"author_name":"Amanda Kowalczyk","author_inst":"University of Pittsburgh"},{"author_name":"Ruby Redlich","author_inst":"Carnegie Mellon University"},{"author_name":"Andreas R Pfenning","author_inst":"Carnegie Mellon University"},{"author_name":"Wynn K. Meyer","author_inst":"Lehigh University"},{"author_name":"Maria Chikina","author_inst":"University of Pittsburgh"},{"author_name":"Nathan L. Clark","author_inst":"University of Pittsburgh"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Single-cell learning in Stentor coeruleus is governed by a fractional-order low-pass filter","rel_doi":"10.64898\/2026.06.06.730631","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.06.730631","rel_abs":"Single cells display a range of complex behaviors normally associated with a nervous system, including basic forms of learning like habituation. The giant ciliate Stentor coeruleus habituates to mechanical stimuli and shows many of the hallmark features characteristic of habituation in animal cells. When Stentor cells are mechanically stimulated by a predator or other stimuli, an action potential fires and leads to calcium-dependent contraction. When the same cell is repeatedly stimulated, it becomes less likely to respond, thus showing habituation. While the molecular basis of habituation in Stentor is not yet known, it has been shown to involve CaMKII, which also plays a key role in learning in neurons. The presence of an action potential, the role of calcium in the response, and the involvement of CaMKII in habituation, all suggest a potential deep conservation of learning mechanisms between single-celled protists and the neurons of animals. A number of different models have been proposed to explain habituation in a single cell but existing data in Stentor are unable to clearly rule out any of these models or favor others. Here we report a frequency domain analysis of habituation in which we measure the response probability of Stentor cells to pulsatile stimuli delivered at a range of frequencies. We find that the Bode plot of the frequency response resembles a classic low pass filter, with a flat passband at low frequencies, a clear corner frequency, and a linear roll-off. However, unlike standard low pass filter, the roll-off occurs with a slope of -30dB\/decade, thus showing a fractional-order behavior. None of the existing models for habituation in Stentor, at least in their current form, predict this form of the frequency response, leading us to look for other explanations. We tested, and ruled out, a model based on a refractory period associated with the re-extension of cells following contraction. Inspired by methods used in analog circuit design to approximate fractional order systems using conventional lumped devices, we developed a model in which a series of distinct molecular species, such as different multimeric complexes of CaMKII, acting in parallel to inhibit the response, produce a fractional-order effect. The fractional order behavior of habituation in Stentor resembles the fractional-order behavior of adaptation in neurons, further supporting the idea that neurons may employ similar mechanisms for learning as were already present in unicellular eukaryotes prior to the evolution of metazoa.","rel_num_authors":12,"rel_authors":[{"author_name":"Salvador Escobedo","author_inst":"UCSF"},{"author_name":"Aline Moran","author_inst":"CCC Summer Course"},{"author_name":"Frank Wu","author_inst":"CCC Summer Course"},{"author_name":"Elvira Magana","author_inst":"CCC Summer Course"},{"author_name":"Akira Bowler","author_inst":"CCC Summer Course"},{"author_name":"Karina Rodriguez","author_inst":"CCC Summer Course"},{"author_name":"Gurleen Kaur","author_inst":"San Francisco State University"},{"author_name":"Julianna Mululu","author_inst":"CCC Summer Course"},{"author_name":"Katlyn Benton","author_inst":"CCC Summer Course"},{"author_name":"Aya Alkabbani","author_inst":"San Francisco State University"},{"author_name":"Ximena Garcia Arceo","author_inst":"UCSF"},{"author_name":"Wallace F Marshall","author_inst":"UCSF"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Distinct neural correlates for focusing on similar memory contents originating from current or previous experience","rel_doi":"10.64898\/2026.06.05.730490","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730490","rel_abs":"Flexible, goal-directed behavior depends on the ability to select and prioritize information from memory representations freshly encoded from the sensory stream as well as retrieved from previous experience. The spatial gating signatures of internal attention in working memory (WM) are increasingly well characterized, but it remains unclear whether the same neurophysiological mechanisms are recruited for orienting attention to items from long-term memory (LTM). We recorded EEG and eye movements while participants focused on WM versus LTM representations in a unified precision-report task. Retrocues improved performance for both WM and LTM items, but with larger behavioral gains for WM items. Neural and oculomotor markers of spatial orienting, including contralateral posterior alpha suppression and gaze biases toward remembered locations, were robust when focusing on WM items; but were reliably weakened or absent when focusing on LTM items. Multivariate pattern analyses provided complementary evidence for the recruitment of dissociable neural mechanisms when focusing on WM vs. LTM items, which unfolded with similar time courses. Together, the results establish the existence of dissociable neural mechanisms for internal attention, which can be deployed flexibly depending on the relevant memory trace to guide performance. The findings raise interesting and tractable questions about whether differences in representational formats or representational domains drive the distinct internal attention mechanisms.","rel_num_authors":3,"rel_authors":[{"author_name":"Dongyu Gong","author_inst":"Yale University"},{"author_name":"Dejan Draschkow","author_inst":"University of Oxford"},{"author_name":"Anna C. Nobre","author_inst":"Yale University"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Social Jet Lag Estimated From CPAP Adherence Data in Two Obstructive Sleep Apnea Cohorts","rel_doi":"10.64898\/2026.06.06.729437","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.06.729437","rel_abs":"Background: Social jet lag (SJL), the discrepancy timing between work nights and free nights, reflects schedule-related circadian misalignment. Time-stamped CPAP adherence records may provide objective, longitudinal estimates of sleep timing and could augment conventional CPAP reports by adding information on sleep regularity and weekday, weekend misalignment. Objectives: To quantify CPAP derived SJL in two independent clinical cohorts, characterize its behavioral correlates and age-related patterns, and assess cross-site reproducibility. Methods: We analyzed CPAP derived sleep timing in patients from Rutgers-RWJ Health (RWJ, N = 1,437) and Hackensack Meridian Health (HMH, N = 1,510) with at least 31 valid nights and at least one valid work night and free night. Mid-sleep on work nights (MSW) and free nights (MSF) was estimated using circular statistics. SJL was defined as the absolute circular difference between MSF and MSW and categorized as none ( less than 1 h), moderate (1 to 2 h), or severe (more than 2 h). Sleep duration, free-night rebound, age-stratified prevalence, and cross-site differences were evaluated using nonparametric and categorical tests. Results: SJL was right-skewed at both sites, with median values below 0.5 h at RWJ and HMH. SJL >1 h was present in 21.2% and 16.4% of patients, respectively; severe SJL occurred in 4.0% and 2.8%. Moderate and severe SJL were associated with shorter work-night sleep and greater free-night rebound, consistent with weekday restriction and weekend compensation. SJL prevalence and variability were highest in younger and middle-aged adults, particularly those aged 26 to 50 years, and declined markedly after age 65. Core timing phenotypes, including MSW, MSF, and free-night rebound, were highly reproducible across sites despite modest differences in absolute sleep duration and overall SJL prevalence. Conclusions: In CPAP-treated cohorts, SJL is common but usually modest, is associated with weekday sleep restriction and free-night rebound, and declines substantially with age. These findings support the use of routinely collected CPAP data as a scalable, low-burden source of device-anchored circadian screening phenotypes. CPAP derived SJL may augment standard adherence reports by helping identify patients who warrant further behavioral, circadian, or activity-based assessment.","rel_num_authors":4,"rel_authors":[{"author_name":"Zachary Yousef","author_inst":"Rutgers University"},{"author_name":"Vedant Ramabadran","author_inst":"Rutgers University"},{"author_name":"Matthew Scharf","author_inst":"Hackensack Meridian Health"},{"author_name":"Ioannis P Androulakis","author_inst":"Rutgers University"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"A microbial-sensory axis drives Pseudomonas aeruginosa-induced mechanical itch","rel_doi":"10.64898\/2026.06.06.730581","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.06.730581","rel_abs":"Cutaneous bacterial infections frequently elicit severe pruritus, prominently featuring alloknesis, a pathological state where innocuous touch provokes intense itch. However, the peripheral mechanisms translating microbial cues into touch-evoked pruritus remain unresolved. Here, we establish an epicutaneous Pseudomonas aeruginosa infection model that robustly isolates mechanical alloknesis from spontaneous scratching. We identify bacterial flagellin as the critical virulence factor driving this specific sensory modality via Toll-like receptor 5 (TLR5) activation exclusively within Calb1+ A{beta} rapidly adapting low-threshold mechanoreceptors (RA-LTMRs). Mechanistically, pathogen-driven TLR5 signaling depletes intracellular PIP2, which suppresses KCNQ4-mediated M-currents and dismantles the biophysical brake on LTMR excitability. Our findings define a distinct microbial-neuronal axis that directly converts tactile stimuli into itch at the peripheral entry point, providing an infection-based framework for dissecting pathogen-sensory neuron interactions and uncovering precise therapeutic targets for chronic, touch-evoked pruritus.","rel_num_authors":17,"rel_authors":[{"author_name":"Pang Zhaohua","author_inst":"Department of Anesthesiology, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, China."},{"author_name":"Ding Huijuan","author_inst":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Shanghai, 201203, China."},{"author_name":"Liu Huan","author_inst":"State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai, 201203, China."},{"author_name":"Wang Qiong","author_inst":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Shanghai, 201203, China."},{"author_name":"Wang Yu","author_inst":"Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China."},{"author_name":"Zhu Qianwen","author_inst":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Shanghai, 201203, China."},{"author_name":"Chen Yao","author_inst":"Department of Anesthesiology, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, China."},{"author_name":"Zhao guodun","author_inst":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Shanghai, 201203, China."},{"author_name":"Hu Ximin","author_inst":"Department of Burn and Plastic Surgery, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, 510000, China."},{"author_name":"Chen Zhenru","author_inst":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Shanghai, 201203, China."},{"author_name":"Zhou liqin","author_inst":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Shanghai, 201203, China."},{"author_name":"wang ting","author_inst":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Shanghai, 201203, China."},{"author_name":"Lan Lefu","author_inst":"University of Chinese Academy of Sciences, Beijing, 100000, China."},{"author_name":"Gao Zhaobing","author_inst":"State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Shanghai, 201203, China."},{"author_name":"Zhang Hong-Fei","author_inst":"Department of Anesthesiology, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, China."},{"author_name":"Feng Jing","author_inst":"Department of Anesthesiology, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, China."},{"author_name":"Li Fengxian","author_inst":"Department of Anesthesiology, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, China."