{"gname":"Oregon Health & Science University","grp_id":"22","rels":[{"rel_title":"A closed-loop language-model agent for target-specific multi-objective hit-to-lead optimization","rel_doi":"10.64898\/2026.09.19.752921","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.19.752921","rel_abs":"Hit-to-lead optimization is a multi-objective molecular-design problem in which binding-related scores must be considered together with drug-likeness and synthetic accessibility. We developed a closed-loop language-model medicinal-chemistry agent that combines target and starting-hit context, PubMed retrieval, molecular-property tools, docking, and feedback from previously scored analogues. In a matched computational benchmark comprising six kinase targets, six methods, a 40-candidate budget, and six independent campaigns per method, the agent achieved the highest mean aggregate score under a pre-specified composite objective on four targets. Re-analysis of the same candidate sets with drug-likeness-gated docking and docking-drug-likeness hypervolume produced different target-level winners, showing that evaluation rules can change the comparative interpretation of an optimization campaign. Candidate distributions and component ablations indicated that the agent's advantage was associated primarily with retention of scored-candidate feedback and higher-QED regions rather than with docking alone. An EGFR case study illustrates a scaffold-preserving in-silico optimization trajectory from erlotinib. The study is a computational benchmark and evaluation framework; the prioritized molecules are hypotheses for subsequent experimental testing, not experimentally validated leads.","rel_num_authors":8,"rel_authors":[{"author_name":"Wentao Cui","author_inst":"Beijing Life Science Academy, Beijing, China; Key Laboratory of Biosynthesis and Biomanufacturing in Model Plants (Beijing Life Science Academy), Ministry of In"},{"author_name":"Limeng Tian","author_inst":"School of Aerospace Engineering, Tsinghua University, Beijing, China"},{"author_name":"Xiaoning Qi","author_inst":"State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China"},{"author_name":"Haoran Wang","author_inst":"State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China"},{"author_name":"Huanhuan Wu","author_inst":"State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China"},{"author_name":"Houxin He","author_inst":"Institute of Automation, Chinese Academy of Sciences, Beijing, China"},{"author_name":"Chen Fang","author_inst":"College of Electronic Engineering, National University of Defense Technology, Hefei, 230031, China"},{"author_name":"Jiaxin Hu","author_inst":"State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"A prefrontal cortex-hypothalamus circuit for heart rate control in non-human primates","rel_doi":"10.64898\/2026.09.18.752614","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.752614","rel_abs":"Humans exhibit changes in heart rate during cognitive and emotional events, and dysregulation of this brain-heart coupling is a hallmark of many psychiatric disorders. Yet, how circuits that regulate cognition exert direct control over heart physiology remains poorly understood, particularly in primates. Here, we identify a prefrontal-hypothalamic circuit that exerts powerful, bidirectional control over heart rate in monkeys. We show that electrical stimulation of a small ventral subregion within the ventrolateral prefrontal cortex (area 47\/12; a12) evokes rapid and robust decreases in heart rate and increases heart rate variability, whereas neighboring prefrontal regions produce weaker or no effects. And a12 neurons are coupled to heart rate on a moment-by-moment basis. Anatomical tracing data reveal projections from a12 to a circumscribed region of lateral hypothalamus (LHA), and stimulation of this LHA target recapitulates the cardiac effects of prefrontal activation. Consistent with a prefrontal-to-hypothalamus system for heart rate control, stimulation of LHA produces faster, stronger, state-independent heart effects, whereas stimulation of a12 produces effects that are sensitive to internal states. Oppositely to its activation, chemogenetic inactivation of a12 or its projections to LHA increases heart rate, demonstrating that this pathway can provide tonic inhibitory control over cardiac function. To make steps towards a more cell-type-specific and minimally invasive causal control of this circuit, we developed a primate sonogenetic approach based on ultrasound activation of CaMKII+ neurons virally transduced with TRPV1. Sonogenetic stimulation of a12 produced increases in heart rate variability, and these effects were attenuated by inactivation of LHA. Finally, we found that sonogenetic and chemogenetic perturbation of the same prefrontal region during a value-based decision-making task bidirectionally alters risky decision making. Together, our work identifies how a12 regulates heart rate and cognition, revealing a mechanistic substrate for brain-body interactions and a potential therapeutic target for disorders of cognitive-autonomic dysregulation.","rel_num_authors":11,"rel_authors":[{"author_name":"Kevin Xu","author_inst":"Washington University in St. Louis"},{"author_name":"Takaya Ogasawara","author_inst":"Washington University in St. Louis; Johns Hopkins University"},{"author_name":"Jinyun Yuan","author_inst":"Washington University in St. Louis"},{"author_name":"Ethan S. Bromberg-Martin","author_inst":"Washington University in St. Louis; Johns Hopkins University"},{"author_name":"Mengxi Yun","author_inst":"Washington University in St. Louis"},{"author_name":"Steven P. Errington","author_inst":"Washington University in St. Louis"},{"author_name":"Andrew H. Stark","author_inst":"Washington University in St. Louis"},{"author_name":"Takafumi Minamimoto","author_inst":"National Institutes for Quantum Science and Technology"},{"author_name":"Ken-ichi Inoue","author_inst":"Kyoto University"},{"author_name":"Hong Chen","author_inst":"Washington University in St. Louis"},{"author_name":"Ilya E. Monosov","author_inst":"Washington University in St. Louis; Johns Hopkins University"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"A prefrontal cortex-hypothalamus circuit for heart rate control in non-human primates","rel_doi":"10.64898\/2026.09.18.752614","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.752614","rel_abs":"Humans exhibit changes in heart rate during cognitive and emotional events, and dysregulation of this brain-heart coupling is a hallmark of many psychiatric disorders. Yet, how circuits that regulate cognition exert direct control over heart physiology remains poorly understood, particularly in primates. Here, we identify a prefrontal-hypothalamic circuit that exerts powerful, bidirectional control over heart rate in monkeys. We show that electrical stimulation of a small ventral subregion within the ventrolateral prefrontal cortex (area 47\/12; a12) evokes rapid and robust decreases in heart rate and increases heart rate variability, whereas neighboring prefrontal regions produce weaker or no effects. And a12 neurons are coupled to heart rate on a moment-by-moment basis. Anatomical tracing data reveal projections from a12 to a circumscribed region of lateral hypothalamus (LHA), and stimulation of this LHA target recapitulates the cardiac effects of prefrontal activation. Consistent with a prefrontal-to-hypothalamus system for heart rate control, stimulation of LHA produces faster, stronger, state-independent heart effects, whereas stimulation of a12 produces effects that are sensitive to internal states. Oppositely to its activation, chemogenetic inactivation of a12 or its projections to LHA increases heart rate, demonstrating that this pathway can provide tonic inhibitory control over cardiac function. To make steps towards a more cell-type-specific and minimally invasive causal control of this circuit, we developed a primate sonogenetic approach based on ultrasound activation of CaMKII+ neurons virally transduced with TRPV1. Sonogenetic stimulation of a12 produced increases in heart rate variability, and these effects were attenuated by inactivation of LHA. Finally, we found that sonogenetic and chemogenetic perturbation of the same prefrontal region during a value-based decision-making task bidirectionally alters risky decision making. Together, our work identifies how a12 regulates heart rate and cognition, revealing a mechanistic substrate for brain-body interactions and a potential therapeutic target for disorders of cognitive-autonomic dysregulation.","rel_num_authors":11,"rel_authors":[{"author_name":"Kevin Xu","author_inst":"Washington University in St. Louis"},{"author_name":"Takaya Ogasawara","author_inst":"Washington University in St. Louis; Johns Hopkins University"},{"author_name":"Jinyun Yuan","author_inst":"Washington University in St. Louis"},{"author_name":"Ethan S. Bromberg-Martin","author_inst":"Washington University in St. Louis; Johns Hopkins University"},{"author_name":"Mengxi Yun","author_inst":"Washington University in St. Louis"},{"author_name":"Steven P. Errington","author_inst":"Washington University in St. Louis"},{"author_name":"Andrew H. Stark","author_inst":"Washington University in St. Louis"},{"author_name":"Takafumi Minamimoto","author_inst":"National Institutes for Quantum Science and Technology"},{"author_name":"Ken-ichi Inoue","author_inst":"Kyoto University"},{"author_name":"Hong Chen","author_inst":"Washington University in St. Louis"},{"author_name":"Ilya E. Monosov","author_inst":"Washington University in St. Louis; Johns Hopkins University"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Convergent evolutionary loss of chemosensory and blood-feeding pathways in non-blood-feeding mosquitoes","rel_doi":"10.64898\/2026.09.23.753750","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.23.753750","rel_abs":"Complex traits that span multiple tissues and systems often integrate large numbers of genes across development, physiology, and behavior, making it challenging to identify their essential components. Blood feeding in mosquitoes is one such trait. It is ancestral to the mosquito family, maintained in most species for ~200 million years, and was independently lost in three lineages. These convergent losses offer a natural experiment to discover the genetic, physiological, and neural features required for blood feeding. We assembled high-quality, chromosome-level genomes for seven mosquito species, along with whole-brain tomographic reconstructions. Our study spanned the three known non-blood-feeding lineages (Toxorhynchites rutilus, Topomyia yanbarensis, and Malaya genurostris), blood-feeding relatives, and the variable blood feeder Wyeomyia smithii. Comparing orthologous gene clades, we detected convergent gene loss specific to the three lineages that had lost blood feeding. The losses include the salivary platelet-aggregation inhibitor Aegyptin, blood-activated serine proteases such as Chymotrypsin-1 and 2, and a carboxylesterase expressed in the female fat body and brain glia. The loss of blood feeding also extended to chemosensation. Non-blood feeders lack two odorant-binding protein clades, two ionotropic receptor clades associated with blood-component taste detection, and odorant receptor clades expressed in a discrete, strongly female-biased population of antennal neurons. Female-biased head gene expression was reduced in non-blood feeders. Finally, examination of whole-brain tomographic reconstructions across the species revealed smaller antennal lobes in non-blood-feeding females, consistent with reduced olfactory input. Together, these findings identify a compact set of genes, expression patterns, and brain regions associated with blood feeding, offering an evolutionary entry point for functional dissection of how this complex and dangerous trait is built and dismantled.","rel_num_authors":18,"rel_authors":[{"author_name":"Leah Houri-Zeevi","author_inst":"The Rockefeller University"},{"author_name":"Philipp Brand","author_inst":"The Rockefeller University"},{"author_name":"Irene Arnoldi","author_inst":"University of Milan"},{"author_name":"Alexandra E DeFoe","author_inst":"The Rockefeller University"},{"author_name":"Jennifer R Balacco","author_inst":"The Rockefeller University"},{"author_name":"Nadav Shai","author_inst":"The Rockefeller University"},{"author_name":"Alex Makunin","author_inst":"Wellcome Sanger Institute"},{"author_name":"Umberto Palatini","author_inst":"The Rockefeller University"},{"author_name":"Takako Toma","author_inst":"University of the Ryukyus Museum (Fujukan)"},{"author_name":"Takao Okazawa","author_inst":"Kanazawa University"},{"author_name":"Christopher M Stone","author_inst":"University of Illinois Urbana-Champaign"},{"author_name":"Anita Schiller","author_inst":"Harris County PCT4 Mosquito Biological Control Initiative"},{"author_name":"Olivier Fedrigo","author_inst":"The Rockefeller University"},{"author_name":"Erich D Jarvis","author_inst":"The Rockefeller University"},{"author_name":"Mara KN Lawniczak","author_inst":"Wellcome Sanger Institute"},{"author_name":"Ichiro Miyagi","author_inst":"University of the Ryukyus Museum (Fujukan)"},{"author_name":"Paolo Gabrieli","author_inst":"University of Milan"},{"author_name":"Leslie B Vosshall","author_inst":"The Rockefeller University"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Sociality in weevils is shaped by sheltering and convergent gene losses","rel_doi":"10.64898\/2026.09.19.752859","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.19.752859","rel_abs":"Eusociality, characterized by overlapping generations, cooperative brood care, and reproductive division of labour, has arisen independently across diverse, phylogenetically distant insect orders, including Hymenoptera (ants, bees, and wasps), Blattodea (termites), and Coleoptera (weevils). While multiple studies have investigated the molecular evolution of sociality from solitary ancestors in Hymenoptera and Blattodea, so far little is known about the evolutionary signatures of social evolution in Coleoptera. Weevils (Curculionidae) provide an ideal system for addressing this question, as they cover the full spectrum of social complexity from parental care, through several origins of facultative eusociality to the only obligately eusocial beetle, Austroplatypus incompertus. We generated genome assemblies for A. incompertus and two facultatively eusocial weevil species, Xylosandrus germanus and Xyleborinus saxesenii, which together with 18 publicly available weevil genomes span two independent evolutionary origins of sociality. Our analyses reveal a genome-wide relaxation of purifying selection with increasing social complexity, which is most pronounced in A. incompertus. We find a significant excess of convergent gene family contractions in lineages where sociality evolved, and no evidence of elevated positive selection. These findings indicate that the molecular mechanisms of social evolution in weevils are primarily characterised by relaxed selection and gene loss, rather than adaptive innovation and gene family expansions. These observations are consistent with sheltering and reduced effective population size playing an important role, a pattern not previously observed in other clades.","rel_num_authors":7,"rel_authors":[{"author_name":"Sarah Rinke","author_inst":"University of Muenster"},{"author_name":"James Bickerstaff","author_inst":"CSIRO"},{"author_name":"Peter H.W. Biedermann","author_inst":"University of Freiburg"},{"author_name":"Carsten Kemena-Rinke","author_inst":"University of Muenster"},{"author_name":"Markus Riegler","author_inst":"Western Sydney University"},{"author_name":"Martin Schebeck","author_inst":"University of Goettingen"},{"author_name":"Mark C Harrison","author_inst":"Coventry University"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Two Ume6 target gene classes in the biofilm regulatory network of Candida albicans","rel_doi":"10.64898\/2026.09.24.753443","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.24.753443","rel_abs":"Biofilm formation by the fungal pathogen Candida albicans is a major source of infection. The biofilm regulator Ume6 forms complexes with partner transcription factors Efg1, Ndt80, and Upc2 to drive expression of biofilm-related genes. Here we present chromatin immunoprecipitation with sequencing (ChIP-seq) data for Ume6-chromatin association in both wild-type and efg1{Delta}\/{Delta} ndt80{Delta}\/{Delta} upc2{Delta}\/{Delta} backgrounds. Ume6 associates with two promoter region classes. For one class, Ume6 association is significantly decreased in the efg1{Delta}\/{Delta} ndt80{Delta}\/{Delta} upc2{Delta}\/{Delta} background. This class includes 577 genes, many with well-established roles in biofilm formation or the related process of filamentation. For the second class, Ume6 association is unperturbed in the triple mutant background. This class includes 534 genes, some with roles in iron homeostasis (e.g., SFU1) and ergosterol synthesis (e.g., ERG11), which may contribute to the impact of Ume6 on ndt80{Delta}\/{Delta} mutant azole drug sensitivity. It also includes FLO9, a putative adhesin gene that is required for the emergent biofilm state produced by efg1{Delta}\/{Delta} ndt80{Delta}\/{Delta} double mutants. The data show that Ume6 binding to ~half of its targets requires known partners, and Ume6 binding to ~half of its targets does not. Ume6 may bind to the latter set of promoter regions independently of any partner, or perhaps with additional partners that have yet to be discovered.","rel_num_authors":3,"rel_authors":[{"author_name":"Eunsoo Do","author_inst":"The University of Georgia"},{"author_name":"Joel McManus","author_inst":"Carnegie Mellon University"},{"author_name":"Aaron P. Mitchell","author_inst":"University of Georgia"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"NLRP3 inflammasome signaling orchestrates hepatic granuloma organization and protective immunity","rel_doi":"10.64898\/2026.09.18.752760","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.752760","rel_abs":"Granulomas are organized immune structures that contribute to host defense against persistent pathogens, yet the mechanisms that coordinate their assembly and protective function remain incompletely understood. Here, using experimental visceral leishmaniasis caused by Leishmania infantum and samples from patients with active disease, we identify the NLRP3 inflammasome as a regulator of protective hepatic granulomatous immunity. Inflammasome-associated mediators were elevated in patients and correlated with systemic inflammation. In mice, L. infantum induced NLRP3 inflammasome activation within hepatic granulomas, while single-cell and spatial transcriptomic analyses revealed enrichment of inflammasome-associated transcription in hepatic macrophages and granuloma-associated regions. NLRP3 deficiency did not prevent granuloma initiation but impaired granuloma expansion, cellular organization, and leukocyte accumulation. This response required Caspase-1\/11 and IL-18, but was independent of IL-1{beta}. Loss of NLRP3 also impaired parasite control despite reducing hepatic inflammation and histopathological alterations. Together, our findings identify NLRP3-Caspase-1\/11-IL-18 signaling as a mechanism that coordinates the cellular and spatial organization of protective hepatic granulomas, revealing granuloma architecture as a previously unrecognized function of inflammasome-mediated immunity and providing mechanistic insight into host resistance in visceral leishmaniasis, a potentially fatal neglected tropical disease.","rel_num_authors":22,"rel_authors":[{"author_name":"Isadora M. de Oliveira","author_inst":"Department of Cellular and Molecular Biology, School of Medicine of Ribeirao Preto, University of Sao Paulo. Ribeirao Preto, SP 14049-900, Brazil"},{"author_name":"Mariana M. Chaves","author_inst":"Department of Cellular and Molecular Biology, School of Medicine of Ribeirao Preto, University of Sao Paulo. Ribeirao Preto, SP 14049-900, Brazil"},{"author_name":"Juliana Costa-Madeira","author_inst":"Department of Cellular and Molecular Biology, School of Medicine of Ribeirao Preto, University of Sao Paulo. Ribeirao Preto, SP 14049-900, Brazil"},{"author_name":"Ana Luisa Barbosa","author_inst":"Department of Cellular and Molecular Biology, School of Medicine of Ribeirao Preto, University of Sao Paulo. Ribeirao Preto, SP 14049-900, Brazil"},{"author_name":"Pedro S. Corradi","author_inst":"Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas G"},{"author_name":"Bianca de Oliveira","author_inst":"Vaccine Technology Center (CT Vacinas), Federal University of Minas Gerais, Parque Tecnologico de Belo Horizonte, Belo Horizonte 31310-260, MG, Brazil."},{"author_name":"Amanda M Becerra","author_inst":"Department of Cellular and Molecular Biology, School of Medicine of Ribeirao Preto, University of Sao Paulo. Ribeirao Preto, SP 14049-900, Brazil"},{"author_name":"Pedro Henrique Marques","author_inst":"Department of Cellular and Molecular Biology, School of Medicine of Ribeirao Preto, University of Sao Paulo. Ribeirao Preto, SP 14049-900, Brazil"},{"author_name":"Tamara S Rodrigues","author_inst":"Department of Cellular and Molecular Biology, School of Medicine of Ribeirao Preto, University of Sao Paulo. Ribeirao Preto, SP 14049-900, Brazil"},{"author_name":"Adriana Simizo","author_inst":"Hospital Israelita Albert Einstein, Sao Paulo, SP, Brazil"},{"author_name":"Lucas Lorenzon","author_inst":"Department of Cellular and Molecular Biology, School of Medicine of Ribeirao Preto, University of Sao Paulo. Ribeirao Preto, SP 14049-900, Brazil"},{"author_name":"Sabrina S Batah","author_inst":"Department of Pathology and Legal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto (SP), Brazil"},{"author_name":"Andrea JR Herrera","author_inst":"Department of Pathology and Legal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto (SP), Brazil"},{"author_name":"Helder I Nakaya","author_inst":"Hospital Israelita Albert Einstein, Sao Paulo, SP, Brazil. Department of Clinical and Toxicological Analyses, University of Sao Paulo, SP, Brazil. Institut Past"},{"author_name":"Amanda M da Silva","author_inst":"Instituto de Doencas Tropicais Natan Portella. Centro de Ciencias da Saude da Universidade Federal do Piaui. Teresina-PI, Brazil."},{"author_name":"Ricardo T Gazzinelli","author_inst":"Vaccine Technology Center (CT Vacinas), Federal University of Minas Gerais, Parque Tecnologico de Belo Horizonte, Belo Horizonte 31310-260, MG, Brazil."},{"author_name":"Angela K Cruz","author_inst":"Department of Cellular and Molecular Biology, School of Medicine of Ribeirao Preto, University of Sao Paulo. Ribeirao Preto, SP 14049-900, Brazil"},{"author_name":"Cristina M Takiya","author_inst":"Instituto de Biofisica Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil."},{"author_name":"Alexandre T Fabro","author_inst":"Department of Pathology, Botucatu Medical School, Sao Paulo State University"},{"author_name":"Gustavo B Menezes","author_inst":"Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas G"},{"author_name":"Carlos HN Costa","author_inst":"Instituto de Doencas Tropicais Natan Portella. Centro de Ciencias da Saude da Universidade Federal do Piaui. Teresina-PI, Brazil."},{"author_name":"Dario S Zamboni","author_inst":"Department of Cellular and Molecular Biology, School of Medicine of Ribeirao Preto, University of Sao Paulo. Ribeirao Preto, SP 14049-900, Brazil"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Standardized human tests show that most vision models are face-blind","rel_doi":"10.64898\/2026.09.18.750666","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.750666","rel_abs":"Face recognition ability varies enormously across humans. Individuals with face-blindness (prosopagnosia) struggle to recognize even close family members while super-recognizers can identify strangers with exceptional accuracy. Where do ANNs fall within the human face recognition spectrum? Here, we administered the standardized tests used to characterize human face recognition ability to a diverse set of models, allowing us to contextualize a model's performance within the distribution of human behavior. We found that the majority 55% of models to be classified as face-blind and that even the best face-trained models do not cross the human threshold to be considered a super-recognizer. Interrogating the internal representations of these models showed that models that performed well on standardized face recognition tasks were more identity-selective and viewpoint-invariant. We also found that low-performing models did contain some identity information in independent representational subspaces. Removing viewpoint-dependent subspace improved face recognition abilities in 49 of the 53 models tested. Targeted unit ablations further identified opposing contributions, with viewpoint-dependent units disrupting identity coding and viewpoint-tolerant units supporting it. Together, our results show that most AI models are face-blind with worse face recognition ability than humans, and demonstrate how differences across AI models can be used generate testable hypotheses about the computational basis of human face recognition in humans which can then be probed in future studies.","rel_num_authors":5,"rel_authors":[{"author_name":"Kushal R Dudipala","author_inst":"Georgia Institute of Technology"},{"author_name":"Florencia Martinez-Addiego","author_inst":"Georgia Institute of Technology"},{"author_name":"Dobromir Rahnev","author_inst":"Georgia Institute of Technology"},{"author_name":"Bradley C Duchaine","author_inst":"Dartmouth College"},{"author_name":"N. Apurva Ratan Murty","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"State-specific binding thermodynamics predicts ligand efficacy across ion-channel families.","rel_doi":"10.64898\/2026.09.22.753602","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.753602","rel_abs":"Predicting ligand efficacy is a critical challenge in drug discovery, as a target's functional response is often determined by the way a ligand shifts conformational equilibria between different functional states, a process that is particularly intricate in ion channels. We classify ligands based on the difference of their binding free energies on putative active and inactive conformations, calculated via free energy perturbation (FEP) for 78 protein-ligand pairs across six ion channels from four structural superfamilies: GluA2, GABAAR {rho}1, 3{beta}4 nAChR, 5-HT3AR, TRPML1, and KCNQ2. This approach accurately distinguishes agonists from antagonists across all these ion-channel families with large or subtle structural differences, including at membrane-facing sites, and enables quantitative prediction of maximum response and partial agonism. Importantly, we find that local binding-pocket conformations encode the bound ligand's efficacy even when global channel states are ambiguous. Our results demonstrate that state-specific binding thermodynamics provides a robust framework for leveraging ion channel structures of diverse conformational states to elucidate mechanisms of action and to advance ion-channel drug discovery beyond simple affinity measurements, enabling the identification of new chemical matter with desired functional attributes.","rel_num_authors":7,"rel_authors":[{"author_name":"Martin V\u00f6gele","author_inst":"Schr\u00f6dinger, Inc."},{"author_name":"Abba E. Leffler","author_inst":"Schr\u00f6dinger, Inc."},{"author_name":"Kevin C. Felt","author_inst":"Department of Pharmacology, Case Western Reserve University"},{"author_name":"Lindsay Denluck","author_inst":"Schr\u00f6dinger, Inc."},{"author_name":"Edward B. Miller","author_inst":"Schr\u00f6dinger, Inc."},{"author_name":"Sudha Chakrapani","author_inst":"Department of Pharmacology, Case Western Reserve University"},{"author_name":"Lingle Wang","author_inst":"Schr\u00f6dinger, Inc."}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Designed IDPs phase separate and mix or demix according to sequence designed parameters","rel_doi":"10.64898\/2026.09.23.753891","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.23.753891","rel_abs":"Biomolecular condensates are condensed assemblies of biomolecules that form through the process of liquid phase separation. Condensates in biology typically function as membraneless organelles, providing compartmentalization in the absence of a dividing lipid membrane. The molecular make-up of different condensates includes diverse multivalent proteins and nucleic acids as the primary drivers, many of them including significant fractions of intrinsically disordered regions (IDRs). To date, the sequence to phase separation relationship of IDRs has focused largely on one protein at a time, studying single-component condensate formation, or single-component partitioning into condensates. The co-phase separation and mixing of two or more IDRs is considerably more complex as both sequences can vary widely in their self- and cross-interactions, as well as their relative abundance in solution. It is unclear that a rule which predicts how a single sequence behaves will also predict what happens when two sequences are mixed. In this study, we disentangle the influence of sequence from that of composition using a set of 18 LAF-1 RGG variants that keep the same length and amino-acid composition and change only the order of the residues. This lets us vary charge patterning and, to a lesser extent, hydropathy patterning while keeping protein composition fixed. By themselves, the sequences phase separation and single-chain compaction are controlled by their degree of charge and hydropathy patterning. Within single-component condensed phases, each sequence adopts a more extended conformational ensemble, due to a more favorable, selfsolvated environment. We find that mixing two IDRs together into a condensate causes this universal scaling behavior to break, impacted by the relative interactions of the two components and overall composition of the slab. We find two different qualitative behaviors, one characterized by cooperative co-condensation when both sequences are subcritical, and the other by scaffold-client behavior when one sequence is supercritical. The scaffold-client systems generally show a high degree of demixing, while the co-condensing systems are generally quite well-mixed in the dense phase. This is surprising because even in cases where both partners have significantly different patterning parameters, they still mix. Thus, the descriptor that predicts a sequence's behavior alone can help indicate whether it will mix with or separate from a second component, but it does not fully determine the outcome on its own.","rel_num_authors":2,"rel_authors":[{"author_name":"Arjun Singh","author_inst":"Department of Chemical and Biochemical Engineering, Rutgers University, Piscataway, NJ, United States"},{"author_name":"Gregory L Dignon","author_inst":"Department of Chemical and Biochemical Engineering, Rutgers University, Piscataway, NJ, United States"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Environmentally-mediated yield effects of vernalization and photoperiod alleles in historic winter wheat trials","rel_doi":"10.64898\/2026.09.18.752491","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.752491","rel_abs":"In common wheat (Triticum aestivum L.), variation at the Vrn1 and Ppd1 loci changes plant phenology, resulting in differential adaptation useful to breeders. Because the effects of phenology on grain yield are conditional on environmental factors, the incorporation of markers for Vrn1 and Ppd1 alleles into breeding approaches has proven difficult. Historic phenotypic, genotypic, and environmental data can provide insight into the relationship between major phenology alleles and grain yield as mediated by environmental variables. Analyses of eight years of breeding trials (1,038 lines at 219 site-years) determined that weak vrn1 alleles and Ppd1 insensitivity alleles have variable effects. These effects change depending on an environment's winter temperature and latitude, respectively, but the environmentally-driven changes in effect of vrn1 alleles are much more variable than effects of Ppd1 alleles. Mediation analyses showed phenologically-dependent environmental variables are one mechanism through which phenological changes created by vrn1 and Ppd1 variants alter yield across multiple developmental stages. Environmentally-driven relationships between flowering time and yield were modeled to estimate yield allele effects as a function of effects on phenology and environmental variables. Weak winter alleles at vrn1 may play a stabilizing role on yield, due to the correlation of winter conditions that drive larger effects with later-season warm temperatures that penalize later maturity. A better mechanistic understanding of how these loci drive environment-specific yield effects may facilitate utilization of markers for these alleles and improve predictive modeling of yield.","rel_num_authors":27,"rel_authors":[{"author_name":"Noah DeWitt","author_inst":"Department of Soil, Plant, and Environmental Sciences, Louisiana State University"},{"author_name":"Zachary Winn","author_inst":"Department of Soil and Crop Sciences, Colorado State University"},{"author_name":"Mohammed Guedira","author_inst":"Department of Crop and Soil Sciences, North Carolina State University"},{"author_name":"Jeanette Lyerly","author_inst":"Department of Crop and Soil Sciences, North Carolina State University"},{"author_name":"Christian Maltecca","author_inst":"Department of Animal Science, North Carolina State University"},{"author_name":"Brian Ward","author_inst":"Forage Genetics International"},{"author_name":"William Stafstrom","author_inst":"Pee Dee Research and Education Center, Clemson University"},{"author_name":"Md. Ali Babar","author_inst":"Agronomy Department, University of Florida"},{"author_name":"Nonoy Bandillo","author_inst":"Department of Crop and Soil Sciences, North Carolina State University"},{"author_name":"Richard Boyles","author_inst":"Pee Dee Research and Education Center, Clemson University"},{"author_name":"Stephen Harrison","author_inst":"Department of Soil, Plant, and Environmental Sciences, Louisiana State University"},{"author_name":"Kimberly Howell","author_inst":"SEA, Plant Science Research, USDA-ARS"},{"author_name":"R. Esten Mason","author_inst":"Department of Soil and Crop Sciences, Colorado State University"},{"author_name":"Ellen Melson","author_inst":"Texas A and M University"},{"author_name":"Mohamed Mergoum","author_inst":"Department of Crop Science, University of Georgia"},{"author_name":"Mohsen Mohammadi","author_inst":"Department of Agronomy, Purdue University"},{"author_name":"J. Paul Murphy","author_inst":"Department of Crop and Soil Sciences, North Carolina State University"},{"author_name":"Eric Olson","author_inst":"Department of Plant, Soil and Microbial Sciences, Michigan State University"},{"author_name":"Jessica Rutkoski","author_inst":"Department of Crop Science, University of Illinois Urbana-Champaign"},{"author_name":"Nicholas Santantonio","author_inst":"Department of Crop and Soil Environmental Sciences, Virginia Polytechnic Institute and State University"},{"author_name":"Jared H. Smith","author_inst":"SEA, Plant Science Research, USDA-ARS"},{"author_name":"Clay Sneller","author_inst":"Department of Horticulture and Crop Science, The Ohio State University"},{"author_name":"Mark Sorrells","author_inst":"School of Integrative Plant Science, Cornell University"},{"author_name":"Russell Sutton","author_inst":"Texas A&M AgriLife Research, Texas A&M University"},{"author_name":"Vijay Tiwari","author_inst":"Department of Plant Science and Landscape Architecture, University of Maryland"},{"author_name":"David A. Van Sanford","author_inst":"Department of Plant and Soil Sciences, University of Kentucky"},{"author_name":"Gina Brown-Guedira","author_inst":"SEA, Plant Science Research, Department of Crop and Soil Sciences, USDA ARS, North Carolina State University"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Environmentally-mediated yield effects of vernalization and photoperiod alleles in historic winter wheat trials","rel_doi":"10.64898\/2026.09.18.752491","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.752491","rel_abs":"In common wheat (Triticum aestivum L.), variation at the Vrn1 and Ppd1 loci changes plant phenology, resulting in differential adaptation useful to breeders. Because the effects of phenology on grain yield are conditional on environmental factors, the incorporation of markers for Vrn1 and Ppd1 alleles into breeding approaches has proven difficult. Historic phenotypic, genotypic, and environmental data can provide insight into the relationship between major phenology alleles and grain yield as mediated by environmental variables. Analyses of eight years of breeding trials (1,038 lines at 219 site-years) determined that weak vrn1 alleles and Ppd1 insensitivity alleles have variable effects. These effects change depending on an environment's winter temperature and latitude, respectively, but the environmentally-driven changes in effect of vrn1 alleles are much more variable than effects of Ppd1 alleles. Mediation analyses showed phenologically-dependent environmental variables are one mechanism through which phenological changes created by vrn1 and Ppd1 variants alter yield across multiple developmental stages. Environmentally-driven relationships between flowering time and yield were modeled to estimate yield allele effects as a function of effects on phenology and environmental variables. Weak winter alleles at vrn1 may play a stabilizing role on yield, due to the correlation of winter conditions that drive larger effects with later-season warm temperatures that penalize later maturity. A better mechanistic understanding of how these loci drive environment-specific yield effects may facilitate utilization of markers for these alleles and improve predictive modeling of yield.","rel_num_authors":27,"rel_authors":[{"author_name":"Noah DeWitt","author_inst":"Department of Soil, Plant, and Environmental Sciences, Louisiana State University"},{"author_name":"Zachary Winn","author_inst":"Department of Soil and Crop Sciences, Colorado State University"},{"author_name":"Mohammed Guedira","author_inst":"Department of Crop and Soil Sciences, North Carolina State University"},{"author_name":"Jeanette Lyerly","author_inst":"Department of Crop and Soil Sciences, North Carolina State University"},{"author_name":"Christian Maltecca","author_inst":"Department of Animal Science, North Carolina State University"},{"author_name":"Brian Ward","author_inst":"Forage Genetics International"},{"author_name":"William Stafstrom","author_inst":"Pee Dee Research and Education Center, Clemson University"},{"author_name":"Md. Ali Babar","author_inst":"Agronomy Department, University of Florida"},{"author_name":"Nonoy Bandillo","author_inst":"Department of Crop and Soil Sciences, North Carolina State University"},{"author_name":"Richard Boyles","author_inst":"Pee Dee Research and Education Center, Clemson University"},{"author_name":"Stephen Harrison","author_inst":"Department of Soil, Plant, and Environmental Sciences, Louisiana State University"},{"author_name":"Kimberly Howell","author_inst":"SEA, Plant Science Research, USDA-ARS"},{"author_name":"R. Esten Mason","author_inst":"Department of Soil and Crop Sciences, Colorado State University"},{"author_name":"Ellen Melson","author_inst":"Texas A and M University"},{"author_name":"Mohamed Mergoum","author_inst":"Department of Crop Science, University of Georgia"},{"author_name":"Mohsen Mohammadi","author_inst":"Department of Agronomy, Purdue University"},{"author_name":"J. Paul Murphy","author_inst":"Department of Crop and Soil Sciences, North Carolina State University"},{"author_name":"Eric Olson","author_inst":"Department of Plant, Soil and Microbial Sciences, Michigan State University"},{"author_name":"Jessica Rutkoski","author_inst":"Department of Crop Science, University of Illinois Urbana-Champaign"},{"author_name":"Nicholas Santantonio","author_inst":"Department of Crop and Soil Environmental Sciences, Virginia Polytechnic Institute and State University"},{"author_name":"Jared H. Smith","author_inst":"SEA, Plant Science Research, USDA-ARS"},{"author_name":"Clay Sneller","author_inst":"Department of Horticulture and Crop Science, The Ohio State University"},{"author_name":"Mark Sorrells","author_inst":"School of Integrative Plant Science, Cornell University"},{"author_name":"Russell Sutton","author_inst":"Texas A&M AgriLife Research, Texas A&M University"},{"author_name":"Vijay Tiwari","author_inst":"Department of Plant Science and Landscape Architecture, University of Maryland"},{"author_name":"David A. Van Sanford","author_inst":"Department of Plant and Soil Sciences, University of Kentucky"},{"author_name":"Gina Brown-Guedira","author_inst":"SEA, Plant Science Research, Department of Crop and Soil Sciences, USDA ARS, North Carolina State University"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"An open imaging and AI resource enabling unbiased quantification of extrachromosomal DNA at scale","rel_doi":"10.64898\/2026.09.18.752721","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.752721","rel_abs":"Quantitative imaging of extrachromosomal DNA (ecDNA) is increasingly important for studying cancer heterogeneity and adaptation, yet automated analysis has been limited by the absence of accessible imaging data, gold standard annotations and adaptable computational tools. Here we establish an open resource for computational ecDNA imaging, integrating 2,986 native-resolution metaphase FISH image sets with manual annotations, standardized benchmarks and open-source quantification frameworks. We use this resource to systematically compare existing and newly developed approaches spanning rule-based computer vision, deep-learning-based segmentation and probabilistic localization. This comparison reveals count-dependent underestimation that distorts ecDNA copy-number distributions and motivates ecCount, a probabilistic localization method developed here to preserve individual ecDNA signals and quantitative burden. ecCount achieves an object-level F1 score of 0.939 on held-out images with minimal count bias. Together, the images, annotations, retrainable models, evaluation tools and guided workflows provide community infrastructure for applying, adapting and improving automated ecDNA quantification across experimental systems.","rel_num_authors":10,"rel_authors":[{"author_name":"Poorya Behnamie","author_inst":"UNC Chapel Hill"},{"author_name":"River Summers","author_inst":"UNC Chapel Hill"},{"author_name":"Jingting Chen","author_inst":"UNC Chapel Hill"},{"author_name":"Aarav Mehta","author_inst":"UNC Chapel Hill"},{"author_name":"Adesuwa Igbinigie","author_inst":"UNC Chapel Hill"},{"author_name":"Qin Liu","author_inst":"UNC Chapel Hill"},{"author_name":"Molly Murray","author_inst":"UNC Chapel Hill"},{"author_name":"Damien Guilbaud","author_inst":"UNC Chapel Hill"},{"author_name":"Marc Niethammer","author_inst":"UCSD"},{"author_name":"Elizabeth Claire Brunk","author_inst":"University of North Carolina at Chapel Hill"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Prime Editing Corrects the HBB Codon 8\/9 (+G) Mutation in Patient-Derived Induced Pluripotent Stem Cells and Restores \u03b2-Globin Expression in iPSC-Derived Erythroid Cells","rel_doi":"10.64898\/2026.09.22.753453","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.753453","rel_abs":"Homozygosity for the HBB codon 8\/9 (+G) frameshift (c.27dup (p.Ser10ValfsTer14)) causes transfusion-dependent {beta}-thalassaemia and is common in South Asia. Prime editing can reverse this insertion without double-strand breaks or donor DNA, but its efficiency depends on pegRNA design. We derived Sendai-reprogrammed iPSCs from a homozygous patient, optimised PEmax editing (spacer, pegRNA extension, secondary nick, MLH1dn) and compared patient, PEmax-treated and control iPSC-derived erythroid cells by flow cytometry, colony assays, RT-qPCR, western blotting and cation-exchange HPLC. Patient iPSCs had a normal 46,XY karyotype, expressed pluripotency markers, formed all three germ layers and were Sendai-free by passage 15. A PAM-disrupting spacer with a +68 nicking sgRNA gave the highest intended-edit frequency 8.4%; MLH1dn added little. PEmax-treated cultures matured and formed colonies more like control than patient cultures, restored HBB transcript (about 4-fold control iPSC-derived cells) and detectable {beta}-globin protein, and contained an HPLC fraction consistent with HbA ( undetectable in patient cells). Fetal haemoglobin (about 80%) and embryonic globin remained predominant. Prime editing corrects HBB c.27dupG in patient iPSCs and restores {beta}-globin expression, with partial restoration of adult haemoglobin in a fetal\/embryonic-type erythroid background. Validation in additional donors, haematopoietic stem cells and in vivo is required.","rel_num_authors":13,"rel_authors":[{"author_name":"irfan hussain","author_inst":"Aga khan University"},{"author_name":"Kainaat Mumtaz","author_inst":"Centre for Regenerative Medicine and Stem Cell Research, Aga Khan University, Karachi, Pakistan"},{"author_name":"Maliha Javed","author_inst":"Centre for Regenerative Medicine and Stem Cell Research, Aga Khan University, Karachi, Pakistan"},{"author_name":"Susheel Fatima","author_inst":"Centre for Regenerative Medicine and Stem Cell Research, Aga Khan University, Karachi, Pakistan"},{"author_name":"Hijab