{"gname":"University of New South Wales","grp_id":"25","rels":[{"rel_title":"Transcriptional networks underlying tumour plasticity in small-cell lung cancer","rel_doi":"10.64898\/2026.09.26.754526","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.26.754526","rel_abs":"Across human malignancies, the ability of cancer cells to switch states (plasticity) drives progression, metastasis, and therapy resistance 1-3. Here we investigated the transcriptional and epigenetic basis of plasticity in small-cell lung cancer (SCLC), an aggressive, treatment-refractory cancer 4, 5. SCLC tumours display plasticity along a neuroendocrine (NE) to nonNE axis; however, the trajectories of lineage transition and the gene regulatory network underlying it, remain poorly defined 6. Using single-cell multi-omics, we resolved distinct transcriptional SCLC cell states, including a previously unrecognised Intermediate state comprised of low-identity immunogenic SCLC cells that serve as an obligatory route in NE to nonNE lineage transition. Using single-cell gene expression and chromatin accessibility data, we next developed a Boolean Bayes model for transcription factor networks (BoBa-T) to predict regulators of SCLC cell states. We validated RORB as a novel gatekeeper of the NE state that represses the nonNE identity in SCLC. RORB inactivation drives NE cells into the Intermediate state, upregulates immunogenic programs, and inhibits tumour growth in immunocompetent hosts. Our work identifies a plastic, immunogenic waypoint for SCLC lineage switching and reveals strategies to target it therapeutically.","rel_num_authors":12,"rel_authors":[{"author_name":"Debadrita Bhattacharya","author_inst":"Stanford University"},{"author_name":"Sarah M. Groves","author_inst":"Vanderbilt University, Nashville, TN, USA"},{"author_name":"Cameron Walker","author_inst":"Stanford University"},{"author_name":"Gina N. Duorino","author_inst":"Stanford School of Medicine"},{"author_name":"Marcus Hsieh","author_inst":"Stanford School of Medicine"},{"author_name":"Yamina Chtourou","author_inst":"Stanford School of Medicine"},{"author_name":"Griffin G. Hartmann","author_inst":"Stanford School of Medicine"},{"author_name":"Wen-Hao Hsu","author_inst":"Stanford School of Medicine"},{"author_name":"Candace Liu","author_inst":"Stanford University"},{"author_name":"Michael Angelo","author_inst":"Stanford University"},{"author_name":"Vito Quaranta","author_inst":"Vanderbilt University"},{"author_name":"Julien Sage","author_inst":"Stanford University School of Medicine"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Agentic transcranial functional ultrasound imaging: @fUS","rel_doi":"10.64898\/2026.09.25.752961","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.25.752961","rel_abs":"Functional ultrasound (fUS) imaging provides deep, wide-field access to brain function, but instrument cost and complex acquisition and analysis workflows restrict its wider adoption. Here we introduce @fUS, an agentic transcranial imaging platform with an open architecture that integrates purpose-built hardware with executable experimental skills and persistent structured memory. The system combines 128-channel, 16-bit acquisition at 125 MHz with GPU-based processing and enables functional imaging through the intact scalp and skull of mice, with approximately 100-m spatial resolution and 10-Hz temporal sampling, providing a basis for longitudinal studies without cranial-window surgery. Its agent connects scientific objectives to experimental design, direct instrument control and data analysis, retaining context across interactions and supporting inspectable workflows through text and hands-free voice control. Neuroscience trainees with limited engineering experience independently configured the system within 30 min. Agent-assisted exploration of whisker-stimulation datasets revealed low-frequency vascular changes beyond conventional response mapping, supported by complementary two-photon measurements of single-vessel diameter. By combining transcranial imaging with accessible instrument control and analysis, @fUS provides a foundation for wider adoption and larger, more diverse neuroscience datasets. More broadly, it offers a framework for scientific instruments in which measurement, computation and experimental reasoning are developed as parts of the same system.","rel_num_authors":23,"rel_authors":[{"author_name":"Zihao CHEN","author_inst":"The Hong Kong Polytechnic University"},{"author_name":"Zexin Yuan","author_inst":"Guangdong Institute of Intelligence Science and Technology"},{"author_name":"Zhaoqi Lu","author_inst":"Guangdong Institute of Intelligence Science and Technology"},{"author_name":"Na Li","author_inst":"The Hong Kong Polytechnic University"},{"author_name":"Ceyi Fu","author_inst":"Tsinghua-Peking Joint Center for Life Sciences & IDG\/McGovern Institute for Brain Research"},{"author_name":"Le Sun","author_inst":"Chinese Institute for Brain Research"},{"author_name":"Hongying Yao","author_inst":"Department of Traditional Chinese Medicine, Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Songjiang Hospital Affili"},{"author_name":"Huizhu Liu","author_inst":"Department of Traditional Chinese Medicine, Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Songjiang Hospital Affili"},{"author_name":"Quanxiang Xian","author_inst":"The Hong Kong Polytechnic University"},{"author_name":"Tianyi Wang","author_inst":"School of Life Sciences, Westlake University"},{"author_name":"Wei Li","author_inst":"Chinese Institute for Brain Research"},{"author_name":"Zirui Liang","author_inst":"Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University"},{"author_name":"Boxing Li","author_inst":"Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University"},{"author_name":"Ying Zhang","author_inst":"Tsinghua-Peking Joint Center for Life Sciences & IDG\/McGovern Institute for Brain Research"},{"author_name":"Ying Li","author_inst":"Chinese Institute for Brain Research"},{"author_name":"Hongsheng Wang","author_inst":"Department of Traditional Chinese Medicine, Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Songjiang Hospital Affili"},{"author_name":"Wen-jie Bian","author_inst":"Westlake Laboratory of Life Sciences and Biomedicine"},{"author_name":"Xiaodong Liu","author_inst":"Department of Anaesthesia and Intensive Care, Faculty of Medicine, The Chinese University of Hong Kong"},{"author_name":"Yan Chen","author_inst":"Guangdong Institute of Intelligence Science and Technology"},{"author_name":"Bo Li","author_inst":"Westlake Laboratory of Life Sciences and Biomedicine"},{"author_name":"Lei SUN","author_inst":"Hong Kong Polytechnic University"},{"author_name":"Yimin Wang","author_inst":"Guangdong Institute of Intelligence Science and Technology"},{"author_name":"Zhihai Qiu","author_inst":"Guangdong Institute of Intelligence Science and Technology"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Browning Lipid Nanoparticles Deliver Metabolic Benefits via Transient Conversion of White Adipose Tissue","rel_doi":"10.64898\/2026.09.25.754464","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.25.754464","rel_abs":"Therapeutic strategies based on increasing uncoupled respiration (browning) in white adipose tissue (WAT) have great potential for treating obesity-related disorders such as diabetes and steatotic liver disease, but have not had a clinical impact because safe and efficient methods for browning WAT have not been developed. Lipid nanoparticles (LNPs) offer a promising platform for adipose-directed siRNA delivery; however, conventional formulations often exhibit limited activity in adipocytes and can induce inflammatory responses that may restrict repeated administration. Here we demonstrate that LNPs that contain ionizable lipids with three lipid tails and siRNAs targeting TLE3 and ZFP423 can efficiently transfect mature adipocytes and induce browning of WAT in vitro and in vivo while providing the biocompatibility needed for repeated subcutaneous injections. Repeated local administration of BLNPs in diet-induced obese mice resulted in sustained target gene silencing, increased expression of thermogenic markers, altered energy metabolism, and decreased hepatic lipid accumulation despite minimal effects on body weight relative to scramble siRNA controls. Collectively, these findings establish BLNPs as a promising platform for adipose-directed RNA delivery and targeted modulation of thermogenic pathways, providing a strategy for investigating how localized adipose tissue remodeling influences metabolic physiology.","rel_num_authors":10,"rel_authors":[{"author_name":"Rohit Sharma","author_inst":"Department of Bioengineering, University of California, Berkeley, California 94720, United States, The Innovative Genomics Institute, 2151 Berkeley Way, Berkele"},{"author_name":"Amanda L Gunawan","author_inst":"Department of Nutritional Sciences and Toxicology, University of California Berkeley, California 94720, United States"},{"author_name":"Yuchen He","author_inst":"Department of Nutritional Sciences and Toxicology, University of California Berkeley, California 94720, United States"},{"author_name":"Lin Qi","author_inst":"Department of Nutritional Sciences and Toxicology, University of California Berkeley, California 94720, United States"},{"author_name":"Nehal Singhal","author_inst":"Department of Bioengineering, University of California, Berkeley, California 94720, United States, The Innovative Genomics Institute, 2151 Berkeley Way, Berkele"},{"author_name":"Jesslyn Lukman","author_inst":"Department of Nutritional Sciences and Toxicology, University of California Berkeley, California 94720, United States"},{"author_name":"Nayiri Kalindjian","author_inst":"Department of Nutritional Sciences and Toxicology, University of California Berkeley, California 94720, United States"},{"author_name":"Vyvylyn Tran","author_inst":"Department of Nutritional Sciences and Toxicology, University of California Berkeley, California 94720, United States"},{"author_name":"Niren Murthy","author_inst":"Department of Bioengineering, University of California, Berkeley, California 94720, United States, The Innovative Genomics Institute, 2151 Berkeley Way, Berkele"},{"author_name":"Andreas Stahl","author_inst":"Department of Nutritional Sciences and Toxicology, University of California Berkeley, California 94720, United States"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Intranasal adenovirus type 5 influenza vaccination enhances milk antibody responses and passive transfer to neonatal ferrets","rel_doi":"10.64898\/2026.09.26.754702","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.26.754702","rel_abs":"Newborns and infants are particularly vulnerable to influenza, largely due to the immaturity of their immune systems. As such, maternal immunization is a valuable strategy to enhance influenza-neutralizing antibodies in both blood and breast milk, ensuring optimal passive immunity transfer to the infant. In our pregnant and lactating ferret maternal-neonatal model, we evaluated antibody responses to an adenovirus type 5-vectored H1N1 hemagglutinin vaccine delivered enterically, intranasally, or intramuscularly. While all three routes elicited a robust antibody response compared to saline-treated controls, intranasal vaccination significantly increased influenza-specific antibodies in dam serum, upper respiratory tract secretions, and milk, and subsequent transfer to suckling kits. Our results suggest that intranasal immunization was the most effective route for inducing functional influenza-specific antibodies in both dam serum and milk, with efficient passive transfer to suckling kits. Leveraging mucosal immune induction may enhance maternal antibody responses, transfer to offspring, and downstream neonatal protection.","rel_num_authors":13,"rel_authors":[{"author_name":"Lauren Stewart Stafford","author_inst":"Case Western Reserve University"},{"author_name":"Pari Baker","author_inst":"Case Western Reserve University"},{"author_name":"Michelle Moyer","author_inst":"Case Western Reserve University"},{"author_name":"Jake Byrne","author_inst":"Duke Human Vaccine Institute"},{"author_name":"Christopher Beverly","author_inst":"University of Kansas School of Medicine"},{"author_name":"Susanna Henry","author_inst":"Case Western Reserve University"},{"author_name":"Yixuan Bai","author_inst":"Case Western Reserve University"},{"author_name":"Yelenna Skomorovska-Prokvolit","author_inst":"Case Western Reserve University"},{"author_name":"Madelyn Cook","author_inst":"Case Western Reserve University"},{"author_name":"Ananya Goel","author_inst":"Case Western Reserve University"},{"author_name":"Francis Sun","author_inst":"Wake Forest University School of Medicine"},{"author_name":"Sean Tucker","author_inst":"Vaxart"},{"author_name":"Stephanie Langel","author_inst":"Case Western Reserve University"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Intranasal adenovirus type 5 influenza vaccination enhances milk antibody responses and passive transfer to neonatal ferrets","rel_doi":"10.64898\/2026.09.26.754702","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.26.754702","rel_abs":"Newborns and infants are particularly vulnerable to influenza, largely due to the immaturity of their immune systems. As such, maternal immunization is a valuable strategy to enhance influenza-neutralizing antibodies in both blood and breast milk, ensuring optimal passive immunity transfer to the infant. In our pregnant and lactating ferret maternal-neonatal model, we evaluated antibody responses to an adenovirus type 5-vectored H1N1 hemagglutinin vaccine delivered enterically, intranasally, or intramuscularly. While all three routes elicited a robust antibody response compared to saline-treated controls, intranasal vaccination significantly increased influenza-specific antibodies in dam serum, upper respiratory tract secretions, and milk, and subsequent transfer to suckling kits. Our results suggest that intranasal immunization was the most effective route for inducing functional influenza-specific antibodies in both dam serum and milk, with efficient passive transfer to suckling kits. Leveraging mucosal immune induction may enhance maternal antibody responses, transfer to offspring, and downstream neonatal protection.","rel_num_authors":13,"rel_authors":[{"author_name":"Lauren Stewart Stafford","author_inst":"Case Western Reserve University"},{"author_name":"Pari Baker","author_inst":"Case Western Reserve University"},{"author_name":"Michelle Moyer","author_inst":"Case Western Reserve University"},{"author_name":"Jake Byrne","author_inst":"Duke Human Vaccine Institute"},{"author_name":"Christopher Beverly","author_inst":"University of Kansas School of Medicine"},{"author_name":"Susanna Henry","author_inst":"Case Western Reserve University"},{"author_name":"Yixuan Bai","author_inst":"Case Western Reserve University"},{"author_name":"Yelenna Skomorovska-Prokvolit","author_inst":"Case Western Reserve University"},{"author_name":"Madelyn Cook","author_inst":"Case Western Reserve University"},{"author_name":"Ananya Goel","author_inst":"Case Western Reserve University"},{"author_name":"Francis Sun","author_inst":"Wake Forest University School of Medicine"},{"author_name":"Sean Tucker","author_inst":"Vaxart"},{"author_name":"Stephanie Langel","author_inst":"Case Western Reserve University"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Intranasal adenovirus type 5 influenza vaccination enhances milk antibody responses and passive transfer to neonatal ferrets","rel_doi":"10.64898\/2026.09.26.754702","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.26.754702","rel_abs":"Newborns and infants are particularly vulnerable to influenza, largely due to the immaturity of their immune systems. As such, maternal immunization is a valuable strategy to enhance influenza-neutralizing antibodies in both blood and breast milk, ensuring optimal passive immunity transfer to the infant. In our pregnant and lactating ferret maternal-neonatal model, we evaluated antibody responses to an adenovirus type 5-vectored H1N1 hemagglutinin vaccine delivered enterically, intranasally, or intramuscularly. While all three routes elicited a robust antibody response compared to saline-treated controls, intranasal vaccination significantly increased influenza-specific antibodies in dam serum, upper respiratory tract secretions, and milk, and subsequent transfer to suckling kits. Our results suggest that intranasal immunization was the most effective route for inducing functional influenza-specific antibodies in both dam serum and milk, with efficient passive transfer to suckling kits. Leveraging mucosal immune induction may enhance maternal antibody responses, transfer to offspring, and downstream neonatal protection.","rel_num_authors":13,"rel_authors":[{"author_name":"Lauren Stewart Stafford","author_inst":"Case Western Reserve University"},{"author_name":"Pari Baker","author_inst":"Case Western Reserve University"},{"author_name":"Michelle Moyer","author_inst":"Case Western Reserve University"},{"author_name":"Jake Byrne","author_inst":"Duke Human Vaccine Institute"},{"author_name":"Christopher Beverly","author_inst":"University of Kansas School of Medicine"},{"author_name":"Susanna Henry","author_inst":"Case Western Reserve University"},{"author_name":"Yixuan Bai","author_inst":"Case Western Reserve University"},{"author_name":"Yelenna Skomorovska-Prokvolit","author_inst":"Case Western Reserve University"},{"author_name":"Madelyn Cook","author_inst":"Case Western Reserve University"},{"author_name":"Ananya Goel","author_inst":"Case Western Reserve University"},{"author_name":"Francis Sun","author_inst":"Wake Forest University School of Medicine"},{"author_name":"Sean Tucker","author_inst":"Vaxart"},{"author_name":"Stephanie Langel","author_inst":"Case Western Reserve University"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"A Human Genome-wide