}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Outbred Drosophila populations reveal diet-dependent genetic effects on development time","rel_doi":"10.64898\/2026.06.05.730474","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730474","rel_abs":"Metabolic effects of genetic variation often depend on diet, yet the loci underlying diet-dependent developmental responses remain incompletely defined. Here we combine multi-trait phenotyping of Drosophila Genetic Reference Panel lines with genome-wide mapping in newly developed Drosophila Recombinant Populations. High sugar causes genotype- and life-stage-dependent changes in metabolic and life-history traits, with development time emerging as a highly heritable, sugar-sensitive phenotype. Mapping in 16 outbred advanced intercross populations reveals distinct association landscapes under low- and high-sugar diets, with a concentrated low-sugar signal, a more distributed high-sugar pattern, and identified genotype-by-diet loci including tap, Eip75B and Cerk. Functional perturbation supports diet-dependent effects for several prioritized candidates. Allele-frequency analyses identify operationally defined thrifty-like variants associated with delayed development under high sugar and relatively earlier development under low sugar; these variants are enriched for cell-adhesion, neurodevelopmental, and morphogenetic processes. Together, these results establish an outbred Drosophila framework for dissecting how dietary sugar remodels the genetic architecture of development time.","rel_num_authors":13,"rel_authors":[{"author_name":"Yulin Bai","author_inst":"University of Arkansas"},{"author_name":"Sumaira Shabbir","author_inst":"University of Arkansas"},{"author_name":"Yuyan Chen","author_inst":"University of Arkansas"},{"author_name":"Fabio Morgante","author_inst":"Clemson University"},{"author_name":"Michael Ludwig","author_inst":"University of Chicago"},{"author_name":"Soo-Young Park","author_inst":"University of Chicago"},{"author_name":"Mohan Acharya","author_inst":"University of Arkansas"},{"author_name":"Yang Li","author_inst":"University of Chicago"},{"author_name":"Sabir Ali","author_inst":"University of Arkansas"},{"author_name":"Abigail Trudnak","author_inst":"University of Arkansas"},{"author_name":"Mutheshree Rajesh","author_inst":"University of Arkansas"},{"author_name":"Martin Kreitman","author_inst":"University of Chicago"},{"author_name":"Xuan Zhuang","author_inst":"University of Arkansas"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Viral load-driven systemic immune exhaustion is an enabler of antibody breadth in HIV infection","rel_doi":"10.64898\/2026.06.05.730519","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730519","rel_abs":"A broadly neutralizing response to a human immunodeficiency virus (HIV) vaccine is a major goal of the field, yet the determinants of antibody breadth remain poorly defined. Antibody responses to HIV evolve over years of infection, developing unusual features such as high mutation rates in the subset of individuals that acquire breadth. Prior studies have established viral load as a key correlate of neutralization breadth; however, whether this reflects the failure of host immune control or virus-intrinsic features remains unclear. Using single-cell RNA sequencing, single-cell proteomics, and plasma neutralization assays in a longitudinal Kenyan cohort of women living with HIV prior to the availability of antiretroviral therapy, we identify systems-level immune correlates of antibody breadth. Broad and narrow neutralizers diverge early in infection along a viral load-driven axis with broad neutralizers exhibiting greater viral loads and CD4 T cell decline. Critically, across NK cells, CD8 T cells, and monocytes, broad neutralizers displayed greater magnitude of immune activation in early infection, followed by exhaustion in late infection, a functional decline that may dampen NK cell-mediated pruning of T follicular helper cells, creating a permissive environment for sustained germinal center activity and antibody maturation. Narrow neutralizers, by contrast, maintain functional cellular immunity but lack the antigenic pressure and permissive exhaustive state associated with breadth. These findings suggest a mechanistic framework in which viral load, cellular activation, and progressive immune exhaustion are multifactorial contributors to breadth. This has implications for immunogen design aimed at recapitulating breadth without exhaustion and cure strategies aimed at revitalizing the cellular immune response to HIV without undermining antibody responses.","rel_num_authors":11,"rel_authors":[{"author_name":"Izumi de los Rios Kobara","author_inst":"Stanford University"},{"author_name":"Uma Mangalanathan","author_inst":"Stanford University"},{"author_name":"Soneida Deline-Caballero","author_inst":"Stanford University"},{"author_name":"Mikayla Stabile","author_inst":"Stanford University"},{"author_name":"Camilo Andres Espinosa Bernal","author_inst":"Stanford University"},{"author_name":"Hannah L Itell","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Vrasha Chohan","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"R Scott McClelland","author_inst":"University of Washington"},{"author_name":"Kishor Mandaliya","author_inst":"Coast Provincial General Hospital"},{"author_name":"Julie Overbaugh","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Catherine A Blish","author_inst":"Stanford University"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Lineage-specific chromatin poising enforced by ETS-IRF composite elements determines the divergent interferon responses of plasmacytoid dendritic cells and epithelial cells","rel_doi":"10.64898\/2026.06.05.730516","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730516","rel_abs":"Plasmacytoid dendritic cells (pDCs) produce robust type I interferons (IFN-I) within hours of viral sensing, while epithelial cells at mucosal surfaces mount a delayed response dominated by type III interferons (IFN-III). Both cell types express pattern recognition receptors that activate similar downstream transcription factors, yet they produce distinct subsets of IFNs. The mechanisms underlying these differences have remained unclear. Here, using Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) in primary human pDCs and intestinal epithelial cells, we show that IFN-I and IFN-III gene loci carry opposing, constitutively established chromatin accessibility landscapes that determine cell-type-specific interferon induction. The IFN-I locus is broadly open in pDCs and constitutively closed in epithelial cells, while the IFN-III locus displays the reciprocal pattern. Motif enrichment analysis of accessible regions at the IFN-I locus in pDCs revealed unexpected and significant enrichment of ETS family binding motifs alongside IRF motifs, which determines the cell-type-specific locus accessibility. The ETS factor PU.1 and IRF8 bind IFN-I promoters, at composite ETS-IRF elements positioned at the Positive Regulatory Domain IV (PRDIV) site of IFNB1 promoter and adjacent to the TATA-proximal IRF motif of IFNA promoters. IFNL gene promoters lack ETS recognition sequences. PU.1-IRF8 composite factor binding extends across intergenic regions of the IFN-I locus, where candidate enhancer elements marked by H3K4me1, H3K27ac, and RNA Pol II occupancy were identified. We propose that this network of ETS-IRF composite-element-anchored enhancers maintains the IFN-I locus in a constitutively poised state in pDCs, licensing the rapid and robust IFN-I response that defines pDCs. In epithelial cells, the absence of PU.1 and IRF8 renders the IFN-I locus epigenetically silent, while the IFN-III locus is constitutively open. Despite this, the delayed IFN-III gene expression in epithelial cells is due to intrinsically weaker promoter activity relative to IFN-I. These findings reveal that the divergent IFN induction of pDCs and epithelial cells is determined by the chromatin architecture prior to infection. Overall, these observations show that lineage-specific ETS-IRF regulatory factors and promoter strength determine the cell-type-specific IFN activation.","rel_num_authors":22,"rel_authors":[{"author_name":"Gargi Mishra","author_inst":"University of Washington"},{"author_name":"Snehal Ozarkar","author_inst":"University of Washington"},{"author_name":"Yo Okamura","author_inst":"University of Washington"},{"author_name":"Meghan Knoll","author_inst":"University of Washington"},{"author_name":"Russell Sam","author_inst":"University of Washington"},{"author_name":"Hongchuan Li","author_inst":"Frederick National Laboratory for Cancer Research"},{"author_name":"Johannes Schwerk","author_inst":"University of Washington"},{"author_name":"Adelle P. McFarland","author_inst":"University of Washington"},{"author_name":"David Constant","author_inst":"Oregon Health & Science University"},{"author_name":"Hayley Waterman","author_inst":"Benaroya Research Institute"},{"author_name":"Manasa Acharya","author_inst":"University of Washington"},{"author_name":"Adam Lacy-Hulbert","author_inst":"Benaroya Research Institute"},{"author_name":"Jason G. Smith","author_inst":"University of Washington"},{"author_name":"Michael Parthun","author_inst":"The Ohio State University"},{"author_name":"Emily Hemann","author_inst":"The Ohio State University"},{"author_name":"Isaac M Barber-Axthelm","author_inst":"University of Washington"},{"author_name":"Weiming Li","author_inst":"University of Washington \/ Seattle Children's Research Institute"},{"author_name":"Vishal Nigam","author_inst":"University of Washington \/ Seattle Children's Research Institute"},{"author_name":"Timothy Nice","author_inst":"Oregon Health & Science University"},{"author_name":"Jessica A. Hammerman","author_inst":"Benaroya Research Institute"},{"author_name":"Stephen K Anderson","author_inst":"Frederick National Laboratory for Cancer Research \/ National Cancer Institute"},{"author_name":"Ram Savan","author_inst":"University of Washington"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Dynamic trajectory cues drive sequenced integration in approach detectors","rel_doi":"10.64898\/2026.06.05.730527","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730527","rel_abs":"Detecting approaching objects is essential for survival, and studies across animals have identified neurons and circuits selective for objects that grow in size over time, a hallmark of visual approach. However, approach as a physical process generates a rich ensemble of correlated cues governed by geometry and physics, of which size expansion is just one, and how the brain incorporates this broader cue structure to detect approach remains unknown. Here, we show that a visual stimulus without size expansion but with modulated luminance, a cue intrinsic to approach, elicits compelling percepts of approach and retreat in both humans and the fruit fly Drosophila, revealing an unsuspected, cross-species percept of approach based on luminance alone. Using targeted genetic silencing and two-photon calcium imaging in flies, we identify neurons that mediate evasive responses to both expansion-based and luminance-based approach, establishing them as general approach detectors. Guided by the geometry of approach, we show that luminance cues should precede detectable expansion signals during naturalistic approach. Consistent with this, these neurons combine luminance and expansion cues synergistically, but only when luminance changes precede expansion, matching their natural temporal order, thus performing sequenced cue integration. Together, these findings anchor a cross-species perceptual phenomenon to a defined circuit computation and reveal how neural circuits are tuned to the dynamic cue structure of natural events.","rel_num_authors":4,"rel_authors":[{"author_name":"Harsh Vashistha","author_inst":"Yale University"},{"author_name":"Natalia CB Matos","author_inst":"Yale University"},{"author_name":"Heng Wu","author_inst":"Yale University"},{"author_name":"Damon A Clark","author_inst":"Yale University"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Distinct fibroblast and perivascular senotypes define spatial niches that regulate fibrosis","rel_doi":"10.64898\/2026.06.08.730636","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.08.730636","rel_abs":"Fibrotic conditions contribute to significant global morbidity and mortality. Yet the underlying processes that orchestrate fibrosis remain poorly understood due to the cellular and spatial complexity of the stromal, immune, and vascular compartments that regulate fibrotic disease progression. Senescent cells (SnCs) have been implicated in fibrosis, but their roles are unclear, as evidence indicates that they serve both pathogenic and reparative functions. Here, we show that fibrosis-associated SnCs contain functionally divergent senotypes that are organized into distinct spatial niches. Using integrated single-cell and spatial transcriptomics analyses and hierarchical factorization in a murine fibrosis model, we identify fibroblast and perivascular SnC subpopulations that upregulate diverse programs related to extracellular matrix (ECM) production, immune signaling, and vascular remodeling. Fibroblast senotypes localize to discrete microenvironments with distinct tissue architectures, including niches associated with fibrotic signaling, immune activity, and cartilage development. Perivascular SnCs occupy interfaces between fibrotic signaling and immune-active niches and upregulate vascular and fibrotic remodeling pathways. Depletion of pericyte-lineage SnCs increases vascular maturation and fibrotic ECM deposition, providing mechanistic validation of the beneficial role of these SnCs related to vascular remodeling and fibrosis modulation. In addition, using a new web-based infrastructure to query the senotype gene signatures in public datasets, we demonstrate that these senotypes are conserved across different murine and human fibrotic conditions. These findings establish senescence as a spatially organized regulator of fibrosis and identify perivascular senescence as a link between vascular remodeling and fibrotic outcomes.","rel_num_authors":20,"rel_authors":[{"author_name":"Alexandra N Rindone","author_inst":"Translational Therapeutics & Regenerative Engineering Center, Department Chemical and Biomolecular Engineering and Biomedical Engineering, Johns Hopkins Univers"},{"author_name":"Sushma Nagaraj","author_inst":"Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD"},{"author_name":"Anna Cho","author_inst":"Translational Therapeutics & Regenerative Engineering Center, Department Chemical and Biomolecular Engineering and Biomedical Engineering, Johns Hopkins Univers"},{"author_name":"Maria Browne","author_inst":"Translational Therapeutics & Regenerative Engineering Center, Department Chemical and Biomolecular Engineering and Biomedical Engineering, Johns Hopkins Univers"},{"author_name":"Kavita Krishnan","author_inst":"Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD; Translational Therapeutics & Regenerative Engineering Center, Departmen"},{"author_name":"Ricky S Adkins","author_inst":"Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD"},{"author_name":"Daniel