{"gname":"Albert Einstein College of Medicine","grp_id":"4","rels":[{"rel_title":"Vasculopathy of the small vessels is common in lacunar stroke - a 7T MRI study","rel_doi":"10.64898\/2026.07.09.26357711","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357711","rel_abs":"Abstract: Background: Lacunar stroke is a common and disabling cerebrovascular disease. Small-vessel vasculopathy is thought to be the most common underlying cause, but this has only been identified on histopathology. 7T MRI allows small vessels to be seen in vivo. This study aimed to investigate rates of small vessel vasculopathy in lacunar stroke using 7T MRI. Methods: Patients with lacunar stroke at an Australian tertiary stroke centre were prospectively screened and recruited to the study. Patients underwent 7T MRI with T1, T2, time-of-flight (TOF), diffusion-weighted imaging (DWI) and susceptibility-weighted imaging (SWI) sequences. Images were interpreted by two blinded neuroradiologists. Results: The likely symptomatic perforator could be identified in 16\/19 (84%) of cases. Amongst cases where the symptomatic perforator was observed, 14\/16 (88%) of the symptomatic perforator vessels had focal stenosis consistent with steno-occlusive vasculopathy. There were 3\/19 (16%) of cases with associated large artery vasculopathy. There were 7\/16 (44%) cases where an occluded perforator was seen. The majority of patients had at least one vascular risk factor (15\/19, 79%) and there were no cases where non-atherosclerotic vasculopathy was suspected. Conclusions: Lacunar stroke is commonly associated with small vessel vasculopathy, likely due to atherosclerosis, which can be identified in vivo with 7T MRI time-of-flight imaging.","rel_num_authors":14,"rel_authors":[{"author_name":"Davor Pavlin-Premrl","author_inst":"Austin Hospital"},{"author_name":"Bradford Moffat","author_inst":"Melbourne Brain Centre - Royal Melbourne Hospital Campus"},{"author_name":"Rebecca Glarin","author_inst":"Melbourne Brain Centre - Royal Melbourne Hospital Campus"},{"author_name":"Vincent S Thijs","author_inst":"Florey"},{"author_name":"Nawaf Yassi","author_inst":"University of Melbourne"},{"author_name":"Mark W Parsons","author_inst":"University of New South Wales South Western Sydney Clinical School, Ingham Institute for Applied Medical Research"},{"author_name":"Peter J Mitchell","author_inst":"The Royal Melbourne Hospital"},{"author_name":"Julian Maingard","author_inst":"Austin Health \/ University of Melbourne"},{"author_name":"Hamed Asadi","author_inst":"Monash Medical Centre\/Austin Hospital\/Deakin University"},{"author_name":"Ashu Jhamb","author_inst":"St. Vincent's Hospital"},{"author_name":"Mark Schembri","author_inst":"Beaumont Hospital"},{"author_name":"Ali Khabaza","author_inst":"Austin Hospital"},{"author_name":"Anna H. Balabanski","author_inst":"The University of Melbourne"},{"author_name":"Bruce C V Campbell","author_inst":"The University of Melbourne Faculty of Medicine Dentistry and Health Sciences"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"MAGIC Composite Score Predicts Outcomes of Second-Line Therapy for Acute GVHD","rel_doi":"10.64898\/2026.07.09.26357664","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357664","rel_abs":"Approximately 30% of patients with acute graft-versus-host disease (GVHD) develop steroid-refractory disease and have very poor outcomes. Ruxolitinib has become the standard of care for steroid-refractory acute GVHD, but it is unclear which patients derive benefit. The MAGIC Composite Score (MCS), an algorithm that combines clinical symptoms and biomarkers, has been validated to predict outcomes at the start of primary GVHD treatment. Here, we evaluated its performance at the initiation of second-line treatment in 278 patients. MCS stratified patients into three risk groups (MCS1-3), with the majority (88%) classified as intermediate or high risk. Increasing MCS score was associated with progressively higher 1-year non-relapse mortality (NRM) rates (16%, 41%, and 73%; p<0.001), lower 1-year survival (77%, 56%, and 24%; p<0.001), and lower complete response (CR) rates at day 28 (47%, 38%, and 20%, respectively; p<0.01). The area under the receiver operating characteristic curve (AUROC) for 1-year NRM was significantly higher with MCS compared to clinical symptoms alone (0.70 vs. 0.63; p=0.023). Among patients treated with ruxolitinib, higher MCS similarly predicted higher NRM and lower survival and CR rates. Patients classified as MCS2\/3 had poor outcomes despite ruxolitinib, underscoring the need for novel therapies in this patient population. In conclusion the MCS is an accurate predictor of outcomes for patients who require second-line treatment and may be of use as an eligibility criterion for future clinical trials in this high-risk population.","rel_num_authors":35,"rel_authors":[{"author_name":"Tara Sebastian","author_inst":"Division of Hematology\/Medical Oncology, The Tisch Cancer Center, Icahn School of Medicine at Mount Sinai"},{"author_name":"Daniela Weber","author_inst":"Department of Hematology and Oncology, Internal Medicine III, University of Regensburg"},{"author_name":"Aaron M. Etra","author_inst":"Division of Hematology\/Medical Oncology, The Tisch Cancer Center, Icahn School of Medicine at Mount Sinai"},{"author_name":"Ingrid Vasova","author_inst":"Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universitat Erlangen-Nurnberg and University Hospital Erlangen"},{"author_name":"Francis Ayuk","author_inst":"Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf"},{"author_name":"Hannah K. Choe","author_inst":"Division of Hematology, Blood and Marrow Transplantation Program, The Ohio State University Comprehensive Cancer Center"},{"author_name":"Zachariah DeFilipp","author_inst":"Hematopoietic Cell Transplant and Cellular Therapy Program, Massachusetts General Hospital"},{"author_name":"Francesco Quagliarella","author_inst":"Department of Pediatric Hematology\/Oncology and of Cell and Gene Therapy, Bambino Gesu Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico"},{"author_name":"Karni Bedirian","author_inst":"Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai"},{"author_name":"Marcio Augusto Diniz","author_inst":"Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai"},{"author_name":"Paibel Aguayo-Hiraldo","author_inst":"Division of Bone Marrow Transplantation, Children's Hospital Los Angeles, University of Southern California"},{"author_name":"Peter Bader","author_inst":"Division of Stem Cell Transplantation and Immunology, Department of Pediatrics, Goethe University Frankfurt"},{"author_name":"Janna Baez","author_inst":"Division of Hematology\/Medical Oncology, The Tisch Cancer Center, Icahn School of Medicine at Mount Sinai"},{"author_name":"Chantiya Chanswangphuwana","author_inst":"Division of Hematology and Center of Excellence in Translational Hematology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospi"},{"author_name":"Gilbert Eng","author_inst":"Division of Hematology\/Medical Oncology, The Tisch Cancer Center, Icahn School of Medicine at Mount Sinai"},{"author_name":"Thomas Francke","author_inst":"Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School"},{"author_name":"Elizabeth O. Hexner","author_inst":"Department of Medicine and Abramson Cancer Center, Perelman School of Medicine"},{"author_name":"Nikolaos Katsivelos","author_inst":"Division of Hematology\/Medical Oncology, The Tisch Cancer Center, Icahn School of Medicine at Mount Sinai"},{"author_name":"Carrie L. Kitko","author_inst":"Pediatric Hematology\/Oncology Division, Vanderbilt University Medical Center"},{"author_name":"Sabrina Kraus","author_inst":"Department of Internal Medicine II, University Hospital of Wurzburg"},{"author_name":"Ioannis E. Louloudis","author_inst":"Division of Hematology\/Medical Oncology, The Tisch Cancer Center, Icahn School of Medicine at Mount Sinai"},{"author_name":"George Morales","author_inst":"Division of Hematology\/Medical Oncology, The Tisch Cancer Center, Icahn School of Medicine at Mount Sinai"},{"author_name":"Ryotaro Nakamura","author_inst":"Department of Hematology\/Hematopoietic Cell Transplantation, City of Hope"},{"author_name":"Timothy S. Olson","author_inst":"Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia"},{"author_name":"Muna Qayed","author_inst":"Department of Pediatrics, Emory University School of Medicine"},{"author_name":"Pavan Reddy","author_inst":"Dan Duncan Cancer Center, Baylor College of Medicine"},{"author_name":"Ran Reshef","author_inst":"Division of Hematology\/Oncology and Columbia Center for Translational Immunology"},{"author_name":"Tal Schechter","author_inst":"Division of Hematology\/Oncology\/Blood and Marrow Transplant, The Hospital for Sick Children, University of Toronto"},{"author_name":"Tingyu Wang","author_inst":"Division of Hematology\/Medical Oncology, The Tisch Cancer Center, Icahn School of Medicine at Mount Sinai"},{"author_name":"Matthias Wolf","author_inst":"Department of Medicine I, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg"},{"author_name":"Rachel Young","author_inst":"Division of Hematology\/Medical Oncology, The Tisch Cancer Center, Icahn School of Medicine at Mount Sinai"},{"author_name":"Robert Zeiser","author_inst":"Department of Medicine I, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg"},{"author_name":"William J. Hogan","author_inst":"Division of Hematology, Mayo Clinic"},{"author_name":"John E. Levine","author_inst":"Division of Hematology\/Medical Oncology, The Tisch Cancer Center, Icahn School of Medicine at Mount Sinai"},{"author_name":"James L.M. Ferrara","author_inst":"Division of Hematology\/Medical Oncology, The Tisch Cancer Center, Icahn School of Medicine at Mount Sinai"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"From Bias Detection to Distributional Calibration: Negative Controls for Shared Systematic Error in Real-world Evidence Pipelines","rel_doi":"10.64898\/2026.07.08.26357550","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357550","rel_abs":"Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been linked to heterogeneous, potentially pleiotropic effects across organ systems, motivating outcome-wide comparative risk profiling in real-world data. A central challenge in such analyses is \\emph{residual bias} that remains after adjustment for observed confounders, which can distort effect estimates and mis-calibrate uncertainty. We present distributional diagnosis and calibration (DC), which uses panels of negative control outcomes (NCOs) to diagnose residual bias and calibrate uncertainty. DC evaluates null behavior via $p$-value uniformity and empirical coverage across NCOs, and uses the empirical distribution of NCO effect estimates to calibrate confidence intervals for prespecified primary outcomes. DC is modular: it can wrap around commonly used causal inference methods and operates directly on summary statistics, supporting collaborative research under data-sharing constraints. Using electronic health records from a large U.S. clinical research network (152.7 million patients), we compared GLP-1RAs with sodium--glucose cotransporter~2 inhibitors across 15 prespecified outcomes spanning cardiovascular, mental health, and genitourinary domains using four causal estimators. Across outcomes and methods, DC diagnostics revealed substantial and method-dependent residual systematic error. DC calibration attenuated systematic error signals observed in negative controls and yielded more stable, better-calibrated estimates for clinical outcomes, supporting DC as a practical strategy to strengthen the credibility of real-world comparative effectiveness research.","rel_num_authors":19,"rel_authors":[{"author_name":"Huiyuan Wang","author_inst":"University of Pennsylvania"},{"author_name":"Bingyu Zhang","author_inst":"University of Pennsylvania"},{"author_name":"Yuqing Lei","author_inst":"University of Pennsylvania"},{"author_name":"Yiwen Lu","author_inst":"University of Pennsylvania"},{"author_name":"Dazheng Zhang","author_inst":"University of Pennsylvania"},{"author_name":"Xinyao Jian","author_inst":"University of Pennsylvania"},{"author_name":"Yuru Zhu","author_inst":"University of Pennsylvania"},{"author_name":"Wenjie Hu","author_inst":"University of Pennsylvania"},{"author_name":"Haitao Chu","author_inst":"Pfizer"},{"author_name":"Yong Chen","author_inst":"Pfizer"},{"author_name":"Marc A Suchard","author_inst":"University of California, Los Angeles"},{"author_name":"Patrick B Ryan","author_inst":"Janssen Research and Development"},{"author_name":"George Hripcsak","author_inst":"Columbia University Irving Medical Center"},{"author_name":"David A Asch","author_inst":"University of Pennsylvania"},{"author_name":"Yun Lu","author_inst":"Food and Drug Administration"},{"author_name":"Yu Bin","author_inst":"University of California Berkeley"},{"author_name":"Martijn J Schuemie","author_inst":"University of California, Los Angeles"},{"author_name":"Yumou Qiu","author_inst":"Peking University"},{"author_name":"Yong Chen","author_inst":"University of Pennsylvania"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"From Bias Detection to Distributional Calibration: Negative Controls for Shared Systematic Error in Real-world Evidence Pipelines","rel_doi":"10.64898\/2026.07.08.26357550","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357550","rel_abs":"Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been linked to heterogeneous, potentially pleiotropic effects across organ systems, motivating outcome-wide comparative risk profiling in real-world data. A central challenge in such analyses is \\emph{residual bias} that remains after adjustment for observed confounders, which can distort effect estimates and mis-calibrate uncertainty. We present distributional diagnosis and calibration (DC), which uses panels of negative control outcomes (NCOs) to diagnose residual bias and calibrate uncertainty. DC evaluates null behavior via $p$-value uniformity and empirical coverage across NCOs, and uses the empirical distribution of NCO effect estimates to calibrate confidence intervals for prespecified primary outcomes. DC is modular: it can wrap around commonly used causal inference methods and operates directly on summary statistics, supporting collaborative research under data-sharing constraints. Using electronic health records from a large U.S. clinical research network (152.7 million patients), we compared GLP-1RAs with sodium--glucose cotransporter~2 inhibitors across 15 prespecified outcomes spanning cardiovascular, mental health, and genitourinary domains using four causal estimators. Across outcomes and methods, DC diagnostics revealed substantial and method-dependent residual systematic error. DC calibration attenuated systematic error signals observed in negative controls and yielded more stable, better-calibrated estimates for clinical outcomes, supporting DC as a practical strategy to strengthen the credibility of real-world comparative effectiveness research.","rel_num_authors":19,"rel_authors":[{"author_name":"Huiyuan Wang","author_inst":"University of Pennsylvania"},{"author_name":"Bingyu Zhang","author_inst":"University of Pennsylvania"},{"author_name":"Yuqing Lei","author_inst":"University of Pennsylvania"},{"author_name":"Yiwen Lu","author_inst":"University of Pennsylvania"},{"author_name":"Dazheng Zhang","author_inst":"University of Pennsylvania"},{"author_name":"Xinyao Jian","author_inst":"University of Pennsylvania"},{"author_name":"Yuru Zhu","author_inst":"University of Pennsylvania"},{"author_name":"Wenjie Hu","author_inst":"University of Pennsylvania"},{"author_name":"Haitao Chu","author_inst":"Pfizer"},{"author_name":"Yong Chen","author_inst":"Pfizer"},{"author_name":"Marc A Suchard","author_inst":"University of California, Los Angeles"},{"author_name":"Patrick B Ryan","author_inst":"Janssen Research and Development"},{"author_name":"George Hripcsak","author_inst":"Columbia University Irving Medical Center"},{"author_name":"David A Asch","author_inst":"University of Pennsylvania"},{"author_name":"Yun Lu","author_inst":"Food and Drug Administration"},{"author_name":"Yu Bin","author_inst":"University of California Berkeley"},{"author_name":"Martijn J Schuemie","author_inst":"University of California, Los Angeles"},{"author_name":"Yumou Qiu","author_inst":"Peking University"},{"author_name":"Yong Chen","author_inst":"University of Pennsylvania"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"From Bias Detection to Distributional Calibration: Negative Controls for Shared Systematic Error in Real-world Evidence Pipelines","rel_doi":"10.64898\/2026.07.08.26357550","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357550","rel_abs":"Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been linked to heterogeneous, potentially pleiotropic effects across organ systems, motivating outcome-wide comparative risk profiling in real-world data. A central challenge in such analyses is \\emph{residual bias} that remains after adjustment for observed confounders, which can distort effect estimates and mis-calibrate uncertainty. We present distributional diagnosis and calibration (DC), which uses panels of negative control outcomes (NCOs) to diagnose residual bias and calibrate uncertainty. DC evaluates null behavior via $p$-value uniformity and empirical coverage across NCOs, and uses the empirical distribution of NCO effect estimates to calibrate confidence intervals for prespecified primary outcomes. DC is modular: it can wrap around commonly used causal inference methods and operates directly on summary statistics, supporting collaborative research under data-sharing constraints. Using electronic health records from a large U.S. clinical research network (152.7 million patients), we compared GLP-1RAs with sodium--glucose cotransporter~2 inhibitors across 15 prespecified outcomes spanning cardiovascular, mental health, and genitourinary domains using four causal estimators. Across outcomes and methods, DC diagnostics revealed substantial and method-dependent residual systematic error. DC calibration attenuated systematic error signals observed in negative controls and yielded more stable, better-calibrated estimates for clinical outcomes, supporting DC as a practical strategy to strengthen the credibility of real-world comparative effectiveness research.","rel_num_authors":19,"rel_authors":[{"author_name":"Huiyuan Wang","author_inst":"University of Pennsylvania"},{"author_name":"Bingyu Zhang","author_inst":"University of Pennsylvania"},{"author_name":"Yuqing Lei","author_inst":"University of Pennsylvania"},{"author_name":"Yiwen Lu","author_inst":"University of Pennsylvania"},{"author_name":"Dazheng Zhang","author_inst":"University of Pennsylvania"},{"author_name":"Xinyao Jian","author_inst":"University of Pennsylvania"},{"author_name":"Yuru Zhu","author_inst":"University of Pennsylvania"},{"author_name":"Wenjie Hu","author_inst":"University of Pennsylvania"},{"author_name":"Haitao Chu","author_inst":"Pfizer"},{"author_name":"Yong Chen","author_inst":"Pfizer"},{"author_name":"Marc A Suchard","author_inst":"University of California, Los Angeles"},{"author_name":"Patrick B Ryan","author_inst":"Janssen Research and Development"},{"author_name":"George Hripcsak","author_inst":"Columbia University Irving Medical Center"},{"author_name":"David A Asch","author_inst":"University of Pennsylvania"},{"author_name":"Yun Lu","author_inst":"Food and Drug Administration"},{"author_name":"Yu Bin","author_inst":"University of California Berkeley"},{"author_name":"Martijn J Schuemie","author_inst":"University of California, Los Angeles"},{"author_name":"Yumou Qiu","author_inst":"Peking University"},{"author_name":"Yong Chen","author_inst":"University of Pennsylvania"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Chlamydia trachomatis and Neisseria gonorrhoeae in newborns with and without neonatal conjunctivitis: cross-sectional study in Papua New Guinea","rel_doi":"10.64898\/2026.07.09.26357364","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357364","rel_abs":"In newborns seen a median of 11 days after birth, 97\/1699 (5.7%) had conjunctivitis, including 13\/97 (13.4%) with Chlamydia trachomatis or Neisseria gonorrhoeae detected. Among all babies, we estimated that 6.6% (95% confidence interval 3.8-9.9%) would have C. trachomatis or N. gonorrhoeae detected, of which 87.0% (74.8-93.8%) would be asymptomatic.","rel_num_authors":15,"rel_authors":[{"author_name":"Nicola Low","author_inst":"University of Bern: Universitat Bern"},{"author_name":"Alice Mengi","author_inst":"Papua New Guinea Institute of Medical Research"},{"author_name":"Lisa M Vallely","author_inst":"The Kirby Institute"},{"author_name":"Claire Descombes","author_inst":"University of Bern: Universitaet Bern"},{"author_name":"Lydia Braunack-Mayer","author_inst":"University of Bern: Universitaet Bern"},{"author_name":"Mitchell Starr","author_inst":"St. Vincent's Hospital, Sydney"},{"author_name":"Philip H Cunningham","author_inst":"St Vincent's Hospital, Sydney"},{"author_name":"Handan Wand","author_inst":"The Kirby Institute"},{"author_name":"Ben D Spycher","author_inst":"University of Bern: Universitaet Bern"},{"author_name":"Steven G Badman","author_inst":"The Kirby Institute"},{"author_name":"Moses Laman","author_inst":"Papua New Guinea Institute of Medical Research"},{"author_name":"William S Pomat","author_inst":"Papua New Guinea Institute of Medical Research"},{"author_name":"Andrew J Vallely","author_inst":"The Kirby Institute"},{"author_name":"Michaela A Riddell","author_inst":"The Kirby Institute"},{"author_name":"WANTAIM Trial Investigators Group","author_inst":"Papua New Guinea Institute of Medical Research"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Enteric pathogen burden and co-infection patterns across age and a rural-urban gradient: findings from the ECoMiD birth cohort, Northern Ecuador","rel_doi":"10.64898\/2026.07.08.26357325","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357325","rel_abs":"Enteric pathogen infections are a major global health challenge, influenced by a variety of host and environmental factors, and their clinical presentation and treatment can be complicated by the presence of co-infections. The prevalence of enteric infections and co-infections tend to vary between rural and urban contexts, likely driven by underlying environmental, geographic, and demographic characteristics. To improve understanding of urbanicity and age on enteric pathogen prevalence and on co-infection risk, we measured 22 enteric pathogens in fecal samples collected from children aged 6, 12, and 18 months across a rural-urban gradient within the ECoMiD birth cohort study (n=473). Enteric pathogen burden was high and increased with age, with at least one pathogen detected in 91% of children at 6 months, 97% at 12 months, and 98% at 18 months. However, prevalence of some pathogens-- notably Salmonella enterica, enterovirus, and rotavirus-- decreased with age. Co-infections were also common (88%), and children were infected with as many as 11 pathogens simultaneously. The most frequently observed co-infection profiles included enteroaggregative E. coli and atypical enteropathogenic E. coli, followed by combinations with diffusely adherent E. coli, enterovirus, enterotoxigenic E. coli, and\/or adenovirus. Enteric pathogen detection generally was higher in more rural settings, though patterns varied by pathogen. These results provide useful information for future examination of pathogen dynamics of co-occurrence. Given the ubiquity of enteric infections in high transmission settings, strategies that aim to reduce overall microbial exposure may be needed to supplement interventions targeting control of individual pathogens.","rel_num_authors":11,"rel_authors":[{"author_name":"Nicolette  Angela Zhou","author_inst":"University of Washington"},{"author_name":"Caitlin Hemlock","author_inst":"University of Washington"},{"author_name":"Kelsey  J. Jesser","author_inst":"University of Washington"},{"author_name":"Christine  S. Fagnant-Sperati","author_inst":"University of Washington"},{"author_name":"Jesse  D. Contreras","author_inst":"University of Michigan"},{"author_name":"Benjamin  F. Arnold","author_inst":"UCSF: University of California San Francisco"},{"author_name":"William Cevallos","author_inst":"Universidad Central del Ecuador"},{"author_name":"Gabriel Trueba","author_inst":"Universidad San Francisco de Quito"},{"author_name":"Gwenyth  O. Lee","author_inst":"Rutgers University Newark"},{"author_name":"Joseph  N.S. Eisenberg","author_inst":"University of Michigan"},{"author_name":"Karen Levy","author_inst":"University of Washington Seattle Campus: University of Washington"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Enteric pathogen burden and co-infection patterns across age and a rural-urban gradient: findings from the ECoMiD birth cohort, Northern Ecuador","rel_doi":"10.64898\/2026.07.08.26357325","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357325","rel_abs":"Enteric pathogen infections are a major global health challenge, influenced by a variety of host and environmental factors, and their clinical presentation and treatment can be complicated by the presence of co-infections. The prevalence of enteric infections and co-infections tend to vary between rural and urban contexts, likely driven by underlying environmental, geographic, and demographic characteristics. To improve understanding of urbanicity and age on enteric pathogen prevalence and on co-infection risk, we measured 22 enteric pathogens in fecal samples collected from children aged 6, 12, and 18 months across a rural-urban gradient within the ECoMiD birth cohort study (n=473). Enteric pathogen burden was high and increased with age, with at least one pathogen detected in 91% of children at 6 months, 97% at 12 months, and 98% at 18 months. However, prevalence of some pathogens-- notably Salmonella enterica, enterovirus, and rotavirus-- decreased with age. Co-infections were also common (88%), and children were infected with as many as 11 pathogens simultaneously. The most frequently observed co-infection profiles included enteroaggregative E. coli and atypical enteropathogenic E. coli, followed by combinations with diffusely adherent E. coli, enterovirus, enterotoxigenic E. coli, and\/or adenovirus. Enteric pathogen detection generally was higher in more rural settings, though patterns varied by pathogen. These results provide useful information for future examination of pathogen dynamics of co-occurrence. Given the ubiquity of enteric infections in high transmission settings, strategies that aim to reduce overall microbial exposure may be needed to supplement interventions targeting control of individual pathogens.","rel_num_authors":11,"rel_authors":[{"author_name":"Nicolette  Angela Zhou","author_inst":"University of Washington"},{"author_name":"Caitlin Hemlock","author_inst":"University of Washington"},{"author_name":"Kelsey  J. Jesser","author_inst":"University of Washington"},{"author_name":"Christine  S. Fagnant-Sperati","author_inst":"University of Washington"},{"author_name":"Jesse  D. Contreras","author_inst":"University of Michigan"},{"author_name":"Benjamin  F. Arnold","author_inst":"UCSF: University of California San Francisco"},{"author_name":"William Cevallos","author_inst":"Universidad Central del Ecuador"},{"author_name":"Gabriel Trueba","author_inst":"Universidad San Francisco de Quito"},{"author_name":"Gwenyth  O. Lee","author_inst":"Rutgers University Newark"},{"author_name":"Joseph  N.S. Eisenberg","author_inst":"University of Michigan"},{"author_name":"Karen Levy","author_inst":"University of Washington Seattle Campus: University of Washington"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Revealing Hidden Myocardial Infarction Signatures from Brief Single-Lead Electrocardiograms: A Novel Framework for Smart Wearable Applications","rel_doi":"10.64898\/2026.07.08.26357521","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357521","rel_abs":"The electrocardiogram (ECG) contains rich nonlinear and non-stationary dynamic information that is only partly captured by conventional ECG interpretation and beat-to-beat metrics, and is increasingly analyzed using black-box artificial intelligence models that often lack interpretability. Here, we introduce the ECG time-frequency \"eyeball\", an interpretable framework that transforms a brief single-lead ECG recording into a geometric signature and a set of low-dimensional rotational and geometrical features using empirical mode decomposition and Hilbert-based analytic signal mapping. In 30-second lead I-equivalent recordings from 170 healthy subjects and 80 patients with acute myocardial infarction (AMI), the proposed \"eyeball\" metrics significantly differentiated groups, with AMI associated with higher rotational frequency metrics, lower envelope metrics, and displaced centroid location. Representative examples revealed a coherent morphologic spectrum from normal patterns to geometries consistent with myocardial ischemia, injury, and infarction. The representation remained stable across recording windows from 30 seconds to 5 minutes, and individual \"eyeball\" features achieved areas under the receiver operating characteristic curve (AUCs) of up to 0.78 for AMI detection. These findings suggest that the ECG time-frequency \"eyeball\" condenses clinically relevant nonlinear ECG dynamics into an interpretable representation that may reveal hidden AMI signatures, complement conventional ECG interpretation, and provide a foundation for accessible single-lead cardiovascular screening using future smart wearables.","rel_num_authors":6,"rel_authors":[{"author_name":"Rashid Alavi","author_inst":"California Institute of Technology (Caltech)"},{"author_name":"Jiajun Li","author_inst":"University of Southern California"},{"author_name":"Ray V. Matthews","author_inst":"University of Southern California"},{"author_name":"Niema M. Pahlevan","author_inst":"University of Southern California"},{"author_name":"Robert A. Kloner","author_inst":"Huntington Medical Research Institutes"},{"author_name":"Morteza Gharib","author_inst":"California Institute of Technology (Caltech)"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Feasibility of Monkeypox virus sequencing from antigen rapid diagnostic tests as a potential tool to enhance genomic surveillance","rel_doi":"10.64898\/2026.07.09.26356424","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26356424","rel_abs":"Background Sequencing of monkeypox virus (MPXV) from antigen rapid diagnostic tests (Ag-RDTs) could expand genomic surveillance during outbreaks in decentralized settings where sequencing equipment and cold chain transportation are unavailable. We aimed to evaluate the efficacy of MPXV sequencing from MPXV antigen Ag-RDTs. Methods We tested MPXV Ag-RDTs from three different brands using serial dilutions of cultured MPXV subclade Ib. Positive Ag-RDTs with different intensities of the test band were stored for 19 days, either at room temperature or at +4 degree C, after which viral DNA was extracted from the pads of the test cassettes. Metagenomic and tiled amplicon-based Oxford Nanopore technology sequencing methods were then performed. Results Viral DNA extraction from MPXV Ag-RDTs showed a consistent decrease in viral load of 3 logs compared to the initial viral load of the applied viral dilution. Both sequencing methods were able to reach high coverage but the tiled amplicon-based demonstrated more consistent results with a coverage always above 85%. Conclusion This proof-of-concept supports the development of this approach in the field, with the aim of combining genomic surveillance with decentralized testing, including in remote areas.","rel_num_authors":8,"rel_authors":[{"author_name":"Charlotte Pronier PRONIER","author_inst":"Hopital Pontchaillou"},{"author_name":"Adriana Renzoni","author_inst":"University Hospitals of Geneva"},{"author_name":"Florian Laubscher","author_inst":"University Hospitals of Geneva"},{"author_name":"Valentin Chudzinski","author_inst":"University Hospitals of Geneva"},{"author_name":"Kenneth Adea","author_inst":"Universite de Geneve"},{"author_name":"Placide Mbala-Kingebeni","author_inst":"INRB: Institut National de Recherche Biomedicale"},{"author_name":"Camille Escadafal","author_inst":"University Hospitals of Geneva"},{"author_name":"Isabella Eckerle","author_inst":"University Hospitals of Geneva"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Population-scale molecular reconstruction of human circadian phase from blood biomarkers","rel_doi":"10.64898\/2026.07.08.26356418","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26356418","rel_abs":"Circadian timing influences human physiology and disease risk, yet scalable measures of molecular circadian phase are lacking. Here we infer circadian phase from circulating blood biomarkers in UK Biobank. Among 3,228 plasma biomarkers, 58% exhibit significant diurnal variation, with harmonic modeling identifying acrophase clustering consistent with canonical circadian patterns and independent constant-routine datasets. Machine-learning models trained on plasma proteomics predict sampling time (R2=0.68) and retain substantial accuracy with ~60 proteins. We define a novel construct, circadian acceleration (CA), as deviation from the population-average phase; CA is temporally stable, associates with chronotype and shift work, and responds to environmental perturbation. CA is heritable (h2SNP=0.10) and genetically correlated with chronotype and accelerometry-derived sleep traits. These results establish plasma proteomics as a scalable approach for population-level molecular circadian phenotyping.","rel_num_authors":18,"rel_authors":[{"author_name":"Clara Albinana","author_inst":"National Centre for Register-based Research, Aarhus University, Aarhus, Denmark, Department of Psychiatry, University of Oxford, Oxford, United Kingdom"},{"author_name":"Rebecca Richmond","author_inst":"Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom, MRC Integrative Epidemiology Unit, University of Bristol, Br"},{"author_name":"Baihan Wang","author_inst":"Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom"},{"author_name":"Lea Urpa","author_inst":"Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA, Center for Genomic Medicine, Massachusetts General Hospital, Bo"},{"author_name":"Jacob Crouse","author_inst":"Brain and Mind Centre, The University of Sydney, Sydney, Australia"},{"author_name":"Yanni Zeng","author_inst":"Department of forensic Psychiatry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China, Department of Psychiatry, University of Oxford, Oxfor"},{"author_name":"Daniel Rosoff","author_inst":"National Institute for Health and Care Research Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, United Kingdom, Oxford Centre for Diabetes, "},{"author_name":"Safia Abdi","author_inst":"Department of Psychiatry, University of Oxford, Oxford, United Kingdom"},{"author_name":"- FinnGen Consortium","author_inst":"-"},{"author_name":"Liming Li","author_inst":"Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China, Peking University Center for Public Health and Epidemi"},{"author_name":"Zhengming Chen","author_inst":"Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom"},{"author_name":"Iona Y. Millwood","author_inst":"Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom"},{"author_name":"Hanna M Ollila","author_inst":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, USA, Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsi"},{"author_name":"Ian Hickie","author_inst":"Brain and Mind Centre, The University of Sydney, Sydney, Australia"},{"author_name":"Frederic Gachon","author_inst":"Department of Biomedicine, Aarhus University, Aarhus, Denmark, Steno Diabetes Center Aarhus, Aarhus, Denmark"},{"author_name":"Achim Kramer","author_inst":"Division of Chronobiology, Charite Universitatsmedizin Berlin, Germany"},{"author_name":"David Ray","author_inst":"National Institute for Health and Care Research Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, United Kingdom, Oxford Centre for Diabetes, "},{"author_name":"Naomi Wray","author_inst":"Department of Psychiatry, University of Oxford, Oxford, United Kingdom, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia, B"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Minimal Residual Disease via circulating tumor DNA Predicts Exceptional Response in HER2-Positive Metastatic Breast Cancer","rel_doi":"10.64898\/2026.07.09.26357137","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357137","rel_abs":"Purpose: Exceptional responses are frequent in patients with HER2-positive (HER2+) metastatic breast cancer (MBC), but predictive biomarkers are lacking. We aimed to investigate the association between detection of minimal residual disease (MRD) via circulating tumor DNA (ctDNA) and exceptional response to first-line HER2 targeted therapy for MBC. Patients and Methods: We identified exceptional (real-world progression-free survival [rwPFS] [&ge;]3 years) and conventional (rwPFS <3 years) responders treated with first-line HER2 targeted therapy for HER2+ MBC and plasma collected at landmark timepoints (e.g., baseline, year [Y] 1, Y2, Y3, at progression). We generated personalized, tissue-informed MRD assays using MAESTRO mutation enrichment sequencing in a pooled format. The primary endpoint was the association between MRD status at Y1 and rwPFS. Results: Of 70 patients, 63 (90%) (40 exceptional and 23 conventional responders) had sufficient samples and successful assay design; MAESTRO was run on 149 samples. A median of 1,823 (range 387-5,000) tumor-specific mutations were tracked per patient. MRD was detected in 49 (32%) samples (median tumor fraction [TFx] 936 ppm; range 3.8-164,068 ppm); 15 (31%) samples had TFx <100 ppm. MRD was associated with outcomes: 0\/27 [0%] exceptional versus 9\/12 [75%] conventional responders (p<0.001) had detectable MRD at Y1. Exceptional responders who remained progression-free were always MRD-negative (n=30) or cleared MRD by Y1 (n=3). Six exceptional responders experienced late progression, and four of them had a Y3 sample: MRD was detected in three patients (lead time range 2.77-13.47 years), one patient had breast-only progression and was MRD-negative. Conclusions: MRD status at key timepoints is associated with exceptional response and late distant progression, supporting prospective clinical trials implementing MRD testing with highly sensitive tumor-informed assays to guide treatment de-escalation.","rel_num_authors":25,"rel_authors":[{"author_name":"Stefania Morganti","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Catherine Song","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Ningxuan Zhou","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Katherine Santos","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Pia Jain","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Laurel Walsh","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Rachel Li","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Justin Rhoades","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Katie Gilligan","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Gregory Kirkner","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Catherine Stever","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Ashka Patel","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Melissa E. Hughes","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Nolan Priedigkeit","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"G. Mike Makrigiorgios","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Ian Krop","author_inst":"Yale Cancer Center"},{"author_name":"Giuseppe Curigliano","author_inst":"European Institute of Oncology"},{"author_name":"Eric P. Winer","author_inst":"Yale Cancer Center"},{"author_name":"Sara M. Tolaney","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Nabihah Tayob","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Hillary Heiling","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Kan Xiong","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Nancy U. Lin","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Viktor A. Adalsteinsson","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Heather A. Parsons","author_inst":"Dana-Farber Cancer Institute"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Minimal Residual Disease via circulating tumor DNA Predicts Exceptional Response in HER2-Positive Metastatic Breast Cancer","rel_doi":"10.64898\/2026.07.09.26357137","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357137","rel_abs":"Purpose: Exceptional responses are frequent in patients with HER2-positive (HER2+) metastatic breast cancer (MBC), but predictive biomarkers are lacking. We aimed to investigate the association between detection of minimal residual disease (MRD) via circulating tumor DNA (ctDNA) and exceptional response to first-line HER2 targeted therapy for MBC. Patients and Methods: We identified exceptional (real-world progression-free survival [rwPFS] [&ge;]3 years) and conventional (rwPFS <3 years) responders treated with first-line HER2 targeted therapy for HER2+ MBC and plasma collected at landmark timepoints (e.g., baseline, year [Y] 1, Y2, Y3, at progression). We generated personalized, tissue-informed MRD assays using MAESTRO mutation enrichment sequencing in a pooled format. The primary endpoint was the association between MRD status at Y1 and rwPFS. Results: Of 70 patients, 63 (90%) (40 exceptional and 23 conventional responders) had sufficient samples and successful assay design; MAESTRO was run on 149 samples. A median of 1,823 (range 387-5,000) tumor-specific mutations were tracked per patient. MRD was detected in 49 (32%) samples (median tumor fraction [TFx] 936 ppm; range 3.8-164,068 ppm); 15 (31%) samples had TFx <100 ppm. MRD was associated with outcomes: 0\/27 [0%] exceptional versus 9\/12 [75%] conventional responders (p<0.001) had detectable MRD at Y1. Exceptional responders who remained progression-free were always MRD-negative (n=30) or cleared MRD by Y1 (n=3). Six exceptional responders experienced late progression, and four of them had a Y3 sample: MRD was detected in three patients (lead time range 2.77-13.47 years), one patient had breast-only progression and was MRD-negative. Conclusions: MRD status at key timepoints is associated with exceptional response and late distant progression, supporting prospective clinical trials implementing MRD testing with highly sensitive tumor-informed assays to guide treatment de-escalation.","rel_num_authors":25,"rel_authors":[{"author_name":"Stefania Morganti","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Catherine Song","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Ningxuan Zhou","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Katherine Santos","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Pia Jain","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Laurel Walsh","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Rachel Li","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Justin Rhoades","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Katie Gilligan","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Gregory Kirkner","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Catherine Stever","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Ashka Patel","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Melissa E. Hughes","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Nolan Priedigkeit","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"G. Mike Makrigiorgios","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Ian Krop","author_inst":"Yale Cancer Center"},{"author_name":"Giuseppe Curigliano","author_inst":"European Institute of Oncology"},{"author_name":"Eric P. Winer","author_inst":"Yale Cancer Center"},{"author_name":"Sara M. Tolaney","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Nabihah Tayob","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Hillary Heiling","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Kan Xiong","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Nancy U. Lin","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Viktor A. Adalsteinsson","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Heather A. Parsons","author_inst":"Dana-Farber Cancer Institute"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Psychometric validation of the Obstetric Quality of Recovery-10 scoring tool across the first month postpartum: a cross-sectional psychometric study","rel_doi":"10.64898\/2026.07.08.26357380","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357380","rel_abs":"Background: Postpartum recovery is a public health concern. The Obstetric Quality of Recovery-10 (ObsQoR-10) is a brief patient-reported outcome measure designed to assess early recovery after childbirth. Its validation is currently limited to the first three days postpartum. This study aimed to evaluate the psychometric properties of the ObsQoR-10 across the first 30 days postpartum. Methods:We conducted a cross-sectional psychometric evaluation of the ObsQoR-10 using baseline data from a national Swiss multilingual cohort (French, German, Italian, and English). Women were recruited within the first week postpartum and completed the ObsQoR-10 and the EuroQol 5-Dimensions 5-Levels (EQ-5D-5L) at a single time point within 30 days postpartum. Clinical data were extracted from medical records. Analyses were performed across three postpartum windows (0-2, 3-7, and 8-30 days). Structural validity, measurement invariance, reliability, and construct validity (convergent and known-groups) were assessed. Results:A total of 1935 women were included. Structural validity supported a stable four-factor structure with excellent model fit (CFI 0.995-0.997; RMSEA 0.055-0.059), and bifactor analysis supported essential unidimensionality. Measurement invariance was confirmed at metric and scalar levels across postpartum windows. Reliability was good (Cronbach's alpha 0.83-0.86). Convergent validity was supported by moderate correlations with the EQ-5D-5L (;0.51 to 0.30), decreasing over time. Known-groups validity was demonstrated by significantly lower scores in women with poorer health status, postpartum haemorrhage, and operative or caesarean birth (all p <0.001). Conclusions:The ObsQoR-10 demonstrates consistent, valid, and reliable psychometric properties for assessing postpartum recovery across the first 30 days.","rel_num_authors":11,"rel_authors":[{"author_name":"Emilienne Celetta","author_inst":"Geneva School of Health Sciences, HES-SO University of Applied Sciences and Arts Western Switzerland, Geneva, Switzerland"},{"author_name":"Elsa Lorthe","author_inst":"Geneva School of Health Sciences, HES-SO University of Applied Sciences and Arts Western Switzerland, Geneva, Switzerland"},{"author_name":"Gilles Cattani","author_inst":"Geneva School of Health Sciences, HES-SO University of Applied Sciences and Arts Western Switzerland, Geneva, Switzerland"},{"author_name":"Manuella Epiney","author_inst":"Division of Obstetrics, Department of Paediatrics, Gynaecology and Obstetrics, Geneva University Hospitals, Faculty of Medicine, University of Geneva, Geneva, S"},{"author_name":"Susanne Grylka-Baeschlin","author_inst":"Research Institute of Midwifery and Reproductive Health, Zurich University of Applied Sciences, Winterthur, Switzerland"},{"author_name":"Antonia Nathalie Mueller","author_inst":"Research Institute of Midwifery and Reproductive Health, Zurich University of Applied Sciences, Winterthur, Switzerland"},{"author_name":"Jessica Di Vincezo-Sormani","author_inst":"Geneva School of Health Sciences, HES-SO University of Applied Sciences and Arts Western Switzerland, Geneva, Switzerland"},{"author_name":"Melanie Suppan","author_inst":"Division of Anesthesiology, Department of Acute Medicine, Geneva University Hospitals, Geneva, Switzerland"},{"author_name":"Isabel Naya Widmer","author_inst":"Research Institute of Midwifery and Reproductive Health, Zurich University of Applied Sciences, Winterthur, Switzerland"},{"author_name":"Thomas Desplanches","author_inst":"Geneva School of Health Sciences, HES-SO University of Applied Sciences and Arts Western Switzerland, Geneva, Switzerland"},{"author_name":"Laurent Gaucher","author_inst":"Geneva School of Health Sciences, HES-SO University of Applied Sciences and Arts Western Switzerland, Geneva, Switzerland"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Amplitude Performance Subtypes in Parkinson's Disease","rel_doi":"10.64898\/2026.07.08.26357552","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357552","rel_abs":"Purpose: The purpose of this study was to identify subgroups of talkers with Parkinsons disease (PD) with shared tongue, lip, and jaw articulatory amplitude behaviors. The study also sought to identify demographic and clinical features that can distinguish the identified kinematic subgroups. Methods: 53 talkers with PD and 54 controls participated. Articulatory amplitudes of the tongue, lip, and jaw were measured during a paragraph reading task using three-dimensional electromagnetic articulography. Amplitude performance profiles of the tongue, lip, and jaw were established for each talker with PD by referencing their performance to that of controls. These profiles were submitted to a hierarchical cluster analysis to identify kinematic-based subgroups. Amplitude performances were compared across subgroups to determine between-group patterns. Demographic and clinical features (e.g., age, sex, disease duration, selected perceptual speech characteristics, dysarthria severity) were compared across the identified kinematic subgroups. Results: Four main kinematic subgroups with differing amplitude performance profiles were identified. One subgroup exhibited normal to mildly exaggerated or mildly reduced amplitudes and was labeled preclinical subgroup (n = 16). Three subgroups exhibited pronounced amplitude reductions of either the tongue (n = 10), the tongue and lips (n = 12), or the tongue, lips, and jaw (n = 10). In addition, there were five talkers with PD whose performance profiles did not align with the identified four subgroups. Their performance was characterized by either pronounced amplitude exaggerations or mildly reduced jaw and lip amplitudes and exaggerated tongue amplitudes. None of the demographic or clinical features differed significantly between the main four subgroups. Conclusion: Findings suggest that the extent to which hypokinesia manifests within the articulatory subsystem can vary in talkers with PD. Longitudinal studies are needed to determine if these subgroups represent different stages of disease progression or distinctly different manifestations of the disease within the articulatory subsystem.","rel_num_authors":4,"rel_authors":[{"author_name":"Antje Mefferd","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Kris Tjaden","author_inst":"University at Buffalo"},{"author_name":"Mary Dietrich","author_inst":"Vanderbilt University"},{"author_name":"Amy E Brown","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Randomized vibrotactile fingertip stimulation modulates beta band in Parkinson's Disease","rel_doi":"10.64898\/2026.07.09.26356470","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26356470","rel_abs":"There is growing interest and need for non-invasive stimulation approaches for the treatment of Parkinson's disease (PD) and other neurological conditions. Pilot studies indicate that vibrotactile stimulation on the fingertips may reduce PD motor symptoms (Pfeifer et al., 2021; Syrkin-Nikolau et al., 2018). PD motor symptoms (e.g., rigidity, bradykinesia) are correlated with exaggerated beta power in the subthalamic nucleus (STN), where neurons are excessively synchronized (Brown 2003; Kuhn et al., 2006; Neumann et al., 2016; Yin et al., 2021), but the effect of vibrotactile stimulation on the STN has not been determined. Here, in 12 PD participants in the OFF deep brain stimulation (DBS) and OFF medication state, we investigated how unilateral vibrotactile stimulation applied to the fingertips affects local field potential (LFP) power in STN. We used a within-participants design to expose each participant to a treatment stimulation pattern, termed randomized vibrotactile stimulation (RVS), and a control stimulation pattern, with the order randomized and with intermittent acquisition of STN LFP. RVS yielded a modest but statistically significant 12% (SEM 4.6%) reduction in mean normalized STN beta power and a 48% (SEM 19%) reduction in peak beta power compared to the DBS-off baseline condition and was significantly different when compared to our control stimulus. Furthermore, we identified a biomarker in STN beta power that predicts which participants may benefit from RVS. We observed that participants that exhibited prominent beta peaks had stronger reductions in mean beta power (17% reduction, SEM 6.1%) and peak beta power (55% reduction, SEM 10%). Regressing against the magnitude of the peak in beta provides a moderate prediction of change in mean and peak beta power due to RVS (R2 = 0.58 for mean and 0.52 for peak). We then used our observations to construct a computational model where beta peaks in a simulated STN varied from prominent to diminished. We found that the efficacy of randomized treatments was dependent on the magnitude of beta peaking, mirroring our clinical findings, and showing that RVS may act by reducing intra-neuronal synaptic strengths in STN. Despite robust changes in STN LFP in our study population, we did not observe a significant change in motor symptoms. These results suggest that peripheral vibrotactile stimulation can reduce STN beta power and motivate additional studies to investigate its long-term effects on motor symptoms across a large population of participants.","rel_num_authors":7,"rel_authors":[{"author_name":"Jesse I. Gilmer","author_inst":"University of Colorado Denver"},{"author_name":"Anthony Y Lee","author_inst":"University of Colorado Denver"},{"author_name":"Shahin Sharafi","author_inst":"University of Ottawa"},{"author_name":"Alexander J Baumgartner","author_inst":"University of Colorado School of Medicine"},{"author_name":"Thomas K Uchida","author_inst":"University of Ottawa"},{"author_name":"John A Thompson","author_inst":"University of Colorado School of Medicine"},{"author_name":"Mazen Al Borno","author_inst":"University of Colorado Denver"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Randomized vibrotactile fingertip stimulation modulates beta band in Parkinson's Disease","rel_doi":"10.64898\/2026.07.09.26356470","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26356470","rel_abs":"There is growing interest and need for non-invasive stimulation approaches for the treatment of Parkinson's disease (PD) and other neurological conditions. Pilot studies indicate that vibrotactile stimulation on the fingertips may reduce PD motor symptoms (Pfeifer et al., 2021; Syrkin-Nikolau et al., 2018). PD motor symptoms (e.g., rigidity, bradykinesia) are correlated with exaggerated beta power in the subthalamic nucleus (STN), where neurons are excessively synchronized (Brown 2003; Kuhn et al., 2006; Neumann et al., 2016; Yin et al., 2021), but the effect of vibrotactile stimulation on the STN has not been determined. Here, in 12 PD participants in the OFF deep brain stimulation (DBS) and OFF medication state, we investigated how unilateral vibrotactile stimulation applied to the fingertips affects local field potential (LFP) power in STN. We used a within-participants design to expose each participant to a treatment stimulation pattern, termed randomized vibrotactile stimulation (RVS), and a control stimulation pattern, with the order randomized and with intermittent acquisition of STN LFP. RVS yielded a modest but statistically significant 12% (SEM 4.6%) reduction in mean normalized STN beta power and a 48% (SEM 19%) reduction in peak beta power compared to the DBS-off baseline condition and was significantly different when compared to our control stimulus. Furthermore, we identified a biomarker in STN beta power that predicts which participants may benefit from RVS. We observed that participants that exhibited prominent beta peaks had stronger reductions in mean beta power (17% reduction, SEM 6.1%) and peak beta power (55% reduction, SEM 10%). Regressing against the magnitude of the peak in beta provides a moderate prediction of change in mean and peak beta power due to RVS (R2 = 0.58 for mean and 0.52 for peak). We then used our observations to construct a computational model where beta peaks in a simulated STN varied from prominent to diminished. We found that the efficacy of randomized treatments was dependent on the magnitude of beta peaking, mirroring our clinical findings, and showing that RVS may act by reducing intra-neuronal synaptic strengths in STN. Despite robust changes in STN LFP in our study population, we did not observe a significant change in motor symptoms. These results suggest that peripheral vibrotactile stimulation can reduce STN beta power and motivate additional studies to investigate its long-term effects on motor symptoms across a large population of participants.","rel_num_authors":7,"rel_authors":[{"author_name":"Jesse I. Gilmer","author_inst":"University of Colorado Denver"},{"author_name":"Anthony Y Lee","author_inst":"University of Colorado Denver"},{"author_name":"Shahin Sharafi","author_inst":"University of Ottawa"},{"author_name":"Alexander J Baumgartner","author_inst":"University of Colorado School of Medicine"},{"author_name":"Thomas K Uchida","author_inst":"University of Ottawa"},{"author_name":"John A Thompson","author_inst":"University of Colorado School of Medicine"},{"author_name":"Mazen Al Borno","author_inst":"University of Colorado Denver"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Feasibility of Patient-Uploaded Videos for Gait Assessment in Multiple Sclerosis","rel_doi":"10.64898\/2026.07.08.26356963","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26356963","rel_abs":"Background: Gait impairment is common among people with multiple sclerosis (PwMS) and is an important marker of disease progression. However, gait assessments typically require in-person evaluations. Objective: To describe the pose-estimation-based method for estimating spatiotemporal gait parameters from a single consumer-grade video, and evaluate the feasibility of home video collection by PwMS. Methods: In a single-center longitudinal digital phenotyping study, ambulatory adults with MS completed a standardized walking task recorded in the frontal plane. Pose estimation (MediaPipe Pose, Ultralytics) and custom scripts were used to estimate gait parameters from videos. Participants were invited to record walking videos at home using personal devices. Adoption and technical feasibility were evaluated across two home video data acquisition phases, with iterative protocol refinements. Results: The in-clinic study included 132 participants; 55 contributed home videos. In Phase I, while home video adoption was low (45% [30\/66]), 87% [26\/30] uploaded [&ge;]1 video of sufficient quality for gait analysis. After protocol refinements, 100% [25\/25] uploaded [&ge;]1 high-quality video. Overall, high-quality frontal-plane videos were obtained at similar rates at home (92% [97\/105]) and in-clinic (91% [423\/467]). Conclusions: Home walking videos can feasibly be collected by PwMS to estimate gait parameters, providing an accessible approach for remote gait monitoring.","rel_num_authors":12,"rel_authors":[{"author_name":"Megan McCune","author_inst":"University of California, San Francisco"},{"author_name":"Yoni Ackerman","author_inst":"University of California, San Francisco"},{"author_name":"Alexis Camacho","author_inst":"University of California, San Francisco"},{"author_name":"Nikki Sisodia","author_inst":"University of California, San Francisco"},{"author_name":"Jaeleene Wijangco","author_inst":"University of California, San Francisco"},{"author_name":"Kyra Henderson","author_inst":"University of California, San Francisco"},{"author_name":"Jeannine Bradsby","author_inst":"University of California, San Francisco"},{"author_name":"Shane Poole","author_inst":"University of California, San Francisco"},{"author_name":"Abel Torres Espin","author_inst":"University of Waterloo"},{"author_name":"Matthew J Miller","author_inst":"University of California, San Francisco"},{"author_name":"Valerie J Block","author_inst":"University of California, San Francisco"},{"author_name":"Riley Bove","author_inst":"University of California, San Francisco"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Drivers of Diagnostic Variation in a Digital Global Kidney Transplant Reader Study","rel_doi":"10.64898\/2026.07.09.26357318","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357318","rel_abs":"Background Diagnostic interpretation of kidney allograft biopsies using the Banff classification remains variable, but the determinants of this variability are not fully defined. We performed a global, fully digital multi-reader study to identify the principal drivers of disagreement in Banff-based assessment. Methods Thirty six kidney transplant biopsies were independently scored by 67 renal pathologists on a standardized digital platform. Readers assessed Banff lesions on hematoxylin and eosin, periodic acid Schiff, and Jones' silver stains; final diagnostic categories were assigned using prespecified Banff-based decision rules. Interobserver agreement was quantified with Gwet's agreement coefficient (AC) statistics. Determinants of diagnostic agreement were evaluated) using pairwise mixed-effects logistic regression, and reader similarity was examined by principal component analysis (PCA) with post hoc molecular annotation. Results Agreement for final diagnostic categories was moderate (Gwet's AC1, 0.55; 95% CI, 0.47 - 0.63). Lesion-level agreement varied substantially, with lowest agreement for selected threshold-dependent inflammatory or semi-quantitative lesions, including interstitial inflammation in areas of IFTA, peritubular capillaritis and arteriolar hyalinosis. Diagnostic concordance differed markedly across biopsies, indicating strong case-level heterogeneity. In pairwise models, differences in active inflammatory and vascular lesion scoring were the strongest correlates of diagnostic disagreement; reader experience and geography contributed minimally. Principal component analysis showed reader variation was organized along two dominant axes: a rejection-calling threshold axis linked mainly to tubulointerstitial inflammatory injury, and a T cell-mediated (TCMR\/TI) and antibody-mediated\/microvascular (AMR\/MVI) inflammation-oriented phenotypic classification axis. Conclusion Interobserver variation in Banff-based kidney transplant biopsy assessment is structured rather than random and driven mainly by how readers threshold and integrate key inflammatory lesion compartments rather than experience or geographic location.","rel_num_authors":77,"rel_authors":[{"author_name":"Rianne Hofstraat-Boersma","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Van 't Hoff Institute for Molecular Sciences, Uni"},{"author_name":"Romy du Long","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Pathology, University Medical Cente"},{"author_name":"Giorgio Buzzanca","author_inst":"Department of Pathology, Systems Pathology Research Group, Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Adeyemi A. Abiola","author_inst":"Department of Histopathology, African Medical Center of Excellence Hospital, Abuja, Nigeria"},{"author_name":"Sam Albadri","author_inst":"Department of Pathology, Mayo Clinic, Mayo Clinic School of Medicine, Rochester, United States"},{"author_name":"Zahabia Ali","author_inst":"Department of Cellular Pathology, Barts NHS Trust, London, United Kingdom"},{"author_name":"Ahmed Altaleb","author_inst":"Histopathology Unit, Mubarak Alkabeer Hospital, Jabriya, Kuwait"},{"author_name":"Andrea Angioi","author_inst":"S.C.D.U. Nefrologia, Dialisi e Trapianto, ARNAS Brotzu Hospital, Cagliari, Italy"},{"author_name":"Sultana G. Banu","author_inst":"Department of Pathology, Bangladesh Medical University, Dhaka, Bangladesh"},{"author_name":"Marc Barry","author_inst":"Department of Pathology, University of Utah, Salt Lake City, United States"},{"author_name":"Ami R. Bhalodia","author_inst":"The Pathology Laboratory, Lake Charles, United States"},{"author_name":"Paola Bianco","author_inst":"S.C. Anatomia Patologia, ARNAS Brotzu Hospital, Cagliari, Italy"},{"author_name":"Verena Broecker","author_inst":"Department of Pathology, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden"},{"author_name":"Roman Buelow","author_inst":"Institute for Pathology, RWTH Aachen University Hospital, Aachen, Germany"},{"author_name":"Bertrand Chauveau","author_inst":"Department of Pathology, Bordeaux University Hospital, Bordeaux, France"},{"author_name":"Guoli Chen","author_inst":"Department of Pathology, Penn State Health, Penn State College of Medicine, Hershey, United States"},{"author_name":"Boonyarit Cheunsuchon","author_inst":"Department of Pathology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand"},{"author_name":"Giovanna M. Crisi","author_inst":"Department of Pathology, UMASS-Chan School of Medical School - Baystate, Springfield, United States"},{"author_name":"Simin Daneshvar","author_inst":"Department of Anatomical Pathology, St. Vincent's Hospital, University of Melbourne, Melbourne, Australia"},{"author_name":"Amelie Dendooven","author_inst":"Department of Pathology, University Hospital of Ghent, Ghent University, Ghent, Belgium; Department of Pathology, Faculty of Medicine and Health Sciences, Unive"},{"author_name":"Pouneh Dokouhaki","author_inst":"Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada; Department of Pathology, St. Paul Hospital, Providence Healt"},{"author_name":"Cinthia B. Drachenberg","author_inst":"Department of Pathology, University of Maryland School of Medicine, Baltimore, United States"},{"author_name":"Alton B. Farris","author_inst":"Department of Pathology and laboratory Medicine, Emory University Hospital, Emory University, Atlanta, United States"},{"author_name":"Sophie Ferlicot","author_inst":"Department of Pathology, Le Kremlin-Bicetre Hospital, Paris-Saclay University, Paris, France"},{"author_name":"Sandrine Florquin","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands"},{"author_name":"Francesco Fontana","author_inst":"Nephrology, Dialysis and Kidney Transplant Unit, University Hospital of Modena, Modena, Italy"},{"author_name":"Jean-Baptiste Gibier","author_inst":"Institute of Pathology, Centre Hospitalier Universitaire de Lille, Lille, France"},{"author_name":"Ian W. Gibson","author_inst":"Department of Pathology, University of Manitoba, Winnipeg, Canada"},{"author_name":"Saurabh Gujarathi","author_inst":"Department of Pathology, Manipal Hospital, Pune, India"},{"author_name":"Allen R. Hendricks","author_inst":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States"},{"author_name":"Sufia Husain","author_inst":"Department of Pathology, College of Medicine, King Saud University - Medical City, Riyadh, Saudi Arabia"},{"author_name":"Jaynul Islam","author_inst":"Department of Pathology, BIRDEM General Hospital, Dhaka, Bangladesh"},{"author_name":"Wesam Ismail","author_inst":"Department of Pathology, Beni-Suef University, Beni-Suef, Egypt"},{"author_name":"Geetha Jagannathan","author_inst":"Department of Pathology and laboratory Medicine, Emory University Hospital, Emory University, Atlanta, United States"},{"author_name":"Johannes Klager","author_inst":"Department of Pathology, General Hospital of Vienna, Medical University of Vienna, Vienna, Austria"},{"author_name":"Nicolas Kozakowski","author_inst":"Department of Pathology, General Hospital of Vienna, Medical University of Vienna, Vienna, Austria"},{"author_name":"Adriana Krizova","author_inst":"Department of Laboratory Medicine, St. Michael's Hospital, University of Toronto, Toronto, Canada"},{"author_name":"Anila A. Kurien","author_inst":"Department of Pathology, Renopath, Center for Renal and Urological Pathology, Chennai, India"},{"author_name":"Boomi Kwon","author_inst":"Department of Pathology, Mater Hospital, Brisbane, Australia"},{"author_name":"Vincenzo L'Imperio","author_inst":"Department of Medicine and Surgery, Pathology, Fondazione IRCCS San Gerardo dei Tintori, University of Milano-Bicocca, Monza, Italy"},{"author_name":"Felipe L. Ledesma","author_inst":"Department of Pathology, University of Sao Paulo Medicine School, Sao Paulo, Brazil"},{"author_name":"Julia P. Low","author_inst":"Department of Anatomical Pathology, Sydpath, St. Vincent's Hospital, Sydney, University of South Wales, Australia"},{"author_name":"Jonne Martin","author_inst":"Department of Cellular Pathology, The Royal London Hospital, Queen Mary University of London, London, United Kingdom"},{"author_name":"Shweta S. Mehta","author_inst":"Department of Pathology, Kauvery Hospital, Bengaluru, India"},{"author_name":"Nidia Messias","author_inst":"Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, United States"},{"author_name":"Salvatore E. Mignano","author_inst":"Department of Pathology & Genomic Medicine, Thomas Jefferson University Hospital, Philadelphia, United States"},{"author_name":"Monik E. Miranda","author_inst":"Department of Anatomical Pathology, Cipto Mangunkusumo Hospital, Universitas Indonesia, Jakarta, Indonesia"},{"author_name":"Gilbert Moeckel","author_inst":"Department of Pathology, Yale New Haven Hospital, Yale University, New Haven, United States"},{"author_name":"Chiara Pala","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Medicine and Surgery, Nephrology Un"},{"author_name":"Brendon Price","author_inst":"Division of Anatomical Pathology, Department of Pathology, NHLS.Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa"},{"author_name":"Marc A. Ranson","author_inst":"Department of Pathology, University of Manitoba, Winnipeg, Canada"},{"author_name":"Andrea N. Rodriguez","author_inst":"Department of Pathology, Hospital Nacional Professor Alejandro Posadas, Buenos Aires, Argentina; Department of Pathology, The Favaloro Foundation University Hos"},{"author_name":"Joris J.T.H. Roelofs","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands"},{"author_name":"Avi Rosenberg","author_inst":"Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States"},{"author_name":"Alireza Sadeghipour","author_inst":"Department of Pathology, Rasoul-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran"},{"author_name":"Miroslav Sekulic","author_inst":"Department of Pathology and Cell Biology, Columbia University Medical Center, Columbia University, New York, United States"},{"author_name":"Suman Setty","author_inst":"Department of Pathology, University of Illinois Hospital and Health Sciences System, University of Illinois at Chicago, Chicago, United States"},{"author_name":"Michael Sheaff","author_inst":"Department of Cellular Pathology, Barts NHS Trust, London, United Kingdom"},{"author_name":"Maria F.S. Soares","author_inst":"Department of Cellular Pathology, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom"},{"author_name":"Jerasit Surintrspanont","author_inst":"Department of Pathology, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand"},{"author_name":"George Terinte-Balcan","author_inst":"Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique-Hopitaux de Paris, Paris, France"},{"author_name":"Francesca Testa","author_inst":"Nephrology, Dialysis and Kidney Transplant Unit, University Hospital of Modena, Modena, Italy"},{"author_name":"David O. Hendriquez Ticas","author_inst":"Department of Pathology, Northwestern Memorial Hospital, Feinberg School of Medicine Northwestern University, Chicago, United States"},{"author_name":"Maria F. Toniolo","author_inst":"Department of Pathology, Instituto de Transplantes y Alta Complejidad, Buenos Aires, Argentina"},{"author_name":"Dominique van Midden","author_inst":"Department of Pathology, Radboud University Medical Center, Radboud University, Nijmegen, Netherlands"},{"author_name":"Ramya K. Velagapudi","author_inst":"Department of Pathology, University of Mississippi Medical Center, Jackson, United States"},{"author_name":"Seethalakshmi Viswanathan","author_inst":"Department of Tissue Pathology, Westmead Hospital, Westmead Clinical School, University of Sydney, Sydney, Australia"},{"author_name":"Saskia von Stillfried","author_inst":"Institute for Pathology, RWTH Aachen University Hospital, Aachen, Germany"},{"author_name":"Chih-Ying Wu","author_inst":"Department of Pathology and laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Institute of Biomedical Sciences, National Chung Hsing Un"},{"author_name":"Nienke Kalverboer","author_inst":"Department of Pathology, Systems Pathology Research Group, Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Imke B. Bruns","author_inst":"Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands"},{"author_name":"Giulia Callegaro","author_inst":"Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands"},{"author_name":"Bob van de Water","author_inst":"Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands"},{"author_name":"Danny van der Helm","author_inst":"Division of Nephrology, Department Internal Medicine; Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Aiko P.J. de Vries","author_inst":"Division of Nephrology, Department Internal Medicine; Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Hessel Peters-Sengers","author_inst":"Center for Infection and Molecular Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands"},{"author_name":"Jesper Kers","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Pathology, Systems Pathology Resear"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Drivers of Diagnostic Variation in a Digital Global Kidney Transplant Reader Study","rel_doi":"10.64898\/2026.07.09.26357318","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357318","rel_abs":"Background Diagnostic interpretation of kidney allograft biopsies using the Banff classification remains variable, but the determinants of this variability are not fully defined. We performed a global, fully digital multi-reader study to identify the principal drivers of disagreement in Banff-based assessment. Methods Thirty six kidney transplant biopsies were independently scored by 67 renal pathologists on a standardized digital platform. Readers assessed Banff lesions on hematoxylin and eosin, periodic acid Schiff, and Jones' silver stains; final diagnostic categories were assigned using prespecified Banff-based decision rules. Interobserver agreement was quantified with Gwet's agreement coefficient (AC) statistics. Determinants of diagnostic agreement were evaluated) using pairwise mixed-effects logistic regression, and reader similarity was examined by principal component analysis (PCA) with post hoc molecular annotation. Results Agreement for final diagnostic categories was moderate (Gwet's AC1, 0.55; 95% CI, 0.47 - 0.63). Lesion-level agreement varied substantially, with lowest agreement for selected threshold-dependent inflammatory or semi-quantitative lesions, including interstitial inflammation in areas of IFTA, peritubular capillaritis and arteriolar hyalinosis. Diagnostic concordance differed markedly across biopsies, indicating strong case-level heterogeneity. In pairwise models, differences in active inflammatory and vascular lesion scoring were the strongest correlates of diagnostic disagreement; reader experience and geography contributed minimally. Principal component analysis showed reader variation was organized along two dominant axes: a rejection-calling threshold axis linked mainly to tubulointerstitial inflammatory injury, and a T cell-mediated (TCMR\/TI) and antibody-mediated\/microvascular (AMR\/MVI) inflammation-oriented phenotypic classification axis. Conclusion Interobserver variation in Banff-based kidney transplant biopsy assessment is structured rather than random and driven mainly by how readers threshold and integrate key inflammatory lesion compartments rather than experience or geographic location.","rel_num_authors":77,"rel_authors":[{"author_name":"Rianne Hofstraat-Boersma","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Van 't Hoff Institute for Molecular Sciences, Uni"},{"author_name":"Romy du Long","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Pathology, University Medical Cente"},{"author_name":"Giorgio Buzzanca","author_inst":"Department of Pathology, Systems Pathology Research Group, Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Adeyemi A. Abiola","author_inst":"Department of Histopathology, African Medical Center of Excellence Hospital, Abuja, Nigeria"},{"author_name":"Sam Albadri","author_inst":"Department of Pathology, Mayo Clinic, Mayo Clinic School of Medicine, Rochester, United States"},{"author_name":"Zahabia Ali","author_inst":"Department of Cellular Pathology, Barts NHS Trust, London, United Kingdom"},{"author_name":"Ahmed Altaleb","author_inst":"Histopathology Unit, Mubarak Alkabeer Hospital, Jabriya, Kuwait"},{"author_name":"Andrea Angioi","author_inst":"S.C.D.U. Nefrologia, Dialisi e Trapianto, ARNAS Brotzu Hospital, Cagliari, Italy"},{"author_name":"Sultana G. Banu","author_inst":"Department of Pathology, Bangladesh Medical University, Dhaka, Bangladesh"},{"author_name":"Marc Barry","author_inst":"Department of Pathology, University of Utah, Salt Lake City, United States"},{"author_name":"Ami R. Bhalodia","author_inst":"The Pathology Laboratory, Lake Charles, United States"},{"author_name":"Paola Bianco","author_inst":"S.C. Anatomia Patologia, ARNAS Brotzu Hospital, Cagliari, Italy"},{"author_name":"Verena Broecker","author_inst":"Department of Pathology, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden"},{"author_name":"Roman Buelow","author_inst":"Institute for Pathology, RWTH Aachen University Hospital, Aachen, Germany"},{"author_name":"Bertrand Chauveau","author_inst":"Department of Pathology, Bordeaux University Hospital, Bordeaux, France"},{"author_name":"Guoli Chen","author_inst":"Department of Pathology, Penn State Health, Penn State College of Medicine, Hershey, United States"},{"author_name":"Boonyarit Cheunsuchon","author_inst":"Department of Pathology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand"},{"author_name":"Giovanna M. Crisi","author_inst":"Department of Pathology, UMASS-Chan School of Medical School - Baystate, Springfield, United States"},{"author_name":"Simin Daneshvar","author_inst":"Department of Anatomical Pathology, St. Vincent's Hospital, University of Melbourne, Melbourne, Australia"},{"author_name":"Amelie Dendooven","author_inst":"Department of Pathology, University Hospital of Ghent, Ghent University, Ghent, Belgium; Department of Pathology, Faculty of Medicine and Health Sciences, Unive"},{"author_name":"Pouneh Dokouhaki","author_inst":"Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada; Department of Pathology, St. Paul Hospital, Providence Healt"},{"author_name":"Cinthia B. Drachenberg","author_inst":"Department of Pathology, University of Maryland School of Medicine, Baltimore, United States"},{"author_name":"Alton B. Farris","author_inst":"Department of Pathology and laboratory Medicine, Emory University Hospital, Emory University, Atlanta, United States"},{"author_name":"Sophie Ferlicot","author_inst":"Department of Pathology, Le Kremlin-Bicetre Hospital, Paris-Saclay University, Paris, France"},{"author_name":"Sandrine Florquin","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands"},{"author_name":"Francesco Fontana","author_inst":"Nephrology, Dialysis and Kidney Transplant Unit, University Hospital of Modena, Modena, Italy"},{"author_name":"Jean-Baptiste Gibier","author_inst":"Institute of Pathology, Centre Hospitalier Universitaire de Lille, Lille, France"},{"author_name":"Ian W. Gibson","author_inst":"Department of Pathology, University of Manitoba, Winnipeg, Canada"},{"author_name":"Saurabh Gujarathi","author_inst":"Department of Pathology, Manipal Hospital, Pune, India"},{"author_name":"Allen R. Hendricks","author_inst":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States"},{"author_name":"Sufia Husain","author_inst":"Department of Pathology, College of Medicine, King Saud University - Medical City, Riyadh, Saudi Arabia"},{"author_name":"Jaynul Islam","author_inst":"Department of Pathology, BIRDEM General Hospital, Dhaka, Bangladesh"},{"author_name":"Wesam Ismail","author_inst":"Department of Pathology, Beni-Suef University, Beni-Suef, Egypt"},{"author_name":"Geetha Jagannathan","author_inst":"Department of Pathology and laboratory Medicine, Emory University Hospital, Emory University, Atlanta, United States"},{"author_name":"Johannes Klager","author_inst":"Department of Pathology, General Hospital of Vienna, Medical University of Vienna, Vienna, Austria"},{"author_name":"Nicolas Kozakowski","author_inst":"Department of Pathology, General Hospital of Vienna, Medical University of Vienna, Vienna, Austria"},{"author_name":"Adriana Krizova","author_inst":"Department of Laboratory Medicine, St. Michael's Hospital, University of Toronto, Toronto, Canada"},{"author_name":"Anila A. Kurien","author_inst":"Department of Pathology, Renopath, Center for Renal and Urological Pathology, Chennai, India"},{"author_name":"Boomi Kwon","author_inst":"Department of Pathology, Mater Hospital, Brisbane, Australia"},{"author_name":"Vincenzo L'Imperio","author_inst":"Department of Medicine and Surgery, Pathology, Fondazione IRCCS San Gerardo dei Tintori, University of Milano-Bicocca, Monza, Italy"},{"author_name":"Felipe L. Ledesma","author_inst":"Department of Pathology, University of Sao Paulo Medicine School, Sao Paulo, Brazil"},{"author_name":"Julia P. Low","author_inst":"Department of Anatomical Pathology, Sydpath, St. Vincent's Hospital, Sydney, University of South Wales, Australia"},{"author_name":"Jonne Martin","author_inst":"Department of Cellular Pathology, The Royal London Hospital, Queen Mary University of London, London, United Kingdom"},{"author_name":"Shweta S. Mehta","author_inst":"Department of Pathology, Kauvery Hospital, Bengaluru, India"},{"author_name":"Nidia Messias","author_inst":"Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, United States"},{"author_name":"Salvatore E. Mignano","author_inst":"Department of Pathology & Genomic Medicine, Thomas Jefferson University Hospital, Philadelphia, United States"},{"author_name":"Monik E. Miranda","author_inst":"Department of Anatomical Pathology, Cipto Mangunkusumo Hospital, Universitas Indonesia, Jakarta, Indonesia"},{"author_name":"Gilbert Moeckel","author_inst":"Department of Pathology, Yale New Haven Hospital, Yale University, New Haven, United States"},{"author_name":"Chiara Pala","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Medicine and Surgery, Nephrology Un"},{"author_name":"Brendon Price","author_inst":"Division of Anatomical Pathology, Department of Pathology, NHLS.Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa"},{"author_name":"Marc A. Ranson","author_inst":"Department of Pathology, University of Manitoba, Winnipeg, Canada"},{"author_name":"Andrea N. Rodriguez","author_inst":"Department of Pathology, Hospital Nacional Professor Alejandro Posadas, Buenos Aires, Argentina; Department of Pathology, The Favaloro Foundation University Hos"},{"author_name":"Joris J.T.H. Roelofs","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands"},{"author_name":"Avi Rosenberg","author_inst":"Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States"},{"author_name":"Alireza Sadeghipour","author_inst":"Department of Pathology, Rasoul-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran"},{"author_name":"Miroslav Sekulic","author_inst":"Department of Pathology and Cell Biology, Columbia University Medical Center, Columbia University, New York, United States"},{"author_name":"Suman Setty","author_inst":"Department of Pathology, University of Illinois Hospital and Health Sciences System, University of Illinois at Chicago, Chicago, United States"},{"author_name":"Michael Sheaff","author_inst":"Department of Cellular Pathology, Barts NHS Trust, London, United Kingdom"},{"author_name":"Maria F.S. Soares","author_inst":"Department of Cellular Pathology, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom"},{"author_name":"Jerasit Surintrspanont","author_inst":"Department of Pathology, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand"},{"author_name":"George Terinte-Balcan","author_inst":"Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique-Hopitaux de Paris, Paris, France"},{"author_name":"Francesca Testa","author_inst":"Nephrology, Dialysis and Kidney Transplant Unit, University Hospital of Modena, Modena, Italy"},{"author_name":"David O. Hendriquez Ticas","author_inst":"Department of Pathology, Northwestern Memorial Hospital, Feinberg School of Medicine Northwestern University, Chicago, United States"},{"author_name":"Maria F. Toniolo","author_inst":"Department of Pathology, Instituto de Transplantes y Alta Complejidad, Buenos Aires, Argentina"},{"author_name":"Dominique van Midden","author_inst":"Department of Pathology, Radboud University Medical Center, Radboud University, Nijmegen, Netherlands"},{"author_name":"Ramya K. Velagapudi","author_inst":"Department of Pathology, University of Mississippi Medical Center, Jackson, United States"},{"author_name":"Seethalakshmi Viswanathan","author_inst":"Department of Tissue Pathology, Westmead Hospital, Westmead Clinical School, University of Sydney, Sydney, Australia"},{"author_name":"Saskia von Stillfried","author_inst":"Institute for Pathology, RWTH Aachen University Hospital, Aachen, Germany"},{"author_name":"Chih-Ying Wu","author_inst":"Department of Pathology and laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Institute of Biomedical Sciences, National Chung Hsing Un"},{"author_name":"Nienke Kalverboer","author_inst":"Department of Pathology, Systems Pathology Research Group, Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Imke B. Bruns","author_inst":"Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands"},{"author_name":"Giulia Callegaro","author_inst":"Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands"},{"author_name":"Bob van de Water","author_inst":"Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands"},{"author_name":"Danny van der Helm","author_inst":"Division of Nephrology, Department Internal Medicine; Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Aiko P.J. de Vries","author_inst":"Division of Nephrology, Department Internal Medicine; Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Hessel Peters-Sengers","author_inst":"Center for Infection and Molecular Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands"},{"author_name":"Jesper Kers","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Pathology, Systems Pathology Resear"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Drivers of Diagnostic Variation in a Digital Global Kidney Transplant Reader Study","rel_doi":"10.64898\/2026.07.09.26357318","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357318","rel_abs":"Background Diagnostic interpretation of kidney allograft biopsies using the Banff classification remains variable, but the determinants of this variability are not fully defined. We performed a global, fully digital multi-reader study to identify the principal drivers of disagreement in Banff-based assessment. Methods Thirty six kidney transplant biopsies were independently scored by 67 renal pathologists on a standardized digital platform. Readers assessed Banff lesions on hematoxylin and eosin, periodic acid Schiff, and Jones' silver stains; final diagnostic categories were assigned using prespecified Banff-based decision rules. Interobserver agreement was quantified with Gwet's agreement coefficient (AC) statistics. Determinants of diagnostic agreement were evaluated) using pairwise mixed-effects logistic regression, and reader similarity was examined by principal component analysis (PCA) with post hoc molecular annotation. Results Agreement for final diagnostic categories was moderate (Gwet's AC1, 0.55; 95% CI, 0.47 - 0.63). Lesion-level agreement varied substantially, with lowest agreement for selected threshold-dependent inflammatory or semi-quantitative lesions, including interstitial inflammation in areas of IFTA, peritubular capillaritis and arteriolar hyalinosis. Diagnostic concordance differed markedly across biopsies, indicating strong case-level heterogeneity. In pairwise models, differences in active inflammatory and vascular lesion scoring were the strongest correlates of diagnostic disagreement; reader experience and geography contributed minimally. Principal component analysis showed reader variation was organized along two dominant axes: a rejection-calling threshold axis linked mainly to tubulointerstitial inflammatory injury, and a T cell-mediated (TCMR\/TI) and antibody-mediated\/microvascular (AMR\/MVI) inflammation-oriented phenotypic classification axis. Conclusion Interobserver variation in Banff-based kidney transplant biopsy assessment is structured rather than random and driven mainly by how readers threshold and integrate key inflammatory lesion compartments rather than experience or geographic location.","rel_num_authors":77,"rel_authors":[{"author_name":"Rianne Hofstraat-Boersma","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Van 't Hoff Institute for Molecular Sciences, Uni"},{"author_name":"Romy du Long","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Pathology, University Medical Cente"},{"author_name":"Giorgio Buzzanca","author_inst":"Department of Pathology, Systems Pathology Research Group, Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Adeyemi A. Abiola","author_inst":"Department of Histopathology, African Medical Center of Excellence Hospital, Abuja, Nigeria"},{"author_name":"Sam Albadri","author_inst":"Department of Pathology, Mayo Clinic, Mayo Clinic School of Medicine, Rochester, United States"},{"author_name":"Zahabia Ali","author_inst":"Department of Cellular Pathology, Barts NHS Trust, London, United Kingdom"},{"author_name":"Ahmed Altaleb","author_inst":"Histopathology Unit, Mubarak Alkabeer Hospital, Jabriya, Kuwait"},{"author_name":"Andrea Angioi","author_inst":"S.C.D.U. Nefrologia, Dialisi e Trapianto, ARNAS Brotzu Hospital, Cagliari, Italy"},{"author_name":"Sultana G. Banu","author_inst":"Department of Pathology, Bangladesh Medical University, Dhaka, Bangladesh"},{"author_name":"Marc Barry","author_inst":"Department of Pathology, University of Utah, Salt Lake City, United States"},{"author_name":"Ami R. Bhalodia","author_inst":"The Pathology Laboratory, Lake Charles, United States"},{"author_name":"Paola Bianco","author_inst":"S.C. Anatomia Patologia, ARNAS Brotzu Hospital, Cagliari, Italy"},{"author_name":"Verena Broecker","author_inst":"Department of Pathology, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden"},{"author_name":"Roman Buelow","author_inst":"Institute for Pathology, RWTH Aachen University Hospital, Aachen, Germany"},{"author_name":"Bertrand Chauveau","author_inst":"Department of Pathology, Bordeaux University Hospital, Bordeaux, France"},{"author_name":"Guoli Chen","author_inst":"Department of Pathology, Penn State Health, Penn State College of Medicine, Hershey, United States"},{"author_name":"Boonyarit Cheunsuchon","author_inst":"Department of Pathology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand"},{"author_name":"Giovanna M. Crisi","author_inst":"Department of Pathology, UMASS-Chan School of Medical School - Baystate, Springfield, United States"},{"author_name":"Simin Daneshvar","author_inst":"Department of Anatomical Pathology, St. Vincent's Hospital, University of Melbourne, Melbourne, Australia"},{"author_name":"Amelie Dendooven","author_inst":"Department of Pathology, University Hospital of Ghent, Ghent University, Ghent, Belgium; Department of Pathology, Faculty of Medicine and Health Sciences, Unive"},{"author_name":"Pouneh Dokouhaki","author_inst":"Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada; Department of Pathology, St. Paul Hospital, Providence Healt"},{"author_name":"Cinthia B. Drachenberg","author_inst":"Department of Pathology, University of Maryland School of Medicine, Baltimore, United States"},{"author_name":"Alton B. Farris","author_inst":"Department of Pathology and laboratory Medicine, Emory University Hospital, Emory University, Atlanta, United States"},{"author_name":"Sophie Ferlicot","author_inst":"Department of Pathology, Le Kremlin-Bicetre Hospital, Paris-Saclay University, Paris, France"},{"author_name":"Sandrine Florquin","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands"},{"author_name":"Francesco Fontana","author_inst":"Nephrology, Dialysis and Kidney Transplant Unit, University Hospital of Modena, Modena, Italy"},{"author_name":"Jean-Baptiste Gibier","author_inst":"Institute of Pathology, Centre Hospitalier Universitaire de Lille, Lille, France"},{"author_name":"Ian W. Gibson","author_inst":"Department of Pathology, University of Manitoba, Winnipeg, Canada"},{"author_name":"Saurabh Gujarathi","author_inst":"Department of Pathology, Manipal Hospital, Pune, India"},{"author_name":"Allen R. Hendricks","author_inst":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States"},{"author_name":"Sufia Husain","author_inst":"Department of Pathology, College of Medicine, King Saud University - Medical City, Riyadh, Saudi Arabia"},{"author_name":"Jaynul Islam","author_inst":"Department of Pathology, BIRDEM General Hospital, Dhaka, Bangladesh"},{"author_name":"Wesam Ismail","author_inst":"Department of Pathology, Beni-Suef University, Beni-Suef, Egypt"},{"author_name":"Geetha Jagannathan","author_inst":"Department of Pathology and laboratory Medicine, Emory University Hospital, Emory University, Atlanta, United States"},{"author_name":"Johannes Klager","author_inst":"Department of Pathology, General Hospital of Vienna, Medical University of Vienna, Vienna, Austria"},{"author_name":"Nicolas Kozakowski","author_inst":"Department of Pathology, General Hospital of Vienna, Medical University of Vienna, Vienna, Austria"},{"author_name":"Adriana Krizova","author_inst":"Department of Laboratory Medicine, St. Michael's Hospital, University of Toronto, Toronto, Canada"},{"author_name":"Anila A. Kurien","author_inst":"Department of Pathology, Renopath, Center for Renal and Urological Pathology, Chennai, India"},{"author_name":"Boomi Kwon","author_inst":"Department of Pathology, Mater Hospital, Brisbane, Australia"},{"author_name":"Vincenzo L'Imperio","author_inst":"Department of Medicine and Surgery, Pathology, Fondazione IRCCS San Gerardo dei Tintori, University of Milano-Bicocca, Monza, Italy"},{"author_name":"Felipe L. Ledesma","author_inst":"Department of Pathology, University of Sao Paulo Medicine School, Sao Paulo, Brazil"},{"author_name":"Julia P. Low","author_inst":"Department of Anatomical Pathology, Sydpath, St. Vincent's Hospital, Sydney, University of South Wales, Australia"},{"author_name":"Jonne Martin","author_inst":"Department of Cellular Pathology, The Royal London Hospital, Queen Mary University of London, London, United Kingdom"},{"author_name":"Shweta S. Mehta","author_inst":"Department of Pathology, Kauvery Hospital, Bengaluru, India"},{"author_name":"Nidia Messias","author_inst":"Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, United States"},{"author_name":"Salvatore E. Mignano","author_inst":"Department of Pathology & Genomic Medicine, Thomas Jefferson University Hospital, Philadelphia, United States"},{"author_name":"Monik E. Miranda","author_inst":"Department of Anatomical Pathology, Cipto Mangunkusumo Hospital, Universitas Indonesia, Jakarta, Indonesia"},{"author_name":"Gilbert Moeckel","author_inst":"Department of Pathology, Yale New Haven Hospital, Yale University, New Haven, United States"},{"author_name":"Chiara Pala","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Medicine and Surgery, Nephrology Un"},{"author_name":"Brendon Price","author_inst":"Division of Anatomical Pathology, Department of Pathology, NHLS.Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa"},{"author_name":"Marc A. Ranson","author_inst":"Department of Pathology, University of Manitoba, Winnipeg, Canada"},{"author_name":"Andrea N. Rodriguez","author_inst":"Department of Pathology, Hospital Nacional Professor Alejandro Posadas, Buenos Aires, Argentina; Department of Pathology, The Favaloro Foundation University Hos"},{"author_name":"Joris J.T.H. Roelofs","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands"},{"author_name":"Avi Rosenberg","author_inst":"Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States"},{"author_name":"Alireza Sadeghipour","author_inst":"Department of Pathology, Rasoul-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran"},{"author_name":"Miroslav Sekulic","author_inst":"Department of Pathology and Cell Biology, Columbia University Medical Center, Columbia University, New York, United States"},{"author_name":"Suman Setty","author_inst":"Department of Pathology, University of Illinois Hospital and Health Sciences System, University of Illinois at Chicago, Chicago, United States"},{"author_name":"Michael Sheaff","author_inst":"Department of Cellular Pathology, Barts NHS Trust, London, United Kingdom"},{"author_name":"Maria F.S. Soares","author_inst":"Department of Cellular Pathology, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom"},{"author_name":"Jerasit Surintrspanont","author_inst":"Department of Pathology, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand"},{"author_name":"George Terinte-Balcan","author_inst":"Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique-Hopitaux de Paris, Paris, France"},{"author_name":"Francesca Testa","author_inst":"Nephrology, Dialysis and Kidney Transplant Unit, University Hospital of Modena, Modena, Italy"},{"author_name":"David O. Hendriquez Ticas","author_inst":"Department of Pathology, Northwestern Memorial Hospital, Feinberg School of Medicine Northwestern University, Chicago, United States"},{"author_name":"Maria F. Toniolo","author_inst":"Department of Pathology, Instituto de Transplantes y Alta Complejidad, Buenos Aires, Argentina"},{"author_name":"Dominique van Midden","author_inst":"Department of Pathology, Radboud University Medical Center, Radboud University, Nijmegen, Netherlands"},{"author_name":"Ramya K. Velagapudi","author_inst":"Department of Pathology, University of Mississippi Medical Center, Jackson, United States"},{"author_name":"Seethalakshmi Viswanathan","author_inst":"Department of Tissue Pathology, Westmead Hospital, Westmead Clinical School, University of Sydney, Sydney, Australia"},{"author_name":"Saskia von Stillfried","author_inst":"Institute for Pathology, RWTH Aachen University Hospital, Aachen, Germany"},{"author_name":"Chih-Ying Wu","author_inst":"Department of Pathology and laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Institute of Biomedical Sciences, National Chung Hsing Un"},{"author_name":"Nienke Kalverboer","author_inst":"Department of Pathology, Systems Pathology Research Group, Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Imke B. Bruns","author_inst":"Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands"},{"author_name":"Giulia Callegaro","author_inst":"Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands"},{"author_name":"Bob van de Water","author_inst":"Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands"},{"author_name":"Danny van der Helm","author_inst":"Division of Nephrology, Department Internal Medicine; Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Aiko P.J. de Vries","author_inst":"Division of Nephrology, Department Internal Medicine; Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Hessel Peters-Sengers","author_inst":"Center for Infection and Molecular Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands"},{"author_name":"Jesper Kers","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Pathology, Systems Pathology Resear"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Drivers of Diagnostic Variation in a Digital Global Kidney Transplant Reader Study","rel_doi":"10.64898\/2026.07.09.26357318","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357318","rel_abs":"Background Diagnostic interpretation of kidney allograft biopsies using the Banff classification remains variable, but the determinants of this variability are not fully defined. We performed a global, fully digital multi-reader study to identify the principal drivers of disagreement in Banff-based assessment. Methods Thirty six kidney transplant biopsies were independently scored by 67 renal pathologists on a standardized digital platform. Readers assessed Banff lesions on hematoxylin and eosin, periodic acid Schiff, and Jones' silver stains; final diagnostic categories were assigned using prespecified Banff-based decision rules. Interobserver agreement was quantified with Gwet's agreement coefficient (AC) statistics. Determinants of diagnostic agreement were evaluated) using pairwise mixed-effects logistic regression, and reader similarity was examined by principal component analysis (PCA) with post hoc molecular annotation. Results Agreement for final diagnostic categories was moderate (Gwet's AC1, 0.55; 95% CI, 0.47 - 0.63). Lesion-level agreement varied substantially, with lowest agreement for selected threshold-dependent inflammatory or semi-quantitative lesions, including interstitial inflammation in areas of IFTA, peritubular capillaritis and arteriolar hyalinosis. Diagnostic concordance differed markedly across biopsies, indicating strong case-level heterogeneity. In pairwise models, differences in active inflammatory and vascular lesion scoring were the strongest correlates of diagnostic disagreement; reader experience and geography contributed minimally. Principal component analysis showed reader variation was organized along two dominant axes: a rejection-calling threshold axis linked mainly to tubulointerstitial inflammatory injury, and a T cell-mediated (TCMR\/TI) and antibody-mediated\/microvascular (AMR\/MVI) inflammation-oriented phenotypic classification axis. Conclusion Interobserver variation in Banff-based kidney transplant biopsy assessment is structured rather than random and driven mainly by how readers threshold and integrate key inflammatory lesion compartments rather than experience or geographic location.","rel_num_authors":77,"rel_authors":[{"author_name":"Rianne Hofstraat-Boersma","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Van 't Hoff Institute for Molecular Sciences, Uni"},{"author_name":"Romy du Long","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Pathology, University Medical Cente"},{"author_name":"Giorgio Buzzanca","author_inst":"Department of Pathology, Systems Pathology Research Group, Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Adeyemi A. Abiola","author_inst":"Department of Histopathology, African Medical Center of Excellence Hospital, Abuja, Nigeria"},{"author_name":"Sam Albadri","author_inst":"Department of Pathology, Mayo Clinic, Mayo Clinic School of Medicine, Rochester, United States"},{"author_name":"Zahabia Ali","author_inst":"Department of Cellular Pathology, Barts NHS Trust, London, United Kingdom"},{"author_name":"Ahmed Altaleb","author_inst":"Histopathology Unit, Mubarak Alkabeer Hospital, Jabriya, Kuwait"},{"author_name":"Andrea Angioi","author_inst":"S.C.D.U. Nefrologia, Dialisi e Trapianto, ARNAS Brotzu Hospital, Cagliari, Italy"},{"author_name":"Sultana G. Banu","author_inst":"Department of Pathology, Bangladesh Medical University, Dhaka, Bangladesh"},{"author_name":"Marc Barry","author_inst":"Department of Pathology, University of Utah, Salt Lake City, United States"},{"author_name":"Ami R. Bhalodia","author_inst":"The Pathology Laboratory, Lake Charles, United States"},{"author_name":"Paola Bianco","author_inst":"S.C. Anatomia Patologia, ARNAS Brotzu Hospital, Cagliari, Italy"},{"author_name":"Verena Broecker","author_inst":"Department of Pathology, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden"},{"author_name":"Roman Buelow","author_inst":"Institute for Pathology, RWTH Aachen University Hospital, Aachen, Germany"},{"author_name":"Bertrand Chauveau","author_inst":"Department of Pathology, Bordeaux University Hospital, Bordeaux, France"},{"author_name":"Guoli Chen","author_inst":"Department of Pathology, Penn State Health, Penn State College of Medicine, Hershey, United States"},{"author_name":"Boonyarit Cheunsuchon","author_inst":"Department of Pathology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand"},{"author_name":"Giovanna M. Crisi","author_inst":"Department of Pathology, UMASS-Chan School of Medical School - Baystate, Springfield, United States"},{"author_name":"Simin Daneshvar","author_inst":"Department of Anatomical Pathology, St. Vincent's Hospital, University of Melbourne, Melbourne, Australia"},{"author_name":"Amelie Dendooven","author_inst":"Department of Pathology, University Hospital of Ghent, Ghent University, Ghent, Belgium; Department of Pathology, Faculty of Medicine and Health Sciences, Unive"},{"author_name":"Pouneh Dokouhaki","author_inst":"Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada; Department of Pathology, St. Paul Hospital, Providence Healt"},{"author_name":"Cinthia B. Drachenberg","author_inst":"Department of Pathology, University of Maryland School of Medicine, Baltimore, United States"},{"author_name":"Alton B. Farris","author_inst":"Department of Pathology and laboratory Medicine, Emory University Hospital, Emory University, Atlanta, United States"},{"author_name":"Sophie Ferlicot","author_inst":"Department of Pathology, Le Kremlin-Bicetre Hospital, Paris-Saclay University, Paris, France"},{"author_name":"Sandrine Florquin","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands"},{"author_name":"Francesco Fontana","author_inst":"Nephrology, Dialysis and Kidney Transplant Unit, University Hospital of Modena, Modena, Italy"},{"author_name":"Jean-Baptiste Gibier","author_inst":"Institute of Pathology, Centre Hospitalier Universitaire de Lille, Lille, France"},{"author_name":"Ian W. Gibson","author_inst":"Department of Pathology, University of Manitoba, Winnipeg, Canada"},{"author_name":"Saurabh Gujarathi","author_inst":"Department of Pathology, Manipal Hospital, Pune, India"},{"author_name":"Allen R. Hendricks","author_inst":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States"},{"author_name":"Sufia Husain","author_inst":"Department of Pathology, College of Medicine, King Saud University - Medical City, Riyadh, Saudi Arabia"},{"author_name":"Jaynul Islam","author_inst":"Department of Pathology, BIRDEM General Hospital, Dhaka, Bangladesh"},{"author_name":"Wesam Ismail","author_inst":"Department of Pathology, Beni-Suef University, Beni-Suef, Egypt"},{"author_name":"Geetha Jagannathan","author_inst":"Department of Pathology and laboratory Medicine, Emory University Hospital, Emory University, Atlanta, United States"},{"author_name":"Johannes Klager","author_inst":"Department of Pathology, General Hospital of Vienna, Medical University of Vienna, Vienna, Austria"},{"author_name":"Nicolas Kozakowski","author_inst":"Department of Pathology, General Hospital of Vienna, Medical University of Vienna, Vienna, Austria"},{"author_name":"Adriana Krizova","author_inst":"Department of Laboratory Medicine, St. Michael's Hospital, University of Toronto, Toronto, Canada"},{"author_name":"Anila A. Kurien","author_inst":"Department of Pathology, Renopath, Center for Renal and Urological Pathology, Chennai, India"},{"author_name":"Boomi Kwon","author_inst":"Department of Pathology, Mater Hospital, Brisbane, Australia"},{"author_name":"Vincenzo L'Imperio","author_inst":"Department of Medicine and Surgery, Pathology, Fondazione IRCCS San Gerardo dei Tintori, University of Milano-Bicocca, Monza, Italy"},{"author_name":"Felipe L. Ledesma","author_inst":"Department of Pathology, University of Sao Paulo Medicine School, Sao Paulo, Brazil"},{"author_name":"Julia P. Low","author_inst":"Department of Anatomical Pathology, Sydpath, St. Vincent's Hospital, Sydney, University of South Wales, Australia"},{"author_name":"Jonne Martin","author_inst":"Department of Cellular Pathology, The Royal London Hospital, Queen Mary University of London, London, United Kingdom"},{"author_name":"Shweta S. Mehta","author_inst":"Department of Pathology, Kauvery Hospital, Bengaluru, India"},{"author_name":"Nidia Messias","author_inst":"Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, United States"},{"author_name":"Salvatore E. Mignano","author_inst":"Department of Pathology & Genomic Medicine, Thomas Jefferson University Hospital, Philadelphia, United States"},{"author_name":"Monik E. Miranda","author_inst":"Department of Anatomical Pathology, Cipto Mangunkusumo Hospital, Universitas Indonesia, Jakarta, Indonesia"},{"author_name":"Gilbert Moeckel","author_inst":"Department of Pathology, Yale New Haven Hospital, Yale University, New Haven, United States"},{"author_name":"Chiara Pala","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Medicine and Surgery, Nephrology Un"},{"author_name":"Brendon Price","author_inst":"Division of Anatomical Pathology, Department of Pathology, NHLS.Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa"},{"author_name":"Marc A. Ranson","author_inst":"Department of Pathology, University of Manitoba, Winnipeg, Canada"},{"author_name":"Andrea N. Rodriguez","author_inst":"Department of Pathology, Hospital Nacional Professor Alejandro Posadas, Buenos Aires, Argentina; Department of Pathology, The Favaloro Foundation University Hos"},{"author_name":"Joris J.T.H. Roelofs","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands"},{"author_name":"Avi Rosenberg","author_inst":"Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States"},{"author_name":"Alireza Sadeghipour","author_inst":"Department of Pathology, Rasoul-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran"},{"author_name":"Miroslav Sekulic","author_inst":"Department of Pathology and Cell Biology, Columbia University Medical Center, Columbia University, New York, United States"},{"author_name":"Suman Setty","author_inst":"Department of Pathology, University of Illinois Hospital and Health Sciences System, University of Illinois at Chicago, Chicago, United States"},{"author_name":"Michael Sheaff","author_inst":"Department of Cellular Pathology, Barts NHS Trust, London, United Kingdom"},{"author_name":"Maria F.S. Soares","author_inst":"Department of Cellular Pathology, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom"},{"author_name":"Jerasit Surintrspanont","author_inst":"Department of Pathology, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand"},{"author_name":"George Terinte-Balcan","author_inst":"Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique-Hopitaux de Paris, Paris, France"},{"author_name":"Francesca Testa","author_inst":"Nephrology, Dialysis and Kidney Transplant Unit, University Hospital of Modena, Modena, Italy"},{"author_name":"David O. Hendriquez Ticas","author_inst":"Department of Pathology, Northwestern Memorial Hospital, Feinberg School of Medicine Northwestern University, Chicago, United States"},{"author_name":"Maria F. Toniolo","author_inst":"Department of Pathology, Instituto de Transplantes y Alta Complejidad, Buenos Aires, Argentina"},{"author_name":"Dominique van Midden","author_inst":"Department of Pathology, Radboud University Medical Center, Radboud University, Nijmegen, Netherlands"},{"author_name":"Ramya K. Velagapudi","author_inst":"Department of Pathology, University of Mississippi Medical Center, Jackson, United States"},{"author_name":"Seethalakshmi Viswanathan","author_inst":"Department of Tissue Pathology, Westmead Hospital, Westmead Clinical School, University of Sydney, Sydney, Australia"},{"author_name":"Saskia von Stillfried","author_inst":"Institute for Pathology, RWTH Aachen University Hospital, Aachen, Germany"},{"author_name":"Chih-Ying Wu","author_inst":"Department of Pathology and laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Institute of Biomedical Sciences, National Chung Hsing Un"},{"author_name":"Nienke Kalverboer","author_inst":"Department of Pathology, Systems Pathology Research Group, Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Imke B. Bruns","author_inst":"Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands"},{"author_name":"Giulia Callegaro","author_inst":"Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands"},{"author_name":"Bob van de Water","author_inst":"Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands"},{"author_name":"Danny van der Helm","author_inst":"Division of Nephrology, Department Internal Medicine; Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Aiko P.J. de Vries","author_inst":"Division of Nephrology, Department Internal Medicine; Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Hessel Peters-Sengers","author_inst":"Center for Infection and Molecular Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands"},{"author_name":"Jesper Kers","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Pathology, Systems Pathology Resear"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Blood DNA Methylation Predicts Long-Term Risk of Dementia in Prospective Cohorts","rel_doi":"10.64898\/2026.07.08.26357554","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357554","rel_abs":"Blood-based DNA methylation may help identify biological changes related to dementia risk before clinical symptoms appear. We conducted an epigenome-wide association study of incident all-cause dementia in 5,999 cognitively healthy women from the Women's Health Initiative Memory Study, 777 of whom developed dementia over up to 25 years of follow-up. Baseline blood DNA methylation was tested for association with time to dementia. One CpG site, cg05917797, was significantly associated with dementia risk, with higher methylation linked to lower risk. This association was only minimally changed after accounting for APOE {varepsilon}4 carrier status, plasma p-tau217, and epigenetic aging measures. cg05917797 also replicated in meta-analysis of four independent prospective cohorts including 10,916 participants and 413 incident dementia cases. In post-mortem brain methylation datasets, higher methylation at cg05917797 was associated with lower Braak stage in temporal gyrus and cerebellum. In meta-analysis of all five prospective cohorts, including 16,915 participants and 1,190 dementia cases, cg05917797 remained the leading association, and three additional CpGs were identified for further study. These findings support cg05917797 as a reproducible blood-based epigenetic marker of long-term dementia risk.","rel_num_authors":19,"rel_authors":[{"author_name":"Adam X Maihofer","author_inst":"UC San Diego"},{"author_name":"Caroline E. Mackey","author_inst":"University of California San Diego"},{"author_name":"Josephine A. Robertson","author_inst":"University of Edinburgh"},{"author_name":"Riccardo E. Marioni","author_inst":"University of Edinburgh"},{"author_name":"Steve Nguyen","author_inst":"UCSD HWSPH"},{"author_name":"Linda K. McEvoy","author_inst":"Wake Forest University School of Medicine"},{"author_name":"Andrea Z. LaCroix","author_inst":"University of California San Diego"},{"author_name":"Mark  Espeland A. Espeland","author_inst":"Wake Forest University School of Medicine"},{"author_name":"Stephen R. Rapp","author_inst":"Wake Forest University School of Medicine"},{"author_name":"Susan M. Resnick","author_inst":"National Institutes of Health"},{"author_name":"Bowei Zhang","author_inst":"University of California - San Diego"},{"author_name":"Steve Horvath","author_inst":"University of California, Los Angeles"},{"author_name":"Kenneth B Beckman","author_inst":"University of Minnesota"},{"author_name":"Towia A. Libermann","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Tom C Russ","author_inst":"University of Edinburgh"},{"author_name":"Simon R Cox","author_inst":"University of Edinburgh"},{"author_name":"Sarah E Harris","author_inst":"University of Edinburgh"},{"author_name":"Maira Pyrgioti","author_inst":"University of Edinburgh"},{"author_name":"Aladdin H Shadyab","author_inst":"University of California San Diego"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"CFD-derived biomarkers in intermediate risk pulmonary embolism patients treated with mechanical thrombectomy","rel_doi":"10.64898\/2026.07.09.26357404","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357404","rel_abs":"Background: Acute pulmonary embolism (PE) is a leading cause of morbidity and mortality with persistent difficulties in choosing interventions and predicting outcomes for patients defined clinically as intermediate risk. Computational fluid dynamics (CFD) tools have been used to understand the hemodynamic environment and plan interventions in the pulmonary arteries across a variety of disease conditions. Several biomechanical metrics have been used to evaluate risk in narrowed vessels, including hemodynamic resistance, power dissipation, and fractional flow reserve (FFR). In this study, we evaluate differences in these CFD-derived biomarkers between healthy controls (HC) and intermediate risk, acute PE patients. Additionally, we examine the response of patient hemodynamics to mechanical thrombectomy and compare values of these biomarkers across post-intervention pressure status. Methods: A CFD framework was developed to simulate patient-specific hemodynamics within the pulmonary vasculature identifiable from clinical imaging. The pipeline involved reconstructing three-dimensional (3D) structures of the pulmonary arteries and modeling blood flow with the finite element method. Patient-specific boundary conditions were derived from matching pre-intervention inlet mPAP to the patient's measured value given their measured CO as steady inflow. Converged simulations allowed for precise quantification of primary hemodynamic characteristics (flow and pressure) as well as secondary flow phenomena, primarily wall shear stress (WSS) and simulated pressure metrics such as fractional flow reserve (FFR). Results: Our simulations revealed significant elevations in resistance, power dissipation, and the number of vessels with low FFR in those patients with acute PE (n=6) compared to HC (n=3). Occlusions of hemodynamic significance were generally found in segmental pulmonary arteries. For patients with normalized pulmonary pressures post-thrombectomy (n=3), we found significantly higher proximal power dissipation and counts of low FFR vessels in comparison to those with elevated pressures after intervention (n=3). Distal resistance, which was derived from the portion of resistance attributed to the outflow boundary conditions, was significantly higher in patients with elevated pressures post-intervention. Across all PE patients, FFR count was significantly correlated with post-thrombectomy pulmonary pressure and cardiac index. Discussion: CFD-derived biomarkers offer a promising tool for understanding disease severity in acute PE. Differences between HCs and acute PE patients reveal expected increases in metrics associated with proximal disease burden. Yet, in examining acute PE patients with varying post-intervention hemodynamics, we found that these metrics of proximal disease burden could also be useful to predict the efficacy of mechanical thrombectomy. Those patients with normalized pressures had higher values for proximal disease metrics and lower values for distal disease metrics than those with continued elevations in pressure. This suggests that accessibility of hemodynamically-significant emboli to thrombectomy may be useful as a predictor for outcomes.","rel_num_authors":4,"rel_authors":[{"author_name":"Mehul Gilani","author_inst":"Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh Medical Center"},{"author_name":"Alexander Barr","author_inst":"Department of Biomedical Engineering, Carnegie Mellon University"},{"author_name":"Mazen O Al-Qadi","author_inst":"Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh Medical Center"},{"author_name":"Jason M Szafron","author_inst":"Department of Biomedical Engineering, Carnegie Mellon University"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Engagement with a Chatbot-based Intervention for the delivery of mailed at-home COVID-19 Testing: a Descriptive Log Analysis Study from the SCALE-UP II Trial","rel_doi":"10.64898\/2026.07.08.26357530","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357530","rel_abs":"Background Promoting at-home tests (e.g., for COVID-19) using chatbots may be a novel and scalable way to improve uptake across underserved populations. Objective The objective of this study was to assess the navigational patterns (i.e., sequence of interactions) of underserved populations when using a chatbot designed to provide education on COVID-19 testing and free order access for at-home COVID-19 test kits. Methods The study was a descriptive analysis of the original data of the chatbot intervention of the SCALE-UP II trial, which compared different digital health modalities (i.e., chatbots versus simple text messages) to deliver free at-home COVID-19 test kits to minority populations in Utah. SCALE-UP II (registration numbers NCT05533918; NCT05533359) was a multisite, pragmatic clinical trial with patients randomized in a 2x2x2 factorial design (smartphone study) to receive (1) chatbot or text messaging, (2) the option to request patient navigation, and (3) intervention frequency every 10 or 30 days. All other participants were randomized in a 2x2 factorial design (nonsmartphone study) to receive the option to request patient navigation and intervention frequency every 10 or 30 days. Eligible patients (1) had an appointment at one of the participating community health centers (CHC) in the last 3 years, (2) were 18 years and older, and (3) had a valid cellphone number recorded in the CHC electronic health record (EHR). The trial enrolled 2117 in the smartphone study and 31,439 in the nonsmartphone study. In the smartphone study, the proportion of participants who requested test kits in the Chatbot arm was lower than in SMS text messaging. In the nonsmartphone study, test kits was higher if they were messaged every 10 days. Sources of funding included the National Institute on Minority Health and Health Disparities (NIMHD) of the US National Institutes of Health (NIH) grant number 5U01MD017421 and by awards from the National Cancer Institute of the NIH (P30CA042014) and the Huntsman Cancer Foundation. Results: Of 1,051 patients randomized to the chatbot intervention, 309 (29%) launched the chatbot, 196 (63%) interacted with it, and 186 (60%) started the COVID-19 test kit ordering process. Among those who launched the chatbot, 170 (55%) completed a test kit order. One patient (0.3%) accessed the chatbot educational content. The median age was 51, with 66% female, 54% Latino\/a, 55% uninsured, and 86% located in an urban area. Conclusion: Ordering of COVID-19 test kits among underserved patients who interacted with the chatbot was high. Thus, chatbots may represent a viable approach to reach underserved populations as a part of public health response in a pandemic. All patients except one placed orders without reviewing educational content. Chatbot design should identify and minimize the number of steps for patients to achieve a specific goal.","rel_num_authors":26,"rel_authors":[{"author_name":"Joni  H Pierce","author_inst":"University of Utah"},{"author_name":"Jiantao Bian","author_inst":"University of Utah"},{"author_name":"Tatyana  V. Kuzmenko","author_inst":"University of Utah"},{"author_name":"Kimberly  A. Kaphingst","author_inst":"University of Utah"},{"author_name":"Leticia Stevens","author_inst":"University of Utah"},{"author_name":"Adriana Rush","author_inst":"University of Utah"},{"author_name":"Ryzen Benson","author_inst":"University of California San Francisco"},{"author_name":"Emerson  P. Borsato","author_inst":"University of Utah"},{"author_name":"Bryan Gibson","author_inst":"University of Utah Health Clinical Neurosciences Center"},{"author_name":"Kensaku Kawamoto","author_inst":"University of Utah"},{"author_name":"Andy  J. King","author_inst":"University of Utah"},{"author_name":"Brian Orleans","author_inst":"University of Utah"},{"author_name":"Jonathan Chipman","author_inst":"University of Utah"},{"author_name":"Tom Greene","author_inst":"University of Utah"},{"author_name":"Ray Meads","author_inst":"University of Utah"},{"author_name":"Tracey Siaperas","author_inst":"AUCH: Association for Utah Community Health"},{"author_name":"Shlisa Hughes","author_inst":"AUCH: Association for Utah Community Health"},{"author_name":"Alan Pruhs","author_inst":"AUCH: Association for Utah Community Health"},{"author_name":"Courtney  Pariera Dinkins","author_inst":"AUCH: Association for Utah Community Health"},{"author_name":"Cho  Y. Lam","author_inst":"Huntsman Cancer Institute Cancer Hospital: University of Utah Health Huntsman Cancer Institute"},{"author_name":"Ryan  C. Cornia","author_inst":"University of Utah"},{"author_name":"Richard  L. Bradshaw","author_inst":"University of Utah"},{"author_name":"Jorie Butler","author_inst":"University of Utah"},{"author_name":"Chelsey  R. Schlechter","author_inst":"University of Utah"},{"author_name":"David  W. Wetter","author_inst":"University of Utah Health Huntsman Cancer Institute"},{"author_name":"Guilherme Del Fiol","author_inst":"University of Utah"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Automatic Classification of Medical Artificial Intelligence Articles by Their Level of Translational Maturity: An Interpretable Supervised Text-Classification Approach","rel_doi":"10.64898\/2026.07.09.26357253","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357253","rel_abs":"The rapid expansion of the medical artificial intelligence (AI) literature has outpaced our ability to judge how far published models have progressed towards clinical use. We investigated whether the translational maturity of a study can be estimated automatically from its abstract. Using PubMed, we assembled a corpus of 11,024 candidate articles, reduced it to 1,816 AI-related articles by heuristic filtering, and manually double-annotated a balanced sample of 524 articles across five maturity classes (internal validation, external validation, prospective evaluation, implementation or governance, and not applicable). Abstracts were represented as TF-IDF features and classified using multinomial logistic regression with a Lasso penalty, chosen for interpretability and suitability for a small, imbalanced dataset. On a stratified held-out test set (n = 104), the model achieved 69.2% accuracy, Cohen's kappa of 0.495, macro-F1 of 0.458 and a weighted AUC of 0.820. Performance was strong for the frequent classes but poor for the rare implementation or governance class, which the model failed to recover. A balanced manual verification of 200 large-corpus predictions confirmed this pattern, with per-class precision ranging from 82.5% (internal validation) to 5.0% (implementation or governance). An interpretable, low-resource classifier can support literature mapping but requires human oversight for advanced maturity levels.","rel_num_authors":2,"rel_authors":[{"author_name":"Sandeep Reddy","author_inst":"Queensland University of Technology"},{"author_name":"Alix Heritier","author_inst":"ENSAI"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Aficamten Reduces Eligibility for Septal Reduction Therapy in Obstructive Hypertrophic Cardiomyopathy: Long-Term Outcomes from FOREST-HCM","rel_doi":"10.64898\/2026.07.08.26357594","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357594","rel_abs":"Background. Septal reduction therapy (SRT) is recommended in drug-refractory, symptomatic obstructive hypertrophic cardiomyopathy (oHCM). We evaluated whether aficamten, a novel cardiac myosin inhibitor, can reliably transition guideline-eligible SRT candidates to ineligibility, and the associated safety profile of aficamten in this group. Methods. We analyzed participants with oHCM enrolled in FOREST-HCM (NCT04848506), the long-term open-label extension study of aficamten, from 28 May 2021 to 9 May 2025. Results. Three hundred and fifteen patients were included, of whom 104 met 2024 ACC\/AHA guideline criteria for SRT eligibility at baseline. The SRT-eligible cohort was predominantly female (57%), with mean resting and Valsalva left ventricular outflow tract (LVOT) gradients of 63 {+\/-} 39 and 109 {+\/-} 42 mmHg, and all were in New York Heart Association (NYHA) class III. All baseline SRT-eligible patients became SRT-ineligible with aficamten therapy during study follow-up over a median of 42 days (IQR: 17, 49), except for one participant who withdrew from the study to pursue SRT (total of 3 participants withdrew). After dose titration, 3\/104 (2.9%) remained guideline-eligible; by week 72 no patients met eligibility criteria. At maintenance, resting and Valsalva LVOT gradients improved by a least-squares mean of ?41 mmHg ([95% CI ?44 to ?37]; P<0.0001) and ?56 mmHg ([95% CI ?62 to ?51]; P<0.0001), respectively. Relative to baseline, NT-proBNP improved by 77% (95% CI 74 ? 80%), high-sensitivity cardiac troponin I decreased by 38% (95% CI 30 ? 46%), KCCQ-CSS improved by a mean of 20.2 (SD 19.3) points, and 95.2% of SRT-eligible patients had improved by ?1 NYHA class. Overall, the safety profile was favorable, with 2 occurrences of left ventricular ejection fraction (LVEF) < 50% over 193.7 patient-years of follow-up (1 event per 100 patient-years), managed by down-titration. There were no baseline SRT-eligible patients who died or developed LVEF <40%. Conclusions. Aficamten resolved guideline eligibility for SRT in nearly all baseline-eligible patients, with rapid and durable improvements in hemodynamics, symptoms, biomarkers and health status sustained for up to 3.5 years. Instances of LVEF <50% were rare and without clinical sequelae. These data support aficamten as a safe and effective alternative to SRT in oHCM.","rel_num_authors":27,"rel_authors":[{"author_name":"Ahmad Masri","author_inst":"Oregon Health & Science University"},{"author_name":"- FOREST-HCM Investigators","author_inst":"-"},{"author_name":"Benjamin Meder","author_inst":"University of Heidelberg"},{"author_name":"Lubna Choudhury","author_inst":"Northwestern University"},{"author_name":"Pablo Garcia-Pavia","author_inst":"Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain"},{"author_name":"Theodore P. Abraham","author_inst":"University of California San Francisco Division of Cardiology"},{"author_name":"Roberto Barriales-Villa","author_inst":"Complexo Hospitalario Universitario A Coru\u00f1a, Universidade da Coru\u00f1a, SERGAS, Instituto de Investigaci\u00f3n Biom\u00e9dica A Coru\u00f1a (INIBIC), CIBERCV"},{"author_name":"Ozlem Bilen","author_inst":"Emory University"},{"author_name":"Perry M. Elliott","author_inst":"University College London"},{"author_name":"Albert Hagege","author_inst":"Hopital Europeen Georges Pompidou Cancerologie"},{"author_name":"Sherif F Nagueh","author_inst":"Methodist DeBakey Heart and Vascular Center"},{"author_name":"Srihari S. Naidu","author_inst":"Westchester Medical Center Foundation"},{"author_name":"Michael E Nassif","author_inst":"University of Missouri Extension"},{"author_name":"Iacopo Olivotto","author_inst":"Meyer Children?s Hospital"},{"author_name":"Artur Oreziak","author_inst":"Institute of Cardiology"},{"author_name":"Anjali T. Owens","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"Omar Wever-Pinzon","author_inst":"University of Miami Health System"},{"author_name":"Florian Rader","author_inst":"Cedars-Sinai Smidt Heart Institute"},{"author_name":"Albree Tower-Rader","author_inst":"Massachusetts General Hospital"},{"author_name":"Justin Godown","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Stephen B. Heitner","author_inst":"Cytokinetics Inc"},{"author_name":"Daniel L Jacoby","author_inst":"Cytokinetics, Incorporated"},{"author_name":"Stuart Kupfer","author_inst":"Cytokinetics"},{"author_name":"Fady I. Malik","author_inst":"Cytokinetics Inc"},{"author_name":"Regina Sohn","author_inst":"Cytokinetics, Incorporated"},{"author_name":"Jenny Wei","author_inst":"Cytokinetics, Inc."},{"author_name":"Sara Saberi","author_inst":"University of Michigan Herbarium"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Aficamten Reduces Eligibility for Septal Reduction Therapy in Obstructive Hypertrophic Cardiomyopathy: Long-Term Outcomes from FOREST-HCM","rel_doi":"10.64898\/2026.07.08.26357594","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357594","rel_abs":"Background. Septal reduction therapy (SRT) is recommended in drug-refractory, symptomatic obstructive hypertrophic cardiomyopathy (oHCM). We evaluated whether aficamten, a novel cardiac myosin inhibitor, can reliably transition guideline-eligible SRT candidates to ineligibility, and the associated safety profile of aficamten in this group. Methods. We analyzed participants with oHCM enrolled in FOREST-HCM (NCT04848506), the long-term open-label extension study of aficamten, from 28 May 2021 to 9 May 2025. Results. Three hundred and fifteen patients were included, of whom 104 met 2024 ACC\/AHA guideline criteria for SRT eligibility at baseline. The SRT-eligible cohort was predominantly female (57%), with mean resting and Valsalva left ventricular outflow tract (LVOT) gradients of 63 {+\/-} 39 and 109 {+\/-} 42 mmHg, and all were in New York Heart Association (NYHA) class III. All baseline SRT-eligible patients became SRT-ineligible with aficamten therapy during study follow-up over a median of 42 days (IQR: 17, 49), except for one participant who withdrew from the study to pursue SRT (total of 3 participants withdrew). After dose titration, 3\/104 (2.9%) remained guideline-eligible; by week 72 no patients met eligibility criteria. At maintenance, resting and Valsalva LVOT gradients improved by a least-squares mean of ?41 mmHg ([95% CI ?44 to ?37]; P<0.0001) and ?56 mmHg ([95% CI ?62 to ?51]; P<0.0001), respectively. Relative to baseline, NT-proBNP improved by 77% (95% CI 74 ? 80%), high-sensitivity cardiac troponin I decreased by 38% (95% CI 30 ? 46%), KCCQ-CSS improved by a mean of 20.2 (SD 19.3) points, and 95.2% of SRT-eligible patients had improved by ?1 NYHA class. Overall, the safety profile was favorable, with 2 occurrences of left ventricular ejection fraction (LVEF) < 50% over 193.7 patient-years of follow-up (1 event per 100 patient-years), managed by down-titration. There were no baseline SRT-eligible patients who died or developed LVEF <40%. Conclusions. Aficamten resolved guideline eligibility for SRT in nearly all baseline-eligible patients, with rapid and durable improvements in hemodynamics, symptoms, biomarkers and health status sustained for up to 3.5 years. Instances of LVEF <50% were rare and without clinical sequelae. These data support aficamten as a safe and effective alternative to SRT in oHCM.","rel_num_authors":27,"rel_authors":[{"author_name":"Ahmad Masri","author_inst":"Oregon Health & Science University"},{"author_name":"- FOREST-HCM Investigators","author_inst":"-"},{"author_name":"Benjamin Meder","author_inst":"University of Heidelberg"},{"author_name":"Lubna Choudhury","author_inst":"Northwestern University"},{"author_name":"Pablo Garcia-Pavia","author_inst":"Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain"},{"author_name":"Theodore P. Abraham","author_inst":"University of California San Francisco Division of Cardiology"},{"author_name":"Roberto Barriales-Villa","author_inst":"Complexo Hospitalario Universitario A Coru\u00f1a, Universidade da Coru\u00f1a, SERGAS, Instituto de Investigaci\u00f3n Biom\u00e9dica A Coru\u00f1a (INIBIC), CIBERCV"},{"author_name":"Ozlem Bilen","author_inst":"Emory University"},{"author_name":"Perry M. Elliott","author_inst":"University College London"},{"author_name":"Albert Hagege","author_inst":"Hopital Europeen Georges Pompidou Cancerologie"},{"author_name":"Sherif F Nagueh","author_inst":"Methodist DeBakey Heart and Vascular Center"},{"author_name":"Srihari S. Naidu","author_inst":"Westchester Medical Center Foundation"},{"author_name":"Michael E Nassif","author_inst":"University of Missouri Extension"},{"author_name":"Iacopo Olivotto","author_inst":"Meyer Children?s Hospital"},{"author_name":"Artur Oreziak","author_inst":"Institute of Cardiology"},{"author_name":"Anjali T. Owens","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"Omar Wever-Pinzon","author_inst":"University of Miami Health System"},{"author_name":"Florian Rader","author_inst":"Cedars-Sinai Smidt Heart Institute"},{"author_name":"Albree Tower-Rader","author_inst":"Massachusetts General Hospital"},{"author_name":"Justin Godown","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Stephen B. Heitner","author_inst":"Cytokinetics Inc"},{"author_name":"Daniel L Jacoby","author_inst":"Cytokinetics, Incorporated"},{"author_name":"Stuart Kupfer","author_inst":"Cytokinetics"},{"author_name":"Fady I. Malik","author_inst":"Cytokinetics Inc"},{"author_name":"Regina Sohn","author_inst":"Cytokinetics, Incorporated"},{"author_name":"Jenny Wei","author_inst":"Cytokinetics, Inc."},{"author_name":"Sara Saberi","author_inst":"University of Michigan Herbarium"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Aficamten Reduces Eligibility for Septal Reduction Therapy in Obstructive Hypertrophic Cardiomyopathy: Long-Term Outcomes from FOREST-HCM","rel_doi":"10.64898\/2026.07.08.26357594","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357594","rel_abs":"Background. Septal reduction therapy (SRT) is recommended in drug-refractory, symptomatic obstructive hypertrophic cardiomyopathy (oHCM). We evaluated whether aficamten, a novel cardiac myosin inhibitor, can reliably transition guideline-eligible SRT candidates to ineligibility, and the associated safety profile of aficamten in this group. Methods. We analyzed participants with oHCM enrolled in FOREST-HCM (NCT04848506), the long-term open-label extension study of aficamten, from 28 May 2021 to 9 May 2025. Results. Three hundred and fifteen patients were included, of whom 104 met 2024 ACC\/AHA guideline criteria for SRT eligibility at baseline. The SRT-eligible cohort was predominantly female (57%), with mean resting and Valsalva left ventricular outflow tract (LVOT) gradients of 63 {+\/-} 39 and 109 {+\/-} 42 mmHg, and all were in New York Heart Association (NYHA) class III. All baseline SRT-eligible patients became SRT-ineligible with aficamten therapy during study follow-up over a median of 42 days (IQR: 17, 49), except for one participant who withdrew from the study to pursue SRT (total of 3 participants withdrew). After dose titration, 3\/104 (2.9%) remained guideline-eligible; by week 72 no patients met eligibility criteria. At maintenance, resting and Valsalva LVOT gradients improved by a least-squares mean of ?41 mmHg ([95% CI ?44 to ?37]; P<0.0001) and ?56 mmHg ([95% CI ?62 to ?51]; P<0.0001), respectively. Relative to baseline, NT-proBNP improved by 77% (95% CI 74 ? 