{"gname":"Fred Hutchinson Cancer Center","grp_id":"28","rels":[{"rel_title":"Genomic basis of developmental defects of enamel and sex-specific effects","rel_doi":"10.64898\/2026.07.06.26355672","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.06.26355672","rel_abs":"We conducted a multi-ancestry genome-wide association study (GWAS) of developmental defects of enamel (DDE) in the primary dentition among 6,061 U.S. preschool-aged children (3--5 years). We investigated four DDE phenotypes (demarcated opacities, diffuse opacities, hypoplastic defects, and a combined DDE trait) leveraging main-effect models, joint gene-sex interaction testing (2df), and sex-stratified analyses. SNP-based heritability for the combined DDE trait was estimated at 20%, with concordance analyses robustly supporting a genetic etiology. We identified 39 unique genome-wide significant loci (P<5 x 10-8;), with five surpassing a study-wide Bonferroni-corrected statistical significance criterion (P<1.25 x 10-9), including Y RNA and ALDH1A1. The main-effect GWAS identified 20 loci, including HBS1L and MYB, genes regulating hematopoiesis with plausible roles in amelogenesis. Joint test and sex-stratified analyses revealed 19 additional loci, including ALDH1A1, TENM2, and DLGAP2, demonstrating sex-specific heterogeneity. Nineteen loci exhibited sex-specific differences after Bonferroni correction (P<2 x 10-3), including genes involved in retinoic acid signaling (ALDH1A1), odontogenesis (TENM2), and neurodevelopment (DLGAP2, CDH10). Pathway enrichment highlighted ectodermal and synapse organization networks, suggesting shared etiological mechanisms between DDE and systemic conditions like neurofibromatosis and autism spectrum disorder. Notably, no locus generalized in an external GWAS of permanent dentition DDE, underscoring fundamental biological differences in the genetic architectures governing primary versus permanent enamel formation. Crucially, a comprehensive cross-trait pleiotropy lookup against early childhood caries (ECC) revealed no shared genetic architecture, supporting the notion that the established clinical and epidemiological association between DDE and ECC is likely driven by structural defects increasing caries lesion susceptibility rather than genetic pleiotropy. By integrating gene-sex interaction testing, this study offers novel insights into the complex, sexually dimorphic genetic etiology of DDE and augments the biological evidence base that can support the development of precision pediatric dentistry.","rel_num_authors":19,"rel_authors":[{"author_name":"Poojan Shrestha","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Mariaelisa Graff","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Yu Gu","author_inst":"The University of Hong Kong"},{"author_name":"Yujie Wang","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Hyunseong Sean Ahn","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Kevin Ngoc Nguyen","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Ayush Khanna","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Christy Leigh Avery","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Heather Michelle Highland","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Jeannie Ginnis","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Miguel Angel Simancas-Pallares","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Andrea G. Ferreira Zandon\u00e1","author_inst":"The Ohio State University College of Dentistry"},{"author_name":"Rasha Nasha Alotaibi","author_inst":"King Saud University"},{"author_name":"Danyu Lin","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"John S. Preisser","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Gary D. Slade","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Mary Louise Marazita","author_inst":"University of Pittsburgh"},{"author_name":"Kari E. North","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Kimon Divaris","author_inst":"University of North Carolina at Chapel Hill"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"Automated Disease Activity Assessment in Systemic Lupus Erythematosus Using Privacy-Preserving Large Language Models","rel_doi":"10.64898\/2026.07.09.26357586","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357586","rel_abs":"The Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) is a crucial but labor-intensive tool for managing SLE. We developed a privacy-preserving, model-agnostic large language model (LLM) framework to automate SLEDAI-2K assessment from real-world electronic health records. The framework was developed on a specialist-verified ground truth of 658 clinical notes and externally validated on 56 MIMIC-IV discharge summaries. Seven open-source LLMs were evaluated using advanced prompting and ensemble strategies. The top-performing model, a two-layered GPT-OSS-120B + verifier, achieved a micro-F1 of 94.2% for descriptor classification and an 86% exact match for SLEDAI-2K scores on the internal set, with corresponding external validation performance of 87.7% and 64%, respectively. To demonstrate clinical utility, the LLMs were deployed on 2,576 serial notes from 108 SLE patients. Patients identified by the LLMs as achieving sustained low disease activity had a significantly lower incidence of stage 3 chronic kidney disease (log-rank p = 0.0053), the need for kidney replacement therapy (p = 0.044), and hospitalization (p = 0.021) over 18.3 years of follow-up. These findings demonstrate that privacy-preserving LLMs, when guided by a well-designed framework, can assist in specialist-level reasoning in autoimmune diseases, offering a scalable solution for clinical decision support and patient management.","rel_num_authors":14,"rel_authors":[{"author_name":"Danting Zhang","author_inst":"The University of Hong Kong"},{"author_name":"Renee L. Leung","author_inst":"The University of Hong Kong"},{"author_name":"Chun-Ka Wong","author_inst":"The University of Hong Kong"},{"author_name":"Shirley Chiu Wai Chan","author_inst":"The University of Hong Kong"},{"author_name":"Yi Li","author_inst":"The University of Hong Kong"},{"author_name":"Eric H. M. Tang","author_inst":"The University of Hong Kong"},{"author_name":"Tingting Wu","author_inst":"The University of Hong Kong"},{"author_name":"Tak Mao Chan","author_inst":"The University of Hong Kong"},{"author_name":"Chak-Sing Lau","author_inst":"The University of Hong Kong"},{"author_name":"Carlos King Ho Wong","author_inst":"London School of Hygiene & Tropical Medicine"},{"author_name":"Kathy Sze Man Leung","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Zoie Shui-Yee Wong","author_inst":"Swinburne University of Technology"},{"author_name":"Joseph Tsz-Kei Wu","author_inst":"The University of Hong Kong"},{"author_name":"Desmond Yat-Hin Yap","author_inst":"The University of Hong Kong"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"Structural Variant Imputation in Samoans Using a Population-Specific Reference Panel","rel_doi":"10.64898\/2026.07.07.26357461","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26357461","rel_abs":"Structural variants (SVs) are often excluded from genetic research because they are difficult to call, but they can have substantial effects on phenotypic traits. SVs have not previously been characterized in Samoans, an understudied population with a high burden of complex diseases. Using short-read whole genome sequencing data, we called SVs in 1,276 Samoans and created a Samoan-specific imputation panel inclusive of both SVs and single nucleotide variants (SNVs), called the Soifua Manuia-SV panel. Using this panel, we imputed SVs and SNVs in 3,611 Samoans with array data, enabling analysis of SV-phenotype associations in a sample of 4,887 Samoan participants. We evaluated imputation performance in Samoans against two other reference panels: (i) an SNV-only Samoan-specific reference panel, to assess whether SV inclusion impacts SNV imputation, and (ii) an SV and SNV, multi-ancestry reference panel composed of 1000 Genomes participants, which did not include Polynesians, to assess the importance of including the target population in the reference panel. The Soifua Manuia-SV panel substantially outperformed the multi-ancestry SV and SNV panel, yielding 5.5 million more high-quality (r2[&ge;]0.8) variants, including over 8,000 more high-quality SVs. SNV imputation based on the two Samoan-specific panels performed similarly overall, suggesting that SV inclusion does not strongly impact SNV imputation quality. This work highlights the importance of population representation for accurate imputation.","rel_num_authors":17,"rel_authors":[{"author_name":"Lauren M. Spor","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Emily M. Liau","author_inst":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Ca"},{"author_name":"Alba Sanchis-Juan","author_inst":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Ca"},{"author_name":"Andrew N. Silva","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Hong Cheng","author_inst":"Department of Environmental and Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA"},{"author_name":"Take Naseri","author_inst":"Naseri and Associates Public Health Consultancy Firm and Family Health Clinic; Department of Epidemiology and Center for Global Public Health, Brown University "},{"author_name":"Muagututi'a Sefuiva Reupena","author_inst":"Lutia i Puava ae Mapu i Fagalele, Apia, Samoa"},{"author_name":"Satupa'itea Viali","author_inst":"Oceania University of Medicine, Samoa; National University of Samoa, Apia, Samoa; Department of Chronic Disease Epidemiology, Yale School of Public Health, New "},{"author_name":"John Tuitele","author_inst":"Department of Public Health, LBJ Tropical Medical Center, Faga'alu, AS, USA"},{"author_name":"Erin E. Kershaw","author_inst":"Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Ranjan Deka Deka","author_inst":"Department of Environmental and Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA"},{"author_name":"Nicola L. Hawley","author_inst":"Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA"},{"author_name":"Stephen T. McGarvey","author_inst":"Department of Anthropology, Brown University, Providence, RI, USA"},{"author_name":"Daniel E. Weeks","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Jenna C. Carlson","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Harrison Brand","author_inst":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Ca"},{"author_name":"Ryan L. Minster","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"Structural Variant Imputation in Samoans Using a Population-Specific Reference Panel","rel_doi":"10.64898\/2026.07.07.26357461","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26357461","rel_abs":"Structural variants (SVs) are often excluded from genetic research because they are difficult to call, but they can have substantial effects on phenotypic traits. SVs have not previously been characterized in Samoans, an understudied population with a high burden of complex diseases. Using short-read whole genome sequencing data, we called SVs in 1,276 Samoans and created a Samoan-specific imputation panel inclusive of both SVs and single nucleotide variants (SNVs), called the Soifua Manuia-SV panel. Using this panel, we imputed SVs and SNVs in 3,611 Samoans with array data, enabling analysis of SV-phenotype associations in a sample of 4,887 Samoan participants. We evaluated imputation performance in Samoans against two other reference panels: (i) an SNV-only Samoan-specific reference panel, to assess whether SV inclusion impacts SNV imputation, and (ii) an SV and SNV, multi-ancestry reference panel composed of 1000 Genomes participants, which did not include Polynesians, to assess the importance of including the target population in the reference panel. The Soifua Manuia-SV panel substantially outperformed the multi-ancestry SV and SNV panel, yielding 5.5 million more high-quality (r2[&ge;]0.8) variants, including over 8,000 more high-quality SVs. SNV imputation based on the two Samoan-specific panels performed similarly overall, suggesting that SV inclusion does not strongly impact SNV imputation quality. This work highlights the importance of population representation for accurate imputation.","rel_num_authors":17,"rel_authors":[{"author_name":"Lauren M. Spor","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Emily M. Liau","author_inst":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Ca"},{"author_name":"Alba Sanchis-Juan","author_inst":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Ca"},{"author_name":"Andrew N. Silva","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Hong Cheng","author_inst":"Department of Environmental and Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA"},{"author_name":"Take Naseri","author_inst":"Naseri and Associates Public Health Consultancy Firm and Family Health Clinic; Department of Epidemiology and Center for Global Public Health, Brown University "},{"author_name":"Muagututi'a Sefuiva Reupena","author_inst":"Lutia i Puava ae Mapu i Fagalele, Apia, Samoa"},{"author_name":"Satupa'itea Viali","author_inst":"Oceania University of Medicine, Samoa; National University of Samoa, Apia, Samoa; Department of Chronic Disease Epidemiology, Yale School of Public Health, New "},{"author_name":"John Tuitele","author_inst":"Department of Public Health, LBJ Tropical Medical Center, Faga'alu, AS, USA"},{"author_name":"Erin E. Kershaw","author_inst":"Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Ranjan Deka Deka","author_inst":"Department of Environmental and Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA"},{"author_name":"Nicola L. Hawley","author_inst":"Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA"},{"author_name":"Stephen T. McGarvey","author_inst":"Department of Anthropology, Brown University, Providence, RI, USA"},{"author_name":"Daniel E. Weeks","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Jenna C. Carlson","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Harrison Brand","author_inst":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Ca"},{"author_name":"Ryan L. Minster","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"Wearable Electrical Impedance Myography for Continuous, Non-Invasive Detection of Acute Compartment Syndrome: A Preclinical Feasibility Study","rel_doi":"10.64898\/2026.07.06.26357418","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.06.26357418","rel_abs":"Introduction: Acute compartment syndrome (ACS) is a limb-threatening complication of extremity trauma that requires timely diagnosis to prevent irreversible muscle and nerve injury. Current diagnostic methods are invasive, intermittent, and operator-dependent. We evaluated the feasibility of a novel, Bluetooth-enabled electrical impedance myography (EIM) device (mAlert, Myolex, Inc., Brookline, MA, USA) for continuous, noninvasive detection of ACS-related tissue changes. Methods: Ten Yorkshire swine underwent anterior tibial compartment monitoring using three ACS models: albumin infusion (ALB, n=3), femoral artery and vein ligation (LIG, n=3), and combined albumin infusion plus ligation (ALB+LIG, n=4). Resistance (R), reactance (X), and phase (P) were measured every minute across 1 to 199 kHz alongside continuous intra-compartmental pressure (ICP) monitoring. Group differences in normalized impedance trends were evaluated using the Kruskal Wallis test with Dunn post hoc correction. As a proof-of-concept human study, nine healthy volunteers wore the device for up to five days to assess electrode durability and signal stability. Tissue ischemia was validated using pimonidazole immunohistochemistry. Results: ALB infusion produced progressive, frequency-dependent decreases in R, X, and P, whereas LIG produced consistent increases in R and X across frequencies. The ALB+LIG model generated mixed responses, reflecting the competing effects of edema and ischemia. Normalized phase slopes differed significantly among groups (H=6.14, p=0.046), with post hoc testing showing significant divergence between the ALB and LIG models (p=0.041). Control limbs remained stable throughout monitoring. Pimonidazole staining confirmed hypoxic injury in the intervention limb. In the human pilot study, three participants completed five days of monitoring, demonstrating sustained signal acquisition, while electrode degradation limited data collection in the remaining participants. Conclusions: This preliminary feasibility study demonstrates that wearable EIM can continuously detect model-specific physiological changes associated with ACS in a large-animal model. These findings support further development and clinical evaluation of wearable EIM as a non-invasive monitoring technology for early ACS detection in trauma patients.","rel_num_authors":11,"rel_authors":[{"author_name":"Mohammad Javad Shariyate","author_inst":"Beth Israel Deaconess MedicalCenter"},{"author_name":"Mohammad Khak","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Buket Sonbas-Cobb","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Maria V. Velasquez Hammerle","author_inst":"Beth Iasrael Deaconess Medical Center"},{"author_name":"Baoguo Wei","author_inst":"Myolex, Inc."},{"author_name":"Sara Robicheau","author_inst":"Myolex, Inc."},{"author_name":"Kirsten Dunlap","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Ahmad Hedayatzadeh Razavi","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Mario Keko","author_inst":"mkeko@bidmc.harvard.edu"},{"author_name":"Seward Rutkove","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Ara Nazarian","author_inst":"Beth Israel Deaconess Medical Center"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"Gene-Temperature Interactions and Risk of Childhood Acute Lymphoblastic Leukemia","rel_doi":"10.64898\/2026.07.09.26357608","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357608","rel_abs":"Background: High ambient temperature in early pregnancy has been linked to an increased risk of childhood acute lymphoblastic leukemia (ALL). To better understand biological mechanisms, the current study evaluated potential interaction between temperature and genetic characteristics. Methods: We used data from California birth records (1982-2008) and California Cancer Registry (1988-2011) to identify ALL cases (n=3,353) diagnosed <=14 years of age and non-cancer controls (n=3,530) matched 1:1 on sex, race, ethnicity, and birth year and month. Weekly ambient temperatures throughout pregnancy were assessed on a 1-km grid around the birth address, while genetic data were available from a genome-wide association study using neonatal blood spots. We evaluated the association between ambient temperature and ALL risk by quartiles of established genetic risk score for ALL. Next, we formally tested gene-temperature interactions in the association with ALL, correcting for multiple testing, for genes previously identified with epigenetic changes due to both temperature and ALL. All analyses were adjusted for potential confounders. Results: The elevated risk of ALL per 5 degrees C increase of weekly mean ambient temperature, confined to early pregnancy, was more pronounced among children with the lowest genetic susceptibility to ALL, especially among Latino children (first quartile: odds ratio [OR] = 1.50, 95% confidence interval [CI]: 1.14-1.97); fourth quartile: OR=1.03, 95% CI: 0.83-1.28). There were significant interactions (p<0.002) between ambient temperature and polymorphisms in BNC1 among non-Latino White children, and suggestive interactions (p<0.05) with TBPL2 and NRXN1 in the full population. Conclusions: Our findings suggest that there may be interactions between ambient temperature in early pregnancy and offspring genotype in the risk of childhood ALL. Impact: If replicated, these findings could help elucidate the biological mechanisms linking high ambient temperature in early pregnancy and the risk of childhood ALL.","rel_num_authors":10,"rel_authors":[{"author_name":"Tormod Rogne","author_inst":"University of Oslo"},{"author_name":"Rong Wang","author_inst":"Yale University School of Public Health"},{"author_name":"Pin Wang","author_inst":"University of Maryland"},{"author_name":"Kai Chen","author_inst":"Yale University School of Public Health"},{"author_name":"Shuangge Ma","author_inst":"Yale University School of Public Health"},{"author_name":"Joshua L Warren","author_inst":"Yale University School of Public Health"},{"author_name":"Catherine Metayer","author_inst":"University of California, Berkeley"},{"author_name":"Joseph L Wiemels","author_inst":"University of Southern California"},{"author_name":"Andrew DeWan","author_inst":"Yale University School of Public Health"},{"author_name":"Xiaomei Ma","author_inst":"Yale University School of Public Health"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"Gene-Temperature Interactions and Risk of Childhood Acute Lymphoblastic Leukemia","rel_doi":"10.64898\/2026.07.09.26357608","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357608","rel_abs":"Background: High ambient temperature in early pregnancy has been linked to an increased risk of childhood acute lymphoblastic leukemia (ALL). To better understand biological mechanisms, the current study evaluated potential interaction between temperature and genetic characteristics. Methods: We used data from California birth records (1982-2008) and California Cancer Registry (1988-2011) to identify ALL cases (n=3,353) diagnosed <=14 years of age and non-cancer controls (n=3,530) matched 1:1 on sex, race, ethnicity, and birth year and month. Weekly ambient temperatures throughout pregnancy were assessed on a 1-km grid around the birth address, while genetic data were available from a genome-wide association study using neonatal blood spots. We evaluated the association between ambient temperature and ALL risk by quartiles of established genetic risk score for ALL. Next, we formally tested gene-temperature interactions in the association with ALL, correcting for multiple testing, for genes previously identified with epigenetic changes due to both temperature and ALL. All analyses were adjusted for potential confounders. Results: The elevated risk of ALL per 5 degrees C increase of weekly mean ambient temperature, confined to early pregnancy, was more pronounced among children with the lowest genetic susceptibility to ALL, especially among Latino children (first quartile: odds ratio [OR] = 1.50, 95% confidence interval [CI]: 1.14-1.97); fourth quartile: OR=1.03, 95% CI: 0.83-1.28). There were significant interactions (p<0.002) between ambient temperature and polymorphisms in BNC1 among non-Latino White children, and suggestive interactions (p<0.05) with TBPL2 and NRXN1 in the full population. Conclusions: Our findings suggest that there may be interactions between ambient temperature in early pregnancy and offspring genotype in the risk of childhood ALL. Impact: If replicated, these findings could help elucidate the biological mechanisms linking high ambient temperature in early pregnancy and the risk of childhood ALL.","rel_num_authors":10,"rel_authors":[{"author_name":"Tormod Rogne","author_inst":"University of Oslo"},{"author_name":"Rong Wang","author_inst":"Yale University School of Public Health"},{"author_name":"Pin Wang","author_inst":"University of Maryland"},{"author_name":"Kai Chen","author_inst":"Yale University School of Public Health"},{"author_name":"Shuangge Ma","author_inst":"Yale University School of Public Health"},{"author_name":"Joshua L Warren","author_inst":"Yale University School of Public Health"},{"author_name":"Catherine Metayer","author_inst":"University of California, Berkeley"},{"author_name":"Joseph L Wiemels","author_inst":"University of Southern California"},{"author_name":"Andrew DeWan","author_inst":"Yale University School of Public Health"},{"author_name":"Xiaomei Ma","author_inst":"Yale University School of Public Health"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"The effect of dietary fiber based on fermentability and viscosity on the gut microbial metabolites in chronic kidney disease: a systematic review and meta-analysis of experimental and clinical trials","rel_doi":"10.64898\/2026.07.09.26357677","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357677","rel_abs":"Background: Chronic kidney disease (CKD) is associated with alterations in the gut microbiome that promote the accumulation of gut-derived uremic solutes and contribute to systemic inflammation, vascular dysfunction, and disease progression. Dietary fiber has emerged as a promising modulator of gut microbial metabolism, yet the influence of fiber physicochemical properties, particularly fermentability and viscosity, on uremic metabolite production in CKD remains poorly understood. Objective: To systematically evaluate the effects of isolated dietary fiber interventions, classified by fermentability and viscosity, on gut microbial metabolites in CKD across experimental rodent models and randomized clinical trials, and to determine whether these fiber properties modify microbial metabolites. Methods: A systematic search of PubMed, Embase, CINAHL, and Cochrane Library (through June 2026) identified randomized controlled trials and controlled rodent studies assessing isolated dietary fiber in CKD. Eligible studies reported at least one gut-derived metabolite (i.e., indoxyl sulfate (IS), p-cresyl sulfate (PCS), trimethylamine-N-oxide (TMAO), tryptophan-derived indoles, or short-chain fatty acids (SCFAs)). Random-effects models were used for pooled estimates using weighted mean differences (WMD) for human studies and standardized mean differences (SMD) for animal studies. Subgroup analyses evaluated fiber fermentability, viscosity, intervention dose, duration, and CKD stage. Risk of bias was assessed with ROB-2 and SYRCLE, and evidence certainty with GRADE. Results: Twenty-eight studies (13 human, 15 animal) met eligibility criteria, comprising 511 participants and 312 animals with CKD. Isolated fiber supplementation, primarily fermentable and non-viscous fibers, reduced IS (human: -0.13 mg\/dL; 95% CI: -0.25, -0.01; p = 0.03; animal: -1.99; 95% CI: -3.06, -0.92; p < 0.0001) and pCS (human: -0.23 mg\/dL; 95% CI: -0.46, 0.001; p = 0.051; animal: -1.56; 95% CI: -2.08, -1.03; p < 0.0001). SCFAs increased in animal studies, including cecal acetate (2.00, 95% CI: 0.78 to 3.22; p = 0.001) and circulating propionate (1.51, 95% CI: 0.054 to 2.96; p=0.04). There were no dose-dependent effects, but longer interventions (>8 weeks) tended to lower pCS (-0.26 mg\/dL, 95% CI: -0.55 to 0.02; p=0.06). Some heterogeneity and low-to-moderate certainty were observed. Conclusion: Isolated dietary fiber reduces major gut-derived uremic solutes in CKD, with fermentability influencing metabolic responsiveness, but with minimal studies on viscous fibers. Larger, longer-duration trials with standardized reporting of total fiber intake and clinical endpoints are needed to guide evidence-based dietary recommendations in CKD.","rel_num_authors":8,"rel_authors":[{"author_name":"Seyedeh Nooshan Mirmohammadali","author_inst":"Purdue University"},{"author_name":"Claudia Carrillo","author_inst":"Iowa State University"},{"author_name":"Jason B. Reed","author_inst":"Purdue University"},{"author_name":"Brandon M. Kistler","author_inst":"Purdue University"},{"author_name":"Hannah E. Wilson","author_inst":"Indiana University School of Medicine"},{"author_name":"Bruce Hamaker","author_inst":"Purdue University"},{"author_name":"Sharon M Moe","author_inst":"Indiana University"},{"author_name":"Annabel Biruete","author_inst":"Purdue University"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"Biomarker-informed CSF proteomics reveals ENPP2-LPA lipid signaling associated with Alzheimer's disease","rel_doi":"10.64898\/2026.07.08.26357565","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357565","rel_abs":"Background: Alzheimer's disease (AD) involves complex molecular alterations in the cerebrospinal fluid (CSF) proteome, yet the links between these protein changes and hallmark AD pathology remain incompletely defined. We investigated the relationship between the CSF proteome with CSF biomarkers of Alzheimer's disease (AD). Methods: CSF was collected in 500 individuals of non-Hispanic white, African Americans, and Caribbean Hispanic individuals. CSF biomarkers of AD were measured including P-tau181, A{beta}40, A{beta}42, total-tau, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). CSF was depleted of abundant proteins followed by precipitation, cysteine reduction\/alkylation, and proteolytic cleavage by trypsin. Peptides were measured using a Q-Exactive HF mass spectrometer (Thermo Scientific). Association of individual and co-abundant modules of proteins were tested using elevated CSF P-tau181 and reduced A{beta}42\/A{beta}40 to confirm the diagnosis of AD. We validated results in CSF from 397 participants in the Accelerated Medicine Partnership-Alzheimer's Disease cohort. Associated proteins were functionally validated in postmortem human brains and zebrafish. Results: We detected 1030 proteins, yielding an overall data completeness value of 97%. CSF levels of 75 (7.3%) proteins were significantly associated with CSF P-tau181 levels after multiple testing correction. Notably phospholipase D3 (PLD3, p=2.41E-09), apoE (p=4.25e-08) and osteopontin (OPN p=1.4E-16) were increased and autotaxin (ATX\/ENPP2, p= 8.39E-09) and ceruloplasmin (CP) (p=2.72E-07) were lower among individuals with high P-tau181 levels. These proteins were also associated with CSF A{beta}42\/A{beta}40 ratio and total tau levels but not with NfL. OPN was also associated with CSF levels of GFAP (p=1.32e-05). Among proteins associated with P-tau181 levels, pathways related to axon development (p=2.4E-12), axonogenesis (p=1.45E-11) and regulation of axonogenesis (p=5.1E-09) were enriched. Immunostaining on postmortem human and zebrafish brain found that ENPP2 expression, the gene encoding ATX, was significantly reduced in AD brain and in the amyloidosis model in zebrafish. Reduced ENPP2 expression was consistent with reduced lysophosphatidic acid (LPA) levels in the CSF of individuals with AD. LPA administration into zebrafish CSF reduced the pathological changes in synapses and vasculature due to A{beta}42. Conclusion: Unbiased profiling of circulating CSF proteins among individuals with antemortem diagnosis of AD, identified key proteins PLD3, apoE, OPN, ATX, and ceruloplasmin. Validation in postmortem human brains and zebrafish models support potential roles in endosomal sorting and APP processing, inflammation, angiogenesis, lipid transport, and oxidative stress.","rel_num_authors":16,"rel_authors":[{"author_name":"Min Qiao","author_inst":"Columbia University"},{"author_name":"Prabesh Bhattarai","author_inst":"Columbia University"},{"author_name":"Elanur Yilmaz","author_inst":"Columbia University"},{"author_name":"Alex Rookyard","author_inst":"Columbia University"},{"author_name":"Lipi A Das","author_inst":"Columbia University"},{"author_name":"Anu Jain","author_inst":"Columbia University"},{"author_name":"Dolly Reyes-Dumeyer","author_inst":"Columbia University Vagelos College of Physicians and Surgeons"},{"author_name":"Annie J Lee","author_inst":"Columbia University"},{"author_name":"Rafael A Lantigua","author_inst":"Columbia University"},{"author_name":"Martin Medrano","author_inst":"Pontificia Universidad Catolica Madre y Maestra"},{"author_name":"Diones Rivera","author_inst":"Department of Neurosurgery, CEDIMAT, Plaza de la Salud, Santo Domingo, Dominican Republic"},{"author_name":"Lawrence S Honig","author_inst":"Columbia University"},{"author_name":"Lewis Brown","author_inst":"Columbia University"},{"author_name":"Caghan Kizil","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Richard Mayeux","author_inst":"Columbia University"},{"author_name":"Badri N Vardarajan","author_inst":"Columbia University"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"A feasibility study of a broadly applicable intervention to strengthen empowerment, self-management, and health among adults living with chronic illness in the United States","rel_doi":"10.64898\/2026.07.07.26357498","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26357498","rel_abs":"Background: Chronic illness is a major public health concern in Europe, the United States, and other high-income countries, limiting individuals capacity for self-management and health promotion. Empowerment interventions improve health outcomes while reducing healthcare utilization.   Aim: This study assessed the feasibility of implementing the Bodyknowledging Program, a broadly applicable health promotion intervention developed in Norway, at the community level in the US to evaluate participants experiences, program components, and self-management outcomes among adults living with chronic illness, and to identify the programs strengths and areas for cultural adaptation to inform its cross-national transferability.  Methods: A multi-method feasibility design was used, including a group of participants living with various chronic illnesses. Reflexive thematic analysis was applied to analyze focus group data, examining participants experiences, program components, and outcomes. Facilitators field notes and post-intervention survey data were additional data sources.   