Lesperance","author_inst":"Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD"},{"author_name":"Joshua Orvis","author_inst":"Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD"},{"author_name":"Prarthana Sanjay Daswani","author_inst":"Translational Therapeutics & Regenerative Engineering Center, Department Chemical and Biomolecular Engineering and Biomedical Engineering, Johns Hopkins Univers"},{"author_name":"Joscelyn C Mej\u00edas","author_inst":"Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech and Emory University, Atlanta, GA"},{"author_name":"Jacob P Rose","author_inst":"Buck Institute for Research on Aging, Novato, CA"},{"author_name":"Christina D King","author_inst":"Buck Institute for Research on Aging, Novato, CA"},{"author_name":"Anna Ruta","author_inst":"Translational Therapeutics & Regenerative Engineering Center, Department Chemical and Biomolecular Engineering and Biomedical Engineering, Johns Hopkins Univers"},{"author_name":"Frank Haoning Yu","author_inst":"Translational Therapeutics & Regenerative Engineering Center, Department Chemical and Biomolecular Engineering and Biomedical Engineering, Johns Hopkins Univers"},{"author_name":"Kofi O Boahene","author_inst":"Department of Otolaryngology, Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD"},{"author_name":"Birgit Schilling","author_inst":"Buck Institute for Research on Aging, Novato, CA"},{"author_name":"Anup A Mahurkar","author_inst":"Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD"},{"author_name":"Owen R White","author_inst":"Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD"},{"author_name":"Elana J Fertig","author_inst":"Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD; Greenebaum Comprehensive Cancer Center, Department of Medicine and Depa"},{"author_name":"Jennifer H Elisseeff","author_inst":"Translational Therapeutics & Regenerative Engineering Center, Department Chemical and Biomolecular Engineering and Biomedical Engineering, Johns Hopkins Univers"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Microchimerism in the human brain, quantitative assessment and single nuclei profiling establish cell types and diversity","rel_doi":"10.64898\/2026.06.05.730225","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.05.730225","rel_abs":"Bi-directional maternal-fetal exchange during pregnancy creates a long-term microchimerism (Mc) legacy in both individuals, but its presence and cellular fate in human brain are largely unknown. We studied surgically resected epilepsy brain specimens with targetable maternal polymorphisms using polymorphism-specific quantitative PCR. Maternal Mc was prevalent, detectable in 70% of patients, and often at striking quantities spanning temporal, frontal, parietal, and hippocampal regions. Next, we employed single nucleus RNA profiling using cellector, a genetic demultiplexing tool designed to detect rare allogeneic cells. We identified Mc across major neural and glial populations. Finally, analysis of publicly available snRNA-seq datasets from neurotypical brains from gestation to late adulthood further revealed widespread Mc, persisting into advanced age, and preferentially adopting L2\/3 intratelencephalic neuronal or microglial\/macrophage-like fates. These data show that naturally acquired Mc is prevalent, diverse, and persistent in human brain, inviting reconsideration of what constitutes 'self', with broad implications for health and disease.","rel_num_authors":13,"rel_authors":[{"author_name":"Sami B Kanaan","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Ashley McDonough","author_inst":"University of Washington"},{"author_name":"Coline Gentil","author_inst":"Immunoconcept, University of Bourdeaux, France"},{"author_name":"Jeffrey Ojemann","author_inst":"Seattle Childrens Research Institute"},{"author_name":"Haynes Heaton","author_inst":"Auburn University"},{"author_name":"Reza Behboudi","author_inst":"Auburn University"},{"author_name":"Dan T A Eisenberg","author_inst":"University of Washington"},{"author_name":"Scott N Furlan","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Daniel E Geraghty","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Joe Rutledge","author_inst":"University of Washington"},{"author_name":"Francesca Urselli","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Jonathan R Weinstein","author_inst":"University of Washington"},{"author_name":"J Lee Nelson","author_inst":"Fred Hutchinson Cancer Center"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Multi-Trait Meta-QTL Analysis Reveals Genomic Hotspot Classes for Strategic Maize Improvement","rel_doi":"10.64898\/2026.06.06.730627","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.06.730627","rel_abs":"Abstract Background Decades of maize (Zea mays L.) QTL mapping have produced fragmented results across hundreds of independent studies, characterized by broad confidence intervals, population-specific effects, and a predominantly single-trait analytical scope. Comprehensive multi-trait integration remains limited, yet it could substantially improve our understanding of trait relationships for strategic breeding. We integrated 2,701 QTLs published over 30 years across five functionally distinct trait categories (grain yield and components; plant development and architecture; plant physiology and stress adaptation; grain quality and nutritional composition; and disease and pest resistance) in order to identify functionally classified genomic hotspots and prioritize candidate genes for multi-trait breeding applications. Results BioMercator V4.2 consolidated 2,518 projectable QTLs into 187 high-confidence meta-QTLs (MQTLs), achieving an average 59% reduction in confidence interval width; 128 of 187 MQTLs (68.4%) achieved dual-platform support through GWAS co-localization. Twenty-three genomic hotspots harbored 132 of 187 MQTLs (70.6%) and were classified into three functional categories: twelve multi-trait hubs that may enable simultaneous improvement of multiple traits through pleiotropic or tightly linked genes; seven single-trait clusters with pathway-specific effects, exemplified by the chromosome 9 starch biosynthesis cluster; and four major-effect loci with reported individual effects exceeding 20% PVE, including vgt1 (54% PVE) and opaque2 (34.2% PVE). Descriptive environmental classification distinguished MQTLs predominantly supported by optimal-condition QTLs (42%) from those predominantly supported by stress-condition QTLs (28%), the latter showing approximately 3.5-fold greater mean contributing-QTL phenotypic variance, directionally consistent with conditional genetic effect amplification under stress. Network-based candidate gene prioritization combined with cross-cereal ortholog analysis showed that 67% of the top candidates possess orthologs in rice, sorghum, wheat, or barley, and 53% are conserved across all four species, identifying priority targets for functional genomics investment. Conclusions This functionally classified and environmentally characterized meta-QTL framework provides breeders with a structured resource for multi-trait hotspot selection, environment-appropriate allele deployment, and functional genomics prioritization, with broader applicability as a transferable analytical template for other crop species confronting analogous challenges of fragmented QTL literature and complex multi-trait breeding objectives.","rel_num_authors":3,"rel_authors":[{"author_name":"Seshasai Parthasarathy","author_inst":"Corteva Agriscience llc"},{"author_name":"Torbert Rocheford","author_inst":"Purdue University"},{"author_name":"Klaus Koehler","author_inst":"Iowa State University"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"A Neuronal Gene Expression Program Underlying Sustained Network Activity","rel_doi":"10.64898\/2026.06.09.731204","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731204","rel_abs":"Neurons function within interconnected networks and must continuously adjust their firing properties to maintain stable network activity. Although these adjustments require long-lasting molecular changes, the neuronal gene expression programs that support sustained network activity remain largely unknown. To address this, we developed CalTRAP-seq, a method for profiling gene expression in active neurons via calcium-dependent ribosome tagging. Applying CalTRAP-seq to primary neurons exhibiting synchronous network bursting revealed a gene expression program distinct from stimulus-induced immediate early gene responses, instead enriched for regulators of neuronal excitability. This program was accompanied by widespread alternative splicing of synaptic genes. Notably, neurons participating in network activity exhibited increased nuclear speckle formation, condensates implicated in splicing regulation. Disruption of nuclear speckles impaired synchronous burst dynamics. Together, these findings identify a gene expression program associated with sustained network activity that is complementary to stimulus-responsive gene expression, providing insight into how neurons coordinate gene expression to support stable network function.","rel_num_authors":8,"rel_authors":[{"author_name":"J. Wren Kim","author_inst":"University of California, Berkeley"},{"author_name":"Rebecca Eliscu","author_inst":"University of California, Berkeley"},{"author_name":"Adeline JH Yong","author_inst":"University of California, San Francisco"},{"author_name":"Sua Lee","author_inst":"University of California, Berkeley"},{"author_name":"Yuh Nung Jan","author_inst":"University of California, San Francisco"},{"author_name":"Taeyoung Hwang","author_inst":"Johns Hopkins University"},{"author_name":"Liana F Lareau","author_inst":"University of California, Berkeley"},{"author_name":"Nicholas T Ingolia","author_inst":"University of California, Berkeley"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"A Neuronal Gene Expression Program Underlying Sustained Network Activity","rel_doi":"10.64898\/2026.06.09.731204","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731204","rel_abs":"Neurons function within interconnected networks and must continuously adjust their firing properties to maintain stable network activity. Although these adjustments require long-lasting molecular changes, the neuronal gene expression programs that support sustained network activity remain largely unknown. To address this, we developed CalTRAP-seq, a method for profiling gene expression in active neurons via calcium-dependent ribosome tagging. Applying CalTRAP-seq to primary neurons exhibiting synchronous network bursting revealed a gene expression program distinct from stimulus-induced immediate early gene responses, instead enriched for regulators of neuronal excitability. This program was accompanied by widespread alternative splicing of synaptic genes. Notably, neurons participating in network activity exhibited increased nuclear speckle formation, condensates implicated in splicing regulation. Disruption of nuclear speckles impaired synchronous burst dynamics. Together, these findings identify a gene expression program associated with sustained network activity that is complementary to stimulus-responsive gene expression, providing insight into how neurons coordinate gene expression to support stable network function.","rel_num_authors":8,"rel_authors":[{"author_name":"J. Wren Kim","author_inst":"University of California, Berkeley"},{"author_name":"Rebecca Eliscu","author_inst":"University of California, Berkeley"},{"author_name":"Adeline JH Yong","author_inst":"University of California, San Francisco"},{"author_name":"Sua Lee","author_inst":"University of California, Berkeley"},{"author_name":"Yuh Nung Jan","author_inst":"University of California, San Francisco"},{"author_name":"Taeyoung Hwang","author_inst":"Johns Hopkins University"},{"author_name":"Liana F Lareau","author_inst":"University of California, Berkeley"},{"author_name":"Nicholas T Ingolia","author_inst":"University of California, Berkeley"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"A Neuronal Gene Expression Program Underlying Sustained Network Activity","rel_doi":"10.64898\/2026.06.09.731204","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.09.731204","rel_abs":"Neurons function within interconnected networks and must continuously adjust their firing properties to maintain stable network activity. Although these adjustments require long-lasting molecular changes, the neuronal gene expression programs that support sustained network activity remain largely unknown. To address this, we developed CalTRAP-seq, a method for profiling gene expression in active neurons via calcium-dependent ribosome tagging. Applying CalTRAP-seq to primary neurons exhibiting synchronous network bursting revealed a gene expression program distinct from stimulus-induced immediate early gene responses, instead enriched for regulators of neuronal excitability. This program was accompanied by widespread alternative splicing of synaptic genes. Notably, neurons participating in network activity exhibited increased nuclear speckle formation, condensates implicated in splicing regulation. Disruption of nuclear speckles impaired synchronous burst dynamics. Together, these findings identify a gene expression program associated with sustained network activity that is complementary to stimulus-responsive gene expression, providing insight into how neurons coordinate gene expression to support stable network function.","rel_num_authors":8,"rel_authors":[{"author_name":"J. Wren Kim","author_inst":"University of California, Berkeley"},{"author_name":"Rebecca Eliscu","author_inst":"University of California, Berkeley"},{"author_name":"Adeline JH Yong","author_inst":"University of California, San Francisco"},{"author_name":"Sua Lee","author_inst":"University of California, Berkeley"},{"author_name":"Yuh Nung