80%), high-sensitivity cardiac troponin I decreased by 38% (95% CI 30 ? 46%), KCCQ-CSS improved by a mean of 20.2 (SD 19.3) points, and 95.2% of SRT-eligible patients had improved by ?1 NYHA class. Overall, the safety profile was favorable, with 2 occurrences of left ventricular ejection fraction (LVEF) < 50% over 193.7 patient-years of follow-up (1 event per 100 patient-years), managed by down-titration. There were no baseline SRT-eligible patients who died or developed LVEF <40%. Conclusions. Aficamten resolved guideline eligibility for SRT in nearly all baseline-eligible patients, with rapid and durable improvements in hemodynamics, symptoms, biomarkers and health status sustained for up to 3.5 years. Instances of LVEF <50% were rare and without clinical sequelae. These data support aficamten as a safe and effective alternative to SRT in oHCM.","rel_num_authors":27,"rel_authors":[{"author_name":"Ahmad Masri","author_inst":"Oregon Health & Science University"},{"author_name":"- FOREST-HCM Investigators","author_inst":"-"},{"author_name":"Benjamin Meder","author_inst":"University of Heidelberg"},{"author_name":"Lubna Choudhury","author_inst":"Northwestern University"},{"author_name":"Pablo Garcia-Pavia","author_inst":"Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain"},{"author_name":"Theodore P. Abraham","author_inst":"University of California San Francisco Division of Cardiology"},{"author_name":"Roberto Barriales-Villa","author_inst":"Complexo Hospitalario Universitario A Coru\u00f1a, Universidade da Coru\u00f1a, SERGAS, Instituto de Investigaci\u00f3n Biom\u00e9dica A Coru\u00f1a (INIBIC), CIBERCV"},{"author_name":"Ozlem Bilen","author_inst":"Emory University"},{"author_name":"Perry M. Elliott","author_inst":"University College London"},{"author_name":"Albert Hagege","author_inst":"Hopital Europeen Georges Pompidou Cancerologie"},{"author_name":"Sherif F Nagueh","author_inst":"Methodist DeBakey Heart and Vascular Center"},{"author_name":"Srihari S. Naidu","author_inst":"Westchester Medical Center Foundation"},{"author_name":"Michael E Nassif","author_inst":"University of Missouri Extension"},{"author_name":"Iacopo Olivotto","author_inst":"Meyer Children?s Hospital"},{"author_name":"Artur Oreziak","author_inst":"Institute of Cardiology"},{"author_name":"Anjali T. Owens","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"Omar Wever-Pinzon","author_inst":"University of Miami Health System"},{"author_name":"Florian Rader","author_inst":"Cedars-Sinai Smidt Heart Institute"},{"author_name":"Albree Tower-Rader","author_inst":"Massachusetts General Hospital"},{"author_name":"Justin Godown","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Stephen B. Heitner","author_inst":"Cytokinetics Inc"},{"author_name":"Daniel L Jacoby","author_inst":"Cytokinetics, Incorporated"},{"author_name":"Stuart Kupfer","author_inst":"Cytokinetics"},{"author_name":"Fady I. Malik","author_inst":"Cytokinetics Inc"},{"author_name":"Regina Sohn","author_inst":"Cytokinetics, Incorporated"},{"author_name":"Jenny Wei","author_inst":"Cytokinetics, Inc."},{"author_name":"Sara Saberi","author_inst":"University of Michigan Herbarium"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Protocol for Implementation and Evaluation of a Reserve-Stress-Rescue Pathway for High-Risk Preoperative Triage.","rel_doi":"10.64898\/2026.07.09.26357629","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357629","rel_abs":"Background High-risk preoperative triage remains fragmented: existing tools often estimate risk without identifying modifiable mechanisms or linking classification to postoperative monitoring, destination planning, and rescue resources. This protocol describes implementation and evaluation of a Reserve-Stress-Rescue (RSR Framework), pathway that operationalizes perioperative high risk as a mismatch among patient physiologic reserve, procedural stress, and system rescue capacity. Approach RSR is a proposed clinician-facing, modular scoring framework for adults undergoing major surgery, especially patients with frailty, multimorbidity, poor functional capacity, anemia or malnutrition, cardiopulmonary disease, or limited postoperative support. Each domain, Reserve, Stress, and Rescue, is scored from 0 to 4 and recorded as both a three-part profile and a total score from 0 to 12. Scores map to Green, Amber, Red, and Crimson triage bands that trigger escalating actions, including targeted optimization, multidisciplinary review, anesthesia and surgical planning, postoperative destination selection, monitoring intensity, and predefined escalation criteria. Validation Plan The initial phase of this study received an exemption determination from the Yale University Institutional Review Board on June 3, 2026, under IRB Protocol ID 2000042729, with exempt categories 2(ii) and 4(iii), including a waiver of HIPAA authorization for access to and use of protected health information as described in the approved protocol. Evaluation will proceed in stages, assessing feasibility, interrater reliability, completeness, acceptability, discrimination, calibration, and clinical utility. Key outcomes include postoperative complications, unplanned escalation of care, intensive care utilization, failure to rescue, mortality, length of stay, triage burden, low-yield testing cascades, and management-changing pathway activation. Conclusion The RSR pathway reframes high-risk status as a modifiable interaction between vulnerability, operative insult, and rescue capacity rather than a fixed patient label. If feasible and valid, RSR may standardize high-risk identification, align perioperative resources with anticipated physiology, improve communication, and support safer, actionable shared decision-making.","rel_num_authors":3,"rel_authors":[{"author_name":"Inwoo Sohn","author_inst":"University of California San Diego"},{"author_name":"Tanush Singh","author_inst":"Philadelphia College of Osteopathic Medicine"},{"author_name":"Zyad  J. Carr","author_inst":"Yale School of Medicine: Yale University School of Medicine"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Protocol for Implementation and Evaluation of a Reserve-Stress-Rescue Pathway for High-Risk Preoperative Triage.","rel_doi":"10.64898\/2026.07.09.26357629","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357629","rel_abs":"Background High-risk preoperative triage remains fragmented: existing tools often estimate risk without identifying modifiable mechanisms or linking classification to postoperative monitoring, destination planning, and rescue resources. This protocol describes implementation and evaluation of a Reserve-Stress-Rescue (RSR Framework), pathway that operationalizes perioperative high risk as a mismatch among patient physiologic reserve, procedural stress, and system rescue capacity. Approach RSR is a proposed clinician-facing, modular scoring framework for adults undergoing major surgery, especially patients with frailty, multimorbidity, poor functional capacity, anemia or malnutrition, cardiopulmonary disease, or limited postoperative support. Each domain, Reserve, Stress, and Rescue, is scored from 0 to 4 and recorded as both a three-part profile and a total score from 0 to 12. Scores map to Green, Amber, Red, and Crimson triage bands that trigger escalating actions, including targeted optimization, multidisciplinary review, anesthesia and surgical planning, postoperative destination selection, monitoring intensity, and predefined escalation criteria. Validation Plan The initial phase of this study received an exemption determination from the Yale University Institutional Review Board on June 3, 2026, under IRB Protocol ID 2000042729, with exempt categories 2(ii) and 4(iii), including a waiver of HIPAA authorization for access to and use of protected health information as described in the approved protocol. Evaluation will proceed in stages, assessing feasibility, interrater reliability, completeness, acceptability, discrimination, calibration, and clinical utility. Key outcomes include postoperative complications, unplanned escalation of care, intensive care utilization, failure to rescue, mortality, length of stay, triage burden, low-yield testing cascades, and management-changing pathway activation. Conclusion The RSR pathway reframes high-risk status as a modifiable interaction between vulnerability, operative insult, and rescue capacity rather than a fixed patient label. If feasible and valid, RSR may standardize high-risk identification, align perioperative resources with anticipated physiology, improve communication, and support safer, actionable shared decision-making.","rel_num_authors":3,"rel_authors":[{"author_name":"Inwoo Sohn","author_inst":"University of California San Diego"},{"author_name":"Tanush Singh","author_inst":"Philadelphia College of Osteopathic Medicine"},{"author_name":"Zyad  J. Carr","author_inst":"Yale School of Medicine: Yale University School of Medicine"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Distinct Patterns of Mobility Recovery After Stroke Using Routine Clinical Data","rel_doi":"10.64898\/2026.07.08.26357600","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357600","rel_abs":"Background: Mobility recovery after stroke is highly variable, yet is typically described using average patterns that obscure meaningful differences between individuals. Identifying distinct recovery trajectories may improve prognostication and guide rehabilitation strategies. Methods: We conducted a retrospective cohort study of adults admitted for stroke to a large health system between 2016 and 2024. Mobility was assessed using Activity Measure for Post-Acute Care (AM-PAC) Basic Mobility, which was collected during routine clinical care. Growth mixture modeling was used to identify subgroups with distinct mobility recovery trajectories during the first 180 days after stroke. Subgroups were then characterized with baseline personal and clinical characteristics. Results: Seven hundred and fifty individuals contributed 3,389 mobility observations (median 4 per person). A five-class solution was selected based on model fit and classification quality. Distinct trajectories were identified: low stable (n=127), low rapidly improving (n=29), mid declining (n=169), mid improving (n=365), and high stable (n=60). Subgroups differed in both baseline mobility and patterns of change over time, with some demonstrating improvement, others remaining stable, and one declining. Individuals in improving subgroups were generally younger, more likely to be independent before stroke, received physical therapy on a greater proportion of hospital days, and were more frequently discharged to inpatient rehabilitation. In contrast, those in low or declining trajectories had lower baseline function, longer hospital stays, and were more likely to be discharged to skilled nursing facilities. Conclusions: The distinct mobility recovery trajectories identified in this work reflect the heterogeneity present in routine clinical practice. Subgroups differed in both recovery patterns and characteristics. Early identification of trajectory membership may improve prognostication and inform more targeted rehabilitation strategies.","rel_num_authors":4,"rel_authors":[{"author_name":"Margaret A. French","author_inst":"University of Utah Health"},{"author_name":"Elisabeth Breese Marsh","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Ryan Thomas Roemmich","author_inst":"Kennedy Krieger Institute"},{"author_name":"Preeti Raghavan","author_inst":"Johns Hopkins"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Glutamine and NAA dissociate in ALS across somatotopically defined motor regions using 7T MRSI","rel_doi":"10.64898\/2026.07.09.26357702","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357702","rel_abs":"Amyotrophic lateral sclerosis (ALS) is increasingly understood as a progressive neurodegenerative disorder with distributed cortical and subcortical involvement, but in vivo metabolic mapping has been limited by the spatial coverage of single-voxel proton magnetic resonance spectroscopy (MRS). We acquired high-resolution whole-brain 7T 3D-CRT-FID-MRSI alongside motor-cortex single-voxel sLASER in five rapidly progressing people living with ALS (plALS) and seven non-neurodegenerative controls (NCs), with up to three sessions per participant. Regional metabolite ratios (N-Acetylaspartate [tNAA], glutamate [Glu], glutamine [Gln] to creatine [tCr], and Glu+Gln [Glx] to tNAA) were modelled with Bayesian hierarchical mixed-effects models, and the primary motor cortex was subdivided along its dorsoventral somatotopic axis (bulbar\/face, hand\/upper-limb, foot\/lower-limb). At baseline, plALS showed a motor-cortex-selective tNAA\/tCr deficit (motor composite -8.7%, 95% credible Interval [CrI] -16.1 to -1.1, posterior probability=0.99) accompanied by cortically diffuse glutamatergic elevation (Gln\/tCr +25.6%, posterior probability=0.96; Glx\/tNAA +10.4%, posterior probability=0.95). Reliable separation of the J-coupled glutamine and glutamate resonances at 7T revealed Gln\/tCr as a more sensitive marker of glutamatergic dysregulation than Glu\/tCr alone in this cohort. Within the somatotopic subdivision, all five plALS showed their peak Gln\/tCr increase in the bulbar\/face zone irrespective of clinical onset, including three lower-limb-onset patients. Annualised metabolite slope by zone correlated with the matched ALSFRS-R domain decline (Glx\/tNAA r=0.82, p<0.001). Group-level longitudinal interactions were modest. Bayesian assurance simulations indicated Glx\/tNAA as the most efficient candidate primary endpoint for a confirmatory cross-sectional study. These findings demonstrate that 7T whole-brain MRSI can resolve a metabolic dissociation between motor-selective neuronal compromised and somatotopically patterned glutamatergic dysregulation in ALS and provide design-ready endpoint and sample-size guidance for utility as a structural biomarker of brain function in clinical trials.","rel_num_authors":12,"rel_authors":[{"author_name":"Zeinab Eftekhari","author_inst":"The University of Queensland"},{"author_name":"Sicong Tu","author_inst":"The University of Sydney"},{"author_name":"Timothy Ballard","author_inst":"The University of Queensland"},{"author_name":"Korbinian Eckstein","author_inst":"Medical University of Vienna"},{"author_name":"Bernhard Strasser","author_inst":"Medical University of Vienna"},{"author_name":"Fabian Niess","author_inst":"Medical University of Vienna"},{"author_name":"Lukas Hingerl","author_inst":"Medical University of Vienna"},{"author_name":"Wolfgang Bogner","author_inst":"Medical University of Vienna"},{"author_name":"Matthew C Kiernan","author_inst":"The University of Sydney"},{"author_name":"Robert D Henderson","author_inst":"The University of Queensland"},{"author_name":"Markus Barth","author_inst":"The University of Queensland"},{"author_name":"Thomas B Shaw","author_inst":"The University of Queensland"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Childhood Sexual Abuse and Long-Term Risk of Self-Harm, Overdose, and Cardiovascular Disease","rel_doi":"10.64898\/2026.07.09.26357627","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357627","rel_abs":"Importance Childhood sexual abuse (CSA) is linked to adverse psychiatric outcomes in adulthood, but evidence on its association with cardiovascular disease and mortality from large, diagnostically ascertained cohorts remains limited. Objective To assess the 10-year risk of all-cause mortality, suicide or self-harm, drug overdose or poisoning, and cardiovascular disease among patients with a diagnosed history of CSA compared with a matched unexposed cohort. Methods In this retrospective cohort study, we used deidentified electronic health record data from 68 health care organizations in the TriNetX US Collaborative Network. Patients diagnosed with confirmed or suspected childhood sexual abuse (CSA) before age 18 between January 1, 2003, and December 31, 2015, who had a subsequent adult encounter, were propensity score matched 1:1 with unexposed patients on age, sex, race and ethnicity, and baseline psychiatric and medical comorbidities (n = 9,083 per cohort). Outcomes--all-cause mortality, suicide or self-harm, drug overdose or poisoning, and cardiovascular disease--were assessed over 10 years from the index adult encounter using risk and time-to-event analyses to estimate risks, risk ratios, and hazard ratios. Results Among 18,166 matched patients (mean [SD] age, 19.0 [2.0] years; 14,813 [81.6%] female), CSA was associated with significantly elevated risk of suicide or self-harm (5.1% vs 2.8%; risk ratio [RR], 1.84; 95% CI, 1.57-2.16), drug overdose or poisoning (5.5% vs 3.7%; RR, 1.47; 95% CI, 1.28-1.69), and cardiovascular disease (12.3% vs 9.3%; RR, 1.31; 95% CI, 1.20-1.44), with concordant hazard ratios (all P < .001). All-cause mortality was numerically higher but not statistically significant (0.5% vs 0.4%; RR, 1.16; 95% CI, 0.75-1.79; P = .51). Conclusions and Relevance A diagnostically confirmed history of CSA was associated with substantially elevated 10-year risk of self-harm, overdose, and cardiovascular disease, independent of baseline demographic and psychiatric comorbidity. These findings support integrated psychiatric and cardiovascular screening for adult survivors of CSA and trauma-informed care extending beyond mental health services alone.","rel_num_authors":12,"rel_authors":[{"author_name":"Oluwasegun Akinyemi","author_inst":"Howard University College of Medicine"},{"author_name":"Olububechukwu Eze","author_inst":"Howard University College of Medicine"},{"author_name":"Mojisola Fasokun","author_inst":"University of Alabama at Birmingham"},{"author_name":"Isaac Olaosebikan","author_inst":"Towson University"},{"author_name":"Temitayo Ogundipe","author_inst":"Sentara Williamsburg Regional Medical Center"},{"author_name":"Delia Singleton","author_inst":"Howard University College of Medicine"},{"author_name":"Ayomide Ogunsakin","author_inst":"Howard University College of Medicine"},{"author_name":"Samar Khalil","author_inst":"Howard University College of Medicine"},{"author_name":"Kaelyn Gordon","author_inst":"Howard University College of Medicine"},{"author_name":"Miriam Micheal","author_inst":"Howard University College of Medicine"},{"author_name":"Kakra Hughes","author_inst":"Howard University College of Medicine"},{"author_name":"Temitope Ogundare","author_inst":"NewYork-Presbyterian Hospital: NewYork-Presbyterian Columbia University Medical Center"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Per- and Polyfluoroalkyl Substances Exposure in New Jersey Prostate Cancer Survivors: A Pilot Biomonitoring Study","rel_doi":"10.64898\/2026.07.08.26357561","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357561","rel_abs":"Background: Men with prostate cancer (PCa) may be especially vulnerable to per- and polyfluoroalkyl substances (PFAS) exposure due to their endocrine-disrupting and cardiometabolic impacts and cardiotoxicity and immune suppression of treatments. Objective: A pilot study was launched to measure serum and tap water PFAS concentrations in PCa survivors. Methods: Men with PCa were recruited from Rutgers Cancer Institute between February 2025 and March 2026, with ongoing enrollment and follow-up. Eligible men were aged [&ge;]40 years and either on active surveillance or within 3-12 months of initial definitive treatment. Participants provided blood and residential tap water samples, which were analyzed using mass spectrometry (serum) and modified EPA method 537 (water). Geometric means were used to summarize PFAS concentrations by race and assess serum-tap water correlations. Results: Of 235 eligible patients, 124 (60%) enrolled. Median age was 64 years; 63% were non-Hispanic White, 43% had a Gleason score [&le;]6. Roughly half of participants provided serum and\/or tap water samples. In serum, six PFAS analytes had >80% detection; of these analytes, median concentrations ranged from 0.13 ng\/mL (IQR: 0.07-0.20) for PFHpS to 2.55 ng\/mL (IQR:1.54-3.82) for nPFOS. Among 74 tap water samples, 9 PFAS analytes had >60% detection; of these, median concentrations of PFNA (0.56 ng\/L; IQR: 0.33-0.75), PFOA (3.75 ng\/L; IQR: 1.21-5.27), and PFOS (2.29 ng\/L; IQR: 0.46-2.89), were below New Jersey Maximum Contaminant Levels. Non-White participants had significantly higher levels of multiple PFAS analytes in both serum and tap water. Serum-tap water correlations were modest (r=0.22-0.41). Significance: The pilot study has demonstrated both the feasibility and importance of studying PFAS exposure pathways as well as potential impacts of PFAS exposure in diverse populations. Keywords: Prostatic Neoplasms, Per- and Polyfluoroalkyl Substances (PFAS), Biomonitoring, Environmental Exposure, Cohort Studies, Pilot study Impact Statement: This study provides some of the first estimates of PFAS exposure among prostate cancer patients in serum and tap water, showing moderate correlations between tap water and serum concentrations of specific PFAS analytes. These findings can support larger studies to identify environmental exposure sources and evaluate the role of PFAS in prostate cancer progression and outcomes.","rel_num_authors":18,"rel_authors":[{"author_name":"Stefanie A. Joseph","author_inst":"Cancer Epidemiology and Health Outcomes, Rutgers Cancer Institute, New Brunswick, NJ"},{"author_name":"Chidinma Opara","author_inst":"Cancer Epidemiology and Health Outcomes, Rutgers Cancer Institute, New Brunswick, NJ"},{"author_name":"Megan R. Shanahan","author_inst":"Cancer Epidemiology and Health Outcomes, Rutgers Cancer Institute, New Brunswick, NJ"},{"author_name":"Julianne Varga","author_inst":"Center for Pharmacoepidemiology and Treatment Science, Rutgers University, New Brunswick, NJ"},{"author_name":"Jennifer Falcon","author_inst":"Cancer Epidemiology and Health Outcomes, Rutgers Cancer Institute, New Brunswick, NJ"},{"author_name":"Uyaiobong Ibanga","author_inst":"Cancer Epidemiology and Health Outcomes, Rutgers Cancer Institute, New Brunswick, NJ"},{"author_name":"Surya Venkatraman","author_inst":"Cancer Epidemiology and Health Outcomes, Rutgers Cancer Institute, New Brunswick, NJ; Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunsw"},{"author_name":"Marley Perlstein","author_inst":"Cancer Epidemiology and Health Outcomes, Rutgers Cancer Institute, New Brunswick, NJ"},{"author_name":"Thomas L. Jang","author_inst":"Urologic Oncology, Rutgers Cancer Institute, New Brunswick, NJ"},{"author_name":"David Golombos","author_inst":"Urologic Oncology, Rutgers Cancer Institute, New Brunswick, NJ"},{"author_name":"Saum Ghodoussipour","author_inst":"Urologic Oncology, Rutgers Cancer Institute, New Brunswick, NJ"},{"author_name":"Tina Fan","author_inst":"Environmental and Chemical Laboratories, Public Health and Environmental Laboratories, New Jersey Department of Health, Ewing, NJ"},{"author_name":"Shawn O'Leary","author_inst":"Environmental and Chemical Laboratories, Public Health and Environmental Laboratories, New Jersey Department of Health, Ewing, NJ"},{"author_name":"Judith M. Graber","author_inst":"Department of Biostatistics and Epidemiology, Rutgers University, Piscataway, NJ; Environmental and Occupational Health Sciences Institute, Rutgers University, "},{"author_name":"Jaime E. Hart","author_inst":"Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA; Channing Division of Network Medicine, Department of Medicine, Brigh"},{"author_name":"Emily S. Barrett","author_inst":"Department of Biostatistics and Epidemiology, Rutgers University, Piscataway, NJ; Environmental and Occupational Health Sciences Institute, Rutgers University, "},{"author_name":"Elisa V. Bandera","author_inst":"Cancer Epidemiology and Health Outcomes, Rutgers Cancer Institute, New Brunswick, NJ; Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunsw"},{"author_name":"Hari S. Iyer","author_inst":"Cancer Epidemiology and Health Outcomes, Rutgers Cancer Institute, New Brunswick, NJ; Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunsw"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Single-nuclear RNA sequencing reveals an ATF3-independent sensory-neuron program after surgical incision","rel_doi":"10.64898\/2026.07.08.737350","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737350","rel_abs":"Background. Acute postoperative pain is common and often treated with opioids, but which sensory-neuron changes are responsible for the peripheral drive of pain is poorly defined. Skin incision induces activating transcription factor 3 (ATF3), the canonical marker of nerve injury, in dorsal root ganglion (DRG) neurons, and ATF3 marks the neurons that remain hyperexcitable. Whether ATF3 is required for postoperative pain is unknown. Methods. Adult mice of both sexes underwent hind-paw plantar incision. Postoperative nociceptive behavior was compared between sensory-neuron-specific ATF3 conditional-knockout mice (Avil^Cre\/+; Atf3^fl\/fl) and littermate controls using assays that probe distinct primary-afferent modalities (von Frey; Hargreaves; dynamic light touch) together with an operator-independent index of spontaneous injury behavior. Single-nucleus RNA sequencing of wild-type and ATF3-null DRG sensory neurons (naive and postoperative day 1) characterized the initiating injury program; transcription-factor-activity inference, RNAscope, and phospho-c-Jun immunostaining examined c-Jun; and the oral dual leucine zipper kinase (DLK) inhibitor GNE-3511, given at the time of incision, was tested behaviorally. Results. Incision transiently induced ATF3 in a subset of DRG neurons, returning to baseline by day 14, in parallel with the two-week course of nociceptive behavior. Deleting ATF3 in sensory neurons did not change the onset or resolution of nociceptive behavior on any readout, in either sex, across mechanical, thermal, and tactile modalities. Single-nucleus profiling showed a broad surgery-responsive nociceptor program in which ATF3 was the most strongly induced gene, yet only 23% of surgery-responsive neurons expressed it. Without ATF3, the program was remodeled but not abolished, and transcription-factor-activity inference nominated c-Jun as a candidate ATF3-independent factor; incision induced c-Jun in vivo. Systemic inhibition of DLK, which activates c-Jun pathway, lowered c-Jun phosphorylation and reduced evoked nociceptive hypersensitivity. Conclusions. Our results indicate that ATF3 marks part of the injured sensory neuron but does not drive acute post-surgical nociceptive behavior, and that it is not required for the postsurgical pain behaviors across afferent modalities carried by molecularly distinct nociceptor classes. The underlying injury program is broader than ATF3 and is nominated to depend on c-Jun. Because DLK inhibition, given at the time of incision, reduced evoked hypersensitivity, we propose the DLK-JNK-c-Jun axis as a candidate perioperative non-opioid target, which will require further genetic validation.","rel_num_authors":6,"rel_authors":[{"author_name":"Po-Yi Paul Su","author_inst":"University of California San Francisco"},{"author_name":"Jessica Yu","author_inst":"University of California San Francisco"},{"author_name":"Jarret AP Weinrich","author_inst":"University of California San Francisco"},{"author_name":"Fang Ye","author_inst":"First Affiliated Hospital, Sun Yat-Sen University"},{"author_name":"Lingyi Zhang","author_inst":"First Affiliated Hospital, Sun Yat-Sen University"},{"author_name":"Zhonghui Guan","author_inst":"University of California San Francisco"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Charge Imbalance Drives Salt-Optimized Nucleosome Phase Separation under Physiological Conditions","rel_doi":"10.64898\/2026.07.08.737367","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737367","rel_abs":"Liquid-liquid phase separation (LLPS) of chromatin contributes to genome organization and regulates genome accessibility to control gene expression. Despite advances in identifying the environmental conditions that promote chromatin condensation, the specific molecular interactions that initiate condensate formation, as well as the physical mechanisms by which DNA mechanics and epigenetic modifications modulate the resulting interaction network, remain unclear. Here, we utilize a residue-resolution, coarse-grained protein-DNA model to simulate nucleosome interactions across diverse ionic and structural conditions. Our simulations reveal non-monotonic salt-dependent phase-separation behavior, with optimal nucleosome condensation occurring under physiological salt conditions. Such a behavior was caused by the charge-imbalanced polyampholytic nature of nucleosomes, which drives competition between local protein-DNA attractions and global DNA-DNA repulsion. We further demonstrate that the conformational flexibility of nucleosomal DNA promotes unwrapping of DNA from the histone core, thereby strengthening histone-DNA interactions and enhancing condensate formation. Finally, we show that acetylation of histone H3 and H4 tails significantly reduces inter-nucleosomal interactions and increases nucleosome dynamics within condensates. Together, our study establishes a quantitative link between microscopic molecular interactions and macroscopic material properties, providing new insights into how mechanical constraints and epigenetic modifications could cooperatively tune genome architecture.","rel_num_authors":4,"rel_authors":[{"author_name":"Irene Silvernail","author_inst":"North Carolina State University"},{"author_name":"Yang Zhang","author_inst":"North Carolina State University"},{"author_name":"Xun Chen","author_inst":"Rice University"},{"author_name":"Xingcheng Lin","author_inst":"North Carolina State University"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Generation of hypoimmunogenic gastric insulin-secreting organoids","rel_doi":"10.64898\/2026.07.08.736836","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.736836","rel_abs":"Gastric insulin-secreting organoids (GINS) represent a promising source of {beta}-like cells for type 1 diabetes (T1D) therapy. In same-donor comparisons with induced pluripotent stem cell-derived islets (iPSC-islets), GINS displayed robust glucose responsiveness and reduced expression of key T1D autoantigens. Importantly, GINS exhibited decreased susceptibility to cytotoxicity mediated by engineered HLA-matched preproinsulin-specific effector T cells (Avatar Teffs) and a distinct transcriptional profile enriched for immune-modulatory and stress-adaptive gene programs. To enhance immune evasion, we engineered gastric stem cells to overexpress Programmed Death Ligand 1 (PD-L1) in an inducible manner. PD-L1+ GINS maintained normal functionality, while exhibiting improved survival under allogeneic Avatar Teff challenge in a MHC class I-independent fashion. We evaluated PD-L1-mediated protection against autologous Avatar Teff attack using an endothelialized microfluidic platform recapitulating physiologic immune interactions. T cells show reduced infiltration into PD-L1 GINS, resulting in significantly higher organoid viability compared to control GINS. Together, these findings identify GINS as a functional and engineerable {beta}-like cell platform with intrinsic hypoimmunogenic features, and support PD-L1 engineering as a strategy to enhance immune protection for both allogeneic and autologous transplantation in T1D.","rel_num_authors":14,"rel_authors":[{"author_name":"Anna Ada Dattoli","author_inst":"Weill Cornell Medicine"},{"author_name":"Matthew E Brown","author_inst":"University of Florida"},{"author_name":"Zachary Feinsten","author_inst":"Weill Cornell Medicine"},{"author_name":"Bradley Pearson","author_inst":"Weill Cornell Medicine"},{"author_name":"Ying Lang","author_inst":"Weill Cornell Medicine"},{"author_name":"Vasumati Polavarapu","author_inst":"Weill Cornell Medicine"},{"author_name":"Max Zhou","author_inst":"Weill Cornell Medicine"},{"author_name":"Ryan Nachman","author_inst":"Weill Cornell Medicine"},{"author_name":"Yosip Kelemen","author_inst":"Weill Cornell Medicine"},{"author_name":"Shahin Rafii","author_inst":"Weill Cornell Medicine"},{"author_name":"Remi J. Creusot","author_inst":"Columbia University"},{"author_name":"Todd Brusko","author_inst":"University of Florida"},{"author_name":"Joe Zhou","author_inst":"Weill Cornell Medicine"},{"author_name":"Xiaofeng Huang","author_inst":"Weill Cornell Medical College"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Activation of mu-opioid receptors slows pacemaking in hypothalamic A11 dopamine neurons","rel_doi":"10.64898\/2026.07.08.737263","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737263","rel_abs":"Hypothalamic A11 dopamine neurons provide the only known source of spinal dopamine and critically modulate pain and motor systems. Yet, the electrophysiological properties of A11 neurons were unknown. Here, we characterized A11 dopamine neurons in mice using brain slice immunohistochemistry, and fluorescence-guided whole-cell patch-clamp and cell-attached electrophysiology. A11 dopamine neurons contained the enzymes necessary to synthesize dopamine, projected to the spinal cord, and were small, morphologically simple, and high resistance. Additionally, they received excitatory glutamatergic and inhibitory GABAergic synaptic input. Most A11 dopamine neurons fired action potentials spontaneously in a rhythmic pacemaker manner at ~5 Hz, while the remainder were quiescent at rest, but fired readily with somatic current injection. Pacemaking A11 dopamine neurons were differentiated from quiescent neurons by a net inward current at subthreshold potentials. Activation of mu-opioid receptors reduced the net inward current at subthreshold potentials via activation of potassium current but also decreased GABAergic synaptic currents onto A11 dopamine neurons. Using cell-attached recording to preserve the natural chloride gradient, we found mu-opioid receptor agonism reduced spontaneous action potential firing of A11 dopamine neurons. The results lay the necessary framework for future studies investigating synaptic and ion channel mechanisms underlying the excitability in A11 dopamine neurons in physiological and pathological conditions.","rel_num_authors":4,"rel_authors":[{"author_name":"Angela F. Smith","author_inst":"University of Iowa"},{"author_name":"Hannah N. Rust","author_inst":"University of Iowa"},{"author_name":"Kathleen A. Sluka","author_inst":"University of Iowa"},{"author_name":"Stephanie C. Gantz","author_inst":"University of Iowa"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"PolliCrop: A high-throughput computer vision pipeline for pollinator monitoring in agroecosystems","rel_doi":"10.64898\/2026.07.08.737348","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737348","rel_abs":"Flower-visiting insect populations are declining since the 1990s, especially because of the decrease of floral resources in agricultural settings. Mass flowering crops can help increase resource availability, and plant breeding can be directed towards selecting varieties attracting more flower-visiting insects. This requires the implementation of an automated high-throughput phenotyping tool for assessing the attractiveness of plant genotypes to flower-visiting insects. In this study, (i) we present a procedure to take standardized images of sunflower heads with camera traps continuously at day and night in the field; (ii) we trained two versions of a deep learning model, named PolliCrop, to automatically detect and identify three classes of the main insects visiting sunflower on these images (non-Bombus bees, bumble bees, lepidopterans); (iii) we assessed and validated the ability of PolliCrop to correctly predict the true visitation frequencies of the insect classes on three sunflower genotypes; (iv) we presented two statistical approaches to compare the insect visitation frequencies between plant genotypes, one including weather variables, and the other one without. One PolliCrop version yielded satisfying performance to correctly detect the three insect classes. In particular, it correctly predicted the insect visitation frequencies on two sunflower genotypes in a range of {+\/-}10%. The other PolliCrop version can be useful in certain contexts of images and objectives. PolliCrop can be extended in the future to other crop species by training PolliCrop on new images captured in these crops. The field experimental design to set up for comparing the attractiveness between genotypes is also discussed.","rel_num_authors":12,"rel_authors":[{"author_name":"Stan Chabert","author_inst":"INRAE"},{"author_name":"Jordan Bernigaud-Samatan","author_inst":"INRAE"},{"author_name":"Benjamin K Blackman","author_inst":"University of California"},{"author_name":"Nicolas Blanchet","author_inst":"INRAE"},{"author_name":"Olivier Catrice","author_inst":"INRAE"},{"author_name":"Cecile Donnadieu","author_inst":"INRAE"},{"author_name":"Marianne Gani","author_inst":"INRAE"},{"author_name":"Remi Grousset","author_inst":"INRAE"},{"author_name":"Salena Husband","author_inst":"Julius Kuhn Institute"},{"author_name":"Guillaume Tueux","author_inst":"INRAE"},{"author_name":"Silvio Erler","author_inst":"Julius Kuhn Institute"},{"author_name":"Nicolas B Langlade","author_inst":"INRAE"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Glutamine Metabolism Supports \u03b1 cell Mass and Glucagon Secretion","rel_doi":"10.64898\/2026.07.09.735845","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.735845","rel_abs":"The liver- cell axis is a finely tuned biological rheostat that regulates whole body amino acid availability. Pancreatic  cells secrete glucagon that regulates amino acid catabolism through gluconeogenesis and ureagenesis, yet the mechanisms linking amino acid levels to  cell growth and function are not fully understood. Here, we identify glutaminase, the enzyme that catalyzes glutamine catabolism, as a critical  cell regulator. Glutaminase is highly enriched in  cells across species.  cell expression of glutaminase is required for nutrient-dependent mTORC1 activation, suppression of AMPK signaling, and sustained expression of the glutamine transporter SLC38A5. This establishes a feed-forward loop linking glutamine metabolism to amino acid sensing and growth. Reduced glutaminase activity impairs dynamic glucagon secretion in response to low glucose and amino acids. Together, these findings highlight the importance of glutamine metabolism in  cell growth and hormone secretion and suggest it may play a role in  cell adaptation to hyperaminoacidemia.","rel_num_authors":29,"rel_authors":[{"author_name":"Anna Marie R Schornack","author_inst":"Vanderbilt University"},{"author_name":"Tyler J Rodgers","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Matthew Shou","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Walter A Siv","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Linlin Yin","author_inst":"Vanderbilt University"},{"author_name":"Katelyn Sellick","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Varsha Chigurupati","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Joshua Debo","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Soham Saraf","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Paula G Nickles","author_inst":"Vanderbilt University"},{"author_name":"Selina Park","author_inst":"Creighton University School of Medicine"},{"author_name":"Shannon E Gibson","author_inst":"Vanderbilt University"},{"author_name":"Nitin Shankar","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jordyn R Dobson","author_inst":"Vanderbilt University"},{"author_name":"Soma Behara","author_inst":"Vanderbilt University"},{"author_name":"Jade E Stanley","author_inst":"Vanderbilt University"},{"author_name":"Angelina Ehara","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Madushika Wimalarathne","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Amber Crabtree","author_inst":"Vanderbilt University"},{"author_name":"Austin Reuter","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alan D. Attie","author_inst":"University of Wisconsin-Madison"},{"author_name":"Elma Zaganjor","author_inst":"Vanderbilt University"},{"author_name":"Katie C Coate","author_inst":"Vanderbilt University"},{"author_name":"Yan Li","author_inst":"Case Western Reserve University"},{"author_name":"Jeffrey C Rathmell","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Mark P Keller","author_inst":"University of Wisconsin Madison"},{"author_name":"David A Jacobson","author_inst":"Vanderbilt University"},{"author_name":"Wenbiao Chen","author_inst":"Vanderbilt University"},{"author_name":"E. Danielle Dean","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Glutamine Metabolism Supports \u03b1 cell Mass and Glucagon Secretion","rel_doi":"10.64898\/2026.07.09.735845","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.735845","rel_abs":"The liver- cell axis is a finely tuned biological rheostat that regulates whole body amino acid availability. Pancreatic  cells secrete glucagon that regulates amino acid catabolism through gluconeogenesis and ureagenesis, yet the mechanisms linking amino acid levels to  cell growth and function are not fully understood. Here, we identify glutaminase, the enzyme that catalyzes glutamine catabolism, as a critical  cell regulator. Glutaminase is highly enriched in  cells across species.  cell expression of glutaminase is required for nutrient-dependent mTORC1 activation, suppression of AMPK signaling, and sustained expression of the glutamine transporter SLC38A5. This establishes a feed-forward loop linking glutamine metabolism to amino acid sensing and growth. Reduced glutaminase activity impairs dynamic glucagon secretion in response to low glucose and amino acids. Together, these findings highlight the importance of glutamine metabolism in  cell growth and hormone secretion and suggest it may play a role in  cell adaptation to hyperaminoacidemia.","rel_num_authors":29,"rel_authors":[{"author_name":"Anna Marie R Schornack","author_inst":"Vanderbilt University"},{"author_name":"Tyler J Rodgers","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Matthew Shou","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Walter A Siv","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Linlin Yin","author_inst":"Vanderbilt University"},{"author_name":"Katelyn Sellick","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Varsha Chigurupati","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Joshua Debo","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Soham Saraf","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Paula G Nickles","author_inst":"Vanderbilt University"},{"author_name":"Selina Park","author_inst":"Creighton University School of Medicine"},{"author_name":"Shannon E Gibson","author_inst":"Vanderbilt University"},{"author_name":"Nitin Shankar","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jordyn R Dobson","author_inst":"Vanderbilt University"},{"author_name":"Soma Behara","author_inst":"Vanderbilt University"},{"author_name":"Jade E Stanley","author_inst":"Vanderbilt University"},{"author_name":"Angelina Ehara","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Madushika Wimalarathne","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Amber Crabtree","author_inst":"Vanderbilt University"},{"author_name":"Austin Reuter","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alan D. Attie","author_inst":"University of Wisconsin-Madison"},{"author_name":"Elma Zaganjor","author_inst":"Vanderbilt University"},{"author_name":"Katie C Coate","author_inst":"Vanderbilt University"},{"author_name":"Yan Li","author_inst":"Case Western Reserve University"},{"author_name":"Jeffrey C Rathmell","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Mark P Keller","author_inst":"University of Wisconsin Madison"},{"author_name":"David A Jacobson","author_inst":"Vanderbilt University"},{"author_name":"Wenbiao Chen","author_inst":"Vanderbilt University"},{"author_name":"E. Danielle Dean","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Glutamine Metabolism Supports \u03b1 cell Mass and Glucagon Secretion","rel_doi":"10.64898\/2026.07.09.735845","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.735845","rel_abs":"The liver- cell axis is a finely tuned biological rheostat that regulates whole body amino acid availability. Pancreatic  cells secrete glucagon that regulates amino acid catabolism through gluconeogenesis and ureagenesis, yet the mechanisms linking amino acid levels to  cell growth and function are not fully understood. Here, we identify glutaminase, the enzyme that catalyzes glutamine catabolism, as a critical  cell regulator. Glutaminase is highly enriched in  cells across species.  