{"gname":"The Rockefeller University","grp_id":"2","rels":[{"rel_title":"Papillary muscles, ventricular loading, and atrial remodelling as beat-to-beat determinants of functional mitral regurgitation: an exploratory Granger causality study","rel_doi":"10.64898\/2026.04.03.26350122","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.03.26350122","rel_abs":"Background Functional mitral regurgitation results from interacting mechanisms whose relative contributions vary between atrial and ventricular subtypes and shift dynamically within each heartbeat, producing temporal patterns that static analyses cannot capture. Objectives To identify which structural determinants predict mitral regurgitation variability beat to beat using Granger causality within vector autoregression, focusing on papillary muscle dynamics across subtypes. Methods Frame-level echocardiographic time series from 41 patients (21 atrial, 20 ventricular; 1,959 frames) were z-score standardised within patient. Individual (lag 3) and pooled (lag 2) vector autoregression models tested whether left ventricular volume, left atrial volume, papillary muscle length, and annulus diameter Granger-predict mitral regurgitation area. Results Individual models revealed marked heterogeneity. In pooled analysis, left ventricular volume was the strongest Granger predictor at short lags (atrial p=0.011; ventricular p=0.006), while left atrial volume emerged at longer lags (lag 7: atrial p=0.043; ventricular p=0.011). Systolic papillary muscle length was not predictive. Full-cycle analysis revealed a subtype-specific dissociation: papillary muscle length Granger-predicted regurgitation only in the ventricular subtype (p=0.001), while regurgitation predicted papillary muscle displacement only in the atrial subtype (p<0.001). Left ventricular volume dominated within-beat prediction but lost cross-beat relevance in the ventricular subtype, while left atrial volume gained cross-beat predictive relevance in the atrial subtype. No structural determinant correlated with severity cross-sectionally. Conclusions Beat-to-beat vector autoregression and Granger modelling reveals heterogeneous, subtype-specific temporal patterns with distinct temporal windows of predictability for ventricular loading and papillary geometry. This framework may support patient-specific temporal phenotyping of functional mitral regurgitation.","rel_num_authors":18,"rel_authors":[{"author_name":"Csilla Andrea Eotvos","author_inst":"Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Cluj, Romania"},{"author_name":"Teodora Avram","author_inst":"Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Romania"},{"author_name":"Eric Daniel Blendea","author_inst":"Emil Racovita National College, Cluj-Napoca, Romania"},{"author_name":"Matei Ioan Munteanu","author_inst":"Institut Polytechnique, Paris, France"},{"author_name":"Adrian Florin Bubuianu","author_inst":"Department of Computer Science, Babes Bolyai University, Cluj-Napoca, Romania"},{"author_name":"Madalina Patricia Moldovan","author_inst":"Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj, Romania"},{"author_name":"Petra Hedesiu","author_inst":"School of Engineering, Columbia University, New York, USA"},{"author_name":"Roxana Daiana Lazar","author_inst":"Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj, Romania"},{"author_name":"Iulia Georgiana Zehan","author_inst":"Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj, Romania"},{"author_name":"Adriana Daniela Sarb","author_inst":"Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj, Romania"},{"author_name":"Giorgia Coseriu","author_inst":"Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj, Romania"},{"author_name":"Patricia Schiop-Tentea","author_inst":"Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj, Romania"},{"author_name":"Diana Larisa Mocan-Hognogi","author_inst":"Emergency Clinical County Hospital, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania"},{"author_name":"Roxana Chiorescu","author_inst":"Emergency Clinical County Hospital, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania"},{"author_name":"Sorin Pop","author_inst":"Emergency Clinical County Hospital, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania"},{"author_name":"Laura Diosan","author_inst":"Department of Computer Science, Babes Bolyai University, Cluj-Napoca, Romania"},{"author_name":"E. Kevin Heist","author_inst":"Massachusetts General Hospital, Harvard Medical School, Boston, MA 02215, USA"},{"author_name":"Dan Blendea","author_inst":"Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Cluj, Romania"}],"rel_date":"2026-04-05","rel_site":"medrxiv"},{"rel_title":"Host Factors Modulate Nirmatrelvir-Ritonavir Efficacy in COVID-19 Patients: A Viral Dynamics Modeling Study","rel_doi":"10.64898\/2026.04.03.26350141","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.03.26350141","rel_abs":"Antiviral therapies such as nirmatrelvir-ritonavir are widely used for COVID-19, yet their real-world effectiveness and sources of heterogeneity in treatment response remain incompletely understood. Here, we integrate longitudinal viral load data from a large cohort of SARS-CoV-2 BA.2-infected patients in Shanghai (n=48,243) with a mechanistic within-host viral dynamics model coupled to pharmacokinetic\/pharmacodynamic principles to quantify in vivo antiviral efficacy. We estimate that nirmatrelvir-ritonavir reduces viral production by approximately 55% on average. Treatment response exhibits substantial heterogeneity, with higher efficacy observed in vaccinated individuals and reduced efficacy in older adults. Sensitivity analyses demonstrate that the vaccination effect is robust across model specifications, whereas age-related differences depend on assumptions about early viral kinetics, highlighting structural identifiability challenges when analyzing sparse real-world data. These findings provide a mechanistic interpretation of heterogeneous treatment effects and establish a generalizable framework for integrating real-world clinical data with within-host models to inform antiviral optimization and personalized treatment strategies.","rel_num_authors":26,"rel_authors":[{"author_name":"Yiyu Liao","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"},{"author_name":"Yan Wang","author_inst":"School of Public Health, Fudan University, Shanghai, China"},{"author_name":"Yuqian Wang","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"},{"author_name":"Jingwen Ai","author_inst":"Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China"},{"author_name":"Boon Kiat Law","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"},{"author_name":"Derrick Lim","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"},{"author_name":"Jiaxin Zhou","author_inst":"School of Public Health, Fudan University, Shanghai, China"},{"author_name":"Hongyu Wang","author_inst":"Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China"},{"author_name":"Yanpeng Wu","author_inst":"School of Public Health, Fudan University, Shanghai, China"},{"author_name":"Po Ying Chia","author_inst":"National Centre for Infectious Diseases, Singapore"},{"author_name":"Hoong Kai Chua","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"},{"author_name":"Conrad En Zuo Chan","author_inst":"Communicable Diseases Agency, Singapore"},{"author_name":"Joshua T. Schiffer","author_inst":"Fred Hutchinson Cancer Center, Seattle, WA, USA"},{"author_name":"Katherine Owens","author_inst":"Fred Hutchinson Cancer Center, Seattle, WA, USA"},{"author_name":"Shadisadat Esmaeili","author_inst":"Fred Hutchinson Cancer Center, Seattle, WA, USA"},{"author_name":"Benjamin J. Cowling","author_inst":"School of Public Health, The University of Hong Kong, Hong Kong SAR, China"},{"author_name":"Matthew E. Cove","author_inst":"National University Hospital, Singapore"},{"author_name":"Hiroki Saito","author_inst":"St Marianna University Yokohama Seibu Hospital, Yokohama, Japan"},{"author_name":"Liang En Wee","author_inst":"Department of Infectious Diseases, Singapore General Hospital, Singapore"},{"author_name":"Barnaby E. Young","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"},{"author_name":"Tat Ming Ng","author_inst":"Division of Pharmacy, Tan Tock Seng Hospital, Singapore"},{"author_name":"Eric Chun Yong Chan","author_inst":"Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, Singapore"},{"author_name":"Marco Ajelli","author_inst":"Indiana University School of Public Health-Bloomington, Bloomington, IN, USA"},{"author_name":"Wenhong Zhang","author_inst":"Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China"},{"author_name":"Hongjie Yu","author_inst":"School of Public Health, Fudan University, Shanghai, China"},{"author_name":"Keisuke Ejima","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"}],"rel_date":"2026-04-05","rel_site":"medrxiv"},{"rel_title":"Host Factors Modulate Nirmatrelvir-Ritonavir Efficacy in COVID-19 Patients: A Viral Dynamics Modeling Study","rel_doi":"10.64898\/2026.04.03.26350141","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.03.26350141","rel_abs":"Antiviral therapies such as nirmatrelvir-ritonavir are widely used for COVID-19, yet their real-world effectiveness and sources of heterogeneity in treatment response remain incompletely understood. Here, we integrate longitudinal viral load data from a large cohort of SARS-CoV-2 BA.2-infected patients in Shanghai (n=48,243) with a mechanistic within-host viral dynamics model coupled to pharmacokinetic\/pharmacodynamic principles to quantify in vivo antiviral efficacy. We estimate that nirmatrelvir-ritonavir reduces viral production by approximately 55% on average. Treatment response exhibits substantial heterogeneity, with higher efficacy observed in vaccinated individuals and reduced efficacy in older adults. Sensitivity analyses demonstrate that the vaccination effect is robust across model specifications, whereas age-related differences depend on assumptions about early viral kinetics, highlighting structural identifiability challenges when analyzing sparse real-world data. These findings provide a mechanistic interpretation of heterogeneous treatment effects and establish a generalizable framework for integrating real-world clinical data with within-host models to inform antiviral optimization and personalized treatment strategies.","rel_num_authors":26,"rel_authors":[{"author_name":"Yiyu Liao","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"},{"author_name":"Yan Wang","author_inst":"School of Public Health, Fudan University, Shanghai, China"},{"author_name":"Yuqian Wang","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"},{"author_name":"Jingwen Ai","author_inst":"Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China"},{"author_name":"Boon Kiat Law","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"},{"author_name":"Derrick Lim","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"},{"author_name":"Jiaxin Zhou","author_inst":"School of Public Health, Fudan University, Shanghai, China"},{"author_name":"Hongyu Wang","author_inst":"Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China"},{"author_name":"Yanpeng Wu","author_inst":"School of Public Health, Fudan University, Shanghai, China"},{"author_name":"Po Ying Chia","author_inst":"National Centre for Infectious Diseases, Singapore"},{"author_name":"Hoong Kai Chua","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"},{"author_name":"Conrad En Zuo Chan","author_inst":"Communicable Diseases Agency, Singapore"},{"author_name":"Joshua T. Schiffer","author_inst":"Fred Hutchinson Cancer Center, Seattle, WA, USA"},{"author_name":"Katherine Owens","author_inst":"Fred Hutchinson Cancer Center, Seattle, WA, USA"},{"author_name":"Shadisadat Esmaeili","author_inst":"Fred Hutchinson Cancer Center, Seattle, WA, USA"},{"author_name":"Benjamin J. Cowling","author_inst":"School of Public Health, The University of Hong Kong, Hong Kong SAR, China"},{"author_name":"Matthew E. Cove","author_inst":"National University Hospital, Singapore"},{"author_name":"Hiroki Saito","author_inst":"St Marianna University Yokohama Seibu Hospital, Yokohama, Japan"},{"author_name":"Liang En Wee","author_inst":"Department of Infectious Diseases, Singapore General Hospital, Singapore"},{"author_name":"Barnaby E. Young","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"},{"author_name":"Tat Ming Ng","author_inst":"Division of Pharmacy, Tan Tock Seng Hospital, Singapore"},{"author_name":"Eric Chun Yong Chan","author_inst":"Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, Singapore"},{"author_name":"Marco Ajelli","author_inst":"Indiana University School of Public Health-Bloomington, Bloomington, IN, USA"},{"author_name":"Wenhong Zhang","author_inst":"Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China"},{"author_name":"Hongjie Yu","author_inst":"School of Public Health, Fudan University, Shanghai, China"},{"author_name":"Keisuke Ejima","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"}],"rel_date":"2026-04-05","rel_site":"medrxiv"},{"rel_title":"Mutation-specific impairment of TET2 and DNMT3A enzymatic activity predicts clonal hematopoiesis disease risk","rel_doi":"10.64898\/2026.04.03.26350108","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.03.26350108","rel_abs":"Clonal hematopoiesis of indeterminate potential (CHIP) driven by somatic mutations in TET2 and DNMT3A is present in >10% of adults over 60 and confers substantial risk for hematologic malignancy and cardiovascular disease, yet the majority of patients with CHIP do not progress to disease. Analyzing 1,020,538 individuals across three biobanks (UK Biobank, All of Us, BioVU), we show that a discrete subset of enzymatically disruptive mutations, TET2 loss-of-function variants and the DNMT3A R882 hotspot, account for the majority of clinical risk in these genes and exhibit the strongest clonal fitness advantage. Because DNMT3A and TET2 encode enzymes that modulate DNA methylation, we reasoned that peripheral blood methylation patterns should reflect the functional impact of individual mutations, enabling a direct readout of enzymatic dysfunction in CHIP patients. We developed and validated methylation-based activity scores for TET2 and DNMT3A as patient specific biomarkers that quantify enzymatic activity. These scores capture functional heterogeneity across mutation subtypes, predict disease risk comparably to clinical risk scores such as the Clonal Hematopoiesis Risk Score and the AHA PREVENT cardiovascular risk model. Integrating the activity score with the clinical models substantially improves prediction of incident cytopenia, myeloid neoplasm, and major adverse cardiovascular events. These findings establish that TET2 and DNMT3A CHIP pathogenicity is proportional to the degree of enzymatic disruption conferred by specific variants, and nominate methylation-based activity scores as a functional biomarker for individualized CHIP risk stratification and monitoring therapeutic response.","rel_num_authors":12,"rel_authors":[{"author_name":"Yash Pershad","author_inst":"Vanderbilt University"},{"author_name":"Kun Zhao","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Joseph C Van Amburg","author_inst":"Vanderbilt University"},{"author_name":"Robert W Corty","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alyssa C Parker","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alexander James Silver","author_inst":"University of Michigan"},{"author_name":"Yara F Almadani","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Ashwin Kishtagari","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Emily Hodges","author_inst":"Vanderbilt University School of Medicine"},{"author_name":"Michael R Savona","author_inst":"Vanderbilt University Medical Center"},{"author_name":"J. Brett Heimlich","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alexander G Bick","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-04-05","rel_site":"medrxiv"},{"rel_title":"OpenAc4C: A gateway to decode the landscape, regulation and pathogenesis of N4-acetylcytidine (ac4C) epitranscriptome","rel_doi":"10.64898\/2026.04.01.714364","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.714364","rel_abs":"N4-acetylcytidine (ac4C) is an ancient and highly conserved chemical marker found in all domains of life. Recent advancements in sequencing techniques have enabled the functional analysis of ac4C occurrence by accurately capturing its locations and levels, shedding light on its significant regulatory potential and emerging role in diseases. The OpenAc4C, the first comprehensive knowledgebase exclusively designed for unraveling the ac4C epitranscriptome across diverse species, spanning vertebrates, mammals, insects, fungi, plants, bacteria, archaea, and viruses. By mining a large array of ac4C epitranscriptome datasets with deep learning-based pipelines, OpenAc4C features a collection of 536,745 ac4C sites identified from four distinct next-generation sequencing (NGS)-based techniques, alongside novel insights from Oxford Nanopore direct RNA sequencing (ONT)-based samples, encompassing a total of 33 species. Beyond the ac4C landscape, a total of 536,986 ac4C-affecting variants were identified in seven species. Among them, 4,766 pathogenic ac4C-SNPs may drive ac4C dysregulation with implications for disease pathogenesis. In addition, OpenAc4C offers a user-friendly graphical interface and a web-based analysis platform for comprehensive querying and interactive exploration of the database collections. Together, OpenAc4C will serve as a valuable integrated resource to facilitate studies of ac4C modification. It is freely accessible at: www.rnamd.org\/ac4cportal.","rel_num_authors":15,"rel_authors":[{"author_name":"Gang Tu","author_inst":"Xi'an Jiaotong-Liverpool University"},{"author_name":"Yigan Zhang","author_inst":"Taihe Hospital, Hubei University of Medicine"},{"author_name":"Xuan Wang","author_inst":"Xi'an Jiaotong-Liverpool University"},{"author_name":"Jishuai Zhang","author_inst":"Peking University"},{"author_name":"An Zhu","author_inst":"Fujian Medical University"},{"author_name":"Kunqi Chen","author_inst":"Fujian Medical University"},{"author_name":"Zhixing Wu","author_inst":"Xi'an Jiaotong-Liverpool University"},{"author_name":"Zekai Wu","author_inst":"Fujian Medical University"},{"author_name":"Yue Wang","author_inst":"Nanjing University of Chinese Medicine"},{"author_name":"Jingxian Zhou","author_inst":"Guangzhou Medical University"},{"author_name":"Zhen Wei","author_inst":"Xi'an Jiaotong-Liverpool University"},{"author_name":"Guifang Jia","author_inst":"Peking university"},{"author_name":"Jia Meng","author_inst":"Xi'an Jiaotong-Liverpool University"},{"author_name":"Daniel J Rigden","author_inst":"University of Liverpool"},{"author_name":"Bowen Song","author_inst":"Nanjing University of Chinese Medicine"}],"rel_date":"2026-04-05","rel_site":"biorxiv"},{"rel_title":"Context-dependent mechanical reconfiguration is necessary for multifunctional behavior in a constrained hydrostat","rel_doi":"10.64898\/2026.04.01.715937","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.715937","rel_abs":"Muscular hydrostats, muscular structures with no rigid skeleton, are ubiquitous within the animal kingdom, from vertebrate tongues to cephalopod arms, but how they perform complex actions remains poorly understood. One model hydrostat studied for its neural control and biomechanics is the feeding system (buccal mass) of the sea hare Aplysia (Fig. 1). The buccal mass (Fig. 1b) performs multiple feeding behaviors by coordinating intrinsic muscles to move a grasper (odontophore). In this paper, we investigated how mechanical reconfiguration from interacting shape-changing elements facilitates large odontophore protractions. During rejection behaviors, mechanical reconfiguration of the odontophore (elongating its shape to a higher aspect ratio) stretches a protractor muscle (I2), allowing I2 to generate stronger protractions. In biting behaviors, the odontophore has a similar range of motion. However, during biting, the odontophore has a lower aspect ratio throughout protraction, meaning the I2 muscle alone is insufficient to reach observed protractions due to its length\/tension property and reduced mechanical advantage. By combining new analysis of MRI movies of Aplysia feeding (Fig. 1) with a new biomechanical model for biting and rejection (Fig. 2), we demonstrate two context-dependent mechanical reconfiguration mechanisms that explain the different ways large protractions are produced in biting and rejection (Fig. 3). The mechanisms integrate shape changes, bending and conforming of muscle structures, and shifts in contact interactions. We propose two mechanical subclasses of muscular hydrostats, \"constrained\" or \"unconstrained\" (Fig. 4), that may be morphologically similar but employ different control strategies depending on whether mechanical constraints are reliably present.","rel_num_authors":7,"rel_authors":[{"author_name":"Michael J Bennington","author_inst":"Carnegie Mellon University"},{"author_name":"Stephen M Rogers","author_inst":"University of Oxford"},{"author_name":"David M Neustadter","author_inst":"Cardiac Success Ltd"},{"author_name":"Roger D Quinn","author_inst":"Case Western Reserve University"},{"author_name":"Gregory P Sutton","author_inst":"University of Lincoln"},{"author_name":"Hillel J Chiel","author_inst":"Case Western Reserve University"},{"author_name":"Victoria A Webster-Wood","author_inst":"Carnegie Mellon University"}],"rel_date":"2026-04-05","rel_site":"biorxiv"},{"rel_title":"Context-dependent mechanical reconfiguration is necessary for multifunctional behavior in a constrained hydrostat","rel_doi":"10.64898\/2026.04.01.715937","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.715937","rel_abs":"Muscular hydrostats, muscular structures with no rigid skeleton, are ubiquitous within the animal kingdom, from vertebrate tongues to cephalopod arms, but how they perform complex actions remains poorly understood. One model hydrostat studied for its neural control and biomechanics is the feeding system (buccal mass) of the sea hare Aplysia (Fig. 1). The buccal mass (Fig. 1b) performs multiple feeding behaviors by coordinating intrinsic muscles to move a grasper (odontophore). In this paper, we investigated how mechanical reconfiguration from interacting shape-changing elements facilitates large odontophore protractions. During rejection behaviors, mechanical reconfiguration of the odontophore (elongating its shape to a higher aspect ratio) stretches a protractor muscle (I2), allowing I2 to generate stronger protractions. In biting behaviors, the odontophore has a similar range of motion. However, during biting, the odontophore has a lower aspect ratio throughout protraction, meaning the I2 muscle alone is insufficient to reach observed protractions due to its length\/tension property and reduced mechanical advantage. By combining new analysis of MRI movies of Aplysia feeding (Fig. 1) with a new biomechanical model for biting and rejection (Fig. 2), we demonstrate two context-dependent mechanical reconfiguration mechanisms that explain the different ways large protractions are produced in biting and rejection (Fig. 3). The mechanisms integrate shape changes, bending and conforming of muscle structures, and shifts in contact interactions. We propose two mechanical subclasses of muscular hydrostats, \"constrained\" or \"unconstrained\" (Fig. 4), that may be morphologically similar but employ different control strategies depending on whether mechanical constraints are reliably present.","rel_num_authors":7,"rel_authors":[{"author_name":"Michael J Bennington","author_inst":"Carnegie Mellon University"},{"author_name":"Stephen M Rogers","author_inst":"University of Oxford"},{"author_name":"David M Neustadter","author_inst":"Cardiac Success Ltd"},{"author_name":"Roger D Quinn","author_inst":"Case Western Reserve University"},{"author_name":"Gregory P Sutton","author_inst":"University of Lincoln"},{"author_name":"Hillel J Chiel","author_inst":"Case Western Reserve University"},{"author_name":"Victoria A Webster-Wood","author_inst":"Carnegie Mellon University"}],"rel_date":"2026-04-05","rel_site":"biorxiv"},{"rel_title":"CellBench-LS: Benchmark Evaluation of Single-cell Foundation Models for Low-supervision Scenarios","rel_doi":"10.64898\/2026.04.01.714123","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.714123","rel_abs":"While single-cell foundation models (SCFMs) have shown promise across various downstream tasks, their generalization performance in label-scarce settings remains a critical bottleneck. The absence of systematic benchmarks for these low-resource scenarios hinders their translation to real-world biomedical research. To bridge this gap, we present CellBench-LS, a comprehensive framework designed to rigorously evaluate SCFMs generalization under low-supervision conditions. This framework employ a stratified evaluation protocol to systematically compare traditional methods and foundation models. We evaluate their zero-shot representational abilities on cell clustering and batch correction tasks, and apply lightweight fine-tuning of task-specific heads for predictive tasks, such as celltype annotation, expression reconstruction, and perturbation prediction. Experimental results demonstrate a biologically stratified landscape, with foundation models showing distinct advantages in tasks critically reliant on celltype recognition, while traditional methods remain competitive in those requiring precise quantification of gene expression patterns. CellBench-LS provides critical guidance for developing more biologically grounded and generalizable computational approaches in single-cell analysis.","rel_num_authors":5,"rel_authors":[{"author_name":"Yongjie Xu","author_inst":"Shandong University"},{"author_name":"Yiyun Li","author_inst":"Chinese University of Hong Kong"},{"author_name":"Yue Yuan","author_inst":"Hunan University of Medicine"},{"author_name":"Chang Yu","author_inst":"Westlake University"},{"author_name":"Zelin Zang","author_inst":"Westlake University"}],"rel_date":"2026-04-05","rel_site":"biorxiv"},{"rel_title":"Expanding the scope of redox-balance growth coupling techniques with a carbon cofeeding strategy","rel_doi":"10.64898\/2026.04.01.713023","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.713023","rel_abs":"Metabolic engineering to produce molecules not naturally synthesized by the host often requires directed evolution to improve pathway enzyme performance. Growth-coupled selection can dramatically increase directed-evolution throughput, and manipulation of redox balance has proven effective for tying reductase fitness to microbial growth. However, most redox-balance selections require feeding the reductase substrate because of stoichiometric constraints. This is impractical for many biosynthetic pathways either due to practical limitations on cost or complexity of bulk substrate synthesis, or the lack of an ability to transport substrate into cells, for example intracellular acyl-CoA\/ACP intermediates. Here we define stoichiometric constraints that make substrate feeding necessary for many acetyl-CoA-derived reduction pathways in NADPH-imbalanced hosts. We overcome these constraints with a dual-feedstock strategy in which glucose provides reducing power while acetate supplies additional acetyl-CoA without directly perturbing redox balance. In an engineered E. coli selection strain, acetate co-feeding enabled growth coupling of acetaldehyde, 3-hydroxybutyrate, and mevalonate production and produced a linear correlation between product formation and growth. We then used this selection to evolve a class II HMG-CoA reductase (HMGR) from Delftia acidovorans toward NADPH utilization, enriching variants with improved NADPH-dependent activity. Finally, propionate co-feeding enabled growth coupling of propionyl-CoA reduction, supporting the generality of carbon co-feeding for selecting enzymes in pathways involving acyl-chain elongation and reduction.","rel_num_authors":11,"rel_authors":[{"author_name":"Aidan E Cowan","author_inst":"Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA 94608, USA"},{"author_name":"Bridgie Cawthon","author_inst":"Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA 94608, USA"},{"author_name":"Mason Hillers","author_inst":"Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA 94608, USA"},{"author_name":"Sean Perea","author_inst":"Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, CA 94720, USA"},{"author_name":"Maxwell Grabovac","author_inst":"Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA 94608, USA"},{"author_name":"Anna Stanton","author_inst":"Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA 94608, USA"},{"author_name":"Samer Saleh","author_inst":"Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, CA 94720, USA"},{"author_name":"Jennifer Gin","author_inst":"Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA 94608, USA"},{"author_name":"Yan Chen","author_inst":"Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA 94608, USA"},{"author_name":"Christopher J Petzold","author_inst":"Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA 94608, USA"},{"author_name":"Jay D Keasling","author_inst":"Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA 94608, USA"}],"rel_date":"2026-04-05","rel_site":"biorxiv"},{"rel_title":"Expanding the scope of redox-balance growth coupling techniques with a carbon cofeeding strategy","rel_doi":"10.64898\/2026.04.01.713023","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.713023","rel_abs":"Metabolic engineering to produce molecules not naturally synthesized by the host often requires directed evolution to improve pathway enzyme performance. Growth-coupled selection can dramatically increase directed-evolution throughput, and manipulation of redox balance has proven effective for tying reductase fitness to microbial growth. However, most redox-balance selections require feeding the reductase substrate because of stoichiometric constraints. This is impractical for many biosynthetic pathways either due to practical limitations on cost or complexity of bulk substrate synthesis, or the lack of an ability to transport substrate into cells, for example intracellular acyl-CoA\/ACP intermediates. Here we define stoichiometric constraints that make substrate feeding necessary for many acetyl-CoA-derived reduction pathways in NADPH-imbalanced hosts. We overcome these constraints with a dual-feedstock strategy in which glucose provides reducing power while acetate supplies additional acetyl-CoA without directly perturbing redox balance. In an engineered E. coli selection strain, acetate co-feeding enabled growth coupling of acetaldehyde, 3-hydroxybutyrate, and mevalonate production and produced a linear correlation between product formation and growth. We then used this selection to evolve a class II HMG-CoA reductase (HMGR) from Delftia acidovorans toward NADPH utilization, enriching variants with improved NADPH-dependent activity. Finally, propionate co-feeding enabled growth coupling of propionyl-CoA reduction, supporting the generality of carbon co-feeding for selecting enzymes in pathways involving acyl-chain elongation and reduction.","rel_num_authors":11,"rel_authors":[{"author_name":"Aidan E Cowan","author_inst":"Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA 94608, USA"},{"author_name":"Bridgie Cawthon","author_inst":"Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA 94608, USA"},{"author_name":"Mason Hillers","author_inst":"Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA 94608, USA"},{"author_name":"Sean Perea","author_inst":"Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, CA 94720, USA"},{"author_name":"Maxwell Grabovac","author_inst":"Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA 94608, USA"},{"author_name":"Anna Stanton","author_inst":"Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA 94608, USA"},{"author_name":"Samer Saleh","author_inst":"Department of Chemical and Biomolecular Engineering, University of California, Berkeley, Berkeley, CA 94720, USA"},{"author_name":"Jennifer Gin","author_inst":"Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA 94608, USA"},{"author_name":"Yan Chen","author_inst":"Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA 94608, USA"},{"author_name":"Christopher J Petzold","author_inst":"Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA 94608, USA"},{"author_name":"Jay D Keasling","author_inst":"Joint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA 94608, USA"}],"rel_date":"2026-04-05","rel_site":"biorxiv"},{"rel_title":"Trajectories of Response Inhibition Development in Adolescence","rel_doi":"10.64898\/2026.04.03.716386","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.03.716386","rel_abs":"Response inhibition is a critical cognitive process that is not fully mature at the time of puberty but continues to improve during adolescence. To understand the neural basis of the maturation process, we obtained longitudinal behavioral, neurophysiological, and imaging data in macaque monkeys as they aged through adolescence. Behavioral performance in several variants of the antisaccade task improved markedly through this period. Neural activity in the prefrontal cortex generally increased, particularly when synchronized to the saccade generation. Trajectories of neural activity and cognitive performance were well predicted by maturation of long-distance white matter tracts connecting the frontal lobe with other brain areas. Our results link the maturation of response inhibition and prefrontal neural activity changes to white matter maturation.","rel_num_authors":7,"rel_authors":[{"author_name":"Junda Zhu","author_inst":"Vanderbilt University"},{"author_name":"Colton R Smith","author_inst":"Vanderbilt University"},{"author_name":"Clement M Garin","author_inst":"CEA"},{"author_name":"Xin Maizie Zhou","author_inst":"Vanderbilt university"},{"author_name":"Finnegan Calabro","author_inst":"University of Pittsburgh"},{"author_name":"Beatriz Luna","author_inst":"University of Pittsburgh"},{"author_name":"Christos Constantinidis","author_inst":"Vanderbilt University"}],"rel_date":"2026-04-05","rel_site":"biorxiv"},{"rel_title":"A Hybrid Machine Learning Framework for Early Prediction of Chronic Kidney Disease Progression Using Longitudinal Claims Data: An XGBoost-LSTM Ensemble with Temporal Attention","rel_doi":"10.64898\/2026.04.03.26349862","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.03.26349862","rel_abs":"Background: Chronic kidney disease (CKD) affects approximately 850 million individuals worldwide and remains a leading cause of morbidity, premature mortality, and escalating healthcare costs. Despite the availability of clinical biomarkers, CKD progression to end stage renal disease (ESRD) is frequently identified late, limiting opportunities for preventive intervention. Conventional predictive models have relied predominantly on static cross sectional laboratory values, failing to capture the temporal dynamics of disease trajectory that longitudinal claims data can provide. Objective: This study proposes a novel hybrid machine learning framework: XGBoost LSTM Attention (XLA), that integrates gradient boosted feature selection with long short-term memory (LSTM) networks and a temporal attention mechanism to improve early prediction of CKD progression from Stage 3 to Stages 4\/5 or ESRD using longitudinal claims based features. Methods: We conducted two complementary analyses. Primary analysis: a cross sectional validation using real NHANES 2015 to 2018 data (n=701 CKD Stage 3 adults) predicting significant proteinuria (UACR greater than or equal to 30 mg\/g) from clinical features excluding UACR. Supplementary analysis: an NHANES-calibrated longitudinal cohort (n=8,412) with simulated quarterly measurements demonstrated XLA performance under real world longitudinal data conditions. All models were evaluated using 5-fold stratified cross-validation. Results: In the primary NHANES cross sectional analysis, the XLA framework achieved AUC ROC of 0.684 (95% CI: 0.641 to 0.727), with all models performing comparably (AUC 0.684 to 0.710), confirming that cross sectional clinical features alone provide limited signal for proteinuria prediction and underscoring the necessity of UACR measurement. In the longitudinal supplementary analysis, XLA achieved AUC ROC of 0.994 versus 0.939 for the best cross-sectional baseline (+5.5%), demonstrating that temporal trajectory features particularly eGFR slope and RAAS adherence trends: confer substantial incremental predictive value when longitudinal data are available. Conclusion: The XLA framework demonstrates meaningful advantages over traditional approaches when applied to longitudinal claims data. Cross sectional findings highlight the irreplaceable role of direct UACR measurement in CKD risk stratification. Together, these results provide actionable evidence for both the limitations of static prediction and the promise of trajectory based approaches in value based care programs managing large CKD populations. Keywords: chronic kidney disease, CKD progression, machine learning, XGBoost, LSTM, temporal attention, claims data, NHANES, proteinuria, healthcare informatics, value based care.","rel_num_authors":3,"rel_authors":[{"author_name":"JASWANT NARENDRA SAXENA","author_inst":"CGI"},{"author_name":"Devi Vara Prasad Potturu","author_inst":"Yale University"},{"author_name":"Ananya Nagraj","author_inst":"Stevens Institute of Technology"}],"rel_date":"2026-04-04","rel_site":"medrxiv"},{"rel_title":"Proteomic-Based Aging Clocks and MRI Markers of Cerebral Small Vessel Disease: ARIC and MESA","rel_doi":"10.64898\/2026.04.02.26350087","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.02.26350087","rel_abs":"Background: This study investigates whether proteomic aging clocks (PACs) are associated with cerebral small vessel disease (CSVD). Methods: We included participants from two US community-based cohorts: the Atherosclerosis Risk in Communities (ARIC) Study and the Multi-Ethnic Study of Atherosclerosis (MESA) Study. These analyses leveraged PACs that were developed in ARIC using proteomics measured by SomaScan in midlife (Visit 2; mean age 56 y; n=1,486) and late-life (Visit 5; mean age 76 y; n=1,496), trained on chronological age. Proteomic age acceleration (PAA) was calculated as residuals from regressing PACs on chronological age. 3T brain MRI data were collected in late-life. We examined associations of PAA with log-transformed white matter hyperintensity (WMH) volume using linear regression and with the presence of microbleeds, and subcortical, lacunar, and cortical infarcts using logistic regression. Associations of PACs with WMH volume and microbleeds were tested in MESA using proteins measured at Exam 1 (mean age 57 y; n=932) and Exam 5 (mean age 66 y; n=934). All associations were quantified per 5-year increase in PAA. All models were adjusted for demographics and cardiovascular risk factors. Results: In ARIC, higher midlife PAA was associated with greater WMH volume (percent difference: 25% [95% CI: 13%, 39%]) and higher odds of subcortical infarcts (OR: 1.24 [1.02, 1.51]). Late-life PAA was associated with all CSVD markers: WMH volume (percent difference: 20% [8%, 34%]), cerebral microbleeds (OR: 1.40 [1.15, 1.69]), subcortical (OR: 1.80 [1.47, 2.22]), lacunar (OR: 1.80 [1.46, 2.23]), and cortical infarcts (OR: 1.39 [1.07, 1.82]). In MESA, higher late-life PAA was associated with greater WMH volume (28% [3%, 58%]) but not with microbleeds. Conclusion: Accelerated proteomic aging is associated with a higher prevalence of MRI markers of CSVD, most predominantly in late-life. Understanding this relationship may help stratify those at higher risk of CSVD at an early stage.","rel_num_authors":22,"rel_authors":[{"author_name":"Saeun Park","author_inst":"University of Minnesota Twin Cities"},{"author_name":"Shuo Wang","author_inst":"University of Minnesota School of Medicine, Minneapolis, MN"},{"author_name":"Jialing Liu","author_inst":"Division of Biostatistics, University of Minnesota"},{"author_name":"Timothy M. Hughes","author_inst":"Wake Forest University School of Medicine, Winston Salem, NC"},{"author_name":"Erika P. Raven","author_inst":"New York University Grossman School of Medicine"},{"author_name":"Jelle Veraart","author_inst":"New York University Langone"},{"author_name":"Mohamad Habes","author_inst":"The University of Texas Health Science Center at San Antonio May Cancer Center"},{"author_name":"Ruth Dubin","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Rajat Deo","author_inst":"University of Pennsylvania"},{"author_name":"Wendy S. Post","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Jerome I. I. Rotter","author_inst":"The Lundquist Institute"},{"author_name":"Alexis C. Wood","author_inst":"Baylor College of Medicine"},{"author_name":"Peter Ganz","author_inst":"University of California, San Francisco; Zuckerberg San Francisco General Hospital"},{"author_name":"Behnam Sabayan","author_inst":"Hennepin Healthcare Research Institute"},{"author_name":"Weihong Tang","author_inst":"University of Minnesota, School of Public Health, Division of Epidemology and Community Health"},{"author_name":"Josef Coresh","author_inst":"New York University Grossman School of Medicine"},{"author_name":"James S. Pankow","author_inst":"University of Minnesota"},{"author_name":"Keenan A. Walker","author_inst":"National Institutes of Health"},{"author_name":"Pamela L. Lutsey","author_inst":"University of Minnesota"},{"author_name":"Weihua Guan","author_inst":"University of Minnesota Twin Cities"},{"author_name":"Anna E. Prizment","author_inst":"Universtiy of Minnesota"},{"author_name":"Sanaz Sedaghat","author_inst":"Division of Epidemiology and Community Health, School of Public Health, University of Minnesota"}],"rel_date":"2026-04-04","rel_site":"medrxiv"},{"rel_title":"Proteomic-Based Aging Clocks and MRI Markers of Cerebral Small Vessel Disease: ARIC and MESA","rel_doi":"10.64898\/2026.04.02.26350087","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.02.26350087","rel_abs":"Background: This study investigates whether proteomic aging clocks (PACs) are associated with cerebral small vessel disease (CSVD). Methods: We included participants from two US community-based cohorts: the Atherosclerosis Risk in Communities (ARIC) Study and the Multi-Ethnic Study of Atherosclerosis (MESA) Study. These analyses leveraged PACs that were developed in ARIC using proteomics measured by SomaScan in midlife (Visit 2; mean age 56 y; n=1,486) and late-life (Visit 5; mean age 76 y; n=1,496), trained on chronological age. Proteomic age acceleration (PAA) was calculated as residuals from regressing PACs on chronological age. 3T brain MRI data were collected in late-life. We examined associations of PAA with log-transformed white matter hyperintensity (WMH) volume using linear regression and with the presence of microbleeds, and subcortical, lacunar, and cortical infarcts using logistic regression. Associations of PACs with WMH volume and microbleeds were tested in MESA using proteins measured at Exam 1 (mean age 57 y; n=932) and Exam 5 (mean age 66 y; n=934). All associations were quantified per 5-year increase in PAA. All models were adjusted for demographics and cardiovascular risk factors. Results: In ARIC, higher midlife PAA was associated with greater WMH volume (percent difference: 25% [95% CI: 13%, 39%]) and higher odds of subcortical infarcts (OR: 1.24 [1.02, 1.51]). Late-life PAA was associated with all CSVD markers: WMH volume (percent difference: 20% [8%, 34%]), cerebral microbleeds (OR: 1.40 [1.15, 1.69]), subcortical (OR: 1.80 [1.47, 2.22]), lacunar (OR: 1.80 [1.46, 2.23]), and cortical infarcts (OR: 1.39 [1.07, 1.82]). In MESA, higher late-life PAA was associated with greater WMH volume (28% [3%, 58%]) but not with microbleeds. Conclusion: Accelerated proteomic aging is associated with a higher prevalence of MRI markers of CSVD, most predominantly in late-life. Understanding this relationship may help stratify those at higher risk of CSVD at an early stage.","rel_num_authors":22,"rel_authors":[{"author_name":"Saeun Park","author_inst":"University of Minnesota Twin Cities"},{"author_name":"Shuo Wang","author_inst":"University of Minnesota School of Medicine, Minneapolis, MN"},{"author_name":"Jialing Liu","author_inst":"Division of Biostatistics, University of Minnesota"},{"author_name":"Timothy M. Hughes","author_inst":"Wake Forest University School of Medicine, Winston Salem, NC"},{"author_name":"Erika P. Raven","author_inst":"New York University Grossman School of Medicine"},{"author_name":"Jelle Veraart","author_inst":"New York University Langone"},{"author_name":"Mohamad Habes","author_inst":"The University of Texas Health Science Center at San Antonio May Cancer Center"},{"author_name":"Ruth Dubin","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Rajat Deo","author_inst":"University of Pennsylvania"},{"author_name":"Wendy S. Post","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Jerome I. I. Rotter","author_inst":"The Lundquist Institute"},{"author_name":"Alexis C. Wood","author_inst":"Baylor College of Medicine"},{"author_name":"Peter Ganz","author_inst":"University of California, San Francisco; Zuckerberg San Francisco General Hospital"},{"author_name":"Behnam Sabayan","author_inst":"Hennepin Healthcare Research