Results: Three themes emerged through the thematic analysis: (1) acceptability of the BKPs health promotion content and approaches among US participants, (2) implementation of the BKP intervention in a US community context, and (3) demand and ideas for continued implementation. Facilitator field notes identified challenges in implementing the hybrid format. Survey data confirmed that participants strongly agreed that the program enhanced their ability to recognize bodily signs and tolerance limits, manage symptoms, prevent deterioration, and promote their health. Participants reached consensus on the value of the programs content, materials, organization, and communication strategies.  Conclusion: The Bodyknowledging Program is feasible and well-suited for implementation in the US. This community-based empowerment intervention leverages existing but unutilized human resources to strengthen self-management and health promotion among people with chronic illnesses across diagnostic categories. Further research across diverse settings is recommended to support broader dissemination.","rel_num_authors":7,"rel_authors":[{"author_name":"Kisha  N. Thompson","author_inst":"Northeastern University - Boston Campus: Northeastern University"},{"author_name":"Marie  Hamilton Larsen","author_inst":"Lovisenberg Diaconal University College: Lovisenberg Diakonale Hogskole"},{"author_name":"Susan Hall","author_inst":"Northeastern University - Boston Campus: Northeastern University"},{"author_name":"Dami Ko","author_inst":"Northeastern University - Boston Campus: Northeastern University"},{"author_name":"J\u00f8rghild Jensen","author_inst":"VID Specialized University: VID Vitenskapelige Hogskole"},{"author_name":"Gyda Singstad","author_inst":"VID Specialized University: VID Vitenskapelige Hogskole"},{"author_name":"Kristin Heggdal","author_inst":"VID Specialized University: VID Vitenskapelige Hogskole"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"Bias-domain triangulation of non-convergent observational evidence in behavioural health research","rel_doi":"10.64898\/2026.07.07.26357342","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26357342","rel_abs":"Observational studies in behavioural health often produce conflicting evidence because exposures are entangled with familial, clinical and social determinants. Rather than treating non-convergence as an obstacle to synthesis, we propose bias-domain triangulation, a causal-structure-aware framework that treats it as a diagnostic target. The framework distinguishes actual covariate adjustments from candidate background causal structures, adjudicates the causal roles of adjustment variables and maps core back-door pathways into distinct bias domains before quantitative synthesis, thereby reframing the question from whether estimates are heterogeneous to which bias structure changes the estimate. We apply this framework to a systematically derived literature on prenatal paracetamol exposure and offspring autism spectrum disorder or attention-deficit\/hyperactivity disorder, comprising 22 studies and 33 adjusted estimates. Stronger overall control was associated with attenuation of the pooled association from 2.08 under weak control to 0.98 under strong control. Domain-specific analyses showed that pooled estimates approached the null only under strong familial\/genetic control, whereas strong control of clinical-indication or social-behavioural domains left residual associations. This pattern suggests that shared familial liability is the bias structure most consistently associated with attenuation in the current evidence. Beyond this case, bias-domain triangulation offers a reusable strategy for diagnosing why observational evidence may persistently diverge, moving evidence synthesis beyond heterogeneity toward structural explanation. This study was registered on PROSPERO (CRD420261365276).","rel_num_authors":3,"rel_authors":[{"author_name":"Xuanyu Shi","author_inst":"Peking University"},{"author_name":"Guanghui Deng","author_inst":"Peking University"},{"author_name":"JIAN DU","author_inst":"Peking University"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"Whole-genome sequencing implicates rare, low-frequency and structural non-coding variation at the SCN5A locus in Brugada syndrome","rel_doi":"10.64898\/2026.07.07.26356386","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26356386","rel_abs":"Brugada syndrome (BrS) is an inherited cardiac condition characterized by a hallmark ECG pattern and an increased risk of sudden cardiac death. Central to the aetiology of BrS, the SCN5A region harbours both common non-coding risk variants and rare coding variants that are causative in approximately 20% of patients. However, rare non-coding genetic variation in this region remains largely unexplored. Here, we used whole-genome sequencing (WGS) of 752 European-ancestry BrS cases and 1,827 ancestry-matched controls to identify BrS-associated rare non-coding genetic variation at the SCN5A locus. Sliding-window and cis-regulatory element (CRE)-based rare-variant aggregate testing implicated three conserved CREs, including a dense aggregation of case singleton variants within a 178 bp enhancer in intron 17 of SCN5A which replicated in an independent BrS cohort. Prioritised BrS-associated rare and low-frequency non-coding variants within these elements were predicted to alter cardiac transcription factor motifs, and altered CRE activity in hiPSC-CM luciferase assays or were associated with BrS-relevant ECG endophenotypes in the UK Biobank. Single-variant analysis across the region identified a Bonferroni-significant five-fold case-enriched low-frequency variant within a known CRE in intron 1 of SCN5A, which replicated, was associated with slower cardiac conduction in the UK Biobank and accounted for part of the BrS GWAS signal at this locus. Structural variant analyses identified a 10.5 kb deletion upstream of SCN5A in a BrS case that encompassed a cardiac CRE and reduced sodium current density in a hiPSC-CM model, as well as a 6 kb BrS-enriched retrotransposon insertion in SCN5A that appeared to underlie part of the GWAS signal in this region. Together, these findings implicate rare and low-frequency non-coding variation at the SCN5A locus in BrS susceptibility and demonstrate the value of targeted WGS analysis of key disease loci.","rel_num_authors":60,"rel_authors":[{"author_name":"Alex Lipov","author_inst":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Manon Baudic","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Pierre Lindenbaum","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Isabella Mengarelli","author_inst":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Matthew J. O'Neill","author_inst":"Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Fernanda M. Bosada","author_inst":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Yanushi Wijeyeratne","author_inst":"Cardiovascular and Genomics Research Institute, City St George's, University of London, London, UK"},{"author_name":"Luis de la Higuera Romero","author_inst":"Health in Code S.L., A Coru\u00f1a, Spain"},{"author_name":"Maarten Kooyman","author_inst":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Marion Gaudin","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Graziella Aquilina","author_inst":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Leander Beekman","author_inst":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Estelle Baron","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Mathilde Bertrand","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Zoya Kingsbury","author_inst":"Illumina Cambridge Ltd, Granta Park, Great Abington, Cambridge, UK"},{"author_name":"Mark T. Ross","author_inst":"Illumina Cambridge Ltd, Granta Park, Great Abington, Cambridge, UK"},{"author_name":"Marre Corver","author_inst":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Paola Lombardi","author_inst":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Ingrid Krapels","author_inst":"Department of Clinical Genetics, Maastricht University Medical Center+, Maastricht, Netherlands"},{"author_name":"Paul G. Volders","author_inst":"Department of Cardiology, CARIM, Maastricht University Medical Center, Maastricht, The Netherlands"},{"author_name":"Rafik Tadros","author_inst":"Department of Medicine, Cardiovascular Genetics Center, Montreal Heart Institute, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Canada"},{"author_name":"Fenna Tuijnenburg","author_inst":"Department of Clinical Cardiology, Heart Centre, Amsterdam University Medical Centre, location AMC, The Netherlands"},{"author_name":"Karel van Duijvenboden","author_inst":"Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Ammar Al-Chalabi","author_inst":"Department of Neurology, King's College London, London, UK"},{"author_name":"Jan H. Veldink","author_inst":"Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands"},{"author_name":"Sean J. Jurgens","author_inst":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Aur\u00e9lie Thollet","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Eric Charpentier","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Camille Maiano","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Philippe Mabo","author_inst":"Service de Cardiologie, CHU de Rennes, Rennes, France"},{"author_name":"Antoine Leenhardt","author_inst":"CNMR Maladies Cardiaques H\u00e9r\u00e9ditaires Rares, H\u00f4pital Bichat, Universit\u00e9 de Paris, Paris, France"},{"author_name":"Frederic Sacher","author_inst":"Cardiac Arrhythmia Department, IHU Liryc, Univ. Bordeaux, INSERM 1045, CHU de Bordeaux, F-Bordeaux, France"},{"author_name":"Arjan C. Houweling","author_inst":"Department of Human Genetics, Amsterdam UMC, Amsterdam, The Netherlands"},{"author_name":"Hanno L. Tan","author_inst":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Vincent M. Christoffels","author_inst":"Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Michael W. Tanck","author_inst":"Epidemiology and Data Science, Amsterdam Public Health, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"},{"author_name":"Andrew Grace","author_inst":"Department of Biochemistry, University of Cambridge, Cambridge, UK"},{"author_name":"Koonlawee Nademanee","author_inst":"Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand"},{"author_name":"Apichai Khongphatthanayothin","author_inst":"Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand"},{"author_name":"Andrew M. Glazer","author_inst":"Vanderbilt Center for Arrhythmia Research and Therapeutics (VanCART), Division of Genetic Medicine and Clinical Pharmacology, Department of Medicine, Vanderbilt"},{"author_name":"Jean-Fran\u00e7ois Deleuze","author_inst":"Centre National de Recherche en G\u00e9nomique Humaine (CNRGH), Institut de Biologie Fran\u00e7ois Jacob, CEA, Universit\u00e9 Paris-Saclay, Evry, France"},{"author_name":"- FranceGenRef consortium","author_inst":""},{"author_name":"Juan Pablo Ochoa","author_inst":"Health in Code S.L., A Coru\u00f1a, Spain"},{"author_name":"J\u00e9r\u00f4me Montnach","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Michel De Waard","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Pieter G. Postema","author_inst":"Department of Clinical Cardiology, Heart Centre, Amsterdam University Medical Centre, location AMC, The Netherlands"},{"author_name":"Ahmad S. Amin","author_inst":"Department of Clinical Cardiology, Heart Centre, Amsterdam University Medical Centre, location AMC, The Netherlands"},{"author_name":"Jean-Baptiste Gourraud","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Pascale Guicheney","author_inst":"INSERM, Sorbonne University, UMRS 1166, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France"},{"author_name":"Dan M. Roden","author_inst":"Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA"},{"author_name":"Jean-Jacques Schott","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Christian Dina","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Vincent Probst","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Pier D. Lambiase","author_inst":"Institute of Cardiovascular Science, University College London (UCL) and Barts Heart Centre, London, UK"},{"author_name":"Elijah R. Behr","author_inst":"Cardiovascular and Genomics Research Institute, City St George's, University of London, London, UK"},{"author_name":"Arthur A.M. Wilde","author_inst":"Department of Clinical Cardiology, Heart Centre, Amsterdam University Medical Centre, location AMC, The Netherlands"},{"author_name":"Richard Redon","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Roddy Walsh","author_inst":"Cardiovascular and Genomics Research Institute, City St George's, University of London, London, UK"},{"author_name":"Julien Barc","author_inst":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, Nantes, France"},{"author_name":"Connie R. Bezzina","author_inst":"Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"MRI-Derived Fat Depots and Cardiometabolic Pathways Underlying Heart Failure Risk: A Mendelian Randomization Study","rel_doi":"10.64898\/2026.07.06.26357230","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.06.26357230","rel_abs":"Background: Obesity is a major modifiable risk factor for heart failure (HF), but body mass index (BMI) does not distinguish biologically distinct fat depots. Whether imaging-derived adipose tissue depots capture specific cardiometabolic pathways underlying HF risk beyond conventional anthropometric measures remains uncertain. Methods: We performed two-sample Mendelian randomization (MR) and multivariable MR mediation analyses using published genome-wide association study summary statistics. General adiposity traits included BMI, waist-to-hip ratio (WHR), and WHR adjusted for BMI from GIANT and UK Biobank meta-analyses of up to 694,649 individuals. MRI-derived visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (ASAT), and gluteofemoral adipose tissue (GFAT) were derived from 38,965 UK Biobank participants. HF outcome data were obtained from the HERMES consortium, including 1,946,349 individuals and 153,174 HF cases. Cardiometabolic mediators included type 2 diabetes (T2D), systolic blood pressure (SBP), LDL cholesterol, HDL cholesterol, and triglycerides. Primary analyses used inverse-variance weighted MR, with sensitivity analyses and directionality testing. Mediation was estimated using joint multivariable MR conditioning on significant cardiometabolic mediators. Results: Among MRI-derived adipose depots, ASAT was the only trait significantly associated with HF risk (odds ratio [OR] 1.64 per 1-SD increase; 95% CI 1.40-1.93; FDR q<0.001). VAT showed a positive but imprecise association (OR 1.38; 95% CI 0.87-2.20), and GFAT was not associated with HF. Among general adiposity measures, BMI (OR 1.65; 95% CI 1.58-1.71) and WHR (OR 1.30; 95% CI 1.23-1.38) were robustly associated with HF, whereas WHR adjusted for BMI was not. ASAT was significantly associated with T2D, SBP, HDL cholesterol, and triglycerides, but not LDL cholesterol. In joint multivariable MR, 67.9% of ASAT's HF effect was mediated through T2D, SBP, HDL cholesterol, and triglycerides (95% CI 49.2-86.8%). In contrast, BMI demonstrated only 8.5% mediation (95% CI -7.4 to 24.4%), and WHR showed non-significant mediation of 36.7% (95% CI -8.3 to 81.7%). Conclusions: MRI-derived abdominal subcutaneous adipose tissue captures a biologically coherent cardiometabolic signal underlying HF risk that is diluted by conventional anthropometric measures. ASAT may represent an imaging biomarker of metabolic syndrome-mediated HF risk and could support more precise risk stratification and mechanistically targeted prevention in HF.","rel_num_authors":2,"rel_authors":[{"author_name":"Pranav Sharma","author_inst":"University of Pennsylvania"},{"author_name":"Michael Levin","author_inst":"University of Pennsylvania Perelman School of Medicine"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"A systematic review to critically appraise methodological rigour in research on ultra-processed food and cardiovascular disease and hypertension","rel_doi":"10.64898\/2026.07.09.26357611","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357611","rel_abs":"Despite growing research linking ultra-processed food (UPF) consumption to risk of cardiovascular disease (CVD) and hypertension, no study has systematically evaluated the methodological rigor underlying these associations. We systematically searched major databases to identify eligible studies. Data were extracted for dietary assessment methods, UPF classification, covariate selection, confounding control, statistical modelling and effect estimates. Random-effects meta-analysis was conducted to pool effect estimates. Meta-regression and sensitivity analyses were performed to explore sources of heterogeneity. Substantial heterogeneity was observed in the application of the NOVA classification for categorising UPFs across the 46 eligible studies. Only two studies employed a directed acyclic graph to inform confounder selection; 43 used models with suboptimal adjustment, and 42 were overfitted due to adjustment for potential mediators. Pooled analyses indicated that higher consumption of UPFs was associated with a 9% higher risk of CVD and a 16% higher risk of hypertension, with stronger associations observed for coronary heart and cerebrovascular diseases. While higher UPF intake is consistently associated with increased risks of CVD and hypertension, methodological limitations may attenuate the observed associations. Strengthening methodological rigour through harmonised UPF classification and causal frameworks is essential to better elucidate the effect of UPF consumption on cardiometabolic health.","rel_num_authors":12,"rel_authors":[{"author_name":"Tefera C Mekonnen","author_inst":"Flinders University"},{"author_name":"Zegeye A Bitew","author_inst":"Flinders University"},{"author_name":"Anteneh M Dessie","author_inst":"Flinders University"},{"author_name":"Teketo Tegegne","author_inst":"Deakin University"},{"author_name":"Tolassa Ushula","author_inst":"Deakin University"},{"author_name":"Kacie Dickinson","author_inst":"Flinders University"},{"author_name":"Catherine Brady","author_inst":"Flinders University"},{"author_name":"Zumin Shi","author_inst":"Qatar University"},{"author_name":"Robert Adams","author_inst":"Flinders University"},{"author_name":"Jason HY Wu","author_inst":"University of New South Wales"},{"author_name":"Mario Siervo","author_inst":"Curtin University"},{"author_name":"Yohannes A Melaku","author_inst":"Flinders University"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"NigBench: A multilingual point-of-care medical query benchmarking study of large language models in Nigeria","rel_doi":"10.64898\/2026.07.05.26356776","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.05.26356776","rel_abs":"In this study, we introduce a novel benchmark comprising over 9,000 real-world, point-of-care, multilingual, and multimodal clinical question-answer pairs sourced from frontline health workers in Nigeria. Using the dataset, we compare local general practitioners to multiple leading open and closed LLMs. Our results reveal several critical insights into the suitability of LLMs as clinical decision support systems in low-resource contexts. The results confirm that performance varies widely by language and input modality (e.g., text vs speech): while models perform best on English text inputs, their accuracy drops significantly for local-language speech. Critically, it is possible to achieve substantial performance gains by transcribing and translating other languages into English before prompting an LLM-- an important insight for non-anglophone product developers. Finally, this benchmark highlights key limitations of SLMs in supporting frontline healthcare in low-resource settings and provides a clear opportunity to track improvements as novel solutions are developed.","rel_num_authors":18,"rel_authors":[{"author_name":"Tobi Olatunji","author_inst":"Intron Health; BioRAMP"},{"author_name":"Chinemelu Aka","author_inst":"Intron Health"},{"author_name":"Chibuzor Okocha","author_inst":"University of Florida; BioRAMP"},{"author_name":"Emmanuel Ayodele","author_inst":"Intron Health"},{"author_name":"Jennifer Orisakwe","author_inst":"Intron Health"},{"author_name":"Toni Adekunle","author_inst":"Intron Health"},{"author_name":"Mardhiyah Sanni","author_inst":"Intron Health"},{"author_name":"Abdulameed Abiola","author_inst":"Intron Health"},{"author_name":"Tassallah Abdullahi","author_inst":"Brown University"},{"author_name":"Oluwatomi Owopetu","author_inst":"University College Hospital"},{"author_name":"Tolu Afolaranmi","author_inst":"University of Jos"},{"author_name":"Peter Suoyo Yougha","author_inst":"InStrat Global Health Solutions"},{"author_name":"Mira Emmanuel-Fabula","author_inst":"PATH, Switzerland"},{"author_name":"Vaishnavi Menon","author_inst":"University of Birmingham, UK"},{"author_name":"Alastair Denniston","author_inst":"University of Birmingham, UK"},{"author_name":"Xiao Liu","author_inst":"University of Birmingham, UK"},{"author_name":"Gwydion Williams","author_inst":"PATH, United Kingdom"},{"author_name":"Bilal A. Mateen","author_inst":"PATH, United Kingdom; University of Birmingham, UK"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"How Best to Explain Machine Learning Models to Clinicians: A User Study of Explanation Types","rel_doi":"10.64898\/2026.06.30.26356761","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.30.26356761","rel_abs":"Background: Explanations play a crucial role in helping clinicians understand how black-box machine learning models make predictions in clinical settings. Several different types of explanations have been developed, each corresponding to a unique approach for characterizing the relationships between model inputs and predictions. However, it remains unclear what types of explanations are the most valued by clinicians. Objective: To improve the utility of machine learning in clinical settings, we aimed to evaluate how different explanation methods are valued by clinicians across clinically important metrics, such as importance, trust, understanding, and how explanations affect clinicians' thinking about patients. Methods: We conducted a user study of 39 critical care and hospital medicine nurses and physicians to compare attribution, counterfactual, and rule-based explanations. We analyzed the impact of each type of explanation on clinicians' trust in and understanding of the predictions made by machine learning models, how well clinicians understood the explanation, and how the explanation affected what they thought were the most important features for determining patients' status. We also assessed clinicians' preferences for the representation of different types of explanations. Results: Clinicians consider explanations of clinical machine learning models important, with physicians perceiving explanations as more important after interacting with them than nurses. All explanation types affected clinicians across all measured dimensions, with attribution explanations having the most significant positive effects on all measured dimensions. Moreover, nearly half of clinicians preferred viewing multiple explanation types together. Conclusions: It is important to provide explanations for predictions made by machine-learning models in clinical settings. When implementing machine learning explanations in these settings, developers should prioritize attribution explanations while allowing for multiple types of explanations to be shown. Furthermore, the development of new explanation methods should be tailored towards specific clinical roles, as nurses and physicians may utilize explanations differently to support their respective workflows.","rel_num_authors":12,"rel_authors":[{"author_name":"Bowman Brown","author_inst":"University of Wisconsin-Madison"},{"author_name":"Madeline Oguss","author_inst":"University of Wisconsin-Madison"},{"author_name":"Kyle A Carey","author_inst":"University of Wisconsin-Madison"},{"author_name":"Jennifer Martin","author_inst":"University of Wisconsin-Madison"},{"author_name":"Charles A Kotula","author_inst":"University of Wisconsin-Madison"},{"author_name":"Oliver T Nguyen","author_inst":"University of Wisconsin-Madison"},{"author_name":"Mary Akel","author_inst":"University of Chicago"},{"author_name":"Douglas A Wiegmann","author_inst":"University of Wisconsin-Madison"},{"author_name":"Dana P Edelson","author_inst":"University of Chicago"},{"author_name":"Anoop Mayampurath","author_inst":"University of Wisconsin-Madison"},{"author_name":"Matthew M Churpek","author_inst":"University of Wisconsin-Madison"},{"author_name":"Mark Craven","author_inst":"University of Wisconsin-Madison"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"Neonatal Seizure Detection Using Combined aEEG and Compressed Spectral Array Features: A Machine-Learning Proof-of-Concept Study","rel_doi":"10.64898\/2026.07.02.26354953","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26354953","rel_abs":"Background To build a clinically translatable neonatal seizure detection algorithm using amplitude-integrated electroencephalography (aEEG) and compressed spectral array (CSA). Methods Using a public dataset of annotated neonatal EEGs, features of the aEEG and CSA were extracted from the left and right centroparietal electrodes. These features were then used to train and test three machine learning classifiers, Random Forest (RF), Support Vector Machines (SVM), and Artificial Neural Networks (ANN). Results The trained RF, SVM, and ANN classifiers had areas under the curve (AUC) of 0.80, 0.69, and 0.79 for capturing seizure time periods and an average accuracy of 0.91, 0.90, and 0.92 respectively for capturing seizure and non-seizure time periods. Median accuracy scores were higher among patients without hypoxic-ischemic encephalopathy (HIE; median = 1 for all three classifiers) than HIE patients (median = 0.92, 0.93, 0.93). Conclusion A clinically interpretable aEEG-CSA algorithm is feasible for neonatal seizure detection by extracting standard EEG features and coupling these features with a supervised ML classifier.","rel_num_authors":5,"rel_authors":[{"author_name":"Sylvia Edoigiawerie","author_inst":"University of Chicago"},{"author_name":"Julia Henry","author_inst":"AdventHealth for Children"},{"author_name":"Brett Beaulieu-Jones","author_inst":"University of Chicago"},{"author_name":"Henry David","author_inst":"University of Chicago"},{"author_name":"Naoum Issa","author_inst":"University of Chicago"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"Mindfulness mediates depressive symptom improvement during heated yoga: A secondary analysis of a randomized controlled trial","rel_doi":"10.64898\/2026.07.01.26353530","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.01.26353530","rel_abs":"Background. Despite growing evidence that lifestyle interventions reduce depressive symptoms, the psychological mechanisms underlying these effects remain poorly understood. This study examined whether mindfulness and rumination mediate the antidepressant effects of heated yoga (HY), a multicomponent intervention combining physical activity, attentional training, and thermoregulatory stress. Methods. This prespecified secondary mediation analysis builds on a randomized controlled trial in which 80 adults with moderate-to-severe depression (IDS-CR > 23) were randomized to 8 weeks of twice-weekly HY or waitlist control. Subsamples with complete mediator data contributed to rumination (n = 56) and mindfulness (n = 60) models. Causal mediation analyses with 10,000 bootstrap resamples estimated indirect effects on Week 8 depression severity via Week 4 mediator changes. Sensitivity analyses assessed unmeasured confounding required to nullify observed effects. ClinicalTrials.gov: NCT02607514. Results. As previously reported, HY produced significantly greater IDS-CR reductions at Week 8 versus controls (p < .001). HY was associated with decreased rumination (p < .01) and increased mindfulness (p < .001) at Week 4. Increased mindfulness was statistically consistent with mediating depressive symptom reductions (ACME: -2.71, 95% CI [-5.42, -0.99]), whereas decreased rumination was not (ACME: -2.41, 95% CI [-6.28, 0.43]). Results were resilient to sensitivity analyses. Conclusion. In this RCT of a behavioral lifestyle intervention, mindfulness but not rumination emerged as a statistically significant mediator of depressive symptom reductions, identifying mindfulness as a key candidate mechanism through which multicomponent lifestyle interventions may exert antidepressant effects and suggesting a target for optimizing behavioral treatments for depression.","rel_num_authors":29,"rel_authors":[{"author_name":"Daniel Copeland","author_inst":"Massachusetts Institute of Technology Institute for Medical Engineering and Science"},{"author_name":"Naoise Mac Giollabhui","author_inst":"Massachusetts General Hospital"},{"author_name":"Louisa Sylvia","author_inst":"Massachusetts General Hospital"},{"author_name":"Doga Cetinkaya","author_inst":"Massachusetts General Hospital"},{"author_name":"Serene  J. Puzak","author_inst":"Massachusetts General Hospital"},{"author_name":"Lindsey  B. Hopkins","author_inst":"Private Practice"},{"author_name":"Chris  C. Streeter","author_inst":"Boston University School of Medicine: Boston University Chobanian & Avedisian School of Medicine"},{"author_name":"Bettina  B. Hoeppner","author_inst":"Massachusetts General Hospital"},{"author_name":"Lisa Uebelacker","author_inst":"Butler Hospital"},{"author_name":"Jill Koontz","author_inst":"Blueprint Wellness, LLC"},{"author_name":"Simmie Foster","author_inst":"Massachusetts General Hospital"},{"author_name":"Christina Dording","author_inst":"Massachusetts General Hospital"},{"author_name":"Albert Yeung","author_inst":"Massachusetts General Hospital"},{"author_name":"Lauren  B. Fisher","author_inst":"Massachusetts General Hospital"},{"author_name":"Cristina Cusin","author_inst":"Massachusetts General Hospital"},{"author_name":"Felipe  A. Jain","author_inst":"Massachusetts General Hospital"},{"author_name":"Paola Pedrelli","author_inst":"Massachusetts General Hospital"},{"author_name":"Grace  A. Ding","author_inst":"Massachusetts General Hospital"},{"author_name":"Heather Raslan","author_inst":"Massachusetts General Hospital"},{"author_name":"Ashley  E. Mason","author_inst":"UCSF: University of California San Francisco"},{"author_name":"Paolo Cassano","author_inst":"Massachusetts General Hospital"},{"author_name":"Darshan  H. Mehta","author_inst":"Massachusetts General Hospital"},{"author_name":"Charles  L. Raison","author_inst":"University of Wisconsin-Madison"},{"author_name":"Christina Sauder","author_inst":"University of Wisconsin-Madison"},{"author_name":"Karen  K. Miller","author_inst":"Harvard Medical School"},{"author_name":"Brian  W. Anthony","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Maurizio Fava","author_inst":"Massachusetts General Hospital"},{"author_name":"David Mischoulon","author_inst":"Massachusetts General Hospital"},{"author_name":"Maren  B. Nyer","author_inst":"Massachusetts General Hospital"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"Integrating Causal Inference into Pharmacovigilance: Target Trial Emulations for Proactive Signal Detection of Atorvastatin Initiation in Medicare Beneficiaries","rel_doi":"10.64898\/2026.07.01.26356874","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.01.26356874","rel_abs":"Importance: Adverse drug events in older adults are a substantial public health burden, yet spontaneous reporting systems detect them poorly owing to underreporting and the lack of a defined population. These limitations are of particular concern for older adults, who are underrepresented in pre-approval trials yet at elevated risk owing to polypharmacy, multimorbidity, and age-related changes in drug metabolism. Objective: To develop and apply an active, claims-based pharmacovigilance framework using sequential target trial emulation to detect adverse drug event signals in older adults, with atorvastatin as the initial application. Methods: Using Medicare fee-for-service claims (2017-2019), we studied statin-naive beneficiaries aged 65 years or older following myocardial or cerebral infarction. We emulated up to 14 daily sequential trials from the discharge date, classifying patients as initiating atorvastatin (A1), initiating a different medication (A2), or no new medication (A0); the primary contrast was A1 versus A2. For each trial, incident outcomes were ascertained and classified into 552 outcomes based on the Clinical Classifications Software Refined categories. Per-protocol effects were estimated over a 6-month follow-up period using Fine-Gray regression models weighted by the inverse probability of treatment and censoring, treating death as a competing risk, with the false discovery rate