{"gname":"University of Illinois Chicago","grp_id":"43","rels":[{"rel_title":"Protonation- and substrate-regulated dimer opening couples brain-type creatine kinase to vesicular and actin-remodeling membranes","rel_doi":"10.64898\/2026.08.04.742861","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.04.742861","rel_abs":"Brain-type creatine kinase (CK-BB) buffers local ATP demand through reversible phosphotransfer between ATP and phosphocreatine, yet how this soluble metabolic enzyme couples to dynamic membrane compartments remains unclear. Here, we integrate immunofluorescence microscopy, DEER spectroscopy, hydrogen-deuterium exchange and native mass spectrometry, DEER- and AlphaFold-guided modeling, and long-timescale molecular dynamics to define the acid- and substrate-regulated conformational landscape of human CK-BB. Acidification redistributes endogenous and recombinant CK-BB from a diffuse cytosolic pool to punctate vesicular structures and membrane ruffles. DEER and modeling reveal a spatially asymmetric dimer in which the convex surface remains comparatively restrained, whereas the concave catalytic-regulatory surface samples pH- and substrate-dependent conformational intermediates. We identify progressive dimer opening as a novel regulatory mechanism by which acidic pH and substrate binding increase dynamics across the convex surface and NTD-NTD interface and sensitize the His191\/Ser199 module to graded pH-dependent exchange. Substrate binding buffers acid-induced deprotection while preserving localized dynamics near this regulatory interface. Together, these data support a model in which protonation and substrate occupancy generate membrane-competent CK-BB conformations, coupling local ATP regeneration to curved vesicular and actin-remodeling membranes.","rel_num_authors":12,"rel_authors":[{"author_name":"Samantha Gies","author_inst":"Saint Louis University School of Medicine"},{"author_name":"Nolan K. McLaughlin","author_inst":"Washington University in St. Louis"},{"author_name":"Ahmed Shubbar","author_inst":"University of Arkansas"},{"author_name":"Chen Kong","author_inst":"Washington University School of Medicine"},{"author_name":"Tianqi Wu","author_inst":"Vanderbilt University"},{"author_name":"Sana Khan","author_inst":"Washington University School of Medicine"},{"author_name":"Alessandro Ustione","author_inst":"Washington University School of Medicine"},{"author_name":"Ian Miller","author_inst":"Saint Louis University School of Medicine"},{"author_name":"David W. Piston","author_inst":"Washington University School of Medicine"},{"author_name":"Mahmoud Moradi","author_inst":"University of Arkansas"},{"author_name":"Michael L. Gross","author_inst":"Washington University"},{"author_name":"Reza Dastvan","author_inst":"Saint Louis University School of Medicine"}],"rel_date":"2026-08-09","rel_site":"biorxiv"},{"rel_title":"Protonation- and substrate-regulated dimer opening couples brain-type creatine kinase to vesicular and actin-remodeling membranes","rel_doi":"10.64898\/2026.08.04.742861","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.04.742861","rel_abs":"Brain-type creatine kinase (CK-BB) buffers local ATP demand through reversible phosphotransfer between ATP and phosphocreatine, yet how this soluble metabolic enzyme couples to dynamic membrane compartments remains unclear. Here, we integrate immunofluorescence microscopy, DEER spectroscopy, hydrogen-deuterium exchange and native mass spectrometry, DEER- and AlphaFold-guided modeling, and long-timescale molecular dynamics to define the acid- and substrate-regulated conformational landscape of human CK-BB. Acidification redistributes endogenous and recombinant CK-BB from a diffuse cytosolic pool to punctate vesicular structures and membrane ruffles. DEER and modeling reveal a spatially asymmetric dimer in which the convex surface remains comparatively restrained, whereas the concave catalytic-regulatory surface samples pH- and substrate-dependent conformational intermediates. We identify progressive dimer opening as a novel regulatory mechanism by which acidic pH and substrate binding increase dynamics across the convex surface and NTD-NTD interface and sensitize the His191\/Ser199 module to graded pH-dependent exchange. Substrate binding buffers acid-induced deprotection while preserving localized dynamics near this regulatory interface. Together, these data support a model in which protonation and substrate occupancy generate membrane-competent CK-BB conformations, coupling local ATP regeneration to curved vesicular and actin-remodeling membranes.","rel_num_authors":12,"rel_authors":[{"author_name":"Samantha Gies","author_inst":"Saint Louis University School of Medicine"},{"author_name":"Nolan K. McLaughlin","author_inst":"Washington University in St. Louis"},{"author_name":"Ahmed Shubbar","author_inst":"University of Arkansas"},{"author_name":"Chen Kong","author_inst":"Washington University School of Medicine"},{"author_name":"Tianqi Wu","author_inst":"Vanderbilt University"},{"author_name":"Sana Khan","author_inst":"Washington University School of Medicine"},{"author_name":"Alessandro Ustione","author_inst":"Washington University School of Medicine"},{"author_name":"Ian Miller","author_inst":"Saint Louis University School of Medicine"},{"author_name":"David W. Piston","author_inst":"Washington University School of Medicine"},{"author_name":"Mahmoud Moradi","author_inst":"University of Arkansas"},{"author_name":"Michael L. Gross","author_inst":"Washington University"},{"author_name":"Reza Dastvan","author_inst":"Saint Louis University School of Medicine"}],"rel_date":"2026-08-09","rel_site":"biorxiv"},{"rel_title":"A Framework for Benchmarking Pathway Reconstruction Algorithms","rel_doi":"10.64898\/2026.08.04.742550","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.04.742550","rel_abs":"Cells coordinate diverse biological processes through interactions among thousands of molecules, but mapping these interactions comprehensively and systematically remains an open problem. Pathway reconstruction algorithms address this problem by linking molecules of interest, identified from high-throughput omics experiments, using prior knowledge encoded as background interaction networks. This process recovers intermediate molecules and interactions that were not directly measured in the experimental data but plausibly connect the observed molecules. It generates testable hypotheses about interactions that drive cell behavior and informs the choice of follow-up experiments. Many algorithms have been created over decades, each optimizing different computational objectives and relying on different assumptions. The resulting heterogeneity has made benchmarking challenging, limiting systematic comparisons. Therefore, selecting an algorithm for a given biological context remains a non-trivial and poorly informed task. This registered report presents a large-scale benchmark of pathway reconstruction algorithms, evaluating 14 algorithms across 822 datasets from four biological settings. To enable this benchmark, we introduce Signaling Pathway Reconstruction Analysis Streamliner (SPRAS), which standardizes algorithm inputs, outputs, and execution into a formal framework, enabling systematic comparison that was previously infeasible. We will assess each algorithm on reconstruction performance against gold standard pathways, algorithm similarity, and computational performance across different biological contexts. Together, these evaluations will provide quantitative evidence for understanding pathway reconstruction algorithm behavior and guiding algorithm selection.","rel_num_authors":23,"rel_authors":[{"author_name":"Neha Talluri","author_inst":"University of Wisconsin-Madison; Morgridge Institute for Research"},{"author_name":"Tristan Figueroa-Reid","author_inst":"Reed College"},{"author_name":"Justin Hiemstra","author_inst":"Morgridge Institute for Research"},{"author_name":"Chris S Magnano","author_inst":"University of Wisconsin-Madison; Morgridge Institute for Research"},{"author_name":"Adam Shedivy","author_inst":"University of Wisconsin-Madison; Morgridge Institute for Research"},{"author_name":"Nistha Panda","author_inst":"University of Wisconsin-Madison; Morgridge Institute for Research"},{"author_name":"Yancheng Liu","author_inst":"Reed College"},{"author_name":"Sumedha Sanjeev","author_inst":"University of Wisconsin-Madison; Morgridge Institute for Research"},{"author_name":"Oliver Faulkner Anderson","author_inst":"Reed College"},{"author_name":"Altaf Barelvi","author_inst":"Reed College"},{"author_name":"Aden O'Brien","author_inst":"Reed College"},{"author_name":"Olivia T Johnson","author_inst":"University of Wisconsin-Madison"},{"author_name":"James A Haddad","author_inst":"University of Wisconsin-Madison"},{"author_name":"Spencer A Halberg-Spencer","author_inst":"University of Wisconsin-Madison"},{"author_name":"Akniyet Nurbol","author_inst":"Reed College"},{"author_name":"Iris Jan","author_inst":"Reed College"},{"author_name":"Mahunan Degbelo","author_inst":"Morgridge Institute for Research"},{"author_name":"Daniel Nachreiner","author_inst":"University of Wisconsin-Madison"},{"author_name":"Canek Llera-Magord","author_inst":"University of Wisconsin-Madison"},{"author_name":"Gabriel Howland","author_inst":"Reed College"},{"author_name":"Grace H Li","author_inst":"University of Wisconsin-Madison"},{"author_name":"Anna Ritz","author_inst":"Reed College"},{"author_name":"Anthony Gitter","author_inst":"University of Wisconsin-Madison; Morgridge Institute for Research"}],"rel_date":"2026-08-09","rel_site":"biorxiv"},{"rel_title":"PEDF\/PEDF-R Signaling Regulates Retinal Phospholipid Homeostasis and Photoreceptor Survival","rel_doi":"10.64898\/2026.08.04.742541","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.04.742541","rel_abs":"Pigment epithelium-derived factor (PEDF) promotes photoreceptor survival through its receptor PEDF-R, a phospholipase involved in retinal lipid metabolism. To define the in vivo function of the PEDF\/PEDF-R axis, we generated mice lacking Serpinf1 (PEDF) and Pnpla2 (PEDF-R). Combined loss of Serpinf1 and Pnpla2 resulted in severe retinal degeneration characterized by outer nuclear layer (ONL) thinning, outer segment (OS) shortening, reduced rhodopsin and cone opsin expression, increased TUNEL-positive nuclei, and enhanced retinal autofluorescence associated with altered lipid distribution. Lipid-associated markers, including TIP47, PLIN5, and BODIPY, exhibited abnormal distribution patterns in mutant retinas, indicating disrupted lipid storage and trafficking. Loss of PEDF\/PEDF-R signaling also impaired photoreceptor-rod bipolar cell connectivity, as demonstrated by reduced PKC\/synaptophysin colocalization, and resulted in diminished electroretinographic responses. Lipid Imaging mass spectrometry revealed decreases in some lipid abundances in photoreceptor outer segment and inner segment\/outer nucleus layer, while lipids containing arachidonic acid and docosahexaenoic acid-containing lipids showed increased abundance. Together these findings identify the PEDF\/PEDF-R signaling axis as a key regulator of retinal phospholipid homeostasis that couples lipid metabolism to photoreceptor survival and visual function.","rel_num_authors":6,"rel_authors":[{"author_name":"Alexandra Bernardo Colon,","author_inst":"NEI-NIH"},{"author_name":"Susan E. Crawford","author_inst":"2.\tDepartment of Cancer Biology, Endeavor Health Research Institute, Affiliate of University of Chicago Pritzker School of Medicine"},{"author_name":"Martin Paul Agbaga","author_inst":"Department of Cell Biology, Department of Ophthalmology, and Dean A. McGee Eye Institute, University of Oklahoma"},{"author_name":"Zhen Wang","author_inst":"Vanderbilt University"},{"author_name":"Kevin L Schey","author_inst":"Vanderbilt University"},{"author_name":"S. Patricia Becerra","author_inst":"NEI-NIH"}],"rel_date":"2026-08-09","rel_site":"biorxiv"},{"rel_title":"PEDF\/PEDF-R Signaling Regulates Retinal Phospholipid Homeostasis and Photoreceptor Survival","rel_doi":"10.64898\/2026.08.04.742541","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.04.742541","rel_abs":"Pigment epithelium-derived factor (PEDF) promotes photoreceptor survival through its receptor PEDF-R, a phospholipase involved in retinal lipid metabolism. To define the in vivo function of the PEDF\/PEDF-R axis, we generated mice lacking Serpinf1 (PEDF) and Pnpla2 (PEDF-R). Combined loss of Serpinf1 and Pnpla2 resulted in severe retinal degeneration characterized by outer nuclear layer (ONL) thinning, outer segment (OS) shortening, reduced rhodopsin and cone opsin expression, increased TUNEL-positive nuclei, and enhanced retinal autofluorescence associated with altered lipid distribution. Lipid-associated markers, including TIP47, PLIN5, and BODIPY, exhibited abnormal distribution patterns in mutant retinas, indicating disrupted lipid storage and trafficking. Loss of PEDF\/PEDF-R signaling also impaired photoreceptor-rod bipolar cell connectivity, as demonstrated by reduced PKC\/synaptophysin colocalization, and resulted in diminished electroretinographic responses. Lipid Imaging mass spectrometry revealed decreases in some lipid abundances in photoreceptor outer segment and inner segment\/outer nucleus layer, while lipids containing arachidonic acid and docosahexaenoic acid-containing lipids showed increased abundance. Together these findings identify the PEDF\/PEDF-R signaling axis as a key regulator of retinal phospholipid homeostasis that couples lipid metabolism to photoreceptor survival and visual function.","rel_num_authors":6,"rel_authors":[{"author_name":"Alexandra Bernardo Colon,","author_inst":"NEI-NIH"},{"author_name":"Susan E. Crawford","author_inst":"2.\tDepartment of Cancer Biology, Endeavor Health Research Institute, Affiliate of University of Chicago Pritzker School of Medicine"},{"author_name":"Martin Paul Agbaga","author_inst":"Department of Cell Biology, Department of Ophthalmology, and Dean A. McGee Eye Institute, University of Oklahoma"},{"author_name":"Zhen Wang","author_inst":"Vanderbilt University"},{"author_name":"Kevin L Schey","author_inst":"Vanderbilt University"},{"author_name":"S. Patricia Becerra","author_inst":"NEI-NIH"}],"rel_date":"2026-08-09","rel_site":"biorxiv"},{"rel_title":"Topographic complexity shapes adaptive genomic variation in co-occurring plant species","rel_doi":"10.64898\/2026.08.07.743600","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.07.743600","rel_abs":"Co-occurring species often face similar selective environments, although adaptive responses to these environments are generally assumed to be species-specific, particularly in complex landscapes where selective pressures are likely to be multi-dimensional. We test this assumption by contrasting genotype-environment associations (GEAs) among a range of co-occurring but unrelated plants with different life histories from an isolated, mountainous national park in south-eastern Australia. Analyses were performed using single nucleotide polymorphism (SNP) loci derived from reduced genome representation sequencing to investigate genomic associations with spatial and environmental drivers across unrelated plant species within the same heterogeneous landscape. Several species showed GEAs that aligned with similar environmental gradients, particularly edaphic features, suggesting that similar selective pressures can shape genomic responses across taxa. Other species exhibited distinct spatial and environmental associations, highlighting idiosyncratic outcomes. Notably, GEAs were detected at fine spatial scales despite generally low levels of genome-wide divergence, suggesting adaptive variants can persist in the face of gene flow under strong selective pressure. This study highlights how community-level genomic diversity is shaped by common environmental processes, with implications for biodiversity management in rapidly changing environments, where diverse ecosystem-level responses to selection may underpin resilience.","rel_num_authors":5,"rel_authors":[{"author_name":"Simon Eduardo Lobos Sr.","author_inst":"Deakin University"},{"author_name":"Collin W Ahrens Sr.","author_inst":"Cesar Australia"},{"author_name":"Paul D Rymer","author_inst":"Western Sydney University"},{"author_name":"Kathryn A Hodgins","author_inst":"Monash University"},{"author_name":"Adam D Miller","author_inst":"RMIT university"}],"rel_date":"2026-08-09","rel_site":"biorxiv"},{"rel_title":"Rapid evolution and functional divergence of the monkeyflower Mimulus lewisii telomerase","rel_doi":"10.64898\/2026.08.05.739867","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.05.739867","rel_abs":"Telomeres are nucleoprotein structures that protect chromosome ends and are maintained by the Telomerase Reverse Transcriptase (TERT) protein that uses a noncoding Telomerase RNA (TR) as a template. In monkeyflowers, Mimulus lewisii had an ancient TR gene duplication, synthesizing an evolutionarily atypical sequence heterogeneous telomere. How TERT interacts with both TR paralogs during telomere maintenance is unknown and answers can shed novel insights underlying telomere function. Using new genome assemblies we discovered TERT is rapidly evolving in lineages sharing the TR duplication. We investigated the functional consequences arising from the rapid evolution, first by using yeast-three-hybrid and testing the physical binding between conspecific and heterospecific TERT-TR combinations. Results showed M. lewisii TERT binds both ancestral (TR1) and derived (TR2) TR paralogs, but not in species without the TR duplication. We located the region of TR binding to amino acids near the KRxR motif of TERT. We then combined next-generation sequencing with Telomeric Repeat Amplification Protocol and discovered M. lewisii had high telomerase activity. Comparative transcriptomics indicated no strong evidence of expression divergence in telomere maintenance genes for M. lewisii, suggesting rapid evolution shaped the telomerase protein sequence. In vivo activity of M. lewisii telomerase was investigated by analyzing F1 telomeres generated by crossing M. lewisii and M. verbenaceus, which doesn't have a functioning TR2. Results showed M. verbenaceus chromosome ends in the F1 had converted into M. lewisii telomeres, suggesting dominance of the M. lewisii telomerase. We demonstrate TERT-TR coevolution can have significant consequences on the evolution of plant telomeres.","rel_num_authors":4,"rel_authors":[{"author_name":"Naseem Samo","author_inst":"University of Kansas"},{"author_name":"Linh Nguyen","author_inst":"University of Kansas"},{"author_name":"Surbhi Kumawat","author_inst":"University of Kansas"},{"author_name":"Jae Young Choi","author_inst":"University of Kansas"}],"rel_date":"2026-08-09","rel_site":"biorxiv"},{"rel_title":"Explainable machine learning relates histological to genomic pathology","rel_doi":"10.64898\/2026.08.03.742582","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.03.742582","rel_abs":"Background & Aims: Haematoxylin and eosin (H&E) staining remains the diagnostic gold standard for solid cancers, including hepatocellular carcinoma, and is increasingly complemented by genomic profiling for precision medicine. Inferring genomic alterations directly from H&E images could streamline testing, but heterogeneity and biases in human training data limit interpretation of genotype-phenotype associations. Here, we aimed to relate histologic to genomic pathology to provide biological explainability for mutation prediction models and assess the impact of germline variation on model performance. Methods: We analysed 597 murine liver tumours with matched whole-genome sequencing and histopathology (163,835 image tiles; 22.9 million nuclei). Our controlled in vivo design accounted for germline variation, biological sex, and causal mutagen (N-diethylnitrosamine), removing confounding factors present in human cohorts. We trained and evaluated deep learning and supervised machine learning models to predict germline variation and cancer driver alterations from H&E. Results: Modelling accurately predicted germline and somatic alterations from histology, at both locus-specific and genome-wide scales. Quantitative image analysis revealed an unexpected association between Egfr driver mutations and hepatic steatosis, linking genotype to an interpretable morphological phenotype. While model performance declined when applied to tumours from unrepresented genetic backgrounds, this limitation was biologically informative, revealing strain-dependent differences in tumour evolution, notably the prevalence of whole-genome duplication. Conclusions: Machine learning integration of histological and genomic pathology enables accurate, interpretable inference of genetic alterations from H&E, potentially reducing reliance on costly ancillary molecular assays. Our predictions are supported by human-interpretable biological features, addressing concerns around 'black-box' technologies. However, caution is required when applying such methods to samples with a genetic background that, even if closely related, is beyond the genetic horizon of training data.","rel_num_authors":13,"rel_authors":[{"author_name":"John Connelly","author_inst":"University of Edinburgh, Edinburgh, UK"},{"author_name":"Barbara Hernando","author_inst":"Yale University, New Haven, CT, USA"},{"author_name":"Juliet Luft","author_inst":"University of Edinburgh, Edinburgh, UK"},{"author_name":"Craig J Anderson","author_inst":"University of Edinburgh, Edinburgh, UK"},{"author_name":"Peter Bankhead","author_inst":"University of Edinburgh, Edinburgh, UK"},{"author_name":"Frances Connor","author_inst":"University of Cambridge, Cambridge, UK"},{"author_name":"Stuart Aitken","author_inst":"University of Edinburgh, Edinburgh, UK"},{"author_name":"- Liver Cancer Evolution Consortium","author_inst":"-"},{"author_name":"Colin A Semple","author_inst":"University of Edinburgh, Edinburgh, UK"},{"author_name":"Paul Flicek","author_inst":"University of Connecticut, Storrs, CT, USA"},{"author_name":"Duncan T Odom","author_inst":"German Cancer Research Centre, (DKFZ), Heidelberg, Germany"},{"author_name":"Martin S Taylor","author_inst":"University of Edinburgh, Edinburgh, UK"},{"author_name":"Sarah J Aitken","author_inst":"Yale University, New Haven, CT, USA"}],"rel_date":"2026-08-09","rel_site":"biorxiv"},{"rel_title":"Contributions of single-cell mechanics and cell-cell adhesion to multicellular spheroid mechanics","rel_doi":"10.64898\/2026.08.04.742605","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.04.742605","rel_abs":"Tumor spheroid mechanics arise from both the mechanical properties of individual cells and the adhesive interactions that organize them into tissues. The relative contribution of these two factors to the bulk mechanical behavior, however, remains difficult to disentangle experimentally. Here, we develop a computational model of micropipette aspiration to compare the mechanical response of isolated cells and multicellular spheroids within a common computational framework. By independently varying single-cell stiffness and cell-cell adhesion, we quantify their effects on aspiration dynamics, effective elastic modulus, and viscoelastic relaxation. Our results show that increasing single-cell stiffness substantially alters the mechanics of isolated cells but has limited influence on the effective elastic modulus of multicellular spheroids. In contrast, changes in cell-cell adhesion produce pronounced effects on spheroid effective elastic modulus. Nevertheless, both parameters increase the retardation time governing the transition from the initial elastic response to long-time viscous deformation. These findings suggest that multicellular elasticity is governed primarily by intercellular mechanical coupling, whereas the dynamical response to applied stress depends jointly on cell-scale mechanics and cell-cell adhesion.","rel_num_authors":4,"rel_authors":[{"author_name":"David Dolgitzer","author_inst":"Johns Hopkins University"},{"author_name":"Eleana Parajon","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Douglas N. Robinson","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Pablo A Iglesias","author_inst":"Johns Hopkins University"}],"rel_date":"2026-08-09","rel_site":"biorxiv"},{"rel_title":"A Reduced Mechanobiological Framework for Platelet Priming: From Hemodynamic Shear to Mechanosensitive Calcium Entry","rel_doi":"10.64898\/2026.08.03.742655","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.03.742655","rel_abs":"Background. Platelet activation in flowing blood is a multiscale process in which vessel-scale hemodynamics, red blood cell (RBC) mechanics, adhesive receptor interactions, and intracellular signalling jointly determine thrombotic risk. Individual components are well studied, but a single reduced description that carries each explicitly from vessel-scale flow to mechanosensitive calcium entry, with dimensionally consistent couplings, remains uncommon. Objectives. We develop and analyse a reduced, six-module mechanobiological framework for platelet priming spanning the cascade from hemodynamic shear to mechanosensitive calcium entry, and we delineate which elements are supported by existing evidence and which are new, testable hypotheses. Methods. The framework comprises six coupled modules: (I) hemodynamic forcing from the incompressible Navier-Stokes equations, with an objective principal-strain-rate measure for extensional flow; (II) RBC-mediated platelet margination and near-wall delivery, closed by a near-wall arrival flux; (III) von Willebrand factor (VWF) activation with a bounded kernel and glycoprotein Ib (GPIb) catch-slip capture, resolved through an explicit contact area and a bond-dependent mobility that progressively immobilises wall-interacting platelets; (IV) a single-load membrane-stimulus formulation; (V) mechanosensitive gating and a dimensionally consistent cytosol-store calcium model with extracellular influx; and (VI) a phenomenological mechanical-memory state. We formally derive that the single-platelet stochastic dynamics and the continuum population balance form a Fokker-Planck pair, with the spatially varying diffusivity handled by an explicit drift correction. Results. The framework yields a family of mechanochemical dimensionless groups delineating priming regimes. Its central prediction is reformulated as a falsifiable, history-sensitive signature: in a conditioning-test protocol, a low-tension conditioning block charges the memory state, and a fixed sub-threshold test pulse then reports a delay-dependent calcium facilitation that decays on the memory time {tau}m and is distinguishable from no-memory gating, channel adaptation, and residual-calcium priming. We show explicitly that the previously proposed pulsatile-versus-monotone contrast is a nonlinear convexity\/thresholding effect of the gating nonlinearity, whose difference-in-differences is approximately zero, and is therefore not a valid test of memory; the conditioning-test signature is. A second prediction links RBC stiffening to reduced near-wall delivery and captured-platelet calcium response, upstream of intrinsic platelet signalling. Conclusions. The framework provides a dimensionally consistent, mechanistically grounded and hypothesis-generating description linking hemodynamic forcing to mechanosensitive calcium entry. It demonstrates how history-dependent platelet priming may arise from a phenomenological sensitisation state and proposes a conditioning-test protocol for comparison against adhesive, channel and intracellular-store persistence. The framework is calibratable rather than validated, and the quantitative outputs shown use representative uncalibrated parameters.","rel_num_authors":5,"rel_authors":[{"author_name":"Yuxin Chen","author_inst":"THE UNIVERSITY OF SYDNEY"},{"author_name":"Xiaochen Liu","author_inst":"The University of Sydney"},{"author_name":"Daniele Vigolo","author_inst":"The University of Sydney"},{"author_name":"Mackenzie Siyuan Zhuang-Hall","author_inst":"The University of Sydney"},{"author_name":"Ken-Tye Yong","author_inst":"The University of Sydney"}],"rel_date":"2026-08-09","rel_site":"biorxiv"},{"rel_title":"Development of the First Cytochrome Oxidase I Barcode and Evidence for a Single Haplotype Associated with the Recent United States Invasion of the Pasture Mealybug Heliococcus summervillei (Pseudococcidae, Hemiptera)","rel_doi":"10.64898\/2026.08.04.742657","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.04.742657","rel_abs":"Heliococcus summervillei is an emerging invasive mealybug that causes severe dieback in grasses in pastures and turfgrass landscapes. It is widespread in Australia and has recently been detected across the Caribbean, Mexico, and the United States. Accurate identification of mealybugs is challenging due to cryptic morphology, overlapping diagnostic characters, and limited taxonomic expertise and literature, which makes molecular tools essential for regulatory diagnostics and management. We developed the first Cytochrome Oxidase I (COI) barcode for H. summervillei and used it to examine mitochondrial variation across available populations. COI sequences reveal approximately a 10.2% mitochondrial split between the Type A and Type B variants. Phylogenetic, haplotype network, and genetic distance analyses show that all invasive range populations share one haplotype associated with a recent invasion in the United States, Australia, Pakistan, and the Caribbean, whereas the Barbados lineage contains two closely related haplotypes that represent a historically stable mitochondrial variant. Together, these results establish the first COI reference library for H. summervillei, clarify mitochondrial lineage structure, and provide a practical barcode tool that enables rapid identification of invasive populations and supports timely regulatory and pest management responses. Recognizing mitochondrial variants also establishes a framework for resolving lineage-specific biological and management traits and strengthens reconstruction of introduction pathways central to regulatory decision-making and limiting further spread.","rel_num_authors":11,"rel_authors":[{"author_name":"Peilin Tan","author_inst":"Clemson University"},{"author_name":"Nisha Yadav","author_inst":"Clemson University"},{"author_name":"Caroline Hauxwell","author_inst":"Queensland University of Technology"},{"author_name":"David R. Kerns","author_inst":"Texas Agricultural and Technology University"},{"author_name":"Blake Wilson","author_inst":"Louisiana State University Agricultural Center"},{"author_name":"Nicole Quinn","author_inst":"University of Florida"},{"author_name":"Isaac L. Esquivel","author_inst":"University of Florida"},{"author_name":"Sachin Rustgi","author_inst":"Clemson University"},{"author_name":"Ynna Hernandez Europa","author_inst":"Queensland University of Technology"},{"author_name":"Darcy Patrick","author_inst":"Queensland University of Technology"},{"author_name":"Muhammad Z Ahmed","author_inst":"Clemson University"}],"rel_date":"2026-08-09","rel_site":"biorxiv"},{"rel_title":"Coexistence of phasmid sensory neurons and caudal glands offers a new perspective on cell type evolution in nematodes","rel_doi":"10.64898\/2026.08.04.741185","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.04.741185","rel_abs":"The highly conserved body plan of nematodes makes members of this phylum excellent models to study cell type evolution. Early branching nematode lineages, mostly occupying aquatic habitats, usually contain caudal glands deployed for underwater attachment to a substrate, but have been thought to lack phasmid sensory organs, resulting in their historical classification as Aphasmidia. With the transition to a terrestrial environment, nematodes lost caudal glands and gained phasmid sensory neurons. The supposed mutually exclusive existence of caudal glands and phasmids has led to the suggestion that phasmid neurons may have evolved from caudal glands. Here, we rule out this possibility through light and electron microscopical analysis of Mononchus aquaticus, a member of the early branching Dorylaimia lineage, showing that phasmid sensory neurons and caudal glands do coexist. This observation not only argues against a proposed cell type evolution scenario accompanying aquatic-to-terrestrial transitions but also indicates that the presence of phasmid sensory organs may have been an ancestral trait of the nematode phylum.","rel_num_authors":6,"rel_authors":[{"author_name":"Hyunsoo Yim","author_inst":"Columbia University"},{"author_name":"Ken CQ Nguyen","author_inst":"Columbia University"},{"author_name":"Luke T Geiger","author_inst":"Columbia University"},{"author_name":"David  H Hall","author_inst":"Yeshiva University Albert Einstein College of Medicine"},{"author_name":"Nathan Schroeder","author_inst":"University of Illinois at Urbana-Champaign"},{"author_name":"Oliver Hobert","author_inst":"Columbia University"}],"rel_date":"2026-08-09","rel_site":"biorxiv"},{"rel_title":"Coexistence of phasmid sensory neurons and caudal glands offers a new perspective on cell type evolution in nematodes","rel_doi":"10.64898\/2026.08.04.741185","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.04.741185","rel_abs":"The highly conserved body plan of nematodes makes members of this phylum excellent models to study cell type evolution. Early branching nematode lineages, mostly occupying aquatic habitats, usually contain caudal glands deployed for underwater attachment to a substrate, but have been thought to lack phasmid sensory organs, resulting in their historical classification as Aphasmidia. With the transition to a terrestrial environment, nematodes lost caudal glands and gained phasmid sensory neurons. The supposed mutually exclusive existence of caudal glands and phasmids has led to the suggestion that phasmid neurons may have evolved from caudal glands. Here, we rule out this possibility through light and electron microscopical analysis of Mononchus aquaticus, a member of the early branching Dorylaimia lineage, showing that phasmid sensory neurons and caudal glands do coexist. This observation not only argues against a proposed cell type evolution scenario accompanying aquatic-to-terrestrial transitions but also indicates that the presence of phasmid sensory organs may have been an ancestral trait of the nematode phylum.","rel_num_authors":6,"rel_authors":[{"author_name":"Hyunsoo Yim","author_inst":"Columbia University"},{"author_name":"Ken CQ Nguyen","author_inst":"Columbia University"},{"author_name":"Luke T Geiger","author_inst":"Columbia University"},{"author_name":"David  H Hall","author_inst":"Yeshiva University Albert Einstein College of Medicine"},{"author_name":"Nathan Schroeder","author_inst":"University of Illinois at Urbana-Champaign"},{"author_name":"Oliver Hobert","author_inst":"Columbia University"}],"rel_date":"2026-08-09","rel_site":"biorxiv"},{"rel_title":"Structural modeling and experimental validation define the MxA-Thogotovirus nucleoprotein interface that drives restriction and escape","rel_doi":"10.64898\/2026.08.07.743570","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.07.743570","rel_abs":"The human MxA (myxovirus resistance protein A) host restriction factor inhibits orthomyxoviruses, such as Thogotovirus (THOV) and influenza A virus (IAV), by binding to their nucleoproteins. Despite being discovered over six decades ago, how MxA interacts with viral targets remains unclear. Earlier studies using evolutionary analysis and mutagenesis showed that the MxA L4 loop, especially a hydrophobic aromatic amino acid at residue 561, is crucial for binding THOV nucleoprotein (NP) and restricting THOV. Here, we combined previous insights with structure prediction methods, molecular dynamics simulations, and experimental validation to define the human MxA L4 loop binding interface to THOV NP. We also evaluated the stability of MxA L4-NP binding through classical all-atom molecular dynamics simulations. Our model revealed MxA L4 binding to a surface-exposed site on THOV NP, including residues previously linked to viral escape from MxA restriction, even though this information was not used to guide our modeling efforts. This MxA-THOV NP interface is distinct from NP's RNA-binding or oligomerization surfaces. Our molecular dynamics simulations also agree with earlier data indicating that F561Y enhances MxA binding to THOV NP, whereas F561W reduces it and F561V ablates it entirely. Based on this model, we predicted specific variants in human MxA or THOV NP that could result in increased host restriction or viral escape. We tested these predictions using a viral minireplicon assay to validate our model. Our efforts will guide vital viral surveillance studies and the development of MxA-based antivirals.","rel_num_authors":5,"rel_authors":[{"author_name":"L. America Chi","author_inst":"University of Idaho"},{"author_name":"Megan Levy","author_inst":"University of Washington"},{"author_name":"Rechel Geiger","author_inst":"University of Washington"},{"author_name":"Harmit Singh Malik","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Jagdish Suresh Patel","author_inst":"University of Idaho"}],"rel_date":"2026-08-09","rel_site":"biorxiv"},{"rel_title":"CRISPR-activation reveals key resistance genes and vulnerabilities of copy number variants in Candida albicans","rel_doi":"10.64898\/2026.08.07.743545","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.07.743545","rel_abs":"Changes in gene copy number are an extremely important source of variation and are frequently observed during the acquisition of drug resistance. The opportunistic human fungal pathogen Candida albicans frequently adapts to antifungal drugs via large copy number variations (CNVs) that amplify hundreds of genes simultaneously. Despite the recurrent amplification of CNVs across diverse clinical isolates, the genes that contribute to drug resistance are not known. Additionally, by amplifying many genes, CNVs might result in cross-adaptation or fitness trade-offs to multiple environments, which has major implications for how CNVs are expected to contribute to adaptation in complex environments like a mammalian host. We use CRISPR-activation to systematically assay the fitness effects of individually overexpressing ~800 genes in four genetically diverse isolates across eight physiologically relevant environments. We identify 198 genes with significant fitness effects in at least one environment in one or more genetic backgrounds. We identify novel genes with positive fitness effects in two different classes of antifungal drug and observe frequent gene-by-environment interactions for the fitness effects of gene overexpression. Additive fitness effects of individual gene overexpression are a significant predictor of the fitness of multiple isolates with CNVs and can explain fitness trade-offs observed between classes of antifungal drug for the CNV isolates. These findings identify genes that increase fitness in drug and those that create vulnerabilities in CNV isolates and can help inform treatment of isolates adapting to antifungal drug via CNVs.","rel_num_authors":7,"rel_authors":[{"author_name":"Petra L Vande Zande","author_inst":"University of Minnesota"},{"author_name":"Nicholas C Gervais","author_inst":"University of Guelph"},{"author_name":"Erika Renee Schell","author_inst":"University of Minnesota"},{"author_name":"Piper Zajac","author_inst":"University of Minnesota"},{"author_name":"Katura M Metzner","author_inst":"University of Minnesota"},{"author_name":"Rebecca S Shapiro","author_inst":"University of Guelph"},{"author_name":"Anna Selmecki","author_inst":"University of Minnesota"}],"rel_date":"2026-08-09","rel_site":"biorxiv"},{"rel_title":"A Low-Cost, Modular Hardware and Software Platform for Head-Fixed Mouse Decision-Making Tasks","rel_doi":"10.64898\/2026.08.03.742587","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.03.742587","rel_abs":"Head-fixed behavior in rodents is a foundational technique in systems neuroscience which enables use of sophisticated imaging techniques in combination with animal behavior. However, accessibility of head-fixed behavior techniques is limited. Animal training consumes a large amount of experimenter labor and commercial setups, when available, are largely inflexible and financially burdensome. Here, we present a low-cost, modular, and open-source hardware and software implementation for head-fixed rodent decision-making tasks. Our design lowers experimenter labor and enables large teams of researchers to participate in animal training with minimal experimenter error using a simple touchscreen GUI and automated training progression. We demonstrate the efficacy of the platform by training a cohort of animals in a two-choice probabilistic rapid-reversal task in which mice continuously update action choices based on recent reward history. The presented design lowers the barrier to entry for laboratories seeking to conduct head-fixed rodent behavior and provides modular solutions for developing custom rigs based on experimental demands.","rel_num_authors":6,"rel_authors":[{"author_name":"Maxwell B Madden","author_inst":"Rutgers University - New Brunswick"},{"author_name":"Mahee Khatri","author_inst":"Rutgers University - New Brunswick"},{"author_name":"Arnav Mohanty","author_inst":"Rutgers University - New Brunswick"},{"author_name":"Disha Prasad","author_inst":"Rutgers University - New Brunswick"},{"author_name":"Nancy K Collie-Beard","author_inst":"Rutgers University - New Brunswick"},{"author_name":"Rafiq Huda","author_inst":"Rutgers University - New