CRISPR-Cas9 Screen Reveals Host Factors That Support Epstein-Barr Virus B cell infection","rel_doi":"10.64898\/2026.09.28.754942","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.28.754942","rel_abs":"Epstein-Barr virus (EBV) infects 90% of the population worldwide and is associated with multiple malignancies, including Burkitt, Hodgkin and post-transplant lymphomas, nasopharyngeal and gastric carcinoma. EBV also triggers autoimmune diseases, including multiple sclerosis and systemic lupus erythematosus. While host factors important for EBV B-cell entry have been defined, including CD21\/CR2, MHC class II and R9AP, much remains to be learned about host factors that support post-entry steps of EBV infection. To gain insight, we conducted a human genome-wide CRISPR-Cas9 screen. In addition to known EBV B cell receptors\/co-receptors, we identified multiple new factors and pathways essential for EBV B cell infection. These included multiple B cell signaling pathways, actin cytoskeleton and nuclear import factors. Knockout of CD19, its tetraspanin chaperone CD81 or karyopherin subunit alpha 1 (KPNA1, also called importin-5) significantly impaired establishment of EBV infection. EBV and CD19 co-localized at early stages of EBV infection, and the CD19 cytoplasmic tail was important for EBV infection, suggesting CD19 signaling supports EBV uptake. Depletion of KPNA1 significantly impaired establishment of EBV infection, but did not impair production of infectious EBV upon reactivation of latently infected B cells. Together, these results provide insights into pathways that support EBV B cell infection and identify potential therapeutic targets.","rel_num_authors":14,"rel_authors":[{"author_name":"Hongbo Wang","author_inst":"Brigham and Women's Hospital"},{"author_name":"Yao Yu Yeo","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Chong wang","author_inst":"University of Minnesota Twin Cities"},{"author_name":"Rui Guo","author_inst":"Tufts University School of Medicine"},{"author_name":"Shaowen White","author_inst":"Brigham and Women's Hospital"},{"author_name":"Yifei Liao","author_inst":"Brigham and Women's Hospital"},{"author_name":"Stephanie Yiu","author_inst":"Harvard Medical School"},{"author_name":"Gloria Liu","author_inst":"Harvard Medical School"},{"author_name":"Alvin Huang","author_inst":"Harvard Medical School"},{"author_name":"David JS Zhao","author_inst":"Harvard Medical School"},{"author_name":"Zongwei Wang","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Sizun Jiang","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Benjamin Gewurz","author_inst":"Harvard Medical School, Brigham and Women's Hospital"},{"author_name":"Bo Zhao","author_inst":"Brigham and Women's Hospital"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Gut microbial phenylalanine metabolism contributes to MASLD in a dietary protein-dependent manner","rel_doi":"10.64898\/2026.09.28.754936","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.28.754936","rel_abs":"Metabolic dysfunction-associated steatotic liver disease (MASLD) affects nearly a third of adults worldwide, yet how diet shapes the microbiota's contribution remains unclear. In a diet-induced mouse model varying protein content independently of caloric intake, microbiota depletion ameliorated hepatic steatosis and liver injury under protein- sufficient but not protein-restricted conditions. Caecal and plasma metabolomics implicated microbial phenylalanine catabolism and its host conjugates phenylacetylglutamine (PAGln) and phenylacetylglycine (PAGly). PAGln supplementation exacerbated steatosis and liver injury without altering body weight, adiposity or glucose homeostasis. Individual-antibiotic perturbation with metagenomics linked bacterial phenylalanine catabolic capacity to disease severity, and in gnotobiotic mice, genetic disruption of bacterial phenylalanine-to-phenylacetic acid conversion lowered circulating conjugates and attenuated steatosis and fibrosis. In a human cohort, circulating PAGln was selectively elevated in cardiometabolic MASLD. These findings identify dietary protein availability as a modifier of the contribution of microbial phenylalanine metabolism to MASLD and highlight PAGln as a microbiota-derived metabolite that exacerbates hepatic disease.","rel_num_authors":10,"rel_authors":[{"author_name":"Yi Rou Bah","author_inst":"Nanyang Technological University"},{"author_name":"Dayang Nurul Asyiqin Binte Mustafa","author_inst":"Nanyang Technological University"},{"author_name":"Frisma Eri Saputri","author_inst":"Nanyang Technological University"},{"author_name":"Takuo Emoto","author_inst":"Kobe University Graduate School of Medicine"},{"author_name":"Sunny H Wong","author_inst":"Nanyang Technological University"},{"author_name":"Rinkoo Dalan","author_inst":"Tan Tock Seng Hospital"},{"author_name":"Wei-Kai Wu","author_inst":"National Taiwan University Hospital"},{"author_name":"Nguan Soon Tan","author_inst":"Nanyang Technological University"},{"author_name":"Torsten Wuestefeld","author_inst":"Nanyang Technological University"},{"author_name":"Kazuyuki Kasahara","author_inst":"Nanyang Technological University"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"A Research-Integrated Curriculum on CAR-T Cell Therapy","rel_doi":"10.64898\/2026.09.23.753877","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.23.753877","rel_abs":"Chimeric antigen receptor (CAR) T cells are patient-derived T cells engineered to recognize specific antigens on malignant cells, representing a major breakthrough in personalized cancer immunotherapy. While CAR-T cell therapy is an established treatment for relapsed or refractory hematologic malignancies, understanding the rationale and methodology behind its development is essential for training the next generation of oncology researchers. Here, we describe a novel, hands-on small-enrollment laboratory course designed to teach upper-level undergraduate and graduate students about immunotherapies and CAR-T cell technology by paralleling a typical bench-scale development process. Students isolated T cells from porcine peripheral blood mononuclear cells (PBMCs) via immunomagnetic selection, followed by flow cytometry to assess purity, viability, and yield. Students then used pre-engineered B7H3 CAR-T cells to perform co-culture assays with U87 glioblastoma cells to evaluate tumor cell killing efficacy. Cytotoxicity was qualitatively evaluated using immunofluorescence microscopy, while IFN-gamma release was quantified using Enzyme-linked Immunosorbent Assay (ELISA). Student performance was evaluated through electronic laboratory notebooks, discussion questions, a capstone project, and student-generated data. Our results demonstrate students high academic performance across assignments and the successful execution of complex laboratory workflows. Collectively, these findings establish the feasibility and implementation of a research-integrated curriculum providing foundational exposure to immuno-oncology research tools and CAR-T cell production techniques.","rel_num_authors":3,"rel_authors":[{"author_name":"Youan H. Khan","author_inst":"North Carolina State University"},{"author_name":"Lauren Rice","author_inst":"North Carolina State University"},{"author_name":"Melissa C. Srougi","author_inst":"North Carolina State University"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Biologically grounded cell profiling across microscopy modalities","rel_doi":"10.64898\/2026.09.23.753678","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.23.753678","rel_abs":"Microscopy-based cell profiling has broad applications in biological discovery, disease characterization, and phenotypic drug screening. Modern microscopy continues to push the limits of resolution, speed, depth and throughput, but better imaging does not automatically lead to better biomedical discovery and translation. A key bottleneck is feature representation: existing features are either handcrafted or learned as black-box embeddings and often lack explicit biological meaning. Here we propose biological grounding as a first principle for cell profiling and implement it through MorphAgent, an AI agent framework in which each quantitative feature originates from a biological hypothesis and is anchored to a cellular structure or process. By integrating biological knowledge, multimodal reasoning and automated validation, MorphAgent makes biologically grounded feature design systematic and scalable. We show biological grounding fundamentally changes the properties of cell profiling features. Across three microscopy modalities, MorphAgent produces compact, expressive and transferable features for drug screening, cell state characterization and disease morphology analysis. In wide-field Cell Painting, a common assay for phenotypic drug screening, it improves perturbation-retrieval mean average precision by 48% over CellProfiler and 20% over DeepProfiler while using substantially fewer dimensions. In confocal mitochondrial imaging, biologically grounded features transfer across independently acquired datasets and imaging resolutions, supporting accurate aging-state classification. In structured illumination microscopy (SIM) imaging of Tau-labeled samples, biologically grounded super resolution features reveal nanoscale morphologies inaccessible at conventional resolution, enhancing the discrimination of disease-associated mutations. Moreover, biologically grounded features provide a hierarchical organization of cellular morphology, enabling multilevel alignment with transcriptomics data and facilitating mechanistic understanding. Biologically grounded cell profiling thus brings AI reasoning closer to biological mechanisms, advancing biomedical discovery and translation.","rel_num_authors":12,"rel_authors":[{"author_name":"Enze Ye","author_inst":"Peking University"},{"author_name":"Xiaoxuan Wu","author_inst":"Peking University"},{"author_name":"Rui Peng","author_inst":"Peking university"},{"author_name":"Wenjia Hu","author_inst":"Peking University"},{"author_name":"Xiangyou Li","author_inst":"Peking University"},{"author_name":"Xuefei Zhang","author_inst":"Peking University"},{"author_name":"Mengxiao Niu","author_inst":"Peking University"},{"author_name":"Yaorong Guo","author_inst":"Peking University"},{"author_name":"Xinlei Sheng","author_inst":"SMART"},{"author_name":"Jinzhuo Wang","author_inst":"Peking University"},{"author_name":"Liangyi Chen","author_inst":"Peking University"},{"author_name":"He Sun","author_inst":"Peking University"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Discrete Morse Graph Construction for High-Dimensional Transcriptomic Data","rel_doi":"10.64898\/2026.09.22.753642","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.753642","rel_abs":"Single-cell transcriptomic atlases resolve thousands of putative brain cell types, yet common analytical workflows often rely on low-dimensional embeddings that can distort neighborhood relationships and obscure continuous variation between closely related populations. We introduce single-cell Discrete Morse Graph Construction (scDMGC), a deterministic framework based on topological data analysis and discrete Morse theory that extracts a compact graph from neighborhood structure in high-dimensional gene-expression space. Because graph edges are derived from the original k-nearest-neighbor complex, scDMGC provides an interpretable multiscale representation of transcriptomic organization without requiring a low-dimensional embedding. Local maxima represent coherent transcriptional states, saddles quantify their separation, and gradient paths capture intermediate states and continuous transitions. Applied to cortical and hippocampal datasets, scDMGC recovers established inhibitory-neuron classes and elucidates transcriptional gradients. In mouse whole-cortex data, Morse graph structure evaluates cell-type hierarchy and type robustness. Persistence across scales provides a quantitative measure of cell-type identity and discrete versus continuous relationships. Finally, in Alzheimers disease single-nucleus data, scDMGC distinguishes changes in cell-type abundance from disease-associated shifts in transcriptional state. scDMGC therefore provides a multiscale framework for quantifying whether transcriptional populations form persistent cell types, how strongly external annotations are supported by intrinsic data structure, how cell types relate to one another, and where discrete organization transitions into continuous variation.","rel_num_authors":10,"rel_authors":[{"author_name":"Lucas J Magee","author_inst":"University of California San Diego"},{"author_name":"Rohan Gala","author_inst":"Allen Institute, Brain Science"},{"author_name":"Kyle J Travaglini","author_inst":"Allen Institute, Brain Health"},{"author_name":"Uygar Sumbul","author_inst":"Allen Institute, Brain Science"},{"author_name":"David R Haynor","author_inst":"University of Washington"},{"author_name":"Samantha Chen","author_inst":"University of California San Diego"},{"author_name":"Tristan Brugere","author_inst":"University of California San Diego"},{"author_name":"Yusu Wang","author_inst":"University of California San Diego"},{"author_name":"Partha P Mitra","author_inst":"Cold Spring Harbor Laboratory"},{"author_name":"Michael J Hawrylycz","author_inst":"Allen Institute, Brain Science"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Discrete Morse Graph Construction for High-Dimensional Transcriptomic Data","rel_doi":"10.64898\/2026.09.22.753642","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.753642","rel_abs":"Single-cell transcriptomic atlases resolve thousands of putative brain cell types, yet common analytical workflows often rely on low-dimensional embeddings that can distort neighborhood relationships and obscure continuous variation between closely related populations. We introduce single-cell Discrete Morse Graph Construction (scDMGC), a deterministic framework based on topological data analysis and discrete Morse theory that extracts a compact graph from neighborhood structure in high-dimensional gene-expression space. Because graph edges are derived from the original k-nearest-neighbor complex, scDMGC provides an interpretable multiscale representation of transcriptomic organization without requiring a low-dimensional embedding. Local maxima represent coherent transcriptional states, saddles quantify their separation, and gradient paths capture intermediate states and continuous transitions. Applied to cortical and hippocampal datasets, scDMGC recovers established inhibitory-neuron classes and elucidates transcriptional gradients. In mouse whole-cortex data, Morse graph structure evaluates cell-type hierarchy and type robustness. Persistence across scales provides a quantitative measure of cell-type identity and discrete versus continuous relationships. Finally, in Alzheimers disease single-nucleus data, scDMGC distinguishes changes in cell-type abundance from disease-associated shifts in transcriptional state. scDMGC therefore provides a multiscale framework for quantifying whether transcriptional populations form persistent cell types, how strongly external annotations are supported by intrinsic data structure, how cell types relate to one another, and where discrete organization transitions into continuous variation.","rel_num_authors":10,"rel_authors":[{"author_name":"Lucas J Magee","author_inst":"University of California San Diego"},{"author_name":"Rohan Gala","author_inst":"Allen Institute, Brain Science"},{"author_name":"Kyle J Travaglini","author_inst":"Allen Institute, Brain Health"},{"author_name":"Uygar Sumbul","author_inst":"Allen Institute, Brain Science"},{"author_name":"David R Haynor","author_inst":"University of Washington"},{"author_name":"Samantha Chen","author_inst":"University of California San Diego"},{"author_name":"Tristan Brugere","author_inst":"University of California San Diego"},{"author_name":"Yusu Wang","author_inst":"University of California San Diego"},{"author_name":"Partha P Mitra","author_inst":"Cold Spring Harbor Laboratory"},{"author_name":"Michael J Hawrylycz","author_inst":"Allen Institute, Brain Science"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"A Thermodynamic Theory of Axon Guidance: Navigation Through High-Entropy Signaling States","rel_doi":"10.64898\/2026.09.22.752727","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.752727","rel_abs":"Precise neural circuit formation requires growth cones to integrate multiple, sometimes competing, guidance signals into persistent yet adaptable movement. Here, we propose a theoretical framework that recasts axon guidance as a thermodynamically regulated computation. An artificial neural network, trained on in vivo genetic data and associated outgrowth patterns, maps the microstates of a localized guidance signaling network to macroscopic outgrowth behaviors. Using the trained model, we simulated axon pathfinding through extracellular gradients of molecular cues and created dynamic entropic landscapes. These results reveal that growth cones navigate high-entropy ridges that preserve plasticity. Navigation along these ridges supports persistent extension, whereas turning and branching occur near boundaries between competing entropic macrostates, consistent with transitions in the cytoskeletal machinery that controls growth-cone movement. More broadly, the framework proposes that robust biological patterning can emerge from microscopic variability when signaling networks operate near boundaries between competing behavioral states.","rel_num_authors":1,"rel_authors":[{"author_name":"William G Wadsworth","author_inst":"Robert Wood Johnson Medical School"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Tri-Modality Representation Learning for Molecular Property Prediction","rel_doi":"10.64898\/2026.09.22.753673","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.753673","rel_abs":"Accurate molecular property prediction requires effective molecular representations that can describe a molecule from multiple complementary perspectives. Existing deep learning approaches typically use SMILES strings, two-dimensional molecular graphs, or three-dimensional conformations as inputs. These representations capture different aspects of molecular information: SMILES encodes a sequential description, molecular graphs describe atom-bond connectivity, and 3D conformations provide spatial information from atomic coordinates. However, these modalities are often learned separately or merged with low effective fusion operations, which may not sufficiently capture interactions among sequential, topological, and geometric features. In this work, we propose Tri-Modality Cross-Attention (TMCA), a multimodal framework that integrates 1D SMILES, 2D molecular graphs, and 3D molecular conformations for molecular property prediction. TMCA uses pretrained encoders for the 1D and 3D branches, with a SMILES-based Transformer for the 1D branch and a recent conformation-aware pretrained model for the 3D branch. At the same time, a trainable 2D graph encoder is designed to support modality fusion. All the parameters from the pretrained models are frozen to make overall training more efficient. We evaluate TMCA on four datasets (i.e., BBBP, BACE, ClinTox, and HIV) from the MoleculeNet database for classification tasks and compare its performance with state-of-the-art competing approaches. Experimental results show that TMCA achieves the best overall performance, demonstrating the value of multi-modality integration for drug property prediction and the effectiveness of our cross-attention-based fusion strategy. The source code of TMCA is available at: https:\/\/github.com\/Ay-Zhao\/TMCA","rel_num_authors":2,"rel_authors":[{"author_name":"Anyin zhao","author_inst":"Case Western Reserve University"},{"author_name":"Jing Li","author_inst":"Case Western Reserve Univ."