controlled via the Benjamini-Hochberg procedure. A signal was declared when the q-value was 0.10 or lower and the subdistribution hazard ratio (sHR) was 1.20 or greater in any prespecified analytic stratum (sensitivity analyses used thresholds of q 0.20 or lower and sHR 1.20 or greater). Results: Of 70,130 eligible patients, 39,948 initiated atorvastatin (A1) and 19,182 initiated another new medication (A2); after weighting, baseline characteristics were closely balanced. After excluding outcomes with sparse cell counts, 295 outcomes were analyzed; five met the primary signal detection criteria: valve disorders (sHR 1.71, 1.20 to 2.43); sprains and strains (sHR 1.79, 1.26 to 2.54); general sensation\/perception symptoms (sHR 1.23, 95 percent CI 1.11 to 1.36); abnormal findings without diagnosis (sHR 1.55, 1.18 to 2.05); and prediabetes (sHR 1.71, 1.24 to 2.36). In the sensitivity analysis, we additionally detected posthemorrhagic anemia, hemorrhagic stroke, varicose veins, and other circulatory and skin conditions. Conclusions: An active, claims-based framework using sequential target trial emulation detected both expected and previously unrecognized adverse drug event signals following atorvastatin initiation in older adults, offering a systematic alternative to passive surveillance that can be extended to other commonly prescribed medications.","rel_num_authors":5,"rel_authors":[{"author_name":"Christopher G Rowan","author_inst":"Veritas Research Foundation, San Clemente, CA, USA"},{"author_name":"John Tazare","author_inst":"London School of Hygiene and Tropical Medicine, Department of Medical Statistics, London, UK"},{"author_name":"Minh Tran","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Shivani Srivastava","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Nancy A Dreyer","author_inst":"Dreyer Strategies LLC, Newton MA, USA"}],"rel_date":"2026-07-10","rel_site":"medrxiv"},{"rel_title":"N-Methyl-D-Aspartate receptors control in vivo striatal calcium and the updating of action policy","rel_doi":"10.64898\/2026.07.06.736480","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736480","rel_abs":"Animals must execute learned behaviors and update them when outcomes change, yet the neural substrates controlling this phenomenon are not fully understood. Here, we show that N-Methyl-D-Aspartate Receptors (NMDARs) in the dorsomedial striatum are necessary for learning from previously rewarded actions. Moreover, blocking of striatal NMDARs almost fully abolished striatal calcium dynamics, but not action potential activity, suggesting a unique function of NMDAR-driven striatal calcium activity in updating action policy.","rel_num_authors":4,"rel_authors":[{"author_name":"Alex A Legaria","author_inst":"Harvard University"},{"author_name":"Mason R Barrett","author_inst":"Washington University in St Louis"},{"author_name":"Jordyn E Czarny","author_inst":"Washington University in St Louis"},{"author_name":"Alexxai V Kravitz","author_inst":"Washington University in St Louis"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Dopamine Compensates for Amyloid-Induced Default Mode Network Dysfunction to Support Learning","rel_doi":"10.64898\/2026.07.07.736872","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.07.736872","rel_abs":"Throughout the preclinical phase of Alzheimer's disease (AD) {beta}-amyloid (A{beta}) accumulates preferentially within the default mode network (DMN), yet the functional and behavioural consequences of this pathological burden remain poorly understood. Using task-based fMRI combined with A{beta}, tau, and dopamine PET in cognitively normal older adults, we show that A{beta} burden impairs learning independent of tau, but this learning performance is recovered with higher dorsolateral striatal dopamine synthesis capacity. Investigating the neural mechanisms that support this learning, we observe that A{beta} positive individuals show attenuated DMN activity to error related feedback, a metric that relates to poorer learning. When estimating the effective connectivity during feedback, computational modelling reveals that A{beta} induces dis-inhibition of the DMN during error processing. Critically, dopamine synthesis capacity in the dorsolateral striatum rebalances effective connectivity between the DMN and frontostriatal network, thereby opposing A{beta} related disruption. These findings establish a systems-level framework in which A{beta} impairs learning by disrupting dynamic DMN modulation during feedback, a disruption for which dopaminergic function can partially compensate. This suggests that learning in the presence of A{beta} may be subserved by dopamine-dependent network rebalancing, a candidate mechanism of cognitive resilience to support learning in preclinical AD.","rel_num_authors":6,"rel_authors":[{"author_name":"Joseph Giorgio","author_inst":"University of California, Berkeley"},{"author_name":"Thomas M. Morin","author_inst":"Brandeis University"},{"author_name":"Hsiang-Yu Chen","author_inst":"Brandeis University"},{"author_name":"Anne S. Berry","author_inst":"Brandeis University"},{"author_name":"Michael Breakspear","author_inst":"University of Newcastle"},{"author_name":"William J Jagust","author_inst":"University of California, Berkeley"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Data-driven oscillatory network modeling with condition-dependent coupling laws: Identifying directed neural interactions in working memory attention dynamics","rel_doi":"10.64898\/2026.07.06.736523","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736523","rel_abs":"Learning new information in the presence of distracters and changing conditions requires the ability to adapt. In the brain, this adaptive capability has been linked to dynamic interactions between attention and working memory, which enable the selective filtering of irrelevant input while preserving behaviorally relevant information. Specific neural oscillations have been implicated in this process. Here, we introduce a phenomenological data-driven framework for oscillatory network modeling that learns condition-dependent coupling laws directly from neural recordings and enables inference of condition-dependent directed pathways. We apply our approach to magnetoencephalography (MEG) data collected while participants performed a working-memory task with and without distracters. Recall dynamics in the non-distracter condition are first modeled using a linear oscillatory network in which each region of interest is represented by two alpha-band harmonic oscillators. We use universal differential equations (UDE), an extension of neural differential equations, to capture distracter-induced changes in coupling laws. Symbolic regression is then used to interpret the modifications identified by UDE as nonlinear functions, and an additional method is proposed to identify the directed pathway from the newly emerging nonlinear terms in the dynamics of brain regions of interest. Despite inter-subject variability, working memory recall data from all four participants examined under distraction showed the emergence of a pathway from the dorsolateral prefrontal cortex (dlPFC) to the primary visual cortex (V1). This finding is consistent with the established role of the dlPFC in cognitive control and suggests that distracter processing recruits a directed interaction from prefrontal to visual regions. More broadly, our results illustrate that combining linear models whose parameters are learned from the data with universal differential equations augmented by interpretability methods enables the identification of condition-dependent coupling laws, their representation as interpretable mathematical functions, and the discovery of candidate directed pathways underlying adaptive changes in oscillatory networks without requiring strong prior assumptions about the underlying mechanisms.","rel_num_authors":4,"rel_authors":[{"author_name":"Mika Ohkawa","author_inst":"Delft University of Technology"},{"author_name":"Ying Joey Zhou","author_inst":"Oxford Centre for Human Brain Activity"},{"author_name":"Saskia Haegens","author_inst":"Department of Psychiatry, Columbia University"},{"author_name":"Matin Jafarian","author_inst":"Delft University of Technology"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"A microbial growth-coupled platform for in vivo interrogation of Rubisco oxygenase activity","rel_doi":"10.64898\/2026.07.10.737725","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737725","rel_abs":"Rubisco catalyzes the primary CO2-fixing reaction of the biosphere, yet its competing oxygenation reaction reduces net global carbon fixation and has resisted direct exploration in living cells. Here, we engineer an auxotrophic Escherichia coli strain in which 2-phosphoglycolate, the direct product of Rubisco oxygenation, becomes essential for growth, making bacterial fitness a quantitative proxy for oxygenation flux in vivo. This provides direct access to catalytic selectivity, something previously inaccessible to carboxylation-coupled assays. The platform enables screening of phylogenetically diverse Form II Rubisco and phosphoribulokinase (Prk) variants circumventing protein purification and extensive in vitro characterization. Adaptive laboratory evolution under oxygenation-selective pressure identified two mutations: Rubisco M115I genetically rebalances the in vivo carboxylation\/oxygenation trade-off (resulting in 6-fold reduction in kcat,C), while Prk N216T improves overall flux without altering selectivity. This platform makes Rubisco's least-studied catalytic function selectable and evolvable in vivo, opening the carboxylation\/oxygenation trade-off to systematic genetic dissection and engineering.","rel_num_authors":14,"rel_authors":[{"author_name":"Enrico Orsi","author_inst":"Technical University of Denmark"},{"author_name":"Kai Kabuth","author_inst":"Technical University of Denmark"},{"author_name":"Simone Cusimano","author_inst":"Technical University of Denmark"},{"author_name":"Mathias Herl\u00f8v-Wagner","author_inst":"Technical University of Denmark"},{"author_name":"Rutger Verbakel","author_inst":"Technical University of Denmark"},{"author_name":"Francesco Luppino","author_inst":"Technical University of Denmark"},{"author_name":"Michele Partipilo","author_inst":"Technical University of Denmark"},{"author_name":"Benoit de Pins","author_inst":"University of Naples Federico II"},{"author_name":"Elad Noor","author_inst":"Weizmann Institute of Science"},{"author_name":"Lena Maria H\u00fcmmler","author_inst":"Charit\u00e9 Universit\u00e4tsmedizin Berlin"},{"author_name":"Michael M\u00fclleder","author_inst":"Charit\u00e9 Universit\u00e4tsmedizin Berlin"},{"author_name":"Steffen N. Lindner","author_inst":"Charit\u00e9 Universit\u00e4tsmedizin Berlin"},{"author_name":"Markus Ralser","author_inst":"Charit\u00e9 Universit\u00e4tsmedizin Berlin"},{"author_name":"Pablo I. Nikel","author_inst":"Technical University of Denmark"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Redundant contacts and force redistribution stabilize limbless vertical climbing","rel_doi":"10.64898\/2026.07.06.736779","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736779","rel_abs":"Animals navigating complex vertical environments must secure stable footholds, a challenge for species without feet. While arboreal climbing has evolved repeatedly in snakes, the physical mechanisms they use to scale broad, nearly flat surfaces remain poorly understood. By measuring three-dimensional body kinematics and per-contact forces on a smooth vertical wall with protruding posts, we show that cornsnakes climb by dynamically balancing forces across a highly redundant network of 5 to 16 simultaneous contacts--far exceeding the three contacts minimally required for physical stability. Using a computational model and a robotic climber, we demonstrate that while simple body undulations and passive friction are mechanically sufficient to climb this terrain, snakes systematically deviate from this passive baseline. While downward climbing relies primarily on friction, ascending snakes actively generate positive mechanical work at their contacts to propel themselves. Furthermore, we found that whenever a snake engages a new contact, it triggers a stereotyped, system-wide redistribution of force that seamlessly integrates the new foothold without disrupting whole-body balance. These results reveal how a continuous, flexible body can transform sparse environmental features into a robust, fault-tolerant network. This mechanism provides a biomechanical framework for understanding the repeated evolution of limbless climbing and offers physical principles for designing agile robots for unstructured terrain.","rel_num_authors":6,"rel_authors":[{"author_name":"Calvin A Riiska","author_inst":"Emory University"},{"author_name":"Michelle Lee","author_inst":"Emory University"},{"author_name":"Yonatan Nemenman","author_inst":"Emory University"},{"author_name":"Gauge Thacker","author_inst":"Emory University"},{"author_name":"Joseph R Mendelson III","author_inst":"Zoo Atlanta, Georgia Institute of Technology"},{"author_name":"Jennifer M Rieser","author_inst":"Emory University"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Daylight, Daily Rhythms, and Downstream Physiology: A Translational Study in Diurnal Nile Grass Rats (Arvicanthis niloticus)","rel_doi":"10.64898\/2026.07.06.733427","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.733427","rel_abs":"The circadian system evolved under natural light\/dark cycles, whereas modern humans spend much of their time indoors under electric lighting that differs substantially from daylight in intensity, spectral composition, and temporal structure. How such lighting environments influence the circadian system has not been systematically examined in a diurnal model under ecologically relevant conditions. In this study, we used the diurnal Nile grass rat (Arvicanthis niloticus) to assess daily locomotor rhythms across four lighting conditions designed to approximate common human exposure scenarios: rectangular daylight (D65-R; ~5,600 lux), semi-sigmoidal daylight mimicking natural intensity dynamics (D65-S; matched peak intensity with ~50% lower cumulative energy), fluorescent indoor light (F12; ~150 lux), and fluorescent light supplemented with a one hour midday daylight pulse (F12+D65-P). Using a within subject design (n = 8), male grass rats were housed under each condition for two weeks. D65 R produced the highest daytime activity levels and the strongest day\/night activity ratio, consistent with robust circadian entrainment. Despite matching peak intensity, D65 S did not yield comparable circadian outcomes, indicating that cumulative photon exposure, rather than peak intensity alone, contributes to entrainment strength. Notably, the addition of a one hour midday daylight pulse (D65-P) partially increased circadian amplitude under otherwise fluorescent conditions, with higher periodogram amplitude relative to F12 alone. Another cohort of males was exposed to D65-R or F12 for six weeks (n = 10\/condition) to assess physiological outcomes, including metabolic and reproductive measures. Compared with the D65-R group, the F12 group exhibited a higher diabetic rate (40% vs. 10%) and reduced sperm motility (19 vs. 45 %), consistent with potential downstream consequence of circadian rhythm disruption. Together, these findings demonstrate that lighting conditions characteristic of indoor environments produce weaker circadian organization than daylight equivalent lighting in a diurnal rodent, which underscores the importance of light quality in shaping circadian rhythms and downstream physiological processes.","rel_num_authors":9,"rel_authors":[{"author_name":"Antony B. Kim","author_inst":"University of California, Berkeley"},{"author_name":"Katrina Linning-Duffy","author_inst":"Michigan State University"},{"author_name":"Melanie Balbach","author_inst":"Michigan State University"},{"author_name":"Nolan Lucera","author_inst":"Michigan State University"},{"author_name":"Marshall Delgado","author_inst":"Michigan State University"},{"author_name":"Nikhil Kummur","author_inst":"Michigan State University"},{"author_name":"Huishi Toh","author_inst":"Meharry Medical College"},{"author_name":"Luisa Caldas","author_inst":"University of California, Berkeley"},{"author_name":"Lily Yan","author_inst":"Michigan State University"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Daylight, Daily Rhythms, and Downstream Physiology: A Translational Study in Diurnal Nile Grass Rats (Arvicanthis niloticus)","rel_doi":"10.64898\/2026.07.06.733427","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.733427","rel_abs":"The circadian system evolved under natural light\/dark cycles, whereas modern humans spend much of their time indoors under electric lighting that differs substantially from daylight in intensity, spectral composition, and temporal structure. How such lighting environments influence the circadian system has not been systematically examined in a diurnal model under ecologically relevant conditions. In this study, we used the diurnal Nile grass rat (Arvicanthis niloticus) to assess daily locomotor rhythms across four lighting conditions designed to approximate common human exposure scenarios: rectangular daylight (D65-R; ~5,600 lux), semi-sigmoidal daylight mimicking natural intensity dynamics (D65-S; matched peak intensity with ~50% lower cumulative energy), fluorescent indoor light (F12; ~150 lux), and fluorescent light supplemented with a one hour midday daylight pulse (F12+D65-P). Using a within subject design (n = 8), male grass rats were housed under each condition for two weeks. D65 R produced the highest daytime activity levels and the strongest day\/night activity ratio, consistent with robust circadian entrainment. Despite matching peak intensity, D65 S did not yield comparable circadian outcomes, indicating that cumulative photon exposure, rather than peak intensity alone, contributes to entrainment strength. Notably, the addition of a one hour midday daylight pulse (D65-P) partially increased circadian amplitude under otherwise fluorescent conditions, with higher periodogram amplitude relative to F12 alone. Another cohort of males was exposed to D65-R or F12 for six weeks (n = 10\/condition) to assess physiological outcomes, including metabolic and reproductive measures. Compared with the D65-R group, the F12 group exhibited a higher diabetic rate (40% vs. 10%) and reduced sperm motility (19 vs. 45 %), consistent with potential downstream consequence of circadian rhythm disruption. Together, these findings demonstrate that lighting conditions characteristic of indoor environments produce weaker circadian organization than daylight equivalent lighting in a diurnal rodent, which underscores the importance of light quality in shaping circadian rhythms and downstream physiological processes.","rel_num_authors":9,"rel_authors":[{"author_name":"Antony B. Kim","author_inst":"University of California, Berkeley"},{"author_name":"Katrina Linning-Duffy","author_inst":"Michigan State University"},{"author_name":"Melanie Balbach","author_inst":"Michigan State University"},{"author_name":"Nolan Lucera","author_inst":"Michigan State University"},{"author_name":"Marshall Delgado","author_inst":"Michigan State University"},{"author_name":"Nikhil Kummur","author_inst":"Michigan State University"},{"author_name":"Huishi Toh","author_inst":"Meharry Medical College"},{"author_name":"Luisa Caldas","author_inst":"University of California, Berkeley"},{"author_name":"Lily Yan","author_inst":"Michigan State University"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Advanced Open-source Experimental-Design Tools for Microplate-Based Assays with Acoustic Liquid Handling","rel_doi":"10.64898\/2026.07.05.735934","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.05.735934","rel_abs":"Acoustic droplet ejection (ADE) enables nanoliter-scale liquid handling for complex microplate assays, yet translating experimental designs into validated, instrument-ready instructions remains a bottleneck. We present PickliPy, an open-source framework that converts spreadsheet-based assay designs into validated ADE picklists. PickliPy.Assay supports combinatorial, dose-response, and multi-addition time-course dispensing, while PickliPy.Screen extends to high-throughput workflows, including library reformatting and shortlisting. Across diverse biological contexts, the framework generated reproducible, assay-ready plates and standardized execution in human cohort studies. Acoustic pre-dispensing deepened bioenergetic phenotyping of isolated human skeletal muscle mitochondria, capturing substrate switching, and sharpened dose-response precision in human pancreatic {beta}-cells, revealing an age-associated change in succinate dehydrogenase kinetics. We benchmarked a wash-free, live-cell screen of mitochondrial function and morphology, in which deep-learning image analysis widened the assay window and ADE enabled integrative dose-response co-response analysis. Together, these tools make complex ADE experiments easier to design, reproduce, and scale from single benches to screening campaigns.","rel_num_authors":22,"rel_authors":[{"author_name":"Varunya M. Kattunga","author_inst":"Buck Institute for Research on Aging, Novato, CA, 94945, USA"},{"author_name":"Steven A. Wrobel","author_inst":"Buck Institute for Research on Aging, Novato, CA, 94945, USA"},{"author_name":"Chad A. Lerner","author_inst":"Buck Institute for Research on Aging, Novato, CA, 94945, USA"},{"author_name":"Victor M. Derycz","author_inst":"Buck Institute for Research on Aging, Novato, CA, 94945, USA"},{"author_name":"Elizabeth B. Stephens","author_inst":"Buck Institute for Research on Aging, Novato, CA, 94945, USA"},{"author_name":"Ian S. Brown","author_inst":"Buck Institute for Research on Aging, Novato, CA, 94945, USA"},{"author_name":"Hao Cheng","author_inst":"Buck Institute for Research on Aging, Novato, CA, 94945, USA"},{"author_name":"Sima Taghizadeh","author_inst":"Buck Institute for Research on Aging, Novato, CA, 94945, USA"},{"author_name":"Josef Byrne","author_inst":"Buck Institute for Research on Aging, Novato, CA, 94945, USA; University of Southern California, Leonard Davis School of Gerontology, 3715 McClintock Ave, Los A"},{"author_name":"Susan Gross","author_inst":"Buck Institute for Research on Aging, Novato, CA, 94945, USA"},{"author_name":"Susan Schneider","author_inst":"Buck Institute for Research on Aging, Novato, CA, 94945, USA"},{"author_name":"Chatura Senadheera","author_inst":"Buck Institute for Research on Aging, Novato, CA, 94945, USA"},{"author_name":"Asia Davis-Castillo","author_inst":"Buck Institute for Research on Aging, Novato, CA, 94945, USA"},{"author_name":"Shane Vistalli-Alvarado","author_inst":"Buck Institute for Research on Aging, Novato, CA, 94945, USA"},{"author_name":"Elena Goncharova","author_inst":"Buck Institute for Research on Aging, Novato, CA, 94945, USA"},{"author_name":"John C. Newman","author_inst":"Buck Institute for Research on Aging, Novato, CA, 94945, USA"},{"author_name":"Brianna J. Stubbs","author_inst":"Buck Institute for Research on Aging, Novato, CA, 94945, USA"},{"author_name":"Simon Melov","author_inst":"Buck Institute for Research on Aging, Novato, CA, 94945, USA"},{"author_name":"Gordon Lithgow","author_inst":"Buck Institute for Research on Aging, Novato, CA, 94945, USA"},{"author_name":"Lisa M. Ellerby","author_inst":"Buck Institute for Research on Aging, Novato, CA, 94945, USA"},{"author_name":"Julie K. Andersen","author_inst":"Buck Institute for Research on Aging, Novato, CA, 94945, USA"},{"author_name":"Akos A. Gerencser","author_inst":"Buck Institute for Research on Aging, Novato, CA, 94945, USA"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"The Energetic Cost of Adrenergic Signaling in Primary Human Fibroblasts","rel_doi":"10.64898\/2026.07.09.737569","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737569","rel_abs":"Stress involves the activation of cellular, physiological, and emotional processes that cost energy--nothing is free in biology. In mammals, the stress response involves hormone release, including norepinephrine (NE), which increases energy expenditure. To quantify the energetic cost of NE signaling in a simple cellular system, we interrogated the dose (0-10 M NE) and time-dependent (up to 10 hours) effects of adrenergic signaling in primary human fibroblasts. Oxygen consumption rates (OCR, reflecting ATP generated by mitochondria) and extracellular acidification rate (ECAR, reflecting ATP generated by glycolysis) were measured continuously using extracellular flux analysis, allowing us to estimate the ATP turnover rates, and thus cellular energy expenditure. Within the first 18 minutes (early phase), glycolysis increases up to 47% whereas respiration decreased 2-5%. Both parameters normalized within 1-2 hours for low NE concentrations. This was followed by an increase in oxidative phosphorylation (OxPhos), peaking around 9-12% by 2-6 hours (mid or late-phase). These minutes-to-hours data reveal the temporal dynamics whereby NE increases cellular energy expenditure in fibroblasts. Blocking OxPhos with oligomycin or piericidin A abolished OxPhos changes post-NE addition while conserving the glycolytic response. Withdrawal of glucose from the media significantly dampened the absolute rise in ECAR in response to NE, and instead increased OxPhos, revealing the metabolic flexibility in fibroblasts. Finally, cells with genetic defects impairing OxPhos exhibited a 50% blunted NE-driven metabolic response, consistent with the existence of an energy constraint in mitochondrial diseases. In summary, we have resolved the dynamics and flexible bioenergetic recalibrations associated with NE-driven hypermetabolism in primary human fibroblasts. Mapping the nature and magnitude of these recalibrations in humans would advance our understanding of the potential energetic forces underlying the damage to health by chronic stress.","rel_num_authors":3,"rel_authors":[{"author_name":"Janell Lisung Manley Smith","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Gabriel Sturm","author_inst":"Biohub, San Francisco, CA"},{"author_name":"Martin Picard","author_inst":"Columbia University Irving Medical Center"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Targeting Autophagy Accelerates Intestinal Repair after Acute Ionizing Radiation","rel_doi":"10.64898\/2026.07.06.736694","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736694","rel_abs":"Radiation exposure induces systemic and cellular damage, contributing to acute radiation syndrome and long-term effects such as premature aging and carcinogenesis. At the cellular level, radiation triggers apoptosis, mutation, and transformation through oxidative damage and activation of pathways including ER stress-mediated autophagy. Autophagy plays a context-dependent dual role in stressed cells, but its contribution to intestinal recovery after acute radiation remains unclear. Here, we evaluated combinatorial radiomodification using gamma radiation (8 Gy) and autophagy modulators in whole-body irradiated C57BL\/6 mice (8-10 weeks old, n = 10). Mice were treated with autophagy inducers or inhibitors and euthanized at 3-, 8-, and 30-day post-irradiation. The jejunal-ileal region was analyzed via antioxidant assays, immunoblotting, H&E staining, and immunohistochemistry. Radiation significantly altered oxidative stress and autophagy markers, including increased LC3-II and decreased SQSTM1\/p62. Autophagy induction enhanced intestinal proliferation (as measured by Ki-67), whereas inhibition impaired regeneration. Rapamycin pretreatment improved survival and reduced markers of intestinal injury following 8 Gy total body irradiation (TBI), whereas chloroquine exacerbated several injury-associated parameters. Overall, our findings suggest that targeted modulation of autophagy is a promising strategy for alleviating radiation-induced gastrointestinal injury and provide mechanistic insights relevant to therapeutic development.","rel_num_authors":4,"rel_authors":[{"author_name":"Madhuri Chaurasia","author_inst":"Weizmann Institute of Science"},{"author_name":"Aayushi Singh","author_inst":"Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, India"},{"author_name":"Krishnamurthy Natarajan","author_inst":"Dr. B. R. Ambedkar Center for Biomedical Research University of Delhi, India"},{"author_name":"KULBHUSHAN SHARMA","author_inst":"University of Oslo, Ahus Campus"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Circulating extracellular vesicles in plasma carry accessible molecular signatures of aging in mice","rel_doi":"10.64898\/2026.07.10.737625","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737625","rel_abs":"Cells release membrane-bound extracellular vesicles into the bloodstream laden with proteins that may reflect their physiological state. How this circulating EV proteome changes across life remains poorly understood. Identifying molecular signatures of aging in accessible biofluids could facilitate earlier intervention and monitoring of age-related disease. Many circulating aging proteome studies rely on affinity-based platforms which suffer from poor cross-species translation, ambiguous signal attribution, and inconsistent agreement between platforms. Here, we present a characterization of the aging plasma EV proteome from a cross-sectional cohort of 86 male and female C57BL\/6J mice (5-31 months). We leveraged a species-agnostic EV enrichment (Mag-Net) and mass spectrometry to detect 2,575 protein groups from 15,969 peptides. Protein abundance heterogeneity increased with age and the abundance of 272 proteins were significantly correlated with chronological age including established senescence and frailty markers. Proteins increasing with age were enriched in genome maintenance pathways, while those decreasing were associated with the extracellular matrix organization and lipid metabolism. Notably, several of the strongest age-increased proteins converged on Alzheimer's and Parkinson's disease pathology. We observed sexual divergence in the aging EV proteome not previously characterized at this resolution. A proteomic clock built from this data accurately predicts chronological age, and peptide-level analysis reveals aging signals invisible at protein-level. These findings demonstrate that EV-enriched plasma proteomics can identify known aging markers, reveal novel sex-specific age-related changes, and generate predictive models of chronological age. This study provides a species-agnostic foundation for proteomic clocks that complement epigenetic approaches to monitor aging and evaluate healthspan.","rel_num_authors":11,"rel_authors":[{"author_name":"Kristine A Tsantilas","author_inst":"Department of Genome Sciences, University of Washington, 1705 NE Pacific Street, Seattle, Washington 98195, United States"},{"author_name":"Michael Riffle","author_inst":"Department of Genome Sciences, University of Washington, 1705 NE Pacific Street, Seattle, Washington 98195, United States"},{"author_name":"Gennifer E Merrihew","author_inst":"Department of Genome Sciences, University of Washington, 1705 NE Pacific Street, Seattle, Washington 98195, United States"},{"author_name":"Christine C Wu","author_inst":"Department of Genome Sciences, University of Washington, 1705 NE Pacific Street, Seattle, Washington 98195, United States"},{"author_name":"Gregory R Keele","author_inst":"The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine, 04609, United States"},{"author_name":"Aaron Maurais","author_inst":"Department of Genome Sciences, University of Washington, 1705 NE Pacific Street, Seattle, Washington 98195, United States"},{"author_name":"Richard S Johnson","author_inst":"Department of Genome Sciences, University of Washington, 1705 NE Pacific Street, Seattle, Washington 98195, United States"},{"author_name":"Alison Luciano","author_inst":"The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine, 04609, United States"},{"author_name":"Laura Robinson","author_inst":"The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine, 04609, United States"},{"author_name":"Gary A Churchill","author_inst":"The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine, 04609, United States"},{"author_name":"Michael J MacCoss","author_inst":"Department of Genome Sciences, University of Washington, 1705 NE Pacific Street, Seattle, Washington 98195, United States"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Therapeutic targeting of MYC- and MYCN-driven medulloblastoma with a novel MYC degrader molecule","rel_doi":"10.64898\/2026.07.09.737604","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737604","rel_abs":"Background: Medulloblastoma (MB) is the most common malignant brain tumour in children, and aggressive subgroups are frequently driven by the oncoproteins MYC or MYCN. Direct therapeutic targeting of MYC\/MYCN has been challenging because of their intrinsically disordered protein structures. The aim of this study was to determine whether novel SE486-11 analogues (UNSW-SCs) can therapeutically