Brunswick"}],"rel_date":"2026-08-09","rel_site":"biorxiv"},{"rel_title":"Eco-evolutionary feedbacks generate bistability in population persistence under gradual environmental change","rel_doi":"10.64898\/2026.08.05.743160","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.05.743160","rel_abs":"Understanding how populations persist in gradually deteriorating environments through evolution is a central question in ecology and evolutionary biology. Previous studies have primarily focused on identifying the critical rate of environmental change beyond which extinction is certain. However, the existence of a viable equilibrium when the rate is below the threshold does not guarantee that a population can survive the transient dynamics to reach it. Using a quantitative genetic model that explicitly incorporates feedback among population size, genetic variance, and mean trait evolution, we show that population persistence can exhibit bistability when the rate of environmental change is below the extinction threshold. Specifically, extinction still occurs if the initial population size and genetic variance fall below a critical level. The initial state also influences the eco-evolutionary dynamics, such that a temporary increase or decline in population size and\/or genetic variance does not necessarily predict the ultimate fate of the population. Therefore, in addition to estimating the critical rate of environmental change for extinction, characterizing current population size, genetic variation, and the degree of maladaptation may improve predictions of extinction risk in deteriorating environments.","rel_num_authors":2,"rel_authors":[{"author_name":"Hao Shen","author_inst":"University of Chicago"},{"author_name":"Kuangyi Xu","author_inst":"University of Toronto"}],"rel_date":"2026-08-09","rel_site":"biorxiv"},{"rel_title":"Habitat and feeding ecology of a Denisovan from Late Pleistocene Taiwan","rel_doi":"10.64898\/2026.08.07.743455","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.07.743455","rel_abs":"Denisovans, originally identified from ancient genome from Denisova Cave in Altai, were a sister group to the Neanderthals and were once widely distributed across diverse terrains in the north and south of eastern Asia1-5. Genomic studies suggest that there were multiple events of interbreeding between modern humans (Homo sapiens) and Denisovans somewhere in Asia6. However, little is known about Denisovan living environments, diet, ecological niche, the timing of their disappearance, and the possible coexistence with modern humans in different regions. Here we report the radiocarbon age and stable isotopic signature of Penghu 3, a large Denisovan tibia from Penghu Channel, Taiwan7. The results showed that Penghu 3 dates to approximately 45,000 years ago, the time when modern humans were already widespread in southern parts of Asia. This Denisovan individual inhabited a C4-dominated ecosystem, open environments such as savannahs and floodplains, or a mixture of both, and consumed a high proportion of animal protein similar to some European Neanderthals8-10, with no clear evidence for the use of aquatic resources. These findings have implications for the behavioral flexibility, large body size7, and eventual disappearance of the Denisovans.","rel_num_authors":7,"rel_authors":[{"author_name":"Minoru Yoneda","author_inst":"The University of Tokyo, Japan"},{"author_name":"Chun-Hsiang Chang","author_inst":"National Museum of Natural Science, Taiwan"},{"author_name":"Yu Itahashi","author_inst":"University of Tsukuba, Japan"},{"author_name":"Takumi Tsutaya","author_inst":"Kyushu University, Japan"},{"author_name":"Cheng-Han Sun","author_inst":"National Taiwan University, Taiwan"},{"author_name":"Cheng-Hsiu Tsai","author_inst":"National Taiwan University, Taiwan"},{"author_name":"Yousuke Kaifu","author_inst":"The University of Tokyo, Japan"}],"rel_date":"2026-08-08","rel_site":"biorxiv"},{"rel_title":"Denisovan leg bones from Taiwan reveal large body size","rel_doi":"10.64898\/2026.08.07.743438","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.07.743438","rel_abs":"Denisovans are an extinct archaic Homo group whose lineage diverged from the Neanderthal lineage approximately 550,000 years ago and were widely distributed across eastern Asia until ~45,000 years ago1-7. Their morphological features are known directly from the existing cranio-dental and phalangeal remains1,2,8-12. However, the body size and postcranial morphology of the Denisovans remain largely unknown. We here report that hominin femoral and tibial fossils recovered from the Penghu Channel, Taiwan, are Denisovans in their proteomic profiles. Morphologically, these specimens are among the largest leg bones known in Pleistocene Homo. They exhibit generally archaic features, but also show some modern human-like morphology, including a strong femoral pilaster. Our findings demonstrate that the Denisovan population at the northern circle had larger body size than earlier Homo erectus as well as Late Pleistocene Homo sapiens in eastern Asia. This challenges the generally held expectation that Pleistocene Homo followed Bergmanns rule that anticipates latitudinal decline of body size, and suggests that the large Denisovan brain resulted from their large body size at least partly. The strong pilaster developed in the Penghu femur suggests some behavioral similarities between the Denisovans and the Upper Palaeolithic modern humans and\/or gene flow from the latter to the former.","rel_num_authors":12,"rel_authors":[{"author_name":"Yousuke Kaifu","author_inst":"The University of Tokyo"},{"author_name":"Chun-Hsiang Chang","author_inst":"National Museum of Natural Science, Taiwan"},{"author_name":"Yumeko Tarusawa","author_inst":"Kyushu University, Japan"},{"author_name":"Rikai Sawafuji","author_inst":"Kyushu University, Japan"},{"author_name":"Shiori Yonemoto","author_inst":"Kyushu University, Japan"},{"author_name":"Shigeru Shimamura","author_inst":"Japan Agency for Marine-Earth Science and Technology, Japan"},{"author_name":"Masanaru Takai","author_inst":"Kyoto University, Japan"},{"author_name":"Reiko T. Kono","author_inst":"Keio University, Tokyo"},{"author_name":"Cheng-Han Sun","author_inst":"National Taiwan University, Taiwan"},{"author_name":"Cheng-Hsiu Tsai","author_inst":"National Taiwan University, Taiwan"},{"author_name":"Minoru Yoneda","author_inst":"The University of Tokyo, Japan"},{"author_name":"Takumi Tsutaya","author_inst":"Kyushu University, Japan"}],"rel_date":"2026-08-08","rel_site":"biorxiv"},{"rel_title":"Genome-wide association study in Heterogeneous Stock rats identifies genetic loci associated with aversion-based learning and cocaine aversion","rel_doi":"10.64898\/2026.08.07.743619","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.07.743619","rel_abs":"Addiction is a complex and heritable trait which progresses through several developmental stages, each of which is presumably influenced by multiple partially overlapping genetic factors. Cocaine initially produces rewarding effects, followed by aversive effects including anxiety, craving, anhedonia, and withdrawal. These aversive effects have been suggested to contribute to the etiology of cocaine use disorders (CUD), as repeated exposure is thought to desensitize the rewarding effects and sensitize the aversive effects through a process involving both aberrant reward-based learning and aberrant avoidance-based learning. We examined the genetic basis of aversion learning using both food-based and cocaine-based behavioral assays in outbred Heterogenous Stock (HS) rats. A total of 1,074 HS rats (35.3% male) underwent runway operant cocaine-seeking, food-based progressive ratio and punishment testing, and locomotion testing. These phenotypes were significantly heritable (with h2 estimates as high as 0.307) and identified significant (p < 0.05) genetic loci related to avoidance-based learning including from the punishment task on Chromosomes 2, 3, 5, and 6, and the cocaine-operant runway latency task on Chromosome X. 172 positional candidate genes were identified from significant and suggestive loci, including Cdh10, Cdh12, Cdh18 which have previously been associated with smoking initiation from human GWAS, Adcy3, Cfap206, and Drc1 which are associated with primary neuronal cilia, as well as SNPs associated with novelty-related and social interaction phenotypes in independent samples of HS rats. Our results suggest that these aversion learning phenotypes are themselves complex heritable traits influenced by multiple genetic loci, which may pleiotropically affect other aspects of addiction biology.","rel_num_authors":17,"rel_authors":[{"author_name":"Zachary Tatom","author_inst":"Department of Psychiatry, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Maya Eid","author_inst":"Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA"},{"author_name":"Thiago Missfeldt Sanches","author_inst":"Department of Psychiatry, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Apurva S. Chitre","author_inst":"Department of Psychiatry, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Gavrila Ang","author_inst":"Department of Psychiatry, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Kendra S Ziegler","author_inst":"Department of Psychiatry, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Beverly Peng","author_inst":"Department of Psychiatry, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Elaine Keung","author_inst":"Department of Psychiatry, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Khai-Minh Nguyen","author_inst":"Department of Psychiatry, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Katarina Cohen","author_inst":"Department of Psychiatry, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Yizhi Wang","author_inst":"Department of Psychiatry, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Riyan Cheng","author_inst":"Department of Psychiatry, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Denghui Chen","author_inst":"Department of Psychiatry, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Benjamin Johnson","author_inst":"Department of Psychiatry, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Oksana Polesskaya","author_inst":"Department of Psychiatry, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Thomas Jhou","author_inst":"Department of Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA"},{"author_name":"Abraham A. Palmer","author_inst":"Department of Psychiatry, University of California San Diego, La Jolla, CA, USA"}],"rel_date":"2026-08-08","rel_site":"biorxiv"},{"rel_title":"Geometric constraints and cognitive inputs jointly shape emergent brain dynamics and topology","rel_doi":"10.64898\/2026.08.07.742341","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.07.742341","rel_abs":"How the brain's physical geometry gives rise to its flexible functional repertoire remains a central question in neuroscience. Here, we trained three classes of recurrent neural networks (RNNs) on a working-memory task, forming a graded hierarchy of spatial constraints: Vanilla RNNs (no spatial constraints), Masked RNNs (projection constraints limiting where information enters and leaves the network), and biophysical RNNs (bioRNNs; projection constraints and spatial embedding of the networks' connectivity using the brain's inter-regional Euclidean geometry). We assessed how well each RNN class predicted empirical fMRI activity without exposing them to it during training. Our results showed that bioRNNs were the only networks to successfully predict empirical brain activity and to organize their dynamics into a spatial pattern that recapitulated the brain's principal hierarchy (the sensorimotor-association axis). Additionally, bioRNNs' ability to predict empirical brain activity emerged along a trajectory in which geometry was laid down first, then partly traded back as the task was mastered. Importantly, brain-like topological features emerged in bioRNNs as they increased their task proficiency while maintaining their ability to predict brain activity. Taken together, our results indicate that physical geometry and cognitive inputs play distinct, complementary roles: while geometry constrains the space of possible brain dynamics, cognitive inputs determine which dynamics are expressed. They also situate topology as the scaffold through which the physically embedded brain reconciles wiring costs and computational demands.","rel_num_authors":4,"rel_authors":[{"author_name":"Ahmad Beyh","author_inst":"Department of Psychiatry, Brain Health Institute, Rutgers University, Piscataway, NJ, USA"},{"author_name":"Jason Z. Kim","author_inst":"Department of Physics, Cornell University, Ithaca, NY, USA"},{"author_name":"Waheed U. Bajwa","author_inst":"Departments of Electrical & Computer Engineering and Statistics, Rutgers University, Piscataway, NJ, USA"},{"author_name":"Linden Parkes","author_inst":"Department of Psychiatry, Brain Health Institute, Rutgers University, Piscataway, NJ, USA"}],"rel_date":"2026-08-08","rel_site":"biorxiv"},{"rel_title":"Two types of response inhibition failures in humans","rel_doi":"10.64898\/2026.08.07.743566","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.07.743566","rel_abs":"Response inhibition is a key control function that allows humans to perform safe, goal-directed behaviors. The dominant behavioral-computational model holds that response inhibition fails when the inhibition process is too slow to intercept unwanted movements. However, many have hypothesized that some inhibitory failures instead result from a failure to launch the inhibition process altogether. Since no method exists to identify individual 'trigger failure' (TF) trials, they are hitherto a largely hypothetical phenomenon. We combined Bayesian process-mixture modeling with likelihood ratio testing and jackknife resampling to identify TF trials in 253 humans. We find that TF indeed represent a separate category from other inhibitory failures. Unlike other inhibitory failures, TF do not result from premature responses. Furthermore, TF lack a stop-signal P3 event-related potential, a neural index of response inhibition. Surprisingly, TF do not result from perceptual\/attentional lapses. Thus, TF are a qualitatively distinct class of executive failure during response inhibition.","rel_num_authors":2,"rel_authors":[{"author_name":"Stein F. Acker","author_inst":"University of Iowa"},{"author_name":"Jan R Wessel","author_inst":"University of Iowa"}],"rel_date":"2026-08-08","rel_site":"biorxiv"},{"rel_title":"Distinct mitochondrial phenotypes align with visual and semantic representations across human cortex","rel_doi":"10.64898\/2026.08.07.743627","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.07.743627","rel_abs":"How cellular energetics relates to the information represented by human cortex is unknown. Using 7T fMRI during natural-scene viewing, image-to-brain encoding frameworks, spatial-autocorrelation-preserving inference and postmortem molecular atlases, we separated cortical variance uniquely attributable to visual versus semantic features. Visual-specific variance aligned negatively with mitochondrial density and respiratory capacity, whereas semantic-specific variance aligned positively with mitochondrial density; convergent transcriptomic enrichment linked these representational axes to opposing mitochondrial and cellular programs.","rel_num_authors":2,"rel_authors":[{"author_name":"Zitong Lu","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Yuxin Wang","author_inst":"University of Chicago"}],"rel_date":"2026-08-08","rel_site":"biorxiv"},{"rel_title":"Video-based gait analysis using pose estimation can quantify gait differences among non-frail, pre-frail, and frail older adults","rel_doi":"10.64898\/2026.08.04.26359742","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.04.26359742","rel_abs":"Frailty is a common consequence of aging that makes individuals increasingly susceptible to adverse health outcomes. Frailty screening can identify pre-frail and frail individuals to prescribe interventions or inform clinical decision making to prevent or slow additional frailty progression. Objective, scalable, and automated frailty assessments may expedite and improve clinical frailty screening. Here, we leveraged human pose estimation for video-based gait analysis in older adults who were non-frail, pre-frail, and frail. We focused on gait because slow walking speed is key diagnostic criteria of frailty, and many gait deviations are often observed in older adults with frailty. We collected videos of 68 older adults (25 non-frail, 25 pre-frail, 18 frail) walking at both self-selected and fast paces and used an established pose estimation-based gait analysis approach to measure and compare gait parameters across frailty statuses. Pose estimation-based step time measurements were strongly correlated with manual annotations (self-selected: R2=0.93, fast: R2=0.80) and showed tight Bland-Altman limits of agreement (self-selected: -0.082 to 0.052s, fast: -0.114 to 0.110s), establishing validity of this video-based gait analysis approach in older adults. We then identified a series of cross-sectional differences in spatiotemporal gait parameters among non-frail, pre-frail, and frail older adults, demonstrating that video-based gait analysis can be useful for measuring gait differences across frailty statuses. This study demonstrates the potential of video-based pose estimation for scalable gait tracking across frailty statuses in older adults.","rel_num_authors":12,"rel_authors":[{"author_name":"Kaleb Burch","author_inst":"Johns Hopkins School of Medicine: The Johns Hopkins University School of Medicine"},{"author_name":"Jaya Hamkins","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Laura McDaniel","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Ana  Raquel Castro e Costa","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Zechen Yang","author_inst":"Kennedy Krieger Institute"},{"author_name":"Jan Stenum","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Andrew Pagliocchini","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Crystal Szczesny","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Jacqueline Langdon","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Rama Chellappa","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Peter Abadir","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Ryan Roemmich","author_inst":"The Johns Hopkins University School of Medicine"}],"rel_date":"2026-08-07","rel_site":"medrxiv"},{"rel_title":"Randomized metformin and cognitive outcomes in the Diabetes Prevention Program Outcomes Study","rel_doi":"10.64898\/2026.08.05.26359234","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.05.26359234","rel_abs":"Importance. Metformin may influence risk of dementia, with prior conflicting observations of protection or harm. Objective. To determine the association of randomization to metformin vs. placebo or intensive lifestyle intervention (ILS) in the Diabetes Prevention Program (DPP) with cognitive outcomes (cognitive impairment syndromes and trajectories of cognitive test performance) during the DPP Outcomes Study (DPPOS). Design, Setting & Participants. Prospective long-term follow-up of DPP\/DPPOS participants at 27 U.S. centers among adults who were at high risk for type 2 diabetes (T2D) at baseline. Exposures. Randomization to metformin, placebo, or ILS (1996-1999) for 3.2 years followed by open-label metformin in the original randomized metformin group until 2021. Main Outcomes & Measures. Cognitive impairment syndromes were adjudicated in 2022-2024 in 1,483 participants (median age 74 [IQR 68, 80]) using the National Alzheimer's Coordinating Center Uniform Dataset version 3. Cognitive performance in executive and memory domains was ascertained with repeated cognitive tests between 2009 and 2024. Multinomial logistic regression and mixed-effects models were fit to examine associations of randomization to metformin with cognitive outcomes. Results. Total metformin exposure (mean {+\/-} SD) was 15.5 {+\/-}7.7 years\/person in the metformin group. Persons in the placebo and ILS groups received out-of-study metformin usually after developing diabetes with mean metformin total exposure of 4.5 {+\/-}5.1 and 3.8 {+\/-}4.8 years\/person in the placebo and ILS groups, respectively. Overall, the frequency distributions of the cognitive syndromes did not differ significantly by treatment group; however, randomization to metformin was associated with a 60% (OR 0.40 [95%CI 0.17, 0.97]) and 62% (OR 0.38 [95%CI 0.16, 0.89]) lower odds of dementia compared with placebo and ILS, respectively, after adjustment for demographics, education, income, and APOE-{varepsilon}4 genotype. Randomization to metformin was also associated with significantly better memory performance over time ( {beta} =0.58; 95%CI: 0.09, 1.1; p=0.02; Cohen's d=0.1). Conclusions and Relevance. Long-term metformin treatment is associated with a reduced risk of dementia and better memory performance among persons with pre-diabetes or T2D. Estimates were imprecise due to a limited number of dementia cases. Longer follow-up with more dementia cases is needed to confirm our findings.","rel_num_authors":18,"rel_authors":[{"author_name":"Pandora L Wander","author_inst":"Veterans Affairs (VA) Puget Sound Health Care System and Department of Medicine, University of Washington"},{"author_name":"Lindsay Doherty","author_inst":"Biostatistics Center and Department of Biostatistics and Bioinformatics, George Washington University"},{"author_name":"Qing Pan","author_inst":"Biostatistics Center and Department of Biostatistics and Bioinformatics, George Washington University"},{"author_name":"Owen Carmichael","author_inst":"Biomedical Imaging Center, Pennington Biomedical Research Center"},{"author_name":"Raymond Turner","author_inst":"Department of Neurology, MedStar Georgetown University Hospital and Georgetown University Medical Center"},{"author_name":"Shihchen Kuo","author_inst":"Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, Medical School, University of Michigan"},{"author_name":"Medha Munshi","author_inst":"Joslin Diabetes Center, Beth Israel Deaconess Medical Center, Harvard Medical School"},{"author_name":"Amisha Wallia","author_inst":"Division of Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine"},{"author_name":"James Noble","author_inst":"Department of Neurology, Taub Institute for Research on Alzheimers Disease and the Aging Brain, and the GH Sergievsky Center, Columbia University"},{"author_name":"Vallabh O Shah","author_inst":"School of Medicine, Int Medicine, University of New Mexico HSC"},{"author_name":"Neelesh K Nadkarni","author_inst":"Department of Medicine, Division of Geriatric Medicine and Gerontology, and Department of Neurology, University of Pittsburgh School of Medicine"},{"author_name":"Sunder Mudaliar","author_inst":"Diabetes\/Metabolism Section, VA San Diego HealthCare System; Clinical Professor of Medicine, University of California at San Diego"},{"author_name":"Dana Dabelea","author_inst":"Departments of Epidemiology and Pediatrics, Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus"},{"author_name":"Marinella Temprosa","author_inst":"Biostatistics Center and Department of Biostatistics and Bioinformatics, George Washington University"},{"author_name":"William C Knowler","author_inst":"Consultant, Biostatistics Center, George Washington University"},{"author_name":"David M Nathan","author_inst":"Diabetes Center, Massachusetts General Hospital and Harvard Medical School"},{"author_name":"Jose A Luchsinger","author_inst":"Departments of Medicine and Epidemiology, Columbia University Irving Medical Center"},{"author_name":"- DPP Research Group","author_inst":"-"}],"rel_date":"2026-08-07","rel_site":"medrxiv"},{"rel_title":"Randomized metformin and cognitive outcomes in the Diabetes Prevention Program Outcomes Study","rel_doi":"10.64898\/2026.08.05.26359234","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.05.26359234","rel_abs":"Importance. Metformin may influence risk of dementia, with prior conflicting observations of protection or harm. Objective. To determine the association of randomization to metformin vs. placebo or intensive lifestyle intervention (ILS) in the Diabetes Prevention Program (DPP) with cognitive outcomes (cognitive impairment syndromes and trajectories of cognitive test performance) during the DPP Outcomes Study (DPPOS). Design, Setting & Participants. Prospective long-term follow-up of DPP\/DPPOS participants at 27 U.S. centers among adults who were at high risk for type 2 diabetes (T2D) at baseline. Exposures. Randomization to metformin, placebo, or ILS (1996-1999) for 3.2 years followed by open-label metformin in the original randomized metformin group until 2021. Main Outcomes & Measures. Cognitive impairment syndromes were adjudicated in 2022-2024 in 1,483 participants (median age 74 [IQR 68, 80]) using the National Alzheimer's Coordinating Center Uniform Dataset version 3. Cognitive performance in executive and memory domains was ascertained with repeated cognitive tests between 2009 and 2024. Multinomial logistic regression and mixed-effects models were fit to examine associations of randomization to metformin with cognitive outcomes. Results. Total metformin exposure (mean {+\/-} SD) was 15.5 {+\/-}7.7 years\/person in the metformin group. Persons in the placebo and ILS groups received out-of-study metformin usually after developing diabetes with mean metformin total exposure of 4.5 {+\/-}5.1 and 3.8 {+\/-}4.8 years\/person in the placebo and ILS groups, respectively. Overall, the frequency distributions of the cognitive syndromes did not differ significantly by treatment group; however, randomization to metformin was associated with a 60% (OR 0.40 [95%CI 0.17, 0.97]) and 62% (OR 0.38 [95%CI 0.16, 0.89]) lower odds of dementia compared with placebo and ILS, respectively, after adjustment for demographics, education, income, and APOE-{varepsilon}4 genotype. Randomization to metformin was also associated with significantly better memory performance over time ( {beta} =0.58; 95%CI: 0.09, 1.1; p=0.02; Cohen's d=0.1). Conclusions and Relevance. Long-term metformin treatment is associated with a reduced risk of dementia and better memory performance among persons with pre-diabetes or T2D. Estimates were imprecise due to a limited number of dementia cases. Longer follow-up with more dementia cases is needed to confirm our findings.","rel_num_authors":18,"rel_authors":[{"author_name":"Pandora L Wander","author_inst":"Veterans Affairs (VA) Puget Sound Health Care System and Department of Medicine, University of Washington"},{"author_name":"Lindsay Doherty","author_inst":"Biostatistics Center and Department of Biostatistics and Bioinformatics, George Washington University"},{"author_name":"Qing Pan","author_inst":"Biostatistics Center and Department of Biostatistics and Bioinformatics, George Washington University"},{"author_name":"Owen Carmichael","author_inst":"Biomedical Imaging Center, Pennington Biomedical Research Center"},{"author_name":"Raymond Turner","author_inst":"Department of Neurology, MedStar Georgetown University Hospital and Georgetown University Medical Center"},{"author_name":"Shihchen Kuo","author_inst":"Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, Medical School, University of Michigan"},{"author_name":"Medha Munshi","author_inst":"Joslin Diabetes Center, Beth Israel Deaconess Medical Center, Harvard Medical School"},{"author_name":"Amisha Wallia","author_inst":"Division of Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine"},{"author_name":"James Noble","author_inst":"Department of Neurology, Taub Institute for Research on Alzheimers Disease and the Aging Brain, and the GH Sergievsky Center, Columbia University"},{"author_name":"Vallabh O Shah","author_inst":"School of Medicine, Int Medicine, University of New Mexico HSC"},{"author_name":"Neelesh K Nadkarni","author_inst":"Department of Medicine, Division of Geriatric Medicine and Gerontology, and Department of Neurology, University of Pittsburgh School of Medicine"},{"author_name":"Sunder Mudaliar","author_inst":"Diabetes\/Metabolism Section, VA San Diego HealthCare System; Clinical Professor of Medicine, University of California at San Diego"},{"author_name":"Dana Dabelea","author_inst":"Departments of Epidemiology and Pediatrics, Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus"},{"author_name":"Marinella Temprosa","author_inst":"Biostatistics Center and Department of Biostatistics and Bioinformatics, George Washington University"},{"author_name":"William C Knowler","author_inst":"Consultant, Biostatistics Center, George Washington University"},{"author_name":"David M Nathan","author_inst":"Diabetes Center, Massachusetts General Hospital and Harvard Medical School"},{"author_name":"Jose A Luchsinger","author_inst":"Departments of Medicine and Epidemiology, Columbia University Irving Medical Center"},{"author_name":"- DPP Research Group","author_inst":"-"}],"rel_date":"2026-08-07","rel_site":"medrxiv"},{"rel_title":"Blood Pressure Severity Modifies the Association Between Atrial Cardiopathy and Stroke Mortality","rel_doi":"10.64898\/2026.08.04.26359746","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.04.26359746","rel_abs":"Background: Electrocardiographic (ECG) markers of atrial cardiopathy (AC) are associated with stroke mortality, but whether this association is modified by blood pressure (BP) is unknown. Methods: We analyzed 7,191 adults free of cardiovascular disease from the Third National Health and Nutrition Examination Survey who underwent baseline ECG. AC was defined by three ECG markers: prolonged P-wave duration 120 ms), abnormal P-wave axis (<0{degrees} or >75{degrees}), and deep terminal negativity of the P wave in V1 (<100 V). AC burden (per additional AC marker) and AC presence (1 vs. 0 markers) were examined in relation to stroke mortality using Cox proportional hazards models. Participants were stratified by BP as normal\/elevated (<130\/80 mmHg), stage 1-2 hypertension (130-159\/80-99 mmHg), or severe hypertension (160\/100 mmHg). Interaction by BP category was assessed. Results: During a median follow-up of 13.8 years, 183 stroke deaths occurred. In multivariable adjusted model, AC burden was associated with a 41% higher risk of stroke mortality (HR (95%CI): 1.41 (1.13-1.77)). This association was significantly modified by BP (interaction P=0.003). The HRs (95% CIs) per additional AC marker were 0.88 (0.52-1.49), 1.39 (1.03-1.88), and 2.94 (1.82-4.75) for normal\/elevated BP, stage 1-2 hypertension, and severe hypertension, respectively. A similar pattern of associations was observed for AC presence, although the interaction with BP was not statistically significant. Conclusions: ECG-defined AC burden was independently associated with stroke mortality, with substantially stronger associations among individuals with severe hypertension, supporting BP as an important modifier of its prognostic significance.","rel_num_authors":8,"rel_authors":[{"author_name":"Asem M Mohsen","author_inst":"Wake Forest University School of Medicine"},{"author_name":"Moustafa Elnewishy","author_inst":"Wake Forest University School of Medicine"},{"author_name":"Patrick Cheon","author_inst":"Wake Forest University School of Medicine"},{"author_name":"Parag Anilkumar Chevli","author_inst":"Wake Forest University School of Medicine, Winston Salem, NC"},{"author_name":"Brian C. Charles Boursiquot","author_inst":"New York-Presbyterian\/Columbia University Irving Medical Center"},{"author_name":"Richard Kazibwe","author_inst":"Wake Forest University School of Medicine"},{"author_name":"Prashant D Bhave","author_inst":"Wake Forest University School of Medicine"},{"author_name":"Elsayed Z. Soliman","author_inst":"Wake Forest University School of Medicine"}],"rel_date":"2026-08-07","rel_site":"medrxiv"},{"rel_title":"DigiAra Computationally Designs Plant Mutants for Resistance to Microbial Infection in Arabidopsis","rel_doi":"10.64898\/2026.08.07.743468","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.07.743468","rel_abs":"Plant breeding is a resource-intensive process that requires repeated cultivation and selection across multiple generations to develop varieties with desirable traits, yet computational tools capable of supporting this process remain limited. Here, we present DigiAra, an AI-based framework for designing Arabidopsis thaliana mutants with targeted traits, particularly enhanced microbial resistance. DigiAra implements an S3 pipeline---simulation, scoring, and screening: it simulates the transcriptional effects of genetic perturbations and microbial infections, scores the predicted responses in terms of relevant traits through biological pathway analysis, and screens candidate perturbations at multiple levels. In doing so, DigiAra enables the computational exploration of the genome-wide effects of genetic perturbations and diverse microbial infections in Arabidopsis. To develop DigiAra, we address two fundamental challenges. Methodologically, we introduce a hybrid architecture that integrates local gene-level interaction modeling with global transcriptional-state modeling to predict perturbation-induced changes in the Arabidopsis transcriptional state. From a data perspective, we establish a standardized pipeline for curating, harmonizing, and processing an integrated Arabidopsis--microbe transcriptional dataset comprising 495 samples from 26 projects. As a result, DigiAra accurately predicts gene-expression changes induced by unobserved genetic perturbations and microbial infections, achieving a Pearson correlation of 0.49. Moreover, it recapitulates the general non-self response (GNSR), a 24-gene program reflecting broad transcriptional reprogramming across bacterial perturbations. In an independent study, the predicted pattern-triggered immunity pathway scores further correlate with bacterial load, with a Pearson correlation of 0.57. Lastly, we deploy DigiAra to identify 27 gene knockouts through genome-wide screening that are predicted to enhance resistance to Pseudomonas syringae pv. tomato DC3000 (Pst DC3000) while limiting growth compromise, 9 of which are supported by published studies. Together, these results establish DigiAra as an effective framework for the computational design of Arabidopsis mutants. We have made our implementation openly available at https:\/\/github.com\/youlab2025\/DigiAra.","rel_num_authors":3,"rel_authors":[{"author_name":"Tonghao Bai","author_inst":"The Chinese University of Hong Kong, Shenzhen"},{"author_name":"Shuguang Cui","author_inst":"The Chinese University of Hong Kong, Shenzhen"},{"author_name":"Yuning You","author_inst":"The Chinese University of Hong Kong, Shenzhen"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"De novo design of a protein fold for small-molecule binding through aromatic \u03c0 stacking","rel_doi":"10.64898\/2026.08.06.743053","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.06.743053","rel_abs":"The de novo design of proteins that bind chemically complex small molecules has broad chemical and biological implications, but strategies typically rely on a small set of protein scaffolds and require extensive experimental screening. Here, we computationally designed proteins around a minimal aromatic {pi}-stacking motif to bind the anthracycline anticancer drug doxorubicin. Experimental characterization of twelve proteins revealed a M doxorubicin binder; two additional design cycles improved scaffold stability and binding affinity to yield an 85-residue protein that binds doxorubicin with a dissociation constant of 85 nM. An X-ray crystal structure of the protein-drug complex confirmed the accuracy of the designed {pi}-{pi} stacking interactions. The designed protein could act to protect cultured cells from doxorubicin-induced cytotoxicity. Unlike previous ligand-binding protein designs based on repeat proteins or naturally occurring folds, the designed protein adopts a previously unobserved 5-helix globular fold, indicating that a broader space of folded, functional proteins exists even for compact tertiary structures smaller than 100 residues. These results demonstrate that motif-guided generative protein design can discover compact de novo protein folds capable of high-affinity recognition of chemically complex small molecules.","rel_num_authors":9,"rel_authors":[{"author_name":"Stephanie T. Ouchida","author_inst":"University of California at San Francisco"},{"author_name":"Maggie T. Horst","author_inst":"University of California at San Francisco"},{"author_name":"Xuxu Gou","author_inst":"University of California at San Francisco"},{"author_name":"Ian Bakanas","author_inst":"University of California at San Francisco"},{"author_name":"A. Katherine Hatstat","author_inst":"University of California at San Francisco"},{"author_name":"Lee Schnaider","author_inst":"University of California at San Francisco"},{"author_name":"Morgan E. Diolaiti","author_inst":"University of California at San Francisco"},{"author_name":"Alan Ashworth","author_inst":"University of California San Francisco"},{"author_name":"William F. DeGrado","author_inst":"University of California at San Francisco"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"Cellular basis of B12 uptake and remodelling in microalgae revealed using a novel bioassay","rel_doi":"10.64898\/2026.08.07.738727","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.07.738727","rel_abs":"Vitamin B12, an essential micronutrient for many microalgae and humans, is synthesised only by certain prokaryotes. B12 is a complex tetrapyrrole that can exist in many forms (vitamers), some more bioavailable than others. Some microalgae are able to interconvert, or remodel, different B12 vitamers. As microalgae are important primary producers, it is crucial to understand how diverse microalgae acquire, utilise, and remodel this micronutrient. Through the development of a novel algal bioassay for B12 quantification that distinguishes between B12 vitamers with different lower axial ligands, and the generation of targeted knock-out lines, we characterised the role of proteins involved in algal B12 uptake and remodelling. We found that the previously characterised protein CoBalamin-Acquisition protein 1 (CBA1) is also necessary for the acquisition of pseudocobalamin, a less bioavailable form of B12. In addition, we provide the first experimental evidence that COBT is required for Chlamydomonas reinhardtii to remodel B12. We apply the algal B12 bioassay to show that the edible alga Chlorella vulgaris can accumulate pseudocobalamin but is unable to remodel it, highlighting the need for thorough investigation of the metabolic requirements and capabilities of microalgae, especially given the growing interest in microalgae-based food additives.","rel_num_authors":10,"rel_authors":[{"author_name":"Ellen L Harrison","author_inst":"Marine Biological Association"},{"author_name":"Freddy Bunbury","author_inst":"University of Chicago"},{"author_name":"Tobias Stadelmann","author_inst":"University of Cambridge"},{"author_name":"Andy Sayer","author_inst":"University of Cambridge"},{"author_name":"Marcel Llavero-Pasquina","author_inst":"Universitat Autonoma de Barcelona"},{"author_name":"Konstantinos P Papadopoulos","author_inst":"University of Cambridge"},{"author_name":"Katrin Geisler","author_inst":"University of Manchester"},{"author_name":"Payam Mehrshahi","author_inst":"Green CoLab"},{"author_name":"Matthew P Davey","author_inst":"Scottish Association for Marine Science"},{"author_name":"Alison G Smith","author_inst":"University of Cambridge"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"CagA delivery by the Helicobacter pylori Cag-Type IV Secretion System confers fitness benefits and costs during stomach infection","rel_doi":"10.64898\/2026.08.07.743500","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.07.743500","rel_abs":"Helicobacter pylori strains encoding the cag-pathogenicity island (cag-PAI) and the effector toxin cagA are associated with worse disease outcomes. The cag-PAI encodes the Cag type IV secretion system (Cag-T4SS) which injects CagA and other bacterial products into gastric epithelial cells. Prior work revealed that host adaptive immunity promotes recombination in the cag-PAI gene cagY to attenuate Cag-T4SS activity during chronic infection, suggesting a fitness cost to assembling an active Cag-T4SS. To explore potential selective benefits and costs for the Cag-T4SS and CagA, we employed single strain and competitive infections at both acute and chronic timepoints in wildtype mice and transgenic mice that either attenuate innate immune responses or promote gastric pathology independent of H. pylori infection to examine the relative fitness of mutant H. pylori strains. Our results suggest that an active Cag-T4SS and CagA confer a fitness benefit during initial colonization through Cag-T4SS activity-dependent epithelial cell interactions that activate cancer-related signaling pathways. However, increasing gastric inflammation confers a fitness cost to CagA translocation, promoting Cag-T4SS shutoff. Targeted and whole genome sequencing revealed multiple mechanisms of Cag-T4SS attenuation, with recombination-mediated changes in cagY prevalent at early timepoints and mutations in a variety of Cag-T4SS structural genes accumulating as disease progresses. The need for Cag-T4SS activity and CagA translocation during initial gland colonization likely underlies the mutational pattern observed. Collectively this work reveals new insights into selective constraints on the H. pylori Cag-T4SS as well as resultant genetic adaptation processes that lead to retention of the cag-PAI and virulence.","rel_num_authors":6,"rel_authors":[{"author_name":"Jazmine Snow","author_inst":"EMC"},{"author_name":"Jacob Frick","author_inst":"McGovern Medical School, University of Texas Health Science Center"},{"author_name":"Valerie Phoebe O'Brien","author_inst":"Purdue University"},{"author_name":"Cynthia Guo","author_inst":"University of Toronto"},{"author_name":"Scott D. Gray-Owen","author_inst":"University of Toronto"},{"author_name":"Nina Salama","author_inst":"Fred Hutchinson Cancer Center"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"Protective pan-betacoronavirus neutralizing antibodies by vaccination","rel_doi":"10.64898\/2026.08.06.743418","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.06.743418","rel_abs":"The continued emergence of betacoronaviruses underscores the urgent need for vaccines that provide broadly protective immunity. Here, we present an epitope-focused vaccine strategy targeting the conserved S2 stem-helix region of the spike fusion machinery, a broadly neutralizing antibody-(bnAb) epitope shared across betacoronaviruses yet partially occluded on the native spike. Immunization of non-human primates with engineered S2 stem-helix nanoparticle immunogens, alone or followed by a SARS-CoV-2 BA.1 spike mRNA boost, elicited broadly cross-reactive antibody responses against sarbecoviruses, merbecoviruses, and embecoviruses and neutralized SARS-CoV-2, multiple variants, other sarbecoviruses, and MERS-CoV. Vaccine-elicited monoclonal antibodies displayed broad in-vitro neutralizing activity and protected against both SARS-CoV-2 and MERS-CoV in-vivo. Structural analyses revealed conserved features between rhesus and human stem-helix bnAbs, supporting the translational potential. Overall, our findings provide proof-of-concept that epitope-focused nanoparticle immunogens can target partially occluded, immunoquiescent bnAb epitopes, laying the groundwork for pan-betacoronavirus vaccines that provide broad protection and strengthen pandemic preparedness.","rel_num_authors":34,"rel_authors":[{"author_name":"Panpan Zhou","author_inst":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Ziqi Feng","author_inst":"Consortium for HIV\/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Wan-ting He","author_inst":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Yuxin Zhu","author_inst":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Meng Yuan","author_inst":"Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Xuduo Li","author_inst":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Yuexiu Zhang","author_inst":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Lina Vo","author_inst":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Tazio Capozzola","author_inst":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Sean Callaghan","author_inst":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Nitesh Mishra","author_inst":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Gabriel Avillion","author_inst":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Katharina Dueker","author_inst":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Bo Liang","author_inst":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Rohan Roy Chowdhury","author_inst":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Rebecca Nedellec","author_inst":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Wen-Hsin Lee","author_inst":"Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Joel D Allen","author_inst":"School of Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK."},{"author_name":"Agnes Walsh","author_inst":"Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Mariane Melo","author_inst":"Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Eileen T. McAnarney","author_inst":"Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"},{"author_name":"Nisha A. Kumar","author_inst":"Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"},{"author_name":"William Rinaldi","author_inst":"Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA."},{"author_name":"Melissa Ferguson","author_inst":"Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA."},{"author_name":"Max M. Crispin","author_inst":"School of Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK."},{"author_name":"Andrew B Ward","author_inst":"Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Darrell J Irvine","author_inst":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Mohamad-Gabriel Alameh","author_inst":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Drew Weissman","author_inst":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Ralph Baric","author_inst":"Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA."},{"author_name":"Lisa E Gralinski","author_inst":"Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA."},{"author_name":"Ian Wilson","author_inst":"Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Dennis R Burton","author_inst":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Raiees Andrabi","author_inst":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"Protective pan-betacoronavirus neutralizing antibodies by vaccination","rel_doi":"10.64898\/2026.08.06.743418","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.06.743418","rel_abs":"The continued emergence of betacoronaviruses underscores the urgent need for vaccines that provide broadly protective immunity. Here, we present an epitope-focused vaccine strategy targeting the conserved S2 stem-helix region of the spike fusion machinery, a broadly neutralizing antibody-(bnAb) epitope shared across betacoronaviruses yet partially occluded on the native spike. Immunization of non-human primates with engineered S2 stem-helix nanoparticle immunogens, alone or followed by a SARS-CoV-2 BA.1 spike mRNA boost, elicited broadly cross-reactive antibody responses against sarbecoviruses, merbecoviruses, and embecoviruses and neutralized SARS-CoV-2, multiple variants, other sarbecoviruses, and MERS-CoV. Vaccine-elicited monoclonal antibodies displayed broad in-vitro neutralizing activity and protected against both SARS-CoV-2 and MERS-CoV in-vivo. Structural analyses revealed conserved features between rhesus and human stem-helix bnAbs, supporting the translational potential. Overall, our findings provide proof-of-concept that epitope-focused nanoparticle immunogens can target partially occluded, immunoquiescent bnAb epitopes, laying the groundwork for pan-betacoronavirus vaccines that provide broad protection and strengthen pandemic preparedness.","rel_num_authors":34,"rel_authors":[{"author_name":"Panpan Zhou","author_inst":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Ziqi Feng","author_inst":"Consortium for HIV\/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Wan-ting He","author_inst":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Yuxin Zhu","author_inst":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Meng Yuan","author_inst":"Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Xuduo Li","author_inst":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Yuexiu Zhang","author_inst":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Lina Vo","author_inst":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Tazio Capozzola","author_inst":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Sean Callaghan","author_inst":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Nitesh Mishra","author_inst":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Gabriel Avillion","author_inst":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Katharina Dueker","author_inst":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Bo Liang","author_inst":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Rohan Roy Chowdhury","author_inst":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Rebecca Nedellec","author_inst":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Wen-Hsin Lee","author_inst":"Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Joel D Allen","author_inst":"School of Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK."},{"author_name":"Agnes Walsh","author_inst":"Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Mariane Melo","author_inst":"Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Eileen T. McAnarney","author_inst":"Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"},{"author_name":"Nisha A. Kumar","author_inst":"Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"},{"author_name":"William Rinaldi","author_inst":"Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA."},{"author_name":"Melissa Ferguson","author_inst":"Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA."},{"author_name":"Max M. Crispin","author_inst":"School of Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK."},{"author_name":"Andrew B Ward","author_inst":"Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Darrell J Irvine","author_inst":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Mohamad-Gabriel Alameh","author_inst":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Drew Weissman","author_inst":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"author_name":"Ralph Baric","author_inst":"Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA."},{"author_name":"Lisa E Gralinski","author_inst":"Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA."},{"author_name":"Ian Wilson","author_inst":"Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Dennis R Burton","author_inst":"Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA."},{"author_name":"Raiees Andrabi","author_inst":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"Propagation electrodynamics and differential conduction of action potentials in geometrically branched squid giant axons","rel_doi":"10.64898\/2026.08.03.742547","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.03.742547","rel_abs":"Classical neuronal cable theory relies on quasi-static electric field approximations and neglects magnetic induction, Lorentz force coupling, and transient electromagnetic currents, limiting its ability to fully characterize action potential propagation within geometrically branched axons and dendrites. This work develops a coupled Maxwell-electromagnetic cable framework by integrating finite-difference time-domain (FDTD) solutions of Maxwell's equations with extended Hodgkin-Huxley and Fitzhugh-Nagumo membrane dynamics, incorporating magnetic gating perturbations, electromagnetic trans-membrane currents $I_{\\text{EM}}$, and nanoscale quantum corrections for thin neural segments. Controlled propagation experiments are designed to quantify deviations from standard cable predictions across asymmetric and symmetric axonal bifurcation geometries. Numerical results demonstrate that inductive magnetic effects lower the critical branch radius for junction conduction failure and break symmetric action potential invasion in geometrically identical child branches under external transverse magnetic fields. An electromagnetic corrected geometric ratio $GR_{\\text{EM}}$ is proposed to revise impedance-matching conditions at branch points, accounting for size-dependent axial current imbalance induced by magnetic and displacement currents. Parent axon conduction velocity deviates substantially from the canonical $\\sqrt{d}$ scaling law when electromagnetic feedback and quantum charge distributions are included, triggering early signal blockage at large cable diameters. Collectively, this study establishes that quasi-static cable models underestimate electromagnetic corrections to propagation speed, waveform shape, and bifurcation transmission fidelity; the coupled Maxwell-cable framework provides a comprehensive multi-physics tool for modeling electrodynamic signal behavior in complex neuronal architectures.","rel_num_authors":3,"rel_authors":[{"author_name":"Xi Liu","author_inst":"Tsinghua University"},{"author_name":"Wenxi Fang","author_inst":"Inner mongolia university of science and technology"},{"author_name":"Ken Perlin","author_inst":"New York University"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"Propagation electrodynamics and differential conduction of action potentials in geometrically branched squid giant axons","rel_doi":"10.64898\/2026.08.03.742547","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.03.742547","rel_abs":"Classical neuronal cable theory relies on quasi-static electric field approximations and neglects magnetic induction, Lorentz force coupling, and transient electromagnetic currents, limiting its ability to fully characterize action potential propagation within geometrically branched axons and dendrites. This work develops a coupled Maxwell-electromagnetic cable framework by integrating finite-difference time-domain (FDTD) solutions of Maxwell's equations with extended Hodgkin-Huxley and Fitzhugh-Nagumo membrane dynamics, incorporating magnetic gating perturbations, electromagnetic trans-membrane currents $I_{\\text{EM}}$, and nanoscale quantum corrections for thin neural segments. Controlled propagation experiments are designed to quantify deviations from standard cable predictions across asymmetric and symmetric axonal bifurcation geometries. Numerical results demonstrate that inductive magnetic effects lower the critical branch radius for junction conduction failure and break symmetric action potential invasion in geometrically identical child branches under external transverse magnetic fields. An electromagnetic corrected geometric ratio $GR_{\\text{EM}}$ is proposed to revise impedance-matching conditions at branch points, accounting for size-dependent axial current imbalance induced by magnetic and displacement currents. Parent axon conduction velocity deviates substantially from the canonical $\\sqrt{d}$ scaling law when electromagnetic feedback and quantum charge distributions are included, triggering early signal blockage at large cable diameters. Collectively, this study establishes that quasi-static cable models underestimate electromagnetic corrections to propagation speed, waveform shape, and bifurcation transmission fidelity; the coupled Maxwell-cable framework provides a comprehensive multi-physics tool for modeling electrodynamic signal behavior in complex neuronal architectures.","rel_num_authors":3,"rel_authors":[{"author_name":"Xi Liu","author_inst":"Tsinghua University"},{"author_name":"Wenxi Fang","author_inst":"Inner mongolia university of science and technology"},{"author_name":"Ken Perlin","author_inst":"New York University"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"A DNA-barcoded Luria-Delbru\u0308ck assay resolves mechanisms of adaptation","rel_doi":"10.64898\/2026.08.03.742544","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.03.742544","rel_abs":"When populations encounter a harsh new environment, they adapt in many different ways -- from spontaneous genetic changes to transient non-genetic plasticity. Distinguishing between mechanisms of adaptation is often difficult, as the key events are rare and hard to observe directly. Here, we introduce HiDenSeq, a Luria-Delbruck assay that uses DNA barcoding and deep sequencing to resolve the Luria-Delbruck distribution -- the statistics of adaptation to a new environment -- over four orders of magnitude. At this statistical depth, the shape of the distribution encodes the underlying adaptive mechanism. We find that DNA mismatch repair mutants shift the distribution's scale without changing its shape, indicating their only effect is as mutator alleles. A pulse of UV mutagenesis, however, adds a second, statistically distinguishable mode atop the spontaneous background, showing that different mechanisms of adaptation can be quantified directly from the distribution. By sampling rare-event statistics with DNA barcodes, HiDenSeq provides a general method for studying mechanisms of adaptation in evolving populations from microbes to cancers.","rel_num_authors":4,"rel_authors":[{"author_name":"Kabir Husain","author_inst":"University College London"},{"author_name":"LaNijah Flagg","author_inst":"University of Chicago"},{"author_name":"David Pincus","author_inst":"University of Chicago"},{"author_name":"Arvind Murugan","author_inst":"University of Chicago"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"Let-7b-5p differentially regulates human first trimester trophoblast migration and sFlt-1 through TLR7 and TLR8","rel_doi":"10.64898\/2026.08.03.742516","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.03.742516","rel_abs":"Introduction: Preeclampsia is characterized by a pro-inflammatory, anti-migratory and anti-angiogenic placental phenotype. Impaired spiral artery remodeling stemming from trophoblast dysfunction is a key pathogenic mechanism. Little is known about the processes that govern trophoblast function normally and in preeclampsia. In preeclampsia, placental Let-7b-5p is reduced. The objectives of this study were to determine the normal function of Let-7b-5p in human trophoblast cells, to examine whether the ssRNA sensors, Toll-like receptor (TLR) 7 and\/or TLR8 are mediators of trophoblast Let-7b-5p function, and whether disruption of this pathway promotes a preeclampsia-like phenotype in the trophoblast. Methods: The human first trimester trophoblast cell line, Sw.71, was transfected with a Let-7b-5p mimic, a Let-7b-5p inhibitor, or scramble control. Cells were treated with or without the TLR7 inhibitor IRS661 or the TLR8 inhibitor CUCPT9a. Trophoblast migration was measured using a two-chamber assay and interactions with human endometrial endothelial cells (HEECs) was measured using a 3D matrigel model. Trophoblast anti-angiogenic sFlt-1 release was measured by ELISA and sFLT1 mRNA measured by RT-qPCR. Results: Transfection of trophoblast cells with a Let-7b-5p mimic elevated migration through activation of TLR7 and TLR8, while in a TLR7-dependent manner, the Let-7b-5p mimic negatively regulated sFlt-1 production. Furthermore, inhibition of trophoblast Let-7b-5p reduced migration, elevated FLT1 mRNA expression and sFlt-1 release, and reduced trophoblast-endometrial endothelial cell interactions. Conclusions: This study highlights a role for TLR7\/TLR8-activating Let-7b-5p in promoting normal trophoblast function and endothelial interactions and that disruption in this miR-driven signaling pathway may be relevant to processes driving a pre-eclamptic placental phenotype.","rel_num_authors":4,"rel_authors":[{"author_name":"Emily G Siegel","author_inst":"Yale School of Medicine"},{"author_name":"Lily C Salmeron","author_inst":"Yale School of Medicine"},{"author_name":"Vikki M Abrahams","author_inst":"Yale School of Medicine"},{"author_name":"Lubna Pal","author_inst":"Yale School of Medicine"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"Myeloid-targeted RNA nanotherapeutics rewire cholesterol metabolism to unleash anti-tumor immunity in glioblastoma","rel_doi":"10.64898\/2026.08.03.741800","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.03.741800","rel_abs":"Tumor-associated myeloid cells (TAMCs) dominate the glioblastoma (GBM) microenvironment and suppress anti-tumor immunity. Here, we identify cholesterol efflux via ABCA1 as a targetable metabolic checkpoint controlling TAMC immunosuppression in GBM. Reprogramming TAMC cholesterol metabolism using TAMC-targeting lipid nanoparticle encapsulating ABCA1 siRNA (ABCA1 LNP) converts TAMCs into potent antigen-presenting cells with enhanced pro-inflammatory activity and antigen-presenting capacity, thereby inducing T cell activation, expansion, and tumor infiltration. Mechanistically, ABCA1 blockade induces cholesterol accumulation in TAMC membranes, promoting lipid raft formation and enhancing MHC-I-mediated antigen presentation. In multiple preclinical GBM models, ABCA1 LNP treatment dramatically induces T cell priming, extends animal survival, and overcomes GBM resistance to radiotherapy and immune checkpoint therapy. This efficacy was well-maintained in stem-like and recurrent GBM models, GBM patient specimens, and a renal cell carcinoma model. Altogether, our work identifies cholesterol efflux as a targetable metabolic vulnerability in TAMCs to overcome therapy resistance in myeloid-rich, immunologically cold tumors.","rel_num_authors":37,"rel_authors":[{"author_name":"Jiawei Huo","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Hanchen Lin","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Yinmeng Li","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Shashwat Tripathi","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Rafal Chojak","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Caylee Silvers","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Yirui Peng","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Lauren Boland","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Jianzhong Zhang","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Kathleen McCortney","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Rasangi M. Perera","author_inst":"Metabolomics Platform, University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA"},{"author_name":"Hinda Najem","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Leah K. Billingham","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Tzu-Yi Chia","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Xiaoyang Chen","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Hanxiang Wang","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Jingqi Sun","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Mark John Siringan","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Leon Jing","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Amaan Musabji","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Harrshavasan Congivaram","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Si Wang","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Aurora Lopez-Rosas","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Priya Kumthekar","author_inst":"Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Department of"},{"author_name":"Pouya Jamshidi","author_inst":"Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Department of"},{"author_name":"Atique U. Ahmed","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Catalina Lee-Chang","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"James P. Chandler","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Mark W. Youngblood","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Adam Sonabend","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Matthew C. Tate","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Hardik Shah","author_inst":"Metabolomics Platform, University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL, USA"},{"author_name":"Edward B. Thorp","author_inst":"Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Center for Human Immunobiology, Feinberg School of Medicine, Nor"},{"author_name":"Maciej S. Lesniak","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Amy B. Heimberger","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Jason Miska","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"},{"author_name":"Peng Zhang","author_inst":"Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Malnati Brain Tumor Institute, Robert H. Lurie Compre"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"Sequence-dependent molecular asymmetry and architecture define electric potential profiles of biomolecular condensates","rel_doi":"10.64898\/2026.08.03.742525","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.03.742525","rel_abs":"Biomolecular condensates, which regulate diverse cellular processes, exhibit distinct electric potential profiles. This potential gradient between the dilute and the dense phases serves as the underlying driving force mediating the unique microenvironment and electrochemical activity of condensates. However, the molecular principles encoding the electric potential profiles of condensates remain unclear. In this study, we show that molecular asymmetry is a unifying origin of electric polarization in condensates. Asymmetric protein-cation and protein-anion affinities alone generate an interfacial electric double layer and a finite potential even in condensates formed by charge-free proteins. The sign of potential gradient follows the direction of the affinity bias, and the magnitude collapses onto a single linear function of dense-phase protein volume fraction across changes in chain length, interaction strength and salt concentration. Further, chain termini preferentially occupy the condensate interface, so charges positioned asymmetrically with respect to the termini create spatial charge separation even in neutral polyampholytes. These interaction-encoded and sequence architecture-encoded asymmetries can reinforce, screen or reverse one another, allowing the magnitude and polarity of the interphase potential to be tuned through sequence design or solvent environments.","rel_num_authors":4,"rel_authors":[{"author_name":"Fangke Chen","author_inst":"Hong Kong Baptist University"},{"author_name":"Runchen Xia","author_inst":"Hong Kong Baptist University"},{"author_name":"Yifan Dai","author_inst":"Washington University in St. Louis"},{"author_name":"Xiangze Zeng","author_inst":"Hong Kong Baptist University"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"HANSEN: An Integrated Structural and Functional Proteome Resource for Structure-Guided Drug Discovery in Mycobacterium leprae","rel_doi":"10.64898\/2026.08.03.741541","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.03.741541","rel_abs":"Structural biology has advanced antimicrobial discovery by enabling drug-target identification and validation and supporting structure-guided inhibitor design. However, Mycobacterium leprae (M. leprae), the obligate intracellular bacillus that causes leprosy (Hansen's disease), remains structurally under-characterised. Only 10 Protein Data Bank (PDB) entries represent seven unique proteins within a proteome encoded by 1,603 protein-coding genes. To address this gap, we present HANSEN (https:\/\/hansen-leprosy.medschl.cam.ac.uk\/home), an integrated structural and functional resource containing computationally predicted three-dimensional models across the M. leprae proteome. Monomeric and oligomeric models were generated using complementary structure-prediction methods, including AlphaFold 3, Boltz-1, Chai-1, and Boltz-2. Models were annotated with predicted Local Distance Difference Test (pLDDT) scores and Predicted Aligned Error (PAE) values. Ligand-binding pockets were predicted using AF2BIND, P2Rank, and fpocket, and ligands from the best-matching PDB templates were modelled within oligomeric complexes. Residue-level B-cell epitope propensity was estimated using DiscoTope-3.0, and ProteomeLM-derived essentiality scores were calculated for each protein. These features were integrated into a relational web database with interactive visualisation through Mol*. We also ranked all 1,603 proteins using a Target Priority Score ranging from 0 to 100. The score combines ProteomeLM-derived essentiality with pocket and AF2BIND predictions, functional annotations, and Boltz-2-associated measures of model quality and tractability. The essentiality model used a logistic-regression head trained on Mycobacterium tuberculosis (M. tuberculosis) Tn-seq labels. It achieved an AUROC of 0.84 in homology-grouped M. tuberculosis cross-validation and a transfer AUROC of 0.78 against the orthologue-aligned M. leprae reference set. Proteins were assigned to four tiers, ranging from high priority to exploratory candidates. Together, HANSEN provides a practical resource for generating and prioritising experimentally testable hypotheses for M. leprae target discovery and structure-guided drug development.","rel_num_authors":11,"rel_authors":[{"author_name":"Sundeep Chaitanya Vedithi","author_inst":"The Victor Phillip Dahdaleh Heart & Lung Research Institute, Department of Medicine, University of Cambridge"},{"author_name":"Rebecca Rees","author_inst":"Swansea University Medical School, Faculty of Medicine, Health and Life Sciences, Swansea, UK"},{"author_name":"Sony Malhotra","author_inst":"Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Campus, Didcot, OX11 0QX, UK"},{"author_name":"Asma Munir","author_inst":"The Victor Phillip Dahdaleh Heart & Lung Research Institute, Department of Medicine, University of Cambridge, Cambridge, UK"},{"author_name":"Modestas Matusevicius","author_inst":"The Victor Phillip Dahdaleh Heart & Lung Research Institute, Department of Medicine, University of Cambridge, Cambridge, UK"},{"author_name":"Ali F. Alsulami","author_inst":"Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia"},{"author_name":"Christopher A. Beaudoin","author_inst":"Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK"},{"author_name":"Kiran Sai Sunkara","author_inst":"Rutgers University, New Brunswick, The State University of New Jersey, 57 US Highway 1, New Brunswick, NJ 08901 8554, USA"},{"author_name":"Madhusmita Das","author_inst":"Hybrinomics Lifesciences and Diagnostics, Doddagubbi, Bengaluru, Karnataka 560077, India"},{"author_name":"Tom L. Blundell","author_inst":"The Victor Phillip Dahdaleh Heart & Lung Research Institute, Department of Medicine, University of Cambridge, Cambridge, UK"},{"author_name":"Rodrigo Andres Floto","author_inst":"The Victor Phillip Dahdaleh Heart & Lung Research Institute, Department of Medicine, University of Cambridge, Cambridge, UK"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"Cross-species analysis of GNB1 I80T encephalopathy: conserved developmental, epileptic and neuronal transcriptome signatures","rel_doi":"10.64898\/2026.08.03.742477","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.03.742477","rel_abs":"GNB1 encephalopathy (GNB1E) is a rare neurodevelopmental disorder caused by mutations in GNB1 gene encoding the G protein subunit G{beta}1. Mechanisms linking these variants to neurological dysfunction remain unclear. We investigated the prevalent p.Ile80Thr (I80T) variant using combined clinical, cellular, and in vivo approaches. Longitudinal evaluation of a GNB1E patient revealed developmental delay, progressive peripheral spasticity, and epilepsy with Spike-Wave Activation in Sleep. Heterozygous knock-in Gnb1I80T\/+ mice exhibited disease-relevant phenotypes, including impaired early development, mild adult motor and cognitive deficits and epileptiform cortical spike-and-wave discharges. Transcriptomic analysis identified 323 genes concordantly dysregulated in mouse cortex and cortical human neuronal cultures from patient-derived induced pluripotent cells. This gene set was enriched for ion-channel function, epilepsy-associated genes, and Gs\/adenylyl cyclase signaling pathway. Our integrated analysis establishes the first cross-species model for GNB1E, suggests common neurological mechanisms and molecular pathways linked to GNB1E, and provides a framework for mechanistic and therapeutic studies.","rel_num_authors":17,"rel_authors":[{"author_name":"Haritha P Reddy","author_inst":"Tel Aviv University"},{"author_name":"Vigneshwar Ranjan","author_inst":"Tel Aviv University"},{"author_name":"Merav Klo","author_inst":"Tel Aviv University"},{"author_name":"Guy Shapiro","author_inst":"Tel Aviv University"},{"author_name":"Haim Bassan","author_inst":"Shamir Medical Center, Israel"},{"author_name":"Gilad Harel","author_inst":"Tel Aviv University"},{"author_name":"Gali Heimer","author_inst":"The Chaim Sheba Medical Center, Israel"},{"author_name":"Bruria Ben Zeev","author_inst":"The Chaim Sheba Medical Center, Israel"},{"author_name":"Tatiana Rabinski","author_inst":"Ben Gurion University"},{"author_name":"Gad D Vatine","author_inst":"Ben Gurion University of the Negev"},{"author_name":"Yakey Yaffe","author_inst":"Tel Aviv University"},{"author_name":"Ben M Maoz","author_inst":"Tel Aviv University"},{"author_name":"Lior Bikovski","author_inst":"Tel Aviv University"},{"author_name":"Noam Shomron","author_inst":"Tel Aviv University"},{"author_name":"Daniel M Yakubovich","author_inst":"Ariel University"},{"author_name":"Moran Rubinstein","author_inst":"Tel Aviv University"},{"author_name":"Nathan Dascal","author_inst":"Tel Aviv University"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"Synthetic Longitudinal Tabular Data Generation via Copula","rel_doi":"10.64898\/2026.08.03.742474","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.03.742474","rel_abs":"Synthetic data generation is increasingly used to enable data sharing and secondary analysis while protecting participant privacy, particularly for longitudinal tabular health data, where repeated measures per subject create within-subject dependence that most synthetic data methods are not designed to preserve. Existing generative methods, particularly generative adversarial network (GAN)-based approaches, can model complex distributions, but their estimated dependence structures are often difficult to interpret and their performance may be unstable or prone to overfitting in modestly sized datasets. Here we show that eCDF-copula, a statistically rooted approach using the empirical cumulative distribution function (eCDF) and copula modeling, preserves within- and between-visit dependence structure. To handle pervasive missing data, we propose a two-stage strategy combining multiple imputation with copula-based synthesis, enabling a variance decomposition that quantifies replication variability across methods. We benchmarked the proposed approach against four established methods on two longitudinal clinical datasets spanning markedly different sample sizes (n=120 vs. n=3,612). eCDF-copula achieved resemblance and utility exceeding those of state-of-the-art synthetic data methods, while maintaining comparable privacy.","rel_num_authors":6,"rel_authors":[{"author_name":"Hanchang Cai","author_inst":"University of California San Diego"},{"author_name":"Wenshan Yu","author_inst":"Georgia State University"},{"author_name":"Ruijin Lu","author_inst":"Washington University in St. Louis"},{"author_name":"Ishanu Chattopadhyay","author_inst":"University of Kentucky College of Medicine"},{"author_name":"Xinlian Zhang","author_inst":"University of California San Diego"},{"author_name":"Jinyuan Liu","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"Synthetic Longitudinal Tabular Data Generation via Copula","rel_doi":"10.64898\/2026.08.03.742474","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.03.742474","rel_abs":"Synthetic data generation is increasingly used to enable data sharing and secondary analysis while protecting participant privacy, particularly for longitudinal tabular health data, where repeated measures per subject create within-subject dependence that most synthetic data methods are not designed to preserve. Existing generative methods, particularly generative adversarial network (GAN)-based approaches, can model complex distributions, but their estimated dependence structures are often difficult to interpret and their performance may be unstable or prone to overfitting in modestly sized datasets. Here we show that eCDF-copula, a statistically rooted approach using the empirical cumulative distribution function (eCDF) and copula modeling, preserves within- and between-visit dependence structure. To handle pervasive missing data, we propose a two-stage strategy combining multiple imputation with copula-based synthesis, enabling a variance decomposition that quantifies replication variability across methods. We benchmarked the proposed approach against four established methods on two longitudinal clinical datasets spanning markedly different sample sizes (n=120 vs. n=3,612). eCDF-copula achieved resemblance and utility exceeding those of state-of-the-art synthetic data methods, while maintaining comparable privacy.","rel_num_authors":6,"rel_authors":[{"author_name":"Hanchang Cai","author_inst":"University of California San Diego"},{"author_name":"Wenshan Yu","author_inst":"Georgia State University"},{"author_name":"Ruijin Lu","author_inst":"Washington University in St. Louis"},{"author_name":"Ishanu Chattopadhyay","author_inst":"University of Kentucky College of Medicine"},{"author_name":"Xinlian Zhang","author_inst":"University of California San Diego"},{"author_name":"Jinyuan Liu","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"Synthetic Longitudinal Tabular Data Generation via Copula","rel_doi":"10.64898\/2026.08.03.742474","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.03.742474","rel_abs":"Synthetic data generation is increasingly used to enable data sharing and secondary analysis while protecting participant privacy, particularly for longitudinal tabular health data, where repeated measures per subject create within-subject dependence that most synthetic data methods are not designed to preserve. Existing generative methods, particularly generative adversarial network (GAN)-based approaches, can model complex distributions, but their estimated dependence structures are often difficult to interpret and their performance may be unstable or prone to overfitting in modestly sized datasets. Here we show that eCDF-copula, a statistically rooted approach using the empirical cumulative distribution function (eCDF) and copula modeling, preserves within- and between-visit dependence structure. To handle pervasive missing data, we propose a two-stage strategy combining multiple imputation with copula-based synthesis, enabling a variance decomposition that quantifies replication variability across methods. We benchmarked the proposed approach against four established methods on two longitudinal clinical datasets spanning markedly different sample sizes (n=120 vs. n=3,612). eCDF-copula achieved resemblance and utility exceeding those of state-of-the-art synthetic data methods, while maintaining comparable privacy.","rel_num_authors":6,"rel_authors":[{"author_name":"Hanchang Cai","author_inst":"University of California San Diego"},{"author_name":"Wenshan Yu","author_inst":"Georgia State University"},{"author_name":"Ruijin Lu","author_inst":"Washington University in St. Louis"},{"author_name":"Ishanu Chattopadhyay","author_inst":"University of Kentucky College of Medicine"},{"author_name":"Xinlian Zhang","author_inst":"University of California San Diego"},{"author_name":"Jinyuan Liu","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"REFCON: Reference-free and robust copy number inference in single-cell tumor transcriptomes","rel_doi":"10.64898\/2026.08.03.742406","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.03.742406","rel_abs":"Single-cell RNA sequencing (scRNA-seq) is widely used to infer copy number profiles from tumor cells. Existing methods build on a reference-based normalization paradigm: normalizing each tumor cell against a reference of normal cells, whether supplied, in-sample, or synthesized. This makes them reference-dependent and as a result, sensitive to cohort composition, and prone to false positives. To address these limitations, we introduce REFCON, a deep learning model that enables reference-free copy number profiling from scRNA seq data. REFCON estimates local copy-number deviations and jointly optimizes them into a genome-wide per-cell profile. It profiles pure tumors, generalizes to unseen tissues and platforms, and stays robust to cohort composition. Predicted copy number profiles distinguish malignant cells with high specificity, producing far fewer false-positive calls, and improve clonal reconstruction. The model can also benefit from reference cells when available, turning a field requirement into an optional refinement. Hence, REFCON extends reliable per-cell copy number profiling to the scRNA-seq data collected without matched normals.","rel_num_authors":2,"rel_authors":[{"author_name":"M. Mert Gencturk","author_inst":"Bilkent University"},{"author_name":"A. Ercument Cicek","author_inst":"Bilkent University"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"scATrans: annotating single-cell differential expression as transcription- or stabilization-weighted using unspliced RNA","rel_doi":"10.64898\/2026.08.03.740741","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.03.740741","rel_abs":"Single-cell differential expression (DE) reports changes in mature mRNA abundance, but the same fold-change can reflect faster synthesis or slower decay. Metabolic labeling resolves this ambiguity but is costly and cannot be applied retrospectively to the vast majority of published scRNA-seq. scATrans closes this gap using layers every standard pipeline already generates: from DE-selected genes, a reference-corrected unspliced residual annotates each change as transcription- or stabilization-weighted, with no additional experiment. Benchmarked against metabolic-labeling systems with independent kinetic ground truth, the residual separates the two mechanisms at matched mature abundance (ROC-AUC 0.68-0.74, full-length NASC-seq2 K562; 0.59-0.63, 3' scEU-seq RPE1); effect size scales with intron capture, not model complexity, and explicit kinetic fitting adds nothing over the static contrast. Per-gene, the residual recovers the classical bulk exon-intron contrast (EISA); what scATrans adds is the inference layer single-cell reanalysis actually needs--DE-defined membership, gene-structure correction, a capture-regime reliability pre-flight, induction-matched testing, and a permutation-calibrated program score--so that confident calls are reserved for where the data support them: gene programs, not single genes. Applied to standard 10x data with no labeling, scATrans recovers textbook post-transcriptional biology: a curated AU-rich-element program is called stabilization-weighted in LPS-stimulated PBMCs (confirmed by per-donor pseudobulk DE in an independent four-donor cohort), while a glucocorticoid-response program is called transcription-weighted in dexamethasone-treated A549 cells-- opposite mechanisms recovered from unlabeled counts. scATrans turns any spliced\/unspliced-resolved DE table into a mechanism-typed one, retrospectively and at scale.