}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Structural variation in repeat elements is widespread in normal human tissues and in tumorigenesis","rel_doi":"10.64898\/2026.09.22.753313","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.753313","rel_abs":"Somatic mosaicism contributes to genomic variation, yet postzygotic structural variants remain under-characterized. We performed long- and short-read WGS from multiple individuals (n=47 normal tissues; n=168 samples) and identified mosaic structural variants in all individuals and germ layers, impacting a median 285.2 kb\/genome. Nearly half of breakpoints were independently validated, with tissue distributions reflecting both early and late developmental origins. Most mosaic variants were repeat-mediated and 8.3% overlapped functional elements, an enrichment compared to germline variants. To extend these analyses in samples where long-read sequencing is infeasible, we measured repeat alterations from short-read sequencing, recapitulating mosaic tissue-specific differences. We characterized tumor- and tissue- specific variation in repeats across 15 cancer types and found tumor-related repeat variation to be similar in scale to that of normal mosaic variation. Tracking repeat changes in cell-free DNA provided a noninvasive approach for tumor monitoring. Our analyses revealed widespread repeat-driven structural variation in health and disease.","rel_num_authors":25,"rel_authors":[{"author_name":"Akshaya V Annapragada","author_inst":"Johns Hopkins University"},{"author_name":"James White","author_inst":"Johns Hopkins University"},{"author_name":"Hope Orjuela","author_inst":"Johns Hopkins University"},{"author_name":"Adrianna Bartolomucci","author_inst":"Johns Hopkins University"},{"author_name":"Alice Eastman","author_inst":"Johns Hopkins University"},{"author_name":"Shashikant Koul","author_inst":"Johns Hopkins University"},{"author_name":"Kaui Lebarbenchon","author_inst":"Johns Hopkins University"},{"author_name":"Daniel Bruhm","author_inst":"Johns Hopkins University"},{"author_name":"Sarah Short","author_inst":"Johns Hopkins University"},{"author_name":"Keerti Boyapati","author_inst":"Johns Hopkins University"},{"author_name":"Noushin Niknafs","author_inst":"Johns Hopkins University"},{"author_name":"Carter Norton","author_inst":"Johns Hopkins University"},{"author_name":"Vishruth Girish","author_inst":"Johns Hopkins University"},{"author_name":"Nicholas Vulpescu","author_inst":"Johns Hopkins University"},{"author_name":"Sofia Velculescu","author_inst":"Johns Hopkins University"},{"author_name":"Julia Velculescu","author_inst":"Johns Hopkins University"},{"author_name":"Vilmos Adleff","author_inst":"Johns Hopkins University"},{"author_name":"Andrew Nelson","author_inst":"University of Minnesota"},{"author_name":"Zachariah Foda","author_inst":"Johns Hopkins University"},{"author_name":"Boris Winterhoff","author_inst":"University of Minnesota"},{"author_name":"Ronny Drapkin","author_inst":"Penn Medicine"},{"author_name":"Michael Schatz","author_inst":"Johns Hopkins University"},{"author_name":"Jillian Phallen","author_inst":"Johns Hopkins University"},{"author_name":"Robert Scharpf","author_inst":"Johns Hopkins University"},{"author_name":"Victor Velculescu","author_inst":"Johns Hopkins University"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"CAR T cell targeting of inflammatory myeloid progenitors in the bone marrow remodels border-associated macrophages and reverses cognitive aging","rel_doi":"10.64898\/2026.09.27.754777","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.27.754777","rel_abs":"Aging is associated with progressive neuroinflammation and cognitive decline, yet the cellular sources that sustain this process and whether they can be targeted peripherally remain unclear. Here, we identify inflammatory border-associated macrophages (BAMs) as key drivers of neuroinflammation in aging and show that their therapeutic and prophylactic elimination through intrathecal CAR T cell therapy restores cognitive performance in mouse models of aging and Alzheimer's disease. Furthermore, targeting of aged inflammatory bone marrow myeloid progenitors through either intravenous CAR T cells, which do not infiltrate the brain, or through transplantation of CAR T-treated progenitors is sufficient to reduce neuroinflammation and cognitive impairment. These findings reveal that bone marrow myeloid progenitors harbor a heritable inflammatory transcriptional state that is transmitted to their BAM progeny, driving neuroinflammation and cognitive deterioration, and conserved in human aging. Critically, this proinflammatory state is marked by the upregulation of surface proteins, enabling precise peripheral CAR T cell targeting of these progenitors for long-lasting therapeutic effects in cognitive aging.","rel_num_authors":15,"rel_authors":[{"author_name":"Alexander S Harris","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA"},{"author_name":"James A Rouse","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA"},{"author_name":"Guangran Guo","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA"},{"author_name":"Ines Fernandez-Maestre","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA"},{"author_name":"Sujay Pal","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA"},{"author_name":"Brian Oh","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA. Graduate Program in Genetics, Stony Brook University, Stony Brook, NY, USA."},{"author_name":"Shuxuan Li","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA"},{"author_name":"Wen Yi See","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA"},{"author_name":"Arianna Anderson","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA"},{"author_name":"Joseph Gewolb","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA"},{"author_name":"Matthew Soethout","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA"},{"author_name":"Jill Habel","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA"},{"author_name":"Rad Utama","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA"},{"author_name":"Christopher R Vakoc","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA"},{"author_name":"Corina Amor","author_inst":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA. Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Predicting the immediate and subsequent effects of commercials on product valuation using EEG and deep learning","rel_doi":"10.64898\/2026.09.22.751523","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.751523","rel_abs":"Neuromarketing mainly seeks to enhance the prediction of marketing stimuli success, such as commercials and movie trailers, by integrating neurophysiological measures with traditional behavioral measures. In the current study, the authors tested whether neural activity could predict consumer valuation and how preferences change after watching commercials, both immediately and over time. Participants (n=161) watched images of products followed by commercials advertising those products while their neural activity was recorded using electroencephalograph (EEG). They watched the product images again a week later without EEG recordings. Immediately after each stimulus exposure, participants stated their willingness to pay (WTP) for the product and how much they liked the commercial. Standard EEG measures showed weak and inconsistent relationships with behavior and yielded near-chance predictions. In contrast, deep learning models applied to the raw neural data achieved substantially higher predictive accuracy, successfully predicting both immediate and delayed WTP and ad liking. Importantly, the authors were able to successfully predict preferences for new participants and\/or new products the models were not trained on. However, accuracy declined as generalization demands increased. Moreover, prediction performance declined as value differences narrow. Together, these findings show that neural responses carry reliable and temporally persistent information about consumer valuation and its evolution over time.","rel_num_authors":4,"rel_authors":[{"author_name":"Inbal Gur Arie","author_inst":"Tel Aviv University"},{"author_name":"Daniel Andrew Atad","author_inst":"University of Haifa"},{"author_name":"Adam Hakim","author_inst":"Tel Aviv University"},{"author_name":"Dino Levy","author_inst":"Tel Aviv University"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Generation of a transgenic cephalopod","rel_doi":"10.64898\/2026.09.23.753964","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.23.753964","rel_abs":"Coleoid cephalopods (cuttlefish, octopus, and squid) are marine mollusks with elaborate nervous systems that support a diverse repertoire of complex behaviors. These include the neural control of the color, pattern, and texture of the skin, facilitating both adaptive camouflage and innate patterning that may reflect internal state. The development of transgenic cephalopods expressing fluorescent proteins, optogenetic actuators, and reporters of neural activity would contribute a new and important technology to cephalopod biology. The generation of transgenic cephalopods, however, has remained a major challenge. Here, we report the development of stable transgenic dwarf cuttlefish (Ascarosepion bandense) expressing ubiquitous nuclear-localized mScarlet, a red fluorescent protein. We evaluated multiple strategies for transgenesis, and established cuttlefish lines using both CRISPR and the transposons Sleeping Beauty and Minos. The stable expression of transgenes enabled live imaging of cell dynamics during embryonic development. The Minos transposon emerged as the most efficient transgenesis strategy and is adaptable to promoters and transgenes of choice. These strategies now enable the generation of diverse genetic tools for mechanistic studies of cephalopod biology.","rel_num_authors":14,"rel_authors":[{"author_name":"Tessa G. Montague","author_inst":"Columbia University"},{"author_name":"Connor J. Gibbons","author_inst":"Columbia University"},{"author_name":"G. Thomas Barlow","author_inst":"Columbia University"},{"author_name":"Elizaveta V. Bashkirova","author_inst":"Columbia University"},{"author_name":"Yilan Xu","author_inst":"Columbia University"},{"author_name":"Eva C. Castagna","author_inst":"Columbia University"},{"author_name":"Thomas J. Mungioli","author_inst":"Columbia University"},{"author_name":"Kelly A. Patrick","author_inst":"Columbia University"},{"author_name":"Adriana Nemes","author_inst":"Columbia University"},{"author_name":"Aalok Varma","author_inst":"University of California, San Diego"},{"author_name":"Loren L. Looger","author_inst":"University of California, San Diego"},{"author_name":"Caroline B. Albertin","author_inst":"Harvard University"},{"author_name":"Stavros Lomvardas","author_inst":"Columbia Unversity"},{"author_name":"Richard Axel","author_inst":"Columbia University"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Generation of a transgenic cephalopod","rel_doi":"10.64898\/2026.09.23.753964","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.23.753964","rel_abs":"Coleoid cephalopods (cuttlefish, octopus, and squid) are marine mollusks with elaborate nervous systems that support a diverse repertoire of complex behaviors. These include the neural control of the color, pattern, and texture of the skin, facilitating both adaptive camouflage and innate patterning that may reflect internal state. The development of transgenic cephalopods expressing fluorescent proteins, optogenetic actuators, and reporters of neural activity would contribute a new and important technology to cephalopod biology. The generation of transgenic cephalopods, however, has remained a major challenge. Here, we report the development of stable transgenic dwarf cuttlefish (Ascarosepion bandense) expressing ubiquitous nuclear-localized mScarlet, a red fluorescent protein. We evaluated multiple strategies for transgenesis, and established cuttlefish lines using both CRISPR and the transposons Sleeping Beauty and Minos. The stable expression of transgenes enabled live imaging of cell dynamics during embryonic development. The Minos transposon emerged as the most efficient transgenesis strategy and is adaptable to promoters and transgenes of choice. These strategies now enable the generation of diverse genetic tools for mechanistic studies of cephalopod biology.","rel_num_authors":14,"rel_authors":[{"author_name":"Tessa G. Montague","author_inst":"Columbia University"},{"author_name":"Connor J. Gibbons","author_inst":"Columbia University"},{"author_name":"G. Thomas Barlow","author_inst":"Columbia University"},{"author_name":"Elizaveta V. Bashkirova","author_inst":"Columbia University"},{"author_name":"Yilan Xu","author_inst":"Columbia University"},{"author_name":"Eva C. Castagna","author_inst":"Columbia University"},{"author_name":"Thomas J. Mungioli","author_inst":"Columbia University"},{"author_name":"Kelly A. Patrick","author_inst":"Columbia University"},{"author_name":"Adriana Nemes","author_inst":"Columbia University"},{"author_name":"Aalok Varma","author_inst":"University of California, San Diego"},{"author_name":"Loren L. Looger","author_inst":"University of California, San Diego"},{"author_name":"Caroline B. Albertin","author_inst":"Harvard University"},{"author_name":"Stavros Lomvardas","author_inst":"Columbia Unversity"},{"author_name":"Richard Axel","author_inst":"Columbia University"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"An immunosuppression imaging gauge prospectively predicts metastatic progression and immunotherapy resistance in breast cancer","rel_doi":"10.64898\/2026.09.22.753629","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.753629","rel_abs":"Systemic immunosuppression promotes metastatic progression and immunotherapy resistance, yet reliable biomarkers and noninvasive tools for longitudinal monitoring remain limited. Building on our finding that CXCL1+ neutrophil abundance in major organs inversely correlates with breast cancer-induced systemic immunosuppression, we developed an imaging-based immunosuppression gauge using CXCR2-expressing cells that mimic CXCL1+ neutrophil trafficking. Following intravenous administration, the biodistribution of engineered CXCR2-overexpressing mesenchymal stem cells or healthy donor neutrophils was imaged at 24 h, with greater organ accumulation indicating lower systemic immunosuppression. These living, distributed biosensors integrate chemokine signals across multiple organs and convert host immune status into an imageable biodistribution pattern. The gauge distinguished tumor aggressiveness at early disease stages, predicted metastatic risk before overt metastatic outgrowth, identified chemoimmunotherapy responders, and informed treatment selection through longitudinal immune monitoring. Mechanistically, nonaggressive tumors failed to induce substantial systemic immunosuppression and were effectively controlled by surgery alone, whereas aggressive tumors continued to drive immunosuppression after resection. Neoadjuvant chemoimmunotherapy produced superior outcomes to adjuvant treatment by intervening before profound immunosuppression developed and more effectively restoring antitumor immunity. Across cancer models, long-term survivors consistently showed resolution of systemic immunosuppression and restoration of immune activity to healthy-host levels. Thus, imaging systemic immunosuppression provides an early, longitudinal indicator of metastatic risk, therapeutic response, and treatment efficacy.","rel_num_authors":2,"rel_authors":[{"author_name":"Yuwei Zhang","author_inst":"Iowa State University"},{"author_name":"Jing Wang","author_inst":"Iowa State University"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Allochthony in stream food webs decreases with temperature across a subcontinental scale","rel_doi":"10.64898\/2026.09.27.752912","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.27.752912","rel_abs":"Riverine and riparian food webs are connected