Institute"},{"author_name":"Weihong Tang","author_inst":"University of Minnesota, School of Public Health, Division of Epidemology and Community Health"},{"author_name":"Josef Coresh","author_inst":"New York University Grossman School of Medicine"},{"author_name":"James S. Pankow","author_inst":"University of Minnesota"},{"author_name":"Keenan A. Walker","author_inst":"National Institutes of Health"},{"author_name":"Pamela L. Lutsey","author_inst":"University of Minnesota"},{"author_name":"Weihua Guan","author_inst":"University of Minnesota Twin Cities"},{"author_name":"Anna E. Prizment","author_inst":"Universtiy of Minnesota"},{"author_name":"Sanaz Sedaghat","author_inst":"Division of Epidemiology and Community Health, School of Public Health, University of Minnesota"}],"rel_date":"2026-04-04","rel_site":"medrxiv"},{"rel_title":"Development and validation of a machine learning model for community-based tuberculosis screening among persons aged >= 15 years in South Africa and Zambia","rel_doi":"10.64898\/2026.03.30.26349632","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.30.26349632","rel_abs":"Introduction: Current tuberculosis (TB) screening tools, such as the WHO four-symptom screen (W4SS), lack sufficient sensitivity and specificity for effective community-based active case finding, contributing to both missed diagnoses and unnecessary diagnostic evaluations. This study aimed to develop and validate a machine learning (ML) model to improve TB risk prediction among persons aged >=15 years in community settings of Zambia and South Africa. Methods: A large, harmonized dataset was created from four community-based TB prevalence surveys in South Africa and Zambia (N=169,813), restricted to individuals not under treatment at the time of survey. A binary reference outcome was defined based on available microbiological and radiographic data, grouping individuals as either 'Possible TB' or 'Unlikely TB'. An XGBoost model was trained on 80% (N=135,854) of the data using demographic, clinical, and socio-economic variables, and model interpretability was assessed using SHapley Additive exPlanations (SHAP) values. Internal validation was performed using a 20% hold-out test set (N=33,959). Model performance was assessed using discrimination, calibration, and clinical utility measures compared to the W4SS and against WHO's 2025 Target Product Profile (TPP) for a tool in a two-step screening algorithm. Results: Overall, 16,413 (9.7%) of individuals were labelled as 'Possible TB'. On the test set, the XGBoost model yielded an area under the curve (AUC) of 79.7% (95% CI: 78.7, 80.7), outperforming the W4SS (AUC 57.0%; 95% CI: 56.1, 57.8). The XGBoost model achieved 81.5% sensitivity (95% CI: 77.6, 84.9) at a 60% specificity threshold. This exceeded the W4SS, which achieved only 38.2% sensitivity (95% CI: 36.5, 39.9) on the same dataset. SHAP analysis identified age, previous TB treatment, times treated for TB and unemployment as the primary contributors to risk. Conclusion: The ML XGBoost model shows promise as a screening tool to support community-based active case finding activities prior to diagnostic testing. However, as performance remained below TPP targets, and adding variables, e.g. on geolocation, could be considered.","rel_num_authors":28,"rel_authors":[{"author_name":"Alexandra J Zimmer","author_inst":"Heidelberg University"},{"author_name":"Henry Loharja","author_inst":"Heidelberg University"},{"author_name":"Kindie Fentahun Muchie","author_inst":"Heidelberg University"},{"author_name":"Lisa Koeppel","author_inst":"Heidelberg University"},{"author_name":"Helen Ayles","author_inst":"London School of Hygiene and Tropical Medicine"},{"author_name":"Maria del Mar Castro","author_inst":"Heidelberg University"},{"author_name":"Evangelia Christodoulou","author_inst":"German Cancer Research Center (DKFZ) Heidelberg"},{"author_name":"Greg J Fox","author_inst":"The University of Sydney"},{"author_name":"Mary Gaeddert","author_inst":"Heidelberg University"},{"author_name":"Yohhei Hamada","author_inst":"University College London"},{"author_name":"Chris Isaacs","author_inst":"Connected Diagnostics"},{"author_name":"Nathan Kapata","author_inst":"Zambia National Public Health Institute"},{"author_name":"Pascalina Chanda-Kapata","author_inst":"Independent Health and Development Consultant (Zambia)"},{"author_name":"Kasra Karimi","author_inst":"Heidelberg University"},{"author_name":"Nkatya Kasese","author_inst":"Zambart"},{"author_name":"Andrew Kerkhoff","author_inst":"UCSF"},{"author_name":"Irwin Law","author_inst":"WHO"},{"author_name":"Lena Maier-Hein","author_inst":"German Cancer Research Center (DKFZ) Heidelberg"},{"author_name":"Florian M Marx","author_inst":"Heidelberg University"},{"author_name":"Minyoi  Mubita Maimbolwa","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Sizulu Moyo","author_inst":"Human Sciences Research Council"},{"author_name":"Thuli Mthiyane","author_inst":"South Africa Medical Research Council"},{"author_name":"Monde Muyoyeta","author_inst":"Center for Infectious Disease Research in Zambia"},{"author_name":"Joacim Rockl\u00f6v","author_inst":"Heidelberg University"},{"author_name":"Albertus Schaap","author_inst":"Zambart"},{"author_name":"Seda Yerlikaya","author_inst":"Heidelberg University"},{"author_name":"Michael Opata","author_inst":"Heidelberg University"},{"author_name":"Claudia M Denkinger","author_inst":"Heidelberg University"}],"rel_date":"2026-04-04","rel_site":"medrxiv"},{"rel_title":"Development and validation of a machine learning model for community-based tuberculosis screening among persons aged >= 15 years in South Africa and Zambia","rel_doi":"10.64898\/2026.03.30.26349632","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.30.26349632","rel_abs":"Introduction: Current tuberculosis (TB) screening tools, such as the WHO four-symptom screen (W4SS), lack sufficient sensitivity and specificity for effective community-based active case finding, contributing to both missed diagnoses and unnecessary diagnostic evaluations. This study aimed to develop and validate a machine learning (ML) model to improve TB risk prediction among persons aged >=15 years in community settings of Zambia and South Africa. Methods: A large, harmonized dataset was created from four community-based TB prevalence surveys in South Africa and Zambia (N=169,813), restricted to individuals not under treatment at the time of survey. A binary reference outcome was defined based on available microbiological and radiographic data, grouping individuals as either 'Possible TB' or 'Unlikely TB'. An XGBoost model was trained on 80% (N=135,854) of the data using demographic, clinical, and socio-economic variables, and model interpretability was assessed using SHapley Additive exPlanations (SHAP) values. Internal validation was performed using a 20% hold-out test set (N=33,959). Model performance was assessed using discrimination, calibration, and clinical utility measures compared to the W4SS and against WHO's 2025 Target Product Profile (TPP) for a tool in a two-step screening algorithm. Results: Overall, 16,413 (9.7%) of individuals were labelled as 'Possible TB'. On the test set, the XGBoost model yielded an area under the curve (AUC) of 79.7% (95% CI: 78.7, 80.7), outperforming the W4SS (AUC 57.0%; 95% CI: 56.1, 57.8). The XGBoost model achieved 81.5% sensitivity (95% CI: 77.6, 84.9) at a 60% specificity threshold. This exceeded the W4SS, which achieved only 38.2% sensitivity (95% CI: 36.5, 39.9) on the same dataset. SHAP analysis identified age, previous TB treatment, times treated for TB and unemployment as the primary contributors to risk. Conclusion: The ML XGBoost model shows promise as a screening tool to support community-based active case finding activities prior to diagnostic testing. However, as performance remained below TPP targets, and adding variables, e.g. on geolocation, could be considered.","rel_num_authors":28,"rel_authors":[{"author_name":"Alexandra J Zimmer","author_inst":"Heidelberg University"},{"author_name":"Henry Loharja","author_inst":"Heidelberg University"},{"author_name":"Kindie Fentahun Muchie","author_inst":"Heidelberg University"},{"author_name":"Lisa Koeppel","author_inst":"Heidelberg University"},{"author_name":"Helen Ayles","author_inst":"London School of Hygiene and Tropical Medicine"},{"author_name":"Maria del Mar Castro","author_inst":"Heidelberg University"},{"author_name":"Evangelia Christodoulou","author_inst":"German Cancer Research Center (DKFZ) Heidelberg"},{"author_name":"Greg J Fox","author_inst":"The University of Sydney"},{"author_name":"Mary Gaeddert","author_inst":"Heidelberg University"},{"author_name":"Yohhei Hamada","author_inst":"University College London"},{"author_name":"Chris Isaacs","author_inst":"Connected Diagnostics"},{"author_name":"Nathan Kapata","author_inst":"Zambia National Public Health Institute"},{"author_name":"Pascalina Chanda-Kapata","author_inst":"Independent Health and Development Consultant (Zambia)"},{"author_name":"Kasra Karimi","author_inst":"Heidelberg University"},{"author_name":"Nkatya Kasese","author_inst":"Zambart"},{"author_name":"Andrew Kerkhoff","author_inst":"UCSF"},{"author_name":"Irwin Law","author_inst":"WHO"},{"author_name":"Lena Maier-Hein","author_inst":"German Cancer Research Center (DKFZ) Heidelberg"},{"author_name":"Florian M Marx","author_inst":"Heidelberg University"},{"author_name":"Minyoi  Mubita Maimbolwa","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Sizulu Moyo","author_inst":"Human Sciences Research Council"},{"author_name":"Thuli Mthiyane","author_inst":"South Africa Medical Research Council"},{"author_name":"Monde Muyoyeta","author_inst":"Center for Infectious Disease Research in Zambia"},{"author_name":"Joacim Rockl\u00f6v","author_inst":"Heidelberg University"},{"author_name":"Albertus Schaap","author_inst":"Zambart"},{"author_name":"Seda Yerlikaya","author_inst":"Heidelberg University"},{"author_name":"Michael Opata","author_inst":"Heidelberg University"},{"author_name":"Claudia M Denkinger","author_inst":"Heidelberg University"}],"rel_date":"2026-04-04","rel_site":"medrxiv"},{"rel_title":"Beyond the TyG Index: Composite Metabolic Metrics Integrating Central Adiposity Improve Atrial Fibrillation Risk Prediction Independent of Genetic Susceptibility","rel_doi":"10.64898\/2026.04.02.26350088","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.02.26350088","rel_abs":"Background: Insulin resistance (IR) and obesity are key drivers of atrial fibrillation (AF). However, the comparative predictive value of the Triglyceride-Glucose (TyG) index versus composite indices combining IR and anthropometric measures such as TyG-BMI, TyG-Waist Circumference (TyG-WC), and Waist-to-Height Ratio (WHtR) remains undefined. We aimed to evaluate these associations and the modifying effect of genetic susceptibility. Methods: We analyzed 293,318 UK Biobank participants free of AF at baseline. Hazard ratios (HRs) were estimated using Cox proportional hazards models, and non-linearity was assessed using restricted cubic splines. Incremental predictive value was evaluated via Net Reclassification Improvement (NRI). Interactions with AF Polygenic Risk Scores (PRS) were examined. Results: During follow-up, 22,707 incident AF cases occurred. While the TyG index was associated with AF in unadjusted models, this association was nullified after full adjustment. In contrast, composite indices (TyG-BMI, TyG-WC) and WHtR showed robust, positive associations (WHtR HR per SD: 1.30, 95% CI 1.28-1.32). Spline analysis identified non-linear threshold effects (e.g., WHtR inflection at 0.556). Adding WHtR or TyG-BMI to baseline models significantly improved risk reclassification (NRI ~10.3-11.8%, P<0.001), whereas TyG alone did not (P=0.73). Elevated metabolic risk increased AF incidence across all genetic categories, with significant interactions suggesting greater relative impact in low-genetic risk groups. Conclusions: Composite indices integrating central obesity and insulin resistance are superior to the TyG index alone in predicting incident AF. The identification of specific risk thresholds and genetic interactions highlights \"metabolic health\" as a crucial, modifiable target for AF prevention.","rel_num_authors":8,"rel_authors":[{"author_name":"Zhang Ke","author_inst":"Beijing Anzhen Hospital Affiliated to Capital Medical University"},{"author_name":"Shengwei Wang","author_inst":"Beijing Anzhen Hospital Affiliated to Capital Medical University"},{"author_name":"Wang Song","author_inst":"Beijing Anzhen Hospital Affiliated to Capital Medical University"},{"author_name":"Shifeng Zhao","author_inst":"Beijing Anzhen Hospital Affiliated to Capital Medical University"},{"author_name":"Meng He","author_inst":"Beijing Anzhen Hospital Affiliated to Capital Medical University"},{"author_name":"Changwei Ren","author_inst":"Beijing Anzhen hospital"},{"author_name":"Hao Cui","author_inst":"Beijing Anzhen Hospital Affiliated to Capital Medical University"},{"author_name":"Yongqiang Lai","author_inst":"Beijing Anzhen Hospital Affiliated to Capital Medical University"}],"rel_date":"2026-04-04","rel_site":"medrxiv"},{"rel_title":"A Manual of Procedures for the Generation of the AI-Ready and Exploratory Atlas for Diabetes Insights (AI-READI) Database.","rel_doi":"10.64898\/2026.03.30.26349552","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.30.26349552","rel_abs":"The ability to understand and affect the course of complex, multi-system diseases like diabetes has been limited by a lack of well-designed, high-quality and large multimodal datasets. The NIH Bridge2AI AI-READI project (aireadi.org) aims to address this shortfall by generating an AI-ready dataset to support AI discoveries in type 2 diabetes mellitus (T2DM). This manual of procedures provides a detailed description of the AI-READI protocol.","rel_num_authors":10,"rel_authors":[{"author_name":"Dawn S Matthies","author_inst":"University of Alabama at Birmingham"},{"author_name":"Jeffrey C Edberg","author_inst":"University of Alabama at Birmingham"},{"author_name":"Sally L Baxter","author_inst":"University of California San Diego"},{"author_name":"Aaron Y Lee","author_inst":"Washington University In St Louis"},{"author_name":"Cecilia S Lee","author_inst":"Washington University In St Louis"},{"author_name":"Gerald McGwin","author_inst":"University of Alabama at Birmingham"},{"author_name":"Julia P Owen","author_inst":"Washington University In St Louis"},{"author_name":"Linda M Zangwill","author_inst":"University of California San Diego"},{"author_name":"Cynthia Owsley","author_inst":"University of Alabama at Birmingham"},{"author_name":"- AI-READI Consortium","author_inst":""}],"rel_date":"2026-04-04","rel_site":"medrxiv"},{"rel_title":"A Manual of Procedures for the Generation of the AI-Ready and Exploratory Atlas for Diabetes Insights (AI-READI) Database.","rel_doi":"10.64898\/2026.03.30.26349552","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.30.26349552","rel_abs":"The ability to understand and affect the course of complex, multi-system diseases like diabetes has been limited by a lack of well-designed, high-quality and large multimodal datasets. The NIH Bridge2AI AI-READI project (aireadi.org) aims to address this shortfall by generating an AI-ready dataset to support AI discoveries in type 2 diabetes mellitus (T2DM). This manual of procedures provides a detailed description of the AI-READI protocol.","rel_num_authors":10,"rel_authors":[{"author_name":"Dawn S Matthies","author_inst":"University of Alabama at Birmingham"},{"author_name":"Jeffrey C Edberg","author_inst":"University of Alabama at Birmingham"},{"author_name":"Sally L Baxter","author_inst":"University of California San Diego"},{"author_name":"Aaron Y Lee","author_inst":"Washington University In St Louis"},{"author_name":"Cecilia S Lee","author_inst":"Washington University In St Louis"},{"author_name":"Gerald McGwin","author_inst":"University of Alabama at Birmingham"},{"author_name":"Julia P Owen","author_inst":"Washington University In St Louis"},{"author_name":"Linda M Zangwill","author_inst":"University of California San Diego"},{"author_name":"Cynthia Owsley","author_inst":"University of Alabama at Birmingham"},{"author_name":"- AI-READI Consortium","author_inst":""}],"rel_date":"2026-04-04","rel_site":"medrxiv"},{"rel_title":"Multi-Task Learning and Soft-Label Supervision for Psychosocial Burden Profiling in Cancer Peer-Support Text","rel_doi":"10.64898\/2026.04.03.26350034","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.03.26350034","rel_abs":"Objective: Online cancer peer-support text contains signals of psychosocial burden beyond emotional tone, including treatment burden, financial strain, uncertainty, and unmet support needs. We evaluated 2 modeling extensions: multi-task learning (MTL) for joint prediction of health economics and outcomes research (HEOR) burden dimensions, and soft-label supervision using large language model (LLM)-derived probability distributions. Materials and Methods: We analyzed 10,392 cancer peer-support posts. GPT-4o-mini generated proxy annotations for HEOR burden subscales, composite burden, high-need status, speaker role, cancer type, and emotion probabilities. Study 1 trained a shared ALBERT encoder under 4 MTL conditions: composite and subscale burden targets, each with and without auxiliary heads, using Kendall uncertainty weighting. Study 2 compared soft-label training on LLM emotion distributions with hard-label baselines under regular and token-augmented inputs, evaluating performance against both human labels and AI distributions. Results: Composite-only MTL achieved R2=0.446 for burden regression and weighted F1=0.810 for high-need screening; subscale classification achieved mean weighted F1=0.646. Adding auxiliary role and cancer-type heads reduced regression performance ({triangleup}R2 = -0.209). Soft-label training reduced weighted F1 by 0.16 versus hard-label baselines (0.68 vs. 0.86), and token augmentation did not improve performance under soft supervision. Discussion: Composite-only MTL supported modeling of multidimensional burden-related signals from forum text, whereas auxiliary prediction heads appeared to compete with primary tasks. Soft-label training aligned poorly with human-labeled emotion categories, suggesting that uncalibrated LLM distributions may propagate bias rather than improve supervision. Conclusion: Composite-only MTL was the strongest burden-modeling approach, and hard-label supervision remained preferable for emotion classification.","rel_num_authors":6,"rel_authors":[{"author_name":"Zhongyan Wang","author_inst":"New York University"},{"author_name":"Yuchen Cao","author_inst":"Northeastern University"},{"author_name":"Xiaorui Shen","author_inst":"Northeastern University"},{"author_name":"Zhanyi Ding","author_inst":"New York University"},{"author_name":"Yunchong Liu","author_inst":"University of Pennsylvania"},{"author_name":"Yeyubei Zhang","author_inst":"University of Pennsylvania"}],"rel_date":"2026-04-04","rel_site":"medrxiv"},{"rel_title":"County-level decarceration atlas: mechanisms, prevalence, and dynamics of decarceration across 2,870 U.S. counties, 1999-2019","rel_doi":"10.64898\/2026.04.02.26349309","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.02.26349309","rel_abs":"Decarceration, the process of reducing incarceration rates, is increasingly viewed as a strategy to improve population health and reduce health inequities. Yet, evidence on its health effects remains limited and may depend on how decarceration occurs. We developed a national decarceration \"atlas\" to characterize the mechanisms and dynamics of decarceration across more than 2,800 U.S. counties between 1999-2019. Using longitudinal county-level jail and prison data, we identified four operational types of decarceration: reduced pretrial detention, reduced jail time, reduced prison admissions, and reduced prison time. Nearly two-thirds of counties, including most rural counties, experienced at least one decarceration type during the study period. Declines typically followed periods of recent growth and were relatively modest in magnitude, with median reductions of 19% to 38% ten years after onset. The frequency and timing of decarceration types varied by urbanicity, state, and region, with many counties experiencing multiple mechanisms concurrently. Validation against documented case studies of state and local decarceration demonstrated alignment with known legislative and de facto drivers, while revealing substantial sub-state heterogeneity. This atlas provides a scalable framework and hypothesis-generating resource to support comparative studies of decarceration's heterogeneous health effects.","rel_num_authors":5,"rel_authors":[{"author_name":"Yiran E Liu","author_inst":"Yale University"},{"author_name":"Beier Li","author_inst":"Yale University"},{"author_name":"Joshua L Warren","author_inst":"Yale University School of Public Health"},{"author_name":"Gregg S Gonsalves","author_inst":"Yale School of Public Health"},{"author_name":"Emily A Wang","author_inst":"Yale University"}],"rel_date":"2026-04-04","rel_site":"medrxiv"},{"rel_title":"Stress-Induced PTBP1 Reprograms Neuronal Function and Activates Cellular Senescence","rel_doi":"10.64898\/2026.04.03.711742","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.03.711742","rel_abs":"Chronic oxidative stress is a major contributor to neuronal aging. Due to the lack of homologous recombination (HR) DNA damage repair, high oxygen consumption in neurons causes DNA damage accumulation with age, resulting in a decline in neuronal function, senescence-like phenotypes and onset of neurodegenerative diseases. Here, we identify increased PTBP1 as a stress-inducible negative regulator of neuronal gene expression and senescence-protectant genes. Oxidative stress robustly increases PTBP1 expression in ShSY-5Y differentiated neurons and primary mouse cortical neurons, coinciding with the loss of neuronal genes, including neuronal PTBP2, and activation of stress-responsive genes. Knockdown of PTBP1 in fibroblasts reduces the expression of key senescence genes. Transcriptomic analyses revealed that PTBP1 overexpression results in coordinated shift in gene expression characterized by repression of neuronal commitment genes and activation of stress and senescence genes. Mechanistically, PTBP1 induction is regulated by stress induced CTCF binding at the PTBP1 promoter. Together, our findings suggest that alteration in levels of PTBP1 acts as a molecular switch between neuronal function and survival, providing insight into transcriptional adaptations associated with aging.","rel_num_authors":5,"rel_authors":[{"author_name":"Priyanka Priyanka","author_inst":"University of California San Diego"},{"author_name":"Amir Gamliel","author_inst":"University of California San Diego Medical Center"},{"author_name":"Havilah Taylor","author_inst":"School and Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA"},{"author_name":"Kenneth A Ohgi","author_inst":"University of California San Diego Medical Center"},{"author_name":"Michael Geoff Rosenfeld","author_inst":"University of California San Diego Medical Center"}],"rel_date":"2026-04-04","rel_site":"biorxiv"},{"rel_title":"Targeting the DNA damage repair protein RAD51 alters fibroblast metabolism and enhances apoptosis in pulmonary fibrosis","rel_doi":"10.64898\/2026.04.01.715935","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.715935","rel_abs":"Background Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by aberrantly activated, apoptosis-resistant profibrotic lung (myo)fibroblasts. Prior research has demonstrated that lung fibroblasts from patients with IPF exhibit resistance to DNA damage, suggesting that this behavior contributes to their persistent survival and continuous proliferation. We propose that elevated levels of the DNA damage repair protein RAD51 regulate myofibroblast activation and apoptosis and provide a potential therapeutic target to impede fibrosis progression. Methods Human lung fibroblasts were transfected with siRNA against RAD51 or treated with RAD51-specific inhibitor B02 and markers of fibrosis, DNA damage, apoptosis, metabolic reprogramming, and mitochondrial dynamics were assessed. The preclinical efficacy of B02 was evaluated in human precision cut lung slices (PCLS) and in a mouse model of pulmonary fibrosis. Findings RAD51 expression was significantly upregulated in the lungs and lung fibroblasts of IPF patients. Knockdown or inhibition of RAD51 in fibroblasts reduced profibrotic marker expression, suppressed mTORC1 signaling and mitochondrial function, and increased apoptosis susceptibility. Pharmacological inhibition of RAD51 shifted the profibrotic phenotype towards a fibrosis-resolving state in human and mouse PCLS, and in a bleomycin-induced mouse model of lung fibrosis. Interpretation The inhibition of RAD51 exerts therapeutic benefits in lung fibrosis by promoting apoptosis. Our findings identify that inhibiting RAD51 with B02 in fibroblasts impairs DNA repair and induces metabolic reprogramming, making it a potential therapeutic target.","rel_num_authors":7,"rel_authors":[{"author_name":"Rahul K Maurya","author_inst":"Washington University in St. Louis"},{"author_name":"Arun K Sharma","author_inst":"Washington University in St.Louis"},{"author_name":"Kyle J Schaefbauer","author_inst":"Mayo Clinic"},{"author_name":"Lina Ma","author_inst":"Washington University in St. Louis"},{"author_name":"Jeffrey R Koenitzer","author_inst":"Washington University in Saint Louis"},{"author_name":"Andrew Limper","author_inst":"Mayo Clinic"},{"author_name":"Malay Choudhury","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-04-04","rel_site":"biorxiv"},{"rel_title":"Humanization of the rpb9 locus in fission yeast reveals conserved and divergent roles of rpb9 and human POLR2I","rel_doi":"10.64898\/2026.04.02.716003","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.02.716003","rel_abs":"Background\/Objectives: RNA polymerase II is a multifunctional complex that is critical for gene regulation and environmental responses. Its POLR2I subunit in human is associated with various pathologies, including cancer chemoresistance. However, much of our understanding of how POLR2I could function indirectly derives from studies of its homologs in yeasts called Rpb9. Here, we endogenously humanized the rpb9 gene of the fission yeast Schizosaccharomyces pombe to examine the functional capabilities of POLR2I. Methods: We edited the genomic rpb9 locus in S. pombe so that it encodes the human POLR2I protein, and investigated functional and structural conservation. Results: With our humanized yeast system, we find widespread functional complementation by human POLR2I of S. pombe rpb9 roles in yeast growth, chronological aging, and stress responses. We also find that POLR2I complements novel roles for yeast rpb9 in facultative heterochromatin assembly, resistance against the chemotherapy 5-fluorouracil, and resistance against the fungicide thiabendazole. In contrast, we find that POLR2I cannot complement the role of rpb9 in resistance against the transcription elongation inhibitor 6-azauracil (6-AU) in our system. Interestingly, POLR2I could complement 6-AU resistance if ectopically expressed. Lastly, we observe extensive structural homology between Rpb9 and POLR2I proteins. Conclusions: Our study establishes an endogenous cross-species gene complementation strategy that uncovers both conserved and rewired functions of fission yeast rpb9 and its human homolog, POLR2I. In addition to validating conserved roles, we also identified conservation of previously unrecognized roles of rpb9 in heterochromatin formation and chemoresistance.","rel_num_authors":9,"rel_authors":[{"author_name":"Jared M. Finkel","author_inst":"Michigan State University"},{"author_name":"Micah G. Williams","author_inst":"Michigan State University"},{"author_name":"Mamta B. Nirmal","author_inst":"Michigan State University"},{"author_name":"Samakshi Pandey","author_inst":"G.G.S. Indraprastha University"},{"author_name":"Erik D. Howe","author_inst":"Michigan State University"},{"author_name":"Cameron T. Liu","author_inst":"Michigan State University"},{"author_name":"Jeremy R. Lohman","author_inst":"Michigan State University"},{"author_name":"Nimisha Sharma","author_inst":"G.G.S. Indraprastha University"},{"author_name":"Tommy V. Vo","author_inst":"Michigan State University"}],"rel_date":"2026-04-04","rel_site":"biorxiv"},{"rel_title":"Hybrid crosses reveal a cell-type-specific landscape of mouse regulatory variation","rel_doi":"10.64898\/2026.04.02.716195","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.02.716195","rel_abs":"Understanding the genetic architecture of gene expression is fundamental to evolutionary biology and medicine. As part of the IGVF Consortium, we present a single-nucleus RNA-seq resource of 6.7 million nuclei across eight tissue groups, featuring seven F1 hybrids from C57BL\/6J dams crossed with the other Collaborative Cross founder strains for comparison against parental strains. We identify 25,777 genes (91% of those detected) exhibiting non-conserved regulatory behavior in at least one of 92 cell types in one or more crosses. Our results show that while cis-acting variation primarily drives divergence, trans-acting effects are substantially more cell-type specific and sensitive to tissue environment. Notably, bulk tissue analyses frequently mask these signals, particularly in smaller populations such as astrocytes. Furthermore, increasing genetic divergence primarily expands the landscape of cis-acting variation, while trans-acting effects remain stable across genetic distances within species. This atlas establishes a foundational framework for decoding the complex interplay between genetic variation and cell-type-specific regulation across the mammalian body.","rel_num_authors":18,"rel_authors":[{"author_name":"Ryan Weber","author_inst":"University of California, Irvine"},{"author_name":"Maria Carilli","author_inst":"California Institute of Technology"},{"author_name":"Elisabeth Rebboah","author_inst":"University of California, Irvine"},{"author_name":"Ghassan Filimban","author_inst":"University of California, Irvine"},{"author_name":"Heidi Yahan Liang","author_inst":"University of California, Irvine"},{"author_name":"Diane Trout","author_inst":"California Institute of Technology"},{"author_name":"Margaret Duffield","author_inst":"University of California, Irvine"},{"author_name":"Parvin Mahdipoor","author_inst":"University of California, Irvine"},{"author_name":"Erisa Taghizadeh","author_inst":"University of California, Irvine"},{"author_name":"Negar Fattahi","author_inst":"University of California, Irvine"},{"author_name":"Romina Mojaverzargar","author_inst":"University of California, Irvine"},{"author_name":"Shimako Kawauchi","author_inst":"University of California, Irvine"},{"author_name":"Brian A Williams","author_inst":"California Institute of Technology"},{"author_name":"Grant MacGregor","author_inst":"University of California, Irvine"},{"author_name":"Barbara Wold","author_inst":"Caltech"},{"author_name":"Lior Pachter","author_inst":"California Institute of Technology"},{"author_name":"Ingileif B. Hallgrimsdottir","author_inst":"California Institute of Technology"},{"author_name":"Ali Mortazavi","author_inst":"University of California, Irvine"}],"rel_date":"2026-04-04","rel_site":"biorxiv"},{"rel_title":"Contrasting effects of geographic distance, environmental distance, and intraspecific diversity on the performance of a marine invertebrate in common gardens","rel_doi":"10.64898\/2026.04.02.716183","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.02.716183","rel_abs":"Restoration and management of natural populations often assume that local genotypes are best suited for transplantation to their local environment. Prioritizing a single local genotype, however, contrasts with the framework of maximizing intraspecific diversity to increase population resilience to environmental change. Local populations may also become maladapted to a rapidly changing environment, motivating alternative frameworks that instead minimize environmental distance between source and transplantation sites. Here, we tested the predictive power of the local is best, maximize intraspecific diversity, and minimize environmental distance frameworks on the survival and growth of Eastern oyster (Crassostrea virginica) genotypes in field common gardens that differed in salinity and disease pressure. Although a genome scan revealed patterns of adaptation to disease, heat stress, and salinity among source populations, we did not find strong support for the local is best framework: geographically distant southern genotypes performed comparably to local selection lines and a local wild population. Higher genetic diversity within monocultures was associated with higher survival, yet highly diverse polycultures survived at lower rates than the best-performing monocultures, providing mixed support for the maximize intraspecific diversity framework. Temperature and salinity of the environments-of-origin of parents predicted the survival of their offspring in common gardens, but the relationship between survival and environmental distance was context-dependent, leading to mixed support for the minimize environmental distance framework. Together, these results demonstrate that no single framework reliably predicted transplantation success, suggesting that effective management strategies may need to integrate genomic and environmental lines of evidence to guide genotype selection.","rel_num_authors":9,"rel_authors":[{"author_name":"Kiran E. Bajaj","author_inst":"Department of Marine and Environmental Sciences, Northeastern University Marine Science Center"},{"author_name":"Nicole Mongillo","author_inst":"Department of Marine and Environmental Sciences, Northeastern University Marine Science Center"},{"author_name":"Madeline G. Eppley","author_inst":"Department of Marine and Environmental Sciences, Northeastern University Marine Science Center"},{"author_name":"Camille A. Rumberger","author_inst":"Department of Marine and Environmental Sciences, Northeastern University Marine Science Center"},{"author_name":"Zea Segnitz","author_inst":"Department of Marine and Environmental Sciences, Northeastern University Marine Science Center"},{"author_name":"Shelley Katsuki","author_inst":"Aquaculture Genetics & Breeding Technology Center, Virginia Institute of Marine Science"},{"author_name":"Ryan Carnegie","author_inst":"Virginia Institute of Marine Science"},{"author_name":"Jessica Small","author_inst":"Aquaculture Genetics & Breeding Technology Center, Virginia Institute of Marine Science"},{"author_name":"Katie E. Lotterhos","author_inst":"Department of Marine and Environmental Sciences, Northeastern University Marine Science Center"}],"rel_date":"2026-04-04","rel_site":"biorxiv"},{"rel_title":"Exon-Skipping Antisense Oligonucleotides for H3.3K27M-Altered Diffuse Midline Glioma Therapy","rel_doi":"10.64898\/2026.04.03.715131","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.03.715131","rel_abs":"Diffuse midline gliomas (DMGs) are a deadly class of pediatric high-grade brain cancers. Approximately 80% of pontine DMGs feature a dominant, somatic, heterozygous point mutation in the non-canonical histone H3.3-coding gene H3-3A. This dominant-negative mutation replaces lysine 27 with methionine (K27M) and prevents global K27 di- and tri-methylation of all wild-type histone H3 proteins. We aimed to target the H3.3K27M onco-histone pre-mRNA with splice-switching antisense oligonucleotides (ASOs) designed to promote skipping of H3-3A exon 2, as this constitutive exon comprises both the K27M mutation and the natural in-frame start codon of the gene. The lead ASO identified in a systematic screen specifically induced H3-3A exon 2 skipping, did not affect expression or splicing of the paralog gene H3-3B--which also encodes histone H3.3--and restored global H3K27me3 marks in patient-derived DMG cells grown as neurospheres. In a patient-derived orthotopic xenograft tumor mouse model, the lead ASO reduced proliferation and extended survival. Our results show the potential of exon-skipping ASOs targeting H3-3A exon 2 as a therapeutic option for H3.3K27M-altered DMG. More generally, they exemplify the strategy of using ASOs to induce skipping of a constitutive exon to effectively achieve gene downregulation.","rel_num_authors":4,"rel_authors":[{"author_name":"Lucia Yang","author_inst":"Stony Brook University"},{"author_name":"Qian Zhang","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"John E Wilkinson","author_inst":"University of Michigan"},{"author_name":"Adrian R Krainer","author_inst":"Cold Spring Harbor Laboratory"}],"rel_date":"2026-04-04","rel_site":"biorxiv"},{"rel_title":"Repurposing anti-phage defenses to differentially arrest the viral lifecycle reveals the regulatory logic of a parasitic satellite","rel_doi":"10.64898\/2026.04.03.716414","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.03.716414","rel_abs":"Mobile genetic elements frequently encode defense mechanisms to protect their bacterial hosts from viral attack. In Vibrio cholerae, these defensive elements include phage-inducible chromosomal island-like elements (PLEs), which are phage satellites that act as highly specialized parasites of the lytic phage ICP1. While PLE transcriptional activation upon ICP1 infection is known to be temporally regulated, the underlying regulatory logic and dependencies on the progression of the phages developmental program required for activation remain unclear. In this study, we took a novel approach to define these dependencies by introducing independent anti-phage defense systems, BREX and DarTG, as molecular roadblocks to impede the ICP1 lifecycle. We discovered that, for both ICP1 and PLE, late-stage gene expression is fundamentally uncoupled from genome replication, representing a striking departure from the standard paradigm for double-stranded DNA phages. While BREX restricts ICP1 to an immediate-early transcriptional state that stalls PLE activation, DarTG allows the phage to execute its full transcriptional cascade despite the total block in DNA replication. This permissive environment provides the necessary cues for complete PLE induction, revealing that the extent of ICP1 transcriptional progression is a key determinant of PLE transcriptional activation. Unlike other phage satellites that rely on a single cue for activation, our results demonstrate that PLE uses a progressive licensing strategy that relies on multiple cues tied to milestones in the phages developmental program. This regulatory architecture ensures robust PLE activation resilient to phage escape.","rel_num_authors":2,"rel_authors":[{"author_name":"S. Tansu Bagdatli","author_inst":"University of California, Berkeley"},{"author_name":"Kimberley Seed","author_inst":"University of California, Berkeley"}],"rel_date":"2026-04-04","rel_site":"biorxiv"},{"rel_title":"Control of cell division by an Acinetobacter baumannii protein with a novel nucleotidyl-cyclase-like fold","rel_doi":"10.64898\/2026.04.03.716176","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.03.716176","rel_abs":"The multidrug-resistant sepsis pathogen Acinetobacter baumannii has diverged from model {gamma}-proteobacteria in fundamental ways, hindering efforts to develop new lines of attack against the microbe. A major area of divergence is cell division. The pathogen lacks several widely conserved division enzymes, such as FtsEX, and instead possesses a suite of atypical gene products showing no sequence similarity to any well-characterized proteins. Key among these unusual proteins is AdvA. In previous Tn-seq studies, we identified AdvA as essential for A. baumannii division and fluoroquinolone resistance. The protein comprises an N-terminal transmembrane\/periplasmic region connected to a C-terminal unannotated cytoplasmic domain. Interestingly, most advA transposon insertions were lethal unless they occurred within the linker between these two regions. The roles of AdvA in cell division and the basis for positional transposon effects were unclear. Here, we combine mutagenesis with fluorescence localization, two-hybrid, and structural analyses to investigate how AdvA domains function in assembling and activating the A. baumannii divisome. We show that AdvA depletion profoundly disrupts divisome construction at Z-rings. This dependence is based on numerous interactions by AdvA with divisome proteins, with its N-terminal region binding multiple components and the cytoplasmic domain binding one (the early protein ZipA). In addition, we identified substitutions in FtsB and FtsW that suppress AdvA essentiality, consistent with a role in divisome protein activation as well as recruitment. Finally, we determined the structure of the AdvA cytoplasmic domain, which revealed a novel 3D-fold resembling adenylyl\/guanylyl cyclases with striking deviations. Most notably, AdvA lacks canonical catalytic and dimerization sites and contains unusual features, including a positively charged tip promoting fluoroquinolone resistance and an extra C-terminal helix essential to divisome interactions and cell division. The critical nature of the most C-terminal structure in AdvA helps explain the positional effects of transposon insertions and facilitated identification of a distant structural homolog in the pathogen Pseudomonas aeruginosa. These results illuminate a new type of control protein governing bacterial division that could be exploited for improved antimicrobial strategies targeting nosocomial infections.","rel_num_authors":12,"rel_authors":[{"author_name":"Andrew Farinha","author_inst":"Northeastern University"},{"author_name":"Mark W Soo","author_inst":"Northeastern University"},{"author_name":"George Minasov","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Nicole L Inniss","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Ludmilla Shuvalova","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Vimisha Dharamdasani","author_inst":"Northeastern University"},{"author_name":"Jessica Finkler","author_inst":"Northeastern University"},{"author_name":"Oliver Stearns","author_inst":"Northeastern University"},{"author_name":"Trisha Shenoy","author_inst":"Northeastern University"},{"author_name":"Christopher Kim","author_inst":"Northeastern University"},{"author_name":"Karla J Satchell","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Edward Geisinger","author_inst":"Northeastern University"}],"rel_date":"2026-04-04","rel_site":"biorxiv"},{"rel_title":"Simian Immunodeficiency Virus and Antiretroviral Therapy Impact Rhesus Macaque Brain Lipid Distribution","rel_doi":"10.64898\/2026.04.03.716347","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.03.716347","rel_abs":"Human immunodeficiency virus (HIV) infection promotes considerable bioenergetic, spatially heterogenous strain to the brain that is incompletely ameliorated through viral suppression afforded by antiretroviral therapy (ART). Disrupted homeostasis of brain lipids after HIV in humans or simian immunodeficiency virus (SIV) infection in rhesus macaques occurs due to elevated energetic demands, neuroinflammation, reactive oxygen species, and barrier leakiness. Brain lipids are particularly vulnerable to HIV-associated dysregulation due to their high abundance, unique composition, and specialized functional roles. Using rhesus macaques exposed to SIV and ART (tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and dolutegravir (DTG), we investigated the spatial distribution and abundance of lipids across brain regions and metabolically relevant peripheral tissues using mass spectrometry imaging. When comparing lipid abundance, individual lipids representing a multitude of species were more varied across tissues than by treatment condition. Further, we discerned either solely SIV infection or ART outweighed one another in altering phospholipids in different tissues Presence of ART had a greater influence on phospholipid homeostasis in the temporal cortex and hippocampus than in the midbrain, possibly due to differences in penetrance and turnover of ART across brain regions. Overall, these data demonstrate ART robustly increased phospholipids across brain regions while SIV infection had a varied impact depending on the brain region. These findings inform the need to further evaluate the neurologic consequences that may result in the brain due to disrupted lipid homeostasis across ART regimens.","rel_num_authors":7,"rel_authors":[{"author_name":"Cory J. White","author_inst":"Emory University School of Medicine"},{"author_name":"Kyle A. Vanderschoot","author_inst":"University of California at Davis"},{"author_name":"Dalton R. Brown","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Alyssa F. Espley","author_inst":"University of California at Davis"},{"author_name":"Elizabeth K. Neumann","author_inst":"University of California at Davis"},{"author_name":"Caitlin M. Tressler","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Dionna W. Williams","author_inst":"Emory University School of Medicine"}],"rel_date":"2026-04-04","rel_site":"biorxiv"},{"rel_title":"Microbe-mediated plant acclimation to drought may be rare in agriculture","rel_doi":"10.64898\/2026.04.02.715620","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.02.715620","rel_abs":"Microbial communities can