target MYC\/MYCN-driven MB. Methods: The anticancer activity of UNSW-SCs was assessed in MB cell lines with differential MYC\/MYCN expression. Target engagement was evaluated using surface plasmon resonance and drug affinity responsive target stability assays. Blood-brain barrier penetration, MYC\/MYCN protein degradation, cell cycle effects, apoptosis, DNA damage, and synergy with histone deacetylase (HDAC) inhibitors were examined. Therapeutic efficacy was evaluated in murine models of MYC- and MYCN-driven human MB. Results: UNSW-SCs showed potent anticancer activity, with preferential selectivity toward MB cells expressing high MYC\/MYCN levels and IC50 values ranging from 0.22 to 1.18 M. The lead molecule, UNSW-SC-22, directly bound MYC, crossed the blood-brain barrier, and achieved a brain-to-plasma ratio of 1.44 at peak concentrations. UNSW-SC-22 induced MYC\/MYCN-dependent cytotoxicity associated with enhanced proteasomal degradation, cell cycle arrest, apoptosis, and DNA damage. Combined treatment with HDAC inhibitors further reduced MYC\/MYCN protein levels, increased DNA damage, and enhanced apoptosis. In vivo, UNSW-SC-22, either alone or with entinostat, significantly suppressed intracranial tumour growth and prolonged survival. Conclusions: UNSW-SC-22 is a brain-penetrant MYC\/MYCN-targeting molecule with potent preclinical activity in MYC\/MYCN-driven MB, supporting its development as a monotherapy or combination strategy with HDAC inhibition.","rel_num_authors":19,"rel_authors":[{"author_name":"Sin Wi Ng","author_inst":"Childrens Cancer Institute"},{"author_name":"Satyanarayana Gadde","author_inst":"Childrens Cancer Institute"},{"author_name":"Nga-yee Chung","author_inst":"Childrens Cancer Institute"},{"author_name":"Qian Wang","author_inst":"Childrens Cancer Institute"},{"author_name":"Larissa Doughty","author_inst":"Bio21 Molecular Science and Biotechnology Institute"},{"author_name":"Tracy L Nero","author_inst":"Bio21 Molecular Science and Biotechnology Institute"},{"author_name":"Nisitha Jayatilleke","author_inst":"Childrens Cancer Institute"},{"author_name":"Janith Seneviratne","author_inst":"Childrens Cancer Institute"},{"author_name":"Daniel R Carter","author_inst":"University of Technology Sydney"},{"author_name":"Marion K Mateos","author_inst":"Childrens Cancer Institute"},{"author_name":"Maria Tsoli","author_inst":"Childrens Cancer Institute"},{"author_name":"David S Ziegler","author_inst":"Childrens Cancer Institute"},{"author_name":"Raelene Endersby","author_inst":"The Kids Research Institute Australia and Centre for Child Health Research"},{"author_name":"Naresh Kumar","author_inst":"School of Chemistry, UNSW Sydney"},{"author_name":"Louis Chesler","author_inst":"Childrens Cancer Institute"},{"author_name":"Tao Liu","author_inst":"Childrens Cancer Institute"},{"author_name":"Michael W Parker","author_inst":"Bio21 Molecular Science and Biotechnology Institute"},{"author_name":"Belamy B Cheung","author_inst":"Childrens Cancer Institute"},{"author_name":"Glenn M Marshall","author_inst":"Childrens Cancer Institute"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"A chronic interorgan wound response appropriated by Drosophila tumors to induce intestinal inflammation","rel_doi":"10.64898\/2026.07.03.735641","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.735641","rel_abs":"Tumors exploit wound healing pathways not only to foster progression but also to lethally disrupt systemic physiology. A prominent example is malignant activation of the clotting cascade, causing pathology through unclear mechanisms that extend beyond thrombosis. Here we show that tumors in a coagulopathy-inducing Drosophila cancer model remotely disrupt intestinal stem cell (ISC) homeostasis. This paraneoplastic, tumor-gut communication axis induces intestinal dysplasia and barrier dysfunction, mimicking remote chronic injury that we show activates inflammation in ISCs via EGFR signaling. Unlike the interorgan responses observed with acute injury, which involves Jak\/STAT signaling to activate regenerative ISC proliferation, dysregulated division in both tumor-bearing and chronically injured flies is sustained only by EGFR activation. We also present evidence that deposition of clot material locally onto gut stroma links tumor-driven coagulopathy to intestinal inflammation. Collectively, these findings distinguish mechanisms of remote responses to chronic versus transient stresses. Furthermore, they show how tumor-initiated, dysregulated wound healing programs can drive tissue-specific, pathological inflammation in a host.","rel_num_authors":4,"rel_authors":[{"author_name":"Katy Lauren Ong","author_inst":"Unviersity of California, Berkeley"},{"author_name":"Jan Mikhale B Cajulao","author_inst":"University of California, Berkeley"},{"author_name":"Karina Mai Anders","author_inst":"University of California, Berkeley"},{"author_name":"David Bilder","author_inst":"University of California, Berkeley"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"LYNX: a deep generative model for linking spatial dynamics and cellinteractions in multimodal spatial data","rel_doi":"10.64898\/2026.07.09.737574","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737574","rel_abs":"Tissues are spatially organized systems in which cell states, functions and interactions vary across spatial coordinates, forming compartments or gradients shaped by local microenvironments. Understanding how molecular features and cell-cell interactions change across space and time is central to studying development, homeostasis and disease. Addressing these questions increasingly requires the integration of multi-modal spatial data, which provides complementary views of cellular and structural organization. However, existing computational approaches typically combine modalities by weighting them equally, overlooking domain-specific technical artifacts, differences in spatial resolution and non-overlapping feature spaces. In addition, methods for spatial cell-cell communication analysis are largely developed for single-modality settings and do not model how interactions vary across the tissue. To address these gaps, we introduce LYNX, a deep generative framework that learns a shared latent representation of spatial dynamics from joint-measured modalities in the 2D or 3D domain, to provide a unified coordinate system for modeling how cell-cell interactions, phenotypes, and molecular programs vary along continuous spatial gradients. LYNX identifies spatial programs difficult to resolve with existing approaches, including metabolically coupled porto-central interaction remodeling in liver, recovery of degraded proteomic signals along the cortico-medullary axis in thymus, and branching trajectories towards DCIS and invasive niches marked by distinct stromal activation-states and immune-tumor crosstalk in breast tumor microenvironment. We demonstrate that LYNX robustly infers spatially resolved gradients, maps functional compartments and cell-cell interactions along spatial axes and is compatible across diverse spatial profiling technologies, modalities, and resolution disparities. LYNX provides a foundational and scalable framework to advance our understanding of healthy tissue physiology and to decode temporal evolution of complex diseases.","rel_num_authors":9,"rel_authors":[{"author_name":"Yinuo Jin","author_inst":"Columbia University"},{"author_name":"Joshua Myers","author_inst":"Columbia University"},{"author_name":"Presha Rajbhandari","author_inst":"Columbia University"},{"author_name":"Jia Yi Zhang","author_inst":"Columbia University"},{"author_name":"Kaylee Fang","author_inst":"Columbia University"},{"author_name":"John Shaw Moazami","author_inst":"Columbia University"},{"author_name":"Noreen Hosny","author_inst":"Princeton University"},{"author_name":"Brent Stockwell","author_inst":"Columbia University"},{"author_name":"Elham Azizi","author_inst":"Columbia University"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Field-Correcting GRAPPA (FCG): a technique to correctspatiotemporal-varying phase errors in Echo Planar Imaging","rel_doi":"10.64898\/2026.07.10.737642","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737642","rel_abs":"Purpose: To develop a Field-Correcting GRAPPA (FCG) technique to correct the spatiotemporal-varying phase errors in EPI caused by eddy currents. Methods: The fast-changing gradient in EPI causes strong eddy current effects and associated spatiotemporal-varying phase errors, producing significant image artifacts. The use of higher gradient amplitude, slew rate, and ramp sampling factor for faster imaging exacerbates this problem. In this work, FCG was developed to address this challenge by using a multi-layer perceptron (MLP) to provide a compact representation of a family of GRAPPA-like kernels that correct the spatiotemporal-varying phase errors in the data. A dedicated calibration pipeline was designed to acquire high-quality source and target data for MLP training in both slice-by-slice and simultaneous multi-slice (SMS) acquisitions. To validate FCG's assumptions and performance, a field camera was used to provide ground-truth measurement of phase patterns. The performance of FCG was further validated on phantom and in vivo experiments using demanding EPI trajectories across multiple 3T and 7T systems. Results: Field camera measurements revealed strong spatiotemporal phase variations along the kx direction that repeat along ky during EPI readouts. The experiments on high-performance systems across 3T and 7T demonstrate that FCG can provide superior correction for the artifacts induced by spatiotemporal-varying phase errors compared with existing approaches. Conclusion: FCG is an effective and robust method for correcting spatiotemporal phase errors in EPI, enabling improved image quality on high-performance systems.","rel_num_authors":19,"rel_authors":[{"author_name":"Nan Wang","author_inst":"Radiology Department, Stanford University, California, USA"},{"author_name":"Daniel Abraham","author_inst":"Radiology Department, Stanford University, California, USA"},{"author_name":"Zachary Shah","author_inst":"Radiology Department, Stanford University, California, USA"},{"author_name":"Yimeng Lin","author_inst":"Radiology Department, Stanford University, California, USA"},{"author_name":"Xiaozhi Cao","author_inst":"Radiology Department, Stanford University, California, USA"},{"author_name":"Hua Wu","author_inst":"Cognitive and Neurobiological Imaging Center, Stanford University, California, USA"},{"author_name":"Jonathan Polimeni","author_inst":"Radiology Department, Stanford University, California, USA"},{"author_name":"Renzo Huber","author_inst":"Mass General Research Institute, Harvard Medical School, Massachusetts, USA"},{"author_name":"Qiang Liu","author_inst":"Department of Psychiatry, Mass General Brigham, Harvard Medical School, Massachusetts, USA"},{"author_name":"Lipeng Ning","author_inst":"Department of Psychiatry, Mass General Brigham, Harvard Medical School, Massachusetts, USA"},{"author_name":"Yogesh Rathi","author_inst":"Department of Psychiatry, Mass General Brigham, Harvard Medical School, Massachusetts, USA"},{"author_name":"Carl-Fredrik Westin","author_inst":"Department of Psychiatry, Mass General Brigham, Harvard Medical School, Massachusetts, USA"},{"author_name":"Hendrik Mattern","author_inst":"Biomedical Magnetic Resonance, Otto von Guericke University Magdeburg, Magdeburg, Germany"},{"author_name":"Oliver Speck","author_inst":"Biomedical Magnetic Resonance, Otto von Guericke University Magdeburg, Magdeburg, Germany"},{"author_name":"Baolian Yang","author_inst":"GE HealthCare Technology Innovation Center, GE Healthcare, New York, USA"},{"author_name":"Nastaren Abad","author_inst":"GE Healthcare, GE Healthcare, New York, USA"},{"author_name":"Congyu Liao","author_inst":"Radiology Department, Stanford University, California, USA"},{"author_name":"Adam Kerr","author_inst":"Electrical Engineering, Stanford University, California, USA"},{"author_name":"Kawin Setsompop","author_inst":"Radiology Department, Stanford University, California, USA"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Interplay between ferroptosis and guttae in an early-onset murine model of Fuchs endothelial corneal dystrophy (FECD)","rel_doi":"10.64898\/2026.07.09.737597","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737597","rel_abs":"Col8a2Q455K\/Q455K (Q455K) mice exhibit features of early-onset Fuchs endothelial corneal dystrophy (FECD), including decreased endothelial cell density (ECD) and guttae formation. Within the context of these clinical features, this study longitudinally evaluates ferroptosis in Q455K and wild-type (WT) mice using in vivo imaging, PCR and immunohistochemistry. Fifty-six Q455K and 56 WT mice were evaluated from 3 to 24 months of age with in vivo confocal microscopy; ECD and guttae were measured. Ferroptosis marker expression was determined with PCR and immunohistochemistry (IHC). Data were analyzed using two-way ANOVA with Tukeys post hoc test, Chi-square test and a paired t-test. The ECD significantly decreased in both groups from 3 to 24 months of age, but more markedly in Q455K (2285-\/+317 to 1012-\/+58 cells\/mmSquare) versus WT mice (2714-\/+139 to 2057-\/+149 cells\/mmSquare, P<0.0001). Guttae were observed exclusively in Q455K mice beginning at 3 months of age and increased over time (P=0.0003). The Q455K mice demonstrate guttae at the vertices of corneal endothelial cells rather than their centers (74.3% vs. 25.7%P<0.001). Expression of ferroptosis-related genes (Tfrc, Slc40a1, Ftl1, Gpx4) were significantly increased in the Q455K versus WT mice (P<0.05). Furthermore, corresponding protein expression (transferrin receptor 1, ferroportin, ferritin and glutathione peroxidase 4) was significantly elevated adjacent to guttae in Q455K versus WT mice (P<0.05). These findings implicate guttae in the initiation of ferroptosis as it relates to the pathophysiology of FECD and provide an optimal window for testing novel FECD therapies using this murine model, particularly those that target ferroptosis.","rel_num_authors":20,"rel_authors":[{"author_name":"Karin W. Handel","author_inst":"UC Davis"},{"author_name":"Jaegook Lim","author_inst":"UC Davis"},{"author_name":"Hiroko Iwashita","author_inst":"UC Davis"},{"author_name":"Sabina Khan","author_inst":"UC Davis"},{"author_name":"Hanna Shevalye","author_inst":"Univ. of Iowa"},{"author_name":"Sangwan Park","author_inst":"UC Davis"},{"author_name":"Nayeli Echeverria","author_inst":"UC Davis"},{"author_name":"Michelle Ferneding","author_inst":"UC Davis"},{"author_name":"Meher J. Khan","author_inst":"UC Davis"},{"author_name":"Karolina P. Roszak","author_inst":"UC Davis"},{"author_name":"Gabriella L. Donovan","author_inst":"UC Davis"},{"author_name":"Mako Iwamoto","author_inst":"UC Davis"},{"author_name":"Jaeho Shim","author_inst":"UC Davis"},{"author_name":"Laura J. Young","author_inst":"UC Davis"},{"author_name":"Monica Ardon","author_inst":"UC Davis"},{"author_name":"Sophie M. Le","author_inst":"UC Davis"},{"author_name":"Brian C. Leonard","author_inst":"UC Davis"},{"author_name":"Jessica M. Skeie","author_inst":"Univ. of Iowa"},{"author_name":"Mark Greiner","author_inst":"University of Iowa, Carver College of Medicine"},{"author_name":"Sara Thomasy","author_inst":"UC Davis"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Interplay between ferroptosis and guttae in an early-onset murine model of Fuchs endothelial corneal dystrophy (FECD)","rel_doi":"10.64898\/2026.07.09.737597","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737597","rel_abs":"Col8a2Q455K\/Q455K (Q455K) mice exhibit features of early-onset Fuchs endothelial corneal dystrophy (FECD), including decreased endothelial cell density (ECD) and guttae formation. Within the context of these clinical features, this study longitudinally evaluates ferroptosis in Q455K and wild-type (WT) mice using in vivo imaging, PCR and immunohistochemistry. Fifty-six Q455K and 56 WT mice were evaluated from 3 to 24 months of age with in vivo confocal microscopy; ECD and guttae were measured. Ferroptosis marker expression was determined with PCR and immunohistochemistry (IHC). Data were analyzed using two-way ANOVA with Tukeys post hoc test, Chi-square test and a paired t-test. The ECD significantly decreased in both groups from 3 to 24 months of age, but more markedly in Q455K (2285-\/+317 to 1012-\/+58 cells\/mmSquare) versus WT mice (2714-\/+139 to 2057-\/+149 cells\/mmSquare, P<0.0001). Guttae were observed exclusively in Q455K mice beginning at 3 months of age and increased over time (P=0.0003). The Q455K mice demonstrate guttae at the vertices of corneal endothelial cells rather than their centers (74.3% vs. 25.7%P<0.001). Expression of ferroptosis-related genes (Tfrc, Slc40a1, Ftl1, Gpx4) were significantly increased in the Q455K versus WT mice (P<0.05). Furthermore, corresponding protein expression (transferrin receptor 1, ferroportin, ferritin and glutathione peroxidase 4) was significantly elevated adjacent to guttae in Q455K versus WT mice (P<0.05). These findings implicate guttae in the initiation of ferroptosis as it relates to the pathophysiology of FECD and provide an optimal window for testing novel FECD therapies using this murine model, particularly those that target ferroptosis.","rel_num_authors":20,"rel_authors":[{"author_name":"Karin W. Handel","author_inst":"UC Davis"},{"author_name":"Jaegook Lim","author_inst":"UC Davis"},{"author_name":"Hiroko Iwashita","author_inst":"UC Davis"},{"author_name":"Sabina Khan","author_inst":"UC Davis"},{"author_name":"Hanna Shevalye","author_inst":"Univ. of Iowa"},{"author_name":"Sangwan Park","author_inst":"UC Davis"},{"author_name":"Nayeli Echeverria","author_inst":"UC Davis"},{"author_name":"Michelle Ferneding","author_inst":"UC Davis"},{"author_name":"Meher J. Khan","author_inst":"UC Davis"},{"author_name":"Karolina P. Roszak","author_inst":"UC Davis"},{"author_name":"Gabriella L. Donovan","author_inst":"UC Davis"},{"author_name":"Mako Iwamoto","author_inst":"UC Davis"},{"author_name":"Jaeho Shim","author_inst":"UC Davis"},{"author_name":"Laura J. Young","author_inst":"UC Davis"},{"author_name":"Monica Ardon","author_inst":"UC Davis"},{"author_name":"Sophie M. Le","author_inst":"UC Davis"},{"author_name":"Brian C. Leonard","author_inst":"UC Davis"},{"author_name":"Jessica M. Skeie","author_inst":"Univ. of Iowa"},{"author_name":"Mark Greiner","author_inst":"University of Iowa, Carver College of Medicine"},{"author_name":"Sara Thomasy","author_inst":"UC Davis"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Interplay between ferroptosis and guttae in an early-onset murine model of Fuchs endothelial corneal dystrophy (FECD)","rel_doi":"10.64898\/2026.07.09.737597","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737597","rel_abs":"Col8a2Q455K\/Q455K (Q455K) mice exhibit features of early-onset Fuchs endothelial corneal dystrophy (FECD), including decreased endothelial cell density (ECD) and guttae formation. Within the context of these clinical features, this study longitudinally evaluates ferroptosis in Q455K and wild-type (WT) mice using in vivo imaging, PCR and immunohistochemistry. Fifty-six Q455K and 56 WT mice were evaluated from 3 to 24 months of age with in vivo confocal microscopy; ECD and guttae were measured. Ferroptosis marker expression was determined with PCR and immunohistochemistry (IHC). Data were analyzed using two-way ANOVA with Tukeys post hoc test, Chi-square test and a paired t-test. The ECD significantly decreased in both groups from 3 to 24 months of age, but more markedly in Q455K (2285-\/+317 to 1012-\/+58 cells\/mmSquare) versus WT mice (2714-\/+139 to 2057-\/+149 cells\/mmSquare, P<0.0001). Guttae were observed exclusively in Q455K mice beginning at 3 months of age and increased over time (P=0.0003). The Q455K mice demonstrate guttae at the vertices of corneal endothelial cells rather than their centers (74.3% vs. 25.7%P<0.001). Expression of ferroptosis-related genes (Tfrc, Slc40a1, Ftl1, Gpx4) were significantly increased in the Q455K versus WT mice (P<0.05). Furthermore, corresponding protein expression (transferrin receptor 1, ferroportin, ferritin and glutathione peroxidase 4) was significantly elevated adjacent to guttae in Q455K versus WT mice (P<0.05). These findings implicate guttae in the initiation of ferroptosis as it relates to the pathophysiology of FECD and provide an optimal window for testing novel FECD therapies using this murine model, particularly those that target ferroptosis.","rel_num_authors":20,"rel_authors":[{"author_name":"Karin W. Handel","author_inst":"UC Davis"},{"author_name":"Jaegook Lim","author_inst":"UC Davis"},{"author_name":"Hiroko Iwashita","author_inst":"UC Davis"},{"author_name":"Sabina Khan","author_inst":"UC Davis"},{"author_name":"Hanna Shevalye","author_inst":"Univ. of Iowa"},{"author_name":"Sangwan Park","author_inst":"UC Davis"},{"author_name":"Nayeli Echeverria","author_inst":"UC Davis"},{"author_name":"Michelle Ferneding","author_inst":"UC Davis"},{"author_name":"Meher J. Khan","author_inst":"UC Davis"},{"author_name":"Karolina P. Roszak","author_inst":"UC Davis"},{"author_name":"Gabriella L. Donovan","author_inst":"UC Davis"},{"author_name":"Mako Iwamoto","author_inst":"UC Davis"},{"author_name":"Jaeho Shim","author_inst":"UC Davis"},{"author_name":"Laura J. Young","author_inst":"UC Davis"},{"author_name":"Monica Ardon","author_inst":"UC Davis"},{"author_name":"Sophie M. Le","author_inst":"UC Davis"},{"author_name":"Brian C. Leonard","author_inst":"UC Davis"},{"author_name":"Jessica M. Skeie","author_inst":"Univ. of Iowa"},{"author_name":"Mark Greiner","author_inst":"University of Iowa, Carver College of Medicine"},{"author_name":"Sara Thomasy","author_inst":"UC Davis"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Glk1p is an actin fold metabolic enzyme whose polymerization is sensitive to nucleotide state","rel_doi":"10.64898\/2026.07.09.731748","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.731748","rel_abs":"The actin fold is present in enzymes ranging from sugar kinases to chaperones. Previous work on the actin fold metabolic enzyme, glucokinase (Glk1p) in S. cerevisiae found it could form filaments in response to its substrates, ATP and glucose (Stoddard et al., 2020). Here, we have identified the product, glucose 6-phosphate (G6P), as a second trigger for Glk1p polymerization in vitro. Furthermore, the addition of ADP to G6P-Glk1p filaments causes filament disassembly, suggesting that polymerization is sensitive to the state of the bound nucleotide and\/or the transfer of the gamma phosphate. We have also identified a specific metabolic state, the accumulation of G6P during stationary phase, that triggers Glk1p polymerization in vivo. While the structures of Glk1p filaments in either the ATP\/glucose or G6P-bound form are not similar to conventional actin filaments, the sensitivity of assembly to the gamma phosphate of the nucleotide provides a conceptual bridge between the cytoskeleton and metabolic regulation via enzyme polymerization.","rel_num_authors":7,"rel_authors":[{"author_name":"Michael D Carver","author_inst":"UC Berkeley"},{"author_name":"Phillip Kyriakakis","author_inst":"Stanford"},{"author_name":"Elena Monfort","author_inst":"Universidad Miguel Hernandez"},{"author_name":"Rachel M Barry","author_inst":"University of California, Irvine"},{"author_name":"Andres E Leschziner","author_inst":"Weill Cornell Medicine"},{"author_name":"Mark A Herzik","author_inst":"University of California, San Diego"},{"author_name":"Jim Wilhelm","author_inst":"University of California, San Diego"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Glk1p is an actin fold metabolic enzyme whose polymerization is sensitive to nucleotide state","rel_doi":"10.64898\/2026.07.09.731748","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.731748","rel_abs":"The actin fold is present in enzymes ranging from sugar kinases to chaperones. Previous work on the actin fold metabolic enzyme, glucokinase (Glk1p) in S. cerevisiae found it could form filaments in response to its substrates, ATP and glucose (Stoddard et al., 2020). Here, we have identified the product, glucose 6-phosphate (G6P), as a second trigger for Glk1p polymerization in vitro. Furthermore, the addition of ADP to G6P-Glk1p filaments causes filament disassembly, suggesting that polymerization is sensitive to the state of the bound nucleotide and\/or the transfer of the gamma phosphate. We have also identified a specific metabolic state, the accumulation of G6P during stationary phase, that triggers Glk1p polymerization in vivo. While the structures of Glk1p filaments in either the ATP\/glucose or G6P-bound form are not similar to conventional actin filaments, the sensitivity of assembly to the gamma phosphate of the nucleotide provides a conceptual bridge between the cytoskeleton and metabolic regulation via enzyme polymerization.","rel_num_authors":7,"rel_authors":[{"author_name":"Michael D Carver","author_inst":"UC Berkeley"},{"author_name":"Phillip Kyriakakis","author_inst":"Stanford"},{"author_name":"Elena Monfort","author_inst":"Universidad Miguel Hernandez"},{"author_name":"Rachel M Barry","author_inst":"University of California, Irvine"},{"author_name":"Andres E Leschziner","author_inst":"Weill Cornell Medicine"},{"author_name":"Mark A Herzik","author_inst":"University of California, San Diego"},{"author_name":"Jim Wilhelm","author_inst":"University of California, San Diego"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"HSV-1 hijacks the DNA repair protein RAD51 at gene promoters to drive viral transcription","rel_doi":"10.64898\/2026.07.09.737117","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737117","rel_abs":"Productive infection by Herpes Simplex Virus type 1 (HSV-1) requires initiation of efficient viral gene expression. Upon nuclear entry, HSV-1 genomes are associated with several cellular factors, including DNA repair proteins. It is unclear how these cellular factors impact viral processes at early stages of infection. In this study, we investigate the role of RAD51, a core homologous recombination (HR) factor. We measured nascent viral transcription and show that RAD51 plays a pro-viral role in infection by promoting immediate-early viral gene expression. We demonstrate that RAD51 binds GC-rich gene promoter of ICP4 and directly promotes gene expression. We also reveal a previously unknown interaction between RAD51 and ADNP, a subunit of the ChAHP complex, known for its role in transcription regulation. We propose a model where RAD51 binds incoming genomes at promoter regions regulating the genome landscape and allowing for efficient transcription initiation.","rel_num_authors":14,"rel_authors":[{"author_name":"Namrata Kumar","author_inst":"The Children's Hospital of Philadelphia"},{"author_name":"Laura E.M. Dunn","author_inst":"Cornell University"},{"author_name":"Tanner M. Tessier","author_inst":"The Children's Hospital of Philadelphia"},{"author_name":"Katharina E.M. Hayer","author_inst":"The Children's Hospital of Philadelphia"},{"author_name":"Sireen Sweed","author_inst":"Tel Aviv University"},{"author_name":"Maya Ralph-Altman","author_inst":"Tel Aviv University"},{"author_name":"Holly M. Chan","author_inst":"The Children's Hospital of Philadelphia"},{"author_name":"Brandon G. Waxman","author_inst":"The Children's Hospital of Philadelphia"},{"author_name":"Edwin Halko","author_inst":"The Children's Hospital of Philadelphia"},{"author_name":"Yuval Altman","author_inst":"Independent Researcher"},{"author_name":"Jonathan Korner","author_inst":"Independent Researcher"},{"author_name":"Oren Kobiler","author_inst":"Tel Aviv University"},{"author_name":"Joel D. Baines","author_inst":"Cornell University"},{"author_name":"Matthew D. Weitzman","author_inst":"The Children's Hospital of Philadelphia"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Actin nucleation promoting factors drive Arp2\/3 dependent endosomal microautophagy","rel_doi":"10.64898\/2026.07.09.737473","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737473","rel_abs":"Autophagy is a catabolic process that degrades damaged organelles and aggregation-prone proteins and plays key roles during development and in maintaining cellular homeostasis. It can be induced by stress including starvation, oxidative stress, or accumulation of misfolded proteins. Autophagy declines with age and there is great interest in manipulating autophagy to improve neurodegenerative diseases, as its stimulation shows promise to improve diseases including Huntington, Alzheimer, and Parkinson. Endosomal microautophagy (e-MI) is a type of autophagy in which cytosolic proteins are delivered to late endosomes and degraded upon incorporation into intraluminal vesicles of multivesicular bodies. Here, we report that the actin nucleation-promoting factors (NPFs) known to activate the Arp2\/3 complex to promote branched actin assembly can alter the dynamics of e-MI. We found that upon stress exposure, overexpression of the NPFs WASp, Wash, or SCAR results in an expedited induction of e-MI. Strikingly, Wash is uniquely required for physiological e-MI induction implying that NPFs are not functionally redundant for e-MI. We show that the WASH complex regulates e-MI on late endosomes acting via Arp2\/3 and thus likely branched actin. Surprisingly, the regulation of e-MI by Wash is independent of retromer that is known to recruit Wash to early endosomes for its role in recycling of membrane proteins and rather reflects a novel degradative aspect of Wash function. Taken together, we identified a novel function of NPFs as upstream regulators of e-MI that could be used to activate e-MI ectopically to improve aggregate clearance during neurodegeneration.","rel_num_authors":2,"rel_authors":[{"author_name":"Satya Surabhi","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Andreas Jenny","author_inst":"Albert Einstein College of Medicine"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Interplay of Proactive and Reactive Control in Language Production","rel_doi":"10.64898\/2026.07.09.737628","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737628","rel_abs":"Language production requires the coordination of multiple cognitive processes. The ability to anticipate and override a habitual response in favor of a contextually-appropriate response are key subprocesses of cognitive control which enable speakers to communicate effectively. Word retrieval involves the co-activation of semantically related alternatives from which the speaker must select the appropriate target representation. Although cognitive control mechanisms have been proposed to contribute to resolving semantic interference during language production, the nature of these control processes remain unclear. Studies investigating the temporal dynamics of cognitive control during decision making tasks have led to a distinction between two operating processes: proactive control, initiated prior to the occurrence of conflict, and reactive control recruited after conflict is detected. We investigated the roles of proactive and reactive control in resolving interference between competing linguistic representations during word retrieval. We analyzed congruency sequence effects combined with delta-plot distributional analyses to dissociate potential adjustments in proactive versus reactive cognitive control in a picture-naming task manipulating semantic context compared to a minimally-linguistic Stroop-like paradigm. Reaction time distributional properties following semantically related trials revealed the engagement of proactive control in semantic interference resolution during word retrieval in the PWI task. In contrast, reactive inhibitory control was engaged in resolving semantic interference following low conflict trials. This distinction was not present in the minimally-linguistic task, which did not appear to engage adaptive control to the same extent. These findings demonstrate that both proactive and reactive cognitive control mechanisms contribute to language production, and are engaged dynamically, adjusting trial-by-trial to resolve semantic interference during word retrieval. In addition, our study provides important insight into the comparison of language with other cognitive domains and positions linguistic paradigms as being instrumental in the study of cognitive control dynamics.","rel_num_authors":3,"rel_authors":[{"author_name":"Katherine D Andrade","author_inst":"University of California, San Diego\/San Diego State University"},{"author_name":"Dakota L. Melton","author_inst":"San Diego State University"},{"author_name":"Stephanie K Ries","author_inst":"San Diego State University"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"A single dynamical property can account for the capacity to learn, from artificial networks to the mammalian brain.","rel_doi":"10.64898\/2026.07.09.737603","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737603","rel_abs":"Every brain must adapt to an unpredictable world, yet individuals differ in how readily they