\n\nAvailability and implementationscATrans requires Python [&ge;]3.9, interoperates with the scverse ecosystem (AnnData, Scanpy), and is released under the Apache-2.0 license. Install with pip install scatrans or from Bioconda. Documentation and tutorials: https:\/\/scatrans.readthedocs.io. Analyses in this manuscript use software version 0.10.9.","rel_num_authors":3,"rel_authors":[{"author_name":"Zhao Li","author_inst":"Department of Pathology, Johns Hopkins University"},{"author_name":"Aaron James","author_inst":"Department of Pathology, Johns Hopkins University"},{"author_name":"Shengxuan Li","author_inst":"Department of Pathology, Johns Hopkins University"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"A modular cranial window enabling maintainable widefield optical access in non-human primates","rel_doi":"10.64898\/2026.08.02.742348","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.02.742348","rel_abs":"Longitudinal optical imaging of the primate cortex requires stable yet maintainable cortical access, but existing cranial window approaches remain limited by mechanical instability and tissue responses that progressively degrade optical clarity. These challenges are amplified in primates, where large craniotomies and physiological variability complicate chronic experiments. Moving beyond conventional fixed cranial windows, we present the PRIME cranial window (Primate Reconfigurable Interchangeable Modular Enclosure), a modular platform enabling maintainable, long-term, and widefield optical access in awake macaques. Built on a modular architecture, PRIME supports non-invasive adjustment, repeated cortical access, and on-demand maintenance, including tissue removal, without surgical re-entry, while a dual-ring sealing mechanism prevents cerebrospinal fluid leakage and contamination. Combined with optimized viral delivery, implantation, and maintenance strategies, PRIME preserves cortical integrity and optical clarity for long-term optical imaging. PRIME establishes a versatile, re-accessible experimental framework for chronic, large-area optical studies of the primate brain.","rel_num_authors":8,"rel_authors":[{"author_name":"Wonjoon Jeong","author_inst":"School of Biological Sciences, College of Natural Sciences, Seoul National University (SNU), Seoul, 08826, Republic of Korea"},{"author_name":"Dongsu Kim","author_inst":"School of Biological Sciences, College of Natural Sciences, Seoul National University (SNU), Seoul, 08826, Republic of Korea"},{"author_name":"Jaehyun Kim","author_inst":"School of Biological Sciences, College of Natural Sciences, Seoul National University (SNU), Seoul, 08826, Republic of Korea"},{"author_name":"Youngjeon Lee","author_inst":"National Primate Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Cheongju, 28116, Republic of Korea; Department of Functional"},{"author_name":"Raehyung Yoo","author_inst":"Non-Clinical Evaluation Center, OSONG Medical Innovation Foundation (KBIOHealth), Cheongju, 28160, Republic of Korea"},{"author_name":"Joonyeol Lee","author_inst":"Department of Biomedical Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea"},{"author_name":"Myunghwan Choi","author_inst":"School of Biological Sciences, College of Natural Sciences, Seoul National University (SNU), Seoul, 08826, Republic of Korea"},{"author_name":"Hyoung F Kim","author_inst":"School of Biological Sciences, College of Natural Sciences, Seoul National University (SNU), Seoul, 08826, Republic of Korea"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"ClinOracle: Hierarchical AI Prediction of Target Binding and Patient-Derived Functional Activity Across Diverse Therapeutic Targets","rel_doi":"10.64898\/2026.08.02.742378","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.02.742378","rel_abs":"AI platforms for drug discovery routinely achieve high hit rates against biochemical targets, yet the central translational challenge remains predicting whether a compound will be functionally active in patient-derived human cells. Here, we present ClinOracle, a hierarchical graph neural network that jointly predicts target binding and patient-derived functional activity by modeling functional activity as conditional on target engagement. Applied across five therapeutic targets spanning oncology, autoimmune, and neuroinflammatory diseases, ClinOracle ranked candidates using a Priority Score integrating translational probability with a developability score based on ADME and drug-likeness, advancing prioritized compounds through multistage prospective validation from biophysical binding to in vivo efficacy. Compounds with the highest Priority Scores consistently outperformed lower-ranked candidates across prospective experimental validation, demonstrating that hierarchical AI can prioritize compounds with patient-derived functional activity directly from molecular structure, rather than biochemical activity alone.","rel_num_authors":2,"rel_authors":[{"author_name":"Somaya Abdel-Rahman","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Moustafa Gabr","author_inst":"Columbia University Irving Medical Center"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"AAV9-mediated \u03b2III-tubulin Ser172 phospho-mimic expression improves arrhythmic and inflammatory remodeling in dystrophic cardiomyopathy","rel_doi":"10.64898\/2026.08.04.742904","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.04.742904","rel_abs":"Background Duchenne muscular dystrophy (DMD) cardiomyopathy is characterized by progressive microtubule remodeling, connexin-43 (Cx43) dysregulation, and ventricular arrhythmias. We previously demonstrated phospho-mimic knock-in of {beta}III-tubulin S172E preserves microtubule organization and attenuates cardiac pathology in mdx mice. However, whether these protective effects can be reproduced using a clinically relevant gene-delivery strategy remains unknown. Methods and Results We generated a cardiomyocyte-specific adeno-associated virus serotype 9 (AAV9) vector expressing phospho-mimic {beta}III-tubulin (Tubb3-S172E) under the cardiac troponin T promoter and delivered it to 4-5-month-old wild-type and mdx mice. Cardiac Tubb3-S172E expression was confirmed by quantitative qPCR and immunoblotting. In mdx mice, AAV9-mediated Tubb3-S172E expression significantly reduced mononuclear inflammatory infiltration, restored Cx43 localization at intercalated discs, and attenuated isoproterenol-induced arrhythmia susceptibility. In contrast, cardiac fibrosis, Nav1.5 protein expression, and peak sodium current density were not significantly improved. Overexpression of wild-type {beta}III-tubulin in healthy hearts increased Cx43 lateralization and arrhythmia susceptibility, indicating that {beta}III-tubulin phosphorylation state rather than protein abundance determines its protective function. Conclusions Cardiomyocyte-targeted delivery of phospho-mimic {beta}III-tubulin partially recapitulates the protective effects observed in the genetic S172E knock-in model. These findings identify {beta}III-tubulin Ser172 phosphorylation as a critical regulator of microtubule-dependent electrical remodeling and support therapeutic modulation of this pathway in Duchenne muscular dystrophy cardiomyopathy.","rel_num_authors":7,"rel_authors":[{"author_name":"Delong Zhou","author_inst":"Rutgers University"},{"author_name":"Vasisht Yegneshwaran","author_inst":"Rutgers University"},{"author_name":"Nehal Kamal Ali","author_inst":"Rutgers University"},{"author_name":"Geovanni Geukgeuzian","author_inst":"Rutgers University"},{"author_name":"Elam Mesa","author_inst":"Rutgers University"},{"author_name":"Lai-Hua Xie","author_inst":"Rutgers New Jersey Medical School Division of Basic Science"},{"author_name":"Diego Fraidenraich","author_inst":"Rutgers University - New Jersey, Medical School"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"Evidence of tornadic phenomena in cerebral aneurysms","rel_doi":"10.64898\/2026.08.07.743435","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.07.743435","rel_abs":"Cerebral aneurysms are abnormal outpouchings of arteries within the brain and occur in ~1 in 30 adults. Their initiation, growth, and rupture have been linked to focal blood flow abnormalities, often termed disturbed or hostile hemodynamics, but commonly-used hemodynamic metrics yield conflicting associations with pathology and lack a unifying mechanistic interpretation. Building on a theoretically-grounded link between wall shear stress and near-wall vorticity, we hypothesized that a topology-based description of near-wall flow can operationalize the concept of hostile hemodynamics in a reproducible way. Inspired by atmospheric tornadic phenomena, we sought a principled taxonomy of coherent near-wall fluid structures with potential mechanobiological and clinical implications. Using high-fidelity computational fluid dynamics simulations in anatomically realistic geometries, we identified coherent near-wall fluid structures whose organization mirrors well-studied atmospheric phenomena: tornado-like columnar rotating cores; downburst-like nonrotating wall-impinging jets with tangential outflow, roll-cloud-like tangential vortices; and mixed configurations. These tornadic events on the aneurysm luminal surface were identified from wall shear stress topology, consistent with its theoretical connection to near-wall vorticity kinematics. The presence of tornadic phenomena, and their imprints on the aneurysm wall, was independently observed in vivo using 4D flow magnetic resonance imaging. By translating concepts from atmospheric physics into vascular biomechanics, this topology-based framework yields a unified mechanistic language for describing near-wall hemodynamics, resolving blood flow complexity into interpretable and reproducible coherent fluid structures, enabling standardized hemodynamic phenotyping, and supporting hypothesis-driven studies of aneurysms and other cardiovascular diseases where greater fluid-mechanical specificity and interpretability may strengthen links between mechanobiology and clinical risk.","rel_num_authors":8,"rel_authors":[{"author_name":"Valentina Mazzi","author_inst":"Politecnico di Torino"},{"author_name":"Diego Gallo","author_inst":"Politecnico di Torino"},{"author_name":"Thangam Natarajan","author_inst":"Georgia Institute of Technology"},{"author_name":"Jonas Schollenberger","author_inst":"University of California San Francisco"},{"author_name":"Karol Cal\u00f2","author_inst":"Politecnico di Torino"},{"author_name":"David Saloner","author_inst":"University of California San Francisco"},{"author_name":"David A Steinman","author_inst":"University of Toronto"},{"author_name":"Umberto Morbiducci","author_inst":"Politecnico di Torino"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"Evidence of tornadic phenomena in cerebral aneurysms","rel_doi":"10.64898\/2026.08.07.743435","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.07.743435","rel_abs":"Cerebral aneurysms are abnormal outpouchings of arteries within the brain and occur in ~1 in 30 adults. Their initiation, growth, and rupture have been linked to focal blood flow abnormalities, often termed disturbed or hostile hemodynamics, but commonly-used hemodynamic metrics yield conflicting associations with pathology and lack a unifying mechanistic interpretation. Building on a theoretically-grounded link between wall shear stress and near-wall vorticity, we hypothesized that a topology-based description of near-wall flow can operationalize the concept of hostile hemodynamics in a reproducible way. Inspired by atmospheric tornadic phenomena, we sought a principled taxonomy of coherent near-wall fluid structures with potential mechanobiological and clinical implications. Using high-fidelity computational fluid dynamics simulations in anatomically realistic geometries, we identified coherent near-wall fluid structures whose organization mirrors well-studied atmospheric phenomena: tornado-like columnar rotating cores; downburst-like nonrotating wall-impinging jets with tangential outflow, roll-cloud-like tangential vortices; and mixed configurations. These tornadic events on the aneurysm luminal surface were identified from wall shear stress topology, consistent with its theoretical connection to near-wall vorticity kinematics. The presence of tornadic phenomena, and their imprints on the aneurysm wall, was independently observed in vivo using 4D flow magnetic resonance imaging. By translating concepts from atmospheric physics into vascular biomechanics, this topology-based framework yields a unified mechanistic language for describing near-wall hemodynamics, resolving blood flow complexity into interpretable and reproducible coherent fluid structures, enabling standardized hemodynamic phenotyping, and supporting hypothesis-driven studies of aneurysms and other cardiovascular diseases where greater fluid-mechanical specificity and interpretability may strengthen links between mechanobiology and clinical risk.","rel_num_authors":8,"rel_authors":[{"author_name":"Valentina Mazzi","author_inst":"Politecnico di Torino"},{"author_name":"Diego Gallo","author_inst":"Politecnico di Torino"},{"author_name":"Thangam Natarajan","author_inst":"Georgia Institute of Technology"},{"author_name":"Jonas Schollenberger","author_inst":"University of California San Francisco"},{"author_name":"Karol Cal\u00f2","author_inst":"Politecnico di Torino"},{"author_name":"David Saloner","author_inst":"University of California San Francisco"},{"author_name":"David A Steinman","author_inst":"University of Toronto"},{"author_name":"Umberto Morbiducci","author_inst":"Politecnico di Torino"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"Engineered caspases directly rewire mutant Ras to cell death","rel_doi":"10.64898\/2026.08.06.743376","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.06.743376","rel_abs":"As central executioners of cell death, caspases that activate exclusively in diseased cells would provide powerful and specific therapeutic agents. Natural caspase regulation exhibits two universal features that facilitate the engineering of such caspases: proximity-induced subunit assembly and modular separation of substrate recruitment from catalysis. Here, we take advantage of these features to engineer \"Raspases,\" split effector caspases that conditionally reconstitute active complexes upon detection of mutant Ras, an oncogene altered in roughly a quarter of all cancers. When delivered as mRNA in lipid nanoparticles, Raspases selectively eliminate Ras-mutant human cancer lines while sparing wild-type cells. The system is built entirely from human protein domains, can be encoded as a single polyprotein, and can be adapted to trigger pyroptosis. Critically, Raspases match or exceed the potency of alternative Ras-targeting interventions in vitro. These results establish retargeted caspases as a generalizable sense-and-kill platform for selective elimination of diseased cells.","rel_num_authors":5,"rel_authors":[{"author_name":"Lukas Moeller","author_inst":"California Institute of Technology"},{"author_name":"Andrew C. Lu","author_inst":"California Institute of Technology"},{"author_name":"Kevin Ho","author_inst":"California Institute of Technology"},{"author_name":"Evan Zhang","author_inst":"California Institute of Technology"},{"author_name":"Michael B Elowitz","author_inst":"California Institute of Technology, Howard Hughes Medical institute"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"Fanconi Anaemia E3 Ligase complex activity is regulated by a druggable metabolite binding site in FANCX","rel_doi":"10.64898\/2026.08.07.743451","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.07.743451","rel_abs":"The Fanconi anaemia (FA) DNA repair pathway is an emerging target for precision cancer therapy. Using a high-throughput FANCD2-monoubiquitination assay, we identified a class of small molecules, including MSG010, that inhibit the FA E3 ligase complex in vitro. Because these molecules, and the metabolite, palmitoyl-CoA, are known to engage allosteric drug and metabolite (ADaM) binding site in AMP-activated kinase (AMPK), we hypothesised that a similar pocket exists within the FA complex. Supporting this, long-chain, but not short-chain, fatty acyl-CoA molecules inhibited the FA E3 ligase complex activity, and sequence analysis revealed similarity between the AMPK ADaM site and a WD40 repeat in the FA subunit FANCX. Targeted mutagenesis of this FANCX region disrupted E3 ligase activity or abolished inhibition by MSG010, suggesting the presence of an ADaM-like site in FANCX. Moreover, MSG010 preferentially killed BRCA1-deficient cells in vitro. These findings identify a putative small-molecule binding site in the FA pathway that may be developed further to test for exploitation as anticancer therapeutics.","rel_num_authors":16,"rel_authors":[{"author_name":"Michael F Sharp","author_inst":"St Vincent's Institute"},{"author_name":"Yi Sing Gee","author_inst":"Monash University"},{"author_name":"Jennii Luu","author_inst":"Peter MacCallum Cancer Centre"},{"author_name":"Karla Cowley","author_inst":"Karla.Cowley@petermac.org"},{"author_name":"Henry Beetham","author_inst":"Murdoch Children's Research Institute"},{"author_name":"Christopher G Langendorf","author_inst":"St Vincent's Institute"},{"author_name":"Jonathan Stuart Oakhill","author_inst":"St Vincent's Institute of Medical Research"},{"author_name":"John W Scott","author_inst":"St Vincent's Institute"},{"author_name":"Debora Cavero","author_inst":"IR Sant Pau"},{"author_name":"Jordi Minguillon","author_inst":"IR Sant Pau"},{"author_name":"Daqing Che","author_inst":"Zhejiang Jiuzhou Pharmaceuticals Inc"},{"author_name":"Jonathan B Baell","author_inst":"School of Pharmaceutical Sciences"},{"author_name":"Andrew J Deans","author_inst":"St Vincent's Institute"},{"author_name":"Jordi Surralles","author_inst":"IR Sant Pau"},{"author_name":"Kaylene J Simpson","author_inst":"Peter MacCallum Cancer Centre"},{"author_name":"Wayne Crismani","author_inst":"St Vincent's Institute of Medical Research"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"Method for modeling oviduct function and impact on embryonic development","rel_doi":"10.64898\/2026.08.06.743297","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.08.06.743297","rel_abs":"Direct experimental analysis of the mammalian oviduct is constrained by limited tissue access and the short lifespan of ex vivo preparations. Extracellular matrix-embedded three-dimensional epithelial organoids provide longer-term in vitro models. However, their inward-facing apical surface and the absence of supporting stromal cells limit physiological studies of the oviduct, including ciliary activity and maternal-embryonic interactions. Here, we provide a step-wise protocol detailing the generation of mouse and human oviductal assembloids in which epithelial cells form an outward-facing (apical-out) layer around a stromal core. Epithelial and stromal cells from adult mouse oviducts or human Fallopian tubes are isolated, expanded separately, and subsequently aggregated in a rotational culture system. The protocol also outlines morphological and immunostaining criteria for confirming cellular organization, whole-mount detection of external cilia, measurement of ciliary beat frequency, and co-culture of mouse assembloids with preimplantation embryos. Mouse and human assembloids retained epithelial and stromal identity and displayed cilia at the accessible outer surface. In a proof-of-concept experiment, embryos co-cultured with the assembloids developed to blastocysts at a rate similar to that of in vivo-derived blastocysts. This reductionist system provides a straightforward and tractable model to investigate oviduct physiology and embryo-maternal communication while allowing direct manipulation and observation of the epithelial interface.","rel_num_authors":9,"rel_authors":[{"author_name":"Kalli K Stephens","author_inst":"University of Missouri"},{"author_name":"Vakil Ahmad","author_inst":"University of Missouri"},{"author_name":"Maria A Silva","author_inst":"University of Missouri"},{"author_name":"Makenna K Shifflett","author_inst":"University of Missouri"},{"author_name":"Jiude Mao","author_inst":"University of Missouri"},{"author_name":"Jason A Rizo","author_inst":"Yale University"},{"author_name":"Mark I Hunter","author_inst":"University of Missouri"},{"author_name":"Andrew M Kelleher","author_inst":"University of Missouri"},{"author_name":"Wipawee Winuthayanon","author_inst":"University of Missouri"}],"rel_date":"2026-08-07","rel_site":"biorxiv"},{"rel_title":"Molecular Epidemiology of HIV in an African Epidemic with Declining HIV incidence but High Prevalence: A Longitudinal, Population-based Study in Uganda","rel_doi":"10.64898\/2026.08.04.26359711","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.04.26359711","rel_abs":"BackgroundAs HIV incidence declines in African settings with high treatment coverage, it remains unclear how transmission is structured within populations and whether new infections arise from external introductions or local transmission. We characterized the molecular epidemiology of ongoing transmission in a mature multi-subtype epidemic in Uganda.\n\nMethodsWe analyzed HIV genome sequences and survey data from the Rakai Community Cohort Study collected between 1994 and 2019. We identified phylogenetic clusters at 5{middle dot}3% and 2{middle dot}5% genetic distance thresholds and inferred long-horizon transmission chains with phylogeographic models. Newly diagnosed infections identified between 2016 and 2019 were mapped onto subtype- specific phylogenies to assess their origins and transmission context. A Bayesian negative binomial branching process model estimated undersampled chain sizes and case reproduction numbers.\n\nFindingsAmong 4215 participants living with HIV between December 2016 and May 2019, 474 were newly diagnosed, of whom 269 had at least one pure-subtype sequence available. We identified 649 phylogenetic clusters at 5{middle dot}3% genetic distance and 673 phylogeographic chains including [&ge;]2 individuals. Most clusters and chains were small (median sizes 2 [IQR 2-3] and 3 [2-4], respectively), with new diagnoses rarely clustered together. Only 46\/269 (17{middle dot}1%) new diagnoses had phylogeographic external origins, while the remaining 82{middle dot}9% were partially or fully linked to local chains. Mixed-subtypes\/recombinant chains were larger and had higher case reproduction numbers (A1\/D: 0.84 [95% CrI: 0.79-0.93]; mixed: 0.84 [0.73-0.97]) than single- subtype chains (A1: 0.56 [0.51-0.60]; D: 0.63 [0.59-0.66]; C: 0.55 [0.41-0.71]), yet all estimates were less than one.\n\nInterpretationHIV transmission was fragmented across numerous, slowly propagating lineages, maintained by local clusters with occasional introduction. Continued transmission across many chains suggests that further reductions in HIV incidence will require maintaining high levels of population-wide treatment and prevention coverage.\n\nFundingThe National Institute of Allergy and Infectious Diseases, the Gates Foundation, and the HIV Prevention Trials Network Laboratory Center","rel_num_authors":19,"rel_authors":[{"author_name":"Seungwon Kim","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Alexandra Blenkinsop","author_inst":"Imperial College London"},{"author_name":"Michael A Martin","author_inst":"Johns Hopkins University"},{"author_name":"Batsirai M Mabvakure","author_inst":"Georgetown University"},{"author_name":"Robert Ssekubugu","author_inst":"Rakai Health Sciences Program"},{"author_name":"Oliver Laeyendecker","author_inst":"NIAID & JHMI"},{"author_name":"Thomas Quinn","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Edward Nelson Kankaka","author_inst":"Rakai Health Sciences Program"},{"author_name":"Gertrude Nakigozi","author_inst":"Rakai Health Sciences Program"},{"author_name":"Godfrey Kigozi","author_inst":"Rakai Health Sciences Program"},{"author_name":"Andrew Rambaut","author_inst":"University of Edinburgh"},{"author_name":"Lucie Abeler-Dorner","author_inst":"University of Oxford"},{"author_name":"Christophe Fraser","author_inst":"University of Oxford"},{"author_name":"David Bonsall","author_inst":"University of Oxford"},{"author_name":"Steven J Reynolds","author_inst":"UNAIDS"},{"author_name":"Larry William Chang","author_inst":"Johns Hopkins University"},{"author_name":"Oliver Ratmann","author_inst":"Imperial College London"},{"author_name":"Ronald M Galiwango","author_inst":"Rakai Health Sciences Program"},{"author_name":"Mary Kate Grabowski","author_inst":"Johns Hopkins University"}],"rel_date":"2026-08-06","rel_site":"medrxiv"},{"rel_title":"Uncertainty-aware prediction of 48-month eGFR decline in type 2 diabetes mellitus: a secondary analysis of ACCORD","rel_doi":"10.64898\/2026.08.04.26359704","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.04.26359704","rel_abs":"BackgroundLong-horizon kidney trajectory prediction in type 2 diabetes mellitus (T2DM) is usually reported as a point estimate or event risk, although clinical decision-making also depends on whether an individual prediction is reliable. We developed an uncertainty-aware model for 48-month estimated glomerular filtration rate (eGFR) decline and tested whether conformal interval width provides a clinically structured, patient-level signal of prediction reliability.\n\nMethodsWe performed a secondary prognostic modeling analysis of Action to Control Cardiovascular Risk in Diabetes (ACCORD) participants with baseline and 48-month eGFR (n=6,853). The outcome was annualized eGFR change, calculated as 48-month minus baseline eGFR divided by four years. The primary baseline feature set excluded serum creatinine since eGFR is creatinine-derived, and also excluded urine biomarkers. Random forest, gradient boosting, penalized linear models, and XGBoost were compared using fixed training, calibration, and test partitions. Split and locally adaptive conformal intervals were evaluated by empirical coverage and interval width. Interval-width analyses were repeated after conditioning on baseline eGFR.\n\nResultsThe best primary model was random forest (R2=0.382, MAE=3.271 mL\/min\/1.73m2). Split 90% conformal intervals achieved empirical coverage of 0.917. Locally adaptive 90% intervals achieved empirical coverage of 0.909 with mean width 13.759 mL\/min\/1.73m2. In unadjusted analyses, wider intervals were associated with larger errors and more rapid decline. After interval-width quintiles were assigned within baseline-eGFR strata, wider intervals remained associated with realized prediction error (annual adjusted increase, 0.151 mL\/min\/1.73m2 per quintile). Beyond baseline eGFR, wider intervals were associated with younger age, female sex, higher HbA1c, higher triglycerides, and higher systolic blood pressure.\n\nConclusionsBaseline clinical variables predicted 48-month eGFR decline with good long-horizon performance in ACCORD, even after excluding serum creatinine and urine biomarkers from the primary model. Conformal prediction provided calibrated patient-specific intervals, and interval width behaved as an informative reliability phenotype rather than a random modeling artifact. These findings support a novel uncertainty-aware framing of kidney trajectory prediction in which rapid and uncertain decline can be identified from baseline clinical data.","rel_num_authors":5,"rel_authors":[{"author_name":"Daniel Olshvang","author_inst":"Department of Biomedical Engineering, Johns Hopkins University School of Medicine"},{"author_name":"Carl W Harris","author_inst":"Department of Biomedical Engineering, Johns Hopkins University School of Medicine"},{"author_name":"Rama Chellappa","author_inst":"Department of Biomedical Engineering, Johns Hopkins University School of Medicine"},{"author_name":"Chirag Parikh","author_inst":"Division of Nephrology, Johns Hopkins University School of Medicine"},{"author_name":"Prasanna Santhanam","author_inst":"Division of Endocrinology, Diabetes, and Metabolism, Johns Hopkins University School of Medicine"}],"rel_date":"2026-08-06","rel_site":"medrxiv"},{"rel_title":"Novel KIR2DS4:HLA-B*35 interaction predicts HLA-B*35 positive patient survival post hematopoietic stem cell transplant","rel_doi":"10.64898\/2026.08.04.26358595","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.04.26358595","rel_abs":"Haplo-identical hematopoietic cell transplantation (haploHCT) is an integral treatment paradigm for patients with leukemia. While overall survival (OS) post-haploHCT has steadily improved, relapse-free survival (RFS) remains relatively stagnant. Upon the discovery of killer immunoglobulin-like receptors (KIRs) on natural killer (NK) cells and their cognate human leukocyte antigen (HLA) ligands, algorithms have been developed to enhance graft versus leukemia effects. However, these algorithms fail to yield consistent predictions in patient outcomes.\n\nWe utilized a combination of in silico protein folding and interactions to determine KIR:HLA reactivity in conjunction with in vitro acoustic force microscopy to measure cell avidity (CA) as a readout for KIR signal strength. CA was determined using monoallelic HLA expressing K562 cell lines, monoallelic KIR Jurkat cells, and peripheral blood NK cells. We extended the CA results and performed standard cytotoxicity assays as well.\n\nWe discovered that HLA-B*35 interacts with KIR2DS4. We applied the newly discovered interaction to predict outcomes for HCT patients. Stratifying patients based on their HLA-B*35 positivity and donor KIR2DS4 status, we delineated a correlation to survival (P=0.061) when donors only had full-length KIR2DS4. Patients who received a haploHCT and NK cell addback from donors with only full-length KIR2DS4 had a significantly improved RFS (P=0.001) and OS (P=0.016) compared to truncated (KIR1D) and full-length KIR2DS4 donors. This was independently validated in a diverse 10\/10 HLA matched European cohort with RFS (P=0.0255) and OS (P=0.0388).\n\nThus, the identified novel KIR2DS4:HLA-B*35 interaction axis predicts patient survival, in both haplo-identical and fully matched, HCT and highlights that our current understanding of the KIR:HLA interactome is incomplete and requires remapping for enhanced therapeutic applications.","rel_num_authors":14,"rel_authors":[{"author_name":"Stephen Gottschalk","author_inst":"St Jude Children's Research Hospital"},{"author_name":"Ying Li","author_inst":"St Jude Children's Research Hospital"},{"author_name":"Subodh Selukar","author_inst":"St Jude Children's Research Hospital"},{"author_name":"Allison Kirk","author_inst":"St Jude Children's Research Hospital"},{"author_name":"Swati Naik","author_inst":"St Jude Children's Research Hospital"},{"author_name":"Daniel F\u00fcrst","author_inst":"Institute of Clinical Transfusion Medicine and Immunogenetics Ulm"},{"author_name":"Sophie Mannes","author_inst":"German Registry for Hematopoietic Stem Cell Transplantation and Cell Therapy"},{"author_name":"Sarah Flossdorf","author_inst":"German Registry for Hematopoietic Stem Cell Transplantation and Cell Therapy"},{"author_name":"Jan Beyersmann","author_inst":"University of Ulm"},{"author_name":"Hubert Schrezenmeier","author_inst":"University Hospital Ulm"},{"author_name":"Georg-Nikolaus Franke","author_inst":"University of Leipzig"},{"author_name":"Paul Thomas","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Brandon Triplett","author_inst":"St Jude Children's Research Hospital"},{"author_name":"Peter Chockley","author_inst":"The Ohio State University"}],"rel_date":"2026-08-06","rel_site":"medrxiv"},{"rel_title":"Proteomic Signatures and an Injury-Stress Endotype in Myositis-Associated Interstitial Lung Disease","rel_doi":"10.64898\/2026.08.04.26359441","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.04.26359441","rel_abs":"RationaleIdiopathic inflammatory myopathy-associated interstitial lung disease (IIM-ILD) is a major cause of morbidity and mortality. We tested whether quantitative myositis-specific autoantibodies and proteomic profiling capture biological heterogeneity and prognosis beyond categorical serology.\n\nMethodsMyositis-specific autoantibodies were quantified using the luciferase immunoprecipitation systems assay, and 184 serum proteins were measured in 226 IIM patients; 199 with higher-ILD-risk autoantibodies (Jo-1\/MDA5\/PL-7\/PL-12\/EJ), 27 with lower- ILD-risk autoantibodies (Mi-2\/NXP2\/TIF1{gamma}) and 35 healthy controls. We identified shared and subgroup-specific differences by comparing each subgroup with controls, then correlated quantitative autoantibody and protein levels within higher-risk subgroups. Additional analyses included pathway enrichment, unsupervised clustering, longitudinal lung-function change, and mortality.\n\nResultsHigher-ILD-risk subgroups shared interferon-responsive CXCR3 chemokine, IL- 6\/JAK\/STAT3, and apoptosis signaling. Dominant autoantibody subgroup profiles differed: interferon\/CXCR3 chemokine signaling with T-cell activation and monocyte recruitment in anti- Jo-1; proteostasis\/antigen-processing and vascular\/cellular stress signals in anti-MDA5; IL- 6\/macrophage and profibrotic signals in anti-PL-12; and apoptotic and innate immune activation with metabolic\/redox-stress signals in anti-PL-7. Within higher-ILD-risk subgroups, autoantibody levels correlated with interferon-response, profibrotic, and metabolic\/vascular proteins (r=0.40- 0.74; nominal p<0.05). Unsupervised clustering identified four proteomic endotypes beyond autoantibody type, including an injury-stress endotype associated with worse lung function and poorer survival, and a chemokine\/checkpoint-high endotype with relatively preserved lung function. Across 203 participants with 38 deaths, a weighted 10-protein score was associated with all-cause mortality (HR, 3.28; 95% CI, 2.12-5.08; p<0.001).\n\nConclusionsIntegrated quantitative autoantibodies and proteomic profiling revealed shared inflammatory biology, autoantibody-associated signatures, and an injury-stress endotype associated with poor survival in IIM-ILD, supporting risk stratification beyond categorical serology.","rel_num_authors":22,"rel_authors":[{"author_name":"Julio Huapaya","author_inst":"NIH Clinical Center"},{"author_name":"Peter Burbelo","author_inst":"National Institute of Dental and Craniofacial Research"},{"author_name":"Eric W Robbins","author_inst":"National Heart, Lung, and Blood Institute"},{"author_name":"Xin Tian","author_inst":"National Heart Lung and Blood Institute"},{"author_name":"Shijinqiu Gao","author_inst":"National Heart Lung and Blood Institute"},{"author_name":"Sevilay Turan","author_inst":"NIH Clinical Center"},{"author_name":"Salina Gairhe","author_inst":"NIH Clinical Center"},{"author_name":"James Ward","author_inst":"National Institute of Environmental Health Sciences"},{"author_name":"Neelam Redekar","author_inst":"National Institute of Allergy and Infectious Diseases"},{"author_name":"Jianliang Li","author_inst":"National Institute of Environmental Health Sciences"},{"author_name":"Gloria Pastor","author_inst":"NIH Clinical Center"},{"author_name":"Neha Gupta","author_inst":"NIH Clinical Center"},{"author_name":"Payam Noroozi Farhadi","author_inst":"National Institute of Environmental Health Sciences"},{"author_name":"Kakali Sarkar","author_inst":"National Institute of Environmental Health Sciences"},{"author_name":"Maria Casal-Dominguez","author_inst":"National Institute of Arthritis and Musculoskeletal and Skin Diseases"},{"author_name":"Iago Pinal-Fernandez","author_inst":"National Institute of Arthritis and Musculoskeletal and Skin Diseases"},{"author_name":"Lisa Christopher-Stine","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Adam Schiffenbauer","author_inst":"National Institute of Environmental Health Sciences"},{"author_name":"Lisa Rider","author_inst":"National Institute of Environmental Health Sciences"},{"author_name":"Andrew L. Mammen","author_inst":"National Institute of Arthritis and Musculoskeletal and Skin Diseases"},{"author_name":"Sonye K. Danoff","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Anthony F. Suffredini","author_inst":"NIH Clinical Center"}],"rel_date":"2026-08-06","rel_site":"medrxiv"},{"rel_title":"Household determinants of animal and human fecal contamination on floors and hands in northwestern coastal Ecuador","rel_doi":"10.64898\/2026.08.04.26359736","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.04.26359736","rel_abs":"Household environments in low-resource settings can become contaminated with fecal matter from multiple sources, including humans and domestic animals. Identifying the source of fecal contamination is critical for designing targeted interventions to reduce exposure to enteric pathogens, particularly for young children who bear the majority of the enteric disease burden. Using data from 140 households with children enrolled in the ECoMiD cohort study in northwestern coastal Ecuador, we (1) characterized source-specific fecal contamination in samples from household floors and maternal and child hands, and (2) identified animal-related and Water, Sanitation and Hygiene (WASH) conditions associated with the presence and concentrations of these markers. We used five qPCR-based microbial source tracking (MST) markers to detect fecal contamination from avian (GFD), canine (DG37), swine (Pig2Bac), ruminant (Rum2Bac), and human (HF183) sources. Prevalence ratios (PR) and mean differences comparing the presence\/absence and concentration, respectively, of MST markers between households with and without each animal-related or WASH condition were estimated using generalized linear models with Poisson and Gaussian distributions. Animal MST markers tracked strongly with several animal-related conditions, whereas associations between the human MST marker and household demographic and WASH conditions were more limited. Animal ownership (PR 1.53; 95% CI: 1.04-2.26) was associated with higher prevalence of animal MST markers on floors. Households reporting animal feces indoors had higher prevalence of animal MST markers on floors (PR 1.84; 95% CI: 1.17-2.89), and higher concentrations of animal MST markers on child hands (mean difference 0.27 gene copies (gc)\/m2; 95% CI: 0.12-0.41) and maternal hands (mean difference 0.10 gc\/m2; CI: 0.02-0.18). Animal feces left unremoved outside the home were associated with higher prevalence of animal MST markers on maternal hands (PR 2.31; 95% CI: 1.11-4.81). Mothers reporting direct contact with animals had higher concentrations of animal MST markers on their children hands (mean difference 0.12 gc\/m2; 95% CI: 0.02-0.21). Higher FECEZ scores, an overall metric for animal exposure, were associated with higher prevalence of animal MST markers on maternal hands (PR 2.94; 95% CI: 1.17-7.40). For human fecal contamination, the presence of E. coli on child hands was associated with higher prevalence of human MST markers on floors (PR 1.30; 95% CI: 1.00-1.68). Our findings reinforce household floors and maternal and child hands as key reservoirs of fecal contamination and point to future potential targets worth exploring for interventions in similar high-burden settings.","rel_num_authors":14,"rel_authors":[{"author_name":"Viviana Alban","author_inst":"Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA"},{"author_name":"Kelsey J. Jesser","author_inst":"Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA; Department of Environmental Health Sciences, U"},{"author_name":"Aldo Lobos","author_inst":"Department of Integrative Biology, University of South Florida, Tampa, Florida, USA"},{"author_name":"Javier Gallard-Gongora","author_inst":"Department of Integrative Biology, University of South Florida, Tampa, Florida, USA"},{"author_name":"April M. Ballard","author_inst":"Department of Population Health Sciences, Georgia State University School of Public Health, Atlanta, GA, USA"},{"author_name":"Gwenyth O. Lee","author_inst":"Rutgers Global Health Institute and Department of Biostatistics and Epidemiology, Rutgers University, New Brunswick, New Jersey, USA"},{"author_name":"Joseph N.S. Eisenberg","author_inst":"Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan, USA."},{"author_name":"Erica R. Fuhrmeister","author_inst":"Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA; Department of Civil and Environmental Engineer"},{"author_name":"Joan A. Casey","author_inst":"Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA"},{"author_name":"Gabriel Trueba","author_inst":"Instituto de Microbiologia, Colegio de Ciencias Biologicas y Ambientales, Universidad San Francisco de Quito, Quito, Ecuador."