shift under drought in ways that enhance plant performance during drought (microbe-mediated acclimation). However, it is also possible for microbial communities to shift in ways that worsen the effects of drought (mal-acclimation). It is unclear how and where microbe-mediated acclimation vs. mal-acclimation occurs, or if there are types of soils or microbial communities that are more likely to harbor microbes that enhance plant acclimation and limit mal-acclimation. We tested for microbe-mediated plant acclimation\/mal-acclimation to drought in soils from 21 maize farms in the midwestern United States, spanning a range of climate, soil types, and management practices. We first conditioned soil microbial communities to drought vs. well-watered conditions in a greenhouse and then tested for microbe-mediated acclimation by growing maize in soils inoculated with the conditioned microbial communities under drought and well-watered conditions. Drought-conditioned soils did not enhance plant performance under drought. In fact, one third of the farms exhibited mal-acclimation, especially under well-watered conditions where wet-conditioned soils reduced plant performance in well-watered contemporary conditions. Farm management practices, climate, soil texture, and microbial diversity generally did not predict when this microbe-mediated mal-acclimation occurred. Overall, these results suggest that in agricultural soils, microbes may frequently impede, rather than facilitate, plant acclimation to soil moisture levels.","rel_num_authors":7,"rel_authors":[{"author_name":"Mia M Howard","author_inst":"University of Michigan"},{"author_name":"Lana G Bolin","author_inst":"University of New Mexico"},{"author_name":"Glade D Bogar","author_inst":"University of California-Davis"},{"author_name":"Sarah E Evans","author_inst":"Michigan State University"},{"author_name":"Jay T Lennon","author_inst":"Indiana University"},{"author_name":"Sandra T Marquart-Pyatt","author_inst":"Michigan State University"},{"author_name":"Jennifer A Lau","author_inst":"Indiana University"}],"rel_date":"2026-04-04","rel_site":"biorxiv"},{"rel_title":"nELAVL phosphorylation by CDKL5 regulates inter-condensates composition and communication to promote experience-dependent maturation of the visual cortex","rel_doi":"10.64898\/2026.04.03.716270","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.03.716270","rel_abs":"Mutations in Cyclin-Dependent Kinase-Like 5 (CDKL5) cause CDKL5 deficiency disorder (CDD), an X-linked neurodevelopmental condition. Through a phosphoproteomic screen, we identified the neuron-specific nELAVL family of RNA-binding proteins as direct activity-dependent substrates of CDKL5. In support of this regulatory axis, single-nuclei transcriptomics of Cdkl5 knockout (KO) cortices revealed an enriched reduction in activity-dependent mRNAs. Mechanistically, we show that nELAVL proteins undergo phase separation to form biomolecular condensates, the size of which is gated by CDKL5 phosphorylation. Loss of CDKL5 leads to enlarged nELAVL condensates, which exhibit reduced binding affinity for the target mRNA Fos, resulting in its accelerated degradation. This disruption extends to inter-condensate communication: phosphodeficient nELAVL show diminished interaction with P-bodies, which themselves become enlarged in CDD mutant iNeurons. Functionally, the absence of nELAVL phosphorylation recapitulates the deficits in experience-dependent visual function observed in Cdkl5 KO mice. Our findings establish a critical molecular mechanism by which CDKL5-mediated phosphorylation governs mRNA metabolism by tuning the properties of nELAVL condensates and their communication with other biomolecular condensates, ultimately promoting experience-dependent maturation of the visual cortex.","rel_num_authors":34,"rel_authors":[{"author_name":"Shiyang Yuan","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Yao Zhu","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Zhongyu Zheng","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Hei Matthew Yip","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Maggie See Wing Chan","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Zhongjie Zhang","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Yue Chai","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Kyle Robert Jenks","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Katya Tsimring","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Gregg Robert Heller","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Jose Carlos Zepeda","author_inst":"Vanderbilt University"},{"author_name":"Marco Celotto","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Hung Kwok Hung","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Yangyang Duan","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Shun-Fat Lau","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Crystal Wing Yan Ho","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Hayley Wing Sum Tsang","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Amy Kit Yu Fu","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Hei Ming Lai","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Andrew John Kwok","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Ho Ko","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Chunbin Gu","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Billy Wai-Lung Ng","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Jinyue Liao","author_inst":"The University of Hong Kong"},{"author_name":"Sin Hang Fung","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Qin Cao","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Stephen Kwok-Wing Tsui","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Taeyun Ku","author_inst":"Korea Advanced Institute of Science and Technology"},{"author_name":"Liming Tan","author_inst":"Shenzhen Institutes of Advanced Technology"},{"author_name":"Andrea Colarusso","author_inst":"Scripps Research"},{"author_name":"Keren Lasker","author_inst":"Scripps Research"},{"author_name":"Yihui Wan","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Jinwei Zhu","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Jacque Pak Kan Ip","author_inst":"The Chinese University of Hong Kong"}],"rel_date":"2026-04-04","rel_site":"biorxiv"},{"rel_title":"nELAVL phosphorylation by CDKL5 regulates inter-condensates composition and communication to promote experience-dependent maturation of the visual cortex","rel_doi":"10.64898\/2026.04.03.716270","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.03.716270","rel_abs":"Mutations in Cyclin-Dependent Kinase-Like 5 (CDKL5) cause CDKL5 deficiency disorder (CDD), an X-linked neurodevelopmental condition. Through a phosphoproteomic screen, we identified the neuron-specific nELAVL family of RNA-binding proteins as direct activity-dependent substrates of CDKL5. In support of this regulatory axis, single-nuclei transcriptomics of Cdkl5 knockout (KO) cortices revealed an enriched reduction in activity-dependent mRNAs. Mechanistically, we show that nELAVL proteins undergo phase separation to form biomolecular condensates, the size of which is gated by CDKL5 phosphorylation. Loss of CDKL5 leads to enlarged nELAVL condensates, which exhibit reduced binding affinity for the target mRNA Fos, resulting in its accelerated degradation. This disruption extends to inter-condensate communication: phosphodeficient nELAVL show diminished interaction with P-bodies, which themselves become enlarged in CDD mutant iNeurons. Functionally, the absence of nELAVL phosphorylation recapitulates the deficits in experience-dependent visual function observed in Cdkl5 KO mice. Our findings establish a critical molecular mechanism by which CDKL5-mediated phosphorylation governs mRNA metabolism by tuning the properties of nELAVL condensates and their communication with other biomolecular condensates, ultimately promoting experience-dependent maturation of the visual cortex.","rel_num_authors":34,"rel_authors":[{"author_name":"Shiyang Yuan","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Yao Zhu","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Zhongyu Zheng","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Hei Matthew Yip","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Maggie See Wing Chan","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Zhongjie Zhang","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Yue Chai","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Kyle Robert Jenks","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Katya Tsimring","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Gregg Robert Heller","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Jose Carlos Zepeda","author_inst":"Vanderbilt University"},{"author_name":"Marco Celotto","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Hung Kwok Hung","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Yangyang Duan","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Shun-Fat Lau","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Crystal Wing Yan Ho","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Hayley Wing Sum Tsang","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Amy Kit Yu Fu","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Hei Ming Lai","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Andrew John Kwok","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Ho Ko","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Chunbin Gu","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Billy Wai-Lung Ng","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Jinyue Liao","author_inst":"The University of Hong Kong"},{"author_name":"Sin Hang Fung","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Qin Cao","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Stephen Kwok-Wing Tsui","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Taeyun Ku","author_inst":"Korea Advanced Institute of Science and Technology"},{"author_name":"Liming Tan","author_inst":"Shenzhen Institutes of Advanced Technology"},{"author_name":"Andrea Colarusso","author_inst":"Scripps Research"},{"author_name":"Keren Lasker","author_inst":"Scripps Research"},{"author_name":"Yihui Wan","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Jinwei Zhu","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Jacque Pak Kan Ip","author_inst":"The Chinese University of Hong Kong"}],"rel_date":"2026-04-04","rel_site":"biorxiv"},{"rel_title":"nELAVL phosphorylation by CDKL5 regulates inter-condensates composition and communication to promote experience-dependent maturation of the visual cortex","rel_doi":"10.64898\/2026.04.03.716270","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.03.716270","rel_abs":"Mutations in Cyclin-Dependent Kinase-Like 5 (CDKL5) cause CDKL5 deficiency disorder (CDD), an X-linked neurodevelopmental condition. Through a phosphoproteomic screen, we identified the neuron-specific nELAVL family of RNA-binding proteins as direct activity-dependent substrates of CDKL5. In support of this regulatory axis, single-nuclei transcriptomics of Cdkl5 knockout (KO) cortices revealed an enriched reduction in activity-dependent mRNAs. Mechanistically, we show that nELAVL proteins undergo phase separation to form biomolecular condensates, the size of which is gated by CDKL5 phosphorylation. Loss of CDKL5 leads to enlarged nELAVL condensates, which exhibit reduced binding affinity for the target mRNA Fos, resulting in its accelerated degradation. This disruption extends to inter-condensate communication: phosphodeficient nELAVL show diminished interaction with P-bodies, which themselves become enlarged in CDD mutant iNeurons. Functionally, the absence of nELAVL phosphorylation recapitulates the deficits in experience-dependent visual function observed in Cdkl5 KO mice. Our findings establish a critical molecular mechanism by which CDKL5-mediated phosphorylation governs mRNA metabolism by tuning the properties of nELAVL condensates and their communication with other biomolecular condensates, ultimately promoting experience-dependent maturation of the visual cortex.","rel_num_authors":34,"rel_authors":[{"author_name":"Shiyang Yuan","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Yao Zhu","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Zhongyu Zheng","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Hei Matthew Yip","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Maggie See Wing Chan","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Zhongjie Zhang","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Yue Chai","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Kyle Robert Jenks","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Katya Tsimring","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Gregg Robert Heller","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Jose Carlos Zepeda","author_inst":"Vanderbilt University"},{"author_name":"Marco Celotto","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Hung Kwok Hung","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Yangyang Duan","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Shun-Fat Lau","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Crystal Wing Yan Ho","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Hayley Wing Sum Tsang","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Amy Kit Yu Fu","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Hei Ming Lai","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Andrew John Kwok","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Ho Ko","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Chunbin Gu","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Billy Wai-Lung Ng","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Jinyue Liao","author_inst":"The University of Hong Kong"},{"author_name":"Sin Hang Fung","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Qin Cao","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Stephen Kwok-Wing Tsui","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Taeyun Ku","author_inst":"Korea Advanced Institute of Science and Technology"},{"author_name":"Liming Tan","author_inst":"Shenzhen Institutes of Advanced Technology"},{"author_name":"Andrea Colarusso","author_inst":"Scripps Research"},{"author_name":"Keren Lasker","author_inst":"Scripps Research"},{"author_name":"Yihui Wan","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Jinwei Zhu","author_inst":"Shanghai Jiao Tong University"},{"author_name":"Jacque Pak Kan Ip","author_inst":"The Chinese University of Hong Kong"}],"rel_date":"2026-04-04","rel_site":"biorxiv"},{"rel_title":"Nonlinear associations between body mass index and brain microstructure across adolescence in the ABCD Study","rel_doi":"10.64898\/2026.04.02.716201","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.02.716201","rel_abs":"Introduction: Body mass index (BMI) is widely used to screen for weight-related health risks during adolescence. Prior neuroimaging studies have assumed a linear relationship between BMI and brain microstructure, potentially obscuring how this association varies across the BMI distribution. Using restriction spectrum imaging (RSI) in the Adolescent Brain Cognitive Development (ABCD) Study, previous work has identified positive linear associations between BMI and weight-related metrics and the restricted normalized isotropic (RNI) signal fraction in subcortical structures, but it remains unclear whether these associations are uniform across the full BMI spectrum or driven by particular portions of the distribution. Methods: We examined the relationship between BMI percentile and voxelwise RNI in subcortical gray matter and white matter structures using data from the ABCD Study 6.1 release, which includes four imaging timepoints spanning ages 9-18 years (22,011 observations from 10,465 unique participants). Sex-stratified generalized additive mixed-effects models with smooth terms for BMI percentile, age, and pubertal development were used to model the shape of the BMI-microstructure association across the full percentile range, controlling for genetic principal components, household income, parental education, and MRI scanner\/software version. Results: The association between BMI percentile and RNI was nonlinear in the bilateral nucleus accumbens, caudate, pallidum, putamen, thalamus, and forceps minor. A modest, positive association was present across most of the BMI range, but the rate of change accelerated markedly above the 80th percentile. This pattern was consistent across structures and sexes, though the overall magnitude of the partial effect was higher for males across most structures, while females showed steeper rates of change in most structures above the 80th percentile. Voxelwise analyses revealed spatial heterogeneity within structures, with stronger effects concentrated in specific subregions including the posterior forceps minor, dorsal pallidum, anterior putamen, and posterior thalamus. Discussion: The relationship between BMI and subcortical brain microstructure during adolescence is not uniform but instead accelerates at the upper end of the BMI distribution, suggesting that prior linear estimates may reflect a blended average of a modest slope across most of the range and a steep slope above the 80th percentile. These findings extend the existing literature by capturing a wider developmental window, employing voxelwise rather than ROI-averaged analyses, identifying the forceps minor as a novel region of interest, and highlighting the advantages of nonlinear modeling in revealing dynamic associations.","rel_num_authors":12,"rel_authors":[{"author_name":"Alison Rigby","author_inst":"University of California, San Diego"},{"author_name":"Diliana Pecheva","author_inst":"J. Craig Venter Institute"},{"author_name":"Pravesh Parekh","author_inst":"J. Craig Venter Institute"},{"author_name":"Diana M. Smith","author_inst":"University of California, San Diego"},{"author_name":"Ashley Becker","author_inst":"University of California, San Diego"},{"author_name":"Janosch Linkersdoerfer","author_inst":"J. Craig Venter Institute"},{"author_name":"Richard Watts","author_inst":"University of Canterbury"},{"author_name":"Robert Loughnan","author_inst":"J. Craig Venter Institute"},{"author_name":"Donald J. Hagler","author_inst":"J. Craig Venter Institute"},{"author_name":"Carolina Makowski","author_inst":"University of California, San Diego"},{"author_name":"Terry L. Jernigan","author_inst":"University of California, San Diego"},{"author_name":"Anders M. Dale","author_inst":"J. Craig Venter Institute"}],"rel_date":"2026-04-04","rel_site":"biorxiv"},{"rel_title":"Deletion of TNFR1 in astrocytes restores memory in aged Alzheimer's disease mice","rel_doi":"10.64898\/2026.04.02.716130","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.02.716130","rel_abs":"Astrocytes participate in local inflammation and cognitive decline in Alzheimer's disease (AD). Aberrant cytokine TNF signaling via astrocyte type-1 receptor (aTNFR1) could causally link the two AD pathology aspects. To verify this hypothesis, we crossed transgenic AD mice with mice enabling astrocyte-specific conditional TNFR1 deletion (aTNFR1KO). Induction of aTNFR1KO at early AD stages, preserved memory and reduced {beta}-amyloid load and astrogliosis in the aged mice. Induction of aTNFR1KO at late AD stages, in mice already memory-impaired, surprisingly produced rapid memory rescue, without affecting {beta}-amyloid load and astrogliosis. Single nucleus-RNA-seq analysis of all hippocampal cell populations revealed that late-stage aTNFR1KO rapidly modifies gene expression mainly in neurons, primarily targeting synaptic pathways, causing combined glutamatergic downregulation and GABAergic up-regulation. Consistently, hippocampal EEGs showed a pro-inhibitory effect of aTNFR1KO, which thus restores memory by \"rebalancing\" hippocampal circuitry excitability. This pro-memory effect identifies a new mechanism and astrocyte target against cognitive decline in AD.","rel_num_authors":8,"rel_authors":[{"author_name":"Toko Kikuchi","author_inst":"Department of Fundamental Neuroscience, University of Lausanne; Lausanne, 1005, Switzerland"},{"author_name":"Ioannis Zalachoras","author_inst":"Wyss Center for Bio and Neuro engineering, Campus Biotech; Geneva, 1202, Switzerland"},{"author_name":"Julien Prados","author_inst":"Bioinformatic Support Platform, University of Geneva; Geneva, 1211, Switzerland"},{"author_name":"Alexis Assens","author_inst":"Department of Basic Neurosciences, University of Geneva; Geneva, 1211, Switzerland"},{"author_name":"Roberta de Ceglia","author_inst":"Department of Fundamental Neuroscience, University of Lausanne; Lausanne, 1005, Switzerland"},{"author_name":"Manuel Mameli","author_inst":"Department of Fundamental Neuroscience, University of Lausanne; Lausanne, 1005, Switzerland"},{"author_name":"Ludovic Telley","author_inst":"Claude Bernard University Lyon 1, Cnrs, UMR5284, Inserm, U1314, MeLiS; Lyon, 69008, France"},{"author_name":"Andrea Volterra","author_inst":"Department of Fundamental Neuroscience, University of Lausanne; Lausanne, 1005, Switzerland"}],"rel_date":"2026-04-04","rel_site":"biorxiv"},{"rel_title":"Impact of sputum quality on Xpert MTB\/RIF Ultra test results for tuberculosis: A multi-country study","rel_doi":"10.64898\/2026.04.01.26350003","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.01.26350003","rel_abs":"Rationale: Sputum-based testing using Xpert MTB\/RIF Ultra (Xpert) is the most common molecular testing method for diagnosing tuberculosis (TB). Objectives: To evaluate whether sputum quality influences Xpert positivity and diagnostic accuracy. Methods: We screened consecutive people for presumptive TB in India, the Philippines, Vietnam, Nigeria, South Africa, Uganda, and Zambia as part of the R2D2 TB Network and ADAPT studies. Participants provided 2-3 sputum samples for Xpert and culture reference testing. The quality of the first sputum sample was graded following standardized procedures by trained research staff and used for Xpert testing. We performed logistic regression to evaluate whether sputum grade was independently associated with Xpert positivity, and calculated sensitivity and specificity of Xpert against a culture-based microbiological reference standard (MRS). Measurements and Main Results: Among 1,855 participants, 798 (43%) were female, 348 (19%) were living with HIV (PLHIV), and 1795 (97%) had a cough of [&ge;]2 weeks. Overall, 313 (17%) had a positive Xpert result. Most sputum samples were salivary (83%). Xpert positivity was lowest among salivary samples (16.1%) and highest among purulent samples (31.2%). After adjusting for demographic and clinical variables, there was no significant association between any sputum grade and Xpert positivity. Xpert sensitivity (salivary: 89%, mucoid: 91%, mucopurulent: 87%, purulent: 100%) and specificity (>98%) were high across sputum grades. Conclusions: Sputum quality was not independently associated with Xpert positivity and Xpert sensitivity was high across all sputum grades. These findings support molecular testing of all sputum samples for TB diagnosis regardless of macroscopic appearance.","rel_num_authors":17,"rel_authors":[{"author_name":"Caitlin A Moe","author_inst":"Division of Pulmonary Diseases and Critical Care Medicine, University of California Irvine"},{"author_name":"Sraoshi Barua","author_inst":"Joe C. Wen School of Population & Public Health, University of California Irvine"},{"author_name":"Shrivaas Vijayan","author_inst":"University of California Davis"},{"author_name":"Alfred O Andama","author_inst":"Makerere University College of Health Sciences, Kampala, Uganda"},{"author_name":"John Bimba","author_inst":"Zankli Research Center, Bingham University, Karu, Nigeria"},{"author_name":"Devasahayam J Christopher","author_inst":"Department of Pulmonary Medicine, Christian Medical College, Vellore, India"},{"author_name":"Van Luong Dinh","author_inst":"Vietnam National Lung Hospital, Hanoi, Vietnam"},{"author_name":"Ha Phan","author_inst":"Centre for the Promotion of Advancement of Society, Hanoi, Vietnam"},{"author_name":"Grant A Theron","author_inst":"Stellenbosch University"},{"author_name":"William Worodria","author_inst":"Makerere University School of Medicine"},{"author_name":"Charles Yu","author_inst":"De La Salle Medical and Health Sciences Institute, Cavite, Philippines"},{"author_name":"Kristin Kremer","author_inst":"Division of Tuberculosis Elimination & Health Systems Innovations, KNCV Tuberculosis Foundation, the Hague, the Netherlands"},{"author_name":"Payam Nahid","author_inst":"University of California San Francisco"},{"author_name":"Seda Yerlikaya","author_inst":"Heidelberg University Medical Faculty, Heidelberg University Hospital, Department of Infectious Disease, Heidelberg, Germany"},{"author_name":"Claudia Denkinger","author_inst":"Heidelberg University Medical Faculty, Heidelberg University Hospital, Department of Infectious Disease, Heidelberg, Germany"},{"author_name":"Adithya Cattamanchi","author_inst":"Division of Pulmonary Diseases and Critical Care Medicine, University of California Irvine"},{"author_name":"Monde Muyoyeta","author_inst":"Center for Infectious Disease Research in Zambia"}],"rel_date":"2026-04-03","rel_site":"medrxiv"},{"rel_title":"Automated Detection of Macro-Reentrant Atrial Tachycardia Circuits Using LAT-Derived Graph Networks","rel_doi":"10.64898\/2026.04.01.26350012","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.01.26350012","rel_abs":"Background: Accurate identification of macro-reentrant atrial tachycardia (AT) circuits is critical for successful ablation but remains challenging with conventional mapping techniques. The aim of this study was to automatically detect macro-reentrant AT loops from high-density local activation time (LAT) maps. Methods: We developed an algorithm for automated detection of macro-reentrant AT circuits using LAT-derived directed graphs. Compared to previous graph-based approaches, the algorithm is designed to identify the fastest-conducting reentrant pathways and cluster them by rotational orientation (clockwise vs. counterclockwise) to distinguish single- from dual-loop circuits. The algorithm was applied retrospectively to 60 macro-reentrant scar-related AT cases mapped with CARTO or Ensite from two institutions. The results were compared with blinded expert electrophysiologist annotations of loop location and single- vs. dual-loop classification. Results: The 60 cases included 16 right atrial and 44 left atrial ATs from 51 patients. Expert review identified 57% single-loop and 43% dual-loop circuits. Compared with expert annotation, the algorithm correctly identified anatomical loop locations with 88% accuracy and correctly distinguished single- vs. dual-loop ATs in 93% of cases. Conclusion: Our LAT graph-based algorithm automatically identified single- and dual-loop macro-reentrant AT circuits. Localizing these pathways may provide insight into circuit mechanisms and help guide ablation.","rel_num_authors":15,"rel_authors":[{"author_name":"Marcus Talke","author_inst":"Columbia University Vagelos College of Physicians and Surgeons"},{"author_name":"Jonah Majumder","author_inst":"Columbia University Fu Foundation School of Engineering and Applied Science"},{"author_name":"Michael Lavelle","author_inst":"Columbia University Medical Center\/New York Presbyterian Hospital"},{"author_name":"Sarah Schwartz","author_inst":"Columbia University"},{"author_name":"Edward J Ciaccio","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Hirad Yarmohammadi","author_inst":"Columbia University"},{"author_name":"Geoffrey Rubin","author_inst":"Columbia University Medical Center"},{"author_name":"Jessica A Hennessey","author_inst":"Columbia University"},{"author_name":"Angelo B Biviano","author_inst":"Columbia University"},{"author_name":"Hasan Garan","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Elaine Y. Wan","author_inst":"Columbia University"},{"author_name":"Seth Goldbarg","author_inst":"New York Hospital Queens"},{"author_name":"Joon-Hyuk Kim","author_inst":"New York Presbyterian Queens, Weill Medical College"},{"author_name":"Christine P Hendon","author_inst":"Columbia University"},{"author_name":"Deepak Saluja","author_inst":"Columbia University"}],"rel_date":"2026-04-03","rel_site":"medrxiv"},{"rel_title":"HHBayes: A Flexible Bayesian Framework for Simulating and Analyzing Household Transmission Dynamics","rel_doi":"10.64898\/2026.04.01.26349903","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.01.26349903","rel_abs":"Household transmission studies are important for understanding infectious disease transmission and evaluating interventions; however, they are frequently constrained by methodological challenges, including in study design and sample size determination, and in estimating parameters of interest after collecting the data. Existing tools often lack flexibility in modeling age-specific susceptibility, infectivity patterns, and the impact of interventions such as vaccination or prophylaxis. Here, we develop HHBayes, an open-source R package that provides a unified framework for simulating and analyzing household transmission data using Bayesian methods. The package enables researchers to: (1) simulate realistic household transmission dynamics with highly customizable variables; (2) incorporate viral load data (measured in viral copies\/mL or cycle threshold values) to model time-varying infectiousness; (3) estimate age-dependent susceptibility and infectivity parameters using Hamiltonian Monte Carlo methods implemented in Stan; and (4) evaluate intervention effects through user-defined covariates that modify susceptibility or infectivity. We demonstrate the capabilities of the package through simulation studies showing accurate parameter recovery and applications to seasonal respiratory virus transmission, including the impact of vaccination and antiviral prophylaxis on household attack rates. HHBayes addresses a critical gap in infectious disease epidemiology by providing researchers with accessible tools for both prospective study design and retrospective data analysis. The flexibility of the package in handling complex household structures, time-varying infectiousness, and intervention effects makes it valuable for studying diverse pathogens.","rel_num_authors":5,"rel_authors":[{"author_name":"Ke Li","author_inst":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Yiren Hou","author_inst":"Department of Biostatistics, Yale School of Public Health, Yale University, New Haven, CT, USA"},{"author_name":"Bhramar Mukherjee","author_inst":"Department of Biostatistics, Yale School of Public Health, Yale University, New Haven, CT, USA"},{"author_name":"Virginia E. Pitzer","author_inst":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Daniel M. Weinberger","author_inst":"Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA"}],"rel_date":"2026-04-03","rel_site":"medrxiv"},{"rel_title":"Consistency of Serial CSF alpha-Synuclein Seed Amplification Assay Results in the Parkinson's Progression Marker Initiative","rel_doi":"10.64898\/2026.04.01.26349969","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.01.26349969","rel_abs":"Studies reporting alpha-synuclein seed amplification assay (aSyn-SAA) results are often cross-sectional. Here we investigated the intra-individual consistency of aSyn-SAA results over time from participants in the Parkinson's Progression Marker Initiative (PPMI). A total of 1238 participants had >1 CSF aSyn-SAA result for analysis (Parkinson's disease [PD]=633, prodromal =563, healthy control [HC]=42) which were collected over a median (min, max) of 2.0 (0.4, 11.4) years. Emphasis was placed on evaluating consistency in less common results such as aSyn-SAA- PD participants, aSyn-SAA+ HC and conversion rates from aSyn-SAA negative to positive results prodromal participants. Of aSyn-SAA+ PD participants, 96% (474\/493, 95%CI 94-98%) remained positive in subsequent samples, and 92% (116\/126, 95%CI 86-96%) of aSyn-SAA- PD participants remained negative. 99% (303\/307, 95%CI 97-99%) of aSyn-SAA+ prodromal participants remained positive, and 95% (234\/247, 95%CI 91-97%) of aSyn-SAA- prodromal participants remained negative. 89% (16\/18, 95%CI 67-97%) of aSyn-SAA+ HC participants remained positive, and 87% (20\/23, 95%CI 68-95%) of aSyn-SAA- HC participants remained negative. These results confirm a high consistency of aSyn-SAA results over time, even in less expected results.","rel_num_authors":11,"rel_authors":[{"author_name":"David Coughlin","author_inst":"University of California San Diego"},{"author_name":"Caroline Gochanour","author_inst":"University of Iowa"},{"author_name":"Jie Yin","author_inst":"University of Iowa"},{"author_name":"Luis Concha-Marambio","author_inst":"Amprion"},{"author_name":"Carly Farris","author_inst":"Amprion"},{"author_name":"Yihua Ma","author_inst":"Amprion"},{"author_name":"David-Erick Lafontant","author_inst":"University of Iowa"},{"author_name":"Edwin Jabbari","author_inst":"UCL Queen Square Institute of Neurology"},{"author_name":"Tanya Simuni","author_inst":"Northwestern University"},{"author_name":"Kenneth Marek","author_inst":"Institute for Neurodegerative Disoders"},{"author_name":"Thomas Tropea","author_inst":"Institute for Neurodegnerative Disease and University of Pennsylvania"}],"rel_date":"2026-04-03","rel_site":"medrxiv"},{"rel_title":"Consistency of Serial CSF alpha-Synuclein Seed Amplification Assay Results in the Parkinson's Progression Marker Initiative","rel_doi":"10.64898\/2026.04.01.26349969","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.01.26349969","rel_abs":"Studies reporting alpha-synuclein seed amplification assay (aSyn-SAA) results are often cross-sectional. Here we investigated the intra-individual consistency of aSyn-SAA results over time from participants in the Parkinson's Progression Marker Initiative (PPMI). A total of 1238 participants had >1 CSF aSyn-SAA result for analysis (Parkinson's disease [PD]=633, prodromal =563, healthy control [HC]=42) which were collected over a median (min, max) of 2.0 (0.4, 11.4) years. Emphasis was placed on evaluating consistency in less common results such as aSyn-SAA- PD participants, aSyn-SAA+ HC and conversion rates from aSyn-SAA negative to positive results prodromal participants. Of aSyn-SAA+ PD participants, 96% (474\/493, 95%CI 94-98%) remained positive in subsequent samples, and 92% (116\/126, 95%CI 86-96%) of aSyn-SAA- PD participants remained negative. 99% (303\/307, 95%CI 97-99%) of aSyn-SAA+ prodromal participants remained positive, and 95% (234\/247, 95%CI 91-97%) of aSyn-SAA- prodromal participants remained negative. 89% (16\/18, 95%CI 67-97%) of aSyn-SAA+ HC participants remained positive, and 87% (20\/23, 95%CI 68-95%) of aSyn-SAA- HC participants remained negative. These results confirm a high consistency of aSyn-SAA results over time, even in less expected results.","rel_num_authors":11,"rel_authors":[{"author_name":"David Coughlin","author_inst":"University of California San Diego"},{"author_name":"Caroline Gochanour","author_inst":"University of Iowa"},{"author_name":"Jie Yin","author_inst":"University of Iowa"},{"author_name":"Luis Concha-Marambio","author_inst":"Amprion"},{"author_name":"Carly Farris","author_inst":"Amprion"},{"author_name":"Yihua Ma","author_inst":"Amprion"},{"author_name":"David-Erick Lafontant","author_inst":"University of Iowa"},{"author_name":"Edwin Jabbari","author_inst":"UCL Queen Square Institute of Neurology"},{"author_name":"Tanya Simuni","author_inst":"Northwestern University"},{"author_name":"Kenneth Marek","author_inst":"Institute for Neurodegerative Disoders"},{"author_name":"Thomas Tropea","author_inst":"Institute for Neurodegnerative Disease and University of Pennsylvania"}],"rel_date":"2026-04-03","rel_site":"medrxiv"},{"rel_title":"Client and Health Care Provider Perspectives on Point-of-Care Testing for Sexually Transmitted Infections in Community Pharmacies in Uganda","rel_doi":"10.64898\/2026.04.02.26350027","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.02.26350027","rel_abs":"IntroductionThe World Health Organization (WHO) recommends testing for sexually transmitted infections (STIs), but laboratory-based and rapid or point-of-care (POC) testing are often unavailable and unaffordable, especially in low-resource settings, leading to empiric (usually antibiotic) treatment. Community pharmacies (CPs) are often the first point of contact for persons with symptoms of STIs, where pharmacists dispense treatment without diagnostic testing or prescriptions. This study evaluated clients, providers, and policymakers perspectives on POC testing for STIs in CPs for targeted treatment.\n\nMethodsWe nested a qualitative study into a study of participants seeking both STI and non-STI treatments in CPs. They were tested for HIV, syphilis, trichomonas, chlamydia, and gonorrhea using both rapid POC tests and a central reference lab. A purposive sample of 50 participants from September 2020 to June 2022 consented to participate in in-depth and key informant interviews. Data were analyzed thematically using an inductive approach.\n\nResultsClients (n=35), health care providers (n=9), and policy makers (n=6) highlighted the benefits of POC tests for HIV and STIs at CPs, including affordability, accessibility, and ensuring convenience. The impact of POC testing for STI diagnosis and treatment was promoting behavioral change, rapid results turnaround time, leading to faster treatment access compared to conventional laboratory methods, and supporting sustainable antimicrobial resistance (AMR) control. Barriers to POC testing included a lack of awareness among clients and health workers, inadequate privacy and space, long wait times, unclear self-sample collection instructions, stigma around HIV testing, and reluctance to test for STIs beyond HIV. To address these, participant recommendations included raising STI awareness, providing more explanation of test results, increasing test access, addressing stigma, provider training, and ensuring a sustainable supply chain for testing kits.\n\nConclusionsPOC testing for STIs and HIV in CP settings was found to be highly acceptable to both pharmacy clients and providers. Integrating POC testing in CPs could be beneficial for national STI management programs. If the existing barriers are addressed, POC tests could improve accessibility to STI diagnostics and facilitate better linkage to care.","rel_num_authors":8,"rel_authors":[{"author_name":"Annet  A. Onzia","author_inst":"Makerere University Infectious Diseases Institute"},{"author_name":"Adelline Twimukye","author_inst":"Makerere University Infectious Diseases Institute"},{"author_name":"Johan  H. Melendez","author_inst":"Johns Hopkins Medicine School of Medicine: The Johns Hopkins University School of Medicine"},{"author_name":"Matthew  M. Hamill","author_inst":"Johns Hopkins School of Medicine: The Johns Hopkins University School of Medicine"},{"author_name":"Peter Kyambadde","author_inst":"Republic of Uganda Ministry of Health"},{"author_name":"Agnes Kiragga","author_inst":"African Population and Health Research Center"},{"author_name":"Yukari  C. Manabe","author_inst":"Johns Hopkins School of Medicine: The Johns Hopkins University School of Medicine"},{"author_name":"Rosalind Parkes-Ratanshi","author_inst":"Queen's University Belfast"}],"rel_date":"2026-04-03","rel_site":"medrxiv"},{"rel_title":"Comparative effectiveness of preferred pharmacological treatment options for bipolar disorder among people with opioid use disorder in British Columbia and Ontario, Canada: protocol for parallel population-based target trial emulations","rel_doi":"10.64898\/2026.04.02.26350000","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.02.26350000","rel_abs":"IntroductionPeople with bipolar disorder (BD) and concurrent opioid use disorder (OUD) experience more severe clinical outcomes, including higher mortality, treatment complexity, and worse psychiatric symptoms, yet they are underserved due to a lack of tailored clinical guidelines and limited supporting research on competing treatment options. While pharmacological treatments for BD are well-established, their use varies widely across settings, and their effectiveness in individuals with co-occurring OUD is unclear. We propose parallel population-based studies to emulate randomized controlled trials to assess the comparative effectiveness of pharmacological treatment options for BD among people with OUD in British Columbia and Ontario, Canada, 2010-2023.\n\nMethods and analysisWe propose emulating a series of parallel target trials using linked population-level health administrative data for all individuals aged 18 years or older diagnosed with both BD and OUD and who initiated treatments for BD between 1 January 2010 and 31 December 2023. All analyses will be conducted in parallel in British Columbia and Ontario. We propose a series of four successive target trial emulations, comparing (i) lithium versus non-antipsychotic mood stabilizers such as divalproex, lamotrigine, and valproic acid; (ii) lithium versus 2nd generation antipsychotics with mood stabilizing properties such as risperidone, olanzapine, aripiprazole, and quetiapine; (iii) lithium versus combination treatments such as lithium and divalproex, lithium and olanzapine, lithium and aripiprazole, lithium and quetiapine, divalproex and olanzapine, and olanzapine and quetiapine; (iv) lithium and valproate (LATVAL) versus lithium and olanzapine, lithium and aripiprazole, lithium and quetiapine, divalproex and olanzapine, and olanzapine and quetiapine. Incident user and prevalent new user analyses are planned for proposed target trials (i)-(iv), pending sufficient data. Stratified analyses will be conducted for BD-I, manic and depressive phases of BD illness. We propose an initiator analysis (intention-to-treat, conditional on medication dispensation) to determine the effectiveness of the treatments and per-protocol analyses to determine the efficacy of the treatments after dealing with treatment switching and recommended dose adjustment. The outcomes will include psychiatric acute-care visits (hospitalizations and emergency department visits), BD treatment discontinuation and all-cause mortality. Subgroup and sensitivity analyses, including cohort and study timeline restrictions, eligibility criteria modifications, and outcome reclassifications, are proposed to assess the robustness of our results. Executing analyses in parallel across settings using a co-developed protocol will allow us to evaluate the replicability of findings.\n\nEthics and disseminationThe protocol, cohort creation, and analysis plan have been classified and approved as a quality improvement initiative by the Providence Health Care Research Ethics Board and the Simon Fraser University Office of Research Ethics. Results will be disseminated to local advocacy groups, clinical groups and decision-makers, national and international clinical guideline developers, presented at international conferences, and published in peer-reviewed journals.\n\nStrengths and limitations of this studyO_LIA target trial using linked health administrative data will be used to determine the comparative effectiveness of preferred pharmacological treatment options for bipolar disorder among people with opioid use disorder, as observed in clinical practice in British Columbia and Ontario.\nC_LIO_LIInverse probability weighting with investigator-specified covariates will be used to address measured confounding, while high-dimensional propensity score and instrumental variable analysis will be used to address potential unmeasured confounding.\nC_LIO_LIPotential confounding bias by severity and other threats to validity will be assessed via a range of sensitivity and subgroup analyses.\nC_LIO_LIProtocol co-development and parallel population-level analyses will address limitations in data capture in each setting and allow direct evaluation of the replicability of findings.\nC_LI","rel_num_authors":9,"rel_authors":[{"author_name":"Md. Belal Hossain","author_inst":"Centre for Advancing Health Outcomes"},{"author_name":"Ruyu Yan","author_inst":"Centre for Advancing Health Outcomes"},{"author_name":"Kristen A Morin","author_inst":"Northern Ontario School of Medicine University"},{"author_name":"Martin Rotenberg","author_inst":"University of Toronto"},{"author_name":"Angela Russolillo","author_inst":"University of British Columbia"},{"author_name":"Marco Solmi","author_inst":"University of Ottawa"},{"author_name":"Tasneem Lalva","author_inst":"Health Sciences North Research Institute"},{"author_name":"David C Marsh","author_inst":"Northern Ontario School of Medicine University"},{"author_name":"Bohdan Nosyk","author_inst":"Simon Fraser University"}],"rel_date":"2026-04-03","rel_site":"medrxiv"},{"rel_title":"Comparative effectiveness of preferred pharmacological treatment options for bipolar disorder among people with opioid use disorder in British Columbia and Ontario, Canada: protocol for parallel population-based target trial emulations","rel_doi":"10.64898\/2026.04.02.26350000","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.02.26350000","rel_abs":"IntroductionPeople with bipolar disorder (BD) and concurrent opioid use disorder (OUD) experience more severe clinical outcomes, including higher mortality, treatment complexity, and worse psychiatric symptoms, yet they are underserved due to a lack of tailored clinical guidelines and limited supporting research on competing treatment options. While pharmacological treatments for BD are well-established, their use varies widely across settings, and their effectiveness in individuals with co-occurring OUD is unclear. We propose parallel population-based studies to emulate randomized controlled trials to assess the comparative effectiveness of pharmacological treatment options for BD among people with OUD in British Columbia and Ontario, Canada, 2010-2023.