Zahra","author_inst":"Centre for Regenerative Medicine and Stem Cell Research, Aga Khan University, Karachi, Pakistan"},{"author_name":"Anwar Alam","author_inst":"Centre for Regenerative Medicine and Stem Cell Research, Aga Khan University, Karachi, Pakistan"},{"author_name":"Muhammad Jameel","author_inst":"Centre for Regenerative Medicine and Stem Cell Research, Aga Khan University, Karachi, Pakistan"},{"author_name":"Naveed Altaf Malik","author_inst":"National Institute for Biotechnology and Genetic Engineering College, Pakistan Institute of Engineering and Applied Sciences, Faisalabad, Pakistan"},{"author_name":"Farhatullah Syed","author_inst":"Cancer Centre of Excellence (CCoE), King Faisal Specialist Hospital & Research Centre , Riyadh, Saudi Arabia"},{"author_name":"Fawad Ur Rehman","author_inst":"Centre for Regenerative Medicine and Stem Cell Research, Aga Khan University, Karachi, Pakistan"},{"author_name":"Salman Kirmani","author_inst":"Centre of Excellence in Women & Child Health, Aga Khan University Hospital, Karachi, Pakistan"},{"author_name":"Ambrin Fatima","author_inst":"Centre for Regenerative Medicine and Stem Cell Research, Aga Khan University, Karachi, Pakistan; Department of Biological and Biomedical Sciences, Aga Khan Univ"},{"author_name":"Afsar  Ali Mian","author_inst":"Centre for Regenerative Medicine and Stem Cell Research, Aga Khan University, Karachi, Pakistan"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"One-Dose Efficacy of Long-Acting Sorfequiline in a Mouse Model of Tuberculosis Preventive Therapy","rel_doi":"10.64898\/2026.09.22.752266","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.752266","rel_abs":"Rationale: Tuberculosis preventive therapy (TPT) is essential for global tuberculosis control, yet estimated coverage remains well below global targets. Current World Health Organization (WHO)-recommended regimens require 1-9 months of treatment and are associated with suboptimal completion rates. Long-acting injectable (LAI) formulations offer the potential to improve TPT uptake and completion, with ideal products providing \"one-and-done\" options via a single administration. Sorfequiline, a second-generation diarylquinoline with superior potency over bedaquiline and lower QT prolongation risk, is a promising candidate for LAI TPT.","rel_num_authors":9,"rel_authors":[{"author_name":"Si-Yang Li","author_inst":"Johns Hopkins University"},{"author_name":"James J. Hobson","author_inst":"University of Liverpool"},{"author_name":"Nicole C. Ammerman","author_inst":"Erasmus MC"},{"author_name":"Henry Pertinez","author_inst":"Department of Molecular and Clinical Pharmacology, University of Liverpool"},{"author_name":"Jo Sharp","author_inst":"University of Liverpool"},{"author_name":"Nader Fotouhi","author_inst":"TB Alliance"},{"author_name":"Stephen Rannard","author_inst":"University of Liverpool"},{"author_name":"Andrew Owen","author_inst":"University of Liverpool"},{"author_name":"Eric L. Nuermberger","author_inst":"Johns Hopkins University School of Medicine"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Refinement of the Pathogenic T Cell Receptor Motif Suggests Type 17 CD8+ T Cells Initiate HLA-B*27-associated Autoimmunity","rel_doi":"10.64898\/2026.09.18.752092","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.752092","rel_abs":"Human leukocyte antigen B*27 (HLA-B*27) is a major risk factor for autoimmune diseases such as axial spondyloarthritis (axSpA), acute anterior uveitis (AAU), and psoriatic arthritis (PsA). HLA-B*27 presents bacterial and self-antigens to disease-associated CD8+ T cells, however, how this leads to a pathogenic IL-17-mediated disease remains unclear. We performed mutational experiments in an established disease-associated TCR and demonstrated that the pathogenic motif encompasses a wider range of TCR sequences than previously appreciated. We next leveraged computational pairing of alpha\/beta TCR sequencing (TCR-seq) to demonstrate that the broadened pathogenic motif distinguishes axSpA and AAU patients from healthy controls. Paired single-cell RNA sequencing and single-cell TCR sequencing datasets demonstrated that the pathogenic cells have a distinct transcriptional signature. We find a coupling of pathogenic TCRs to this transcriptional signature in public datasets from axSpA and PsA joint fluid and AAU ocular fluid. Finally, we detect the pathogenic CD8+ T cells in the gut and demonstrate that they express a Type 17 program. Our findings suggest that HLA-B*27+ axSpA, AAU, and PsA are initiated by HLA-B*27-restricted pathogenic CD8+ T cells that undergo Type 17 differentiation in response to intestinal antigens.","rel_num_authors":20,"rel_authors":[{"author_name":"Isabel Risch","author_inst":"Washington University in St. Louis"},{"author_name":"Qingping Wu","author_inst":"Washington University in St. Louis"},{"author_name":"Rahul Devkota","author_inst":"Washington University in St. Louis"},{"author_name":"Sophia Y Li","author_inst":"Washington University in St. Louis"},{"author_name":"Joy Um","author_inst":"Washington University in St. Louis"},{"author_name":"Tertuliano Alves Pereira Neto","author_inst":"Washington University in St. Louis"},{"author_name":"Sarah Walden","author_inst":"Washington University in St. Louis"},{"author_name":"Paulo Henrique Arantes de Faria","author_inst":"Washington University in St. Louis"},{"author_name":"Andrei Belean","author_inst":"Washington University in St. Louis"},{"author_name":"Lucy Durham","author_inst":"Kings College London"},{"author_name":"Michael Tang","author_inst":"University Health Network"},{"author_name":"Zoya Qaiyum","author_inst":"University Health Network"},{"author_name":"Robert D. Inman","author_inst":"University Health Network"},{"author_name":"Leonie S Taams","author_inst":"King's College London"},{"author_name":"Xinbo Yang","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Philip A Mudd","author_inst":"Washington University School of Medicine"},{"author_name":"Nicholas Borcherding","author_inst":"Washington University in St Louis"},{"author_name":"Malachi Griffith","author_inst":"Washington University"},{"author_name":"Obi L Griffith","author_inst":"McDonnell Genome Institute, Washington University"},{"author_name":"Michael A Paley","author_inst":"Washington University in St Louis"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"TRPV1-expressing neurons are dispensable for photophobia: evidence from a novel mouse light sensitivity assay","rel_doi":"10.64898\/2026.09.16.752141","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.16.752141","rel_abs":"Background: Light hypersensitivity, or photophobia, affects nearly 80% of people with migraine and is the most prevalent symptom after headache. Despite its high prevalence, the neural pathways underlying migraine-associated light hypersensitivity remain poorly understood, in part due to the lack of behavioral assays that directly assess light sensitivity in mice. Consequently, whether nociceptors contribute to the development of photophobia remains unclear. Methods: We established a novel light sensitivity assay (LSA) to quantify the response to light in mice by measuring facial grimacing. The assay was applied to evaluate light hypersensitivity elicited by three established migraine triggers: calcitonin gene-related peptide (CGRP), nitric oxide donor (sodium nitroprusside), and repeated stress. To determine the contribution of TRPV1 nociceptors, mice were treated with resiniferatoxin (RTX) to ablate these neurons. Results: The LSA detected light hypersensitivity following administration of CGRP, sodium nitroprusside, and repeated stress in wild-type (WT) mice. Sex differences were not observed in CGRP- or stress-induced light hypersensitivity. Furthermore, ablation of TRPV1 nociceptors did not reduce light hypersensitivity induced by migraine triggers. Conclusions: These findings present the LSA as a robust, reproducible, and easy to implement behavioral assay for measuring light sensitivity in preclinical migraine models. Our results further demonstrate that TRPV1 nociceptors are dispensable for the development of migraine-associated light hypersensitivity. This assay provides a useful method for investigating the mechanisms underlying light sensitivity and for evaluating potential therapeutic strategies.","rel_num_authors":4,"rel_authors":[{"author_name":"Jaewon Sim","author_inst":"Michigan State University"},{"author_name":"Alex D Chapman","author_inst":"Michigan State University"},{"author_name":"Gwendolyn R Urbain","author_inst":"Michigan State University"},{"author_name":"Geoffroy Laumet","author_inst":"Michigan State University"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Cannabis THC:CBD Composition Affects Oligodendrocyte Progenitor Cell Characteristics Following Acute Cannabis Vapor Inhalation in Adult Male and Female Mice","rel_doi":"10.64898\/2026.09.18.752658","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.752658","rel_abs":"Cannabis is one of the most widely consumed substances in the world. Consumers seek out cannabis cultivars with varying levels of phytocannabinoids, primarily delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). The effects of THC, CBD or the combination of THC:CBD have distinct outcomes on cognitive processes, cellular functions, and phytocannabinoid pharmacokinetics. The majority of research on cannabis effects on the brain has focussed on neurons, and few studies have investigated the impact of different cannabis cultivars on glia. In particular, the impact of varying levels of THC:CBD on oligodendrocyte lineage cells, which play numerous support roles in the brain essential to proper neuronal communication, is relatively unknown. This study set out to examine the acute impact of different cultivars of vaporized cannabis on oligodendrocyte lineage cells in the forceps minor of adult male and female mice. Mice were exposed to vapor from cannabis flower high in THC, high in CBD or balanced in THC:CBD over 15 minutes, and brains were fixed 30 minutes post-cannabis onset. Using immunofluorescence microscopy, we observed significant changes to oligodendrocyte progenitor cell (OPC) morphology in mice exposed to balanced cannabis, and, using correlative light and electron microscopy, we observed alterations to OPC mitochondria. The alterations observed (i.e., enlarged soma and nucleus volume, reduced density and increased area of mitochondria in the soma) in OPCs due to balanced cannabis are reminiscent of the very early changes seen during OPC differentiation. This study highlights the differing effects of cannabis cultivars on OPCs and the rapidity of the OPC response to inhaled phytocannabinoids.","rel_num_authors":10,"rel_authors":[{"author_name":"Colin J. Murray","author_inst":"School of Medical Sciences, University of Victoria, Victoria, BC, Canada"},{"author_name":"Hayley H.A. Thorpe","author_inst":"Department of Anatomy and Cell Biology, Schulich School of Medicine, Western University, London, Ontario, Canada."},{"author_name":"Hakan Kayir","author_inst":"Department of Anatomy and Cell Biology, Schulich School of Medicine, Western University, London, Ontario, Canada."},{"author_name":"Emiko Osborne","author_inst":"School of Medical Sciences, University of Victoria, Victoria, BC, Canada."},{"author_name":"Sean W. Foster","author_inst":"School of Medical Sciences, University of Victoria, Victoria, BC, Canada."},{"author_name":"Sophia Loewen","author_inst":"School of Medical Sciences, University of Victoria, Victoria, BC, Canada."},{"author_name":"Mika Rogers","author_inst":"School of Medical Sciences, University of Victoria, Victoria, BC, Canada."},{"author_name":"Haley A. Vecchiarelli","author_inst":"School of Psychology, Faculty of Social Sciences, University of Ottawa, Ottawa, Ontario, Canada."},{"author_name":"Jibran Y. Khokhar","author_inst":"Department of Anatomy and Cell Biology, Schulich School of Medicine, Western University, London, Ontario, Canada."},{"author_name":"Marie-\u00c8ve Tremblay","author_inst":"School of Medical Sciences, University of Victoria, Victoria, BC, Canada."}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Cannabis THC:CBD Composition Affects Oligodendrocyte Progenitor Cell Characteristics Following Acute Cannabis Vapor Inhalation in Adult Male and Female Mice","rel_doi":"10.64898\/2026.09.18.752658","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.752658","rel_abs":"Cannabis is one of the most widely consumed substances in the world. Consumers seek out cannabis cultivars with varying levels of phytocannabinoids, primarily delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). The effects of THC, CBD or the combination of THC:CBD have distinct outcomes on cognitive processes, cellular functions, and phytocannabinoid pharmacokinetics. The majority of research on cannabis effects on the brain has focussed on neurons, and few studies have investigated the impact of different cannabis cultivars on glia. In particular, the impact of varying levels of THC:CBD on oligodendrocyte lineage cells, which play numerous support roles in the brain essential to proper neuronal communication, is relatively unknown. This study set out to examine the acute impact of different cultivars of vaporized cannabis on oligodendrocyte lineage cells in the forceps minor of adult male and female mice. Mice were exposed to vapor from cannabis flower high in THC, high in CBD or balanced in THC:CBD over 15 minutes, and brains were fixed 30 minutes post-cannabis onset. Using immunofluorescence microscopy, we observed significant changes to oligodendrocyte progenitor cell (OPC) morphology in mice exposed to balanced cannabis, and, using correlative light and electron microscopy, we observed alterations to OPC mitochondria. The alterations observed (i.e., enlarged soma and nucleus volume, reduced density and increased area of mitochondria in the soma) in OPCs due to balanced cannabis are reminiscent of the very early changes seen during OPC differentiation. This study highlights the differing effects of cannabis cultivars on OPCs and the rapidity of the OPC response to inhaled phytocannabinoids.","rel_num_authors":10,"rel_authors":[{"author_name":"Colin J. Murray","author_inst":"School of Medical Sciences, University of Victoria, Victoria, BC, Canada"},{"author_name":"Hayley H.A. Thorpe","author_inst":"Department of Anatomy and Cell Biology, Schulich School of Medicine, Western University, London, Ontario, Canada."},{"author_name":"Hakan Kayir","author_inst":"Department of Anatomy and Cell Biology, Schulich School of Medicine, Western University, London, Ontario, Canada."},{"author_name":"Emiko Osborne","author_inst":"School of Medical Sciences, University of Victoria, Victoria, BC, Canada."},{"author_name":"Sean W. Foster","author_inst":"School of Medical Sciences, University of Victoria, Victoria, BC, Canada."},{"author_name":"Sophia Loewen","author_inst":"School of Medical Sciences, University of Victoria, Victoria, BC, Canada."},{"author_name":"Mika Rogers","author_inst":"School of Medical Sciences, University of Victoria, Victoria, BC, Canada."},{"author_name":"Haley A. Vecchiarelli","author_inst":"School of Psychology, Faculty of Social Sciences, University of Ottawa, Ottawa, Ontario, Canada."},{"author_name":"Jibran Y. Khokhar","author_inst":"Department of Anatomy and Cell Biology, Schulich School of Medicine, Western University, London, Ontario, Canada."},{"author_name":"Marie-\u00c8ve Tremblay","author_inst":"School of Medical Sciences, University of Victoria, Victoria, BC, Canada."}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Signal peptidase complexes set species-specific rules for signal peptide cleavage","rel_doi":"10.64898\/2026.09.20.752496","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.20.752496","rel_abs":"Protein secretion is essential for cell function and begins when signal peptides direct nascent proteins into the secretory pathway, where they are cleaved by the signal peptidase complex (SPC). Although this pathway is highly conserved, signal peptides do not always function efficiently across species, and the molecular basis for this incompatibility remains unclear. Here, we show that human signal peptides with longer hydrophobic cores efficiently target and translocate nascent proteins in both yeast and human but are frequently left uncleaved in yeast, identifying signal peptide cleavage as a major barrier to cross-species compatibility. Molecular dynamics (MD) simulations reveal that, despite their highly conserved architectures, yeast and human SPCs generate distinct membrane-thinning profiles near the signal peptide-binding region. Our results support a model in which SPC-lipid interactions tune the local membrane environment to accommodate signal peptides of distinct hydrophobic core length, providing a biophysical mechanism for species-specific signal peptide recognition. These findings offer a mechanistic framework for understanding and potentially engineering protein secretion across diverse expression hosts.","rel_num_authors":9,"rel_authors":[{"author_name":"Yeonji Chung","author_inst":"Seoul National University"},{"author_name":"Gilberto P Pereira","author_inst":"Ecole Normale Superieure de Lyon, France and Zymvol Biomodeling, Spain"},{"author_name":"Young June Lee","author_inst":"Seoul National University, South Korea"},{"author_name":"Achille Agnesa","author_inst":"Seoul National University, South Korea and University Cote dAzur, France"},{"author_name":"Lisbeth R Kjolby","author_inst":"Universite Claude Bernard Lyon 1, France"},{"author_name":"Henrik Nielsen","author_inst":"DTU"},{"author_name":"Gunnar Von Heijne","author_inst":"Stockholm University"},{"author_name":"Paulo C. T. Souza","author_inst":"Ecole Normale Superieure de Lyon, France"},{"author_name":"Hyun (Joy) Kim","author_inst":"Seoul National University"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Contribution of the novel oxazolidinone TBD09 (MK-7762) to regimens with bedaquiline and pretomanid in a mouse model of tuberculosis","rel_doi":"10.64898\/2026.09.23.753971","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.23.753971","rel_abs":"Linezolid is a key component of the bedaquiline, pretomanid, linezolid (BPaL) regimen for rifampin-resistant tuberculosis, but dose- and duration-dependent mitochondrial toxicity frequently limits its use. TBD09 (formerly MK-7762) is a novel oxazolidinone developed to maintain antitubercular potency comparable to linezolid while reducing related adverse events. We evaluated the contribution of TBD09 to the bactericidal and sterilizing activities of BPa-based regimens in a murine tuberculosis model. BALB\/c mice were aerosol-infected with Mycobacterium tuberculosis H37Rv and treated starting 2 weeks post-infection. In Experiment 1, dose-ranging bactericidal activity of TBD09 (50, 100, 200 mg\/kg) was assessed alone and in combination with BPa, with comparison to linezolid and sutezolid. In Experiment 2, the sterilizing activity of TBD09 (200 mg\/kg) in combination with BPa and BPa plus moxifloxacin (M) was assessed by evaluating relapse after treatment durations of 4-22 weeks. TBD09 monotherapy was bacteriostatic, similar to linezolid over the first 4 weeks of treatment. The addition of TBD09 to BPa significantly enhanced bactericidal activity comparable to the addition of linezolid. In relapse assessments, BPa+TBD09 resulted in significantly fewer relapses compared to BPa alone after 14 weeks of treatment, and BPaM+TBD09 resulted in significantly fewer relapses compared to BPaM after 10 weeks. Model-based analysis estimated the treatment duration to 95% cure for BPa+TBD09 at 2.7 weeks, compared to 3.2 weeks for BPaL, although the time to 50% cure was similar. These results demonstrate that TBD09 provides bactericidal and sterilizing activity similar to linezolid in combination with BPa(M), supporting further clinical development of TBD09 for tuberculosis.","rel_num_authors":8,"rel_authors":[{"author_name":"Deepak V Almeida","author_inst":"Johns Hopkins University"},{"author_name":"Paul J Converse","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Courtney Schill","author_inst":"Johns Hopkins University"},{"author_name":"Jin I. Lee","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Micha Levi","author_inst":"Bill & Melinda Gates Medical Research Institute"},{"author_name":"Alexander Berg","author_inst":"Gates Foundation"},{"author_name":"Mdluli Khisi","author_inst":"Bill & Melinda Gates Medical Research Institute"},{"author_name":"Eric L. Nuermberger","author_inst":"Johns Hopkins University School of Medicine"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Removing an S-layer enables endolysin-derived probes to detect Paenibacillus thiaminolyticus in mixed bacterial populations","rel_doi":"10.64898\/2026.09.23.753664","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.23.753664","rel_abs":"The emerging neonatal bacterial pathogen Paenibacillus thiaminolyticus causes sepsis and postinfectious hydrocephalus, yet few tools are available to study or specifically detect it. We developed fluorescent probes based on cell wall-binding domains (CBDs) from bacteriophage-derived cell-wall hydrolases. CBDs can target structurally conserved cell-wall glycans, making them attractive affinity reagents for bacterial detection. None of the 11 probes we designed labeled intact cells under standard conditions, and we identified a surface layer (S-layer) that prevented access to their cell-wall targets. Brief acidic treatment (pH 2.0) released abundant high-molecular-mass proteins from the cell surface and enabled labeling by five distinct CBD probes, each containing a single C-terminal S-layer homology domain. Mass spectrometry identified the main released protein as an ortholog of the P. alvei SpaA S-layer protein, which we designate SlsA. Across 26 surveyed P. thiaminolyticus genomes, we identified four distinct SlsA variants with 58-79% pairwise amino acid identity, encoded within a conserved cluster homologous to the P. alvei S-layer-associated locus. After either the acidic treatment or a quick flame fixation, the lead probe mGL-BDPt9 labeled six P. thiaminolyticus strains, including three Ugandan clinical isolates, as well as a P. dendritiformis clinical isolate from a US infant, and three additional Paenibacillus species. mGL-BDPt9 also distinguished P. thiaminolyticus from five gram-positive sepsis pathogens in pairwise mixtures and detected it in a five-species suspension. Together, these findings establish the presence of an S-layer in P. thiaminolyticus and provide a rapid fluorescent labeling strategy for multiple Paenibacillus pathogens associated with neonatal paenibacilliosis.","rel_num_authors":12,"rel_authors":[{"author_name":"Sarah K Szwed","author_inst":"Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA"},{"author_name":"Danielle McGrath","author_inst":"Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA"},{"author_name":"Morgan C Serbagi","author_inst":"Department of Medical Laboratory Sciences, Hunter College, City University of New York, New York, New York, USA"},{"author_name":"Chad W Euler","author_inst":"Department of Medical Laboratory Sciences, Hunter College, City University of New York, New York, New York, USA"},{"author_name":"Joseph N Paulson","author_inst":"Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, USA"},{"author_name":"Sarah U Morton","author_inst":"Boston Children's Hospital, Boston, Massachussets, USA"},{"author_name":"Jessica  E. Ericson","author_inst":"Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA"},{"author_name":"Marwan Osman","author_inst":"Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, USA"},{"author_name":"James R Broach","author_inst":"Department of Molecular and Precision Medicine, Penn State College of Medicine, Hershey, Pennsylvania, USA"},{"author_name":"Steven J Schiff","author_inst":"National Institutes of Health, 9000 Rockville Pike, 31 Center Drive MSC 2220, Bethesda, Maryland, USA"},{"author_name":"Vincent A Fischetti","author_inst":"Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA"},{"author_name":"Edmondo Campisi","author_inst":"Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Removing an S-layer enables endolysin-derived probes to detect Paenibacillus thiaminolyticus in mixed bacterial populations","rel_doi":"10.64898\/2026.09.23.753664","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.23.753664","rel_abs":"The emerging neonatal bacterial pathogen Paenibacillus thiaminolyticus causes sepsis and postinfectious hydrocephalus, yet few tools are available to study or specifically detect it. We developed fluorescent probes based on cell wall-binding domains (CBDs) from bacteriophage-derived cell-wall hydrolases. CBDs can target structurally conserved cell-wall glycans, making them attractive affinity reagents for bacterial detection. None of the 11 probes we designed labeled intact cells under standard conditions, and we identified a surface layer (S-layer) that prevented access to their cell-wall targets. Brief acidic treatment (pH 2.0) released abundant high-molecular-mass proteins from the cell surface and enabled labeling by five distinct CBD probes, each containing a single C-terminal S-layer homology domain. Mass spectrometry identified the main released protein as an ortholog of the P. alvei SpaA S-layer protein, which we designate SlsA. Across 26 surveyed P. thiaminolyticus genomes, we identified four distinct SlsA variants with 58-79% pairwise amino acid identity, encoded within a conserved cluster homologous to the P. alvei S-layer-associated locus. After either the acidic treatment or a quick flame fixation, the lead probe mGL-BDPt9 labeled six P. thiaminolyticus strains, including three Ugandan clinical isolates, as well as a P. dendritiformis clinical isolate from a US infant, and three additional Paenibacillus species. mGL-BDPt9 also distinguished P. thiaminolyticus from five gram-positive sepsis pathogens in pairwise mixtures and detected it in a five-species suspension. Together, these findings establish the presence of an S-layer in P. thiaminolyticus and provide a rapid fluorescent labeling strategy for multiple Paenibacillus pathogens associated with neonatal paenibacilliosis.","rel_num_authors":12,"rel_authors":[{"author_name":"Sarah K Szwed","author_inst":"Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA"},{"author_name":"Danielle McGrath","author_inst":"Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA"},{"author_name":"Morgan C Serbagi","author_inst":"Department of Medical Laboratory Sciences, Hunter College, City University of New York, New York, New York, USA"},{"author_name":"Chad W Euler","author_inst":"Department of Medical Laboratory Sciences, Hunter College, City University of New York, New York, New York, USA"},{"author_name":"Joseph N Paulson","author_inst":"Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, USA"},{"author_name":"Sarah U Morton","author_inst":"Boston Children's Hospital, Boston, Massachussets, USA"},{"author_name":"Jessica  E. Ericson","author_inst":"Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA"},{"author_name":"Marwan Osman","author_inst":"Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut, USA"},{"author_name":"James R Broach","author_inst":"Department of Molecular and Precision Medicine, Penn State College of Medicine, Hershey, Pennsylvania, USA"},{"author_name":"Steven J Schiff","author_inst":"National Institutes of Health, 9000 Rockville Pike, 31 Center Drive MSC 2220, Bethesda, Maryland, USA"},{"author_name":"Vincent A Fischetti","author_inst":"Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA"},{"author_name":"Edmondo Campisi","author_inst":"Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Hepatic cholinergic T cell signaling mediates an adaptive response to alcohol-induced liver stress","rel_doi":"10.64898\/2026.09.18.752097","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.752097","rel_abs":"Alcohol-associated liver disease (ALD) is a major cause of liver-related morbidity and mortality, yet no targeted, disease-modifying therapy exists and the immune mechanisms driving disease progression remain poorly defined. Acetylcholine-producing cholinergic immune cells have emerged as regulators of homeostasis across tissues and in disease, but their role in alcohol-induced hepatic stress is unknown. Here, we characterized the hepatic cholinergic immune landscape during alcohol-induced stress using flow cytometry and single-cell RNA-sequencing of ChAT-eGFP reporter mice. Alcohol feeding expanded hepatic cholinergic immune cells, with T cells constituting a substantial and dynamic fraction of this population that showed a broad increase in acetylcholine signaling and shifted towards a repressed, anergy-like transcriptional state. CD4 T cells underwent coordinated suppression of cholesterol biosynthesis, while CD8 T cells instead adopted a cytotoxic activation program. Together, these findings identify cholinergic T cell signaling, and cholesterol metabolism within CD4 T cells specifically, as a previously unrecognized adaptive response to alcohol-induced liver stress, nominating candidate therapeutic targets for a disease that is marred by critically limited treatment options.","rel_num_authors":4,"rel_authors":[{"author_name":"Alexander J Knights","author_inst":"Washington University"},{"author_name":"Shanshan Liu","author_inst":"University of Michigan"},{"author_name":"Evan J Kim","author_inst":"Washington University"},{"author_name":"Jun Wu","author_inst":"University of Michigan"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Reducing Neutrophil Sialic Acid Residues Alleviates Cerebral Hypoperfusion in Alzheimer's Models","rel_doi":"10.64898\/2026.09.23.753660","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.23.753660","rel_abs":"Objective: Dysregulation of the immune system is increasingly recognized as a contributor to Alzheimer's disease (AD) progression, partly through neutrophil adhesion to the cerebral vasculature, which promotes hypoperfusion in AD. Because sialic acid (SA) residues on membrane glycoproteins regulate neutrophil-endothelial interactions, we investigated whether neutrophil sialylation is altered in AD and whether reducing it improves cerebral vascular function. Approach and Results: Lectin blots of isolated neutrophils showed increased SA levels in two AD mouse models, 5xFAD and APP-SAA. We identified 2,3 sialyltransferase-IN-1 as a small-molecule inhibitor that reduces sialylation in vivo. Treating 5xFAD mice with this inhibitor decreased SA on neutrophil membranes, increased cerebral blood flow, and reduced capillary stalling. Leukocytes from patients with preclinical AD and mild cognitive impairment also had higher SA levels than those from age-matched healthy controls. Conclusions: Elevated terminal sialylation of neutrophil glycoproteins contributes to capillary stalling and cerebral hypoperfusion in AD. Neutrophil sialylation may serve as both a biomarker and a therapeutic target for improving cerebral blood flow and slowing disease progression.","rel_num_authors":10,"rel_authors":[{"author_name":"Nairuti Nikhil Bhatt","author_inst":"University of Miami"},{"author_name":"Zeynab Tabrizi","author_inst":"University of Southern California"},{"author_name":"Jolie Janulis","author_inst":"University of Southern California"},{"author_name":"Supriya Chakraborty","author_inst":"University of Miami"},{"author_name":"Madeleine Weick","author_inst":"University of Southern California"},{"author_name":"Sofia Andrea Franciosa","author_inst":"University of Miami"},{"author_name":"Gabriela Rodriguez Moore","author_inst":"University of Southern California"},{"author_name":"Christian Agatemor","author_inst":"University of Miami"},{"author_name":"James E Galvin","author_inst":"University of Miami Miller School of Medicine"},{"author_name":"Oliver Bracko","author_inst":"University of Southern California"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"LGR5 and SOX2 expressing progenitor cells in the adult and aged human and mouse inner ear have the potential to produce Myosin 7A positive cells in vitro","rel_doi":"10.64898\/2026.09.18.752313","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.752313","rel_abs":"Hearing loss and deafness as a result of hair cell loss cannot be restored due to the incapacity of spontaneous regeneration of these cells. Compounds that manipulate key signaling pathways can potentially regenerate cochlear hair cells. In order to test different compounds that promote hair cell regeneration in vitro models can be used. Three-dimensional cultures have allowed the expansion and experimentation of human and mouse inner ear organoids. This is mainly performed in the embryonic or the early postnatal developmental stage. However, since the majority of patients with hearing loss are adult, it is crucial to understand the adult inner ear regenerative capacity. Here, we evaluated progenitor cell markers in the adult human and mouse inner ear and the generation, expansion and differentiation of cochlear organoids derived from the adult human and mouse inner ear. Cochlear and vestibular sensory epithelium from adult humans; and from adult and aged mice express the progenitor markers SOX2 and LGR5; and can generate organoids in vitro. By optimizing the culture conditions, organoids derived from the cochlea and vestibular organ from adult human and adult and aged mouse differentiated to Myosin 7A positive cells. This indicates that the adult inner ear has regenerative capacity. These findings are encouraging for future regenerative therapies to cure hair cell-related hearing loss and deafness.","rel_num_authors":12,"rel_authors":[{"author_name":"Georgina E Fenton","author_inst":"UMC Utrecht"},{"author_name":"Tobias Pieper","author_inst":"UMC Utrecht"},{"author_name":"Cindy Cleypool","author_inst":"UMC Utrecht"},{"author_name":"Stephanie Sgroi","author_inst":"The Inner Ear and Olfaction Lab, Department of Clinical Neurosciences, Faculty of Medicine, University of Geneva"},{"author_name":"Francis Rousset","author_inst":"The Inner Ear and Olfaction Lab, Department of Clinical Neurosciences, Faculty of Medicine, University of Geneva"},{"author_name":"Cecilia de Heus","author_inst":"UMC Utrecht"},{"author_name":"Nalan Liv","author_inst":"University Medical Center Utrecht"},{"author_name":"Hans GXM Thomeer","author_inst":"UMC Utrecht"},{"author_name":"Pascal Senn","author_inst":"The Inner Ear and Olfaction Lab, Department of Clinical Neurosciences, Faculty of Medicine, University of Geneva"},{"author_name":"Robert J Stokroos","author_inst":"UMC Utrecht"},{"author_name":"Louise V. Straatman","author_inst":"UMC Utrecht"},{"author_name":"Natalia Smith Cortinez","author_inst":"UMC Utrecht"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Multimodal imaging maps spinal glymphatic transport in health and its disruption after injury","rel_doi":"10.64898\/2026.09.16.752122","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.16.752122","rel_abs":"Spinal cord injury (SCI) is an incurable neurological condition in which post-traumatic edema contributes to secondary ischemic damage because the spinal cord is confined within the rigid vertebral canal. However, glymphatic transport in the healthy and injured spinal cord remains poorly characterized. We hypothesized that spinal cerebrospinal (CSF) and glymphatic transport is shaped by anatomy, administration route, and molecular size of the tracer; is disrupted after SCI; and is further impaired by loss of aquaporin-4 (AQP4). CSF tracers were administered by cisterna magna or lumbar intrathecal injection to anesthetized adult C57BL\/6 mice. Dynamic contrast-enhanced MRI, ex vivo fluorescence imaging, and histology were used to characterize tracer distribution, influx, and clearance. Constrictions of the spinal subarachnoid space at C3-C7, T6-T12 and L5-S1 spinal segments accelerated contrast-agent dispersion, demonstrating that local anatomy regulates spinal CSF transport. Tracer influx into the cord itself occurred primarily along periarterial pathways.Tracer distribution depended on the administration route: cisterna magna injection preferentially labeled white matter in the upper spinal cord, whereas lumbar injection preferentially labeled grey matter in the lower spinal cord. Gadobutrol and ovalbumin penetrated and dispersed throughout the parenchyma, whereas fibrinogen remained confined to the meninges. Under physiological conditions, intraparenchymal tracers cleared within 24 h. SCI was modeled using a minimally invasive NMDA-induced lesion at T11 that produced focal necrosis while preserving the dura and vertebral structures. Glymphatic transport, lesion volume, and motor recovery were compared between wild-type and AQP4-knockout mice using imaging, the Basso Mouse Scale, and voluntary wheel running. After SCI, intrathecal contrast propagated more rapidly, especially at T7-T8 segments and at the S1 segment, but tissue clearance was profoundly impaired, with tracer retention persisting for up to seven days. AQP4-knockout mice showed greater clearance impairment, larger lesions, and poorer motor recovery than wild-type controls compared at 24 h. These findings define major determinants of spinal glymphatic transport and show that accelerated tracer propagation after SCI does not indicate effective clearance. Instead, SCI produces glymphatic dysfunction that is exacerbated by loss of AQP4 and associated with greater tissue damage and functional impairment. The results extend the glymphatic framework to the spinal cord and identify fluid-clearance pathways as potential therapeutic targets for limiting edema and secondary injury. Future studies should determine whether restoring glymphatic function improves neurological recovery after SCI.","rel_num_authors":6,"rel_authors":[{"author_name":"Jaspreet Kaur","author_inst":"Center for Translational Neuromedicine, University of Copenhagen, Blegdamsvej 3, Copenhagen N, 2200 DENMARK, Department of Neuroscience, University of Copenhage"},{"author_name":"Michael J Giannetto","author_inst":"Center for Translational Neuromedicine, University of Rochester Medical School, Elmwood Avenue 601, Rochester, NY 14642, USA"},{"author_name":"Devin T Wong","author_inst":"Department of Mechanical Engineering, University of Rochester, 240 Hutchison Dr., Rochester, NY 14620, USA"},{"author_name":"Douglas H Kelley","author_inst":"Department of Mechanical Engineering, University of Rochester, 240 Hutchison Dr., Rochester, NY 14620, USA"},{"author_name":"Pia Weikop","author_inst":"Center for Translational Neuromedicine, University of Rochester Medical School, Elmwood Avenue 601, Rochester, NY 14642, USA"},{"author_name":"Maiken Nedergaard","author_inst":"Center for Translational Neuromedicine, University of Copenhagen, Blegdamsvej 3, Copenhagen N, 2200 DENMARK, Center for Translational Neuromedicine, University "}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Plasmodium berghei is resistant to aryl amino acetamides that inhibit P. falciparum growth by targeting the phospholipid transfer protein PfSTART1.","rel_doi":"10.64898\/2026.09.22.753445","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.753445","rel_abs":"In a previous screen for compounds that inhibit Plasmodium falciparum merozoite invasion of red blood cells, we identified the Medicines for Malaria Venture compound MMV006833. This compound inhibits PfSTART1, a protein implicated in the expansion of the nascent parasitophorous vacuole membrane following invasion, to accommodate the developing ring-stage parasite. Live-cell lattice light-sheet microscopy of invading merozoites revealed that mNeonGreen-tagged PfSTART1 is released from structures within the merozoite into the nascent parasitophorous vacuole approximately 109 seconds after invasion. Expansion microscopy of PfSTART1-HA merozoites further showed that these punctate PfSTART1-containing structures do not colocalise with known secretory organelles (rhoptries, micronemes and dense granules). Although analogues of MMV006833 are highly potent against P. falciparum, they were previously found to be ineffective against P. berghei parasites in the mouse malaria model. Here, we demonstrate that PbSTART1 is highly resistant to MMV006833 and its analogues when expressed in P. falciparum, indicating that structural differences between the orthologous proteins reduce inhibitor potency. The crystal structure of PfSTART1 in complex with WEHI-991 revealed the molecular basis for inhibition and provided a structural explanation for the reduced potency of this family of compounds against P. berghei. To sensitise P. berghei parasites to MMV006833 analogues, the parasites were engineered to express PfSTART1; however, these chimeric parasites remained insensitive to the compounds. This suggests that factors beyond target engagement, such as compound half-life or bioavailability, contribute to the lack of efficacy observed in the mouse malaria model.","rel_num_authors":22,"rel_authors":[{"author_name":"Claudia BG Barnes","author_inst":"Burnet Institute"},{"author_name":"Mrittika Chowdury","author_inst":"Deakin University"},{"author_name":"Dawson B Ling","author_inst":"Walter and Eliza Hall Institute of Medical Research"},{"author_name":"Thomas McClean","author_inst":"Walter and Eliza Hall Institute of Medical Research"},{"author_name":"Alysha H Literski","author_inst":"Burnet Institute"},{"author_name":"Natalie A Counihan","author_inst":"Deakin University"},{"author_name":"Oliver Looker","author_inst":"Burnet Institute"},{"author_name":"Thorey K Jonsdottir","author_inst":"Burnet Institute"},{"author_name":"Coralie Boulet","author_inst":"Burnet Institute"},{"author_name":"William Nguyen","author_inst":"The Walter and Eliza Hall Institute of Medical Research"},{"author_name":"Madeline Dans","author_inst":"Deakin University"},{"author_name":"Emma Yuxin Mao","author_inst":"The University of Adelaide"},{"author_name":"Alan F Cowman","author_inst":"The Walter and Eliza Hall Institute of Medical Research"},{"author_name":"Niall D Geoghegan","author_inst":"Walter and Eliza Hall Institute of Medical Research"},{"author_name":"Kelly Rogers","author_inst":"Walter and Eliza Hall Institute"},{"author_name":"Danny W. Wilson","author_inst":"The University of Adelaide"},{"author_name":"Brendan Crabb","author_inst":"Burnet Institute"},{"author_name":"Stephen W Scally","author_inst":"Walter and Eliza Hall Institute of Medical Research"},{"author_name":"Brad E Sleebs","author_inst":"The Walter and Eliza Hall Institute of Medical Research"},{"author_name":"Hayley E Bullen","author_inst":"Burnet Institute"},{"author_name":"Tania F de Koning-Ward","author_inst":"Deakin University"},{"author_name":"Paul R Gilson","author_inst":"Burnet Institute"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"A CD4-CD8 T-cell circuit converts cardiac inflammation into tissue injury","rel_doi":"10.64898\/2026.09.18.751575","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.751575","rel_abs":"Inflammatory T-cell infiltration is widely considered a hallmark of cardiac immune-mediated tissue injury, yet whether inflammation alone is sufficient to cause cardiac damage remains unclear. Using a spontaneous genetic model of immune checkpoint inhibitor myocarditis, we show that cardiac immune infiltration and tissue injury are separable processes. CD4+ T-cells promote disease by licensing pathogenic CD8+ T-cell responses through CD40L signaling, whereas perforin-dependent CD8+ cytotoxicity is specifically required to induce cardiomyocyte death and cardiac arrhythmias. Loss of perforin prevented cardiac injury and rescued survival despite persistent myocardial inflammation, demonstrating that inflammatory infiltration is insufficient to produce lethal myocarditis in the absence of a cytotoxic effector program. CD40L blockade similarly attenuated pathogenic CD8+ T-cell activation, myocardial inflammation, and mortality. These findings identify a cooperative CD4-CD8 T-cell circuit that governs autoimmune cardiac injury and establish that acquisition of cytotoxic effector function, rather than inflammation alone, determines the transition from immune infiltration to tissue destruction.","rel_num_authors":10,"rel_authors":[{"author_name":"Amir Z. Munir","author_inst":"UCSF"},{"author_name":"Alan Gutierrez","author_inst":"Yale University School of Medicine"},{"author_name":"Cade J Krawiec","author_inst":"UCSF"},{"author_name":"Riad Ghandour","author_inst":"UCSF"},{"author_name":"Richard A Baylis","author_inst":"UCSF"},{"author_name":"Anya C Shyani","author_inst":"UCSF"},{"author_name":"Eva Rodriguez","author_inst":"UCSF"},{"author_name":"Aishwarya Nene","author_inst":"Memorial Sloan Kettering"},{"author_name":"Enrique Ortega-Sollero","author_inst":"CNIC"},{"author_name":"Javid J Moslehi","author_inst":"UCSF"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"A CD4-CD8 T-cell circuit converts cardiac inflammation into tissue injury","rel_doi":"10.64898\/2026.09.18.751575","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.751575","rel_abs":"Inflammatory T-cell infiltration is widely considered a hallmark of cardiac immune-mediated tissue injury, yet whether inflammation alone is sufficient to cause cardiac damage remains unclear. Using a spontaneous genetic model of immune checkpoint inhibitor myocarditis, we show that cardiac immune infiltration and tissue injury are separable processes. CD4+ T-cells promote disease by licensing pathogenic CD8+ T-cell responses through CD40L signaling, whereas perforin-dependent CD8+ cytotoxicity is specifically required to