},{"author_name":"Christine Fagnant-Sperati","author_inst":"Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA"},{"author_name":"Valerie J. Harwood","author_inst":"Department of Integrative Biology, University of South Florida, Tampa, Florida, USA"},{"author_name":"Karen Levy","author_inst":"Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA"},{"author_name":"- ECoMiD Authorship Group","author_inst":""}],"rel_date":"2026-08-06","rel_site":"medrxiv"},{"rel_title":"Ceftazidime therapeutic drug monitoring in patients with melioidosis","rel_doi":"10.64898\/2026.08.04.26359527","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.04.26359527","rel_abs":"Background: Most patients with melioidosis receive prolonged intravenous ceftazidime during the intensive phase of their antibiotic therapy. Contemporary guidelines use weight and renal function to guide dosing, but therapeutic drug monitoring (TDM) might enable further individualisation of therapy. Objective: To examine the potential utility of ceftazidime TDM in the management of melioidosis. Methods: We reviewed consecutive serum free ceftazidime concentrations in patients with culture-confirmed melioidosis at an Australian referral hospital. We documented the minimum inhibitory concentration (MIC) for ceftazidime Burkholderia pseudomallei isolates of the patients. We then recorded the ceftazidime dosing regimen for each patient, their serum free ceftazidime concentration and if any adverse drug reactions occurred during their treatment. Results: Trough concentrations were measured in 31 patients receiving intermittent ceftazidime dosing, while random concentrations were measured in 91 patients receiving a continuous infusion. The median (range) trough concentration:MIC ratio was 37.7 (2.7-156.6) in those receiving intermittent dosing and 47.5 (8.1-181.5) in those receiving a continuous infusion. Serum ceftazidime concentrations correlated with neurotoxicity, which was documented in 5\/31 (16%) receiving intermittent dosing and in 4\/91 (4%) receiving a continuous infusion. Serum ceftazidime concentrations were also higher in individuals who died from their infection than in those who survived. There was no association between ceftazidime concentrations and subsequent disease recurrence. Conclusion: Current dosing recommendations for the treatment of melioidosis achieve serum ceftazidime concentrations that greatly exceed the MIC of B. pseudomallei in this region of Australia. TDM-guided reductions in the ceftazidime dose and\/or dosing frequency may mitigate the risk of ceftazidime toxicity.","rel_num_authors":3,"rel_authors":[{"author_name":"Christopher W Reilly","author_inst":"Cairns Hospital"},{"author_name":"Simon Smith","author_inst":"Cairns Hospital"},{"author_name":"Josh Hanson","author_inst":"Kirby Institute, University of New South Wales"}],"rel_date":"2026-08-06","rel_site":"medrxiv"},{"rel_title":"Service disruptions and stockouts: Ongoing impacts of U.S. funding freezes on HIV care across clinics in 38 low- and middle-income countries in late 2025","rel_doi":"10.64898\/2026.08.04.26359701","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.04.26359701","rel_abs":"IntroductionAfter U.S. foreign assistance was frozen in January 2025, empirical data on the status of the HIV response has been limited. To better understand the ongoing impacts of changes in U.S. foreign assistance, we launched an open survey to assess disruptions in HIV-related care among clinics and programs in low- and middle-income countries (LMICs).\n\nMethodsConducted from August to December 2025, the survey explored U.S. foreign assistance-related disruptions in HIV service delivery, medication availability, laboratory services and clinic operations; whether disruptions were fully resolved at the survey timepoint; and the introduction of clinic mitigation strategies. Data on other impacts of U.S. funding changes were explored through an open-ended question. A convergent mixed-methods design, involving parallel quantitative and qualitative analyses and merging of findings from each, was used to examine the impacts of U.S. funding freezes on HIV-related care.\n\nResultsWe received 158 responses from 38 LMICs, including 30 countries supported by the U.S. Presidents Emergency Fund for AIDS Relief (PEPFAR) at the beginning of 2025 (n=123 responses) and eight non-PEPFAR countries (n=35 responses). Respondents represented health centers (25%), hospitals (31%), dedicated HIV clinics and drop-in centers (39%), and multi-site programs (4%), with a majority (59%) in the non-governmental\/private sector. Overall, 81% reported disruptions in at least one HIV-related service since January 2025 because of changes in U.S. foreign assistance, with most also reporting disruptions in medication availability, laboratory services, and clinic operations. The largest reported disruptions were in the areas of pre-exposure prophylaxis (67%) and HIV testing (63%), along with patient tracing (67%), adherence support (63%) and services to key populations (64%). Disruptions were more prevalent in PEPFAR-supported countries and were more likely to be \"not fully resolved\" by time of survey completion. Qualitative data highlighted the impact of U.S. foreign assistance disruptions on the erosion of client trust in the health system and strains on staff morale.\n\nConclusionsSubstantial and sustained disruptions in HIV prevention and care reported by diverse clinics in LMICs reinforce concerns that recent funding shifts could reverse progress in ending the HIV epidemic, particularly for vulnerable and key populations.","rel_num_authors":7,"rel_authors":[{"author_name":"Ellen Brazier","author_inst":"Institute for Implementation Science in Population Health, City University of New York School of Public Health"},{"author_name":"Maabo Kludze","author_inst":"City University of New York, Graduate School of Public Health and Health Policy"},{"author_name":"Fernanda Maruri","author_inst":"Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center"},{"author_name":"Annabelle Niyongabo","author_inst":"Association Nationale de Soutien aux S\u00e9ropositifs et malades du sida-Sant\u00e9 PLUS (ANSS-Sant\u00e9 PLUS)"},{"author_name":"Philip Kreniske","author_inst":"Institute for Implementation Science in Population Health, City University of New York, Graduate School of Public Health and Health Policy, New York, NY, United"},{"author_name":"Stephany N Duda","author_inst":"Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, United States"},{"author_name":"Denis Nash","author_inst":"Institute for Implementation Science in Population Health, City University of New York, Graduate School of Public Health and Health Policy, New York, NY, United"}],"rel_date":"2026-08-06","rel_site":"medrxiv"},{"rel_title":"Continuous Value Tokenization Improves Medical Event Foundation Models","rel_doi":"10.64898\/2026.08.04.26359713","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.04.26359713","rel_abs":"Medical foundation models convert patient records into token sequences for autoregressive prediction, but numeric values such as lab results, vital signs, and time intervals are typically discretized into bins, losing precision and misaligning with clinical thresholds. We trained decoder-only transformer models (47 million parameters) on MIMIC-IV data (364,627 patients; 375 million observations) to compare three tokenization strategies: Discrete (binned values), Continuous Factored (continuous values preserving sequence length), and Continuous Fused (continuous values fused with measurement-type tokens). We evaluated next-token prediction, numeric value prediction, and three clinical tasks: ED disposition at triage, ICD code prediction, and DRG prediction at discharge. Continuous Fused tokenization reduced median sequence length by 34%, reached the Discrete models final next-token loss in 30% of training iterations, and improved numeric prediction accuracy by 30.25% median nRMSE reduction. ICD code prediction favored Continuous Fused (AU-PRC 0.457 vs. 0.446; p < 0.001); DRG prediction was equivalent between Continuous Fused and Discrete; ED disposition accuracy was equivalent across all models ([~]0.900), though Discrete achieved better calibration. We additionally explain why predictive performance improves with Monte Carlo sample count and derive a scaling law to predict performance gains from increasing simulation budget. Continuous-value tokenization offers substantial efficiency and precision gains while maintaining comparable clinical task performance, with no modifications to the standard transformer architecture.\n\nAuthor SummaryMedical event foundation models are increasingly used to forecast clinical outcomes. These models predict using patient records as sequences of \"tokens,\" much like a language model predicts next words. Numerical values such as lab results and vital signs pose a problem: they are usually grouped into discrete bins before being tokenized, which loses precision and ignores the fact that medical decisions often depend on specific numerical thresholds. We compared three ways of representing continuous values in medical foundation models: the standard binning approach and two new approaches that preserve the actual values. The continuous-value approaches trained about three times faster, produced 34% shorter sequences, and achieved comparable accuracy on clinical prediction tasks including emergency department triage, ICD diagnosis codes, and hospital billing codes. These gains require no modifications to the standard transformer architecture. We also discovered that commonly used evaluation metrics exhibit a systematic bias depending on the number of simulated predictions, and that this bias follows a predictable mathematical pattern, enabling researchers to estimate full-scale performance from smaller, less expensive simulation experiments.","rel_num_authors":7,"rel_authors":[{"author_name":"Kent A McCann","author_inst":"Yale School of Medicine"},{"author_name":"Ikgyu Shin","author_inst":"Yale School of Medicine"},{"author_name":"Huan Li","author_inst":"Yale School of Medicine"},{"author_name":"Davis White","author_inst":"Epic Systems"},{"author_name":"Edward R Melnick","author_inst":"Yale School of Medicine"},{"author_name":"Mark S Iscoe","author_inst":"Yale School of Medicine"},{"author_name":"Andrew J Loza","author_inst":"Yale University"}],"rel_date":"2026-08-06","rel_site":"medrxiv"},{"rel_title":"Towards understanding the disease landscape of clinical trials in Germany: Ontology and embedding-based pipelines versus Large Language Models for ICD-10 Harmonization","rel_doi":"10.64898\/2026.08.04.26359616","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.04.26359616","rel_abs":"BackgroundClinical trials conducted in Germany are registered across multiple registries, including the German Clinical Trials Register (DRKS), ClinicalTrials.gov, the EU Clinical Trials Register (EUCTR), and, since 2023, the Clinical Trials Information System (CTIS). These registries record health conditions using different classification systems and terminologies, including ICD-10-GM, MeSH, MedDRA, and free text, making cross-registry analyses difficult. We developed and evaluated a pipeline for harmonizing trial condition descriptions to WHO ICD-10 and compared its performance with that of a large language model (LLM) and to health conditions coded by humans.\n\nMethodsWe developed a four-stage, registry-aware mapping pipeline consisting of: (i) condition mention extraction and normalization; (ii) classification of ICD-mappable versus non-mappable mentions; (iii) ontology-based candidate generation using UMLS links between MeSH, MedDRA, ICD-10-GM, and WHO ICD-10; and (iv) SapBERT-based semantic retrieval with hybrid confidence scoring. A second variant additionally applied cross-encoder reranking of the top candidate codes. A stratified sample of 500 condition mentions was manually coded to create an expert reference standard. GPT-4o was evaluated in parallel using the same structured decision framework as the human reviewers. Performance was assessed using accuracy, precision, F1 score, and Cohens k at the three-character, block, and chapter levels of ICD-10.\n\nResultsThe pipeline was applied to 23,061 clinical trials and identified 39,512 ICD-mappable condition mentions, of which 72.4% received a high-confidence assignment. Against 390 expert-coded mentions, the baseline pipeline achieved 49.0% accuracy at the three-character ICD-10 level (k = 0.487), increasing to 58.7% at the chapter level (k = 0.561). The cross-encoder method produced small but consistent improvements across all evaluation levels. Candidate-recall analysis showed that the correct code was present in the retrieved candidate set in only 73.7% of cases. The LLM substantially outperformed both pipeline variants, achieving 96.7% accuracy and near-perfect agreement with expert coding (k = 0.966) at the three-character level. The LLM also assigned clinically plausible codes to 82.4% of rejected mentions, 62.8% of Tier-3 exclusions, and 92.3% of review-band mentions.\n\nConclusionAutomated harmonization of clinical trial condition data across heterogeneous registries is feasible and supports the use of a common ICD-10 framework for cross-registry analyses. The LLMs achieved high agreement with expert coding, and performed better than the deterministic ontology and embedding pipeline, which achieved moderate agreement. These findings indicate that LLMs can support analyses of the distribution of health conditions investigated in clinical trials in Germany.They are a promising tool for classification of other non-standardised trial characteristics in registries.","rel_num_authors":12,"rel_authors":[{"author_name":"Rodrigue Ndabashinze","author_inst":"German Center for Child and Adolescent Health (DZKJ), Partner Site Greifswald\/Rostock, Rostock, Germany"},{"author_name":"Delwen Franzen","author_inst":"Berlin Institute of Health at Charit\u00e9, Universit\u00e4tsmedizin Berlin, QUEST Center for Responsible Research, Berlin, Germany"},{"author_name":"Emilia Kozuch","author_inst":"German Center for Child and Adolescent Health (DZKJ), Partner Site Greifswald\/Rostock, Rostock, Germany"},{"author_name":"Jannik Aagerup","author_inst":"German Center for Child and Adolescent Health (DZKJ), Partner Site Greifswald\/Rostock, Rostock, Germany; NHMRC Clinical Trials Centre, University of Sydney, Cam"},{"author_name":"Anne Fink","author_inst":"German Center for Child and Adolescent Health (DZKJ), Partner Site Greifswald\/Rostock, Rostock, Germany"},{"author_name":"Samruddhi Suresh Yerunkar","author_inst":"Berlin Institute of Health at Charit\u00e9, Universit\u00e4tsmedizin Berlin, QUEST Center for Responsible Research, Berlin, Germany"},{"author_name":"Kylie Hunter","author_inst":"NHMRC Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia"},{"author_name":"Evan Mayo-Wilson","author_inst":"Department of Epidemiology, School of Global Public Health, University of North Carolina Gillings, Chapel Hill, NC, USA"},{"author_name":"Xiangji Ying","author_inst":"Department of Epidemiology, School of Global Public Health, University of North Carolina Gillings, Chapel Hill, NC, USA"},{"author_name":"Halil Kilicoglu","author_inst":"School of Information Sciences, University of Illinois, Urbana-Champaign, Champaign, IL, USA"},{"author_name":"Susanne Gabriele Schorr","author_inst":"Berlin Institute of Health at Charit\u00e9, Universit\u00e4tsmedizin Berlin, QUEST Center for Responsible Research, Berlin, Germany"},{"author_name":"Anna Lene Seidler","author_inst":"German Center for Child and Adolescent Health (DZKJ), Partner Site Greifswald\/Rostock, Rostock, Germany; NHMRC Clinical Trials Centre, University of Sydney, Cam"}],"rel_date":"2026-08-06","rel_site":"medrxiv"},{"rel_title":"Heritability of Age-Related Macular Degeneration in the Amish","rel_doi":"10.64898\/2026.08.04.26359695","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.04.26359695","rel_abs":"PurposeAge-related Macular Degeneration (AMD), a degenerative disease of aging, leads to central vision loss and has a strong genetic risk. Genetic heritability, used to quantify genetic influence on a trait, has mainly focused on twin study designs but these are vulnerable to bias. Studying relatives beyond twins is necessary to bring clarity to the genetic burden of AMD and help focus the search for additional genetic risk loci.\n\nMethodsThrough both single nucleotide polymorphism (SNP) and pedigree-based heritability methods, the heritability of AMD was analyzed using relationship informed analyses of families from an Amish population (n = 525). AMD status was determined using the Beckman grading scale (285 controls and 240 cases). An estimate of genetic relatedness preceded SNP heritability estimation, whereas the pedigree heritability model utilized genealogical reports. Primary models were adjusted for age, sex, and population structure. A comparison of SNP- and pedigree-based models followed heritability estimation. Sensitivity models adjusting for all possible combinations of three known strong AMD genetic risk variants were constructed.\n\nResultsSNP heritability is 55% +\/- 13% (p= 9.87e-06) and the pedigree heritability is 49% +\/- 18% (p= 3.06e-04). The sensitivity analyses revealed that the estimates were robust to changes in the inclusion of AMD variants as covariates.\n\nConclusionsThese heritability estimates support existing twin and SNP-based AMD heritability estimates and corroborate the substantial involvement of genetics in AMD. Adjusting for known AMD variants revealed that additional genetic contribution exists, supporting a large polygenic effect in AMD.","rel_num_authors":23,"rel_authors":[{"author_name":"Noel C Moore","author_inst":"Case Western Reserve University"},{"author_name":"Yeunjoo E Song","author_inst":"Case Western Reserve University"},{"author_name":"Alexander V Gulyayev","author_inst":"University of Miami"},{"author_name":"Kristy Miskimen","author_inst":"Case Western Reserve University"},{"author_name":"Penelope Miron","author_inst":"Case Western Reserve University"},{"author_name":"Renee A Laux","author_inst":"Case Western Reserve University"},{"author_name":"Audrey Lynn","author_inst":"Case Western Reserve University"},{"author_name":"Sarada L Fuzzell","author_inst":"Case Western Reserve University"},{"author_name":"Sherri D Hochstetler","author_inst":"Case Western Reserve University"},{"author_name":"Dawn Miller","author_inst":"Case Western Reserve University"},{"author_name":"Laura J Caywood","author_inst":"University of Miami"},{"author_name":"Jason E Clouse","author_inst":"University of Miami"},{"author_name":"Sharlene D Herington","author_inst":"University of Miami"},{"author_name":"Ping Wang","author_inst":"Case Western Reserve University"},{"author_name":"Yining Liu","author_inst":"Case Western Reserve University"},{"author_name":"Daniel A Dorfsman","author_inst":"University of Miami"},{"author_name":"Jeffery M Vance","author_inst":"University of Miami"},{"author_name":"Muneeswar Gupta Nittala","author_inst":"Doheny Eye Institute"},{"author_name":"Srinivas R Sadda","author_inst":"Doheny Eye Institute"},{"author_name":"Dwight Stambolian","author_inst":"University of Pennsylvania"},{"author_name":"William K Scott","author_inst":"University of Miami"},{"author_name":"Margaret A Pericak-Vance","author_inst":"University of Miami"},{"author_name":"Jonathan L Haines","author_inst":"Case Western Reserve University"}],"rel_date":"2026-08-06","rel_site":"medrxiv"},{"rel_title":"TLS-Tractor: A transfer learning framework for incorporating summary-statistics into local ancestry-aware GWAS in admixed populations","rel_doi":"10.64898\/2026.08.04.26359626","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.04.26359626","rel_abs":"Including recently admixed populations in genome-wide association studies (GWAS) is important for equitable and ancestry-resolved genetic discovery. The existing popular method, Tractor, estimates ancestry-specific effects from individual-level data but cannot leverage external GWAS summary statistics due to mismatches in underlying model parameters. We introduce TLS-Tractor, a transfer-learning method that uses the generalized method of moments to integrate external GWAS summary statistics with internal individual-level data for local ancestry-aware association analysis. In simulations, TLS-Tractor controlled type I error, accurately estimated ancestry-specific effects, and increased power relative to the internal-only Tractor. Analyses integrating African-European admixed participants from All of Us with Million Veteran Program summary statistics corroborated these gains and showed that local ancestry adjustment can improve calibration, localization, and interpretation, whereas standard GWAS meta-analysis often provides greater power. We introduce an efficient tlstractor R package that achieves over 200x faster local ancestry tract extraction and 4-32x faster association testing than the original Tractor implementation.","rel_num_authors":3,"rel_authors":[{"author_name":"Wenxuan Lu","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Ruzhang Zhao","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Nilanjan Chatterjee","author_inst":"Johns Hopkins Bloomberg School of Public Health"}],"rel_date":"2026-08-06","rel_site":"medrxiv"},{"rel_title":"Higher Blood-to-Tissue Tumor Mutational Burden Ratio Is Associated With Poorer Overall Survival in Advanced Non-Small Cell Lung Cancer","rel_doi":"10.64898\/2026.08.04.26359280","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.04.26359280","rel_abs":"IntroductionBlood-based and tissue-based tumor mutational burden (bTMB and tTMB) show only moderate concordance in advanced non-small cell lung cancer (NSCLC). We hypothesized that discordance between the two measures reflects tumor heterogeneity and carries prognostic information beyond either measure alone.\n\nMethodsWe retrospectively identified 105 patients with advanced NSCLC who underwent both blood-based (Guardant360) and tissue-based next-generation sequencing between October 2020 and September 2024. A blood-to-tissue TMB ratio was defined as ln(1+bTMB) - ln(1+tTMB). Multivariable Cox proportional hazards models estimated associations with overall survival (OS) and progression-free survival (PFS), adjusted for age, sex, ECOG performance status, smoking history, histology, and line of therapy.\n\nResultsMedian follow-up was 32 months (66 deaths, 83 progression events). A higher blood-to-tissue TMB ratio was independently associated with shorter OS (HR per 1-unit increase 1.60, 95% CI 1.10-2.31; p=0.01) but not PFS (HR 1.07; p=0.67). Neither component was independently prognostic when modeled alone, whereas in a joint model ln(1+bTMB) and ln(1+tTMB) were associated with survival in opposite directions. The ratio remained associated with OS after adjustment for the highest variant allele frequency, radiographic tumor burden, and extrathoracic metastatic organ count, and was uncorrelated with each of these measures. The poorest OS occurred in the discordant High bTMB\/Low tTMB group (HR 2.97, 95% CI 1.32-6.66).\n\nConclusionsBlood-to-tissue TMB discordance was independently associated with shorter overall survival, independent of ctDNA shedding and baseline disease extent. Validation in prospective cohorts with contemporaneous sampling is required.","rel_num_authors":7,"rel_authors":[{"author_name":"Leeseul Kim","author_inst":"The University of Chicago Medical Center"},{"author_name":"Jongyeop Kim","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Jongwoo Kim","author_inst":"MetroWest Medical Center"},{"author_name":"Seungah Yoo","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Minkyu Shin","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Lucas Santana Dos Santos","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Young Kwang Chae","author_inst":"Northwestern University Feinberg School of Medicine"}],"rel_date":"2026-08-06","rel_site":"medrxiv"},{"rel_title":"Deep Learning of Fluorescence Lifetime Imaging Ophthalmoscopy for Type 2 Diabetes Classification","rel_doi":"10.64898\/2026.08.04.26359728","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.04.26359728","rel_abs":"PurposeTo evaluate whether fluorescence lifetime imaging ophthalmoscopy (FLIO) combined with deep learning can detect metabolic signatures for classification of type 2 diabetes mellitus (T2DM).\n\nDesignCross-sectional analysis of participants included in the AI-READI dataset (version 3) with FLIO imaging and hemoglobin A1c (HbA1c) measurement.\n\nSubjects1,783 participants from the AI-READI dataset (version 3) with HbA1c measurements and FLIO imaging scans (6,912 total): 671 normoglycemic, 726 prediabetic, and 386 diabetic.\n\nMethodsMean fluorescence lifetime maps were generated using a center-of-mass approach and used as inputs to AI models. We trained convolutional neural networks (CNNs), ResNet-18, and XGBoost under three-class (normal, prediabetic, diabetic) and two binary (normal vs. impaired; normal vs. diabetic) classification schemes, using nested 5-fold cross-validation with participant-level grouping.\n\nMain Outcome MeasuresMacro-averaged area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, accuracy, F1 score, and positive predictive value (PPV).\n\nResultsGroup-averaged lifetime maps showed longer lifetimes in prediabetic and diabetic participants than in normoglycemic participants in the SSC (p = 0.001), with no significant difference across groups in the LSC (p = 0.056). The CNN achieved the best overall performance in the 3-class classification (accuracy 0.41 {+\/-} 0.03, F1 score 0.39 {+\/-} 0.02, AUROC 0.58 {+\/-} 0.02), compared to the random classifier for 3-class classification (AUROC = 0.50; accuracy = F1 = 0.33). ResNet-18 and XGBoost showed similar performance (AUROC 0.53-0.58). Confusion matrices revealed substantial overlap between classes, with frequent misclassification toward the prediabetes group. Binary reformulation (normal vs. diabetic) improved performance substantially, with the CNN resulting in AUROC 0.63 {+\/-} 0.02 and XGBoost 0.67 {+\/-} 0.07.\n\nConclusionsFLIO-derived lifetime maps capture metabolic signals associated with glycemic status but yield modest classification performance with current AI models. These findings highlight both the potential and the challenges of using FLIO for early metabolic screening and monitoring, informing future development of clinically applicable imaging biomarkers.","rel_num_authors":4,"rel_authors":[{"author_name":"SeongJun Kwon","author_inst":"Washington University in St. Louis"},{"author_name":"Cecilia S Lee","author_inst":"Washington University In St Louis"},{"author_name":"Aaron Y Lee","author_inst":"Washington University In St Louis"},{"author_name":"Linying Zhang","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-08-06","rel_site":"medrxiv"},{"rel_title":"Truncated ASXL3 Alters Chromatin Accessibility and Epigenetic Landscape in Bainbridge-Ropers Syndrome Suggesting a Gain-of-Function Etiology","rel_doi":"10.64898\/2026.08.04.26359647","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.04.26359647","rel_abs":"Bainbridge-Ropers syndrome (BRS) is a rare neurodevelopmental disorder caused by truncating mutations in the epigenetic regulator ASXL3. While traditionally considered a haploinsufficiency disorder, the precise molecular mechanisms driving BRS remain poorly understood. Here, we combine patient-derived cellular lines and novel mouse models to elucidate the molecular function of disease-associated ASXL3 variants. We show that several pathogenic ASXL3 variants escape nonsense-mediated decay (NMD), possibly leading to the accumulation of truncated protein, and widespread epigenetic changes, resulting in distinct transcriptomic and proteomic profiles. These changes include increased chromatin accessibility and global DNA hypomethylation, particularly at promoters and imprinted loci. A knock-in Asxl3 mouse model harboring a mutation corresponding to one diagnosed in BRS-patient recapitulated the molecular features BRS-patient derived cellular model, including the escape from NMD and Polycomb Repressive Complex 2 (PRC2)-related transcriptomic dysregulation. In contrast, heterozygous Asxl3 knockout mice and transient knockdown models showed no phenotype, indicating that truncated ASXL3 that may exert dominant-negative effects rather than simple loss of function. This molecular dissection offers new venues for treatment, including allele-specific Antisense Oligonucleotides (ASO), which were used by us in patient-derived cells to downregulate the expression of the mutated allele, and were able to induce partial recovery of the proteomic profile. Taken together, our results support a dominant-negative mechanism for BRS causing truncating mutations, offering a compelling rationale for allele-specific ASO therapeutic strategy.\n\nOne sentence SummaryPatient-derived neuronal models and mouse models reveal that truncated ASXL3 drive epigenetic dysregulation through a gain-of-function mechanism.","rel_num_authors":17,"rel_authors":[{"author_name":"Nofar Mor","author_inst":"Sheba Medical Center"},{"author_name":"Inna Shomer","author_inst":"Sheba Medical Center"},{"author_name":"Shaul Raviv","author_inst":"Sheba Medical Center"},{"author_name":"Noga Budick-Harmelin","author_inst":"Sheba Medical Center"},{"author_name":"Tanya Matzevitch","author_inst":"Sheba Medical Center"},{"author_name":"Shalhevet Azriel","author_inst":"Sheba Medical Center"},{"author_name":"Joseph G Gleeson","author_inst":"UCSD and RCIGM"},{"author_name":"Yoach Rais","author_inst":"Sheba Medical Center"},{"author_name":"Rebecca Haffner","author_inst":"Weizmann Institute of Science"},{"author_name":"Shifra Ben-Dor","author_inst":"Weizmann Institute of Science"},{"author_name":"Omri Nayshool","author_inst":"Sheba Medical Center"},{"author_name":"Sharon Avkin-Nachum","author_inst":"Sheba Medical Center"},{"author_name":"Adi Yahalom","author_inst":"Sheba Medical Center"},{"author_name":"Efrat Glick-Saar","author_inst":"Sheba Medical Center"},{"author_name":"Gali Heimer","author_inst":"Sheba Medical Center"},{"author_name":"Gidi Rechavi","author_inst":"Sheba Medical Center"},{"author_name":"Dan Dominissini","author_inst":"Sheba Medical Center"}],"rel_date":"2026-08-05","rel_site":"medrxiv"},{"rel_title":"Truncated ASXL3 Alters Chromatin Accessibility and Epigenetic Landscape in Bainbridge-Ropers Syndrome Suggesting a Gain-of-Function Etiology","rel_doi":"10.64898\/2026.08.04.26359647","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.04.26359647","rel_abs":"Bainbridge-Ropers syndrome (BRS) is a rare neurodevelopmental disorder caused by truncating mutations in the epigenetic regulator ASXL3. While traditionally considered a haploinsufficiency disorder, the precise molecular mechanisms driving BRS remain poorly understood. Here, we combine patient-derived cellular lines and novel mouse models to elucidate the molecular function of disease-associated ASXL3 variants. We show that several pathogenic ASXL3 variants escape nonsense-mediated decay (NMD), possibly leading to the accumulation of truncated protein, and widespread epigenetic changes, resulting in distinct transcriptomic and proteomic profiles. These changes include increased chromatin accessibility and global DNA hypomethylation, particularly at promoters and imprinted loci. A knock-in Asxl3 mouse model harboring a mutation corresponding to one diagnosed in BRS-patient recapitulated the molecular features BRS-patient derived cellular model, including the escape from NMD and Polycomb Repressive Complex 2 (PRC2)-related transcriptomic dysregulation. In contrast, heterozygous Asxl3 knockout mice and transient knockdown models showed no phenotype, indicating that truncated ASXL3 that may exert dominant-negative effects rather than simple loss of function. This molecular dissection offers new venues for treatment, including allele-specific Antisense Oligonucleotides (ASO), which were used by us in patient-derived cells to downregulate the expression of the mutated allele, and were able to induce partial recovery of the proteomic profile. Taken together, our results support a dominant-negative mechanism for BRS causing truncating mutations, offering a compelling rationale for allele-specific ASO therapeutic strategy.\n\nOne sentence SummaryPatient-derived neuronal models and mouse models reveal that truncated ASXL3 drive epigenetic dysregulation through a gain-of-function mechanism.","rel_num_authors":17,"rel_authors":[{"author_name":"Nofar Mor","author_inst":"Sheba Medical Center"},{"author_name":"Inna Shomer","author_inst":"Sheba Medical Center"},{"author_name":"Shaul Raviv","author_inst":"Sheba Medical Center"},{"author_name":"Noga Budick-Harmelin","author_inst":"Sheba Medical Center"},{"author_name":"Tanya Matzevitch","author_inst":"Sheba Medical Center"},{"author_name":"Shalhevet Azriel","author_inst":"Sheba Medical Center"},{"author_name":"Joseph G Gleeson","author_inst":"UCSD and RCIGM"},{"author_name":"Yoach Rais","author_inst":"Sheba Medical Center"},{"author_name":"Rebecca Haffner","author_inst":"Weizmann Institute of Science"},{"author_name":"Shifra Ben-Dor","author_inst":"Weizmann Institute of Science"},{"author_name":"Omri Nayshool","author_inst":"Sheba Medical Center"},{"author_name":"Sharon Avkin-Nachum","author_inst":"Sheba Medical Center"},{"author_name":"Adi Yahalom","author_inst":"Sheba Medical Center"},{"author_name":"Efrat Glick-Saar","author_inst":"Sheba Medical Center"},{"author_name":"Gali Heimer","author_inst":"Sheba Medical Center"},{"author_name":"Gidi Rechavi","author_inst":"Sheba Medical Center"},{"author_name":"Dan Dominissini","author_inst":"Sheba Medical Center"}],"rel_date":"2026-08-05","rel_site":"medrxiv"},{"rel_title":"Antemortem \u03b1-Synuclein levels from neuron-derived extracellular vesicles identify Lewy Body pathology in Parkinson's Disease and Alzheimer Disease","rel_doi":"10.64898\/2026.08.03.26359636","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.03.26359636","rel_abs":"ImportanceAlzheimer disease (AD) is frequently accompanied by co-pathologies such as Lewy bodies, intracellular protein aggregates consisting of misfolded -synuclein, ubiquitin and several other proteins. These aggregated proteins contribute to the pathological and clinical heterogeneity of AD and are associated with a more rapid progression. Cerebrospinal fluid (CSF) measurement of aggregated -synuclein or skin biopsy histochemistry are the current biomarkers for Lewy body pathology in individuals with Parkinsons disease and related synucleinopathies but are invasive, not easily scalable for large studies or practical in clinical practice. Neuron-derived extracellular vesicles (nEVs) provide a feasible and tolerable alternative to detect Lewy body pathology. nEVs exit across the blood-brain barrier and deliver neuron-derived proteins into the systemic circulation, offering direct access to brain-level protein concentrations from peripheral blood, not afforded by conventional plasma biomarkers.\n\nObjectiveTo use nEVs extracted from plasma to measure brain-derived -synuclein levels as a clinical biomarker of Lewy body pathology and synucleinopathy across clinically and pathologically characterized cohorts.\n\nDesign, Setting, and ParticipantsThis multicohort observational study evaluated plasma nEV-derived -synuclein levels in 1,304 individuals, including 794 (61%) individuals without dementia, 469 (36%) individuals with AD, and 41 (3%) individuals with PD across four cohorts. Postmortem validation was performed from autopsy data in 127 individuals, including 96 (76%) individuals without, and 31 (24%) with, Lewy body pathology. Cerebrospinal fluid (CSF) -synuclein seed amplification assay data were available in a small subset of 54 (4.1%) of the group. Amyloid positron emission tomography (PET) data were available in 901(69.1%) of the total group.\n\nExposureClinical diagnosis, AD biomarker positivity, Lewy body pathology, CSF -synuclein seed assay status, and amyloid PET positivity.\n\nMain Outcomes and MeasuresPlasma nEV-derived -synuclein levels normalized to CD9 and assessed in relation to clinical diagnosis, AD biomarker status, neuropathologically confirmed Lewy body pathology, CSF seed assay results, and amyloid PET positivity.\n\nResultsCompared with controls, plasma -synuclein levels from nEVs were significantly elevated among individuals with PD (controls mean 0.51, SD=0.24 vs PD mean=0.69, SD=0.23, P=8.66x10- {square}). nEV-derived -synuclein levels were also significantly higher in P-tau181 and P- tau217 positive individuals with and without cognitive impairment compared to P-tau negative individuals. Elevated nEV-derived -synuclein levels were subsequently validated in individuals with postmortem Lewy body pathology (28.6% higher mean levels, P=0.02). Among 54 individuals with CSF -synuclein seed amplification assay, 8 (15%) were positive and showed a 18.2% increase in mean nEV -synuclein levels compared to individuals with negative - synuclein seed amplification. nEV-derived -synuclein levels were also significantly elevated in amyloid PET positive individuals with and without dementia (5.8% higher mean levels, P=8.50E-03) and clinical AD (9.3% higher mean levels, P=6.38E-12).\n\nConclusions and RelevancePlasma -synuclein levels from nEVs likely reflect underlying synuclein pathology in the brain and have potential as a blood-based biomarker for detecting Lewy body pathology in PD and in AD and related dementias. nEVs cross the blood-brain barrier and carry neuron-derived cargo directly into the bloodstream, thus providing a unique window into brain -synuclein levels that is not accessible through conventional plasma biomarkers.","rel_num_authors":11,"rel_authors":[{"author_name":"TAMIL INIYAN GUNASEKARAN","author_inst":"Columbia University"},{"author_name":"Dolly Reyes-Dumeyer","author_inst":"Columbia University Vagelos College of Physicians and Surgeons"},{"author_name":"Yian Y Gu","author_inst":"Columbia University"},{"author_name":"Olga Volpert","author_inst":"NeuroDex Inc."},{"author_name":"Doug Beauregard","author_inst":"Global Alzheimer's Platform Foundation"},{"author_name":"Lammert Albers","author_inst":"Global Alzheimer's Platform Foundation"},{"author_name":"Andrew Teich","author_inst":"Columbia University"},{"author_name":"Lawrence S. Honig","author_inst":"Columbia University"},{"author_name":"Richard Mayeux","author_inst":"Columbia University"},{"author_name":"Erez Eitan","author_inst":"NeuroDex Inc."},{"author_name":"Badri N Vardarajan","author_inst":"Columbia University"}],"rel_date":"2026-08-05","rel_site":"medrxiv"},{"rel_title":"prevalence and Factors associated with post-natal growth restriction among low-birth-weight infants at a rural county referral hospital, Kenya: A retrospective observational study","rel_doi":"10.64898\/2026.08.04.26359674","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.04.26359674","rel_abs":"BackgroundThe globally low birth weight is estimated to account for about 15-20% of all births. Global annual preterm delivery is about fifteen million, more than 60% of which occurs in Asia and Sub-Saharan Africa. The Kenyan preterm birth rate is estimated to be 14 per 100 live births. Prematurity, the leading cause of low birth weight, and its associated complications account for a large proportion of neonatal and under 5 morbidity and mortality. Premature and low birth weight (LBW) infants have rapid growth with increased nutritional demands despite their inadequate nutrient stores. This predisposes them to post-natal growth restriction (PNGR). Timely and adequate nutrition is important to prevent PNGR that has been shown to have long term neurodevelopmental and growth consequences. Immaturity and clinical instability of these infants makes providing adequate nutrition for them a great challenge. This study was done to determine the prevalence of and factors associated with PNGR among LBW infants at discharge from a rural public referral hospital in Kenya.\n\nMethodsThis was a single center retrospective descriptive study, of infants with birth weight <1800g discharged between 1st January 2022 and 31st December 2023, done to determine the prevalence of and the factors associated with PNGR among these infants at discharge. PNGR was defined as poor growth after birth during the initial hospitalization period. Cross sectional PNGR was discharge weight less than 10th centile while longitudinal PNGR was a drop in centiles lines for weight at discharge. Moderate PNGR was discharge weight between 3rd and 10th centile while severe PNGR was discharge weight less than the 3rd centile. Weight at birth and discharge was obtained and presented as Z scores and centiles using the respective gender specific intergrowth 21 charts. Maternal, clinical and nutritional data were also obtained from the patient files and analyzed to determine their association with PNGR.\n\nResultsAmong the 143 LBW infants included in the study, the prevalence of PNGR was 63% (n=90) (severe 44.8%) and 53.2% (n=76) (severe 16.1%) for cross sectional and longitudinal PNGR respectively. Statistically significant associations for longitudinal PNGR were found in patients who received any supplements aOR(95%CI) 3.0(1.1-8.3) p=0.037, took 14 days or more to regain birth weight aOR (95%CI) 0.1(0.1-0.4) p=<0.01 and were admitted for 30 days or more aOR(95%CI) 0.3(0.1-0.9) p=0.025.\n\nConclusionMore than half of LBW infants in Nyeri County Referral Hospital are discharged with PNGR, a sizeable proportion with severe form. There is need to update local LBW infants feeding protocols to include breast milk fortification, parenteral nutrition and avail resources to support the high nutritional needs of this population.","rel_num_authors":3,"rel_authors":[{"author_name":"Lucy N Lyanda","author_inst":"Nyeri County Referral Hospital"},{"author_name":"Roseline Ochieng","author_inst":"Aga Khan University Hospital- Nairobi"},{"author_name":"Alfred Keter","author_inst":"Aga Khan University Nairobi"}],"rel_date":"2026-08-05","rel_site":"medrxiv"},{"rel_title":"Health impacts of national and local air pollution control policies targeting electric generating units, mobile sources, and port activities in three US cities","rel_doi":"10.64898\/2026.08.04.26359640","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.04.26359640","rel_abs":"ObjectiveOver the past decades, US policies intended to reduce air pollution emissions from electric generating units (EGUs), mobile sources (e.g., cars and trucks), and port activities have been implemented to improve air quality. This study aimed to estimate and compare counterfactual air pollution concentrations (i.e., concentrations that would have occurred without these policies) to observed concentrations, and then evaluate the health impacts of such policies in New York City, Los Angeles, and Atlanta from 2005 to 2019.