\n\nMethods and analysisWe propose emulating a series of parallel target trials using linked population-level health administrative data for all individuals aged 18 years or older diagnosed with both BD and OUD and who initiated treatments for BD between 1 January 2010 and 31 December 2023. All analyses will be conducted in parallel in British Columbia and Ontario. We propose a series of four successive target trial emulations, comparing (i) lithium versus non-antipsychotic mood stabilizers such as divalproex, lamotrigine, and valproic acid; (ii) lithium versus 2nd generation antipsychotics with mood stabilizing properties such as risperidone, olanzapine, aripiprazole, and quetiapine; (iii) lithium versus combination treatments such as lithium and divalproex, lithium and olanzapine, lithium and aripiprazole, lithium and quetiapine, divalproex and olanzapine, and olanzapine and quetiapine; (iv) lithium and valproate (LATVAL) versus lithium and olanzapine, lithium and aripiprazole, lithium and quetiapine, divalproex and olanzapine, and olanzapine and quetiapine. Incident user and prevalent new user analyses are planned for proposed target trials (i)-(iv), pending sufficient data. Stratified analyses will be conducted for BD-I, manic and depressive phases of BD illness. We propose an initiator analysis (intention-to-treat, conditional on medication dispensation) to determine the effectiveness of the treatments and per-protocol analyses to determine the efficacy of the treatments after dealing with treatment switching and recommended dose adjustment. The outcomes will include psychiatric acute-care visits (hospitalizations and emergency department visits), BD treatment discontinuation and all-cause mortality. Subgroup and sensitivity analyses, including cohort and study timeline restrictions, eligibility criteria modifications, and outcome reclassifications, are proposed to assess the robustness of our results. Executing analyses in parallel across settings using a co-developed protocol will allow us to evaluate the replicability of findings.\n\nEthics and disseminationThe protocol, cohort creation, and analysis plan have been classified and approved as a quality improvement initiative by the Providence Health Care Research Ethics Board and the Simon Fraser University Office of Research Ethics. Results will be disseminated to local advocacy groups, clinical groups and decision-makers, national and international clinical guideline developers, presented at international conferences, and published in peer-reviewed journals.\n\nStrengths and limitations of this studyO_LIA target trial using linked health administrative data will be used to determine the comparative effectiveness of preferred pharmacological treatment options for bipolar disorder among people with opioid use disorder, as observed in clinical practice in British Columbia and Ontario.\nC_LIO_LIInverse probability weighting with investigator-specified covariates will be used to address measured confounding, while high-dimensional propensity score and instrumental variable analysis will be used to address potential unmeasured confounding.\nC_LIO_LIPotential confounding bias by severity and other threats to validity will be assessed via a range of sensitivity and subgroup analyses.\nC_LIO_LIProtocol co-development and parallel population-level analyses will address limitations in data capture in each setting and allow direct evaluation of the replicability of findings.\nC_LI","rel_num_authors":9,"rel_authors":[{"author_name":"Md. Belal Hossain","author_inst":"Centre for Advancing Health Outcomes"},{"author_name":"Ruyu Yan","author_inst":"Centre for Advancing Health Outcomes"},{"author_name":"Kristen A Morin","author_inst":"Northern Ontario School of Medicine University"},{"author_name":"Martin Rotenberg","author_inst":"University of Toronto"},{"author_name":"Angela Russolillo","author_inst":"University of British Columbia"},{"author_name":"Marco Solmi","author_inst":"University of Ottawa"},{"author_name":"Tasneem Lalva","author_inst":"Health Sciences North Research Institute"},{"author_name":"David C Marsh","author_inst":"Northern Ontario School of Medicine University"},{"author_name":"Bohdan Nosyk","author_inst":"Simon Fraser University"}],"rel_date":"2026-04-03","rel_site":"medrxiv"},{"rel_title":"Corpus for Benchmarking Clinical Speech De-identification","rel_doi":"10.64898\/2026.03.31.26349906","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349906","rel_abs":"ObjectivesPublicly available datasets dedicated to clinical speech deidentification tasks remain scarce due to privacy constraints and the complexity of speech-level annotation. To address this gap, we compiled the SREDH-AICup sensitive health information (SHI) speech corpus, a time-aligned clinical speech dataset annotated across 38 SHI categories.\n\nMethodsTwo publicly available English medical-domain datasets were adapted to support speech-level de-identification, including script reformulation and controlled re-recorded by 25 participants. Additional Mandarin Chinese clinical-style materials were incorporated to extend linguistic coverage. All audio data were annotated with million-level, time-aligned SHI spans using Label Studio. Inter-annotator agreement was evaluated using Cohens kappa, following iterative calibration rounds. The resulting corpus supports both automatic speech recognition (ASR) and speech-level recognition of SHIs.\n\nResultsThe final dataset comprises 20 hours of annotated audio, divided into training (10 hours, 1,539 files), validation (5 hours, 775 files), and test (5 hours, 710 files) subsets, totalling 7,830 SHI entities. The language distribution reflects the composition of the selected source materials, with 19.36 hours of English and 0.89 hours of Mandarin Chinese speech.\n\nDiscussionThe corpus exhibits a long-tail distribution consistent with clinical documentation patterns and highlights the limited availability of Chinese medical speech resources. These characteristics underscore both the realism of the dataset and structural challenges associated with multilingual speech de-identification.\n\nConclusionThe SREDH-AICup SHI speech corpus provides a clinically grounded, time-aligned speech dataset supporting automated medical speech de-identification research and facilitating future development of multilingual speech-based privacy protection systems.\n\nKey messageO_ST_ABSWhat is already known on this topicC_ST_ABS- There is a scarcity of publicly available clinical speech datasets containing time-aligned sensitive health information (SHI) annotations for de-identification research.\n\n\nWhat this study adds- The SREDH-AICup SHI speech corpus introduces a clinically grounded speech dataset with millisecond-level, time-aligned SHI annotations across 38 categories.\n- The corpus integrates structured annotation protocols and standardised data processing to support reproducible benchmarking of speech-based de-identification models.\n\n\nHow this study might affect research, practice or policy- The availability of time-aligned SHI annotations may facilitate research on real-time or streaming de-identification systems beyond conventional transcription-focused approaches.\n- The dataset may support the development of multilingual privacy-preserving technologies in clinical speech environments.","rel_num_authors":14,"rel_authors":[{"author_name":"Hong-Jie Dai","author_inst":"Intelligent System Laboratory, Department of Electrical Engineering, College of Electrical Engineering and Computer Science, National Kaohsiung University of Sc"},{"author_name":"Liang-Chun Fang","author_inst":"Intelligent System Laboratory, Department of Electrical Engineering, College of Electrical Engineering and Computer Science, National Kaohsiung University of Sc"},{"author_name":"Tatheer Hussain Mir","author_inst":"Intelligent System Laboratory, Department of Electrical Engineering, College of Electrical Engineering and Computer Science, National Kaohsiung University of Sc"},{"author_name":"Ching-Tai Chen","author_inst":"Machine Learning and Bioinformatics Lab, Department of Computer Science, University of Taipei, Taipei, Taiwan"},{"author_name":"Hui-Hsien Feng","author_inst":"Department of English, National Kaohsiung University of Science and Technology, Kaohsiung, Taiwan"},{"author_name":"Jiunn-Ru Lai","author_inst":"Wireless Networking and Mobile Computing Research Lab, Department of Electrical Engineering, College of Electrical Engineering and Computer Science, National Ka"},{"author_name":"Hsieh-Chih Hsu","author_inst":"Intelligent System Laboratory, Department of Electrical Engineering, College of Electrical Engineering and Computer Science, National Kaohsiung University of Sc"},{"author_name":"Pratham Nandy","author_inst":"CGD Health Pvt. Ltd, Mumbai, India"},{"author_name":"Omkar Panchal","author_inst":"CGD Health Pvt. Ltd. Mumbai, India"},{"author_name":"Wei-Hsiang Liao","author_inst":"Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan"},{"author_name":"You-Zhen Tien","author_inst":"Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan"},{"author_name":"Pin-Zhen Chen","author_inst":"Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan"},{"author_name":"Yun-Ru Lin","author_inst":"Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan"},{"author_name":"Jitendra Jonnagaddala","author_inst":"UNSW Sydney"}],"rel_date":"2026-04-03","rel_site":"medrxiv"},{"rel_title":"Molecular surveillance of Falciparum malaria in Rwanda: Shifts in parasite prevalence and risk factors between the 2014\/15 and 2019\/20 Rwanda Demographics and Health Surveys","rel_doi":"10.64898\/2026.04.01.26349976","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.01.26349976","rel_abs":"Rwanda is a malaria endemic country and a focal point for emerging Plasmodium falciparum artemisinin partial resistance (ART-R). While Demographic and Health Surveys (DHS) provide both national and province-level representative data, malaria testing in Rwandan DHS (RDHS) studies has been limited to a subset of adult women and children under 5 years using RDT and\/or microscopy. Recent work using ultra-sensitive quantitative real time PCR on residual dried blood spots (DBS) from the 2014-15 RDHS revealed a significantly higher P. falciparum prevalence than detected by standard DHS diagnostics. Building on this study, we analyzed 7,127 adult DBS samples collected for HIV testing in the 2019-20 RDHS to generate updated prevalence measures. We found a national P. falciparum infection prevalence of 7.7% (95%CI [6.8%, 8.7%]), with predominantly low-density infections (median parasitemia: 7.3 parasites\/uL). We assessed covariates of P. falciparum malaria infection, identifying male sex, lower household wealth, lower educational achievement, and residence at lower elevation as significant predictors. Notably, national P. falciparum prevalence decreased 53% relative to the parallel 2014-15 RDHS study, despite reports of increasing ART-R-associated mutations in Rwanda. These findings demonstrate the utility of ultra-sensitive molecular surveillance, and suggest that national malaria control efforts have substantially reduced malaria burden in Rwanda even amid rising antimalarial parasite prevalence. Subsequent studies on this data set will provide measures of minor Plasmodium species prevalence, as well as temporospatial analysis of antimalarial resistance markers in P. falciparum positive samples.","rel_num_authors":16,"rel_authors":[{"author_name":"Jenna Zuromski","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Neeva Wernsman Young","author_inst":"Brown University"},{"author_name":"Pierre Gashema","author_inst":"Repolicy Research Centre"},{"author_name":"Vincent Iradukunda","author_inst":"Institut dEnseignement Superieur Ruhengeri"},{"author_name":"Ntwari Jean Bosco","author_inst":"Institut dEnseignement Superieur Ruhengeri"},{"author_name":"Jacob M Sadler","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Claudia Gaither","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Tharcisse Munyaneza","author_inst":"National Reference Laboratory Rwanda"},{"author_name":"Sean Connelly","author_inst":"University of North Carolina Chapel Hill"},{"author_name":"Lauren E Lee","author_inst":"Brown University"},{"author_name":"Varun Goel","author_inst":"University of South Carolina"},{"author_name":"Claude Mambo Muvunyi","author_inst":"Rwanda Biomedical Center"},{"author_name":"Jean De Dieu Butera","author_inst":"National Reference Laboratory Rwanda"},{"author_name":"Jean Baptise Mazarati","author_inst":"Institut dEnseignement Superieur Ruhengeri"},{"author_name":"Jonathan J. Juliano","author_inst":"University of North Carolina School of Medicine"},{"author_name":"Jeffrey A Bailey","author_inst":"Brown University"}],"rel_date":"2026-04-03","rel_site":"medrxiv"},{"rel_title":"Estimating tau onset age from tau PET imaging in two longitudinal cohorts using sampled iterative local approximation","rel_doi":"10.64898\/2026.04.01.26349872","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.01.26349872","rel_abs":"Understanding the time course of Alzheimers disease biomarkers of amyloid and tau pathology and their temporal relation to clinical symptoms is key to identifying optimal windows for disease intervention and planning future drug trials. The goal of this work was to determine the extent to which Sampled Iterative Local Approximation (SILA), an algorithm extensively validated for amyloid PET, is capable of modeling longitudinal tau (T) PET trajectories and estimating person-level tau positivity onset ages in two commonly analyzed brain regions and two tracers from two different cohorts\n\nMethods385 participants from the Alzheimers Disease Neuroimaging Initiative (ADNI; mean (SD) age = 73.4 (7.3) years) with longitudinal flortaucipir tau PET and 288 participants from the Wisconsin Registry for Alzheimers Prevention and Wisconsin Alzheimers Disease Research Center (collectively referred to as WISC; mean (SD) age = 67.4 (6.7) years) with longitudinal MK-6240 tau PET were included in the study. Standard uptake value ratios (SUVRs) in the entorhinal cortex and a meta-temporal ROI were modeled with SILA separately, for each cohort and region. Forward and backward SUVR and T+\/- prediction were characterized with ten-fold cross-validation and in-sample validation techniques. Accuracy of estimated T+ onset ages (ETOA) was characterized in T- to T+ converters. Differences in ETOA were tested between APOE-e4 carriers and non-carriers, as well as differences in time T+ between levels of cognitive impairment.\n\nResultsSILA was able to accurately estimate retrospective change in tau SUVR in the meta-temporal region regardless of age, sex, APOE-e4 carriage, tau SUVR, and dementia (p >0.05) whereas dementia was associated with model residuals in entorhinal cortex (p [&le;]0.05; ADNI). In subsets of observed T- to T+ converters, the difference between \"observed\" and estimated meta-temporal T+ onset age [95% CI] was 0.12 [-0.27, 0.52] years for ADNI and -0.09 [0.93, 0.74] years for WISC. ETOA was significantly earlier, and odds of SILA-estimated T+ status were higher amongst APOE-e4 carriers (p <0.05) and those with dementia (p <0.05).\n\nConclusionsOur results suggest SILA can be used to accurately model longitudinal tau PET trajectories and retrospectively estimate individual T+ onset ages in the meta-temporal region. The accuracy of SILA time estimates in entorhinal cortex worsened amongst those with dementia in ADNI suggesting entorhinal cortex may only be suitable for studying the temporal progression of tau during the preclinical time frame.","rel_num_authors":10,"rel_authors":[{"author_name":"Tobey J Betthauser","author_inst":"Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"},{"author_name":"Jordan P Teague","author_inst":"University of Wisconsin-Madison, School of Medicine and Public Health"},{"author_name":"Hailey Bruzzone","author_inst":"University of Wisconsin-Madison, School of Medicine and Public Health"},{"author_name":"Margo Heston","author_inst":"University of Wisconsin-Madison, School of Medicine and Public Health"},{"author_name":"William Coath","author_inst":"University of Wisconsin-Madison, School of Medicine and Public Health"},{"author_name":"Elena Ruiz de Chavez","author_inst":"University of Wisconsin-Madison, School of Medicine and Public Health"},{"author_name":"Finnuella Carey","author_inst":"University of Wisconsin-Madison, School of Medicine and Public Health"},{"author_name":"Ruvini Navaratna","author_inst":"University of Wisconsin-Madison, School of Medicine and Public Health"},{"author_name":"Karly Cody","author_inst":"Stanford Univeristy"},{"author_name":"Rebecca E Langhough","author_inst":"University of Wisconsin-Madison, School of Medicine and Public Health"}],"rel_date":"2026-04-03","rel_site":"medrxiv"},{"rel_title":"Feature consistency in transdiagnostic connectome-based models of sustained attention and autism symptoms","rel_doi":"10.64898\/2026.04.01.26349372","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.01.26349372","rel_abs":"Sustained attention is an important neurobiological process. Difficulties with attention play a key role in neurodevelopmental disorders, such as attention-deficit\/hyperactivity disorder (ADHD) and autism. Here, we identified functional connections consistently associated with sustained attention across datasets, participant populations, and fMRI scan types. We interrogated five transdiagnostic, previously published connectome-based models predicting attention and autistic phenotypes. All models were related to sustained attention, including in samples comprising participants with autism. We found that model similarity was associated with participant characteristics, including age and clinical diagnosis, and predicted behavioral measure. As expected, models predicting attention phenotypes shared more similar features with each other than models predicting autism symptoms. Furthermore, predictive features overlapped more between datasets that included participants of similar ages (i.e., youth vs. adult) and diagnostic status (autism diagnosis vs. no diagnosis). This suggests that functional connectivity patterns predicting individual differences in behavior are phenotype-specific and may vary as a function of age and clinical diagnosis.","rel_num_authors":16,"rel_authors":[{"author_name":"Corey Horien","author_inst":"University of Pennsylvania"},{"author_name":"Francesca Mandino","author_inst":"Yale University"},{"author_name":"Anna Corriveau","author_inst":"University of Chicago"},{"author_name":"Abigail S. Greene","author_inst":"Harvard University"},{"author_name":"David O'Connor","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Xilin Shen","author_inst":"Yale University"},{"author_name":"Arielle keller","author_inst":"University of Connecticut"},{"author_name":"Erica B Baller","author_inst":"University of Pennsylvania"},{"author_name":"Marvin M. Chun","author_inst":"Yale University"},{"author_name":"Emily S. Finn","author_inst":"Dartmouth University"},{"author_name":"Katarzyna Chawarska","author_inst":"Yale University"},{"author_name":"Evelyn MR Lake","author_inst":"Yale University"},{"author_name":"Dustin Scheinost","author_inst":"Yale University;"},{"author_name":"Theodore D Satterthwaite","author_inst":"University of Pennsylvania"},{"author_name":"Monica D. Rosenberg","author_inst":"University of Chicago"},{"author_name":"R. Todd Constable","author_inst":"Yale University"}],"rel_date":"2026-04-03","rel_site":"medrxiv"},{"rel_title":"Feature consistency in transdiagnostic connectome-based models of sustained attention and autism symptoms","rel_doi":"10.64898\/2026.04.01.26349372","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.01.26349372","rel_abs":"Sustained attention is an important neurobiological process. Difficulties with attention play a key role in neurodevelopmental disorders, such as attention-deficit\/hyperactivity disorder (ADHD) and autism. Here, we identified functional connections consistently associated with sustained attention across datasets, participant populations, and fMRI scan types. We interrogated five transdiagnostic, previously published connectome-based models predicting attention and autistic phenotypes. All models were related to sustained attention, including in samples comprising participants with autism. We found that model similarity was associated with participant characteristics, including age and clinical diagnosis, and predicted behavioral measure. As expected, models predicting attention phenotypes shared more similar features with each other than models predicting autism symptoms. Furthermore, predictive features overlapped more between datasets that included participants of similar ages (i.e., youth vs. adult) and diagnostic status (autism diagnosis vs. no diagnosis). This suggests that functional connectivity patterns predicting individual differences in behavior are phenotype-specific and may vary as a function of age and clinical diagnosis.","rel_num_authors":16,"rel_authors":[{"author_name":"Corey Horien","author_inst":"University of Pennsylvania"},{"author_name":"Francesca Mandino","author_inst":"Yale University"},{"author_name":"Anna Corriveau","author_inst":"University of Chicago"},{"author_name":"Abigail S. Greene","author_inst":"Harvard University"},{"author_name":"David O'Connor","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Xilin Shen","author_inst":"Yale University"},{"author_name":"Arielle keller","author_inst":"University of Connecticut"},{"author_name":"Erica B Baller","author_inst":"University of Pennsylvania"},{"author_name":"Marvin M. Chun","author_inst":"Yale University"},{"author_name":"Emily S. Finn","author_inst":"Dartmouth University"},{"author_name":"Katarzyna Chawarska","author_inst":"Yale University"},{"author_name":"Evelyn MR Lake","author_inst":"Yale University"},{"author_name":"Dustin Scheinost","author_inst":"Yale University;"},{"author_name":"Theodore D Satterthwaite","author_inst":"University of Pennsylvania"},{"author_name":"Monica D. Rosenberg","author_inst":"University of Chicago"},{"author_name":"R. Todd Constable","author_inst":"Yale University"}],"rel_date":"2026-04-03","rel_site":"medrxiv"},{"rel_title":"The associations between recreational water contact, water quality measures, and acute gastrointestinal illness among Canadian beachgoers: a prospective cohort study","rel_doi":"10.64898\/2026.04.01.26349959","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.01.26349959","rel_abs":"BackgroundBeaches are popular summertime destinations in Canada. However, they can be affected by specific fecal pollution sources, increasing the risk of recreational water illness.\n\nObjectivesThis study was conducted to determine the risks of acute gastrointestinal illness (AGI) among Canadian beachgoers and to evaluate the influence of different fecal indicator bacteria (FIB) and other water quality measures on assessing these risks.\n\nMethodsIn a prospective cohort design, beachgoers were recruited at sites across Canada from 2023 to 2025. Sociodemographic characteristics and exposures were determined through an on-site survey, with a 7-day follow-up survey to determine risks of AGI. Bayesian mixed-effects logistic regression models were fitted to evaluate the effects of an ordinal water contact variable (no contact, minimal contact, body immersion, and swallowed water) on the incident risk of AGI, with an interaction included for water quality indicators. The levels of six FIB and water quality measures were assessed: Escherichia coli, enterococci DNA, three microbial source tracking DNA markers (human HF183\/BacR287, human mitochondria, seagull Gull4), and turbidity.\n\nResultsA total of 4085 participants were recruited, with 67.6% completing the follow-up survey. The overall incident risk of AGI was 2.6%. Both swallowing water and body immersion increased AGI risks compared to no water contact: median of 20 excess cases (95% Credible Interval [CrI]: 4, 64) and 5 excess cases (95% CrI: 1, 19) of AGI predicted per 1000 beachgoers, respectively. Escherichia coli and seagull DNA marker levels were associated with AGI among those who had water contact, particularly among those who reported swallowing water.\n\nDiscussionWhile the overall burden of AGI due to beach water contact in Canada was low, increased risks are associated with E. coli levels particularly among those who swallow water. This could be related to fecal contamination from seagulls. However, there is substantial uncertainty in the predicted effect sizes.","rel_num_authors":18,"rel_authors":[{"author_name":"Ian Young","author_inst":"Toronto Metropolitan University"},{"author_name":"Rachel Jardine","author_inst":"Toronto Metropolitan University"},{"author_name":"Binyam D Desta","author_inst":"University of Guelph"},{"author_name":"Thomas A Edge","author_inst":"McMaster University"},{"author_name":"Faizan Saleem","author_inst":"McMaster University"},{"author_name":"David L Pearl","author_inst":"University of Guelph"},{"author_name":"Shannon E Majowicz","author_inst":"University of Waterloo"},{"author_name":"Teresa Brooks","author_inst":"Health Canada"},{"author_name":"Andrea Nesbitt","author_inst":"Public Health Agency of Canada"},{"author_name":"J. Johanna Sanchez","author_inst":"Toronto Metropolitan University"},{"author_name":"Herb E Schellhorn","author_inst":"McMaster University"},{"author_name":"Sarah Elton","author_inst":"University of Toronto"},{"author_name":"Michael Schwandt","author_inst":"Vancouver Coastal Health"},{"author_name":"Dylan Lyng","author_inst":"Manitoba Environment and Climate"},{"author_name":"Brandon Krupa","author_inst":"Public Health Niagara Region"},{"author_name":"Elizabeth Montgomery","author_inst":"Halifax Regional Municipality"},{"author_name":"Mahesh Patel","author_inst":"Toronto Public Health"},{"author_name":"Jordan Tustin","author_inst":"Toronto Metropolitan University"}],"rel_date":"2026-04-03","rel_site":"medrxiv"},{"rel_title":"Safety and immunogenicity of an HIV envelope trimer immunogen that elicits CD4 binding site neutralizing antibody precursors (HVTN 300)","rel_doi":"10.64898\/2026.03.31.26349761","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349761","rel_abs":"Background: Induction of HIV envelope (Env)-specific broadly neutralizing antibodies (bnAbs) is considered a key objective for HIV-1 vaccine development. One approach is to vaccinate with HIV Env immunogens that initially target the naive B cell receptors of a bnAb type and boost with a series of HIV Env variants. We chose a priming immunogen, the CH505 transmitted\/founder Env with high affinity for the naive B cell receptor of the prototype CD4 binding site (bs) bnAb lineage, CH103, as a candidate priming immunogen to induce the initial critical step in CD4bs bnAb development. Methods: HVTN 300 is a first-in-human, open-label Phase 1 study evaluating the safety and immunogenicity of a CH505 TF chimeric (ch) Trimer adjuvanted with 3M-052-AF (a TLR7\/8 agonist) + Alum. The immunogen is a recombinant, stabilized chimeric Env trimer protein with the N-terminal sequence of CH505 TF gp120 Env transplanted into the BG505 SOSIP sequence. Participants received the adjuvanted protein administered in both deltoid muscles at months 0, 2, 4, 8, and 12. Results: Adults (n=18) aged 18 to 55 were screened at a single site in Boston, USA, and 13 were enrolled. Local and systemic reactogenicity was typically mild to moderate. One participant had severe pain\/tenderness, and five participants reported transient severe systemic symptoms at least once. Five participants chose to stop further vaccination due to reactogenicity. No vaccine-related SAEs occurred. Vaccine-specific B-cell response rates reached 100% two weeks post third and fifth vaccinations. Antibody blocking experiments with monoclonal antibodies demonstrated that most participants had antibodies directed to the CD4bs. Four out of 11 participants had serum neutralization signatures for CD4bs bnAb precursors. Conclusions: No safety concerns were identified. The adjuvanted CH505 TF chTrimer elicited serum antibodies capable of CD4bs-mediated neutralization against strains designed to detect early precursors of the CD4bs B-cell lineages. Trial Registration: NCT04915768 Disclosure: Presented in part at HIVR4P 2024, Lima, Peru, October 6-10, 2024","rel_num_authors":28,"rel_authors":[{"author_name":"Stephen Walsh","author_inst":"Brigham & Women's Hospital"},{"author_name":"William O Hahn","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Wilton B Williams","author_inst":"Duke University School of Medicine"},{"author_name":"Ollivier Hyrien","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Pei-Chun Yu","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"K. Rachael Parks","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Robert J Edwards","author_inst":"Duke University"},{"author_name":"Rob Parks","author_inst":"Duke University"},{"author_name":"Maggie Barr","author_inst":"Duke University"},{"author_name":"Laura  L. Polakowski","author_inst":"National Institute of Allergy and Infectious Diseases"},{"author_name":"India Tindale","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Megan Jones","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Claudio Yurdadon","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Randy Burnham","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Chen-Hao Yeh","author_inst":"Duke University"},{"author_name":"Jack Heptinstall","author_inst":"Duke University"},{"author_name":"Kelly Seaton","author_inst":"Duke University"},{"author_name":"Jessica Andriesen","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Zachary Sagawa","author_inst":"Access to Advanced Health Institute"},{"author_name":"Maurine D Miner","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Stephen De Rosa","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"M. Juliana McElrath","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Lawrence Corey","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Georgia  D. Tomaras","author_inst":"Duke University"},{"author_name":"David C Montefiori","author_inst":"Duke University"},{"author_name":"Barton F Haynes","author_inst":"Duke University"},{"author_name":"Kenneth  H Mayer","author_inst":"Harvard Medical School"},{"author_name":"Lindsey R Baden","author_inst":"Harvard University"}],"rel_date":"2026-04-03","rel_site":"medrxiv"},{"rel_title":"Single-cell, clonal and spatial atlases of cranial placodes illuminate their specification and evolution","rel_doi":"10.64898\/2026.04.01.715621","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.715621","rel_abs":"The vertebrate head is defined by complex sensory structures derived from cranial placodes. Placodes arise alongside the neural crest at the neural plate border, yet the mechanisms governing their identity, diversification, and evolutionary origins are unclear. We present an integrated single-cell, spatial, and clonal atlas of placode development to resolve the dynamics of their lineage segregation. Combining single-cell RNA-sequencing, spatial transcriptomics, and high-resolution clonal tracing, we show that placodal and neighboring progenitors form a continuous transcriptional landscape with gradual transitions between domains. Domain boundary cells co-express markers of adjacent territories, suggesting transient bipotent states. Consistent with this, clonal analysis reveals sharing of progenitors between neighboring placodes, supporting a model of competitive segregation. Comparisons with amphioxus suggests that vertebrate olfactory placodes emerged from an ancestral neuroectoderm that later partitioned into distinct neural and olfactory domains. Our findings provide a unified framework for understanding the developmental and evolutionary origins of vertebrate sensory organs.","rel_num_authors":23,"rel_authors":[{"author_name":"Aliia Murtazina","author_inst":"Karolinska Institutet"},{"author_name":"Yuliia Fatieieva","author_inst":"Medical University Vienna"},{"author_name":"Felix Waern","author_inst":"Karolinska Institutet"},{"author_name":"Helen R. Maunsell","author_inst":"Baylor College of Medicine"},{"author_name":"Ankita Thawani","author_inst":"Washington University School of Medicine"},{"author_name":"Bettina Semsch","author_inst":"Karolinska Institutet"},{"author_name":"Johan Bostrom","author_inst":"Medical University Vienna"},{"author_name":"Caleb C. Reagor","author_inst":"Karolinska Institutet"},{"author_name":"Polina Kameneva","author_inst":"St. Anna Children's Cancer Research Institute, Vienna, Austria"},{"author_name":"Karina Araslanova","author_inst":"Medical University Vienna"},{"author_name":"Sergey Isaev","author_inst":"Medical University Vienna"},{"author_name":"Franziska Schelb","author_inst":"German Cancer Research Center (DKFZ)"},{"author_name":"Kaj Fried","author_inst":"Karolinska Institutet"},{"author_name":"Alek G. Erickson","author_inst":"Stockholm University"},{"author_name":"Alexander Klimovich","author_inst":"Christian-Albrechts University of Kiel"},{"author_name":"Andrea Streit","author_inst":"King's College London"},{"author_name":"Lena M. Kutscher","author_inst":"German Cancer Research Center (DKFZ)"},{"author_name":"Iryna Kozmikova","author_inst":"Institute of Molecular Genetics of the Czech Academy of Sciences"},{"author_name":"Zbynek Kozmik","author_inst":"Institute of Molecular Genetics of the Czech Academy of Sciences"},{"author_name":"Emma R. Andersson","author_inst":"Karolinska Institutet"},{"author_name":"Gerhard Schlosser","author_inst":"University of Galway"},{"author_name":"Andrew K. Groves","author_inst":"Washington University School of Medicine"},{"author_name":"Igor Adameyko","author_inst":"Karolinska Institutet"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"Single-cell, clonal and spatial atlases of cranial placodes illuminate their specification and evolution","rel_doi":"10.64898\/2026.04.01.715621","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.715621","rel_abs":"The vertebrate head is defined by complex sensory structures derived from cranial placodes. Placodes arise alongside the neural crest at the neural plate border, yet the mechanisms governing their identity, diversification, and evolutionary origins are unclear. We present an integrated single-cell, spatial, and clonal atlas of placode development to resolve the dynamics of their lineage segregation. Combining single-cell RNA-sequencing, spatial transcriptomics, and high-resolution clonal tracing, we show that placodal and neighboring progenitors form a continuous transcriptional landscape with gradual transitions between domains. Domain boundary cells co-express markers of adjacent territories, suggesting transient bipotent states. Consistent with this, clonal analysis reveals sharing of progenitors between neighboring placodes, supporting a model of competitive segregation. Comparisons with amphioxus suggests that vertebrate olfactory placodes emerged from an ancestral neuroectoderm that later partitioned into distinct neural and olfactory domains. Our findings provide a unified framework for understanding the developmental and evolutionary origins of vertebrate sensory organs.","rel_num_authors":23,"rel_authors":[{"author_name":"Aliia Murtazina","author_inst":"Karolinska Institutet"},{"author_name":"Yuliia Fatieieva","author_inst":"Medical University Vienna"},{"author_name":"Felix Waern","author_inst":"Karolinska Institutet"},{"author_name":"Helen R. Maunsell","author_inst":"Baylor College of Medicine"},{"author_name":"Ankita Thawani","author_inst":"Washington University School of Medicine"},{"author_name":"Bettina Semsch","author_inst":"Karolinska Institutet"},{"author_name":"Johan Bostrom","author_inst":"Medical University Vienna"},{"author_name":"Caleb C. Reagor","author_inst":"Karolinska Institutet"},{"author_name":"Polina Kameneva","author_inst":"St. Anna Children's Cancer Research Institute, Vienna, Austria"},{"author_name":"Karina Araslanova","author_inst":"Medical University Vienna"},{"author_name":"Sergey Isaev","author_inst":"Medical University Vienna"},{"author_name":"Franziska Schelb","author_inst":"German Cancer Research Center (DKFZ)"},{"author_name":"Kaj Fried","author_inst":"Karolinska Institutet"},{"author_name":"Alek G. Erickson","author_inst":"Stockholm University"},{"author_name":"Alexander Klimovich","author_inst":"Christian-Albrechts University of Kiel"},{"author_name":"Andrea Streit","author_inst":"King's College London"},{"author_name":"Lena M. Kutscher","author_inst":"German Cancer Research Center (DKFZ)"},{"author_name":"Iryna Kozmikova","author_inst":"Institute of Molecular Genetics of the Czech Academy of Sciences"},{"author_name":"Zbynek Kozmik","author_inst":"Institute of Molecular Genetics of the Czech Academy of Sciences"},{"author_name":"Emma R. Andersson","author_inst":"Karolinska Institutet"},{"author_name":"Gerhard Schlosser","author_inst":"University of Galway"},{"author_name":"Andrew K. Groves","author_inst":"Washington University School of Medicine"},{"author_name":"Igor Adameyko","author_inst":"Karolinska Institutet"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"Single-cell ATAC-seq Reveals OVOL2 as a Downstream Negative Regulator of PRL-Mediated Chromatin Accessibility","rel_doi":"10.64898\/2026.04.01.715828","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.715828","rel_abs":"Maternal pancreatic {beta}-cells undergo functional and structural changes to adapt to increased metabolic demands during pregnancy. Lactogen signaling via the prolactin receptor (PRLR) contributes to these adaptations by increasing {beta}-cell mass, insulin transcription and glucose-stimulated insulin secretion[1-4]. In other lactogen-responsive tissues such as the mammary glands and specific hypothalamic nuclei, gestation induces epigenetic changes, some of which persist long after birth[5, 6]. We have previously found that prolactin treatment in islets regulates the expression of epigenetic modifiers[7, 8]. However, whether lactogen signaling in {beta}-cells mediates epigenetic changes to regulate chromatin accessibility has not been examined. Therefore, our objective was to determine whether PRLR signaling alters chromatin accessibility of {beta}-cells to facilitate transcriptional regulation. Using single-cell ATAC-sequencing, we identified differentially accessible regions (DARs) in {beta}-cells which had 718 overrepresented motifs following prolactin treatment of murine islets. Validating this approach, these included motifs bound by established PRLR signaling effectors such as the STAT family of transcription factors (TFs). Using RNA-sequencing we identified transcriptional changes in 41 TFs whose motifs were overrepresented in DARs, including several previously linked to PRLR signaling within {beta}-cells, including Myc, Mafb and Esr1. Importantly, we also identified TFs not previously associated with PRLR signaling, including OVOL2 an established regulator of epigenetic landscape within cells. OVOL2 is a transcription factor involved in EMT inhibition and energy homeostasis with unknown roles in pancreatic {beta}-cells. Here, we establish that OVOL2 acts as a negative regulator of lactogen-dependent effects on {beta}-cell proliferation, establishing a novel regulator of PRLR signaling.","rel_num_authors":3,"rel_authors":[{"author_name":"Nelmari D Ruiz Otero","author_inst":"Johns Hopkins University"},{"author_name":"Jin-Yong Chung","author_inst":"University of Arizona College of Medicine-Tucson"},{"author_name":"Ronadip R Banerjee","author_inst":"University of Arizona College of Medicine-Tucson"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"Identification of Human Transferrin Receptor as an Entry Co-receptor for Parvovirus B19 Infection of Human Erythroid Progenitor Cells","rel_doi":"10.64898\/2026.04.02.715920","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.02.715920","rel_abs":"Parvovirus B19 (B19V), a member of the genus Erythroparvovirus within the Parvoviridae family, infects human erythroid progenitor cells (EPCs) of bone marrow and fetal liver, and causes various hematological disorders. The minor capsid protein VP1 of B19V contains a unique N-terminal region (VP1u) that facilitates virus binding and internalization into EPCs via its receptor-binding domain (RBD). We previously identified tyrosine protein kinase receptor UFO (AXL) as a proteinaceous receptor for B19V infection of EPCs. In this study, we employed an ascorbate peroxidase 2 (APEX2)-based proximity labeling method to identify host proteins that are associated with B19V VP1u during entry. This analysis revealed human transferrin receptor 1 (hTfR) as a key host protein associated with VP1u. hTfR knockdown in UT7\/Epo-S1 cells, a B19V-permissive human megakaryoblastoid leukemia cell line, showed significantly reduced B19V internalization and replication. Biolayer interferometry (BLI) assays confirmed a direct interaction between B19V VP1u and hTfR extracellular domain (ECD). Inhibition of VP1u interaction with hTfR ECD, either by a monoclonal antibody targeting the apical domain of the ECD or human ferritin, a natural ligand of hTfR that binds the apical domain, significantly reduced VP1u binding to hTfR, as well as B19V internalization and B19V replication in ex vivo-expanded EPCs. Furthermore, mutant RBD proteins that bear amino acid substitutions in the three helical domains nearly abolished RBD binding to hTfR and significantly reduced the ability to inhibit B19V infection of EPCs. Collectively, our findings establish hTfR as a B19V entry co-receptor that mediates B19V internalization into its natural host EPCs.