induce cardiomyocyte death and cardiac arrhythmias. Loss of perforin prevented cardiac injury and rescued survival despite persistent myocardial inflammation, demonstrating that inflammatory infiltration is insufficient to produce lethal myocarditis in the absence of a cytotoxic effector program. CD40L blockade similarly attenuated pathogenic CD8+ T-cell activation, myocardial inflammation, and mortality. These findings identify a cooperative CD4-CD8 T-cell circuit that governs autoimmune cardiac injury and establish that acquisition of cytotoxic effector function, rather than inflammation alone, determines the transition from immune infiltration to tissue destruction.","rel_num_authors":10,"rel_authors":[{"author_name":"Amir Z. Munir","author_inst":"UCSF"},{"author_name":"Alan Gutierrez","author_inst":"Yale University School of Medicine"},{"author_name":"Cade J Krawiec","author_inst":"UCSF"},{"author_name":"Riad Ghandour","author_inst":"UCSF"},{"author_name":"Richard A Baylis","author_inst":"UCSF"},{"author_name":"Anya C Shyani","author_inst":"UCSF"},{"author_name":"Eva Rodriguez","author_inst":"UCSF"},{"author_name":"Aishwarya Nene","author_inst":"Memorial Sloan Kettering"},{"author_name":"Enrique Ortega-Sollero","author_inst":"CNIC"},{"author_name":"Javid J Moslehi","author_inst":"UCSF"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"A CD4-CD8 T-cell circuit converts cardiac inflammation into tissue injury","rel_doi":"10.64898\/2026.09.18.751575","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.751575","rel_abs":"Inflammatory T-cell infiltration is widely considered a hallmark of cardiac immune-mediated tissue injury, yet whether inflammation alone is sufficient to cause cardiac damage remains unclear. Using a spontaneous genetic model of immune checkpoint inhibitor myocarditis, we show that cardiac immune infiltration and tissue injury are separable processes. CD4+ T-cells promote disease by licensing pathogenic CD8+ T-cell responses through CD40L signaling, whereas perforin-dependent CD8+ cytotoxicity is specifically required to induce cardiomyocyte death and cardiac arrhythmias. Loss of perforin prevented cardiac injury and rescued survival despite persistent myocardial inflammation, demonstrating that inflammatory infiltration is insufficient to produce lethal myocarditis in the absence of a cytotoxic effector program. CD40L blockade similarly attenuated pathogenic CD8+ T-cell activation, myocardial inflammation, and mortality. These findings identify a cooperative CD4-CD8 T-cell circuit that governs autoimmune cardiac injury and establish that acquisition of cytotoxic effector function, rather than inflammation alone, determines the transition from immune infiltration to tissue destruction.","rel_num_authors":10,"rel_authors":[{"author_name":"Amir Z. Munir","author_inst":"UCSF"},{"author_name":"Alan Gutierrez","author_inst":"Yale University School of Medicine"},{"author_name":"Cade J Krawiec","author_inst":"UCSF"},{"author_name":"Riad Ghandour","author_inst":"UCSF"},{"author_name":"Richard A Baylis","author_inst":"UCSF"},{"author_name":"Anya C Shyani","author_inst":"UCSF"},{"author_name":"Eva Rodriguez","author_inst":"UCSF"},{"author_name":"Aishwarya Nene","author_inst":"Memorial Sloan Kettering"},{"author_name":"Enrique Ortega-Sollero","author_inst":"CNIC"},{"author_name":"Javid J Moslehi","author_inst":"UCSF"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Cholinergic activation of HLH-30\/TFEB promotes C. elegans infection resilience.","rel_doi":"10.64898\/2026.09.18.752639","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.752639","rel_abs":"Innate host defense depends on transcriptional programs, which support survival through two strategies that can vary independently. Resistance lowers pathogen burden, while resilience limits the damage a given burden causes. In Caenorhabditis elegans infected with Staphylococcus aureus, the highly conserved transcription factor HLH-30\/TFEB drives most of the host response, which mediates infection resilience. We previously showed that EGL-30\/Gq, PLC-1\/PLC{varepsilon}, and DKF-1\/PRKD activate HLH-30\/TFEB during infection. The same phospholipase C and protein kinase D step activates TFEB in mouse macrophages infected with Salmonella or S. aureus. However, the input that drives the EGL-30\/Gq, PLC-1\/PLC{varepsilon}, and DKF-1\/PRKD module to activate HLH-30\/TFEB during infection remained unknown. Here we report that acetylcholine, acting on muscarinic receptors, is one such input. Atropine and scopolamine, two muscarinic antagonists in clinical use, as well as muscarinic receptor gene silencing blunted HLH-30\/TFEB activation by infection. Moreover, a mutation of unc-17\/SLC18A3 that lowers acetylcholine release from neurons impaired HLH-30\/TFEB activation and induction of its target genes, while pathogen burden remained high. In uninfected animals, muscarinic agonist arecoline was sufficient to activate HLH-30\/TFEB, in a muscarinic receptor-dependent manner. Nicotine, in contrast, had no effect. The agonist also lengthened survival of infection without lowering pathogen burden, in an HLH-30\/TFEB-dependent manner. Silencing egl-30\/GNAQ, plc-1\/PLCE1, or dkf-1\/PRKD1-3 cut activation by the agonist just as it cut activation by infection, showing that both stimuli require the same module. In mammals the link documented so far between acetylcholine and TFEB runs through nicotinic receptors, so whether the muscarinic route is conserved remains open. Thus, we favor a model in which infection drives neurons to release acetylcholine onto the intestinal epithelium, where muscarinic receptors acting through EGL-30\/Gq, PLC-1\/PLC{varepsilon}, and DKF-1\/PRKD activate HLH-30\/TFEB and strengthen infection resilience.","rel_num_authors":5,"rel_authors":[{"author_name":"Swarupa Mallick","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Xavier Gonzalez","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Khursheed  A Wani","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Sid  A Labed","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Javier  E. Irazoqui","author_inst":"University of Massachusetts Chan Medical School"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Cholinergic activation of HLH-30\/TFEB promotes C. elegans infection resilience.","rel_doi":"10.64898\/2026.09.18.752639","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.752639","rel_abs":"Innate host defense depends on transcriptional programs, which support survival through two strategies that can vary independently. Resistance lowers pathogen burden, while resilience limits the damage a given burden causes. In Caenorhabditis elegans infected with Staphylococcus aureus, the highly conserved transcription factor HLH-30\/TFEB drives most of the host response, which mediates infection resilience. We previously showed that EGL-30\/Gq, PLC-1\/PLC{varepsilon}, and DKF-1\/PRKD activate HLH-30\/TFEB during infection. The same phospholipase C and protein kinase D step activates TFEB in mouse macrophages infected with Salmonella or S. aureus. However, the input that drives the EGL-30\/Gq, PLC-1\/PLC{varepsilon}, and DKF-1\/PRKD module to activate HLH-30\/TFEB during infection remained unknown. Here we report that acetylcholine, acting on muscarinic receptors, is one such input. Atropine and scopolamine, two muscarinic antagonists in clinical use, as well as muscarinic receptor gene silencing blunted HLH-30\/TFEB activation by infection. Moreover, a mutation of unc-17\/SLC18A3 that lowers acetylcholine release from neurons impaired HLH-30\/TFEB activation and induction of its target genes, while pathogen burden remained high. In uninfected animals, muscarinic agonist arecoline was sufficient to activate HLH-30\/TFEB, in a muscarinic receptor-dependent manner. Nicotine, in contrast, had no effect. The agonist also lengthened survival of infection without lowering pathogen burden, in an HLH-30\/TFEB-dependent manner. Silencing egl-30\/GNAQ, plc-1\/PLCE1, or dkf-1\/PRKD1-3 cut activation by the agonist just as it cut activation by infection, showing that both stimuli require the same module. In mammals the link documented so far between acetylcholine and TFEB runs through nicotinic receptors, so whether the muscarinic route is conserved remains open. Thus, we favor a model in which infection drives neurons to release acetylcholine onto the intestinal epithelium, where muscarinic receptors acting through EGL-30\/Gq, PLC-1\/PLC{varepsilon}, and DKF-1\/PRKD activate HLH-30\/TFEB and strengthen infection resilience.","rel_num_authors":5,"rel_authors":[{"author_name":"Swarupa Mallick","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Xavier Gonzalez","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Khursheed  A Wani","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Sid  A Labed","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Javier  E. Irazoqui","author_inst":"University of Massachusetts Chan Medical School"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"B cells sustain tumor-specific CD4 T cells to promote response to PD-1 targeted therapy","rel_doi":"10.64898\/2026.09.18.751292","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.751292","rel_abs":"Immunotherapy transformed cancer treatment, yet precise correlates of response remain to be defined. While intratumoral follicular helper like (Tfhl) CD4 T cells and IgG1+ B cells have been associated with improved outcomes to PD-1 blockade for hepatocellular carcinoma (HCC), their mechanisms contributing to response are unclear. To address this question, we developed a murine model of HCC and examined CD8, CD4 and B cell responses. Increasing CD4-help sensitizes mice to PD-1 blockade, in a CD4- and CD8-dependent manner. Tumor-specific CD4 T cells contained Tfhl and Th1 populations, and both Bcl6 and T-bet were required for efficacy. Antigen-specific B cells were essential for CD4-helper expansion, yet secretion of antibodies was not required for long-term survival. Thus, B cells are critical for effective immunotherapy, but secreted antibodies are not.","rel_num_authors":23,"rel_authors":[{"author_name":"Abishek Vaidya","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Etienne Humblin","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Nataliya Prokhnevska","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Verena van der Heide","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Laurine Binet","author_inst":"The Rockefeller University"},{"author_name":"Jachym Harwood","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Raphael Mattiuz","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Anthony Lozano","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Pauline Hamon","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Bruno Cogliati","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Simon Goldstein","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Isabel Korpas","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Katherine E Lindblad","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Suhaana Sriram","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Harald Hartweger","author_inst":"The Rockefeller University"},{"author_name":"Glaucia Furtado","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Sacha Gnjatic","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Edgar Gonzalez-Kozlova","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Brad  R Rosenberg","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Amaia Lujambio","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Miriam Merad","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Michel C Nussenzweig","author_inst":"The Rockefeller University"},{"author_name":"Alice O Kamphorst","author_inst":"Icahn School of Medicine at Mount Sinai"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Selfing-aware demographic inference highlights local population structure and bottlenecks in Hawaiian Caenorhabditis elegans","rel_doi":"10.64898\/2026.09.22.753446","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.753446","rel_abs":"Demographic inference based on sequentially Markovian coalescent (SMC) model is widely used for disentangling the evolutionary history of species and populations. However, the genetic effects of self-fertilization, including the expected reduction of population-level genetic diversity and hence effective population size (Ne), are often ignored in demographic inference, despite the fact that selfing is a common reproductive mode in both invertebrates and plants. To investigate how self-fertilization could bias demographic inference, we apply eSMC2, a selfing-aware demographic inference method, to Hawaiian populations of Caenorhabditis elegans, a predominantly self-fertilizing nematode. Using an expanded dataset that contains more Hawaiian strains than in previous studies, we recovered previously reported genetic groups, including one largely consisting of strains from the Big Island. Population substructure is also detected among these Big Island subpopulations, highlighting the importance of identifying subgroups to avoid misinterpretations of demography. For different Big Island subpopulations, we estimate high selfing rates compatible with previous studies and infer consistent population declines. Population sizes inferred using eSMC2 are smaller than those inferred using PSMC', which does not account for selfing. However, rescaling PSMC' parameters to account for self-fertilization produces a similar demographic trajectory as eSMC2 inference. Our study thus demonstrates how one can account for effects of selfing when using SMC-based methods. It also indicates that the Hawaiian group shows population declines similar to those previously found outside Hawaii.","rel_num_authors":5,"rel_authors":[{"author_name":"Chenxi Wang","author_inst":"The University of Edinburgh"},{"author_name":"Robyn E Tanny","author_inst":"Johns Hopkins University"},{"author_name":"Konrad Lohse","author_inst":"University of Edinburgh"},{"author_name":"Erik Andersen","author_inst":"Johns Hopkins University"},{"author_name":"Matthew Hartfield","author_inst":"The University of Edinburgh"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Pathogenic variants of the mitochondrial copper chaperones SCO1 and SCO2 reshape their respective interactomes and disrupt cellular phospholipid metabolism","rel_doi":"10.64898\/2026.09.23.753947","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.23.753947","rel_abs":"SCO1 and SCO2 are required for copper delivery to COX2, a copper-containing subunit of cytochrome c oxidase (COX), yet how mutations in these genes cause distinct, tissue-specific forms of human disease remains poorly understood. To gain further insight into the molecular underpinnings of this clinical heterogeneity, we used BioID to map the interactomes of four pathogenic SCO variants (SCO1 G132S, SCO1 P174L, SCO1 M294V and SCO2 E140K) and the wild-type proteins. While this approach identified many proteins common to both wild-type neighbourhoods, several potential interacting partners unique to each SCO protein were also observed that were consistent with their known roles in COX assembly. Follow-up analyses revealed that SCO1 interacts with COX16 and that this interaction is stabilized within the membrane by a coiled-coil helix-helix interface, with the soluble C-terminal region of COX16 physically bridging SCO1 and COX2 within a ternary complex to facilitate copper delivery. We further observed that COX16 abundance is relatively low in the brain and its association with SCO1 is most severely impaired by the M294V substitution associated with a fatal encephalopathy. Intriguingly, our BioID analyses also detected significant enrichment in each SCO neighbourhood for biosynthetic enzymes and lipases critical to phospholipid metabolism and found that the affinity for these candidate interactors was uniquely perturbed by various pathogenic variants of SCO1 and SCO2. Collectively, our data emphasize the potential of proximity labelling to further define the molecular roles of disease-causing variants that perturb mitochondrial function and suggest that SCO proteins impinge upon phospholipid metabolism.","rel_num_authors":9,"rel_authors":[{"author_name":"Sampurna Ghosh","author_inst":"University of Saskatchewan"},{"author_name":"Zakery N. Baker","author_inst":"Washington University School of Medicine"},{"author_name":"Rachel M. Guerra","author_inst":"Washington University School of Medicine"},{"author_name":"Hana Antonicka","author_inst":"McGill University"},{"author_name":"Abhinav B. Swaminathan","author_inst":"Texas A & M University"},{"author_name":"Vishal M. Gohil","author_inst":"Texas A & M University"},{"author_name":"David Pagliarini","author_inst":"Washington University School of Medicine"},{"author_name":"Stanley A. Moore","author_inst":"University of Saskatchewan"},{"author_name":"Scot C Leary","author_inst":"University of Saskatchewan"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Adaptive-like features of the \u03b3\u03b4 TCR couple chronic BTNL recognition to NK-like tissue immunity","rel_doi":"10.64898\/2026.09.17.751481","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.751481","rel_abs":"Intestinal V{gamma}4 {gamma}{delta} intraepithelial lymphocytes (IELs) persistently bind the constitutively expressed epithelial ligand BTNL3\/8 through germline-encoded T cell receptor (TCR) determinants. While they resemble innate-like T cells such as NKT cells, unlike these populations, V{gamma}4 IELs encounter ligand only after thymic development. Moreover, unlike conventional {beta} T cells, V{gamma}4 IELs sustain persistent physiological ligand engagement without becoming exhausted. Here, using biophysical, functional, and multimodal single-cell approaches, we show how V{gamma}4 IELs address this challenge. While germline-encoded TCR regions broadly mediate BTNL3 recognition, productive activation requires additional non-germline TCR features that license responsiveness to BTNL3\/8 and enable local selection in the gut. Rather than driving exhaustion, BTNL3\/8 reactivity directly promotes expression of an NK-like program marked by adaptor molecules that license innate-like signaling in healthy tissue. These findings reveal how combined innate and adaptive features of the {gamma}{delta}TCR enable durable tissue specialization under conditions of persistent physiological ligand engagement.","rel_num_authors":17,"rel_authors":[{"author_name":"Benjamin D McDonald","author_inst":"Department of Medicine, University of Chicago, Chicago, IL"},{"author_name":"Hope D Anderson","author_inst":"Biophysical Sciences Graduate Program, University of Chicago, Chicago, IL, USA"},{"author_name":"Toufic Mayassi","author_inst":"Department of Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Chhon Ling Sok","author_inst":"Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia"},{"author_name":"Veronica Locher","author_inst":"Department of Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Magdalena Justyniarska","author_inst":"Department of Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Megan E Borregard","author_inst":"Department of Medicine, University of Chicago, Chicago, IL, USA"},{"author_name":"Caroline Kaiser","author_inst":"Department of Human Genetics, University of Chicago, Chicago, IL, USA"},{"author_name":"Kristin Ladell","author_inst":"Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK"},{"author_name":"James E McLaren","author_inst":"Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK"},{"author_name":"David A Price","author_inst":"Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK"},{"author_name":"Narutoshi Hibino","author_inst":"Section of Pediatric Cardiac Surgery, Comer's Children's Hospital, University of Chicago, Chicago, IL, USA"},{"author_name":"Andrew S Koh","author_inst":"Department of Pathology, University of Chicago, Chicago, IL, USA"},{"author_name":"Jamie Rossjohn","author_inst":"Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia"},{"author_name":"Benjamin S Gully","author_inst":"Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia"},{"author_name":"Samantha J Riesenfeld","author_inst":"Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA"},{"author_name":"Bana Jabri","author_inst":"Department of Medicine, University of Chicago, Chicago, IL, USA"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"The balance of local and distributed excitation shapes brain stability and reflects aging- and Alzheimer's disease-related alterations","rel_doi":"10.64898\/2026.09.17.752536","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752536","rel_abs":"Human brain function emerges from the interplay between recurrent local activity and distributed inter-regional interactions. However, a biologically interpretable framework for quantifying this balance between the two factors at the whole-brain level remains lacking. Here, we extended an established biophysical model to quantify inter-regional excitation and newly introduced the recurrent ratio (R-ratio), a measure of the relative balance between intra- and inter-regional excitation. Dynamical analyses showed that an optimal R-ratio supports a trade-off between network stability and flexibility. Applying this framework to healthy aging and Alzheimer's disease revealed progressively increased R-ratios with advancing age and disease severity. In healthy individuals, higher R-ratios were associated with age-related alterations in brain morphology, molecular pathology, and cognitive function, whereas Alzheimer's disease was characterized by increased R-ratios accompanied by reduced dynamical persistence. Together, these findings establish the R-ratio as a biologically interpretable marker of whole-brain excitation balance and demonstrate its utility for linking biophysical mechanisms with large-scale brain dynamics, aging, and neurodegeneration.","rel_num_authors":6,"rel_authors":[{"author_name":"Yeongjun Park","author_inst":"Korea University"},{"author_name":"Sunghun Kim","author_inst":"Korea University"},{"author_name":"Hyunjin Park","author_inst":"Sungkyunkwan University"},{"author_name":"Theodore D Satterthwaite","author_inst":"University of Pennsylvania"},{"author_name":"Boris Bernhardt","author_inst":"McGill University"},{"author_name":"Bo-yong Park","author_inst":"Korea University"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"The Orai3 channel and AHNAK2 scaffold protein promote the activation of primary human muscle stem cells in vitro","rel_doi":"10.64898\/2026.09.23.753807","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.23.753807","rel_abs":"Skeletal muscle is a dynamic tissue able to regenerate in response to injury. This regeneration relies primarily on the activation of precursor cells, known as muscle stem cells (MuSC). Upon activation, skeletal MuSC re-enter the cell cycle and proliferate as myoblasts, which subsequently either differentiate and fuse to form new fibers or return to quiescence to maintain long-term regenerative capacity. From primary human myoblasts, we generated reserve cells (RCs), quiescent cells similar to MuSC, and investigated their activation after stimulation with a growth medium containing serum. Here, we show that Orai3 calcium channel is primarily expressed in RC, where it promotes RC activation in a calcium-independent manner. We demonstrate that Orai3 does not contribute to store-operated calcium entry (SOCE) or calcium response induced by serum stimulation in RC cells, supporting the hypothesis that Orai3 plays a unique role in RC, distinct from its calcium channel activity. Using a protein proximity assay (BioID), we identified the large scaffold protein AHNAK2 as a potential partner of Orai3. AHNAK2 is expressed at high level in myotubes, and has a similar effect on RC activation than Orai3. Both Orai3 and AHNAK2 are necessary for proper myoblast differentiation and RC activation, while acting through different signaling pathways. Specifically, we show that Orai3 directly influences the RC fate, whereas AHNAK2 facilitates RC activation via signals derived from myotubes. These findings provide new insights into the molecular mechanisms underlying the activation and quiescence of human MuSC.","rel_num_authors":4,"rel_authors":[{"author_name":"Axel Tollance","author_inst":"Department of Cell Physiology, University of Geneva, Switzerland"},{"author_name":"Melanie Fourgeaud","author_inst":"Department of Cell Physiology, University of Geneva, Switzerland"},{"author_name":"Stephane Koenig","author_inst":"Department of Cell Pyhsiology and Metabolism, University of Geneva, Switzerland"},{"author_name":"Maud Frieden","author_inst":"Deparment of Cell Physiology and Metabolism, University of Geneva,Switzerland"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"A repair-associated bronchial epithelial differentiation trajectory through KRT14+ basal and hillock-like cells drives airway inflammation and remodelling in childhood-onset asthma","rel_doi":"10.64898\/2026.09.16.752044","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.16.752044","rel_abs":"The bronchial epithelium in asthma is vulnerable to damage and has impaired barrier function, but the mechanisms by which it contributes to airway inflammation and remodelling remain unclear. Here, we dissect these epithelial and immunological disease mechanisms by establishing a comprehensive single cell atlas of the bronchial wall from 21 patients with childhood-onset asthma and 25 matched healthy controls. We identify a novel asthma-associated non-canonical epithelial differentiation trajectory in which a repair-associated KLF4+ basal cell subset differentiates into KRT13+ hillock-like cells through a proliferative KRT14+ intermediate. In vitro cultured matched primary bronchial epithelial cells show that this trajectory is retained in absence of exogenous factors. We find that IL-13 induces hillock-like cell differentiation into CEACAM5hi goblet cells, driving goblet cell metaplasia. Repair-associated basal cells and transitioning CEACAM5hi hillock-like cells strongly contribute to airway inflammation and remodelling. In turn, dendritic cells and mast cells promote a state of highly active epithelial differentiation, which shows increased multiciliated cell fate decisions, in concordance with an increase in multiciliated cell death observed in asthma. Proportions of the epithelial cells of the non-canonical differentiation trajectory are associated with clinical outcomes such as disease severity, FeNO, and small airway function.","rel_num_authors":39,"rel_authors":[{"author_name":"Tessa E Gillett","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Aurore CA Gay","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Jelmer R Vlasma","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Alexandra B Firsova","author_inst":"Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Science for Life Laboratory, Stockholm University, Stockhol"},{"author_name":"Martin B Banchero","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Anna K Renner","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Amanda J Oliver","author_inst":"Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK"},{"author_name":"Marijn Berg","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Sjors Maassen","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pulmonology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Leonie Apperloo","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Bao-Han Ly","author_inst":"University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Department of Pediatric Pulmonology and Pediatric Allergology, GRIAC "},{"author_name":"Djoke van Gosliga","author_inst":"University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Department of Pediatric Pulmonology and Pediatric Allergology, GRIAC "},{"author_name":"Marnix R. Jonker","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Waradon Sungnak","author_inst":"Department of Microbiology, Faculty of Science, Mahidol University, Bangkok, Thailand; Integrative Computational BioScience (ICBS) center, Mahidol University, N"},{"author_name":"Orestes A Carpaij","author_inst":"University of Groningen, University Medical Center Groningen, Department of Intensive Care, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Tessa M Kole","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pulmonology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Laura Hesse","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Sharon Brouwer","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Petra L van der Velde","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Marissa Wisman","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Akshaya K Saikumar Jayalatha","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Bas G Doddema","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Frederique Alleblas","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Putri A Fajar","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"A Alexandros Imprachim","author_inst":"Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Science for Life Laboratory, Stockholm University, Stockhol"},{"author_name":"Rosalie C van Hulst","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Marjan Luinge","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Monique E. Lodewijk","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Janna Bakker","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Markus Weckmann","author_inst":"Division of Epigenetics of Chronic Lung Diseases, Priority Area Chronic Lung Diseases, Research Center Borstel - Leibniz Lung Center, Borstel, Germany; Departme"},{"author_name":"Corry-Anke Brandsma","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Wim Timens","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Judith M Vonk","author_inst":"University of Groningen, University Medical Center Groningen, Department of Epidemiology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Sarah A Teichmann","author_inst":"Dept Medicine & Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Puddicombe Way, Cambridge CB2 0AW, UK"},{"author_name":"Christos Samakovlis","author_inst":"Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University, Stockholm, Sweden; Science for Life Laboratory, Stockholm University, Stockhol"},{"author_name":"Kerstin B Meyer","author_inst":"Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK"},{"author_name":"Gerard H Koppelman","author_inst":"University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Department of Pediatric Pulmonology and Pediatric Allergology, GRIAC "},{"author_name":"Maarten van den Berge","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pulmonology, GRIAC Research Institute, Groningen, Netherlands"},{"author_name":"Martijn C Nawijn","author_inst":"University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC Research Institute, Groningen, Netherlands"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Controlling membrane tension by dynamic DNA nanorings","rel_doi":"10.64898\/2026.09.22.753646","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.753646","rel_abs":"Membrane tension, defined as the energy cost to expand the membrane surface area, is a fundamental mechanical property of the lipid bilayer and an important modulator of various cellular processes. Liposomes provide model systems to study protein-mediated membrane dynamics, where membrane tension can be controlled by osmotic pressure and micropipette aspiration. However, it is challenging to individually control membrane tension of nanometer-sized liposomes, such as small unilamellar vesicles (SUVs), that are widely used for modeling subcellular membrane structures and drug delivery. To bridge this technological gap, we present reconfigurable DNA origami rings for dynamically controlling membrane tension of sub-100 nm liposomes. The DNA nanorings template the formation of uniformly sized SUVs and undergo trigger-responsive dilation and contraction, thus applying controlled and reversible mechanical stress to the SUV membranes. Electron microscopy analyses show deformed liposomes with ~2.5% expanded membrane area following ring dilation. The corresponding increase in membrane tension opens a mechanosensitive ion channel MscL with gating tension of ~10 mN\/m. Selectively manipulating a mixture of SUV populations enables timed release of their distinct molecular cargos, either concurrently or one at a time. Furthermore, vesicles with expanded membranes are more conducive to SNARE-mediated fusion. The nanomechanical device thus provides a programmable platform for engineering the mechanics of synthetic nano-vesicles and studying membrane tension modulated processes at the molecular level.","rel_num_authors":11,"rel_authors":[{"author_name":"Longfei Liu","author_inst":"Yale University"},{"author_name":"Eason Cao","author_inst":"Yale University"},{"author_name":"Chunxiang Wu","author_inst":"Yale University"},{"author_name":"Abhijith Radhakrishnan","author_inst":"Yale University"},{"author_name":"Manindra Bera","author_inst":"Yale School of Medicine"},{"author_name":"Sudhanshu Gautam","author_inst":"Yale University"},{"author_name":"Aniruddha Panda","author_inst":"Yale University"},{"author_name":"Kallol Gupta","author_inst":"Yale University"},{"author_name":"Yong Xiong","author_inst":"Yale University"},{"author_name":"Frederic Pincet","author_inst":"Ecole Normal Superieure"},{"author_name":"Chenxiang Lin","author_inst":"Yale University"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Extracting interpretable single-cell metabolic states with graph-guided representation learning","rel_doi":"10.64898\/2026.09.17.751504","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.751504","rel_abs":"Metabolism shapes cellular function and state, yet measuring single-cell metabolic states at scale remains a challenge. We present Metabolic Representation Net (MeRN), a graph-guided variational autoencoder that leverages prior metabolic knowledge as a topology graph to learn latent representations of metabolic state and reaction activity from single-cell transcriptomes. MeRN's scalable estimation of reaction activity enables the definition of data-driven pathways (DDPs): context-specific metabolic modules supported by transcriptomic evidence and agnostic of standard pathway definitions. Using DDPs, we introduce the weakest link analysis to identify metabolic network rewiring. MeRN recovers metabolic zonation in the mouse intestine, links a folate deficiency-induced break in de novo purine synthesis to embryonic neural tube defects, shows cytokines with similar non-metabolic effects can elicit divergent T cell metabolism, and identifies metabolic drivers of T cell exhaustion and therapy response in human cancers. Our results establish MeRN as a unified method for metabolic analysis of single-cell transcriptomes.","rel_num_authors":7,"rel_authors":[{"author_name":"Daniel P. Lewinsohn","author_inst":"University of California, Berkeley"},{"author_name":"Nicolas Dias","author_inst":"Yale School of Medicine"},{"author_name":"Adelina Chau","author_inst":"University of California, Berkeley"},{"author_name":"Yuko Koike","author_inst":"University of California, Berkeley"},{"author_name":"Zachary D. Smith","author_inst":"Yale School of Medicine"},{"author_name":"Nilah M. Ioannidis","author_inst":"University of California, Berkeley"},{"author_name":"Allon Wagner","author_inst":"University of California, Berkeley"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Extracting interpretable single-cell metabolic states with graph-guided representation learning","rel_doi":"10.64898\/2026.09.17.751504","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.751504","rel_abs":"Metabolism shapes cellular function and state, yet measuring single-cell metabolic states at scale remains a challenge. We present Metabolic Representation Net (MeRN), a graph-guided variational autoencoder that leverages prior metabolic knowledge as a topology graph to learn latent representations of metabolic state and reaction activity from single-cell transcriptomes. MeRN's scalable estimation of reaction activity enables the definition of data-driven pathways (DDPs): context-specific metabolic modules supported by transcriptomic evidence and agnostic of standard pathway definitions. Using DDPs, we introduce the weakest link analysis to identify metabolic network rewiring. MeRN recovers metabolic zonation in the mouse intestine, links a folate deficiency-induced break in de novo purine synthesis to embryonic neural tube defects, shows cytokines with similar non-metabolic effects can elicit divergent T cell metabolism, and identifies metabolic drivers of T cell exhaustion and therapy response in human cancers. Our results establish MeRN as a unified method for metabolic analysis of single-cell transcriptomes.","rel_num_authors":7,"rel_authors":[{"author_name":"Daniel P. Lewinsohn","author_inst":"University of California, Berkeley"},{"author_name":"Nicolas Dias","author_inst":"Yale School of Medicine"},{"author_name":"Adelina Chau","author_inst":"University of California, Berkeley"},{"author_name":"Yuko Koike","author_inst":"University of California, Berkeley"},{"author_name":"Zachary D. Smith","author_inst":"Yale School of Medicine"},{"author_name":"Nilah M. Ioannidis","author_inst":"University of California, Berkeley"},{"author_name":"Allon Wagner","author_inst":"University of California, Berkeley"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Evolution of NELL binding by dual-ligand-responsive axon guidance receptor Robo","rel_doi":"10.64898\/2026.09.23.753883","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.23.753883","rel_abs":"Robo receptors are conserved across bilaterians and best known for their ability to mediate axonal repulsion in response to Slit family ligands. In mammals, this applies to Robo1 and Robo2, but mammalian Robo3 binds NELL proteins instead of Slits. The evolutionary origin of NELL-Robo interactions and the possible existence of dual-ligand responsiveness across species remain unknown. Here, we systematically analyzed Robo and NELL homologs across bilaterians and found that NELL-Robo binding is conserved among chordate Robos, but not in protostomes. We show that cephalochordate Robo and NELL can mediate axon repulsion in vitro, suggesting conserved functionality. We observed that conformational masking of the NELL-binding site is prevalent among chordate Robos, modulating NELL-Robo affinity. We also demonstrate that NELL-Robo complexes undergo liquid-liquid phase separation in vitro, a property preserved from cephalochordates to mammals. Our findings support a model in which an ancestral chordate Robo receptor was dual-responsive to Slit and NELL, still the case for some extant Robos, and vertebrate paralogs subfunctionalized, with full ligand specialization emerging in mammals.","rel_num_authors":8,"rel_authors":[{"author_name":"Joseph S. Pak","author_inst":"The University of Chicago"},{"author_name":"Lakshmi Prakash","author_inst":"Brown University"},{"author_name":"Yeonwoo Park","author_inst":"The University of Chicago"},{"author_name":"Wioletta I. Nawrocka","author_inst":"The University of Chicago"},{"author_name":"Raunak Kundagrami","author_inst":"The University of Chicago"},{"author_name":"Joseph W. Thornton","author_inst":"The University of Chicago"},{"author_name":"Alexander Jaworski","author_inst":"Brown University"},{"author_name":"Engin \u00d6zkan","author_inst":"The University of Chicago"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Evolution of NELL binding by dual-ligand-responsive axon guidance receptor Robo","rel_doi":"10.64898\/2026.09.23.753883","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.23.753883","rel_abs":"Robo receptors are conserved across bilaterians and best known for their ability to mediate axonal repulsion in response to Slit family ligands. In mammals, this applies to Robo1 and Robo2, but mammalian Robo3 binds NELL proteins instead of Slits. The evolutionary origin of NELL-Robo interactions and the possible existence of dual-ligand responsiveness across species remain unknown. Here, we systematically analyzed Robo and NELL homologs across bilaterians and found that NELL-Robo binding is conserved among chordate Robos, but not in protostomes. We show that cephalochordate Robo and NELL can mediate axon repulsion in vitro, suggesting conserved functionality. We observed that conformational masking of the NELL-binding site is prevalent among chordate Robos, modulating NELL-Robo affinity. We also demonstrate that NELL-Robo complexes undergo liquid-liquid phase separation in vitro, a property preserved from cephalochordates to mammals. Our findings support a model in which an ancestral chordate Robo receptor was dual-responsive to Slit and NELL, still the case for some extant Robos, and vertebrate paralogs subfunctionalized, with full ligand specialization emerging in mammals.","rel_num_authors":8,"rel_authors":[{"author_name":"Joseph S. Pak","author_inst":"The University of Chicago"},{"author_name":"Lakshmi Prakash","author_inst":"Brown University"},{"author_name":"Yeonwoo Park","author_inst":"The University of Chicago"},{"author_name":"Wioletta I. Nawrocka","author_inst":"The University of Chicago"},{"author_name":"Raunak Kundagrami","author_inst":"The University of Chicago"},{"author_name":"Joseph W. Thornton","author_inst":"The University of Chicago"},{"author_name":"Alexander Jaworski","author_inst":"Brown University"},{"author_name":"Engin \u00d6zkan","author_inst":"The University of Chicago"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Isoleucine absence from adult human hemoglobin is mirrored in mosquito proteomes and limits malaria parasite growth","rel_doi":"10.64898\/2026.09.23.753855","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.23.753855","rel_abs":"Amino acid composition within a proteome is conventionally viewed as a property of individual protein function. However, specific nutrient scarcity has been shown to reshape which amino acids are encoded in the genome of microbes. Mosquitoes have fed on blood for 200 million years, relying on blood amino acids for reproduction. We wondered whether this ancient dependency has left an imprint on the mosquito proteome. Here we show a proteome-wide shift to lower isoleucine usage in blood-feeding mosquitoes, mirroring the known isoleucine deficiency of adult human hemoglobin. In comparing amino acid composition across the proteomes of blood-feeding and non-blood-feeding mosquitoes, we found that blood feeders show systematically lower isoleucine usage and that highly expressed gut enzymes that digest the blood meal are nearly isoleucine free. Analysis of 707 vertebrate genomes reveals that isoleucine deficiency in major hemoglobin subunits is shared among mammals. Specifically, all non-Malagasy primates, including humans, lack isoleucine in their adult hemoglobin subunits while retaining it in fetal and embryonic subunits. We find that two other major blood proteins, serum albumin and immunoglobulin G, also have reduced isoleucine levels (~1.4%) compared to the human proteome-wide average of 4.38%. Finally, we reasoned that this widespread isoleucine restriction could serve to defend adult red blood cells against isoleucine-dependent blood parasites that feed on them. We tested this hypothesis with the malaria parasite Plasmodium falciparum, which is known to arrest growth in adult red blood cells when extracellular isoleucine is withdrawn. We found that neonatal red blood cells purified from umbilical cord blood, which contain isoleucine-rich fetal hemoglobin, permit growth without extracellular isoleucine. This work demonstrates that nutritional scarcity is reflected in the genomes of animals, and that amino acid depletion of host protein sequences may serve a protective function against blood parasites.","rel_num_authors":4,"rel_authors":[{"author_name":"Leah Houri-Zeevi","author_inst":"The Rockefeller University"},{"author_name":"Martin Kampmann","author_inst":"Harvard T. H. Chan School of Public Health"},{"author_name":"Manoj T Duraisingh","author_inst":"Harvard T. H. Chan School of Public Health"},{"author_name":"Leslie B Vosshall","author_inst":"The Rockefeller University"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Decoding subtype development and function in human pluripotent stem cell-derived midbrain dopaminergic neurons","rel_doi":"10.64898\/2026.09.23.753784","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.23.753784","rel_abs":"Midbrain dopaminergic (mDA) neurons comprise molecularly and functionally distinct subtypes with differential vulnerability in neurodegenerative and psychiatric disorders. However, the mechanisms specifying subtype identity remain poorly understood, and protocols for the selective derivation of human mDA subtypes are lacking. Here we establish a strategy to derive substantia nigra (A9) and ventral tegmental area (A10) mDA neurons from human pluripotent stem cells (hPSCs). A9 identity is specified by dual-SMAD activation through Activin A and BMP7 at the midbrain floor-plate progenitor stage, whereas A10 identity is promoted by BMP inhibition. A9 mDA neurons are purified based on ALDH1A1 expression, and subtype identity is maintained by continued TGF-{beta} modulation and ESRRB activation in vitro and upon transplantation in vivo. Single-cell RNA sequencing and biochemical analyses demonstrate that hPSC-derived A9 neurons exhibit increased oxidative phosphorylation, neuromelanin-like pigmentation, elevated dopamine synthesis and release, and electrophysiological