learn. Theoretical work suggests that learning is fastest when a system, whether biological or synthetic, is initialized in a state close to instability - i.e., near criticality - because critical dynamics are imbued with a diverse repertoire of patterns and multi-scale correlations. Here, we empirically estimate distance to criticality in the brain and show that it predicts the rate of adaptability underlying learning, neuronal tuning, and general intelligence. In mouse motor cortex, proximity to criticality forecasts learning rate of two future complex tasks: prey capture hunt and ladder crossing. In contrast, distance to criticality predicted neither an animal's naive ability nor its asymptotic skill - isolating the rate of learning itself. In visual cortex of young ferrets, proximity to criticality predicts how strongly experience reshapes neural tuning. In human frontal cortex, it correlates with general cognitive ability. A minimal recurrent network model reproduced these results and offers a mechanism: proximity to criticality defines the timescale over which a system can learn from its past experiences, directly setting the rate of learning. A single dynamical property can account for the capacity to learn, from artificial networks to the mammalian brain.","rel_num_authors":14,"rel_authors":[{"author_name":"Keith B Hengen","author_inst":"Washington University In St. Louis"},{"author_name":"Ravi Chopra","author_inst":"Washington University in Saint Louis"},{"author_name":"Juntao Zhong","author_inst":"Washington University in Saint Louis"},{"author_name":"Ezra S Miller","author_inst":"Washington University in Saint Louis"},{"author_name":"Gemechu Bekele Tolossa","author_inst":"Washington University in Saint Louis"},{"author_name":"Leandro J Fosque","author_inst":"Washington University in Saint Louis"},{"author_name":"Jordan A Meza","author_inst":"Washington University in Saint Louis"},{"author_name":"Nicholas W DeKorver","author_inst":"Washington University in Saint Louis"},{"author_name":"Rejean Guerriero","author_inst":"Washington University in Saint Louis"},{"author_name":"Neil J Ritter","author_inst":"Brandeis University"},{"author_name":"Mary E Lambo","author_inst":"Washington University in Saint Louis"},{"author_name":"Kiran Bhaskaran-Nair","author_inst":"Washington University in Saint Louis"},{"author_name":"Stephen D Van Hooser","author_inst":"Brandeis University"},{"author_name":"Woodrow Shew","author_inst":"University of Arkansas"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"An internal PDZ-binding motif in Densin-180 promotes activity-dependent SHANK scaffold remodelling","rel_doi":"10.64898\/2026.07.07.736929","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.07.736929","rel_abs":"SHANK proteins form core postsynaptic density (PSD) scaffolds that organise synaptic signalling complexes through multiple protein-protein interaction domains, including PDZ domains that typically recognise C-terminal peptide motifs. Here, we identify an internal PDZ recognition mechanism that links the synaptic protein Densin-180 to SHANK and promotes SHANK scaffold assembly. We map SHANK binding to an internal PDZ-binding motif in Densin-180 (residues 843-863) and show by NMR spectroscopy and fluorescence polarisation that this motif binds SHANK1-3 PDZ domains with high affinity and specificity, competing with canonical C-terminal ligands. The crystal structure of the Densin-180-SHANK complex reveals that Phe858 inserts into the hydrophobic pocket of the PDZ domain despite the absence of a terminal carboxylate. In neurons, this interaction mediates Densin-180 recruitment to dendritic spines and drives activity-dependent reorganisation of postsynaptic SHANK3 assemblies, whereas mutation of Phe858 disrupts both processes. Disrupting the Densin-180-SHANK interaction using a Densin-180-derived peptide impairs activity-dependent structural plasticity of spines, accompanied by defects in PSD organisation and actin cytoskeleton remodelling. These findings define an internal mode of PDZ recognition and reveal how Densin-180 couples neuronal activity to the remodelling of postsynaptic SHANK scaffolds.","rel_num_authors":9,"rel_authors":[{"author_name":"Yasumi Otani","author_inst":"University of Liverpool"},{"author_name":"Vignesh Srinivasan","author_inst":"University of Helsinki"},{"author_name":"Julia T\u00f6ller","author_inst":"University Medical Center Hamburg-Eppendorf"},{"author_name":"Till Kallem","author_inst":"University of Liverpool"},{"author_name":"Neil Ball","author_inst":"University of Liverpool"},{"author_name":"Igor Barsukov","author_inst":"University of Liverpool"},{"author_name":"Juha Saarikangas","author_inst":"University of Helsinki"},{"author_name":"Hans-J\u016drgen Kreienkamp","author_inst":"University Medical Center Hamburg-Eppendorf"},{"author_name":"Benjamin Thomas Goult","author_inst":"University of Liverpool"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"The exchange dynamics of client molecules in biomolecular condensates","rel_doi":"10.64898\/2026.07.06.736877","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.06.736877","rel_abs":"Biomolecular condensates are dynamic assemblies whose functions depend on continuous exchange of molecular components with the surrounding environment. While scaffold molecules drive phase separation and condensate architecture, many functional components are clients that are recruited through interactions with the scaffold-rich environment. Despite their prevalence, how client-scaffold interactions shape client exchange dynamics remains poorly understood. Here, we develop a reaction-diffusion model for client exchange in scaffold-driven condensates, in which clients switch between a scaffold-bound state and an unbound state. Bound clients exchange through scaffold-mediated transport, whereas unbound clients diffuse through the pore space of the condensate. Using the fluorescence recovery of fully photobleached condensates as a measure of client exchange, we compare transport through these two pathways with bound-unbound conversion and identify three limiting regimes. In the slow-conversion regime, bound and unbound clients recover through distinct scaffold- and pore-mediated pathways. In the intermediate-conversion regime, recovery of bound clients becomes limited by client unbinding. In the fast-conversion regime, local equilibrium between bound and unbound clients produces an effective single-state recovery. We further propose a unifying description that connects these regimes and quantitatively captures the apparent recovery timescales extracted from numerical simulations across condensate sizes. Our results provide a framework for interpreting component-specific exchange dynamics, and highlight client size, client-scaffold binding, and condensate porosity as key regulators of client turnover in multicomponent condensates.","rel_num_authors":3,"rel_authors":[{"author_name":"Ross Kliegman","author_inst":"Johns Hopkins University"},{"author_name":"Vladimir Grigorev","author_inst":"Johns Hopkins University"},{"author_name":"Yaojun Zhang","author_inst":"Johns Hopkins University"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Programmable CRISPRtune dissects the transcriptional repressive activity of MeCP2","rel_doi":"10.64898\/2026.07.08.737375","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737375","rel_abs":"The ability to control the expression of human genes is a major goal in synthetic biology, enables dissection of gene function, and can be harnessed for therapeutic applications. Advances in genome editing and transcriptional engineering often result in complete gene inactivation or full transcriptional repression. However, programmable tools to dial transcription at intermediate levels remain challenging. Here, we present CRISPRtune - a synthetic fusion of MeCP2 to catalytically dead dCas9 that tunes down transcription of endogenous genes in human cells by harnessing the mild repressor activity of MeCP2. Using pooled genome-scale CRISPR screens, we tune the expression of thousands of endogenous genes and define the targeting rules of CRISPRtune in human cells. With a platform to target MeCP2 at defined genomic sites, we show the direct epigenetic changes induced by MeCP2 at gene promoters and we identify its genetic dependency partners for productive transcriptional repression. Rett syndrome-associated mutations of MeCP2 show defects for transcriptional repression due to their failure to remodel the local epigenetic landscape of target genes. Together, we present a programmable method for transcriptional tuning in mammalian cells and offer an orthogonal platform to dissect the mechanistic function of chromatin regulators in living cells.","rel_num_authors":13,"rel_authors":[{"author_name":"Jinna I Brim","author_inst":"University of California, Berkeley"},{"author_name":"Izaiah J Ornelas","author_inst":"University of California, Berkeley"},{"author_name":"Peter J Colias","author_inst":"University of California, Berkeley"},{"author_name":"Nikita S Divekar","author_inst":"University of California, Berkeley"},{"author_name":"Da Xu","author_inst":"University of California, Berkeley"},{"author_name":"Justin P Lubin","author_inst":"University of California, Berkeley"},{"author_name":"Sophia I Ferrel","author_inst":"University of California, Berkeley"},{"author_name":"Luis Gal\u00e1n Palma","author_inst":"University of California, Berkeley"},{"author_name":"Mitzi G Hern\u00e1ndez Zamora","author_inst":"University of California, Berkeley"},{"author_name":"Rithu K Pattali","author_inst":"University of California, Berkeley"},{"author_name":"Jameel J McDaniel","author_inst":"University of California, Berkeley"},{"author_name":"Sarah E Chasins","author_inst":"University of California, Berkeley"},{"author_name":"James K Nu\u00f1ez","author_inst":"University of California, Berkeley"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Convergent evolutionary selection unravels the genetic basis of audition in moths","rel_doi":"10.64898\/2026.07.08.736348","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.736348","rel_abs":"Hearing in Lepidoptera mediates a range of ecologically important behaviours, including mate communication, predator avoidance, and acoustic signalling. In moths, the evolution of predator-prey interactions with bats has further shaped hearing through a sensory arms race, with repeated co-option of auditory organs to detect and evade echolocating predators. Despite significant prior characterization of the neurophysiology and behaviour of hearing in moths, the genetic basis of hearing is poorly understood in most insects. In this study, we identify a core set of putative auditory genes in Lepidoptera using a combination of homology-based searches from Drosophila and evolutionary rate analyses. We find 56 genes present across all species and investigate whether gene copy number varies among non-hearing and hearing lineages and among 3 different ear types. We discovered seven genes associated with ear type and one with ear presence, but did not find significant losses in gene copy number in non-hearing species. We identified three genes (btv, Dnai2, and nompB) with strong evidence of selection in hearing clades and five genes with weaker evidence of selection. We discuss the potential roles of btv, nompB, and Dnai2 in ciliary transport and the aging of hair cells, as well as the possibility of actively amplified hearing. Our study serves as a primer and resource for further gene mining and functional testing of auditory genes in moths and other insects.","rel_num_authors":8,"rel_authors":[{"author_name":"Scott D Cinel","author_inst":"McGuire Center for Lepidoptera and Biodiversity, Florida Museum of Natural History, University of Florida, Gainesville, FL 32611 USA"},{"author_name":"Quentin Flattmann","author_inst":"Department of Biology, Case Western Reserve University, Cleveland, OH 44106 USA"},{"author_name":"Chandra Earl","author_inst":"National Ecological Observatory Network Biorepository, Arizona State University, Tempe, AZ 85282 USA"},{"author_name":"Emily Ellis","author_inst":"McGuire Center for Lepidoptera and Biodiversity, Florida Museum of Natural History, University of Florida, Gainesville, FL 32611 USA"},{"author_name":"Jesse Barber","author_inst":"Center for Biodiversity and Conservation, Division of Invertebrate Zoology, American Museum of Natural History, New York, NY 10024 USA"},{"author_name":"Yash Sondhi","author_inst":"Department of Biology, Case Western Reserve University, Cleveland, OH 44106 USA"},{"author_name":"Natasha D Mhatre","author_inst":"Department of Biology, University of Western Ontario, London, ON N6A 5B7 Canada"},{"author_name":"Akito Y Kawahara","author_inst":"McGuire Center for Lepidoptera and Biodiversity, Florida Museum of Natural History, University of Florida, Gainesville, FL 32611 USA"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Learning the wiring rules of a mammalian cortical column","rel_doi":"10.64898\/2026.07.09.737432","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737432","rel_abs":"Characterization of neural circuits' architecture typically relies on measurable neuronal features such as morphology, molecular identity, and spatial location. While generative models leveraging these properties have proven accurate, they remain constrained by available measurements and our assumptions regarding the prospective features. Here, we present an alternative approach using representational learning and use it to model the circuitry of a column of the mouse primary visual cortex. Our framework learns jointly low-dimensional embeddings of neurons in an abstract feature space alongside wiring rules that predict synaptic connectivity. These embedding-based models accurately predict individual synapses, connectivity degrees, and network motif statistics -- outperforming standard generative models that depend on detailed cell-type classifications -- using only a handful of embedding dimensions and wiring rules. Crucially, the learned representations prove interpretable, recapitulating cortical depth, cell type, and dendritic morphology. The resulting wiring blueprint is both simple and biologically meaningful, suggesting that cortical connectivity follows surprisingly parsimonious logic. This framework offers a general and exportable tool for learning minimal generative models of connectomes.","rel_num_authors":2,"rel_authors":[{"author_name":"Oren Richter","author_inst":"Weizmann Institute of Science"},{"author_name":"Elad Schneidman","author_inst":"Weizmann Institute of Science"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"TAOK3 inhibition constrains invasion, potentiates paclitaxel, and reprograms the tumor microenvironment toward anti-tumor immunity in cervical cancer","rel_doi":"10.64898\/2026.07.04.736128","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.04.736128","rel_abs":"TAOK3 is a lesser-studied MAPK family serine\/threonine kinase our group has shown to be targeted by HPV integration, suggesting a potential role in driving invasive cervical cancer (ICC). Here, we profiled TAOK3 expression in patient tumors, metastases, and cervical cancer models and localized TAOK3 within a tumor epithelial subpopulation by integrating two single-cell RNA-seq datasets. Functional consequences of TAOK3 loss were assessed with siRNA and CRISPRi in cell lines and 3D spheroids. In vivo effects were evaluated in intracervical xenografts with species-specific RNA-seq to resolve tumor versus microenvironmental responses. TAOK3 mRNA\/protein were elevated in primary and metastatic ICC and primarily localized to a keratin-positive epithelial subset (T3epi) enriched for cadherin\/S100 binding, vesicle\/endocytic pathways, and leading-edge programs. TAOK3 silencing reprogrammed transcriptomes and proteomes toward reduced WNT\/cell-cycle and motility signaling, altered endocytosis and cytoskeleton organization, and reshaped phospho-networks linked to chromatin remodeling and ERBB2-ERBB3\/cytoskeletal kinase activity. Functionally, TAOK3 inhibition prolonged G2\/M, suppressed invasion, and enhanced sensitivity to low dose paclitaxel. Prolonged inactivation induced methuosis-like cell death with extracellular ATP release. In xenografts, TAOK3 knockdown reduced tumor burden, downregulated KRT14--a leader cell marker--within the human tumor compartment, and enriched microenvironmental pathways for immune activation, with a specific decrease in CD206+ M2 macrophages. TAOK3 delineates an invasion-competent epithelial state in ICC and coordinates cell-cycle control, cytoskeleton-membrane dynamics, and tumor-immune crosstalk. Genetic or pharmacologic TAOK3 inhibition constrains tumor growth, potentiates paclitaxel, and remodels the microenvironment toward anti-tumor immunity, supporting TAOK3 as a potential therapeutic target and biomarker in ICC.\n\nStatement of SignificanceTAOK3 marks an invasion-competent epithelial subpopulation in cervical cancer. TAOK3 inhibition slows tumor growth, enhances chemoresponse, and reduces M2 macrophages, revealing TAOK3 as a potential therapeutic target and biomarker for patient stratification.","rel_num_authors":19,"rel_authors":[{"author_name":"Marissa Iden","author_inst":"Medical College of Wisconsin"},{"author_name":"Rachel Schmidt","author_inst":"Medical College of Wisconsin"},{"author_name":"Rameesa Darul Amne Syed Mohammed","author_inst":"Medical College of Wisconsin"},{"author_name":"Theresa A Dlugi","author_inst":"Medical College of Wisconsin"},{"author_name":"Roshan Kumar","author_inst":"Medical College of Wisconsin"},{"author_name":"Shirng-Wern Tsaih","author_inst":"Medical College of Wisconsin"},{"author_name":"Bakhtiyor Nosirov","author_inst":"Medical College of Wisconsin"},{"author_name":"Ishaque P Kadamberi","author_inst":"Medical College of Wisconsin"},{"author_name":"Sonam Mittal","author_inst":"Washington University"},{"author_name":"Shruti L Narayan","author_inst":"Medical College of Wisconsin"},{"author_name":"William H Bradley","author_inst":"Medical College of Wisconsin"},{"author_name":"Beth Erickson","author_inst":"Medical College of Wisconsin"},{"author_name":"Rebecca C Czaja","author_inst":"Medical College of Wisconsin"},{"author_name":"Juan C Felix","author_inst":"Medical College of Wisconsin"},{"author_name":"Victor X Jin","author_inst":"Medical College of Wisconsin"},{"author_name":"Akinyemi I Ojesina","author_inst":"Medical College of Wisconsin"},{"author_name":"Sunila Pradeep","author_inst":"Medical College of Wisconsin"},{"author_name":"Janet S Rader","author_inst":"Medical College of Wisconsin"},{"author_name":"Brian C Smith","author_inst":"Medical College of Wisconsin"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Endotome as a Source of Human Peri-Aortic Brown Adipocytes","rel_doi":"10.64898\/2026.07.04.735132","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.04.735132","rel_abs":"Brown adipocytes (BAs) hold therapeutic promise for obesity and metabolic diseases. While interscapular BAs derive from Pax3+\/Myf5+ dermomyotome, peri-aortic BAs are inferred from an unknown Pax3+\/Myf5- somitic origin. Here, we identify human endotome as an MYF5-independent source of peri-aortic BAs. Through interrogating public mouse organogenesis and in-house human trunk embryoid single-cell data, we show that the early endotome cells are MYF5-independent and are primed by TGF-{beta}-induced epithelial-to-mesenchymal transition. Mechanistically, endotome-to-BA specification requires sequential BMP inhibition and Wnt activation. This roadmap results in UCP1-expressing and metabolically active BAs that transcriptionally resemble in vivo peri-aortic BAT. The multipotent endotome cells also give rise to vascular smooth muscle and endothelial cells, offering a self-sufficient source for BAT vasculature. Endotome-derived BAs show accelerated differentiation, reduced heterogeneity, and sustained Wnt activity. Thus, the endotome provides a versatile platform for generating BAs and supporting vasculature, with implications for cell-based therapy and tissue engineering in metabolic disease.","rel_num_authors":8,"rel_authors":[{"author_name":"Hao Yu","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Weiman Xiang","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Kexin Teng","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Ethel S.K. Ng","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Angel Y.F. Kam","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Siwakorn Punyawatthananukool","author_inst":"Mahidol University"},{"author_name":"Stephen Dalton","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Tianming Wu","author_inst":"The Chinese University of Hong Kong"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"APOBEC3-driven neoantigen-rich cancers co-opt 1q23.3 amplification for tumor-intrinsic immune cloaking","rel_doi":"10.64898\/2026.07.01.735125","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735125","rel_abs":"Hypermutational processes, including those driven by the APOBEC3 family of cytidine deaminases, generate abundant neoantigens yet give rise to tumors that evade immune recognition. Here, using multi-omics analyses followed by functional validation, we identified a tumor-intrinsic immune-cloaking mechanism in neoantigen-rich epithelial cancers, characterized by coordinated suppression of antigen presentation, immune-recruiting cytokines and immune-checkpoint programs. In bladder cancer, genome-wide copy-number analysis identified recurrent 1q23.3 amplification as a genomic feature of a neoantigen-high\/CD8-low tumor state. Within this locus, NECTIN4 emerged as the dominant candidate effector, outperforming extrachromosomal DNA status as a predictor of immune-neoantigen discordance. Similar associations were observed across breast and lung cancers. Functional studies demonstrated that NECTIN4 was sufficient to establish a T-cell-poor tumor microenvironment and confer resistance to PD-1 blockade in immunocompetent mice. Mechanistically, NECTIN4 engaged a DDR1-SHP2 axis that suppressed STAT1 phosphorylation, silencing tumor-cell immune-engagement programs. NECTIN4 blockade restored STAT1 activity and reduced tumor growth, indicating that the cloaked state is pharmacologically reversible. Mutational signature, breakpoint motif, timing and clonality analyses, together with APOBEC3B expression and germline genetic evidence, linked APOBEC3-mediated mutagenesis to recurrent 1q23.3 amplification encompassing NECTIN4. These findings reveal how neoantigen-generating mutational processes can be coupled to structural genome evolution to enable tumor-intrinsic immune cloaking through a therapeutically targetable NECTIN4-DDR1-SHP2 axis.","rel_num_authors":19,"rel_authors":[{"author_name":"Dhanusha Yesudhas","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Bilal Lone","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Ecem Unal","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Arup Chakraborty","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Ayse G. Keskus","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Jaimie Ryou","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Kelly Butler","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Tania Colon Aquino","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Abbas Yousefi-Rad","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Weiming Yang","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Lisa M Jenkins","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Raju Chelluri","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Elias B. A. Chandran","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Vladimir A. Valera Romero","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Salah Boudjadi","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Sandeep Gurram","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Mikhail Kolmogorov","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Andrea B. Apolo","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"A. Rouf Banday","author_inst":"National Cancer Institute, National Institutes of Health"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Adaptive 2.5D base-pairing subgraph search detects RNA small-molecule binding sites","rel_doi":"10.64898\/2026.07.07.737024","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.07.737024","rel_abs":"Ribo-LENS is a geometric deep-learning framework for detecting small-molecule binding sites in RNA structures. It is designed to exploit two properties of RNA base-pairing networks: their robustness to conformational fluctuation and the functional signatures they encode. By reasoning directly in the space of base-pairing subgraphs, Ribo-LENS assembles coherent binding sites, in contrast to methods that score residues independently. In extensive experiments, Ribo-LENS is competitive with, and often outperforms, large all-atom co-folding models (AlphaFold3, Chai-1), fine-tuned language models (GerNA-Bind), and structure-based tools (RNAsite), raising mean MCC to 0.380 (versus 0.321 for the state-of-the-art GerNA-Bind). It is strongly robust to apo\/holo rearrangement, with its accuracy tracking the base-pairing graph (Spearman rho = 0.82 with binding-site graph edit distance) rather than backbone displacement (rho = -0.15 with RMSD), and depends far less on sequence homology than competing predictors. In an end-to-end, sequence-based virtual screen of the ROBIN assay (approximately 25,000 compounds), Ribo-LENS guides docking to a small predicted pocket, matching a blind all-atom cavity search (enrichment factors up to 6.1) at a fraction of the search cost; on two SARS-CoV-2 targets its predicted sites align with NMR chemical-shift perturbations. Ribo-LENS turns coarse base-pairing structure into a practical entry point for screening the vast, largely unexplored RNA target space.","rel_num_authors":3,"rel_authors":[{"author_name":"David Nitchi","author_inst":"McGill University"},{"author_name":"Jerome Waldispuhl","author_inst":"McGill University"},{"author_name":"Carlos Oliver","author_inst":"Vanderbilt University"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Xeno-Free Peptide-Functionalized Hydrogels Support hiPSC Encapsulation and In Situ Differentiation into Structurally Mature Cardiomyocytes","rel_doi":"10.64898\/2026.07.08.737331","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737331","rel_abs":"While defined synthetic substrates can replace Matrigel for human induced pluripotent stem cell (hiPSC) culture and hiPSC-derived cardiomyocyte (hiPSC-CM) production, existing approaches culture cells on two-dimensional surfaces and yield structurally immature cardiomyocytes, limiting their use in disease modeling and regenerative medicine. Here, we developed a xeno-free, fully-defined cyclic RGD (cRGD)-functionalized alginate platform in which we encapsulated hiPSCs to support their expansion and in situ cardiac differentiation. cRGD functionalization was essential for hiPSC survival and pluripotency, with maximal support achieved at a low ligand density (25 M). In the presence of cRGD, hiPSC encapsulation into softer gels made from lower molecular weight alginates led to enhanced hiPSC expansion and improved cardiogenesis. Strikingly, differentiation in situ with 3D gels led to hiPSC-CM with higher structural maturity, including a markedly increased proportion of Desmin positive cardiomyocytes. Finally, after enzymatic retrieval from hydrogels, cardiomyocytes derived from softer gels formed tissue-engineered myocardium with superior contractile force compared to tissue fashioned from hiPSC-CM derived from more rigid gels. Together, these results demonstrate the promise of this defined, tunable platform for biomanufacturing of structurally mature cardiomyocytes from hiPSC.","rel_num_authors":8,"rel_authors":[{"author_name":"Mohammadjafar Hashemi","author_inst":"Washington University in St. Louis"},{"author_name":"Nongmaithem Debeni Devi","author_inst":"Washington University in St. Louis"},{"author_name":"Yasaman Kargar Gaz Kooh","author_inst":"Washington University in St. Louis"},{"author_name":"Charlotte Chen","author_inst":"Washington University in St. Louis"},{"author_name":"Bahareh Bahmani","author_inst":"Washington University in St. Louis"},{"author_name":"Ganesh Malayath","author_inst":"Washington University in St. Louis"},{"author_name":"Julia Victor","author_inst":"Washington University in St. Louis"},{"author_name":"Nathaniel Huebsch","author_inst":"Washington University in Saint Louis"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Denuded peptidoglycan oligosaccharides enable the biochemical investigation of bacterial cell wall recognition, modification, and degradation","rel_doi":"10.64898\/2026.07.08.737370","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737370","rel_abs":"Peptidoglycan is an essential component of the bacterial cell wall, providing mechanical strength and maintaining cell shape. It consists of glycan chains crosslinked by short peptide stems, resulting in a chemically heterogeneous macromolecule that remains challenging to study in a well-defined form. Access to discrete peptidoglycan fragments has therefore been critical for advancing biochemical and structural studies of cell wall-active enzymes. However, current synthetic, semi-synthetic, and cell wall extraction approaches remain limited by the complexity of carbohydrate chemistry and the difficulty of isolating pure, well-defined material. Here, we report a facile enzymatic approach for generating defined, denuded peptidoglycan oligosaccharides from the cell walls of two Staphylococcus species. These oligosaccharides, which terminate in N-acetylglucosamine and range from two to five disaccharide units in length, serve as substrates for a diverse panel of peptidoglycan-active enzymes that cleave or chemically modify the glycan backbone. We further show that these denuded oligosaccharides can be used in lysozyme-catalyzed transglycosylation reactions to generate p-nitrophenyl derivatives, enabling continuous colorimetric monitoring of peptidoglycan-cleaving enzymes. This method provides a practical route to defined peptidoglycan glycans and establishes a platform for further structural diversification, including stem peptide reattachment, quantitative enzyme assays, and structural characterization of peptidoglycan-binding proteins.","rel_num_authors":6,"rel_authors":[{"author_name":"Benjamin G Emmanuel","author_inst":"University of Waterloo"},{"author_name":"Grace DelMistro","author_inst":"University of Waterloo"},{"author_name":"Alexander C Anderson","author_inst":"University of Guelph"},{"author_name":"Chris Vandenende","author_inst":"University of Guelph"},{"author_name":"Anthony J Clarke","author_inst":"University of Guelph"},{"author_name":"David Sychantha","author_inst":"University of Waterloo"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Tracing developmental and adult hematopoiesis with an endogenous zebrafish runx1-2A-CreERT2 CRISPR knock-in","rel_doi":"10.64898\/2026.07.03.736368","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736368","rel_abs":"Zebrafish combines the power of genetics and unparalleled in vivo imaging for investigating the dynamics of vertebrate hematopoietic development. Across species, the transcription factor Runx1 is essential for definitive hematopoiesis. We generated a zebrafish runx1-2A-creERT2 CRISPR knock-in for tamoxifen-regulated Cre recombinase Runx1 lineage tracing and characterized its activity using the ubi:Switch recombinase-dependent fluorescence reporter, microscopic live imaging and flow cytometry. Tamoxifen treatment beginning at gastrula stage labeled all expected Runx1 lineages in the early embryo, including neuroectodermal olfactory placode and Rohan-Beard neurons, primitive hematopoietic blood cells, and nascent hematopoietic stem and progenitor cells (HSPCs) in the dorsal aorta. Runx1 HSPCs colonized the larval caudal hematopoietic tissue and thymus from three to five days of development. Timed tamoxifen induction of Cre activity allowed separation of Runx1 primitive hematopoiesis from definitive HSPC emergence and larval stem cell niche colonization. Flow cytometry of kidney marrow and peripheral blood from adults treated with tamoxifen at gastrula stage revealed Runx1 embryonic hematopoietic cells contributed to adult hematopoietic precursors, myeloid, lymphoid, and peripheral blood lineages. Labeling of all blood lineages was also effective by tamoxifen treatment of 5-month-old adults. The zebrafish runx1-2A-creERT2 line provides a powerful tool for precise spatial and temporal analysis of Runx1 progenitor mechanisms in developmental and adult hematopoiesis.