\n\nSignificanceB19V causes severe hematological disorders, including transient aplastic crisis, chronic pure red cell aplasia, and hydrops fetalis, by selectively infecting erythroid progenitor cells (EPCs). Despite its clinical impact, no approved antivirals or vaccines exist, largely due to limited understanding of viral entry mechanisms. A unique feature of B19V is the externalization of the VP1 unique region (VP1u) from the viral capsid, which mediates receptor engagement. Our prior studies identified AXL as an attachment receptor for B19V. Here, we identify that human transferrin receptor 1 (hTfR) acts as a critical co-receptor that directly binds VP1u and promotes viral internalization. Inhibition of the VP1u-hTfR interaction by competitive binding of hTfR with either an anti-hTfR monoclonal antibody or human ferritin significantly reduces B19V internalization and replication in ex vivo-expanded EPCs, highlighting a link between VP1u binding to the apical domain of hTfR and viral internalization. RBD mutants that disrupt its interaction with hTfR barely inhibited B19V infection in EPCs. These findings support a receptor-switch model in which AXL mediates attachment and hTfR drives internalization. Defining these mechanisms provides a foundation for developing antiviral strategies targeting B19V entry into EPCs.","rel_num_authors":9,"rel_authors":[{"author_name":"Shane McFarlin","author_inst":"University of Kansas Medical Center"},{"author_name":"Kang Ning","author_inst":"University of Kansas Medical Center"},{"author_name":"Xiujuan Zhang","author_inst":"University of Kansas Medical Center"},{"author_name":"Cagla Aksu Kuz","author_inst":"University of Kansas Medical Center"},{"author_name":"Wei Zou","author_inst":"University of Kansas Medical Center"},{"author_name":"Fang Cheng","author_inst":"University of Kansas Medical Center"},{"author_name":"Steve Kleiboeker","author_inst":"Viracor Eurofins Laboratories"},{"author_name":"Mario Mietzsch","author_inst":"University of Florida"},{"author_name":"Jianming Qiu","author_inst":"University of Kansas Medical Center"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"A Tissue Virus Microenvironment with Activated Stress Responses Underlies Durable SIV Persistence","rel_doi":"10.64898\/2026.04.02.716177","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.02.716177","rel_abs":"HIV persistence during suppressive antiretroviral therapy (ART) remains a central barrier to cure, with the majority of reservoirs residing in gut-associated lymphoid tissues (GALT). Here, we define a spatially organized viral microenvironment (VME) that sustains reservoir durability and governs early viral rebound by comparing animals initiating ART early after infection (transient reservoirs) versus late (persistent reservoirs). Using immunoPET\/CT-guided sampling of SIV-infected rhesus macaques combined with spatial transcriptomics, we interrogated tissue sites of viral production during the eclipse phase following analytical treatment interruption (ATI). Our results revealed that viral rebound from persistent reservoirs arises from discrete, transcriptionally active foci enriched in the mucosa lining the gut lumen. Eclipse phase persistent reservoirs were characterized by increased proviral burden and a distinct tissue state marked by activation of stress-response, metabolic, mitochondrial, and cell cycle programs coupled to repression of cytoplasmic translation and increased cellular senescence. These features co-occurred with immunosuppressive cellular architectures resembling tertiary lymphoid structures enriched for Treg cells, innate lymphoid cells, and mast cells, regulated by Treg-centered cell-cell interaction networks. In contrast, transient reservoirs displayed enhanced translational and metabolic activity and were embedded within immune-active environments enriched for CD8+ T cells, Th17, Tfh, and activated CD4+ T cells. Machine learning identified stress adaptation, hypoxia, metabolic rewiring, and cytoskeletal remodeling pathways as dominant predictors of viral density within persistent VMEs, with strong convergence on programs observed in tumor microenvironments (TME). Orthogonal validation confirmed activation of the integrated stress response (ISR) at sites of viral production in concurrence with results of immunofluorescent microscopy revealing SIV gag expression in two populations primarily in the mucosa, differentiated by the phosphorylation of eIF2alpha. Together, these findings establish the VME as a critical determinant of reservoir persistence, integrating immune regulation, tissue remodeling, and translational control to enable viral survival. This framework suggests that effective HIV cure strategies will require coordinated disruption of VME-supportive functions in addition to targeting infected cells.","rel_num_authors":24,"rel_authors":[{"author_name":"Thomas J. Hope","author_inst":"Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University"},{"author_name":"Eliana U. Crentsil","author_inst":"Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University"},{"author_name":"Muhammad S. Arif","author_inst":"Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University"},{"author_name":"Yanique Thomas","author_inst":"Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University"},{"author_name":"Ellen Zhang","author_inst":"Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University"},{"author_name":"Christopher T. Thuruthiyil","author_inst":"Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University"},{"author_name":"Ryan V. Moriarty","author_inst":"Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University"},{"author_name":"Flora Engelmann","author_inst":"Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University"},{"author_name":"Sean C. Pascoe","author_inst":"Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University"},{"author_name":"Jenna M. Hasson","author_inst":"Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University"},{"author_name":"Seth H. Borrowman","author_inst":"Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University"},{"author_name":"Maryam A. Shaaban","author_inst":"Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University"},{"author_name":"Edward J. Allen","author_inst":"Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University"},{"author_name":"Anne Monette","author_inst":"Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University"},{"author_name":"Ann M. Carias","author_inst":"Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University"},{"author_name":"Douglas Ferrell","author_inst":"New Iberia Research Center, University of Louisiana at Lafayette"},{"author_name":"Nawal Ouguirti","author_inst":"New Iberia Research Center, University of Louisiana at Lafayette"},{"author_name":"Isabelle Clerc","author_inst":"Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University"},{"author_name":"Judd F. Hultquist","author_inst":"Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University"},{"author_name":"Richard T. D'Aquila","author_inst":"Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University"},{"author_name":"Michael D. McRaven","author_inst":"Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University"},{"author_name":"Mariluz Arainga","author_inst":"New Iberia Research Center, University of Louisiana at Lafayette"},{"author_name":"Francois Villinger","author_inst":"New Iberia Research Center, University of Louisiana at Lafayette"},{"author_name":"Ramon Lorenzo-Redondo","author_inst":"Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"Several multiple sequence alignment perturbation methods enhance AlphaFold3 sampling of alternative protein states","rel_doi":"10.64898\/2026.04.02.716037","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.02.716037","rel_abs":"Protein function often involves multiple conformational states. Several multiple sequence alignment-perturbing strategies, including stochastic subsampling, clustering, and column masking, have been shown to enhance AlphaFold2 (AF2) sampling of alternative protein states. Here, we evaluate these strategies on AlphaFold3 (AF3) and compare their performance with the BioEmu Boltzmann sampling model on 107 proteins with multiple experimentally solved conformational states. We find that unperturbed AF3 samples alternative states with significantly higher TM-scores compared to AF2 and comparable to BioEmu. In particular, all MSA perturbation methods improve AF3 sampling at a statistically significant level, improving the top 1% TM-score by at least 0.05 in approximately 20% of cases each, while rarely worsening the performance. Furthermore, we find that different choices of amino acid masks can improve column-masked AF3 sampling for specific targets. Our results highlight how MSA perturbations remain relevant in AF3, providing a useful tool for understanding dynamic biological processes.","rel_num_authors":5,"rel_authors":[{"author_name":"Samuel Eriksson Lidbrink","author_inst":"Stockholm University"},{"author_name":"Ivan Nissen","author_inst":"KTH Royal Institute of Technology"},{"author_name":"Jonathan Kenichi Ahrlind","author_inst":"KTH Royal Institute of Technology"},{"author_name":"Rebecca J Howard","author_inst":"Stockholm University"},{"author_name":"Erik Lindahl","author_inst":"Stockholm University"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"Human TBC1 domain-containing kinase is a class I multidomain pseudokinase","rel_doi":"10.64898\/2026.04.02.716191","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.02.716191","rel_abs":"TBCK-related encephalopathy (TBCKE) is a neurodevelopmental disorder associated with biallelic mutations in TBCK. Despite the increasing number of reported cases worldwide, the biochemical and biophysical properties of TBCK remain unclear, hindering molecular understanding of its role in disease. Here, we present the successful expression, purification, and biochemical characterization of full-length human TBCK produced in Spodoptera frugiperda cells. Biochemical and biophysical analyses reveal that the catalytically inactive pseudokinase domain of TBCK lacks nucleotide binding, consistent with the absence of the canonical VAIK, HRD, and DFG motifs required for catalysis. These findings support that TBCK is a class I pseudokinase and provide a foundation for future structural and functional studies to elucidate its biological role.","rel_num_authors":4,"rel_authors":[{"author_name":"Shiwangi Maurya","author_inst":"Florida State University"},{"author_name":"Lilly E. Cheek","author_inst":"Florida State University"},{"author_name":"Anthony T. Iavarone","author_inst":"University of California, Berkeley"},{"author_name":"Wen Zhu","author_inst":"Florida State University"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"Beyond the mean: genetic control of gene expression fidelity and dispersion","rel_doi":"10.64898\/2026.04.01.715853","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.715853","rel_abs":"For decades, molecular biologists have interpreted gene regulation through measurements of mean gene expression, because they could not resolve regulatory variation among individual cells. The advent of single-cell genomics has now made that variation measurable, revealing pervasive differences in gene expression among apparently similar cells. Whether this variation mainly reflects stochastic noise or an informative regulatory property remains unclear. Here we show that mean-corrected gene expression dispersion is a reproducible and biologically structured feature of gene regulation that reflects regulatory fidelity. In heterogeneous differentiated cardiac cultures, genes with low dispersion are shared across cell types, enriched for housekeeping functions, depleted for expression quantitative trait loci, and more highly connected in transcriptional and protein interaction networks. In a comparative single-cell system spanning human, chimpanzee, and allotetraploid cells, a substantial subset of interspecies differences in regulatory dispersion persists in a shared trans environment, indicating that gene expression fidelity is often regulated in cis. Our findings establish gene expression dispersion as a genetically encoded dimension of gene regulation that is distinct from mean expression, and places dispersion along a fidelity-plasticity axis with implications for development, disease, and threshold-dependent cellular phenotypes.","rel_num_authors":5,"rel_authors":[{"author_name":"Yoav Gilad","author_inst":"University of Chicago"},{"author_name":"Brendan Jamison","author_inst":"University of Chicago"},{"author_name":"Alexander Chen","author_inst":"University of Chicago"},{"author_name":"Erik McIntire","author_inst":"University of Chicago"},{"author_name":"Xin He","author_inst":"University of Chicago"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"Gut Microbiome Alterations in Canine Idiopathic Epilepsy: A Pairwise Case-Control Study","rel_doi":"10.64898\/2026.04.02.716098","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.02.716098","rel_abs":"BackgroundIdiopathic epilepsy (IE) is the most common chronic nervous system disorder of dogs, and its cause is poorly understood. Emerging evidence suggests that microbiome alterations can occur with IE via the microbiota-gut-brain axis. Therefore, we analyzed the fecal microbiomes of 98 dogs (49 IE, 49 control) in a pairwise case-control observational study using 16S rRNA gene sequencing.\n\nResultsAlthough the microbial community was mostly similar between groups, IE was associated with a modest but significant shift in Weighted-Unifrac distance (P = 0.042). We used six differential abundance (DA) methods to identify differentially abundant amplicon sequencing variants (ASVs) between IE and control groups. Notably, one Collinsella ASV was found to be significantly more abundant in IE dogs by all six methods. The gut microbial compositions varied drastically across households (accounting for about 69% of the total variation), but did not have significant differences between sex, age, or breed. Phenobarbital administration in IE dogs had a significant effect on seizure control, and was not associated with changes in the microbiome.\n\nConclusionOur findings suggest a relationship between gut microbiomes and IE. However, the specific mechanism needs to be further investigated.","rel_num_authors":5,"rel_authors":[{"author_name":"Yixuan Yang","author_inst":"North Carolina State University"},{"author_name":"Julie Nettifee","author_inst":"North Carolina State University"},{"author_name":"M. Andrea Azcarate-Peril","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Karen Munana","author_inst":"North Carolina State University"},{"author_name":"Benjamin Callahan","author_inst":"North Carolina State University"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"Double Mutations in Plasmodium falciparum Kelch13 drive resistance to next-generation artemisinin derivatives in malaria parasites","rel_doi":"10.64898\/2026.04.02.716214","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.02.716214","rel_abs":"New antimalarial compounds are urgently required to overcome artemisinin partial resistance that has emerged in Asia and now Africa. Ozonides are promising next-generation artemisinins that offer the improved pharmacokinetic property of a prolonged in vivo half-life. To assess the potential for parasite resistance to ozonides in an artemisinin-resistant background, we subjected Cambodian Kelch13 (K13) mutant parasites to increasing artefenomel (OZ439) pressure up to in vivo physiological concentrations. Whole-genome sequencing identified a novel non-propeller K13 A212T mutation in OZ439-resistant parasites. Gene editing and drug susceptibility assays revealed that the K13 double mutation R539T+A212T is a determinant of OZ439 resistance. In extended parasite recovery assays, this resistance mechanism was associated with accelerated parasite recrudescence following OZ439 or OZ277 exposure. This phenotype was also observed in K13 C580Y+A212T double mutant parasites. Global metabolomic profiling revealed no changes in the levels of hemoglobin-derived peptides in OZ439-resistant parasites, suggesting that resistance is not associated with drug activation. Instead, double mutant parasites exhibited increased levels of metabolites linked to glutathione, nucleotide, and aspartate-glutamate metabolism, suggesting a higher capacity for redox regulation to tolerate drug-induced oxidative damage. Our findings demonstrate that ozonide resistance can emerge through a novel K13 mutation on the background of existing artemisinin-resistance k13 alleles.","rel_num_authors":12,"rel_authors":[{"author_name":"Christopher Bower-Lepts","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Kurt E Ward","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Sergio Wittlin","author_inst":"Swiss Tropical and Public Health Institute"},{"author_name":"Barbara H Stokes","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Tomas Yeo","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Tarrick Qahash","author_inst":"Pennsylvania State University"},{"author_name":"Jennifer L Small-Saunders","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Heekuk Park","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Anne-Catrin Uhlemann","author_inst":"Columbia University Medical Center"},{"author_name":"Manuel Llinas","author_inst":"Pennsylvania State University"},{"author_name":"David A Fidock","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Sachel Mok","author_inst":"Columbia University Irving Medical Center"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"Fatty acid scavenging enables cancer escape from KRAS inhibition","rel_doi":"10.64898\/2026.04.01.715565","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.715565","rel_abs":"Although inhibitors of oncogenic KRAS have shown clinical efficacy1, resistance to KRAS inhibition is common2, and its molecular basis remains unclear. Here we show that KRASi-resistant cancer cells sustain mitochondrial bioenergetics through enhanced fatty acid (FA) metabolism, despite suppression of canonical KRAS signaling. Specifically, KRASi-resistant pancreatic cancer cells exploit macropinocytosis to scavenge FA released from adipose tissue, fueling beta-oxidation independently of KRAS-PI3K signaling. This adaptive metabolic program is driven by the adhesion G protein-coupled receptor ADGRB1, which activates non-canonical PI3K{gamma}-PAK1 signaling to stimulate macropinocytosis and maintain metabolic homeostasis under KRASi. Disruption of ADGRB1-PI3K{gamma} signaling dismantles this metabolic program and restores KRASi sensitivity. This pathway operates across multiple KRAS-mutated cancers and is associated with poor therapeutic response and outcome. These findings offer a promising strategy for overcoming KRASi resistance.","rel_num_authors":12,"rel_authors":[{"author_name":"Zihang Yuan","author_inst":"Institutes of Biomedical Sciences, Fudan University, Shanghai, China;Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical Univers"},{"author_name":"Bo Lin","author_inst":"Institutes of Biomedical Sciences, Fudan University, Shanghai, China"},{"author_name":"Chunlan Wang","author_inst":"Institutes of Biomedical Sciences, Fudan University, Shanghai, China"},{"author_name":"Yingying Miao","author_inst":"Institutes of Biomedical Sciences, Fudan University, Shanghai, China"},{"author_name":"Da Zhang","author_inst":"Institutes of Biomedical Sciences, Fudan University, Shanghai, China"},{"author_name":"Ziru Meng","author_inst":"Institutes of Biomedical Sciences, Fudan University, Shanghai, China"},{"author_name":"Gangqi Wang","author_inst":"Institutes of Biomedical Sciences, Fudan University, Shanghai, China"},{"author_name":"Andrew M Lowy","author_inst":"Department of Surgery, Division of Surgical Oncology, University of California, San Diego Moores Cancer Center, La Jolla, CA, USA"},{"author_name":"Michael Karin","author_inst":"Center for Metabolic and Liver Diseases, SBP Medical Discovery Institute, La Jolla, CA, USA"},{"author_name":"Fei Yang","author_inst":"Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China; MOE Innovation Center for Basic Research in Tumor "},{"author_name":"Beicheng Sun","author_inst":"Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China; MOE Innovation Center for Basic Research in Tumor "},{"author_name":"Hua Su","author_inst":"Institutes of Biomedical Sciences, Fudan University, Shanghai, China; Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"A confined gene drive for population modification in the malaria vector Anopheles stephensi","rel_doi":"10.64898\/2026.04.01.715791","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.715791","rel_abs":"Gene drives are genetic elements that bias their own inheritance to spread desired traits in target populations, enabling population modification or suppression. Although homing-based drives can propagate efficiently, their potential for uncontrolled spread may present a challenge for field deployment. Thus, confined drive systems are needed. Here, we developed a confined modification drive, called Toxin-Antidote Recessive Embryo (TARE) drive, in the globally important malaria vector Anopheles stephensi. This drive works by cleaving and disrupting wild-type alleles in the germline or early embryo from maternally deposited Cas9. Disrupted alleles are recessive lethal, thus increasing the drive in a frequency-dependent manner. Inheritance bias was moderate in crosses between drive heterozygote mosquitoes, possibly due to low gRNA activity and thus moderate germline cleavage rates. Single-release cage trials confirmed the TARE drives ability to spread, although the drive ultimately declined due to fitness costs and resistance alleles associated with repetitive elements. Nonetheless our modelling analysis indicate that this TARE system could achieve population spread if the resistance issue is addressed. These findings demonstrate a functional prototype TARE drive in Anopheles stephensi and highlight key parameters governing its performance. Minor design optimizations could substantially improve efficiency and integrity, enabling rapid but confined population modification.","rel_num_authors":7,"rel_authors":[{"author_name":"Xuejiao Xu","author_inst":"Peking University"},{"author_name":"Yiran Liu","author_inst":"Peking University"},{"author_name":"Xihua Jia","author_inst":"Peking University"},{"author_name":"Jie Yang","author_inst":"Peking University"},{"author_name":"Yunchen Xia","author_inst":"Peking University"},{"author_name":"Jingheng Chen","author_inst":"Peking University"},{"author_name":"Jackson Champer","author_inst":"Peking University"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"Patient-derived organoid xenografts reveal the multifaceted role of the lncRNA MALAT1 in breast cancer progression","rel_doi":"10.64898\/2026.04.02.716096","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.02.716096","rel_abs":"Background: Long non-coding RNAs (lncRNAs) have emerged as key regulators of tumor biology, however, thus far none have translated to cancer therapies. The lncRNA MALAT1 is overexpressed in more than 20 cancers, including breast cancer and has been shown to function via various mechanisms in a context-dependent manner, in 2D cell lines and mouse models. However, its functional role and therapeutic potential have not been evaluated in clinically relevant patient-derived models. Methods: We investigated the therapeutic potential of a MALAT1-targeting antisense oligonucleotide (ASO) for breast cancer, using clinically relevant 3D human patient-derived organoids (PDOs) and PDO-xenograft (PDO-X) models. We systematically evaluated the efficiency of MALAT1-targeting ASOs using a biobank of 28 PDO models. Using three independent PDO-X models of triple negative breast cancer (TNBC), we targeted MALAT1 in vivo to study its impact on transcription, alternative splicing, stromal remodeling and metastasis. Results: Across PDO-X models, MALAT1 depletion reproducibly drove widespread alternative splicing changes across all event types, particularly intron retention events, accompanied by modest gene expression alterations. Differentially spliced transcripts were enriched for targets of shared cancer-associated transcription factors, and MALAT1 knockdown altered the relative abundance of previously unannotated splicing isoforms. Beyond tumor-intrinsic effects, tumor-specific MALAT1 depletion induced a consistent reduction in macrophage-associated gene signatures and reduced lung metastatic burden. Conclusions: Our data define the multifaceted role of MALAT1 in TNBC, coordinating alternative splicing, transcriptional fine-tuning, tumor-stroma crosstalk, and metastatic progression. Our study provides strong preclinical evidence supporting MALAT1-targeted ASO therapy and establishes PDO-X models as a clinically relevant platform for functional interrogation of TNBC therapies.","rel_num_authors":20,"rel_authors":[{"author_name":"Disha Aggarwal","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA and Genetics Graduate Program, Stony Brook University, Stony Brook, New York, USA"},{"author_name":"Suzanne Russo","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA"},{"author_name":"Kendall Anderson","author_inst":"Envisagenics, Long Island City, New York, USA"},{"author_name":"Taylor Floyd","author_inst":"Envisagenics, Long Island City, New York, USA"},{"author_name":"Raditya Utama","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA"},{"author_name":"James A. Rouse","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA"},{"author_name":"Payal Naik","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA"},{"author_name":"Sara Pawlak","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA"},{"author_name":"Shruti V. Iyer","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA"},{"author_name":"Melissa Kramer","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA"},{"author_name":"Shuchismita Satpathy","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA and Division of Medical Oncology\/Hematology, Northwell Health, New Hyde Park, New York, USA"},{"author_name":"John E. Wilkinson","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA"},{"author_name":"Qing Gao","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA"},{"author_name":"Sonam Bhatia","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA"},{"author_name":"Gayatri Arun","author_inst":"Envisagenics, Long Island City, New York, USA"},{"author_name":"Martin Akerman","author_inst":"Envisagenics, Long Island City, New York, USA"},{"author_name":"W. Richard McCombie","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA"},{"author_name":"Alexey Revenko","author_inst":"Ionis Pharmaceuticals, Carlsbad, California, USA"},{"author_name":"Karen Kostroff","author_inst":"Division of Surgical Oncology, Northwell Health, New Hyde Park, New York, USA"},{"author_name":"David L. Spector","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA and Genetics Graduate Program, Stony Brook University, Stony Brook, New York, USA"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"DNA damage drives a unique, Alzheimer's disease-relevant senescent state in neurons","rel_doi":"10.64898\/2026.04.02.716205","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.02.716205","rel_abs":"Alzheimer's disease (AD) shares molecular hallmarks with the canonical drivers of cellular senescence. Senescent cells have also been shown to accumulate in the brain with age, yet the mechanisms linking AD pathology to the accumulation of senescent cells in the brain remain unclear. Here, we demonstrate that DNA damage in patient-derived directly induced neurons (iNs) drives a senescent-like cell state with relevance to AD. DNA damage-induced senescent iNs show significant transcriptional concordance with human AD neurons and a weighted gene co-expression network analysis (WGCNA) uncovers candidate regulators associated with the senescent-like state in neurons. Direct comparison of iNs to the original patient fibroblasts reveals striking cell-type specific senescence signatures following DNA damage. iNs adopt a p21-associated senescent-like state characterized by a senescence-associated secretory phenotype (SASP) and predicted activation of NF-{kappa}{beta}1. In contrast, fibroblasts develop a p16-associated senescent state lacking a SASP phenotype and show a predicted repression of NF-{kappa}{beta}1. Early responses to DNA damage further reveal divergent DNA damage response (DDR), with neurons exhibiting higher accumulation of damage lesions relative to fibroblasts. Together, these findings demonstrate that DNA damage drives a unique senescent-like neuronal state that models molecular features of AD, while also revealing fundamental cell-type specific differences in senescent-like phenotypes and DDR.","rel_num_authors":21,"rel_authors":[{"author_name":"Jun-Wei B. Hughes","author_inst":"Buck Institute for Research on Aging, University of Southern California"},{"author_name":"Anja Sandholm","author_inst":"Buck Institute for Research on Aging"},{"author_name":"Duncan Croll","author_inst":"Buck Institute for Research on Aging"},{"author_name":"Fiona Senchyna","author_inst":"Buck Institute for Research on Aging"},{"author_name":"Kevin Schneider Dr.","author_inst":"Buck Institute for Research on Aging"},{"author_name":"Rachel Butterfield","author_inst":"Buck Institute for Research on Aging"},{"author_name":"Tyne L M McHugh Dr.","author_inst":"Buck Institute for Research on Aging, University of Southern California"},{"author_name":"Ian Brown","author_inst":"Buck Institute for Research on Aging"},{"author_name":"Hideto Deguchi Dr.","author_inst":"Buck Institute for Research on Aging"},{"author_name":"Tyler A. U. Hilsabeck Dr.","author_inst":"Buck Institute for Research on Aging"},{"author_name":"Sally Mak Dr.","author_inst":"Buck Institute for Research on Aging"},{"author_name":"Kenneth A. Wilson Dr.","author_inst":"Buck Institute for Research on Aging"},{"author_name":"Hayk Davtyan","author_inst":"University of California, Irvine"},{"author_name":"Mathew Blurton-Jones","author_inst":"University of California, Irvine"},{"author_name":"Joseph Herdy Dr.","author_inst":"The Salk Institute for Biological Studies"},{"author_name":"Ryo Higuchi-Sanabria Dr.","author_inst":"University of Southern California"},{"author_name":"Fred H. Gage Dr.","author_inst":"The Salk Institute for Biological Studies"},{"author_name":"David Furman Dr.","author_inst":"Buck Institute for Research on Aging"},{"author_name":"Lisa M. Ellerby Dr.","author_inst":"Buck Institute for Research on Aging, University of Southern California"},{"author_name":"Pierre-Yves Desprez Dr.","author_inst":"Buck Institute for Research on Aging, California Pacific Medical Center"},{"author_name":"Judith Campisi Dr.","author_inst":"Buck Institute for Research on Aging, University of Southern California"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"Left atrial flow and thrombosis risk from 4D CT contrast dynamics by physics-informed neural network and indicator dilution theory","rel_doi":"10.64898\/2026.03.31.715623","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715623","rel_abs":"Atrial fibrillation (AF) promotes blood stasis and thrombus formation, most often within the left atrial appendage (LAA), and can lead to stroke or transient ischemic attack (TIA). Time-resolved contrast-enhanced computed tomography (4D CT) captures left atrial (LA) opacification and washout, but it does not directly provide quantitative stasis metrics such as blood residence time. Patient-specific computational fluid dynamics (CFD) can quantify LA\/LAA residence time, yet routine clinical use is limited by computational cost and sensitivity to patient-specific boundary conditions. Here, we present two complementary approaches to infer time-resolved 3D residence time fields directly from contrast dynamics. First, a physics-informed neural network (PINN) treats contrast as a passive scalar and jointly reconstructs velocity and residence time by enforcing the incompressible Navier--Stokes equations and transport equations for contrast concentration and residence time in moving, patient-specific LA anatomies. Second, an indicator dilution theory (IDT) formulation computes voxelwise, time-resolved residence time maps from contrast time curves alone by constructing a PV-referenced impulse response and modeling transport with a tank-in-series model with spatially dependent parameters. Both methods are benchmarked against patient-specific CFD in six cases spanning diverse LA function, including three patients with TIA or thrombus in the LAA and three patients free of events. Both approaches reproduce expected spatial and temporal trends, with higher residence time in the distal LAA and higher LAA residence time in cases with TIA or thrombus. IDT demonstrates the closest agreement with CFD across the full range of residence times and produces maps in seconds, facilitating clinical translation. In contrast, the PINN additionally recovers phase-dependent atrial flow structures, but tends to smooth and underestimate the highest residence-time regions and requires hours of training. Together, these results support a scalable workflow in which IDT enables rapid stasis screening from contrast CT, and PINNs provide a complementary pathway for detailed, patient-specific hemodynamic inference when full-field flow information is needed.","rel_num_authors":12,"rel_authors":[{"author_name":"Bahetihazi Maidu","author_inst":"Dept. of Mechanical Engineering, University of Washington, Seattle, WA, USA"},{"author_name":"Alejandro Gonzalo","author_inst":"Dept. of Mechanical Engineering, University of Washington, Seattle, WA, USA"},{"author_name":"Manuel Guerrero-Hurtado","author_inst":"Dept. of Cardiology, Hospital General Universitario Gregorio Mara\u00f1\u00f3n, Facultad de Medicina, Universidad Complutense de Madrid, Instituto de Investigaci\u00f3n Sanita"},{"author_name":"Clarissa Bargellini","author_inst":"Dept. of Mechanical Engineering, University of Washington, Seattle, WA, USA"},{"author_name":"Pablo Martinez-Legazpi","author_inst":"Dept. of Mathematical Physics and Fluids. Universidad Nacional de Educaci\u00f3n a Distancia & CIBERCV, Madrid, Spain"},{"author_name":"Javier Bermejo","author_inst":"Dept. of Cardiology, Hospital General Universitario Gregorio Mara\u00f1\u00f3n, Facultad de Medicina, Universidad Complutense de Madrid, Instituto de Investigaci\u00f3n Sanita"},{"author_name":"Francisco Contijoch","author_inst":"Dept. of Bioengineering & Dept. of Radiology, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Oscar Flores","author_inst":"Dept. of Aerospace Engineering, Universidad Carlos III de Madrid, Leganes, Spain"},{"author_name":"Manuel Garcia-Villalba","author_inst":"Institute of Fluid Mechanics and Heat Transfer, TU Wien, Vienna, Austria"},{"author_name":"Elliot McVeigh","author_inst":"Division of Cardiovascular Medicine, Dept. of Bioengineering, Dept. of Radiology, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Andrew Kahn","author_inst":"Division of Cardiovascular Medicine, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Juan C. del Alamo","author_inst":"Dept. of Mechanical Engineering, University of Washington, Seattle, WA, USA"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"CRISPR\/Cas9-mutagenesis reveals that varying dependence on HSF1 is associated with differences in coral heat tolerance","rel_doi":"10.64898\/2026.04.01.714264","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.714264","rel_abs":"Coral reefs face declines due to increasing water temperatures associated with climate change. Major research efforts have focused on determining the mechanisms corals can use to adapt to heat stress and identifying molecular indicators for this adaptation. CRISPR\/Cas9-based genomic editing promises a new avenue to study gene function in corals; however, these methods are limited by the annual spawning of corals in the wild. Here, we shifted spawning of the reef-building coral Galaxea fascicularis to access gametes multiple times a year in the lab. We discovered the remarkable plasticity and programmability in coral spawning, which enabled the development of a genetically tractable model coral. To investigate the molecular responses of corals to heat stress, we profiled transcriptional changes in heat-tolerant G. fascicularis and heat-sensitive Acropora millepora during acute heat stress. Comparison of the transcriptional responses to heat stress in larvae of the two species revealed that A. millepora has a stronger magnitude of the early heat stress response than G. fascicularis. This increased response in A. millepora included the upregulation of the conserved transcriptional regulator of heat stress response, Heat Shock Transcription Factor 1 (HSF1), and its predicted targets. CRISPR\/Cas9 mutagenesis of HSF1 in both species showed that the heat-tolerant G. fascicularis is less dependent on HSF1 than A. millepora for survival during acute heat stress. These results suggest that differences in HSF1 expression after heat exposure contribute to variation in coral heat tolerance and may be used as biomarkers to predict heat tolerance in wild corals.","rel_num_authors":14,"rel_authors":[{"author_name":"Natalie Swinhoe","author_inst":"Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA"},{"author_name":"Amanda Tinoco","author_inst":"Department of Embryology, Carnegie Science, Baltimore, MD 21218, USA"},{"author_name":"Dania Nanes Sarfati","author_inst":"Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA"},{"author_name":"Catherine F Henderson","author_inst":"Department of Embryology, Carnegie Science, Baltimore, MD 21218, USA"},{"author_name":"Griffin P Kowalewski","author_inst":"Department of Embryology, Carnegie Science, Baltimore, MD 21218, USA"},{"author_name":"Emily K Meier","author_inst":"Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA"},{"author_name":"John M Urban","author_inst":"Department of Embryology, Carnegie Science, Baltimore, MD 21218, USA"},{"author_name":"Shumpei Maruyama","author_inst":"Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA"},{"author_name":"Evan C Lawrence","author_inst":"Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA"},{"author_name":"Ryan E Hulett","author_inst":"Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA"},{"author_name":"Ty R Engelke","author_inst":"Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA"},{"author_name":"Jamie Craggs","author_inst":"Horniman Museum and Gardens, Forest Hill, London SE23 3PQ, UK"},{"author_name":"Line K Bay","author_inst":"Australian Institute of Marine Science, Townsville, QLD 4810, Australia"},{"author_name":"Phillip A Cleves","author_inst":"Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"Epilepsy-associated potassium channel KCNT1 is required for multiciliated cell development in Xenopus","rel_doi":"10.64898\/2026.03.31.710877","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.710877","rel_abs":"Pathogenic variants in the gene KCNT1, which encodes a sodium-activated potassium channel, cause a severe neurodevelopmental disorder with intractable epilepsy. In addition to seizures, affected individuals commonly present with severe respiratory issues and structural heart defects not commonly observed in other genetic pediatric epilepsies, suggesting additional developmental functions for KCNT1 in organs beyond the brain. Here we characterized the spectrum of clinical diagnoses present in a cohort of 46 individuals with pathogenic variants in KCNT1, ranging from 0 to 19 years of age, by medical record review. We documented the prevalence of diagnoses across organ systems, including dependence on assisted breathing, congenital structural heart defects, urinary dysfunction, and spine deformities, among others. Next, we explored the embryonic expression and function of KCNT1 in diploid frogs (Xenopus tropicalis) and observed expression in developing ciliated tissues such as the brain, heart, kidney, and epidermis. Embryonic perturbation of KCNT1 disrupted developmental signaling pathways and caused ciliogenesis defects in the mucociliary epidermis, a common model for the human airway. Loss of KCNT1 disrupted development of multiciliated cells, reminiscent of recent work on the ion channel Piezo1. Consistently, pharmacological inhibition of Piezo signaling enhanced the ciliogenesis phenotype observed following KCNT1 inhibition, while activation of Piezo1 activity partially rescued ciliogenesis in the context of KCNT1 inhibition. Together, this work establishes that KCNT1 has embryonic functions in Xenopus beyond regulating neuronal activity, specifically in multiciliated cell development, and identifies an interaction with pharmacologically-tractable Piezo channels that may be productive for therapeutic efforts.","rel_num_authors":5,"rel_authors":[{"author_name":"Angeline K Chemel","author_inst":"University of California, San Francisco"},{"author_name":"Kate E McCluskey","author_inst":"University of California, San Francisco"},{"author_name":"Matthew N Tran","author_inst":"University of California, San Francisco"},{"author_name":"Aliza T Ehrlich","author_inst":"University of California, San Francisco"},{"author_name":"Helen Rankin Willsey","author_inst":"University of California, San Francisco"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"Unpredictable intermittent access exacerbates loss of control over ethanol drinking","rel_doi":"10.64898\/2026.03.31.715677","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715677","rel_abs":"Background: Loss of control over drinking is a hallmark feature of alcohol use disorder (AUD) that is modeled preclinically through escalation of ethanol consumption and aversion-resistant drinking. Prior work with other reinforcers suggests that within-session unpredictable, intermittent access (uIntA) promotes loss of control over intake. However, the effect of uIntA on voluntary ethanol consumption is unknown. Methods: Male and female Long-Evans rats (n=9-10\/group) underwent seven weeks of daily voluntary ethanol (20% v\/v) drinking sessions under either a continuous access (ContA) or uIntA schedule. Following four weeks of baseline, rats were rendered dependent using a two-week chronic intermittent ethanol vapor exposure procedure. Daily testing was maintained through one week into withdrawal from vapor exposure. On the final day of testing, ethanol was adulterated with quinine (30 mg\/L) to assess aversion-resistant drinking. Results: Rats drinking under ContA and uIntA exhibited similar levels of average daily ethanol consumption at baseline. However, uIntA elicited a more robust dependence-induced escalation of ethanol consumption compared to ContA, with uIntA sustaining escalation through early protracted withdrawal. Additionally, while rats with ContA to ethanol remained sensitive to quinine even after chronic ethanol vapor exposure, uIntA promoted aversion-resistant drinking in ethanol dependent rats. Conclusions: These results demonstrate that, compared to ContA, uIntA maintains ethanol drinking and exacerbates AUD-related symptomatology while also providing researchers with the ability to capture additional measures of motivation and drinking patterns without increasing experimental burden. This work positions uIntA as a powerful tool to assess psychological and neurobiological factors underlying loss of control over drinking.","rel_num_authors":5,"rel_authors":[{"author_name":"Eric H Mitten","author_inst":"University of Illinois Chicago"},{"author_name":"Jada M Caldwell","author_inst":"University of Illinois Chicago"},{"author_name":"Gerardo Zambrano","author_inst":"University of Illinois Chicago"},{"author_name":"Nathaly M Arce Soto","author_inst":"University of Illinois Chicago"},{"author_name":"Elizabeth J Glover","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"Short-term synaptic plasticity at neuron-OPC synapses in the corpus callosum during postnatal development of mice: experimental and computational study","rel_doi":"10.64898\/2026.03.31.715637","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715637","rel_abs":"Glutamatergic neuronal synapses in the mouse neocortex mature during the first two months after birth. A key event during synaptic maturation is a change in short-term synaptic plasticity (STP), i.e. a switch from strong synaptic depression to a weaker depression or even facilitation. Glutamatergic pyramidal neurons located in the cortical layers II\/III, layer V, and layer VI project axons through the corpus callosum where they release glutamate along their shafts and form glutamatergic synapses with oligodendrocyte precursor cells (OPCs). Here, we used single-cell electrophysiological recordings in brain slices to investigate synaptic plasticity at neuron-OPC synapses along axonal shafts in the white matter, and applied computation approaches to pinpoint the mechanisms of this plasticity. We found that during postnatal development of mice, there is a switch from short-term synaptic depression to short-term synaptic facilitation at glutamatergic neuron-OPC synapses in the corpus callosum. Synaptic delay of phasic neuron-OPC excitatory postsynaptic current shortens, and the amount of asynchronous release at neuron-OPC synapses decrease as animals mature, indicating that glutamate release becomes more synchronized. Our computational modelling suggests that both pre- and postsynaptic changes may contribute to the functional development and changes of plasticity at neuron-OPC synapses in the white matter. Taking together, our findings indicate that synaptic release machineries located at different sites along the same axon (i.e. axonal shaft in the white matter vs synaptic boutons in the grey matter) mature in a very similar fashion, STP occurs at both synaptic sites, and STP dynamics represent an important event during brain maturation.","rel_num_authors":7,"rel_authors":[{"author_name":"Bartosz Kula","author_inst":"Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA"},{"author_name":"Ting-Jiun Chen","author_inst":"Icahn School of Medicine, Mount Sinai Hospital, New York City, NY, USA"},{"author_name":"Balint Nagy","author_inst":"Toxi-Coop Toxicological Research Center Ltd, Budapest, Hungary"},{"author_name":"Anahit Hovhannisyan","author_inst":"College of Science and Mathematics, Fresno State University, Fresno, CA, USA"},{"author_name":"David Terman","author_inst":"Department of Mathematics, The Ohio State University, Columbus, Ohio, USA"},{"author_name":"Wenjing Sun","author_inst":"Department of Neuroscience, Wexner Medical Center, Ohio State University, Columbus, OH, USA"},{"author_name":"Maria Kukley","author_inst":"Achucarro Basque Centre for Neuroscience, Leioa, Spain"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"Molecular dynamics of Brodmann Area 22 in development and autism","rel_doi":"10.64898\/2026.03.31.715694","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715694","rel_abs":"Challenges in verbal communication are a prominent feature of autism. However, gene regulatory programs in speech-related cortical regions remain poorly characterized. In parallel, it remains unclear whether the heterogeneous genetic factors underlying autism converge on shared neurobiological mechanisms. To address these gaps, we generated paired transcriptomic and epigenomic data from post-mortem human brain tissue across 100 donors. Here, we show that transcriptional differences in the speech-related Brodmann Area 22 in individuals with neurodevelopmental conditions, including autism, are strongest among those with a known genetic diagnosis. A similar but attenuated signature is observed in those without a genetic diagnosis. These transcriptional differences are most pronounced in neurons, with glutamatergic L4\/5 intratelencephalic neurons affected across multiple modalities. Finally, multimodal analysis implicates altered RFX3-dependent networks as a central hub in autism, particularly among L4\/5 intratelencephalic neurons in non-verbal individuals. Together, our study identifies regulatory architecture linking chromatin state, transcriptional output, and variation in verbal ability in autism.","rel_num_authors":19,"rel_authors":[{"author_name":"Varun Suresh","author_inst":"UCSF"},{"author_name":"Emilie M Wigdor","author_inst":"University of Oxford"},{"author_name":"Yuhan Hao","author_inst":"UCSF"},{"author_name":"Rachel Leonard","author_inst":"UCSF"},{"author_name":"Joseph Asfouri","author_inst":"UCSF"},{"author_name":"Micheal Griffiths","author_inst":"University of Oxford"},{"author_name":"Clements Evans","author_inst":"UCSF"},{"author_name":"Guohua Yuan","author_inst":"UCSF"},{"author_name":"Narjes Rohani","author_inst":"Uniersity of Oxford"},{"author_name":"Jakob Weiss","author_inst":"University of Oxford"},{"author_name":"Chimmi Dema","author_inst":"University of Oxford"},{"author_name":"Tanzila Mukhthar","author_inst":"UCSF"},{"author_name":"Frederik Lassen","author_inst":"University of Oxford"},{"author_name":"Nicole Schafer","author_inst":"University of Oxford"},{"author_name":"Shan Dong","author_inst":"UCSF"},{"author_name":"Duncan S Palmer","author_inst":"University of Oxford."