\n\nMaterials and MethodsWe obtained data on respiratory emergency department (ED) visits and cardiovascular disease ED visits that result in hospitalizations for the three cities from 2005-2019. Daily concentrations of fine particulate matter (PM2.5), criteria gases [carbon monoxide (CO), nitrogen dioxide (NO2), sulfur dioxide (SO2), and ozone (O3)], and 1-in-3-day measured concentrations of PM2.5 components and PM sources estimated using positive matrix factorization were acquired from six monitoring sites in the three cities. To estimate health impacts of selected EGU, mobile, and port policies we estimated: 1) counterfactual daily pollutant concentrations at each of the 6 city-sites; 2) associations between daily pollutant concentrations and rates of cardiorespiratory visits using city-site specific multi-pollutant Poisson models; and 3) the percent of cardiorespiratory visits prevented by the implementation of the selected policies, through applying observed and counterfactual concentrations to the fitted health models.\n\nResultsAir quality policies were estimated to reduce ambient pollutant concentrations across the three cities, with median PM2.5 reductions of 27%-62% due to all policies combined during 2005-2019. Changes in criteria-pollutant concentrations associated with the selected policies were estimated to avert 7.1% (95% UI: 5.4%, 8.9%) of respiratory visits in New York City, 2.4% (95% UI: 1.4%, 3.4%) in Los Angeles, and 4.5% (95% UI: 0.8%, 8.2%) in Atlanta. In addition, 2.6% (95% UI: 0.9%, 4.2%) and 1.2% (95% UI: 0.3%, 2.1%) of cardiovascular visits were averted in New York City and Los Angeles, while the estimate in Atlanta did not indicate cardiovascular visits averted.\n\nConclusionThe selected EGU, mobile-source, and port policies evaluated during 2005-2019 were estimated to reduce ambient pollutant concentrations and avert respiratory visits in all three cities and cardiovascular visits in New York City and Los Angeles.","rel_num_authors":9,"rel_authors":[{"author_name":"Haisu Zhang","author_inst":"Gangarosa Department of Environmental Health, Emory University, Atlanta, GA"},{"author_name":"Howard H. Chang","author_inst":"Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA"},{"author_name":"Ziqi Gao","author_inst":"Civil and Environmental Engineering, Georgia Institute of Technology, GA"},{"author_name":"Rohan R. D'Souza","author_inst":"Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA"},{"author_name":"Noah Scovronick","author_inst":"Gangarosa Department of Environmental Health, Emory University, Atlanta, GA"},{"author_name":"Philip K. Hopke","author_inst":"Department of Environmental Medicine and Public Health Sciences, University of Rochester School of Medicine and Dentistry, Rochester, NY"},{"author_name":"David Q. Rich","author_inst":"Department of Environmental Medicine and Public Health Sciences, University of Rochester School of Medicine and Dentistry, Rochester, NY"},{"author_name":"Armistead G. Russell","author_inst":"Civil and Environmental Engineering, Georgia Institute of Technology, GA"},{"author_name":"Stefanie Ebelt","author_inst":"Gangarosa Department of Environmental Health, Emory University, Atlanta, GA"}],"rel_date":"2026-08-05","rel_site":"medrxiv"},{"rel_title":"Vitamin D Status and Supplementation in Patients Undergoing Spine Surgery: A Systematic Review and Meta-analysis","rel_doi":"10.64898\/2026.08.02.26359512","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.02.26359512","rel_abs":"BackgroundVitamin D may influence bone healing and recovery after spine surgery, but its clinical effects remain uncertain.\n\nObjectiveTo evaluate clinical, functional, and bone-related outcomes associated with vitamin D status and supplementation in patients undergoing spine surgery.\n\nMethodsThis systematic review and meta-analysis was registered in PROSPERO (CRD420261321165) and reported according to PRISMA 2020. PubMed\/MEDLINE, Scopus, Web of Science, Embase, and the Cochrane Library were searched from inception through 15 January 2026. Random-effects meta-analyses used mean differences (MDs) for continuous outcomes and risk ratios (RRs) for dichotomous outcomes. Direct supplementation analyses were prioritized; analyses combining supplementation, baseline vitamin D status, or co-interventions were exploratory. Risk of bias was assessed using design-specific Joanna Briggs Institute tools.\n\nResultsThirteen studies were included. Four supplementation studies involving 177 participants showed no significant reduction in postoperative pain (MD -0.82, 95% CI -2.50 to 0.86; I{superscript 2} = 84.3%). Three studies involving 277 participants showed lower Oswestry Disability Index scores in an exploratory analysis (MD -6.40, 95% CI -10.41 to -2.39; I{superscript 2} = 96.8%). Three supplementation studies involving 128 participants showed no significant improvement in fusion rate (RR 1.17, 95% CI 0.78-1.74; I{superscript 2} = 31.5%). An exploratory four-study fusion analysis was also nonsignificant (RR 1.24, 95% CI 0.98-1.57; I{superscript 2} = 45.5%).\n\nConclusionCurrent evidence does not establish that vitamin D supplementation independently improves postoperative pain or fusion rates after spine surgery. Possible benefits for disability and other bone-related outcomes remain uncertain because of small study numbers, heterogeneity, co- interventions, and residual confounding. Larger randomized trials stratified by baseline vitamin D status are needed.","rel_num_authors":15,"rel_authors":[{"author_name":"Farzan Fahim","author_inst":"Shohada-e Tajrish Hospital"},{"author_name":"Fatemeh Vosoughian","author_inst":"Shahid Beheshti University of Medical Sciences"},{"author_name":"Amirmahdi Mojtahedzadeh","author_inst":"Shahid Beheshti University of Medical Sciences"},{"author_name":"Mahla Rakhshani","author_inst":"Tehran University of Medical Sciences"},{"author_name":"Barbod Mahdavi","author_inst":"Shahid Beheshti University of Medical Sciences"},{"author_name":"Kiana taghipoor","author_inst":"Shahid Beheshti University of Medical Sciences"},{"author_name":"Rauf Rostami","author_inst":"Shahid Beheshti University of Medical Sciences"},{"author_name":"Reihane Qahremani","author_inst":"Shahid Beheshti University of Medical Sciences"},{"author_name":"Fatemeh Gheibi","author_inst":"Shahid Beheshti University of Medical Sciences"},{"author_name":"Fatemeh Deldar","author_inst":"Shahid Beheshti University of Medical Sciences"},{"author_name":"Ramtin Shemshadigolafzani","author_inst":"Shahid Beheshti University of Medical Sciences"},{"author_name":"Saeed Rezaali","author_inst":"Shahid Beheshti University of Medical Sciences"},{"author_name":"Nahal Badavi","author_inst":"Shahid Beheshti University of Medical Sciences"},{"author_name":"Pardis Fathabadi","author_inst":"Shahid Beheshti University of Medical Sciences"},{"author_name":"Alireza Zali","author_inst":"Shohada-e Tajrish Hospital"}],"rel_date":"2026-08-04","rel_site":"medrxiv"},{"rel_title":"Effect of five years of biannual azithromycin mass drug administration on enteric fever seroincidence in Niger: A randomized control trial","rel_doi":"10.64898\/2026.08.03.26359544","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.03.26359544","rel_abs":"BackgroundEnteric fever, caused by Salmonella enterica serovars Typhi and Paratyphi, remains a major cause of morbidity in low- and middle-income countries, yet burden estimation is challenging in regions without blood culture surveillance. Azithromycin is effective for treating enteric fever, and mass drug administration (MDA) to young children reduces all-cause mortality in sub-Saharan Africa, but its impact on community-level enteric fever burden is unknown. We assessed enteric fever seroincidence in rural Niger and evaluated the effect of biannual azithromycin MDA affected.\n\nPrincipal FindingsThis was a secondary analysis of the MORDOR trial (NCT02048007), a cluster-randomized, placebo-controlled study in 30 communities in Dosso Region, Niger. Children aged 1-59 months received biannual azithromycin or placebo. Dried blood spots collected at baseline (2015) and Year 5 (2020) were tested for IgA and IgG antibodies against Hemolysin E using kinetic ELISA. Seroincidence was estimated using maximum likelihood methods based on antibody kinetics from blood culture-confirmed enteric fever patients. Samples from 1,417 children were analyzed (423 baseline; 994 Year 5). Overall seroincidence approximately doubled from baseline to Year 5, increasing from 68.5 (95% CI 58.0-80.7) to 145.2 (95% CI 132.3-159.3) per 100 person-years in placebo communities and from 74.7 (95% CI 56.5-98.7) to 135.2 (95% CI 112.4-162.6) in azithromycin communities, with no significant difference between arms (difference-in-differences -16.2; 95% CI -53.1-20.8 ). Among children <2 years, the increase in seroincidence was smaller in the azithromycin arm (37.5; 95% CI: 1.3-73.6) compared to placebo (81.1; 95% CI 54.0-108.2), with a difference-in-differences of -43.7 per 100 person-years (95% CI -88.8 - 1.5 to 0.02).\n\nSignificanceEnteric fever seroincidence among young children in rural Niger is high and increased substantially over the five-year study period. Biannual azithromycin MDA did not significantly reduce overall seroincidence, though a potential attenuation was observed among children under 2 years of age. These findings underscore the importance of Nigers recent typhoid conjugate vaccine introduction and highlight the value of serosurveillance for monitoring enteric fever infection intensity in settings without blood culture surveillance.","rel_num_authors":19,"rel_authors":[{"author_name":"Kristen Aiemjoy","author_inst":"University of California Davis"},{"author_name":"Jessica Seidman","author_inst":"Albert B Sabin Vaccine Institute: Sabin Vaccine Institute"},{"author_name":"Ahmed  M Arzika","author_inst":"Centre de Recherche et d\u2019Intervention en Sant\u00e9 Publique"},{"author_name":"Ramatou Maliki","author_inst":"Centre de Recherche et d\u2019Intervention en Sant\u00e9 Publique"},{"author_name":"Amza Abdou","author_inst":"Programme Nationale de Sant\u00e9 Oculaire"},{"author_name":"Douglas  Ezra Morrison","author_inst":"University of California Davis"},{"author_name":"Kristina  W Lai","author_inst":"UC Davis: University of California Davis"},{"author_name":"Denise  O Garrett","author_inst":"Albert B Sabin Vaccine Institute: Sabin Vaccine Institute"},{"author_name":"Claire Munroe","author_inst":"Massachusetts General Hospital"},{"author_name":"Abel Gonzalez","author_inst":"Massachusetts General Hospital"},{"author_name":"Leah Sukri","author_inst":"University of Maryland School of Medicine"},{"author_name":"Elodie Lebas","author_inst":"UCSF: University of California San Francisco"},{"author_name":"Catherine Cook","author_inst":"UCSF: University of California San Francisco"},{"author_name":"Benjamin  F Arnold","author_inst":"UCSF: University of California San Francisco"},{"author_name":"Thomas  M Leitman","author_inst":"UCSF: University of California San Francisco"},{"author_name":"Kathleen  M Neuzil","author_inst":"University of Maryland School of Medicine"},{"author_name":"Jason  R Andrews","author_inst":"Stanford University School of Medicine"},{"author_name":"Jeremy  D Keenan","author_inst":"UCSF: University of California San Francisco"},{"author_name":"Richelle  C Charles","author_inst":"Massachusetts General Hospital"}],"rel_date":"2026-08-04","rel_site":"medrxiv"},{"rel_title":"Incidence and Management of Early Breakthrough HSV Infection Among Allogeneic Hematopoietic Stem Cell Transplant Recipients","rel_doi":"10.64898\/2026.08.02.26359522","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.02.26359522","rel_abs":"BackgroundReactivation of herpes simplex viruses (HSV) can occur in the early post-allogeneic hematopoietic cell transplant (aHCT) period despite antiviral prophylaxis. Few studies have assessed HSV infection in the modern era, in which acyclovir\/valacyclovir is recommended for up to 1 year post aHCT. We evaluated the incidence and management of breakthrough HSV during the first 100 days post-aHCT over two decades.\n\nMethodsPatients who received their first aHCT at Fred Hutchinson Cancer Center between 2002-2022 were reviewed for breakthrough HSV infection within the first 100 days on prophylaxis (acyclovir 800 mg or valacyclovir 500 mg twice daily). Cases were identified via culture, polymerase chain reaction, and\/or direct fluorescent antibody testing; clinical records were reviewed for symptoms, outcomes, and prophylaxis\/treatment regimens. Refractory\/resistant (R\/R) infections were defined according to consensus guidelines.\n\nResultsWe reviewed data from 4,357 aHCT recipients aged [&ge;]18 years, among whom 3,749 (86%) were HSV seropositive and 23 developed breakthrough HSV infection (observed probability = 0.6%). Among those who had an infection, the median time from transplant to first positive test was 46 days (IQR: 24.0-69.5). Oral and genital mucosa were the most common sites of infection. In total, 11 of 23 (47.8%) patients with breakthrough HSV developed R\/R infection.\n\nConclusionsBreakthrough HSV infections are rare in the first 100 days after aHCT among patients receiving antiviral prophylaxis. Refractory\/resistant infections were uncommon but represented almost half of breakthrough cases. Our findings highlight the sustained effectiveness of universal prophylaxis in the early post-transplant period.\n\nSummaryThe incidence of breakthrough herpes simplex virus infections among adult allogeneic hematopoietic cell transplant recipients was low over a 20-year period at our center. Nonetheless, refractory\/resistant infections represented almost half of breakthrough cases, highlighting the need for novel treatment strategies.","rel_num_authors":12,"rel_authors":[{"author_name":"Molly D Fischer","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Ria Mohan","author_inst":"Virginia Commonwealth University"},{"author_name":"Anna D Wald","author_inst":"University of Washington"},{"author_name":"Amanda I Phipps","author_inst":"University of Washington"},{"author_name":"Emily Ford","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Ted Gooley","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Frank Tverdek","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Melinda A Biernacki","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Denise J McCulloch","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Michael J Boeckh","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Christine Johnston","author_inst":"University of Washington"},{"author_name":"Steven Pergam","author_inst":"Fred Hutchinson Cancer Center"}],"rel_date":"2026-08-04","rel_site":"medrxiv"},{"rel_title":"Twenty-site HDSS mapping after thoracoscopic sympathectomy for primary palmar hyperhidrosis: a secondary complete-case analysis of a multicenter randomized trial.","rel_doi":"10.64898\/2026.08.02.26359508","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.02.26359508","rel_abs":"ObjectiveTo map, using the Hyperhidrosis Disease Severity Scale (HDSS), the preoperative distribution and six-month regional evolution of sweating severity across 20 anatomical sites after dominant-side unilateral versus one-stage bilateral R4 video-assisted thoracoscopic sympathectomy for primary palmar hyperhidrosis.\n\nMethodsThis was a secondary complete-case, site-level analysis of a prospective multicenter randomized trial. Adults undergoing one-stage bilateral thoracic sympathectomy (BTS) or dominant-side unilateral sympathectomy (UniS) were eligible when baseline and six-month HDSS data were complete for all 20 prespecified sites. HDSS was grouped as 1, 2, or 3-4. Regional outcomes were classified as improvement, stability, or worsening and were stratified by baseline HDSS.\n\nResultsNinety-two patients were included: 36 BTS and 56 UniS. Before surgery, severe sweating was present in 182 of 184 hand-site observations, 168 of 184 foot-site observations, and 75 of 184 axillary-site observations. At six months, improvement was more frequent after BTS than UniS in the hands (88.9% vs 52.7%) and axillae (72.2% vs 29.5%). Worsening was concentrated mainly in abdominal, hemidorsal, and thoracic sites. Among observations that were normal at baseline, progression to HDSS 3-4 occurred in 10.8% after BTS and 7.7% after UniS. Among observations with baseline HDSS 3-4, complete resolution to HDSS 1 occurred in 47.2% after BTS and 21.8% after UniS.\n\nConclusionBaseline-stratified 20-site HDSS mapping may improve preoperative counseling and postoperative outcome assessment by distinguishing true new-onset compensatory hyperhidrosis from worsening or persistence of pre-existing sweating.\n\nTrial registrationClinicalTrials.gov NCT03921320","rel_num_authors":16,"rel_authors":[{"author_name":"NELSON WOLOSKER","author_inst":"FACULDADE ISRAELITA DA SAUDE ALBERT EINSTEIN"},{"author_name":"Niura N Hamilton","author_inst":"Heart Institute (InCor), Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil."},{"author_name":"Miguel L Tedde","author_inst":"Heart Institute (InCor), Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil."},{"author_name":"Marina B Wolosker","author_inst":"Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil."},{"author_name":"Wolfgang W S Aguiar","author_inst":"Hospital Universitario Oswaldo Cruz, Recife, PE, Brazil."},{"author_name":"Hylas P C Ferreira","author_inst":"Hospital Liga Norte Riograndense Contra o Cancer, Natal, RN, Brazil."},{"author_name":"Fernando L Westphal","author_inst":"Hospital da Universidade Federal do Amazonas, Manaus, AM, Brazil."},{"author_name":"Alexandre M R Lima","author_inst":"Hospital Geral Dr. Cesar Cals, Fortaleza, CE, Brazil."},{"author_name":"Humberto A Oliveira","author_inst":"h: Hospital de Base, Brasilia, DF, Brazil."},{"author_name":"Sergio T L F Pereira","author_inst":"Hospital Santa Isabel, Salvador, BA, Brazil."},{"author_name":"Fabio O Riuto","author_inst":"Hospital da Universidade Federal de Grande Dourados, Dourados, MS, Brazil."},{"author_name":"Guilherme C Resende","author_inst":"Hospital da Universidade de Brasilia, Brasilia, DF, Brazil."},{"author_name":"Marina M K Brenner","author_inst":"l: Hospital Universitario de Santa Maria, Santa Maria, RS, Brazil."},{"author_name":"Daniel O Bonomi","author_inst":"Hospital das Clinicas da Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil."},{"author_name":"Caroline E B Valero","author_inst":"Empresa Brasileira de Servicos Hospitalares, Brasilia, DF, Brazil."},{"author_name":"Paulo M Pego-Fernandes","author_inst":"Heart Institute (InCor), Hospital das Clinicas, University of Sao Paulo, Sao Paulo, Brazil."}],"rel_date":"2026-08-04","rel_site":"medrxiv"},{"rel_title":"The extent and durability of improvement in depressive symptoms, quality of life, and daily function with three years of vagus nerve stimulation in markedly treatment-resistant depression: A RECOVER study report","rel_doi":"10.64898\/2026.07.31.26358854","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.31.26358854","rel_abs":"BackgroundManagement of markedly treatment-resistant depression is characterized by low initial benefit and poor durability. Treatments with sustained benefits are needed. This report summarizes clinical outcomes and durability of both the active treatment arm (Early-Active) and the initially sham treatment arm (Delayed-Active) over the second and third years of the multicenter, prospective, implanted vagus nerve stimulation (VNS) RECOVER trial.\n\nMethodsA total of 436 participants (N=221 Early-Active and N=215 Delayed-Active, 65.8% females) were studied. Within each group, analyses of change in benefit (depressive symptoms, clinical impression, quality of life [QoL], daily function, and a composite measure) occurred with assessments at 12, 18, 24, 30, and 36 months. Two within-group methods of benefit appraisal over time were conducted: 1) a comparison of the degree of benefit change, and 2) a comparison of proportions of participants achieving benefit categories. Additionally, the degree of durability of benefit was assessed, comparing 12-24 months, 24-36 months, and 12-36 months.\n\nResultsO_ST_ABSFor the Early-Active groupC_ST_ABSThe 12-24-month and 12-36-month periods, but not the 24-36-month period, demonstrated significant improvement in benefit categories for depressive symptoms and clinical impression measures. Similarly, statistically significant increases in the proportions of participants achieving benefit during Year 2 for depressive and clinical impression measures occurred.\n\nFor the Delayed-Active groupThe 12-24-month (first exposure of this group to active VNS) and 12-36-month periods, but not the 24-36-month period, demonstrated statistically significant improvements in benefit categories for depressive symptoms and clinical impression measures. Additionally, statistically significant increases in the proportions of participants achieving benefit during Year 2 for depressive symptoms, clinical impression, QoL, daily function, and the composite measure were observed. Averaged across the depressive symptom and clinical impression measures, the Early-Active group demonstrated continued progression to higher benefit categories during Years 2 and 3, whereas the Delayed-Active group was characterized by the emergence of new benefit during Year 2 followed by further progression to higher benefit categories during Year 3.\n\nDurabilityRobust durability of response was observed for both groups across all time intervals, with a median of 71.1% and 69.0% maintaining or improving benefit from 12 to 36 months for Early-Active and Delayed-Active, respectively.\n\nConclusionsIn a highly chronic and markedly resistant depressed sample, active VNS produced benefits that often emerged gradually, sometimes beyond one year after initiation, continued to improve in degree of benefit over time, and were highly durable. The time-associated benefit patterns observed in the sham group (Delayed-Active) closely resembled those of the initially active group (Early-Active) but were delayed by approximately one year, consistent with the delay in therapy activation.","rel_num_authors":31,"rel_authors":[{"author_name":"Charles R. Conway","author_inst":"Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States"},{"author_name":"Scott T. Aaronson","author_inst":"Institute for Advanced Diagnostics and Therapeutics, Sheppard Pratt Health System, Baltimore, MD, United States"},{"author_name":"A. John Rush","author_inst":"Duke-NUS Medical School, Singapore; Curbstone Consultant LLC, Dallas, TX, United States"},{"author_name":"Ying-Chieh (Lisa) Lee","author_inst":"LivaNova PLC (or a subsidiary), London, United Kingdom"},{"author_name":"Olivia Shy","author_inst":"LivaNova PLC (or a subsidiary), London, United Kingdom"},{"author_name":"Mark T. Bunker","author_inst":"LivaNova PLC (or a subsidiary), London, United Kingdom"},{"author_name":"Charles Gordon","author_inst":"LivaNova PLC (or a subsidiary), London, United Kingdom"},{"author_name":"Patricio Riva-Posse","author_inst":"Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States"},{"author_name":"Kevin Reeves","author_inst":"Department of Psychiatry and Behavioral Health, The Ohio State University Wexner Medical Center, Columbus, OH, United States"},{"author_name":"Mark S. George","author_inst":"Department of Psychiatry, Medical University of South Carolina, Charleston, SC, United States; Ralph H. Johnson VA Health Care System, Charleston, SC, United St"},{"author_name":"John Zajecka","author_inst":"Department of Psychiatry and Behavioral Sciences, Rush University Medical Center, Chicago, IL, United States; Psychiatric Medicine Associates, LLC, Skokie, IL, "},{"author_name":"Ziad Nahas","author_inst":"Department of Psychiatry and Behavioral Sciences, University of Minnesota, Minneapolis, MN, United States"},{"author_name":"David L. Dunner","author_inst":"Center for Anxiety and Depression, Mercer Island, WA, United States"},{"author_name":"Martijn Figee","author_inst":"Nash Family Center for Advanced Circuit Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY"},{"author_name":"Brian J. Mickey","author_inst":"Department of Psychiatry, Huntsman Mental Health Institute, University of Utah, Salt Lake City, UT, United States"},{"author_name":"Rebecca M. Allen","author_inst":"Seattle Neuropsychiatric Treatment Center, Seattle, WA, United States"},{"author_name":"Donald Bohnenkamp","author_inst":"Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States"},{"author_name":"Christopher L. Kriedt","author_inst":"Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States"},{"author_name":"Vasilis C. Hristidis","author_inst":"Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States"},{"author_name":"Joao Quevedo","author_inst":"Center for Interventional Psychiatry, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science"},{"author_name":"Charles F. Zorumski","author_inst":"Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States"},{"author_name":"Matthew Macaluso","author_inst":"UAB Department of Psychiatry and Behavioral Neurobiology, Birmingham, AL, United States"},{"author_name":"Walter Duffy","author_inst":"Alivation Research, Lincoln, NE, United States"},{"author_name":"Yvette Sheline","author_inst":"University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States"},{"author_name":"Gustavo Alva","author_inst":"ATP Clinical Research, Costa Mesa, CA, United States"},{"author_name":"Cristina Cusin","author_inst":"Depression Clinical & Research Program, Mass General Psychiatry, Boston, MA, United States"},{"author_name":"Jeffrey I. Bennett","author_inst":"Department of Psychiatry, SIU Neuroscience Institute, Springfield, IL, United States"},{"author_name":"Quyen Tran","author_inst":"LivaNova PLC (or a subsidiary), London, United Kingdom"},{"author_name":"Roger S. McIntyre","author_inst":"Department of Psychiatry, University of Toronto, Toronto, ON, Canada"},{"author_name":"Richard Hamish McAllister-Williams","author_inst":"Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom; Northern Centre for Mood Disorders, Newcastle Universi"},{"author_name":"Harold A. Sackeim","author_inst":"Department of Psychiatry, Medical University of South Carolina, Charleston, SC, United States"}],"rel_date":"2026-08-04","rel_site":"medrxiv"},{"rel_title":"Reduced option generation reveals distinct profiles of apathy in schizophrenia","rel_doi":"10.64898\/2026.08.03.26359552","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.03.26359552","rel_abs":"Apathy is a major driver of long-term disability in schizophrenia, yet existing accounts focus on how patients evaluate the cost of action while neglecting their capacity to generate options for action in the first place. Using a brief, culture-fair option generation task (OGT) within the international CHANSS study, we examined this process in 150 patients with different stages of schizophrenia and 100 healthy controls across the UK, Spain, and China. The OGT requires drawing as many different paths as possible between two points on a touchscreen, yielding two measures: fluency (the number of paths that they generate) and uniqueness (the distinctiveness of those paths). Patients drew as many paths as controls but produced options roughly half as unique. Across patients, uniqueness was positively associated with verbal fluency and depressive symptom severity, but negatively associated with self-reported behavioural apathy. This suggests that increased apathy is associated with reduced ability to generate unique options (paths on the task).\n\nTo examine the cognitive mechanisms further, we decomposed uniqueness into four exploratory measures: roaming entropy (spatial breadth of exploration), option elaboration (within-path development), perseveration (local repetition), and novelty maintenance (sustaining diversity over time). Together these explained 69% of the variance in motor-residualised uniqueness and attenuated the group difference by 80%, with roaming entropy as the dominant contributor. K-means clustering revealed three distinct patient profiles, each with a different clinical signature. A small subgroup generated options much like the control group. A larger subgroup retained spatial exploration but developed each option less and reported more depressive symptoms. A third subgroup showed broadly impaired exploration and the lowest verbal fluency. These findings establish option generation as a measurable behavioural phenotype in schizophrenia that relates to apathy and can be decomposed into specific cognitive mechanisms. They suggest that an impoverished option space, marked by reduced generation of unique possibilities for action, may be a remediable component of apathy.","rel_num_authors":21,"rel_authors":[{"author_name":"Noham Wolpe","author_inst":"Department of Physical Therapy, The Stanley Steyer School of Health Professions, Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv 699780"},{"author_name":"Cheng-Lin Wu","author_inst":"Clinical Research Center for Mental Disorders, Shanghai Pudong New Area Mental Health Center, School of Medicine, Tongji University"},{"author_name":"Claudia Aymerich","author_inst":"Spanish Network for Research in Mental Health, Carlos III Institute (CIBERSAM, ISCIII), 28029 Madrid, Spain; Department of Child and Adolescent Psychiatry, Inst"},{"author_name":"Marta Martin-Subero","author_inst":"Spanish Network for Research in Mental Health, Carlos III Institute (CIBERSAM, ISCIII), 28029 Madrid, Spain; Instituto de Salud Mental, Parc de Salut Mar, Barce"},{"author_name":"Paloma Fuentes-Perez","author_inst":"Spanish Network for Research in Mental Health, Carlos III Institute (CIBERSAM, ISCIII), 28029 Madrid, Spain; Instituto de Investigacion Sanitaria Valdecilla (ID"},{"author_name":"Claudia Ovejas-Catalan","author_inst":"Spanish Network for Research in Mental Health, Carlos III Institute (CIBERSAM, ISCIII), 28029 Madrid, Spain; Instituto de Investigacion Sanitaria Valdecilla (ID"},{"author_name":"Renata Zirilli","author_inst":"Cambridgeshire and Peterborough NHS Foundation Trust"},{"author_name":"Sophie Shatford","author_inst":"Cambridgeshire and Peterborough NHS Foundation Trust"},{"author_name":"Rebecca Cox","author_inst":"Clinical Research Unit, South West London & St. George's Mental Health NHS Trust"},{"author_name":"Megan Cartier","author_inst":"Clinical Research Unit, South West London & St. George's Mental Health NHS Trust"},{"author_name":"Ana Catalan","author_inst":"Spanish Network for Research in Mental Health, Carlos III Institute (CIBERSAM, ISCIII), 28029 Madrid, Spain; Department of Neuroscience, University of the Basqu"},{"author_name":"Anna Mane","author_inst":"Spanish Network for Research in Mental Health, Carlos III Institute (CIBERSAM, ISCIII), 28029 Madrid, Spain; Grup MERITT, Institut de Recerca Sant Joan de Deu, "},{"author_name":"John Pratt","author_inst":"Research Team, Humber NHS Foundation Trust"},{"author_name":"Lisa Airey","author_inst":"Research Team, Humber NHS Foundation Trust"},{"author_name":"Javier Vazquez-Bourgon","author_inst":"Spanish Network for Research in Mental Health, Carlos III Institute (CIBERSAM, ISCIII), 28029 Madrid, Spain; Instituto de Investigacion Sanitaria Valdecilla (ID"},{"author_name":"Nuria Segarra","author_inst":"Cambridgeshire and Peterborough NHS Foundation Trust"},{"author_name":"Yi-Jie Zhao","author_inst":"Clinical Research Center for Mental Disorders, Shanghai Pudong New Area Mental Health Center, School of Medicine, Tongji University"},{"author_name":"Paul C Fletcher","author_inst":"Cambridgeshire and Peterborough NHS Foundation Trust; Department of Psychiatry, University of Cambridge, UK; Wellcome Trust MRC Institute of Metabolic Science, "},{"author_name":"Peter B Jones","author_inst":"Cambridgeshire and Peterborough NHS Foundation Trust; Department of Psychiatry, University of Cambridge, UK"},{"author_name":"Masud Husain","author_inst":"Department of Experimental Psychology, University of Oxford, UK; Nuffield Department of Clinical Neurosciences, University of Oxford, UK"},{"author_name":"Emilio Fernandez-Egea","author_inst":"Cambridgeshire and Peterborough NHS Foundation Trust; Department of Psychiatry, University of Cambridge, UK"}],"rel_date":"2026-08-04","rel_site":"medrxiv"},{"rel_title":"Identifying leptospirosis hotspots in Fiji using a One Health model that incorporates watershed-scale pathogen transport","rel_doi":"10.64898\/2026.08.03.26359543","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.03.26359543","rel_abs":"Leptospirosis is a water-related zoonotic disease with complex transmission pathways, including direct transmission from infected animals and indirect transmission through contaminated soil and water. Identifying key areas to implement targeted infection prevention and control strategies is challenging, as a range of risk factors across different scales can drive human infection. We aimed to develop an epidemiological modelling approach to predict key transmission pathways driving leptospirosis infection, including risks ranging from household level factors to the movement of pathogens across watersheds. We combined a causal Bayesian network with a novel hydrological pathogen transport model to predict leptospirosis across Fiji and found key infection hotspots adjacent to rivers and within degraded watersheds; a dynamic overlooked by previous epidemiological models. We used a wide range of data for model parameterisation (e.g., expert elicitation, epidemiological surveys, and environmental data) and found that predictive validity improved when expert input on risk factors was used to guide model parameterisation, improving R2 for predicted versus observed seroprevalence from 0.71 to 0.91. Our One Health modelling approach can be used to support the design and evaluation of environment-based disease prevention strategies at national scales.","rel_num_authors":8,"rel_authors":[{"author_name":"Ama Ravindi Wakwella","author_inst":"The University of Queensland"},{"author_name":"Carissa  J Klein","author_inst":"The University of Queensland"},{"author_name":"Owen Woodberry","author_inst":"Monash University"},{"author_name":"Colleen  L Lau","author_inst":"The University of Queensland"},{"author_name":"Amelia Wenger","author_inst":"The University of Queensland"},{"author_name":"Stacy  D Jupiter","author_inst":"Wildlife Conservation Society"},{"author_name":"Aaron  P Jenkins","author_inst":"The University of Sydney"},{"author_name":"Helen  J Mayfield","author_inst":"The University of Queensland"}],"rel_date":"2026-08-04","rel_site":"medrxiv"},{"rel_title":"Inferring heterogeneous transmission and community introduction of antibiotic-resistant bacteria in hospital settings","rel_doi":"10.64898\/2026.08.02.26359521","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.02.26359521","rel_abs":"Antimicrobial-resistant organisms (AMROs) impose a major burden on healthcare systems, yet routine surveillance cannot readily distinguish colonization imported at admission from transmission acquired within hospitals. This gap is especially consequential because both processes may vary substantially across wards, while asymptomatic carriage, incomplete testing, imperfect diagnostic sensitivity, and patient movement obscure the underlying transmission dynamics. To address this challenge, we developed a blockwise agent-based iterated filter (BAIF) for inference in a patient-level transmission model on a dynamic ward co-location network. The model tracks susceptible and colonized patients as they move across wards, represents unobserved colonization histories, and incorporates the recorded testing schedule and imperfect diagnostic sensitivity. BAIF uses blockwise likelihood evaluation and resampling to estimate ward-block-specific transmission rates and importation probabilities in this high-dimensional latent system. Synthetic experiments showed that BAIF recovered these parameters from partially observed outbreaks. We then applied the framework to hospitalization and microbiological surveillance data collected from 2012 to 2016 at an urban quaternary care hospital in New York City for four AMROs. Transmission and importation were highly heterogeneous across ward blocks. Elevated transmission was repeatedly concentrated in the same ward groups, whereas blocks with the highest importation varied by pathogen. By distinguishing importation-dominated from transmission-dominated ward blocks, the framework can inform more targeted surveillance and infection-control strategies. More broadly, BAIF provides an effective inference framework for high-dimensional, partially observed agent-based models on dynamic contact networks.\n\nSignificance StatementAntimicrobial-resistant organisms can enter hospitals with already-colonized patients or spread after admission, but routine testing often cannot tell these pathways apart. Many carriers have no symptoms, are never tested, or receive imperfect test results, and patients move among wards. We developed a new modeling approach that estimates heterogeneous, ward-group-specific hospital transmission and community introduction from patient movement and surveillance data. Applied to four resistant organisms at an urban quaternary care hospital in New York City, the method revealed large differences among ward groups in both imported colonization and within-hospital spread. Distinguishing these drivers can support more targeted control, including admission screening where importation is high and stronger infection-prevention measures where transmission is elevated.","rel_num_authors":4,"rel_authors":[{"author_name":"Jifan Li","author_inst":"Texas A&M University"},{"author_name":"Qing Yao","author_inst":"Columbia University Mailman School of Public Health"},{"author_name":"Sen Pei","author_inst":"Columbia University Mailman School of Public Health"},{"author_name":"Ning Ning","author_inst":"Texas A&M University"}],"rel_date":"2026-08-04","rel_site":"medrxiv"},{"rel_title":"VPM1002 for tuberculosis prevention in India: a 1,296-compartment dynamic model with disaggregated pulmonary and extrapulmonary efficacy, Bayesian evidence synthesis, and dual-perspective health economics","rel_doi":"10.64898\/2026.07.31.26359434","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.31.26359434","rel_abs":"BackgroundTuberculosis (TB) kills 1{middle dot}3 million people annually. Global efforts focus on ending pulmonary TB (PTB); however, extrapulmonary TB (EPTB) is rising and poses significant health and economic burden. The PreVenTB Phase III trial evaluated VPM1002 in household contacts aged [&ge;]6 years across India, and did not meet its primary composite endpoint for all TB. Disaggregated prespecified secondary endpoints revealed a substantially stronger EPTB signal (vaccine efficacy 42{middle dot}3%, 95% CI -9{middle dot}1 to 69{middle dot}4, p=0{middle dot}09) in the modified intention-to-treat (mITT) population. No existing TB model translates these disaggregated hazard ratios into population-level effectiveness across heterogeneous demographics, or against a dynamic baseline accounting for ongoing National Tuberculosis Elimination Programme (NTEP)-driven incidence decline.\n\nMethodsWe developed a 1,296-compartment deterministic dynamic compartmental model (4 age x 2 HIV x 3 BMI x 3 socioeconomic strata x 18 states). Separate PTB and EPTB vaccine-efficacy posteriors were derived by Bayesian evidence synthesis of the PreVenTB trials per-protocol and mITT analyses (power-prior-adjusted conjugate normal-normal update; =0{middle dot}082) and propagated through Monte Carlo simulation (n=1,000 iterations per scenario). A dynamic no-vaccine baseline was constructed by fitting time-varying case-detection-rate CDR(t) and treatment-success-rate TSR(t) logistic curves to WHO\/NTEP data (2015 to 2024; incidence validation R2=0{middle dot}896, RMSE 4{middle dot}90 per 100,000), projecting PTB and EPTB incidence to 2050. Economic analysis used societal (value-of-statistical-life-inclusive BCR) and health-system (cost-effectiveness acceptability curves) perspectives, discounted at 3% annually.\n\nFindingsPosterior vaccine effectiveness was substantially higher against EPTB than PTB (EPTB 40{middle dot}0% [95% CI -5{middle dot}6 to 69{middle dot}1%] vs PTB 12{middle dot}8% [-19{middle dot}0 to 37{middle dot}9%]; all-TB 16{middle dot}2% [-11{middle dot}7 to 38{middle dot}6%]). EPTB accounted for 74% of deaths averted (381 of 513) and 73% of DALYs averted (5,347 of 7,308) in the 10-year\/dynamic scenario. EPTB cases averted exceeded PTB and concurrent disease combined in every scenario. Mean cases averted ranged from 2,047 (3-year protection, dynamic baseline) to 3,394 (10-year, static) per 1,000,000 vaccinated; mean disability-adjusted life years (DALYs) averted ranged from 4,792 to 8,125. The benefit-cost ratio (BCR; societal perspective) ranged from 3{middle dot}4 (3-year protection, dynamic baseline) to 8{middle dot}2 (10-year protection, static baseline), exceeding break-even in every scenario. Median gross incremental cost-effectiveness ratio (ICER) ranged from US$647 (10-year static) to US$1,568 (3-year dynamic) per DALY averted, below Indias 3x gross domestic product (GDP)-per-capita threshold (approximately US$8,084) in every scenario.