\n\nKey PointsO_LIzebrafish endogenous runx1-2A-creERT2 provides inducible Cre recombinase genetic analysis in all runx1 neuromesodermal and blood lineages\nC_LIO_LIzebrafish runx1-2A-creERT2 line enables in vivo spatial and temporal analysis of embryonic and adult hematopoiesis\nC_LI","rel_num_authors":7,"rel_authors":[{"author_name":"James A Preston","author_inst":"Iowa State University"},{"author_name":"Masuma K Usha","author_inst":"Iowa State University"},{"author_name":"Stephen C Ekker","author_inst":"University of Texas at Austin"},{"author_name":"Karl J Clark","author_inst":"Texas AandM University, College Station, Texas, US"},{"author_name":"Jeffrey Essner","author_inst":"Iowa State University"},{"author_name":"Raquel Espin Palazon","author_inst":"Iowa State University"},{"author_name":"Maura McGrail","author_inst":"Iowa State University"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Single-molecule m6A profiling reveals position-dependent mRNA regulation and non-canonical roles for Ythdf2 in early embryogenesis","rel_doi":"10.64898\/2026.07.03.736379","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736379","rel_abs":"The maternal-to-zygotic transition (MZT) requires coordinated clearance and deadenylation of maternally deposited mRNAs, yet the underlying molecular mechanisms remain poorly understood. N6-methyladenosine (m6A) has emerged as a key regulator of maternal mRNA fate, but prior studies have relied on population-averaged short-read methods that cannot resolve modification state, poly(A) tail length, or isoform identity on the same molecule. Here, we employ nanopore direct RNA sequencing on zebrafish embryos across MZT to resolve the interplay between m6A deposition, mRNA clearance, and poly(A) tail length dynamics at single-molecule resolution. We find that 78% of expressed maternal genes harbor m6A-modified isoforms, significantly exceeding prior bulk estimates. Within-isoform comparisons demonstrate that m6A promotes mRNA decay, with CDS m6A contributing more to maternal mRNA clearance than 3-UTR m6A. The positional context of m6A alone is sufficient to determine the temporal regulation of poly(A) tail lengths. CDS m6A constitutively suppresses tail length throughout MZT, while 3'-UTR m6A acquires shortening activity only after zygotic genome activation (ZGA). Transcriptomic analysis of ythdf2 knockout embryos reveals two unrecognized roles. Ythdf2 stabilizes m6A-marked maternal transcripts to set stoichiometry at MZT onset, and is also responsible for maintaining global poly(A) tail homeostasis prior to ZGA through an m6A-independent mechanism. Together, these findings define the single-molecule logic by which m6A modifications shape transcript fate during vertebrate MZT.","rel_num_authors":8,"rel_authors":[{"author_name":"Sarah Ann Alshawi","author_inst":"University of Connecticut Health"},{"author_name":"Anna Delgado-Tejedor","author_inst":"Centre for Genomic Regulation (CRG)"},{"author_name":"Srihari Madhavan","author_inst":"University of Connecticut Health"},{"author_name":"Laia Llovera","author_inst":"Centre for Genomic Regulation (CRG)"},{"author_name":"Rebeca Medina","author_inst":"Centre for Genomic Regulation (CRG)"},{"author_name":"Cassandra Kontur","author_inst":"Yale University"},{"author_name":"Eva Maria Novoa","author_inst":"CRG"},{"author_name":"Jean-Denis Beaudoin","author_inst":"University of Connecticut Health Center"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Single-molecule m6A profiling reveals position-dependent mRNA regulation and non-canonical roles for Ythdf2 in early embryogenesis","rel_doi":"10.64898\/2026.07.03.736379","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736379","rel_abs":"The maternal-to-zygotic transition (MZT) requires coordinated clearance and deadenylation of maternally deposited mRNAs, yet the underlying molecular mechanisms remain poorly understood. N6-methyladenosine (m6A) has emerged as a key regulator of maternal mRNA fate, but prior studies have relied on population-averaged short-read methods that cannot resolve modification state, poly(A) tail length, or isoform identity on the same molecule. Here, we employ nanopore direct RNA sequencing on zebrafish embryos across MZT to resolve the interplay between m6A deposition, mRNA clearance, and poly(A) tail length dynamics at single-molecule resolution. We find that 78% of expressed maternal genes harbor m6A-modified isoforms, significantly exceeding prior bulk estimates. Within-isoform comparisons demonstrate that m6A promotes mRNA decay, with CDS m6A contributing more to maternal mRNA clearance than 3-UTR m6A. The positional context of m6A alone is sufficient to determine the temporal regulation of poly(A) tail lengths. CDS m6A constitutively suppresses tail length throughout MZT, while 3'-UTR m6A acquires shortening activity only after zygotic genome activation (ZGA). Transcriptomic analysis of ythdf2 knockout embryos reveals two unrecognized roles. Ythdf2 stabilizes m6A-marked maternal transcripts to set stoichiometry at MZT onset, and is also responsible for maintaining global poly(A) tail homeostasis prior to ZGA through an m6A-independent mechanism. Together, these findings define the single-molecule logic by which m6A modifications shape transcript fate during vertebrate MZT.","rel_num_authors":8,"rel_authors":[{"author_name":"Sarah Ann Alshawi","author_inst":"University of Connecticut Health"},{"author_name":"Anna Delgado-Tejedor","author_inst":"Centre for Genomic Regulation (CRG)"},{"author_name":"Srihari Madhavan","author_inst":"University of Connecticut Health"},{"author_name":"Laia Llovera","author_inst":"Centre for Genomic Regulation (CRG)"},{"author_name":"Rebeca Medina","author_inst":"Centre for Genomic Regulation (CRG)"},{"author_name":"Cassandra Kontur","author_inst":"Yale University"},{"author_name":"Eva Maria Novoa","author_inst":"CRG"},{"author_name":"Jean-Denis Beaudoin","author_inst":"University of Connecticut Health Center"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Mechanochemical Feedback between Cell Shape and Intracellular Mechanics Revealed by a Finite-Element Framework","rel_doi":"10.64898\/2026.07.03.736361","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736361","rel_abs":"Cell shape and mechanics are intricately connected and tightly regulated by mechanochemical events including biochemical signaling, cytoskeletal remodeling, and plasma membrane mechanics. While experimental advances in microscopy have shed light on the intricate coordination involved in cell shape change in response to different cues, the ability to conduct three-dimensional simulations in realistic geometries remains an open computational challenge. In this work, we develop a finite-element framework that incorporates advection-diffusion-reaction equations coupled with equations governing the kinematics of a deformable interface representing the cell membrane. We applied this framework to three distinct coupled mechanochemical systems, each governed by geometric partial differential equations, resulting in large deformations of the interface. In all three examples, our simulations revealed the emergence of feedback between cellular signaling, cytoskeletal organization, and cell shape. In our first two sets of simulations, we observed that cell migration and neutrophil protrusion were regulated by membrane tension-mediated feedback. In our final application, we predicted shape changes of a dendritic spine starting from a realistic geometry, and found that the complex shape of the spine gives rise to localized regimes of actin cytoskeleton remodeling not previously observed with idealized geometries. Thus, our finite-element framework allows us to generate new mechanistic insights for biophysical problems.","rel_num_authors":4,"rel_authors":[{"author_name":"Alessandro Contri","author_inst":"Norwegian University of Science and Technology"},{"author_name":"Emmet A. Francis","author_inst":"University of California San Diego"},{"author_name":"Andre Massing","author_inst":"Norwegian University of Science and Technology"},{"author_name":"Padmini Rangamani","author_inst":"University of California San Diego"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Reversible Actin modifications by Mical and SelR regulate dynamic actomyosin ring functions during cell wound repair","rel_doi":"10.64898\/2026.07.05.736623","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.05.736623","rel_abs":"Cell wound repair requires rapid and coordinated remodeling of the actin cytoskeleton to restore cortex integrity. Here, we show that a Rab35-Mical-SelR pathway regulates actomyosin ring dynamics through reversible actin redox. We find that Rab35 is recruited to wounds and is essential for proper actin ring assembly and disassembly. Rab35 regulates the recruitment of Mical, an actin-oxidizing enzyme, and SelR, a reductase that reverses oxidation, to the cell wound. Mical and SelR knockdowns disrupt actin ring formation and wound closure, whereas double knockdown partially rescues these defects, indicating a balanced redox cycle is required. Super-resolution microscopy reveals that Mical and SelR differentially regulate F-actin architecture and orientation. Mutation of actin at Methionine 44 does not fully recapitulate Mical knockdown phenotypes, suggesting the presence of additional targets and enzymes. Taken together, our results indicate that reversible actin modifications dynamically regulate F-actin architecture and orientation for actin ring assembly and disassembly.","rel_num_authors":3,"rel_authors":[{"author_name":"Mitsutoshi Nakamura","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Justin Hui","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Susan M Parkhurst","author_inst":"Fred Hutchinson Cancer Center"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Immobilised enzyme reactors for post-production glycan modification of purified glycoproteins","rel_doi":"10.64898\/2026.07.09.737398","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737398","rel_abs":"Controlling protein glycosylation as a critical quality attribute of biopharmaceuticals remains challenging when glycosylation is coupled to cellular production systems. Here, we present a proof-of-concept glycosyltransferase immobilised enzyme reactor (IMER) housed within a 3D-printed column that enables directed post-production glycan modification of purified glycoproteins. Using {beta}-1,4-galactosyltransferase ({beta}4GalT1-IMER) and -2,6-sialyltransferase (ST6Gal1-IMER) immobilised on Ni-NTA resin, the IMER achieved near-complete galactosylation and substantial sialylation of partially deglycosylated bovine fetuin N-glycans with their respective substrates with a maximum substrate-enzyme contact time of four minutes. Isomeric-level analysis revealed arm-specific addition preferences for both enzymes, consistent with known specificities. The modular IMER design permits sequential connection of individual enzyme chambers, potentially offering a scalable, plug-and-play platform for constructing defined glycan structures on recombinant glycoprotein therapeutics.","rel_num_authors":6,"rel_authors":[{"author_name":"Nicholas J DeBono","author_inst":"Institute for Biomedicine and Glycomics, Griffith University"},{"author_name":"Joel A. Cain","author_inst":"The University of Sydney School of Life and Environmental Science"},{"author_name":"Chi-Hung Lin","author_inst":"Institute for Biomedicine and Glycomics, Griffith University, Gold Coast, Australia"},{"author_name":"Nicolle H Packer","author_inst":"ARC Centre of Excellence in Synthetic Biology, Macquarie University, Sydney, Australia"},{"author_name":"Nicolle Packer","author_inst":"ARC Centre of Excellence in Synthetic Biology, Macquarie University, Sydney, Australia"},{"author_name":"Edward S.X. Moh","author_inst":"ARC Centre of Excellence in Synthetic Biology, Macquarie University, Sydney, Australia"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Fabrication and Use of a 32-Well LED-Embedded Microplate for Optogenetic Dynamic Control","rel_doi":"10.64898\/2026.07.08.737360","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737360","rel_abs":"Optogenetic control enables light-actuated regulation of gene expression and provides a programmable interface between living cells and electronic systems. However, routine prototyping of optogenetic constructs remains limited by infrastructure. Existing closed-loop platforms often require chemostats, microfluidics, robotic handling, or custom optical sensors, which can increase cost, reduce accessibility, or constrain measurement performance. Here, we present LEMOS 2.0, an updated LED-Embedded Microplate for Optogenetic Studies, a low-cost device for optogenetic stimulation and gene-circuit characterization inside standard off-the-shelf microplate readers. LEMOS 2.0 builds on the original LEMOS platform by increasing throughput from 16 to 32 microwells and reducing light leakage between adjacent microwells, allowing dark conditions to be used as an additional illumination state. The device consists of a 3D-printed frame, individually addressable LEDs positioned next to each microwell, a rechargeable battery, and an onboard microcontroller for Bluetooth-based wireless communication. Biocompatible polydimethylsiloxane microwells are cast directly into the device by replica molding, allowing bacterial cultures to be stimulated while optical density and fluorescence are measured by the microplate reader. This protocol describes the full LEMOS 2.0 workflow, including device fabrication, circuit assembly, Arduino programming, PDMS microwell casting, plate-reader setup, strain and culture preparation, automated experiment execution, device cleanup, and fluorescence\/OD600 data analysis. As a demonstration, the protocol uses the CcaSR optogenetic system, in which sfGFP expression is activated by green light and repressed by red light. LEMOS 2.0 is intended to make optogenetic perturbation and gene-expression characterization more accessible to wet-lab users, enabling faster design-build-test-learn cycles without requiring specialized bioreactor or microfluidic infrastructure.","rel_num_authors":5,"rel_authors":[{"author_name":"Bhavya Jaiswal","author_inst":"Texas AM University"},{"author_name":"Trevor Black","author_inst":"Texas AM University"},{"author_name":"Hari Rajesh Namboothiri","author_inst":"Texas AM University"},{"author_name":"Krishna Pochana","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Chelsea Y. Hu","author_inst":"Texas AM University"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"PsbS confers limited adaptive benefit to C4 photosynthesis under fluctuating light","rel_doi":"10.64898\/2026.07.09.737394","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737394","rel_abs":"Adaptation of plant photosynthesis to dynamic light conditions experienced in natural environments is achieved through specific protective mechanisms. Energy-dependent non-photochemical quenching (qE), regulated by Photosystem II Subunit S (PsbS), is a key process facilitating acclimation to fluctuating light in C3 plants, which operate conventional photosynthesis. C4 plants, which include some of the world's most productive and agriculturally important crops, have evolved a distinct high-efficiency photosynthetic pathway. Little is known about the role of specific processes, like qE, in acclimation of C4 plants to dynamic light environments. We generated gene-edited lines of the model C4 grass Setaria viridis lacking PsbS, which were found to be deficient in qE. This deficiency resulted in a modest increase in PSII photoinhibition and a CO2 assimilation penalty under light stress in short-term experiments, but photosynthesis and growth under fluctuating light were unaffected. Instead, keeping Photosystem I oxidised through photosynthetic control, negative feedback regulation of the Cytochrome b6f complex, was critical. Therefore, unlike in C3 plants, qE does not provide a significant adaptive advantage to C4 plants under dynamic light conditions. These findings provide important insights into the biology of C4 plants and help prioritise future strategies for improving the productivity and resilience of C4 crops.","rel_num_authors":7,"rel_authors":[{"author_name":"Russell Woodford","author_inst":"Monash University"},{"author_name":"Emma Faraone","author_inst":"Monash University"},{"author_name":"Jacinta Watkins","author_inst":"Queensland University of Technology"},{"author_name":"Samuel J Nix","author_inst":"Australian National University"},{"author_name":"Susanne von Caemmerer","author_inst":"Australian National University"},{"author_name":"Robert T Furbank","author_inst":"Australian National University"},{"author_name":"Maria Ermakova","author_inst":"Monash University"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"TFAP2A links drug resistance to antitumor immunity","rel_doi":"10.64898\/2026.07.08.735861","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.735861","rel_abs":"Combination targeted therapy with BRAF\/MEK inhibitors and immune therapy show promising therapeutic outcomes in melanoma; however, the development of drug resistance still represents a formidable challenge. Remaining unexplored is the possibility that BRAF\/MEK inhibitors themselves inadvertently compromise the tumor immune microenvironment, limiting the efficacy of immunotherapy when it is used in combination with targeted inhibitors. Herein, we profiled the landscape of the BRAF regulatome identifying a novel transcription factor, TFAP2A, newly linking BRAF\/MEK drug resistance to antitumor immunity. Specifically, we found that BRAF\/MEK inhibitors significantly upregulate TFAP2A. Further, genetic disruption of TFAP2A overcomes BRAF\/MEK-inhibitor resistance, promotes stromal enrichment, and enhances intratumoral infiltration of macrophages in an immune-compromised mouse model. In a syngeneic mouse model, TFAP2a knockout not only suppresses tumor growth but also induces potent anti-tumor tertiary lymphoid structures (TLSs). Single cell transcriptomics revealed that the absence of TFAP2A shapes the antitumor microenvironment with an influx of M1-like macrophages, CD8+ T cells and mature dendritic cells. By identifying TFAP2A as a shared driver of both targeted therapy resistance and immunosuppression, our work offers a one-stone-two-bird strategy to overcome drug resistance and elicit antitumor immunity.","rel_num_authors":11,"rel_authors":[{"author_name":"Haiwei Mou","author_inst":"The Wistar Institute"},{"author_name":"Veronika Yakovishina","author_inst":"The Wistar Institute"},{"author_name":"Kristen DeRosa","author_inst":"Thomas Jefferson University"},{"author_name":"Yeqing Chen","author_inst":"The Wistar Institute"},{"author_name":"Min Xiao","author_inst":"The Wistar Institute"},{"author_name":"Maggie Dunne","author_inst":"The Wistar Institute"},{"author_name":"Nancy Shi","author_inst":"The Wistar Institute"},{"author_name":"Monzy Thomas","author_inst":"The Wistar Institute"},{"author_name":"Jordan L. Smith","author_inst":"Oregon Health & Science University"},{"author_name":"Qin Liu","author_inst":"The Wistar Institute"},{"author_name":"Meenhard Herlyn","author_inst":"The Wistar Institute"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Functions of TIAM1 at the interface of centriole assembly and autolysosome cycling","rel_doi":"10.64898\/2026.07.02.735969","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.735969","rel_abs":"Centrosome amplification is frequently associated with chromosomal instability and tumor progression, but how cells coordinate centriole assembly with the control of centrosome numbers and quality remains poorly understood. TIAM1 is a RAC1 guanine nucleotide exchange factor previously implicated in centrosome-associated signaling and {beta}TrCP-dependent control of PLK4 abundance. Here, we examined how Tiam1 regulates autophagy-lysosome homeostasis in mouse embryonic fibroblasts induced to overexpress PLK4. In contrast to a previous model in which Tiam1 loss promotes productive centriole overduplication, we found, by super-resolution imaging and expansion microscopy, an abnormal distribution of PLK4 on the centrioles centriole-associated structures following TIAM1 depletion, suggesting that TIAM1 may support the organization or maturation of centrioles. TIAM1 depletion also resulted in increased LC3B-positive puncta and enlarged LAMP1-positive compartments, but this was not accompanied by increased LC3B-II accumulation after bafilomycin A1 treatment.\n\nThese findings suggest that TIAM1 may act at the interface between centriole assembly and endolysosomal\/autolysosomal organization, linking TIAM1 to lysosome-associated centrosome quality-control pathways.","rel_num_authors":3,"rel_authors":[{"author_name":"Paula Almeida Coelho","author_inst":"California Instittue of Technology"},{"author_name":"Chenrong Yu","author_inst":"California Institute of Technology"},{"author_name":"David M. Glover","author_inst":"California Institute of Technology"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"Gene Supplementation of MYO7A or activation of Myo7b for treatment of Usher syndrome 1B","rel_doi":"10.64898\/2026.07.02.736025","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736025","rel_abs":"Mutations in MYO7A result in the most severe subtype of Usher syndrome, the leading genetic cause of deafblindness. The large size of MYO7A requires dual adeno-associated virus (AAV) vectors for gene transfer or alternative methods to treat retinal defects. Here, we evaluated two treatment approaches: i) Supplementation of the human MYO7A gene via dual mRNA trans-splicing AAVs, and ii) CRISPR\/Cas-mediated activation of the related murine Myo7b gene. Upon MYO7A supplementation, the transgenic MYO7A transcript and protein were expressed and correctly localized in retinal pigment epithelial (RPE) and photoreceptors of mice, pigs, and human retinal organoids. In RPE-and photoreceptor-specific Myo7a knockout mice, we could restore MYO7A expression and localization of melanosomes in RPE cells to wild-type levels. Myo7b activation led to partial restoration of melanosome localization, and the localization of MYO7B protein was largely comparable to MYO7A. These findings indicate that both approaches are in principle suitable for the therapy of Usher syndrome.","rel_num_authors":35,"rel_authors":[{"author_name":"David M. Mittas","author_inst":"Laboratory for Retinal Gene Therapy, Department of Ophthalmology, University Hospital Zurich, University of Zurich, Switzerland"},{"author_name":"Dina Otify","author_inst":"Laboratory for Retinal Gene Therapy, Department of Ophthalmology, University Hospital Zurich, University of Zurich, Switzerland"},{"author_name":"Zoran Gavrilov","author_inst":"Laboratory for Retinal Gene Therapy, Department of Ophthalmology, University Hospital Zurich, University of Zurich, Switzerland"},{"author_name":"Thomas Heigl","author_inst":"Laboratory for Retinal Gene Therapy, Department of Ophthalmology, University Hospital Zurich, University of Zurich, Switzerland"},{"author_name":"Jan Suchomski","author_inst":"Laboratory for Retinal Gene Therapy, Department of Ophthalmology, University Hospital Zurich, University of Zurich, Switzerland"},{"author_name":"Paulina Deltuvaite","author_inst":"Laboratory for Retinal Gene Therapy, Department of Ophthalmology, University Hospital Zurich, University of Zurich, Switzerland"},{"author_name":"Klara Hinrichsmeyer","author_inst":"Laboratory for Retinal Gene Therapy, Department of Ophthalmology, University Hospital Zurich, University of Zurich, Switzerland"},{"author_name":"Olivier Mercey","author_inst":"University of Geneva"},{"author_name":"Franz Kynast","author_inst":"Department of Ophthalmology, LMU University Hospital, LMU Munich, Munich, Germany"},{"author_name":"Jan Motlik","author_inst":"Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov, 27721, Czech Republic"},{"author_name":"Zdenka Ellederova","author_inst":"Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov, 27721, Czech Republic"},{"author_name":"Taras Ardan","author_inst":"Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov, 27721, Czech Republic"},{"author_name":"Andreas Klingl","author_inst":"Plant Development & Electron Microscopy, Biocenter LMU Munich, Germany"},{"author_name":"Jennifer Gruenert","author_inst":"Plant Development & Electron Microscopy, Biocenter LMU Munich, Germany"},{"author_name":"Verena Mehlfeld","author_inst":"Department of Pharmacy, Center for Drug Research, LMU Munich, Germany"},{"author_name":"Anastasiia Kolesnikova","author_inst":"Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic"},{"author_name":"Ruslan Nyshchuk","author_inst":"Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic"},{"author_name":"Jana Juhasova","author_inst":"Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov, 27721, Czech Republic"},{"author_name":"Stefan Juhas","author_inst":"Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov, 27721, Czech Republic"},{"author_name":"Saskia Drutovic","author_inst":"Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Libechov, 27721, Czech Republic"},{"author_name":"M. Dominik Fischer","author_inst":"Oxford Eye Hospital, Oxford University Hospitals National Health Service Foundation Trust, Oxford OX3 9DU, UK"},{"author_name":"Miroslav Veith","author_inst":"3rd Faculty of Medicine, Charles University in Prague, Vinohrady Teaching Hospital, Department of Ophthalmology, Prague, 10034, Czech Republic"},{"author_name":"Zbynek Stranak","author_inst":"3rd Faculty of Medicine, Charles University in Prague, Vinohrady Teaching Hospital, Department of Ophthalmology, Prague, 10034, Czech Republic"},{"author_name":"Nanda Boon","author_inst":"Department of Ophthalmology, Leiden University Medical Center (LUMC), 2333 ZA, Leiden, The Netherlands"},{"author_name":"Jan Wijnholds","author_inst":"Department of Ophthalmology, Leiden University Medical Center (LUMC), 2333 ZA, Leiden, The Netherlands"},{"author_name":"Andreas Wiest","author_inst":"Department of Chemistry, Ludwig Maximilian University, Munich, Germany"},{"author_name":"Pavel Kielkowski","author_inst":"Department of Chemistry, Ludwig Maximilian University, Munich, Germany"},{"author_name":"Guelce Goekce","author_inst":"Department of Ophthalmology, LMU University Hospital, LMU Munich, Munich, Germany"},{"author_name":"Paul Guichard","author_inst":"University of Geneva"},{"author_name":"Virginie Hamel","author_inst":"University of Geneva"},{"author_name":"Hermann Ammer","author_inst":"Department of Veterinary Sciences, LMU, 80539 Munich, Germany"},{"author_name":"Stylianos Michalakis","author_inst":"LMU Munich"},{"author_name":"Susanne Koch","author_inst":"Department of Pharmacy, Center for Drug Research, LMU Munich, Germany"},{"author_name":"Martin Biel","author_inst":"Department of Pharmacy, Center for Drug Research, LMU Munich, Germany"},{"author_name":"Elvir Becirovic","author_inst":"Laboratory for Retinal Gene Therapy, Department of Ophthalmology, University Hospital Zurich, University of Zurich, Switzerland"}],"rel_date":"2026-07-10","rel_site":"biorxiv"},{"rel_title":"HIV as a Host Susceptibility State for Severe Drug Hypersensitivity: Disentangling Biological Susceptibility from Drug Exposure in the FAERS Database","rel_doi":"10.64898\/2026.07.07.26356279","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26356279","rel_abs":"Background: HIV infection has long been associated with increased incidence of severe cutaneous adverse reactions (SCAR). It remains unknown whether this increased incidence is a direct biological result of HIV infection, differences in drug exposure, or other demographic factors. Objective: To evaluate the association between HIV and SCAR and determine whether this relationship persists after adjusting for demographic factors and structured drug exposure. Methods: We analyzed reports from the FDA Adverse Event Reporting System (FAERS) from 2013-2023. SCAR outcomes included Stevens-Johnson syndrome\/toxic epidermal necrolysis (SJS\/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and generalized bullous fixed drug eruption (GBFDE). HIV status was determined using antiretroviral exposure, indication text, and machine-learning imputation. Logistic regression models were constructed sequentially: unadjusted, demographic-adjusted, and fully adjusted with drug principal components to account for polypharmacy. Drug-level disproportionality and HIV-drug interaction analyses were also performed. Results: In unadjusted models, HIV was strongly associated with SCAR (OR ~2.0-2.7). Adjustment for demographics attenuated this association, and further adjustment for drug exposure reduced the effect to near null for overall SCAR and DRESS. A modest residual association persisted for SJS\/TEN (OR ~1.3). Disproportionality analyses demonstrated enrichment of specific high-risk drugs in PLWH. Interaction modeling revealed drug-specific amplification of SCAR risk in HIV, notably for carbamazepine and clarithromycin, whereas other drugs showed minimal interaction. Conclusion: The association between HIV and SCAR is largely explained by differences in drug exposure and demographic factors. Residual risk is drug-specific rather than uniform, supporting a model in which HIV modifies susceptibility to select drug triggers rather than acting as a global risk factor. Further prospective and retrospective studies are required to quantify associations.","rel_num_authors":7,"rel_authors":[{"author_name":"Eric M Mukherjee","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Dodie Park","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Amir Asiaee","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Matthew S Krantz","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Cosby A Stone Jr.","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Michelle D Martin-Pozo","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Elizabeth Jane Phillips","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"An epigenetic speedometer to measure Pace of Aging: FraminghamPACE","rel_doi":"10.64898\/2026.07.07.26357388","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26357388","rel_abs":"Geroscience clinical trials need biomarker surrogate endpoints for healthspan. Leading candidates are omics-based composites developed from machine learning analysis of aging phenotypes including calendar age, survival, functional capacity, and Pace of Aging. Existing Pace of Aging biomarkers were developed in the Dunedin Longitudinal Study, limiting inference about strengths\/weaknesses of the method as distinct from the Study, a unique single-year birth cohort followed through midlife with near-perfect retention and uniform measurement of multi-organ-system function across two decades of follow-up. We adapted our Pace of Aging method for mixed-age cohorts with variable follow-up of organ-function measures and applied it to develop a novel DNA methylation biomarker of Pace of Aging in data from the Framingham Heart Study Offspring Cohort, FraminghamPACE. Validation analyses across four independent cohorts and one clinical trial establish advantages for the Pace of Aging method in developing biomarkers that are both predictive of healthspan and responsive to geroprotective intervention.","rel_num_authors":10,"rel_authors":[{"author_name":"William T Marella","author_inst":"Robert N Butler Columbia Aging Center, Columbia University Mailman School of Public Health"},{"author_name":"Calen P Ryan","author_inst":"Robert N Butler Columbia Aging Center, Columbia University Mailman School of Public Health"},{"author_name":"David Corcoran","author_inst":"Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill"},{"author_name":"Claire Eckstein Indik","author_inst":"Robert N Butler Columbia Aging Center, Columbia University Mailman School of Public Health"},{"author_name":"Alex Furuya","author_inst":"Department of Epidemiology, Columbia University Mailman School of Public Health"},{"author_name":"Michael S Kobor","author_inst":"Edwin S. Leong Centre for Healthy Aging, University of British Columbia"},{"author_name":"Karen Sugden","author_inst":"Department of Psychology and Neuroscience, Duke University"},{"author_name":"Avshalom Caspi","author_inst":"Department of Psychology and Neuroscience, Duke University"},{"author_name":"Terrie Moffitt","author_inst":"Department of Psychology and Neuroscience, Duke University"},{"author_name":"Daniel W Belsky","author_inst":"Robert N Butler Columbia Aging Center, Columbia University Mailman School of Public Health"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"Integrated molecular analysis of NSCLC brain metastasis tissue and multimodal ctDNA reveals distinct signatures of patient outcomes","rel_doi":"10.64898\/2026.06.29.26355802","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26355802","rel_abs":"While recent therapeutic advances have extended the survival of patients with non-small cell lung cancer (NSCLC), overcoming metastatic progression in the CNS remains a significant challenge. Some patients with NSCLC may require concurrent management of CNS and extracranial metastases, while others develop isolated brain metastasis or leptomeningeal disease. These heterogenous clinical outcomes are difficult to predict and diagnose for early intervention with current surveillance modalities. Herein, we comprehensively analyzed gene mutations, copy number variations, and DNA methylation of NSCLC brain metastasis tissue collected at the time of craniotomy, combined with ctDNA sequencing of paired plasma and CSF liquid biopsies. We confirmed a high concordance between the molecular features of brain metastasis tissue with ctDNA from CSF which were largely distinct from ctDNA alterations in paired plasma samples. Plasma ctDNA tumor fraction and ctDNA hypermethylation were most significantly associated with extracranial metastasis and overall survival. Alternatively, we identified specific hypermethylated DNA loci in brain metastasis tissue and CSF ctDNA as significant correlates of brain metastasis progression and risk of leptomeningeal disease. Our findings support the utility of integrating ctDNA testing from CSF and plasma, while revealing distinct epigenetic features and biomarkers of brain metastasis or leptomeningeal disease.","rel_num_authors":16,"rel_authors":[{"author_name":"Darin Dolezal","author_inst":"Yale University School of Medicine"},{"author_name":"Sampada Chande","author_inst":"Yale University School of Medicine"},{"author_name":"Giancarlo Bonora","author_inst":"Predicine Inc."