},{"author_name":"Edward F Chang","author_inst":"University of California, San Francisco"},{"author_name":"Stephan J Sanders","author_inst":"University of Oxford"},{"author_name":"Tomasz J. Nowakowski","author_inst":"UCSF"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"Top-down regulation of ingestive behavior fragmentation","rel_doi":"10.64898\/2026.03.31.715709","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715709","rel_abs":"In natural environments, animals rarely feed continuously to satiation; instead, feeding occurs in brief bouts separated by pauses. This fragmentation is thought to balance internal drives with external demands, yet its underlying neural mechanisms remain unclear. By combining bidirectional neural activity mapping and behavioral phenotyping, we identify a projection from the dorsal subiculum (dSub) of the hippocampus to the mammillary body (MB) as a key regulator of this fragmentation. Activity along the dSub-MB pathway tracks and gates the duration of individual feeding bouts, independent of homeostatic state. A simple bistable attractor model captures both dSub-MB neural dynamics and associated behaviors across optogenetic and behavioral perturbations. Together, these findings identify a top-down circuit mechanism that implements action selection in a naturalistic setting.","rel_num_authors":15,"rel_authors":[{"author_name":"Tianbo Qi","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA Howard Hughes Medical Institute; Chevy Chase, MD, USA"},{"author_name":"Colton Krull","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA Howard Hughes Medical Institute; Chevy Chase, MD, USA"},{"author_name":"Verina H Leung","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA Howard Hughes Medical Institute; Chevy Chase, MD, USA"},{"author_name":"Vlad Mardare","author_inst":"Institute for Systems Physiology, Faculty of Medicine and University Hospital Cologne, University of Cologne; Cologne, Germany Cluster of Excellence Cellular St"},{"author_name":"Dong Yang","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA"},{"author_name":"Neeraj Lal","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA"},{"author_name":"Jingrui Ma","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA Howard Hughes Medical Institute; Chevy Chase, MD, USA"},{"author_name":"Shiqi Wang","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA Howard Hughes Medical Institute; Chevy Chase, MD, USA"},{"author_name":"Hanbing Shen","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA Howard Hughes Medical Institute; Chevy Chase, MD, USA"},{"author_name":"Alan Zhang","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA Howard Hughes Medical Institute; Chevy Chase, MD, USA"},{"author_name":"Bohan Zhao","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA Howard Hughes Medical Institute; Chevy Chase, MD, USA"},{"author_name":"Saba Heydari Seradj","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA Howard Hughes Medical Institute; Chevy Chase, MD, USA"},{"author_name":"Tatiana Korotkova","author_inst":"Institute for Systems Physiology, Faculty of Medicine and University Hospital Cologne, University of Cologne; Cologne, Germany Cluster of Excellence Cellular St"},{"author_name":"Ann Kennedy","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA"},{"author_name":"Li Ye","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA Howard Hughes Medical Institute; Chevy Chase, MD, USA"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"Top-down regulation of ingestive behavior fragmentation","rel_doi":"10.64898\/2026.03.31.715709","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715709","rel_abs":"In natural environments, animals rarely feed continuously to satiation; instead, feeding occurs in brief bouts separated by pauses. This fragmentation is thought to balance internal drives with external demands, yet its underlying neural mechanisms remain unclear. By combining bidirectional neural activity mapping and behavioral phenotyping, we identify a projection from the dorsal subiculum (dSub) of the hippocampus to the mammillary body (MB) as a key regulator of this fragmentation. Activity along the dSub-MB pathway tracks and gates the duration of individual feeding bouts, independent of homeostatic state. A simple bistable attractor model captures both dSub-MB neural dynamics and associated behaviors across optogenetic and behavioral perturbations. Together, these findings identify a top-down circuit mechanism that implements action selection in a naturalistic setting.","rel_num_authors":15,"rel_authors":[{"author_name":"Tianbo Qi","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA Howard Hughes Medical Institute; Chevy Chase, MD, USA"},{"author_name":"Colton Krull","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA Howard Hughes Medical Institute; Chevy Chase, MD, USA"},{"author_name":"Verina H Leung","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA Howard Hughes Medical Institute; Chevy Chase, MD, USA"},{"author_name":"Vlad Mardare","author_inst":"Institute for Systems Physiology, Faculty of Medicine and University Hospital Cologne, University of Cologne; Cologne, Germany Cluster of Excellence Cellular St"},{"author_name":"Dong Yang","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA"},{"author_name":"Neeraj Lal","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA"},{"author_name":"Jingrui Ma","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA Howard Hughes Medical Institute; Chevy Chase, MD, USA"},{"author_name":"Shiqi Wang","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA Howard Hughes Medical Institute; Chevy Chase, MD, USA"},{"author_name":"Hanbing Shen","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA Howard Hughes Medical Institute; Chevy Chase, MD, USA"},{"author_name":"Alan Zhang","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA Howard Hughes Medical Institute; Chevy Chase, MD, USA"},{"author_name":"Bohan Zhao","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA Howard Hughes Medical Institute; Chevy Chase, MD, USA"},{"author_name":"Saba Heydari Seradj","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA Howard Hughes Medical Institute; Chevy Chase, MD, USA"},{"author_name":"Tatiana Korotkova","author_inst":"Institute for Systems Physiology, Faculty of Medicine and University Hospital Cologne, University of Cologne; Cologne, Germany Cluster of Excellence Cellular St"},{"author_name":"Ann Kennedy","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA"},{"author_name":"Li Ye","author_inst":"Department of Neuroscience, Dorris Neuroscience Center, Scripps Research; San Diego, CA, USA Howard Hughes Medical Institute; Chevy Chase, MD, USA"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"Rectifying AI-generated protein structure ensembles for equilibrium using physics-based computations","rel_doi":"10.64898\/2026.03.24.714034","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.24.714034","rel_abs":"Recently, a number of tools have been released that generate ensembles of protein structures based on artificial intelligence (AI) approaches. Although ensembles generated by the tools differ significantly, we demonstrate a computational path to harmonizing the various outputs under a stationary condition using two complementary physics-based approaches. In the first stage, the AI ensemble is used to seed a weighted ensemble (WE) simulation, promoting relaxation toward the steady state. In the second stage, trajectory segments generated by WE are reweighted to steady state using the recently developed RiteWeight (RW) algorithm. We applied this approach to generate an atomically- detailed equilibrium ensemble of unliganded adenylate kinase conformations, starting from ensembles produced by three AI tools: AFSample2, ESMFlow-PDB (trained from PDB structures), and ESMFlow-MD (trained from molecular dynamics simulation data). Dramatic differences in the AI-generated ensembles are largely erased during the WE-RW process, yielding a consistent description of the equilibrium ensemble for a given force field.","rel_num_authors":4,"rel_authors":[{"author_name":"Lisa Otten","author_inst":"Oregon Health and Science University"},{"author_name":"Jeremy M. G. Leung","author_inst":"University of Pittsburgh"},{"author_name":"Lillian Chong","author_inst":"University of Pittsburgh"},{"author_name":"Daniel M Zuckerman","author_inst":"Oregon Health & Science University"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"PARP16 is a Druggable Regulator of Ribosome MARylation and Protein Homeostasis in Ovarian Cancer Cells","rel_doi":"10.64898\/2026.04.01.715986","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.715986","rel_abs":"Cytosolic NAD synthesis supports ovarian cancer growth by enabling PARP16-dependent mono(ADP-ribosyl)ation (MARylation) of ribosomal proteins, thereby fine-tuning translation and maintaining protein homeostasis. While genetic depletion of PARP16 disrupts ribosome MARylation and impairs tumor cell growth, the therapeutic potential of pharmacologic PARP16 inhibition in this pathway remains unexplored. Here, we characterized the effects of DB008, a tool compound that functions as a selective inhibitor of PARP16, in ovarian cancer cells. Biochemical analyses demonstrated that PARP16 undergoes NAD-dependent auto-MARylation and that NMNAT-2 supplies NAD to support this activity. DB008 potently inhibited PARP16 auto-MARylation in vitro. In ovarian cancer cells, DB008 engaged PARP16, reduced its MARylation, and decreased ribosome-associated MARylation. Consistent with PARP16 depletion, DB008 enhanced global protein synthesis, increased protein aggregation, and suppressed cell growth and anchorage-independent colony formation. CRISPR-mediated deletion of the PARP16 gene in ovarian cancer cells abolished the effects of DB008 on translation, protein aggregation, and proliferation, demonstrating on-target activity. Moreover, cells expressing a PARP16 mutant resistant to DB008 were unaffected by inhibitor treatment, further confirming that the cellular effects of DB008 require on-target inhibition. Finally, DB008 significantly inhibited tumor growth in OVCAR3 xenografts, with on-target engagement of PARP16 in the xenograft tumors. Collectively, these findings establish PARP16 as a druggable regulator of ribosome MARylation and protein homeostasis in ovarian cancer and provide pharmacologic proof-of-concept that disrupting ribosomal MARylation impairs tumor growth.","rel_num_authors":7,"rel_authors":[{"author_name":"Sridevi Challa","author_inst":"University of Chicago"},{"author_name":"Morgan Morgan Dasovich","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Jonathan C Abshier","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Komal Pekhale","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Lu Yang","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Cristel V. Camacho","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"W. Lee Kraus","author_inst":"University of Texas Southwestern Medical Center"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"Disentangling shape and size in a population of unusually large Threespine Stickleback (Gasterosteus aculeatus) from Vancouver Island, British Columbia","rel_doi":"10.64898\/2026.04.01.715936","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.715936","rel_abs":"Sarita Lake, British Columbia houses a distinctive population of threespine stickleback (Gastrosteus aculeatus L.) with a phenotype characterized by unusually large individuals relative to nearby conspecifics. We tested the hypothesis that members of this population are not isometrically larger but rather exhibit variation in allometric trajectories that reflect changes in developmental timing impacting the developmental-genetic architecture of the phenotype. We used 3D geometric morphometrics to characterize the size and shape of skulls, pectoral girdles and pelvic girdles from a sample of individuals from nearby freshwater and marine populations and compare them to a sample from Sarita Lake. We showed that individuals from the Sarita Lake population are larger in each body region compared to most other populations examined. Further, these individuals have dorsally expanded skulls and relatively robust pelvic armour. We also showed that the relationship between size and shape is differently structured among body regions and is heavily influenced by non-uniform sexually-mediated variation across populations sampled. Our results reflect complex underlying developmental trajectories, and we suggest that the 'large' phenotype observed may be driven by fecundity selection on female size in combination with a limnetic trophic niche and relatively increased predation pressure in Sarita Lake.","rel_num_authors":3,"rel_authors":[{"author_name":"Sara Perry","author_inst":"University of Guelph"},{"author_name":"Kevin K Duclos","author_inst":"Vanier College"},{"author_name":"Heather Jamniczky","author_inst":"University of Calgary"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"Disentangling shape and size in a population of unusually large Threespine Stickleback (Gasterosteus aculeatus) from Vancouver Island, British Columbia","rel_doi":"10.64898\/2026.04.01.715936","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.715936","rel_abs":"Sarita Lake, British Columbia houses a distinctive population of threespine stickleback (Gastrosteus aculeatus L.) with a phenotype characterized by unusually large individuals relative to nearby conspecifics. We tested the hypothesis that members of this population are not isometrically larger but rather exhibit variation in allometric trajectories that reflect changes in developmental timing impacting the developmental-genetic architecture of the phenotype. We used 3D geometric morphometrics to characterize the size and shape of skulls, pectoral girdles and pelvic girdles from a sample of individuals from nearby freshwater and marine populations and compare them to a sample from Sarita Lake. We showed that individuals from the Sarita Lake population are larger in each body region compared to most other populations examined. Further, these individuals have dorsally expanded skulls and relatively robust pelvic armour. We also showed that the relationship between size and shape is differently structured among body regions and is heavily influenced by non-uniform sexually-mediated variation across populations sampled. Our results reflect complex underlying developmental trajectories, and we suggest that the 'large' phenotype observed may be driven by fecundity selection on female size in combination with a limnetic trophic niche and relatively increased predation pressure in Sarita Lake.","rel_num_authors":3,"rel_authors":[{"author_name":"Sara Perry","author_inst":"University of Guelph"},{"author_name":"Kevin K Duclos","author_inst":"Vanier College"},{"author_name":"Heather Jamniczky","author_inst":"University of Calgary"}],"rel_date":"2026-04-03","rel_site":"biorxiv"},{"rel_title":"When Care Depends on the Caregiver: Lived Experiences of Latino Families Navigating Dementia Care Pathways","rel_doi":"10.64898\/2026.03.29.26349413","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.29.26349413","rel_abs":"IntroductionLatino families shoulder a disproportionate share of dementia care in the United States, yet encounter multilayered barriers that shape access, timeliness, and quality. This study explores the experiences of Latino care partners, focusing on how system-level, cultural, and linguistic factors shape dementia care.\n\nMethodsWe conducted a qualitative study using semi-structured interviews with care partners of Latino individuals living with Alzheimers disease and related dementias (ADRD). Interviews were conducted by phone or videoconference by a bilingual interviewer, and the interviews were recorded and transcribed verbatim. Data was analyzed using reflexive thematic analysis.\n\nResultsTwenty-three participants were recruited. Two meta-themes captured participants experiences. (1) Mismatch Between the Healthcare System and the Lived Realities of Latino Families Affected by Dementia, which included three subthemes: a) Linguistic barriers that referred to the quality and dialect fit (over-literal jargon, unfamiliar regional vocabulary, poor adaptation to literacy); b) Cultural misfit, were dementia-care programs were not culturally or linguistically appropriate, or programs where cultural norms were disregarded; and c) Structural and systemic barriers, such as communication failures (e.g. voicemail loops, no responsiveness) and long waits\/fragmented pathways that broke clinical momentum (e.g. months to a year for specialty appointment). The second theme was: The Central Role of the Latino Caregiver in Navigating Dementia Care, where, in the absence of pathway ownership, care partners served as navigators, interpreters, coordinators, and safety monitors, while also bearing the emotional and financial strain.\n\nDiscussionThe narratives from care partners reveal specific mechanisms (e.g., caregiver hyper-advocacy and \"maze-like\" coordination failures) that, if addressed, can guide intervention design and policy aimed at redistributing coordination back to the system and improving outcomes for Latino families.","rel_num_authors":6,"rel_authors":[{"author_name":"Maria C Mora Pinzon","author_inst":"University of Wisconsin - Madison"},{"author_name":"Rosie Pasqualini","author_inst":"University of Kansas Medical Center"},{"author_name":"Veronica Navarro","author_inst":"University of Kansas Medical Center"},{"author_name":"Maria del Carmen Rosales","author_inst":"United Community Center"},{"author_name":"Olivia Franzese","author_inst":"University of Wisconsin, Madison"},{"author_name":"Jaime Perales-Puchalt","author_inst":"University of Kansas Medical Center"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Methods of adjustment for public health and social measures in post-licensure vaccine studies in children in sub-Saharan Africa: a systematic review","rel_doi":"10.64898\/2026.04.01.26349767","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.01.26349767","rel_abs":"BackgroundPost-licensure vaccine effectiveness and impact studies provide evidence on how vaccines perform under routine programme conditions in the real world. In sub-Saharan Africa (SSA), vaccine introductions frequently coincide with concurrent public health and social measures that may influence disease risk and transmission. Failure to account for these concurrent interventions may affect the interpretation of vaccine effects.\n\nMethodsWe conducted a systematic review of post-licensure vaccine effectiveness and impact studies conducted in children under five years of age in SSA. Electronic databases were searched for peer-reviewed studies published between January 2000 and December 2019. Eligible studies used observational designs to estimate vaccine effectiveness or population-level impact. Two reviewers independently screened studies, extracted data, and assessed methodological quality using Joanna Briggs Institute tools. We examined study designs, vaccines evaluated, outcomes assessed, and whether public health and social measures (PHSMs) were measured or adjusted for. A narrative synthesis was undertaken. In addition, we conducted a meta-analysis for rotavirus and pneumococcal conjugate vaccines where we explored the heterogeneity in individual-level effectiveness estimates where designs and outcomes were comparable.\n\nResultsSixty-four studies met the inclusion criteria, covering eight vaccine-preventable diseases. Rotavirus vaccines were most frequently evaluated, followed by pneumococcal conjugate vaccines. Case-control and ecological designs were most common, while cohort and time-series analyses were less frequently used. None of the included studies collected, reported, or adjusted for PHSMs such as nutrition, WASH, or access to healthcare. The implications of this omission varied by pathogen. Rotavirus vaccine effectiveness estimates from comparable individual-level designs were consistent across settings, with no evidence of between-study heterogeneity. Pneumococcal vaccine effectiveness estimates showed substantial heterogeneity, which appeared to reflect differences in outcome definitions, host risk profiles, and study context. Estimates for other vaccines were generally protective in direction, although the magnitude and precision varied across studies.\n\nConclusionsPost-licensure vaccine effectiveness and impact studies in SSA rarely account for concurrent PHSMs. The consequences of this omission are not uniform across vaccines. For some pathogens, effectiveness estimates appear robust to unmeasured contextual change, while for others they are highly sensitive to outcome choice and setting. Future evaluations should prioritise systematic measurement of key PHSMs and consider study designs that better account for time-varying context. Strengthening routine data systems to capture these factors is essential for generating interpretable evidence to inform immunisation policy.\n\nFundingMRC Discovery Medicine North (DiMeN) Doctoral Training Partnership (UKRI), National Institute for Health and Care Research (NIHR) Global Health Research Group on Gastrointestinal Infections and Wellcome through the core grant to the Malawi-Liverpool-Wellcome Research Programme.","rel_num_authors":6,"rel_authors":[{"author_name":"Latif Ndeketa","author_inst":"University of Liverpool, Institute of Infection Veterinary and Ecological Sciences"},{"author_name":"Natasha Marcella Vaselli","author_inst":"University of Liverpool, Institute of Infection Veterinary and Ecological Sciences"},{"author_name":"Virginia E. Pitzer","author_inst":"Yale School of Public Health, Department of Epidemiology of Microbial Diseases and Public Health Modeling Unit"},{"author_name":"Peter J. Dodd","author_inst":"University of Sheffield, Sheffield Centre for Health and Related Research"},{"author_name":"Daniel Hungerford","author_inst":"University of Liverpool, Institute of Infection Veterinary and Ecological Sciences"},{"author_name":"Neil French","author_inst":"University of Liverpool, Institute of Infection Veterinary and Ecological Sciences"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"High risk of hypoxemic COVID-19 pneumonia in myasthenia gravis patients with type I IFN autoantibodies","rel_doi":"10.64898\/2026.03.27.26349525","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.27.26349525","rel_abs":"Patients with myasthenia gravis (MG) may produce autoantibodies neutralizing type I interferons (AAN-I-IFN), which have been shown to underlie severe viral diseases, including critical COVID-19 pneumonia, in patients without MG. We studied an international cohort of 85 unvaccinated SARS-CoV-2-infected MG patients with no antiviral treatment. Hypoxemic pneumonia occurred in 48 of these patients, including 22 (45.8%) with AAN-I-IFN, which neutralized both IFN-2 and IFN-{omega} in 14 (29.2%) patients. Six (16.2%) of the remaining 37 patients had AAN-I-IFN, which neutralized both IFN-2 and IFN-{omega} in three patients. The risk of hypoxemic pneumonia was greater in MG patients with AAN-I-IFN neutralizing 10 ng\/mL of both IFN-2 and IFN-{omega} (odds ratio and 95% confidence interval (OR [95% CI]): 12.7 [2.1-78.9], p=0. 0010) or IFN-2 at any dose (4.7 [1.5-15.0], p=0.0054) than in those without such autoantibodies. The risk of AAN-I-IFN production was much higher in MG patients than in the general population (28.9 [10.8-77.7], p=4.9x10-27). Fourteen patients had thymoma, which increased the risk of AAN-I-IFN (64% versus 27%, (OR [95% CI]: 5.6 [1.6-19.4], p=0.0050) and hypoxemic pneumonia (9.2 [1.9-44.2]; p=0.0019). Thymoma is, thus, associated with a higher risk of producing AAN-I-IFN, and these autoantibodies are associated with a higher risk of developing life-threatening COVID-19 pneumonia in patients with MG.\n\nSignificance StatementPatients with myasthenia gravis (MG) have a higher risk of developing life-threatening COVID-19 pneumonia. In an international cohort of unvaccinated, untreated SARS-CoV-2-infected MG patients, we found that autoantibodies neutralizing type I interferons (AAN-I-IFN) were strongly associated with severe hypoxemic pneumonia. Thymoma further increased the risk of both AAN-I-IFN production and severe disease. These findings suggest a crucial immunological mechanism that could guide risk stratification and targeted interventions for MG patients during viral infections, such as COVID-19.","rel_num_authors":69,"rel_authors":[{"author_name":"Adrian Gervais","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Astrid Marchal","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Alexis Maillard","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Tom Le Voyer","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Jeremie Rosain","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Quentin Philipot","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Lucy Bizien","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Jessica Peel","author_inst":"The Rockefeller University"},{"author_name":"Axel Cederholm","author_inst":"Uppsala Universitet"},{"author_name":"Melanie Migaud","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Sylvie Pons","author_inst":"Joint Research Unit Civil Hospices of Lyon-bioMerieux, Hospices Civils de Lyon, Lyon Sud Hospital"},{"author_name":"Kahina Saker","author_inst":"University of Lyon"},{"author_name":"Pascal Laforet","author_inst":"Raymond-Poincare Teaching Hospital, AP-HP"},{"author_name":"Melodie Aubart","author_inst":"Necker Hospital for Sick Children, AP-HP"},{"author_name":"Cyril Gitiaux","author_inst":"Necker Hospital for Sick Children, AP-HP"},{"author_name":"Catherine Biggs","author_inst":"The University of British Columbia"},{"author_name":"Rafael Leon Lopez","author_inst":"Hospital Universitario Reina Sofia, Universidad de Cordoba"},{"author_name":"Sarah Souvannanorath","author_inst":"AP-HP Groupe hospitalier Henri Mondor"},{"author_name":"Celine Tard","author_inst":"CHU Lille"},{"author_name":"Aleksandra Nadaj Pakleza","author_inst":"University Hospitals of Strasbourg"},{"author_name":"Aude-Marie Grapperon","author_inst":"Aix-Marseille University"},{"author_name":"Nicholas Heming","author_inst":"University Paris Saclay"},{"author_name":"Djillali Annane","author_inst":"University Paris Saclay"},{"author_name":"Annie Verschueren","author_inst":"Aix-Marseille University"},{"author_name":"Shahram Attarian","author_inst":"Aix-Marseille University"},{"author_name":"Kevin Bigaut","author_inst":"University Hospitals of Strasbourg"},{"author_name":"Karolina Hankiewicz","author_inst":"CH St-Denis"},{"author_name":"Ludivine Kouton","author_inst":"Aix-Marseille University"},{"author_name":"Rocio-Nur Villar-Quiles","author_inst":"Sorbonne Universite Centre de Recherche en Myologie"},{"author_name":"Cecile Cauquil","author_inst":"Paris Saclay University"},{"author_name":"Marie-Celine Fleury","author_inst":"University Hospitals of Strasbourg"},{"author_name":"Emilie Rocher","author_inst":"University Hospitals of Strasbourg"},{"author_name":"Guillaume Nicolas","author_inst":"Raymond-Poincare Teaching Hospital, AP-HP"},{"author_name":"Eduardo de Paula Estephan","author_inst":"Faculdade de Medicina da Universidade de Sao Paulo"},{"author_name":"Maria da Penha Ananias Morita","author_inst":"Faculdade de Medicina de Sao Jose do Rio Preto"},{"author_name":"Edmar Zanoteli","author_inst":"Federal University of Sao Paulo"},{"author_name":"Zakaria Saied","author_inst":"National Institute Mongi Ben Hamida of Neurology - Faculty of Medicine Tunis El Manar University"},{"author_name":"Amine Rachdi","author_inst":"National Institute Mongi Ben Hamida of Neurology - Faculty of Medicine Tunis El Manar University"},{"author_name":"Amouri Rim","author_inst":"National Institute Mongi Ben Hamida of Neurology - Faculty of Medicine Tunis El Manar University"},{"author_name":"Samir Belal","author_inst":"National Institute Mongi Ben Hamida of Neurology - Faculty of Medicine Tunis El Manar University"},{"author_name":"Samia Ben Sassi","author_inst":"National Institute Mongi Ben Hamida of Neurology - Faculty of Medicine Tunis El Manar University"},{"author_name":"Annemarie Hubers","author_inst":"University Hospital Dusseldorf"},{"author_name":"Emmanuel Faure","author_inst":"CHU Lille"},{"author_name":"Isabelle Desguerre","author_inst":"Necker Hospital for Sick Children, AP-HP"},{"author_name":"Clemence Basse","author_inst":"Institut du Thorax Curie Montsouris, Institut Curie"},{"author_name":"Nicolas Girard","author_inst":"Institut du Thorax Curie-Montsouris"},{"author_name":"Vivien Beziat","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Qiang Pan-Hammarstrom","author_inst":"Karolinska Institutet"},{"author_name":"Lennart Hammarstrom","author_inst":"Karolinska Institutet"},{"author_name":"Aaron Bodansky","author_inst":"University of California, San Francisco"},{"author_name":"Audrey V Parent","author_inst":"University of California, San Francisco"},{"author_name":"Mark S Anderson","author_inst":"University of California, San Francisco"},{"author_name":"Joseph L L DeRisi","author_inst":"University of California, San Francisco"},{"author_name":"Sophie Demeret","author_inst":"Pitie Salpetriere"},{"author_name":"Frederique Truffault","author_inst":"Sorbonne UniversiteS"},{"author_name":"Romain Fort","author_inst":"Lyon Sud Hospital, Hospices Civils de Lyon"},{"author_name":"Florence Ader","author_inst":"Hospices Civils de Lyon, Hopital de la Croix Rousse"},{"author_name":"Florent Wallet","author_inst":"Centre Hospitalier Universitaire Lyon Sud, Hospices Civiles de Lyon"},{"author_name":"Laurent Abel","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Thierry Molina","author_inst":"Necker Hospital for Sick Children, AP-HP"},{"author_name":"Marie-Alexandra Alyanakian","author_inst":"Necker Hospital for Sick Children, AP-HP"},{"author_name":"Rozen Le Panse","author_inst":"CNRS UMR7215\/INSERM U974\/UPMC UM76\/AIM"},{"author_name":"Guilhem Sole","author_inst":"University of Bordeaux"},{"author_name":"Aurelie Cobat","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Nils Landegren","author_inst":"Karolinska Institute"},{"author_name":"Jean-Laurent Casanova","author_inst":"The Rockfeller University"},{"author_name":"Anne Puel","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Paul Bastard","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Emmanuelle Jouanguy","author_inst":"Institut Imagine; INSERM U1163"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"High risk of hypoxemic COVID-19 pneumonia in myasthenia gravis patients with type I IFN autoantibodies","rel_doi":"10.64898\/2026.03.27.26349525","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.27.26349525","rel_abs":"Patients with myasthenia gravis (MG) may produce autoantibodies neutralizing type I interferons (AAN-I-IFN), which have been shown to underlie severe viral diseases, including critical COVID-19 pneumonia, in patients without MG. We studied an international cohort of 85 unvaccinated SARS-CoV-2-infected MG patients with no antiviral treatment. Hypoxemic pneumonia occurred in 48 of these patients, including 22 (45.8%) with AAN-I-IFN, which neutralized both IFN-2 and IFN-{omega} in 14 (29.2%) patients. Six (16.2%) of the remaining 37 patients had AAN-I-IFN, which neutralized both IFN-2 and IFN-{omega} in three patients. The risk of hypoxemic pneumonia was greater in MG patients with AAN-I-IFN neutralizing 10 ng\/mL of both IFN-2 and IFN-{omega} (odds ratio and 95% confidence interval (OR [95% CI]): 12.7 [2.1-78.9], p=0. 0010) or IFN-2 at any dose (4.7 [1.5-15.0], p=0.0054) than in those without such autoantibodies. The risk of AAN-I-IFN production was much higher in MG patients than in the general population (28.9 [10.8-77.7], p=4.9x10-27). Fourteen patients had thymoma, which increased the risk of AAN-I-IFN (64% versus 27%, (OR [95% CI]: 5.6 [1.6-19.4], p=0.0050) and hypoxemic pneumonia (9.2 [1.9-44.2]; p=0.0019). Thymoma is, thus, associated with a higher risk of producing AAN-I-IFN, and these autoantibodies are associated with a higher risk of developing life-threatening COVID-19 pneumonia in patients with MG.\n\nSignificance StatementPatients with myasthenia gravis (MG) have a higher risk of developing life-threatening COVID-19 pneumonia. In an international cohort of unvaccinated, untreated SARS-CoV-2-infected MG patients, we found that autoantibodies neutralizing type I interferons (AAN-I-IFN) were strongly associated with severe hypoxemic pneumonia. Thymoma further increased the risk of both AAN-I-IFN production and severe disease. These findings suggest a crucial immunological mechanism that could guide risk stratification and targeted interventions for MG patients during viral infections, such as COVID-19.","rel_num_authors":69,"rel_authors":[{"author_name":"Adrian Gervais","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Astrid Marchal","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Alexis Maillard","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Tom Le Voyer","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Jeremie Rosain","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Quentin Philipot","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Lucy Bizien","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Jessica Peel","author_inst":"The Rockefeller University"},{"author_name":"Axel Cederholm","author_inst":"Uppsala Universitet"},{"author_name":"Melanie Migaud","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Sylvie Pons","author_inst":"Joint Research Unit Civil Hospices of Lyon-bioMerieux, Hospices Civils de Lyon, Lyon Sud Hospital"},{"author_name":"Kahina Saker","author_inst":"University of Lyon"},{"author_name":"Pascal Laforet","author_inst":"Raymond-Poincare Teaching Hospital, AP-HP"},{"author_name":"Melodie Aubart","author_inst":"Necker Hospital for Sick Children, AP-HP"},{"author_name":"Cyril Gitiaux","author_inst":"Necker Hospital for Sick Children, AP-HP"},{"author_name":"Catherine Biggs","author_inst":"The University of British Columbia"},{"author_name":"Rafael Leon Lopez","author_inst":"Hospital Universitario Reina Sofia, Universidad de Cordoba"},{"author_name":"Sarah Souvannanorath","author_inst":"AP-HP Groupe hospitalier Henri Mondor"},{"author_name":"Celine Tard","author_inst":"CHU Lille"},{"author_name":"Aleksandra Nadaj Pakleza","author_inst":"University Hospitals of Strasbourg"},{"author_name":"Aude-Marie Grapperon","author_inst":"Aix-Marseille University"},{"author_name":"Nicholas Heming","author_inst":"University Paris Saclay"},{"author_name":"Djillali Annane","author_inst":"University Paris Saclay"},{"author_name":"Annie Verschueren","author_inst":"Aix-Marseille University"},{"author_name":"Shahram Attarian","author_inst":"Aix-Marseille University"},{"author_name":"Kevin Bigaut","author_inst":"University Hospitals of Strasbourg"},{"author_name":"Karolina Hankiewicz","author_inst":"CH St-Denis"},{"author_name":"Ludivine Kouton","author_inst":"Aix-Marseille University"},{"author_name":"Rocio-Nur Villar-Quiles","author_inst":"Sorbonne Universite Centre de Recherche en Myologie"},{"author_name":"Cecile Cauquil","author_inst":"Paris Saclay University"},{"author_name":"Marie-Celine Fleury","author_inst":"University Hospitals of Strasbourg"},{"author_name":"Emilie Rocher","author_inst":"University Hospitals of Strasbourg"},{"author_name":"Guillaume Nicolas","author_inst":"Raymond-Poincare Teaching Hospital, AP-HP"},{"author_name":"Eduardo de Paula Estephan","author_inst":"Faculdade de Medicina da Universidade de Sao Paulo"},{"author_name":"Maria da Penha Ananias Morita","author_inst":"Faculdade de Medicina de Sao Jose do Rio Preto"},{"author_name":"Edmar Zanoteli","author_inst":"Federal University of Sao Paulo"},{"author_name":"Zakaria Saied","author_inst":"National Institute Mongi Ben Hamida of Neurology - Faculty of Medicine Tunis El Manar University"},{"author_name":"Amine Rachdi","author_inst":"National Institute Mongi Ben Hamida of Neurology - Faculty of Medicine Tunis El Manar University"},{"author_name":"Amouri Rim","author_inst":"National Institute Mongi Ben Hamida of Neurology - Faculty of Medicine Tunis El Manar University"},{"author_name":"Samir Belal","author_inst":"National Institute Mongi Ben Hamida of Neurology - Faculty of Medicine Tunis El Manar University"},{"author_name":"Samia Ben Sassi","author_inst":"National Institute Mongi Ben Hamida of Neurology - Faculty of Medicine Tunis El Manar University"},{"author_name":"Annemarie Hubers","author_inst":"University Hospital Dusseldorf"},{"author_name":"Emmanuel Faure","author_inst":"CHU Lille"},{"author_name":"Isabelle Desguerre","author_inst":"Necker Hospital for Sick Children, AP-HP"},{"author_name":"Clemence Basse","author_inst":"Institut du Thorax Curie Montsouris, Institut Curie"},{"author_name":"Nicolas Girard","author_inst":"Institut du Thorax Curie-Montsouris"},{"author_name":"Vivien Beziat","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Qiang Pan-Hammarstrom","author_inst":"Karolinska Institutet"},{"author_name":"Lennart Hammarstrom","author_inst":"Karolinska Institutet"},{"author_name":"Aaron Bodansky","author_inst":"University of California, San Francisco"},{"author_name":"Audrey V Parent","author_inst":"University of California, San Francisco"},{"author_name":"Mark S Anderson","author_inst":"University of California, San Francisco"},{"author_name":"Joseph L L DeRisi","author_inst":"University of California, San Francisco"},{"author_name":"Sophie Demeret","author_inst":"Pitie Salpetriere"},{"author_name":"Frederique Truffault","author_inst":"Sorbonne UniversiteS"},{"author_name":"Romain Fort","author_inst":"Lyon Sud Hospital, Hospices Civils de Lyon"},{"author_name":"Florence Ader","author_inst":"Hospices Civils de Lyon, Hopital de la Croix Rousse"},{"author_name":"Florent Wallet","author_inst":"Centre Hospitalier Universitaire Lyon Sud, Hospices Civiles de Lyon"},{"author_name":"Laurent Abel","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Thierry Molina","author_inst":"Necker Hospital for Sick Children, AP-HP"},{"author_name":"Marie-Alexandra Alyanakian","author_inst":"Necker Hospital for Sick Children, AP-HP"},{"author_name":"Rozen Le Panse","author_inst":"CNRS UMR7215\/INSERM U974\/UPMC UM76\/AIM"},{"author_name":"Guilhem Sole","author_inst":"University of Bordeaux"},{"author_name":"Aurelie Cobat","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Nils Landegren","author_inst":"Karolinska Institute"},{"author_name":"Jean-Laurent Casanova","author_inst":"The Rockfeller University"},{"author_name":"Anne Puel","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Paul Bastard","author_inst":"Institut Imagine; INSERM U1163"},{"author_name":"Emmanuelle Jouanguy","author_inst":"Institut Imagine; INSERM U1163"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Multimorbidity Patterns and Associated Factors Among Middle-Aged and Older Adults in China: Evidence from the CHARLS Study","rel_doi":"10.64898\/2026.03.31.26349821","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349821","rel_abs":"BackgroundDespite the growing global burden of multimorbidity, the patterns of disease combinations, have not been extensively categorized. We aimed to explore the predictors, health consequences, and patterns of discordant and concordant multimorbidity.\n\nMethodsWe used the 2018 China Health and Retirement Longitudinal Study (CHARLS), a representative database of adults aged >45 years from China. We conducted logistic regression analyses to assess the likelihood of having discordant (conditions from different disease systems) versus concordant (only cardiometabolic, or only respiratory diseases) multimorbidity, and to compare the health status and healthcare utilization between patients with discordant and concordant multimorbidity. Latent class analysis (LCA) was applied to both the entire sample and to patients with discordant multimorbidity to identify clusters of disease combinations.\n\nResultsThe sample included 1668 patients with concordant (mainly cardiometabolic), and 7306 patients with discordant, multimorbidity. Female patients, patients living in rural settings, former and current smokers, and patients engaging in high-intensity physical activity, were more likely to have discordant instead of concordant multimorbidity. Depression, limitations in daily activities, poor self-reported health, and frequent healthcare use were more common in patients with discordant than concordant multimorbidity. The LCA identified five clusters when all multimorbid patients were included (cardiometabolic, arthritis-digestive, respiratory, multisystem, and arthritis-hypertension classes), and four clusters when restricted to discordant multimorbidity (digestive, arthritis-cardiometabolic, respiratory, and multisystem classes).\n\nConclusionDiscordant multimorbidity is associated with poorer health and increased use of healthcare. Cardiometabolic diseases, arthritis, and digestive diseases have a central role in defining disease patterns.","rel_num_authors":4,"rel_authors":[{"author_name":"Zijun Wang","author_inst":"School of Basic Medical Sciences, Lanzhou University"},{"author_name":"Soren T. Skou","author_inst":"The Research and Implementation Unit PROgrez, Department of Physiotherapy and Occupational Therapy, Central and West Zealand Hospital"},{"author_name":"Yaolong Chen","author_inst":"School of Basic Medical Sciences, Lanzhou University"},{"author_name":"Janne Estill","author_inst":"Institute of Global Health, University of Geneva"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Course of Itch from Systemic Sclerosis Onset: a Scleroderma Patient-Centred Intervention Network Cohort Longitudinal Study","rel_doi":"10.64898\/2026.03.31.26349869","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349869","rel_abs":"BackgroundItch in systemic sclerosis (SSc) is thought to be most significant in early disease, but no longitudinal studies have examined itch course. We estimated itch presence and severity from SSc disease onset, accounting for participant age and time since onset at each assessment.\n\nMethodsPeople with SSc from the multinational Scleroderma Patient-centred Intervention Network Cohort completed past-week itch severity assessments (0 to 10 numerical rating scale) at enrolment and longitudinally at 3-month intervals. To estimate itch probability (score > 0) and, if present, itch severity, we used two-stage mixed effects models with basis splines to address non-linearity. The primary predictor was age at each assessment, partitioned into age at non-Raynaud phenomenon symptom onset and time since onset. We estimated prevalence and severity for onset ages of 20, 30, 40, 50 and 60 years and, for each onset age, at 2 years, 3 years, 4 years, 5 years, 7 years, and 5-year intervals 10 years to 35 years post-onset.\n\nFindingsWe included 2173 participants with 19 733 itch assessments (mean [standard deviation] 9{middle dot}1 [6{middle dot}9] assessments). 1896 of 2173 (87{middle dot}3%) participants were women. Mean age at enrolment was 54{middle dot}7 (SD 12{middle dot}7) years. 873 (40{middle dot}2%) participants had diffuse cutaneous SSc. Predicted itch probability was between 35{middle dot}0% (95% CI 31{middle dot}8% to 38{middle dot}5%) and 36{middle dot}8% (95% CI 33{middle dot}3% to 40{middle dot}4%) at all onset age and disease duration combinations. Mean itch severity, when present, was moderate, between 4{middle dot}1 (95% CI 4{middle dot}1 to 4{middle dot}1) and 4{middle dot}4 (95% CI 4{middle dot}3 to 4{middle dot}4), for all age and duration combinations.\n\nInterpretationItch prevalence and mean severity were stable across onset ages and over time within onset ages. Findings suggest that itch is common in SSc and not as closely related to disease duration as previously thought. Research is needed to elucidate itch pathophysiology and identify effective management strategies.\n\nFundingFunding for the study was provided by a Skin Investigation Network of Canada Team Development Award. Funding for the Scleroderma Patient-centred Intervention Network Cohort has been received from the Canadian Institutes of Health Research (TR3-119192; PJT-149073; PJT-148504; PJT-195879; PJT-203755); the Arthritis Society; the Lady Davis Institute for Medical Research of the Jewish General Hospital, Montreal, Quebec, Canada; the Jewish General Hospital Foundation, Montreal, Quebec, Canada; McGill University, Montreal, Quebec, Canada Scleroderma Society of Ontario; Scleroderma Canada; Sclerodermie Quebec; Scleroderma Manitoba; Scleroderma Atlantic; the Scleroderma Association of BC; Scleroderma SASK; Scleroderma Australia; Scleroderma New South Wales; Scleroderma Victoria; and the Scleroderma Foundation of California.