Jan","author_inst":"University of California, San Francisco"},{"author_name":"Taeyoung Hwang","author_inst":"Johns Hopkins University"},{"author_name":"Liana F Lareau","author_inst":"University of California, Berkeley"},{"author_name":"Nicholas T Ingolia","author_inst":"University of California, Berkeley"}],"rel_date":"2026-06-10","rel_site":"biorxiv"},{"rel_title":"Burden of Chronic Kidney Disease in China, 1990-2021: Findings from the 2021 Global Burden of Disease Study","rel_doi":"10.64898\/2026.06.06.26355056","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.06.26355056","rel_abs":"Introduction: To investigate the epidemiological characteristics of chronic kidney diseases (CKD) in China in 2021 and its trends between 1990 and 2021, in the context of significant population growth and lifestyle changes over the past 30 years that have likely influenced the CKD spectrum. Methods: Data on CKD prevalence, mortality, disability-adjusted life-years (DALY), and risk factors were obtained from the Global Burden of Disease Study 2021. The estimated decadal percentage changes were calculated to evaluate changes in trends in prevalence, mortality and disease burden. Results: In 2021, an estimated 118.4 (95% UI 109.4 to 127.5) million people in China were affected by CKD, contributing to 204 230 (95% UI 164 736 to 246 372) deaths and 6.13 (95% UI 5.18 to 7.21) million DALY. Although CKD due to diabetes mellitus and hypertension accounted for less than a quarter of all cases, they were responsible for over 90% of CKD-related deaths. Over the past three decades, CKD mortality and DALY rates have steadily increased, although the prevalence has stabilized in the last decade. Diabetes mellitus type 2 and hypertension have emerged as key drivers of CKD burden in China. Conclusions: The CKD burden in China shows a dual pattern of rising incidence and high mortality from diabetes and hypertension-related chronic kidney disease, alongside persistently high years lived with disability from glomerulonephritis and other causes.","rel_num_authors":5,"rel_authors":[{"author_name":"Mengwei Wang","author_inst":"Shanxi Medical University"},{"author_name":"Taoran Zhao","author_inst":"Shanxi Medical University"},{"author_name":"Heng Wang","author_inst":"The University of Sydney"},{"author_name":"Shulin Hou","author_inst":"Shanxi Medical University"},{"author_name":"Yongqiang Fu","author_inst":"Shanxi Bethune Hospital"}],"rel_date":"2026-06-09","rel_site":"medrxiv"},{"rel_title":"Polypore Mushroom Mycelia for Treatment of Active COVID-19 Infection: A Randomized Clinical Trial","rel_doi":"10.64898\/2026.06.01.26354267","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.01.26354267","rel_abs":"Use of fungal mycelia, which has antiviral properties, constitutes a novel strategy for addressing existing and newly emerging viral diseases. We evaluated safety and feasibility of fungal mycelia (Fomitopsis officinalis and Trametes versicolor, FoTv) for treatment of COVID-19 and assessed its antiviral effects and potential to reduce symptoms. In a randomized, double-blind, placebo-controlled, dual site (UCSD\/UCLA medical centers) clinical trial we examined non-hospitalized patients who contracted mild-to-moderate COVID-19 [&le;] 96 hours, and experienced symptom onset [&le;] nine days, before enrollment. FoTv was safe, well-tolerated, and feasible for COVID-19 treatment. Minor differences in biochemical markers were observed between groups (26 FoTv, 24 Placebo). FoTv significantly reduced the number and severity of symptoms, particularly sore throat\/cough, and in vitro SARS-CoV-2 (pseudovirus) cellular infection. In conclusion, FoTv was safe and reduced COVID-19 symptoms and cellular viral infection. Future studies should investigate therapeutic benefits of fungal mycelia for SARS-CoV-2 and other viruses. Clinicaltrials.gov registration:NCT04667247.","rel_num_authors":16,"rel_authors":[{"author_name":"Gordon Saxe MD\/PHD","author_inst":"University of California San Diego"},{"author_name":"Andrew Shubov MD","author_inst":"University of California Los Angeles"},{"author_name":"Christine N Smith PHD","author_inst":"University of California San Diego"},{"author_name":"Shahrokh Golshan PHD","author_inst":"University of California San Diego"},{"author_name":"Tatyana Shekhtman MS","author_inst":"University of California San Diego"},{"author_name":"Stephen Wilson PHD","author_inst":"Botnar Institute of Immune Engineering"},{"author_name":"Daniel Slater MD\/FAAFP","author_inst":"University of California San Diego"},{"author_name":"Zolton J Bair PHD","author_inst":"Fungi Perfecti, LLC"},{"author_name":"Chase Beathard PHD","author_inst":"Fungi Perfecti, LLC"},{"author_name":"Renee A Davis MA","author_inst":"University of Washington"},{"author_name":"Lauray MacElhern MBA","author_inst":"University of California San Diego"},{"author_name":"Lan K Kao DACM","author_inst":"University of California Los Angeles"},{"author_name":"Phoebe Senowitz MEd","author_inst":"University of California San Diego"},{"author_name":"Natalie Gosnell BS","author_inst":"Cornell University"},{"author_name":"David Buchholz PHD","author_inst":"University of California Los Angeles"},{"author_name":"Hector Aguilar-Carreno PHD","author_inst":"University of California Los Angeles"}],"rel_date":"2026-06-09","rel_site":"medrxiv"},{"rel_title":"Aperiodic and oscillatory activity of the human brain during induced emotional states","rel_doi":"10.64898\/2026.06.02.26354146","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.02.26354146","rel_abs":"Normal emotional experience depends on dynamic modulation of neural excitability across limbic and prefrontal circuits, yet the spectral markers that reflect these shifts in humans remain incompletely understood. In this study, we combined a validated video-based emotion induction paradigm with stereotactic electroencephalography (SEEG) in 31 patients with drug-resistant epilepsy to investigate how positive and negative affective states modulate oscillatory and aperiodic (asynchronous) neural activity. Using spectral parameterization to dissociate oscillatory power from the aperiodic 1\/f component, we found that emotional valence robustly altered the aperiodic slope in a regionally specific manner: negative valence flattened the slope in thalamus, posterior insula, and posterior cingulate cortex, whereas positive valence produced flattening in dorsolateral prefrontal cortex. Simultaneous oscillatory changes included increased high-frequency activity and decreased alpha\/beta power during negative affect, and reduced alpha power during positive affect, which were elucidated after adjusting for broadband aperiodic spectral shifts. These effects persisted after controlling for audiovisual stimulus or physiological features and were not evident in simultaneously recorded scalp EEG, underscoring their localization to intracranial sites. Together, these results provide the first direct evidence that active induction of emotional states modulates the aperiodic slope of human intracranial field potentials, reflecting valence-dependent shifts in local circuit excitability. The findings highlight the 1\/f slope as a sensitive neural marker of affective brain states and for mood dysregulation.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC=\"FIGDIR\/small\/26354146v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (40K):\norg.highwire.dtl.DTLVardef@3f9bb1org.highwire.dtl.DTLVardef@68ad3org.highwire.dtl.DTLVardef@18429d6org.highwire.dtl.DTLVardef@1d6c962_HPS_FORMAT_FIGEXP  M_FIG C_FIG HighlightsO_LIEmotional valence modulates broadband neural activity: Using intracranial SEEG recordings, transient emotional states were shown to alter the aperiodic 1\/f slope of human cortical and subcortical spectra in a regionally specific manner.\nC_LIO_LIValence-specific circuit engagement: Negative emotion flattened the 1\/f slope in the thalamus, posterior insula, and posterior cingulate cortex, whereas positive emotion induced similar flattening in the dorsolateral prefrontal cortex.\nC_LIO_LIDistinct oscillatory patterns accompany broadband shifts: Negative affect increased highfrequency activity and suppressed alpha\/beta oscillation in subcortical and midline regions, while positive affect primarily reduced alpha power in the prefrontal cortex.\nC_LIO_LI1\/f slope as a marker of affective state: Findings identify the aperiodic spectral slope as a sensitive index of valence-dependent shifts in local neural excitability and a potential biomarker for mood-related dysregulation.\nC_LI","rel_num_authors":9,"rel_authors":[{"author_name":"Haeorum Park","author_inst":"Washington University in St. Louis"},{"author_name":"Carl Hacker","author_inst":"Emory University School of Medicine"},{"author_name":"Hohyun Cho","author_inst":"University of Alabama at Birmingham"},{"author_name":"Tao Xie","author_inst":"Washington University in St. Louis"},{"author_name":"Alexis Simmons","author_inst":"Washington University in St. Louis"},{"author_name":"Gansheng Tan","author_inst":"Washington University In St Louis"},{"author_name":"Eric C Leuthardt","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Peter Brunner","author_inst":"Washington University In St Louis: Washington University in St Louis"},{"author_name":"Jon Willie","author_inst":"University of Texas at Austin"}],"rel_date":"2026-06-09","rel_site":"medrxiv"},{"rel_title":"Mortality in people with attention-deficit\/hyperactivity disorder (ADHD): Examining how risk is embodied in a pooling of two prospective cohort studies","rel_doi":"10.64898\/2026.06.08.26355148","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.08.26355148","rel_abs":"Background. Nascent findings suggest that people with attention-deficit\/hyperactivity disorder (ADHD) experience higher rates of mortality. To date, study samples have been insufficiently well-characterized to examine the mechanisms via which this neurodevelopmental condition elevates mortality risk. Methods. We used data from the 2007 and 2011 waves of the US National Health Interview Survey, a general population-based cohort study comprising 52097 adults (28675 women) aged 18 years or older at baseline. ADHD diagnosis and an array of demographic, socioeconomic, lifestyle, and co-morbidity (somatic and psychiatric) covariates were self-reported. Findings. At baseline, compared with unaffected individuals, participants with ADHD were more likely to be socioeconomically disadvantaged, smoke cigarettes, consume alcohol, and report symptoms of psychological distress. A median 7.75 years of mortality surveillance (range: 7.25-12.25) gave rise to 6597 deaths from all-causes. After adjustment for age, sex, ethnicity, and survey year, ADHD was associated with a markedly elevated risk of death (hazard ratio [95% confidence interval]: 1.58 [1.20-2.09]). Statistical adjustment for socioeconomic circumstances (11% attenuation), physical co-morbidities (15%), and lifestyle factors (17%) had only a modest impact on the ADHD-death gradient, with the greatest explanatory power apparent for symptoms of depression and anxiety (58%). The magnitude of the association of ADHD with mortality was commensurate to that for several well-established risk factors such as poverty (1.66 [1.55-1.78]), hypertension (1.41 [1.32-1.51]), and diabetes (1.71 [1.59-1.85]) but somewhat lower than cigarette smoking (2.51 [2.29-2.76]) after controlling for age, sex, ethnicity, and survey year. Associations between ADHD and cause-specific mortality from cardiovascular disease, cancer, and chronic respiratory disease were inconclusive. Interpretation. In the present study, the influence of ADHD on total mortality appears to be largely embodied via a series of malleable characteristics, particularly mental illness. If confirmed elsewhere, these results raise the possibility that risk factor modification via standard pharmacological and behavioral interventions could help reduce rates of premature mortality in this patient group. Funding. This paper received no direct funding. GDB is supported by the UK Medical Research Council (MR\/P023444\/1) and the US National Institute on Aging (1R56AG052519-01, 1R01AG052519-01A1).","rel_num_authors":5,"rel_authors":[{"author_name":"Haibin Li","author_inst":"Capital Medical University"},{"author_name":"Tamsin Ford","author_inst":"University of Cambridge"},{"author_name":"Varun Warrier","author_inst":"University of Cambridge"},{"author_name":"Steven Bell","author_inst":"UCL"},{"author_name":"George David Batty","author_inst":"University College London"}],"rel_date":"2026-06-09","rel_site":"medrxiv"},{"rel_title":"STDP-inspired temporal transition modeling for adaptive clinical risk prediction from electronic health records","rel_doi":"10.64898\/2026.06.04.26354919","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354919","rel_abs":"Electronic health record (EHR) prediction models often summarize longitudinal histories as static patient-level features, which may omit potentially informative event ordering. We developed a simplified spike-timing-dependent plasticity (STDP)-inspired framework that represents asynchronous EHR data as sparse, directional transition features. The approach encodes whether one clinical event precedes another within prespecified temporal windows, preserving event identity, directionality, and approximate timing while retaining feature-level interpretability. We evaluated this framework in two retrospective prediction tasks with different temporal scales: incident acute kidney injury (AKI) prediction in 17,351 MIMIC-IV ICU stays and early postoperative recurrence prediction in 713 CUMC patients with pancreatic ductal adenocarcinoma (PDAC). Models were compared with static burden features (demographics, comorbidities, raw lab measurements) and in addition with STDP transitional feature sets using patient-level cross-validation and rolling prediction horizons. In AKI, a calibrated STDP ensemble model showed higher discrimination than static burden alone at the 24-hour decision snapshot for AKI by 72 hours, with AUROC 0.838 versus 0.800, and at 48 hours for near-term AKI prediction, with AUROC 0.868 versus 0.827. In PDAC, STDP transition features modestly improved Day -30 preoperative recurrence prediction, with AUROC 0.611 versus 0.587 and AUPRC 0.323 versus 0.318 for static burden and showed similar performance at Day 0 (7 days before recorded surgery date), with AUROC 0.681 and AUPRC 0.363. Decision-curve and feature analyses suggested that selected temporal transitions were clinically interpretable across renal, inflammatory, hepatobiliary, hematologic, glycemic, and nutritional trajectories. These findings suggest that STDP-inspired transition features may provide a practical, interpretable way to incorporate temporal ordering into EHR-based risk prediction across both acute and longitudinal settings","rel_num_authors":8,"rel_authors":[{"author_name":"Liyuan Gong","author_inst":"Columbia University"},{"author_name":"Nitish Aswani","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Peter Shahinian","author_inst":"Columbia University"},{"author_name":"Jeong Yun Yang","author_inst":"Columbia University"},{"author_name":"Despina Kontos","author_inst":"Columbia University"},{"author_name":"Gulam Manji","author_inst":"Columbia University"},{"author_name":"Stella Kang","author_inst":"Columbia University"},{"author_name":"Chin Hur","author_inst":"Columbia University"}],"rel_date":"2026-06-09","rel_site":"medrxiv"},{"rel_title":"Neonatal Brain Network Integration Trajectories Predict Neurodevelopment in Congenital Heart","rel_doi":"10.64898\/2026.06.06.26355074","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.06.26355074","rel_abs":"Impact statementO_LIIn infants with critical congenital heart disease, perioperative growth in whole-brain network integration was associated with cognitive, language, and motor outcomes in early childhood.