},{"author_name":"Yong Huang","author_inst":"Predicine Inc."},{"author_name":"Myles Walsh","author_inst":"Predicine Inc."},{"author_name":"Savannah Kandigian","author_inst":"Yale University School of Medicine"},{"author_name":"Wei Wei","author_inst":"Yale University School of Medicine"},{"author_name":"Anna Arnal-Estape","author_inst":"Yale University School of Medicine"},{"author_name":"Kurt Schalper","author_inst":"Yale University School of Medicine"},{"author_name":"Sarah Goldberg","author_inst":"Yale University School of Medicine"},{"author_name":"Darren Cross","author_inst":"Bioscience, Early Oncology TDE, AstraZeneca"},{"author_name":"Massimo Squatrito","author_inst":"AstraZeneca, Translational Medicine, AstraZeneca"},{"author_name":"Nicholas Blondin","author_inst":"Yale University School of Medicine"},{"author_name":"Shidong Jia","author_inst":"Predicine Inc."},{"author_name":"Veronica Chiang","author_inst":"Yale University School of Medicine"},{"author_name":"Don X Nguyen","author_inst":"Yale University School of Medicine"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"A pan-organ exposomic atlas of human aging for precision environmental health","rel_doi":"10.64898\/2026.06.26.26356646","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356646","rel_abs":"Environmental exposures are major modifiable determinants of human aging, yet the evidence remains fragmented across organ-agnostic summaries and rarely confronts population inequity. Here we present an exposomic atlas of pan-organ aging in ~300,000 UK Biobank adults, mapping 164 environmental and behavioural exposures onto biological aging of the whole body and nine organ subsystems. Comprising 1,476 systematically tested exposure-subsystem associations, the atlas reveals that environmental effects on human aging are pervasively organ-specific, with 65.9% of exposures acting divergently across organ subsystems. This landscape resolves into nine navigable modules that preserve organ selectivity, predict 23 major age-related diseases, and expose distinct dimensions of health inequity. In-silico analyses further show that priorities for ameliorating aging are target-dependent rather than universal, diverge markedly from the whole-body ranking (Kendall's {tau} = 0.52 to 0.39), reorder substantially across population strata, with findings externally validated in an ethnically distinct cohort. The atlas establishes an organ-resolved and target-aware foundation for precision environmental health.","rel_num_authors":3,"rel_authors":[{"author_name":"Shaopeng Yang","author_inst":"Sun Yat-sen University"},{"author_name":"Zhuoyao Xin","author_inst":"Johns Hopkins University"},{"author_name":"Wei Wang","author_inst":"Sun Yat-sen University"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"The Circadian Disruption Index: development, validation, and responsiveness to circadian health education","rel_doi":"10.64898\/2026.07.08.26357517","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357517","rel_abs":"Study Objectives To develop and initially validate the Circadian Disruption Index (CDI), a self-report measure of circadian disruption, and obtain preliminary evidence of its responsiveness to circadian health education. Methods In Study 1, 244 participants completed a 22-item CDI version and external measures. The sample was randomly divided for exploratory and confirmatory factor analyses. Internal consistency, external associations, and discrimination of poor sleep quality were examined. In Study 2, 72 postgraduate students completed the CDI before and 1 week after a 16-hour circadian health education program in an uncontrolled pre-post design. Results Analyses yielded a 15-item, three-factor structure comprising rhythm stability and light exposure, behavioral habits and diet, and sleep quality and subjective complaints. Total-score internal consistency was acceptable (Cronbach's  = 0.871). Confirmatory factor analysis showed a comparative fit index of 0.902 and a root mean square error of approximation of 0.072, although the Tucker-Lewis index was 0.882. CDI scores correlated with sleep quality, chronotype, corrected midsleep on free days, depression, and anxiety, but not social jetlag. The area under the curve for poor sleep quality was 0.807 (95% confidence interval, 0.753-0.862), with an exploratory cutoff of [&le;] 23. In Study 2, CDI scores decreased from 22.26 to 19.88 (p = 0.002; Cohen's dz = 0.36). Conclusions The CDI demonstrated satisfactory internal consistency, a meaningful multidimensional structure, and responsiveness to short-term changes following circadian health education, supporting its potential utility for assessing circadian disruption and monitoring circadian-related behavioral changes.","rel_num_authors":15,"rel_authors":[{"author_name":"Yimei Fan","author_inst":"Guangzhou medical university"},{"author_name":"Mingyu Tian","author_inst":"The affiliated brain hospital of Guangzhou Medical University"},{"author_name":"Jiaying Xu","author_inst":"The affiliated brain hospital of Guangzhou Medical University"},{"author_name":"Mingxin Cao","author_inst":"The affiliated brain hospital of Guangzhou Medical University"},{"author_name":"Nana Zheng","author_inst":"The affiliated brain hospital of Guangzhou Medical University"},{"author_name":"Yaping Liu","author_inst":"The affiliated brain hospital of Guangzhou Medical University"},{"author_name":"Sizhi Ai","author_inst":"The affiliated brain hospital of Guangzhou Medical University"},{"author_name":"Yannis Yan Liang","author_inst":"The affiliated brain hospital of Guangzhou Medical University"},{"author_name":"Jing Wang","author_inst":"The affiliated brain hospital of Guangzhou Medical University"},{"author_name":"Xiaoqing Hu","author_inst":"Department of Psychology, The University of Hong Kong, Hong Kong, SAR, China."},{"author_name":"Xiao Tan","author_inst":"Department of Psychiatry, Sir Run Run Shaw Hospital, Zhejiang University School"},{"author_name":"Christian Benedict","author_inst":"Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden"},{"author_name":"Yun Kwok Wing","author_inst":"Li Chiu Kong Family Sleep Assessment Unit, Department of Psychiatry, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, SAR, China."},{"author_name":"Jihui Zhang","author_inst":"The affiliated brain hospital of Guangzhou Medical University"},{"author_name":"Hongliang Feng","author_inst":"The affiliated brain hospital of Guangzhou Medical University"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"A study of sex-specific genetic effects underlying risk of orofacial clefts also highlights the potential impact of sequencing errors due to short read mis-mapping","rel_doi":"10.64898\/2026.07.07.26357463","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26357463","rel_abs":"Orofacial clefts (OFCs), including cleft lip (CL), cleft palate (CP), and cleft lip with cleft palate (CLP), are among the most common craniofacial malformations in humans, with a birth prevalence of approximately 1 in 1,000 live births globally. Non-syndromic forms of OFC are predominantly genetic, with significant variability in prevalence across populations. Understanding the genetic underpinnings of OFCs remains a key public health priority, given the substantial medical and societal burden of these conditions. Recent genome-wide association studies (GWAS) have implicated numerous genetic loci, but challenges remain due to genetic heterogeneity and complex gene-environment interactions. This study aimed to identify sex-specific genetic risk factors for cleft lip with or without cleft palate (CL\/P) through a meta-analysis of whole genome sequencing (WGS) data from 1,922 case-parent trios across eight diverse cohorts. Our approach revealed four SNPs in three distinct regions that showed genome-wide significant sex-specific effects. However, despite each of these SNPs passing standard quality control filters, follow-up analyses showed that these signals most likely were technical artifacts caused by sequencing errors, in particular mis-mapped reads due to sequence similarities with the sex chromosomes. These findings highlight the necessity for careful scrutiny when studying differences between the sexes in genetic association studies.","rel_num_authors":16,"rel_authors":[{"author_name":"Kanika Kanchan","author_inst":"National Institute of Allergy and Infectious Diseases"},{"author_name":"Zeynep ERDO\u011eAN-YILDIRIM","author_inst":"University of Pittsburgh, School of Dental Medicine"},{"author_name":"Seth R Berke","author_inst":"Princeton University"},{"author_name":"Nandita Mukhopadhyay","author_inst":"Univ. of Pittsburgh"},{"author_name":"Debashree Ray","author_inst":"Johns Hopkins University"},{"author_name":"Claire Louise Simpson","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Jacqueline A Bidinger","author_inst":"Johns Hopkins University"},{"author_name":"Sarah W Curtis","author_inst":"Emory University"},{"author_name":"Azeez Butali","author_inst":"University of Iowa"},{"author_name":"Holger Schwender","author_inst":"Heinrich-Heine-Universitaet"},{"author_name":"Alan F Scott","author_inst":"Johns Hopkins University"},{"author_name":"Joan Bailey Wilson","author_inst":"National Human Genome Research Institute"},{"author_name":"Terri  H. Beaty","author_inst":"Johns Hopkins University"},{"author_name":"Elizabeth Leslie","author_inst":"Emory University"},{"author_name":"Mary  L. Marazita","author_inst":"University of Pittsburgh"},{"author_name":"Ingo Ruczinski","author_inst":"Johns Hopkins University"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"A study of sex-specific genetic effects underlying risk of orofacial clefts also highlights the potential impact of sequencing errors due to short read mis-mapping","rel_doi":"10.64898\/2026.07.07.26357463","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26357463","rel_abs":"Orofacial clefts (OFCs), including cleft lip (CL), cleft palate (CP), and cleft lip with cleft palate (CLP), are among the most common craniofacial malformations in humans, with a birth prevalence of approximately 1 in 1,000 live births globally. Non-syndromic forms of OFC are predominantly genetic, with significant variability in prevalence across populations. Understanding the genetic underpinnings of OFCs remains a key public health priority, given the substantial medical and societal burden of these conditions. Recent genome-wide association studies (GWAS) have implicated numerous genetic loci, but challenges remain due to genetic heterogeneity and complex gene-environment interactions. This study aimed to identify sex-specific genetic risk factors for cleft lip with or without cleft palate (CL\/P) through a meta-analysis of whole genome sequencing (WGS) data from 1,922 case-parent trios across eight diverse cohorts. Our approach revealed four SNPs in three distinct regions that showed genome-wide significant sex-specific effects. However, despite each of these SNPs passing standard quality control filters, follow-up analyses showed that these signals most likely were technical artifacts caused by sequencing errors, in particular mis-mapped reads due to sequence similarities with the sex chromosomes. These findings highlight the necessity for careful scrutiny when studying differences between the sexes in genetic association studies.","rel_num_authors":16,"rel_authors":[{"author_name":"Kanika Kanchan","author_inst":"National Institute of Allergy and Infectious Diseases"},{"author_name":"Zeynep ERDO\u011eAN-YILDIRIM","author_inst":"University of Pittsburgh, School of Dental Medicine"},{"author_name":"Seth R Berke","author_inst":"Princeton University"},{"author_name":"Nandita Mukhopadhyay","author_inst":"Univ. of Pittsburgh"},{"author_name":"Debashree Ray","author_inst":"Johns Hopkins University"},{"author_name":"Claire Louise Simpson","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Jacqueline A Bidinger","author_inst":"Johns Hopkins University"},{"author_name":"Sarah W Curtis","author_inst":"Emory University"},{"author_name":"Azeez Butali","author_inst":"University of Iowa"},{"author_name":"Holger Schwender","author_inst":"Heinrich-Heine-Universitaet"},{"author_name":"Alan F Scott","author_inst":"Johns Hopkins University"},{"author_name":"Joan Bailey Wilson","author_inst":"National Human Genome Research Institute"},{"author_name":"Terri  H. Beaty","author_inst":"Johns Hopkins University"},{"author_name":"Elizabeth Leslie","author_inst":"Emory University"},{"author_name":"Mary  L. Marazita","author_inst":"University of Pittsburgh"},{"author_name":"Ingo Ruczinski","author_inst":"Johns Hopkins University"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"Trends in the Incidence of Kaposi Sarcoma among Adults Attending HIV Care Facilities in East Africa and Latin America in the Treat-All Era","rel_doi":"10.64898\/2026.06.26.26356374","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356374","rel_abs":"Abstract Background: In resource-rich regions, such as the U.S. and Europe, the incidence of Kaposi sarcoma (KS) amongst persons living with HIV (PWH) has dramatically declined with the advent of combination antiretroviral therapy (ART). In contrast, in low- and middle-income countries (LMICs), much less is known, particularly since the World Health Organization's recommendation in late 2015 to use ART in all PWH. We take advantage of the coincident electronic clinical data capture at HIV care facilities to estimate the incidence of KS among PWH in care with ready access to ART, piloting a data validation approach to address errors in these routine clinic data. Methods: We evaluated PWH enrolled from January 2010 to December 2019 in 13 HIV care clinics in 8 countries participating in the East Africa (EA-IeDEA) and Caribbean, Central and South America (CCASAnet) regions of the International Epidemiology Databases to Evaluate AIDS (IeDEA) consortium. Selected measurements were validated via chart review on a subset of PWH, and we estimated KS incidence in both unvalidated and validated data via generalized raking techniques. Results: A total of 235,474 PWH from EA-IeDEA and 19,683 from CCASAnet gave rise to 719 and 103 incident cases of KS, respectively. A total of 824 eligible records were validated. ART use was substantially lower in EA-IeDEA than CCASAnet in 2010 but equalized by 2019. From 2010 to 2019, KS incidence decreased on average 21% per year (incidence rate ratio [IRR] 0.79; 95% CI 0.75-0.82) in EA-IeDEA but only 6% (IRR=0.94; 95% CI 0.83-1.06) in CCASAnet. Conclusions: Among PWH attending HIV care facilities in East Africa, we observed a trend suggesting a reduction in KS incidence that paralleled increased Treat All era ART use in these clinics. In the Caribbean, Central and South America, there was hardly a change in the incidence, despite high-frequency ART use in the region as well.","rel_num_authors":27,"rel_authors":[{"author_name":"Aggrey Semeere","author_inst":"Infectious Diseases Institute, Makerere University"},{"author_name":"Joshua Slone","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Gustavo Amorim","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Beverly Musick","author_inst":"Indiana University"},{"author_name":"Brenda Crabtree-Ram\u00edrez","author_inst":"Departamento de Infectolog\u00eda, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n"},{"author_name":"Lameck Diero","author_inst":"Moi University"},{"author_name":"Larissa Otero","author_inst":"Instituto de Medicina Tropical Alexander von Humboldt"},{"author_name":"Hilary Vansell Riley","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Antony Ngeresa","author_inst":"Moi University"},{"author_name":"Mark Nsumba","author_inst":"Infectious Diseases Institute, Makerere University"},{"author_name":"Haruna Ssemuwemba","author_inst":"Masaka Regional Referral Hospital"},{"author_name":"Paul Enyel","author_inst":"Mbarara Regional Referral Hospital"},{"author_name":"Gertrude Nakigozi","author_inst":"Rakai Health Sciences Program"},{"author_name":"Godloveness Rubega","author_inst":"Morogoro Regional Referral Hospital"},{"author_name":"Jerome Lwali","author_inst":"Tumbi Regional Referral Hospital"},{"author_name":"Guisela Salgado","author_inst":"Instituto Hondure\u00f1o de Seguridad Social"},{"author_name":"Guilherme Calvet","author_inst":"Instituto Nacional de Infectolog\u00eda Evandro Chagas"},{"author_name":"Maria Fernanda Rodriguez","author_inst":"Fundaci\u00f3n Arriar\u00e1n y Universidad de Chile"},{"author_name":"Ana Grana","author_inst":"Instituto de Medicina Tropical Alexander von Humboldt"},{"author_name":"Karen Juarez","author_inst":"Departamento de Infectolog\u00eda, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n"},{"author_name":"Ran Tao","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Stephany Duda","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Constantin Yiannoutsos","author_inst":"City University New York"},{"author_name":"Thomas Lumley","author_inst":"University of Auckland"},{"author_name":"Jeffrey Martin","author_inst":"University of California, San Francisco"},{"author_name":"Pamela A. Shaw","author_inst":"Kaiser Permanente Washington Health Research Institute"},{"author_name":"Bryan E. Shepherd","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"Data-driven Prediction of Fifteen-Year All-Cause Mortality among 2.3 Million Individuals in the VA","rel_doi":"10.64898\/2026.06.29.26356460","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26356460","rel_abs":"We present a data-driven framework to predict 15-year all-cause mortality using outpatient administrative records for 2.3 million Veterans in the largest integrated U.S. healthcare system. Rather than relying on predefined clinical phenotypes, we used the 1,000 most common outpatient medical codes from each of three data types\/modalities: ICD-9 (Dx), Current Procedural Terminology (CPT), and prescription drugs (Rx), encoded as binary features. Using these features, we trained three machine learning (ML) algorithms (logistic regression with lasso, random forest, and a 3-layered feed-forward neural network) to predict 15-year mortality risk. The features were also mapped to variables for the widely used Charlson Comorbidity Index (CCI), Elixhauser, and Veterans Aging Cohort Study (VACS) indices, refitted for 15-year mortality prediction, for baseline comparison. All our models significantly outperformed the widely used CCI, Elixhauser, and VACS indices, with C-statistics ranging from 0.82 to 0.84 versus 0.739 to 0.804 for the baselines. Relative improvements in C-statistics of our approach over the baselines were consistent across different subgroups (age groups of <65 years, those 65+years, Blacks, Hispanics, etc.) Our approach enabled the identification of high-impact predictors with clinical grounding , without requiring hand-curated phenotypes. Cardiovascular diseases and mental health diagnoses\/treatments emerged as leading long-term mortality indicators. Using unsupervised ML techniques including PCA and K-means clustering, we associated interpretable patterns and complex interactions between diagnoses and treatments, highlighting comorbidities, disease trajectories, and healthcare utilization patterns. The ability to achieve the predictive performance and algorithmically detect such relationships purely from outpatient data supports the scalability and broad applicability of our framework. This framework not only improves mortality risk stratification over existing clinical indices, but also enables better understanding of how medical codes, regardless of category, interact to predict long-term outcomes.","rel_num_authors":15,"rel_authors":[{"author_name":"Sayera Dhaubhadel","author_inst":"Los Alamos National Laboratory"},{"author_name":"Judith D Cohn","author_inst":"Los Alamos National Laboratory"},{"author_name":"Tanmoy Bhattacharya","author_inst":"Los Alamos National Laboratory"},{"author_name":"Ruy M. Ribeiro","author_inst":"Los Alamos National Laboratory"},{"author_name":"Kumkum Ganguly","author_inst":"Los Alamos National Laboratory"},{"author_name":"Nicolas  W Hengartner","author_inst":"Los Alamos National Laboratory"},{"author_name":"Janet P Tate","author_inst":"Yale University"},{"author_name":"Lauren Costa","author_inst":"Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC), VA Boston Healthcare System, Boston, USA"},{"author_name":"Yuk-Lam Ho","author_inst":"VA Boston Healthcare System"},{"author_name":"Kelly Cho","author_inst":"VA Boston Healthcare System"},{"author_name":"Lauren Costa","author_inst":"Dept. of Veterans Affairs"},{"author_name":"Jean  C. Beckham","author_inst":"Durham Veterans Affairs (VA) Health Care System; Duke University"},{"author_name":"Nathan A Kimbrel","author_inst":"Durham Veterans Affairs (VA) Health Care System; Duke University"},{"author_name":"Amy C. Justice","author_inst":"VA Connecticut Healthcare System; Yale University"},{"author_name":"Benjamin  H. McMahon","author_inst":"Los Alamos National Laboratory"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"Cell-type-specific polygenic risk scores reveal adipocyte-related interactions with lipids in coronary artery disease","rel_doi":"10.64898\/2026.07.07.26357510","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26357510","rel_abs":"Background: Genome-wide polygenic risk scores (PRSs) for coronary artery disease (CAD) aggregate genetic effects across the genome and may obscure biologically distinct mechanisms. We aimed to develop cell-type-specific PRSs (csPRSs) using single-cell RNA sequencing (scRNA-seq) data and investigate their interactions with lipids on CAD risk. Methods: Using publicly available scRNA-seq data from human heart tissue, we identified cell-type-specific genes across 13 major cell types and 64 subpopulations and grouped them into 10 cell clusters. Variants from a CAD genome-wide association study (GWAS) were mapped to cluster-specific genes to construct csPRSs for European-ancestry participants from the UK Biobank (UKB). Interactions between csPRSs and lipid-related phenotypes were evaluated using Cox proportional hazards models and stratified analyses, with significant findings further assessed in an internal validation dataset. Results: Distinct interaction patterns with lipid phenotypes were observed across csPRSs. Low-density lipoprotein (LDL)-related lipid traits, including apolipoprotein B (ApoB), low-density lipoprotein cholesterol (LDL-C), and total cholesterol (cholesterol), primarily interacted with adipocytes (Adip), whereas high-density lipoprotein (HDL) traits interacted with endothelial-mesothelial (EC-Meso), fibroblast (FB), and immune-cell csPRSs. Notably, interactions for Adip csPRSs were replicated in internal validation analyses. Conclusions: Cell-type-specific decomposition of genome-wide PRSs for CAD identified biologically distinct lipid interactions that were not captured by the genome-wide PRS. Adipocyte genetic factors may influence how LDL lipids affect CAD risk. These findings highlight the potential of cell-type-informed PRSs to improve the biological interpretation of PRSs and provide insights into the heterogeneous mechanisms underlying CAD.","rel_num_authors":5,"rel_authors":[{"author_name":"Jiaqi Hu","author_inst":"Yale School of Public Health"},{"author_name":"Leqi Xu","author_inst":"Yale School of Public Health"},{"author_name":"Tianyu Liu","author_inst":"Yale School of Public Health"},{"author_name":"Wangjie Zheng","author_inst":"Yale School of Public Health"},{"author_name":"Hong-yu Zhao","author_inst":"Yale School of Public Health"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"SSRI prescription during acute COVID-19 and risk of Long COVID symptoms and conditions among patients with depression","rel_doi":"10.64898\/2026.07.06.26357401","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.06.26357401","rel_abs":"Background: Long COVID is a syndrome characterized by symptoms and conditions across all biological systems. This breadth of Long COVID phenotypes impedes efforts to identify the mechanistic pathways of Long COVID. Low serotonin may play a role in long-term sequelae of COVID-19, and selective serotonin reuptake inhibitors (SSRIs) may prevent these sequelae. Evaluation of the relationship between SSRIs and distinct categories of symptoms and conditions associated with Long COVID can highlight the mechanistic pathways that drive these relationships. Methods: We evaluated electronic health record data from a retrospective cohort of patients in the National Clinical Cohort Collaborative with comorbid depression and COVID-19 between October 2021 and February 2024. We estimated the relationship between SSRI prescription (versus no SSRI prescription) during acute COVID-19 and the one-year cumulative incidence of Long COVID-related conditions and symptoms across 14 human phenotype ontology categories. We applied Super Learner and targeted maximum likelihood estimation to estimate risk ratios while adjusting for confounders of interest and correcting for false discoveries from repeated testing. Results: We evaluated EHR data from 542,938 patients. We found that patients who were prescribed SSRIs during COVID-19 had a significantly lower risk of symptoms and conditions related to gastrointestinal factors (adjusted risk ratio (aRR) 0.95, 95% CI 0.92, 0.97), general health (aRR 0.91, 95% CI 0.88, 0.95), headaches (aRR 0.96, 95% CI 0.92, 0.99) and skin (aRR 0.92, 95% CI 0.87, 0.98). Discussion: We found that the prescription of SSRIs during acute COVID-19 was associated with a significantly lower risk of post-COVID sequelae related to gastrointestinal, headache-related, skin-related, and general symptoms and conditions, compared with no SSRI prescription. These findings highlight the role of serotonin in Long COVID and specific sequelae that may be reduced by SSRIs.","rel_num_authors":11,"rel_authors":[{"author_name":"Zachary Butzin-Dozier","author_inst":"Stanford University, Stanford, CA USA"},{"author_name":"Yunwen Ji","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Lin-Chiun Wang","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Manav Kumar","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"A. Jerrod Anzalone","author_inst":"University of Nebraska Medical Center, Omaha, NE, USA"},{"author_name":"Ariana Budhihartanto","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Eric Hurwitz","author_inst":"University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Rena C. Patel","author_inst":"University of Alabama at Birmingham, Birmingham, AL, USA"},{"author_name":"Alan E. Hubbard","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Jodi Halpern","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"- on behalf of the National Clinical Cohort Collaborative","author_inst":"-"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"Metformin and Severe Post-COVID-19 Outcomes Among Individuals with Diabetes Mellitus","rel_doi":"10.64898\/2026.07.06.26357398","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.06.26357398","rel_abs":"Background: Metformin is one of the most commonly prescribed medications for individuals with diabetes and may provide protection against long-term sequelae of COVID-19. Methods: We evaluated a retrospective cohort of individuals in the National Clinical Cohort Collaborative with type 2 diabetes mellitus and COVID-19 who were prescribed metformin or a dipeptidyl peptidase-4 inhibitor (DPP4i) at least 30 days before the onset of acute COVID-19 between October 1, 2021, and November 15, 2023. We compared the 12-month cumulative incidence of Long COVID diagnosis (ICD-10 U09.9: Post COVID-19 condition, unspecified), probable Long COVID (based on a model-derived phenotype), and mortality between individuals prescribed metformin vs. DPP4i. We applied Super Learner and targeted maximum likelihood estimation to obtain risk ratios while adjusting for covariates of interest. Results: In our sample of 53,332 individuals with type 2 diabetes and COVID-19, we found that metformin prescription was associated with a lower risk of all-cause mortality after COVID-19 (adjusted risk ratio [aRR] 0.61, 95% CI 0.51, 0.73). We also observed that metformin users, compared to DPP4i users, had a slightly lower risk of probable Long COVID (aRR 0.87, 95% CI 0.81, 0.94) but did not detect a significant relationship with Long COVID diagnosis (aRR 0.90, 95% CI 0.68, 1.20), although we observed similar point estimates across Long COVID outcomes. Conclusions: These findings support the hypothesis that metformin prescription during acute COVID-19 may be associated with lower mortality among adults with diabetes. These analyses also provide modest evidence of a protective association against Long COVID in adults with diabetes, although estimates were imprecise.","rel_num_authors":21,"rel_authors":[{"author_name":"Zachary Butzin-Dozier","author_inst":"Stanford University, Stanford, CA USA"},{"author_name":"Yunwen Ji","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Lin-Chiun Wang","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"A. Jerrod Anzalone","author_inst":"University of Nebraska Medical Center, Omaha, NE, USA"},{"author_name":"Oluwasolape Olawore","author_inst":"University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Ryan Hafen","author_inst":"Purdue University, West Lafayette, IN, USA"},{"author_name":"Eric Hurwitz","author_inst":"University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Manav Kumar","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Rena C. Patel","author_inst":"University of Alabama at Birmingham, Birmingham, AL, USA"},{"author_name":"Ariana Budhihartanto","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Mark van der Laan","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"John M. Colford Jr.","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Alan E. Hubbard","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"John B. Buse","author_inst":"University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Steven Johnson","author_inst":"University of Minnesota, Minneapolis, MN, USA"},{"author_name":"Jane Reusch","author_inst":"University of Colorado, Anschutz, Aurora, CO, USA"},{"author_name":"Lauren E. Chan","author_inst":"University of Chicago, Chicago, IL, USA"},{"author_name":"Richard Moffitt","author_inst":"Renaissance School of Medicine, Stony Brook University, New York, NY, USA"},{"author_name":"Rachel Wong","author_inst":"Renaissance School of Medicine, Stony Brook University, New York, NY, USA"},{"author_name":"Carolyn Bramante","author_inst":"University of Minnesota, Minneapolis, MN, USA"},{"author_name":"- on behalf of the National Clinical Cohort Collaborative","author_inst":"-"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"Metformin and Severe Post-COVID-19 Outcomes Among Individuals with Diabetes Mellitus","rel_doi":"10.64898\/2026.07.06.26357398","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.06.26357398","rel_abs":"Background: Metformin is one of the most commonly prescribed medications for individuals with diabetes and may provide protection against long-term sequelae of COVID-19. Methods: We evaluated a retrospective cohort of individuals in the National Clinical Cohort Collaborative with type 2 diabetes mellitus and COVID-19 who were prescribed metformin or a dipeptidyl peptidase-4 inhibitor (DPP4i) at least 30 days before the onset of acute COVID-19 between October 1, 2021, and November 15, 2023. We compared the 12-month cumulative incidence of Long COVID diagnosis (ICD-10 U09.9: Post COVID-19 condition, unspecified), probable Long COVID (based on a model-derived phenotype), and mortality between individuals prescribed metformin vs. DPP4i. We applied Super Learner and targeted maximum likelihood estimation to obtain risk ratios while adjusting for covariates of interest. Results: In our sample of 53,332 individuals with type 2 diabetes and COVID-19, we found that metformin prescription was associated with a lower risk of all-cause mortality after COVID-19 (adjusted risk ratio [aRR] 0.61, 95% CI 0.51, 0.73). We also observed that metformin users, compared to DPP4i users, had a slightly lower risk of probable Long COVID (aRR 0.87, 95% CI 0.81, 0.94) but