cell expression of glutaminase is required for nutrient-dependent mTORC1 activation, suppression of AMPK signaling, and sustained expression of the glutamine transporter SLC38A5. This establishes a feed-forward loop linking glutamine metabolism to amino acid sensing and growth. Reduced glutaminase activity impairs dynamic glucagon secretion in response to low glucose and amino acids. Together, these findings highlight the importance of glutamine metabolism in  cell growth and hormone secretion and suggest it may play a role in  cell adaptation to hyperaminoacidemia.","rel_num_authors":29,"rel_authors":[{"author_name":"Anna Marie R Schornack","author_inst":"Vanderbilt University"},{"author_name":"Tyler J Rodgers","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Matthew Shou","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Walter A Siv","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Linlin Yin","author_inst":"Vanderbilt University"},{"author_name":"Katelyn Sellick","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Varsha Chigurupati","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Joshua Debo","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Soham Saraf","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Paula G Nickles","author_inst":"Vanderbilt University"},{"author_name":"Selina Park","author_inst":"Creighton University School of Medicine"},{"author_name":"Shannon E Gibson","author_inst":"Vanderbilt University"},{"author_name":"Nitin Shankar","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jordyn R Dobson","author_inst":"Vanderbilt University"},{"author_name":"Soma Behara","author_inst":"Vanderbilt University"},{"author_name":"Jade E Stanley","author_inst":"Vanderbilt University"},{"author_name":"Angelina Ehara","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Madushika Wimalarathne","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Amber Crabtree","author_inst":"Vanderbilt University"},{"author_name":"Austin Reuter","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alan D. Attie","author_inst":"University of Wisconsin-Madison"},{"author_name":"Elma Zaganjor","author_inst":"Vanderbilt University"},{"author_name":"Katie C Coate","author_inst":"Vanderbilt University"},{"author_name":"Yan Li","author_inst":"Case Western Reserve University"},{"author_name":"Jeffrey C Rathmell","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Mark P Keller","author_inst":"University of Wisconsin Madison"},{"author_name":"David A Jacobson","author_inst":"Vanderbilt University"},{"author_name":"Wenbiao Chen","author_inst":"Vanderbilt University"},{"author_name":"E. Danielle Dean","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Isolation and characterization of novel filamentous phages from Swiss-type cheeses infecting the Gram-positive bacterium Propionibacterium freudenreichii","rel_doi":"10.64898\/2026.07.11.737922","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737922","rel_abs":"Filamentous phages infecting Gram-positive bacteria remain largely unexplored. Notably, only two filamentous phages, B5 and Philemon infecting Propionibacterium freudenreichii, have been described to date in the phage-rich dairy ecosystem. Although both were genomically characterized, only B5 was confirmed to be an infective filamentous single-stranded DNA phage. The aim of this study was to isolate and characterize new filamentous phages from Swiss-type cheese to investigate their diversity, structural features, host specificity, and potential adaptation to the dairy environment. Thirty raw and pasteurized milk cheeses from France were screened for phages infecting P. freudenreichii strains. Eleven phages were isolated, nine of which displayed a filamentous morphology. Named MINOG1 to MINOG9, these filamentous phages exhibited genomic features typical of this morphotype, including small single-stranded DNA genomes with collinear genes organized into functional modules. Comparison with B5 and Philemon revealed sequence divergence ranging from 0.1% to 7%. These phages also exhibited a diverse host range. To further explore phage-P. freudenreichii interactions, we screened the genomes of the strains used in this study, as well as additional genomes retrieved from the NCBI database, for CRISPR spacers predicted to target these filamentous phages. Numerous strains contained CRISPR spacers showing 79 to 100% identity to genomic regions of these phages. Two P. freudenreichii strains displayed markedly different phage resistance levels despite exact spacer-protospacer matches with phages B5, MINOG1, MINOG2, and MINOG8. Conversely, several strains were resistant to nearly all tested phages despite lacking CRISPR spacers targeting them suggesting the presence of additional defense systems in P. freudenreichii.","rel_num_authors":8,"rel_authors":[{"author_name":"Noel Grosset","author_inst":"Agrocampus-ouest\/INRA UMR STLO"},{"author_name":"Aur\u00e9lie Nicolas","author_inst":"INRAE, Institut Agro"},{"author_name":"Julien Jardin","author_inst":"INRAE, Institut Agro"},{"author_name":"Frank Oechslin","author_inst":"University of Ottawa"},{"author_name":"Antoine Culot","author_inst":"Rime Bioinformatics SAS"},{"author_name":"Sylvain Moineau","author_inst":"Universite Laval"},{"author_name":"Michel Gautier","author_inst":"Agrocampus Ouest"},{"author_name":"\u00c9ric GU\u00c9DON","author_inst":"Science et Technologie du Lait et de l'Oeuf"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Isolation and characterization of novel filamentous phages from Swiss-type cheeses infecting the Gram-positive bacterium Propionibacterium freudenreichii","rel_doi":"10.64898\/2026.07.11.737922","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737922","rel_abs":"Filamentous phages infecting Gram-positive bacteria remain largely unexplored. Notably, only two filamentous phages, B5 and Philemon infecting Propionibacterium freudenreichii, have been described to date in the phage-rich dairy ecosystem. Although both were genomically characterized, only B5 was confirmed to be an infective filamentous single-stranded DNA phage. The aim of this study was to isolate and characterize new filamentous phages from Swiss-type cheese to investigate their diversity, structural features, host specificity, and potential adaptation to the dairy environment. Thirty raw and pasteurized milk cheeses from France were screened for phages infecting P. freudenreichii strains. Eleven phages were isolated, nine of which displayed a filamentous morphology. Named MINOG1 to MINOG9, these filamentous phages exhibited genomic features typical of this morphotype, including small single-stranded DNA genomes with collinear genes organized into functional modules. Comparison with B5 and Philemon revealed sequence divergence ranging from 0.1% to 7%. These phages also exhibited a diverse host range. To further explore phage-P. freudenreichii interactions, we screened the genomes of the strains used in this study, as well as additional genomes retrieved from the NCBI database, for CRISPR spacers predicted to target these filamentous phages. Numerous strains contained CRISPR spacers showing 79 to 100% identity to genomic regions of these phages. Two P. freudenreichii strains displayed markedly different phage resistance levels despite exact spacer-protospacer matches with phages B5, MINOG1, MINOG2, and MINOG8. Conversely, several strains were resistant to nearly all tested phages despite lacking CRISPR spacers targeting them suggesting the presence of additional defense systems in P. freudenreichii.","rel_num_authors":8,"rel_authors":[{"author_name":"Noel Grosset","author_inst":"Agrocampus-ouest\/INRA UMR STLO"},{"author_name":"Aur\u00e9lie Nicolas","author_inst":"INRAE, Institut Agro"},{"author_name":"Julien Jardin","author_inst":"INRAE, Institut Agro"},{"author_name":"Frank Oechslin","author_inst":"University of Ottawa"},{"author_name":"Antoine Culot","author_inst":"Rime Bioinformatics SAS"},{"author_name":"Sylvain Moineau","author_inst":"Universite Laval"},{"author_name":"Michel Gautier","author_inst":"Agrocampus Ouest"},{"author_name":"\u00c9ric GU\u00c9DON","author_inst":"Science et Technologie du Lait et de l'Oeuf"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"White-Matter BOLD Encoding Beyond Marginal Connectivity","rel_doi":"10.64898\/2026.07.08.737282","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737282","rel_abs":"Functional MRI studies have traditionally focused on gray matter, whereas white-matter BOLD signals have often been treated as weak or artifactual. Recent work suggests that white-matter BOLD fluctuations contain reproducible functional information, but most gray-to-white matter analyses rely on marginal functional connectivity, which cannot separate pairwise coupling from shared variance among distributed cortical systems. Here, we used a multivariate cortical encoding framework to test whether spontaneous white-matter BOLD activity can be predicted from distributed cortical gray-matter activity and whether this predictive structure reveals organization beyond marginal connectivity. Resting-state fMRI data from 81 Human Connectome Project young adult participants were analyzed using a strict white-matter mask with no overlap with cortical predictors. For each white-matter voxel, time series from 400 Schaefer cortical parcels were used to predict held-out white-matter BOLD signals with nested leave-one-run-out ridge regression. Cortical activity modestly but reliably predicted white-matter BOLD dynamics, demonstrating consistent cross-validated prediction accuracy across a broad spatial extent of the white matter. Ridge beta fingerprints strongly recapitulated marginal functional connectivity fingerprints, indicating a shared functional backbone, but their first gradients diverged reproducibly. This beta-FC divergence axis organized FC-adjusted prediction residuals and remained robust after controlling for gray-matter proximity, mask-boundary distance, white-matter prevalence, temporal signal variability, spatial coordinates, and spatial autocorrelation. The high-divergence end showed relatively low marginal FC but high FC-adjusted prediction residuals and was enriched for posterior thalamic\/optic-radiation and posterior corona-radiata anatomy. These findings suggest that multivariate cortical encoding reveals a tract-organized dimension of white-matter functional coupling not captured by pairwise connectivity alone.","rel_num_authors":3,"rel_authors":[{"author_name":"Muwei Li","author_inst":"Vanderbilt University Institute of Imaging Science"},{"author_name":"Zhaohua Ding","author_inst":"Vanderbilt University Institute of Imaging Science"},{"author_name":"John C Gore","author_inst":"Vanderbilt University Institute of Imaging Science"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Associative Visual Memory in Aphantasia: Evidence for Intact Object and Spatial Memory, Metacognitive Awareness, but Different Strategies","rel_doi":"10.64898\/2026.07.08.736656","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.736656","rel_abs":"Many forms of memory are thought to rely on visual imagery, but individuals who report lacking visual imagery (aphantasia) can still perform various memory tasks. There is, however, evidence that aphantasia may lead to less detailed autobiographical memories, suggesting there may be deficits in the underlying cognitive processes that support personal memories. One such process is associative memory, which requires binding of different types of information. Here, we tested whether associative visual memory is intact in aphantasia. We assessed 72 self-identified individuals with aphantasia and 77 controls who reported having visual imagery. Participants completed an associative memory task which involved memorising displays where a unique object in a specific location was associated with a particular colour fixation point. Individuals with aphantasia performed equivalently to controls for object locations and outperformed controls on the associated object-identity. In addition, whereas controls were significantly worse at remembering associated object-identity than object-location, individuals with aphantasia showed no such difference. Both groups showed good metacognitive performance evidenced by a positive correlation between confidence and accuracy; there were no significant differences in confidence between the groups. Reported strategies varied between groups: a large proportion of control participants reported using visual imagery and self-reported use of imagery positively correlated with performance. Conversely, individuals with aphantasia mostly reported using nonvisual strategies to remember the associations. Overall, the findings suggest that individuals with aphantasia can form associative memories using nonvisual strategies. Thus, difficulties with autobiographical memory in aphantasia seem unlikely to be due to fundamental issues with associative memory.","rel_num_authors":3,"rel_authors":[{"author_name":"Rebecca Keogh","author_inst":"Macquarie University"},{"author_name":"Zoey Isherwood","author_inst":"University of New South Wales"},{"author_name":"Anina  N Rich","author_inst":"Macquarie University"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Biomarker Variability Limits Individualized Amyloid Time Estimation in Alzheimer Disease","rel_doi":"10.64898\/2026.07.08.737258","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737258","rel_abs":"Objective: Disease progression modeling (DPM) or \"amyloid time\" is increasingly used to stage Alzheimer disease (AD). DPM performance depends on within-individual heterogeneity in rates of pathological accumulation as well as test-retest reliability of the biomarker. The relative contributions of these variabilities have not been systematically assessed. This would be particularly relevant if extrapolations from DPM were to be used to make individual-level predictions for research, clinical trials, or potentially future clinical practice. Methods: We conducted simulation studies incorporating empirically-derived noise properties from amyloid biomarkers to assess the contributions of inter- and intra-individual variability. Findings generalized in an autosomal dominant AD cohort with amyloid positron emission tomography (PET), cerebrospinal fluid (CSF), and plasma biomarkers and in a sporadic AD cohort with both amyloid PET and plasma biomarkers. We assessed group level DPM performance via mean average error (MAE) and root mean squared error (RMSE). At the individual level, we evaluated distinctness of distributions of biomarker levels associated with specific disease timings. Results: Inter-individual variability was the dominant source of error in temporal estimates. Intra-individual variability reduced estimate stability. Optimal performance occurred in biomarkers with positive average accumulation rates where a subset of individuals had exceptionally high levels of accumulation. In research study data, amyloid PET outperformed CSF and plasma biomarkers. Interpretation: DPM is fundamentally constrained by dynamic range, variability, and test-retest reliability of the biomarker of interest. Current DPM approaches are more robust at the group level, particularly when applied to biomarkers with more than 10-15% variability like fluid biomarkers. Funding: National Institute on Aging, Alzheimer's Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Korean Ministry of Health & Welfare and Ministry of Science and ICT, Spanish Institute of Health.","rel_num_authors":25,"rel_authors":[{"author_name":"Julie K Wisch","author_inst":"Washington University Medical School"},{"author_name":"Ziqiao Jiao","author_inst":"Washington University School of Medicine"},{"author_name":"Peter R Millar","author_inst":"Washington University in St. Louis"},{"author_name":"Nicole S McKay","author_inst":"Washington University School of Medicine"},{"author_name":"Aleksandra Beric","author_inst":"Washington University in St. Louis"},{"author_name":"Wenjing Lin","author_inst":"Washington University School of Medicine"},{"author_name":"Bryce Baker","author_inst":"Washington University School of Medicine"},{"author_name":"Jennifer Stauber","author_inst":"Washington University School of Medicine"},{"author_name":"Sam Preminger","author_inst":"Washington University School of Medicine"},{"author_name":"Mathias Jucker","author_inst":"University of Tubingen"},{"author_name":"Nicolas R Barthelemy","author_inst":"Washington University School of Medicine"},{"author_name":"Jasmeer Chhatwal","author_inst":"BWH\/MGH\/Harvard Medical School"},{"author_name":"Natalie S. Ryan","author_inst":"University College London Queen Square"},{"author_name":"Suzanne E Schindler","author_inst":"Washington University in St. Louis"},{"author_name":"Carlos Cruchaga","author_inst":"Washington University"},{"author_name":"Tammie Lee Smith Benzinger","author_inst":"Washington University in Saint Louis"},{"author_name":"Celeste Karch","author_inst":"Washington University in St Louis"},{"author_name":"RJ Bateman","author_inst":"Washington University School of Medicine, Department of Neurology,"},{"author_name":"Eric McDade","author_inst":"Washington University in St. Louis"},{"author_name":"Jorge Llibre-Guerra","author_inst":"Washington University in St. Louis"},{"author_name":"- The Dominantly Inherited Alzheimer Network","author_inst":""},{"author_name":"- The Alzheimer Disease Neuroimaging Initiative","author_inst":""},{"author_name":"Brian A Gordon","author_inst":"Washington University School of Medicine"},{"author_name":"Beau Ances","author_inst":"Washington University in St. Louis"},{"author_name":"Laura Ibanez","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Development of Shelf-Stable Reagents and Assay Kits for Bioluminescence Applications using the Capillary-Assisted Vitrification Platform Stabilization Technology","rel_doi":"10.64898\/2026.07.11.737891","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737891","rel_abs":"Luminescence is a powerful method for detecting trace analytes and monitoring biological processes. However, most bioluminescence reagents, including luciferase and its substrates, are sensitive to temperature, limiting their useable shelf lives, and resulting in inconsistent performance. Enhancing the stability of these reagents could improve data quality, simplify workflows, and address cold chain storage issues. In this study, we demonstrate the application of the platform stabilization technology, capillary-assisted vitrification (CAV), as a tool to stabilize different luciferases and their substrates, and the application of the stabilized reagents in both in vitro and in vivo bioluminescent assays. We demonstrate that CAV-stabilized reagents can be stored and shipped ambiently, maintain consistent performance over time, and are suitable for use in cell viability quantification, tumor monitoring, in vivo imaging, microbial detection, and immunoassays. Additionally, different reagents can be co-formulated to make ready-to-use assay kits that can also be shipped and stored ambiently. Our results demonstrate that CAV stabilization is a viable alternative to traditional storage methods, with broad potential to improve bioluminescence workflows.","rel_num_authors":15,"rel_authors":[{"author_name":"Mary Shank-Retzlaff","author_inst":"Ambient Biosciences"},{"author_name":"Shari Radford","author_inst":"Ambient Biosciences"},{"author_name":"Yolanda Peris-Taverner","author_inst":"Ambient Biosciences"},{"author_name":"Michael Dibble","author_inst":"Promega Corporation"},{"author_name":"Kevin Corn","author_inst":"Vanderbilt University"},{"author_name":"Tian Zhu","author_inst":"Vanderbilt University"},{"author_name":"Shannon Martello","author_inst":"Vanderbilt University"},{"author_name":"McKenzie Mayeau","author_inst":"Vanderbilt University"},{"author_name":"Amanda Ladd","author_inst":"Ambient Biosciences"},{"author_name":"Sankar Renu","author_inst":"Ambient Biosciences"},{"author_name":"Tejasvi Chunduri","author_inst":"Ambient Biosciences"},{"author_name":"Aniket Jadhav","author_inst":"Ambient Biosciences"},{"author_name":"Melanie Dart","author_inst":"Promega Corporation"},{"author_name":"Marjan Rafat","author_inst":"Vanderbilt University"},{"author_name":"Laura Bronsart","author_inst":"Ambient Biosciences"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Prior Context Scaffolds Sentential Semantic Integration during Noisy Speech Comprehension","rel_doi":"10.64898\/2026.07.11.737996","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737996","rel_abs":"Understanding speech in noise is a central challenge of everyday communication, yet listeners often succeed by using prior context. How the brain uses such context remains debated: it may refine predictions about upcoming words, or it may provide a higher-level framework that helps degraded speech cohere into meaning. Here we combined simultaneous EEG-fNIRS recording with hierarchical multivariate encoding models to track how prior context shapes speech processing from acoustics to words and sentential meaning. Participants listened to natural spoken narratives under clear speech, noisy speech, and context-supported noisy speech conditions. Context brought comprehension of noisy speech close to clear-speech levels. EEG revealed that contextual support reduced neural encoding of lexical surprisal and entropy, indicating weaker tracking of local word-level prediction demands. In contrast, when context was available, fNIRS showed enhanced encoding of sentence-level semantic integration across frontal regions and the right angular gyrus, and stronger angular gyrus encoding predicted better comprehension. By combining EEG and fNIRS to capture complementary electrophysiological and hemodynamic signals, this multimodal approach reveals a hierarchical shift in degraded speech comprehension: prior context does not simply improve word-by-word prediction, but scaffolds the integration of noisy input into coherent discourse.","rel_num_authors":3,"rel_authors":[{"author_name":"Xinmiao Zhang","author_inst":"Tsinghua University"},{"author_name":"Zhuoran Li","author_inst":"University of Iowa"},{"author_name":"Dan Zhang","author_inst":"Tsinghua University"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"amR: an R package suite to predict antimicrobial resistance in bacterial pathogens","rel_doi":"10.64898\/2026.07.10.734579","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.734579","rel_abs":"Motivation: Identifying bacterial antimicrobial resistance (AMR) is critical for diagnostics and treatment, but resistance is a complex trait arising from myriad mechanisms spanning multiple molecular scales. Existing computational approaches often function as black boxes and rarely explore cross-species or multi-drug patterns. We developed amR, an integrated R package suite that provides a complete framework from bacterial genome data curation to interpretable AMR predictions, enabling identification of resistance mechanisms across species and drugs. Results: The amR R package suite contains three modular packages. amRdata downloads genomes and paired antimicrobial susceptibility testing data from BV-BRC and processes them, constructs pangenomes, and extracts features at gene\/protein cluster, protein domain, annotated Clusters of Orthologous Groups and ResFinder AMR-associated features, and structural variant scales; data are stored in memory-efficient formats (Parquet, DuckDB). amRml trains interpretable machine learning models per species-drug combination, calculates feature importance and performance metrics, and provides rich ground for hypothesis generation and mechanism discovery. amRviz provides an interactive Shiny dashboard to explore metadata distributions and model performance across species and drugs, visualize top predictive AMR features, and analyze cross-model patterns across geographic\/temporal strata. We apply the suite to Shigella sonnei, achieving a median Matthews Correlation Coefficient of 0.89 across 23 drugs and drug classes. With thousands of genomes, multi-scale features, and interpretable models, amR provides an accessible, comprehensive framework for AMR research. The amR package suite is installable via GitHub (https:\/\/github.com\/JRaviLab\/amR; BSD-3-Clause license).","rel_num_authors":9,"rel_authors":[{"author_name":"Abhirupa Ghosh","author_inst":"University of Colorado Anschutz"},{"author_name":"Evan P Brenner","author_inst":"University of Colorado Anschutz"},{"author_name":"Emily A Boyer","author_inst":"University of Colorado Anschutz"},{"author_name":"Alexander P McKim","author_inst":"University of Colorado Anschutz"},{"author_name":"Charmie K Vang","author_inst":"University of Colorado Anschutz"},{"author_name":"Ethan P Wolfe","author_inst":"University of Colorado Anschutz"},{"author_name":"David A Mayer","author_inst":"University of Colorado Anschutz"},{"author_name":"Raymond L Lesiyon","author_inst":"University of Colorado Anschutz"},{"author_name":"Janani Ravi","author_inst":"University of Colorado Anschutz"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Regulatory T cells establish an IL-10-IL10R immunometabolic checkpoint that limits HSL activation and lipolysis","rel_doi":"10.64898\/2026.07.12.738050","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.12.738050","rel_abs":"Adipose tissue harbors a significant population of regulatory T (Treg) cells that enforce immune homeostasis, yet whether Tregs function as an immunometabolic checkpoint to directly regulate core adipocyte signaling programs remains incompletely defined. Here we show that adipose Tregs function as a dominant, time-dependent checkpoint on {beta}-adrenergic signal-driven lipolytic program and signal transduction in adipocytes. Our integrated scRNA-seq, flow cytometry, and phosphoproteomics data show that prolonged adrenergic stimulation induces a progressive attenuation of activation of key lipase hormone-sensitive lipase (HSL) that coincides with Treg depletion in circulation and accumulation within white adipose tissue. Genetic perturbations establish Treg-derived interleukin-10 (IL-10) as the key mediator of this brake. IL-10 signaling through adipocyte IL-10R suppresses adrenergic HSL activation and rewires downstream signaling nodes that govern catecholamine responsiveness, lipolysis, and systemic energy homeostasis. Mechanistically, IL-10R engages a STAT3-dependent transcriptional program that induces the G-protein regulators RGS2 and RGS3, diminished PKA flux to HSL that reinforces suppression of the HSL activation state and lipolysis. Together, these findings define an adrenergic-immune feedback circuit in which Tregs fine tune the amplitude and duration of catecholamine responsiveness in adipocytes, establishing immune control of a core lipolytic pathway with implications for obesity-associated adipose dysfunction.","rel_num_authors":12,"rel_authors":[{"author_name":"Ramazan Yildiz","author_inst":"Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029"},{"author_name":"Kajal Davi","author_inst":"Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029"},{"author_name":"Niki F. Brisnovali","author_inst":"Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029; Cardiovascular Research Institute, Icahn School "},{"author_name":"James W.R. McMullen","author_inst":"Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029"},{"author_name":"Chung Hwan Cho","author_inst":"Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029"},{"author_name":"Khatanzul Ganbold","author_inst":"Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029"},{"author_name":"YoungUk Jang","author_inst":"Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029"},{"author_name":"Njeri Z.R. Sparman","author_inst":"Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029"},{"author_name":"Aidan Warnock","author_inst":"Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029"},{"author_name":"Gabriel Deards","author_inst":"Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029"},{"author_name":"Leigh Goedeke","author_inst":"Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029; Cardiovascular Research Institute, Icahn School "},{"author_name":"Prashant Rajbhandari","author_inst":"Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Phasis: a software tool for register-resolved discovery of plant phased small RNA loci","rel_doi":"10.64898\/2026.07.11.737977","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737977","rel_abs":"Plant PHAS locus discovery remains challenging because phasiRNA-producing loci must be distinguished from other sRNA-producing regions with high abundance or apparent periodicity. This problem is especially acute for reproductive 24-PHAS loci, which occur within genomes that also produce abundant 24-nt siRNAs from non-PHAS regions. We present Phasis, an open-source Python software tool for plant PHAS-locus discovery from small RNA sequencing data. Phasis combines statistical evidence for phased accumulation with locus-level features and a Register-Resolved Locus Interpretation Layer that evaluates whether candidate loci show coherent phased architecture. Across diverse plant datasets, Phasis recovered validated or annotated 21- and 24-PHAS loci with a strong balance between call-level precision and reference-locus recall, and generally outperformed PhaseTank and ShortStack in matched benchmark analyses. The register-resolved interpretation layer reduced unsupported calls by separating coherent phased loci from ambiguous sRNA-producing regions. In maize dcl5 mutant libraries, Phasis showed strong depletion of 24-PHAS recovery, supporting DCL5-dependent recovery of reproductive 24-PHAS signal. Together, these results support Phasis as a biologically interpretable tool for large-scale discovery of plant DCL-dependent phasiRNA loci.","rel_num_authors":5,"rel_authors":[{"author_name":"Thales Henrique Cherubino Ribeiro","author_inst":"University of California - Davis"},{"author_name":"Atul Kakrana","author_inst":"University of Delaware"},{"author_name":"Vinicius Andrade Maia","author_inst":"Federal University of Lavras"},{"author_name":"Scott Lewis","author_inst":"Washington University in St. Louis"},{"author_name":"Blake C. Meyers","author_inst":"University of California - Davis"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Single cell multi-omics enables high-resolution identification and functionalpurification of human acute myeloid leukemia stem cells","rel_doi":"10.64898\/2026.07.12.737989","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.12.737989","rel_abs":"In human acute myeloid leukemia (AML), a sub-population of leukemia stem cells (LSCs) drive disease initiation, therapeutic resistance, and relapse. However, the lack of reliable markers to distinguish LSCs from bulk leukemia cells has impeded progress in studying LSC pathogenesis and developing meaningful LSC-specific diagnostics and therapeutics. Existing LSC gene signatures, derived from bulk populations, cannot definitively identify LSCs at single-cell resolution. To address this, we analyzed large patient cohorts with bulk gene expression data and single-cell multi-omic assays to identify a prognostic gene signature that is specifically enriched in a clinically adverse AML sub-population. Using this signature, we defined and prospectively isolated CD34+CD90-CLL1-CD69+CD53- immunophenotypic LSCs that are significantly enriched for LSC content based on limiting dilution xenotransplantation assays. Our findings demonstrate the power of single-cell multi-omics to precisely identify a clinically relevant LSC population and establish a clear framework for future translational research in AML.","rel_num_authors":11,"rel_authors":[{"author_name":"Asiri Ediriwickrema","author_inst":"Stanford University"},{"author_name":"Yusuke Nakauchi","author_inst":"Stanford University"},{"author_name":"Thomas Kohnke","author_inst":"Stanford University"},{"author_name":"Amy C. Fan","author_inst":"Stanford University"},{"author_name":"Xiaoyi Hu","author_inst":"Stanford University"},{"author_name":"Brooks A. Benard","author_inst":"Stanford University"},{"author_name":"Daiki Karigane","author_inst":"Stanford University"},{"author_name":"Miles H. Linde","author_inst":"Stanford University"},{"author_name":"Aaron M. Newman","author_inst":"Stanford University"},{"author_name":"Andrew J. Gentles","author_inst":"Stanford University"},{"author_name":"Ravindra Majeti","author_inst":"Stanford University"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Single cell multi-omics enables high-resolution identification and functionalpurification of human acute myeloid leukemia stem cells","rel_doi":"10.64898\/2026.07.12.737989","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.12.737989","rel_abs":"In human acute myeloid leukemia (AML), a sub-population of leukemia stem cells (LSCs) drive disease initiation, therapeutic resistance, and relapse. However, the lack of reliable markers to distinguish LSCs from bulk leukemia cells has impeded progress in studying LSC pathogenesis and developing meaningful LSC-specific diagnostics and therapeutics. Existing LSC gene signatures, derived from bulk populations, cannot definitively identify LSCs at single-cell resolution. To address this, we analyzed large patient cohorts with bulk gene expression data and single-cell multi-omic assays to identify a prognostic gene signature that is specifically enriched in a clinically adverse AML sub-population. Using this signature, we defined and prospectively isolated CD34+CD90-CLL1-CD69+CD53- immunophenotypic LSCs that are significantly enriched for LSC content based on limiting dilution xenotransplantation assays. Our findings demonstrate the power of single-cell multi-omics to precisely identify a clinically relevant LSC population and establish a clear framework for future translational research in AML.","rel_num_authors":11,"rel_authors":[{"author_name":"Asiri Ediriwickrema","author_inst":"Stanford University"},{"author_name":"Yusuke Nakauchi","author_inst":"Stanford University"},{"author_name":"Thomas Kohnke","author_inst":"Stanford University"},{"author_name":"Amy C. Fan","author_inst":"Stanford University"},{"author_name":"Xiaoyi Hu","author_inst":"Stanford University"},{"author_name":"Brooks A. Benard","author_inst":"Stanford University"},{"author_name":"Daiki Karigane","author_inst":"Stanford University"},{"author_name":"Miles H. Linde","author_inst":"Stanford University"},{"author_name":"Aaron M. Newman","author_inst":"Stanford University"},{"author_name":"Andrew J. Gentles","author_inst":"Stanford University"},{"author_name":"Ravindra Majeti","author_inst":"Stanford University"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"A Method for Image-Based Modeling of Uterine Passive Mechanics During Late Pregnancy","rel_doi":"10.64898\/2026.07.10.737823","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737823","rel_abs":"Purpose: Computational models of the uterus during pregnancy enable analysis of electro-chemo-mechanical pathways to predict labor timing and guide treatment planning. We aim to develop a robust image-based modeling pipeline to investigate uterine passive mechanics during late pregnancy. Methods: A parametric model of the uterus and cervix was created using a patient's MRI measurements at 38 weeks of gestation. Inspired by advances in cardiac mechanics models, we created Laplace-Dirichlet solutions to inform tissue domains, fiber structure within the uterus and cervix, and spatially varying Robin boundary conditions. Prior imaging and mechanical testing data were used to fit material parameters. Boundary condition parameters were tuned to match the displacements of a previously established approach that employed contact with surrounding tissue. The tissue mechanical response to a physiologic load was assessed across varying material properties and fiber architectures. Results: Discrepancies in nodal displacements between the current approach and the contact-based model were limited to 3.4{+\/-}1.8 mm, yielding nearly 90% computational savings. Uterine tensile strains were more sensitive to ground substance elastic modulus (E) compared to fiber properties. Reduced (E) and fiber stiffness increased cervical strains and compression. Fiber dispersion and architecture modulated the opening of the cervical internal ostium but had a reduced impact on compression. Conclusion: We developed a novel workflow for modeling passive uterine mechanics, informed by patient-specific measurements and in vitro mechanical tests. The robust workflow may prove useful for studying labor progression and conducting longitudinal studies to enhance our understanding of normal and pathological pregnancies.","rel_num_authors":6,"rel_authors":[{"author_name":"Olivia Mergler","author_inst":"Columbia University"},{"author_name":"Abigail Laughlin","author_inst":"Columbia University"},{"author_name":"Erin Marie Louwagie","author_inst":"Columbia University"},{"author_name":"Lei Shi","author_inst":"Kennesaw State University"},{"author_name":"Kristin Marie Myers","author_inst":"Columbia University"},{"author_name":"Vijay Vedula","author_inst":"Columbia University"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Retrograde trafficking inhibitors allosterically trap Get3 to block tail-anchored protein biogenesis","rel_doi":"10.64898\/2026.07.11.737968","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737968","rel_abs":"Retro-1 and Retro-2 are structurally distinct small molecules that protect cells from diverse toxins and viruses by disrupting retrograde trafficking, yet their mechanism of action has remained elusive. We show that both compounds target Get3, the ATPase chaperone of the guided entry of tail-anchored proteins (GET) pathway, which mediates biogenesis of tail-anchored SNARE proteins required for retrograde transport to the ER membrane. Cryo-electron microscopy reveals that Retro compounds bind a cryptic pocket in Get3, allosterically stabilizing Get3 in a stalled complex with upstream pathway components. Our work uncovers the GET pathway as an unsuspected vulnerability in pathogen entry, provides clear routes toward compound optimization, and establishes stabilization of dynamic protein complexes as a therapeutic strategy.","rel_num_authors":11,"rel_authors":[{"author_name":"Juliet A Lee","author_inst":"California Institute of Technology"},{"author_name":"Xilin Gu","author_inst":"University of California San Francisco"},{"author_name":"Charlene Chan","author_inst":"Harvard Medical School"},{"author_name":"Vida Storm Robertson","author_inst":"California Institute of Technology"},{"author_name":"Victor Garcia-Ruiz","author_inst":"California Institute of Technology"},{"author_name":"Yancheng E Li","author_inst":"California Institute ofTechnology"},{"author_name":"Anna Huyen Ngo","author_inst":"California Institute of Technology"},{"author_name":"Philip Alabi","author_inst":"University of California San Francisco"},{"author_name":"Vladimir Denic","author_inst":"Harvard University"},{"author_name":"Jason K Sello","author_inst":"University of Californai San Francisco"},{"author_name":"William Clemons","author_inst":"Caltech"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Retrograde trafficking inhibitors allosterically trap Get3 to block tail-anchored protein biogenesis","rel_doi":"10.64898\/2026.07.11.737968","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737968","rel_abs":"Retro-1 and Retro-2 are structurally distinct small molecules that protect cells from diverse toxins and viruses by disrupting retrograde trafficking, yet their mechanism of action has remained elusive. We show that both compounds target Get3, the ATPase chaperone of the guided entry of tail-anchored proteins (GET) pathway, which mediates biogenesis of tail-anchored SNARE proteins required for retrograde transport to the ER membrane. Cryo-electron microscopy reveals that Retro compounds bind a cryptic pocket in Get3, allosterically stabilizing Get3 in a stalled complex with upstream pathway components. Our work uncovers the GET pathway as an unsuspected vulnerability in pathogen entry, provides clear routes toward compound optimization, and establishes stabilization of dynamic protein complexes as a therapeutic strategy.","rel_num_authors":11,"rel_authors":[{"author_name":"Juliet A Lee","author_inst":"California Institute of Technology"},{"author_name":"Xilin Gu","author_inst":"University of California San Francisco"},{"author_name":"Charlene Chan","author_inst":"Harvard Medical School"},{"author_name":"Vida Storm Robertson","author_inst":"California Institute of Technology"},{"author_name":"Victor Garcia-Ruiz","author_inst":"California Institute of Technology"},{"author_name":"Yancheng E Li","author_inst":"California Institute ofTechnology"},{"author_name":"Anna Huyen Ngo","author_inst":"California Institute of Technology"},{"author_name":"Philip Alabi","author_inst":"University of California San Francisco"},{"author_name":"Vladimir Denic","author_inst":"Harvard University"},{"author_name":"Jason K Sello","author_inst":"University of Californai San Francisco"},{"author_name":"William Clemons","author_inst":"Caltech"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Influence of Primary Coordination Sphere on Anion Rebound Selectivity in Nonheme Fe Enzyme-Catalyzed C(sp3)-H Functionalization: A Comparative Experimental and Computational Study of EgtB and ACCO","rel_doi":"10.64898\/2026.07.10.737789","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737789","rel_abs":"Developing enzymatic mechanisms for C-F bond formation remains a long-standing challenge. Here, we repurposed the biosynthetic nonheme Fe enzyme EgtB, which features a three-histidine facial triad, to catalyze C(sp3)-H fluorination reactions. Directed evolution of EgtB afforded two new-to-nature fluorine atom transferases with opposite enantiopreference, EgtBCHF1 and EgtBCHF2, with up to 28-fold improved total activity. In contrast to our previously evolved nonheme Fe fluorine atom transfer biocatalyst ACCOCHF, which contains a two-histidine-one-carboxylate facial triad, the evolved EgtBCHF variants displayed unexpected hydroxylation activity. 