properties characteristic of A9 mDA neurons in vivo. Integration with human fetal midbrain datasets confirms strong transcriptional concordance between in vitro-derived and in vivo mDA subtypes. Neuromelanin-like structures produced by hPSC-derived A9 neurons trigger pro-inflammatory cytokine secretion from hPSC-derived microglia, and A9 neurons are primed to upregulate MHC-I genes in response to interferon-{gamma}, features which may contribute to the selective vulnerability of A9 neurons. Together, these results establish a robust in vitro platform to interrogate human mDA subtype development, function, and selective vulnerability, enabling mechanistic studies relevant to Parkinson's disease and the development of cell-based therapies.","rel_num_authors":18,"rel_authors":[{"author_name":"Donghe Yang","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Sejoon Choi","author_inst":"Columbia University Medical Center"},{"author_name":"Jinghua Piao","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Alessandro Evangelisti","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Zhe Yang","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Vittoria Dickinson Bocchi","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Shkurte Ademi Donohue","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Nidia Claros","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Johannes Jungverdorben","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Mega Sidharta","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Youjun Wu","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Hilda Amalia Pasolli","author_inst":"The Rockefeller University"},{"author_name":"Tae Wan Kim","author_inst":"Daegu Gyeongbuk Institute of Science and Technology"},{"author_name":"Ting Zhou","author_inst":"Memorial Sloan Kettering Cancer Center,"},{"author_name":"David Sulzer","author_inst":"Columbia University Medical Center"},{"author_name":"Eugene Mosharov","author_inst":"Columbia University Medical Center"},{"author_name":"Viviane Tabar","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Lorenz Studer","author_inst":"Memorial Sloan Kettering Cancer Center"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Decoding subtype development and function in human pluripotent stem cell-derived midbrain dopaminergic neurons","rel_doi":"10.64898\/2026.09.23.753784","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.23.753784","rel_abs":"Midbrain dopaminergic (mDA) neurons comprise molecularly and functionally distinct subtypes with differential vulnerability in neurodegenerative and psychiatric disorders. However, the mechanisms specifying subtype identity remain poorly understood, and protocols for the selective derivation of human mDA subtypes are lacking. Here we establish a strategy to derive substantia nigra (A9) and ventral tegmental area (A10) mDA neurons from human pluripotent stem cells (hPSCs). A9 identity is specified by dual-SMAD activation through Activin A and BMP7 at the midbrain floor-plate progenitor stage, whereas A10 identity is promoted by BMP inhibition. A9 mDA neurons are purified based on ALDH1A1 expression, and subtype identity is maintained by continued TGF-{beta} modulation and ESRRB activation in vitro and upon transplantation in vivo. Single-cell RNA sequencing and biochemical analyses demonstrate that hPSC-derived A9 neurons exhibit increased oxidative phosphorylation, neuromelanin-like pigmentation, elevated dopamine synthesis and release, and electrophysiological properties characteristic of A9 mDA neurons in vivo. Integration with human fetal midbrain datasets confirms strong transcriptional concordance between in vitro-derived and in vivo mDA subtypes. Neuromelanin-like structures produced by hPSC-derived A9 neurons trigger pro-inflammatory cytokine secretion from hPSC-derived microglia, and A9 neurons are primed to upregulate MHC-I genes in response to interferon-{gamma}, features which may contribute to the selective vulnerability of A9 neurons. Together, these results establish a robust in vitro platform to interrogate human mDA subtype development, function, and selective vulnerability, enabling mechanistic studies relevant to Parkinson's disease and the development of cell-based therapies.","rel_num_authors":18,"rel_authors":[{"author_name":"Donghe Yang","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Sejoon Choi","author_inst":"Columbia University Medical Center"},{"author_name":"Jinghua Piao","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Alessandro Evangelisti","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Zhe Yang","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Vittoria Dickinson Bocchi","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Shkurte Ademi Donohue","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Nidia Claros","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Johannes Jungverdorben","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Mega Sidharta","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Youjun Wu","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Hilda Amalia Pasolli","author_inst":"The Rockefeller University"},{"author_name":"Tae Wan Kim","author_inst":"Daegu Gyeongbuk Institute of Science and Technology"},{"author_name":"Ting Zhou","author_inst":"Memorial Sloan Kettering Cancer Center,"},{"author_name":"David Sulzer","author_inst":"Columbia University Medical Center"},{"author_name":"Eugene Mosharov","author_inst":"Columbia University Medical Center"},{"author_name":"Viviane Tabar","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Lorenz Studer","author_inst":"Memorial Sloan Kettering Cancer Center"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"A tripartite mechanism licenses RNA polymerase import into the phage nucleus","rel_doi":"10.64898\/2026.09.21.753271","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.753271","rel_abs":"Nucleus-forming jumbo phages import a phage-encoded non-virion RNA polymerase (nvRNAP) into a proteinaceous nucleus, but how it is selected for import is unknown. Here, we identify an import pathway that couples nvRNAP subunit interactions with phage-encoded import factors. Maximal nvRNAP import requires a novel factor Imp7 (gp166) and the essential import factor Imp1. Imp7 is essential at environmental temperatures (20 C), where impaired nvRNAP import causes a profound loss of middle and late transcription and blocks phage DNA replication. Import of individual nvRNAP subunits also depends on other subunits, consistent with import licensing at the level of an assembled complex. In the absence of middle transcription and DNA replication, the phage nucleus surprisingly still assembles and segregates from the cytoplasm, demonstrating that nvRNAP nuclear localization and activity are not a critical checkpoint for nucleus assembly. Together, these findings define a specialized pathway for nuclear import of the multi-subunit RNAP and reveal that nuclear compartment assembly precedes the transcriptional and replicative programs required for its maturation.","rel_num_authors":8,"rel_authors":[{"author_name":"Claire Kokontis","author_inst":"UCSF"},{"author_name":"Deepto Mozumdar","author_inst":"UCSF"},{"author_name":"Daphne Chen","author_inst":"UCSF"},{"author_name":"Iris Zheng","author_inst":"UCSF"},{"author_name":"Wearn-Xin Yee","author_inst":"UCSF"},{"author_name":"David Bulkley","author_inst":"UCSF"},{"author_name":"David Agard","author_inst":"UCSF"},{"author_name":"Joseph Bondy-Denomy","author_inst":"UCSF"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"A tripartite mechanism licenses RNA polymerase import into the phage nucleus","rel_doi":"10.64898\/2026.09.21.753271","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.753271","rel_abs":"Nucleus-forming jumbo phages import a phage-encoded non-virion RNA polymerase (nvRNAP) into a proteinaceous nucleus, but how it is selected for import is unknown. Here, we identify an import pathway that couples nvRNAP subunit interactions with phage-encoded import factors. Maximal nvRNAP import requires a novel factor Imp7 (gp166) and the essential import factor Imp1. Imp7 is essential at environmental temperatures (20 C), where impaired nvRNAP import causes a profound loss of middle and late transcription and blocks phage DNA replication. Import of individual nvRNAP subunits also depends on other subunits, consistent with import licensing at the level of an assembled complex. In the absence of middle transcription and DNA replication, the phage nucleus surprisingly still assembles and segregates from the cytoplasm, demonstrating that nvRNAP nuclear localization and activity are not a critical checkpoint for nucleus assembly. Together, these findings define a specialized pathway for nuclear import of the multi-subunit RNAP and reveal that nuclear compartment assembly precedes the transcriptional and replicative programs required for its maturation.","rel_num_authors":8,"rel_authors":[{"author_name":"Claire Kokontis","author_inst":"UCSF"},{"author_name":"Deepto Mozumdar","author_inst":"UCSF"},{"author_name":"Daphne Chen","author_inst":"UCSF"},{"author_name":"Iris Zheng","author_inst":"UCSF"},{"author_name":"Wearn-Xin Yee","author_inst":"UCSF"},{"author_name":"David Bulkley","author_inst":"UCSF"},{"author_name":"David Agard","author_inst":"UCSF"},{"author_name":"Joseph Bondy-Denomy","author_inst":"UCSF"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Type 2 Deiodinase in Cancer-Associated Fibroblasts: A Potential Therapeutic Target in Many Types of Cancer","rel_doi":"10.64898\/2026.09.14.26362848","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26362848","rel_abs":"Background: Cancer-associated fibroblasts (CAF) are major regulators of the tumor microenvironment (TME), yet the pathways governing CAF function remain incompletely understood. Type 2 deiodinase (DIO2, D2), which converts thyroxine (T4) to the active thyroid hormone triiodothyronine (T3), has not been systematically investigated in CAF across different solid tumors. Methods: We analyzed DIO2 expression using single-cell RNA sequencing (scRNA-seq) from primary thyroid tumors, a large integrated scRNASeq thyroid cancer atlas, and publicly available scRNA-seq datasets representing six additional solid tumor types. Bulk RNA sequencing data from the Oncology Research Information Exchange Network (ORIEN) database were used to examine correlations among DIO2, CAF subtype markers, and overall survival (OS). A genetically engineered TPO-CreERT2\/BrafV600E\/Trp53-deficient (TBP) mouse model was evaluated for CAF-specific Dio2 expression and pharmacologic inhibition of D2 activity. TBP mice were crossed with Dio2-\/- (Dio2 KO) mice to investigate the role of Dio2 in cancer development and progression. Results: DIO2 expression was highly restricted to CAF and was largely absent from epithelial-derived cancer, immune, and endothelial cells. Across thyroid cancer and six additional malignancies, DIO2 was consistently detected in CAF, demonstrating that CAF-specific DIO2 expression is a conserved feature of multiple tumor types. Within thyroid cancer, DIO2 was enriched in myofibroblastic CAF (myCAF) compared with inflammatory CAF (iCAF), and bulk transcriptomic analyses demonstrated stronger correlations between DIO2 expression and canonical myCAF markers than iCAF markers across numerous cancers. Elevated DIO2 expression was associated with worse OS in pancreatic and bladder cancers, paralleling the adverse prognostic impact of increased myCAF abundance. In contrast, thyroid cancer demonstrated an inverse association attributable to loss of epithelial DIO2 expression during tumor dedifferentiation. The TBP mouse model recapitulated human disease, with Dio2 expression restricted to CAF, robust stromal fibrosis, and measurable D2 enzymatic activity that was suppressed by cefuroxime and lenvatinib. Genetic loss of Dio2 in the TME resulted in significantly reduced tumor growth. Conclusions: DIO2 is a conserved marker of CAF, and myCAF, across multiple solid tumors and is associated with adverse clinical outcomes in some cancers. The TBP mouse provides a robust preclinical model to define the mechanistic role of DIO2 in CAF biology and to evaluate DIO2-directed therapeutic strategies targeting the tumor microenvironment.","rel_num_authors":32,"rel_authors":[{"author_name":"Mary Grace Carroll","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Noha Mukhtar","author_inst":"King Faisal Specialist Hospital and Research Centre"},{"author_name":"Jacob Calhoun","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Breaunna Garza","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Matthew A Loberg","author_inst":"Vanderbilt University"},{"author_name":"Hua-Chang Chen","author_inst":"Vanderbilt University"},{"author_name":"Quanhu Sheng","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alyse Staley","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Tatiana L Fonseca","author_inst":"University of Texas Medical Branch"},{"author_name":"Antonio C Bianco","author_inst":"University of Texas Medical Branch"},{"author_name":"Matthew D Ringel","author_inst":"The Ohio State University"},{"author_name":"Pamela Brock","author_inst":"The Ohio Satae University"},{"author_name":"Andrew J Gunderson","author_inst":"The Ohio State University"},{"author_name":"Ahamd A Tarhini","author_inst":"Moffitt Cancer Center"},{"author_name":"W Douglas Cress","author_inst":"Moffitt Cancer Center"},{"author_name":"Michael J Cavnar","author_inst":"University of Kentucky"},{"author_name":"Stephen Edge","author_inst":"Roswell Park Comprehensive Cancer Center"},{"author_name":"Varinder Kaur","author_inst":"University of Virginia"},{"author_name":"George J Weiner","author_inst":"University of Iowa"},{"author_name":"Janice L Farlow","author_inst":"Indiana University"},{"author_name":"Robert Dood","author_inst":"University of Utah"},{"author_name":"Roman Groisberg","author_inst":"Rutgers Cancer Institute of New Jersey"},{"author_name":"Abdul Rafeh Naquash","author_inst":"University of Oklahoma"},{"author_name":"Craig Shriver","author_inst":"Walter Reed National Military Medical Center"},{"author_name":"Dinesh Pal Mudaranthakam","author_inst":"University of Kansas Medical Center"},{"author_name":"Jose A Oliveras","author_inst":"Ponce Health Sciences University"},{"author_name":"Robert J Rounbehler","author_inst":"Aster Insights"},{"author_name":"Michelle L. Churchman","author_inst":"Aster Insights"},{"author_name":"Vivian L Weiss","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Rebecca E Schweppe","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Nikita Pozdeyev","author_inst":"University of Colorado Anschutz"},{"author_name":"Bryan R Haugen","author_inst":"Universtiy of Colorado Anschutz"}],"rel_date":"2026-09-23","rel_site":"medrxiv"},{"rel_title":"Type 2 Deiodinase in Cancer-Associated Fibroblasts: A Potential Therapeutic Target in Many Types of Cancer","rel_doi":"10.64898\/2026.09.14.26362848","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26362848","rel_abs":"Background: Cancer-associated fibroblasts (CAF) are major regulators of the tumor microenvironment (TME), yet the pathways governing CAF function remain incompletely understood. Type 2 deiodinase (DIO2, D2), which converts thyroxine (T4) to the active thyroid hormone triiodothyronine (T3), has not been systematically investigated in CAF across different solid tumors. Methods: We analyzed DIO2 expression using single-cell RNA sequencing (scRNA-seq) from primary thyroid tumors, a large integrated scRNASeq thyroid cancer atlas, and publicly available scRNA-seq datasets representing six additional solid tumor types. Bulk RNA sequencing data from the Oncology Research Information Exchange Network (ORIEN) database were used to examine correlations among DIO2, CAF subtype markers, and overall survival (OS). A genetically engineered TPO-CreERT2\/BrafV600E\/Trp53-deficient (TBP) mouse model was evaluated for CAF-specific Dio2 expression and pharmacologic inhibition of D2 activity. TBP mice were crossed with Dio2-\/- (Dio2 KO) mice to investigate the role of Dio2 in cancer development and progression. Results: DIO2 expression was highly restricted to CAF and was largely absent from epithelial-derived cancer, immune, and endothelial cells. Across thyroid cancer and six additional malignancies, DIO2 was consistently detected in CAF, demonstrating that CAF-specific DIO2 expression is a conserved feature of multiple tumor types. Within thyroid cancer, DIO2 was enriched in myofibroblastic CAF (myCAF) compared with inflammatory CAF (iCAF), and bulk transcriptomic analyses demonstrated stronger correlations between DIO2 expression and canonical myCAF markers than iCAF markers across numerous cancers. Elevated DIO2 expression was associated with worse OS in pancreatic and bladder cancers, paralleling the adverse prognostic impact of increased myCAF abundance. In contrast, thyroid cancer demonstrated an inverse association attributable to loss of epithelial DIO2 expression during tumor dedifferentiation. The TBP mouse model recapitulated human disease, with Dio2 expression restricted to CAF, robust stromal fibrosis, and measurable D2 enzymatic activity that was suppressed by cefuroxime and lenvatinib. Genetic loss of Dio2 in the TME resulted in significantly reduced tumor growth. Conclusions: DIO2 is a conserved marker of CAF, and myCAF, across multiple solid tumors and is associated with adverse clinical outcomes in some cancers. The TBP mouse provides a robust preclinical model to define the mechanistic role of DIO2 in CAF biology and to evaluate DIO2-directed therapeutic strategies targeting the tumor microenvironment.","rel_num_authors":32,"rel_authors":[{"author_name":"Mary Grace Carroll","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Noha Mukhtar","author_inst":"King Faisal Specialist Hospital and Research Centre"},{"author_name":"Jacob Calhoun","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Breaunna Garza","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Matthew A Loberg","author_inst":"Vanderbilt University"},{"author_name":"Hua-Chang Chen","author_inst":"Vanderbilt University"},{"author_name":"Quanhu Sheng","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alyse Staley","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Tatiana L Fonseca","author_inst":"University of Texas Medical Branch"},{"author_name":"Antonio C Bianco","author_inst":"University of Texas Medical Branch"},{"author_name":"Matthew D Ringel","author_inst":"The Ohio State University"},{"author_name":"Pamela Brock","author_inst":"The Ohio Satae University"},{"author_name":"Andrew J Gunderson","author_inst":"The Ohio State University"},{"author_name":"Ahamd A Tarhini","author_inst":"Moffitt Cancer Center"},{"author_name":"W Douglas Cress","author_inst":"Moffitt Cancer Center"},{"author_name":"Michael J Cavnar","author_inst":"University of Kentucky"},{"author_name":"Stephen Edge","author_inst":"Roswell Park Comprehensive Cancer Center"},{"author_name":"Varinder Kaur","author_inst":"University of Virginia"},{"author_name":"George J Weiner","author_inst":"University of Iowa"},{"author_name":"Janice L Farlow","author_inst":"Indiana University"},{"author_name":"Robert Dood","author_inst":"University of Utah"},{"author_name":"Roman Groisberg","author_inst":"Rutgers Cancer Institute of New Jersey"},{"author_name":"Abdul Rafeh Naquash","author_inst":"University of Oklahoma"},{"author_name":"Craig Shriver","author_inst":"Walter Reed National Military Medical Center"},{"author_name":"Dinesh Pal Mudaranthakam","author_inst":"University of Kansas Medical Center"},{"author_name":"Jose A Oliveras","author_inst":"Ponce Health Sciences University"},{"author_name":"Robert J Rounbehler","author_inst":"Aster Insights"},{"author_name":"Michelle L. Churchman","author_inst":"Aster Insights"},{"author_name":"Vivian L Weiss","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Rebecca E Schweppe","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Nikita Pozdeyev","author_inst":"University of Colorado Anschutz"},{"author_name":"Bryan R Haugen","author_inst":"Universtiy of Colorado Anschutz"}],"rel_date":"2026-09-23","rel_site":"medrxiv"},{"rel_title":"Type 2 Deiodinase in Cancer-Associated Fibroblasts: A Potential Therapeutic Target in Many Types of Cancer","rel_doi":"10.64898\/2026.09.14.26362848","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26362848","rel_abs":"Background: Cancer-associated fibroblasts (CAF) are major regulators of the tumor microenvironment (TME), yet the pathways governing CAF function remain incompletely understood. Type 2 deiodinase (DIO2, D2), which converts thyroxine (T4) to the active thyroid hormone triiodothyronine (T3), has not been systematically investigated in CAF across different solid tumors. Methods: We analyzed DIO2 expression using single-cell RNA sequencing (scRNA-seq) from primary thyroid tumors, a large integrated scRNASeq thyroid cancer atlas, and publicly available scRNA-seq datasets representing six additional solid tumor types. Bulk RNA sequencing data from the Oncology Research Information Exchange Network (ORIEN) database were used to examine correlations among DIO2, CAF subtype markers, and overall survival (OS). A genetically engineered TPO-CreERT2\/BrafV600E\/Trp53-deficient (TBP) mouse model was evaluated for CAF-specific Dio2 expression and pharmacologic inhibition of D2 activity. TBP mice were crossed with Dio2-\/- (Dio2 KO) mice to investigate the role of Dio2 in cancer development and progression. Results: DIO2 expression was highly restricted to CAF and was largely absent from epithelial-derived cancer, immune, and endothelial cells. Across thyroid cancer and six additional malignancies, DIO2 was consistently detected in CAF, demonstrating that CAF-specific DIO2 expression is a conserved feature of multiple tumor types. Within thyroid cancer, DIO2 was enriched in myofibroblastic CAF (myCAF) compared with inflammatory CAF (iCAF), and bulk transcriptomic analyses demonstrated stronger correlations between DIO2 expression and canonical myCAF markers than iCAF markers across numerous cancers. Elevated DIO2 expression was associated with worse OS in pancreatic and bladder cancers, paralleling the adverse prognostic impact of increased myCAF abundance. In contrast, thyroid cancer demonstrated an inverse association attributable to loss of epithelial DIO2 expression during tumor dedifferentiation. The TBP mouse model recapitulated human disease, with Dio2 expression restricted to CAF, robust stromal fibrosis, and measurable D2 enzymatic activity that was suppressed by cefuroxime and lenvatinib. Genetic loss of Dio2 in the TME resulted in significantly reduced tumor growth. Conclusions: DIO2 is a conserved marker of CAF, and myCAF, across multiple solid tumors and is associated with adverse clinical outcomes in some cancers. The TBP mouse provides a robust preclinical model to define the mechanistic role of DIO2 in CAF biology and to evaluate DIO2-directed therapeutic strategies targeting the tumor microenvironment.","rel_num_authors":32,"rel_authors":[{"author_name":"Mary Grace Carroll","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Noha Mukhtar","author_inst":"King Faisal Specialist Hospital and Research Centre"},{"author_name":"Jacob Calhoun","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Breaunna Garza","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Matthew A Loberg","author_inst":"Vanderbilt University"},{"author_name":"Hua-Chang Chen","author_inst":"Vanderbilt University"},{"author_name":"Quanhu Sheng","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alyse Staley","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Tatiana L Fonseca","author_inst":"University of Texas Medical Branch"},{"author_name":"Antonio C Bianco","author_inst":"University of Texas Medical Branch"},{"author_name":"Matthew D Ringel","author_inst":"The Ohio State University"},{"author_name":"Pamela Brock","author_inst":"The Ohio Satae University"},{"author_name":"Andrew J Gunderson","author_inst":"The Ohio State University"},{"author_name":"Ahamd A Tarhini","author_inst":"Moffitt Cancer Center"},{"author_name":"W Douglas Cress","author_inst":"Moffitt Cancer Center"},{"author_name":"Michael J Cavnar","author_inst":"University of Kentucky"},{"author_name":"Stephen Edge","author_inst":"Roswell Park Comprehensive Cancer Center"},{"author_name":"Varinder Kaur","author_inst":"University of Virginia"},{"author_name":"George J Weiner","author_inst":"University of Iowa"},{"author_name":"Janice L Farlow","author_inst":"Indiana University"},{"author_name":"Robert Dood","author_inst":"University of Utah"},{"author_name":"Roman Groisberg","author_inst":"Rutgers Cancer Institute of New Jersey"},{"author_name":"Abdul Rafeh Naquash","author_inst":"University of Oklahoma"},{"author_name":"Craig Shriver","author_inst":"Walter Reed National Military Medical Center"},{"author_name":"Dinesh Pal Mudaranthakam","author_inst":"University of Kansas Medical Center"},{"author_name":"Jose A Oliveras","author_inst":"Ponce Health Sciences University"},{"author_name":"Robert J Rounbehler","author_inst":"Aster Insights"},{"author_name":"Michelle L. Churchman","author_inst":"Aster Insights"},{"author_name":"Vivian L Weiss","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Rebecca E Schweppe","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Nikita Pozdeyev","author_inst":"University of Colorado Anschutz"},{"author_name":"Bryan R Haugen","author_inst":"Universtiy of Colorado Anschutz"}],"rel_date":"2026-09-23","rel_site":"medrxiv"},{"rel_title":"Type 2 Deiodinase in Cancer-Associated Fibroblasts: A Potential Therapeutic Target in Many Types of Cancer","rel_doi":"10.64898\/2026.09.14.26362848","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26362848","rel_abs":"Background: Cancer-associated fibroblasts (CAF) are major regulators of the tumor microenvironment (TME), yet the pathways governing CAF function remain incompletely understood. Type 2 deiodinase (DIO2, D2), which converts thyroxine (T4) to the active thyroid hormone triiodothyronine (T3), has not been systematically investigated in CAF across different solid tumors. Methods: We analyzed DIO2 expression using single-cell RNA sequencing (scRNA-seq) from primary thyroid tumors, a large integrated scRNASeq thyroid cancer atlas, and publicly available scRNA-seq datasets representing six additional solid tumor types. Bulk RNA sequencing data from the Oncology Research Information Exchange Network (ORIEN) database were used to examine correlations among DIO2, CAF subtype markers, and overall survival (OS). A genetically engineered TPO-CreERT2\/BrafV600E\/Trp53-deficient (TBP) mouse model was evaluated for CAF-specific Dio2 expression and pharmacologic inhibition of D2 activity. TBP mice were crossed with Dio2-\/- (Dio2 KO) mice to investigate the role of Dio2 in cancer development and progression. Results: DIO2 expression was highly restricted to CAF and was largely absent from epithelial-derived cancer, immune, and endothelial cells. Across thyroid cancer and six additional malignancies, DIO2 was consistently detected in CAF, demonstrating that CAF-specific DIO2 expression is a conserved feature of multiple tumor types. Within thyroid cancer, DIO2 was enriched in myofibroblastic CAF (myCAF) compared with inflammatory CAF (iCAF), and bulk transcriptomic analyses demonstrated stronger correlations between DIO2 expression and canonical myCAF markers than iCAF markers across numerous cancers. Elevated DIO2 expression was associated with worse OS in pancreatic and bladder cancers, paralleling the adverse prognostic impact of increased myCAF abundance. In contrast, thyroid cancer demonstrated an inverse association attributable to loss of epithelial DIO2 expression during tumor dedifferentiation. The TBP mouse model recapitulated human disease, with Dio2 expression restricted to CAF, robust stromal fibrosis, and measurable D2 enzymatic activity that was suppressed by cefuroxime and lenvatinib. Genetic loss of Dio2 in the TME resulted in significantly reduced tumor growth. Conclusions: DIO2 is a conserved marker of CAF, and myCAF, across multiple solid tumors and is associated with adverse clinical outcomes in some cancers. The TBP mouse provides a robust preclinical model to define the mechanistic role of DIO2 in CAF biology and to evaluate DIO2-directed therapeutic strategies targeting the tumor microenvironment.","rel_num_authors":32,"rel_authors":[{"author_name":"Mary Grace Carroll","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Noha Mukhtar","author_inst":"King Faisal Specialist Hospital and Research Centre"},{"author_name":"Jacob Calhoun","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Breaunna Garza","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Matthew A Loberg","author_inst":"Vanderbilt University"},{"author_name":"Hua-Chang Chen","author_inst":"Vanderbilt University"},{"author_name":"Quanhu Sheng","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alyse Staley","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Tatiana L Fonseca","author_inst":"University of Texas Medical Branch"},{"author_name":"Antonio C Bianco","author_inst":"University of Texas Medical Branch"},{"author_name":"Matthew D Ringel","author_inst":"The Ohio State University"},{"author_name":"Pamela Brock","author_inst":"The Ohio Satae University"},{"author_name":"Andrew J Gunderson","author_inst":"The Ohio State University"},{"author_name":"Ahamd A Tarhini","author_inst":"Moffitt Cancer Center"},{"author_name":"W Douglas Cress","author_inst":"Moffitt Cancer Center"},{"author_name":"Michael J Cavnar","author_inst":"University of Kentucky"},{"author_name":"Stephen Edge","author_inst":"Roswell Park Comprehensive Cancer Center"},{"author_name":"Varinder Kaur","author_inst":"University of Virginia"},{"author_name":"George J Weiner","author_inst":"University of Iowa"},{"author_name":"Janice L Farlow","author_inst":"Indiana University"},{"author_name":"Robert Dood","author_inst":"University of Utah"},{"author_name":"Roman Groisberg","author_inst":"Rutgers Cancer Institute of New Jersey"},{"author_name":"Abdul Rafeh Naquash","author_inst":"University of Oklahoma"},{"author_name":"Craig Shriver","author_inst":"Walter Reed National Military Medical Center"},{"author_name":"Dinesh Pal Mudaranthakam","author_inst":"University of Kansas Medical Center"},{"author_name":"Jose A Oliveras","author_inst":"Ponce Health Sciences University"},{"author_name":"Robert J Rounbehler","author_inst":"Aster Insights"},{"author_name":"Michelle L. Churchman","author_inst":"Aster Insights"},{"author_name":"Vivian L Weiss","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Rebecca E Schweppe","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Nikita Pozdeyev","author_inst":"University of Colorado Anschutz"},{"author_name":"Bryan R Haugen","author_inst":"Universtiy of Colorado Anschutz"}],"rel_date":"2026-09-23","rel_site":"medrxiv"},{"rel_title":"Caregiver knowledge and Attitudes toward Human Papillomavirus Vaccination among adolescent girls living with HIV in Sierra Leone: A health facility-based cross-sectional study","rel_doi":"10.64898\/2026.09.21.26363609","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363609","rel_abs":"Objective To assess the knowledge, willingness and barriers to human papillomavirus (HPV) vaccination among caregivers of adolescent girls living with HIV in Sierra Leone. Methods This cross-sectional study examined HPV vaccine knowledge, willingness, and barriers among 249 caregivers of adolescent girls living with HIV in Sierra Leone. Data were collected through structured questionnaires at public tertiary hospitals and high-volume HIV clinics, and associations were assessed using chi-square tests, logistic regression, and Kruskal-Wallis analyses. Results Only 32.1% (80\/249) of caregivers had heard of HPV, with even fewer aware of its link to cervical cancer (24.4%, 60\/246) or prevention methods of cervical cancer (31.9%, 79\/248). Misconceptions were prevalent; 16.3% (36\/221) erroneously linked oral contraceptives to cervical cancer, and 61.1% (44\/72) of caregivers unwilling to vaccinate cited distrust in vaccine efficacy. While tertiary-educated caregivers exhibited the highest level of knowledge (45.5%, p < 0.001), their willingness to vaccinate (50%, 33\/66) was comparable to that of less-educated groups, highlighting a knowledge-action gap. Structural barriers dominated, with 66.1% (154\/233) citing unawareness of the vaccine and 10.3% (24\/233) missing school-based vaccination days. Relationship dynamics significantly influenced willingness: extended family members showed the highest willingness (69.4%, p = 0.029), whereas grandparents were least willing (31%, 9\/29). Although systemic gaps such disrupted vaccination services, vaccines supplies and cold chain limited uptake, healthcare workers emerged as the most effective information source (rank sum = 889.5, p = 0.039). Conclusion The study highlights needs for culturally tailored education to dispel myths, community-driven strategies engaging trusted actors like healthcare workers and extended families.This study justifies the need for integration of HPV vaccination and cervical cancer screening into HIV care services.","rel_num_authors":16,"rel_authors":[{"author_name":"Darlinda  Fatmata Jiba","author_inst":"College of Medicine and Allied Health Sciences, University of Sierra Leone"},{"author_name":"Mamadu Baldeh","author_inst":"London School of Hygiene & Tropical Medicine"},{"author_name":"Patrick Turay","author_inst":"UNIMAK: University of Makeni"},{"author_name":"Saidu Kanu","author_inst":"University of Makeni"},{"author_name":"Matilda  N Kamara","author_inst":"Government of Sierra Leone"},{"author_name":"Lynda  M. L Farma-Grant","author_inst":"Government of Sierra Leone"},{"author_name":"Umu Barrie","author_inst":"Infectious Disease Research Network, Freetown, Sierra Leone"},{"author_name":"Waheed  O Awonuga","author_inst":"Government of Sierra Leone"},{"author_name":"Mary  M Baio","author_inst":"Government of Sierra Leone"},{"author_name":"Daniel Sesay","author_inst":"Government of Sierra Leone"},{"author_name":"Diana Shehab","author_inst":"Government of Sierra Leone"},{"author_name":"Rosaline Sinnah","author_inst":"Government of Sierra Leone"},{"author_name":"Enanga  S Namanga","author_inst":"Government of Sierra Leone"},{"author_name":"Phildys  M D Johnson","author_inst":"Government of Sierra Leone"},{"author_name":"Sulaiman Lakoh","author_inst":"University of Sierra Leone"},{"author_name":"J.  Andrew Dykens","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-09-23","rel_site":"medrxiv"},{"rel_title":"Childhood and adolescent immunisation intentions post-COVID-19 in Lusaka, Zambia","rel_doi":"10.64898\/2026.09.21.26363608","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363608","rel_abs":"Background: Since the COVID-19 pandemic, parental delays and refusals of well-established, safe, and effective childhood vaccinations have contributed to the resurgence of infectious diseases. This raises concerns that COVID-19 vaccine hesitancy may also extend to novel vaccines for children when introduced in the future. This study examined caregivers, who included healthcare workers (HCWs), perceptions of novel vaccinations for children ages 0-17 years old and intentions to vaccinate children and adolescents ages 12-17 years against COVID-19. Methods: We conducted a secondary data analysis of a larger cross-sectional survey administered to parents\/caregivers of children ages 0-17 years in Lusaka, Zambia, between 13 November and 15 December 2023. Vaccination intention for COVID-19 was specifically focused on caregivers of adolescents ages 12-17 years, following COVID-19 vaccination guidelines during the study. Descriptive statistics were used to explore demographic characteristics, vaccination history, and caregivers COVID-19 vaccination status, along with their childrens routine childhood vaccine histories and perceptions of COVID-19 and novel vaccinations. Results: Among 277 caregivers (66.8% women, median age: 35 years), 93.1% reported that their child had received all recommended routine childhood vaccinations. COVID-19 vaccine uptake was higher among HCWs (68.2% with [&ge;]2 doses) than among community members (40.8%) and having [&ge;]2 doses was associated with higher COVID-19 vaccine uptake among their adolescents ages 12-17 years. 58.0% of caregivers indicated that their 12-17 years old adolescents had received at least one COVID-19 vaccine dose. Overall intention to further vaccinate children against COVID-19, especially among those already unvaccinated, remained low, with 24.7% of caregivers reporting no intent to vaccinate their children. Protection from hospitalization and death from malaria, TB, HIV, pneumonia, influenza, and diarrheal diseases were the most cited reason (79.1%) for intention to vaccinate children with novel vaccines for these diseases. The most prominent reasons for reluctance towards future vaccines were the fear of potential side effects (45.5%) and insufficient knowledge about vaccination benefits and risks (31.8%). Caregivers most trusted the Ministry of Health (86.6%) and healthcare professionals (66.8%) as sources of vaccine information. Conclusions: While routine childhood vaccine uptake remained high, acceptance of COVID-19 and future novel vaccines for children was lower and was influenced by caregivers own vaccination status. Targeted and transparent communication through trusted sources such as the Ministry of Health and healthcare professionals may be critical for addressing safety concerns and strengthening confidence in novel childhood vaccines.","rel_num_authors":11,"rel_authors":[{"author_name":"Mwiza Nyasa","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Anjali Sharma","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Andrew  D Kerkhoff","author_inst":"University of California San Francisco"},{"author_name":"Dennis Ngosa","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Bertha Shamoya","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Kombatende Sikombe","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Sandra Simbeza","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Nelly Zulu","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Elvin  H Geng","author_inst":"Washington University In Saint Louis: Washington University in St Louis"},{"author_name":"Jake  M Pry","author_inst":"UC Davis: University of California Davis"},{"author_name":"Noelle Tourneau","author_inst":"Zuckerberg San Francisco General Hospital and Trauma Center"}],"rel_date":"2026-09-23","rel_site":"medrxiv"},{"rel_title":"Childhood and adolescent immunisation intentions post-COVID-19 in Lusaka, Zambia","rel_doi":"10.64898\/2026.09.21.26363608","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363608","rel_abs":"Background: Since the COVID-19 pandemic, parental delays and refusals of well-established, safe, and effective childhood vaccinations have contributed to the resurgence of infectious diseases. This raises concerns that COVID-19 vaccine hesitancy may also extend to novel vaccines for children when introduced in the future. This study examined caregivers, who included healthcare workers (HCWs), perceptions of novel vaccinations for children ages 0-17 years old and intentions to vaccinate children and adolescents ages 12-17 years against COVID-19. Methods: We conducted a secondary data analysis of a larger cross-sectional survey administered to parents\/caregivers of children ages 0-17 years in Lusaka, Zambia, between 13 November and 15 December 2023. Vaccination intention for COVID-19 was specifically focused on caregivers of adolescents ages 12-17 years, following COVID-19 vaccination guidelines during the study. Descriptive statistics were used to explore demographic characteristics, vaccination history, and caregivers COVID-19 vaccination status, along with their childrens routine childhood vaccine histories and perceptions of COVID-19 and novel vaccinations. Results: Among 277 caregivers (66.8% women, median age: 35 years), 93.1% reported that their child had received all recommended routine childhood vaccinations. COVID-19 vaccine uptake was higher among HCWs (68.2% with [&ge;]2 doses) than among community members (40.8%) and having [&ge;]2 doses was associated with higher COVID-19 vaccine uptake among their adolescents ages 12-17 years. 58.0% of caregivers indicated that their 12-17 years old adolescents had received at least one COVID-19 vaccine dose. Overall intention to further vaccinate children against COVID-19, especially among those already unvaccinated, remained low, with 24.7% of caregivers reporting no intent to vaccinate their children. Protection from hospitalization and death from malaria, TB, HIV, pneumonia, influenza, and diarrheal diseases were the most cited reason (79.1%) for intention to vaccinate children with novel vaccines for these diseases. The most prominent reasons for reluctance towards future vaccines were the fear of potential side effects (45.5%) and insufficient knowledge about vaccination benefits and risks (31.8%). Caregivers most trusted the Ministry of Health (86.6%) and healthcare professionals (66.8%) as sources of vaccine information. Conclusions: While routine childhood vaccine uptake remained high, acceptance of COVID-19 and future novel vaccines for children was lower and was influenced by caregivers own vaccination status. Targeted and transparent communication through trusted sources such as the Ministry of Health and healthcare professionals may be critical for addressing safety concerns and strengthening confidence in novel childhood vaccines.","rel_num_authors":11,"rel_authors":[{"author_name":"Mwiza Nyasa","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Anjali Sharma","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Andrew  D Kerkhoff","author_inst":"University of California San Francisco"},{"author_name":"Dennis Ngosa","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Bertha Shamoya","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Kombatende Sikombe","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Sandra Simbeza","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Nelly Zulu","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Elvin  H Geng","author_inst":"Washington University In Saint Louis: Washington University in St Louis"},{"author_name":"Jake  M Pry","author_inst":"UC Davis: University of California Davis"},{"author_name":"Noelle Tourneau","author_inst":"Zuckerberg San Francisco General Hospital and Trauma Center"}],"rel_date":"2026-09-23","rel_site":"medrxiv"},{"rel_title":"Adaptation and Validation of Brief Tablet-Based Cognitive Assessment Tool in Uganda","rel_doi":"10.64898\/2026.09.21.26363152","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363152","rel_abs":"Background: Sub-Saharan Africa (sSA) faces accelerated growth in Alzheimer's disease and related dementias (ADRDs), including in older people living with HIV (PLWH). However, there are limited contextually relevant diagnostic tools to assess cognitive impairment in the region. The Tablet-based Cognitive Assessment Tool (TabCAT) is a digital platform hosting cognitive tests with automated scoring that can be administered by non-specialists and are designed for use across diverse cultures, languages, and education levels. We translated, adapted, and assessed the validity of a brief battery of TabCAT tests in the Uganda Aging and Dementia Cohort Study (UADCS), a prospective cohort of older PLWH and age- and sex-similar adults not living with HIV in southwestern Uganda. Methods: Four TabCAT tests were translated and culturally adapted through expert review and focus groups of adults at study sites. Psychometric validity was examined by assessing floor and ceiling effects, association with known demographic predictors, and concurrent and divergent validity against a reference-standard cognitive testing battery previously validated and employed in Uganda. Z-scores on all tests were derived using a regression-based normative approach to adjust for age, sex, education, urbanicity, and literacy. Receiver Operating Characteristic (ROC) curves were fit to assess the TabCAT Composite Score performance in discriminating objective cognitive impairment (defined using Jak\/Bondi criteria) in the total sample, then stratified by HIV serostatus. Results: TabCAT tests were reported by local experts and focus groups to have acceptable face and content validity. Participants (n=563, mean age 60{+\/-}6.4, 50% female, 51% did not complete primary school, 16% were not literate, 49% PLWH) completed the reference-standard and TabCAT battery. For TabCAT tests, there were no notable floor or ceiling effects, and test scores were associated with age and education as expected. Correlations between TabCAT and reference-standard tests were stronger in aligning cognitive domains (memory, executive function) than in non-aligning domains (motor). The TabCAT Composite Score discriminated cognitive impairment with good performance (c-statistic 0.77; 95% CI 0.72-0.81), including among PLWH. Discussion: TabCAT tests demonstrated face, content, construct, concurrent, and criterion validity for measuring cognition and detecting objective cognitive impairment among older adults in Uganda, including PLWH. These results support the potential of tablet-based brief cognitive assessment tools to measure cognitive performance and detect cognitive impairment in Uganda, including among older PLWH, and in populations with lower levels of education and literacy.","rel_num_authors":24,"rel_authors":[{"author_name":"Roslyn Valdespino","author_inst":"Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA"},{"author_name":"Gabrielle Hromas","author_inst":"Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA"},{"author_name":"Chen-Pin Wang","author_inst":"Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA"},{"author_name":"Robert Paul","author_inst":"University of Missouri- St Louis, St. Louis, MO, USA"},{"author_name":"Noeline Nakasujja","author_inst":"Makerere University, Kampala, Uganda"},{"author_name":"Zahra Reynolds","author_inst":"Massachusetts General Hospital (MGH), Boston, MA, USA"},{"author_name":"Flavia Atwiine","author_inst":"Mbarara University of Science & Technology, Mbarara, Uganda"},{"author_name":"Edna Tindimwebwa","author_inst":"Kabwohe Clinical Research Centre, Sheema, Uganda"},{"author_name":"Meredith Greene","author_inst":"Indiana University School of Medicine, Indianapolis, IN, US"},{"author_name":"Eliza Passell","author_inst":"Massachusetts General Hospital (MGH), Boston, MA, USA"},{"author_name":"Christine S. Ritchie","author_inst":"Massachusetts General Hospital (MGH), Boston, MA, USA"},{"author_name":"Susanne S. Hoeppner","author_inst":"Massachusetts General Hospital (MGH), Boston, MA, USA"},{"author_name":"Alexander C. Tsai","author_inst":"Massachusetts General Hospital (MGH), Boston, MA, USA"},{"author_name":"Janet Seeley","author_inst":"Department of Global Health and Development, London School of Hygiene & Tropical Medicine, London, UK"},{"author_name":"Amy Werry","author_inst":"Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA"},{"author_name":"Emi Varfaj","author_inst":"Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA"},{"author_name":"Sudha Seshadri","author_inst":"Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA"},{"author_name":"Samson Okello","author_inst":"University of North Carolina - Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Stephen Asiimwe","author_inst":"Massachusetts General Hospital (MGH), Boston, MA, USA"},{"author_name":"Deanna Saylor","author_inst":"University of North Carolina - Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Katherine L. Possin","author_inst":"Global Brain Health Institute (GBHI), University of California San Francisco (UCSF)"},{"author_name":"Elena Tsoy","author_inst":"Global Brain Health Institute (GBHI), University of California San Francisco (UCSF)"},{"author_name":"Mark J. Siedner","author_inst":"Massachusetts General Hospital (MGH), Boston, MA, USA"},{"author_name":"Jeremy A. Tanner","author_inst":"Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA"}],"rel_date":"2026-09-23","rel_site":"medrxiv"},{"rel_title":"Cysteine supplementation reverses immune dysfunction in cancer patients with severe COVID-19","rel_doi":"10.64898\/2026.09.21.26363550","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363550","rel_abs":"Severe COVID-19 infection in patients with cancer is characterized by a unique pattern of immunologic dysfunction including muted adaptive immune responses. The molecular drivers of immune dysfunction in cancer patients with severe COVID-19 remain unclear, and therapeutic strategies to overcome immune dysfunction in this setting have not been identified.