\n\nInterpretationThis 1,296-compartment model provides the first dynamically-baselined, dual-perspective health-economic evaluation of VPM1002 to separately track pulmonary and extrapulmonary outcomes. EPTB protection is VPM1002s proportionally larger and more statistically reliable efficacy signal and drives a majority of averted cases, mortality, and DALYs. Policy assessments anchored to composite pulmonary endpoints systematically underestimate this vaccines population value.\n\nFundingIn part funded by Serum Life Science Europe GmbH.\n\nResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed and preprint servers (medRxiv, bioRxiv) up to July 17, 2026, using various combinations of the terms \"tuberculosis vaccine model\", \"LMICs\", \"TB vaccine cost-effectiveness\", \"VPM1002\", \"pulmonary and extrapulmonary tuberculosis (E\/PTB) model\", and \"TB dynamic transmission model India\". Searches returned 4 to 313 results depending on the term combination used; references were screened by title and abstract for relevance to TB vaccine modelling, cost-effectiveness, or EPTB. Existing TB vaccine modelling studies for India and other high-burden low- and middle-income countries (LMICs) have relied on aggregate vaccine efficacy estimates combining PTB and EPTB into a single endpoint. Landmark analyses by Clark, Yerramsetti, Harris, and Weerasuriya and colleagues used efficacy assumptions derived primarily from M72\/AS01{square} or BCG-revaccination trials, in adults or paediatric models, none of which reported disaggregated PTB or EPTB outcomes. Models have assumed homogeneous mixing and evaluated vaccine impact against static programmatic baselines. No published model has tracked EPTB as a separate disease compartment, stratified impact simultaneously by age, HIV status, BMI, and socioeconomic status (SES), or projected impact against a dynamic NTEP trajectory calibrated to observed incidence data.\n\nAdded value of this studyThis 1,296-compartment model is the first to propagate disaggregated PTB and EPTB VPM1002 efficacy posteriors, derived by Bayesian evidence synthesis of the PreVenTB Phase III trial, through a stratified population model. We construct a dynamic no-vaccine baseline calibrated to WHO\/NTEP data from 2015 to 2024, enabling marginal vaccine impact to be expressed against a realistically declining programmatic trajectory. Dual-perspective economic outputs (societal benefit-cost ratio and health-system incremental cost-effectiveness ratio) are reported alongside cost-effectiveness acceptability curves. The model shows that EPTB accounts for the majority of averted cases, deaths, and DALYs across all scenarios, a finding that is indiscernible in models using composite efficacy endpoints.\n\nImplications of all the available evidenceVPM1002 is cost-effective at conventional willingness-to-pay thresholds in every modelled scenario. The EPTB-specific efficacy signal, statistically more reliable than the composite endpoint and consistent with VPM1002s mechanism of action, drives a disproportionate share of averted mortality and DALY burden. Policy assessments relying solely on composite pulmonary endpoints will underestimate this vaccines population value. The framework is directly relevant to National Technical Advisory Group on Immunisation (NTAGI) deliberations and Health Technology Assessment in India (HTAIn) appraisals, and is extensible to other high-burden LMICs and TB vaccine candidates.","rel_num_authors":5,"rel_authors":[{"author_name":"M. Revathy","author_inst":"Narsee Monjee Institute of Management Studies, Bengaluru, India"},{"author_name":"Vidya Niranjan","author_inst":"MIT Vishwaprayag University, Solapur, Maharashtra, India"},{"author_name":"Varun Swaminathan","author_inst":"Aseesa Inc."},{"author_name":"Alessandro Carrese","author_inst":"Aseesa Inc."},{"author_name":"Aditi Bhargava","author_inst":"Aseesa Inc., and UCSF"}],"rel_date":"2026-08-03","rel_site":"medrxiv"},{"rel_title":"Effects of Social Prescribing on Mental, Physical, and Social Health Outcomes: A Systematic Review and Meta-Analysis of Randomised Trials","rel_doi":"10.64898\/2026.08.02.26359484","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.02.26359484","rel_abs":"ImportanceSocial prescribing is implemented to address unmet social needs and improve health, but expansion has outpaced evidence from randomized trials.\n\nObjectiveTo quantify the effects of social prescribing on mental, physical, and social health outcomes in adults.\n\nData SourcesMedline, Embase, Cochrane Central, AMED, CINAHL, PsycInfo, Web of Science, NHS EED, CEA registry, clinicaltrials.gov, OpenGrey, and WHO ICTRP (English language). Trials published from 1992 through 2022 were identified from 23 reviews, supplemented by searches from January 2023 through September 2025.\n\nStudy SelectionRandomized trials comparing usual care or waitlist with interventions facilitating connection to community-based resources delivered by non-health care professionals.\n\nData Extraction and SynthesisPairs of reviewers screened studies, extracted data, and assessed risk of bias using Cochrane Risk of Bias 2. Random-effects meta-analyses pooled mean differences or standardized mean differences as Hedges g with 95% CIs.\n\nMain Outcomes and MeasuresMental health, blood pressure, metabolic and anthropometric outcomes, physical activity, loneliness and social isolation, quality of life, health care use, and adverse events.\n\nResultsThirty-three randomized trials involving 13 714 participants were included. High risk of bias was identified in 40% of trials. Social prescribing was associated with reduced depressive symptoms (7 trials; 1087 participants; standardized mean difference [SMD], -0.23; 95% CI, -0.38 to -0.08), lower systolic blood pressure (11 trials; 2817 participants; mean difference, -2.69 mm Hg; 95% CI, -5.36 to -0.02), increased physical activity (7 trials; 3409 participants; SMD, 0.16; 95% CI, 0.06-0.25), and improved quality of life (10 trials; 3134 participants; SMD, 0.15; 95% CI, 0.01-0.29). No clear benefit was found for anxiety, loneliness and social isolation, glycemic control, blood lipids, anthropometric outcomes, or health care use. One trial reported a process evaluation, 7 included economic evaluations, and adverse events were infrequently reported.\n\nConclusions and RelevanceSocial prescribing was associated with modest improvements in depressive symptoms, systolic blood pressure, physical activity, and quality of life. Evidence was lacking for other claimed benefits, and process and economic evaluations were uncommon, identifying priorities for future trials.\n\nKEY POINTSO_ST_ABSQuestionC_ST_ABSWhat are the effects of social prescribing on mental, physical, and social health outcomes in adults?\n\nFindingsIn this systematic review and meta-analysis of 33 randomized clinical trials involving 13 714 participants, social prescribing was associated with modest improvements in depressive symptoms, systolic blood pressure, physical activity, and quality of life. There was no clear evidence of benefit for anxiety, loneliness and social isolation, glycemic control, blood lipids, anthropometric outcomes, or health care use; process evaluations, economic evaluations, and analyses of mechanisms were largely absent.\n\nMeaningSocial prescribing may improve selected health outcomes, but randomized trial evidence does not support many of the broader benefits commonly attributed to these interventions. More rigorous evaluation of effectiveness, safety, costs, and mechanisms is needed to support robust, equitable, and sustainable implementation.","rel_num_authors":8,"rel_authors":[{"author_name":"Xiaoqi Feng","author_inst":"UNSW"},{"author_name":"Raju Kanukula","author_inst":"University of Sydney"},{"author_name":"Nicole Evangelidis","author_inst":"University of Sydney"},{"author_name":"Bruce Neal","author_inst":"The George Institute for Global Health"},{"author_name":"Patricia Davidson","author_inst":"UNSW"},{"author_name":"Bogda Koczwara","author_inst":"UNSW"},{"author_name":"Kheng Hock Lee","author_inst":"SingHealth"},{"author_name":"Thomas Astell-Burt","author_inst":"University of Sydney"}],"rel_date":"2026-08-03","rel_site":"medrxiv"},{"rel_title":"Effects of Social Prescribing on Mental, Physical, and Social Health Outcomes: A Systematic Review and Meta-Analysis of Randomised Trials","rel_doi":"10.64898\/2026.08.02.26359484","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.02.26359484","rel_abs":"ImportanceSocial prescribing is implemented to address unmet social needs and improve health, but expansion has outpaced evidence from randomized trials.\n\nObjectiveTo quantify the effects of social prescribing on mental, physical, and social health outcomes in adults.\n\nData SourcesMedline, Embase, Cochrane Central, AMED, CINAHL, PsycInfo, Web of Science, NHS EED, CEA registry, clinicaltrials.gov, OpenGrey, and WHO ICTRP (English language). Trials published from 1992 through 2022 were identified from 23 reviews, supplemented by searches from January 2023 through September 2025.\n\nStudy SelectionRandomized trials comparing usual care or waitlist with interventions facilitating connection to community-based resources delivered by non-health care professionals.\n\nData Extraction and SynthesisPairs of reviewers screened studies, extracted data, and assessed risk of bias using Cochrane Risk of Bias 2. Random-effects meta-analyses pooled mean differences or standardized mean differences as Hedges g with 95% CIs.\n\nMain Outcomes and MeasuresMental health, blood pressure, metabolic and anthropometric outcomes, physical activity, loneliness and social isolation, quality of life, health care use, and adverse events.\n\nResultsThirty-three randomized trials involving 13 714 participants were included. High risk of bias was identified in 40% of trials. Social prescribing was associated with reduced depressive symptoms (7 trials; 1087 participants; standardized mean difference [SMD], -0.23; 95% CI, -0.38 to -0.08), lower systolic blood pressure (11 trials; 2817 participants; mean difference, -2.69 mm Hg; 95% CI, -5.36 to -0.02), increased physical activity (7 trials; 3409 participants; SMD, 0.16; 95% CI, 0.06-0.25), and improved quality of life (10 trials; 3134 participants; SMD, 0.15; 95% CI, 0.01-0.29). No clear benefit was found for anxiety, loneliness and social isolation, glycemic control, blood lipids, anthropometric outcomes, or health care use. One trial reported a process evaluation, 7 included economic evaluations, and adverse events were infrequently reported.\n\nConclusions and RelevanceSocial prescribing was associated with modest improvements in depressive symptoms, systolic blood pressure, physical activity, and quality of life. Evidence was lacking for other claimed benefits, and process and economic evaluations were uncommon, identifying priorities for future trials.\n\nKEY POINTSO_ST_ABSQuestionC_ST_ABSWhat are the effects of social prescribing on mental, physical, and social health outcomes in adults?\n\nFindingsIn this systematic review and meta-analysis of 33 randomized clinical trials involving 13 714 participants, social prescribing was associated with modest improvements in depressive symptoms, systolic blood pressure, physical activity, and quality of life. There was no clear evidence of benefit for anxiety, loneliness and social isolation, glycemic control, blood lipids, anthropometric outcomes, or health care use; process evaluations, economic evaluations, and analyses of mechanisms were largely absent.\n\nMeaningSocial prescribing may improve selected health outcomes, but randomized trial evidence does not support many of the broader benefits commonly attributed to these interventions. More rigorous evaluation of effectiveness, safety, costs, and mechanisms is needed to support robust, equitable, and sustainable implementation.","rel_num_authors":8,"rel_authors":[{"author_name":"Xiaoqi Feng","author_inst":"UNSW"},{"author_name":"Raju Kanukula","author_inst":"University of Sydney"},{"author_name":"Nicole Evangelidis","author_inst":"University of Sydney"},{"author_name":"Bruce Neal","author_inst":"The George Institute for Global Health"},{"author_name":"Patricia Davidson","author_inst":"UNSW"},{"author_name":"Bogda Koczwara","author_inst":"UNSW"},{"author_name":"Kheng Hock Lee","author_inst":"SingHealth"},{"author_name":"Thomas Astell-Burt","author_inst":"University of Sydney"}],"rel_date":"2026-08-03","rel_site":"medrxiv"},{"rel_title":"An Integrative Multimodal Model for Early Diagnosis of Dementia and Differential Diagnosis of Alzheimer's Disease Using Neuroimaging, Polygenic Risk, and Cognitive Assessments","rel_doi":"10.64898\/2026.07.31.26359317","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.31.26359317","rel_abs":"BackgroundEarly diagnosis and etiological classification of dementia remain challenging, as clinicians typically lack tools to integrate cognitive, neuroimaging, and genetic data quantitatively. We developed and validated multimodal risk models to support early diagnosis of dementia and differential diagnosis of Alzheimers disease (AD) versus non-AD dementias in real-world clinical settings and translated model outputs into individualized risk reports.\n\nMethodsUtilizing real-world clinical cohorts (n = 1,100 for early diagnosis of dementia, using clinical diagnoses up to three years after clinical assessment; n = 788 for AD differential diagnosis) from Norwegian Memory Clinics, we trained and validated the Multimodal Hazard Score for Real-World Data (MHS-RWD) model integrating demographics (age, sex), cognitive assessments (MMSE-NR3 or CERAD 10-word delayed recall), the MRI-derived Imaging Hazard Score, and the Polygenic Hazard Score. Discrimination performance was examined using the area under the receiver operating characteristic curve (AUC).\n\nResultsIn real-world clinical data, the MHS-RWD consistently outperformed any single predictor used alone. For early diagnosis of dementia, the full model achieved an AUC of 0.89 in females and 0.84 in males. For the differential diagnosis of AD from other dementias, the multimodal model yielded an AUC of 0.91 in females and 0.83 in males. A patient-level risk report was designed to present individualized risk estimates.\n\nConclusionsMultimodal integration of cognitive, neuroimaging, and polygenic data in the MHS-RWD tool yields strong discrimination for both early diagnosis of dementia and AD differential diagnosis. The tool relies on data obtainable in clinical care, and genetic information that is becoming increasingly available in routine practice. Delivered through intuitive patient-level risk reports, it could support etiologically informed dementia decisions in real-world settings, with potential utility in primary care.","rel_num_authors":18,"rel_authors":[{"author_name":"Tahir Tekin Filiz","author_inst":"Centre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway"},{"author_name":"Vera Fominykh","author_inst":"Centre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway"},{"author_name":"Karin Persson","author_inst":"Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway"},{"author_name":"Mona Michelet","author_inst":"Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway"},{"author_name":"Iris J. Broce","author_inst":"Center for Multimodal Imaging and Genetics, J. Craig Venter Institute, La Jolla, CA, USA"},{"author_name":"Ingrid T\u00f8ndel Medb\u00f8en","author_inst":"Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway"},{"author_name":"Stina Aam","author_inst":"Department of Geriatric Medicine, Clinic of Medicine, St. Olav's University Hospital, Trondheim, Norway"},{"author_name":"Alexey Shadrin","author_inst":"Centre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway"},{"author_name":"Dag Aln\u00e6s","author_inst":"Centre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway"},{"author_name":"Lavinia Athanasiu","author_inst":"Centre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway"},{"author_name":"Xin Wang","author_inst":"Department of Neurosciences, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Gisele Sanda","author_inst":"Department of Neurosciences, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Ingvild Tina Saltvedt","author_inst":"Department of Geriatric Medicine, Clinic of Medicine, St. Olav's University Hospital, Trondheim, Norway"},{"author_name":"Anne-Brita Knapskog","author_inst":"Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway"},{"author_name":"Geir Selb\u00e6k","author_inst":"Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway"},{"author_name":"Anders M. Dale","author_inst":"Department of Neurosciences, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Ole A. Andreassen","author_inst":"Centre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway"},{"author_name":"Oleksandr Frei","author_inst":"Centre for Precision Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway"}],"rel_date":"2026-08-03","rel_site":"medrxiv"},{"rel_title":"Electroencephalographic Transient Beta Event Rates in Autism and Related Neurogenetic Conditions","rel_doi":"10.64898\/2026.08.02.26359366","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.02.26359366","rel_abs":"Transient beta events (TBE) during electroencephalography (EEG) reflect thalamocortical activity, bridging genotype to phenotype and impacting sensory responsivity. Compared to typically developing controls, we found elevated TBE rate in some children with idiopathic Autism Spectrum Disorder (ASD) and a majority of children with Phelan-McDermid Syndrome, Rett Syndrome, and SYNGAP1-related disorder. TBE rate thus offers promise as a stratification biomarker with divergent and convergent properties across ASD and neurogenetic conditions, respectively.","rel_num_authors":52,"rel_authors":[{"author_name":"Gerardo Parra","author_inst":"Boston Children's Hospital"},{"author_name":"Klara Szilagyi","author_inst":"Boston Children's Hospital"},{"author_name":"Yael Braverman","author_inst":"Boston Children's Hospital"},{"author_name":"Devorah Kranz","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"E Martina Bebin","author_inst":"University of Alabama School of Medicine"},{"author_name":"Raphael A Bernier","author_inst":"University of Washington"},{"author_name":"Jonathan A Bernstein","author_inst":"Stanford University School of Medicine"},{"author_name":"Elizabeth Berry-Kravis","author_inst":"Rush University Medical Center"},{"author_name":"Joseph D Buxbaum","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Katarzyna Chawarska","author_inst":"Yale University"},{"author_name":"Emma E Condy","author_inst":"National Institutes of Health"},{"author_name":"Laura Cornelissen","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Geraldine Dawson","author_inst":"Duke University"},{"author_name":"Abigail Dickinson","author_inst":"University of California, Los Angeles"},{"author_name":"James Dziura","author_inst":"Yale University"},{"author_name":"Charis Eng","author_inst":"Cleveland Clinic; Lerner College of Medicine of Case Western Reserve University"},{"author_name":"Susan Faja","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Jennifer H Foss-Feig","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Antonio Y Hardan","author_inst":"Stanford University"},{"author_name":"Ellen Hanson","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Shafali Jeste","author_inst":"University of California, Los Angeles"},{"author_name":"Linnea Joffe-Nelson","author_inst":"Boston Children's Hospital"},{"author_name":"Alexander Kolevzon","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Darcy A Krueger","author_inst":"Cincinnati Children's Hospital Medical Center; University of Cincinnati College of Medicine"},{"author_name":"Balu Krishnan","author_inst":"Cleveland Clinic"},{"author_name":"Robert Law","author_inst":"Boston Children's Hospital"},{"author_name":"David N Lieberman","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Claire MacKay","author_inst":"Boston Children's Hospital"},{"author_name":"Julian A Martinez-Agosto","author_inst":"David Geffen School of Medicine, University of California, Los Angeles"},{"author_name":"Adam J Naples","author_inst":"Yale University"},{"author_name":"Charles A Nelson","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Hope Northrup","author_inst":"McGovern Medical School, University of Texas Health Science Center at Houston"},{"author_name":"Ernest Pedapati","author_inst":"Cincinnati Children's Hospital Medical Center; University of Cincinnati College of Medicine"},{"author_name":"Annapurna Poduri","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Vineet Punia","author_inst":"Cleveland Clinic"},{"author_name":"Rajsekar R Rajaraman","author_inst":"UCLA Mattel Children's Hospital, David Geffen School of Medicine"},{"author_name":"David M Ritter","author_inst":"Cincinnati Children's Hospital Medical Center; University of Cincinnati College of Medicine"},{"author_name":"Celine Saulnier","author_inst":"Neurodevelopmental Assessment and Consulting Services"},{"author_name":"Frederick Shic","author_inst":"Seattle Children's Research Institute; University of Washington"},{"author_name":"Latha Valluripalli Soorya","author_inst":"Rush University Medical Center"},{"author_name":"Catherine A Sugar","author_inst":"University of California, Los Angeles"},{"author_name":"Kyle E Takach","author_inst":"Boston Children's Hospital; Loyola Medical School"},{"author_name":"Audrey Thurm","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Sara J Webb","author_inst":"Seattle Children's Research Institute"},{"author_name":"Kimberly Wiltrout","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Damla \u015eent\u00fcrk","author_inst":"University of California, Los Angeles"},{"author_name":"Jeffrey P Gavornik","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Stephanie Jones","author_inst":"Brown University; Providence VA Medical Center"},{"author_name":"Michela Fagiolini","author_inst":"Boston Children's Hospital; Harvard Medical School; Hock E. Tan and K. Lisa Yang Center for Autism Research at Harvard University; International Research Center"},{"author_name":"James C McPartland","author_inst":"Yale University"},{"author_name":"Mustafa Sahin","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"April R Levin","author_inst":"Boston Children's Hospital; Harvard Medical School"}],"rel_date":"2026-08-03","rel_site":"medrxiv"},{"rel_title":"Electroencephalographic Transient Beta Event Rates in Autism and Related Neurogenetic Conditions","rel_doi":"10.64898\/2026.08.02.26359366","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.02.26359366","rel_abs":"Transient beta events (TBE) during electroencephalography (EEG) reflect thalamocortical activity, bridging genotype to phenotype and impacting sensory responsivity. Compared to typically developing controls, we found elevated TBE rate in some children with idiopathic Autism Spectrum Disorder (ASD) and a majority of children with Phelan-McDermid Syndrome, Rett Syndrome, and SYNGAP1-related disorder. TBE rate thus offers promise as a stratification biomarker with divergent and convergent properties across ASD and neurogenetic conditions, respectively.","rel_num_authors":52,"rel_authors":[{"author_name":"Gerardo Parra","author_inst":"Boston Children's Hospital"},{"author_name":"Klara Szilagyi","author_inst":"Boston Children's Hospital"},{"author_name":"Yael Braverman","author_inst":"Boston Children's Hospital"},{"author_name":"Devorah Kranz","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"E Martina Bebin","author_inst":"University of Alabama School of Medicine"},{"author_name":"Raphael A Bernier","author_inst":"University of Washington"},{"author_name":"Jonathan A Bernstein","author_inst":"Stanford University School of Medicine"},{"author_name":"Elizabeth Berry-Kravis","author_inst":"Rush University Medical Center"},{"author_name":"Joseph D Buxbaum","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Katarzyna Chawarska","author_inst":"Yale University"},{"author_name":"Emma E Condy","author_inst":"National Institutes of Health"},{"author_name":"Laura Cornelissen","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Geraldine Dawson","author_inst":"Duke University"},{"author_name":"Abigail Dickinson","author_inst":"University of California, Los Angeles"},{"author_name":"James Dziura","author_inst":"Yale University"},{"author_name":"Charis Eng","author_inst":"Cleveland Clinic; Lerner College of Medicine of Case Western Reserve University"},{"author_name":"Susan Faja","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Jennifer H Foss-Feig","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Antonio Y Hardan","author_inst":"Stanford University"},{"author_name":"Ellen Hanson","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Shafali Jeste","author_inst":"University of California, Los Angeles"},{"author_name":"Linnea Joffe-Nelson","author_inst":"Boston Children's Hospital"},{"author_name":"Alexander Kolevzon","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Darcy A Krueger","author_inst":"Cincinnati Children's Hospital Medical Center; University of Cincinnati College of Medicine"},{"author_name":"Balu Krishnan","author_inst":"Cleveland Clinic"},{"author_name":"Robert Law","author_inst":"Boston Children's Hospital"},{"author_name":"David N Lieberman","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Claire MacKay","author_inst":"Boston Children's Hospital"},{"author_name":"Julian A Martinez-Agosto","author_inst":"David Geffen School of Medicine, University of California, Los Angeles"},{"author_name":"Adam J Naples","author_inst":"Yale University"},{"author_name":"Charles A Nelson","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Hope Northrup","author_inst":"McGovern Medical School, University of Texas Health Science Center at Houston"},{"author_name":"Ernest Pedapati","author_inst":"Cincinnati Children's Hospital Medical Center; University of Cincinnati College of Medicine"},{"author_name":"Annapurna Poduri","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Vineet Punia","author_inst":"Cleveland Clinic"},{"author_name":"Rajsekar R Rajaraman","author_inst":"UCLA Mattel Children's Hospital, David Geffen School of Medicine"},{"author_name":"David M Ritter","author_inst":"Cincinnati Children's Hospital Medical Center; University of Cincinnati College of Medicine"},{"author_name":"Celine Saulnier","author_inst":"Neurodevelopmental Assessment and Consulting Services"},{"author_name":"Frederick Shic","author_inst":"Seattle Children's Research Institute; University of Washington"},{"author_name":"Latha Valluripalli Soorya","author_inst":"Rush University Medical Center"},{"author_name":"Catherine A Sugar","author_inst":"University of California, Los Angeles"},{"author_name":"Kyle E Takach","author_inst":"Boston Children's Hospital; Loyola Medical School"},{"author_name":"Audrey Thurm","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Sara J Webb","author_inst":"Seattle Children's Research Institute"},{"author_name":"Kimberly Wiltrout","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Damla \u015eent\u00fcrk","author_inst":"University of California, Los Angeles"},{"author_name":"Jeffrey P Gavornik","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Stephanie Jones","author_inst":"Brown University; Providence VA Medical Center"},{"author_name":"Michela Fagiolini","author_inst":"Boston Children's Hospital; Harvard Medical School; Hock E. Tan and K. Lisa Yang Center for Autism Research at Harvard University; International Research Center"},{"author_name":"James C McPartland","author_inst":"Yale University"},{"author_name":"Mustafa Sahin","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"April R Levin","author_inst":"Boston Children's Hospital; Harvard Medical School"}],"rel_date":"2026-08-03","rel_site":"medrxiv"},{"rel_title":"Electroencephalographic Transient Beta Event Rates in Autism and Related Neurogenetic Conditions","rel_doi":"10.64898\/2026.08.02.26359366","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.02.26359366","rel_abs":"Transient beta events (TBE) during electroencephalography (EEG) reflect thalamocortical activity, bridging genotype to phenotype and impacting sensory responsivity. Compared to typically developing controls, we found elevated TBE rate in some children with idiopathic Autism Spectrum Disorder (ASD) and a majority of children with Phelan-McDermid Syndrome, Rett Syndrome, and SYNGAP1-related disorder. TBE rate thus offers promise as a stratification biomarker with divergent and convergent properties across ASD and neurogenetic conditions, respectively.","rel_num_authors":52,"rel_authors":[{"author_name":"Gerardo Parra","author_inst":"Boston Children's Hospital"},{"author_name":"Klara Szilagyi","author_inst":"Boston Children's Hospital"},{"author_name":"Yael Braverman","author_inst":"Boston Children's Hospital"},{"author_name":"Devorah Kranz","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"E Martina Bebin","author_inst":"University of Alabama School of Medicine"},{"author_name":"Raphael A Bernier","author_inst":"University of Washington"},{"author_name":"Jonathan A Bernstein","author_inst":"Stanford University School of Medicine"},{"author_name":"Elizabeth Berry-Kravis","author_inst":"Rush University Medical Center"},{"author_name":"Joseph D Buxbaum","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Katarzyna Chawarska","author_inst":"Yale University"},{"author_name":"Emma E Condy","author_inst":"National Institutes of Health"},{"author_name":"Laura Cornelissen","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Geraldine Dawson","author_inst":"Duke University"},{"author_name":"Abigail Dickinson","author_inst":"University of California, Los Angeles"},{"author_name":"James Dziura","author_inst":"Yale University"},{"author_name":"Charis Eng","author_inst":"Cleveland Clinic; Lerner College of Medicine of Case Western Reserve University"},{"author_name":"Susan Faja","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Jennifer H Foss-Feig","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Antonio Y Hardan","author_inst":"Stanford University"},{"author_name":"Ellen Hanson","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Shafali Jeste","author_inst":"University of California, Los Angeles"},{"author_name":"Linnea Joffe-Nelson","author_inst":"Boston Children's Hospital"},{"author_name":"Alexander Kolevzon","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Darcy A Krueger","author_inst":"Cincinnati Children's Hospital Medical Center; University of Cincinnati College of Medicine"},{"author_name":"Balu Krishnan","author_inst":"Cleveland Clinic"},{"author_name":"Robert Law","author_inst":"Boston Children's Hospital"},{"author_name":"David N Lieberman","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Claire MacKay","author_inst":"Boston Children's Hospital"},{"author_name":"Julian A Martinez-Agosto","author_inst":"David Geffen School of Medicine, University of California, Los Angeles"},{"author_name":"Adam J Naples","author_inst":"Yale University"},{"author_name":"Charles A Nelson","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Hope Northrup","author_inst":"McGovern Medical School, University of Texas Health Science Center at Houston"},{"author_name":"Ernest Pedapati","author_inst":"Cincinnati Children's Hospital Medical Center; University of Cincinnati College of Medicine"},{"author_name":"Annapurna Poduri","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Vineet Punia","author_inst":"Cleveland Clinic"},{"author_name":"Rajsekar R Rajaraman","author_inst":"UCLA Mattel Children's Hospital, David Geffen School of Medicine"},{"author_name":"David M Ritter","author_inst":"Cincinnati Children's Hospital Medical Center; University of Cincinnati College of Medicine"},{"author_name":"Celine Saulnier","author_inst":"Neurodevelopmental Assessment and Consulting Services"},{"author_name":"Frederick Shic","author_inst":"Seattle Children's Research Institute; University of Washington"},{"author_name":"Latha Valluripalli Soorya","author_inst":"Rush University Medical Center"},{"author_name":"Catherine A Sugar","author_inst":"University of California, Los Angeles"},{"author_name":"Kyle E Takach","author_inst":"Boston Children's Hospital; Loyola Medical School"},{"author_name":"Audrey Thurm","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Sara J Webb","author_inst":"Seattle Children's Research Institute"},{"author_name":"Kimberly Wiltrout","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Damla \u015eent\u00fcrk","author_inst":"University of California, Los Angeles"},{"author_name":"Jeffrey P Gavornik","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"Stephanie Jones","author_inst":"Brown University; Providence VA Medical Center"},{"author_name":"Michela Fagiolini","author_inst":"Boston Children's Hospital; Harvard Medical School; Hock E. Tan and K. Lisa Yang Center for Autism Research at Harvard University; International Research Center"},{"author_name":"James C McPartland","author_inst":"Yale University"},{"author_name":"Mustafa Sahin","author_inst":"Boston Children's Hospital; Harvard Medical School"},{"author_name":"April R Levin","author_inst":"Boston Children's Hospital; Harvard Medical School"}],"rel_date":"2026-08-03","rel_site":"medrxiv"},{"rel_title":"Household Transmission of Human Metapneumovirus and Human Parainfluenza Viruses 1-4 in the United States, 2022-2024","rel_doi":"10.64898\/2026.08.02.26359491","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.08.02.26359491","rel_abs":"Human metapneumovirus (HMPV) and human parainfluenza viruses (HPIV-1-4) are common causes of seasonal respiratory illness, but their household transmission dynamics remain poorly defined. We analyzed weekly symptom data and nasal swabs from a prospective household surveillance study in Washington and Oregon from June 2022-March 2024. Swabs were tested for HMPV and HPIV, and a subset underwent whole-genome sequencing. Distinct index cases occurred in 236 (23%) and 341 (36%) of 1,040 households for HMPV and HPIV, respectively. Household secondary attack rates (SAR) and median generation times were similar for HMPV (8.7%, 7 days) and HPIV (7.3%, 7 days). Sequenced samples reflected contemporaneous circulating strains during the same period, with household sequences clustering closely together. High-quality viral whole genome sequences were recovered for two or more individuals within a household in a total of 26 households for HMPV and 45 households for HPIV. Intra-household pairwise nucleotide (nt) distance ranged from 0 to 14 nt (median 0) for HMPV and 0-8 nt (median 1) for HPIV when cases occurred 0-15 days apart. Transmission occurred primarily from children to adults, emphasizing the importance of childcare-and school-associated spread and supporting child-focused prevention strategies to reduce household transmission.","rel_num_authors":31,"rel_authors":[{"author_name":"Pavitra Roychoudhury","author_inst":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, "},{"author_name":"Anna Elias-Warren","author_inst":"Departments of Medicine and Epidemiology, University of Washington, Seattle, WA"},{"author_name":"Erica Wetzler","author_inst":"Departments of Medicine and Epidemiology, University of Washington, Seattle, WA"},{"author_name":"Hyeong Geon Kim","author_inst":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA"},{"author_name":"Kevin Kong","author_inst":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA"},{"author_name":"Hong Xie","author_inst":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA"},{"author_name":"Cassey Spring","author_inst":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA"},{"author_name":"Margaret G. Mills","author_inst":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA"},{"author_name":"Alex Harteloo","author_inst":"Departments of Medicine and Epidemiology, University of Washington, Seattle, WA"},{"author_name":"Collrane Frivold","author_inst":"Departments of Medicine and Epidemiology, University of Washington, Seattle, WA"},{"author_name":"Madison Hollcroft","author_inst":"Departments of Medicine and Epidemiology, University of Washington, Seattle, WA"},{"author_name":"Mark Drummond","author_inst":"Departments of Medicine and Epidemiology, University of Washington, Seattle, WA"},{"author_name":"Tara Hatchie","author_inst":"Departments of Medicine and Epidemiology, University of Washington, Seattle, WA"},{"author_name":"Erica Clark","author_inst":"Departments of Medicine and Epidemiology, University of Washington, Seattle, WA"},{"author_name":"Brenna Ehmen","author_inst":"Brotman Baty Institute for Precision Medicine, Seattle, WA"},{"author_name":"Peter D. Han","author_inst":"Brotman Baty Institute for Precision Medicine, Seattle, WA"},{"author_name":"Luis Gamboa","author_inst":"Brotman Baty Institute for Precision Medicine, Seattle, WA"},{"author_name":"Sally Grindstaff","author_inst":"Brotman Baty Institute for Precision Medicine, Seattle, WA"},{"author_name":"Jeremy Stone","author_inst":"Brotman Baty Institute for Precision Medicine, Seattle, WA"},{"author_name":"Katherine L. Hoffman","author_inst":"Department of Biostatistics, University of Washington, Seattle, WA"},{"author_name":"Alexander L. Greninger","author_inst":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, "},{"author_name":"Lea M. Starita","author_inst":"Brotman Baty Institute for Precision Medicine, Seattle, WA"},{"author_name":"Christina Lockwood","author_inst":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA"},{"author_name":"Janet A. Englund","author_inst":"Department of Pediatrics, University of Washington, and Seattle Children's Research Institute"},{"author_name":"Ana A. Weil","author_inst":"Departments of Medicine and Epidemiology, University of Washington, Seattle, WA"},{"author_name":"Sacha L. Reich","author_inst":"Kaiser Permanente Center for Health Research, Portland, OR"},{"author_name":"Richard A. Mularski","author_inst":"Kaiser Permanente Center for Health Research, Portland, OR"},{"author_name":"Mark A. Schmidt","author_inst":"Kaiser Permanente Center for Health Research, Portland, OR"},{"author_name":"Jennifer L. Kuntz","author_inst":"Kaiser Permanente Center for Health Research, Portland, OR"},{"author_name":"Allison L. Naleway","author_inst":"Kaiser Permanente Center for Health Research, Portland, OR"},{"author_name":"Helen Y. Chu","author_inst":"Departments of Medicine and Epidemiology, University of Washington, Seattle, WA"}],"rel_date":"2026-08-03","rel_site":"medrxiv"},{"rel_title":"Harmonized Carceral Mortality Database: a dataset on mortality in state-operated correctional facilities","rel_doi":"10.64898\/2026.07.29.26359256","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.29.26359256","rel_abs":"Documenting and measuring mortality in correctional facilities is essential for understanding the health consequences of incarceration, identifying preventable deaths, and informing policy interventions. We undertook a compilation of publicly available mortality records in state-operated correctional facilities, encompassing data gathered from administrative, nonprofit, and public records. The Harmonized Carceral Mortality Database (HCMD) standardizes decedent characteristics, facility identifiers, locations, dates of death, and causes of death to enable epidemiologic analyses of mortality in U.S. prisons, outside of federal reporting. At the time of writing, the HCMD includes 49,682 deaths from at least 1,089 prisons in 50 states, spanning 1996 - 2024, with regular updates annually. The HCMD supports carceral health research across a range of disciplines from environmental health to sociology to criminology and supports use beyond the scientific community, including journalists, lawyers, and community-based organizers.","rel_num_authors":3,"rel_authors":[{"author_name":"Ufuoma Ovienmhada","author_inst":"University of Arizona"},{"author_name":"Gabriela Daza","author_inst":"Columbia University"},{"author_name":"Robbie Parks","author_inst":"Columbia University"}],"rel_date":"2026-08-03","rel_site":"medrxiv"},{"rel_title":"Beyond the Red Complex: De Novo Marker Discovery Uncovers Novel Periodontitis-Associated Taxa and Enables Non-Invasive Machine Learning Diagnosis","rel_doi":"10.64898\/2026.07.31.26359396","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.31.26359396","rel_abs":"BackgroundPeriodontitis affects over 1 billion people worldwide, yet diagnosis relies on clinical measures that capture tissue destruction rather than underlying microbial dysbiosis. Most microbial-biomarker studies use 16S rRNA sequencing or reference-database mapping, systematically under-detecting uncultivated or divergent taxa.\n\nMethodsWe assembled 341 supra- and subgingival shotgun metagenomes (218 periodontitis, 123 health) across nine countries\/regions. Using MetaMarker, a de novo, reference-free pipeline, we identified conserved genomic markers directly from reads in a 305-sample discovery pool without database mapping. Markers were taxonomically annotated against the Human Oral Microbiome Database, functionally annotated with Prodigal\/eggNOG-mapper, and used for eight machine-learning classifiers, externally validated on three independent held-out cohorts (36 samples).