18O-labeling experiments showed that the hydroxy group originated from water rather than residual O2. Computational studies suggested that the three-histidine-supported Fe(III) center exhibits enhanced Lewis acidity compared to the two-histidine-one-carboxylate system, allowing deprotonation of Fe(III)-bound water to form a Fe(III)-OH species to catalyze radical hydroxylation. Primary coordination-sphere mutagenesis in EgtB and ACCO further supported the critical role of Fe coordination chemistry in controlling radical rebound reactivity and selectivity. Computational studies revealed that Fe coordination chemistry strongly influences both fluorine atom abstraction and radical rebound, with the intrinsic C-X (X = F, OH, and N3) bond forming radical rebound preference following the order N3 > OH > F. Furthermore, multivariate linear regression analysis revealed that fluorine atom abstraction is primarily governed by the intrinsic Fe-F bond strength, whereas fluorine rebound is predominantly controlled by the electronic structure of the Fe(III) intermediate. Together, these findings provide mechanistic insights into nonheme Fe enzymology and reprogramming toward selective radical rebound reactions, including challenging C-H fluorination.","rel_num_authors":6,"rel_authors":[{"author_name":"Yang Yang","author_inst":"Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, California 93106, United States"},{"author_name":"Liupeng Zhao","author_inst":"Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, California 93106, United States"},{"author_name":"Rui Guo","author_inst":"Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, California 93106, United States"},{"author_name":"Binh Khanh Mai","author_inst":"Department of Chemistry, University of Pittsburgh, Pennsylvania 15260, United States"},{"author_name":"Heyu Chen","author_inst":"Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, California 93106, United States"},{"author_name":"Peng Liu","author_inst":"Department of Chemistry, University of Pittsburgh, Pennsylvania 15260, United States"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"APOBEC3G expression marks a TMB-high, T cell-inflamed tumor state and is associated with response to immune checkpoint blockade in multiple cancer cohorts","rel_doi":"10.64898\/2026.07.08.737369","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737369","rel_abs":"Immune checkpoint therapies have transformed clinical practice; however, reliable biomarkers to predict response remain limited. Tumor mutational burden (TMB) has emerged as an important biomarker because it is thought to reflect neoantigen load, yet its predictive utility has been inconsistent. This limitation may partly arise because TMB primarily captures tumor-intrinsic immunogenicity, which is heterogeneous and does not fully reflect the state of antitumor immunity. To identify transcriptomic surrogates that capture both high mutational burden and antitumor immune activation, we investigated whether mRNA expression of mutagenic APOBEC3 family members could identify tumors with high TMB and T cell-rich immune states. Using a pan-cancer computational framework, we evaluated the association of four APOBEC3 genes with mutational burden, neoantigen load, immune infiltration, and immune checkpoint blockade response. Among APOBEC3A, APOBEC3B, APOBEC3G, and APOBEC3H, APOBEC3G emerged as the strongest and most consistent marker of TMB-high\/CD8-high and neoantigen-high\/CD8-high tumor phenotypes. Single-cell analyses further demonstrated that APOBEC3G is enriched in both malignant cells and T cells compared with other APOBEC3 family members, with APOBEC3G-positive CD8 T cells exhibiting elevated activation markers, including GZMB and IFNG. Importantly, retrospective analyses of 50 immune checkpoint blockade cohorts showed that APOBEC3G had the most consistent association among APOBEC3 family members with treatment response and clinical outcomes. Together, these findings identify APOBEC3G as a candidate transcriptomic marker of a TMB-associated, T cell-inflamed tumor state linked to immune checkpoint blockade benefit, warranting further prospective validation.","rel_num_authors":4,"rel_authors":[{"author_name":"Kelly Butler","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Dhanusha Yesudhas","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Bilal Lone","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"A. Rouf Banday","author_inst":"National Cancer Institute, National Institutes of Health"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Drought degrades riparian subsidy quality and constrains aquatic ecosystem functioning","rel_doi":"10.64898\/2026.07.10.737855","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737855","rel_abs":"The exchange of energy and organisms across habitat boundaries links aquatic and terrestrial ecosystems and sustains ecosystem functioning. Although disturbance may disrupt these linkages, the mechanisms at play remain poorly understood. Here, we investigated the extent to which flow intermittency may disrupt riparian-aquatic ecosystem linkages by altering consumer communities in the recipient ecosystem or by altering resource quality in the donor ecosystem. We ran an experiment in an intermittent river network in California, focusing on a critical forest-to-river subsidy (organic matter in the form of leaf litter), its transformation, and its reciprocal benefit (aquatic insect production). Using three riparian species (willow, cottonwood, and oak) at sites spanning a gradient of flow permanence, we quantified intraspecific plasticity in leaf traits (specific leaf area, nitrogen and phosphorus concentrations, and d13C), measured decomposition rates, and estimated the secondary production of aquatic shredders (Plecoptera). Across all leaf species, decomposition rates were 16-36% lower at intermittent than perennial sites, an effect largely driven by intraspecific leaf trait plasticity rather than changes in consumer abundance. At high flow intermittency, willow experienced water stress (enriched d13C) and reduced specific leaf area, while cottonwood showed primarily stoichiometric responses (reduced leaf nitrogen and phosphorus). Despite these divergent strategies, all species produced lower-quality litter at intermittent sites. Variance partitioning confirmed that initial litter quality uniquely explained 51.5% of variation in decomposition rates, more than double the contribution of invertebrate community metrics; and structural equation modeling revealed that both leaf traits and stonefly (Plecoptera) secondary production significantly predicted decomposition rates, with leaf traits exerting the stronger effect. Notably, stonefly secondary production was 37-98% lower at intermittent sites across leaf species. Because these insects later emerge as terrestrial adults, they provide a significant energy flux to riparian predators, and, thus, impoverished litter quality suppresses the reciprocal transfer of energy back to terrestrial food webs. As drought intensifies globally, the decoupling of terrestrial-aquatic linkages may begin in the riparian canopy.","rel_num_authors":2,"rel_authors":[{"author_name":"Rose Marie Mohammadi","author_inst":"University of California, Berkeley"},{"author_name":"Albert Ruh\u00ed","author_inst":"University of California, Berkeley"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Microbial Ecosystems Reveal a Universal Signature of Ecological Assembly","rel_doi":"10.64898\/2026.07.10.737833","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737833","rel_abs":"Microbial communities obey universal macroecological scaling laws, but which sub-processes generate them remains debated across competing theoretical frameworks. Here we calibrate a modified Yule-Simon model to metagenomic data from 11 distinct microbial environments, revealing that microbial ecosystems occupy a qualitatively distinct region of a two-parameter mechanistic space, characterized by near-neutral recruitment (i.e., linear preferential attachment) and broad diversification strategies, unlike any previously studied complex system, including prokaryotic proteomes and urban economies. This distinctive position, confirmed analytically and validated against sparse-data robustness tests, provides both a mechanistic explanation for observed self-similarities in microbial rank-frequency distributions and a quantitative signature of ecological assembly.","rel_num_authors":4,"rel_authors":[{"author_name":"James Holehouse","author_inst":"Washington University in St. Louis"},{"author_name":"Geoffrey B. West","author_inst":"The Santa Fe Institute"},{"author_name":"Christopher P Kempes","author_inst":"The Santa Fe Institute"},{"author_name":"Anshuman Swain","author_inst":"University of Michigan"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"USP18-STAT2 axis enhances hepatic resilience under proteotoxic stress","rel_doi":"10.64898\/2026.07.11.737961","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737961","rel_abs":"The liver is a metabolic hub with a high protein turnover that renders it uniquely susceptible to proteotoxic stress. Perturbation of proteostasis, either by proteasomal inhibitors or in chronic liver diseases, could adversely impact liver physiology. Here, we show that proteasomal inhibition unexpectedly suppresses basal type I interferon (IFN I) signaling in the murine liver. Proteasomal inhibition by bortezomib selectively downregulates a subset of interferon-stimulated genes (ISGs), among which USP18 and ISG15 emerge as critical determinants of hepatocellular survival. We identify USP18 as a central cytoprotective factor that prevents proteotoxic apoptosis independently of its deubiquitinase activity, but strictly requires its scaffolding function mediated by isoleucine-60 and interaction with STAT2. Mechanistically, proteotoxic stress disrupts IRF9 nuclear translocation, attenuating USP18 transcription, and drives USP18 and other ISGs into insoluble aggregates with kinetics distinct from canonical IFN I induced insolubility. Strikingly, IFN alpha priming preserves ISG solubility, restores USP18 abundance, and confers resistance to proteotoxic cell death. Together, these findings uncover an unanticipated link between proteostasis and innate immune signaling, and establish the USP18-STAT2 axis to enhance hepatic resilience under proteotoxic stress.","rel_num_authors":3,"rel_authors":[{"author_name":"Abhishek Sen","author_inst":"CSIR-IICB, AcSIR"},{"author_name":"SAHELI CHOWDHURY","author_inst":"CSIR-INDIAN INSTITUTE OF CHEMICAL BIOLOGY, Columbia University Irving Medical Center, New York, USA"},{"author_name":"Partha Chakrabarti","author_inst":"CSIR-IICB, AcSIR"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Pluripotency and Transcriptional Pausing Disrupt Circadian Rhythms to Facilitate the Enrichment of Cancer Stem Cells","rel_doi":"10.64898\/2026.07.10.737844","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737844","rel_abs":"Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype, enriched for cancer stem cells (CSCs), which are the cause of tumor recurrence. CSCs are responsible for tumor initiation and propagation; however, the molecular mechanisms underlying their formation remain largely unclear. We show that carboplatin treated TNBC cells lose their circadian rhythms and promote the enrichment of CSCs. Notably, genetic ablation of the circadian clock by itself, without carboplatin treatment, facilitated the formation of CSCs along with their ability to generate 3D tumorspheres and mouse tumors enriched with CSCs. Mechanistically, we identified an antagonistic interplay between the circadian clock and pluripotency, whereby the core pluripotent factor OCT4 disrupts the expression of circadian timekeeping genes to disable the circadian clock. Furthermore, we uncovered a transcriptional pausing program, controlling the circadian clock, to be perturbed in carboplatin treated TNBC cells. Concordantly, based on gene expression analysis from The Cancer Genome Atlas (TCGA), we found that the uncoupling of transcriptional pausing and the circadian clock correlated with low survivability across diverse cancer types. Moreover, cancer patients with poor prognosis exhibit low expression of the core timekeeping genes Clock, Npas2, Bmal1 and Rorc. Lastly, we restored circadian rhythms in Oct4 deficient TNBC cells and impaired their ability to generate tumorspheres and decreased the number of CSCs in mouse tumors. Overall, our findings demonstrate an unprecedented mechanism for the formation of CSCs that is dependent on the loss of circadian rhythms and thereby has eminent implications for developing new cancer therapies.","rel_num_authors":13,"rel_authors":[{"author_name":"Edward A Gonzalez","author_inst":"Rutgers University-Newark"},{"author_name":"Dahui Wang","author_inst":"Rutgers University-Newark"},{"author_name":"Maciej C Jeziorek","author_inst":"Rutgers University-Newark"},{"author_name":"Shahd Mohamed","author_inst":"Rutgers University-Newark"},{"author_name":"Lauren S Sherman","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Premananda Indic","author_inst":"University of Texas at Tyler"},{"author_name":"Patricia Soteropoulos","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Mainul Hoque","author_inst":"New Jersey Medical School"},{"author_name":"Seth R Goldman","author_inst":"Harvard Medical School"},{"author_name":"Karen Adelman","author_inst":"Harvard Medical School"},{"author_name":"Lanjing Zhang","author_inst":"Princeton Medical Center\/Rutgers University"},{"author_name":"Pranela Rameshwar","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Jean-Pierre Etchegaray","author_inst":"Rutgers University"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Capillary Network Generation Framework for Estimating Volumetric Capillary Density from Histological Vascular Measurements","rel_doi":"10.64898\/2026.07.10.737824","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737824","rel_abs":"Angiogenesis drives the formation and remodeling of capillary networks throughout tissue repair, regulating the vascular environment that supports healing and tissue remodeling. Experimental characterization of these processes is commonly performed using CD31-stained histological tissue sections to quantify capillary surface density and morphology throughout healing. However, these measurements provide only two-dimensional characterization of an underlying three-dimensional (3D) vascular network, limiting direct estimation of volumetric capillary density and vascular architecture. To address this limitation, an experimentally informed framework was developed to generate representative 3D capillary networks, enabling estimation of volumetric capillary density from histologically quantified vascular measurements. CD31-stained histological sections obtained from a longitudinal porcine lumpectomy study were analyzed to quantify the percentage of CD31-positive area (%CD31+) and capillary morphology within healthy tissue and healing surgical cavities. Histologically quantified morphology distributions and literature-informed vascular branching characteristics were incorporated into a capillary network generation framework to construct representative 3D vascular networks. Capillary branches were iteratively generated within representative tissue volumes until virtual histological sections reproduced experimental \\%CD31+ measurements, enabling estimation of volumetric capillary density. Generated capillary networks demonstrated good agreement with experimentally characterized 3D vascular architecture, while simulated histological sections accurately reproduced experimentally quantified capillary counts and vascularization measurements. Application of the framework to the porcine lumpectomy dataset captured temporal changes in vascular remodeling throughout healing, revealing progressive increases in volumetric capillary density and vascular maturation. Collectively, this framework provides an experimentally informed methodology for relating histological vascular measurements to volumetric capillary density estimates, supporting future computational studies of angiogenesis and tissue repair.","rel_num_authors":6,"rel_authors":[{"author_name":"Zachary Joseph Harbin","author_inst":"Purdue University"},{"author_name":"Carla S. Fisher","author_inst":"Indiana University School of Medicine"},{"author_name":"Rachel A. Morrison","author_inst":"Purdue University"},{"author_name":"Hector Gomez","author_inst":"Purdue University"},{"author_name":"Sherry Voytik-Harbin","author_inst":"Purdue University"},{"author_name":"Adrian B. Buganza Tepole","author_inst":"Columbia University"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"APOBEC3 activity and polymerase-\u03b5 deficiency are associated with distinct IDH1 R132 hotspot mutations","rel_doi":"10.64898\/2026.07.10.737816","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737816","rel_abs":"IDH1 R132 mutations are among the most frequent hotspot mutations in cancer, but their mutational origins have remained unclear. Here, we provide evidence that IDH1 R132C, the predominant IDH1 mutation in cholangiocarcinoma, acute myeloid leukemia, and melanoma, likely arises through APOBEC3-mediated mutagenesis. IDH1 R132C is a TpC>TpT substitution on the lagging-strand DNA template within a hairpin-forming sequence context, consistent with APOBEC3 susceptibility. In vitro assays showed that APOBEC3A can deaminate the relevant cytosine, and APOBEC3A and APOBEC3B were relatively highly expressed in tumor types with recurrent IDH1 R132C mutations. IDH1 R132G, a TpC>TpG substitution at the same site, may similarly result from APOBEC3 activity. By contrast, IDH1 R132H, the predominant IDH1 mutation in lower grade glioma and glioblastoma, is a CpG>TpG substitution at a methylated cytosine on the leading-strand DNA template, a pattern more consistent with DNA polymerase epsilon replication error. Concordantly, tumor types enriched for IDH1 R132H showed relatively low POLE expression. Together, these in vitro and bioinformatic analyses provide insight into the distinct mutational mechanisms that likely underlie recurrent IDH1 hotspot mutations in cancer.","rel_num_authors":4,"rel_authors":[{"author_name":"Kelly E. Butler","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Bilal Lone","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Ecem Unal","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"A. Rouf Banday","author_inst":"National Cancer Institute, National Institutes of Health"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"A model for PIP2\/3 and Rnd1 effects on Plexin-B1 GAP activity on Rap1b GTPase derived from molecular dynamics simulations","rel_doi":"10.64898\/2026.07.09.737506","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737506","rel_abs":"Plexin-B1 is a transmembrane receptor that integrates signals from Rho-family and Ras-family (Rap1b) GTPases to regulate cellular processes. While ligand simulated activation of the receptor is largely understood, the role of membrane composition and GTPase allosteric effects on plexin structure, internal protein dynamics, and function is still to be elucidated. Here, we performed multi-replica one-microsecond all-atom simulations of Plexin-B1-GTPase complexes on PIP2- and PIP3-containing membranes to investigate the effects of these two signaling lipids, as well as on the GTPases. We found that both Rap1b and Rnd1 stably associate with the membrane, with PIP2 promoting broader lipid engagement and stronger Rap1b-Plexin-B1 interactions, whereas PIP3 enhances Rnd1-Plexin contacts and induces a membrane proximal orientation of the Plexin juxtamembrane helix and makes contacts with a previously discovered activation switch loop. Contact map and network analyses revealed lipid-dependent shifts in allosteric communication, with PIP2 favoring Rap1b-centric hotspots and PIP3 favoring Rnd1-centric pathways. These predictions allow us to suggest a model for plexin intracellular region activation where both the identity of phosphoinositides and GTPase context synergistically stabilize Plexin-B1 membrane engagement, alter structural dynamics, and allosteric networks. Thus, we propose that the membrane is an active modulator of plexin receptor signaling.","rel_num_authors":3,"rel_authors":[{"author_name":"Nisha Bhattarai","author_inst":"Case Western Reserve University"},{"author_name":"Amita Rani Sahoo","author_inst":"Case Western Reserve University"},{"author_name":"Matthias Buck","author_inst":"Case Western Reserve University"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"De novo design of selective kinase modulators","rel_doi":"10.64898\/2026.07.10.737808","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737808","rel_abs":"Protein kinases are critical regulators of cellular signaling, but precise modulation of their activity remains challenging due to their high structural conservation. Here, we present de novo designed genetically encoded miniproteins capable of activating or inhibiting focal adhesion kinase (FAK) by directly targeting the kinase domain itself. Among 96 binders designed to stabilize distinct conformational states of FAK, 33 modulated kinase activity. Biochemical characterization of the four most potent modulators revealed that two designs inhibit FAK with low-nanomolar IC50 values while the remaining two potentiated FAK activity by more than two-fold. When expressed in cells, the modulators preserved the same inhibitory and activating effects observed in vitro, establishing that designed conformational binders can directly tune FAK signaling in living cells. Taking advantage of the high similarity between kinases, we redesigned the FAK inhibitors to inhibit Src kinase. Our approach establishes a versatile platform for selective and genetically encoded kinase control as a way to rewire cell signaling and as a starting point for the discovery of novel modulatory sites of kinases.","rel_num_authors":23,"rel_authors":[{"author_name":"Magnus S. Bauer","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA."},{"author_name":"Saurav Kumar","author_inst":"Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA."},{"author_name":"Mia S. Donald Paladino","author_inst":"Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA."},{"author_name":"Dongyang Li","author_inst":"Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA."},{"author_name":"Kody A. Klupt","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; De"},{"author_name":"Matthias Gl\u00f6gl","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Ho"},{"author_name":"Ana Mar\u00eda Fern\u00e1ndez-Escamilla","author_inst":"Institute for Research in Biotechnology and Health (IDiBE), Miguel Hernandez University, 03202 Elche, Alicante, Spain."},{"author_name":"Thomas Schlichthaerle","author_inst":"Professorship of AI-Guided Protein Design, Department of Bioscience, TUM School of Natural Sciences, Technical University of Munich, Garching, Germany."},{"author_name":"Edin Muratspahi\u0107","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Ho"},{"author_name":"Xinru Wang","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Ce"},{"author_name":"Ludwig Schmiderer","author_inst":"Division of Molecular Medicine and Gene Therapy, Department of Laboratory Medicine and Lund Stem Cell Center, Lund University, 221 00 Lund, Sweden."},{"author_name":"Sebastian Kenny","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA."},{"author_name":"Brian Coventry","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA."},{"author_name":"Bulat Faezov","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Ho"},{"author_name":"Wei Chen","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Ho"},{"author_name":"Alexander F. Shida","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Ho"},{"author_name":"Gyu Rie Lee","author_inst":"Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea."},{"author_name":"Yang Hsia","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Ho"},{"author_name":"Ryan D. Kibler","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Ho"},{"author_name":"Michael B. Elowitz","author_inst":"Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA."},{"author_name":"Daniel Lietha","author_inst":"Molecular and Cellular Biosciences, Margarita Salas Center for Biological Research, Spanish National Research Council, Madrid 28040, Spain."},{"author_name":"Behnam Nabet","author_inst":"Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Department of Pharmacology, University of Washington, Seattle, WA 98195, USA."},{"author_name":"David Baker","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Ho"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"De novo design of selective kinase modulators","rel_doi":"10.64898\/2026.07.10.737808","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737808","rel_abs":"Protein kinases are critical regulators of cellular signaling, but precise modulation of their activity remains challenging due to their high structural conservation. Here, we present de novo designed genetically encoded miniproteins capable of activating or inhibiting focal adhesion kinase (FAK) by directly targeting the kinase domain itself. Among 96 binders designed to stabilize distinct conformational states of FAK, 33 modulated kinase activity. Biochemical characterization of the four most potent modulators revealed that two designs inhibit FAK with low-nanomolar IC50 values while the remaining two potentiated FAK activity by more than two-fold. When expressed in cells, the modulators preserved the same inhibitory and activating effects observed in vitro, establishing that designed conformational binders can directly tune FAK signaling in living cells. Taking advantage of the high similarity between kinases, we redesigned the FAK inhibitors to inhibit Src kinase. Our approach establishes a versatile platform for selective and genetically encoded kinase control as a way to rewire cell signaling and as a starting point for the discovery of novel modulatory sites of kinases.","rel_num_authors":23,"rel_authors":[{"author_name":"Magnus S. Bauer","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA."},{"author_name":"Saurav Kumar","author_inst":"Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA."},{"author_name":"Mia S. Donald Paladino","author_inst":"Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA."},{"author_name":"Dongyang Li","author_inst":"Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA."},{"author_name":"Kody A. Klupt","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; De"},{"author_name":"Matthias Gl\u00f6gl","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Ho"},{"author_name":"Ana Mar\u00eda Fern\u00e1ndez-Escamilla","author_inst":"Institute for Research in Biotechnology and Health (IDiBE), Miguel Hernandez University, 03202 Elche, Alicante, Spain."},{"author_name":"Thomas Schlichthaerle","author_inst":"Professorship of AI-Guided Protein Design, Department of Bioscience, TUM School of Natural Sciences, Technical University of Munich, Garching, Germany."},{"author_name":"Edin Muratspahi\u0107","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Ho"},{"author_name":"Xinru Wang","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Ce"},{"author_name":"Ludwig Schmiderer","author_inst":"Division of Molecular Medicine and Gene Therapy, Department of Laboratory Medicine and Lund Stem Cell Center, Lund University, 221 00 Lund, Sweden."},{"author_name":"Sebastian Kenny","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA."},{"author_name":"Brian Coventry","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA."},{"author_name":"Bulat Faezov","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Ho"},{"author_name":"Wei Chen","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Ho"},{"author_name":"Alexander F. Shida","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Ho"},{"author_name":"Gyu Rie Lee","author_inst":"Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea."},{"author_name":"Yang Hsia","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Ho"},{"author_name":"Ryan D. Kibler","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Ho"},{"author_name":"Michael B. Elowitz","author_inst":"Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA."},{"author_name":"Daniel Lietha","author_inst":"Molecular and Cellular Biosciences, Margarita Salas Center for Biological Research, Spanish National Research Council, Madrid 28040, Spain."},{"author_name":"Behnam Nabet","author_inst":"Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Department of Pharmacology, University of Washington, Seattle, WA 98195, USA."},{"author_name":"David Baker","author_inst":"Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Ho"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Adenylyl cyclases combinatorially integrate opposing dopamine receptor signals","rel_doi":"10.64898\/2026.07.10.737756","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737756","rel_abs":"Dopamine receptors are divided into two families which exert opposing effects on the second messenger cyclic AMP (cAMP). While most neuronal cell types express a single receptor subtype, some neurons co-express opposing receptor subtypes. It remains unclear how these cells could resolve simultaneous stimulatory and inhibitory inputs. Here, we introduce a multiplexed assay that quantifies surface receptor abundance and dynamic cAMP output in single cells. Using this assay, together with mathematical modeling, we demonstrate that signals from opposing receptor subtypes are integrated flexibly by downstream adenylyl cyclases (ACs) rather than at the receptor level. Because AC isoforms exhibit unique biochemical properties, a cell's AC expression profile determines whether conflicting inputs are cancelled, suppressed, or amplified. Brain transcriptome analysis indicates that co-expression of opposing dopamine receptors is associated with expression of specific AC isoforms predicted to sustain signaling during multi-receptor activation. Our results show that dopamine signal integration depends on the expression profiles of receptors and AC isoforms in a predictable way.","rel_num_authors":2,"rel_authors":[{"author_name":"Jan Gregrowicz","author_inst":"California Institute of Technology"},{"author_name":"Michael B Elowitz","author_inst":"Caltech, Howard Hughes Medical institute"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Microbial Invasion and Immunosuppression Drives Adenoma Progression in Early Colorectal Cancer Development","rel_doi":"10.64898\/2026.07.10.737736","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737736","rel_abs":"Several inherited predispositions to colorectal cancer exist, most notably familial adenomatous polyposis (FAP), which typically involves a germline loss-of-function mutation in one APC allele. A second hit in APC or related loci leads to aberrant Wnt signalling, triggering adenoma formation with near-complete penetrance. Yet, substantial variability in disease onset and severity, even among siblings with identical APC germline mutations, implicates environmental modifiers. Emerging evidence points to the gut microbiome as a critical regulator of adenoma initiation and progression, particularly in early-onset CRC. Here, we show that bacterial invasion is associated with neutrophil immunosuppression, T-cell exclusion and adenoma progression in a porcine model of FAP. Longitudinal mapping of progressing and regressing polyps using single-cell RNA sequencing, spatial transcriptomics and integrated microbiome profiling resolved the cellular and microbial architecture underlying these divergent lesion states. Single-cell RNA-seq identified 35 cell subpopulations and showed that regressing polyps are enriched for central-memory CD4+ T cells, cytotoxic CD8+ T cells and inflammatory neutrophils, whereas progressing polyps contain immunosuppressive\/PD-L1-associated neutrophils, regulatory and dysfunctional T cells. Spatial transcriptomics with a custom host panel and targeted bacterial probes linked bacterial-high adenomatous regions to immunosuppressive neutrophil niches and T cell exclusion, while regressing lesions showed predominantly lumen-adjacent bacterial localization and spatially organized immune surveillance. These results provide a spatially resolved map of cellular and microbial organisation in early colorectal polyp progression and regression and reveal a microbiome-driven, neutrophil-mediated mechanism of early tumour progression with implications for CRC interception.","rel_num_authors":18,"rel_authors":[{"author_name":"Wei Liang","author_inst":"Chair of Infection Pathogenesis, School of Life Sciences, Technical University of Munich, Germany"},{"author_name":"Lisa Falk","author_inst":"Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technical University of Munic"},{"author_name":"Daniele Lucarelli","author_inst":"Technical University of Munich"},{"author_name":"Philipp Putze","author_inst":"Technical University of Munich"},{"author_name":"Amira Metwaly","author_inst":"TECHNICAL UNIVERSITY OF MUNICH"},{"author_name":"Yiran Zheng","author_inst":"Helmholtz Pioneer Campus, Helmholtz Zentrum Munich"},{"author_name":"Fabian Springer","author_inst":"EMBL Heidelberg"},{"author_name":"Thomas Winogrodzki","author_inst":"Columbia University Irving Medical Centre"},{"author_name":"Qixia Chan","author_inst":"Technical University of Munich"},{"author_name":"Yue Zhang","author_inst":"Columbia University Irving Medical Centre"},{"author_name":"Georg Zeller","author_inst":"European Molecular Biology Laboratory Heidelberg"},{"author_name":"Matthias Meier","author_inst":"University of Leipzig"},{"author_name":"Angelika Schnieke","author_inst":"Technical University of Munich"},{"author_name":"Friederike Ebner","author_inst":"Technical University of Munich"},{"author_name":"Dirk Haller","author_inst":"Technical University of Munich"},{"author_name":"Tatiana Flisikowska","author_inst":"Technical University of Munich"},{"author_name":"Dieter Saur","author_inst":"German Cancer Research Center and Technical University of Munich"},{"author_name":"Krzysztof Flisikowski","author_inst":"Technical University of Munich"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Specific F1 ATP synthase inhibition delivers transient mitochondrial stress for selective targeting of acute myeloid leukemia","rel_doi":"10.64898\/2026.07.10.737821","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737821","rel_abs":"Targeting oxidative phosphorylation (OXPHOS) represents an attractive therapeutic strategy in acute myeloid leukemia, which exhibits exceptional dependence on mitochondrial respiration compared to normal hematopoietic cells. However, clinical attempts to exploit this vulnerability have been limited by on-target toxicity to healthy tissue. Here, we comprehensively compare the cellular consequences of inhibiting distinct nodes of the electron transport chain in AML. We demonstrate that selective inhibition of the F1 subunit of ATP synthase with EB2023 (ammocidin A) delivers an energetic stress to AML cells without the profound redox stress that characterizes complex I inhibition, preventing NAD\/NADH imbalance and allowing continued TCA cycling. Further, the duration of OXPHOS inhibition is transient in nature in vivo, a finding revealed through pharmacokinetic and serial pharmacodynamic monitoring of AMPK phosphorylation accompanied by OPA1-mediated mitochondrial structural remodeling that primes AML cells for BCL2 inhibitor synergy. EB2023 in combination with venetoclax demonstrates potent anti-AML activity across cell lines and patient-derived xenograft models at doses that spare normal hematopoietic progenitors and avoid the neuropathy and sustained detrimental systemic metabolic rewiring in healthy tissues associated with prior efforts to target OXPHOS. These findings establish F1-selective ATP synthase inhibition as a clinically actionable therapeutic strategy in AML and establish the duration of OXPHOS inhibition as a critical and previously underappreciated determinant of therapeutic index.","rel_num_authors":23,"rel_authors":[{"author_name":"Matthew T Villaume","author_inst":"Mayo Clinic"},{"author_name":"Haley E Ramsey","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Valeria Impedovo","author_inst":"The University of Texas at Austin"},{"author_name":"Michael Davidson","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Maria Pia Arrate","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Anand K Singh","author_inst":"MD Anderson Cancer Center"},{"author_name":"Yujin Lee","author_inst":"The University of Texas at Austin"},{"author_name":"Ann Skwarska","author_inst":"Montefiore Einstein Cancer Center"},{"author_name":"Yara F Almadani","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Natalia Baran","author_inst":"Bern University Hospital"},{"author_name":"Sovira Chaudhry","author_inst":"Montefiore Einstein Cancer Center"},{"author_name":"Benjamin J Reisman","author_inst":"Johns Hopkins University School of Medicine,"},{"author_name":"Eden G TenBarge","author_inst":"University of Tennessee, Knoxville"},{"author_name":"Ming Jiang","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Andrew J Monteith","author_inst":"University of Tennessee, Knoxville"},{"author_name":"Sarah Olmstead","author_inst":"University of Michigan School of Medicine"},{"author_name":"Agnes E Gorska","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Zhiguo Zhao","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Perter M Grace","author_inst":"MD Anderson Cancer Center"},{"author_name":"Brian O Bachmann","author_inst":"Vanderbilt University"},{"author_name":"Marina Konopleva","author_inst":"Montefiore Einstein Cancer Center"},{"author_name":"Stefano Tiziani","author_inst":"The University of Texas at Austin"},{"author_name":"Michael R Savona","author_inst":"Vanderbilt University School of Medicine"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Specific F1 ATP synthase inhibition delivers transient mitochondrial stress for selective targeting of acute myeloid leukemia","rel_doi":"10.64898\/2026.07.10.737821","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737821","rel_abs":"Targeting oxidative phosphorylation (OXPHOS) represents an attractive therapeutic strategy in acute myeloid leukemia, which exhibits exceptional dependence on mitochondrial respiration compared to normal hematopoietic cells. However, clinical attempts to exploit this vulnerability have been limited by on-target toxicity to healthy tissue. Here, we comprehensively compare the cellular consequences of inhibiting distinct nodes of the electron transport chain in AML. We demonstrate that selective inhibition of the F1 subunit of ATP synthase with EB2023 (ammocidin A) delivers an energetic stress to AML cells without the profound redox stress that characterizes complex I inhibition, preventing NAD\/NADH imbalance and allowing continued TCA cycling. Further, the duration of OXPHOS inhibition is transient in nature in vivo, a finding revealed through pharmacokinetic and serial pharmacodynamic monitoring of AMPK phosphorylation accompanied by OPA1-mediated mitochondrial structural remodeling that primes AML cells for BCL2 inhibitor synergy. EB2023 in combination with venetoclax demonstrates potent anti-AML activity across cell lines and patient-derived xenograft models at doses that spare normal hematopoietic progenitors and avoid the neuropathy and sustained detrimental systemic metabolic rewiring in healthy tissues associated with prior efforts to target OXPHOS. These findings establish F1-selective ATP synthase inhibition as a clinically actionable therapeutic strategy in AML and establish the duration of OXPHOS inhibition as a critical and previously underappreciated determinant of therapeutic index.","rel_num_authors":23,"rel_authors":[{"author_name":"Matthew T Villaume","author_inst":"Mayo Clinic"},{"author_name":"Haley E Ramsey","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Valeria Impedovo","author_inst":"The University of Texas at Austin"},{"author_name":"Michael Davidson","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Maria Pia Arrate","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Anand K Singh","author_inst":"MD Anderson Cancer Center"},{"author_name":"Yujin Lee","author_inst":"The University of Texas at Austin"},{"author_name":"Ann Skwarska","author_inst":"Montefiore Einstein Cancer Center"},{"author_name":"Yara F Almadani","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Natalia Baran","author_inst":"Bern University Hospital"},{"author_name":"Sovira Chaudhry","author_inst":"Montefiore Einstein Cancer Center"},{"author_name":"Benjamin J Reisman","author_inst":"Johns Hopkins University School of Medicine,"},{"author_name":"Eden G TenBarge","author_inst":"University of Tennessee, Knoxville"},{"author_name":"Ming Jiang","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Andrew J Monteith","author_inst":"University of Tennessee, Knoxville"},{"author_name":"Sarah Olmstead","author_inst":"University of Michigan School of Medicine"},{"author_name":"Agnes E Gorska","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Zhiguo Zhao","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Perter M Grace","author_inst":"MD Anderson Cancer Center"},{"author_name":"Brian O Bachmann","author_inst":"Vanderbilt University"},{"author_name":"Marina Konopleva","author_inst":"Montefiore Einstein Cancer Center"},{"author_name":"Stefano Tiziani","author_inst":"The University of Texas at Austin"},{"author_name":"Michael R Savona","author_inst":"Vanderbilt University School of Medicine"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Specific F1 ATP synthase inhibition delivers transient mitochondrial stress for selective targeting of acute myeloid leukemia","rel_doi":"10.64898\/2026.07.10.737821","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737821","rel_abs":"Targeting oxidative phosphorylation (OXPHOS) represents an attractive therapeutic strategy in acute myeloid leukemia, which exhibits exceptional dependence on mitochondrial respiration compared to normal hematopoietic cells. However, clinical attempts to exploit this vulnerability have been limited by on-target toxicity to healthy tissue. Here, we comprehensively compare the cellular consequences of inhibiting distinct nodes of the electron transport chain in AML. We demonstrate that selective inhibition of the F1 subunit of ATP synthase with EB2023 (ammocidin A) delivers an energetic stress to AML cells without the profound redox stress that characterizes complex I inhibition, preventing NAD\/NADH imbalance and allowing continued TCA cycling. Further, the duration of OXPHOS inhibition is transient in nature in vivo, a finding revealed through pharmacokinetic and serial pharmacodynamic monitoring of AMPK phosphorylation accompanied by OPA1-mediated mitochondrial structural remodeling that primes AML cells for BCL2 inhibitor synergy. EB2023 in combination with venetoclax demonstrates potent anti-AML activity across cell lines and patient-derived xenograft models at doses that spare normal hematopoietic progenitors and avoid the neuropathy and sustained detrimental systemic metabolic rewiring in healthy tissues associated with prior efforts to target OXPHOS. These findings establish F1-selective ATP synthase inhibition as a clinically actionable therapeutic strategy in AML and establish the duration of OXPHOS inhibition as a critical and previously underappreciated determinant of therapeutic index.","rel_num_authors":23,"rel_authors":[{"author_name":"Matthew T Villaume","author_inst":"Mayo Clinic"},{"author_name":"Haley E Ramsey","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Valeria Impedovo","author_inst":"The University of Texas at Austin"},{"author_name":"Michael Davidson","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Maria Pia Arrate","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Anand K Singh","author_inst":"MD Anderson Cancer Center"},{"author_name":"Yujin Lee","author_inst":"The University of Texas at Austin"},{"author_name":"Ann Skwarska","author_inst":"Montefiore Einstein Cancer Center"},{"author_name":"Yara F Almadani","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Natalia Baran","author_inst":"Bern University Hospital"},{"author_name":"Sovira Chaudhry","author_inst":"Montefiore Einstein Cancer Center"},{"author_name":"Benjamin J Reisman","author_inst":"Johns Hopkins University School of Medicine,"},{"author_name":"Eden G TenBarge","author_inst":"University of Tennessee, Knoxville"},{"author_name":"Ming Jiang","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Andrew J Monteith","author_inst":"University of Tennessee, Knoxville"},{"author_name":"Sarah Olmstead","author_inst":"University of Michigan School of Medicine"},{"author_name":"Agnes E Gorska","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Zhiguo Zhao","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Perter M Grace","author_inst":"MD Anderson Cancer Center"},{"author_name":"Brian O Bachmann","author_inst":"Vanderbilt University"},{"author_name":"Marina Konopleva","author_inst":"Montefiore Einstein Cancer Center"},{"author_name":"Stefano Tiziani","author_inst":"The University of Texas at Austin"},{"author_name":"Michael R Savona","author_inst":"Vanderbilt University School of Medicine"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Tissue nanotransfection-mediated induction of neurogenic programs promotes myoprotective responses in denervated skeletal muscle","rel_doi":"10.64898\/2026.07.10.737742","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737742","rel_abs":"Peripheral nerve injuries often result in prolonged skeletal muscle denervation, leading to progressive atrophy, fibrosis, neuromuscular instability, and loss of regenerative capacity before axons can reinnervate distal targets. Here, we developed a non-viral strategy using tissue nanotransfection (TNT) to deliver the neurogenic transcription factor cocktail Ascl1, Brn2, and Myt1l (ABM) directly to denervated skeletal muscle. In vitro, ABM-transfected myoblasts sustained expression of the reprogramming factors, acquired neuron-like morphologies, upregulated neuronal markers including Tuj1, Map2, and Syp, and exhibited electrophysiological properties consistent with membrane excitability. RNA sequencing confirmed broad activation of neurogenic transcriptional programs, with enrichment of pathways associated with neuronal fate commitment, neuron differentiation, axon guidance, synaptogenesis, and developmental signaling. In a mouse model of sciatic nerve transection, TNT enabled localized ABM expression in denervated gastrocnemius muscle. ABM-TNT treatment accelerated resolution of denervation-associated fibrillation potentials and showed trends toward improved twitch and tetanic torque, compound muscle action potential amplitudes, and muscle mass preservation. Transcriptomic profiling of treated muscles 5 weeks after injury revealed distinct gene expression programs enriched for muscle regeneration, neuromuscular organization, trophic support, extracellular matrix remodeling, angiogenesis, myogenesis, and metabolic adaptation. Network analyses further identified activation of neurogenic regulators, neurotrophic signaling, and vascular-support pathways. These findings establish TNT-mediated ABM delivery as a non-viral platform for inducing neurogenic and myoprotective programs in denervated muscle, suggesting a potential strategy to preserve muscle viability during the prolonged interval required for peripheral nerve regeneration.","rel_num_authors":20,"rel_authors":[{"author_name":"Ana I Salazar Puerta","author_inst":"The Ohio State University"},{"author_name":"Sara Kheirkhah","author_inst":"The Ohio State University"},{"author_name":"Jordan T Moore","author_inst":"The Ohio State University"},{"author_name":"Carlos A Vasquez Martinez","author_inst":"The Ohio State University"},{"author_name":"Carolina Velasquez Quintero","author_inst":"The Ohio State University"},{"author_name":"Hallie Harris","author_inst":"The Ohio State University"},{"author_name":"Manami Fukuda","author_inst":"The Ohio State University"},{"author_name":"Megumi E Fukuda","author_inst":"The Ohio State University"},{"author_name":"Jonathan P Stranan","author_inst":"The Ohio State University"},{"author_name":"Fangli Zhao","author_inst":"The Ohio State University"},{"author_name":"Kavya Dathathreya","author_inst":"The Ohio State University"},{"author_name":"Jared Albert","author_inst":"The Ohio State University"},{"author_name":"Prameela Bobbili","author_inst":"The Ohio State University"},{"author_name":"Charles D Wendt","author_inst":"The Ohio State University"},{"author_name":"Jonathan Winograd","author_inst":"Massachusetts General Hospital"},{"author_name":"Ian L Valerio","author_inst":"Massachusetts General Hospital"},{"author_name":"Candice Askwith","author_inst":"The Ohio State University"},{"author_name":"Amy M Moore","author_inst":"The Ohio State University"},{"author_name":"W David Arnold","author_inst":"University of Missouri"},{"author_name":"Daniel Gallego Perez","author_inst":"The Ohio State University"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Engineering a flexible loop in S-adenosyl-L-methionine synthetase enables production of SAM nucleobase analogues with selective biochemical and cellular activity","rel_doi":"10.64898\/2026.07.10.737877","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737877","rel_abs":"S-adenosyl-L-methionine (SAM), an essential cofactor in all forms of life, is synthesized by the enzyme methionine adenosyltransferase (MAT) from methionine and ATP. The adenine moiety in SAM appears to have no direct function in catalysis, and some MAT homologs can utilize natural nucleotide triphosphates in vitro, producing the corresponding SAM nucleobase analogues. However, the molecular determinants of nucleotide choice of the MAT enzyme and the cellular significance of the nucleobase in SAM are unclear. In this study, using structure- and bioinformatics-guided mutagenesis, we identify a flexible active-site loop as a major determinant of nucleotide specificity in MAT. Loop mutations and loop swaps convert ATP-selective Escherichia coli MAT into variants that accept GTP, CTP, and UTP, enabling enzymatic synthesis and purification of S-guanosyl-, S-cytosyl-, and S-uracyl-L-methionine. Further, we show that these analogues partially rescue the growth of an E. coli SAM auxotroph under SAM-limited growth conditions. Biochemical assays show that the analogues bind the tested SAM-utilizing enzymes; they serve as substrates for E. coli SAM decarboxylase but do not support detectable methyl transfer by E. coli DNA adenine methyltransferase. These results establish the flexible loop as a gatekeeper of MAT nucleotide specificity and show that this loop can be engineered to produce SAM analogues which can selectively participate in downstream cellular metabolism.","rel_num_authors":6,"rel_authors":[{"author_name":"Amrita B Hazra","author_inst":"Indian Institute of Science Education and Research (IISER) Pune"},{"author_name":"Dhritiraj Bastav Kalita","author_inst":"Indian Institute of Science Education Research, Pune"},{"author_name":"Aditya Bhattacharyya","author_inst":"Department of Chemistry and Chemical Biology, Cornell University"},{"author_name":"Vruta Gupte","author_inst":"Indian Institute of Science Education and Research, Pune"},{"author_name":"Vikram Venugopal","author_inst":"Stowers Institute for Medical Research: Kansas City, Missouri, US"},{"author_name":"Anjali Pattathil","author_inst":"Indian Institute of Science Education and Research, Pune"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"High-throughput stomatal phenotyping provides selection targets for stress-resilient wheat","rel_doi":"10.64898\/2026.07.10.737162","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737162","rel_abs":"Phenotyping stomatal traits and their developmental plasticity is time-consuming but holds potential to improve water use efficiency and photosynthesis for designing stress-tolerant crops under climate change. Here, we