via 'allochthonous' resource flows from neighboring ecosystems. These resources, such as terrestrial leaf litter, contribute to benthic macroinvertebrate diets, supporting higher trophic levels. While allochthony occurs in streams globally, its sensitivity to broad environmental gradients remains poorly understood. We explored the drivers of allochthony across six river basins within the contiguous United States, including climate, stream size, and flow permanence. We used Bayesian mixing models to estimate macroinvertebrate dietary proportions in four functional feeding groups. Air temperature best predicted allochthony, with consumers relying less on allochthonous resources with increasing temperature. Our models indicate that macroinvertebrate diets become primarily autochthonous at approximately 15{degrees}C mean annual air temperature, with leaf litter-consuming shredders showing a slightly higher threshold for this shift. We also found increased allochthony in smaller, non-perennial streams. These findings highlight the complexity of stream allochthony and responses to multi-scale environmental factors.","rel_num_authors":17,"rel_authors":[{"author_name":"Kierstyn T Higgins","author_inst":"The Pennsylvania State University"},{"author_name":"Michael T Bogan","author_inst":"The University of Arizona"},{"author_name":"Albert Ruh\u00ed","author_inst":"University of California, Berkeley"},{"author_name":"Meryl C Mims","author_inst":"Virginia Polytechnic Institute and State University"},{"author_name":"Carla L Atkinson","author_inst":"University of Alabama"},{"author_name":"Michelle H Busch","author_inst":"Michigan State University Extension"},{"author_name":"Brian A Gill","author_inst":"The University of Arizona"},{"author_name":"Chelsea R Smith","author_inst":"University of Alabama"},{"author_name":"Thomas M Neeson","author_inst":"The University of Oklahoma"},{"author_name":"Yang Hong","author_inst":"The University of Oklahoma"},{"author_name":"Travis M Apgar","author_inst":"University of California, Berkeley"},{"author_name":"Arial J Shogren","author_inst":"University of Alabama"},{"author_name":"Megan C Malish","author_inst":"Michigan State University"},{"author_name":"Samuel C Silknetter","author_inst":"Virginia Polytechnic Institute and State Universityy"},{"author_name":"Rose M Mohammadi","author_inst":"University of California, Berkeley"},{"author_name":"Alice M Belskis","author_inst":"The Pennsylvania State University"},{"author_name":"Daniel C Allen","author_inst":"The Pennsylvania State University"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Allochthony in stream food webs decreases with temperature across a subcontinental scale","rel_doi":"10.64898\/2026.09.27.752912","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.27.752912","rel_abs":"Riverine and riparian food webs are connected via 'allochthonous' resource flows from neighboring ecosystems. These resources, such as terrestrial leaf litter, contribute to benthic macroinvertebrate diets, supporting higher trophic levels. While allochthony occurs in streams globally, its sensitivity to broad environmental gradients remains poorly understood. We explored the drivers of allochthony across six river basins within the contiguous United States, including climate, stream size, and flow permanence. We used Bayesian mixing models to estimate macroinvertebrate dietary proportions in four functional feeding groups. Air temperature best predicted allochthony, with consumers relying less on allochthonous resources with increasing temperature. Our models indicate that macroinvertebrate diets become primarily autochthonous at approximately 15{degrees}C mean annual air temperature, with leaf litter-consuming shredders showing a slightly higher threshold for this shift. We also found increased allochthony in smaller, non-perennial streams. These findings highlight the complexity of stream allochthony and responses to multi-scale environmental factors.","rel_num_authors":17,"rel_authors":[{"author_name":"Kierstyn T Higgins","author_inst":"The Pennsylvania State University"},{"author_name":"Michael T Bogan","author_inst":"The University of Arizona"},{"author_name":"Albert Ruh\u00ed","author_inst":"University of California, Berkeley"},{"author_name":"Meryl C Mims","author_inst":"Virginia Polytechnic Institute and State University"},{"author_name":"Carla L Atkinson","author_inst":"University of Alabama"},{"author_name":"Michelle H Busch","author_inst":"Michigan State University Extension"},{"author_name":"Brian A Gill","author_inst":"The University of Arizona"},{"author_name":"Chelsea R Smith","author_inst":"University of Alabama"},{"author_name":"Thomas M Neeson","author_inst":"The University of Oklahoma"},{"author_name":"Yang Hong","author_inst":"The University of Oklahoma"},{"author_name":"Travis M Apgar","author_inst":"University of California, Berkeley"},{"author_name":"Arial J Shogren","author_inst":"University of Alabama"},{"author_name":"Megan C Malish","author_inst":"Michigan State University"},{"author_name":"Samuel C Silknetter","author_inst":"Virginia Polytechnic Institute and State Universityy"},{"author_name":"Rose M Mohammadi","author_inst":"University of California, Berkeley"},{"author_name":"Alice M Belskis","author_inst":"The Pennsylvania State University"},{"author_name":"Daniel C Allen","author_inst":"The Pennsylvania State University"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Identification of alcohol use disorder-associated and ethanol-responsive proteins and candidate biomarkers using human cortical organoids","rel_doi":"10.64898\/2026.09.27.754852","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.27.754852","rel_abs":"Genome-wide association studies of alcohol use disorder (AUD) have identified >100 loci, yet the functional impact and the downstream molecular mechanisms are not well understood. As functional effectors of genes, proteins provide direct insight into disease mechanisms. However, most proteomic alterations in postmortem human brains of AUD likely reflect a combination of inherited susceptibility (AUD-associated), the consequences of alcohol exposure (ethanol-responsive), other environmental and lifestyle factors, as well as sample preparation. Here, we profiled the proteome of human microglia-containing cortical organoids derived from human induced pluripotent stem cells from individuals with AUD (n=11) and without (n=5), paired with or without intermittent ethanol exposure. To maximize statistical power, donors were selected based on high or low genetic liability for AUD as measured by polygenic scores. Among 8,952 proteins that passed quality control, 1,038 were AUD-associated and 718 were ethanol-responsive. AUD-associated proteins were enriched for neuronal signaling, immune, mitochondrial, and extracellular matrix pathways, whereas ethanol-responsive proteins were enriched for RNA processing, ribosome biogenesis, protein translation, vesicle trafficking, and membrane transport pathways. Twenty ethanol-responsive proteins were replicated in a postmortem human prefrontal cortex proteomic dataset. Using UK Biobank plasma proteomics data, we identified 26 candidate AUD-associated biomarkers and 9 candidate ethanol-responsive biomarkers. We also found that major proteomic variation was significantly correlated with AUD polygenic scores. Together, these findings reveal distinct proteomic signatures of inherited susceptibility to AUD and ethanol exposure, providing new insights into mechanisms underlying AUD and identifying candidate circulating biomarkers for further investigation.","rel_num_authors":14,"rel_authors":[{"author_name":"Xindi Li","author_inst":"Rutgers University"},{"author_name":"Andrew J Boreland","author_inst":"Rutgers University"},{"author_name":"Arpana Agrawal","author_inst":"Washington University School of Medicine"},{"author_name":"Chella Kamarajan","author_inst":"SUNY Downstate Health Sciences University, Brooklyn, NY 11203, USA"},{"author_name":"Paul Slesinger","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Jay A. Tischfield","author_inst":"Rutgers University"},{"author_name":"Yue Wang","author_inst":"Indiana University School of Medicine"},{"author_name":"Howard J. Edenberg","author_inst":"Indiana University School of Medicine"},{"author_name":"Tatiana Foroud","author_inst":"Indiana University School of Medicine"},{"author_name":"Yunlong Liu","author_inst":"Indiana University School of Medicine"},{"author_name":"Jubao Duan","author_inst":"University of Chicago"},{"author_name":"Ronald P Hart","author_inst":"Rutgers University"},{"author_name":"Zhiping P. Pang","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Dongbing Lai","author_inst":"Indiana University School of Medicine"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Identification of alcohol use disorder-associated and ethanol-responsive proteins and candidate biomarkers using human cortical organoids","rel_doi":"10.64898\/2026.09.27.754852","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.27.754852","rel_abs":"Genome-wide association studies of alcohol use disorder (AUD) have identified >100 loci, yet the functional impact and the downstream molecular mechanisms are not well understood. As functional effectors of genes, proteins provide direct insight into disease mechanisms. However, most proteomic alterations in postmortem human brains of AUD likely reflect a combination of inherited susceptibility (AUD-associated), the consequences of alcohol exposure (ethanol-responsive), other environmental and lifestyle factors, as well as sample preparation. Here, we profiled the proteome of human microglia-containing cortical organoids derived from human induced pluripotent stem cells from individuals with AUD (n=11) and without (n=5), paired with or without intermittent ethanol exposure. To maximize statistical power, donors were selected based on high or low genetic liability for AUD as measured by polygenic scores. Among 8,952 proteins that passed quality control, 1,038 were AUD-associated and 718 were ethanol-responsive. AUD-associated proteins were enriched for neuronal signaling, immune, mitochondrial, and extracellular matrix pathways, whereas ethanol-responsive proteins were enriched for RNA processing, ribosome biogenesis, protein translation, vesicle trafficking, and membrane transport pathways. Twenty ethanol-responsive proteins were replicated in a postmortem human prefrontal cortex proteomic dataset. Using UK Biobank plasma proteomics data, we identified 26 candidate AUD-associated biomarkers and 9 candidate ethanol-responsive biomarkers. We also found that major proteomic variation was significantly correlated with AUD polygenic scores. Together, these findings reveal distinct proteomic signatures of inherited susceptibility to AUD and ethanol exposure, providing new insights into mechanisms underlying AUD and identifying candidate circulating biomarkers for further investigation.","rel_num_authors":14,"rel_authors":[{"author_name":"Xindi Li","author_inst":"Rutgers University"},{"author_name":"Andrew J Boreland","author_inst":"Rutgers University"},{"author_name":"Arpana Agrawal","author_inst":"Washington University School of Medicine"},{"author_name":"Chella Kamarajan","author_inst":"SUNY Downstate Health Sciences University, Brooklyn, NY 11203, USA"},{"author_name":"Paul Slesinger","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Jay A. Tischfield","author_inst":"Rutgers University"},{"author_name":"Yue Wang","author_inst":"Indiana University School of Medicine"},{"author_name":"Howard J. Edenberg","author_inst":"Indiana University School of Medicine"},{"author_name":"Tatiana Foroud","author_inst":"Indiana University School of Medicine"},{"author_name":"Yunlong Liu","author_inst":"Indiana University School of Medicine"},{"author_name":"Jubao Duan","author_inst":"University of Chicago"},{"author_name":"Ronald P Hart","author_inst":"Rutgers University"},{"author_name":"Zhiping P. Pang","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Dongbing Lai","author_inst":"Indiana University School of Medicine"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Identification of alcohol use disorder-associated and ethanol-responsive proteins and candidate biomarkers using human cortical organoids","rel_doi":"10.64898\/2026.09.27.754852","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.27.754852","rel_abs":"Genome-wide association studies of alcohol use disorder (AUD) have identified >100 loci, yet the functional impact and the downstream molecular mechanisms are not well understood. As functional effectors of genes, proteins provide direct insight into disease mechanisms. However, most proteomic alterations in postmortem human brains of AUD likely reflect a combination of inherited susceptibility (AUD-associated), the consequences of alcohol exposure (ethanol-responsive), other environmental and lifestyle factors, as well as sample preparation. Here, we profiled the proteome of human microglia-containing cortical organoids derived from human induced pluripotent stem cells from individuals with AUD (n=11) and without (n=5), paired with or without intermittent ethanol exposure. To maximize statistical power, donors were selected based on high or low genetic liability for AUD as measured by polygenic scores. Among 8,952 proteins that passed quality control, 1,038 were AUD-associated and 718 were ethanol-responsive. AUD-associated proteins were enriched for neuronal signaling, immune, mitochondrial, and extracellular matrix pathways, whereas ethanol-responsive proteins were enriched for RNA processing, ribosome biogenesis, protein translation, vesicle trafficking, and membrane transport pathways. Twenty ethanol-responsive proteins were replicated in a postmortem human prefrontal cortex proteomic dataset. Using UK Biobank plasma proteomics data, we identified 26 candidate AUD-associated biomarkers and 9 candidate ethanol-responsive biomarkers. We also found that major proteomic variation was significantly correlated with AUD polygenic scores. Together, these findings reveal distinct proteomic signatures of inherited susceptibility to AUD and ethanol exposure, providing new insights into mechanisms underlying AUD and identifying candidate circulating biomarkers for further investigation.","rel_num_authors":14,"rel_authors":[{"author_name":"Xindi Li","author_inst":"Rutgers University"},{"author_name":"Andrew J Boreland","author_inst":"Rutgers University"},{"author_name":"Arpana Agrawal","author_inst":"Washington University School of Medicine"},{"author_name":"Chella Kamarajan","author_inst":"SUNY Downstate Health Sciences University, Brooklyn, NY 11203, USA"},{"author_name":"Paul Slesinger","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Jay A. Tischfield","author_inst":"Rutgers University"},{"author_name":"Yue Wang","author_inst":"Indiana University School of Medicine"},{"author_name":"Howard J. Edenberg","author_inst":"Indiana University School of Medicine"},{"author_name":"Tatiana Foroud","author_inst":"Indiana University School of Medicine"},{"author_name":"Yunlong Liu","author_inst":"Indiana University School of Medicine"},{"author_name":"Jubao Duan","author_inst":"University of Chicago"},{"author_name":"Ronald P Hart","author_inst":"Rutgers University"},{"author_name":"Zhiping P. Pang","author_inst":"Rutgers Robert Wood Johnson Medical School"},{"author_name":"Dongbing Lai","author_inst":"Indiana University School of Medicine"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"ST6GAL1 sialyltransferase promotes acinar cell survival and tissue regeneration during pancreatitis","rel_doi":"10.64898\/2026.09.26.754701","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.26.754701","rel_abs":"The role of aberrant glycosylation in pancreatitis remains an under-investigated area of research. Here, we determined that the ST6GAL1 sialyltransferase, which adds 2-6-linked sialic acids to N-glycoproteins, was upregulated in pancreatic tissues from patients with acute (AP) and chronic (CP) pancreatitis, and in mice with experimental AP. Within these tissues, ST6GAL1 was selectively expressed in acinar cells undergoing acinar to ductal metaplasia (ADM), a process whereby injured acinar cells de-differentiate and re-enter the cell cycle to enable tissue repair. To study the functional role of ST6GAL1 in pancreatitis, we used HPNE pancreatic epithelial cells with modulated ST6GAL1 expression, along with pancreatic organoids from mice with transgenic expression of ST6GAL1 (SC mice). In these models, ST6GAL1 activity promoted the activation of EGFR (a well-known ADM-driver), ERK, and AKT. ST6GAL1-expressing cells also displayed an ERK-dependent upregulation of the anti-apoptotic proteins, Mcl-1 and Bcl-xL, and impaired apoptotic signaling by the TNFR1 and Fas death receptors. Unbiased kinomics profiling revealed that ST6GAL1 induced the activation of many receptor tyrosine kinases associated with cell survival and proliferation (e.g., EGFR, PDGFR, MET). Furthermore, ST6GAL1 enhanced the survival and proliferation of cells exposed to stress-inducing conditions such as serum withdrawal. Based on these findings, we hypothesized that the pro-survival phenotype imparted by ST6GAL1 would facilitate tissue healing following a bout of pancreatitis. Accordingly, we induced AP in wild type and SC mice via L-arginine injection and found that SC mice had more rapid and efficient tissue repair, evidenced by accelerated restoration of the acini, diminished acinar apoptosis, and reduced immune cell infiltration. Together, these findings highlight a novel glycosylation-dependent mechanism that drives cell survival, positioning ST6GAL1 as a key adaptive mediator of pancreatic regeneration.","rel_num_authors":9,"rel_authors":[{"author_name":"Michael P Marciel","author_inst":"University of Alabama at Birmingham"},{"author_name":"Nikita Umakant Bhalerao","author_inst":"University of Alabama at Birmingham"},{"author_name":"Barnita