\nC_LIO_LIWhite matter injury was associated with slower growth in network integration, whereas cardiac physiology subtype was not associated with network development.\nC_LIO_LIThis study extends prior work by showing that a longitudinal measure of neonatal whole-brain network development, rather than a single imaging timepoint, predicts neurodevelopment across multiple domains.\nC_LIO_LIThese findings identify early network development as a potential biomarker of neurodevelopmental risk and resilience, and support future risk-stratification and intervention studies in this population.\nC_LI\n\nBackgroundInfants with critical congenital heart disease (CHD) are at high risk for abnormal brain development and later neurodevelopmental impairment. We hypothesized that the trajectory of perioperative whole-brain network development would predict neurodevelopmental outcomes in early childhood.\n\nMethodsThis prospective longitudinal cohort of neonates with critical CHD (n = 97) underwent preoperative and\/or postoperative brain MRI with diffusion imaging. Whole-brain network measures were derived from structural connectomes. Neurodevelopment was assessed between 1 and 4 years using the Bayley Scales of Infant and Toddler Development.\n\nResultsWhite matter injury was associated with slower perioperative growth in global efficiency (p = 0.013), a measure of network integration, whereas cardiac physiology was not associated with network development. Infants with greater perioperative increases in global efficiency had higher cognitive (p = 0.001), language (p < 0.001), and motor (p = 0.008) scores. For each 1-standard deviation increase in the trajectory of global efficiency, cognitive scores increased by 8.2 points (95% CI, 3.64-12.78), independent of brain injury and socioeconomic factors.\n\nConclusionIn infants with critical CHD, longitudinal whole-brain network development was associated with neurodevelopment across multiple domains. Early network development may represent a candidate biomarker of neurodevelopmental risk and resilience in this population.","rel_num_authors":7,"rel_authors":[{"author_name":"Lauren Harasymiw","author_inst":"University of California, San Francisco"},{"author_name":"Amy Kuang","author_inst":"University of California, San Francisco"},{"author_name":"Duan Xu","author_inst":"University of California, San Francisco"},{"author_name":"Aaron Scheffler","author_inst":"University of California, San Francisco"},{"author_name":"Elizabeth George","author_inst":"University of California, San Francisco"},{"author_name":"Shabnam Peyvandi","author_inst":"University of California, San Francisco"},{"author_name":"Patrick McQuillen","author_inst":"University of California, San Francisco"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Associations between initial treatments for acute low back pain and opioid use disorder and overdose risk in Medicaid patients","rel_doi":"10.64898\/2026.06.05.26355003","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26355003","rel_abs":"IntroductionAcute low back pain is a leading cause of disability worldwide. Clinical guidelines recommend non-pharmacological therapies as first-line treatment and advise caution with opioid prescribing. However pharmacological therapies, including opioids and gabapentinoids, remain commonly used. The comparative risks of subsequent opioid use disorder (OUD) and overdose diagnosis associated with initial treatment modality in large, real-world populations is not well characterized. We estimated the incidence of new-onset OUD and overdose diagnosis among opioid-naive, Medicaid-insured adults with newly diagnosed acute low back pain and estimated the association between initial treatment modalities and subsequent OUD and overdose diagnosis risk.\n\nMethodsWe conducted a retrospective cohort study using Medicaid T-MSIS Analytic files from 25 states (2016-2019). We identified opioid-naive adults with a new diagnosis of acute low back pain who initiated pharmacologic or non-pharmacologic treatment within 1 month of diagnosis. The primary outcome was incident OUD and overdose diagnosis (based on diagnosis codes in claims) during follow-up. Associations between initial treatment modality and OUD and overdose diagnosis risk were estimated using a non-parametric, doubly robust estimator to adjust for measured confounding.\n\nResultsThe cohort included 525,002 opioid-naive adults initiating treatment for low back pain. The cumulative incidence of OUD and overdose diagnosis was 1.5% and 2.4% at 7 and 13 months, respectively. Compared to non-use, use of gabapentinoids during the first month of treatment was associated with the highest relative risk (increasing risk by 130.1%, 95% confidence interval (CI): 117.8%, 142.3%), the second-highest relative risk was estimated for higher-dose opioids, defined as > 50 daily Morphine Milligram Equivalents (MME) (118.1%, 95% CI: 99.2%, 137.0%). Lower-dose, short-duration opioids ([&le;] 50 MME, [&le;] 7 days) were also associated with elevated risk, though substantially smaller in magnitude (20.8%, 95% CI: 13.8%, 27.9%). In contrast, non-pharmacologic, non-interventional therapies were associated with reduced OUD and overdose diagnosis risk, with physical therapy demonstrating the largest relative reduction of 34.0% (95% CI: -40.9%, -27.1%).\n\nDiscussionIn opioid-naive Medicaid patients with acute low back pain, initial non-pharmacologic treatment was associated with reduced OUD and overdose diagnosis risk. Gabapentinoids and opioids were each associated with increased risk; for opioids, the degree of risk increased with higher doses and durations. These results support guideline recommendations favoring non-pharmacologic treatment as first-line therapy and indicate the importance of cautious prescribing when pharmacologic treatment is considered.","rel_num_authors":5,"rel_authors":[{"author_name":"Lisa V Doan","author_inst":"New York University Grossman School of Medicine"},{"author_name":"Anton M Hung","author_inst":"Columbia University"},{"author_name":"Mark Olfson","author_inst":"Columbia University"},{"author_name":"Nicholas T Williams","author_inst":"University of California at Berkeley"},{"author_name":"Kara E Rudolph","author_inst":"Columbia University"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Multi-ancestry analysis of POLG variants in Parkinson's disease","rel_doi":"10.64898\/2026.06.07.26354811","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.07.26354811","rel_abs":"IntroductionVariants in the polymerase gamma (POLG) gene are associated with a wide range of mitochondrial disorders. Emerging evidence suggests a potential link between POLG variants and Parkinsons disease (PD); yet, results remain inconclusive.\n\nObjectivesTo investigate the genetic spectrum and prevalence of POLG variants in PD across diverse ancestries.\n\nMethodsWe leveraged multi-ancestry genetic data from the Global Parkinsons Genetics Program (GP2), including genotyping data from 98,589 and short-read sequencing data from 36,022 individuals. We performed a POLG rare variant screen, case-control association, and gene-level burden analyses.\n\nResultsFive PD cases carried potentially biallelic rare pathogenic\/likely pathogenic POLG variants. Additionally, 228 individuals (<1%; 161 PD cases, 28 individuals with other neurological disorders, and 39 controls) carried 34 distinct rare pathogenic\/likely pathogenic heterozygous variants, with no significant frequency differences between cases and controls, except for the p.Ala467Thr variant in the European population. The co-inherited pathogenic variants p.Thr251Ile and p.Pro587Leu were present in <1% of both cases and controls, with no significant group differences. Burden and variant-level association analyses showed no association between rare POLG variant burden or common POLG variant enrichment and PD.\n\nConclusionsPOLG variants are overall rare in PD. The identification of rare pathogenic variants among PD cases suggests that POLG-related mitochondrial dysfunction may contribute to PD in isolated instances, particularly under recessive inheritance. Our findings support a role for POLG variants in select cases and underscore the need for larger-scale sequencing and functional studies.","rel_num_authors":14,"rel_authors":[{"author_name":"Yi Wen Tay","author_inst":"University of Malaya, Malaysia"},{"author_name":"Inas Elsayed","author_inst":"University of Gezira, Wad Medani, Sudan"},{"author_name":"Dennis Yeow","author_inst":"Neuroscience Research Australia, Randwick, New South Wales, Australia"},{"author_name":"Mikayla James","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Pin-Jui Kung","author_inst":"National Taiwan University Hospital, Taipei, Taiwan"},{"author_name":"Laurel Screven","author_inst":"GP2, Bethesda, USA"},{"author_name":"Allison A. Dilliott","author_inst":"Parkinsons Foundation, NewYork, NY 10018, USA"},{"author_name":"Roy N. Alcalay","author_inst":"Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel"},{"author_name":"Zih-Hua Fang","author_inst":"DataTecnica LLC, Washington, DC 20037, USA"},{"author_name":"Ai Huey Tan","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"- Global Parkinson's Genetics Program (GP2)","author_inst":"-"},{"author_name":"Carolyn M Sue","author_inst":"Neuroscience Research Australia, Randwick, New South Wales, Australia"},{"author_name":"Lara M Lange","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Maria Teresa Perinan","author_inst":"Queen Mary University of London, London, United Kingdom"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Multi-ancestry analysis of POLG variants in Parkinson's disease","rel_doi":"10.64898\/2026.06.07.26354811","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.07.26354811","rel_abs":"IntroductionVariants in the polymerase gamma (POLG) gene are associated with a wide range of mitochondrial disorders. Emerging evidence suggests a potential link between POLG variants and Parkinsons disease (PD); yet, results remain inconclusive.\n\nObjectivesTo investigate the genetic spectrum and prevalence of POLG variants in PD across diverse ancestries.\n\nMethodsWe leveraged multi-ancestry genetic data from the Global Parkinsons Genetics Program (GP2), including genotyping data from 98,589 and short-read sequencing data from 36,022 individuals. We performed a POLG rare variant screen, case-control association, and gene-level burden analyses.\n\nResultsFive PD cases carried potentially biallelic rare pathogenic\/likely pathogenic POLG variants. Additionally, 228 individuals (<1%; 161 PD cases, 28 individuals with other neurological disorders, and 39 controls) carried 34 distinct rare pathogenic\/likely pathogenic heterozygous variants, with no significant frequency differences between cases and controls, except for the p.Ala467Thr variant in the European population. The co-inherited pathogenic variants p.Thr251Ile and p.Pro587Leu were present in <1% of both cases and controls, with no significant group differences. Burden and variant-level association analyses showed no association between rare POLG variant burden or common POLG variant enrichment and PD.