develop a robust, high-throughput pipeline for phenotyping 14 stomatal traits in winter wheat related to size, variation, maximum conductance, and spatial patterning. We (1) analyze over 25,000 images from 60 wheat cultivars grown in growth chamber, greenhouse, and field conditions; (2) investigate the impact of light, temperature, and reduced water and nitrogen supply on stomatal traits and their developmental plasticity across adaxial and abaxial surfaces; and (3) evaluate genetic diversity and breeding progress of stomatal traits. Stomatal traits were highly broad-sense heritable, were largely plastic in response to environmental conditions, and showed genotype-specific responses. Stomatal traits of third leaves under controlled environments with stable light and temperature conditions reliably captured the genetic variance of flag leaves under field conditions. Our data suggests that the upper leaf surface contributed more to transpiration and cooling through consistently higher stomatal density, area, and maximum conductance, while the lower surface facilitated CO2 diffusion via systematic proper patterning and spacing. Breeding maintains the genetic diversity of stomatal traits, and our pipeline facilitates breeders to target them to enhance water use efficiency in high-yielding modern cultivars.","rel_num_authors":16,"rel_authors":[{"author_name":"Mahmoud Mabrouk","author_inst":"Humboldt University of Berlin"},{"author_name":"Nicholas J. Russell","author_inst":"Humboldt University of Berlin"},{"author_name":"Emilio Villar Alegria","author_inst":"Humboldt University of Berlin"},{"author_name":"Tien-Cheng Wang","author_inst":"Humboldt University of Berlin"},{"author_name":"Jui-An Liang","author_inst":"National Taiwan University"},{"author_name":"Fang-Jin Wu","author_inst":"National Taiwan University"},{"author_name":"Yunfeng Huang","author_inst":"Dortmund University"},{"author_name":"Benjamin Wittkop","author_inst":"Justus Liebig University"},{"author_name":"Rod Snowdon","author_inst":"Justus Liebig University"},{"author_name":"Lukas F\u00f6rter","author_inst":"Justus Liebig University"},{"author_name":"Anna Moritz","author_inst":"Justus Liebig University"},{"author_name":"Eva Herzog","author_inst":"Justus Liebig University"},{"author_name":"Eliyeh Ganji","author_inst":"Julius Kuehn Institute"},{"author_name":"Gwendolin Wehner","author_inst":"Julius Kuehn Institute"},{"author_name":"Andreas Stahl","author_inst":"Julius Kuehn Institute"},{"author_name":"Tsu-Wei Chen","author_inst":"Humboldt University of Berlin"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Fertility Gene Introns Harbor Transposable Elements that Shape Y-Loop Architecture","rel_doi":"10.64898\/2026.07.08.737335","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737335","rel_abs":"Transposable elements (TEs) are powerful drivers of genome evolution, yet how they persist under selection and become incorporated into host regulatory networks remains poorly understood. In the Drosophila male germline, TEs are highly expressed during the spermatocyte stage, coinciding with activation of giant fertility genes on the Y chromosome. These genes contain megabase-scale introns enriched for repetitive DNA, and three of these genes form prominent nuclear structures known as Y-loops, providing a unique system to investigate gene regulation. Here, we show that multiple TEs expressed in spermatocytes are transcribed from the introns of Y-linked fertility genes. RNA fluorescence in situ hybridization (FISH) targeting several TEs, including accord2, Juan, and HMS Beagle, illuminates distinct nuclear regions corresponding to kl-2, kl-3, and kl-5, respectively. Genetic perturbation of these fertility gene loci or disruption of RNA-processing factors eliminates these TE transcripts, demonstrating that these TE sequences are embedded within Y chromosome-associated nascent transcripts rather than being independently transcribed. The identity and expression patterns of Y-loop-associated TEs vary extensively among closely related Drosophila species, consistent with the previously documented rapid evolution of Y-linked loci and suggesting that TEs may contribute to the genetic diversification of these giant fertility genes. We propose that continual turnover of repetitive elements within Y-linked introns provides a mechanism by which rapidly evolving repetitive DNA influences germline gene regulation, male fertility, and speciation.","rel_num_authors":4,"rel_authors":[{"author_name":"E K Beard","author_inst":"Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut, USA"},{"author_name":"Jeffrey P Gamer","author_inst":"Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut, USA"},{"author_name":"Amelie Raz","author_inst":"Whitehead Institute for Biomedical Research, Cambridge, MA, USA"},{"author_name":"Mayu Inaba","author_inst":"Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut, USA"}],"rel_date":"2026-07-12","rel_site":"biorxiv"},{"rel_title":"Striatal cholinergic and dopaminergic driven astrocyte Ca2+ activity is disrupted in Parkinsonian mice","rel_doi":"10.64898\/2026.07.08.737296","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737296","rel_abs":"Brain neuromodulatory systems exert powerful effects on local neuronal circuit function and behavior. In addition to classical actions directly on neurons, growing evidence indicates that neuromodulators also recruit Ca2+-dependent astrocyte mechanisms to regulate synaptic plasticity and network function. The dorsal striatum integrates cortical and thalamic inputs under strong dopamine (DA) and acetylcholine (ACh) neuromodulatory control. To what extent the circuit and behavioral effects of striatal ACh and DA depend on astrocyte Ca2+ activity remains unclear. We show that locomotion elicits robust DA, ACh, and astrocyte Ca2+ activity in the dorsolateral striatum (DLS). DA and ACh release exhibits a negative correlation on a fast time scale but shows a positive correlation during continuous locomotion as slower astrocyte Ca2+ activity builds. Higher ACh and DA release is associated with higher astrocyte events, suggesting that both neurotransmitters drive astrocyte activity. In agreement, pharmacological blockade of muscarinic ACh or D1\/D2 DA receptors decreases locomotion-evoked astrocyte Ca2+. Closed-loop optogenetic inhibition of striatal cholinergic interneurons (CINs) during locomotion reduces astrocyte Ca2+ activity, demonstrating a causal contribution of ACh release to astrocyte activity. Locomotion related ACh release was severely compromised in a mouse model of Parkinsons disease (PD), with the dual loss of DA and ACh attenuating astrocyte Ca2+ activity. Facilitating astrocyte cholinergic signaling via chemogenetics improved both calcium activity and motor deficits in our recent work. Thus, the pathophysiology of PD in part involves attenuated astrocyte Ca2+ signaling, placing these non-neuronal cells as a prime underexplored therapeutic target for PD.","rel_num_authors":5,"rel_authors":[{"author_name":"Wesley Ryne Evans","author_inst":"Rutgers, the State University of New Jersey"},{"author_name":"Hunter G Wells","author_inst":"Rutgers, the State University of New Jersey"},{"author_name":"Cynthia Jacob","author_inst":"Rutgers, the State University of New Jersey"},{"author_name":"Angelica Vellore","author_inst":"Rutgers, the State University of New Jersey"},{"author_name":"Rafiq Huda","author_inst":"Rutgers, the State University of New Jersey"}],"rel_date":"2026-07-12","rel_site":"biorxiv"},{"rel_title":"Spatial Glyco-Codes Define Human Liver Pathology and Progression","rel_doi":"10.64898\/2026.07.08.737217","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737217","rel_abs":"Glycosylation is a fundamental process regulating cellular function, tissue organization, and disease progression. However, comprehensive glycan profiling at single cell spatial resolution remains largely inaccessible, particularly in clinical archival tissues. Here we develop spatial GPT, a multimodal platform for simultaneous profiling of glycans, proteins, and\/or transcripts in archival formalin-fixed paraffin-embedded (FFPE) tissues. Using a panel of 30 DNA encoded lectins recognizing major mammalian glycan motifs and structural classes, sequencing-based spatial-GPT (DBiT GPT) mapped the spatial glycome, proteome, and transcriptome across 16 human liver specimens encompassing steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), leading to identification of spatial glyco codes. combinatorial glycan states associated with distinct cellular identities, tissue features, and pathological processes. Unexpectedly, glyco codes alone were sufficient to resolve major cell types, disease states, and HCC subtypes, revealing a previously unappreciated level of biological information encoded within the tissue glycome. Spatial glycomics uncovered tumor-like glyco-codes in premalignant regions, suggesting that glycan reprogramming may precede overt malignant transformation. Using imaging-based single-cell spatial glycan protein profiling (CODEX GP), we track glyco codes across the whole-tissue architecture of 3 representative HCC samples. We further examined the glyco-codes across more than 300 patient specimens and quantified cell-type- and disease-specific glyco codes as well as glycan-defined immuneevasion, T-cell-exhaustion, and steato fibrotic niches. Together, these findings establish spatial glyco-codes as a previously unrecognized layer of tissue organization that encodes cellular identity, tissue function, and disease progression. The ability of glyco-codes to distinguish major liver pathologies across independent patient cohorts further highlights their potential as a new class of molecular histopathology biomarkers.","rel_num_authors":24,"rel_authors":[{"author_name":"Xialong Tian","author_inst":"Yale University"},{"author_name":"Anthony A. Fung","author_inst":"Yale University"},{"author_name":"Xingbo Shang","author_inst":"Yale University"},{"author_name":"Dingyao Zhang","author_inst":"Yale University"},{"author_name":"Binfan Chen","author_inst":"Yale University"},{"author_name":"Lei Zhang","author_inst":"Yale University"},{"author_name":"Keyi Li","author_inst":"Yale University"},{"author_name":"Mei Zhong","author_inst":"Yale University"},{"author_name":"Yifan Deng","author_inst":"Yale University"},{"author_name":"Mingyu Yang","author_inst":"Yale University"},{"author_name":"Yao Lu","author_inst":"Yale University"},{"author_name":"Bo Tao","author_inst":"Yale University"},{"author_name":"Fu Gao","author_inst":"Yale University"},{"author_name":"Alev Baysoy","author_inst":"Yale University"},{"author_name":"Xiao Louise Lin","author_inst":"Yale University"},{"author_name":"Aleksandra Ivovic","author_inst":"Boehringer Ingelheim"},{"author_name":"Sidi Chen","author_inst":"Yale University"},{"author_name":"Frank Li","author_inst":"Boehringer Ingelheim.com"},{"author_name":"Mina L Xu","author_inst":"Yale University"},{"author_name":"Xuchen Zhang","author_inst":"Yale University"},{"author_name":"Mark Gerstein","author_inst":"Yale University"},{"author_name":"Xiaoyong Yang","author_inst":"Yale University School of Medicine"},{"author_name":"Chen Liu","author_inst":"Yale University"},{"author_name":"Rong Fan","author_inst":"Yale University"}],"rel_date":"2026-07-12","rel_site":"biorxiv"},{"rel_title":"A geometric atlas of how ESM3 organizes modalities across depth","rel_doi":"10.64898\/2026.07.08.737319","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737319","rel_abs":"Protein language models learn general-purpose representations from large collections of protein sequences and structures, and have advanced the prediction of protein structure and function. ESM3 is a multimodal protein language model that ingests a protein through several channels at once, including amino-acid sequence, three-dimensional structure, secondary structure (SS8), solvent accessibility (SASA), and discrete functional annotations, summing their embeddings into a single residual stream. Little is known about whether these modalities occupy separate subspaces and the depth at which they fuse. The present analysis examines ESM3 (esm3-sm-open-v1; 1.4 billion parameters; 48 transformer layers) once per modality in isolation and applies representational-similarity analysis across all 48 layers. The four physical modalities (sequence, structure, SS8, SASA) begin in distinct subspaces, remain maximally separated through roughly the first half of layers, and then fuse into a shared low-dimensional subspace between layers 25 and 35. The fusion is ordered. The structure-derived modalities (structure, SS8, SASA) are mutually aligned from the input, whereas sequence joins last, after layer 28. The functional-annotation modality never fuses; instead, it remains representationally orthogonal to the physical modalities at every layer, and this orthogonality holds whether the annotation is supplied as whole-protein or per-residue, suggesting that it is content-driven rather than a tokenization artifact. The fusion is a learned property, absent in a randomly initialized model of the same architecture, holds at the residue level below the mean-pool, and reorganizes variance, converting between-condition variance into within-condition variance while the stream never approaches isotropy. Fusion depth is independent of protein length but is delayed by structural disorder. The phenomenon is universal across diverse organisms. Across 5,555 proteins from 12 organisms spanning eukaryota, bacteria, and archaea, every superkingdom (and every individual organism) reaches peak modality fusion at the same network depth (layer 35).","rel_num_authors":1,"rel_authors":[{"author_name":"Jacob L Steenwyk","author_inst":"University of California, Berkeley"}],"rel_date":"2026-07-12","rel_site":"biorxiv"},{"rel_title":"Genomic Annotation Infrastructure (GAIn): Pipelines and Resource Repositories for Annotating Variants, Positions, and Regions","rel_doi":"10.64898\/2026.07.08.737273","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737273","rel_abs":"Interpretation of genomic variants, positions, and regions depends on reliable annotation - adding evidence such as predicted effect, conservation, population frequency, and gene-level context - yet the underlying resources are numerous, versioned, and assembly-specific. We present the Genomic Annotation Infrastructure (GAIn), a platform that generates transparent, reproducible annotations via declarative pipelines that define annotation tasks as ordered lists of components, called annotators, that produce annotation attributes using genomic resources from Genomic Resource Repositories (GRRs). We provide two public GRRs: a main repository containing more than 250 heterogeneous genomic resources, and a separate GRR-ENCODE repository containing resources derived from thousands of ENCODE (Encyclopedia of DNA Elements) project experiments. Users can use the annotation pipelines we made available, author custom annotation pipelines, and execute annotation tasks with these pipelines via GAIn's web and command-line interfaces. The web interface can be used without any setup, but it relies on shared computational infrastructure and imposes limits on the size of annotation tasks. The command-line interface requires setup but supports arbitrarily large annotation tasks through simple-to-use parallelization and offers a broader set of features. For example, command-line GAIn can be extended by using custom GRRs or creating custom annotators via its plugin architecture. In addition, GAIn's re-annotation feature, which updates annotations as they evolve, substantially simplifies maintaining annotations in a large genomics analysis project. GAIn's resource management, explicit versioning, and pipeline abstraction provide an auditable, maintainable, and efficient foundation for modern genomic annotation across reference assemblies and use cases.","rel_num_authors":7,"rel_authors":[{"author_name":"Murat Cokol","author_inst":"Rodop Biotechnology"},{"author_name":"Lubomir Chorbadjiev","author_inst":"SeqPipe Limited"},{"author_name":"Yoon-ha Lee","author_inst":"Cold Spring Harbor Laboratory"},{"author_name":"Minal Jamsandekar","author_inst":"Cold Spring Harbor Laboratory"},{"author_name":"Ilina Gergova","author_inst":"SeqPipe Limited"},{"author_name":"Ivo Todorov","author_inst":"SeqPipe Limited"},{"author_name":"Ivan Iossifov","author_inst":"CSHL"}],"rel_date":"2026-07-12","rel_site":"biorxiv"},{"rel_title":"Synovium-Restricted Armored PD-1-Targeted CAR-T Cells Reprogram Immunity and Resolve Experimental Arthritis","rel_doi":"10.64898\/2026.07.09.737520","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737520","rel_abs":"Despite major therapeutic advances, a substantial fraction of patients with autoimmune disease remains refractory to treatment. While B cell-targeted CAR-T therapies have shown considerable efficacy, the central contribution of pathogenic T cells to rheumatoid arthritis (RA) suggests that complementary T cell-directed strategies may enable deeper disease control. Using single-cell multi-omics of human RA and experimental models, PDCD1 was identified as a selective marker of synovial disease-associated T cells. We developed PD-1-directed CAR-T cells that potently eliminate these cells in vitro and in vivo, leading to marked attenuation of synovitis in RA models. To limit off-target activity, we engineered NR4A2-driven CAR-responsive biosensors to restrict CAR activity to inflamed synovium. To couple anti-PD-1 CAR-mediated cytotoxicity with microenvironmental modulation, we further engineered these CAR-T cells to secrete soluble TNF receptor II (sTNFRII), counteracting baseline inflammation and CAR-induced IFN response and promoting a tissue-reparative myeloid state. PD-1-targeted CAR-T therapy thus represents a promising, specific, and safe strategy for autoimmune diseases involving disease-associated T cells.","rel_num_authors":24,"rel_authors":[{"author_name":"Chamutal Gur","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel; Rheumatology Department, Hadassah Medical Center, Faculty of Medicine, Hebrew "},{"author_name":"Lior Ravkaie","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Reut Sharet-Eshed","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Rotem Shalita","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Roberto Avellino","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Einat Rauchbach","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Ken Xie","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Eyal David","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Gal Yagel","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Mor Zada","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Maya Ben Yehuda","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Kfir Mazuz","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Michelle Nathalie Von Locquenghien","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Hagit Peleg","author_inst":"Rheumatology Department, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Israel"},{"author_name":"Yaakov Naparstek","author_inst":"Rheumatology Department, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Israel"},{"author_name":"Karine Atlan","author_inst":"Department of Pathology, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel"},{"author_name":"Shlomit Kfir-Erenfeld","author_inst":"Department of Bone Marrow Transplantation, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Israel"},{"author_name":"Yuri Kuznetsov","author_inst":"Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Reut Tzemach","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel; Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel"},{"author_name":"Merav Lidar","author_inst":"Rheumatology Unit, Sheba Medical Center, Tel Hashomer and Gray Faculty of Medical and Health Sciences, Tel Aviv University, Israel"},{"author_name":"Alexandra Balbir-Gurman","author_inst":"Rheumatology Institute, Rambam Health Care Campus, Rappaport Faculty of Medicine, Technion-Israeli Institute of Technology, Haifa, Israel"},{"author_name":"Truong San Phan","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Kiara Freitag","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Ido Amit","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"}],"rel_date":"2026-07-12","rel_site":"biorxiv"},{"rel_title":"Synovium-Restricted Armored PD-1-Targeted CAR-T Cells Reprogram Immunity and Resolve Experimental Arthritis","rel_doi":"10.64898\/2026.07.09.737520","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737520","rel_abs":"Despite major therapeutic advances, a substantial fraction of patients with autoimmune disease remains refractory to treatment. While B cell-targeted CAR-T therapies have shown considerable efficacy, the central contribution of pathogenic T cells to rheumatoid arthritis (RA) suggests that complementary T cell-directed strategies may enable deeper disease control. Using single-cell multi-omics of human RA and experimental models, PDCD1 was identified as a selective marker of synovial disease-associated T cells. We developed PD-1-directed CAR-T cells that potently eliminate these cells in vitro and in vivo, leading to marked attenuation of synovitis in RA models. To limit off-target activity, we engineered NR4A2-driven CAR-responsive biosensors to restrict CAR activity to inflamed synovium. To couple anti-PD-1 CAR-mediated cytotoxicity with microenvironmental modulation, we further engineered these CAR-T cells to secrete soluble TNF receptor II (sTNFRII), counteracting baseline inflammation and CAR-induced IFN response and promoting a tissue-reparative myeloid state. PD-1-targeted CAR-T therapy thus represents a promising, specific, and safe strategy for autoimmune diseases involving disease-associated T cells.","rel_num_authors":24,"rel_authors":[{"author_name":"Chamutal Gur","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel; Rheumatology Department, Hadassah Medical Center, Faculty of Medicine, Hebrew "},{"author_name":"Lior Ravkaie","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Reut Sharet-Eshed","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Rotem Shalita","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Roberto Avellino","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Einat Rauchbach","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Ken Xie","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Eyal David","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Gal Yagel","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Mor Zada","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Maya Ben Yehuda","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Kfir Mazuz","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Michelle Nathalie Von Locquenghien","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Hagit Peleg","author_inst":"Rheumatology Department, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Israel"},{"author_name":"Yaakov Naparstek","author_inst":"Rheumatology Department, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Israel"},{"author_name":"Karine Atlan","author_inst":"Department of Pathology, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel"},{"author_name":"Shlomit Kfir-Erenfeld","author_inst":"Department of Bone Marrow Transplantation, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Israel"},{"author_name":"Yuri Kuznetsov","author_inst":"Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Reut Tzemach","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel; Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel"},{"author_name":"Merav Lidar","author_inst":"Rheumatology Unit, Sheba Medical Center, Tel Hashomer and Gray Faculty of Medical and Health Sciences, Tel Aviv University, Israel"},{"author_name":"Alexandra Balbir-Gurman","author_inst":"Rheumatology Institute, Rambam Health Care Campus, Rappaport Faculty of Medicine, Technion-Israeli Institute of Technology, Haifa, Israel"},{"author_name":"Truong San Phan","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Kiara Freitag","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"},{"author_name":"Ido Amit","author_inst":"Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel"}],"rel_date":"2026-07-12","rel_site":"biorxiv"},{"rel_title":"Mapping Genetic Susceptibility to Urinary Tract Infection from Kidney Papilla to Bladder","rel_doi":"10.64898\/2026.07.07.26357417","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26357417","rel_abs":"Urinary tract infections (UTIs) are among the most common bacterial infections, yet the genetic factors influencing susceptibility remain poorly understood. We performed a genome-wide association study of recurrent UTI involving 1,860,836 individuals (213,869 cases and 1,646,967 controls). We identified 36 independent non-HLA genome-wide significant loci encoding kidney epithelial and immune response genes and demonstrated that some loci have sex-specific effects. Integrative functional annotation, expression and protein quantitative trait locus colocalization, and single-cell multi-omic analyses revealed that UTI risk alleles preferentially modulated gene expression in kidney, ureter, and bladder epithelia. Multi-omic prioritization converged on a number of pathogenic pathways: epithelial barrier and mucosal glycocalyx defense (PSCA, UMOD, CLPTM1L, FUT2), innate immune regulation (FES, PTPRC, NEK7, HOTAIR, NFATC1, BTN3A2), infection resolution and regulated cell death (STK3, CASP7, TAX1BP1, ZFP36L2), epithelial identity maintenance (GLIS2, CLDN10, ZFHX3, SPDEF, MPP7), urinary tract development (FGFR2, BMP7, HGF, MET, HOXA9, TSHZ2, WNT7B\/LINC00899), and nutritional immunity through iron sequestration (SLC11A2, FAM210B, RPS10). Approximately one-third of loci colocalized with gene expression in kidney tubules, suggesting direct modulation of epithelial host-defense programs. Among all loci, PSCA, which encodes a GPI-anchored epithelial surface protein expressed in the kidney papilla and urinary tract epithelia, emerged as the strongest candidate causal gene. We demonstrated that PSCA was secreted into urine, bound uropathogenic E. coli, and inhibited bacterial growth in vitro, implicating it as a constitutive epithelial defense factor. We also demonstrated that while PSCA was protective against urinary infections and duodenal ulcers, it was associated with increased risk of bladder, prostate, and gastric cancers, suggesting antagonistic pleiotropy between mucosal defenses and oncogenesis. Together, our findings define the polygenic architecture of UTI susceptibility, highlighting epithelial surface defense, innate immune regulation, developmental patterning, and nutritional immunity as central components of host defense, providing a new framework for host-directed, non-antibiotic interventions.","rel_num_authors":45,"rel_authors":[{"author_name":"Katherine Xu","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Atlas Khan","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Ning Shang","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Wenjie Zeng","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Chen Wang","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Cecilia Berrouet","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Tian Huai Shen","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Padma Narayanan","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Jenny Deng","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Chiara DiPerna","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Charlotte Williams","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Sarah Cuacuas","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Timothy R. Olsen","author_inst":"Biohub, New York, NY, USA"},{"author_name":"Jeffrey Arace","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Aryan Ghotra","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Wayne Monical","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Oleg Borisov","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany"},{"author_name":"Stefan Haug","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany"},{"author_name":"Hongbo Liu","author_inst":"Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Eunji Ha","author_inst":"Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Run Banlengchit","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Abraham Levitman","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Diya Patel","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Claire Chou","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Bartlomiej Halibart","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Tai Wei Guo","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Shawn Simmons","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Sanya Goswami","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Kivanc Nesanir","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Masashi Fujita","author_inst":"Department of Neurology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Iftikhar J. Kullo","author_inst":"Division of Cardiovascular Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Gail P. Jarvik","author_inst":"Departments of Medicine (Medical Genetics) and Genome Sciences, Division of Medical Genetics, University of Washington Medical Center, Seattle, Washington, USA"},{"author_name":"Wei-Qi Wei","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"QiPing Feng","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Lan Jiang","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"C. Michael Stein","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Chunhua Weng","author_inst":"Department of Biomedical Informatics, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"George Hripcsak","author_inst":"Department of Biomedical Informatics, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Ali G. Gharavi","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Katalin Susztak","author_inst":"Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Philip L. De Jager","author_inst":"Department of Neurology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Anna K\u00f6ttgen","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany; CIBSS - Centre for Integrative Biol"},{"author_name":"Jonathan Barasch","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Peter A. Sims","author_inst":"Department of Systems Biology, Columbia University, New York, NY, USA; Biohub, New York, NY, USA"},{"author_name":"Krzysztof Kiryluk","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"}],"rel_date":"2026-07-11","rel_site":"medrxiv"},{"rel_title":"Mapping Genetic Susceptibility to Urinary Tract Infection from Kidney Papilla to Bladder","rel_doi":"10.64898\/2026.07.07.26357417","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26357417","rel_abs":"Urinary tract infections (UTIs) are among the most common bacterial infections, yet the genetic factors influencing susceptibility remain poorly understood. We performed a genome-wide association study of recurrent UTI involving 1,860,836 individuals (213,869 cases and 1,646,967 controls). We identified 36 independent non-HLA genome-wide significant loci encoding kidney epithelial and immune response genes and demonstrated that some loci have sex-specific effects. Integrative functional annotation, expression and protein quantitative trait locus colocalization, and single-cell multi-omic analyses revealed that UTI risk alleles preferentially modulated gene expression in kidney, ureter, and bladder epithelia. Multi-omic prioritization converged on a number of pathogenic pathways: epithelial barrier and mucosal glycocalyx defense (PSCA, UMOD, CLPTM1L, FUT2), innate immune regulation (FES, PTPRC, NEK7, HOTAIR, NFATC1, BTN3A2), infection resolution and regulated cell death (STK3, CASP7, TAX1BP1, ZFP36L2), epithelial identity maintenance (GLIS2, CLDN10, ZFHX3, SPDEF, MPP7), urinary tract development (FGFR2, BMP7, HGF, MET, HOXA9, TSHZ2, WNT7B\/LINC00899), and nutritional immunity through iron sequestration (SLC11A2, FAM210B, RPS10). Approximately one-third of loci colocalized with gene expression in kidney tubules, suggesting direct modulation of epithelial host-defense programs. Among all loci, PSCA, which encodes a GPI-anchored epithelial surface protein expressed in the kidney papilla and urinary tract epithelia, emerged as the strongest candidate causal gene. We demonstrated that PSCA was secreted into urine, bound uropathogenic E. coli, and inhibited bacterial growth in vitro, implicating it as a constitutive epithelial defense factor. We also demonstrated that while PSCA was protective against urinary infections and duodenal ulcers, it was associated with increased risk of bladder, prostate, and gastric cancers, suggesting antagonistic pleiotropy between mucosal defenses and oncogenesis. Together, our findings define the polygenic architecture of UTI susceptibility, highlighting epithelial surface defense, innate immune regulation, developmental patterning, and nutritional immunity as central components of host defense, providing a new framework for host-directed, non-antibiotic interventions.","rel_num_authors":45,"rel_authors":[{"author_name":"Katherine Xu","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Atlas Khan","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Ning Shang","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Wenjie Zeng","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Chen Wang","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Cecilia Berrouet","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Tian Huai Shen","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Padma Narayanan","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Jenny Deng","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Chiara DiPerna","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Charlotte Williams","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Sarah Cuacuas","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Timothy R. Olsen","author_inst":"Biohub, New York, NY, USA"},{"author_name":"Jeffrey Arace","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Aryan Ghotra","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Wayne Monical","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Oleg Borisov","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany"},{"author_name":"Stefan Haug","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany"},{"author_name":"Hongbo Liu","author_inst":"Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Eunji Ha","author_inst":"Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Run Banlengchit","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Abraham Levitman","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Diya Patel","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Claire Chou","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Bartlomiej Halibart","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Tai Wei Guo","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Shawn Simmons","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Sanya Goswami","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Kivanc Nesanir","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Masashi Fujita","author_inst":"Department of Neurology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Iftikhar J. Kullo","author_inst":"Division of Cardiovascular Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Gail P. Jarvik","author_inst":"Departments of Medicine (Medical Genetics) and Genome Sciences, Division of Medical Genetics, University of Washington Medical Center, Seattle, Washington, USA"},{"author_name":"Wei-Qi Wei","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"QiPing Feng","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Lan Jiang","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"C. Michael Stein","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Chunhua Weng","author_inst":"Department of Biomedical Informatics, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"George Hripcsak","author_inst":"Department of Biomedical Informatics, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Ali G. Gharavi","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Katalin Susztak","author_inst":"Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Philip L. De Jager","author_inst":"Department of Neurology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Anna K\u00f6ttgen","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany; CIBSS - Centre for Integrative Biol"},{"author_name":"Jonathan Barasch","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Peter A. Sims","author_inst":"Department of Systems Biology, Columbia University, New York, NY, USA; Biohub, New York, NY, USA"},{"author_name":"Krzysztof Kiryluk","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"}],"rel_date":"2026-07-11","rel_site":"medrxiv"},{"rel_title":"Mapping Genetic Susceptibility to Urinary Tract Infection from Kidney Papilla to Bladder","rel_doi":"10.64898\/2026.07.07.26357417","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26357417","rel_abs":"Urinary tract infections (UTIs) are among the most common bacterial infections, yet the genetic factors influencing susceptibility remain poorly understood. We performed a genome-wide association study of recurrent UTI involving 1,860,836 individuals (213,869 cases and 1,646,967 controls). We identified 36 independent non-HLA genome-wide significant loci encoding kidney epithelial and immune response genes and demonstrated that some loci have sex-specific effects. Integrative functional annotation, expression and protein quantitative trait locus colocalization, and single-cell multi-omic analyses revealed that UTI risk alleles preferentially modulated gene expression in kidney, ureter, and bladder epithelia. Multi-omic prioritization converged on a number of pathogenic pathways: epithelial barrier and mucosal glycocalyx defense (PSCA, UMOD, CLPTM1L, FUT2), innate immune regulation (FES, PTPRC, NEK7, HOTAIR, NFATC1, BTN3A2), infection resolution and regulated cell death (STK3, CASP7, TAX1BP1, ZFP36L2), epithelial identity maintenance (GLIS2, CLDN10, ZFHX3, SPDEF, MPP7), urinary tract development (FGFR2, BMP7, HGF, MET, HOXA9, TSHZ2, WNT7B\/LINC00899), and nutritional immunity through iron sequestration (SLC11A2, FAM210B, RPS10). Approximately one-third of loci colocalized with gene expression in kidney tubules, suggesting direct modulation of epithelial host-defense programs. Among all loci, PSCA, which encodes a GPI-anchored epithelial surface protein expressed in the kidney papilla and urinary tract epithelia, emerged as the strongest candidate causal gene. We demonstrated that PSCA was secreted into urine, bound uropathogenic E. coli, and inhibited bacterial growth in vitro, implicating it as a constitutive epithelial defense factor. We also demonstrated that while PSCA was protective against urinary infections and duodenal ulcers, it was associated with increased risk of bladder, prostate, and gastric cancers, suggesting antagonistic pleiotropy between mucosal defenses and oncogenesis. Together, our findings define the polygenic architecture of UTI susceptibility, highlighting epithelial surface defense, innate immune regulation, developmental patterning, and nutritional immunity as central components of host defense, providing a new framework for host-directed, non-antibiotic interventions.","rel_num_authors":45,"rel_authors":[{"author_name":"Katherine Xu","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Atlas Khan","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Ning Shang","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Wenjie Zeng","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Chen Wang","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Cecilia Berrouet","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Tian Huai Shen","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Padma Narayanan","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Jenny Deng","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Chiara DiPerna","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Charlotte Williams","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Sarah Cuacuas","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Timothy R. Olsen","author_inst":"Biohub, New York, NY, USA"},{"author_name":"Jeffrey Arace","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Aryan Ghotra","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Wayne Monical","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Oleg Borisov","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany"},{"author_name":"Stefan Haug","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany"},{"author_name":"Hongbo Liu","author_inst":"Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Eunji Ha","author_inst":"Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Run Banlengchit","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Abraham Levitman","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Diya Patel","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Claire Chou","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Bartlomiej Halibart","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Tai Wei Guo","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Shawn Simmons","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Sanya Goswami","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Kivanc Nesanir","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Masashi Fujita","author_inst":"Department of Neurology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Iftikhar J. Kullo","author_inst":"Division of Cardiovascular Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Gail P. Jarvik","author_inst":"Departments of Medicine (Medical Genetics) and Genome Sciences, Division of Medical Genetics, University of Washington Medical Center, Seattle, Washington, USA"},{"author_name":"Wei-Qi Wei","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"QiPing Feng","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Lan Jiang","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"C. Michael Stein","author_inst":"Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Chunhua Weng","author_inst":"Department of Biomedical Informatics, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"George Hripcsak","author_inst":"Department of Biomedical Informatics, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Ali G. Gharavi","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Katalin Susztak","author_inst":"Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Philip L. De Jager","author_inst":"Department of Neurology, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Anna K\u00f6ttgen","author_inst":"Institute of Epidemiology and Prevention, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany; CIBSS - Centre for Integrative Biol"},{"author_name":"Jonathan Barasch","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"},{"author_name":"Peter A. Sims","author_inst":"Department of Systems Biology, Columbia University, New York, NY, USA; Biohub, New York, NY, USA"},{"author_name":"Krzysztof Kiryluk","author_inst":"Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, NY, USA"}],"rel_date":"2026-07-11","rel_site":"medrxiv"},{"rel_title":"Placental invasion mismatch underlines pregnancy disorders and cancers","rel_doi":"10.64898\/2026.07.06.736876","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736876","rel_abs":"Mammalian placentas vary dramatically in invasiveness, parallel aggressive cancers, and are dysregulated in pregnancy disorders, yet whether they share regulatory architecture remains unclear. We investigated single-cell transcriptomes of the maternal-fetal interface across nine mammals spanning all major placental morphotypes and integrated it with thirteen cancers and five pregnancy complications. A conserved cellular framework is deployed through three discrete regulatory programs: a cancer-like program in hemochorials, endothelial-cooperation program in endotheliochorials, and collagen-rich invasion-suppressing program in epitheliochorials. Aggressive cancers selectively converge on hemochorial program, and we functionally validated share invasion regulators including the VGLL3-TEAD1 interaction and APOE. Pregnancy disorders are partially, mismatched deployments of these programs; placental APOE knockdown in mice phenocopies preeclampsia with concurrent collapse of both M1\/M2 macrophage programs. These findings unify placental diversity, cancer convergence, and obstetric disorders under a regulatory-mismatch principle, whereby evolved placental invasion programs becomes pathological when deployed outside their evolutionary context.","rel_num_authors":20,"rel_authors":[{"author_name":"Xin Li","author_inst":"Zhejiang University"},{"author_name":"Ruixue Chen","author_inst":"Zhejiang University"},{"author_name":"Yangyi Zhang","author_inst":"Zhejiang University"},{"author_name":"Yuchen Sun","author_inst":"Zhejiang University"},{"author_name":"Wenqiang Du","author_inst":"University of Connecticut Health Center"},{"author_name":"Dan Yu","author_inst":"Zhejiang University"},{"author_name":"Yanlin Lu","author_inst":"Zhejiang University"},{"author_name":"Yiqing Yang","author_inst":"Zhejiang University"},{"author_name":"Xupeng Bi","author_inst":"Zhejiang University"},{"author_name":"Yijun Yang","author_inst":"Zhejiang University"},{"author_name":"Jintian Zhu","author_inst":"Zhejiang University"},{"author_name":"Kailin Sun","author_inst":"Zhejiang University"},{"author_name":"Jing Liang","author_inst":"Zhejiang University"},{"author_name":"Lin Jiang","author_inst":"Zhejiang University"},{"author_name":"Yunqiu He","author_inst":"Zhejiang University"},{"author_name":"Liqun Sun","author_inst":"Zhejiang University"},{"author_name":"Junhua Shen","author_inst":"Zhejiang University"},{"author_name":"Kshitiz","author_inst":"University of Connecticut Health"},{"author_name":"Dan Zhang","author_inst":"Zhejiang University"},{"author_name":"Guojie Zhang","author_inst":"Zhejiang University"}],"rel_date":"2026-07-11","rel_site":"biorxiv"},{"rel_title":"Genomic basis of developmental defects of enamel and sex-specific effects","rel_doi":"10.64898\/2026.07.06.26355672","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.06.26355672","rel_abs":"We