\n\nRESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed using the terms \"itch\" or \"pruritus\" with \"systemic sclerosis\" or \"scleroderma\" on March 26, 2025, to identify previous studies that have evaluated the trajectory of itch prevalence or severity in systemic sclerosis (SSc) from the time of disease onset. We did not find any longitudinal studies. We identified 4 cross-sectional studies, and none found statistically significant associations between disease duration and itch. Three of the studies included between 56 and 126 participants. The fourth study included 959 participants and found that itch was experienced on most days in the last month based on a single dichotomous item among 46% of participants between 1 and 4{middle dot}9 years since non-Raynaud phenomenon (non-RP) symptom onset and 41% for those 5 or more years since onset (not statistically significant).\n\nAdded value of this studyThis was the first longitudinal study of itch prevalence and severity in SSc. We evaluated 2173 Scleroderma Patient-Centred Intervention Network participants from 7 countries who reported itch severity in the past week (0 to 10 numerical rating scale) at cohort enrolment and subsequently at 3-month intervals (19 733 total itch assessments). We simultaneously modelled probability of having any itch and, if present, itch severity. We accounted for both normal aging and SSc disease duration by including age of onset of non-RP symptoms and time since onset in our models. We found that itch prevalence and mean severity were stable across the course of the disease. Between 35% and 37% of participants reported itch (numerical rating scale score > 0) across all ages of onset and time since onset combinations. Mean itch severity, among participants with itch, was between 4{middle dot}1 and 4{middle dot}4 points, a moderate level, at all onset age and disease duration combinations. Findings were consistent for subgroups defined by participant country, sex, and diffuse versus limited cutaneous SSc.\n\nImplications of all the available evidenceItch is rarely researched in SSc, and itch assessment and management are typically not part of routine SSc care. It is commonly assumed that itch is most prominent, if present, in early disease. Our study showed that, contrary to this assumption, itch is present for many people with SSc across the course of the disease; itch prevalence and mean severity were stable across time regardless of age of SSc onset. Findings from our study underline the need for research on the pathogenesis of itch in SSc and the development and testing of treatments. Itch assessment and management should be part of routine SSc care.","rel_num_authors":33,"rel_authors":[{"author_name":"Meira Goldberg","author_inst":"Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada"},{"author_name":"Marie-Eve Carrier","author_inst":"Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada"},{"author_name":"Gil Yosipovitch","author_inst":"University of Miami Miller School of Medicine, Coral Gables, Florida, United States"},{"author_name":"Cassidy Dal Santo","author_inst":"McGill University, Montreal, Quebec, Canada"},{"author_name":"Linda Kwakkenbos","author_inst":"Radboud University, Nijmegen, the Netherlands"},{"author_name":"Tracy Frech","author_inst":"Vanderbilt University Medical Center, Nashville, Tennessee, United States"},{"author_name":"Sabrina Hoa","author_inst":"University of Montreal, Montreal, Quebec, Canada"},{"author_name":"Elena Netchiporouk","author_inst":"McGill University Health Centre, Montreal, Quebec, Canada"},{"author_name":"Laurent Misery","author_inst":"Brest University Hospital, Brest, France"},{"author_name":"Jo-Ann Lapointe McKenzie","author_inst":"Scleroderma Manitoba, Oak Bluff, Manitoba, Canada"},{"author_name":"Tracy Mieszczak","author_inst":"Scleroderma Patient-centered Intervention Network, Rochester, New York, United States"},{"author_name":"Sandra Rideout","author_inst":"Scleroderma Atlantic, Halifax, Nova Scotia, Canada"},{"author_name":"Maureen Sauve","author_inst":"Scleroderma Canada, Hamilton, Ontario, Canada"},{"author_name":"Anie Philip","author_inst":"McGill University, Montreal, Quebec, Canada"},{"author_name":"Janet Pope","author_inst":"Western University, London, Ontario, Canada"},{"author_name":"Susan J. Bartlett","author_inst":"McGill University, Montreal, Quebec, Canada"},{"author_name":"Benjamin Chaigne","author_inst":"Cochin Hospital, University of Paris Cite, Paris, France"},{"author_name":"Catherine Fortune","author_inst":"Ottawa Scleroderma Support Group, Ottawa, Ontario, Canada"},{"author_name":"Amy Gietzen","author_inst":"Steffens Scleroderma Foundation, Albany, New York, United States"},{"author_name":"Karen Gottesman","author_inst":"National Scleroderma Foundation, Los Angeles, California, United States"},{"author_name":"Genevieve Guillot","author_inst":"Sclerodermie Quebec, Longueuil, Quebec, Canada"},{"author_name":"Laura K. Hummers","author_inst":"Johns Hopkins University School of Medicine, Baltimore, Maryland, United States"},{"author_name":"Amanda Lawrie-Jones","author_inst":"Scleroderma Australia, Melbourne, Victoria, Australia"},{"author_name":"Vanessa L. Malcarne","author_inst":"San Diego State University, San Diego, California, United States"},{"author_name":"Maureen D. Mayes","author_inst":"University of Texas McGovern School of Medicine, Houston, Texas, United States"},{"author_name":"Yanne Perriault","author_inst":"Association des sclerodermiques de France, Baccon, France"},{"author_name":"Danielle Rice","author_inst":"St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada"},{"author_name":"Michelle Richard","author_inst":"Scleroderma Atlantic, Halifax, Nova Scotia, Canada"},{"author_name":"James Stempel","author_inst":"Scleroderma Foundation of Greater Chicago, Chicago, Illinois, United States"},{"author_name":"Robyn K. Wojeck","author_inst":"Amgen Inc, Thousand Oaks, California, United Sates"},{"author_name":"Luc Mouthon","author_inst":"Cochin Hospital, University of Paris Cite, Paris, France"},{"author_name":"Andrea Benedetti","author_inst":"McGill University, Montreal, Quebec, Canada"},{"author_name":"Brett D. Thombs","author_inst":"McGill University, Montreal, Quebec, Canada"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Course of Itch from Systemic Sclerosis Onset: a Scleroderma Patient-Centred Intervention Network Cohort Longitudinal Study","rel_doi":"10.64898\/2026.03.31.26349869","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349869","rel_abs":"BackgroundItch in systemic sclerosis (SSc) is thought to be most significant in early disease, but no longitudinal studies have examined itch course. We estimated itch presence and severity from SSc disease onset, accounting for participant age and time since onset at each assessment.\n\nMethodsPeople with SSc from the multinational Scleroderma Patient-centred Intervention Network Cohort completed past-week itch severity assessments (0 to 10 numerical rating scale) at enrolment and longitudinally at 3-month intervals. To estimate itch probability (score > 0) and, if present, itch severity, we used two-stage mixed effects models with basis splines to address non-linearity. The primary predictor was age at each assessment, partitioned into age at non-Raynaud phenomenon symptom onset and time since onset. We estimated prevalence and severity for onset ages of 20, 30, 40, 50 and 60 years and, for each onset age, at 2 years, 3 years, 4 years, 5 years, 7 years, and 5-year intervals 10 years to 35 years post-onset.\n\nFindingsWe included 2173 participants with 19 733 itch assessments (mean [standard deviation] 9{middle dot}1 [6{middle dot}9] assessments). 1896 of 2173 (87{middle dot}3%) participants were women. Mean age at enrolment was 54{middle dot}7 (SD 12{middle dot}7) years. 873 (40{middle dot}2%) participants had diffuse cutaneous SSc. Predicted itch probability was between 35{middle dot}0% (95% CI 31{middle dot}8% to 38{middle dot}5%) and 36{middle dot}8% (95% CI 33{middle dot}3% to 40{middle dot}4%) at all onset age and disease duration combinations. Mean itch severity, when present, was moderate, between 4{middle dot}1 (95% CI 4{middle dot}1 to 4{middle dot}1) and 4{middle dot}4 (95% CI 4{middle dot}3 to 4{middle dot}4), for all age and duration combinations.\n\nInterpretationItch prevalence and mean severity were stable across onset ages and over time within onset ages. Findings suggest that itch is common in SSc and not as closely related to disease duration as previously thought. Research is needed to elucidate itch pathophysiology and identify effective management strategies.\n\nFundingFunding for the study was provided by a Skin Investigation Network of Canada Team Development Award. Funding for the Scleroderma Patient-centred Intervention Network Cohort has been received from the Canadian Institutes of Health Research (TR3-119192; PJT-149073; PJT-148504; PJT-195879; PJT-203755); the Arthritis Society; the Lady Davis Institute for Medical Research of the Jewish General Hospital, Montreal, Quebec, Canada; the Jewish General Hospital Foundation, Montreal, Quebec, Canada; McGill University, Montreal, Quebec, Canada Scleroderma Society of Ontario; Scleroderma Canada; Sclerodermie Quebec; Scleroderma Manitoba; Scleroderma Atlantic; the Scleroderma Association of BC; Scleroderma SASK; Scleroderma Australia; Scleroderma New South Wales; Scleroderma Victoria; and the Scleroderma Foundation of California.\n\nRESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed using the terms \"itch\" or \"pruritus\" with \"systemic sclerosis\" or \"scleroderma\" on March 26, 2025, to identify previous studies that have evaluated the trajectory of itch prevalence or severity in systemic sclerosis (SSc) from the time of disease onset. We did not find any longitudinal studies. We identified 4 cross-sectional studies, and none found statistically significant associations between disease duration and itch. Three of the studies included between 56 and 126 participants. The fourth study included 959 participants and found that itch was experienced on most days in the last month based on a single dichotomous item among 46% of participants between 1 and 4{middle dot}9 years since non-Raynaud phenomenon (non-RP) symptom onset and 41% for those 5 or more years since onset (not statistically significant).\n\nAdded value of this studyThis was the first longitudinal study of itch prevalence and severity in SSc. We evaluated 2173 Scleroderma Patient-Centred Intervention Network participants from 7 countries who reported itch severity in the past week (0 to 10 numerical rating scale) at cohort enrolment and subsequently at 3-month intervals (19 733 total itch assessments). We simultaneously modelled probability of having any itch and, if present, itch severity. We accounted for both normal aging and SSc disease duration by including age of onset of non-RP symptoms and time since onset in our models. We found that itch prevalence and mean severity were stable across the course of the disease. Between 35% and 37% of participants reported itch (numerical rating scale score > 0) across all ages of onset and time since onset combinations. Mean itch severity, among participants with itch, was between 4{middle dot}1 and 4{middle dot}4 points, a moderate level, at all onset age and disease duration combinations. Findings were consistent for subgroups defined by participant country, sex, and diffuse versus limited cutaneous SSc.\n\nImplications of all the available evidenceItch is rarely researched in SSc, and itch assessment and management are typically not part of routine SSc care. It is commonly assumed that itch is most prominent, if present, in early disease. Our study showed that, contrary to this assumption, itch is present for many people with SSc across the course of the disease; itch prevalence and mean severity were stable across time regardless of age of SSc onset. Findings from our study underline the need for research on the pathogenesis of itch in SSc and the development and testing of treatments. Itch assessment and management should be part of routine SSc care.","rel_num_authors":33,"rel_authors":[{"author_name":"Meira Goldberg","author_inst":"Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada"},{"author_name":"Marie-Eve Carrier","author_inst":"Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada"},{"author_name":"Gil Yosipovitch","author_inst":"University of Miami Miller School of Medicine, Coral Gables, Florida, United States"},{"author_name":"Cassidy Dal Santo","author_inst":"McGill University, Montreal, Quebec, Canada"},{"author_name":"Linda Kwakkenbos","author_inst":"Radboud University, Nijmegen, the Netherlands"},{"author_name":"Tracy Frech","author_inst":"Vanderbilt University Medical Center, Nashville, Tennessee, United States"},{"author_name":"Sabrina Hoa","author_inst":"University of Montreal, Montreal, Quebec, Canada"},{"author_name":"Elena Netchiporouk","author_inst":"McGill University Health Centre, Montreal, Quebec, Canada"},{"author_name":"Laurent Misery","author_inst":"Brest University Hospital, Brest, France"},{"author_name":"Jo-Ann Lapointe McKenzie","author_inst":"Scleroderma Manitoba, Oak Bluff, Manitoba, Canada"},{"author_name":"Tracy Mieszczak","author_inst":"Scleroderma Patient-centered Intervention Network, Rochester, New York, United States"},{"author_name":"Sandra Rideout","author_inst":"Scleroderma Atlantic, Halifax, Nova Scotia, Canada"},{"author_name":"Maureen Sauve","author_inst":"Scleroderma Canada, Hamilton, Ontario, Canada"},{"author_name":"Anie Philip","author_inst":"McGill University, Montreal, Quebec, Canada"},{"author_name":"Janet Pope","author_inst":"Western University, London, Ontario, Canada"},{"author_name":"Susan J. Bartlett","author_inst":"McGill University, Montreal, Quebec, Canada"},{"author_name":"Benjamin Chaigne","author_inst":"Cochin Hospital, University of Paris Cite, Paris, France"},{"author_name":"Catherine Fortune","author_inst":"Ottawa Scleroderma Support Group, Ottawa, Ontario, Canada"},{"author_name":"Amy Gietzen","author_inst":"Steffens Scleroderma Foundation, Albany, New York, United States"},{"author_name":"Karen Gottesman","author_inst":"National Scleroderma Foundation, Los Angeles, California, United States"},{"author_name":"Genevieve Guillot","author_inst":"Sclerodermie Quebec, Longueuil, Quebec, Canada"},{"author_name":"Laura K. Hummers","author_inst":"Johns Hopkins University School of Medicine, Baltimore, Maryland, United States"},{"author_name":"Amanda Lawrie-Jones","author_inst":"Scleroderma Australia, Melbourne, Victoria, Australia"},{"author_name":"Vanessa L. Malcarne","author_inst":"San Diego State University, San Diego, California, United States"},{"author_name":"Maureen D. Mayes","author_inst":"University of Texas McGovern School of Medicine, Houston, Texas, United States"},{"author_name":"Yanne Perriault","author_inst":"Association des sclerodermiques de France, Baccon, France"},{"author_name":"Danielle Rice","author_inst":"St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada"},{"author_name":"Michelle Richard","author_inst":"Scleroderma Atlantic, Halifax, Nova Scotia, Canada"},{"author_name":"James Stempel","author_inst":"Scleroderma Foundation of Greater Chicago, Chicago, Illinois, United States"},{"author_name":"Robyn K. Wojeck","author_inst":"Amgen Inc, Thousand Oaks, California, United Sates"},{"author_name":"Luc Mouthon","author_inst":"Cochin Hospital, University of Paris Cite, Paris, France"},{"author_name":"Andrea Benedetti","author_inst":"McGill University, Montreal, Quebec, Canada"},{"author_name":"Brett D. Thombs","author_inst":"McGill University, Montreal, Quebec, Canada"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Multidimensional analysis of the clinical spectrum and symptom burden of unexplained myofascial pain","rel_doi":"10.64898\/2026.03.27.26349456","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.27.26349456","rel_abs":"ObjectiveMyofascial pain (MP) is a leading cause of disability globally. Pain quality and severity vary widely for people with MP, making it difficult to accurately assess the spectrum of symptoms and develop appropriate treatments. We assessed potential contributors to variability in the clinical spectrum of unexplained neck\/shoulder pain and associated myofascial component(s).\n\nDesignProspective cross-sectional study of adults reporting neck\/shoulder pain and pain-free individuals.\n\nOutcomes MeasuresPain intensity and interference (PEG); Symptom burden measured using patient-reported outcomes and objective measures: pain catastrophizing (PCS); PROMIS physical function (PF); sleep disturbance; anxiety (GAD-2); depression (PHQ-2); hypermobility (Beighton\/Brighton); Objective measures in the medial upper trapezius: pressure pain threshold (PPT) and quantitative sensory testing (QST).\n\nResultsOf the 96 adults recruited for the study, 82 had complete records (age 32.2 +\/-13.1 years, 57% women). On physical exam, 23 were assessed to be in an active group (those with spontaneous MP without provocation), 38 in a latent group (those with MP upon provocation), and 21 in a normal group (no MP in neck and shoulder). The symptom burden explained 75% of the variance in PEG in the overall sample, 85% in the active group and 92% in the normal group. PF and PCS are key predictors of PEG. Network analysis identified unique symptom clusters in the active and latent groups.\n\nConclusionsThe symptom burden explains the variability in the clinical spectrum of pain intensity and interference in unexplained neck\/shoulder MP. Network analysis can further improve clinical risk stratification. These findings represent a step towards an eventual goal of developing multidisciplinary clinical guidance for managing the whole patient, rather than the current emphasis on regional pain contributors in MP.","rel_num_authors":13,"rel_authors":[{"author_name":"Siddhartha Sikdar","author_inst":"George Mason University"},{"author_name":"Secili DeStefano","author_inst":"Optimal Motion Physical Therapy"},{"author_name":"Mar\u00eda Jos\u00e9 Guzm\u00e1n Pav\u00f3n","author_inst":"University of Castilla-La Mancha"},{"author_name":"Yu-Lin Hsu","author_inst":"George Mason University"},{"author_name":"Seiyon Lee","author_inst":"George Mason University"},{"author_name":"John Srbely","author_inst":"University of Guelph"},{"author_name":"Jay Shah","author_inst":"National Institutes of Health"},{"author_name":"William Rosenberger","author_inst":"George Mason University"},{"author_name":"Samuel Acu\u00f1a","author_inst":"George Mason University"},{"author_name":"Yonathan Assefa","author_inst":"National Institutes of Health"},{"author_name":"Matin Jahani Jirsaraei","author_inst":"George Mason University"},{"author_name":"Antonio Stecco","author_inst":"New York University"},{"author_name":"Lynn H Gerber","author_inst":"George Mason University"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Clinicopathological Factors Associated with Gastric Signet Ring Cell Carcinoma in CDH1 Pathogenic Variant Carriers: Report from the GASTRIC Consortium","rel_doi":"10.64898\/2026.03.27.26349321","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.27.26349321","rel_abs":"BackgroundGastric cancer surveillance in CDH1 pathogenic variant carriers is challenging, as predictors of localized (stage T1a) and advanced (stage >T1a) signet ring cell carcinoma (SRCC) are not well defined. We established the Group of investigAtors STriving toward Research In CDH1 (GASTRIC) consortium to identify clinicopathological factors associated with localized and advanced SRCC.\n\nMethodsA retrospective observational study (1998-2025) of CDH1 carriers across twelve academic centers was performed. Clinical, endoscopic, and pathological data were compared between carriers with and without SRCC on endoscopy, and between those with advanced versus localized or no cancer on gastrectomy specimens.\n\nResultsOverall, 390 CDH1 carriers from 235 families were included. Presence of SRCCs on endoscopy was significantly associated with thickened folds, nodularity, masses, and intestinal metaplasia, while gastritis was negatively associated. Of 196 carriers (52.4%) undergoing gastrectomy, 11 (5.6%) had advanced cancers, 10(90.9%) of which showed endoscopic abnormalities. Identification of SRCC on baseline endoscopy was the most sensitive feature for advanced disease (0.81) but had moderate specificity (0.74), whereas masses and thickened folds were highly specific (0.99 and 0.96, respectively) but less sensitive. Negative predictive values were high (0.94-1.0), while positive predictive values were modest (0.13-0.66). On multivariate analysis, masses and SRCC foci on baseline endoscopy were independent predictors of advanced disease.\n\nConclusionAmong CDH1 carriers, absence of endoscopic findings was reassuring, whereas significance of detected endoscopic and pathological abnormalities was less certain. Advanced cancer occurred in a small number of carriers, with endoscopic abnormalities in nearly all cases. Endoscopic surveillance might be an alternative to surgery in carriers without worrisome mucosal findings.\n\nWhat You Need to KnowO_ST_ABSBackgroundC_ST_ABSPredictors of advanced stage disease in CDH1 carriers, which could help in risk stratification and management of these individuals, are not well defined. Identifying associated features could improve risk stratification and management.\n\nFindingsEndoscopic and histologic features associated with advanced disease showed variable sensitivity and specificity. Absence of abnormalities had high negative predictive value, whereas presence of findings had limited ability to reliably predict advanced disease.\n\nImplications for Patient CareAbsence of worrisome findings is reassuring and may support continued surveillance. Detected abnormalities warrant close evaluation and discussion of surgery, though their presence alsone does not reliably indicate advanced disease.","rel_num_authors":36,"rel_authors":[{"author_name":"Ophir Gilad","author_inst":"University of Chicago"},{"author_name":"Christine M. Drogan","author_inst":"University of Chicago"},{"author_name":"Emma Keel","author_inst":"University of Chicago"},{"author_name":"Guimin Gao","author_inst":"University of Chicago"},{"author_name":"Carol Swallow","author_inst":"Sinai Health System"},{"author_name":"Anand Govindarajan","author_inst":"Sinai Health System"},{"author_name":"Savtaj Brar","author_inst":"Sinai Health System"},{"author_name":"Melissa Heller","author_inst":"University of Pennsylvania"},{"author_name":"Taylor Apostolico","author_inst":"University of Pennsylvania"},{"author_name":"Michelle F. Jacobs","author_inst":"University of Michigan"},{"author_name":"Kebire Gofar","author_inst":"The Ohio State University"},{"author_name":"Beth Dudley","author_inst":"University of Pittsburgh"},{"author_name":"Eve Karloski","author_inst":"University of Pittsburgh"},{"author_name":"Conner Lombardi","author_inst":"University of Colorado"},{"author_name":"Michelle Springer","author_inst":"University of Colorado"},{"author_name":"Souvik Saha","author_inst":"University of Kansas"},{"author_name":"Devin Cox","author_inst":"University of Kansas"},{"author_name":"Benjamin A. Lerner","author_inst":"Yale University"},{"author_name":"George Hanna","author_inst":"Yale University"},{"author_name":"Yana Chertock","author_inst":"Fox Chase Cancer Center"},{"author_name":"Afshin Khan","author_inst":"University of California San Francisco"},{"author_name":"Sarah Ertan","author_inst":"University of California San Francisco"},{"author_name":"Kimberly Hilfrank","author_inst":"Columbia University"},{"author_name":"Sheila D. Rustgi","author_inst":"Columbia University"},{"author_name":"Aparajita Singh","author_inst":"University of California San Francisco"},{"author_name":"Michael J. Hall","author_inst":"Fox Chase Cancer Center"},{"author_name":"Xavier Llor","author_inst":"Yale University"},{"author_name":"Ajay Bansal","author_inst":"University of Kansas"},{"author_name":"Swati G. Patel","author_inst":"University of Colorado"},{"author_name":"Randall E. Brand","author_inst":"University of Pittsburgh"},{"author_name":"Maegan E. Roberts","author_inst":"The Ohio State University"},{"author_name":"Peter P. Stanich","author_inst":"The Ohio State University"},{"author_name":"Elena Stoffel","author_inst":"University of Michigan"},{"author_name":"Bryson W. Katona","author_inst":"University of Pennsylvania"},{"author_name":"Melyssa Aronson","author_inst":"Sinai Health System"},{"author_name":"Sonia S. Kupfer","author_inst":"University of Chicago"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Clinicopathological Factors Associated with Gastric Signet Ring Cell Carcinoma in CDH1 Pathogenic Variant Carriers: Report from the GASTRIC Consortium","rel_doi":"10.64898\/2026.03.27.26349321","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.27.26349321","rel_abs":"BackgroundGastric cancer surveillance in CDH1 pathogenic variant carriers is challenging, as predictors of localized (stage T1a) and advanced (stage >T1a) signet ring cell carcinoma (SRCC) are not well defined. We established the Group of investigAtors STriving toward Research In CDH1 (GASTRIC) consortium to identify clinicopathological factors associated with localized and advanced SRCC.\n\nMethodsA retrospective observational study (1998-2025) of CDH1 carriers across twelve academic centers was performed. Clinical, endoscopic, and pathological data were compared between carriers with and without SRCC on endoscopy, and between those with advanced versus localized or no cancer on gastrectomy specimens.\n\nResultsOverall, 390 CDH1 carriers from 235 families were included. Presence of SRCCs on endoscopy was significantly associated with thickened folds, nodularity, masses, and intestinal metaplasia, while gastritis was negatively associated. Of 196 carriers (52.4%) undergoing gastrectomy, 11 (5.6%) had advanced cancers, 10(90.9%) of which showed endoscopic abnormalities. Identification of SRCC on baseline endoscopy was the most sensitive feature for advanced disease (0.81) but had moderate specificity (0.74), whereas masses and thickened folds were highly specific (0.99 and 0.96, respectively) but less sensitive. Negative predictive values were high (0.94-1.0), while positive predictive values were modest (0.13-0.66). On multivariate analysis, masses and SRCC foci on baseline endoscopy were independent predictors of advanced disease.\n\nConclusionAmong CDH1 carriers, absence of endoscopic findings was reassuring, whereas significance of detected endoscopic and pathological abnormalities was less certain. Advanced cancer occurred in a small number of carriers, with endoscopic abnormalities in nearly all cases. Endoscopic surveillance might be an alternative to surgery in carriers without worrisome mucosal findings.\n\nWhat You Need to KnowO_ST_ABSBackgroundC_ST_ABSPredictors of advanced stage disease in CDH1 carriers, which could help in risk stratification and management of these individuals, are not well defined. Identifying associated features could improve risk stratification and management.\n\nFindingsEndoscopic and histologic features associated with advanced disease showed variable sensitivity and specificity. Absence of abnormalities had high negative predictive value, whereas presence of findings had limited ability to reliably predict advanced disease.\n\nImplications for Patient CareAbsence of worrisome findings is reassuring and may support continued surveillance. Detected abnormalities warrant close evaluation and discussion of surgery, though their presence alsone does not reliably indicate advanced disease.","rel_num_authors":36,"rel_authors":[{"author_name":"Ophir Gilad","author_inst":"University of Chicago"},{"author_name":"Christine M. Drogan","author_inst":"University of Chicago"},{"author_name":"Emma Keel","author_inst":"University of Chicago"},{"author_name":"Guimin Gao","author_inst":"University of Chicago"},{"author_name":"Carol Swallow","author_inst":"Sinai Health System"},{"author_name":"Anand Govindarajan","author_inst":"Sinai Health System"},{"author_name":"Savtaj Brar","author_inst":"Sinai Health System"},{"author_name":"Melissa Heller","author_inst":"University of Pennsylvania"},{"author_name":"Taylor Apostolico","author_inst":"University of Pennsylvania"},{"author_name":"Michelle F. Jacobs","author_inst":"University of Michigan"},{"author_name":"Kebire Gofar","author_inst":"The Ohio State University"},{"author_name":"Beth Dudley","author_inst":"University of Pittsburgh"},{"author_name":"Eve Karloski","author_inst":"University of Pittsburgh"},{"author_name":"Conner Lombardi","author_inst":"University of Colorado"},{"author_name":"Michelle Springer","author_inst":"University of Colorado"},{"author_name":"Souvik Saha","author_inst":"University of Kansas"},{"author_name":"Devin Cox","author_inst":"University of Kansas"},{"author_name":"Benjamin A. Lerner","author_inst":"Yale University"},{"author_name":"George Hanna","author_inst":"Yale University"},{"author_name":"Yana Chertock","author_inst":"Fox Chase Cancer Center"},{"author_name":"Afshin Khan","author_inst":"University of California San Francisco"},{"author_name":"Sarah Ertan","author_inst":"University of California San Francisco"},{"author_name":"Kimberly Hilfrank","author_inst":"Columbia University"},{"author_name":"Sheila D. Rustgi","author_inst":"Columbia University"},{"author_name":"Aparajita Singh","author_inst":"University of California San Francisco"},{"author_name":"Michael J. Hall","author_inst":"Fox Chase Cancer Center"},{"author_name":"Xavier Llor","author_inst":"Yale University"},{"author_name":"Ajay Bansal","author_inst":"University of Kansas"},{"author_name":"Swati G. Patel","author_inst":"University of Colorado"},{"author_name":"Randall E. Brand","author_inst":"University of Pittsburgh"},{"author_name":"Maegan E. Roberts","author_inst":"The Ohio State University"},{"author_name":"Peter P. Stanich","author_inst":"The Ohio State University"},{"author_name":"Elena Stoffel","author_inst":"University of Michigan"},{"author_name":"Bryson W. Katona","author_inst":"University of Pennsylvania"},{"author_name":"Melyssa Aronson","author_inst":"Sinai Health System"},{"author_name":"Sonia S. Kupfer","author_inst":"University of Chicago"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Clinicopathological Factors Associated with Gastric Signet Ring Cell Carcinoma in CDH1 Pathogenic Variant Carriers: Report from the GASTRIC Consortium","rel_doi":"10.64898\/2026.03.27.26349321","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.27.26349321","rel_abs":"BackgroundGastric cancer surveillance in CDH1 pathogenic variant carriers is challenging, as predictors of localized (stage T1a) and advanced (stage >T1a) signet ring cell carcinoma (SRCC) are not well defined. We established the Group of investigAtors STriving toward Research In CDH1 (GASTRIC) consortium to identify clinicopathological factors associated with localized and advanced SRCC.\n\nMethodsA retrospective observational study (1998-2025) of CDH1 carriers across twelve academic centers was performed. Clinical, endoscopic, and pathological data were compared between carriers with and without SRCC on endoscopy, and between those with advanced versus localized or no cancer on gastrectomy specimens.\n\nResultsOverall, 390 CDH1 carriers from 235 families were included. Presence of SRCCs on endoscopy was significantly associated with thickened folds, nodularity, masses, and intestinal metaplasia, while gastritis was negatively associated. Of 196 carriers (52.4%) undergoing gastrectomy, 11 (5.6%) had advanced cancers, 10(90.9%) of which showed endoscopic abnormalities. Identification of SRCC on baseline endoscopy was the most sensitive feature for advanced disease (0.81) but had moderate specificity (0.74), whereas masses and thickened folds were highly specific (0.99 and 0.96, respectively) but less sensitive. Negative predictive values were high (0.94-1.0), while positive predictive values were modest (0.13-0.66). On multivariate analysis, masses and SRCC foci on baseline endoscopy were independent predictors of advanced disease.\n\nConclusionAmong CDH1 carriers, absence of endoscopic findings was reassuring, whereas significance of detected endoscopic and pathological abnormalities was less certain. Advanced cancer occurred in a small number of carriers, with endoscopic abnormalities in nearly all cases. Endoscopic surveillance might be an alternative to surgery in carriers without worrisome mucosal findings.\n\nWhat You Need to KnowO_ST_ABSBackgroundC_ST_ABSPredictors of advanced stage disease in CDH1 carriers, which could help in risk stratification and management of these individuals, are not well defined. Identifying associated features could improve risk stratification and management.\n\nFindingsEndoscopic and histologic features associated with advanced disease showed variable sensitivity and specificity. Absence of abnormalities had high negative predictive value, whereas presence of findings had limited ability to reliably predict advanced disease.\n\nImplications for Patient CareAbsence of worrisome findings is reassuring and may support continued surveillance. Detected abnormalities warrant close evaluation and discussion of surgery, though their presence alsone does not reliably indicate advanced disease.","rel_num_authors":36,"rel_authors":[{"author_name":"Ophir Gilad","author_inst":"University of Chicago"},{"author_name":"Christine M. Drogan","author_inst":"University of Chicago"},{"author_name":"Emma Keel","author_inst":"University of Chicago"},{"author_name":"Guimin Gao","author_inst":"University of Chicago"},{"author_name":"Carol Swallow","author_inst":"Sinai Health System"},{"author_name":"Anand Govindarajan","author_inst":"Sinai Health System"},{"author_name":"Savtaj Brar","author_inst":"Sinai Health System"},{"author_name":"Melissa Heller","author_inst":"University of Pennsylvania"},{"author_name":"Taylor Apostolico","author_inst":"University of Pennsylvania"},{"author_name":"Michelle F. Jacobs","author_inst":"University of Michigan"},{"author_name":"Kebire Gofar","author_inst":"The Ohio State University"},{"author_name":"Beth Dudley","author_inst":"University of Pittsburgh"},{"author_name":"Eve Karloski","author_inst":"University of Pittsburgh"},{"author_name":"Conner Lombardi","author_inst":"University of Colorado"},{"author_name":"Michelle Springer","author_inst":"University of Colorado"},{"author_name":"Souvik Saha","author_inst":"University of Kansas"},{"author_name":"Devin Cox","author_inst":"University of Kansas"},{"author_name":"Benjamin A. Lerner","author_inst":"Yale University"},{"author_name":"George Hanna","author_inst":"Yale University"},{"author_name":"Yana Chertock","author_inst":"Fox Chase Cancer Center"},{"author_name":"Afshin Khan","author_inst":"University of California San Francisco"},{"author_name":"Sarah Ertan","author_inst":"University of California San Francisco"},{"author_name":"Kimberly Hilfrank","author_inst":"Columbia University"},{"author_name":"Sheila D. Rustgi","author_inst":"Columbia University"},{"author_name":"Aparajita Singh","author_inst":"University of California San Francisco"},{"author_name":"Michael J. Hall","author_inst":"Fox Chase Cancer Center"},{"author_name":"Xavier Llor","author_inst":"Yale University"},{"author_name":"Ajay Bansal","author_inst":"University of Kansas"},{"author_name":"Swati G. Patel","author_inst":"University of Colorado"},{"author_name":"Randall E. Brand","author_inst":"University of Pittsburgh"},{"author_name":"Maegan E. Roberts","author_inst":"The Ohio State University"},{"author_name":"Peter P. Stanich","author_inst":"The Ohio State University"},{"author_name":"Elena Stoffel","author_inst":"University of Michigan"},{"author_name":"Bryson W. Katona","author_inst":"University of Pennsylvania"},{"author_name":"Melyssa Aronson","author_inst":"Sinai Health System"},{"author_name":"Sonia S. Kupfer","author_inst":"University of Chicago"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Clinicopathological Factors Associated with Gastric Signet Ring Cell Carcinoma in CDH1 Pathogenic Variant Carriers: Report from the GASTRIC Consortium","rel_doi":"10.64898\/2026.03.27.26349321","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.27.26349321","rel_abs":"BackgroundGastric cancer surveillance in CDH1 pathogenic variant carriers is challenging, as predictors of localized (stage T1a) and advanced (stage >T1a) signet ring cell carcinoma (SRCC) are not well defined. We established the Group of investigAtors STriving toward Research In CDH1 (GASTRIC) consortium to identify clinicopathological factors associated with localized and advanced SRCC.\n\nMethodsA retrospective observational study (1998-2025) of CDH1 carriers across twelve academic centers was performed. Clinical, endoscopic, and pathological data were compared between carriers with and without SRCC on endoscopy, and between those with advanced versus localized or no cancer on gastrectomy specimens.\n\nResultsOverall, 390 CDH1 carriers from 235 families were included. Presence of SRCCs on endoscopy was significantly associated with thickened folds, nodularity, masses, and intestinal metaplasia, while gastritis was negatively associated. Of 196 carriers (52.4%) undergoing gastrectomy, 11 (5.6%) had advanced cancers, 10(90.9%) of which showed endoscopic abnormalities. Identification of SRCC on baseline endoscopy was the most sensitive feature for advanced disease (0.81) but had moderate specificity (0.74), whereas masses and thickened folds were highly specific (0.99 and 0.96, respectively) but less sensitive. Negative predictive values were high (0.94-1.0), while positive predictive values were modest (0.13-0.66). On multivariate analysis, masses and SRCC foci on baseline endoscopy were independent predictors of advanced disease.\n\nConclusionAmong CDH1 carriers, absence of endoscopic findings was reassuring, whereas significance of detected endoscopic and pathological abnormalities was less certain. Advanced cancer occurred in a small number of carriers, with endoscopic abnormalities in nearly all cases. Endoscopic surveillance might be an alternative to surgery in carriers without worrisome mucosal findings.\n\nWhat You Need to KnowO_ST_ABSBackgroundC_ST_ABSPredictors of advanced stage disease in CDH1 carriers, which could help in risk stratification and management of these individuals, are not well defined. Identifying associated features could improve risk stratification and management.\n\nFindingsEndoscopic and histologic features associated with advanced disease showed variable sensitivity and specificity. Absence of abnormalities had high negative predictive value, whereas presence of findings had limited ability to reliably predict advanced disease.\n\nImplications for Patient CareAbsence of worrisome findings is reassuring and may support continued surveillance. Detected abnormalities warrant close evaluation and discussion of surgery, though their presence alsone does not reliably indicate advanced disease.","rel_num_authors":36,"rel_authors":[{"author_name":"Ophir Gilad","author_inst":"University of Chicago"},{"author_name":"Christine M. Drogan","author_inst":"University of Chicago"},{"author_name":"Emma Keel","author_inst":"University of Chicago"},{"author_name":"Guimin Gao","author_inst":"University of Chicago"},{"author_name":"Carol Swallow","author_inst":"Sinai Health System"},{"author_name":"Anand Govindarajan","author_inst":"Sinai Health System"},{"author_name":"Savtaj Brar","author_inst":"Sinai Health System"},{"author_name":"Melissa Heller","author_inst":"University of Pennsylvania"},{"author_name":"Taylor Apostolico","author_inst":"University of Pennsylvania"},{"author_name":"Michelle F. Jacobs","author_inst":"University of Michigan"},{"author_name":"Kebire Gofar","author_inst":"The Ohio State University"},{"author_name":"Beth Dudley","author_inst":"University of Pittsburgh"},{"author_name":"Eve Karloski","author_inst":"University of Pittsburgh"},{"author_name":"Conner Lombardi","author_inst":"University of Colorado"},{"author_name":"Michelle Springer","author_inst":"University of Colorado"},{"author_name":"Souvik Saha","author_inst":"University of Kansas"},{"author_name":"Devin Cox","author_inst":"University of Kansas"},{"author_name":"Benjamin A. Lerner","author_inst":"Yale University"},{"author_name":"George Hanna","author_inst":"Yale University"},{"author_name":"Yana Chertock","author_inst":"Fox Chase Cancer Center"},{"author_name":"Afshin Khan","author_inst":"University of California San Francisco"},{"author_name":"Sarah Ertan","author_inst":"University of California San Francisco"},{"author_name":"Kimberly Hilfrank","author_inst":"Columbia University"},{"author_name":"Sheila D. Rustgi","author_inst":"Columbia University"},{"author_name":"Aparajita Singh","author_inst":"University of California San Francisco"},{"author_name":"Michael J. Hall","author_inst":"Fox Chase Cancer Center"},{"author_name":"Xavier Llor","author_inst":"Yale University"},{"author_name":"Ajay Bansal","author_inst":"University of Kansas"},{"author_name":"Swati G. Patel","author_inst":"University of Colorado"},{"author_name":"Randall E. Brand","author_inst":"University of Pittsburgh"},{"author_name":"Maegan E. Roberts","author_inst":"The Ohio State University"},{"author_name":"Peter P. Stanich","author_inst":"The Ohio State University"},{"author_name":"Elena Stoffel","author_inst":"University of Michigan"},{"author_name":"Bryson W. Katona","author_inst":"University of Pennsylvania"},{"author_name":"Melyssa Aronson","author_inst":"Sinai Health System"},{"author_name":"Sonia S. Kupfer","author_inst":"University of Chicago"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Clinicopathological Factors Associated with Gastric Signet Ring Cell Carcinoma in CDH1 Pathogenic Variant Carriers: Report from the GASTRIC Consortium","rel_doi":"10.64898\/2026.03.27.26349321","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.27.26349321","rel_abs":"BackgroundGastric cancer surveillance in CDH1 pathogenic variant carriers is challenging, as predictors of localized (stage T1a) and advanced (stage >T1a) signet ring cell carcinoma (SRCC) are not well defined. We established the Group of investigAtors STriving toward Research In CDH1 (GASTRIC) consortium to identify clinicopathological factors associated with localized and advanced SRCC.\n\nMethodsA retrospective observational study (1998-2025) of CDH1 carriers across twelve academic centers was performed. Clinical, endoscopic, and pathological data were compared between carriers with and without SRCC on endoscopy, and between those with advanced versus localized or no cancer on gastrectomy specimens.\n\nResultsOverall, 390 CDH1 carriers from 235 families were included. Presence of SRCCs on endoscopy was significantly associated with thickened folds, nodularity, masses, and intestinal metaplasia, while gastritis was negatively associated. Of 196 carriers (52.4%) undergoing gastrectomy, 11 (5.6%) had advanced cancers, 10(90.9%) of which showed endoscopic abnormalities. Identification of SRCC on baseline endoscopy was the most sensitive feature for advanced disease (0.81) but had moderate specificity (0.74), whereas masses and thickened folds were highly specific (0.99 and 0.96, respectively) but less sensitive. Negative predictive values were high (0.94-1.0), while positive predictive values were modest (0.13-0.66). On multivariate analysis, masses and SRCC foci on baseline endoscopy were independent predictors of advanced disease.\n\nConclusionAmong CDH1 carriers, absence of endoscopic findings was reassuring, whereas significance of detected endoscopic and pathological abnormalities was less certain. Advanced cancer occurred in a small number of carriers, with endoscopic abnormalities in nearly all cases. Endoscopic surveillance might be an alternative to surgery in carriers without worrisome mucosal findings.\n\nWhat You Need to KnowO_ST_ABSBackgroundC_ST_ABSPredictors of advanced stage disease in CDH1 carriers, which could help in risk stratification and management of these individuals, are not well defined. Identifying associated features could improve risk stratification and management.\n\nFindingsEndoscopic and histologic features associated with advanced disease showed variable sensitivity and specificity. Absence of abnormalities had high negative predictive value, whereas presence of findings had limited ability to reliably predict advanced disease.