\n\nWe performed integrated proteomic and metabolomic profiling of matched cohorts of cancer and non-cancer patients with or without COVID-19 and identified dysfunctional cysteine metabolism as uniquely associated with severe COVID-19 in cancer patients. Treatment of patients with cancer and steroid-refractory COVID-19 with N-acetylcysteine in a prospective clinical trial (NCT04374461) improved clinical outcomes compared with disease severity-matched hospitalized patients during the period immediately preceding clinical trial initiation. N-AC treatment reduced circulating markers of innate inflammation, decreased severe disease-associated MHC-II low monocytes, and increased circulating CD8+ T cell abundance, activation, and effector differentiation. Mechanistically, N-AC reduced prostaglandin E2-driven interactions between suppressive monocytes and T cells, which we confirmed was sufficient to limit T cell expansion and effector differentiation in a dose- and avidity-dependent fashion. Moreover, N-AC reduced the activity of inhibitory, redox sensitive transcription factors such as KLF6, enabling clonal expansion and effector T cell differentiation. We confirmed these observations in two murine models of severe respiratory viral infection, in which N-AC treatment significantly enhanced lung-infiltrating CD8+ T cell abundance. These findings establish cysteine supplementation as a viable therapeutic strategy to reverse redox-driven immune dysregulation in severe respiratory viral infection, particularly in the high-risk cancer population.\n\nOne Sentence SummaryMerlinsky et al show that cysteine supplementation can therapeutically reverse immune dysregulation in cancer patients with severe COVID-19 infection.","rel_num_authors":24,"rel_authors":[{"author_name":"Tiffany Merlinsky","author_inst":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"Jahan Rahman","author_inst":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"William T Johnson","author_inst":"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"Lisa McGary","author_inst":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"Simon Grassmann","author_inst":"Immunology Program, Sloan Kettering Institute for Cancer Research; New York, NY, USA."},{"author_name":"Jennifer Zhang","author_inst":"Immunology Program, Sloan Kettering Institute for Cancer Research; New York, NY, USA."},{"author_name":"Abdulraouf Abdulraouf","author_inst":"Laboratory of Single Cell Genomics and Population Dynamics, The Rockefeller University; New York, NY, USA"},{"author_name":"Hannah L Kalvin","author_inst":"Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"Katherine Panageas","author_inst":"Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"Jasmine Nicodemus","author_inst":"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"Elizabeth Cathcart","author_inst":"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"Ya-Hui Lin","author_inst":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"Kinga K Hosszu","author_inst":"Stem Cell Transplantation and Cellular Therapies, MSK Kids, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"Mirela Berisa","author_inst":"Metabolomics Core, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"author_name":"Olga Lyudovyk","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Gilles Salles","author_inst":"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"Jaap J Boelens","author_inst":"Stem Cell Transplantation and Cellular Therapies, MSK Kids, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"N Esther Babady","author_inst":"Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"Junyue Cao","author_inst":"Laboratory of Single Cell Genomics and Population Dynamics, The Rockefeller University; New York, NY, USA"},{"author_name":"Jedd D Wolchok","author_inst":"Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine; New York, NY, USA"},{"author_name":"Joseph C Sun","author_inst":"Immunology Program, Sloan Kettering Institute for Cancer Research; New York, NY, USA."},{"author_name":"James Heath","author_inst":"Institute for Systems Biology; Seattle, WA, USA"},{"author_name":"Benjamin Greenbaum","author_inst":"Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"Santosha Vardhana","author_inst":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center; New York, NY, USA"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"CREBRF rs373863828 minimally regulates gene expression in subcutaneous adipose tissue of Samoan adults","rel_doi":"10.64898\/2026.09.21.26363571","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363571","rel_abs":"A population-specific missense variant, rs373863828 (G>A, p.Arg457Gln), has been identified in Pacific Islanders and is associated with increased body mass index and lower odds of type 2 diabetes. However, the mechanism underlying these associations is unknown. The variant is located in exon 5 of CREBRF, a gene which is rapidly upregulated in response to nutrient deprivation. This study aimed to assess the effect of rs373863828 on gene expression in adipose tissue from Samoan adults from the Soifua Manuia (\"Good Health\") study. Needle subcutaneous adipose (upper buttock) biopsies were obtained in Apia, Samoa, from fasting Samoans without diabetes. RNA isolated from adipose tissue (n=91, 65.9% female) was subjected to bulk paired-end mRNA-sequencing (2x150 base pair). Differential gene expression among the three rs373863828 genotypes (GG, AG, AA) was assessed using a likelihood-ratio test implemented in DESeq2, and overrepresentation analysis for significant differentially expressed genes (DEGs) (padj < 0.1) was performed with clusterProfiler and oRG.DB. Bulk expression was deconvoluted to determine the cell type composition of the adipose tissue. Twenty-two DEGs were associated with rs373863828 genotype including CBX7 (padj=0.026) and SELENOM (padj= 0.004), both of which have roles in adipogenesis and metabolism. A single expression profile comprising 13 of the 22 DEGs corresponding to CREBRF genotype was identified, and overrepresentation analysis supported this finding, with terms such as \"keratinocyte differentiation\" and \"skin development\" enriched among significant DEGs. However, PERMANOVA of adipose cell type proportions showed no difference (p > 0.05) among the three genotypes. rs373863828 genotype was associated with expression of 22 genes in whole subcutaneous adipose tissue of this sample of fasting Samoan adults without diabetes. Future work should assess cell- and tissue-specific rs373863828 genotype effects using a combination of single-cell approaches and human cell models with perturbations associated with nutritional stress.\n\nAUTHOR SUMMARYA genetic variant (change in DNA, G >A) is associated with higher body mass index and lower risk for type 2 diabetes. This variant, called rs373863828, is only present in people of Pacific Islander ancestry, who are underrepresented in genetic and genomic studies, and is in the CREBRF gene, which is not well-understood. Studies in mice, flies, and cells from humans and mice suggest CREBRF is important for cellular growth and stress response, and that rs373863828 increases these functions. In this study, we tested the hypothesis that CREBRF affects these cellular processes by controlling gene expression--how genes are \"turned on or off\" -in fat tissue from Samoan adults as part of the Soifua Manuia (\"Good Health\") study. We found 22 genes that were affected by how many G to A changes (0, 1, or 2) an individual has at this position in CREBRF. We also found that the variant did not affect the proportion of the cell types that make up adipose tissue. This work helps us to better understand the function of the CREBRF gene in human fat and gives some clues about how the variant affects BMI and type 2 diabetes risk in healthy Samoan adults.","rel_num_authors":25,"rel_authors":[{"author_name":"Samantha L Manna","author_inst":"Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, "},{"author_name":"Anna C Rivara","author_inst":"Department of Social and Behavioral Sciences, O'Donnell School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"author_name":"Angela T Prescott","author_inst":"Department of Plastic and Reconstructive Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA"},{"author_name":"Corina S Penaia","author_inst":"Department of Health Policy and Management, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA"},{"author_name":"Muagututia Sefuiva Reupena","author_inst":"Lutia I Puava Ae Mapu I Fagalele, Apia, Samoa"},{"author_name":"Take Naseri","author_inst":"Ministry of Health, Apia, Samoa"},{"author_name":"Satupaitea Viali","author_inst":"Oceania University of Medicine, Samoa; Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Melania Selu","author_inst":"Obesity, Lifestyle and Genetic Adaptations Study Group, Apia, Samoa"},{"author_name":"Gloria Siufaga","author_inst":"Obesity, Lifestyle and Genetic Adaptations Study Group, Apia, Samoa"},{"author_name":"Kima Faasalele-Savusa","author_inst":"Obesity, Lifestyle and Genetic Adaptations Study Group, Apia, Samoa"},{"author_name":"Folla Unasa","author_inst":"Obesity, Lifestyle and Genetic Adaptations Study Group, Apia, Samoa"},{"author_name":"Vaimoana Lupematisila","author_inst":"Obesity, Lifestyle and Genetic Adaptations Study Group, Apia, Samoa"},{"author_name":"Alysa Pomer","author_inst":"Center for Surgery and Public Health, Brigham and Women's Hospital, Boston, MA, USA"},{"author_name":"Elizabeth C Lawrence","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Jenna C Carlson","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biostatistics and Health Data Science, Schoo"},{"author_name":"Emily M Russell","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Mohanraj Krishnan","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biostatistics and Health Data Science, Schoo"},{"author_name":"Katie L Whytock","author_inst":"Translational Research Institute, AdventHealth, Orlando, Florida, USA"},{"author_name":"Lacey W Heinsberg","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Health Promotion and Development, School of "},{"author_name":"Erin E Kershaw","author_inst":"Division of Endocrinology and Metabolism, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Ryan L Minster","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Daniel E Weeks","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biostatistics and Health Data Science, Schoo"},{"author_name":"Stephen T McGarvey","author_inst":"Center for Global Public Health, Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA; Department of Anthropology, Brown Un"},{"author_name":"Nicola L Hawley","author_inst":"Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Zsolt Urban","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"CREBRF rs373863828 minimally regulates gene expression in subcutaneous adipose tissue of Samoan adults","rel_doi":"10.64898\/2026.09.21.26363571","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363571","rel_abs":"A population-specific missense variant, rs373863828 (G>A, p.Arg457Gln), has been identified in Pacific Islanders and is associated with increased body mass index and lower odds of type 2 diabetes. However, the mechanism underlying these associations is unknown. The variant is located in exon 5 of CREBRF, a gene which is rapidly upregulated in response to nutrient deprivation. This study aimed to assess the effect of rs373863828 on gene expression in adipose tissue from Samoan adults from the Soifua Manuia (\"Good Health\") study. Needle subcutaneous adipose (upper buttock) biopsies were obtained in Apia, Samoa, from fasting Samoans without diabetes. RNA isolated from adipose tissue (n=91, 65.9% female) was subjected to bulk paired-end mRNA-sequencing (2x150 base pair). Differential gene expression among the three rs373863828 genotypes (GG, AG, AA) was assessed using a likelihood-ratio test implemented in DESeq2, and overrepresentation analysis for significant differentially expressed genes (DEGs) (padj < 0.1) was performed with clusterProfiler and oRG.DB. Bulk expression was deconvoluted to determine the cell type composition of the adipose tissue. Twenty-two DEGs were associated with rs373863828 genotype including CBX7 (padj=0.026) and SELENOM (padj= 0.004), both of which have roles in adipogenesis and metabolism. A single expression profile comprising 13 of the 22 DEGs corresponding to CREBRF genotype was identified, and overrepresentation analysis supported this finding, with terms such as \"keratinocyte differentiation\" and \"skin development\" enriched among significant DEGs. However, PERMANOVA of adipose cell type proportions showed no difference (p > 0.05) among the three genotypes. rs373863828 genotype was associated with expression of 22 genes in whole subcutaneous adipose tissue of this sample of fasting Samoan adults without diabetes. Future work should assess cell- and tissue-specific rs373863828 genotype effects using a combination of single-cell approaches and human cell models with perturbations associated with nutritional stress.\n\nAUTHOR SUMMARYA genetic variant (change in DNA, G >A) is associated with higher body mass index and lower risk for type 2 diabetes. This variant, called rs373863828, is only present in people of Pacific Islander ancestry, who are underrepresented in genetic and genomic studies, and is in the CREBRF gene, which is not well-understood. Studies in mice, flies, and cells from humans and mice suggest CREBRF is important for cellular growth and stress response, and that rs373863828 increases these functions. In this study, we tested the hypothesis that CREBRF affects these cellular processes by controlling gene expression--how genes are \"turned on or off\" -in fat tissue from Samoan adults as part of the Soifua Manuia (\"Good Health\") study. We found 22 genes that were affected by how many G to A changes (0, 1, or 2) an individual has at this position in CREBRF. We also found that the variant did not affect the proportion of the cell types that make up adipose tissue. This work helps us to better understand the function of the CREBRF gene in human fat and gives some clues about how the variant affects BMI and type 2 diabetes risk in healthy Samoan adults.","rel_num_authors":25,"rel_authors":[{"author_name":"Samantha L Manna","author_inst":"Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, "},{"author_name":"Anna C Rivara","author_inst":"Department of Social and Behavioral Sciences, O'Donnell School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"author_name":"Angela T Prescott","author_inst":"Department of Plastic and Reconstructive Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA"},{"author_name":"Corina S Penaia","author_inst":"Department of Health Policy and Management, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA"},{"author_name":"Muagututia Sefuiva Reupena","author_inst":"Lutia I Puava Ae Mapu I Fagalele, Apia, Samoa"},{"author_name":"Take Naseri","author_inst":"Ministry of Health, Apia, Samoa"},{"author_name":"Satupaitea Viali","author_inst":"Oceania University of Medicine, Samoa; Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Melania Selu","author_inst":"Obesity, Lifestyle and Genetic Adaptations Study Group, Apia, Samoa"},{"author_name":"Gloria Siufaga","author_inst":"Obesity, Lifestyle and Genetic Adaptations Study Group, Apia, Samoa"},{"author_name":"Kima Faasalele-Savusa","author_inst":"Obesity, Lifestyle and Genetic Adaptations Study Group, Apia, Samoa"},{"author_name":"Folla Unasa","author_inst":"Obesity, Lifestyle and Genetic Adaptations Study Group, Apia, Samoa"},{"author_name":"Vaimoana Lupematisila","author_inst":"Obesity, Lifestyle and Genetic Adaptations Study Group, Apia, Samoa"},{"author_name":"Alysa Pomer","author_inst":"Center for Surgery and Public Health, Brigham and Women's Hospital, Boston, MA, USA"},{"author_name":"Elizabeth C Lawrence","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Jenna C Carlson","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biostatistics and Health Data Science, Schoo"},{"author_name":"Emily M Russell","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Mohanraj Krishnan","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biostatistics and Health Data Science, Schoo"},{"author_name":"Katie L Whytock","author_inst":"Translational Research Institute, AdventHealth, Orlando, Florida, USA"},{"author_name":"Lacey W Heinsberg","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Health Promotion and Development, School of "},{"author_name":"Erin E Kershaw","author_inst":"Division of Endocrinology and Metabolism, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Ryan L Minster","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Daniel E Weeks","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biostatistics and Health Data Science, Schoo"},{"author_name":"Stephen T McGarvey","author_inst":"Center for Global Public Health, Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA; Department of Anthropology, Brown Un"},{"author_name":"Nicola L Hawley","author_inst":"Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Zsolt Urban","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Interrater reliability of Tremor Characterization","rel_doi":"10.64898\/2026.09.21.26363551","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363551","rel_abs":"BackgroundTremor is a repetitive, oscillatory movement with multiple subtypes requiring accurate characterization for diagnosis and treatment. While frequency, amplitude, and context are routinely used to describe tremor, recent recommendations have emphasized oscillation shape and regularity. However, these descriptors lack strict operational definitions, and differences in how clinicians interpret them introduce inconsistency into tremor classification.\n\nObjectiveWe quantified inter-rater reliability for commonly used tremor descriptors and determined which objectively measured signal parameters: peak amplitude, peak frequency, and frequency variability best explained inconsistency in rater assessments.\n\nMethodsWe developed the Tremor Waveform Morphology Questionnaire (TWMQ) and obtained standardized video recordings of 34 individuals with upper-extremity tremor performing rest, postural, and kinetic tasks, with simultaneous kinematic recordings using an inertial sensor. Movement disorder experts rated tremor presence, shape, symmetry, regularity, rhythmicity, and diagnosis. We assessed inter-rater reliability, cross-feature dependencies, and modeled the influence of objective signal parameters on each subjective rating.\n\nResultsTremor presence and symmetry showed high agreement, whereas jerkiness, rhythmicity, amplitude stability, and clinical diagnosis showed lower reliability. Modeling revealed that peak amplitude primarily influenced judgments of tremor presence, jerkiness, and diagnosis, while frequency variability drove ratings of rhythmicity and amplitude stability.\n\nConclusionsMorphology-based descriptors remain subjective, but disagreement systematically reflects measurable signal properties. Objective definitions based on peak amplitude and frequency variability may improve the reliability and reproducibility of tremor characterization.","rel_num_authors":9,"rel_authors":[{"author_name":"Prajakta Joshi","author_inst":"Case Western Reserve University"},{"author_name":"Yuri Ferreira Felloni Borges","author_inst":"University of Toronto"},{"author_name":"Sanjay Pandey","author_inst":"Amrita Hospital, Faridabad"},{"author_name":"Marie Vidailhet","author_inst":"Paris Brain Institute"},{"author_name":"Victor Fung","author_inst":"University of Sydney"},{"author_name":"Mark Hallett","author_inst":"NIH"},{"author_name":"Hyder A Jinnah","author_inst":"Emory University"},{"author_name":"Aasef G Shaikh","author_inst":"Case Western Reserve University"},{"author_name":"Alfonso Fasano","author_inst":"University of Toronto"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Interrater reliability of Tremor Characterization","rel_doi":"10.64898\/2026.09.21.26363551","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363551","rel_abs":"BackgroundTremor is a repetitive, oscillatory movement with multiple subtypes requiring accurate characterization for diagnosis and treatment. While frequency, amplitude, and context are routinely used to describe tremor, recent recommendations have emphasized oscillation shape and regularity. However, these descriptors lack strict operational definitions, and differences in how clinicians interpret them introduce inconsistency into tremor classification.\n\nObjectiveWe quantified inter-rater reliability for commonly used tremor descriptors and determined which objectively measured signal parameters: peak amplitude, peak frequency, and frequency variability best explained inconsistency in rater assessments.\n\nMethodsWe developed the Tremor Waveform Morphology Questionnaire (TWMQ) and obtained standardized video recordings of 34 individuals with upper-extremity tremor performing rest, postural, and kinetic tasks, with simultaneous kinematic recordings using an inertial sensor. Movement disorder experts rated tremor presence, shape, symmetry, regularity, rhythmicity, and diagnosis. We assessed inter-rater reliability, cross-feature dependencies, and modeled the influence of objective signal parameters on each subjective rating.\n\nResultsTremor presence and symmetry showed high agreement, whereas jerkiness, rhythmicity, amplitude stability, and clinical diagnosis showed lower reliability. Modeling revealed that peak amplitude primarily influenced judgments of tremor presence, jerkiness, and diagnosis, while frequency variability drove ratings of rhythmicity and amplitude stability.\n\nConclusionsMorphology-based descriptors remain subjective, but disagreement systematically reflects measurable signal properties. Objective definitions based on peak amplitude and frequency variability may improve the reliability and reproducibility of tremor characterization.","rel_num_authors":9,"rel_authors":[{"author_name":"Prajakta Joshi","author_inst":"Case Western Reserve University"},{"author_name":"Yuri Ferreira Felloni Borges","author_inst":"University of Toronto"},{"author_name":"Sanjay Pandey","author_inst":"Amrita Hospital, Faridabad"},{"author_name":"Marie Vidailhet","author_inst":"Paris Brain Institute"},{"author_name":"Victor Fung","author_inst":"University of Sydney"},{"author_name":"Mark Hallett","author_inst":"NIH"},{"author_name":"Hyder A Jinnah","author_inst":"Emory University"},{"author_name":"Aasef G Shaikh","author_inst":"Case Western Reserve University"},{"author_name":"Alfonso Fasano","author_inst":"University of Toronto"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Personalized Pediatrician-Scientist Training Program Optimizes Institutional Research Investment","rel_doi":"10.64898\/2026.09.21.26363577","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363577","rel_abs":"ObjectivePhysician-scientists are a diminishing subset of the pediatrician work force, uniquely trained to advance child health through scientific discovery. The current financial landscape of academic medical centers makes traditional resource-intensive training programs untenable.Continued renewal of this critical pediatric workforce requires new resource-efficient methodologies. Thus, we evaluated the impact of the NICHD supported Vanderbilt K12 program, a personalized, intensive training program.\n\nStudy DesignWe tracked academic outcomes for scholars with K12 appointments between January 2015 and December 2022. Our primary outcome was receipt of a mentored career development award (K08 or K23). Successful transition from mentored to independent NIH funding (K to R transition) was used as a secondary outcome. Academic outcomes for faculty participating in a large, institutional training program, the Vanderbilt Faculty Research Scholars program (VFRS), served as a comparison cohort. A complementary qualitative evaluation of the K12 program was performed.\n\nResultsK12 scholars earned career development awards (73%) at an equivalent rate to VFRS faculty (71%) and transitioned K to R funding at equivalent rates, 45% of K12 scholars compared to 50% for VFRS. Qualitative analysis demonstrated K12 scholars valued a personalized training program that incorporated self-efficacy and adaptability, key tenets of Social Cognitive Career Theory.\n\nConclusionPersonalized physician-scientist training programs may enhance efficient utilization of research resources in Pediatric academic departments and serve as a viable alternative to traditional programs. Our qualitative evaluation suggests scholar self-efficacy and adaptability can be achieved through a personalized training program.","rel_num_authors":8,"rel_authors":[{"author_name":"Erin Plosa","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Mark R. Denison","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Kemberlee Bonnet","author_inst":"Vanderbilt University"},{"author_name":"Anika Yarlagadda","author_inst":"University of North Carolina"},{"author_name":"Nikita Muthakana","author_inst":"University of North Carolina"},{"author_name":"David Schlundt","author_inst":"Vanderbilt University"},{"author_name":"Julie Bastarache","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Michael DeBaun","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"SickMix: Temporal Changes in Social Contact Patterns among People with Acute Infection and Their Close Contacts","rel_doi":"10.64898\/2026.09.21.26362162","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26362162","rel_abs":"Infected individuals drive infectious disease transmission, yet empirical data on social interactions during acute infection remain limited. We conducted a prospective longitudinal study of 1,000 medically attended acute gastroenteritis and acute respiratory infection cases and 709 household members in the northwestern United States from 2024 to 2025 to quantify illness-associated changes in social contacts and their implications for transmission modeling. Cases substantially reduced social contacts during peak illness; weighted mean number of contacts increased 2.0-fold (95% confidence interval, 1.8-2.2) over the two-week follow-up. In transmission modeling, the simulated outbreak trajectory and estimated effectiveness of interventions differed substantially between models that did and did not account for temporal reductions in social contacts during acute infection. These findings show that behavioral responses during acute infection could substantially influence transmission dynamics and intervention evaluation, and provide an empirical framework for incorporating illness-associated behavioral change into infectious disease models.","rel_num_authors":12,"rel_authors":[{"author_name":"Jessica C Ibiebele","author_inst":"Boston University Center on Emerging Infectious Diseases"},{"author_name":"Aarushi Tuli","author_inst":"Boston University School of Public Health"},{"author_name":"Grissel Lopes","author_inst":"Boston University School of Public Health"},{"author_name":"Gina Lombard","author_inst":"Boston University School of Public Health"},{"author_name":"Anne Shapiro","author_inst":"Boston University School of Public Health"},{"author_name":"Judy Donald","author_inst":"Kaiser Permanente Northwest"},{"author_name":"Mark A Schmidt","author_inst":"Kaiser Permanente Northwest"},{"author_name":"Maria Litvinova","author_inst":"Indiana University School of Public Health"},{"author_name":"Dehao Chen","author_inst":"Emory University Rollins School of Public Health"},{"author_name":"Samuel Jenness","author_inst":"Emory University Rollins School of Public Health"},{"author_name":"Ben Lopman","author_inst":"Emory University Rollins School of Public Health"},{"author_name":"Kayoko Shioda","author_inst":"Boston University School of Public Health"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Beyond Words: Natural Language Sampling of Lexical and Non-Word Vocalizations in Preschool Children with Autism, Down Syndrome, and Fragile X Syndrome","rel_doi":"10.64898\/2026.09.21.26363560","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363560","rel_abs":"PurposeThis study examined whether word-based and non-word natural language sampling (NLS) measures complement standardized language scores in characterizing expressive communication among preschool children with autism with language impairment (AUT-LI), Down syndrome (DS), and fragile X syndrome (FXS).\n\nMethodParticipants included 82 preschool children with AUT-LI (n = 32), DS (n = 34), or FXS (n = 16). Expressive communication was characterized using the Preschool Language Scales and 10-minute natural language samples collected during a standardized play-based protocol. NLS measures included traditional word-based metrics, such as lexical diversity, intelligibility, and word approximations, as well as tiered non-word vocalization measures, including non-speech, single-phoneme, and multi-phoneme vocalizations. Analyses examined age associations, diagnostic group differences, between group differences in variability, and exploratory communication profiles derived using principal component analysis and partitioning around medoids clustering.\n\nResultsDiagnostic groups did not significantly differ on standardized expressive language scores. Children with FXS showed higher performance than the AUT-LI and DS groups on several word-based NLS measures, whereas non-word vocalization measures primarily revealed differences in within-group variability. Word-based NLS measures were consistently associated with standardized expressive language skills, while associations for non-word vocalizations varied by vocalizations type. Cluster-validity indices factored a two-cluster solution. A hypothesis-informed three cluster solution that included non-word vocalizations suggested Higher Language, Lower Output, and High Output-Low Structure profiles.\n\nConclusionsStandardized and NLS measures provide complementary descriptions of expressive communication in children with neurodevelopmental disorders. Non-word vocalization coding may be especially useful for describing clinical meaningful variation among children with limited expressive language.","rel_num_authors":22,"rel_authors":[{"author_name":"Anna S Adekogbe","author_inst":"Harvard University"},{"author_name":"Anna S Adekogbe","author_inst":"Harvard University"},{"author_name":"Antuan Tran","author_inst":"Boston Children's Hospital"},{"author_name":"Antuan Tran","author_inst":"Boston Children's Hospital"},{"author_name":"Gabriela Miller","author_inst":"Boston Children's Hospital"},{"author_name":"Gabriela Miller","author_inst":"Boston Children's Hospital"},{"author_name":"Margaret Norberg","author_inst":"Boston Children's Hospital"},{"author_name":"Margaret Norberg","author_inst":"Boston Children's Hospital"},{"author_name":"Alexis Monk","author_inst":"Harvard University"},{"author_name":"Alexis Monk","author_inst":"Harvard University"},{"author_name":"Tanisha Chanda","author_inst":"Georgia Institute of Technology"},{"author_name":"Tanisha Chanda","author_inst":"Georgia Institute of Technology"},{"author_name":"Xinran Hou","author_inst":"Boston Children's Hospital"},{"author_name":"Xinran Hou","author_inst":"Boston Children's Hospital"},{"author_name":"Katherine Palowski","author_inst":"Boston Children's Hospital"},{"author_name":"Katherine Palowski","author_inst":"Boston Children's Hospital"},{"author_name":"Nicole Baumer","author_inst":"University of Colorado Anschutz Medical Center"},{"author_name":"Nicole Baumer","author_inst":"University of Colorado Anschutz Medical Center"},{"author_name":"Kristina T Johnson","author_inst":"Northeastern University"},{"author_name":"Kristina T Johnson","author_inst":"Northeastern University"},{"author_name":"Carol Wilkinson","author_inst":"Boston Children's Hospital"},{"author_name":"Carol Wilkinson","author_inst":"Boston Children's Hospital"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Beyond Words: Natural Language Sampling of Lexical and Non-Word Vocalizations in Preschool Children with Autism, Down Syndrome, and Fragile X Syndrome","rel_doi":"10.64898\/2026.09.21.26363560","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363560","rel_abs":"PurposeThis study examined whether word-based and non-word natural language sampling (NLS) measures complement standardized language scores in characterizing expressive communication among preschool children with autism with language impairment (AUT-LI), Down syndrome (DS), and fragile X syndrome (FXS).\n\nMethodParticipants included 82 preschool children with AUT-LI (n = 32), DS (n = 34), or FXS (n = 16). Expressive communication was characterized using the Preschool Language Scales and 10-minute natural language samples collected during a standardized play-based protocol. NLS measures included traditional word-based metrics, such as lexical diversity, intelligibility, and word approximations, as well as tiered non-word vocalization measures, including non-speech, single-phoneme, and multi-phoneme vocalizations. Analyses examined age associations, diagnostic group differences, between group differences in variability, and exploratory communication profiles derived using principal component analysis and partitioning around medoids clustering.\n\nResultsDiagnostic groups did not significantly differ on standardized expressive language scores. Children with FXS showed higher performance than the AUT-LI and DS groups on several word-based NLS measures, whereas non-word vocalization measures primarily revealed differences in within-group variability. Word-based NLS measures were consistently associated with standardized expressive language skills, while associations for non-word vocalizations varied by vocalizations type. Cluster-validity indices factored a two-cluster solution. A hypothesis-informed three cluster solution that included non-word vocalizations suggested Higher Language, Lower Output, and High Output-Low Structure profiles.\n\nConclusionsStandardized and NLS measures provide complementary descriptions of expressive communication in children with neurodevelopmental disorders. Non-word vocalization coding may be especially useful for describing clinical meaningful variation among children with limited expressive language.","rel_num_authors":22,"rel_authors":[{"author_name":"Anna S Adekogbe","author_inst":"Harvard University"},{"author_name":"Anna S Adekogbe","author_inst":"Harvard University"},{"author_name":"Antuan Tran","author_inst":"Boston Children's Hospital"},{"author_name":"Antuan Tran","author_inst":"Boston Children's Hospital"},{"author_name":"Gabriela Miller","author_inst":"Boston Children's Hospital"},{"author_name":"Gabriela Miller","author_inst":"Boston Children's Hospital"},{"author_name":"Margaret Norberg","author_inst":"Boston Children's Hospital"},{"author_name":"Margaret Norberg","author_inst":"Boston Children's Hospital"},{"author_name":"Alexis Monk","author_inst":"Harvard University"},{"author_name":"Alexis Monk","author_inst":"Harvard University"},{"author_name":"Tanisha Chanda","author_inst":"Georgia Institute of Technology"},{"author_name":"Tanisha Chanda","author_inst":"Georgia Institute of Technology"},{"author_name":"Xinran Hou","author_inst":"Boston Children's Hospital"},{"author_name":"Xinran Hou","author_inst":"Boston Children's Hospital"},{"author_name":"Katherine Palowski","author_inst":"Boston Children's Hospital"},{"author_name":"Katherine Palowski","author_inst":"Boston Children's Hospital"},{"author_name":"Nicole Baumer","author_inst":"University of Colorado Anschutz Medical Center"},{"author_name":"Nicole Baumer","author_inst":"University of Colorado Anschutz Medical Center"},{"author_name":"Kristina T Johnson","author_inst":"Northeastern University"},{"author_name":"Kristina T Johnson","author_inst":"Northeastern University"},{"author_name":"Carol Wilkinson","author_inst":"Boston Children's Hospital"},{"author_name":"Carol Wilkinson","author_inst":"Boston Children's Hospital"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Diagnostic Accuracy of WHO IMCI Visual Inspection for Neonatal Jaundice: A Prospective Multi-Country Cohort","rel_doi":"10.64898\/2026.09.16.26362263","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.16.26362263","rel_abs":"BACKGROUNDAdverse consequences of neonatal hyperbilirubinemia disproportionately affect babies in low- and middle-income countries. Laboratory measurement of total serum bilirubin is limited in low-resource settings, necessitating simpler alternatives. Our study aimed to evaluate the diagnostic accuracy of visual inspection of jaundice via the World Health Organization Integrated Management of Childhood Illnesses algorithm compared to transcutaneous bilirubinometry for the identification of hyperbilirubinemia in community settings.\n\nMETHODSHyperbilirubinemia was assessed by visual inspection for jaundice and transcutaneous bilirubinometry at 0-72 hours, 3-5 days, and 5-14 days postnatal in the PRISMA prospective cohort study in six sites in Asia and Africa. We assessed sensitivity, specificity, and positive and negative percent agreement.\n\nRESULTSWe analyzed data from 14,331 infants, including 1,852 preterm infants. 15% had hyperbilirubinemia, as defined by transcutaneous bilirubin values and the NICE nomograms, at 3-5 days postnatal. Visual inspection had a sensitivity of 16%, specificity of 96%, positive percent agreement of 56%, and negative percent agreement of 86% at 3-5 days postnatal age, pooled across all sites and gestational ages, versus transcutaneous bilirubin defined by NICE nomograms.\n\nCONCLUSIONThe poor sensitivity of visual inspection underscores an urgent need for accurate, affordable screening tools to improve screening for hyperbilirubinemia.\n\nImpact StatementO_LIWe found poor sensitivity of visual inspection, identifying fewer than one in five neonatal jaundice cases, suggesting much worse diagnostic accuracy in this community-based context across five low- and middle-income countries (LMICs) as compared to the previous studies conducted in health facilities.\nC_LIO_LIAmong preterm infants, sensitivity was modestly higher than in term infants but remained clinically inadequate, reinforcing that visual inspection alone is insufficient for this high-risk group.\nC_LIO_LIDespite standardized training and biannual refresher sessions, our study suggests that training for health care workers alone is unlikely to make visual inspection a reliable case-detection tool.\nC_LIO_LIOur findings suggest that the WHO should re-evaluate the IMCI recommendations to include tools with higher diagnostic accuracy to identify neonatal jaundice.\nC_LIO_LICommunity-level jaundice screening should move beyond visual inspection alone towards validated, low-cost, objective tools; icterometers and smartphone apps with high diagnostic accuracy are promising alternatives.\nC_LI","rel_num_authors":31,"rel_authors":[{"author_name":"Amna Khan","author_inst":"Department of Paediatrics and Child Health, Aga Khan University (AKU), Karachi, Pakistan"},{"author_name":"Alyssa Shapiro","author_inst":"Department of Global Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States"},{"author_name":"Nida Salman Yazdani","author_inst":"Department of Paediatrics and Child Health, Aga Khan University (AKU), Karachi, Pakistan"},{"author_name":"Sebin George Abraham","author_inst":"Department of Community Health, Christian Medical College (CMC) Vellore, Vellore, India"},{"author_name":"Victor Akelo","author_inst":"1:Kenya Medical Research Institute, Kisumu, Kenya; 2: Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, England"},{"author_name":"Kwaku Poku Asante","author_inst":"Kintampo Health Research Center, Research and Development Division, Ghana Health"},{"author_name":"Florence Aweyo","author_inst":"Department of Family Health Unit, Kenya Medical Research Institute, Kisumu, Kenya"},{"author_name":"Anne George Cherian","author_inst":"Department of Community Medicine (OG), Christian Medical College (CMC) Vellore, Vellore, India"},{"author_name":"Munita Jat","author_inst":"Implementation Science Domain, Society for Applied Studies, New Delhi, India"},{"author_name":"Fyezah Jehan","author_inst":"Department of Paediatrics and Child Health, Aga Khan University (AKU), Karachi, Pakistan"},{"author_name":"Indhumathi K","author_inst":"Department of Community Health, Christian Medical College (CMC) Vellore, Vellore, India"},{"author_name":"Kevin Kasadhe","author_inst":"Department of Family Health Unit, Kenya Medical Research Institute, Kisumu, Kenya"},{"author_name":"Margaret Kasaro","author_inst":"1: University of North Carolina--Global Projects Zambia, Lusaka, Zambia; 2: Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill"},{"author_name":"Anne CC Lee","author_inst":"Department of Pediatrics, Global Alliance for Infant and Maternal Health Research, Warren Alpert Medical School of Brown University, Providence, RI, US"},{"author_name":"Azqa Mazhar","author_inst":"Department of Paediatrics and Child Health, Aga Khan University (AKU), Karachi, Pakistan"},{"author_name":"Sarmila Mazumder","author_inst":"Implementation Science Domain, Society for Applied Studies, New Delhi, India"},{"author_name":"Christopher Mores","author_inst":"Department of Global Health, Milken Institute School for Public Health, George Washington University (GWU), Washington, DC, United States"},{"author_name":"Wilbroad Mutale","author_inst":"University of North Carolina--Global Projects Zambia, Lusaka, Zambia"},{"author_name":"Humphrey Mwape","author_inst":"University of North Carolina--Global Projects Zambia, Lusaka, Zambia"},{"author_name":"Sam Newton","author_inst":"Kintampo Health Research Center, Research and Development Division, Ghana Health"},{"author_name":"Muhammad Imran Nisar","author_inst":"Department of Paediatrics and Child Health, Aga Khan University (AKU), Karachi, Pakistan"},{"author_name":"Linda Ogala","author_inst":"Department of Family Health Unit, Kenya Medical Research Institute, Kisumu, Kenya"},{"author_name":"Nancy Ogola","author_inst":"Department of Family Health Unit, Kenya Medical Research Institute, Kisumu, Kenya"},{"author_name":"Neeraj Sharma","author_inst":"Implementation Science Domain, Society for Applied Studies, New Delhi, India"},{"author_name":"M. Bridget Spelke","author_inst":"Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States"},{"author_name":"Jasmine Sugirtha","author_inst":"Department of Community Health, Christian Medical College (CMC) Vellore, Vellore, India"},{"author_name":"Yipeng Wei","author_inst":"Department of Statistics, George Washington University (GWU), Washington, DC, United States"},{"author_name":"Wen-Chien Yang","author_inst":"Department of Global Health, Milken Institute School of Public Health, George Washington University (GWU), Washington, DC, United States"},{"author_name":"Zahra Hoodbhoy","author_inst":"Department of Paediatrics and Child Health, Aga Khan University (AKU), Karachi, Pakistan"},{"author_name":"Qing Pan","author_inst":"Department of Biostatistics and Bioinformatics, George Washington University (GWU), Washington, DC, United States"},{"author_name":"Emily R. Smith","author_inst":"Department of Global Health, Milken Institute School of Public Health, George Washington University (GWU), Washington, DC, United States"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Diagnostic Accuracy of WHO IMCI Visual Inspection for Neonatal Jaundice: A Prospective Multi-Country Cohort","rel_doi":"10.64898\/2026.09.16.26362263","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.16.26362263","rel_abs":"BACKGROUNDAdverse consequences of neonatal hyperbilirubinemia disproportionately affect babies in low- and middle-income countries. Laboratory measurement of total serum bilirubin is limited in low-resource settings, necessitating simpler alternatives. Our study aimed to evaluate the diagnostic accuracy of visual inspection of jaundice via the World Health Organization Integrated Management of Childhood Illnesses algorithm compared to transcutaneous bilirubinometry for the identification of hyperbilirubinemia in community settings.