conducted a multi-ancestry genome-wide association study (GWAS) of developmental defects of enamel (DDE) in the primary dentition among 6,061 U.S. preschool-aged children (3-5 years). We investigated four DDE phenotypes (demarcated opacities, diffuse opacities, hypoplastic defects, and a combined DDE trait) leveraging main-effect models, joint gene-sex interaction testing (2df), and sex-stratified analyses. SNP-based heritability for the combined DDE trait was estimated at 20%, with concordance analyses robustly supporting a genetic etiology. We identified 39 unique genome-wide significant loci (P<5x10{square}{square}), with five surpassing a study-wide Bonferroni-corrected statistical significance criterion (P<1.25x10{square}{square}), including Y RNA and ALDH1A1. The main-effect GWAS identified 20 loci, including HBS1L and MYB, genes regulating hematopoiesis with plausible roles in amelogenesis. Joint test and sex-stratified analyses revealed 19 additional loci, including ALDH1A1, TENM2, and DLGAP2, demonstrating sex-specific heterogeneity. Nineteen loci exhibited sex-specific differences after Bonferroni correction (P<2x10-3), including genes involved in retinoic acid signaling (ALDH1A1), odontogenesis (TENM2), and neurodevelopment (DLGAP2, CDH10). Pathway enrichment highlighted ectodermal and synapse organization networks, suggesting shared etiological mechanisms between DDE and systemic conditions like neurofibromatosis and autism spectrum disorder. Notably, no locus generalized in an external GWAS of permanent dentition DDE, underscoring fundamental biological differences in the genetic architectures governing primary versus permanent enamel formation. Crucially, a comprehensive cross-trait pleiotropy lookup against early childhood caries (ECC) revealed no shared genetic architecture, supporting the notion that the established clinical and epidemiological association between DDE and ECC is likely driven by structural defects increasing caries lesion susceptibility rather than genetic pleiotropy. By integrating gene-sex interaction testing, this study offers novel insights into the complex, sexually dimorphic genetic etiology of DDE and augments the biological evidence base that can support the development of precision pediatric dentistry.","rel_num_authors":19,"rel_authors":[{"author_name":"Poojan Shrestha","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Mariaelisa Graff","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Yu Gu","author_inst":"The University of Hong Kong"},{"author_name":"Yujie Wang","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Hyunseong Sean Ahn","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Kevin Ngoc Nguyen","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Ayush Khanna","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Christy Leigh Avery","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Heather Michelle Highland","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Jeannie Ginnis","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Miguel Angel Simancas-Pallares","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Andrea G. Ferreira Zandon\u00e1","author_inst":"The Ohio State University College of Dentistry"},{"author_name":"Rasha Nasha Alotaibi","author_inst":"King Saud University"},{"author_name":"Danyu Lin","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"John S. Preisser","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Gary D. Slade","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Mary Louise Marazita","author_inst":"University of Pittsburgh"},{"author_name":"Kari E. North","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Kimon Divaris","author_inst":"University of North Carolina at Chapel Hill"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"Automated Disease Activity Assessment in Systemic Lupus Erythematosus Using Privacy-Preserving Large Language Models","rel_doi":"10.64898\/2026.07.09.26357586","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357586","rel_abs":"The Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) is a crucial but labor-intensive tool for managing SLE. We developed a privacy-preserving, model-agnostic large language model (LLM) framework to automate SLEDAI-2K assessment from real-world electronic health records. The framework was developed on a specialist-verified ground truth of 658 clinical notes and externally validated on 56 MIMIC-IV discharge summaries. Seven open-source LLMs were evaluated using advanced prompting and ensemble strategies. The top-performing model, a two-layered GPT-OSS-120B + verifier, achieved a micro-F1 of 94.2% for descriptor classification and an 86% exact match for SLEDAI-2K scores on the internal set, with corresponding external validation performance of 87.7% and 64%, respectively. To demonstrate clinical utility, the LLMs were deployed on 2,576 serial notes from 108 SLE patients. Patients identified by the LLMs as achieving sustained low disease activity had a significantly lower incidence of stage 3 chronic kidney disease (log-rank p = 0.0053), the need for kidney replacement therapy (p = 0.044), and hospitalization (p = 0.021) over 18.3 years of follow-up. These findings demonstrate that privacy-preserving LLMs, when guided by a well-designed framework, can assist in specialist-level reasoning in autoimmune diseases, offering a scalable solution for clinical decision support and patient management.","rel_num_authors":14,"rel_authors":[{"author_name":"Danting Zhang","author_inst":"The University of Hong Kong"},{"author_name":"Renee L. Leung","author_inst":"The University of Hong Kong"},{"author_name":"Chun-Ka Wong","author_inst":"The University of Hong Kong"},{"author_name":"Shirley Chiu Wai Chan","author_inst":"The University of Hong Kong"},{"author_name":"Yi Li","author_inst":"The University of Hong Kong"},{"author_name":"Eric H. M. Tang","author_inst":"The University of Hong Kong"},{"author_name":"Tingting Wu","author_inst":"The University of Hong Kong"},{"author_name":"Tak Mao Chan","author_inst":"The University of Hong Kong"},{"author_name":"Chak-Sing Lau","author_inst":"The University of Hong Kong"},{"author_name":"Carlos King Ho Wong","author_inst":"London School of Hygiene & Tropical Medicine"},{"author_name":"Kathy Sze Man Leung","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Zoie Shui-Yee Wong","author_inst":"Swinburne University of Technology"},{"author_name":"Joseph Tsz-Kei Wu","author_inst":"The University of Hong Kong"},{"author_name":"Desmond Yat-Hin Yap","author_inst":"The University of Hong Kong"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"Structural Variant Imputation in Samoans Using a Population-Specific Reference Panel","rel_doi":"10.64898\/2026.07.07.26357461","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26357461","rel_abs":"Structural variants (SVs) are often excluded from genetic research because they are difficult to call, but they can have substantial effects on phenotypic traits. SVs have not previously been characterized in Samoans, an understudied population with a high burden of complex diseases. Using short-read whole genome sequencing data, we called SVs in 1,276 Samoans and created a Samoan-specific imputation panel inclusive of both SVs and single nucleotide variants (SNVs), called the Soifua Manuia-SV panel. Using this panel, we imputed SVs and SNVs in 3,611 Samoans with array data, enabling analysis of SV-phenotype associations in a sample of 4,887 Samoan participants. We evaluated imputation performance in Samoans against two other reference panels: (i) an SNV-only Samoan-specific reference panel, to assess whether SV inclusion impacts SNV imputation, and (ii) an SV and SNV, multi-ancestry reference panel composed of 1000 Genomes participants, which did not include Polynesians, to assess the importance of including the target population in the reference panel. The Soifua Manuia-SV panel substantially outperformed the multi-ancestry SV and SNV panel, yielding 5.5 million more high-quality (r2 [&ge;] 0.8) variants, including over 8,000 more high-quality SVs. SNV imputation based on the two Samoan-specific panels performed similarly overall, suggesting that SV inclusion does not strongly impact SNV imputation quality. This work highlights the importance of population representation for accurate imputation.","rel_num_authors":17,"rel_authors":[{"author_name":"Lauren M. Spor","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Emily M. Liau","author_inst":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Ca"},{"author_name":"Alba Sanchis-Juan","author_inst":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Ca"},{"author_name":"Andrew N. Silva","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Hong Cheng","author_inst":"Department of Environmental and Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA"},{"author_name":"Take Naseri","author_inst":"Naseri and Associates Public Health Consultancy Firm and Family Health Clinic; Department of Epidemiology and Center for Global Public Health, Brown University "},{"author_name":"Muagututi'a Sefuiva Reupena","author_inst":"Lutia i Puava ae Mapu i Fagalele, Apia, Samoa"},{"author_name":"Satupa'itea Viali","author_inst":"Oceania University of Medicine, Samoa; National University of Samoa, Apia, Samoa; Department of Chronic Disease Epidemiology, Yale School of Public Health, New "},{"author_name":"John Tuitele","author_inst":"Department of Public Health, LBJ Tropical Medical Center, Faga'alu, AS, USA"},{"author_name":"Erin E. Kershaw","author_inst":"Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Ranjan Deka Deka","author_inst":"Department of Environmental and Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA"},{"author_name":"Nicola L. Hawley","author_inst":"Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA"},{"author_name":"Stephen T. McGarvey","author_inst":"Department of Anthropology, Brown University, Providence, RI, USA"},{"author_name":"Daniel E. Weeks","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Jenna C. Carlson","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Harrison Brand","author_inst":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Ca"},{"author_name":"Ryan L. Minster","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"Structural Variant Imputation in Samoans Using a Population-Specific Reference Panel","rel_doi":"10.64898\/2026.07.07.26357461","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26357461","rel_abs":"Structural variants (SVs) are often excluded from genetic research because they are difficult to call, but they can have substantial effects on phenotypic traits. SVs have not previously been characterized in Samoans, an understudied population with a high burden of complex diseases. Using short-read whole genome sequencing data, we called SVs in 1,276 Samoans and created a Samoan-specific imputation panel inclusive of both SVs and single nucleotide variants (SNVs), called the Soifua Manuia-SV panel. Using this panel, we imputed SVs and SNVs in 3,611 Samoans with array data, enabling analysis of SV-phenotype associations in a sample of 4,887 Samoan participants. We evaluated imputation performance in Samoans against two other reference panels: (i) an SNV-only Samoan-specific reference panel, to assess whether SV inclusion impacts SNV imputation, and (ii) an SV and SNV, multi-ancestry reference panel composed of 1000 Genomes participants, which did not include Polynesians, to assess the importance of including the target population in the reference panel. The Soifua Manuia-SV panel substantially outperformed the multi-ancestry SV and SNV panel, yielding 5.5 million more high-quality (r2 [&ge;] 0.8) variants, including over 8,000 more high-quality SVs. SNV imputation based on the two Samoan-specific panels performed similarly overall, suggesting that SV inclusion does not strongly impact SNV imputation quality. This work highlights the importance of population representation for accurate imputation.","rel_num_authors":17,"rel_authors":[{"author_name":"Lauren M. Spor","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Emily M. Liau","author_inst":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Ca"},{"author_name":"Alba Sanchis-Juan","author_inst":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Ca"},{"author_name":"Andrew N. Silva","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Hong Cheng","author_inst":"Department of Environmental and Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA"},{"author_name":"Take Naseri","author_inst":"Naseri and Associates Public Health Consultancy Firm and Family Health Clinic; Department of Epidemiology and Center for Global Public Health, Brown University "},{"author_name":"Muagututi'a Sefuiva Reupena","author_inst":"Lutia i Puava ae Mapu i Fagalele, Apia, Samoa"},{"author_name":"Satupa'itea Viali","author_inst":"Oceania University of Medicine, Samoa; National University of Samoa, Apia, Samoa; Department of Chronic Disease Epidemiology, Yale School of Public Health, New "},{"author_name":"John Tuitele","author_inst":"Department of Public Health, LBJ Tropical Medical Center, Faga'alu, AS, USA"},{"author_name":"Erin E. Kershaw","author_inst":"Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Ranjan Deka Deka","author_inst":"Department of Environmental and Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA"},{"author_name":"Nicola L. Hawley","author_inst":"Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA"},{"author_name":"Stephen T. McGarvey","author_inst":"Department of Anthropology, Brown University, Providence, RI, USA"},{"author_name":"Daniel E. Weeks","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Jenna C. Carlson","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Harrison Brand","author_inst":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Ca"},{"author_name":"Ryan L. Minster","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"Wearable Electrical Impedance Myography for Continuous, Non-Invasive Detection of Acute Compartment Syndrome: A Preclinical Feasibility Study","rel_doi":"10.64898\/2026.07.06.26357418","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.06.26357418","rel_abs":"Introduction: Acute compartment syndrome (ACS) is a limb-threatening complication of extremity trauma that requires timely diagnosis to prevent irreversible muscle and nerve injury. Current diagnostic methods are invasive, intermittent, and operator-dependent. We evaluated the feasibility of a novel, Bluetooth-enabled electrical impedance myography (EIM) device (mAlert, Myolex, Inc., Brookline, MA, USA) for continuous, noninvasive detection of ACS-related tissue changes. Methods: Ten Yorkshire swine underwent anterior tibial compartment monitoring using three ACS models: albumin infusion (ALB, n=3), femoral artery and vein ligation (LIG, n=3), and combined albumin infusion plus ligation (ALB+LIG, n=4). Resistance (R), reactance (X), and phase (P) were measured every minute across 1 to 199 kHz alongside continuous intra-compartmental pressure (ICP) monitoring. Group differences in normalized impedance trends were evaluated using the Kruskal Wallis test with Dunn post hoc correction. As a proof-of-concept human study, nine healthy volunteers wore the device for up to five days to assess electrode durability and signal stability. Tissue ischemia was validated using pimonidazole immunohistochemistry. Results: ALB infusion produced progressive, frequency-dependent decreases in R, X, and P, whereas LIG produced consistent increases in R and X across frequencies. The ALB+LIG model generated mixed responses, reflecting the competing effects of edema and ischemia. Normalized phase slopes differed significantly among groups (H=6.14, p=0.046), with post hoc testing showing significant divergence between the ALB and LIG models (p=0.041). Control limbs remained stable throughout monitoring. Pimonidazole staining confirmed hypoxic injury in the intervention limb. In the human pilot study, three participants completed five days of monitoring, demonstrating sustained signal acquisition, while electrode degradation limited data collection in the remaining participants. Conclusions: This preliminary feasibility study demonstrates that wearable EIM can continuously detect model-specific physiological changes associated with ACS in a large-animal model. These findings support further development and clinical evaluation of wearable EIM as a non-invasive monitoring technology for early ACS detection in trauma patients.","rel_num_authors":11,"rel_authors":[{"author_name":"Mohammad Javad Shariyate","author_inst":"Beth Israel Deaconess MedicalCenter"},{"author_name":"Mohammad Khak","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Buket Sonbas-Cobb","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Maria V. Velasquez Hammerle","author_inst":"Beth Iasrael Deaconess Medical Center"},{"author_name":"Baoguo Wei","author_inst":"Myolex, Inc."},{"author_name":"Sara Robicheau","author_inst":"Myolex, Inc."},{"author_name":"Kirsten Dunlap","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Ahmad Hedayatzadeh Razavi","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Mario Keko","author_inst":"mkeko@bidmc.harvard.edu"},{"author_name":"Seward Rutkove","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Ara Nazarian","author_inst":"Beth Israel Deaconess Medical Center"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"Gene-Temperature Interactions and Risk of Childhood Acute Lymphoblastic Leukemia","rel_doi":"10.64898\/2026.07.09.26357608","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357608","rel_abs":"Background: High ambient temperature in early pregnancy has been linked to an increased risk of childhood acute lymphoblastic leukemia (ALL). To better understand biological mechanisms, the current study evaluated potential interaction between temperature and genetic characteristics. Methods: We used data from California birth records (1982-2008) and California Cancer Registry (1988-2011) to identify ALL cases (n=3,353) diagnosed <=14 years of age and non-cancer controls (n=3,530) matched 1:1 on sex, race, ethnicity, and birth year and month. Weekly ambient temperatures throughout pregnancy were assessed on a 1-km grid around the birth address, while genetic data were available from a genome-wide association study using neonatal blood spots. We evaluated the association between ambient temperature and ALL risk by quartiles of established genetic risk score for ALL. Next, we formally tested gene-temperature interactions in the association with ALL, correcting for multiple testing, for genes previously identified with epigenetic changes due to both temperature and ALL. All analyses were adjusted for potential confounders. Results: The elevated risk of ALL per 5 degrees C increase of weekly mean ambient temperature, confined to early pregnancy, was more pronounced among children with the lowest genetic susceptibility to ALL, especially among Latino children (first quartile: odds ratio [OR] = 1.50, 95% confidence interval [CI]: 1.14-1.97); fourth quartile: OR=1.03, 95% CI: 0.83-1.28). There were significant interactions (p<0.002) between ambient temperature and polymorphisms in BNC1 among non-Latino White children, and suggestive interactions (p<0.05) with TBPL2 and NRXN1 in the full population. Conclusions: Our findings suggest that there may be interactions between ambient temperature in early pregnancy and offspring genotype in the risk of childhood ALL. Impact: If replicated, these findings could help elucidate the biological mechanisms linking high ambient temperature in early pregnancy and the risk of childhood ALL.","rel_num_authors":10,"rel_authors":[{"author_name":"Tormod Rogne","author_inst":"University of Oslo"},{"author_name":"Rong Wang","author_inst":"Yale University School of Public Health"},{"author_name":"Pin Wang","author_inst":"University of Maryland"},{"author_name":"Kai Chen","author_inst":"Yale University School of Public Health"},{"author_name":"Shuangge Ma","author_inst":"Yale University School of Public Health"},{"author_name":"Joshua L Warren","author_inst":"Yale University School of Public Health"},{"author_name":"Catherine Metayer","author_inst":"University of California, Berkeley"},{"author_name":"Joseph L Wiemels","author_inst":"University of Southern California"},{"author_name":"Andrew DeWan","author_inst":"Yale University School of Public Health"},{"author_name":"Xiaomei Ma","author_inst":"Yale University School of Public Health"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"Gene-Temperature Interactions and Risk of Childhood Acute Lymphoblastic Leukemia","rel_doi":"10.64898\/2026.07.09.26357608","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357608","rel_abs":"Background: High ambient temperature in early pregnancy has been linked to an increased risk of childhood acute lymphoblastic leukemia (ALL). To better understand biological mechanisms, the current study evaluated potential interaction between temperature and genetic characteristics. Methods: We used data from California birth records (1982-2008) and California Cancer Registry (1988-2011) to identify ALL cases (n=3,353) diagnosed <=14 years of age and non-cancer controls (n=3,530) matched 1:1 on sex, race, ethnicity, and birth year and month. Weekly ambient temperatures throughout pregnancy were assessed on a 1-km grid around the birth address, while genetic data were available from a genome-wide association study using neonatal blood spots. We evaluated the association between ambient temperature and ALL risk by quartiles of established genetic risk score for ALL. Next, we formally tested gene-temperature interactions in the association with ALL, correcting for multiple testing, for genes previously identified with epigenetic changes due to both temperature and ALL. All analyses were adjusted for potential confounders. Results: The elevated risk of ALL per 5 degrees C increase of weekly mean ambient temperature, confined to early pregnancy, was more pronounced among children with the lowest genetic susceptibility to ALL, especially among Latino children (first quartile: odds ratio [OR] = 1.50, 95% confidence interval [CI]: 1.14-1.97); fourth quartile: OR=1.03, 95% CI: 0.83-1.28). There were significant interactions (p<0.002) between ambient temperature and polymorphisms in BNC1 among non-Latino White children, and suggestive interactions (p<0.05) with TBPL2 and NRXN1 in the full population. Conclusions: Our findings suggest that there may be interactions between ambient temperature in early pregnancy and offspring genotype in the risk of childhood ALL. Impact: If replicated, these findings could help elucidate the biological mechanisms linking high ambient temperature in early pregnancy and the risk of childhood ALL.","rel_num_authors":10,"rel_authors":[{"author_name":"Tormod Rogne","author_inst":"University of Oslo"},{"author_name":"Rong Wang","author_inst":"Yale University School of Public Health"},{"author_name":"Pin Wang","author_inst":"University of Maryland"},{"author_name":"Kai Chen","author_inst":"Yale University School of Public Health"},{"author_name":"Shuangge Ma","author_inst":"Yale University School of Public Health"},{"author_name":"Joshua L Warren","author_inst":"Yale University School of Public Health"},{"author_name":"Catherine Metayer","author_inst":"University of California, Berkeley"},{"author_name":"Joseph L Wiemels","author_inst":"University of Southern California"},{"author_name":"Andrew DeWan","author_inst":"Yale University School of Public Health"},{"author_name":"Xiaomei Ma","author_inst":"Yale University School of Public Health"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"The effect of dietary fiber based on fermentability and viscosity on the gut microbial metabolites in chronic kidney disease: a systematic review and meta-analysis of experimental and clinical trials","rel_doi":"10.64898\/2026.07.09.26357677","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357677","rel_abs":"BackgroundChronic kidney disease (CKD) is associated with alterations in the gut microbiome that promote the accumulation of gut-derived uremic solutes and contribute to systemic inflammation, vascular dysfunction, and disease progression. Dietary fiber has emerged as a promising modulator of gut microbial metabolism, yet the influence of fiber physicochemical properties, particularly fermentability and viscosity, on uremic metabolite production in CKD remains poorly understood.\n\nObjectiveTo systematically evaluate the effects of isolated dietary fiber interventions, classified by fermentability and viscosity, on gut microbial metabolites in CKD across experimental rodent models and randomized clinical trials, and to determine whether these fiber properties modify microbial metabolites.\n\nMethodsA systematic search of PubMed, Embase, CINAHL, and Cochrane Library (through June 2026) identified randomized controlled trials and controlled rodent studies assessing isolated dietary fiber in CKD. Eligible studies reported at least one gut-derived metabolite (i.e., indoxyl sulfate (IS), p-cresyl sulfate (PCS), trimethylamine-N-oxide (TMAO), tryptophan-derived indoles, or short-chain fatty acids (SCFAs)). Random-effects models were used for pooled estimates using weighted mean differences (WMD) for human studies and standardized mean differences (SMD) for animal studies. Subgroup analyses evaluated fiber fermentability, viscosity, intervention dose, duration, and CKD stage. Risk of bias was assessed with ROB-2 and SYRCLE, and evidence certainty with GRADE.\n\nResultsTwenty-eight studies (13 human, 15 animal) met eligibility criteria, comprising 511 participants and 312 animals with CKD. Isolated fiber supplementation, primarily fermentable and non-viscous fibers, reduced IS (human: -0.13 mg\/dL; 95% CI: -0.25, -0.01; p = 0.03; animal: -1.99; 95% CI: -3.06, -0.92; p < 0.0001) and pCS (human: -0.23 mg\/dL; 95% CI: -0.46, 0.001; p = 0.051; animal: -1.56; 95% CI: -2.08, -1.03; p < 0.0001). SCFAs increased in animal studies, including cecal acetate (2.00, 95% CI: 0.78 to 3.22; p = 0.001) and circulating propionate (1.51, 95% CI: 0.054 to 2.96; p=0.04). There were no dose-dependent effects, but longer interventions (>8 weeks) tended to lower pCS (-0.26 mg\/dL, 95% CI: -0.55 to 0.02; p=0.06). Some heterogeneity and low-to-moderate certainty were observed.\n\nConclusionIsolated dietary fiber reduces major gut-derived uremic solutes in CKD, with fermentability influencing metabolic responsiveness, but with minimal studies on viscous fibers. Larger, longer-duration trials with standardized reporting of total fiber intake and clinical endpoints are needed to guide evidence-based dietary recommendations in CKD.\n\nStatement of SignificanceThis is the first systematic review and meta-analysis examining the effects of isolated dietary fiber on gut-derived metabolites comprising human and rodent models in CKD.\n\nThis trial was registered at PROSPERO as CRD42023483468.","rel_num_authors":8,"rel_authors":[{"author_name":"Seyedeh Nooshan Mirmohammadali","author_inst":"Purdue University"},{"author_name":"Claudia Carrillo","author_inst":"Iowa State University"},{"author_name":"Jason B. Reed","author_inst":"Purdue University"},{"author_name":"Brandon M. Kistler","author_inst":"Purdue University"},{"author_name":"Hannah E. Wilson","author_inst":"Indiana University School of Medicine"},{"author_name":"Bruce Hamaker","author_inst":"Purdue University"},{"author_name":"Sharon M Moe","author_inst":"Indiana University"},{"author_name":"Annabel Biruete","author_inst":"Purdue University"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"Biomarker-informed CSF proteomics reveals ENPP2-LPA lipid signaling associated with Alzheimer's disease","rel_doi":"10.64898\/2026.07.08.26357565","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357565","rel_abs":"BackgroundAlzheimers disease (AD) involves complex molecular alterations in the cerebrospinal fluid (CSF) proteome, yet the links between these protein changes and hallmark AD pathology remain incompletely defined. We investigated the relationship between the CSF proteome with CSF biomarkers of Alzheimers disease (AD).\n\nMethodsCSF was collected in 500 individuals of non-Hispanic white, African Americans, and Caribbean Hispanic individuals. CSF biomarkers of AD were measured including P-tau181, A{beta}40, A{beta}42, total-tau, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). CSF was depleted of abundant proteins followed by precipitation, cysteine reduction\/alkylation, and proteolytic cleavage by trypsin. Peptides were measured using a Q-Exactive HF mass spectrometer (Thermo Scientific). Association of individual and co-abundant modules of proteins were tested using evelated CSF P-tau181 and reduced A{beta}42\/A{beta}40 to confirm the diagnosis of AD. We validated results in CSF from 397 participants in the Accelerated Medicine Partnership-Alzheimers Disease cohort. Associated proteins were functionally validated in postmortem human brains and zebrafish.\n\nResultsWe detected 1030 proteins, yielding an overall data completeness value of 97%. CSF levels of 75 (7.3%) proteins were significantly associated with CSF P-tau181 levels after multiple testing correction. Notably phospholipase D3 (PLD3, p=2.41E-09), apoE (p=4.25e-08) and osteopontin (OPN p=1.4E-16) were increased and autotaxin (ATX\/ENPP2, p= 8.39E-09) and ceruloplasmin (CP) (p=2.72E-07) were lower among individuals with high P-tau181 levels. These proteins were also associated with CSF A{beta}42\/A{beta}40 ratio and total tau levels but not with NfL. OPN was also associated with CSF levels of GFAP (p=1.32e-05).\n\nAmong proteins associated with P-tau181 levels, pathways related to axon development (p=2.4E-12), axonogenesis (p=1.45E-11) and regulation of axonogenesis (p=5.1E-09) were enriched. Immunostaining on postmortem human and zebrafish brain found that ENPP2 expression, the gene encoding ATX, was significantly reduced in AD brain and in the amyloidosis model in zebrafish. Reduced ENPP2 expression was consistent with reduced lysophosphatidic acid (LPA) levels in the CSF of individuals with AD. LPA administration into zebrafish CSF reduced the pathological changes in synapses and vasculature due to A{beta}42.\n\nConclusionUnbiased profiling of circulating CSF proteins among individuals with antemortem diagnosis of AD, identified key proteins PLD3, apoE, OPN, ATX, and ceruloplasmin. Validation in postmortem human brains and zebrafish models support potential roles in endosomal sorting and APP processing, inflammation, angiogenesis, lipid transport, and oxidative stress.\n\nOne sentence summaryReduced autotaxin and lysophosphatidic acid were among 75 cerebrospinal fluid (CSF) proteins associated with biomarker-defined Alzheimers disease pathology.","rel_num_authors":16,"rel_authors":[{"author_name":"Min Qiao","author_inst":"Columbia University"},{"author_name":"Prabesh Bhattarai","author_inst":"Columbia University"},{"author_name":"Elanur Yilmaz","author_inst":"Columbia University"},{"author_name":"Alex Rookyard","author_inst":"Columbia University"},{"author_name":"Lipi A Das","author_inst":"Columbia University"},{"author_name":"Anu Jain","author_inst":"Columbia University"},{"author_name":"Dolly Reyes-Dumeyer","author_inst":"Columbia University Vagelos College of Physicians and Surgeons"},{"author_name":"Annie J Lee","author_inst":"Columbia University"},{"author_name":"Rafael A Lantigua","author_inst":"Columbia University"},{"author_name":"Martin Medrano","author_inst":"Pontificia Universidad Catolica Madre y Maestra"},{"author_name":"Diones Rivera","author_inst":"Department of Neurosurgery, CEDIMAT, Plaza de la Salud, Santo Domingo, Dominican Republic"},{"author_name":"Lawrence S Honig","author_inst":"Columbia University"},{"author_name":"Lewis Brown","author_inst":"Columbia University"},{"author_name":"Caghan Kizil","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Richard Mayeux","author_inst":"Columbia University"},{"author_name":"Badri N Vardarajan","author_inst":"Columbia University"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"A feasibility study of a broadly applicable intervention to strengthen empowerment, self-management, and health among adults living with chronic illness in the United States","rel_doi":"10.64898\/2026.07.07.26357498","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26357498","rel_abs":"BackgroundChronic illness is a major public health concern in Europe, the United States, and other high-income countries, limiting individuals capacity for self-management and health promotion. Empowerment interventions improve health outcomes while reducing healthcare utilization.\n\nAimThis study assessed the feasibility of implementing the Bodyknowledging Program, a broadly applicable health promotion intervention developed in Norway, at the community level in the US to evaluate participants experiences, program components, and self-management outcomes among adults living with chronic illness, and to identify the programs strengths and areas for cultural adaptation to inform its cross-national transferability.\n\nMethodsA multi-method feasibility design was used, including a group of participants living with various chronic illnesses. Reflexive thematic analysis was applied to analyze focus group data, examining participants experiences, program components, and outcomes. Facilitators field notes and post-intervention survey data were additional data sources.\n\nResultsThree themes emerged through the thematic analysis: (1) acceptability of the BKPs health promotion content and approaches among US participants, (2) implementation of the BKP intervention in a US community context, and (3) demand and ideas for continued implementation. Facilitator field notes identified challenges in implementing the hybrid format. Survey data confirmed that participants strongly agreed that the program enhanced their ability to recognize bodily signs and tolerance limits, manage symptoms, prevent deterioration, and promote their health. Participants reached consensus on the value of the programs content, materials, organization, and communication strategies.\n\nConclusionThe Bodyknowledging Program is feasible and well-suited for implementation in the US. This community-based empowerment intervention leverages existing but unutilized human resources to strengthen self-management and health promotion among people with chronic illnesses across diagnostic categories. Further research across diverse settings is recommended to support broader dissemination.","rel_num_authors":7,"rel_authors":[{"author_name":"Kisha  N. Thompson","author_inst":"Northeastern University - Boston Campus: Northeastern University"},{"author_name":"Marie  Hamilton Larsen","author_inst":"Lovisenberg Diaconal University College: Lovisenberg Diakonale Hogskole"},{"author_name":"Susan Hall","author_inst":"Northeastern University - Boston Campus: Northeastern University"},{"author_name":"Dami Ko","author_inst":"Northeastern University - Boston Campus: Northeastern University"},{"author_name":"J\u00f8rghild Jensen","author_inst":"VID Specialized University: VID Vitenskapelige Hogskole"},{"author_name":"Gyda Singstad","author_inst":"VID Specialized University: VID Vitenskapelige Hogskole"},{"author_name":"Kristin Heggdal","author_inst":"VID Specialized University: VID Vitenskapelige Hogskole"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"Bias-domain triangulation of non-convergent observational evidence in behavioural health research","rel_doi":"10.64898\/2026.07.07.26357342","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26357342","rel_abs":"Observational studies in behavioural health often produce conflicting evidence because exposures are entangled with familial, clinical and social determinants. Rather than treating non-convergence as an obstacle to synthesis, we propose bias-domain triangulation, a causal-structure-aware framework that treats it as a diagnostic target. The framework distinguishes actual covariate adjustments from candidate background causal structures, adjudicates the causal roles of adjustment variables and maps core back-door pathways into distinct bias domains before quantitative synthesis, thereby reframing the question from whether estimates are heterogeneous to which bias structure changes the estimate. We apply this framework to a systematically derived literature on prenatal paracetamol exposure and offspring autism spectrum disorder or attention-deficit\/hyperactivity disorder, comprising 22 studies and 33 adjusted estimates. Stronger overall control was associated with attenuation of the pooled association from 2.08 under weak control to 0.98 under strong control. Domain-specific analyses showed that pooled estimates approached the null only under strong familial\/genetic control, whereas strong control of clinical-indication or social-behavioural domains left residual associations. This pattern suggests that shared familial liability is the bias structure most consistently associated with attenuation in the current evidence. Beyond this case, bias-domain triangulation offers a reusable strategy for diagnosing why observational evidence may persistently diverge, moving evidence synthesis beyond heterogeneity toward structural explanation. This study was registered on PROSPERO (CRD420261365276).","rel_num_authors":3,"rel_authors":[{"author_name":"Xuanyu Shi","author_inst":"Peking University"},{"author_name":"Guanghui Deng","author_inst":"Peking University"},{"author_name":"JIAN DU","author_inst":"Peking University"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"Whole-genome sequencing implicates rare, low-frequency and structural non-coding variation at the SCN5A locus in Brugada syndrome","rel_doi":"10.64898\/2026.07.07.26356386","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26356386","rel_abs":"Brugada syndrome (BrS) is an inherited cardiac condition characterized by a hallmark ECG pattern and an increased risk of sudden cardiac death. Central to the aetiology of BrS, the SCN5A region harbours both common non-coding risk variants and rare coding variants that are causative in approximately 20% of patients. However, rare non-coding genetic variation in this region remains largely unexplored. Here, we used whole-genome sequencing (WGS) of 752 European-ancestry BrS cases and 1,827 ancestry-matched controls to identify BrS-associated rare non-coding genetic variation at the SCN5A locus. Sliding-window and cis-regulatory element (CRE)-based rare-variant aggregate testing implicated three conserved CREs, including a dense aggregation of case singleton variants within a 178 bp enhancer in intron 17 of SCN5A which replicated in an independent BrS cohort. Prioritised BrS-associated rare and low-frequency non-coding variants within these elements were predicted to alter cardiac transcription factor motifs, and altered CRE activity in hiPSC-CM luciferase assays or were associated with BrS-relevant ECG endophenotypes in the UK Biobank. Single-variant analysis across the region identified a Bonferroni-significant five-fold case-enriched low-frequency variant within a known CRE in intron 1 of SCN5A, which replicated, was associated with slower cardiac conduction in the UK Biobank and accounted for part of the BrS GWAS signal at this locus. Structural variant analyses identified a 10.5 kb deletion upstream of SCN5A in a BrS case that encompassed a cardiac CRE and reduced sodium current density in a hiPSC-CM model, as well as a 6 kb BrS-enriched retrotransposon insertion in SCN5A that appeared to underlie part of the GWAS signal in this region. Together, these findings implicate rare and low-frequency non-coding variation at the SCN5A locus in BrS susceptibility and demonstrate the value of targeted WGS analysis of key disease loci.","rel_num_authors":60,"rel_authors":[{"author_name":"Alex Lipov","author_inst":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Manon Baudic","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Pierre Lindenbaum","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Isabella Mengarelli","author_inst":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Matthew J. O'Neill","author_inst":"Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Fernanda M. Bosada","author_inst":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Yanushi Wijeyeratne","author_inst":"Cardiovascular and Genomics Research Institute, City St George's, University of London, London, UK"},{"author_name":"Luis de la Higuera Romero","author_inst":"Health in Code S.L., A Coru\u00f1a, Spain"},{"author_name":"Maarten Kooyman","author_inst":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Marion Gaudin","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Graziella Aquilina","author_inst":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Leander Beekman","author_inst":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Estelle Baron","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Mathilde Bertrand","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Zoya Kingsbury","author_inst":"Illumina Cambridge Ltd, Granta Park, Great Abington, Cambridge, UK"},{"author_name":"Mark T. Ross","author_inst":"Illumina Cambridge Ltd, Granta Park, Great Abington, Cambridge, UK"},{"author_name":"Marre Corver","author_inst":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Paola Lombardi","author_inst":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Ingrid Krapels","author_inst":"Department of Clinical Genetics, Maastricht University Medical Center+, Maastricht, Netherlands"},{"author_name":"Paul G. Volders","author_inst":"Department of Cardiology, CARIM, Maastricht University Medical Center, Maastricht, The Netherlands"},{"author_name":"Rafik Tadros","author_inst":"Department of Medicine, Cardiovascular Genetics Center, Montreal Heart Institute, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Canada"},{"author_name":"Fenna Tuijnenburg","author_inst":"Department of Clinical Cardiology, Heart Centre, Amsterdam University Medical Centre, location AMC, The Netherlands"},{"author_name":"Karel van Duijvenboden","author_inst":"Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Ammar Al-Chalabi","author_inst":"Department of Neurology, King's College London, London, UK"},{"author_name":"Jan H. Veldink","author_inst":"Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands"},{"author_name":"Sean J. Jurgens","author_inst":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Aur\u00e9lie Thollet","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Eric Charpentier","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Camille Maiano","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Philippe Mabo","author_inst":"Service de Cardiologie, CHU de Rennes, Rennes, France"},{"author_name":"Antoine Leenhardt","author_inst":"CNMR Maladies Cardiaques H\u00e9r\u00e9ditaires Rares, H\u00f4pital Bichat, Universit\u00e9 de Paris, Paris, France"},{"author_name":"Frederic Sacher","author_inst":"Cardiac Arrhythmia Department, IHU Liryc, Univ. Bordeaux, INSERM 1045, CHU de Bordeaux, F-Bordeaux, France"},{"author_name":"Arjan C. Houweling","author_inst":"Department of Human Genetics, Amsterdam UMC, Amsterdam, The Netherlands"},{"author_name":"Hanno L. Tan","author_inst":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Vincent M. Christoffels","author_inst":"Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Michael W. Tanck","author_inst":"Epidemiology and Data Science, Amsterdam Public Health, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Andrew Grace","author_inst":"Department of Biochemistry, University of Cambridge, Cambridge, UK"},{"author_name":"Koonlawee Nademanee","author_inst":"Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand"},{"author_name":"Apichai Khongphatthanayothin","author_inst":"Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand"},{"author_name":"Andrew M. Glazer","author_inst":"Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART), Division of Genetic Medicine and Clinical Pharmacology, Department of Medicine, Vanderbilt"},{"author_name":"Jean-Fran\u00e7ois Deleuze","author_inst":"Centre National de Recherche en G\u00e9nomique Humaine (CNRGH), Institut de Biologie Fran\u00e7ois Jacob, CEA, Universit\u00e9 Paris-Saclay, Evry, France"},{"author_name":"- FranceGenRef consortium","author_inst":""},{"author_name":"Juan Pablo Ochoa","author_inst":"Health in Code S.L., A Coru\u00f1a, Spain"},{"author_name":"J\u00e9r\u00f4me Montnach","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Michel De Waard","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Pieter G. Postema","author_inst":"Department of Clinical Cardiology, Heart Centre, Amsterdam University Medical Centre, location AMC, The Netherlands"},{"author_name":"Ahmad S. Amin","author_inst":"Department of Clinical Cardiology, Heart Centre, Amsterdam University Medical Centre, location AMC, The Netherlands"},{"author_name":"Jean-Baptiste Gourraud","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Pascale Guicheney","author_inst":"INSERM, Sorbonne University, UMRS 1166, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France"},{"author_name":"Dan M. Roden","author_inst":"Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Jean-Jacques Schott","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Christian Dina","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Vincent Probst","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Pier D. Lambiase","author_inst":"Institute of Cardiovascular Science, University College London (UCL) and Barts Heart Centre, London, UK"},{"author_name":"Elijah R. Behr","author_inst":"Cardiovascular and Genomics Research Institute, City St George's, University of London, London, UK"},{"author_name":"Arthur A.M. Wilde","author_inst":"Department of Clinical Cardiology, Heart Centre, Amsterdam University Medical Centre, location AMC, The Netherlands"},{"author_name":"Richard Redon","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Roddy Walsh","author_inst":"Cardiovascular and Genomics Research Institute, City St George's, University of London, London, UK"},{"author_name":"Julien Barc","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Connie R. Bezzina","author_inst":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"}],"rel_date":"2026-07-10","rel_site":"medrxiv"}]}