\n\nImplications for Patient CareAbsence of worrisome findings is reassuring and may support continued surveillance. Detected abnormalities warrant close evaluation and discussion of surgery, though their presence alsone does not reliably indicate advanced disease.","rel_num_authors":36,"rel_authors":[{"author_name":"Ophir Gilad","author_inst":"University of Chicago"},{"author_name":"Christine M. Drogan","author_inst":"University of Chicago"},{"author_name":"Emma Keel","author_inst":"University of Chicago"},{"author_name":"Guimin Gao","author_inst":"University of Chicago"},{"author_name":"Carol Swallow","author_inst":"Sinai Health System"},{"author_name":"Anand Govindarajan","author_inst":"Sinai Health System"},{"author_name":"Savtaj Brar","author_inst":"Sinai Health System"},{"author_name":"Melissa Heller","author_inst":"University of Pennsylvania"},{"author_name":"Taylor Apostolico","author_inst":"University of Pennsylvania"},{"author_name":"Michelle F. Jacobs","author_inst":"University of Michigan"},{"author_name":"Kebire Gofar","author_inst":"The Ohio State University"},{"author_name":"Beth Dudley","author_inst":"University of Pittsburgh"},{"author_name":"Eve Karloski","author_inst":"University of Pittsburgh"},{"author_name":"Conner Lombardi","author_inst":"University of Colorado"},{"author_name":"Michelle Springer","author_inst":"University of Colorado"},{"author_name":"Souvik Saha","author_inst":"University of Kansas"},{"author_name":"Devin Cox","author_inst":"University of Kansas"},{"author_name":"Benjamin A. Lerner","author_inst":"Yale University"},{"author_name":"George Hanna","author_inst":"Yale University"},{"author_name":"Yana Chertock","author_inst":"Fox Chase Cancer Center"},{"author_name":"Afshin Khan","author_inst":"University of California San Francisco"},{"author_name":"Sarah Ertan","author_inst":"University of California San Francisco"},{"author_name":"Kimberly Hilfrank","author_inst":"Columbia University"},{"author_name":"Sheila D. Rustgi","author_inst":"Columbia University"},{"author_name":"Aparajita Singh","author_inst":"University of California San Francisco"},{"author_name":"Michael J. Hall","author_inst":"Fox Chase Cancer Center"},{"author_name":"Xavier Llor","author_inst":"Yale University"},{"author_name":"Ajay Bansal","author_inst":"University of Kansas"},{"author_name":"Swati G. Patel","author_inst":"University of Colorado"},{"author_name":"Randall E. Brand","author_inst":"University of Pittsburgh"},{"author_name":"Maegan E. Roberts","author_inst":"The Ohio State University"},{"author_name":"Peter P. Stanich","author_inst":"The Ohio State University"},{"author_name":"Elena Stoffel","author_inst":"University of Michigan"},{"author_name":"Bryson W. Katona","author_inst":"University of Pennsylvania"},{"author_name":"Melyssa Aronson","author_inst":"Sinai Health System"},{"author_name":"Sonia S. Kupfer","author_inst":"University of Chicago"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Evaluating the Use of GLP-1 Receptor Agonists in Wolfram syndrome Patients","rel_doi":"10.64898\/2026.03.31.26349885","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349885","rel_abs":"Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene, characterized by early-onset diabetes mellitus, optic atrophy, sensorineural hearing loss, arginine vasopressin deficiency, and progressive neurodegeneration. The condition selectively affects pancreatic {beta} cells and neurons via chronic endoplasmic reticulum (ER) stress, and no proven disease-modifying therapy currently exists. Diabetes mellitus is typically the first manifestation, presenting at a mean age of 6 years as an insulin-dependent phenotype with preserved C-peptide and negative diabetes-related autoantibodies.\n\nGlucagon-like peptide-1 receptor agonists (GLP-1 RAs) are well-established agents in the management of type 2 diabetes, augmenting glucose-dependent insulin secretion, suppressing glucagon, slowing gastric emptying, and promoting satiety. Preclinical evidence further suggests that GLP-1 RAs preserve {beta}-cell mass, attenuate ER stress, and confer neuroprotective effects, properties of particular therapeutic relevance to Wolfram syndrome.\n\nWe conducted a retrospective cohort study of 84 participants with genetically confirmed Wolfram syndrome and insulin-dependent diabetes mellitus enrolled in the Washington University Wolfram Syndrome International Registry and Clinical Study. Clinical data were extracted from medical records; for participants concurrently enrolled in the Tracking Neurodegeneration in Early Wolfram Syndrome study, longitudinal data were obtained from that source as well. Thirty-five percent of eligible participants had received a GLP-1 RA at some point during follow-up. We characterize the prevalence of GLP-1 RA use, documented rationale for initiation, observed effects on glycemic control and visual outcomes, adverse effects, and reasons for discontinuation. No statistically significant changes in hemoglobin A1c (HbA1c) or body mass index (BMI) were observed. Visual acuity declined significantly at two years, consistent with expected disease progression. Gastrointestinal adverse effects were common and contributed to frequent discontinuation.\n\nThese observational data provide important clinical context and a foundation for future prospective trials evaluating GLP-1 RAs as a potential disease-modifying strategy in Wolfram syndrome.","rel_num_authors":11,"rel_authors":[{"author_name":"Laura Lee","author_inst":"Washington University School of Medicine"},{"author_name":"Abby F Tang","author_inst":"Washington University School of Medicine"},{"author_name":"Anna Asako","author_inst":"Washington University School of Medicine"},{"author_name":"Sarah F Ning","author_inst":"Washington University School of Medicine"},{"author_name":"Hayden A Reed","author_inst":"Washington University School of Medicine"},{"author_name":"Eleanor Duncan","author_inst":"Washington University School of Medicine"},{"author_name":"Heather M Lugar","author_inst":"Washington University School of Medicine"},{"author_name":"James Hoekel","author_inst":"Washington University School of Medicine"},{"author_name":"Bess A Marshall","author_inst":"Washington University School of Medicine"},{"author_name":"Tamara Hershey","author_inst":"Washington University School of Medicine"},{"author_name":"Fumihiko Urano","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Influenza vaccine effectiveness against influenza A-associated hospitalization and severe in-hospital outcomes among adults in the United States, 2024-2025","rel_doi":"10.64898\/2026.03.31.26349873","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349873","rel_abs":"BackgroundThe U.S. 2024-2025 influenza season was characterized by sustained elevated activity from November 2024-April 2025, with circulation of both influenza A(H1N1)pdm09 and A(H3N2), the latter of which included some antigenically drifted viruses.\n\nMethodsFrom October 1, 2024, to April 30, 2025, a multistate respiratory virus surveillance network enrolled adults hospitalized with acute respiratory illness in 26 U.S. medical centers. Influenza vaccine effectiveness (VE) against influenza-associated hospitalization and severe in-hospital outcomes was estimated using a test-negative study. The odds of influenza vaccination among influenza-positive case patients and influenza-negative control patients were compared using multivariable logistic regression; VE was calculated as (1 - adjusted odds ratio for vaccination) x 100, expressed as a percent.\n\nResultsThe 2024-2025 seasonal influenza vaccine was effective against influenza-associated hospitalization (VE: 40% [95% confidence interval (CI): 32%-47%]), consistent across age group and influenza A subtypes. Influenza vaccination also reduced the overall risk of all severe in-hospital outcomes evaluated, including standard oxygen therapy (VE: 41% [95% CI: 31%-50%]), non-invasive advanced respiratory support (VE: 38% [95% CI: 19%-52%]), invasive organ support (VE: 58% [95% CI: 44%-69%]), ICU admission (VE: 58% [95% CI: 47%-67%]), and death (VE: 52% [95% CI: 18%-71%]) with effectiveness varying by influenza A subtype and age.\n\nConclusionsInfluenza vaccination reduced the risk of influenza-related hospitalization and severe in-hospital outcomes in adults during the severe 2024-2025 influenza season compared to those not vaccinated.","rel_num_authors":32,"rel_authors":[{"author_name":"Nathaniel M Lewis","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Seana Cleary","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Elizabeth J Harker","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Basmah Safdar","author_inst":"Department of Emergency Medicine, Yale University, New Haven, Connecticut, USA"},{"author_name":"Adit A Ginde","author_inst":"University of Colorado School of Medicine"},{"author_name":"Ithan D Peltan","author_inst":"Intermountain Medical Center, Murray, Utah, USA"},{"author_name":"Manjusha Gaglani","author_inst":"College of Medicine, Baylor University, Temple, Texas, USA"},{"author_name":"Cristie Columbus","author_inst":"Department of Medicine, Baylor Scott & White Health, Dallas, Texas, USA"},{"author_name":"Emily Toth Martin","author_inst":"University of Michigan-Ann Arbor"},{"author_name":"Adam S. Lauring","author_inst":"University of Michigan"},{"author_name":"Jay S Steingrub","author_inst":"Department of Medicine, Baystate Medical Center, Springfield, Massachusetts, USA"},{"author_name":"David N Hager","author_inst":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"},{"author_name":"Amira Mohamed","author_inst":"Department of Medicine, Montefiore Medical Center, Bronx, New York, USA"},{"author_name":"Nicholas J Johnson","author_inst":"University of Washington\/Harborview Medical Center"},{"author_name":"Akram Khan","author_inst":"Oregon Health and Science University, Portland, Oregon, USA"},{"author_name":"Abhijit Duggal","author_inst":"Cleveland Clinic"},{"author_name":"Jennifer G Wilson","author_inst":"Department of Emergency Medicine, Stanford University, Stanford, California, USA"},{"author_name":"Nida Qadir","author_inst":"Department of Medicine, University of California, Los Angeles, California, USA"},{"author_name":"Laurence W Busse","author_inst":"Department of Medicine, Emory University, Atlanta, Georgia, USA"},{"author_name":"Jennie H Kwon","author_inst":"Department of Medicine, Northwestern University, Chicago, Illinois, USA"},{"author_name":"Matthew C Exline","author_inst":"Department of Medicine, The Ohio State University, Columbus, Ohio, USA"},{"author_name":"Ivana A Vaughn","author_inst":"Department of Public Health Sciences, Henry Ford Health, Detroit, Michigan, USA"},{"author_name":"Jarrod M Mosier","author_inst":"Department of Emergency Medicine, University of Arizona, Tucson, Arizona, USA"},{"author_name":"Estelle S Harris","author_inst":"Department of Medicine, University of Utah, Salt Lake City, Utah, USA"},{"author_name":"Yuwei Zhu","author_inst":"Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Carlos G Grijalva","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Natasha B Halasa","author_inst":"Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"James Chappell","author_inst":"Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Diya Surie","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Fatimah S Dawood","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Sascha R Ellington","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Wesley H. Self","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Influenza vaccine effectiveness against influenza A-associated hospitalization and severe in-hospital outcomes among adults in the United States, 2024-2025","rel_doi":"10.64898\/2026.03.31.26349873","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349873","rel_abs":"BackgroundThe U.S. 2024-2025 influenza season was characterized by sustained elevated activity from November 2024-April 2025, with circulation of both influenza A(H1N1)pdm09 and A(H3N2), the latter of which included some antigenically drifted viruses.\n\nMethodsFrom October 1, 2024, to April 30, 2025, a multistate respiratory virus surveillance network enrolled adults hospitalized with acute respiratory illness in 26 U.S. medical centers. Influenza vaccine effectiveness (VE) against influenza-associated hospitalization and severe in-hospital outcomes was estimated using a test-negative study. The odds of influenza vaccination among influenza-positive case patients and influenza-negative control patients were compared using multivariable logistic regression; VE was calculated as (1 - adjusted odds ratio for vaccination) x 100, expressed as a percent.\n\nResultsThe 2024-2025 seasonal influenza vaccine was effective against influenza-associated hospitalization (VE: 40% [95% confidence interval (CI): 32%-47%]), consistent across age group and influenza A subtypes. Influenza vaccination also reduced the overall risk of all severe in-hospital outcomes evaluated, including standard oxygen therapy (VE: 41% [95% CI: 31%-50%]), non-invasive advanced respiratory support (VE: 38% [95% CI: 19%-52%]), invasive organ support (VE: 58% [95% CI: 44%-69%]), ICU admission (VE: 58% [95% CI: 47%-67%]), and death (VE: 52% [95% CI: 18%-71%]) with effectiveness varying by influenza A subtype and age.\n\nConclusionsInfluenza vaccination reduced the risk of influenza-related hospitalization and severe in-hospital outcomes in adults during the severe 2024-2025 influenza season compared to those not vaccinated.","rel_num_authors":32,"rel_authors":[{"author_name":"Nathaniel M Lewis","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Seana Cleary","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Elizabeth J Harker","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Basmah Safdar","author_inst":"Department of Emergency Medicine, Yale University, New Haven, Connecticut, USA"},{"author_name":"Adit A Ginde","author_inst":"University of Colorado School of Medicine"},{"author_name":"Ithan D Peltan","author_inst":"Intermountain Medical Center, Murray, Utah, USA"},{"author_name":"Manjusha Gaglani","author_inst":"College of Medicine, Baylor University, Temple, Texas, USA"},{"author_name":"Cristie Columbus","author_inst":"Department of Medicine, Baylor Scott & White Health, Dallas, Texas, USA"},{"author_name":"Emily Toth Martin","author_inst":"University of Michigan-Ann Arbor"},{"author_name":"Adam S. Lauring","author_inst":"University of Michigan"},{"author_name":"Jay S Steingrub","author_inst":"Department of Medicine, Baystate Medical Center, Springfield, Massachusetts, USA"},{"author_name":"David N Hager","author_inst":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"},{"author_name":"Amira Mohamed","author_inst":"Department of Medicine, Montefiore Medical Center, Bronx, New York, USA"},{"author_name":"Nicholas J Johnson","author_inst":"University of Washington\/Harborview Medical Center"},{"author_name":"Akram Khan","author_inst":"Oregon Health and Science University, Portland, Oregon, USA"},{"author_name":"Abhijit Duggal","author_inst":"Cleveland Clinic"},{"author_name":"Jennifer G Wilson","author_inst":"Department of Emergency Medicine, Stanford University, Stanford, California, USA"},{"author_name":"Nida Qadir","author_inst":"Department of Medicine, University of California, Los Angeles, California, USA"},{"author_name":"Laurence W Busse","author_inst":"Department of Medicine, Emory University, Atlanta, Georgia, USA"},{"author_name":"Jennie H Kwon","author_inst":"Department of Medicine, Northwestern University, Chicago, Illinois, USA"},{"author_name":"Matthew C Exline","author_inst":"Department of Medicine, The Ohio State University, Columbus, Ohio, USA"},{"author_name":"Ivana A Vaughn","author_inst":"Department of Public Health Sciences, Henry Ford Health, Detroit, Michigan, USA"},{"author_name":"Jarrod M Mosier","author_inst":"Department of Emergency Medicine, University of Arizona, Tucson, Arizona, USA"},{"author_name":"Estelle S Harris","author_inst":"Department of Medicine, University of Utah, Salt Lake City, Utah, USA"},{"author_name":"Yuwei Zhu","author_inst":"Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Carlos G Grijalva","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Natasha B Halasa","author_inst":"Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"James Chappell","author_inst":"Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Diya Surie","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Fatimah S Dawood","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Sascha R Ellington","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Wesley H. Self","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Influenza vaccine effectiveness against influenza A-associated hospitalization and severe in-hospital outcomes among adults in the United States, 2024-2025","rel_doi":"10.64898\/2026.03.31.26349873","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349873","rel_abs":"BackgroundThe U.S. 2024-2025 influenza season was characterized by sustained elevated activity from November 2024-April 2025, with circulation of both influenza A(H1N1)pdm09 and A(H3N2), the latter of which included some antigenically drifted viruses.\n\nMethodsFrom October 1, 2024, to April 30, 2025, a multistate respiratory virus surveillance network enrolled adults hospitalized with acute respiratory illness in 26 U.S. medical centers. Influenza vaccine effectiveness (VE) against influenza-associated hospitalization and severe in-hospital outcomes was estimated using a test-negative study. The odds of influenza vaccination among influenza-positive case patients and influenza-negative control patients were compared using multivariable logistic regression; VE was calculated as (1 - adjusted odds ratio for vaccination) x 100, expressed as a percent.\n\nResultsThe 2024-2025 seasonal influenza vaccine was effective against influenza-associated hospitalization (VE: 40% [95% confidence interval (CI): 32%-47%]), consistent across age group and influenza A subtypes. Influenza vaccination also reduced the overall risk of all severe in-hospital outcomes evaluated, including standard oxygen therapy (VE: 41% [95% CI: 31%-50%]), non-invasive advanced respiratory support (VE: 38% [95% CI: 19%-52%]), invasive organ support (VE: 58% [95% CI: 44%-69%]), ICU admission (VE: 58% [95% CI: 47%-67%]), and death (VE: 52% [95% CI: 18%-71%]) with effectiveness varying by influenza A subtype and age.\n\nConclusionsInfluenza vaccination reduced the risk of influenza-related hospitalization and severe in-hospital outcomes in adults during the severe 2024-2025 influenza season compared to those not vaccinated.","rel_num_authors":32,"rel_authors":[{"author_name":"Nathaniel M Lewis","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Seana Cleary","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Elizabeth J Harker","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Basmah Safdar","author_inst":"Department of Emergency Medicine, Yale University, New Haven, Connecticut, USA"},{"author_name":"Adit A Ginde","author_inst":"University of Colorado School of Medicine"},{"author_name":"Ithan D Peltan","author_inst":"Intermountain Medical Center, Murray, Utah, USA"},{"author_name":"Manjusha Gaglani","author_inst":"College of Medicine, Baylor University, Temple, Texas, USA"},{"author_name":"Cristie Columbus","author_inst":"Department of Medicine, Baylor Scott & White Health, Dallas, Texas, USA"},{"author_name":"Emily Toth Martin","author_inst":"University of Michigan-Ann Arbor"},{"author_name":"Adam S. Lauring","author_inst":"University of Michigan"},{"author_name":"Jay S Steingrub","author_inst":"Department of Medicine, Baystate Medical Center, Springfield, Massachusetts, USA"},{"author_name":"David N Hager","author_inst":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"},{"author_name":"Amira Mohamed","author_inst":"Department of Medicine, Montefiore Medical Center, Bronx, New York, USA"},{"author_name":"Nicholas J Johnson","author_inst":"University of Washington\/Harborview Medical Center"},{"author_name":"Akram Khan","author_inst":"Oregon Health and Science University, Portland, Oregon, USA"},{"author_name":"Abhijit Duggal","author_inst":"Cleveland Clinic"},{"author_name":"Jennifer G Wilson","author_inst":"Department of Emergency Medicine, Stanford University, Stanford, California, USA"},{"author_name":"Nida Qadir","author_inst":"Department of Medicine, University of California, Los Angeles, California, USA"},{"author_name":"Laurence W Busse","author_inst":"Department of Medicine, Emory University, Atlanta, Georgia, USA"},{"author_name":"Jennie H Kwon","author_inst":"Department of Medicine, Northwestern University, Chicago, Illinois, USA"},{"author_name":"Matthew C Exline","author_inst":"Department of Medicine, The Ohio State University, Columbus, Ohio, USA"},{"author_name":"Ivana A Vaughn","author_inst":"Department of Public Health Sciences, Henry Ford Health, Detroit, Michigan, USA"},{"author_name":"Jarrod M Mosier","author_inst":"Department of Emergency Medicine, University of Arizona, Tucson, Arizona, USA"},{"author_name":"Estelle S Harris","author_inst":"Department of Medicine, University of Utah, Salt Lake City, Utah, USA"},{"author_name":"Yuwei Zhu","author_inst":"Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Carlos G Grijalva","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Natasha B Halasa","author_inst":"Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"James Chappell","author_inst":"Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Diya Surie","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Fatimah S Dawood","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Sascha R Ellington","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Wesley H. Self","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Influenza vaccine effectiveness against influenza A-associated hospitalization and severe in-hospital outcomes among adults in the United States, 2024-2025","rel_doi":"10.64898\/2026.03.31.26349873","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349873","rel_abs":"BackgroundThe U.S. 2024-2025 influenza season was characterized by sustained elevated activity from November 2024-April 2025, with circulation of both influenza A(H1N1)pdm09 and A(H3N2), the latter of which included some antigenically drifted viruses.\n\nMethodsFrom October 1, 2024, to April 30, 2025, a multistate respiratory virus surveillance network enrolled adults hospitalized with acute respiratory illness in 26 U.S. medical centers. Influenza vaccine effectiveness (VE) against influenza-associated hospitalization and severe in-hospital outcomes was estimated using a test-negative study. The odds of influenza vaccination among influenza-positive case patients and influenza-negative control patients were compared using multivariable logistic regression; VE was calculated as (1 - adjusted odds ratio for vaccination) x 100, expressed as a percent.\n\nResultsThe 2024-2025 seasonal influenza vaccine was effective against influenza-associated hospitalization (VE: 40% [95% confidence interval (CI): 32%-47%]), consistent across age group and influenza A subtypes. Influenza vaccination also reduced the overall risk of all severe in-hospital outcomes evaluated, including standard oxygen therapy (VE: 41% [95% CI: 31%-50%]), non-invasive advanced respiratory support (VE: 38% [95% CI: 19%-52%]), invasive organ support (VE: 58% [95% CI: 44%-69%]), ICU admission (VE: 58% [95% CI: 47%-67%]), and death (VE: 52% [95% CI: 18%-71%]) with effectiveness varying by influenza A subtype and age.\n\nConclusionsInfluenza vaccination reduced the risk of influenza-related hospitalization and severe in-hospital outcomes in adults during the severe 2024-2025 influenza season compared to those not vaccinated.","rel_num_authors":32,"rel_authors":[{"author_name":"Nathaniel M Lewis","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Seana Cleary","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Elizabeth J Harker","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Basmah Safdar","author_inst":"Department of Emergency Medicine, Yale University, New Haven, Connecticut, USA"},{"author_name":"Adit A Ginde","author_inst":"University of Colorado School of Medicine"},{"author_name":"Ithan D Peltan","author_inst":"Intermountain Medical Center, Murray, Utah, USA"},{"author_name":"Manjusha Gaglani","author_inst":"College of Medicine, Baylor University, Temple, Texas, USA"},{"author_name":"Cristie Columbus","author_inst":"Department of Medicine, Baylor Scott & White Health, Dallas, Texas, USA"},{"author_name":"Emily Toth Martin","author_inst":"University of Michigan-Ann Arbor"},{"author_name":"Adam S. Lauring","author_inst":"University of Michigan"},{"author_name":"Jay S Steingrub","author_inst":"Department of Medicine, Baystate Medical Center, Springfield, Massachusetts, USA"},{"author_name":"David N Hager","author_inst":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"},{"author_name":"Amira Mohamed","author_inst":"Department of Medicine, Montefiore Medical Center, Bronx, New York, USA"},{"author_name":"Nicholas J Johnson","author_inst":"University of Washington\/Harborview Medical Center"},{"author_name":"Akram Khan","author_inst":"Oregon Health and Science University, Portland, Oregon, USA"},{"author_name":"Abhijit Duggal","author_inst":"Cleveland Clinic"},{"author_name":"Jennifer G Wilson","author_inst":"Department of Emergency Medicine, Stanford University, Stanford, California, USA"},{"author_name":"Nida Qadir","author_inst":"Department of Medicine, University of California, Los Angeles, California, USA"},{"author_name":"Laurence W Busse","author_inst":"Department of Medicine, Emory University, Atlanta, Georgia, USA"},{"author_name":"Jennie H Kwon","author_inst":"Department of Medicine, Northwestern University, Chicago, Illinois, USA"},{"author_name":"Matthew C Exline","author_inst":"Department of Medicine, The Ohio State University, Columbus, Ohio, USA"},{"author_name":"Ivana A Vaughn","author_inst":"Department of Public Health Sciences, Henry Ford Health, Detroit, Michigan, USA"},{"author_name":"Jarrod M Mosier","author_inst":"Department of Emergency Medicine, University of Arizona, Tucson, Arizona, USA"},{"author_name":"Estelle S Harris","author_inst":"Department of Medicine, University of Utah, Salt Lake City, Utah, USA"},{"author_name":"Yuwei Zhu","author_inst":"Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Carlos G Grijalva","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Natasha B Halasa","author_inst":"Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"James Chappell","author_inst":"Vanderbilt University Medical Center, Nashville, Tennessee, USA"},{"author_name":"Diya Surie","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Fatimah S Dawood","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Sascha R Ellington","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Wesley H. Self","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-04-02","rel_site":"medrxiv"},{"rel_title":"Chromosomal rearrangements 1 and sequence similarity drivepreferential allosyndetic introgression from a wild relative into wheat","rel_doi":"10.64898\/2026.03.31.715614","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.03.31.715614","rel_abs":"Recombination in polyploid genomes is generally constrained to homologous or homoeologous chromosomes; however, how chromosomal rearrangements influence recombination between chromosomes remains unclear. Here, we demonstrate that large-scale chromosomal rearrangements in the wild relatives of wheat are associated with recombination involving non-homoeologous chromosomes or arms during alien gene introgression under conditions that permit homoeologous recombination mediated by ph1b. Using a wheat chromosome 6A monosomic-induced 6AS\/6CL Robertsonian translocation combined with ph1b-mediated recombination, we generated 17 independent recombinants carrying a new stem rust resistance gene, Sr69, from Aegilops caudata chromosome arm 6CL. Unexpectedly, 94.1% (16 of 17) of recombinants resulted from exchanges with wheat group-7 chromosomes rather than with the homoeologous group-6 chromosome. Comparative sequence- and marker-based analyses identified a 67-Mb rearranged interval on Ae. caudata 6CL that corresponds to telomeric regions of the long arms of wheat group-7 chromosomes. Sequence similarity within this interval was quantitatively associated with recombination frequency, with higher similarity corresponding to more frequent translocations. Physical and optical mapping showed that recombination within the rearranged interval generated compensating 7A\/6C, 7B\/6C, and 7D\/6C translocations, whereas recombination outside this region produced non-compensating 6A\/6C exchanges. An independent case involving the powdery mildew resistance gene Pm7C showed a similar correspondence between a rearranged 7CL region and preferential introgression into wheat 7DS. Together, these results indicate that ph1b-mediated recombination involving structurally altered chromosomes is driven by local chromosomal structure and sequence similarity rather than strict homoeologous group identity. This provides a mechanistic basis for harnessing untapped beneficial genes from structurally rearranged alien genomes.","rel_num_authors":24,"rel_authors":[{"author_name":"Honglian Ye","author_inst":"Department of Plant Sciences, University of California, Davis, CA 95616"},{"author_name":"Qijun Zhang","author_inst":"North Dakota State University"},{"author_name":"Prakitchai Chotewutmontri","author_inst":"USDA-ARS, Crop Improvement and Genetic Research Unit, Western Regional Research Center, Albany, CA 94710"},{"author_name":"Swarupa Nanda Mandal","author_inst":"UC Davis"},{"author_name":"Zhixia Niu","author_inst":"USDA"},{"author_name":"Yunming Long","author_inst":"UC Berkeley"},{"author_name":"Jianqiang Shen","author_inst":"UC Berkeley"},{"author_name":"Rebecca B. Whetten","author_inst":"USDA"},{"author_name":"Genqiao Li","author_inst":"USDA"},{"author_name":"Yue Jin","author_inst":"Departmen of Plant Pathology, University of Minnesota, St. Paul, MN 55108"},{"author_name":"Sam Gale","author_inst":"USDA-ARS, Cereal Disease Laboratory, Saint Paul, MN 55108"},{"author_name":"Timothy L. Friesen","author_inst":"USDA-ARS, Cereal Crops Improvement Research Unit, Edward T. Schafer Agricultural Research Center"},{"author_name":"Amanda Peters Haugrud","author_inst":"USDA-ARS, Edward T. Schafer Agricultural Research Center"},{"author_name":"Xiangyang Xu","author_inst":"USDA-ARS Wheat, Peanut, and Other Field Crop Research Unit, Stillwater, OK 74075"},{"author_name":"Justin Faris","author_inst":"USDA-ARS, Cereal Crops Improvement Research Unit, Edward T. Schafer Agricultural Research Center, Fargo, ND 58102"},{"author_name":"Shengming Yang","author_inst":"USDA-ARS, Cereal Crops Improvement Research Unit, Edward T. Schafer Agricultural Research Center, Fargo, ND 58102"},{"author_name":"Christina Cowger","author_inst":"USDA-ARS, Plant Science Research Unit, Raleigh, NC 27695;"},{"author_name":"Jianli Chen","author_inst":"Department of Plant Sciences, University of Idaho Aberdeen Research & Extension Center, ID 83210"},{"author_name":"Xiwen Cai","author_inst":"USDA-ARS, Wheat, Sorghum & Forage Research Unit, Lincoln, NE 68583"},{"author_name":"Xiaofei Zhang","author_inst":"Department of Plant Sciences, University of California, Davis, CA 95616"},{"author_name":"Sheng Luan","author_inst":"Department of Plant and Microbial Biology, University of California, Berkeley, CA 94720"},{"author_name":"Yong Gu","author_inst":"USDA-ARS, Crop Improvement and Genetic Research Unit, Western Regional Research Center, Albany, CA 94710"},{"author_name":"Daryl L. Klindworth","author_inst":"USDA-ARS, Cereal Crops Improvement Research Unit, Edward T. Schafer Agricultural Research Center, Fargo, ND 58102"},{"author_name":"Steven S. Xu","author_inst":"USDA-ARS, Crop Improvement and Genetic Research Unit, Western Regional Research Center, Albany, CA 94710"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"A versatile cryopreservation method for peri-gastrulation squamate embryos optimised using the veiled chameleon (C. calyptratus)","rel_doi":"10.64898\/2026.04.01.715795","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.04.01.715795","rel_abs":"Stem cell technologies have become a vital component of conservation efforts around the globe. Biobanks and pluripotent stem cell lines help to ensure species and their genetic diversity are preserved. These efforts have however, focussed mostly on mammals and birds, and the cryopreservation protocols for embryos and cells were developed decades ago laying the basis for artificial reproductive techniques for species conservation. With over 20% of non-avian reptile species facing extinction, it is imperative to establish protocols for reptiles to ensure species preservation and also to facilitate the establishment of new reptile model organisms to match the standard of mammals. Here, we have generated a cryopreservation method for preserving early gastrulating veiled chameleon embryos as a representative squamate species. To this end, we first developed a tissue culture method for maintaining cells extracted from peri-gastrulation chameleon embryos and then tested different cryopreservation methods altering the concentration of the penetrating cryoprotectant DMSO and assessing the effect of the addition of non-penetrating cryoprotectants Trehalose and Sucrose. We then optimised a protocol for whole embryo vitrification in 20% DMSO with added Trehalose or Sucrose that can easily be adapted for fieldwork. Taken together, our method not only provides a protocol for conservation efforts but also lays the basis for mechanistic studies of early squamate embryo development by enabling cryopreservation of whole embryos in a fieldwork setting, which facilitates their live transport back to a laboratory for functional experiments or molecular analyses.","rel_num_authors":8,"rel_authors":[{"author_name":"Antonia Weberling","author_inst":"University of Oxford"},{"author_name":"Michael Durnin","author_inst":"Stowers Institute for Medical Research"},{"author_name":"Natalia A Shylo","author_inst":"Rowan University, Glassboro"},{"author_name":"Mary Cathleen McKinney","author_inst":"Stowers Institute for Medical Research"},{"author_name":"Hannah Wilson","author_inst":"Stowers Institute for Medical Research"},{"author_name":"Richard Kupronis","author_inst":"Stowers Institute for Medical Research"},{"author_name":"Suzannah A Williams","author_inst":"University of Oxford"},{"author_name":"Paul Trainor","author_inst":"Stowers Institue for Medical Research"}],"rel_date":"2026-04-02","rel_site":"biorxiv"},{"rel_title":"Chinese College Student Gamers Cohort (CCSGC): Multimodal Longitudinal Insights into Internet Gaming Disorder's Biopsychosocial Mechanisms and Risk Trajectories","rel_doi":"10.64898\/2026.04.01.26349949","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.04.01.26349949","rel_abs":"Internet gaming disorder (IGD) presents a significant public health challenge, yet its complex biopsychosocial mechanisms and dynamic risk trajectories remain poorly understood due to a scarcity of comprehensive longitudinal and multimodal cohorts. To address this critical gap, we established the Chinese College Student Gamers Cohort (CCSGC), a prospective, multimodal longitudinal study of 793 first-year undergraduates primarily playing Honor of Kings from 2022 Sept. The CCSGC integrates semi-annual psychosocial questionnaires, annual neuroimaging (EEG\/fMRI), and biospecimen collection over multiple years. Baseline data revealed individuals with IGD (n=211) exhibited significantly higher gaming craving, psychological distress (depression, anxiety), impulsivity, and maladaptive motivational features compared to non-IGD gamers (regular players (RP) n=400; casual players (CP) n=182). Longitudinal analyses across four waves indicated bidirectional temporal associations between IGD severity and mental symptoms, and a stabilization of IGD incidence after an initial decrease. Furthermore, specific neurophysiological (e.g., N400 amplitude to game cues) and neuroimaging (e.g., superior parietal activation) markers were identified that correlated with IGD severity and predicted one-year outcomes in gaming disorder or social functioning. The CCSGC provides an invaluable resource for dissecting the heterogeneity, comorbidity, and intricate biopsychosocial mechanisms of IGD, holding significant potential to advance risk prediction, early identification, and targeted intervention strategies.","rel_num_authors":14,"rel_authors":[{"author_name":"Huang Yuchen","author_inst":"Department of Neurobiology, School of Basic Medical Sciences, National Institute on Drug Dependence, Peking University, Beijing, China"},{"author_name":"Zhou Guangdong","author_inst":"Faculty of Psychology, Tianjin Normal University, Tianjin 300387, China"},{"author_name":"Liu Yifan","author_inst":"Department of Neurobiology, School of Basic Medical Sciences, National Institute on Drug Dependence, Peking University, Beijing, China"},{"author_name":"Xiang Shitong","author_inst":"Institute of Science and Technology for Brain - Inspired Intelligence, Fudan University"},{"author_name":"Zheng Qihong","author_inst":"Department of Neurobiology, School of Basic Medical Sciences, National Institute on Drug Dependence, Peking University, Beijing, China"},{"author_name":"Wang Zifeng","author_inst":"Faculty of Psychology, Tianjin Normal University, Tianjin 300387, China"},{"author_name":"Song Yixuan","author_inst":"Department of Neurobiology, School of Basic Medical Sciences, National Institute on Drug Dependence, Peking University, Beijing, China"},{"author_name":"Liu Wangyue","author_inst":"Department of Neurobiology, School of Basic Medical Sciences, National Institute on Drug Dependence, Peking University, Beijing, China"},{"author_name":"Wu Taoyu","author_inst":"Department of Neurobiology, School of Basic Medical Sciences, National Institute on Drug Dependence, Peking University, Beijing, China"},{"author_name":"Meng Shiqiu","author_inst":"Department of Neurobiology, School of Basic Medical Sciences, National Institute on Drug Dependence, Peking University, Beijing, China"},{"author_name":"Liao Yanhui","author_inst":"Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"},{"author_name":"Jia Tianye","author_inst":"Department of Neurobiology, School of Basic Medical Sciences, National Institute on Drug Dependence, Peking University, Beijing, China"},{"author_name":"Shi Jie","author_inst":"Department of Neurobiology, School of Basic Medical Sciences, National Institute on Drug Dependence, Peking University, Beijing, China"},{"author_name":"Sun Yan","author_inst":"Department of Neurobiology, School of Basic Medical Sciences, National Institute on Drug Dependence, Peking University, Beijing, China"}],"rel_date":"2026-04-01","rel_site":"medrxiv"},{"rel_title":"Data sharing policies, requirements, and support from public and private clinical trial sponsors: a survey on top sponsors of clinical trials in Europe","rel_doi":"10.64898\/2026.03.31.26349853","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349853","rel_abs":"ObjectiveTo map the presence, public availability, and content of clinical trial data sharing policies (DSP), data management and sharing plans (DMSP), and data use agreements (DUA) among the most prolific public and private clinical trial sponsors operating in the European Union, and to identify key areas of convergence, divergence, and constraint in the context of General Data Protection Regulation (GDPR).\n\nEligibility criteriaWe included organisation-level documents describing approaches to clinical trial data sharing or data management from the top 20 public and top 20 private sponsors ranked by the number of trials registered in the EU Clinical Trials Information System (CTIS). Eligible materials comprised publicly available or sponsor-shared policies, guidelines, statements, templates, and agreements relevant to clinical trial data sharing or management.\n\nSources of evidenceEvidence was identified through systematic searches of sponsors public websites, structured Google searches, and major data management plan platforms (DMPTool, DMPonline, DMP Assistant), complemented by direct contact with sponsors to verify findings and request missing documentation. All sources were archived and catalogued.\n\nCharting methodsTwo reviewers independently extracted data using a structured form, capturing the existence, accessibility, and content of data sharing policies, data management and sharing plans, and data use agreements. Quantitative data were summarised descriptively, and a non-interpretive descriptive content analysis was conducted to characterise recurring policy elements and areas of heterogeneity.\n\nResultsAmong 40 sponsors, private sponsors were substantially more likely than public sponsors to make trial-specific data sharing policies and data use agreements publicly accessible, often via established data sharing platforms. Public sponsors more frequently referenced data management and sharing plans, but these were heterogeneous in scope and often embedded within broader institutional governance documents rather than tailored to clinical trials. Across sectors, GDPR compliance, data protection, and legal safeguards were emphasised, while operational aspects such as dataset readiness, review criteria, and downstream responsibilities varied widely. Overall response rate to sponsor verification was 37.5%.\n\nConclusionClinical trial data sharing governance in the EU shows a marked sectoral imbalance among the top sponsors. Private sponsors tend to provide more detailed and operationally explicit documentation, whereas public sponsors often articulate high-level commitments without trial-specific guidance. Greater clarity and standardisation, particularly among public sponsors, could improve transparency and facilitate responsible data reuse, while remaining compatible with GDPR requirements.","rel_num_authors":7,"rel_authors":[{"author_name":"Ka Hin Tai","author_inst":"Universit\u00e9 de Rennes"},{"author_name":"Giulia Varvar\u00e0","author_inst":"Universit\u00e9 de Rennes"},{"author_name":"Emma Escoffier","author_inst":"Universit\u00e9 de Rennes"},{"author_name":"Ulrich Mansmann","author_inst":"University of Munich"},{"author_name":"Nicholas J DeVito","author_inst":"University of Oxford"},{"author_name":"Anna Catharina Vieira Armond","author_inst":"University of Ottawa Heart Institute"},{"author_name":"Florian Naudet","author_inst":"Universit\u00e9 de Rennes"}],"rel_date":"2026-04-01","rel_site":"medrxiv"},{"rel_title":"Data sharing policies, requirements, and support from public and private clinical trial sponsors: a survey on top sponsors of clinical trials in Europe","rel_doi":"10.64898\/2026.03.31.26349853","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.03.31.26349853","rel_abs":"ObjectiveTo map the presence, public availability, and content of clinical trial data sharing policies (DSP), data management and sharing plans (DMSP), and data use agreements (DUA) among the most prolific public and private clinical trial sponsors operating in the European Union, and to identify key areas of convergence, divergence, and constraint in the context of General Data Protection Regulation (GDPR).\n\nEligibility criteriaWe included organisation-level documents describing approaches to clinical trial data sharing or data management from the top 20 public and top 20 private sponsors ranked by the number of trials registered in the EU Clinical Trials Information System (CTIS). Eligible materials comprised publicly available or sponsor-shared policies, guidelines, statements, templates, and agreements relevant to clinical trial data sharing or management.\n\nSources of evidenceEvidence was identified through systematic searches of sponsors public websites, structured Google searches, and major data management plan platforms (DMPTool, DMPonline, DMP Assistant), complemented by direct contact with sponsors to verify findings and request missing documentation. All sources were archived and catalogued.\n\nCharting methodsTwo reviewers independently extracted data using a structured form, capturing the existence, accessibility, and content of data sharing policies, data management and sharing plans, and data use agreements. Quantitative data were summarised descriptively, and a non-interpretive descriptive content analysis was conducted to characterise recurring policy elements and areas of heterogeneity.\n\nResultsAmong 40 sponsors, private sponsors were substantially more likely than public sponsors to make trial-specific data sharing policies and data use agreements publicly accessible, often via established data sharing platforms. Public sponsors more frequently referenced data management and sharing plans, but these were heterogeneous in scope and often embedded within broader institutional governance documents rather than tailored to clinical trials. Across sectors, GDPR compliance, data protection, and legal safeguards were emphasised, while operational aspects such as dataset readiness, review criteria, and downstream responsibilities varied widely. Overall response rate to sponsor verification was 37.5%.\n\nConclusionClinical trial data sharing governance in the EU shows a marked sectoral imbalance among the top sponsors. Private sponsors tend to provide more detailed and operationally explicit documentation, whereas public sponsors often articulate high-level commitments without trial-specific guidance. Greater clarity and standardisation, particularly among public sponsors, could improve transparency and facilitate responsible data reuse, while remaining compatible with GDPR requirements.","rel_num_authors":7,"rel_authors":[{"author_name":"Ka Hin Tai","author_inst":"Universit\u00e9 de Rennes"},{"author_name":"Giulia Varvar\u00e0","author_inst":"Universit\u00e9 de Rennes"},{"author_name":"Emma Escoffier","author_inst":"Universit\u00e9 de Rennes"},{"author_name":"Ulrich Mansmann","author_inst":"University of Munich"},{"author_name":"Nicholas J DeVito","author_inst":"University of Oxford"},{"author_name":"Anna Catharina Vieira Armond","author_inst":"University of Ottawa Heart Institute"},{"author_name":"Florian Naudet","author_inst":"Universit\u00e9 de Rennes"}],"rel_date":"2026-04-01","rel_site":"medrxiv"}]}