Haldar","author_inst":"University of Alabama at Birmingham"},{"author_name":"Sejal S Shinde","author_inst":"University of Alabama at Birmingham"},{"author_name":"Joshua C Anderson","author_inst":"University of Alabama at Birmingham"},{"author_name":"Christopher D Willey","author_inst":"University of Alabama at Birmingham"},{"author_name":"Srikanth Iyer","author_inst":"University of Iowa"},{"author_name":"Vikas Dudeja","author_inst":"University of Iowa"},{"author_name":"Susan L Bellis","author_inst":"University of Alabama at Birmingham"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"ST6GAL1 sialyltransferase promotes acinar cell survival and tissue regeneration during pancreatitis","rel_doi":"10.64898\/2026.09.26.754701","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.26.754701","rel_abs":"The role of aberrant glycosylation in pancreatitis remains an under-investigated area of research. Here, we determined that the ST6GAL1 sialyltransferase, which adds 2-6-linked sialic acids to N-glycoproteins, was upregulated in pancreatic tissues from patients with acute (AP) and chronic (CP) pancreatitis, and in mice with experimental AP. Within these tissues, ST6GAL1 was selectively expressed in acinar cells undergoing acinar to ductal metaplasia (ADM), a process whereby injured acinar cells de-differentiate and re-enter the cell cycle to enable tissue repair. To study the functional role of ST6GAL1 in pancreatitis, we used HPNE pancreatic epithelial cells with modulated ST6GAL1 expression, along with pancreatic organoids from mice with transgenic expression of ST6GAL1 (SC mice). In these models, ST6GAL1 activity promoted the activation of EGFR (a well-known ADM-driver), ERK, and AKT. ST6GAL1-expressing cells also displayed an ERK-dependent upregulation of the anti-apoptotic proteins, Mcl-1 and Bcl-xL, and impaired apoptotic signaling by the TNFR1 and Fas death receptors. Unbiased kinomics profiling revealed that ST6GAL1 induced the activation of many receptor tyrosine kinases associated with cell survival and proliferation (e.g., EGFR, PDGFR, MET). Furthermore, ST6GAL1 enhanced the survival and proliferation of cells exposed to stress-inducing conditions such as serum withdrawal. Based on these findings, we hypothesized that the pro-survival phenotype imparted by ST6GAL1 would facilitate tissue healing following a bout of pancreatitis. Accordingly, we induced AP in wild type and SC mice via L-arginine injection and found that SC mice had more rapid and efficient tissue repair, evidenced by accelerated restoration of the acini, diminished acinar apoptosis, and reduced immune cell infiltration. Together, these findings highlight a novel glycosylation-dependent mechanism that drives cell survival, positioning ST6GAL1 as a key adaptive mediator of pancreatic regeneration.","rel_num_authors":9,"rel_authors":[{"author_name":"Michael P Marciel","author_inst":"University of Alabama at Birmingham"},{"author_name":"Nikita Umakant Bhalerao","author_inst":"University of Alabama at Birmingham"},{"author_name":"Barnita Haldar","author_inst":"University of Alabama at Birmingham"},{"author_name":"Sejal S Shinde","author_inst":"University of Alabama at Birmingham"},{"author_name":"Joshua C Anderson","author_inst":"University of Alabama at Birmingham"},{"author_name":"Christopher D Willey","author_inst":"University of Alabama at Birmingham"},{"author_name":"Srikanth Iyer","author_inst":"University of Iowa"},{"author_name":"Vikas Dudeja","author_inst":"University of Iowa"},{"author_name":"Susan L Bellis","author_inst":"University of Alabama at Birmingham"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Highly inducible transcription is impaired in cells lacking Cyclin T1 (CycT1) of the positive transcription factor b (P-TEFb).","rel_doi":"10.64898\/2026.09.26.754677","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.26.754677","rel_abs":"In eukaryotic cells, the positive transcription elongation factor b (P-TEFb) plays a critical role in the transition of RNAPII from the paused state to actively transcribing mode. Although three different cyclin (Cyc) T (CycT1, T2a, and T2b) interact with CDK9 to form functional P-TEFb, a majority of P-TEFb complexes are comprised of the CycT1 and CDK9. To analyze the role of the CycT1 subunit of P-TEFb on cellular transcription, we established HEK293T cells lacking CycT1 proteins (CycT1-KO cells). While no apparent growth defects were observed with CYcT1-KO cells, the level of CDK9 was decreased and no compensatory over-expression of CycT2 was observed, suggesting that the reduced level of functional P-TEFb complexes is sufficient for the normal cell growth. Reporter gene assays indicate that NF-kappaB-dependent transcription induced by PMA was impaired in CycT1-KO cells although the function of NF-kappaB (P65) per se was not affected. On the other hand, AP1-dependent transactivation induced by PMA was unaffected in CycT1-KO cells. Moreover, transcription stimulated by JQ1, a strong P-TEFb inducer, was reduced in CycT1-KO cells. Data of biochemical analysis indicate that P-TEFb with CycT1 (P-TEFb (CDK9:CycT1)) was efficiently released from 7SKsnRNP by JQ1 while P-TEFb (CDK9:CycT2) was not affected by JQ1. Transcriptome analysis indicated that the lack of CycT1 had a minor effect on the steady-state transcription. However, expression of JQ1-dependent genes was severely reduced in CycT1-KO cells. Interestingly, referring to gene expression profiles of 33 different types of cancer revealed that 11 out of 13 top JQ1-dependent genes were also highly upregulated in Pancreatic Adenocarcinoma. From these results, we conclude that although many genes can be regulated by both P-TEFb (CDK9:CycT1) and P-TEFb (CDK9:CycT2), CycT1 plays a critical role in regulating highly inducible genes, which are also aberrantly regulated in a particular type of cancer.","rel_num_authors":6,"rel_authors":[{"author_name":"Takuya Kajitani","author_inst":"University of California, San Francisco"},{"author_name":"Fang Huang","author_inst":"University of California, San Francisco"},{"author_name":"Kenji Nishiura","author_inst":"University of California, San Francisco"},{"author_name":"Dan Irwin","author_inst":"University of California, San Francisco"},{"author_name":"Aung Chein","author_inst":"University of California, San Francisco"},{"author_name":"Koh Fujinaga","author_inst":"UCSF"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Mutation Order and Selection Shape Intratumor Heterogeneity in Tumor Evolution","rel_doi":"10.64898\/2026.09.24.754285","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.24.754285","rel_abs":"Cancer progression often requires the accumulation of multiple driver mutations, yet the same set of drivers may be acquired in different orders. How these alternative mutation-order pathways jointly shape tumor clonal structure remains unclear. We develop a multitype branching-process model in which malignant transformation requires two driver mutations and distinguish malignant cells both by their mutation order and by the independent transformation event that founded their clone. Under a successive exponential approximation, we establish point-process limits for the pathway-specific clone-size processes and derive a closed-form expression for the limiting expected Simpson's index of the combined malignant population. When the two mutation orders produce malignant cells with the same net growth rate, the limiting index separates into effective pathway weights, determined by mutation rates and birth-death dynamics at preceding stages, and within-pathway concentration terms, determined by intermediate-to-malignant growth-rate ratios. This decomposition shows that a driver's effect on heterogeneity depends critically on when it is acquired. A strong driver acquired early expands the intermediate lineage and increases the supply of independent malignant founders, whereas the same driver acquired at the final transition strengthens the growth and age advantage of early-founded malignant clones. Under additive fitness effects, these counteracting mechanisms can produce a non-monotone relationship between selective advantage and clonal concentration. We further show that threshold-like non-additive fitness effects can generate highly concentrated malignant populations, while order-dependent terminal fitness leads the faster-growing pathway to dominate asymptotically. Together, these results reveal how mutation order, mutational accessibility, selection, and epistasis jointly determine lineage-level intratumor heterogeneity.","rel_num_authors":4,"rel_authors":[{"author_name":"Yichen Chu","author_inst":"The Chinese University of Hong Kong, Shenzhen"},{"author_name":"Xiaoxia Sheng","author_inst":"The Chinese University of Hong Kong, Shenzhen"},{"author_name":"Xuanming Zhang","author_inst":"University of Minnesota, Twin Cities"},{"author_name":"Zicheng Wang","author_inst":"The Chinese University of Hong Kong - Shenzhen"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Trustworthy super-resolution reconstruction across spatial omics modalities","rel_doi":"10.64898\/2026.09.25.754471","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.25.754471","rel_abs":"Sequencing-based spatial omics platforms provide scalable and unbiased profiling of transcriptomic, epigenomic, and isoform-resolved signals, but their spatial resolution remains limited because each capture unit aggregates molecular information from multiple cells. Existing computational enhancement methods reconstruct high-resolution spatial gene expression from spot-level data by integrating histology, but most are designed primarily for spatial transcriptomics, rely predominantly on histological features, and lack appropriate validation strategies, leading to overfitting, spurious spatial patterns, and limited reliability. Here we present spEnhance, a generalizable and trustworthy computational framework for super-resolution enhancement of spot-level spatial omics data. spEnhance integrates histological features with complementary molecular information, including single-cell RNA-seq references and gene co-expression structure, to reconstruct high-resolution spatial molecular profiles. To enable reliable model selection from a single tissue section, spEnhance introduces a count-splitting strategy that generates statistically independent training and validation sets from spot-level measurements. spEnhance further quantifies prediction reliability through predictive residuals, providing an interpretable proxy for spatially resolved uncertainty. Comprehensive benchmarking across multiple tissues, platforms, and molecular modalities demonstrates that spEnhance achieves state-of-the-art accuracy, recovers fine-grained tissue structures, mitigates overfitting, and provides calibrated reliability estimates. Beyond spatial transcriptomics, spEnhance extends to isoform-level, epigenomics, proteomic and metabolomic spatial omics. Collectively, spEnhance establishes a modality-general and trustworthy framework for enhancing spatial omics data, enabling more accurate and reliable investigation of spatially resolved molecular regulation.","rel_num_authors":7,"rel_authors":[{"author_name":"Menghan Li","author_inst":"Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, MA, United States"},{"author_name":"Xutao Wang","author_inst":"Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, 06030, CT, United States; Division of Infectious Diseases, Cent"},{"author_name":"Su Xu","author_inst":"Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, 06030, CT, United States"},{"author_name":"Yuxin Yin","author_inst":"Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, 06030, CT, United States"},{"author_name":"Dong Chen","author_inst":"Department of Pathology and Laboratory Medicine, University of Connecticut Health Center, Farmington, 06030, CT, United States"},{"author_name":"Xingche Guo","author_inst":"Department of Statistics, University of Connecticut, Storrs, 06269, CT, United States"},{"author_name":"Dongyuan Song","author_inst":"Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, 06030, CT, United States"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Spiral brain dynamics track the temporal unfolding of subjective intensity during the N,N-dimethyltryptamine experience","rel_doi":"10.64898\/2026.09.22.753116","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.753116","rel_abs":"Psychedelic compounds such as N,N-dimethyltryptamine (DMT) induce rapid and profound changes in conscious experience, requiring neuroimaging measures that capture how brain dynamics evolve across space and time. Emerging evidence suggests that rotational (vortex-like) dynamics may contribute to the coordination of large-scale neural activity. Here, we introduce two vorticity-based metrics; spiral vorticity (SV) and spatial spiral vorticity dispersion (SSVD), to quantify the rotational organization and spatial heterogeneity of large-scale cortical phase dynamics. Using fMRI data acquired under placebo and DMT in a within-subject design, we assessed these measures globally, across resting-state networks, and regionally to examine their relationship to subjective intensity. DMT increased SV and SSVD and reduced temporal irreversibility, indicating stronger rotational organization, greater spatial heterogeneity, and altered directional structure of cortical dynamics. Effects were non-uniform across functional systems, with the largest changes in default mode, visual, frontoparietal, and dorsal attention networks. Both vorticity measures tracked the temporal evolution of subjective intensity globally, while network-level analyses revealed spatially heterogeneous brain-experience coupling. Spatiotemporally resolved analyses further showed that the strongest reorganization of spiral dynamics emerged during offset and recovery rather than at peak subjective intensity. These findings identify spiral dynamics as a time-resolved neural signature of the DMT experience. By quantifying the rotational structure and spatial heterogeneity of cortical phase flow, vorticity-based measures provide a framework for linking large-scale brain dynamics to evolving subjective experience.","rel_num_authors":8,"rel_authors":[{"author_name":"Gabriela Sawicka","author_inst":"Pompeu Fabra University"},{"author_name":"Marian Mart\u00ednez-Mar\u00edn","author_inst":"Universitat Pompeu Fabra"},{"author_name":"Christopher Timmermann","author_inst":"University College London"},{"author_name":"Robin Carhart-Harris","author_inst":"UCSF"},{"author_name":"Morten L Kringelbach","author_inst":"University of Oxford"},{"author_name":"Yonatan Sanz Perl","author_inst":"Universitat Pompeu Fabra"},{"author_name":"Jakub Vohryzek","author_inst":"UNIVERSITAT POMPEU FABRA"},{"author_name":"Gustavo Deco","author_inst":"UPF"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Sensing the heart, seeing the world: Neural mechanisms of attentional allocation between interoception and exteroception","rel_doi":"10.64898\/2026.09.22.751480","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.751480","rel_abs":"Adaptive behaviour requires the flexible allocation of attention between sensory information arising from the external environment (exteroception) and signals originating within the body (interoception). While the neural mechanisms supporting exteroceptive attention have been extensively characterised, considerably less is known about how attention is allocated between competing interoceptive and exteroceptive sources of information. To address this question, we used functional magnetic resonance imaging (fMRI) to compare cardiac interoceptive attention during heartbeat counting with a carefully matched visual target counting task. Importantly, external visual input was held constant during both tasks, and behavioural accuracy and subjective confidence ratings for task difficulty did not differ significantly between conditions. This provided a controlled comparison in which attention was selectively allocated between internal bodily signals and external sensory information. Cardiac interoceptive and visual exteroceptive attention engaged largely distinct cortical networks. Cardiac interoceptive attention recruited a distributed insula-centred network supporting interoceptive processing and cognitive control. In contrast, visual target counting engaged a dorsal frontoparietal attention network and selectively shaped activity within visual cortex, enhancing regions representing task-relevant central visual information while suppressing regions representing task-irrelevant peripheral visual information. Despite this functional segregation, activity within these systems was not independent of where attention was directed. Exteroceptive attention suppressed activity within the posterior insula, suggesting down-regulation of interoceptive processing. Conversely, peripheral visual regions remained suppressed during interoceptive attention, suggesting that externally directed sensory processing is also down-regulated when attention is directed towards the body. More accurate heartbeat counting was additionally associated with less engagement of the right inferior parietal lobule, consistent with reduced bottom-up attentional capture by external sensory information. Together, these findings are consistent with competitive allocation of attentional resources between neural systems supporting internal bodily signals and external sensory information. More broadly, they provide a system-level account of how the human brain flexibly balances internal and external information during goal-directed behaviour.","rel_num_authors":4,"rel_authors":[{"author_name":"Sukhbinder Kumar","author_inst":"Department of Neurosurgery, University of Iowa, Iowa City, IA, 52242, USA."},{"author_name":"Joel S Winston","author_inst":"Kings College London, London, WC2R 2LS, United Kingdom"},{"author_name":"Hugo D Critchley","author_inst":"Department of Neuroscience, Brighton and Sussex Medical School, University of Brighton and University of Sussex, Brighton, BN1 9PX, United Kingdom."