\n\nMETHODSHyperbilirubinemia was assessed by visual inspection for jaundice and transcutaneous bilirubinometry at 0-72 hours, 3-5 days, and 5-14 days postnatal in the PRISMA prospective cohort study in six sites in Asia and Africa. We assessed sensitivity, specificity, and positive and negative percent agreement.\n\nRESULTSWe analyzed data from 14,331 infants, including 1,852 preterm infants. 15% had hyperbilirubinemia, as defined by transcutaneous bilirubin values and the NICE nomograms, at 3-5 days postnatal. Visual inspection had a sensitivity of 16%, specificity of 96%, positive percent agreement of 56%, and negative percent agreement of 86% at 3-5 days postnatal age, pooled across all sites and gestational ages, versus transcutaneous bilirubin defined by NICE nomograms.\n\nCONCLUSIONThe poor sensitivity of visual inspection underscores an urgent need for accurate, affordable screening tools to improve screening for hyperbilirubinemia.\n\nImpact StatementO_LIWe found poor sensitivity of visual inspection, identifying fewer than one in five neonatal jaundice cases, suggesting much worse diagnostic accuracy in this community-based context across five low- and middle-income countries (LMICs) as compared to the previous studies conducted in health facilities.\nC_LIO_LIAmong preterm infants, sensitivity was modestly higher than in term infants but remained clinically inadequate, reinforcing that visual inspection alone is insufficient for this high-risk group.\nC_LIO_LIDespite standardized training and biannual refresher sessions, our study suggests that training for health care workers alone is unlikely to make visual inspection a reliable case-detection tool.\nC_LIO_LIOur findings suggest that the WHO should re-evaluate the IMCI recommendations to include tools with higher diagnostic accuracy to identify neonatal jaundice.\nC_LIO_LICommunity-level jaundice screening should move beyond visual inspection alone towards validated, low-cost, objective tools; icterometers and smartphone apps with high diagnostic accuracy are promising alternatives.\nC_LI","rel_num_authors":31,"rel_authors":[{"author_name":"Amna Khan","author_inst":"Department of Paediatrics and Child Health, Aga Khan University (AKU), Karachi, Pakistan"},{"author_name":"Alyssa Shapiro","author_inst":"Department of Global Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States"},{"author_name":"Nida Salman Yazdani","author_inst":"Department of Paediatrics and Child Health, Aga Khan University (AKU), Karachi, Pakistan"},{"author_name":"Sebin George Abraham","author_inst":"Department of Community Health, Christian Medical College (CMC) Vellore, Vellore, India"},{"author_name":"Victor Akelo","author_inst":"1:Kenya Medical Research Institute, Kisumu, Kenya; 2: Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, England"},{"author_name":"Kwaku Poku Asante","author_inst":"Kintampo Health Research Center, Research and Development Division, Ghana Health"},{"author_name":"Florence Aweyo","author_inst":"Department of Family Health Unit, Kenya Medical Research Institute, Kisumu, Kenya"},{"author_name":"Anne George Cherian","author_inst":"Department of Community Medicine (OG), Christian Medical College (CMC) Vellore, Vellore, India"},{"author_name":"Munita Jat","author_inst":"Implementation Science Domain, Society for Applied Studies, New Delhi, India"},{"author_name":"Fyezah Jehan","author_inst":"Department of Paediatrics and Child Health, Aga Khan University (AKU), Karachi, Pakistan"},{"author_name":"Indhumathi K","author_inst":"Department of Community Health, Christian Medical College (CMC) Vellore, Vellore, India"},{"author_name":"Kevin Kasadhe","author_inst":"Department of Family Health Unit, Kenya Medical Research Institute, Kisumu, Kenya"},{"author_name":"Margaret Kasaro","author_inst":"1: University of North Carolina--Global Projects Zambia, Lusaka, Zambia; 2: Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill"},{"author_name":"Anne CC Lee","author_inst":"Department of Pediatrics, Global Alliance for Infant and Maternal Health Research, Warren Alpert Medical School of Brown University, Providence, RI, US"},{"author_name":"Azqa Mazhar","author_inst":"Department of Paediatrics and Child Health, Aga Khan University (AKU), Karachi, Pakistan"},{"author_name":"Sarmila Mazumder","author_inst":"Implementation Science Domain, Society for Applied Studies, New Delhi, India"},{"author_name":"Christopher Mores","author_inst":"Department of Global Health, Milken Institute School for Public Health, George Washington University (GWU), Washington, DC, United States"},{"author_name":"Wilbroad Mutale","author_inst":"University of North Carolina--Global Projects Zambia, Lusaka, Zambia"},{"author_name":"Humphrey Mwape","author_inst":"University of North Carolina--Global Projects Zambia, Lusaka, Zambia"},{"author_name":"Sam Newton","author_inst":"Kintampo Health Research Center, Research and Development Division, Ghana Health"},{"author_name":"Muhammad Imran Nisar","author_inst":"Department of Paediatrics and Child Health, Aga Khan University (AKU), Karachi, Pakistan"},{"author_name":"Linda Ogala","author_inst":"Department of Family Health Unit, Kenya Medical Research Institute, Kisumu, Kenya"},{"author_name":"Nancy Ogola","author_inst":"Department of Family Health Unit, Kenya Medical Research Institute, Kisumu, Kenya"},{"author_name":"Neeraj Sharma","author_inst":"Implementation Science Domain, Society for Applied Studies, New Delhi, India"},{"author_name":"M. Bridget Spelke","author_inst":"Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States"},{"author_name":"Jasmine Sugirtha","author_inst":"Department of Community Health, Christian Medical College (CMC) Vellore, Vellore, India"},{"author_name":"Yipeng Wei","author_inst":"Department of Statistics, George Washington University (GWU), Washington, DC, United States"},{"author_name":"Wen-Chien Yang","author_inst":"Department of Global Health, Milken Institute School of Public Health, George Washington University (GWU), Washington, DC, United States"},{"author_name":"Zahra Hoodbhoy","author_inst":"Department of Paediatrics and Child Health, Aga Khan University (AKU), Karachi, Pakistan"},{"author_name":"Qing Pan","author_inst":"Department of Biostatistics and Bioinformatics, George Washington University (GWU), Washington, DC, United States"},{"author_name":"Emily R. Smith","author_inst":"Department of Global Health, Milken Institute School of Public Health, George Washington University (GWU), Washington, DC, United States"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Multi-Ancestry Genome-wide Association Analyses Identify Shared and Specific Genetic Architecture in Mild and Moderate-to-Severe Asthma","rel_doi":"10.64898\/2026.09.20.26363488","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.20.26363488","rel_abs":"BackgroundModerate-to-severe asthma affects 15-30% of asthma patients, but accounts for over 50% of healthcare costs and disproportionate morbidity. However, the genetic mechanisms underlying moderate-to-severe versus mild asthma remain poorly understood.\n\nMethodsWe performed separate pooled multi-ancestry GWAS of mild (N = 14,372) and moderate-to-severe asthma (N = 7,096) versus non-asthma controls (N = 28,816) among adult participants in the NIH All of Us Research Program (version 8). European, African, and Latino\/admixed ancestry-specific GWAS were combined using fixed-effect meta-analysis. Lung expression quantitative trait loci (eQTL) and pathway analyses were performed to identify candidate genes and biological pathways across asthma phenotypes.\n\nResultsMild and moderate-to-severe asthma shared susceptibility loci at IL1RL1, IKZF3, and the GTF3AP1-IL33, GTF3AP1-RANBP6, LINC02757-EMSY and HLA-DRB1-HLA-DQA1 regions. Shared lung eQTLs implicated IL18R1, IL18RAP, HLA genes, IL33, LRRC32, GRB7, MIEN1 and GSDMB. In contrast, the phenotypes exhibited distinct genetic architectures. Mild asthma was characterized by broader HLA class II signals and associations at SMAD3 and GSDMB, with enrichment of antigen presentation, T-helper cell differentiation, and TGF-{beta} regulation, consistent with adaptive immune mechanisms. Moderate-to-severe asthma was characterized by WDR36 and PTCH1, with lung eQTLs implicating TSLP, CAMK4, and FANCC. Pathway analysis identified enrichment of IL-13, IL-6, and IL-10 production, myeloid leukocyte differentiation, and oxidative stress responses, consistent with innate inflammation and pathways implicated in steroid resistance. The IL33 signals showed a severity-gradient effect, with stronger associations in moderate-to-severe asthma.\n\nConclusionMild and moderate-to-severe asthma exhibit shared and distinct genetic architectures that support existing biologic targets and suggest novel therapeutic candidates.","rel_num_authors":8,"rel_authors":[{"author_name":"Angelico Mendy","author_inst":"Louisiana State University Health Sciences Center"},{"author_name":"Yadu Gautam","author_inst":"Indiana University School of Medicine"},{"author_name":"Bradley H. Rosen","author_inst":"Indiana University School of Medicine"},{"author_name":"Joseph Castlen","author_inst":"Indiana University School of Medicine"},{"author_name":"Michael B. Fessler","author_inst":"National Institute for Environmental Health Sciences"},{"author_name":"Darryl C. Zeldin","author_inst":"National Institute for Environmental Health Sciences"},{"author_name":"Peter S. Thorne","author_inst":"University of Iowa"},{"author_name":"Tesfaye B. Mersha","author_inst":"Indiana University School of Medicine"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Polygenic effects on cortical size and ADHD converge on a mid-gestational progenitor-to-neuron transition programme","rel_doi":"10.64898\/2026.09.21.26363544","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363544","rel_abs":"Neurodevelopmental and psychiatric conditions have long been hypothesised to emerge from changes in the structure and function of the brain. However, the molecular and cellular mechanisms linking brain structure to these conditions remain unknown. Here, using genetic and structural\/diffusion neuroimaging data from 59,283 individuals spanning adults, children and neonates, we identify widespread genetic associations between ADHD, anxiety and depression and multiple phenotypes indexing cortical size and subcortical volume. Multivariate genetic analyses demonstrate that these associations are largely driven by a common cortical size genetic factor and ADHD. Mendelian randomisation indicates that genetically predicted reduced cortical size is causal for ADHD and not vice versa. Using single-nucleus RNA sequencing of the developing cortex, we further demonstrate that although cortical size and ADHD are enriched in different cell types - proliferating progenitors and postmitotic neurons, respectively, they converge on neurogenic genetic programmes active during the transition between the two cell types. This programme peaks at mid-gestation and is localised to the outer subventricular and intermediate zones, the regions where progenitor amplification and early neuronal migration drive human cortical expansion, and is enriched for genes that are differentially expressed in human and macaque developing cortex. Separately, the negative genetic correlation between ADHD and cortical size measures are strongest in cortical regions that have expanded most in humans relative to macaques. Together, these findings identify a novel, spatiotemporally restricted molecular mechanism underlying neurogenesis that is enriched for polygenic effects of both cortical size and ADHD.","rel_num_authors":31,"rel_authors":[{"author_name":"Yuankai He","author_inst":"University of Cambridge"},{"author_name":"Amir Ebneabbasi","author_inst":"University of Cambridge"},{"author_name":"Koen Rademaker","author_inst":"Wellcome Sanger Institute"},{"author_name":"Elina Z Jin","author_inst":"Wellcome Sanger Institute"},{"author_name":"Yuanjun Gu","author_inst":"University of Cambridge"},{"author_name":"Fani Femi","author_inst":"Wellcome Sanger Institute"},{"author_name":"Clara M.L. Riegis","author_inst":"University of Cambridge"},{"author_name":"Bess Pearson","author_inst":"Imperial College, London"},{"author_name":"Renato Polimanti","author_inst":"Yale University"},{"author_name":"Jakob Grove","author_inst":"Aarhus University"},{"author_name":"Anders B\u00f8rglum","author_inst":"Aarhus University"},{"author_name":"Nadine Parker","author_inst":"University of Oslo"},{"author_name":"Ole Andreassen","author_inst":"Oslo University Hospital and University of Oslo"},{"author_name":"Oleksandr Frei","author_inst":"University of Oslo"},{"author_name":"Darren Cameron","author_inst":"Cardiff University"},{"author_name":"Nicholas J Bray","author_inst":"Cardiff University"},{"author_name":"Ang Li","author_inst":"University of Oxford"},{"author_name":"Jian Zeng","author_inst":"University of Queensland"},{"author_name":"Naomi R. Wray","author_inst":"University of Oxford"},{"author_name":"Rafael Romero-Garcia","author_inst":"University of Seville"},{"author_name":"Timothy Rittman","author_inst":"University of Cambridge"},{"author_name":"Simon Baron-Cohen","author_inst":"University of Cambridge"},{"author_name":"Melissa J. Gladstone","author_inst":"University of Liverpool"},{"author_name":"Shivaram Avula","author_inst":"Alder Hey Children's Hospital"},{"author_name":"Mary-Ellen Lynall","author_inst":"University of Cambridge"},{"author_name":"Sarah Rae","author_inst":"University of Cambridge"},{"author_name":"Duncan Astle","author_inst":"University of Cambridge"},{"author_name":"Richard A.I. Bethlehem","author_inst":"University of Cambridge"},{"author_name":"Edward T. Bullmore","author_inst":"King's College London"},{"author_name":"Omer A. Bayraktar","author_inst":"Wellcome Sanger Institute"},{"author_name":"Varun Warrier","author_inst":"University of Cambridge"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Concordance Between Capillary Dried Plasma Spot and Venous Plasma Biomarkers in Traumatic Brain Injury: An Analytical Feasibility Pilot Study","rel_doi":"10.64898\/2026.09.16.26361861","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.16.26361861","rel_abs":"BackgroundTraumatic brain injury (TBI) increases long-term risk for cognitive decline and neurodegeneration, motivating objective blood biomarkers that can be measured repeatedly over time. However, reliance on venipuncture limits longitudinal monitoring, particularly outside clinic settings.\n\nObjectiveWe conducted a pilot feasibility study comparing fingerstick capillary blood collected as dried plasma spots (DPS) with matched venous EDTA plasma for quantification of glial fibrillary acidic protein (GFAP) and neurofilament light (NfL).\n\nMethodsPaired samples were collected prospectively across matched time points spanning hours to decades post-injury and assayed using high-sensitivity immunoassays.\n\nResultsAbsolute protein recovery from DPS was lower and more variable than venous plasma, but paired GFAP and NfL measurements remained well-correlated. We further evaluated the GFAP\/NfL ratio as an internal, sample-based normalization strategy and observed improved concordance between capillary DPS and venous plasma compared with either analyte alone.\n\nConclusionsThese pilot findings support the analytical feasibility of capillary DPS sampling for GFAP and NfL measurement in TBI and identify the GFAP\/NfL ratio as an exploratory internal-normalization approach. Formal analytical and clinical validation -- including outcome linkage and prospective evaluation -- will be required before capillary DPS can be considered for clinical monitoring applications.\n\nHighlightsO_LIFirst high-frequency (twice-daily for 14 days) paired capillary-DPS \/ venous-plasma GFAP and NfL trajectories in acute TBI (Cohort #1, n = 4).\nC_LIO_LIStrong within-subject capillary-venous correlations for GFAP ({rho} up to 0.647) and NfL ({rho} up to 0.902); the GFAP \/ NfL ratio reaches {rho} = 0.797-0.977.\nC_LIO_LICross-sectional capillary-DPS biomarkers separate acute, subacute, and chronic TBI populations across a multi-site cohort (Cohort #2).\nC_LIO_LIConcurrent work by Bouthors et al. (CCLM 2026) supports prioritizing GFAP and NfL over UCH-L1 for capillary panels because UCH-L1 is intra-erythrocytic and hemolysis-sensitive.\nC_LIO_LICapillary DPS sampling establishes analytical feasibility for paired capillary-venous GFAP and NfL measurement; formal validation of context-of-use, unsupervised collection, and outcome linkage is required before clinical deployment.\nC_LI","rel_num_authors":14,"rel_authors":[{"author_name":"Devin Jackson","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Katie Tehas","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Kristy Radeker","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Anthony DeLizza","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Caroline Popper","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Elaine Peskind","author_inst":"VA Northwest Mental Illness Research, Education and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, WA 98108, USA; and Department of Psych"},{"author_name":"Ava Puccio","author_inst":"Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA"},{"author_name":"Raquel C. Gardner","author_inst":"Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel HaShomer, Ramat Gan 52621, Israel; and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Is"},{"author_name":"John B. Williamson","author_inst":"Brain Rehabilitation Research Center, North Florida\/South Georgia Veterans Affairs Medical Center, Gainesville, FL 32608, USA; and Department of Psychiatry, McK"},{"author_name":"Abigail B. Waters","author_inst":"Brain Rehabilitation Research Center, North Florida\/South Georgia Veterans Affairs Medical Center, Gainesville, FL 32608, USA; and Department of Clinical and He"},{"author_name":"Lisa H. Merck","author_inst":"Department of Emergency Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA; Warren Alpert Medical School of Brown University"},{"author_name":"Geoff Manley","author_inst":"Department of Neurological Surgery, University of California San Francisco, and Brain and Spinal Injury Center, Zuckerberg San Francisco General Hospital, San F"},{"author_name":"Kevin K. Wang","author_inst":"Center for Neurotrauma, Multiomics & Biomarkers (CNMB), Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive SW,"},{"author_name":"William E. Haskins","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA; Owl Therapeutics, 255 Main St Ste 200, Cambridge, MA 02142, USA"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Concordance Between Capillary Dried Plasma Spot and Venous Plasma Biomarkers in Traumatic Brain Injury: An Analytical Feasibility Pilot Study","rel_doi":"10.64898\/2026.09.16.26361861","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.16.26361861","rel_abs":"BackgroundTraumatic brain injury (TBI) increases long-term risk for cognitive decline and neurodegeneration, motivating objective blood biomarkers that can be measured repeatedly over time. However, reliance on venipuncture limits longitudinal monitoring, particularly outside clinic settings.\n\nObjectiveWe conducted a pilot feasibility study comparing fingerstick capillary blood collected as dried plasma spots (DPS) with matched venous EDTA plasma for quantification of glial fibrillary acidic protein (GFAP) and neurofilament light (NfL).\n\nMethodsPaired samples were collected prospectively across matched time points spanning hours to decades post-injury and assayed using high-sensitivity immunoassays.\n\nResultsAbsolute protein recovery from DPS was lower and more variable than venous plasma, but paired GFAP and NfL measurements remained well-correlated. We further evaluated the GFAP\/NfL ratio as an internal, sample-based normalization strategy and observed improved concordance between capillary DPS and venous plasma compared with either analyte alone.\n\nConclusionsThese pilot findings support the analytical feasibility of capillary DPS sampling for GFAP and NfL measurement in TBI and identify the GFAP\/NfL ratio as an exploratory internal-normalization approach. Formal analytical and clinical validation -- including outcome linkage and prospective evaluation -- will be required before capillary DPS can be considered for clinical monitoring applications.\n\nHighlightsO_LIFirst high-frequency (twice-daily for 14 days) paired capillary-DPS \/ venous-plasma GFAP and NfL trajectories in acute TBI (Cohort #1, n = 4).\nC_LIO_LIStrong within-subject capillary-venous correlations for GFAP ({rho} up to 0.647) and NfL ({rho} up to 0.902); the GFAP \/ NfL ratio reaches {rho} = 0.797-0.977.\nC_LIO_LICross-sectional capillary-DPS biomarkers separate acute, subacute, and chronic TBI populations across a multi-site cohort (Cohort #2).\nC_LIO_LIConcurrent work by Bouthors et al. (CCLM 2026) supports prioritizing GFAP and NfL over UCH-L1 for capillary panels because UCH-L1 is intra-erythrocytic and hemolysis-sensitive.\nC_LIO_LICapillary DPS sampling establishes analytical feasibility for paired capillary-venous GFAP and NfL measurement; formal validation of context-of-use, unsupervised collection, and outcome linkage is required before clinical deployment.\nC_LI","rel_num_authors":14,"rel_authors":[{"author_name":"Devin Jackson","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Katie Tehas","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Kristy Radeker","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Anthony DeLizza","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Caroline Popper","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Elaine Peskind","author_inst":"VA Northwest Mental Illness Research, Education and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, WA 98108, USA; and Department of Psych"},{"author_name":"Ava Puccio","author_inst":"Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA"},{"author_name":"Raquel C. Gardner","author_inst":"Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel HaShomer, Ramat Gan 52621, Israel; and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Is"},{"author_name":"John B. Williamson","author_inst":"Brain Rehabilitation Research Center, North Florida\/South Georgia Veterans Affairs Medical Center, Gainesville, FL 32608, USA; and Department of Psychiatry, McK"},{"author_name":"Abigail B. Waters","author_inst":"Brain Rehabilitation Research Center, North Florida\/South Georgia Veterans Affairs Medical Center, Gainesville, FL 32608, USA; and Department of Clinical and He"},{"author_name":"Lisa H. Merck","author_inst":"Department of Emergency Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA; Warren Alpert Medical School of Brown University"},{"author_name":"Geoff Manley","author_inst":"Department of Neurological Surgery, University of California San Francisco, and Brain and Spinal Injury Center, Zuckerberg San Francisco General Hospital, San F"},{"author_name":"Kevin K. Wang","author_inst":"Center for Neurotrauma, Multiomics & Biomarkers (CNMB), Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive SW,"},{"author_name":"William E. Haskins","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA; Owl Therapeutics, 255 Main St Ste 200, Cambridge, MA 02142, USA"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Concordance Between Capillary Dried Plasma Spot and Venous Plasma Biomarkers in Traumatic Brain Injury: An Analytical Feasibility Pilot Study","rel_doi":"10.64898\/2026.09.16.26361861","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.16.26361861","rel_abs":"BackgroundTraumatic brain injury (TBI) increases long-term risk for cognitive decline and neurodegeneration, motivating objective blood biomarkers that can be measured repeatedly over time. However, reliance on venipuncture limits longitudinal monitoring, particularly outside clinic settings.\n\nObjectiveWe conducted a pilot feasibility study comparing fingerstick capillary blood collected as dried plasma spots (DPS) with matched venous EDTA plasma for quantification of glial fibrillary acidic protein (GFAP) and neurofilament light (NfL).\n\nMethodsPaired samples were collected prospectively across matched time points spanning hours to decades post-injury and assayed using high-sensitivity immunoassays.\n\nResultsAbsolute protein recovery from DPS was lower and more variable than venous plasma, but paired GFAP and NfL measurements remained well-correlated. We further evaluated the GFAP\/NfL ratio as an internal, sample-based normalization strategy and observed improved concordance between capillary DPS and venous plasma compared with either analyte alone.\n\nConclusionsThese pilot findings support the analytical feasibility of capillary DPS sampling for GFAP and NfL measurement in TBI and identify the GFAP\/NfL ratio as an exploratory internal-normalization approach. Formal analytical and clinical validation -- including outcome linkage and prospective evaluation -- will be required before capillary DPS can be considered for clinical monitoring applications.\n\nHighlightsO_LIFirst high-frequency (twice-daily for 14 days) paired capillary-DPS \/ venous-plasma GFAP and NfL trajectories in acute TBI (Cohort #1, n = 4).\nC_LIO_LIStrong within-subject capillary-venous correlations for GFAP ({rho} up to 0.647) and NfL ({rho} up to 0.902); the GFAP \/ NfL ratio reaches {rho} = 0.797-0.977.\nC_LIO_LICross-sectional capillary-DPS biomarkers separate acute, subacute, and chronic TBI populations across a multi-site cohort (Cohort #2).\nC_LIO_LIConcurrent work by Bouthors et al. (CCLM 2026) supports prioritizing GFAP and NfL over UCH-L1 for capillary panels because UCH-L1 is intra-erythrocytic and hemolysis-sensitive.\nC_LIO_LICapillary DPS sampling establishes analytical feasibility for paired capillary-venous GFAP and NfL measurement; formal validation of context-of-use, unsupervised collection, and outcome linkage is required before clinical deployment.\nC_LI","rel_num_authors":14,"rel_authors":[{"author_name":"Devin Jackson","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Katie Tehas","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Kristy Radeker","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Anthony DeLizza","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Caroline Popper","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Elaine Peskind","author_inst":"VA Northwest Mental Illness Research, Education and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, WA 98108, USA; and Department of Psych"},{"author_name":"Ava Puccio","author_inst":"Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA"},{"author_name":"Raquel C. Gardner","author_inst":"Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel HaShomer, Ramat Gan 52621, Israel; and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Is"},{"author_name":"John B. Williamson","author_inst":"Brain Rehabilitation Research Center, North Florida\/South Georgia Veterans Affairs Medical Center, Gainesville, FL 32608, USA; and Department of Psychiatry, McK"},{"author_name":"Abigail B. Waters","author_inst":"Brain Rehabilitation Research Center, North Florida\/South Georgia Veterans Affairs Medical Center, Gainesville, FL 32608, USA; and Department of Clinical and He"},{"author_name":"Lisa H. Merck","author_inst":"Department of Emergency Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA; Warren Alpert Medical School of Brown University"},{"author_name":"Geoff Manley","author_inst":"Department of Neurological Surgery, University of California San Francisco, and Brain and Spinal Injury Center, Zuckerberg San Francisco General Hospital, San F"},{"author_name":"Kevin K. Wang","author_inst":"Center for Neurotrauma, Multiomics & Biomarkers (CNMB), Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive SW,"},{"author_name":"William E. Haskins","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA; Owl Therapeutics, 255 Main St Ste 200, Cambridge, MA 02142, USA"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Menstrual Health in South India: Knowledge, Stigma, and Barriers to Participation","rel_doi":"10.64898\/2026.09.16.26363278","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.16.26363278","rel_abs":"Menstrual health remains a neglected public health challenge in India, where persistent stigma, incomplete education, inadequate sanitation, and limited access to menstrual health resources can adversely affect health and social participation. Institution-based educational programs represent an underexplored opportunity to improve menstrual health literacy while promoting more inclusive discussions surrounding menstruation. Bridging this gap, an exploratory, prospective educational evaluation was conducted at a hospital in Coimbatore, Tamil Nadu and an engineering college in Wayanad, Kerala. Anonymous pre- and post-course surveys assessed menstrual health knowledge, attitudes, practices, perceived barriers, and perspectives on emerging digital health technologies. Quantitative responses were summarized descriptively, and open-ended responses were reviewed to identify recurring perspectives that contextualized the quantitative findings. The standardized educational program integrated evidence-based menstrual health education with discussions of bioengineering and wearable technologies. Eighty-three participants completed the pre-course survey, 68 attended the educational program, and 20 completed the post-course survey. Because responses could not be linked at the individual level, the survey cohorts were compared descriptively. At baseline, 80 of 82 respondents (97.6%) recognized menstruation as a biological process, yet only 38 of 82 (46.3%) indicated that it was not solely a womans issue. The mean agreement that menstruation remained taboo was 7.44 of 10 (SD 1.99; n=78), and 51 of 77 respondents (66.2%) reported that they or others avoided activities during menstruation. Painful periods were identified as a barrier by 56 of 67 respondents (83.6%), and 18 of 67 (26.9%) considered institutional or community toilets insufficiently clean and private for menstrual management. Open-ended responses illustrated how pain, fear of leakage, stigma, and inadequate facilities constrained participation in school, physical activity, and social life. These findings document a marked gap between basic biological recognition and the social normalization and practical support of menstruation in two South Indian institutions, and support further evaluation of gender-inclusive, context-responsive menstrual health education using paired assessments, stronger follow-up, comparison groups, and long-term outcomes.","rel_num_authors":3,"rel_authors":[{"author_name":"Rupa Ravi","author_inst":"Lehigh University"},{"author_name":"Joseph  A. Amitrano","author_inst":"Lehigh University"},{"author_name":"Dhruv Seshadri","author_inst":"Lehigh University"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"How Autism impacts mothers in a selected autism center in Karachi, Pakistan- A qualitative study","rel_doi":"10.64898\/2026.09.16.26361740","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.16.26361740","rel_abs":"BackgroundThe mothers of children with autism spectrum disorder (ASD) are more stressed than those of neurotypical or any other children with special needs. There remains a notable lack of contextually grounded evidence on the experiences of mothers raising children with autism in resource-constrained settings of a lower middle-income country (LMIC).\n\nMethodologyA qualitative phenomenological study was carried out at a government-run autism rehabilitation center over a period of six months. The main purpose of the study was to explore the lived experiences of the mothers of autistic children in a setting like Karachi, Pakistan. Twenty-five mothers of 3-18 years old children enrolled in the selected facility participated in two focus group discussions (FGD) and seven In-depth interviews (IDIs) until data saturation was achieved. Consolidated Criteria for Reporting Qualitative Research (COREQ) guidelines and Gubas constructs of trustworthiness were followed.\n\nResultsSeveral themes were derived, corresponding to the different layers of the Ecological Systems Theory. Themes included maternal emotional journey, interpersonal relationships, societal perceptions, access to support services and adaptation over time.\n\nConclusionMothers of children with Autism in Pakistan face significant challenges at the personal, family, societal, and support systems levels. Removing misconceptions and improving access and quality of services to children with Autism and their families is essential for easing their burden.\n\nARTICLE SUMMARYO_LIThis study provides in-depth insight into mothers lived experiences in an under-researched LMIC setting.\nC_LIO_LIMethodological rigor was enhanced through COREQ, triangulation, member checking, and an audit trail.\nC_LIO_LIConducting the study at a single public-sector center limits transferability. 4-Exclusion of fathers limits broader family perspectives\nC_LI\n\nWhat is already known on the topicThe mothers of children with autism spectrum disorder (ASD) are more stressed than those of neurotypical or any other type of special needs children.\n\nSocioeconomic problems, societal stigma and lack of service availability are reported as the major contributors to the caregiver strain experienced by them.\n\nWhat this study addsThe study highlights key needs, barriers, and contextual realities faced by mothers of children with autism within the setting of an LMIC.\n\nEffect on research, practice or policyIt can help greatly in managing stigma related to mental health through the perspective of the mothers. Another possible benefit can be the evidence-based formulation of policies and infrastructure required for inclusion of children with ASD into the society.","rel_num_authors":3,"rel_authors":[{"author_name":"Aroosa Nighat","author_inst":"APPNA Institute of Public Health, Jinnah Sindh Medical University"},{"author_name":"Hira Tariq","author_inst":"Department of Community Health Sciences, The Aga Khan University, Karachi"},{"author_name":"Fatima Bismah Athar","author_inst":"Dow Medical College, Dow University of Health Sciences"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Gene-Based Rare Variant Burden Analyses Across Biobanks Identify Novel High-Risk Genes for Thoracic Aortic Disease","rel_doi":"10.64898\/2026.09.16.26363254","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.16.26363254","rel_abs":"BackgroundThoracic aortic aneurysms enlarge silently and can cause fatal aortic dissection without timely surgical repair, underscoring the need for improved approaches to identify individuals at high risk. Rare pathogenic variants in established heritable thoracic aortic disease (HTAD) genes explain only a subset of familial and fewer nonfamilial thoracic aortic disease (TAD) cases.\n\nMethodsWe performed phenotype-stratified, genome-wide, gene-based rare-variant burden analyses of ultrarare damaging missense and predicted loss-of-function variants. Primary analyses focused on aortic dissection, thoracic aortic aneurysm requiring surgical repair, and their combined phenotype. Broader thoracic aortic aneurysm (TAA) was evaluated as a secondary phenotype. Discovery analyses were conducted in the UK Biobank and All of Us, followed by independent replication in the Penn Medicine BioBank, Mass General Brigham Biobank, and Million Veteran Program. Discovery and replication results were subsequently combined in an overall fixed-effect, inverse-variance-weighted meta-analysis across up to five biobanks. Implicated genes were further evaluated in additional clinically ascertained TAD cohorts and using single-cell transcriptomic data from human thoracic aortic tissue.\n\nResultsDiscovery analyses identified 80 genes reaching study-wide significance across the prespecified TAD phenotypes. These included six established and two putative HTAD genes. Fourteen genes demonstrated independent replication support and reached study-wide significance in the overall meta-analysis across up to five biobanks, which included more than 10,000 cases and 880,000 controls. The eight novel candidate genes among these were FNDC3B, ROCK1, URM1, SLFN11, ENPP1, CLEC16A, CREM, and VCAN. Associations were strongest for dissection and TAA requiring surgical repair. Four novel associations were driven exclusively by missense variants. FNDC3B was observed in a family with HTAD, while additional variants were identified primarily in sporadic dissection or aortic surgery cohorts, suggesting that other genetic or physiologic factors may influence penetrance. The implicated genes showed cell-type-specific expression patterns in human thoracic aortic tissue.\n\nConclusionsThese findings expand the genetic architecture of TAD by identifying eight novel candidate genes and demonstrate the utility of phenotype-stratified rare variant burden analyses across large biobanks for gene discovery.","rel_num_authors":23,"rel_authors":[{"author_name":"David R Murdock","author_inst":"The University of Texas Health Science Center at Houston"},{"author_name":"Pujun Guan","author_inst":"UTHealth Houston"},{"author_name":"Dongchuan Guo","author_inst":"UTHealth Houston"},{"author_name":"Francisca Bermudez","author_inst":"University of Pennsylvania"},{"author_name":"John DePaolo","author_inst":"University of Pennsylvania"},{"author_name":"John Cabot","author_inst":"Stanford University School of Medicine"},{"author_name":"Sumaiya Nazeen","author_inst":"Harvard Medical School; Brigham and Women's Hospital; Broad Institute of MIT and Harvard"},{"author_name":"Habib Nasir","author_inst":"Harvard Medical School"},{"author_name":"Rajat Gupta","author_inst":"Brigham and Women's Hospital; Harvard Medical School"},{"author_name":"Alok Jha","author_inst":"Weill Cornell Medicine"},{"author_name":"John Elefteriades","author_inst":"Yale-New Haven Hospital; Yale University School of Medicine"},{"author_name":"Bobbi McGivern","author_inst":"GeneDx, LLC"},{"author_name":"Kirsty McWalter","author_inst":"GeneDx, LLC"},{"author_name":"Samantha Anderson","author_inst":"Rush University Medical Center"},{"author_name":"Carolyn Jones","author_inst":"Rush University Medical Center"},{"author_name":"Julie Lynch","author_inst":"VA Informatics and Computing Infrastructure (VINCI); University of Utah School of Medicine"},{"author_name":"Kyong-Mi Chang","author_inst":"Corporal Michael J. Crescenz VA Medical Center; University of Pennsylvania"},{"author_name":"Philip Tsao","author_inst":"Stanford University School of Medicine; VA Palo Alto Health Care System"},{"author_name":"- VA Million Veteran Program","author_inst":""},{"author_name":"- Penn Medicine BioBank","author_inst":""},{"author_name":"Scott Damrauer","author_inst":"University of Pennsylvania; Corporal Michael J. Crescenz VA Medical Center"},{"author_name":"Han Chen","author_inst":"UTHealth Houston"},{"author_name":"Dianna Milewicz","author_inst":"UTHealth Houston"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"A Genome-wide Genetic Data Resource for the 45 and Up Study","rel_doi":"10.64898\/2026.09.20.26363524","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.20.26363524","rel_abs":"Large population-based cohorts enable investigation of disease risk and precision prevention, but often lack genome-wide genetic data. We generated and validated new genomic data within the Australian 45 and Up Study, one of the largest Southern Hemisphere cohorts (recruited 2005-2009) with extensive longitudinal and linked health data.\n\nIn 2022-2023, 30,541 participants were invited (random sub-cohort and all individuals with history of four most common invasive cancers: breast, prostate, melanoma, colorectal), with in-depth mapping of participants characteristics for people who consented to provide a DNA sample and those who did not. Low-coverage whole-genome sequencing data (0.4-6.3x) followed by imputation yielded [~]79 million variants for n=7,408 individuals; data for n=6,827 passed stringent quality control. Genotype concordance was high between duplicates (n=85) and with dense genotyping arrays (n=188). Most unrelated participants with high-quality data had inferred European genetic ancestry (n=6,631, 98%), with n=141 (2%) of inferred non-European or admixed ancestry. As proof-of-principle integration of new genomic data with extensive existing linked health records, polygenic risk scores (PGS) for four most common cancers showed predictive performance broadly consistent with previous studies, including association between PGS and earlier age at prostate cancer diagnosis, and no meaningful differences in cancer stage at diagnosis by PGS.\n\nThis new resource has substantially enhanced the 45 and Up Study, supporting investigations of disease aetiology, risk stratification, and precision health in Australia and globally.","rel_num_authors":12,"rel_authors":[{"author_name":"Hamzeh Mesrian Tanha","author_inst":"The Daffodil Centre, The University of Sydney and Cancer Council NSW, Sydney, Australia"},{"author_name":"David Goldsbury","author_inst":"The Daffodil Centre, The University of Sydney and Cancer Council NSW, Sydney, Australia"},{"author_name":"Richard Parker","author_inst":"QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia"},{"author_name":"Natalie Garden","author_inst":"QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia"},{"author_name":"Erika de Guzman","author_inst":"Central Analytical Research Facility (CARF), Queensland University of Technology (QUT), Brisbane, QLD, Australia"},{"author_name":"Greer Dawson","author_inst":"Sax Institute, Sydney, NSW, Australia"},{"author_name":"Kerrin Bleicher","author_inst":"Sax Institute, Sydney, NSW, Australia"},{"author_name":"Alison Cowle","author_inst":"Sax Institute, Sydney, NSW, Australia"},{"author_name":"Martin McNamara","author_inst":"Sax Institute, Sydney, NSW, Australia"},{"author_name":"Anne E Cust","author_inst":"The Daffodil Centre, The University of Sydney and Cancer Council NSW, Sydney, Australia"},{"author_name":"Nicholas G Martin","author_inst":"QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia"},{"author_name":"Julia Steinberg","author_inst":"The Daffodil Centre, The University of Sydney and Cancer Council NSW, Sydney, Australia"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"A Genome-wide Genetic Data Resource for the 45 and Up Study","rel_doi":"10.64898\/2026.09.20.26363524","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.20.26363524","rel_abs":"Large population-based cohorts enable investigation of disease risk and precision prevention, but often lack genome-wide genetic data. We generated and validated new genomic data within the Australian 45 and Up Study, one of the largest Southern Hemisphere cohorts (recruited 2005-2009) with extensive longitudinal and linked health data.\n\nIn 2022-2023, 30,541 participants were invited (random sub-cohort and all individuals with history of four most common invasive cancers: breast, prostate, melanoma, colorectal), with in-depth mapping of participants characteristics for people who consented to provide a DNA sample and those who did not. Low-coverage whole-genome sequencing data (0.4-6.3x) followed by imputation yielded [~]79 million variants for n=7,408 individuals; data for n=6,827 passed stringent quality control. Genotype concordance was high between duplicates (n=85) and with dense genotyping arrays (n=188). Most unrelated participants with high-quality data had inferred European genetic ancestry (n=6,631, 98%), with n=141 (2%) of inferred non-European or admixed ancestry. As proof-of-principle integration of new genomic data with extensive existing linked health records, polygenic risk scores (PGS) for four most common cancers showed predictive performance broadly consistent with previous studies, including association between PGS and earlier age at prostate cancer diagnosis, and no meaningful differences in cancer stage at diagnosis by PGS.