\n\nConclusionsPOLG variants are overall rare in PD. The identification of rare pathogenic variants among PD cases suggests that POLG-related mitochondrial dysfunction may contribute to PD in isolated instances, particularly under recessive inheritance. Our findings support a role for POLG variants in select cases and underscore the need for larger-scale sequencing and functional studies.","rel_num_authors":14,"rel_authors":[{"author_name":"Yi Wen Tay","author_inst":"University of Malaya, Malaysia"},{"author_name":"Inas Elsayed","author_inst":"University of Gezira, Wad Medani, Sudan"},{"author_name":"Dennis Yeow","author_inst":"Neuroscience Research Australia, Randwick, New South Wales, Australia"},{"author_name":"Mikayla James","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Pin-Jui Kung","author_inst":"National Taiwan University Hospital, Taipei, Taiwan"},{"author_name":"Laurel Screven","author_inst":"GP2, Bethesda, USA"},{"author_name":"Allison A. Dilliott","author_inst":"Parkinsons Foundation, NewYork, NY 10018, USA"},{"author_name":"Roy N. Alcalay","author_inst":"Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel"},{"author_name":"Zih-Hua Fang","author_inst":"DataTecnica LLC, Washington, DC 20037, USA"},{"author_name":"Ai Huey Tan","author_inst":"University of Malaya, Kuala Lumpur, Malaysia"},{"author_name":"- Global Parkinson's Genetics Program (GP2)","author_inst":"-"},{"author_name":"Carolyn M Sue","author_inst":"Neuroscience Research Australia, Randwick, New South Wales, Australia"},{"author_name":"Lara M Lange","author_inst":"National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Maria Teresa Perinan","author_inst":"Queen Mary University of London, London, United Kingdom"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Stochastic Morphodynamics of the Human Aorta Across the Lifespan","rel_doi":"10.64898\/2026.06.05.26355015","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26355015","rel_abs":"Biological systems evolve as continuous dynamical processes, but at organ-scale and across human lifespans they are rarely observed longitudinally---population data typically exist instead as sparse, cross-sectional snapshots. Inferring lifespan dynamics from such data requires methods distinct from those used at cellular and tissue scales where dense observations are accessible. We address this problem in the thoracic aorta, where surgical decisions currently rest on static, age- and sex-agnostic diameter thresholds that reduce three-dimensional morphology to a single scalar. Treating normal aortic morphology as a stochastic dynamical system, we pose a continuous-time drift-diffusion process in a two-coordinate state space of normalized surface area (A) and normalized fluctuation in integrated Gaussian curvature [Formula], and fit closed-form solutions of the Fokker-Planck equation by maximum likelihood to a sex-balanced, age-uniform cohort spanning infancy to age 99. Inter-individual variability is treated as a fitted diffusion parameter rather than as residual scatter, which is distinct from prior normative studies that report variability as scatter around a regression line. The framework identifies two growth regimes for aortic size (childhood expansion followed by persistent adult growth, with adult males growing approximately 70% faster than adult females) and a single dynamical regime for aortic shape, with heteroscedastic variability accumulating at a rate comparable to the mean drift over the lifespan. Applied to independent cohorts of acute and chronic thoracic aortic dissections, the multivariate model identifies over 95% as statistical outliers via Mahalanobis distance, consistently outperforming either coordinate alone. The same probabilistic envelope that describes normal aging thus defines a baseline against which disease can be detected, supporting a shift toward dynamic, age- and sex-aware assessment of thoracic aortic pathology.","rel_num_authors":6,"rel_authors":[{"author_name":"Kelly C. Twohig","author_inst":"University of Chicago"},{"author_name":"Michael Mansour","author_inst":"University of Chicago"},{"author_name":"Joseph A. Pugar","author_inst":"University of Chicago"},{"author_name":"Karen Yuan","author_inst":"Northwestern University"},{"author_name":"Luka Pocivavsek","author_inst":"University of Chicago"},{"author_name":"Andrei A. Klishin","author_inst":"University of Hawai'i at Manoa"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Parental educational attainment polygenic scores contribute to phenotypic heterogeneity in offspring with autism","rel_doi":"10.64898\/2026.06.03.26354779","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.03.26354779","rel_abs":"Educational attainment-related polygenic scores have been implicated in autism spectrum disorder (ASD), but how parental polygenic scores shape offspring phenotypes remains unclear. Using genotyping and exome-sequencing data from 142,357 individuals (55,252 ASD cases) in a large ASD cohort, we dissected the direct and indirect genetic effects of educational attainment-related polygenic scores on ASD phenotypes. Trio-model analyses showed that parental polygenic scores for educational attainment (PGSEA) were associated with milder core ASD symptoms, including social deficits and repetitive behaviors, predominantly through indirect genetic effects, whereas their associations with comorbidities were driven predominantly by direct genetic effects. PGSEA was also significantly negatively associated with rare variant burden and prenatal factors, although these factors contributed largely independently to most phenotypes. Adjustment for full-scale intelligence quotient (FSIQ) and socioeconomic status (SES) partially attenuated the indirect effects of PGSEA on offspring phenotypes. Finally, higher parental PGSEA was associated with later age at diagnosis in offspring, partly through its protective effects on ASD phenotypes. These findings indicate that indirect genetic effects of parental PGSEA contribute substantially to phenotypic variation in ASD and highlight family-mediated pathways as an important component of ASD heterogeneity.","rel_num_authors":7,"rel_authors":[{"author_name":"Shilin Gao","author_inst":"Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing 100191, China."},{"author_name":"Yang Sui","author_inst":"Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA."},{"author_name":"Panhui Tian","author_inst":"Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing 100191, China."},{"author_name":"Xiaoli Rao","author_inst":"Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing 100191, China."},{"author_name":"Chenghao Yan","author_inst":"Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing 100191, China."},{"author_name":"Yue Xu","author_inst":"Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing 100191, China."},{"author_name":"Tianyun Wang","author_inst":"Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing 100191, China."}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Integrated cardiometabolic and nutritional risk profiling identifies pregnancy loss as a marker of systemic metabolic vulnerability","rel_doi":"10.64898\/2026.06.04.26354910","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354910","rel_abs":"BackgroundPregnancy loss has important implications for womens health. Although maternal age is a well-established risk factor, the contribution of routinely measured cardiometabolic and behavioral markers at population-scale remains incompletely characterized.\n\nObjectiveTo examine associations between cardiometabolic, nutritional, and behavioral risk markers and pregnancy loss among U.S. women of reproductive age.\n\nMethodsWe conducted a cross-sectional analysis of 4,842 U.S. women aged 20-44 years with [&ge;]1 pregnancy using the National Health and Nutrition Examination Survey data (2013-2023). Pregnancy loss was defined as [&ge;]1 prior miscarriages. Exposures included body mass index, smoking exposure (cotinine), lipid biomarkers, vitamin D and folate, and a composite cardiometabolic-nutritional risk score. Survey-weighted logistic regression estimated adjusted odds ratios (aORs) and 95% confidence intervals, with bootstrap resampling for predictor robustness.\n\nResultsThe weighted prevalence of pregnancy loss was 23%. Higher odds of pregnancy loss were associated with increasing age (aOR per year=1.02; 95% CI: 1.00-1.04), Non-Hispanic Black race (aOR=1.32; 95% CI: 1.00-1.74), overweight (aOR=1.56; 95% CI: 1.16-2.11), obesity (aOR=2.06; 95% CI: 1.39-3.05), and smoking (aOR=1.58; 95% CI: 1.19-2.10).\n\nAdverse lipid profiles, particularly elevated triglycerides (aOR=1.83; 95% CI: 1.16-2.90) and high low-density lipoprotein (aOR=2.97; 95% CI: 1.45-6.61), were independently associated with pregnancy loss. Vitamin D\/folate were not stable predictors. Higher composite cardiometabolic-nutritional risk scores were observed among women with pregnancy loss (P=0.026).\n\nConclusionPregnancy loss clustered with adverse cardiometabolic and behavioral risk markers in a nationally representative population. These findings highlight pregnancy loss as a marker of broader metabolic vulnerability supporting the need for longitudinal studies and cardiometabolic profiling to inform preconception care and risk stratification.","rel_num_authors":3,"rel_authors":[{"author_name":"Tanya Agarwal","author_inst":"Rutgers University: Rutgers The State University of New Jersey"},{"author_name":"Janaki  Ramya Namburu","author_inst":"Rutgers University: Rutgers The State University of New Jersey"},{"author_name":"Priyadarshini Kachroo","author_inst":"Rutgers The State University of New Jersey"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"A mechanistic model for genetic regulation of postmenopausal bone loss","rel_doi":"10.64898\/2026.06.04.26354968","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354968","rel_abs":"Bone remodeling is a tightly regulated physiological process that maintains bone health through coordinated action of bone-resorbing osteoclasts and bone-forming osteoblasts. Disruption of this balance, such as the one induced by estrogen decline after menopause, results in bone loss and osteoporosis. Genetic factors play an important role in determining bone mineral density (BMD) loss over time. However, translating genetic associations into individualized risk prediction remains challenging due to small effect size of individuals variants and non-linear interactions within the bone remodeling unit. Here, we present a bone cell population dynamics model that includes major regulatory pathways, such as the RANK\/RANKL\/OPG axis, Wnt signaling, and hormonal regulation by estrogen, parathyroid hormone, and TGF-{beta}. We calibrate the model on clinical data from healthy postmenopausal women, and women with reduced BMD undergoing anti-osteoporotic therapy. The calibrated model captures healthy BMD decline in postmenopausal women and therapeutic response to anti-osteoporotic medications. We mechanistically incorporate the effect of 22 variants across 8 genes involved in bone remodeling and simulate BMD trajectories in 1,000 virtual subjects differing by ancestry and genetic makeup. The median predicted 5-year BMD loss was 3.57% (95% prediction interval: 1.31-5.24), consistent with the values reported in the literature. The virtual individuals with African ancestry were predicted to experience the highest average 5-year BMD loss. The strongest genetic risk factors for bone loss were predicted to be CYP19A1 rs727479 and OPG rs3102735, while LRP5 rs11228240 emerged as a protective factor that could partially counteract the detrimental effects of other variants. Several epistatic effects were observed in the genetic interaction analysis. Mechanistically, our model suggested that estrogen exerts its effect on bone remodeling primarily by modulating osteoclast apoptosis. Overall, this framework demonstrates a proof-of-concept for integration of genetic risk factors into mechanistic models of disease and can be extended to other conditions with polygenic inheritance.","rel_num_authors":4,"rel_authors":[{"author_name":"Ilia Rattsev","author_inst":"Johns Hopkins University"},{"author_name":"Feilim Mac Gabhann","author_inst":"Johns Hopkins University"},{"author_name":"Daniel Hertz","author_inst":"University of Michigan"},{"author_name":"Casey Overby Taylor","author_inst":"Johns Hopkins University"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Characterizing artificial intelligence (AI) psychosis in a large academic medical setting: evidence of the new clinical phenomenon and the vulnerability of those in early phases of psychosis","rel_doi":"10.64898\/2026.06.04.26354939","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354939","rel_abs":"Background: Concerns about \"AI psychosis\" have swirled in the media since ChatGPT's release, but few systematic analyses exist. We therefore conducted an electronic health record (EHR) analysis to identify the frequency, clinical characteristics, and quality of AI interactions in patients experiencing psychosis treated in a medical center. Methods: AI keywords (e.g., ChatGPT, AI) were used to search Vanderbilt University Medical Center's EHR from 12\/1\/2022-4\/1\/2026. Records were discarded if they were not AI-related or if the primary diagnosis did not include psychosis. Three raters read notes to determine if a patient was experiencing AI psychosis and classified the interactions using 4 a-priori categories (Catalyst, Amplifier, Co-Author, Object) formulated to explain how AI-related negative outcomes emerge. Findings: 73 patients met our criteria. 