},{"author_name":"Timothy D Griffiths","author_inst":"Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom."}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Reciprocal control of the stomach and intestine by viscerosensory neurons in caudal brainstem","rel_doi":"10.64898\/2026.09.21.753299","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.753299","rel_abs":"Digestion requires precisely timed transit of food through the gastrointestinal tract. Here we show that emptying of food from the stomach occurs in discrete pulses, separated by pauses that allow the proximal duodenum to clear before the next bolus arrives. By combining X-ray fluoroscopy of the gut with calcium imaging of the brainstem, we identify a population of neurons defined by expression of neuropeptide FF (NPFF) that tracks these duodenal dynamics. Stimulation of NPFF neurons induces a coordinated response that inhibits gastric emptying and accelerates intestinal transit, thereby clearing the proximal intestine for the next bolus of food. These neurons also bidirectionally control food intake through cholinergic signaling in the gut. These findings reveal a mechanism by which brainstem transforms the sensory detection of nutrients in the duodenum into the opposing control of the stomach and intestine. They also establish an experimental approach for dissecting gut-brain signaling in behaving animals.","rel_num_authors":15,"rel_authors":[{"author_name":"Naz Dundar","author_inst":"UCSF"},{"author_name":"Ilayda Alkislar","author_inst":"UCSF"},{"author_name":"Brooke C Jarvie","author_inst":"University of California, San Francisco"},{"author_name":"Ho Namkung","author_inst":"UCSF"},{"author_name":"Kathryn Xie","author_inst":"UCSF"},{"author_name":"Mahekdeep Kaur","author_inst":"UCSF"},{"author_name":"Queenie Li","author_inst":"UCSF"},{"author_name":"Anagh S Ravi","author_inst":"UCSF"},{"author_name":"Alejandro Lopez","author_inst":"UCSF"},{"author_name":"Antionette Spina","author_inst":"UCSF"},{"author_name":"Longhui Qui","author_inst":"UCSF"},{"author_name":"Truong Ly","author_inst":"University of California, San Francisco"},{"author_name":"Jun Oh","author_inst":"UCSF"},{"author_name":"Kevin Yackle","author_inst":"University of California San Francisco"},{"author_name":"Zachary A Knight","author_inst":"University of California, San Francisco"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Degraded neural representations foreshadow failures of sustained attention","rel_doi":"10.64898\/2026.09.21.753248","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.753248","rel_abs":"Attention prioritizes relevant information from the environment, but does not do so consistently over time. Instead, we sometimes experience poor attentional states which are characterized by a higher degree of performance failures, or \"lapses.\" The source of these lapses--whether they arise from attentional disengagement, failures of attentional selection, or simply failures of response control--is not clear. This study tests whether the strength of neural representations differs as a function of both attentional selection and modulation over time. We recorded electroencephalography (EEG) data while participants performed a sustained attention task requiring the selection of task-relevant items and withholding of responses to rare targets. Results show that relevant items receive prioritized processing in brain signals, as measured with EEG decoding. Yet, their neural representational fidelity weakens under poor sustained attentional states, foreshadowing upcoming behavioral failures. These findings support a neural basis of disengagement during poor attentional states, suggesting that lapses may arise from a decoupling of brain activity from task processing. Finally, pre-item representational strength predicted memory success for targets, suggesting that neural fidelity indexes an encoding-ready state. Results suggest that the quality of neural representations is affected by ongoing attention and plays a key role in processing and memory.","rel_num_authors":5,"rel_authors":[{"author_name":"Anna Corriveau","author_inst":"The University of Chicago"},{"author_name":"Dongfang Tian","author_inst":"University of Chicago"},{"author_name":"Matthieu Chidharom","author_inst":"University of Chicago"},{"author_name":"Edward  K. Vogel","author_inst":"University of Chicago Department of Psychology"},{"author_name":"Monica D. Rosenberg","author_inst":"University of Chicago"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Decoding natural scenes from patterned optogenetic responses in mouse visual cortex","rel_doi":"10.64898\/2026.09.21.753135","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.753135","rel_abs":"A central challenge in developing visual cortical prostheses is to determine how visual stimuli should be transformed into effective patterns of cortical stimulation. Although advances in stimulation technologies, including optogenetics, provide increasingly precise control over cortical activity, it remains unclear whether artificially evoked activity can reproduce the information content of naturally evoked visual representations. Here we establish a quantitative framework for evaluating visual encoding strategies by decoding cortical responses evoked by natural vision and patterned optogenetic stimulation. We developed a novel dual-modal paradigm in awake mice to bridge the gap between endogenous photostimulation and artificial network driving. By co-expressing the high-performance calcium indicator GCaMP6s and the red-shifted, ultra-sensitive opsin rsChRmine-oScarlet in the primary visual cortex (V1), we successfully translated dynamic natural movie frames into patterned, spatiotemporal optogenetic stimulation. Quantitative comparisons of macro-scale dynamics demonstrated that this patterned optogenetic injection evokes cortical states highly comparable and representationally aligned with those driven by actual visual photostimulation. To systematically evaluate the fidelity of these responses, we developed STAR, a deep learning model featuring spatial and temporal attention mechanisms, and successfully reconstructed the frames of natural movies from V1 signals under both experimental modalities. Collectively, our results demonstrate that complex sensory information can be both naturally encoded and synthetically injected into V1 circuits with high decoding fidelity. This work provides an empirical and computational proof-of-concept for intelligent, closed-loop biomimetic encoders, establishing a robust framework for next-generation cortical visual neuroprostheses and bidirectional brain-machine interfaces.","rel_num_authors":10,"rel_authors":[{"author_name":"Shanshan Jia","author_inst":"The Hong Kong Polytechnic University"},{"author_name":"Tianyu Xin","author_inst":"Chinese Institute for Brain Research"},{"author_name":"Chunpeng Li","author_inst":"Chinese Institute for Brain Research"},{"author_name":"Haofu Ji","author_inst":"Peking University"},{"author_name":"Ruixiang Wu","author_inst":"Chinese Institute for Brain Research"},{"author_name":"Shu Wang","author_inst":"Chinese Institute for Brain Research"},{"author_name":"Qingchun Guo","author_inst":"Chinese Institute for Brain Research"},{"author_name":"Zhaofei Yu","author_inst":"Peking University"},{"author_name":"Jian K. Liu","author_inst":"University of Birmingham"},{"author_name":"Ya-tang Li","author_inst":"Chinese Institute for Brain Research"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"\u03b1-Synuclein Seeding in Dopaminergic Neurons Transplanted into the Putamen of Parkinson's Disease Patients","rel_doi":"10.64898\/2026.09.22.751740","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.751740","rel_abs":"Healthy embryonic neurons grafted into the putamen of Parkinson's disease (PD) patients start to develop Lewy pathology 10 years after transplantation. It remains unclear whether this pathology is initiated by the spread of host-derived -synuclein (syn) aggregates which seed aggregation in the grafted cells or arises independently from a hostile PD environment (e.g., chronic inflammation). To distinguish these possibilities, we identified syn seeding sites in the human brain using a multiplex in situ seed immunodetection (isSID) assay. In PD and dementia with Lewy bodies (DLB), isSID labeled a subset of Lewy pathology (LP) as puncta along neurites and within inclusions. In multiple system atrophy (MSA), isSID labeled Papp-Lantos bodies and microglia. In progressive supranuclear palsy (PSP), isSID labeled tufted astrocytes. isSID labeled neuromelanin in the substantia nigra independent of diagnosis. In 16- and 27-year intraputamenal neuronal grafts, isSID labeled within and proximal to Lewy pathology, as well as outside the grafted tissue. Younger grafts (18 months and 4 years) lacked Lewy pathology. In the 18-month graft, isSID labeled grafted neurons; at 4 years, isSID was confined to amorphous deposits in the graft and was absent from tyrosine hydroxylase-positive grafted neurons. In conclusion, syn seeding is detectable in grafted neurons before and during LP formation. Because seeding accompanies melanization, but is not explained by melanization alone, these findings support host-derived seeds as a contributor to graft pathology.","rel_num_authors":10,"rel_authors":[{"author_name":"Jayda B. Duvernay","author_inst":"Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA"},{"author_name":"Bryan A Killinger","author_inst":"Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA"},{"author_name":"Solji G Choi","author_inst":"Department of Pathology, University of California San Diego, San Diego, CA, USA"},{"author_name":"Tyler Tittle","author_inst":"Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA"},{"author_name":"Atousa Bahrami","author_inst":"Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA"},{"author_name":"Marla E Tharp","author_inst":"Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA"},{"author_name":"Gabriela Mercado","author_inst":"Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA."},{"author_name":"Yaping Chu","author_inst":"ASU-Banner Neurodegenerative Disease Research Center and School of Life Sciences, Arizona State University, Tempe, AZ, USA"},{"author_name":"Patrik Brundin","author_inst":"Roche Pharma Research and Early Development (pRED), Roche Innovation Center, F. Hoffmann-La Roche, Basel, Switzerland"},{"author_name":"Jeffrey H Kordower","author_inst":"ASU-Banner Neurodegenerative Disease Research Center and School of Life Sciences, Arizona State University, Tempe, AZ, USA"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"\u03b1-Synuclein Seeding in Dopaminergic Neurons Transplanted into the Putamen of Parkinson's Disease Patients","rel_doi":"10.64898\/2026.09.22.751740","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.751740","rel_abs":"Healthy embryonic neurons grafted into the putamen of Parkinson's disease (PD) patients start to develop Lewy pathology 10 years after transplantation. It remains unclear whether this pathology is initiated by the spread of host-derived -synuclein (syn) aggregates which seed aggregation in the grafted cells or arises independently from a hostile PD environment (e.g., chronic inflammation). To distinguish these possibilities, we identified syn seeding sites in the human brain using a multiplex in situ seed immunodetection (isSID) assay. In PD and dementia with Lewy bodies (DLB), isSID labeled a subset of Lewy pathology (LP) as puncta along neurites and within inclusions. In multiple system atrophy (MSA), isSID labeled Papp-Lantos bodies and microglia. In progressive supranuclear palsy (PSP), isSID labeled tufted astrocytes. isSID labeled neuromelanin in the substantia nigra independent of diagnosis. In 16- and 27-year intraputamenal neuronal grafts, isSID labeled within and proximal to Lewy pathology, as well as outside the grafted tissue. Younger grafts (18 months and 4 years) lacked Lewy pathology. In the 18-month graft, isSID labeled grafted neurons; at 4 years, isSID was confined to amorphous deposits in the graft and was absent from tyrosine hydroxylase-positive grafted neurons. In conclusion, syn seeding is detectable in grafted neurons before and during LP formation. Because seeding accompanies melanization, but is not explained by melanization alone, these findings support host-derived seeds as a contributor to graft pathology.","rel_num_authors":10,"rel_authors":[{"author_name":"Jayda B. Duvernay","author_inst":"Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA"},{"author_name":"Bryan A Killinger","author_inst":"Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA"},{"author_name":"Solji G Choi","author_inst":"Department of Pathology, University of California San Diego, San Diego, CA, USA"},{"author_name":"Tyler Tittle","author_inst":"Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA"},{"author_name":"Atousa Bahrami","author_inst":"Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA"},{"author_name":"Marla E Tharp","author_inst":"Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA"},{"author_name":"Gabriela Mercado","author_inst":"Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA."},{"author_name":"Yaping Chu","author_inst":"ASU-Banner Neurodegenerative Disease Research Center and School of Life Sciences, Arizona State University, Tempe, AZ, USA"},{"author_name":"Patrik Brundin","author_inst":"Roche Pharma Research and Early Development (pRED), Roche Innovation Center, F. Hoffmann-La Roche, Basel, Switzerland"},{"author_name":"Jeffrey H Kordower","author_inst":"ASU-Banner Neurodegenerative Disease Research Center and School of Life Sciences, Arizona State University, Tempe, AZ, USA"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"The p53-p21-Cyclin D2 regulatory axis drives metabolic reprogramming and a distinct senescent macrophage senotype during aging and MASLD.","rel_doi":"10.64898\/2026.09.22.753597","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.753597","rel_abs":"Aging drives chronic disease in part through senescent cells, including macrophages, which fuel inflammation. Senescent macrophages are functionally heterogeneous: canonical p16-high macrophages promote tumorigenesis or, in other contexts, disease tolerance, whereas we previously identified a distinct p21-high, p16-low senotype that drives metabolic dysfunction-associated steatotic liver disease (MASLD). The molecular basis of this senotype has remained undefined. Using genetic and multi-omic approaches, we show that a p53-p21-dependent program actively represses p16 and is required for senescent macrophage viability. We identify Cyclin D2 as a non-canonical downstream effector that redistributes from the nucleus to mitochondria and lipid droplets, where it partners with MIC60 to drive metabolic reprogramming and modulates AKT1-mTORC1 signaling that sustains the SASP. Cyclin D2-p21 double-positive macrophages accumulate with aging and MASLD in mice and in human liver cirrhosis, and can be selectively depleted by senolytic treatment. Together, these findings define a druggable p53-p21-Cyclin D2 axis that specifies macrophage senotype.","rel_num_authors":30,"rel_authors":[{"author_name":"Grasiela Torres","author_inst":"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA."},{"author_name":"Ivan A. Salladay-Perez","author_inst":"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA."},{"author_name":"Christina Y. Deng","author_inst":"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA."},{"author_name":"Itzetl Avila","author_inst":"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA."},{"author_name":"Yennifer Delgado","author_inst":"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA."},{"author_name":"Gregory Tong","author_inst":"Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA"},{"author_name":"Jesus Munoz-Estrada","author_inst":"Department of Computational Biomedicine, Cedars Sinai Medical Center, Los Angeles, CA, USA."},{"author_name":"Lizeth Estrada","author_inst":"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA."},{"author_name":"Anika Dhingra","author_inst":"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA."},{"author_name":"Wesley R. Armstrong","author_inst":"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA."},{"author_name":"Aishini Singh","author_inst":"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA."},{"author_name":"Isabella Cooper","author_inst":"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA."},{"author_name":"Eduardo Enriquez","author_inst":"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA."},{"author_name":"Prashant Kaushal","author_inst":"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA."},{"author_name":"Jocelyn Ni","author_inst":"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA."},{"author_name":"Kushan Chowdhury","author_inst":"Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los A"},{"author_name":"Calvin Pan","author_inst":"Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los A"},{"author_name":"Linsey Stiles","author_inst":"Department of Medicine, Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA."},{"author_name":"Cristiane Beninca","author_inst":"University of California, Los Angeles (UCLA)"},{"author_name":"Simon T. Hui","author_inst":"University of California, Los Angeles"},{"author_name":"Abigail Krall","author_inst":"UCLA"},{"author_name":"Heather Christofk","author_inst":"UCLA"},{"author_name":"Aldons Jake Lusis","author_inst":"UCLA"},{"author_name":"Timothy E. O'Sullivan","author_inst":"UCLA"},{"author_name":"Jesse G. Meyer","author_inst":"Department of Computational Biomedicine, Cedars Sinai Medical Center, Los Angeles, CA, USA."