\n\nThis new resource has substantially enhanced the 45 and Up Study, supporting investigations of disease aetiology, risk stratification, and precision health in Australia and globally.","rel_num_authors":12,"rel_authors":[{"author_name":"Hamzeh Mesrian Tanha","author_inst":"The Daffodil Centre, The University of Sydney and Cancer Council NSW, Sydney, Australia"},{"author_name":"David Goldsbury","author_inst":"The Daffodil Centre, The University of Sydney and Cancer Council NSW, Sydney, Australia"},{"author_name":"Richard Parker","author_inst":"QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia"},{"author_name":"Natalie Garden","author_inst":"QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia"},{"author_name":"Erika de Guzman","author_inst":"Central Analytical Research Facility (CARF), Queensland University of Technology (QUT), Brisbane, QLD, Australia"},{"author_name":"Greer Dawson","author_inst":"Sax Institute, Sydney, NSW, Australia"},{"author_name":"Kerrin Bleicher","author_inst":"Sax Institute, Sydney, NSW, Australia"},{"author_name":"Alison Cowle","author_inst":"Sax Institute, Sydney, NSW, Australia"},{"author_name":"Martin McNamara","author_inst":"Sax Institute, Sydney, NSW, Australia"},{"author_name":"Anne E Cust","author_inst":"The Daffodil Centre, The University of Sydney and Cancer Council NSW, Sydney, Australia"},{"author_name":"Nicholas G Martin","author_inst":"QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia"},{"author_name":"Julia Steinberg","author_inst":"The Daffodil Centre, The University of Sydney and Cancer Council NSW, Sydney, Australia"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Pathogenic variants in myoferlin (MYOF) cause arrhythmogenic cardiomyopathy","rel_doi":"10.64898\/2026.09.21.26363590","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363590","rel_abs":"Arrhythmogenic cardiomyopathy (ACM) is an inherited disease characterized by fibrofatty remodeling and sudden cardiac death linked to desmosomal dysfunction. Yet, 40% of cases remain genetically unexplained, and non-desmosomal mutations offer insight into ACM pathophysiology. Myoferlin (MYOF), a calcium (Ca{superscript 2})-binding protein in cardiomyocytes, is linked to cardiomyopathy, but its mechanism remains unknown. Whole-exome sequencing identified a heterozygous MYOF missense variant (p.G1654S) in an ACM family; we subsequently found three unrelated p.G1654S cases. We hypothesized that MYOF deficiency promotes Ca{superscript 2} handling deficits and arrhythmogenesis in ACM. In patient iPSC-derived cardiomyocytes, MYOF p.G1654S protein dimerized with wild-type protein and underwent accelerated lysosomal degradation, showed disrupted Ca{superscript 2} handling, and displayed increased arrhythmia burden - all rescued by genomic correction. MYOF interacted with CaV1.2, and verapamil pharmacologically rescued arrhythmias. Heterozygous Myof knockout mice showed systolic dysfunction and fibrosis. These findings establish MYOF as a causative ACM gene and therapeutic target that mediates arrhythmogenesis by disrupting MYOF-CaV1.2.\n\nOne Sentence SummaryMYOF deficiency disrupts MYOF-CaV1.2 interaction and calcium handling, causing arrhythmogenic cardiomyopathy.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=144 HEIGHT=200 SRC=\"FIGDIR\/small\/26363590v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (41K):\norg.highwire.dtl.DTLVardef@225f0org.highwire.dtl.DTLVardef@108bef4org.highwire.dtl.DTLVardef@1309516org.highwire.dtl.DTLVardef@8c147c_HPS_FORMAT_FIGEXP  M_FIG C_FIG","rel_num_authors":32,"rel_authors":[{"author_name":"Anna Kirillova","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Metin Aytekin","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Irene Chan","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Amir I Mina","author_inst":"Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Yucheng Shao","author_inst":"Carnegie Mellon University, Department of Computational Biology, Pittsburgh, PA, USA"},{"author_name":"Almina Kirdar","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"David Y Zhang","author_inst":"Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Nishita Kalepalli","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"William S Girard","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Yassmin Y Al Aaraj","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Chloe Reuter","author_inst":"Stanford Health Care, Stanford, CA, USA"},{"author_name":"Jeffery S Annis","author_inst":"Vanderbilt University Medical Center, Nashville, TN"},{"author_name":"Yunshan Yue","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Siyi Jiang","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Rashmi J Rao","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"S Mehdi Nouraie","author_inst":"Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"},{"author_name":"Joseph Park","author_inst":"Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Ying Tang","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Christopher Flores","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Michael D Creager","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Paul J Kim","author_inst":"UC San Diego Health, San Diego, California, USA"},{"author_name":"Evan L Brittain","author_inst":"Vanderbilt University Medical Center, Nashville, TN"},{"author_name":"Stuart A Scott","author_inst":"Clinical Genomics Laboratory, Stanford Health Care, Palo Alto, CA, USA"},{"author_name":"Janet R Manning","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Satoshi Okawa","author_inst":"Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"},{"author_name":"Guy Salama","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Haodi Wu","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Manling Zhang","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Carlos J Camacho","author_inst":"Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"},{"author_name":"Michael S Gold","author_inst":"Department of Anesthesiology, Center for Pain Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"},{"author_name":"Victoria N Parikh","author_inst":"Stanford Center for Inherited Cardiovascular Disease, Stanford, CA, USA"},{"author_name":"Stephen Y Chan","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Pathogenic variants in myoferlin (MYOF) cause arrhythmogenic cardiomyopathy","rel_doi":"10.64898\/2026.09.21.26363590","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363590","rel_abs":"Arrhythmogenic cardiomyopathy (ACM) is an inherited disease characterized by fibrofatty remodeling and sudden cardiac death linked to desmosomal dysfunction. Yet, 40% of cases remain genetically unexplained, and non-desmosomal mutations offer insight into ACM pathophysiology. Myoferlin (MYOF), a calcium (Ca{superscript 2})-binding protein in cardiomyocytes, is linked to cardiomyopathy, but its mechanism remains unknown. Whole-exome sequencing identified a heterozygous MYOF missense variant (p.G1654S) in an ACM family; we subsequently found three unrelated p.G1654S cases. We hypothesized that MYOF deficiency promotes Ca{superscript 2} handling deficits and arrhythmogenesis in ACM. In patient iPSC-derived cardiomyocytes, MYOF p.G1654S protein dimerized with wild-type protein and underwent accelerated lysosomal degradation, showed disrupted Ca{superscript 2} handling, and displayed increased arrhythmia burden - all rescued by genomic correction. MYOF interacted with CaV1.2, and verapamil pharmacologically rescued arrhythmias. Heterozygous Myof knockout mice showed systolic dysfunction and fibrosis. These findings establish MYOF as a causative ACM gene and therapeutic target that mediates arrhythmogenesis by disrupting MYOF-CaV1.2.\n\nOne Sentence SummaryMYOF deficiency disrupts MYOF-CaV1.2 interaction and calcium handling, causing arrhythmogenic cardiomyopathy.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=144 HEIGHT=200 SRC=\"FIGDIR\/small\/26363590v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (41K):\norg.highwire.dtl.DTLVardef@225f0org.highwire.dtl.DTLVardef@108bef4org.highwire.dtl.DTLVardef@1309516org.highwire.dtl.DTLVardef@8c147c_HPS_FORMAT_FIGEXP  M_FIG C_FIG","rel_num_authors":32,"rel_authors":[{"author_name":"Anna Kirillova","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Metin Aytekin","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Irene Chan","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Amir I Mina","author_inst":"Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Yucheng Shao","author_inst":"Carnegie Mellon University, Department of Computational Biology, Pittsburgh, PA, USA"},{"author_name":"Almina Kirdar","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"David Y Zhang","author_inst":"Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Nishita Kalepalli","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"William S Girard","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Yassmin Y Al Aaraj","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Chloe Reuter","author_inst":"Stanford Health Care, Stanford, CA, USA"},{"author_name":"Jeffery S Annis","author_inst":"Vanderbilt University Medical Center, Nashville, TN"},{"author_name":"Yunshan Yue","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Siyi Jiang","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Rashmi J Rao","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"S Mehdi Nouraie","author_inst":"Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"},{"author_name":"Joseph Park","author_inst":"Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Ying Tang","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Christopher Flores","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Michael D Creager","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Paul J Kim","author_inst":"UC San Diego Health, San Diego, California, USA"},{"author_name":"Evan L Brittain","author_inst":"Vanderbilt University Medical Center, Nashville, TN"},{"author_name":"Stuart A Scott","author_inst":"Clinical Genomics Laboratory, Stanford Health Care, Palo Alto, CA, USA"},{"author_name":"Janet R Manning","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Satoshi Okawa","author_inst":"Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"},{"author_name":"Guy Salama","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Haodi Wu","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Manling Zhang","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Carlos J Camacho","author_inst":"Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"},{"author_name":"Michael S Gold","author_inst":"Department of Anesthesiology, Center for Pain Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"},{"author_name":"Victoria N Parikh","author_inst":"Stanford Center for Inherited Cardiovascular Disease, Stanford, CA, USA"},{"author_name":"Stephen Y Chan","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Immunogenicity and vaccine effectiveness of COVID-19 vaccines in people on immunosuppressive therapies","rel_doi":"10.64898\/2026.09.16.26363194","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.16.26363194","rel_abs":"Neutralizing antibodies are a correlate of protection (CoP) of SARS-CoV-2 vaccine efficacy. However, data informing CoPs often explicitly exclude people on immunosuppressive therapies who are at an increased risk of symptomatic and severe COVID-19, delayed viral clearance, and death. Investigating the relationship between antibodies and protection for people on immunosuppressive therapies could provide insights into mechanisms of protection.\n\nWe performed a systematic search to identify studies reporting SARS-CoV-2 binding antibody levels after mRNA vaccination in people with hematological malignancies, neurological disorders, rheumatic diseases, and mixed immune-mediated inflammatory disorders (IMIDs) on immunosuppressive therapies including B-cell depletion, JAK inhibitors, and S1P inhibitors, as well as healthy controls. Binding antibody levels varied between cohorts receiving different immunosuppressive treatments. Compared to healthy controls the lowest antibody levels were observed in subjects treated with B-cell depletion (54.5-fold reduction, 95% CI: 34.5-86.2) and S1P inhibitors (24.8-fold reduction, 95% CI: 13.2-46.7).\n\nTo assess the association between antibody level and protection, we used data from a previous study of COVID-19 vaccine effectiveness in people with the same underlying conditions. We linked vaccine effectiveness estimates with the predicted antibody level in people on immunosuppressive therapies (using antibody data including this meta-analysis of binding antibody levels). Predicted neutralizing antibody levels were correlated with vaccine effectiveness both for infection and hospitalization (p<0.0001 and p<0.0001, respectively). However, we found that for any given antibody level, people who are immunosuppressed had lower protection against infection and hospitalization than a healthy population.","rel_num_authors":13,"rel_authors":[{"author_name":"Eva Stadler","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Shanchita R Khan","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Karen M Elias","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Ece Egilmezer","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Chansavath Phetsouphanh","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Priyanka Hastak","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Rehana V Hewavisenti","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Ruchika V Joshi","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Tari Turner","author_inst":"School of Public Health and Preventive Medicine, Monash University"},{"author_name":"Deborah Cromer","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Sarah C Sasson","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Miles P Davenport","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"David S Khoury","author_inst":"Kirby Institute, UNSW Sydney"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Genomic Landscape of Early-Onset and Familial Latin American Parkinson's Patients","rel_doi":"10.64898\/2026.09.16.26359514","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.16.26359514","rel_abs":"BackgroundParkinsons disease (PD), the most common neurodegenerative movement disorder, is commonly thought of as an aging and sporadic disease; however, 5-14% of individuals experience disease onset before the age of 50 years (early-onset PD; EOPD) and about 20% have a positive family history. In the case of both EOPD and people with a family history of PD, evidence suggests higher rates of a disease-causing genetic contribution.\n\nObjectivesOur goal was to perform a variant screening of seven PD-related genes and 21 genes associated with related parkinsonian disorders to identify pathogenic\/likely pathogenic variants and variants of uncertain significance within EOPD and family-history-positive individuals within the Latin American Research Consortium on the Genetics of PD (LARGE-PD).\n\nMethodsWe performed short-read whole-genome sequencing on a subset of 263 individuals with EOPD and\/or a familial history of PD who had no known pathogenic PD variant in genotyping data.\n\nResultsOf the analyzed individuals, a monogenic burden in primary and secondary PD genes due to pathogenic or likely pathogenic variants for PD was observed in 4.7%, an additional 5.5% had pathogenic or likely pathogenic variants for Gauchers disease, and 2.7% had known risk variants in GBA1.\n\nConclusionsBy expanding the reported spectrum of disease-associated variants in a Latin American population, we identified previously unreported or underrepresented variants that would likely be missed by array-based or targeted screening approaches and contribute to the characterization of EOPD and familial PD in Latin America.","rel_num_authors":40,"rel_authors":[{"author_name":"Emily Waldo","author_inst":"Cleveland Clinic Foundation"},{"author_name":"Henry Mauricio Chaparro-Solano","author_inst":"Cleveland Clinic Foundation; Cleveland Clinic Lerner College of Medicine, Case Western Reserve University"},{"author_name":"Mariam Isayan","author_inst":"Cleveland Clinic Foundation"},{"author_name":"Thiago P Leal","author_inst":"Morehouse School of Medicine; Cleveland Clinic Foundation"},{"author_name":"Felipe Duarte-Zambrano","author_inst":"Cleveland Clinic Foundation"},{"author_name":"Miguel Inca-Martinez","author_inst":"Cleveland Clinic Foundation"},{"author_name":"Janvi Ramchandra","author_inst":"University of California San Diego"},{"author_name":"Maria Rivera Paz","author_inst":"Cleveland Clinic Foundation; Case Western Reserve University"},{"author_name":"Mary Makarious","author_inst":"DataTecnica LLC"},{"author_name":"Carlos F. Hernandez","author_inst":"Universidad del Desarrollo"},{"author_name":"Emilia M Gatto","author_inst":"Sanatorio de la Trinidad Mitre"},{"author_name":"Natalia Gonzalez Rojas","author_inst":"Sanatorio de la Trinidad Mitre"},{"author_name":"Martin Cesarini","author_inst":"Sanatorio de la Trinidad Mitre"},{"author_name":"Bruno Lopes Santos-Lobato","author_inst":"Universidade Federal do Para; Hospital Ophir Loyola"},{"author_name":"Grace Helena Letro","author_inst":"Hospital da Pontificia Catolica de Campinas"},{"author_name":"Jorge Luis Orozco","author_inst":"Fundacion Valle del Lili"},{"author_name":"Beatriz Munoz Ospina","author_inst":"Universidad Icesi; Fundacion Valle del Lili"},{"author_name":"Pedro Chana-Cuevas","author_inst":"Universida de Santiago de Chile"},{"author_name":"Natalia Andrea Rojas","author_inst":"Centro de Trastornos del Movimiento"},{"author_name":"David Aguillon","author_inst":"Universidad de Antioquia"},{"author_name":"Valentina Muller","author_inst":"Hospital General Jose de San Martin"},{"author_name":"Pedro Braga-Neto","author_inst":"Federal University of Ceara; State University of Ceara"},{"author_name":"Mayela Rodriguez-Violante","author_inst":"Instituto Nacional de Neurologia y Neurocirugia"},{"author_name":"Amin Cervantes-Arriaga","author_inst":"Instituto Nacional de Neurologia y Neurocirugia"},{"author_name":"Artur Schuh","author_inst":"Universidade Federal do Rio Grande do Sul; Hospital de Clinicas de Porto Alegre"},{"author_name":"Mario Cornejo-Olivas","author_inst":"Universidad Cientifica del Sur; Instituto Nacional de Ciencias Neurologicas"},{"author_name":"Koni Mejia Rojas","author_inst":"Instituto Nacional de Ciencias Neurologicas"},{"author_name":"Cintia Armas","author_inst":"EDMECON Medical Center; Daniel Alcides Carrion National Hospital"},{"author_name":"Angel Vinuela","author_inst":"Fundacion Parkinson Puerto Rico"},{"author_name":"Alan Osvaldo Espinal Martinez","author_inst":"Fundacion Parkinson Puerto Rico; Neurosciences Institute Manati Medical Center"},{"author_name":"Vitor Tumas","author_inst":"Ribeirao Preto Medical School - University of Sao Paulo"},{"author_name":"Vanderci Borges","author_inst":"Universidade Federal de Sao Paulo"},{"author_name":"Cesar Luis Avila","author_inst":"UNT-CONICET"},{"author_name":"Patricio Olguin","author_inst":"Universidad de Chile"},{"author_name":"Sarael Alcauter","author_inst":"Universidad Nacional Autonoma de Mexico"},{"author_name":"Marcelo Kauffman","author_inst":"Hospital JM Ramos Mejia"},{"author_name":"Dolores Gonzalez-Moron","author_inst":"Hospital JM Ramos Mejia"},{"author_name":"Susana Lissette Pena Martinez","author_inst":"Universidad Dr. Andres Bello (UNAB)"},{"author_name":"Ignacio F Mata","author_inst":"Cleveland Clinic Foundation"},{"author_name":"- Latin American Research consortium on the Genetics of Parkinson's Disease (LARGE-PD)","author_inst":"-"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Genomic Landscape of Early-Onset and Familial Latin American Parkinson's Patients","rel_doi":"10.64898\/2026.09.16.26359514","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.16.26359514","rel_abs":"BackgroundParkinsons disease (PD), the most common neurodegenerative movement disorder, is commonly thought of as an aging and sporadic disease; however, 5-14% of individuals experience disease onset before the age of 50 years (early-onset PD; EOPD) and about 20% have a positive family history. In the case of both EOPD and people with a family history of PD, evidence suggests higher rates of a disease-causing genetic contribution.\n\nObjectivesOur goal was to perform a variant screening of seven PD-related genes and 21 genes associated with related parkinsonian disorders to identify pathogenic\/likely pathogenic variants and variants of uncertain significance within EOPD and family-history-positive individuals within the Latin American Research Consortium on the Genetics of PD (LARGE-PD).\n\nMethodsWe performed short-read whole-genome sequencing on a subset of 263 individuals with EOPD and\/or a familial history of PD who had no known pathogenic PD variant in genotyping data.\n\nResultsOf the analyzed individuals, a monogenic burden in primary and secondary PD genes due to pathogenic or likely pathogenic variants for PD was observed in 4.7%, an additional 5.5% had pathogenic or likely pathogenic variants for Gauchers disease, and 2.7% had known risk variants in GBA1.\n\nConclusionsBy expanding the reported spectrum of disease-associated variants in a Latin American population, we identified previously unreported or underrepresented variants that would likely be missed by array-based or targeted screening approaches and contribute to the characterization of EOPD and familial PD in Latin America.","rel_num_authors":40,"rel_authors":[{"author_name":"Emily Waldo","author_inst":"Cleveland Clinic Foundation"},{"author_name":"Henry Mauricio Chaparro-Solano","author_inst":"Cleveland Clinic Foundation; Cleveland Clinic Lerner College of Medicine, Case Western Reserve University"},{"author_name":"Mariam Isayan","author_inst":"Cleveland Clinic Foundation"},{"author_name":"Thiago P Leal","author_inst":"Morehouse School of Medicine; Cleveland Clinic Foundation"},{"author_name":"Felipe Duarte-Zambrano","author_inst":"Cleveland Clinic Foundation"},{"author_name":"Miguel Inca-Martinez","author_inst":"Cleveland Clinic Foundation"},{"author_name":"Janvi Ramchandra","author_inst":"University of California San Diego"},{"author_name":"Maria Rivera Paz","author_inst":"Cleveland Clinic Foundation; Case Western Reserve University"},{"author_name":"Mary Makarious","author_inst":"DataTecnica LLC"},{"author_name":"Carlos F. Hernandez","author_inst":"Universidad del Desarrollo"},{"author_name":"Emilia M Gatto","author_inst":"Sanatorio de la Trinidad Mitre"},{"author_name":"Natalia Gonzalez Rojas","author_inst":"Sanatorio de la Trinidad Mitre"},{"author_name":"Martin Cesarini","author_inst":"Sanatorio de la Trinidad Mitre"},{"author_name":"Bruno Lopes Santos-Lobato","author_inst":"Universidade Federal do Para; Hospital Ophir Loyola"},{"author_name":"Grace Helena Letro","author_inst":"Hospital da Pontificia Catolica de Campinas"},{"author_name":"Jorge Luis Orozco","author_inst":"Fundacion Valle del Lili"},{"author_name":"Beatriz Munoz Ospina","author_inst":"Universidad Icesi; Fundacion Valle del Lili"},{"author_name":"Pedro Chana-Cuevas","author_inst":"Universida de Santiago de Chile"},{"author_name":"Natalia Andrea Rojas","author_inst":"Centro de Trastornos del Movimiento"},{"author_name":"David Aguillon","author_inst":"Universidad de Antioquia"},{"author_name":"Valentina Muller","author_inst":"Hospital General Jose de San Martin"},{"author_name":"Pedro Braga-Neto","author_inst":"Federal University of Ceara; State University of Ceara"},{"author_name":"Mayela Rodriguez-Violante","author_inst":"Instituto Nacional de Neurologia y Neurocirugia"},{"author_name":"Amin Cervantes-Arriaga","author_inst":"Instituto Nacional de Neurologia y Neurocirugia"},{"author_name":"Artur Schuh","author_inst":"Universidade Federal do Rio Grande do Sul; Hospital de Clinicas de Porto Alegre"},{"author_name":"Mario Cornejo-Olivas","author_inst":"Universidad Cientifica del Sur; Instituto Nacional de Ciencias Neurologicas"},{"author_name":"Koni Mejia Rojas","author_inst":"Instituto Nacional de Ciencias Neurologicas"},{"author_name":"Cintia Armas","author_inst":"EDMECON Medical Center; Daniel Alcides Carrion National Hospital"},{"author_name":"Angel Vinuela","author_inst":"Fundacion Parkinson Puerto Rico"},{"author_name":"Alan Osvaldo Espinal Martinez","author_inst":"Fundacion Parkinson Puerto Rico; Neurosciences Institute Manati Medical Center"},{"author_name":"Vitor Tumas","author_inst":"Ribeirao Preto Medical School - University of Sao Paulo"},{"author_name":"Vanderci Borges","author_inst":"Universidade Federal de Sao Paulo"},{"author_name":"Cesar Luis Avila","author_inst":"UNT-CONICET"},{"author_name":"Patricio Olguin","author_inst":"Universidad de Chile"},{"author_name":"Sarael Alcauter","author_inst":"Universidad Nacional Autonoma de Mexico"},{"author_name":"Marcelo Kauffman","author_inst":"Hospital JM Ramos Mejia"},{"author_name":"Dolores Gonzalez-Moron","author_inst":"Hospital JM Ramos Mejia"},{"author_name":"Susana Lissette Pena Martinez","author_inst":"Universidad Dr. Andres Bello (UNAB)"},{"author_name":"Ignacio F Mata","author_inst":"Cleveland Clinic Foundation"},{"author_name":"- Latin American Research consortium on the Genetics of Parkinson's Disease (LARGE-PD)","author_inst":"-"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"The United States CADASIL Consortium: Baseline Findings from a Natural History Study","rel_doi":"10.64898\/2026.09.20.26363512","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.20.26363512","rel_abs":"Background and ObjectivesVascular contributions to cognitive impairment and dementia (VCID) represent the second leading cause of dementia and a common comorbidity for reduced functional capacity in many individuals, but clinical management and clinical trial readiness are severely hindered by extreme phenotypic and mechanistic heterogeneity. This study establishes the baseline clinical, functional, and multimodal biomarker characteristics of the first United States (US) cohort of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), serving as a single-cause, monogenic small vessel disease model for sporadic VCID.\n\nMethodsCross-sectional analysis of baseline data collected from October 2022 through January 2025 from a longitudinal cohort at 12 US enrollment sites. Adults from families with a documented NOTCH3 variant were recruited through clinical referrals, medical record review, advocacy organizations, and community outreach. Exclusion criteria included other conditions that prevented interpretation of findings and modified Rankin Scale (mRS) scores greater than 3. Central genetic characterization assigned persons with a pathogenic or likely pathogenic NOTCH3 variant to low-, medium-, or high-risk tiers based on epidermal growth factor-like repeat domains. Standardized assessments included clinical histories, exams, objective cognitive and physical assessments, self-reported, companion-reported, and clinician-rated measures, MRI, genetics, and proteomics acquired under harmonized protocols. Group comparisons used Fishers exact and Kruskal-Wallis tests. Multivariable regression used adjustment for age, sex, race, and education.\n\nResultsOf 560 participants completing baseline visits, 46 had variants of unknown significance, and 55 had pending genetic analyses. The analytic cohort included 343 persons with a CADASIL-causing NOTCH3 variant and 116 non-carrier family controls. Median age was 47.9 years (IQR 38.7-59.1), median education was 16 years (IQR 14-17), 62.5% were female, and 91.4% were White. Carriers were classified in CADASIL risk tiers: low (7.0%), medium (18.4%), or high (74.6%). Compared with controls, adjusted odds of classification into a more impaired CDR category were higher in all tiers (OR 2.55-5.08, 95% CI 1.22-11.34).\n\nDiscussionThe US CADASIL Consortium has established a large, genetics-confirmed cohort spanning presymptomatic to moderate disease stages, providing a robust, harmonized platform to define early biomarker signatures and endpoints for targeted VCID therapies.","rel_num_authors":26,"rel_authors":[{"author_name":"Jane S. Paulsen","author_inst":"University of Wisconsin-Madison"},{"author_name":"H. Jeremy Bockholt","author_inst":"Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology, Emory Universit"},{"author_name":"William H. Adams","author_inst":"Loyola University Chicago"},{"author_name":"Deven K. Burks","author_inst":"University of Wisconsin-Madison"},{"author_name":"Jennifer J. Majersik","author_inst":"The University of Utah"},{"author_name":"Stephen P. Salloway","author_inst":"Butler Hospital"},{"author_name":"Songmi Lee","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Myriam Fornage","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Cara Joyce","author_inst":"Loyola University Chicago"},{"author_name":"Jamie L. Elliott","author_inst":"University of Wisconsin-Madison"},{"author_name":"Edward D. Huey","author_inst":"Butler Hospital"},{"author_name":"Megan R. Caruso","author_inst":"Butler Hospital"},{"author_name":"Suman Jayadev","author_inst":"University of Washington"},{"author_name":"Jose Biller","author_inst":"Loyola University Chicago"},{"author_name":"Helmi L. Lutsep","author_inst":"Oregon Health & Science University"},{"author_name":"Sara J. Doyle","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"David S. Liebeskind","author_inst":"University of Southern California"},{"author_name":"Kelsey Eklund","author_inst":"University of Colorado, Anschutz"},{"author_name":"Imama A. Naqvi","author_inst":"Columbia University"},{"author_name":"Arash Salardini","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Sudha Seshadri","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Jason D. Hinman","author_inst":"David Geffen School of Medicine, University of California, Los Angeles"},{"author_name":"Lisa C. Krishnamurthy","author_inst":"Emory University"},{"author_name":"Barbara L. Fischer","author_inst":"University of Wisconsin-Madison"},{"author_name":"Michael D. Geschwind","author_inst":"University of California, San Francisco"},{"author_name":"- The United States CADASIL Consortium","author_inst":""}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"The United States CADASIL Consortium: Baseline Findings from a Natural History Study","rel_doi":"10.64898\/2026.09.20.26363512","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.20.26363512","rel_abs":"Background and ObjectivesVascular contributions to cognitive impairment and dementia (VCID) represent the second leading cause of dementia and a common comorbidity for reduced functional capacity in many individuals, but clinical management and clinical trial readiness are severely hindered by extreme phenotypic and mechanistic heterogeneity. This study establishes the baseline clinical, functional, and multimodal biomarker characteristics of the first United States (US) cohort of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), serving as a single-cause, monogenic small vessel disease model for sporadic VCID.\n\nMethodsCross-sectional analysis of baseline data collected from October 2022 through January 2025 from a longitudinal cohort at 12 US enrollment sites. Adults from families with a documented NOTCH3 variant were recruited through clinical referrals, medical record review, advocacy organizations, and community outreach. Exclusion criteria included other conditions that prevented interpretation of findings and modified Rankin Scale (mRS) scores greater than 3. Central genetic characterization assigned persons with a pathogenic or likely pathogenic NOTCH3 variant to low-, medium-, or high-risk tiers based on epidermal growth factor-like repeat domains. Standardized assessments included clinical histories, exams, objective cognitive and physical assessments, self-reported, companion-reported, and clinician-rated measures, MRI, genetics, and proteomics acquired under harmonized protocols. Group comparisons used Fishers exact and Kruskal-Wallis tests. Multivariable regression used adjustment for age, sex, race, and education.\n\nResultsOf 560 participants completing baseline visits, 46 had variants of unknown significance, and 55 had pending genetic analyses. The analytic cohort included 343 persons with a CADASIL-causing NOTCH3 variant and 116 non-carrier family controls. Median age was 47.9 years (IQR 38.7-59.1), median education was 16 years (IQR 14-17), 62.5% were female, and 91.4% were White. Carriers were classified in CADASIL risk tiers: low (7.0%), medium (18.4%), or high (74.6%). Compared with controls, adjusted odds of classification into a more impaired CDR category were higher in all tiers (OR 2.55-5.08, 95% CI 1.22-11.34).\n\nDiscussionThe US CADASIL Consortium has established a large, genetics-confirmed cohort spanning presymptomatic to moderate disease stages, providing a robust, harmonized platform to define early biomarker signatures and endpoints for targeted VCID therapies.","rel_num_authors":26,"rel_authors":[{"author_name":"Jane S. Paulsen","author_inst":"University of Wisconsin-Madison"},{"author_name":"H. Jeremy Bockholt","author_inst":"Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology, Emory Universit"},{"author_name":"William H. Adams","author_inst":"Loyola University Chicago"},{"author_name":"Deven K. Burks","author_inst":"University of Wisconsin-Madison"},{"author_name":"Jennifer J. Majersik","author_inst":"The University of Utah"},{"author_name":"Stephen P. Salloway","author_inst":"Butler Hospital"},{"author_name":"Songmi Lee","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Myriam Fornage","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Cara Joyce","author_inst":"Loyola University Chicago"},{"author_name":"Jamie L. Elliott","author_inst":"University of Wisconsin-Madison"},{"author_name":"Edward D. Huey","author_inst":"Butler Hospital"},{"author_name":"Megan R. Caruso","author_inst":"Butler Hospital"},{"author_name":"Suman Jayadev","author_inst":"University of Washington"},{"author_name":"Jose Biller","author_inst":"Loyola University Chicago"},{"author_name":"Helmi L. Lutsep","author_inst":"Oregon Health & Science University"},{"author_name":"Sara J. Doyle","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"David S. Liebeskind","author_inst":"University of Southern California"},{"author_name":"Kelsey Eklund","author_inst":"University of Colorado, Anschutz"},{"author_name":"Imama A. Naqvi","author_inst":"Columbia University"},{"author_name":"Arash Salardini","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Sudha Seshadri","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Jason D. Hinman","author_inst":"David Geffen School of Medicine, University of California, Los Angeles"},{"author_name":"Lisa C. Krishnamurthy","author_inst":"Emory University"},{"author_name":"Barbara L. Fischer","author_inst":"University of Wisconsin-Madison"},{"author_name":"Michael D. Geschwind","author_inst":"University of California, San Francisco"},{"author_name":"- The United States CADASIL Consortium","author_inst":""}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"The United States CADASIL Consortium: Baseline Findings from a Natural History Study","rel_doi":"10.64898\/2026.09.20.26363512","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.20.26363512","rel_abs":"Background and ObjectivesVascular contributions to cognitive impairment and dementia (VCID) represent the second leading cause of dementia and a common comorbidity for reduced functional capacity in many individuals, but clinical management and clinical trial readiness are severely hindered by extreme phenotypic and mechanistic heterogeneity. This study establishes the baseline clinical, functional, and multimodal biomarker characteristics of the first United States (US) cohort of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), serving as a single-cause, monogenic small vessel disease model for sporadic VCID.\n\nMethodsCross-sectional analysis of baseline data collected from October 2022 through January 2025 from a longitudinal cohort at 12 US enrollment sites. Adults from families with a documented NOTCH3 variant were recruited through clinical referrals, medical record review, advocacy organizations, and community outreach. Exclusion criteria included other conditions that prevented interpretation of findings and modified Rankin Scale (mRS) scores greater than 3. Central genetic characterization assigned persons with a pathogenic or likely pathogenic NOTCH3 variant to low-, medium-, or high-risk tiers based on epidermal growth factor-like repeat domains. Standardized assessments included clinical histories, exams, objective cognitive and physical assessments, self-reported, companion-reported, and clinician-rated measures, MRI, genetics, and proteomics acquired under harmonized protocols. Group comparisons used Fishers exact and Kruskal-Wallis tests. Multivariable regression used adjustment for age, sex, race, and education.\n\nResultsOf 560 participants completing baseline visits, 46 had variants of unknown significance, and 55 had pending genetic analyses. The analytic cohort included 343 persons with a CADASIL-causing NOTCH3 variant and 116 non-carrier family controls. Median age was 47.9 years (IQR 38.7-59.1), median education was 16 years (IQR 14-17), 62.5% were female, and 91.4% were White. Carriers were classified in CADASIL risk tiers: low (7.0%), medium (18.4%), or high (74.6%). Compared with controls, adjusted odds of classification into a more impaired CDR category were higher in all tiers (OR 2.55-5.08, 95% CI 1.22-11.34).\n\nDiscussionThe US CADASIL Consortium has established a large, genetics-confirmed cohort spanning presymptomatic to moderate disease stages, providing a robust, harmonized platform to define early biomarker signatures and endpoints for targeted VCID therapies.","rel_num_authors":26,"rel_authors":[{"author_name":"Jane S. Paulsen","author_inst":"University of Wisconsin-Madison"},{"author_name":"H. Jeremy Bockholt","author_inst":"Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology, Emory Universit"},{"author_name":"William H. Adams","author_inst":"Loyola University Chicago"},{"author_name":"Deven K. Burks","author_inst":"University of Wisconsin-Madison"},{"author_name":"Jennifer J. Majersik","author_inst":"The University of Utah"},{"author_name":"Stephen P. Salloway","author_inst":"Butler Hospital"},{"author_name":"Songmi Lee","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Myriam Fornage","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Cara Joyce","author_inst":"Loyola University Chicago"},{"author_name":"Jamie L. Elliott","author_inst":"University of Wisconsin-Madison"},{"author_name":"Edward D. Huey","author_inst":"Butler Hospital"},{"author_name":"Megan R. Caruso","author_inst":"Butler Hospital"},{"author_name":"Suman Jayadev","author_inst":"University of Washington"},{"author_name":"Jose Biller","author_inst":"Loyola University Chicago"},{"author_name":"Helmi L. Lutsep","author_inst":"Oregon Health & Science University"},{"author_name":"Sara J. Doyle","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"David S. Liebeskind","author_inst":"University of Southern California"},{"author_name":"Kelsey Eklund","author_inst":"University of Colorado, Anschutz"},{"author_name":"Imama A. Naqvi","author_inst":"Columbia University"},{"author_name":"Arash Salardini","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Sudha Seshadri","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Jason D. Hinman","author_inst":"David Geffen School of Medicine, University of California, Los Angeles"},{"author_name":"Lisa C. Krishnamurthy","author_inst":"Emory University"},{"author_name":"Barbara L. Fischer","author_inst":"University of Wisconsin-Madison"},{"author_name":"Michael D. Geschwind","author_inst":"University of California, San Francisco"},{"author_name":"- The United States CADASIL Consortium","author_inst":""}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"The United States CADASIL Consortium: Baseline Findings from a Natural History Study","rel_doi":"10.64898\/2026.09.20.26363512","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.20.26363512","rel_abs":"Background and ObjectivesVascular contributions to cognitive impairment and dementia (VCID) represent the second leading cause of dementia and a common comorbidity for reduced functional capacity in many individuals, but clinical management and clinical trial readiness are severely hindered by extreme phenotypic and mechanistic heterogeneity. This study establishes the baseline clinical, functional, and multimodal biomarker characteristics of the first United States (US) cohort of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), serving as a single-cause, monogenic small vessel disease model for sporadic VCID.\n\nMethodsCross-sectional analysis of baseline data collected from October 2022 through January 2025 from a longitudinal cohort at 12 US enrollment sites. Adults from families with a documented NOTCH3 variant were recruited through clinical referrals, medical record review, advocacy organizations, and community outreach. Exclusion criteria included other conditions that prevented interpretation of findings and modified Rankin Scale (mRS) scores greater than 3. Central genetic characterization assigned persons with a pathogenic or likely pathogenic NOTCH3 variant to low-, medium-, or high-risk tiers based on epidermal growth factor-like repeat domains. Standardized assessments included clinical histories, exams, objective cognitive and physical assessments, self-reported, companion-reported, and clinician-rated measures, MRI, genetics, and proteomics acquired under harmonized protocols. Group comparisons used Fishers exact and Kruskal-Wallis tests. Multivariable regression used adjustment for age, sex, race, and education.\n\nResultsOf 560 participants completing baseline visits, 46 had variants of unknown significance, and 55 had pending genetic analyses. The analytic cohort included 343 persons with a CADASIL-causing NOTCH3 variant and 116 non-carrier family controls. Median age was 47.9 years (IQR 38.7-59.1), median education was 16 years (IQR 14-17), 62.5% were female, and 91.4% were White. Carriers were classified in CADASIL risk tiers: low (7.0%), medium (18.4%), or high (74.6%). Compared with controls, adjusted odds of classification into a more impaired CDR category were higher in all tiers (OR 2.55-5.08, 95% CI 1.22-11.34).\n\nDiscussionThe US CADASIL Consortium has established a large, genetics-confirmed cohort spanning presymptomatic to moderate disease stages, providing a robust, harmonized platform to define early biomarker signatures and endpoints for targeted VCID therapies.","rel_num_authors":26,"rel_authors":[{"author_name":"Jane S. Paulsen","author_inst":"University of Wisconsin-Madison"},{"author_name":"H. Jeremy Bockholt","author_inst":"Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology, Emory Universit"},{"author_name":"William H. Adams","author_inst":"Loyola University Chicago"},{"author_name":"Deven K. Burks","author_inst":"University of Wisconsin-Madison"},{"author_name":"Jennifer J. Majersik","author_inst":"The University of Utah"},{"author_name":"Stephen P. Salloway","author_inst":"Butler Hospital"},{"author_name":"Songmi Lee","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Myriam Fornage","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Cara Joyce","author_inst":"Loyola University Chicago"},{"author_name":"Jamie L. Elliott","author_inst":"University of Wisconsin-Madison"},{"author_name":"Edward D. Huey","author_inst":"Butler Hospital"},{"author_name":"Megan R. Caruso","author_inst":"Butler Hospital"},{"author_name":"Suman Jayadev","author_inst":"University of Washington"},{"author_name":"Jose Biller","author_inst":"Loyola University Chicago"},{"author_name":"Helmi L. Lutsep","author_inst":"Oregon Health & Science University"},{"author_name":"Sara J. Doyle","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"David S. Liebeskind","author_inst":"University of Southern California"},{"author_name":"Kelsey Eklund","author_inst":"University of Colorado, Anschutz"},{"author_name":"Imama A. Naqvi","author_inst":"Columbia University"},{"author_name":"Arash Salardini","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Sudha Seshadri","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Jason D. Hinman","author_inst":"David Geffen School of Medicine, University of California, Los Angeles"},{"author_name":"Lisa C. Krishnamurthy","author_inst":"Emory University"},{"author_name":"Barbara L. Fischer","author_inst":"University of Wisconsin-Madison"},{"author_name":"Michael D. Geschwind","author_inst":"University of California, San Francisco"},{"author_name":"- The United States CADASIL Consortium","author_inst":""}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Human-centred co-design of a dual-purpose heart failure dashboard","rel_doi":"10.64898\/2026.09.20.26363523","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.20.26363523","rel_abs":"IntroductionHeart failure care requires coordination across hospital and community settings, yet information is often fragmented across electronic medical records and clinical systems. Clinical dashboards can bring together and display information to support care delivery and service management; however, existing dashboards have generally focused on specific measures, interventions and monitoring pathways. This study aimed to co-design, iteratively develop and user-test an integrated heart failure dashboard that links patient-level clinical decision-making with service-level management.