28 patients were rated as experiencing AI psychosis, 17 had neutral interactions, and 28 expressed delusional content related to AI without documented evidence of conversational AI use. ChatGPT was the matching keyword for 53.6% patients experiencing AI psychosis. The majority of AI psychosis cases were documented after ChatGPT's \"4o\" model was released in May 2024. Notably, the AI Psychosis group had significantly more patients experiencing a first psychotic episode (60.7%) compared to the other two groups. Amplifier was the most common (64.3%) qualitative rating in the AI Psychosis group. Interpretation: \"AI psychosis\" is an infrequent but real phenomenon observed in clinical practice. Most affected patients were experiencing their first psychotic episode and presented with AI psychosis following the release of the more sycophantic GPT-4o. Among the affected patients, AI most often exacerbated an existing condition by reinforcing distorted ideas.","rel_num_authors":7,"rel_authors":[{"author_name":"Zachary Bergson","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Sarah G Vassall","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Adam Wright","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Allison B McCoy","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Katherine M Schafer","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Margaret C Achee","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Julia M Sheffield","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Clonal Hematopoiesis of Indeterminate Potential Refines Cardiovascular Risk Stratification in Cardiovascular-Kidney-Metabolic Syndrome Stages 0-3","rel_doi":"10.64898\/2026.06.04.26354963","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354963","rel_abs":"BackgroundChronic low-grade inflammation drives cardiovascular-kidney-metabolic (CKM) syndrome. Clonal hematopoiesis of indeterminate potential (CHIP), an age-related driver of systemic inflammation, is linked to several cardiometabolic disorders. However, whether CHIP modifies CKM progression and contributes to heterogeneity in cardiovascular disease (CVD) risk within the CKM framework remains uninvestigated.\n\nMethodsThis cohort study included 307,025 UK Biobank participants at CKM stages 0-3 free of baseline CVD. CHIP status was identified via whole-exome sequencing (WES). The association between CHIP and baseline CKM severity was examined, along with the independent and joint effects of CHIP and CKM stages on incident CVD risk. The joint effects of CHIP and polygenic risk scores (PRS) were further assessed, and the incremental predictive value of incorporating CHIP into the AHA PREVENT equations was evaluated.\n\nResultsCHIP carriers were more likely to present with advanced CKM stages [OR 1.14 (1.09-1.20), P < 0.001] and exhibited higher incident CVD risk during follow-up [HR 1.13 (1.08-1.18), P < 0.001]. Significant joint effects between CHIP and CKM stages were observed, with the highest risk among CHIP carriers at CKM stage 3 [HR 1.63 (1.50-1.78), P < 0.001]. Large or multiple CHIP mutations conferred greater hazards, with distinct gene-specific effects observed. Moreover, CHIP and high genetic risk also jointly amplified CVD susceptibility. Most importantly, incorporating CHIP into AHA PREVENT significantly improved risk discrimination.\n\nConclusionsCHIP is a significant risk factor associated with more advanced CKM stages and amplifies incident CVD risk. Integrating CHIP into existing prevention strategies may refine CVD risk stratification.\n\nGraphic Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=159 HEIGHT=200 SRC=\"FIGDIR\/small\/26354963v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (54K):\norg.highwire.dtl.DTLVardef@a28708org.highwire.dtl.DTLVardef@4f3623org.highwire.dtl.DTLVardef@6b4c9corg.highwire.dtl.DTLVardef@72a664_HPS_FORMAT_FIGEXP  M_FIG C_FIG Clinical PerspectiveO_ST_ABSWhat Is New?C_ST_ABSO_LIThis study provides large-scale evidence that clonal hematopoiesis of indeterminate potential (CHIP) is associated with more advanced cardiovascular-kidney-metabolic (CKM) stages and jointly amplifies future cardiovascular disease (CVD) risk within the CKM staging framework.\nC_LIO_LISomatic CHIP and germline polygenic susceptibility were jointly associated with CKM severity and CVD risk, with the greatest risk observed among individuals with both high polygenic risk and CHIP.\nC_LI\n\nWhat Are the Clinical Implications?O_LICHIP significantly refines CVD risk stratification across AHA PREVENT risk categories and provides incremental predictive value. Incorporating CHIP into CKM-based prevention strategies may help identify individuals with excess residual cardiovascular risk before the development of clinical CVD.\nC_LI","rel_num_authors":7,"rel_authors":[{"author_name":"Jian Lu","author_inst":"China-Japan Friendship Hospital"},{"author_name":"Shuaigang Sun","author_inst":"China-Japan Friendship Hospital"},{"author_name":"Zekai Deng","author_inst":"Xuanwu Hospital Capital Medical University"},{"author_name":"Shunwei Wang","author_inst":"Capital Medical University"},{"author_name":"Chenping Wei","author_inst":"Capital Medical University"},{"author_name":"Shimin Jiang","author_inst":"China-Japan Friendship Hospital"},{"author_name":"Wenge Li","author_inst":"China-Japan Friendship Hospital"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"A Decade of the Center for Disease Control and Prevention's FluSight Influenza Forecasting","rel_doi":"10.64898\/2026.06.05.26354941","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.05.26354941","rel_abs":"Since the U.S. 2013\/14 influenza season, the CDCs FluSight Challenge has provided a platform for evaluating influenza forecasting models and fostering collaboration across institutions. The Challenge aims to improve the science and enhance the utility of infectious disease forecasts for public health decision making. We analyzed ten years of submitted forecasts (2014\/15-2019\/20 (influenza-like illness seasons) and 2021\/22-2024\/25 (hospital admissions seasons)) across a range of model types, including statistical, mechanistic, machine learning, and hybrid models. Influenza-like illness (ILI) forecasts were evaluated using the exponentiated logarithmic score (skill metric) while hospital admissions forecasts were evaluated using the log transformed relative Weighted Interval Score. Corresponding potential performance differences were assessed using Wilcoxon rank-sum tests, and associations with team participation history were evaluated using Spearmans rank correlation. Model performance varied by season, and no single model type consistently outperformed others. In ILI seasons, statistical models generally performed better than mechanistic and machine learning models, though consistent differences were not observed in more recent hospital admissions seasons. Ensemble forecasts showed better overall performance across seasons, and the CDCs FluSight ensemble ranked among the top-performing forecasts every year. We also found a positive correlation between forecast accuracy and the number of years a team participated in the Challenge, with statistically significant associations in four seasons. These findings highlight the benefits of ensemble approaches and sustained engagement in improving forecasting performance, while also underscoring the continued value of forecast evaluation before and following the COVID-19 pandemic. Insights from the FluSight Challenge can guide future infectious disease forecasting efforts and support more effective public health preparedness.","rel_num_authors":6,"rel_authors":[{"author_name":"Annabella G Hines","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Sarabeth M. Mathis","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Michael A. Johansson","author_inst":"Northeastern University"},{"author_name":"Matthew Biggerstaff","author_inst":"Centers for Disease Control & Prevention"},{"author_name":"Carrie Reed","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Rebecca Borchering","author_inst":"Centers for Disease Control and Prevention"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Albuminuria Changes as a surrogate endpoint in Apolipoprotein L1 Mediated Kidney Disease in Vanderbilt BioVU and the Million Veteran Program","rel_doi":"10.64898\/2026.06.04.26354945","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354945","rel_abs":"ImportanceRecently, proteinuria has been accepted as a surrogate end point for clinical trials in focal segmental glomerulosclerosis (FSGS) ang IgA nephropathy. However, proteinuria has not been evaluated in Apolipoprotein L1 (APOL1)-mediated kidney disease (AMKD).\n\nMethodsReal world data (RWD) analysis of 128 patients of African ancestry with APOL1 high risk genotypes, without diabetes, enrolled in the Million Veteran Program (MVP; n=109) or the biorepository at Vanderbilt University (BioVU; n=19), who had urine albumin-creatinine ratio (UACR) >= 420 mg\/g (PCR[~]0.9 g\/g) with a concurrent GFR value. The main predictor was change in the log-UACR at 12 months. The primary outcome was annual GFR slope over 24 months. Secondary outcomes included a kidney composite of a sustained 30% GFR decline, end stage kidney disease (ESKD) or death and ESKD as a single outcome. Linear regression and Cox proportional hazards models were used to assess the effect of changes in UACR and the outcomes.\n\nResultsIn the pooled analysis the mean age was 56.8 (SD 15.5) y, 116 were male (90.6%) and three patients had diagnosis of FSGS at baseline. Mean baseline eGFR was 46.8 (SD 16.1) mL\/min\/1.73m2, mean baseline UACR was 1240.8 (1107.7) mg\/g, mean eGFR slope was - 4.67[-6.00, -3.33] mL\/min\/1.73m2\/year and the geometric mean percentage changes in the UACR at 12 months were -57.5% [-65.0%, -48.4%]. For every 1 unit of log (UACR) increment at 12 months, the annual eGFR slope decreased by -1.80 [-2.56, -1.03] mL\/min\/1.73m2 in the pooled analysis. For every 1 unit of log (UACR) increment at 12 months, the Cox regression showed a 61% increase in the risk of a kidney composite (p=0.002) and a 98% increase in the risk of ESKD (p<0.001). It was estimated that a 50% reduction of UACR at 12 months was associated with a 28% reduction in the kidney composite endpoint (adjusted hazard ratio [aHR]=0.72; 95% confidence interval [CI]:0.59-0.88; p=0.002), and a 38% reduction in the risk of ESKD (aHR=0.62; 95% CI:0.49-0.80; p<0.001).\n\nConclusions and relevanceChanges in UACR at 12 months significantly modify the rate of decline of GFR over 24 months and clinically meaningful endpoints, supporting the use of UACR changes as surrogate endpoint in AMKD.","rel_num_authors":13,"rel_authors":[{"author_name":"Fatih Mamak","author_inst":"Vanderbilt Health"},{"author_name":"Zhihong Yu","author_inst":"Vanderbilt University"},{"author_name":"Jefferson L Triozzi","author_inst":"Nashville VA (TVHS) and Vanderbilt University"},{"author_name":"Robert Corty","author_inst":"Nashville VA (TVHS) and Vanderbilt University"},{"author_name":"Lee Wheless","author_inst":"Nashville VA (TVHS) and Vanderbilt University"},{"author_name":"Guanchao Wang","author_inst":"Nashville VA (TVHS) and Vanderbilt University"},{"author_name":"Ayush Giri","author_inst":"Vanderbilt University"},{"author_name":"Hua Chang Chen","author_inst":"Nashville VA (TVHS) and Vanderbilt University"},{"author_name":"Otis Wilson Wilson","author_inst":"Nashville VA (TVHS) and Vanderbilt University"},{"author_name":"Alexander G Bick","author_inst":"Vanderbilt University"},{"author_name":"J. Michael Gaziano","author_inst":"VA Boston Healthcare and Harvard Medical School"},{"author_name":"Ran Tao","author_inst":"Nashville VA (TVHS) and Vanderbilt University"},{"author_name":"Adriana M Hung","author_inst":"Nashville VA (TVHS) and Vanderbilt University"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Using colorectal cancer screening evidence to stratify for personal risk among those with a family history of colorectal cancer: a 42-year cohort study","rel_doi":"10.64898\/2026.06.04.26354891","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354891","rel_abs":"ObjectiveTo determine if it is possible to assess individual patient risk of the development of colorectal cancer (CRC) in people in high-risk groups due to their family history.\n\nDesign\/MethodRetrospective observational study of prospectively collected data from consecutive patients referred for a colonoscopy. 2,478 consecutive patients were referred to a single colorectal surgical practice in Sydney, Australia between 1977 and 2018 for a colonoscopy because of a family history of CRC. Of these, 1,963 have been followed for more than 10 years and are the subject of this paper. Histopathological findings categorised as normal (N), non-advanced adenoma (NAA) or advanced neoplasia (AN) with AN proven to be the precursor to CRC.\n\nInterventionColonoscopic screening on the basis of contemporary practice to 2006 and subsequently according to Australian National Health and Medical Research Council guidelines.\n\nResultsParticipants with normal or low-risk findings in the first decade remain at lower risk of CRC for 30 years from the commencement of screening.\n\nConclusionIt is possible to stratify individual patients in a high relative risk cohort into those with high or low personal risk of CRC based on colonoscopic findings in the first 10 years of surveillance. Those with no AN in the first ten years have a lower 30-year risk of developing AN than the general community. This offers the possibility of structuring surveillance programs around individual risk rather than group risk, lessening the need for multiple surveillance colonoscopies in the majority of such patients and improving the cost effectiveness of CRC screening at the population level.","rel_num_authors":8,"rel_authors":[{"author_name":"Denis  W King","author_inst":"University of New South Wales - Kensington Campus: University of New South Wales"},{"author_name":"Pamela  E King","author_inst":"University of New South Wales - Kensington Campus: University of New South Wales"},{"author_name":"Megan  W Blanchard","author_inst":"University of New South Wales - Kensington Campus: University of New South Wales"},{"author_name":"Nickson  W Ning","author_inst":"University of New South Wales - Kensington Campus: University of New South Wales"},{"author_name":"Sebastian  K King","author_inst":"The Royal Children's Hospital Melbourne"},{"author_name":"Michael  C Grimm","author_inst":"University of New South Wales - Kensington Campus: University of New South Wales"},{"author_name":"Tam Ha","author_inst":"University of Wollongong"},{"author_name":"Kathy Eagar","author_inst":"University of New South Wales - Kensington Campus: University of New South Wales"}],"rel_date":"2026-06-08","rel_site":"medrxiv"},{"rel_title":"Elevated HbA1c is associated with advanced brain age in severe obesity","rel_doi":"10.64898\/2026.06.04.26354935","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354935","rel_abs":"IntroductionBrain-predicted age, estimated from structural MRI data, is a machine learning biomarker of biological brain aging. Greater brain age gap (BAG) indicates advanced brain aging and is associated with cognitive decline and mortality. Cardiometabolic risk factors, including elevated blood glucose, body mass index (BMI), blood pressure, and cholesterol, increase risk of cognitive impairment and dementia in aging. Their relationship with BAG in severe obesity remains poorly characterized despite increased prevalence of cardiometabolic risk factors among this population.