},{"author_name":"Rajat Singh","author_inst":"Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los A"},{"author_name":"Valerie A. Tornini","author_inst":"UCLA"},{"author_name":"Orian S. Shirihai","author_inst":"UCLA"},{"author_name":"Mehdi Bouhaddou","author_inst":"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA."},{"author_name":"Anthony J. Covarrubias","author_inst":"Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA."}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Attention Across Scales: From Individual Variation to Social Hierarchies and Brain Networks in Semi-Free-Ranging Macaques","rel_doi":"10.64898\/2026.09.21.752444","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.752444","rel_abs":"Attention is a fundamental brain function supporting perception, decision-making, and social behavior, and its dysfunction profoundly impairs daily life. It is both dynamic and stable, varying across observations and individuals, changing across the lifespan, and being shaped by social and environmental experience. Yet capturing this complexity remains a central challenge in neuroscience. Here, we integrated longitudinal behavioral assessments of semi-free-ranging macaques living in naturalistic social groups with resting-state fMRI. We quantified performance across days, ages, and social hierarchies and related it to intrinsic brain organization. Distinct attentional phenotypes emerged, including individuals with reduced attentional control. Performance followed an inverted-U lifespan trajectory, improving from childhood to adulthood before declining. Social status modulated attentional performance. Critically, nonlinear lifespan trajectories and associations with individual attentional differences were most clearly expressed in frontoparietal connectivity. Together, these findings reveal how sustained attention is organized across scales, providing a biological framework for its individual diversity, social modulation, and neural basis.","rel_num_authors":5,"rel_authors":[{"author_name":"Simona Vaitekunaite","author_inst":"University of Geneva"},{"author_name":"Sarah Silvere","author_inst":"University of Strasbourg"},{"author_name":"Helene Meunier","author_inst":"LNCA: Laboratoire de neurosciences cognitives et adaptatives"},{"author_name":"Sebastien Ballesta","author_inst":"University of Strasbourg"},{"author_name":"Ilaria Sani","author_inst":"University of Geneva"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Aggregated Low-Density Lipoprotein (agLDL) Triggers Inflammatory Responses in Macrophages through Toll-Like Receptor 4 (TLR4)","rel_doi":"10.64898\/2026.09.24.754244","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.24.754244","rel_abs":"Atherosclerosis is a chronic inflammatory disease primarily initiated by the sub-endothelial retention and modification of low-density lipoproteins (LDL), such as oxidation and aggregation. While oxidized LDL (oxLDL) exists in atherosclerotic lesions, aggregated lipoproteins are also prominent. Aggregated LDL (agLDL), for instance, is viewed as a passive substrate for macrophages to uptake and form foam cells. Recent studies show that agLDL, through toll-like receptor 4 (TLR4), induces formation of lysosomal synapses, which drive agLDL degradation by macrophages, a process described as \"digestive exophagy\". As TLR4 is one of the pattern-recognition receptors for inflammatory responses in macrophages, we postulated that agLDL could initiate macrophage inflammation along with lipoprotein degradation\/internalization, thereby contributing to a low degree of chronic inflammation in atherosclerosis. Here, we demonstrate that agLDL directly activates the canonical NF-{kappa}B signaling pathway and triggers a pro-inflammatory transcriptional program through TLR4, which closely resembles classical lipopolysaccharide (LPS)-mediated TLR4 activation. In addition, agLDL also activates TLR4 to generate inflammatory macrophages that recruit immune cells, a key process in the development of atherosclerotic lesions. Our findings therefore support a novel dual functionality of agLDL: a lipid donor and an inflammatory agonist. This establishes the agLDL-TLR4-NF-{kappa}B axis as a direct link between LDL aggregation in the intima and the initiation of sterile vascular inflammation. It also strengthens the understanding of the role of digestive exophagy with new mechanistic details.","rel_num_authors":8,"rel_authors":[{"author_name":"Xiaohui Zha","author_inst":"Ottawa Hospital Research Institute"},{"author_name":"Samia Kadri","author_inst":"Ottawa Health Research Institute"},{"author_name":"Zeina Salloum","author_inst":"Ottawa Hospital Research Institute"},{"author_name":"Judy Chen","author_inst":"University of Ottawa"},{"author_name":"Cheng-I J. Ma","author_inst":"Cornell University Weill Cornell Medicine"},{"author_name":"Dajiang Zhang","author_inst":"Ottawa Hospital Research Institute"},{"author_name":"Thomas Lagace","author_inst":"Ottawa Heart Institute"},{"author_name":"Frederick  R. Maxfield","author_inst":"Cornell University Weill Cornell Medicine"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Aggregated Low-Density Lipoprotein (agLDL) Triggers Inflammatory Responses in Macrophages through Toll-Like Receptor 4 (TLR4)","rel_doi":"10.64898\/2026.09.24.754244","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.24.754244","rel_abs":"Atherosclerosis is a chronic inflammatory disease primarily initiated by the sub-endothelial retention and modification of low-density lipoproteins (LDL), such as oxidation and aggregation. While oxidized LDL (oxLDL) exists in atherosclerotic lesions, aggregated lipoproteins are also prominent. Aggregated LDL (agLDL), for instance, is viewed as a passive substrate for macrophages to uptake and form foam cells. Recent studies show that agLDL, through toll-like receptor 4 (TLR4), induces formation of lysosomal synapses, which drive agLDL degradation by macrophages, a process described as \"digestive exophagy\". As TLR4 is one of the pattern-recognition receptors for inflammatory responses in macrophages, we postulated that agLDL could initiate macrophage inflammation along with lipoprotein degradation\/internalization, thereby contributing to a low degree of chronic inflammation in atherosclerosis. Here, we demonstrate that agLDL directly activates the canonical NF-{kappa}B signaling pathway and triggers a pro-inflammatory transcriptional program through TLR4, which closely resembles classical lipopolysaccharide (LPS)-mediated TLR4 activation. In addition, agLDL also activates TLR4 to generate inflammatory macrophages that recruit immune cells, a key process in the development of atherosclerotic lesions. Our findings therefore support a novel dual functionality of agLDL: a lipid donor and an inflammatory agonist. This establishes the agLDL-TLR4-NF-{kappa}B axis as a direct link between LDL aggregation in the intima and the initiation of sterile vascular inflammation. It also strengthens the understanding of the role of digestive exophagy with new mechanistic details.","rel_num_authors":8,"rel_authors":[{"author_name":"Xiaohui Zha","author_inst":"Ottawa Hospital Research Institute"},{"author_name":"Samia Kadri","author_inst":"Ottawa Health Research Institute"},{"author_name":"Zeina Salloum","author_inst":"Ottawa Hospital Research Institute"},{"author_name":"Judy Chen","author_inst":"University of Ottawa"},{"author_name":"Cheng-I J. Ma","author_inst":"Cornell University Weill Cornell Medicine"},{"author_name":"Dajiang Zhang","author_inst":"Ottawa Hospital Research Institute"},{"author_name":"Thomas Lagace","author_inst":"Ottawa Heart Institute"},{"author_name":"Frederick  R. Maxfield","author_inst":"Cornell University Weill Cornell Medicine"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Targeting ALCAT1 Ameliorates Cardiomyopathy in Barth Syndrome","rel_doi":"10.64898\/2026.09.24.754267","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.24.754267","rel_abs":"Background: Barth syndrome (BTHS) is an X-linked mitochondrial disorder caused by loss-of-function mutations in TAFAZZIN (TAZ), resulting in defective cardiolipin (CL) remodeling, cardiomyopathy, and premature death. The mechanisms linking TAZ deficiency to impaired mitochondrial quality control remain incompletely understood, and there are no disease-modifying therapies available for BTHS. Here, we investigated the role of Acyl-CoA Lysocardiolipin Acyltransferase-1 (ALCAT1), a stress-inducible phospholipid-remodeling enzyme, in BTHS cardiomyopathy. Methods: Inducible TAZ knockdown (TAZKD) and cardiomyocyte-specific TAZ knockout (TAZcKO) mice were used to determine the effects of genetic ALCAT1 deletion or pharmacological inhibition with Juvenatin, a highly selective small molecule ALCAT1 inhibitor. Cardiac function, exercise capacity, mitochondrial function, lipid remodeling, lysosomal function, and mitophagic flux were assessed. Results: ALCAT1 was markedly upregulated in TAZ-deficient hearts. Genetic ALCAT1 deletion attenuated cardiac dysfunction in TAZKD mice. Juvenatin similarly improved cardiac function in TAZKD mice and reversed established cardiomyopathy in TAZcKO mice. Genetic or pharmacological ALCAT1 inhibition improved mitochondrial ultrastructure and respiration and reduced mitochondrial oxidative stress. These benefits occurred without correcting the characteristic CL abnormalities caused by TAZ deficiency. Instead, ALCAT1 deletion or inhibition corrected pathological phosphatidylinositol remodeling, normalized phosphoinositide signaling, and restored lysosomal function and mitophagic flux, leading to improved mitochondrial quality control in TAZ-deficient cells. Conclusions: ALCAT1 contributes to BTHS cardiomyopathy through a CL-independent pathway involving dysregulated phosphatidylinositol\/phosphoinositide signaling, lysosomal dysfunction, and impaired mitophagy. Genetic and pharmacological targeting of ALCAT1 restores mitochondrial and cardiac function despite persistent CL abnormalities, establishing ALCAT1 as a promising disease-modifying therapeutic target for BTHS.","rel_num_authors":5,"rel_authors":[{"author_name":"Jun Zhang","author_inst":"The University of Texas Health Science Center at San Antonio"},{"author_name":"Qianqian Ye","author_inst":"University of California Irvine"},{"author_name":"Xi Fang","author_inst":"University of California San Diego"},{"author_name":"Wendong Huang","author_inst":"City of Hope Beckman Research Institute"},{"author_name":"Yuguang Shi","author_inst":"The University of Texas Health Science Center at San Antonio"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"A Novel PD-L1 Splice Isoform Modulates \u03b2 Cell Communication in Response to Interferon Signaling","rel_doi":"10.64898\/2026.09.25.754099","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.25.754099","rel_abs":"{beta} cell expression of the immune checkpoint ligand PD-L1 (encoded by CD274) limits autoimmune {beta} cell destruction in type 1 diabetes (T1D). {beta} cell display PD-L1 not only at the cell surface but also secreted on extracellular vesicles (EVs), which bind PD-1 and restrain CD8+ T cell activation. {beta} cell IFN signaling is an early driver of T1D pathogenesis, yet the mechanisms linking IFN signaling to the fate of PD-L1 protein remain undefined. Here, we identify an IFN- and coxsackievirus-inducible alternatively spliced isoform of PD-L1, PD-L1{Delta}3, lacking cassette exon 3 and generated in human {beta} cells and islets in response to IFN signaling or viral infection. PD-L1{Delta}3 transcripts are elevated in islets from donors with single autoantibody positivity (AAB+) and T1D. Unlike full-length PD-L1, which localizes to the plasma membrane, PD-L1{Delta}3 is retained intracellularly and loses the capacity to bind PD-1. Functionally, PD-L1{Delta}3 fails to suppress CD8+ and CD4+ T cell proliferation, activation, and cytotoxic cytokine release, and is not efficiently sorted into EVs. Convergently, a germline CD274 splice-site variant (c.682+1G>A) found in siblings with neonatal T1D yields a protein with the same intracellular retention, reduced {beta} cell PD-1 binding, and reduced {beta} cell and circulating EV PD-L1. Together these findings define PD-L1{Delta}3 as an IFN-induced splice variant that diverts PD-L1 away from its immunoregulatory, EV-competent form, revealing a post-transcriptional axis that shapes {beta} cell immune communication.","rel_num_authors":15,"rel_authors":[{"author_name":"Chaitra Rao","author_inst":"Indiana University School of Medicine"},{"author_name":"Fei Huang","author_inst":"The University of Chicago"},{"author_name":"Saptarshi Roy","author_inst":"Indiana University School of Medicine"},{"author_name":"Matthew C Austin","author_inst":"Indiana University School of Medicine"},{"author_name":"Matthew B Johnson","author_inst":"University of Exeter"},{"author_name":"Kerim B Kaylan","author_inst":"The University of Chicago"},{"author_name":"Irene Amalraj","author_inst":"Indiana University School of Medicine"},{"author_name":"Andre G De Oliveira","author_inst":"Indiana University School of Medicine"},{"author_name":"Decio L Eizirik","author_inst":"University Libre de Bruxelles"},{"author_name":"Carmella Evans-Molina","author_inst":"Indiana University School of Medicine"},{"author_name":"Amelia K Linnemann","author_inst":"Indiana University School of Medicine"},{"author_name":"Jon D Piganelli","author_inst":"Indiana University School of Medicine"},{"author_name":"Richard Oram","author_inst":"University of Exeter"},{"author_name":"Raghavendra Mirmira","author_inst":"The University of Chicago"},{"author_name":"Emily Kristen Sims","author_inst":"Indiana University School of Medicine"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Differential requirement for the Ire1 luminal domain in Candida albicans drug susceptibility and pathogenicity","rel_doi":"10.64898\/2026.09.24.753484","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.24.753484","rel_abs":"The opportunistic human pathogen Candida albicans depends on the unfolded protein response (UPR) for cell wall integrity, antifungal tolerance, filamentous growth, and virulence. The UPR is driven by the conserved transmembrane sensor Ire1, which is activated either by misfolded proteins through its luminal domain or by lipid bilayer stress (LBS) through its transmembrane domain. In budding yeast, these two activation modes deploy divergent transcriptional programs. Whether the requirement for these two input domains is separable in C. albicans, where the cell membrane and cell wall are themselves the targets of major antifungal drug classes, remains unknown. Here, we engineered a C. albicans strain expressing Ire1 lacking an intact luminal domain (ire1{Delta}LD), which no longer detects proteotoxic stress. The ire1{Delta}LD strain grew in the presence of the azole antifungals fluconazole and miconazole but was highly sensitive to heat shock, cell wall stress, and the echinocandin caspofungin. It was also unable to sustain filamentous growth and showed reduced virulence in a Caenorhabditis elegans infection model. RNA sequencing revealed only modest changes to the steady-state transcriptome of ire1{Delta}LD cells. Together, these findings define a differential requirement for the input domains of C. albicans Ire1, uncoupling growth under azole-induced membrane stress from the cell wall, thermal, and virulence-associated outputs that depend on proteotoxic sensing, a distinction that could inform antifungal strategies targeting the UPR.","rel_num_authors":8,"rel_authors":[{"author_name":"Samuel Stack-Couture","author_inst":"Western University"},{"author_name":"Nathan Towriss","author_inst":"Western University"},{"author_name":"Iwona Skulska","author_inst":"University of Guelph"},{"author_name":"Anna Kalabina","author_inst":"Western University"},{"author_name":"Julie Genereaux","author_inst":"Western University"},{"author_name":"Vanessa Dumeaux","author_inst":"Western University"},{"author_name":"Rebecca S Shapiro","author_inst":"University of Guelph"},{"author_name":"Patrick Lajoie","author_inst":"Western University"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Domains of RNA-binding protein Ssd1 required for tolerating chromosome amplification in yeast","rel_doi":"10.64898\/2026.09.25.754501","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.25.754501","rel_abs":"Many RNA-binding proteins play pleiotropic roles in the cell, often through disparate domains that can be decoupled. Here we undertook a mutational analysis of yeast RNA-binding protein Ssd1 to better understand domains and processes required for tolerating extra chromosomes, a special class of aneuploidy. Ssd1 is important for cellular fitness when cells carry extra chromosomes, for reasons that are not clear. Ssd1 has multiple distinct domains, many of which are poorly characterized, including multiple RNA binding folds, nuclear import and export signals, an intrinsically disordered domain, an RNA polymerase II-interacting region, and many phosphorylation sites. We measured multiple phenotypes, including the ability to tolerate an extra copy of yeast chromosome XII as a representative aneuploid. Mutating RNA binding domains disrupts fitness in aneuploid, but not euploid, cells and ablates binding of a representative Ssd1 target. However, mutations affecting phase separation or interaction with the kinase Cbk1, which regulates Ssd1 granule formation during the cell cycle, did not affect aneuploidy tolerance. Evaluating correlations across these and other growth phenotypes informed on functional relationships among domains. We discuss implications for Ssd1 function and its role in aneuploidy tolerance in yeast.","rel_num_authors":4,"rel_authors":[{"author_name":"Audrey P. Gasch","author_inst":"University of Wisconsin-Madison"},{"author_name":"Adam Jochem","author_inst":"Morgridge Institute for Research"},{"author_name":"Jamie M. Ahrens","author_inst":"University of Wisconsin-Madison"},{"author_name":"Emma M. Mayhew","author_inst":"University of Wisconsin-Madison"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Sperm