\n\nMethodsA human-centred design approach comprising needs identification, collaborative ideation, iterative prototype development and end-user testing was applied across two complementary operational and clinical dashboard streams. Thirty-six clinicians, health service managers, data and implementation scientists, and consumers from metropolitan and regional services participated.\n\nResultsFor operational decision-making, participants prioritised real-time visibility of patients across heart failure services, patient trajectories, service-performance information, and identification of variation in guideline-directed care and outcomes. Clinical priorities included rapid synthesis of longitudinal information, optimisation of guideline-directed medical therapy, continuity across care settings, and clinical workload prioritisation. These requirements informed the dashboard prototypes. Many prioritised information elements were incompletely represented in structured data and distributed across disconnected systems and structured and unstructured clinical data sources.\n\nConclusionHuman-centred co-design identified complementary patient- and service-level information needs and translated them into linked dashboard prototypes. The proposed dashboard brings together current clinical status and longitudinal heart failure care history at the patient-level alongside service-level patterns. Implementation is required to evaluate whether these linked views improve care processes and patient outcomes.","rel_num_authors":8,"rel_authors":[{"author_name":"Victoria K Blake","author_inst":"Centre for Big Data Research in Health, UNSW"},{"author_name":"Sarah Emily Craig","author_inst":"eHealth NSW"},{"author_name":"Liesl Carvalho","author_inst":"eHealth NSW"},{"author_name":"Michelle Thomson","author_inst":"eHealth NSW"},{"author_name":"Jennifer Yu","author_inst":"Prince of Wales Hospital"},{"author_name":"Louisa Jorm","author_inst":"Centre for Big Data Research in Health, UNSW"},{"author_name":"Nigel Lovell","author_inst":"University of New South Wales"},{"author_name":"Sze-Yuan Ooi","author_inst":"Prince of Wales Hospital"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Evaluation of an eHealth Assistive Device Provision Training Tool: A Quasi-Experimental Study","rel_doi":"10.64898\/2026.09.20.26363517","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.20.26363517","rel_abs":"Background: Approximately 2.5 billion people require assistive products (APs), yet access remains limited partly because of shortages of trained personnel. eHealth tools may help strengthen workforce capacity and translate evidence into practice. The World Health Organization's Training in Assistive Products (TAP) program is an open-access eHealth tool designed to strengthen AP provision. However, its impact on learner outcomes remains insufficiently evaluated. This study assessed the usability and acceptability of the TAP module and changes in self-efficacy in mobility aid provision. Methods: We conducted a quasi-experimental pre-post study with health science students who completed the WHO TAP \"Introduction to Assistive Products\" module. We assessed usability using the System Usability Scale, acceptability using the Technology Acceptance Model and Theoretical Framework of Acceptability, and self-efficacy using an adapted version of Bandura's Multidimensional Scales of Perceived Self-Efficacy. We analyzed data using descriptive statistics and paired-samples t-tests. Results: Of 53 participants, 33 completed both assessments. Usability exceeded established benchmarks (76.97 +\/- 9.66), indicating a positive user experience. Acceptability findings demonstrated favourable responses across domains, with high ratings for ease of use and intervention coherence, and comparatively lower burden scores. Mean self-efficacy increased across all competencies from 2.32 +\/- 0.58 before the module to 4.23 +\/- 0.36 afterward (p < 0.001), reflecting substantial gains in confidence in AP provision. Conclusion: The eHealth TAP module demonstrated above-average usability and favourable acceptability, while significantly improving self-efficacy in AP provision. These findings highlight the potential for eHealth training implementation to strengthen workforce capacity and bridge training gaps in global health.","rel_num_authors":3,"rel_authors":[{"author_name":"Rachel Sudhakar","author_inst":"University of Ottawa"},{"author_name":"Katrine Sauv\u00e9-Schenk","author_inst":"University of Ottawa"},{"author_name":"Jennifer O'Neil","author_inst":"University of Ottawa"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Evaluation of an eHealth Assistive Device Provision Training Tool: A Quasi-Experimental Study","rel_doi":"10.64898\/2026.09.20.26363517","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.20.26363517","rel_abs":"Background: Approximately 2.5 billion people require assistive products (APs), yet access remains limited partly because of shortages of trained personnel. eHealth tools may help strengthen workforce capacity and translate evidence into practice. The World Health Organization's Training in Assistive Products (TAP) program is an open-access eHealth tool designed to strengthen AP provision. However, its impact on learner outcomes remains insufficiently evaluated. This study assessed the usability and acceptability of the TAP module and changes in self-efficacy in mobility aid provision. Methods: We conducted a quasi-experimental pre-post study with health science students who completed the WHO TAP \"Introduction to Assistive Products\" module. We assessed usability using the System Usability Scale, acceptability using the Technology Acceptance Model and Theoretical Framework of Acceptability, and self-efficacy using an adapted version of Bandura's Multidimensional Scales of Perceived Self-Efficacy. We analyzed data using descriptive statistics and paired-samples t-tests. Results: Of 53 participants, 33 completed both assessments. Usability exceeded established benchmarks (76.97 +\/- 9.66), indicating a positive user experience. Acceptability findings demonstrated favourable responses across domains, with high ratings for ease of use and intervention coherence, and comparatively lower burden scores. Mean self-efficacy increased across all competencies from 2.32 +\/- 0.58 before the module to 4.23 +\/- 0.36 afterward (p < 0.001), reflecting substantial gains in confidence in AP provision. Conclusion: The eHealth TAP module demonstrated above-average usability and favourable acceptability, while significantly improving self-efficacy in AP provision. These findings highlight the potential for eHealth training implementation to strengthen workforce capacity and bridge training gaps in global health.","rel_num_authors":3,"rel_authors":[{"author_name":"Rachel Sudhakar","author_inst":"University of Ottawa"},{"author_name":"Katrine Sauv\u00e9-Schenk","author_inst":"University of Ottawa"},{"author_name":"Jennifer O'Neil","author_inst":"University of Ottawa"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Differentiating nonfluent\/agrammatic and logopenic primary progressive aphasia in Catalan-Spanish bilinguals by applying multilingual multimodal machine learning to connected speech","rel_doi":"10.64898\/2026.09.18.26363435","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.18.26363435","rel_abs":"BackgroundThe nonfluent\/agrammatic (nfv) and logopenic (lv) variants of primary progressive aphasia (PPA) disrupt fluency through distinct underlying neurocognitive mechanisms. Differential diagnosis currently requires hours of cognitive-linguistic testing, with additional barriers for bilingual patients due to a shortage of bilingual service providers and a lack of well-established assessment methods. In English speakers, a promising automated approach for differentiating nfvPPA and lvPPA is to derive speech-timing measures and linguistic features from connected speech as input to machine learning (ML) classification algorithms. To our knowledge, this approach has not been evaluated in the context of bilingualism.\n\nMethodsThirty-four Catalan-Spanish simultaneous bilingual patients (lv = 24, nfv = 10) were asked to describe a picture (Western Aphasia Battery Picnic Scene) in both their dominant and non-dominant language. From the participants recorded response, we derived four feature sets: speech-timing measures, derived with PRAAT; word-level parameters, derived from corpora; linguistic features, derived with the natural language processing tools SpaCy and CLAN; image-text congruence scores, derived with the vision-language encoder Multilingual-CLIP. Each feature set was fed into classification algorithms for differentiating nfv from lv in participants non-dominant and dominant samples. Then, we combined each feature sets classifier into an ensemble model. We used the McNemar test to determine the statistical significance of differences in classification performance between responses in the non-dominant and dominant language.\n\nResultsThe best-performing classifier achieved F1 macro scores of 93% (word-level parameters) and 92% (ensemble) in the non-dominant and dominant language, respectively. For all feature sets and ensemble models, classification performance did not significantly differ between the non-dominant and dominant language. Ensemble modeling did not significantly improve classification performance in either language.\n\nConclusionsTaking advantage of recent advances in multilingual multimodal machine learning, we accurately differentiate Spanish-Catalan bilingual individuals with nfvPPA and lvPPA using a largely automated, time-efficient (1-2 minutes), and ecologically valid connected-speech-based approach. Future directions include evaluating this approach on larger datasets balanced by PPA subtype, using automated transcriptions of connected speech. Our study represents a step towards addressing current inequities in PPA differential diagnosis for non-English-speaking bilingual speakers.\n\nTrial registrationData from the clinical trial NCT05741853 was retrospectively analyzed","rel_num_authors":21,"rel_authors":[{"author_name":"Lokesha Srinivas Pugalenthi","author_inst":"Rice University"},{"author_name":"Andrew Parker Collins","author_inst":"University of Connecticut"},{"author_name":"N\u00faria Montagut Colomer","author_inst":"Hospital Cl\u00ednic de Barcelona"},{"author_name":"Sonia-Karin Marqu\u00e9s-Kiderle","author_inst":"Hospital Cl\u00ednic de Barcelona"},{"author_name":"Camille Wagner Rodriguez","author_inst":"The University of Texas at Austin"},{"author_name":"Jan Christian Holst Chaires","author_inst":"The University of Texas at Austin"},{"author_name":"Whendy Avila Motta","author_inst":"The University of Texas at Austin"},{"author_name":"Julia Filella-Merc\u00e8","author_inst":"Hospital de la Santa Creu i Sant Pau"},{"author_name":"Junyi Jessy Li","author_inst":"The University of Texas at Austin"},{"author_name":"Fernando Llanos","author_inst":"The University of Texas at Austin"},{"author_name":"Nuole Zhu","author_inst":"Hospital de la Santa Creu i Sant Pau"},{"author_name":"Sara Rubio-Guerra","author_inst":"Hospital de la Santa Creu i Sant Pau"},{"author_name":"Ignacio Illan-Gala","author_inst":"Hospital de la Santa Creu i Sant Pau"},{"author_name":"Sergi Borrego-\u00c9cija","author_inst":"Hospital de la Santa Creu i Sant Pau"},{"author_name":"Albert Llad\u00f3","author_inst":"Hospital Cl\u00ednic de Barcelona"},{"author_name":"Juan Fortea","author_inst":"Hospital de la Santa Creu i Sant Pau"},{"author_name":"Alberto Lle\u00f3","author_inst":"Hospital de la Santa Creu i Sant Pau"},{"author_name":"Raquel S\u00e1nchez-Valle","author_inst":"Hospital Cl\u00ednic de Barcelona"},{"author_name":"Maya L. Henry","author_inst":"The University of Texas at Austin"},{"author_name":"Miguel \u00c1ngel Santos Santos","author_inst":"Hospital de la Santa Creu i Sant Pau"},{"author_name":"Stephanie M. Grasso","author_inst":"The University of Texas at Austin"}],"rel_date":"2026-09-21","rel_site":"medrxiv"},{"rel_title":"Privacy-Aware Distillation of Large Language Models for Enhanced Multimorbidity Scoring","rel_doi":"10.64898\/2026.09.19.26363476","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.19.26363476","rel_abs":"The truthful use of large language models (LLMs) is a growing challenge in safeguarding sensitive patient data from leakage. We introduce and evaluate a privacy-preserving knowledge distillation framework for LLM-based clinical modeling, using multimorbidity scoring as a healthcare task. Although LLMs can encode rich clinical knowledge and improve upon traditional rule-based comorbidity scoring, their direct evaluation on large-scale biobank data remains constrained by patient privacy. In our framework, multimorbidity reasoning is distilled from state-of-the-art LLM teacher models into compact student models (CoLLMs) using synthetic cohorts that preserve UK Biobank distributions, without exposing real patient data. This approach achieves high-fidelity knowledge transfer (Spearman {rho} = 0.75-0.89). Independent LLM-as-Judge evaluation confirms the clinical significance of the distilled knowledge and reveals substantial variability among teacher models. When applied to real UK Biobank data, CoLLM-derived multimorbidity scores improve survival prediction (C-index up to 0.91) and exhibit higher SNP heritability (h2 {approx} 0.05). Our work establishes a trustworthy, privacy-compliant pathway for large-scale healthcare applications of LLMs.","rel_num_authors":4,"rel_authors":[{"author_name":"Raghav Awasthi","author_inst":"Case Western Reserve University"},{"author_name":"Yihe Yang","author_inst":"Case Western Reserve University"},{"author_name":"Mengxuan Li","author_inst":"Case Western Reserve University"},{"author_name":"Xiaofeng Zhu","author_inst":"Case Western Reserve university"}],"rel_date":"2026-09-21","rel_site":"medrxiv"},{"rel_title":"Weighing the Odds: Body Mass Index and Recurrence-Free Survival in Early-Onset Colorectal Cancer","rel_doi":"10.64898\/2026.09.19.26363465","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.19.26363465","rel_abs":"BackgroundEarly-Onset Colorectal Cancer (EOCRC, < 50 years) is rising sharply in many parts of the world. The \"obesity paradox\", where overweight correlates with better outcome despite obesity being a risk factor, is established in colorectal cancer (CRC) overall but remains ambiguous in EOCRC.\n\nAimTo investigate the association of Body Mass Index (BMI) at diagnosis and recurrence-free survival (RFS) in EOCRC and compare it to average-onset colorectal cancer (AOCRC, [&ge;] 50 years).\n\nMethodsA retrospective cohort study at Sahlgrenska University Hospital included 1,459 patients with curative-intent colorectal adenocarcinoma surgery comprising EOCRC (n=159) and AOCRC (n=1,300) cohorts. Cox proportional hazards models assessed the relation of BMI to RFS, adjusted for tumour stage, location, and differentiation. Restricted cubic splines were used to model BMI as a continuous variable, and model fit was assessed with likelihood-ratio tests (LRT).\n\nResultsIn EOCRC, continuous BMI was significantly associated with RFS (LRT p=0.02), displaying a U-shaped association with the lowest hazard at BMI 27 and highest at BMI <20 and >30. In AOCRC continuous BMI was not associated with RFS (LRT p=0.15) and the spline curve was flat. An interaction analysis showed a significant difference between the cohorts (LRT p=0.046).\n\nConclusionContinuous BMI was significantly associated with RFS in EOCRC but not in AOCRC suggesting the \"obesity paradox\" may be specific to EOCRC. This may reflect differences in body composition, tumour biology and systemic metabolism between EOCRC and AOCRC or may be due to methodological biases. Future research should incorporate biomarkers, as well as refined measures of body composition.","rel_num_authors":4,"rel_authors":[{"author_name":"Erik Delryd","author_inst":"Institute of Clinical Science, Sahlgrenska Academy"},{"author_name":"Andy Tran","author_inst":"University of Iowa"},{"author_name":"Elinor Bexe Lindskog","author_inst":"Institute of Clinical Sciences, Sahlgrenska Academy"},{"author_name":"David Ljungman","author_inst":"Institute of Clinical Sciences, Sahlgrenska Academy"}],"rel_date":"2026-09-21","rel_site":"medrxiv"},{"rel_title":"Decision Support in Publicly Available Patient Information Policies at U.S. Osteopathic Medical Schools: A Vignette-Based Document Analysis","rel_doi":"10.64898\/2026.09.18.26363437","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.18.26363437","rel_abs":"Research ObjectivesTo evaluate whether publicly available institutional guidance supports patient-information decisions across scenarios and schools, and characterize document synthesis and evaluation consistency.\n\nMethodsWe conducted an exploratory, vignette-based document analysis of a geographically diverse nonprobability sample of 20 U.S. osteopathic medical schools. Eight educational vignettes yielded 160 school-vignette pairs. Each pair underwent three separate AI-assisted retrieval-and-evaluation runs, classifying decision support as Explicitly Supported, Inferable, Ambiguous, or Not Addressed. Response selection prioritized greater support for discordant pairs, followed by fewer contributing documents and run order. One investigator verified or revised selected discordant classifications against cited evidence. Explicitly Supported and Inferable were grouped post hoc as sufficient decision support. Analyses were descriptive and included an exploratory two-school model-investigator comparison.\n\nResultsAt least one eligible source was retrieved for 159 of 160 pairs (99.4%). Final classifications were Explicitly Supported for 18 pairs (11.3%), Inferable for 3 (1.9%), Ambiguous for 132 (82.5%), and Not Addressed for 7 (4.4%). Sufficient support occurred in 21 pairs (13.1%), most frequently for generative AI-assisted reflective writing (7\/20 schools, 35%), and in none for personal cloud notes or official clinical logs. Ten schools had no sufficiently supported vignette; the maximum was four of eight. Multiple documents contributed to 111 evaluations (69.4%). Three-run ratings were unanimous for 113 pairs (70.6%), with 80.2% pairwise exact agreement. Investigator review retained 44 of 47 selected discordant ratings and revised three upward. In the two-school comparison, the investigator more frequently judged evidence sufficient when models judged it insufficient than the reverse.\n\nConclusionsRelevant public guidance was frequently retrieved, but few school-vignette pairs were classified as providing sufficient scenario-specific decision support. These findings highlight a gap between identifying relevant guidance and determining an appropriate course of action within this evaluation framework. They support institutional review of how student-facing materials explain information use, storage, sharing, and approval requirements. Vignette-based review identifies questions requiring clarification. Evaluation with learners and assessment of internal and clinical-site guidance would help determine how these findings translate to students decisions.","rel_num_authors":2,"rel_authors":[{"author_name":"Na Dai","author_inst":"Independent Researcher"},{"author_name":"Kirsten L Waarala","author_inst":"College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA"}],"rel_date":"2026-09-21","rel_site":"medrxiv"},{"rel_title":"Compound climate extremes, socioeconomic conditions and human mobility influence dengue dynamics heterogeneously across Vietnam","rel_doi":"10.64898\/2026.09.19.26363468","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.19.26363468","rel_abs":"Dengue presents a major public health challenge in Vietnam, driven by biological, behavioural, and environmental factors. Compound climate extremes, such as sequential hydrometeorological events, can influence dengue risk yet remain understudied. We evaluated the effects of compound climate extremes, socioeconomic conditions, and human mobility on dengue relative risk across 670 districts in Vietnam over 20 years, stratifying by eight subregions spanning emerging to endemic transmission. Dengue risk was greatest following dry-then-wet conditions in seven subregions. Higher temperatures increased risk across North and Central Vietnam, but had limited effect in the South. Mobility associations followed an urban-rural gradient, with increased risk in highly rural districts where residents travelled more frequently to fewer destinations, and in urban districts with more visitors and dispersed outgoing mobility. Stratifying climatic and socioeconomic effects by subregion improved predictive skill at lead times of 1 to 6 months over unstratified and baseline models, with substantial spatial variation. Accounting for compound extremes across distinct spatial contexts could strengthen disease early warning systems in Vietnam and beyond.","rel_num_authors":15,"rel_authors":[{"author_name":"Chloe Fletcher","author_inst":"Barcelona Supercomputing Center"},{"author_name":"Sophie Belman","author_inst":"Yale School of Public Health"},{"author_name":"Kien Quoc Do","author_inst":"Pasteur Institute in Ho Chi Minh City"},{"author_name":"Quang Duy Pham","author_inst":"Pasteur Institute in Ho Chi Minh City"},{"author_name":"Thi Thanh Thao Nguyen","author_inst":"Pasteur Institute in Ho Chi Minh City"},{"author_name":"Rory Gibb","author_inst":"University College London"},{"author_name":"Phan Trong Lan","author_inst":"National Institute of Hygiene and Epidemiology"},{"author_name":"Tran Cong Tu","author_inst":"National Institute of Hygiene and Epidemiology"},{"author_name":"Nguyen Hai Tuan","author_inst":"National Institute of Hygiene and Epidemiology"},{"author_name":"Daniela L\u00fchrsen","author_inst":"Barcelona Supercomputing Center"},{"author_name":"Gina Tsarouchi","author_inst":"HR Wallingford"},{"author_name":"Quillon Harpham","author_inst":"HR Wallingford"},{"author_name":"Felipe J Col\u00f3n-Gonz\u00e1lez","author_inst":"Wellcome Trust"},{"author_name":"John Rossman Bertholf Palmer","author_inst":"Universitat Pompeu Fabra"},{"author_name":"Rachel Lowe","author_inst":"Barcelona Supercomputing Center"}],"rel_date":"2026-09-21","rel_site":"medrxiv"},{"rel_title":"Multi-component chlorination intervention to reduce neonatal infections in healthcare facilities in western Kenya (CLEAN Trial): study protocol for a cluster randomized controlled trial","rel_doi":"10.64898\/2026.09.18.26363445","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.18.26363445","rel_abs":"BackgroundThe proportion of births occurring at healthcare facilities is rising globally, yet the birthing environment in healthcare facilities in low-income settings is often contaminated with bacterial pathogens, including antibiotic-resistant pathogens, that can lead to serious infections for newborns and their mothers. There is a need for effective strategies to reduce environmental contamination in healthcare facilities to reduce infection risks among facility-born neonates and their mothers.\n\nMethodsWe designed the CLEAN (ChLorine to reduce Enteric and Antibiotic resistant infections in Neonates) cluster randomized controlled trial in western Kenya to evaluate the impact of a multi-component chlorination intervention on environmental contamination and maternal and neonatal infection risks. Thirty-six medium-sized public health facilities will be randomized in a 1:1 allocation ratio to receive a passive chlorination technology for water supply treatment paired with a reliable supply of chlorine-based disinfectant or status quo. Up to 22,500 mothers-neonate dyads will be enrolled and followed from birth through 28 days to collect symptoms of infection and mortality, with a subset of mother-neonate dyads selected for rectal swab collection to measure rectal colonization with sepsis-associated bacterial species. Environmental samples will be collected to measure bacterial pathogens on staff hands, high-touch surfaces, and in water supply. The primary objectives of the study are to evaluate the impact of the intervention on the following outcomes: (1) rectal carriage of bacterial pathogens one week post-birth among facility-born neonates and their mothers, (2) cumulative incidence in the first 7 days post-birth of possible serious bacterial infection among facility-born neonates, and (3) cumulative incidence in the first 7 days post-birth of symptoms of possible maternal sepsis.\n\nDiscussionThis study will generate evidence on the effectiveness of a novel chlorination intervention to reduce healthcare associated infections, including antibiotic resistant infections, and improve maternal and neonatal survival.\n\nTrial registrationClinical Trials NCT06824350. Registered 7 February 2025, https:\/\/clinicaltrials.gov\/study\/NCT06824350","rel_num_authors":25,"rel_authors":[{"author_name":"Mwale Chiyenge","author_inst":"University of California, Berkeley"},{"author_name":"Yoshika Crider","author_inst":"University of Minnesota"},{"author_name":"Erick Odoyo","author_inst":"Walter Reed Army Institute of Research-Africa, Kenya"},{"author_name":"Mwale Chiyenge","author_inst":"University of California, Berkeley"},{"author_name":"Joyce Kisiangani","author_inst":"University of California, Berkeley"},{"author_name":"Erick Odoyo","author_inst":"Walter Reed Army Institute of Research-Africa, Kenya"},{"author_name":"Jeremy Lowe","author_inst":"University of California, Berkeley"},{"author_name":"Joyce Kisiangani","author_inst":"University of California, Berkeley"},{"author_name":"Josline Wangia","author_inst":"Kenya Medical Research Institute"},{"author_name":"Jeremy Lowe","author_inst":"University of California, Berkeley"},{"author_name":"Blastus Bwire","author_inst":"Remit Kenya"},{"author_name":"Josline Wangia","author_inst":"Kenya Medical Research Institute"},{"author_name":"Mwanzia Kioko","author_inst":"CARE"},{"author_name":"Blastus Bwire","author_inst":"Remit Kenya"},{"author_name":"Kelly Alexander","author_inst":"CARE"},{"author_name":"Mwanzia Kioko","author_inst":"CARE"},{"author_name":"Carol Nekesa","author_inst":"Remit Kenya"},{"author_name":"Kelly Alexander","author_inst":"CARE"},{"author_name":"Lillian Musila","author_inst":"Kenya Medical Research Institute"},{"author_name":"Carol Nekesa","author_inst":"Remit Kenya"},{"author_name":"Phelgona Otieno","author_inst":"Kenya Medical Research Institute"},{"author_name":"Lillian Musila","author_inst":"Kenya Medical Research Institute"},{"author_name":"Amy Pickering","author_inst":"University of California, Berkeley"},{"author_name":"Phelgona Otieno","author_inst":"Kenya Medical Research Institute"},{"author_name":"Amy Pickering","author_inst":"University of California, Berkeley"}],"rel_date":"2026-09-21","rel_site":"medrxiv"},{"rel_title":"Smartphone Passive Digital Phenotyping in Frontotemporal Lobar Degeneration","rel_doi":"10.64898\/2026.09.18.26363439","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.18.26363439","rel_abs":"IntroductionFrontotemporal lobar degeneration (FTLD) is a devastating disease that commonly results in early onset dementia, yet its rarity and heterogeneity limit large-scale research and clinical trials. Remote monitoring via low-burden digital health tools may overcome these barriers. We evaluated clinical utility of passive smartphone monitoring in FTLD using a multi-domain mobile assessment platform.\n\nMethodsParticipants were 567 adults (53% clinically normal, 21% prodromal FTLD, 26% symptomatic FTLD) who completed an in-person study visit and downloaded the ALLFTD Mobile App on their personal smartphones. The app delivered unsupervised cognitive tests and passively collected continuous data on battery percentage (proxy for smartphone use) and step count. Longitudinal follow-up included smartphone monitoring and annual in-person study visits. Primary analyses examined associations between passive smartphone features and markers of disease severity at baseline and longitudinally, and tested whether passive features added incremental value beyond app-based cognitive testing.\n\nResultsPassive smartphone features were feasible to collect and showed excellent reliability with <2 weeks of monitoring (ICCs>0.9). Features capturing smartphone use and movement demonstrated sensitivity to gold-standard clinical measures of disease severity both at baseline and longitudinally. A classification model combining passive features, the app-based cognitive composite score, and demographics detected longitudinal functional decline (AUC=0.89); passive features alone (AUC=0.84) performed comparably to a cognitive screener (AUC=0.85).\n\nDiscussionPassive smartphone monitoring is a valid, zero-burden measure of disease severity and progression in FTLD that adds modest incremental value beyond app-based cognitive testing. Findings support its use as a scalable digital endpoint in longitudinal FTLD research.","rel_num_authors":51,"rel_authors":[{"author_name":"Emily W Paolillo","author_inst":"University of California, San Francisco"},{"author_name":"Sreya Dhanam","author_inst":"University of California, San Francisco"},{"author_name":"Jack Carson Taylor","author_inst":"University of California, San Francisco"},{"author_name":"Mark Sanderson-Cimino","author_inst":"University of California, San Francisco"},{"author_name":"Ray Fregly","author_inst":"University of California, San Francisco"},{"author_name":"Rowan Saloner","author_inst":"University of California, San Francisco"},{"author_name":"Kaitlin B Casaletto","author_inst":"University of California, San Francisco"},{"author_name":"Joel H Kramer","author_inst":"University of California, San Francisco"},{"author_name":"Bruce L Miller","author_inst":"University of California, San Francisco"},{"author_name":"William W Seeley","author_inst":"University of California, San Francisco"},{"author_name":"Maria Luisa Gorno-Tempini","author_inst":"University of California, San Francisco"},{"author_name":"Peter A Ljubenkov","author_inst":"University of California, San Francisco"},{"author_name":"Julio C Rojas","author_inst":"University of California, San Francisco"},{"author_name":"Suzee Lee","author_inst":"University of California, San Francisco"},{"author_name":"Virginia Sturm","author_inst":"University of California, San Francisco"},{"author_name":"Brian Appleby","author_inst":"Case Western Reserve University"},{"author_name":"Ece Bayram","author_inst":"University of Colorado Anschutz"},{"author_name":"David Clark","author_inst":"Indiana University"},{"author_name":"Ciaran M Considine","author_inst":"Vanderbilt University"},{"author_name":"Richard R Darby","author_inst":"Vanderbilt University"},{"author_name":"Gregory S Day","author_inst":"Mayo Clinic, Jacksonville"},{"author_name":"Alyssa De Vito","author_inst":"Brown University"},{"author_name":"Mark Eldaief","author_inst":"Massachusetts General Hospital & Harvard Medical School"},{"author_name":"Julie A Fields","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Nupur Ghoshal","author_inst":"Washington University"},{"author_name":"Edward D Huey","author_inst":"Brown University"},{"author_name":"David J Irwin","author_inst":"University of Pennsylvania"},{"author_name":"Kejal Kantarci","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Justin Y Kwan","author_inst":"National Institutes of Health"},{"author_name":"Ian R Mackenzie","author_inst":"University of British Columbia"},{"author_name":"Joseph C Masdeu","author_inst":"Houston Methodist"},{"author_name":"Chiadi U Onyike","author_inst":"Johns Hopkins University"},{"author_name":"Alexander Pantelyat","author_inst":"Johns Hopkins University"},{"author_name":"Belen Pascual","author_inst":"Houston Methodist"},{"author_name":"Tanav Popli","author_inst":"University of Michigan"},{"author_name":"Katya Rascovsky","author_inst":"University of Pennsylvania"},{"author_name":"Neguine Rezaii","author_inst":"Massachusetts General Hospital"},{"author_name":"Sonja W Scholz","author_inst":"National Institutes of Health"},{"author_name":"Allison Snyder","author_inst":"National Institutes of Health"},{"author_name":"M. Carmela Tartaglia","author_inst":"University of Toronto"},{"author_name":"Bryan J Traynor","author_inst":"National Institutes of Health"},{"author_name":"Bonnie Wong","author_inst":"MGH"},{"author_name":"John Kornak","author_inst":"University of California, San Francisco"},{"author_name":"Walter K Kremers","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Leah K Forsberg","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Hilary W Heuer","author_inst":"University of California, San Francisco"},{"author_name":"Bradley F Boeve","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Howard J Rosen","author_inst":"University of California, San Francisco"},{"author_name":"Adam L Boxer","author_inst":"University of California, San Francisco"},{"author_name":"Adam M Staffaroni","author_inst":"University of California, San Francisco"},{"author_name":"- ALLFTD Consortium","author_inst":""}],"rel_date":"2026-09-21","rel_site":"medrxiv"},{"rel_title":"Smartphone Passive Digital Phenotyping in Frontotemporal Lobar Degeneration","rel_doi":"10.64898\/2026.09.18.26363439","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.18.26363439","rel_abs":"IntroductionFrontotemporal lobar degeneration (FTLD) is a devastating disease that commonly results in early onset dementia, yet its rarity and heterogeneity limit large-scale research and clinical trials. Remote monitoring via low-burden digital health tools may overcome these barriers. We evaluated clinical utility of passive smartphone monitoring in FTLD using a multi-domain mobile assessment platform.\n\nMethodsParticipants were 567 adults (53% clinically normal, 21% prodromal FTLD, 26% symptomatic FTLD) who completed an in-person study visit and downloaded the ALLFTD Mobile App on their personal smartphones. The app delivered unsupervised cognitive tests and passively collected continuous data on battery percentage (proxy for smartphone use) and step count. Longitudinal follow-up included smartphone monitoring and annual in-person study visits. Primary analyses examined associations between passive smartphone features and markers of disease severity at baseline and longitudinally, and tested whether passive features added incremental value beyond app-based cognitive testing.\n\nResultsPassive smartphone features were feasible to collect and showed excellent reliability with <2 weeks of monitoring (ICCs>0.9). Features capturing smartphone use and movement demonstrated sensitivity to gold-standard clinical measures of disease severity both at baseline and longitudinally. A classification model combining passive features, the app-based cognitive composite score, and demographics detected longitudinal functional decline (AUC=0.89); passive features alone (AUC=0.84) performed comparably to a cognitive screener (AUC=0.85).\n\nDiscussionPassive smartphone monitoring is a valid, zero-burden measure of disease severity and progression in FTLD that adds modest incremental value beyond app-based cognitive testing. Findings support its use as a scalable digital endpoint in longitudinal FTLD research.","rel_num_authors":51,"rel_authors":[{"author_name":"Emily W Paolillo","author_inst":"University of California, San Francisco"},{"author_name":"Sreya Dhanam","author_inst":"University of California, San Francisco"},{"author_name":"Jack Carson Taylor","author_inst":"University of California, San Francisco"},{"author_name":"Mark Sanderson-Cimino","author_inst":"University of California, San Francisco"},{"author_name":"Ray Fregly","author_inst":"University of California, San Francisco"},{"author_name":"Rowan Saloner","author_inst":"University of California, San Francisco"},{"author_name":"Kaitlin B Casaletto","author_inst":"University of California, San Francisco"},{"author_name":"Joel H Kramer","author_inst":"University of California, San Francisco"},{"author_name":"Bruce L Miller","author_inst":"University of California, San Francisco"},{"author_name":"William W Seeley","author_inst":"University of California, San Francisco"},{"author_name":"Maria Luisa Gorno-Tempini","author_inst":"University of California, San Francisco"},{"author_name":"Peter A Ljubenkov","author_inst":"University of California, San Francisco"},{"author_name":"Julio C Rojas","author_inst":"University of California, San Francisco"},{"author_name":"Suzee Lee","author_inst":"University of California, San Francisco"},{"author_name":"Virginia Sturm","author_inst":"University of California, San Francisco"},{"author_name":"Brian Appleby","author_inst":"Case Western Reserve University"},{"author_name":"Ece Bayram","author_inst":"University of Colorado Anschutz"},{"author_name":"David Clark","author_inst":"Indiana University"},{"author_name":"Ciaran M Considine","author_inst":"Vanderbilt University"},{"author_name":"Richard R Darby","author_inst":"Vanderbilt University"},{"author_name":"Gregory S Day","author_inst":"Mayo Clinic, Jacksonville"},{"author_name":"Alyssa De Vito","author_inst":"Brown University"},{"author_name":"Mark Eldaief","author_inst":"Massachusetts General Hospital & Harvard Medical School"},{"author_name":"Julie A Fields","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Nupur Ghoshal","author_inst":"Washington University"},{"author_name":"Edward D Huey","author_inst":"Brown University"},{"author_name":"David J Irwin","author_inst":"University of Pennsylvania"},{"author_name":"Kejal Kantarci","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Justin Y Kwan","author_inst":"National Institutes of Health"},{"author_name":"Ian R Mackenzie","author_inst":"University of British Columbia"},{"author_name":"Joseph C Masdeu","author_inst":"Houston Methodist"},{"author_name":"Chiadi U Onyike","author_inst":"Johns Hopkins University"},{"author_name":"Alexander Pantelyat","author_inst":"Johns Hopkins University"},{"author_name":"Belen Pascual","author_inst":"Houston Methodist"},{"author_name":"Tanav Popli","author_inst":"University of Michigan"},{"author_name":"Katya Rascovsky","author_inst":"University of Pennsylvania"},{"author_name":"Neguine Rezaii","author_inst":"Massachusetts General Hospital"},{"author_name":"Sonja W Scholz","author_inst":"National Institutes of Health"},{"author_name":"Allison Snyder","author_inst":"National Institutes of Health"},{"author_name":"M. Carmela Tartaglia","author_inst":"University of Toronto"},{"author_name":"Bryan J Traynor","author_inst":"National Institutes of Health"},{"author_name":"Bonnie Wong","author_inst":"MGH"},{"author_name":"John Kornak","author_inst":"University of California, San Francisco"},{"author_name":"Walter K Kremers","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Leah K Forsberg","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Hilary W Heuer","author_inst":"University of California, San Francisco"},{"author_name":"Bradley F Boeve","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Howard J Rosen","author_inst":"University of California, San Francisco"},{"author_name":"Adam L Boxer","author_inst":"University of California, San Francisco"},{"author_name":"Adam M Staffaroni","author_inst":"University of California, San Francisco"},{"author_name":"- ALLFTD Consortium","author_inst":""}],"rel_date":"2026-09-21","rel_site":"medrxiv"},{"rel_title":"Smartphone Passive Digital Phenotyping in Frontotemporal Lobar Degeneration","rel_doi":"10.64898\/2026.09.18.26363439","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.18.26363439","rel_abs":"IntroductionFrontotemporal lobar degeneration (FTLD) is a devastating disease that commonly results in early onset dementia, yet its rarity and heterogeneity limit large-scale research and clinical trials. Remote monitoring via low-burden digital health tools may overcome these barriers. We evaluated clinical utility of passive smartphone monitoring in FTLD using a multi-domain mobile assessment platform.\n\nMethodsParticipants were 567 adults (53% clinically normal, 21% prodromal FTLD, 26% symptomatic FTLD) who completed an in-person study visit and downloaded the ALLFTD Mobile App on their personal smartphones. The app delivered unsupervised cognitive tests and passively collected continuous data on battery percentage (proxy for smartphone use) and step count. Longitudinal follow-up included smartphone monitoring and annual in-person study visits. Primary analyses examined associations between passive smartphone features and markers of disease severity at baseline and longitudinally, and tested whether passive features added incremental value beyond app-based cognitive testing.\n\nResultsPassive smartphone features were feasible to collect and showed excellent reliability with <2 weeks of monitoring (ICCs>0.9). Features capturing smartphone use and movement demonstrated sensitivity to gold-standard clinical measures of disease severity both at baseline and longitudinally. A classification model combining passive features, the app-based cognitive composite score, and demographics detected longitudinal functional decline (AUC=0.89); passive features alone (AUC=0.84) performed comparably to a cognitive screener (AUC=0.85).\n\nDiscussionPassive smartphone monitoring is a valid, zero-burden measure of disease severity and progression in FTLD that adds modest incremental value beyond app-based cognitive testing. Findings support its use as a scalable digital endpoint in longitudinal FTLD research.","rel_num_authors":51,"rel_authors":[{"author_name":"Emily W Paolillo","author_inst":"University of California, San Francisco"},{"author_name":"Sreya Dhanam","author_inst":"University of California, San Francisco"},{"author_name":"Jack Carson Taylor","author_inst":"University of California, San Francisco"},{"author_name":"Mark Sanderson-Cimino","author_inst":"University of California, San Francisco"},{"author_name":"Ray Fregly","author_inst":"University of California, San Francisco"},{"author_name":"Rowan Saloner","author_inst":"University of California, San Francisco"},{"author_name":"Kaitlin B Casaletto","author_inst":"University of California, San Francisco"},{"author_name":"Joel H Kramer","author_inst":"University of California, San Francisco"},{"author_name":"Bruce L Miller","author_inst":"University of California, San Francisco"},{"author_name":"William W Seeley","author_inst":"University of California, San Francisco"},{"author_name":"Maria Luisa Gorno-Tempini","author_inst":"University of California, San Francisco"},{"author_name":"Peter A Ljubenkov","author_inst":"University of California, San Francisco"},{"author_name":"Julio C Rojas","author_inst":"University of California, San Francisco"},{"author_name":"Suzee Lee","author_inst":"University of California, San Francisco"},{"author_name":"Virginia Sturm","author_inst":"University of California, San Francisco"},{"author_name":"Brian Appleby","author_inst":"Case Western Reserve University"},{"author_name":"Ece Bayram","author_inst":"University of Colorado Anschutz"},{"author_name":"David Clark","author_inst":"Indiana University"},{"author_name":"Ciaran M Considine","author_inst":"Vanderbilt University"},{"author_name":"Richard R Darby","author_inst":"Vanderbilt University"},{"author_name":"Gregory S Day","author_inst":"Mayo Clinic, Jacksonville"},{"author_name":"Alyssa De Vito","author_inst":"Brown University"},{"author_name":"Mark Eldaief","author_inst":"Massachusetts General Hospital & Harvard Medical School"},{"author_name":"Julie A Fields","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Nupur Ghoshal","author_inst":"Washington University"},{"author_name":"Edward D Huey","author_inst":"Brown University"},{"author_name":"David J Irwin","author_inst":"University of Pennsylvania"},{"author_name":"Kejal Kantarci","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Justin Y Kwan","author_inst":"National Institutes of Health"},{"author_name":"Ian R Mackenzie","author_inst":"University of British Columbia"},{"author_name":"Joseph C Masdeu","author_inst":"Houston Methodist"},{"author_name":"Chiadi U Onyike","author_inst":"Johns Hopkins University"},{"author_name":"Alexander Pantelyat","author_inst":"Johns Hopkins University"},{"author_name":"Belen Pascual","author_inst":"Houston Methodist"},{"author_name":"Tanav Popli","author_inst":"University of Michigan"},{"author_name":"Katya Rascovsky","author_inst":"University of Pennsylvania"},{"author_name":"Neguine Rezaii","author_inst":"Massachusetts General Hospital"},{"author_name":"Sonja W Scholz","author_inst":"National Institutes of Health"},{"author_name":"Allison Snyder","author_inst":"National Institutes of Health"},{"author_name":"M. Carmela Tartaglia","author_inst":"University of Toronto"},{"author_name":"Bryan J Traynor","author_inst":"National Institutes of Health"},{"author_name":"Bonnie Wong","author_inst":"MGH"},{"author_name":"John Kornak","author_inst":"University of California, San Francisco"},{"author_name":"Walter K Kremers","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Leah K Forsberg","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Hilary W Heuer","author_inst":"University of California, San Francisco"},{"author_name":"Bradley F Boeve","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Howard J Rosen","author_inst":"University of California, San Francisco"},{"author_name":"Adam L Boxer","author_inst":"University of California, San Francisco"},{"author_name":"Adam M Staffaroni","author_inst":"University of California, San Francisco"},{"author_name":"- ALLFTD Consortium","author_inst":""}],"rel_date":"2026-09-21","rel_site":"medrxiv"}]}