\n\nResultsWe recovered 2,142 significant markers (1,999 periodontitis-enriched, 143 health-enriched; q<0.05), recapitulating the canonical red\/orange-complex dysbiotic shift. Beyond established pathogens, 128 periodontitis markers (6.4%) were novel, including an uncultivated Paludibacteraceae genus and divergent Fretibacterium fastidiosum strains. Case markers encoded a coherent virulence programme spanning proteolysis, haem\/iron acquisition, and Type IX secretion. On external validation, boosted-tree classifiers generalized best (XGBoost and gradient boosting, AUC=0.96), and a compact SHAP-ranked 20-marker panel spanning five taxa reproduced full-set directionality.\n\nConclusionsReference-free metagenomic marker discovery recovers known periodontal pathobiology while revealing unrecognized candidate biomarkers and supports an accurate, externally validated, non-invasive classifier with translational potential as a compact diagnostic panel.","rel_num_authors":2,"rel_authors":[{"author_name":"Mohamad Koohi-Moghadam","author_inst":"The University of Hong Kong"},{"author_name":"Wai Keung Leung","author_inst":"University of Hong Kong"}],"rel_date":"2026-08-03","rel_site":"medrxiv"},{"rel_title":"Power and sample size calculations for evaluating spillover effects in networks with non-randomized interventions","rel_doi":"10.64898\/2026.07.31.26359421","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.31.26359421","rel_abs":"Determining the appropriate sample size for desired statistical power is crucial for obtaining reliable research outcomes. While methods exist for multiple types of studies, the method for evaluating power of estimating spillover effects in sociometric network-based studies with non-randomized interventions remain inadequately explored. We conducted a simulation study to assess how the design parameters (i.e., number of components, number of nodes, node degree, transitivity, and effect size) affects the statistical power for estimating spillover effects in non-randomized, network-based studies. Both simulated networks and a real-world network from Transmission Reduction Intervention Project (TRIP) were used in this study. Our simulation results suggests that: (1) power increases with more nodes or a larger effect size, but not necessarily with more components when the number of nodes is fixed; (2) A higher node degree or greater transitivity results in reduced power; (3) Highly unbalanced networks (e.g., most of the nodes are in one component) can drastically reduce power. Furthermore, the power calculated using a closed-form expression developed in this work also shows that power remained the same or even decreases slightly with more components when the number of nodes are fixed, aligning with the simulation findings. All the results were specific to the inverse probability weighting estimator we employed in this study and assumptions it required. An alternative estimator or interference assumption may lead to different results.\n\nAuthor summarySpillover effects occur when an intervention or treatment for one individual possibly affects the outcome of another. This phenomenon is commonly observed in sociometric networks and can influence the overall impact of an intervention in a population. Inference for spillover requires studies with sufficient statistical power. This needs to be considered at the study design stage, such as determining the minimum sample size required to achieve a desired level of statistical power for assessing spillover in an observational study. However, existing methods for power and sample size analysis primarily address randomized studies or evaluate overall effects.\n\nThis paper explores how different network features (e.g., number of components, number of nodes, node degree, transitivity) and the magnitude of the true spillover effect (i.e., effect size) impact the statistical power of evaluating spillover effect in network-based studies with non-randomized intervention. Our simulation results indicated that statistical power increases with a larger number of individuals, but not necessarily with a larger number of network components. In addition, power decreases significantly when the network is denser or when a component includes most of the individuals in a given network. These findings have important implications for future study design, implying potential strategies to ensure adequately powered studies when evaluating spillover effect in network-based research with non-randomized interventions.","rel_num_authors":6,"rel_authors":[{"author_name":"Ke Zhang","author_inst":"University of Rhode Island"},{"author_name":"Ashley Buchanan","author_inst":"University of Rhode Island"},{"author_name":"Natallia Katenka","author_inst":"University of Rhode Island"},{"author_name":"Jing Wu","author_inst":"University of Rhode Island"},{"author_name":"Youjin Lee","author_inst":"Brown University"},{"author_name":"Georgios Nikolopoulos","author_inst":"University of Cyprus"}],"rel_date":"2026-08-03","rel_site":"medrxiv"},{"rel_title":"Systematic Integration of genomics with transcriptomics for the Study of Coronary Artery Disease and Subclinical Atherosclerosis","rel_doi":"10.64898\/2026.07.31.26357396","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.31.26357396","rel_abs":"IntroductionCoronary artery disease (CAD) is a leading cause of death and disability worldwide. Although genome-wide association studies (GWAS) have identified over 300 loci associated with CAD risk, the molecular mechanisms linking these variants to disease and subclinical atherosclerosis are not fully understood.\n\nMethodsWe performed integration of multi-ancestry CAD GWAS with transcriptomic data from the Multi-Ethnic Study of Atherosclerosis (MESA) obtained through the Trans-Omics for Precision Medicine (TOPMed) program. For integration, we applied Bayesian colocalization analysis with and without statistical fine-mapping to identify genes whose expression levels colocalize with CAD-associated loci. We further applied causal weighted gene co-expression network analysis (cWGCNA) to identify gene co-expression modules and key driver genes associated with subclinical atherosclerosis traits in MESA.\n\nResultsWe identified 108 genes showing evidence of colocalization with CAD loci, including 24 shared between the two colocalization approaches and 48 novel genes not previously reported in CAD GWAS. Follow-up replication and validation analyses prioritized 5 novel (CCDC30, ZEB1-AS1, ZPR1, PLEKHJ1 and AC018816.3) and 8 previously reported genes (DHDDS, DDX59, LNPEP, DAGLA, ZKSCAN1, LIPA, OPRL1 and EIF2B2) with putative roles in both CAD and subclinical atherosclerosis. cWGCNA identified five gene modules significantly associated with subclinical atherosclerosis in MESA. Additionally, three key driver genes (ATG9B, PRAM1 and ZBTB46) identified by cWGCNA were also identified as CAD-colocalized genes.\n\nDiscussionOur integrative analysis highlights key genetic drivers and regulatory networks underlying CAD and subclinical atherosclerosis. These findings underscore the value of incorporating statistical fine-mapping in colocalization studies and demonstrate the utility of combining colocalization with co-expression network analysis to prioritize functional genes and pathways.","rel_num_authors":30,"rel_authors":[{"author_name":"Chaojie Yang","author_inst":"University Of Virginia"},{"author_name":"Francois Aguet","author_inst":"Broad Institute"},{"author_name":"Gaelle Auguste","author_inst":"University of Virginia"},{"author_name":"Kristin G Ardlie","author_inst":"The Broad Institute of Harvard and MIT"},{"author_name":"Robert E Gerszten","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Wendy S. Post","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Heather E Wheeler","author_inst":"Loyola University Chicago Department of Biology"},{"author_name":"Kent D. Taylor","author_inst":"Harbor-UCLA  Medical Center,"},{"author_name":"Silva Kasela","author_inst":"New York Genome Center Inc"},{"author_name":"Tuuli Lappalainen","author_inst":"New York Genome Center Inc"},{"author_name":"Hae Kyung lm","author_inst":"Section of Genetic Medicine, Department of Medicine, University of Chicago"},{"author_name":"Peter Durda","author_inst":"University of Vermont Department of Pathology and Laboratory Medicine"},{"author_name":"W. Craig Johnson","author_inst":"University of Washington"},{"author_name":"Xiuqing Guo","author_inst":"Harbor-UCLA Medical Center"},{"author_name":"Yongmei Liu","author_inst":"Duke University"},{"author_name":"Joseph F. Polak","author_inst":"Tufts Medical Center"},{"author_name":"David M. Herrington","author_inst":"Wake Forest University"},{"author_name":"Clary B. Clish","author_inst":"Broad Institute"},{"author_name":"David Van Den Berg","author_inst":"Keck School of Medicine of the University of Southern California"},{"author_name":"Russell P. Tracy","author_inst":"University Of Vermont"},{"author_name":"Elaine Cornell","author_inst":"University Of Vermont"},{"author_name":"Thomas W. Blackwell","author_inst":"University of Michigan"},{"author_name":"George J Papanicolaou","author_inst":"National Institutes of Health"},{"author_name":"Jose D. Vargas","author_inst":"Washington DC VA Medical Center"},{"author_name":"Stefan Bekiranov","author_inst":"University of Virginia Library"},{"author_name":"Coleen A McNamara","author_inst":"University of Virginia"},{"author_name":"Clint L Miller","author_inst":"University of Virginia Library"},{"author_name":"Jerome I. I. Rotter","author_inst":"The Lundquist Institute"},{"author_name":"Stephen S. S. Rich","author_inst":"University of Virginia"},{"author_name":"Ani W. Manichaikul","author_inst":"University of Virginia Library"}],"rel_date":"2026-08-03","rel_site":"medrxiv"},{"rel_title":"Systematic Integration of genomics with transcriptomics for the Study of Coronary Artery Disease and Subclinical Atherosclerosis","rel_doi":"10.64898\/2026.07.31.26357396","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.31.26357396","rel_abs":"IntroductionCoronary artery disease (CAD) is a leading cause of death and disability worldwide. Although genome-wide association studies (GWAS) have identified over 300 loci associated with CAD risk, the molecular mechanisms linking these variants to disease and subclinical atherosclerosis are not fully understood.\n\nMethodsWe performed integration of multi-ancestry CAD GWAS with transcriptomic data from the Multi-Ethnic Study of Atherosclerosis (MESA) obtained through the Trans-Omics for Precision Medicine (TOPMed) program. For integration, we applied Bayesian colocalization analysis with and without statistical fine-mapping to identify genes whose expression levels colocalize with CAD-associated loci. We further applied causal weighted gene co-expression network analysis (cWGCNA) to identify gene co-expression modules and key driver genes associated with subclinical atherosclerosis traits in MESA.\n\nResultsWe identified 108 genes showing evidence of colocalization with CAD loci, including 24 shared between the two colocalization approaches and 48 novel genes not previously reported in CAD GWAS. Follow-up replication and validation analyses prioritized 5 novel (CCDC30, ZEB1-AS1, ZPR1, PLEKHJ1 and AC018816.3) and 8 previously reported genes (DHDDS, DDX59, LNPEP, DAGLA, ZKSCAN1, LIPA, OPRL1 and EIF2B2) with putative roles in both CAD and subclinical atherosclerosis. cWGCNA identified five gene modules significantly associated with subclinical atherosclerosis in MESA. Additionally, three key driver genes (ATG9B, PRAM1 and ZBTB46) identified by cWGCNA were also identified as CAD-colocalized genes.\n\nDiscussionOur integrative analysis highlights key genetic drivers and regulatory networks underlying CAD and subclinical atherosclerosis. These findings underscore the value of incorporating statistical fine-mapping in colocalization studies and demonstrate the utility of combining colocalization with co-expression network analysis to prioritize functional genes and pathways.","rel_num_authors":30,"rel_authors":[{"author_name":"Chaojie Yang","author_inst":"University Of Virginia"},{"author_name":"Francois Aguet","author_inst":"Broad Institute"},{"author_name":"Gaelle Auguste","author_inst":"University of Virginia"},{"author_name":"Kristin G Ardlie","author_inst":"The Broad Institute of Harvard and MIT"},{"author_name":"Robert E Gerszten","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Wendy S. Post","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Heather E Wheeler","author_inst":"Loyola University Chicago Department of Biology"},{"author_name":"Kent D. Taylor","author_inst":"Harbor-UCLA  Medical Center,"},{"author_name":"Silva Kasela","author_inst":"New York Genome Center Inc"},{"author_name":"Tuuli Lappalainen","author_inst":"New York Genome Center Inc"},{"author_name":"Hae Kyung lm","author_inst":"Section of Genetic Medicine, Department of Medicine, University of Chicago"},{"author_name":"Peter Durda","author_inst":"University of Vermont Department of Pathology and Laboratory Medicine"},{"author_name":"W. Craig Johnson","author_inst":"University of Washington"},{"author_name":"Xiuqing Guo","author_inst":"Harbor-UCLA Medical Center"},{"author_name":"Yongmei Liu","author_inst":"Duke University"},{"author_name":"Joseph F. Polak","author_inst":"Tufts Medical Center"},{"author_name":"David M. Herrington","author_inst":"Wake Forest University"},{"author_name":"Clary B. Clish","author_inst":"Broad Institute"},{"author_name":"David Van Den Berg","author_inst":"Keck School of Medicine of the University of Southern California"},{"author_name":"Russell P. Tracy","author_inst":"University Of Vermont"},{"author_name":"Elaine Cornell","author_inst":"University Of Vermont"},{"author_name":"Thomas W. Blackwell","author_inst":"University of Michigan"},{"author_name":"George J Papanicolaou","author_inst":"National Institutes of Health"},{"author_name":"Jose D. Vargas","author_inst":"Washington DC VA Medical Center"},{"author_name":"Stefan Bekiranov","author_inst":"University of Virginia Library"},{"author_name":"Coleen A McNamara","author_inst":"University of Virginia"},{"author_name":"Clint L Miller","author_inst":"University of Virginia Library"},{"author_name":"Jerome I. I. Rotter","author_inst":"The Lundquist Institute"},{"author_name":"Stephen S. S. Rich","author_inst":"University of Virginia"},{"author_name":"Ani W. Manichaikul","author_inst":"University of Virginia Library"}],"rel_date":"2026-08-03","rel_site":"medrxiv"},{"rel_title":"Pain-Reporting Variability and Reliability as Predictors of Placebo Effects: A Cross-Sectional Experimental Pain Study","rel_doi":"10.64898\/2026.07.31.26359372","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.31.26359372","rel_abs":"Placebo analgesia varies substantially across individuals, yet the sources of this heterogeneity remain incompletely understood. Pain-reporting variability may represent an underrecognized predictor of placebo responsiveness. This study examined whether variability and reliability of pain reporting predict placebo analgesia in an experimental pain setting.\n\nEight hundred and three participants (401 individuals with temporomandibular disorder and 400 healthy controls) completed a standardized thermal pain paradigm involving calibration, placebo conditioning, and testing phases. We obtained repeated heat temperatures (four) during thermal calibration and pain ratings during conditioning test (24 trials). We used these measurements to quantify within-person pain-reporting variability using standard deviation (SD) and coefficient of variation (CoV), and reliability using intraclass correlation coefficients (ICC). Placebo analgesia was calculated as the difference in pain ratings between control and placebo cue trials during testing. Regression models examined associations between reporter characteristics and placebo analgesia controlling for age, sex, race and experimenters.\n\nVariability of thermal pain responses during calibration did not predict placebo analgesia. Greater pain-reporting variability during conditioning was associated with reduced placebo analgesia (higher SD and CoV), and this effect was mediated by slower acquisition of the cue- pain contingency. Conditioning-phase reliability was not associated with placebo analgesia, whereas three clusters of learning profiles predicted placebo effects. Thus, individual differences in pain-reporting variability during conditioning, rather than baseline sensory variability, contribute to heterogeneity in placebo analgesia. These findings suggest that variability during acquisition processing matters more than general sensory variability influencing the magnitude of placebo effects.","rel_num_authors":11,"rel_authors":[{"author_name":"James Arthur Rene Cottam","author_inst":"University of Maryland Baltimore"},{"author_name":"Yang Wang","author_inst":"University of Maryland, Baltimore"},{"author_name":"Titilola Akintola","author_inst":"University of Maryland, Baltimore"},{"author_name":"John Farrar","author_inst":"University of Pennsylvania"},{"author_name":"Chixiang Chen","author_inst":"University of Maryland, Baltimore"},{"author_name":"Patrick McArdle","author_inst":"University of Maryland Baltimore"},{"author_name":"Seth A Ament","author_inst":"University of Maryland School of Medicine"},{"author_name":"Philip A Corlett","author_inst":"Yale University"},{"author_name":"Susan G Dorsey","author_inst":"University of Maryland Baltimore"},{"author_name":"Roi Treister","author_inst":"University of Haifa"},{"author_name":"Luana Colloca","author_inst":"University of Maryland School of Nursing"}],"rel_date":"2026-08-03","rel_site":"medrxiv"},{"rel_title":"Natural History and Post-transplant Outcomes Among Patients with Kidney Leukocyte Cell- Derived","rel_doi":"10.64898\/2026.07.31.26359278","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.31.26359278","rel_abs":"IntroductionALECT2 is the third most common cause of renal amyloidosis in the United States, with a strong predilection for Hispanic patients in the Southwest. (PMID:24522497) Despite its regional prevalence, data on the trajectory of kidney function decline and post-transplant outcomes remain poorly characterized.\n\nMethodsThis is a retrospective study of patients diagnosed with ALECT2 by kidney biopsy at UNM from January 2014 to April 2024. Pre- and post-biopsy eGFR trajectories and post-transplant allograft function were analyzed.\n\nResultsTwelve patients had pre-biopsy data available, with a mean age at diagnosis of 64 {+\/-} 12.0 years; 8 (67%) were female, and 8 identified as Hispanic. Mean eGFR at diagnosis was 31 (SD 29), indicating advanced kidney disease, with 67% diagnosed as CKD stage 4 or 5. Concomitant kidney pathology was identified in 50% of patients, with diabetic nephropathy present in two-thirds of those cases. A significant change in the eGFR trajectory was identified at the time of biopsy through change-point analysis [Figures A, C, D]. Among the four patients who underwent kidney transplantation, allograft eGFR remained stable over more than 60 months of follow-up [Figure D].\n\nConclusionIn this cohort of predominantly Hispanic patients, ALECT2 amyloidosis presented with advanced CKD and accelerated loss of kidney function, which prompted a biopsy that detected the disease. Post-transplant allograft function was well maintained, supporting kidney transplantation as a viable treatment strategy for ALECT2-associated kidney disease.","rel_num_authors":8,"rel_authors":[{"author_name":"Iqra Fatima Munawar Ali","author_inst":"Aga Khan University"},{"author_name":"Pedro A Lopez-Gutierrez","author_inst":"University of New Mexico"},{"author_name":"Nimra Iftikhar","author_inst":"University of New Mexico"},{"author_name":"Valeria Hanson","author_inst":"University of New Mexico"},{"author_name":"Shumaila Afrin","author_inst":"University of Texas Southwestern"},{"author_name":"Lorena Saelices Gomez","author_inst":"University of Texas Southwestern"},{"author_name":"Pablo R Garcia","author_inst":"University of New Mexico"},{"author_name":"Christos P Argyropoulos","author_inst":"University of New Mexico"}],"rel_date":"2026-08-03","rel_site":"medrxiv"},{"rel_title":"Establishing a physiological normative value of area-based hypoxic burden in obstructive sleep apnea","rel_doi":"10.64898\/2026.07.31.26359352","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.31.26359352","rel_abs":"Background and ObjectivesArea-based hypoxic burden, termed as hypoxic dip area (HDA) has been studied as a novel obstructive sleep apnea (OSA) metric that may better characterize intermittent hypoxemia in OSA and thereby better predict outcomes. However, to be of use in routine clinical care, a physiological normative value is necessary. Here we attempt to use several large cohorts to establish a percentile-based threshold that can classify individuals with normal vs. abnormal physiological profiles.\n\nMethodsData from 10 cohorts (EPISONO, FINS, Dayfun, MrOS, MESA, SHHS, APPLES, WSC, CFS, and AIRS [Mount Sinai Clinical Cohort]; n=14,031 subjects) were included. HDA was defined as the area bounded by SpO2 nadirs ([&ge;]2% desaturation) flanking left\/right peaks. The 97.5th percentile of HDA among asymptomatic subjects (n=136) from EPISONO, FINS, and DAYFUN (aged 20-52 years; 46 [33.8%] male) was used to define normal and elevated HDA levels. Physiological features, clinical comorbidities, and incident cardiovascular disease (CVD) events and mortality were compared between normal\/elevated HDA groups. Sensitivity analyses were conducted using age-, sex-, and BMI-adjusted threshold derived from multivariable regression model.\n\nResultsThe 97.5% percentile cutoff of HDA was 8.6%min\/h, classifying 4,500 individuals as normal HDA and 9,531 as elevated HDA. Individuals with elevated HDA ([&ge;]8.6%min\/h) demonstrated greater nocturnal hypoxemia (lower baseline SpO2, higher T90, T85, T80 and oxygen desaturation index), higher AHI (apnea-hypopnea index) and arousal index, and greater daytime sleepiness as well as a higher prevalence of lifetime CVD and hypertension across cohorts. Elevated HDA was related with a higher prevalence of incident CVD events and mortality in unadjusted analyses, although these associations were attenuated after adjustment for confounding factors. Results were similar using alternative thresholds derived from multivariable regression analyses.\n\nConclusionsA physiologically derived cutoff of 8.6% min\/h for HDA effectively distinguishes physiological profiles across respiratory, arousal, and oxygenation domains and generalizes across multiple cohorts. Those with elevated HDA had a higher prevalence of incident CVD outcomes, although observed relationships were attenuated after further adjustment. Our findings provide a physiologically interpretable threshold for HDA that can be readily used in clinical use.","rel_num_authors":19,"rel_authors":[{"author_name":"Li Zhou","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Siyun Yang","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Sajila D Wickramaratne","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Pavel Boulgakov","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Zachary Roberts","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Sarah Chu","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Ankita kumar","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Eriko Hamada","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Thomas M. Tolbert","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Korey Kam","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Andrew W. Varga","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Luciana B. M. de Godoy","author_inst":"Universidade Federal de Sao Paulo (UNIFESP\/EPM)"},{"author_name":"Luciana O. Palombini","author_inst":"Universidade Federal de Sao Paulo (UNIFESP\/EPM)"},{"author_name":"Monica L. Andersen","author_inst":"Universidade Federal de Sao Paulo (UNIFESP\/EPM)"},{"author_name":"Sergio Tufik","author_inst":"Universidade Federal de Sao Paulo (UNIFESP\/EPM)"},{"author_name":"Katie L Stone","author_inst":"California Pacific Medical Center Research Institute"},{"author_name":"Indu Ayappa","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"David M. Rapoport","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Ankit Parekh","author_inst":"Icahn School of Medicine at Mount Sinai"}],"rel_date":"2026-08-03","rel_site":"medrxiv"},{"rel_title":"Stress-Related Methylation Risk Scores Predict Coronary Heart Disease","rel_doi":"10.64898\/2026.07.31.26359423","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.31.26359423","rel_abs":"BackgroundPsychosocial stress is a key risk factor for coronary heart disease (CHD), particularly in postmenopausal women who face both a high stress burden and elevated cardiovascular risk. DNA methylation (DNAm) - a critical epigenetic modification bridging environment and health - remains understudied as a contributor to stress- related CHD.\n\nMethodsWe conducted an epigenome-wide association study (EWAS) of stress in the Womens Health Initiative (WHI), an ancestrally diverse cohort of postmenopausal women (n=3,857). At screening visit, participants completed a questionnaire assessing stressful life events and provided whole blood for DNAm. Incident CHD was then longitudinally ascertained (follow-up mean\/SD: 16.7\/8.4 years), and DNAm signatures were evaluated as CHD predictors using Cox regression. Predictive models were independently validated in the Jackson Heart Study (JHS; n=3,053) and Multi-Ethnic Study of Atherosclerosis (MESA; n=870). The bulk-level DNAm associations were computationally deconvolved at the cell-type-specific level using tensor composition analysis (TCA).\n\nResultsThe EWAS in WHI identified 841 stress-related DNAm sites (99 hypermethylated, 742 hypomethylated with stress) after FDR correction, with 13 significant after Bonferroni correction, including sites located on immune and CHD- related genes (e.g., TNF, ALDH2). Methylation risk scores (MRSs) integrating the 841 FDR-significant sites (MRS841) and 13 Bonferroni-significant sites (MRS13) predicted incident CHD (HR=1.33-1.37; p[&le;]0.0008) and mediated 16.5-17.7% of the association between stress and CHD. In JHS and MESA, MRS13 independently predicted CHD (HR=1.34; p=0.036), whereas MRS841 was suggestively associated with CHD (HR=1.27; p=0.087). TCA indicated that the greatest number of stress-related sites predictive of CHD was specifically in monocytes (133 total), with directions consistent with bulk-level associations (9 hypermethylated, 124 hypomethylated with stress).\n\nConclusionOur study supports methylation risk scores as novel biomarkers of stress- related CHD and uncovers epigenetic regulation in monocytes as a potential underlying mechanism. These findings highlight biological pathways linking stress and disease and may promote personalized interventions in high-risk populations.","rel_num_authors":21,"rel_authors":[{"author_name":"Sofia Benavides","author_inst":"Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA, UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel H"},{"author_name":"Hazel Milla","author_inst":"Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA, Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, "},{"author_name":"Helena Palma-Gudiel","author_inst":"Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA"},{"author_name":"David Checknita","author_inst":"Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA, AbbVie Corporation, Saint-Laurent, Canada"},{"author_name":"Bjoernar Tuftin","author_inst":"Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Kai Xia","author_inst":"Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA"},{"author_name":"Charles Kooperberg","author_inst":"Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA"},{"author_name":"Alexander P. Reiner","author_inst":"Department of Epidemiology, University of Washington & Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA"},{"author_name":"JoAnn E. Manson","author_inst":"Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Themistocles L. Assimes","author_inst":"Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA, VA Palo Alto Healthcare System, Palo Alt"},{"author_name":"Parveen Bhatti","author_inst":"Population Health Sciences, BC Cancer Research Institute, Vancouver, British Columbia, Canada, School of Population and Public Health, University of British Col"},{"author_name":"Kent D. Taylor","author_inst":"The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Med"},{"author_name":"W. Craig Johnson","author_inst":"Department of Biostatistics, University of Washington, Seattle, WA, USA"},{"author_name":"Stephen S. Rich","author_inst":"Department of Genome Sciences, University of Virginia, Charlottesville, VA, USA"},{"author_name":"Jerome I. Rotter","author_inst":"The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Med"},{"author_name":"Linda C. Gallo","author_inst":"Department of Psychology, San Diego State University, San Diego, CA, USA"},{"author_name":"David R. Rubinow","author_inst":"Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA"},{"author_name":"Elior Rahmani","author_inst":"Division of Computational Medicine, Department of Medicine, Stanford University, Stanford, CA, USA"},{"author_name":"Laura M. Raffield","author_inst":"Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Eric A. Whitsel","author_inst":"Department of Epidemiology, UNC Gillings School of Public Health, Chapel Hill, NC, USA, Department of Medicine, UNC School of Medicine, Chapel Hill, NC, USA"},{"author_name":"Anthony S. Zannas","author_inst":"Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA, UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel H"}],"rel_date":"2026-08-03","rel_site":"medrxiv"},{"rel_title":"Employing Data-Driven Techniques to Explore the Lay Public's Health Concerns with Vaping E-Cigarettes","rel_doi":"10.64898\/2026.07.29.26359262","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.29.26359262","rel_abs":"While the public perceives e-cigarettes as less harmful than combustible tobacco, little is known about their specific health concerns regarding vaping. We demonstrate a data-driven strategy to discover the publics health concerns about vaping e-cigarettes expressed on social media. We obtained all public posts from the largest e-cigarette-related subreddit, r\/electronic_cigarette, from its inception on September 17, 2008, through April 1, 2022 (N = 10,403,433). We identified health concerns attributed to vaping by (a) selecting all cause phrases containing \"cause\" and its inflections, (b) calculating the empirical frequency ratio of words and bi-grams occurring in these phrases relative to random phrases, (c) retaining the 10% of words with the greatest empirical frequency of occurring in cause phrases, and (d) annotating this sample for health-relevant concerns and their subjects. In total, 76,342 posts contained cause phrases, with increased volume over time. Of the 425 words most strongly associated with cause phrases compared to random phrases, 53.4% (95%CI, 48.7-58.1) were identified as health-relevant. The top health-related concern was lipoid pneumonia, cited in 5.9% (95%CI, 5.0-6.8) of all cause phrases, followed by pneumonia (4.1%; 95%CI, 3.3-4.9), and nausea (2.7%;95%CI, 2.0-3.4). The top health concern subjects were respiratory, representing 23.7% (95%CI, 18.5-29.5) of all cause phrases, followed by gastrointestinal (12.7%; 95%CI, 8.8-17.2) and cardiovascular (8.5%; 95%CI, 5.3-12.3) concerns. Other subjects included neurological, dermatological, oral health, sexual health, psychiatric, oncologic, addiction, and sleep concerns. Because our strategy relies on data-driven techniques, our analysis can be integrated into routine social media monitoring and applied across different types of social media and text data, potentially leading to more timely identification of emerging concerns and a broader understanding across platforms. As a result, experts can craft messaging that accounts for current perceptions held by the public using our method.","rel_num_authors":8,"rel_authors":[{"author_name":"John  W. Ayers","author_inst":"Harvard Medical School"},{"author_name":"Adam Poliak","author_inst":"Bryn Mawr College"},{"author_name":"Alexandra DeLucia","author_inst":"JHU"},{"author_name":"Zechariah Zhu","author_inst":"UCSD"},{"author_name":"Stephanie Pitts","author_inst":"FDA"},{"author_name":"Mario Navarro","author_inst":"FDA: US Food and Drug Administration"},{"author_name":"Sharareh Shojaie","author_inst":"FDA"},{"author_name":"Mark Dredze","author_inst":"JHU"}],"rel_date":"2026-08-02","rel_site":"medrxiv"},{"rel_title":"Smartphone Imaging for Remote Monitoring of Inflammatory Arthritis in a Real-World Cohort: Longitudinal Evaluation of a Machine Learning-Based Finger Fold Biomarker","rel_doi":"10.64898\/2026.07.30.26359295","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.30.26359295","rel_abs":"BackgroundSmartphone enabled remote patient monitoring has the potential to complement conventional follow-up in inflammatory arthritis. We previously presented the finger fold index (FFI) derived from hand photographs as ratio of automated detected proximal interphalangeal (PIP) joint diameter and surface of dorsal finger folds as a digital biomarker for clinical joint swelling and disease activity in rheumatoid arthritis (RA) and psoriatic arthritis (PsA).\n\nObjectiveTo evaluate the feasibility, image quality, patient engagement, and clinical utility of both HCP- and patient-collected hand photographs integrated into a national rheumatology registry, and to assess the performance of the FFI as an image-derived digital biomarker for clinical joint swelling of the proximal interphalangeal joints in a real-world arthritis cohort.\n\nMethodsIn this longitudinal multicenter study, a photo function with written instructions were integrated into the Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) registry and their mySCQM mobile application, respectively. Patients with RA or PsA contributed longitudinal smartphone photographs together with patient-reported outcomes (PROs) via the mySCQM mobile application while health care professionals (HCPs) acquired images during routine visits. After manual quality assessment, images were processed using an automated computer vision pipeline to derive the FFI, a digital biomarker based on dorsal finger-fold morphology. Image quality was evaluated for both HCP- and participant-collected photographs, and patient engagement was assessed. Associations between FFI, clinical proximal interphalangeal (PIP) joint swelling, RADAI-5, DAS28-CRP and longitudinal changes were assessed. A generalized linear mixed model was used to estimate the association between FFI and joint swelling while accounting for repeated measures and within-subject correlations.\n\nResultsBetween 2023 and 2025, 374 RA and PsA patients were included. HCPs captured 977 hand images while 174 patients collected 1228 hand images via the mySCQM app. Patients demonstrated sustained engagement after instruction, contributing a mean of seven images during data collection. Following quality control, 1729 hand images comprising 4048 PIP joints were included for analysis. Image quality was comparable between patient-acquired and HCP-acquired photographs; 78.3% of the patient-acquired vs. 73.5% of the HCP-acquired hand images were suitable to run the ML-model. 23.1% of the cropped joints had to be removed after the running of the FFI algorithm due to false diameter or finger fold detection e.g. due to wrong hand positioning. In images taken by HCPs, mean FFI and DAS28-CRP were weakly but significantly correlated (Spearmans {rho} = 0.164; 95% CI [0.004 to 0.317]; p = 0.039). Conversely, RADAI-5 scores did not correlate with the mean FFI in RA patients (r = 0.007, p = 0.932, 95% CI [-0.169-0.183]). At follow-up visits, clinical swelling resolved in 40 joints, of which in 68.0% the direction of the delta FFI was concordant with the clinical change. In contrast, 13 joints developed incident clinical swelling, of which 87.5% had a direction of the delta FFI that was concordant with the clinical change. However, the GLMM showed no significant associations between swelling and joint location or time-varying FFI, and no evidence of interaction between FFI and PIP joint.\n\nConclusionIntegration of patient self-imaging into a remote monitoring application for inflammatory arthritis is feasible and achieves image quality comparable to clinician acquired photographs. The FFI derived from collected images shows association with clinical joint swelling and disease activity scores, but not PROs. In a substantial proportion of images, the FFI algorithm could not be applied because of insufficient image quality. More standardized image acquisition and further refinement of the FFI algorithm are warranted.","rel_num_authors":18,"rel_authors":[{"author_name":"Cinja Nadana Koller","author_inst":"University Hospital Lausanne (CHUV)"},{"author_name":"Jules Maglione","author_inst":"Department of Rheumatology, University Hospital Lausanne (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland"},{"author_name":"Marc Blanchard","author_inst":"Department of Rheumatology, University Hospital Lausanne (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland"},{"author_name":"Alexandre Dumusc","author_inst":"Department of Rheumatology, University Hospital Lausanne (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland"},{"author_name":"Diana Dan","author_inst":"Department of Rheumatology, University Hospital Lausanne (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland"},{"author_name":"Laure Brulhart","author_inst":"Department of Rheumatology, Reseau Hospitalier Neuchateloise de la Chaux de fonds, Switzerland"},{"author_name":"Michael Nissen","author_inst":"Department of Rheumatology, University Hospital of Geneva (HUG) and University of Geneva, Geneva, Switzerland"},{"author_name":"Michael Andor","author_inst":"Rheumatologie im Zuercher Oberland (RZO), Uster, Switzerland"},{"author_name":"Raphael Micheroli","author_inst":"Department of Rheumatology, University Hospital of Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland"},{"author_name":"Almut Scherer","author_inst":"SCQM Foundation, Zurich, Switzerland"},{"author_name":"Christos Polysopoulos","author_inst":"SCQM Foundation, Zurich, Switzerland"},{"author_name":"Andrea Rubbert-Roth","author_inst":"Department of Rheumatology, Health Ostschweiz, Kantonsspital St. Gallen (HOCH), Switzerland"},{"author_name":"Christof Iking-Konert","author_inst":"Department of Rheumatology, Stadtspital Zurich, Zurich, Switzerland"},{"author_name":"Tobias Manigold","author_inst":"Rheumatology Inselspital, Bern, Switzerland"},{"author_name":"Burkhard Moeller","author_inst":"Rheumatology Inselspital, Bern, Switzerland"},{"author_name":"Chrisa Manolarki","author_inst":"Rheumabasel, Basel, Switzerland"},{"author_name":"Jeroen Geurts","author_inst":"Department of Rheumatology, University Hospital Lausanne (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland"},{"author_name":"Thomas Huegle","author_inst":"Department of Rheumatology, University Hospital Lausanne (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland"}],"rel_date":"2026-07-31","rel_site":"medrxiv"},{"rel_title":"The Case for Interpretable Geometry: Statistical Shape Models vs. Curvature-Based Descriptors in Aortic Disease Classification","rel_doi":"10.64898\/2026.07.29.26359299","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.29.26359299","rel_abs":"PurposeQuantifying aortic morphology is central to surgical planning for thoracic endovascular aortic repair (TEVAR), yet no consensus exists on how best to represent three-dimensional aortic shape for outcome prediction. Two broad strategies have emerged: statistical shape analysis (SSA), which relies on statistical methods and dimensionality reduction to capture the most significant shape modes, and geometrically-informed approaches that extract descriptors grounded in differential geometry. Here, we directly compare these paradigms on a cohort of 290 CTA scans classified by surgical outcome (non-pathological, successful TEVAR, failed TEVAR).\n\nMethodsFor the geometrically-informed approach, we use a two-dimensional feature space using normalized fluctuation in integrated Gaussian curvature [Formula] and mean aortic radius R. For SSA, we construct a point-cloud shape model with dimensionality reduction using Principal Component Analysis (PCA) and evaluate classification performance as a function of the number of retained principal components.\n\nResultsSSAs leading principal components encode variations in global aortic size and are statistically redundant with (R, [Formula]), yet they lack a one-to-one correspondence with interpretable anatomical quantities. Testing on an unseen, independent dataset reveals that the geometrically-informed approach provided better generalizability than SSA. Using Gaussian process classification with 10-fold cross-validation, we find that the geometrically-informed approach achieves a higher weighted F1 score than SSA achieves with up to 20 principal components. While SSAs full-dataset accuracy rises above 90% with increasing dimensionality, this gain is driven by overfitting rather than genuine discriminative power.\n\nConclusionThese results demonstrate that geometrically-informed descriptors offer a more interpretable, robust, and clinically translatable framework for aortic disease classification than data-driven statistical shape representations.","rel_num_authors":3,"rel_authors":[{"author_name":"Luka Pocivavsek","author_inst":"The University of Chicago"},{"author_name":"Duc Manh Nguyen","author_inst":"University of Chicago"},{"author_name":"Joseph Pugar","author_inst":"University of Chicago"}],"rel_date":"2026-07-31","rel_site":"medrxiv"}]}