development requires TMC5-dependent mechanoresponsive calcium entry","rel_doi":"10.64898\/2026.09.26.754653","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.26.754653","rel_abs":"Spermiogenesis, the transformation of round spermatids into streamlined, fertilization-competent sperm, represents cellular morphogenesis at its most extreme. Despite decades of effort, spermiogenesis remains difficult to recapitulate outside the testis, highlighting the importance of cues within the native tissue environment. The nature of these cues, however, remains poorly understood. Here, we discover that mechanical stimulation elicits Ca2+ entry in spermatids and identify transmembrane channel-like protein 5 (TMC5) as a principal mediator of this response. In both mouse and human testes, TMC5 is selectively expressed in spermatids and localized to the plasma membrane. TMC5 associates with TMC7 and calcium- and integrin-binding (CIB) proteins, mirroring TMC-CIB mechanotransduction complexes in sensory organs. Mechanistically, loss of Tmc5 blocks mechanically evoked Ca2+ entry, leading to disruptions in cytoskeletal remodeling and failure of CREM [&tau] dependent transcriptional programs required for spermiogenesis. Thus, TMC5 is required to couple mechanical cues to sperm development, with direct implications for male infertility.","rel_num_authors":17,"rel_authors":[{"author_name":"Wenxuan Sharon Zheng","author_inst":"University of Virginia"},{"author_name":"Lorena Roa-de la Cruz","author_inst":"University of Texas at San Antonio"},{"author_name":"John Duncan","author_inst":"University of Virginia"},{"author_name":"Liam James McFarlin Slocomb","author_inst":"University of Virginia"},{"author_name":"Betta Chopard","author_inst":"East Carolina University"},{"author_name":"Michelina Kierzek","author_inst":"Washington University"},{"author_name":"Fan Lin","author_inst":"University of Virginia"},{"author_name":"Alexander Webb","author_inst":"University of Virginia"},{"author_name":"Erin Jeffery","author_inst":"University of Virginia"},{"author_name":"Celia M. Santi","author_inst":"Washington University School of Medicine in Saint Louis: Washington University in St Louis School of Medicine"},{"author_name":"Jung-Bum Shin","author_inst":"University of Virginia"},{"author_name":"Sameer S. Bajikar","author_inst":"University of Virginia"},{"author_name":"Gloria M Sheynkman","author_inst":"University of Virginia"},{"author_name":"Bimal N. Desai","author_inst":"University of Virginia"},{"author_name":"Brian P. Hermann","author_inst":"University of Texas at San Antonio"},{"author_name":"Christopher B. Geyer","author_inst":"East Carolina University"},{"author_name":"Seham Ebrahim","author_inst":"University of Virginia"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Nucleosome-scale p53-hormone receptor grammar distributed by Alu elements","rel_doi":"10.64898\/2026.09.26.754600","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.26.754600","rel_abs":"The tumor suppressor p53 and the transcription factors estrogen receptor and androgen receptor regulate growth in a sex-dependent hormone-responsive manner, as in breast and prostate tumors and muscle tissue. Using a model of transcriptional regulation, we investigated co-regulation between p53 and hormone receptors in different cellular contexts and highlight an enrichment in mammary and muscle cell types. Sequence, structural and epigenomic evidence demonstrate a broadly distributed functional 73-bp p53-estrogen receptor grammar spanning nucleosome entry\/exit to dyad, while p53-androgen receptor grammar spans 146 bp. At a functional breast cancer enhancer regulating Cyclin D, varied spacing led to lower predicted p53 binding. Genome-wide analysis found a major role of Alu sequences in distributing this grammar, in particular in mTORC1 pathway genes, with an evolutionary association of primate body-size sexual dimorphism and muscle aging.","rel_num_authors":5,"rel_authors":[{"author_name":"Xi Fu","author_inst":"Columbia University"},{"author_name":"Qingyuan Cai","author_inst":"Columbia University"},{"author_name":"Pranay Satya","author_inst":"Columbia University"},{"author_name":"Raul Rabadan","author_inst":"Columbia University"},{"author_name":"Arnold J. Levine","author_inst":"Institute for Advanced Study"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Quantitative machine learning of protein interactions reveals the multiscale organization and molecular syntax of signaling networks","rel_doi":"10.64898\/2026.09.25.754499","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.25.754499","rel_abs":"Cells employ dense networks of transient protein-protein interactions mediated by modular peptide-binding domains and unstructured peptidic motifs for high-fidelity information processing. How these networks physically execute computations through protein interactions governed by complex intra- and intermolecular mechanisms remains indiscernible from current, sparse and non-quantitative, maps of the human interactome. Here, we introduce a quantitative statistical mechanical modeling (QSM) approach for machine learning domain-peptide affinities with experimental-level accuracy. Leveraging a new, principled algorithm for data harmonization and a biophysically informed neural network architecture, QSM learns to predict dissociation constants directly from amino acid sequences with calibrated confidence. We use QSM to construct the first quantitative drafts of human signaling networks and study these networks across three physical scales--recognition mechanisms of modular binding domains, combinatorial logic of multi-dentate proteins, and pathways inferred from de novo inference of protein interaction networks. We find that (i) modular domains, based on their binding preferences, selectivities, and strengths, fall into a limited number of biophysical equivalence groups, (ii) those domains, along with peptidic motifs, are \"syntactically\" combined within proteins to yield multivalent recognition mechanisms, and (iii) the organization of cellular function can be traced back to algorithmically detectable modules induced by domain-mediated interactions. In aggregate, these analyses instantiate a tractable roadmap towards a comprehensive, mechanistic, and simulatable articulation of the systems biology of signaling.","rel_num_authors":4,"rel_authors":[{"author_name":"Julia R Rogers","author_inst":"Columbia University"},{"author_name":"Loren P Cardani","author_inst":"Columbia University"},{"author_name":"Neel H Shah","author_inst":"Columbia University"},{"author_name":"Mohammed AlQuraishi","author_inst":"Columbia University"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"Systemic tumor-cell reprogramming converts solid tumors into in situ biofactories for immunotherapy","rel_doi":"10.64898\/2026.09.26.754636","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.26.754636","rel_abs":"A central challenge in oncology is delivering potent drugs to tumors without harming healthy tissues. We therefore asked whether tumor cells themselves could be genetically programmed to produce therapeutic molecules directly within the tumor. We present LENTRA (LENtiviral Tumor-Reprogramming Activator), an antigen-targeted lentiviral platform that enables selective transduction and genetic modification of tumor cells in vivo. Following intravenous administration, LENTRA achieves tumor restricted expression of immune checkpoint inhibitors, cytokines, or therapeutic enzymes in multiple murine solid tumor models. Local production of anti CTLA 4 or IL 12 triggered potent antitumor responses while avoiding systemic toxicities. Tumor restricted secretion of sialidase enhanced dendritic cell and T cell infiltration, and reprogrammed tumor associated macrophages toward an immunostimulatory phenotype, resulting in tumor regression and durable immune memory, including in tumors with heterogeneous antigen expression. In patient derived tumor explants, LENTRA mediated efficient transduction, immune remodeling, and reduced tumor viability. By engineering tumors to produce therapeutic proteins, LENTRA converts resistant tumors into autonomous therapeutic sources and active immune hubs, achieving local TME reprogramming and systemic antitumor immunity with an improved safety profile.","rel_num_authors":8,"rel_authors":[{"author_name":"Shihui Wang","author_inst":"Hangzhou Institute of Medicine, Chinese Academy of Sciences"},{"author_name":"Qing Xu","author_inst":"Hangzhou Institute of Medicine, Chinese Academy of Sciences"},{"author_name":"Mengyao Wu","author_inst":"First Affiliated Hospital of Soochow University"},{"author_name":"Jiarong Duan","author_inst":"Hangzhou Institute of Medicine, Chinese Academy of Sciences"},{"author_name":"Qin Gao","author_inst":"Hangzhou Institute of Medicine, Chinese Academy of Sciences"},{"author_name":"Haimin Ma","author_inst":"Hangzhou Institute of Medicine, Chinese Academy of Sciences"},{"author_name":"Wei Li","author_inst":"First Affiliated Hospital of Soochow University"},{"author_name":"Tianqing Zheng","author_inst":"Hangzhou Institute of Medicine, Chinese Academy of Science"}],"rel_date":"2026-09-28","rel_site":"biorxiv"},{"rel_title":"No Strings Attached: Predicting Tricuspid Valve Deformation Without In Vivo Chordal Geometry","rel_doi":"10.64898\/2026.09.25.754571","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.25.754571","rel_abs":"Predictive biomechanical models of the tricuspid valve require accurate representation of the chordae tendineae, yet subject-specific chordal geometry is difficult to reconstruct from non-invasive imaging. Here, we adopt a framework for generating functionally equivalent synthetic chordae without prior knowledge of in vivo chordal attachments. To this end, we first adapt an anatomy-informed hyperelastic shape-matching method that establishes correspondence between end-diastolic and end-systolic leaflet configurations using chordal-mimicking forces, a rigid contact template, and a Gaussian-smoothed locally corrective pressure field. We then generate synthetic chordal insertion sites using zone-based rejection sampling and calibrate the unloaded length of each chord by combining reaction forces with the chordal stress-stretch relationship. The framework was evaluated using Texas TriValve 1.1, a high-fidelity finite element model of a human tricuspid valve validated against beating-heart echocardiography. We found that shape matching reproduced the target end-systolic geometry with a mean inter-surface distance of 0.29 {+\/-} 0.35 mm. Moreover, synthetic chordal insertions faithfully reproduce end-systolic leaflet deformations. We subsequently examined synthetic chordal configurations containing 202, 225, and 450 insertions, informed by measurements from eight explanted human tricuspid valves. Here, increasing insertion number reduced mean inter-surface distance from 0.63 {+\/-} 0.52 mm to 0.49 {+\/-} 0.44 mm and reduced contact area errors from 3.52% to 0.59%. Across all configurations, mean maximum principal stretch errors in leaflet belly regions remained below 2.4%, while areal strain errors ranged from 0.34% to 10.01%. These results demonstrate that anatomically informed shape matching coupled with stress-based chordal calibration can reproduce tricuspid valve closure without explicit subject-specific chordal geometry. This framework provides a foundation for generating synthetic subvalvular anatomy for future imaging-derived, predictive tricuspid valve models.","rel_num_authors":16,"rel_authors":[{"author_name":"Mrudang Mathur","author_inst":"Walker Department of Mechanical Engineering, The University of Texas at Austin; Department of Cardiothoracic Surgery, Stanford University"},{"author_name":"Collin E. Haese","author_inst":"Walker Department of Mechanical Engineering, The University of Texas at Austin"},{"author_name":"Vijay K. Dubey","author_inst":"Walker Department of Mechanical Engineering, The University of Texas at Austin"},{"author_name":"Sumedh Seetharam","author_inst":"Department of Biomedical Engineering, The University of Texas at Austin"},{"author_name":"William D. Meador","author_inst":"Department of Biomedical Engineering, The University of Texas at Austin"},{"author_name":"Tomasz Jazwiec","author_inst":"Department of Cardiac, Vascular and Endovascular Surgery and Transplantology, Silesian Centre for Heart Disease, Medical University of Silesia in Katowice"},{"author_name":"Natalie T. Simonian","author_inst":"Department of Biomedical Engineering, The University of Texas at Austin"},{"author_name":"Michael S. Sacks","author_inst":"Department of Biomedical Engineering, The University of Texas at Austin; The Oden Institute of Computational Science and Engineering, The University of Texas at"},{"author_name":"Marcin Malinowski","author_inst":"Department of Cardiac Surgery, Wojewodzki Szpital im. Sw. Ojca Pio"},{"author_name":"Jan Fuhg","author_inst":"The Oden Institute of Computational Science and Engineering, The University of Texas at Austin; Department of Aerospace Engineering & Engineering Mechanics, The"},{"author_name":"Issam Moussa","author_inst":"Carle Illinois College of Medicine, University of Illinois at Urbana-Champaign"},{"author_name":"Joshua A. Cohen","author_inst":"Sentara Heart Valve Center, Sentara Heart Hospital"},{"author_name":"Matthew R. Summers","author_inst":"Sentara Heart Valve Center, Sentara Heart Hospital"},{"author_name":"Tomasz A. Timek","author_inst":"Division of Cardiothoracic Surgery, Corewell Health West; College of Human Medicine, Michigan State University"},{"author_name":"William Hiesinger","author_inst":"Department of Cardiothoracic Surgery, Stanford University"},{"author_name":"Manuel K. Rausch","author_inst":"Department of Biomedical Engineering, The University of Texas at Austin; The Oden Institute of Computational Science and Engineering, The University of Texas at"}],"rel_date":"2026-09-28","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":"BackgroundCancer-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.\n\nMethodsWe 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.\n\nResultsDIO2 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.\n\nConclusions\n\nDIO2 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":"BackgroundCancer-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.\n\nMethodsWe 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.\n\nResultsDIO2 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.\n\nConclusions\n\nDIO2 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":"BackgroundCancer-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.\n\nMethodsWe 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.\n\nResultsDIO2 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.\n\nConclusions\n\nDIO2 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":"BackgroundCancer-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.\n\nMethodsWe 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.\n\nResultsDIO2 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.\n\nConclusions\n\nDIO2 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":"ObjectiveTo assess the knowledge, willingness and barriers to human papillomavirus (HPV) vaccination among caregivers of adolescent girls living with HIV in Sierra Leone.\n\nMethodsThis 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.\n\nResultsOnly 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 as disrupted vaccination services, vaccine supplies and cold chain limited uptake, healthcare workers emerged as the most effective information source (rank sum = 889.5, p = 0.039).\n\nConclusionThe study highlights the need for culturally tailored education to dispel myths and 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":"BackgroundSince 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.\n\nMethodsWe 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.\n\nResultsAmong 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.\n\nConclusionsWhile 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":"BackgroundSince 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.\n\nMethodsWe 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.\n\nResultsAmong 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.\n\nConclusionsWhile 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":"BackgroundSub-Saharan Africa (sSA) faces accelerated growth in Alzheimers 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.\n\nMethodsFour 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.\n\nResultsTabCAT 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.\n\nDiscussionTabCAT 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@6a49f5org.highwire.dtl.DTLVardef@1d7b37org.highwire.dtl.DTLVardef@1848b3aorg.highwire.dtl.DTLVardef@d0b391_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@6a49f5org.highwire.dtl.DTLVardef@1d7b37org.highwire.dtl.DTLVardef@1848b3aorg.highwire.dtl.DTLVardef@d0b391_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":"BackgroundApproximately 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 Organizations 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.\n\nMethodsWe 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 Banduras Multidimensional Scales of Perceived Self-Efficacy. We analyzed data using descriptive statistics and paired-samples t-tests.\n\nResultsOf 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.\n\nConclusionThe 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":"BackgroundApproximately 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 Organizations 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.\n\nMethodsWe 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 Banduras Multidimensional Scales of Perceived Self-Efficacy. We analyzed data using descriptive statistics and paired-samples t-tests.\n\nResultsOf 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.\n\nConclusionThe 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"}]}