\n\nMethodsT1-weighted MRI data from 97 adults (BMI 35-73) were used to calculate BAG using ENIGMA and Pyment brain age models. Associations between BAG and HbA1c, BMI, hypertension, and hyperlipidemia were examined using multiple linear regression and MM-estimation robust regression, adjusting for age, sex, and race. Post hoc analyses stratified models by clinical HbA1c cutoffs (normoglycemic, prediabetic, diabetic).\n\nResultsHigher HbA1c was associated with greater BAGENIGMA (B = 1.58, p = .014) and BAGPyment (B = 0.93, p = .013) in linear regression models. In robust models, HbA1c remained significantly associated with BAGENIGMA (B = 1.70, p = .002) but not BAGPyment (B = 0.71, p = .13). BMI, hypertension, and hyperlipidemia were not associated with BAG in either linear or robust models. HbA1c was associated with greater BAGENIGMA (B = 2.15, p = .01) and BAGPyment (B =1.21, p = .04) in those at or above prediabetic levels and with BAGENIGMA (B = 2.49, p = .047) in those with diabetes.\n\nConclusionsElevated HbA1c is associated with accelerated brain aging in individuals with severe obesity. BAG was not associated with BMI, hypertension, and hyperlipidemia, which may reflect the restricted BMI range inherent to the sample with severe obesity.\n\nHIGHLIGHTSO_LIElevated HbA1c was associated with advanced brain aging in individuals with severe obesity.\nC_LIO_LIHbA1c-BAG associations were seen primarily in the context of clinically elevated levels (i.e. prediabetes and diabetes).\nC_LIO_LIThe study did not provide evidence to support that BMI, hypertension, and hyperlipidemia are associated with BAG in individuals with severe obesity\nC_LIO_LIENIGMA and Pyment models showed limited agreement in BAG estimates in a sample of individuals with severe obesity.\nC_LI","rel_num_authors":10,"rel_authors":[{"author_name":"Joshua Juhasz","author_inst":"University of Florida"},{"author_name":"Brittany DeFeis","author_inst":"University of Florida"},{"author_name":"Mark K Britton","author_inst":"Yale University"},{"author_name":"Hannah Hoogerwoerd","author_inst":"University of Florida"},{"author_name":"Kate Worwag","author_inst":"University of Florida"},{"author_name":"Keyanni J Johnson","author_inst":"University of Florida"},{"author_name":"Angel Uribe","author_inst":"San Diego State University"},{"author_name":"John B Williamson","author_inst":"University of Florida"},{"author_name":"Eric C Porges","author_inst":"University of Florida"},{"author_name":"Ronald A Cohen","author_inst":"University of Florida"}],"rel_date":"2026-06-06","rel_site":"medrxiv"},{"rel_title":"Serological thresholds of risk reduction for infant group B streptococcus disease","rel_doi":"10.64898\/2026.05.29.26353453","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.29.26353453","rel_abs":"Vaccines to prevent infant group B streptococcus (GBS) disease are advancing, with licensure likely based on safety and immunologic endpoints rather than clinical efficacy data. This approach requires robust, generalisable serological thresholds of risk reduction (SToRRs). We combined data from six case-control studies in Europe and Africa to define SToRRs for early-onset (EOD) and late-onset (LOD) GBS disease. Across diverse epidemiological and healthcare settings, anti-capsular polysaccharide IgG concentrations were consistently higher in infants who remained disease free than in those who developed disease. Higher antibody concentrations were required to reduce the risk of EOD than LOD, and higher concentrations were required for serotype Ia than for serotype III. This study provides a quantitative framework to support correlates-based evaluation and potential licensure of maternal GBS vaccines.","rel_num_authors":26,"rel_authors":[{"author_name":"Liberty Cantrell","author_inst":"Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK & NIHR Oxford Biomedical Research Centre"},{"author_name":"Kostas Karampatsas","author_inst":"Centre for Neonatal and Paediatric Infection & Vaccine Institute, City St George's, University of London, London, UK"},{"author_name":"Nick Andrews","author_inst":"UK Health Security Agency, London, UK"},{"author_name":"Simon Beach","author_inst":"Centre for Neonatal and Paediatric Infection & Vaccine Institute, City St George's, University of London, London, UK"},{"author_name":"Emily Bentley","author_inst":"Centre for Neonatal and Paediatric Infection & Vaccine Institute, City St George's, University of London, London, UK"},{"author_name":"Alberto Berardi","author_inst":"Neonatal Intensive Care Unit, Azienda Ospedaliero-Universitaria Policlinico, Policlinico,Modena, Italy"},{"author_name":"Merijn W Bijlsma","author_inst":"Department of Paediatrics, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands."},{"author_name":"Cemal Cagil Kocana","author_inst":"Centre for Neonatal and Paediatric Infection & Vaccine Institute, City St George's, University of London, London, UK"},{"author_name":"Olwenn Daniel","author_inst":"Centre for Neonatal and Paediatric Infection & Vaccine Institute, City St George's, University of London, London, UK"},{"author_name":"Neil French","author_inst":"University of Liverpool, Liverpool, UK; Malawi Liverpool Wellcome Research Programme, Blantyre, Malawi"},{"author_name":"Tom Hall","author_inst":"Centre for Neonatal and Paediatric Infection & Vaccine Institute, City St George's, University of London, London, UK"},{"author_name":"Alane Izu","author_inst":"South African Medical Research Council Wits Vaccines and Infectious Diseases Analytics Research Unit, Faculty of Health Sciences, University of the Witwatersran"},{"author_name":"Asma Khalil","author_inst":"City St George's, University of London, London, UK"},{"author_name":"Gaurav Kwatra","author_inst":"South African Medical Research Council Wits Vaccines and Infectious Diseases Analytics Research Unit, Faculty of Health Sciences, University of the Witwatersran"},{"author_name":"Mary Kyohere","author_inst":"Centre for Neonatal and Paediatric Infection & Vaccine Institute, City St George's, University of London, London, UK; Makerere University-Johns Hopkins Universi"},{"author_name":"Shabir A Madhi","author_inst":"University of the Witwatersrand"},{"author_name":"Robert Mboizi","author_inst":"Makerere University-Johns Hopkins University Research Collaboration, Kampala, Uganda"},{"author_name":"Francesca Miselli","author_inst":"Neonatal Intensive Care Unit, Azienda Ospedaliero-Universitaria Policlinico, Policlinico,Modena, Italy"},{"author_name":"Maryke Nielsen","author_inst":"London School of Hygiene and Tropical Medicine, London, UK"},{"author_name":"Natasha Thorn","author_inst":"Centre for Neonatal and Paediatric Infection & Vaccine Institute, City St George's, University of London, London, UK"},{"author_name":"Diederik van de Beek","author_inst":"Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands"},{"author_name":"Kate Walker","author_inst":"Centre for Perinatal Research (CePR), University of Nottingham, Nottingham, UK"},{"author_name":"Paul T Heath","author_inst":"Centre for Neonatal and Paediatric Infection & Vaccine Institute, City St George's, University of London, London, UK"},{"author_name":"Kirsty Le Doare","author_inst":"Centre for Neonatal and Paediatric Infection & Vaccine Institute, City St George's, University of London, London, UK; Makerere University-Johns Hopkins Universi"},{"author_name":"Merryn Voysey","author_inst":"Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK & NIHR Oxford Biomedical Research Centre"},{"author_name":"- PREPARE WP3 Study Group","author_inst":""}],"rel_date":"2026-06-06","rel_site":"medrxiv"},{"rel_title":"Functionally Focused Evaluation: A Novel Comparative Protocol for Wearable Electroencephalography Headsets","rel_doi":"10.64898\/2026.06.03.26354802","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.03.26354802","rel_abs":"With the emergence of electroencephalography (EEG) as a tool in the cognitive domain, new demands are being placed on the technology to keep up with functional applications - especially in the context of at-home neural monitoring. New use cases have fostered development of wearable EEG (wEEG) devices: portable, low-cost headsets used for EEG monitoring. This evolution of technology and application has not been accompanied by development in technology evaluation, often relying on function-agnostic markers to assess devices for efficacy in this new space. With current methods limited in scope, this study designed, tested and evaluated a novel functionally-focused comparative protocol for wEEG devices. Eight participants undertook a protocol for the evaluation of four established wEEG devices, assessing cognitive resolution and general usability. Compared to a well-established traditional analysis method (eyes open\/eyes closed protocol), the novel design proposed here enabled the same analysis of headset resolution, while also providing additional context into user preferences and opening downstream possibilities for specific cognitive insights. Future research could enable the development of this protocol into a standardised method to ensure the performance of wEEG technology can satisfy emerging clinical needs.","rel_num_authors":5,"rel_authors":[{"author_name":"Anand Bhuyan","author_inst":"University of Sydney"},{"author_name":"Michael Wong","author_inst":"The University of Sydney"},{"author_name":"Alistair McEwan","author_inst":"The University of Sydney"},{"author_name":"Cameron Higgins","author_inst":"The University of Oxford"},{"author_name":"Navin Cooray","author_inst":"CSIRO"}],"rel_date":"2026-06-05","rel_site":"medrxiv"},{"rel_title":"Education\/training for health workers\/students on inclusive and gender-affirmative care for trans and gender-diverse people: a systematic review","rel_doi":"10.64898\/2026.06.04.26354880","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.04.26354880","rel_abs":"IntroductionTrans and gender-diverse (TGD) individuals often face stigma and discrimination in healthcare, hindering access to gender-affirming care. Training healthcare workers on TGD health aims to foster inclusive and affirming care practices. This review aimed to evaluate the effectiveness of TGD health training programs for healthcare workers.\n\nMethodsThis systematic review followed the PRISMA guidelines and was registered with PROSPERO (CRD42023443288). We searched 13 databases for studies up to March 2024, with no language\/geographic restrictions. Ten reviewers screened studies in pairs, resolving discrepancies via discussion or third-reviewer input. We included randomized\/non-randomized comparative and before-after studies for quantitative analysis (mean difference [MD] or standardized mean difference [SMD] with 95% CIs), and qualitative\/mixed-methods studies for thematic synthesis. Evidence certainty was assessed using GRADE (quantitative) and GRADE-CERQual (qualitative). Outcomes included knowledge, attitudes, skills, discrimination, competence, comfort, TGD quality of life, and stakeholder preferences.\n\nResultsFrom 20,188 records, 85 studies were included. Training appears to have improved healthcare workers knowledge (SMD=1.08, 95% CI 0.78-1.39), attitudes (SMD=0.22, 95% CI 0.05-0.39), skills (SMD=0.96, 95% CI 0.56-1.37), competence (SMD=0.55, 95% CI 0.29-0.81), and comfort (SMD=0.69, 95% CI 0.17-1.21). Qualitative analysis of 130 findings identified 18 categories and four key themes on intervention design and impact.\n\nConclusionsTGD training programs may enhance health workers knowledge, attitudes, skills, competence, and comfort. Well-structured, interactive, and inclusive programs showed promise, but evidence certainty was low with limited follow-up. Further high-quality research is needed to confirm these findings.","rel_num_authors":13,"rel_authors":[{"author_name":"Jun Xia","author_inst":"Nottingham Ningbo GRADE Centre, School of Economics, University of Nottingham Ningbo, China"},{"author_name":"Zheng Zhu","author_inst":"Fudan University"},{"author_name":"Guowen Zhang","author_inst":"The University of Hong Kong"},{"author_name":"Quan Shen","author_inst":"The Third Xiangya Hospital of Central South University, Changsha, China"},{"author_name":"Esther Su","author_inst":"The University of Sydney, Australia"},{"author_name":"Jan Schoones","author_inst":"Leiden University Medical Center, Leiden, The Netherlands"},{"author_name":"Jon Arcelus","author_inst":"School of Medicine, University of Nottingham, UK"},{"author_name":"Tiantian Hu","author_inst":"Fudan University School of Nursing, Fudan University, Shanghai, China"},{"author_name":"Mengqi Xu","author_inst":"The Nethersole School of Nursing, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China"},{"author_name":"Xiaoxin Zhang","author_inst":"School of Nursing, Chinese Academy of Medical Sciences & Peking Union Medical College,Beijing,China"},{"author_name":"Zhan Zhao","author_inst":"Tianjin Suyuan Evience based Technology Co.,Ltd., Tianjin, China"},{"author_name":"Zheng Ye","author_inst":"Systematic Review Solution (SRS) Ltd, UK"},{"author_name":"Xiaomei Yao","author_inst":"Department of Health Research Methods, Evidence and Impact; Department of Oncology, McMaster University, Canada"}],"rel_date":"2026-06-05","rel_site":"medrxiv"}]}