did not detect a significant relationship with Long COVID diagnosis (aRR 0.90, 95% CI 0.68, 1.20), although we observed similar point estimates across Long COVID outcomes. Conclusions: These findings support the hypothesis that metformin prescription during acute COVID-19 may be associated with lower mortality among adults with diabetes. These analyses also provide modest evidence of a protective association against Long COVID in adults with diabetes, although estimates were imprecise.","rel_num_authors":21,"rel_authors":[{"author_name":"Zachary Butzin-Dozier","author_inst":"Stanford University, Stanford, CA USA"},{"author_name":"Yunwen Ji","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Lin-Chiun Wang","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"A. Jerrod Anzalone","author_inst":"University of Nebraska Medical Center, Omaha, NE, USA"},{"author_name":"Oluwasolape Olawore","author_inst":"University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Ryan Hafen","author_inst":"Purdue University, West Lafayette, IN, USA"},{"author_name":"Eric Hurwitz","author_inst":"University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Manav Kumar","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Rena C. Patel","author_inst":"University of Alabama at Birmingham, Birmingham, AL, USA"},{"author_name":"Ariana Budhihartanto","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Mark van der Laan","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"John M. Colford Jr.","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"Alan E. Hubbard","author_inst":"School of Public Health, University of California, Berkeley, Berkeley, CA USA"},{"author_name":"John B. Buse","author_inst":"University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Steven Johnson","author_inst":"University of Minnesota, Minneapolis, MN, USA"},{"author_name":"Jane Reusch","author_inst":"University of Colorado, Anschutz, Aurora, CO, USA"},{"author_name":"Lauren E. Chan","author_inst":"University of Chicago, Chicago, IL, USA"},{"author_name":"Richard Moffitt","author_inst":"Renaissance School of Medicine, Stony Brook University, New York, NY, USA"},{"author_name":"Rachel Wong","author_inst":"Renaissance School of Medicine, Stony Brook University, New York, NY, USA"},{"author_name":"Carolyn Bramante","author_inst":"University of Minnesota, Minneapolis, MN, USA"},{"author_name":"- on behalf of the National Clinical Cohort Collaborative","author_inst":"-"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"A higher polygenic score for peripheral artery disease is associated with younger age at surgery among patients undergoing revascularization","rel_doi":"10.64898\/2026.06.25.26356619","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356619","rel_abs":"We examined whether polygenic risk for peripheral artery disease (PAD) is associated with severity among patients undergoing lower extremity revascularization at Yale New Haven Hospital. Patients were classified into European (EUR) and non-European (non-EUR) ancestry groups. Associations between the 19-variant polygenic score (PGS) and nine severity indicators were evaluated using linear and Cox regression models stratified by ancestry, followed by meta-analysis. Significant findings (p < 0.05) were assessed for replication in the UK Biobank (UKB). After quality control, 68 EUR and 59 non-EUR patients were included. In EUR patients, higher PGS was associated with increased risk for stroke (HR = 2.43, 95% CI 1.06-5.57). Meta-analysis revealed a significant association between higher PGS and younger age at surgery ({beta} = -2.90, SE = 1.28), which was replicated in the UKB ({beta} = -0.58, SE = 0.15). These results suggest genetic risk contributes to PAD severity.","rel_num_authors":8,"rel_authors":[{"author_name":"Jiaqi Hu","author_inst":"Yale School of Public Health"},{"author_name":"Dana Alameddine","author_inst":"Yale School of Medicine"},{"author_name":"Shreef Said","author_inst":"Yale School of Medicine"},{"author_name":"He Wang","author_inst":"Stony Brook University"},{"author_name":"Mingfu Yu","author_inst":"Yale School of Medicine"},{"author_name":"Michael Murray","author_inst":"Icahn Chool of Medicine at Mount Sinai"},{"author_name":"Andrew DeWan","author_inst":"Yale School of Public Health"},{"author_name":"Cassius Iyad Ochoa Chaar","author_inst":"Yale School of Medicine"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"Sequential Word Properties in Verbal Fluency: Detecting High-Proficiency Cognitive Impairment","rel_doi":"10.64898\/2026.07.06.26357360","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.06.26357360","rel_abs":"Verbal fluency (VF) tasks are widely used to differentiate patients with cognitive impairment from healthy controls, but total word count produced during these tasks becomes unreliable when patients and controls exhibit comparable proficiency. This study examined, in detail, whether item-level and sequential properties of words produced during a VF task could reliably differentiate high-proficiency patients indistinguishable from controls by word count alone. Seventy-seven native Mandarin Chinese speakers (38 controls and 39 patients with mild cognitive impairment or mild dementia) completed a semantic VF task. Participants were subdivided by proficiency into four groups: high-proficiency controls (HC), low-proficiency controls (LC), high-proficiency patients (HP), and low-proficiency patients (LP). The LC and HP subgroups were matched on semantic fluency scores and thus provided a key focus for the investigation. We examined item-level properties (word frequency, contextual diversity, semantic diversity, surprisal) and sequential properties (positional frequency variation) of the words produced. Significant group differences emerged across item-level psycholinguistic properties, though these were primarily driven by the LP group, with no reliable differentiation between LC and HP. Crucially, positional frequency variation distinguished LC from HP. LC participants began their lists with high-frequency words followed by a systematic decline, whereas HP patients produced words within a consistently narrow frequency band throughout. These findings indicate that item-level psycholinguistic properties alone are insufficient to differentiate HP from LC, whereas sequential word frequency variation provides a potential index of cognitive impairment, reflecting underlying differences in semantic retrieval and memory organisation. Future work with larger samples is needed to validate generalisability.","rel_num_authors":5,"rel_authors":[{"author_name":"Ya-Ning Chang","author_inst":"Miin Wu School of Computing, National Cheng Kung University, Tainan, Taiwan"},{"author_name":"Yi-Hsuan Wang","author_inst":"College of Medicine, National Cheng Kung University, Tainan, Taiwan"},{"author_name":"Chia-Ju Chou","author_inst":"Cardinal Tien Hospital, New Taipei City, Taiwan"},{"author_name":"Yi-Chien Liu","author_inst":"Cardinal Tien Hospital, New Taipei City, Taiwan"},{"author_name":"Matthew A. Lambon Ralph","author_inst":"MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, United Kingdom"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"Heterogeneous Treatment Effects in HFpEF: Distinguishing Drug-Specific Response from Prognostic Phenotypes Across Randomized Trials","rel_doi":"10.64898\/2026.07.06.26357251","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.06.26357251","rel_abs":"Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome comprising multiple pathophysiological phenotypes. HFpEF trials have largely enrolled diverse populations and reported average treatment effects, consistently yielding neutral results that may obscure drug-specific benefits within distinct subgroups. To address this issue, we employ an interaction-based that incorporates treatment-by-variable interactions to uncover drug-specific responses. Methods: We leveraged four HFpEF clinical trials (TOPCAT, RELAX, NEAT-HFpEF, INDIE-HFpEF) and developed a framework comprising two complementary approaches. The first employed a prognostic responder model to evaluate whether conventional responder definitions reflect treatment-specific benefit or instead capture favorable clinical trajectories common to both treatment and placebo groups. The second used an interaction-based individual treatment effect (ITE) modeling to identify baseline variables that modify therapy effect, distinguishing drug-specific response from prognostic phenotypes. Results: Although the prognostic responder model demonstrated good discrimination, further analisys suggested it primarily captured a prognostic signal associated with favorable clinical trajectories common to both treatment and placebo arms. In contrast, the ITE model identified distinct, drug-specific effect modifiers across trials (cardiorenal-inflammatory for spironolactone (TOPCAT), NO-mediated anti-inflammatory for isosorbide mononitrate (NEAT-HFpEF), afterload-reducing for inorganic nitrite (INDIE-HFpEF), and anti-volume-overload for sildenafil (RELAX). Each ITE model demonstrated significance only within its own trial suggesting drug-specific signal. Conclusions: The proposed method identifies mechanism-specific effect modifiers, and uncovers clinically meaningful heterogeneity in treatment response, which is not captured by conventional MCID-based approaches. Although exploratory, these findings support phenotype-guided therapy in HFpEF and argue for phenotype-informed trial design to enhance treatment-effect detection and therapy targeting.","rel_num_authors":30,"rel_authors":[{"author_name":"Clodomir Santana","author_inst":"University of California, Davis, USA"},{"author_name":"Asuka Katayama","author_inst":"University of California, Davis, USA"},{"author_name":"Aditya Ballal","author_inst":"University of California, Davis, USA"},{"author_name":"Padmini Sirish","author_inst":"University of California, Davis, USA"},{"author_name":"David A. Liem","author_inst":"University of California, Davis, USA"},{"author_name":"Julie T. Bidwell","author_inst":"University of California, Davis, USA"},{"author_name":"Chao-Yin Chen","author_inst":"University of California, Davis, USA"},{"author_name":"Miriam Nuno","author_inst":"University of California, Davis, USA"},{"author_name":"Imo Ebong","author_inst":"University of California, Davis, USA"},{"author_name":"Xiao-Dong Zhang","author_inst":"University of California, Davis, USA"},{"author_name":"Leighton Izu","author_inst":"University of California, Davis, USA"},{"author_name":"Barry A. Borlaug","author_inst":"Mayo Clinic, Rochester, Minnesota, USA"},{"author_name":"Julio A. Chirinos","author_inst":"University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA"},{"author_name":"Akshay S. Desai","author_inst":"Brigham and Women's Hospital, Boston, Massachusetts, USA"},{"author_name":"Patrice Desvigne-Nickens","author_inst":"Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA"},{"author_name":"Michael M. Givertz","author_inst":"Brigham and Women's Hospital, Boston, Massachusetts, USA"},{"author_name":"Sadiya S. Khan","author_inst":"Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA"},{"author_name":"Dalane W. Kitzman","author_inst":"Wake Forest University School of Medicine, Winston Salem, North Carolina, USA"},{"author_name":"Gregory D. Lewis","author_inst":"Massachusetts General Hospital, Boston, Massachusetts, USA"},{"author_name":"Laura J. Rasmussen-Torvik","author_inst":"Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA"},{"author_name":"Margaret M. Redfield","author_inst":"Mayo Clinic, Rochester, Minnesota, USA"},{"author_name":"Vandana Sachdev","author_inst":"Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA"},{"author_name":"Svati H. Shah","author_inst":"Duke Clinical Research Institute, Chapel Hill, North Carolina, USA"},{"author_name":"Kavita Sharma","author_inst":"Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"},{"author_name":"Emily Tinsley","author_inst":"Foundation for the National Institutes of Health, North Bethesda, Maryland, USA"},{"author_name":"Renee Wong","author_inst":"Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA"},{"author_name":"Sanjiv J. Shah","author_inst":"Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA"},{"author_name":"Javier E. Lopez","author_inst":"University of California, Davis, USA"},{"author_name":"Nipavan Chiamvimonvat","author_inst":"University of Arizona, Phoenix, Arizona, USA"},{"author_name":"Martin Cadeiras","author_inst":"University of California, Davis, USA"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"In Vivo Spatial Transcriptomics for Bleeding-free Profiling Human Internal Organs","rel_doi":"10.64898\/2026.07.06.26357355","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.06.26357355","rel_abs":"Despite the significant technical advancement in spatial transcriptomics, its clinical usage is largely untapped. Here, we develop an integrated system, ENDO-Genome, for minimally invasive in-body transcript sampling to facilitate live spatial transcriptomic analysis of human internal organs. This is achieved by integrating a nanoarrayed biochip with existing endoscope to perform pressure-sensor-calibrated \"Touch & Go\" RNA extraction directly from human internal organs, including the highly vascularized liver or kidney, without the need for tissue biopsy, voiding any bleeding risks. By a demonstration using gastrointestinal endoscopy, multiplexed landscape of 55 mRNA transcripts was obtained from multiple locations of human intestinal tract via a 5-minute operation in routine examinations. Benefiting from a sequencing-free approach, each assay costs less than 10 US dollars. For the clinical study involving 15 Crohn' s disease (CD) patients, no complication case was reported out of 47 ENDO-Genome operations, showcasing the gentle deposition and excellent safety of the technique. The live spatial transcriptomics provides direct in vivo pictures of the heterogenous spatial transcriptional programs underlying CD pathological response at different intestinal locations, revealing distinct ileal phenotypes. This is manifested by unique microscale scattering of inflammation gene clusters, along with the discovery of a tissue-specific cooperative mechanisms between inflammation and RNA methylation regulations at single- or multi-cell scales.","rel_num_authors":20,"rel_authors":[{"author_name":"Hailiang Sun","author_inst":"City University of Hong Kong"},{"author_name":"Feng Guo","author_inst":"City University of Hong Kong"},{"author_name":"Xinzhe Zhao","author_inst":"Sun Yat-sen University"},{"author_name":"Youyang Wan","author_inst":"City University of Hong Kong"},{"author_name":"Xijian Zhang","author_inst":"Sun Yat-sen University"},{"author_name":"Jiachen Sun","author_inst":"Sun Yat-sen University"},{"author_name":"Xingdao He","author_inst":"City University of Hong Kong"},{"author_name":"Baowen Gai","author_inst":"Sun Yat-sen University"},{"author_name":"Chuxiao Xiong","author_inst":"City University of Hong Kong"},{"author_name":"Yutao Ma","author_inst":"City University of Hong Kong"},{"author_name":"Jin Qu","author_inst":"City University of Hong Kong"},{"author_name":"Pengyu Li","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Feng Gao","author_inst":"Sun Yat-sen University"},{"author_name":"Xi Zhao","author_inst":"City University of Hong Kong"},{"author_name":"Xianglin Ji","author_inst":"City University of Hong Kong"},{"author_name":"Zhengbao Yang","author_inst":"The Hong Kong University of Science and Technology"},{"author_name":"Lung-Yi Mak","author_inst":"The University of Hong Kong"},{"author_name":"Yat Hin Yap","author_inst":"The University of Hong Kong"},{"author_name":"Jia Ke","author_inst":"Sun Yat-sen University"},{"author_name":"Peng Shi","author_inst":"City University of Hong Kong"}],"rel_date":"2026-07-09","rel_site":"medrxiv"},{"rel_title":"Foundation Model RNAGAN Enhances Biomedical Insight of Nasopharyngeal Carcinoma Metastasis","rel_doi":"10.64898\/2026.07.02.736240","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736240","rel_abs":"RNAGAN (version 2.0, https:\/\/github.com\/ZhaozhengHou-HKU\/RNAGAN-2.0.git) is a published foundation model that analyzes single-cell and bulk-level RNA sequencing samples and enables multiple applications that enhance medical insights. Here we applied this model to Nasopharyngeal Carcinoma (NPC) as in-context few-short format (i.e., the model was never trained with any NPC data). We conducted all four supported functions, which include sample stratification, vectorization, pseudo data generation, and marker identification. The results were then used for identifying metastatic NPC and to investigate mechanisms associated with NPC metastasis.\n\nExamination with stratification showed that the accuracy of RNAGAN results for evaluating the metastasis risk in NPC patients are comparable to or outcompeted recently published risk estimation linear prediction model. Vectorization results present consistency across multiple cohorts and RNAGAN model versions. In the task of identifying markers and mechanisms related to NPC metastasis, incorporating pseudo data substantially enhanced the representativeness of single-cohort-based differential expression (DE) analysis. Moreover, RNAGAN identified metastasis-related marker genes based on single cohort, were concordant with the ground truth obtained across multiple cohorts (p=1.05e-9).\n\nRegarding biomedical mechanisms, RNAGAN enabled second-order feature extraction, unveiling a remarkable domination of the protective function of adaptive immune responses (as indicated by IL21R levels) over the hazardous function of chronic, non-resolving innate inflammation (as indicated by S100A8 levels) against NPC metastasis after first-line treatment. This association demonstrates a high degree of consistency with the external cohort.\n\nThis study demonstrates the utility of the foundation model RNAGAN in uncovering therapeutic insights for novel cancer types without extra training. We reveal a critical spatial mechanism preventing distant metastasis via humoral anti-tumor immunity in NPC. High S100A8 expression by innate antigen-presenting cells (APCs) triggers an inflammatory cascade promoting epithelial-mesenchymal transition (EMT) and metastasis. However, when germinal center IL21R+ B cells simultaneously colocalize with these innate signals, they override this suppressive tissue stress. Spatial analysis shows that a high S100A8\/IL21R intersection within tumor regions strictly distinguishes treatment responders, whereas non-responders display spatial mismatch or S100A8+ hyper-infiltration. This coordinated innate-adaptive cross-talk sustains functional tertiary lymphoid structures (TLS) that mature IgG-secreting plasma cells, which opsonize and eliminate emerging EMT tumor cells before systemic escape. Consequently, while S100A8 alone is an unreliable prognosticator, its spatial colocalization with IL21R is a robust protective indicator overlooked by conventional bulk analysis methods.","rel_num_authors":7,"rel_authors":[{"author_name":"Zhaozheng HOU","author_inst":"University of Hong Kong"},{"author_name":"Yijia Qian","author_inst":"University of Hong Kong"},{"author_name":"Victor Ho-Fun Lee","author_inst":"University of Hong Kong"},{"author_name":"Dora Lai-Wan Kwong","author_inst":"University of Hong Kong"},{"author_name":"Xinyuan Guan","author_inst":"University of Hong Kong"},{"author_name":"Zhonghua Liu","author_inst":"Columbia University"},{"author_name":"Wei Dai","author_inst":"University of Hong Kong"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Foundation Model RNAGAN Enhances Biomedical Insight of Nasopharyngeal Carcinoma Metastasis","rel_doi":"10.64898\/2026.07.02.736240","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736240","rel_abs":"RNAGAN (version 2.0, https:\/\/github.com\/ZhaozhengHou-HKU\/RNAGAN-2.0.git) is a published foundation model that analyzes single-cell and bulk-level RNA sequencing samples and enables multiple applications that enhance medical insights. Here we applied this model to Nasopharyngeal Carcinoma (NPC) as in-context few-short format (i.e., the model was never trained with any NPC data). We conducted all four supported functions, which include sample stratification, vectorization, pseudo data generation, and marker identification. The results were then used for identifying metastatic NPC and to investigate mechanisms associated with NPC metastasis.\n\nExamination with stratification showed that the accuracy of RNAGAN results for evaluating the metastasis risk in NPC patients are comparable to or outcompeted recently published risk estimation linear prediction model. Vectorization results present consistency across multiple cohorts and RNAGAN model versions. In the task of identifying markers and mechanisms related to NPC metastasis, incorporating pseudo data substantially enhanced the representativeness of single-cohort-based differential expression (DE) analysis. Moreover, RNAGAN identified metastasis-related marker genes based on single cohort, were concordant with the ground truth obtained across multiple cohorts (p=1.05e-9).\n\nRegarding biomedical mechanisms, RNAGAN enabled second-order feature extraction, unveiling a remarkable domination of the protective function of adaptive immune responses (as indicated by IL21R levels) over the hazardous function of chronic, non-resolving innate inflammation (as indicated by S100A8 levels) against NPC metastasis after first-line treatment. This association demonstrates a high degree of consistency with the external cohort.\n\nThis study demonstrates the utility of the foundation model RNAGAN in uncovering therapeutic insights for novel cancer types without extra training. We reveal a critical spatial mechanism preventing distant metastasis via humoral anti-tumor immunity in NPC. High S100A8 expression by innate antigen-presenting cells (APCs) triggers an inflammatory cascade promoting epithelial-mesenchymal transition (EMT) and metastasis. However, when germinal center IL21R+ B cells simultaneously colocalize with these innate signals, they override this suppressive tissue stress. Spatial analysis shows that a high S100A8\/IL21R intersection within tumor regions strictly distinguishes treatment responders, whereas non-responders display spatial mismatch or S100A8+ hyper-infiltration. This coordinated innate-adaptive cross-talk sustains functional tertiary lymphoid structures (TLS) that mature IgG-secreting plasma cells, which opsonize and eliminate emerging EMT tumor cells before systemic escape. Consequently, while S100A8 alone is an unreliable prognosticator, its spatial colocalization with IL21R is a robust protective indicator overlooked by conventional bulk analysis methods.","rel_num_authors":7,"rel_authors":[{"author_name":"Zhaozheng HOU","author_inst":"University of Hong Kong"},{"author_name":"Yijia Qian","author_inst":"University of Hong Kong"},{"author_name":"Victor Ho-Fun Lee","author_inst":"University of Hong Kong"},{"author_name":"Dora Lai-Wan Kwong","author_inst":"University of Hong Kong"},{"author_name":"Xinyuan Guan","author_inst":"University of Hong Kong"},{"author_name":"Zhonghua Liu","author_inst":"Columbia University"},{"author_name":"Wei Dai","author_inst":"University of Hong Kong"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Telomerase RNA regulates the epigenome primed for human lineage commitment","rel_doi":"10.64898\/2026.07.03.736284","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736284","rel_abs":"Telomerase RNA (TERC) is known as the essential template for telomere elongation. Here, we report an unexpected role for TERC in regulating chromatin accessibility, which is primed for determining the cell fate of human embryonic stem cells (hESCs). TERC-deficient hESCs retain critical markers for pluripotency but fail to undergo lineage differentiation as shown by standard in vivo teratoma formation as well as in vitro differentiation assays, which is consistent with repressed transcription during differentiation into the three germ lineages. Notably, transient re-introduction of TERC into TERC-deficient hESCs rescued lineage differentiation capacity without restoring telomere length. TERC binds to the promoters and enhancers of developmental genes marked by H3K27ac to maintain an open chromatin state. Loss of TERC reduces H3K27ac deposition and decreases chromatin accessibility through the remodelling of three-dimensional genome organization, including TAD boundary insulation and compartment switching. Collectively, our findings reveal that TERC is a chromatin-associated noncoding RNA that regulates the epigenomic architecture that governs cell fate for lineage commitment during development.","rel_num_authors":16,"rel_authors":[{"author_name":"Jie Li","author_inst":"Nankai University"},{"author_name":"Peng Su","author_inst":"Nankai University"},{"author_name":"Mingqi Gao","author_inst":"Peking University"},{"author_name":"Chang Liu","author_inst":"Nankai University"},{"author_name":"Niannian Li","author_inst":"Weifang People's Hospital"},{"author_name":"Guofeng Feng","author_inst":"Nankai University"},{"author_name":"Yongqin Yu","author_inst":"Nankai University"},{"author_name":"Zhifei Chen","author_inst":"Nankai University"},{"author_name":"Guoxing Yin","author_inst":"Nankai University"},{"author_name":"Xiaoying Ye","author_inst":"Nankai University"},{"author_name":"Jiangtao Lu","author_inst":"Nankai University"},{"author_name":"Ziyi Jin","author_inst":"Nankai University"},{"author_name":"Zhengmao Zhu","author_inst":"Nankai University"},{"author_name":"Haiying Liu","author_inst":"Sun Yat-sen University"},{"author_name":"Hua Wang","author_inst":"Peking University"},{"author_name":"Lin Liu","author_inst":"Nankai University"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Environment-dependent landscapes of coding variant impacts on coproporphyrinogen oxidase","rel_doi":"10.64898\/2026.07.02.735896","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.735896","rel_abs":"Hereditary coproporphyria (HCP) -- caused by variants in coproporphyrinogen oxidase (CPOX) -- can be diagnosed via genome sequencing. However, 74% of clinically-reported CPOX missense variants are classified as variants of uncertain significance (VUS) due to lack of evidence. CPOX variant classification is further complicated by environment-dependence: For example, the CPOX variant p.Asn272His (c.814A>C) is classified as benign yet has been associated with HCP-like symptoms in the context of mercury exposure. Here we measured the functional impact of nearly all possible CPOX amino acid substitutions in both the presence and absence of mercury. The resulting CPOX variant effect maps reflect known protein structure and mutational tolerance patterns while also offering new sequence-structure-function insights. Scores from this atlas not only distinguish pathogenic from benign variants but also identify mercury-dependent variant impacts, thus informing our clinical, structural, and functional understanding of CPOX deficiency and illustrating the value of systematic context-dependent multiplexed assays of genetic variant effects.","rel_num_authors":17,"rel_authors":[{"author_name":"Warren van Loggerenberg","author_inst":"University of Pittsburgh"},{"author_name":"Haotian Zhang","author_inst":"University of Pittsburgh"},{"author_name":"Vignesh Senguttuvan","author_inst":"University of Pittsburgh"},{"author_name":"Michael J Chambers","author_inst":"University of Pittsburgh"},{"author_name":"Mailoan Panchalingam","author_inst":"University of Toronto"},{"author_name":"Alireza Rasoulzadeh","author_inst":"University of Pittsburgh"},{"author_name":"Anna Axakova","author_inst":"University of Toronto"},{"author_name":"Marinella Gebbia","author_inst":"University of Toronto"},{"author_name":"Robert J Desnick","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Bruce Wang","author_inst":"University of California San Francisco"},{"author_name":"Caroline Schmitt","author_inst":"French Centre of Porphyrias"},{"author_name":"Laurent Gouya","author_inst":"French Centre of Porphyrias"},{"author_name":"Jordi To-Figueras","author_inst":"University of Barcelona"},{"author_name":"Alexander Wahl","author_inst":"Labcorp Genetics"},{"author_name":"Ivet Bahar","author_inst":"Stony Brook University"},{"author_name":"Pemra Doruker","author_inst":"Allotar Therapeutics"},{"author_name":"Frederick P Roth","author_inst":"University of Pittsburgh"}],"rel_date":"2026-07-09","rel_site":"biorxiv"},{"rel_title":"Evaluation of Large Language Models for Post-Cystectomy Sexual Health Counseling in Women: A Pilot Study","rel_doi":"10.64898\/2026.06.25.26356154","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356154","rel_abs":"ObjectiveTo evaluate the adherence to guidelines and readability of large language model-generated sexual health information related to female sexual dysfunction following cystectomy, and to determine whether adherence differs across models and prompt formats. A secondary objective was to introduce an analytic strategy using principal component analysis to examine the dimensions of readability metrics.\n\nMethodsThree large language models (LLMs), ChatGPT, Gemini, and Perplexity were prompted with six clinical questions related to sexual function after cystectomy. Questions were phrased in long-form and short-form language. Responses were independently graded by two reviewers, derived from guideline recommendations. Linear mixed-effects models predicted adherence as functions of LLM, prompt, and reviewer, with clinical questions as a random intercept. Readability was assessed using five metrics, and principal component analysis (PCA) was used to determine latent structure.\n\nResultsChatGPT demonstrated the highest (estimated marginal mean [emm] = 0.769), outperforming Gemini (0.499) and Perplexity (0.457). Shorter, less complex prompts elicited higher adherence than more complex, clinical prompts. All models produced content that exceeded recommended reading levels. PCA demonstrated that a single dominant component accounted for 76.7% of variance across readability indices, indicating a shared underlying construct.\n\nConclusionChatGPT produced the most guideline-concordant information overall. High linguistic complexity was seen across models, highlighting a barrier to patient comprehension. These findings characterize large language models as variable medical information systems whose outputs rely heavily on prompt structure and model type.","rel_num_authors":7,"rel_authors":[{"author_name":"Faheed Shafau","author_inst":"Michigan State University College of Human Medicine"},{"author_name":"Aakash A Dave","author_inst":"Michigan State University"},{"author_name":"Ibukunoluwa Omole","author_inst":"Michigan State University College of Human Medicine"},{"author_name":"Taeris Guzman","author_inst":"Northeast Ohio Medical University"},{"author_name":"Najibha Rehman","author_inst":"Henry Ford Health System"},{"author_name":"Ekene Enemchukwu","author_inst":"Stanford University School of Medicine"},{"author_name":"Larissa Bresler","author_inst":"Northwestern University Feinberg School of Medicine"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Artificially sweetened beverage intake and risk of liver-related adverse events in individuals with MASLD: A prospective UK Biobank cohort study","rel_doi":"10.64898\/2026.07.04.26357265","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.04.26357265","rel_abs":"PurposeMetabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of chronic liver disease and liver-related morbidity worldwide. Although dietary factors may influence MASLD progression, the long-term liver-specific implications of artificially sweetened beverage (ASB) intake remain unclear. We aimed to examine the association between ASB intake and the risk of liver-related adverse events and liver-related death among individuals with MASLD.\n\nMethodsThis prospective cohort study included 50,562 participants with MASLD from the UK Biobank. ASB intake was assessed using 24-hour dietary recalls and categorized as 0, >0-1, and >1 serving\/day. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for liver-related adverse events and liver-related death. Restricted cubic spline models were used to assess dose-response patterns, and competing-risk analyses were performed by treating liver-related death as a competing event for liver-related adverse events. Additional substitution, subgroup and sensitivity analyses were conducted to evaluate the robustness of the findings.\n\nResultsDuring a median follow-up of 12.8 years, 292 liver-related adverse events and 91 liver-related deaths occurred. Compared with participants reporting no ASB intake, those consuming >1 serving\/day had a higher risk of liver-related adverse events in the fully adjusted model (HR 1.40, 95% CI 1.02-1.93; P = 0.039), whereas the association for >0-1 serving\/day was not statistically significant (HR 1.26, 95% CI 0.92-1.71; P = 0.149). The risk of liver-related adverse events increased across ASB intake categories (P for trend = 0.023). Restricted cubic spline analysis indicated a positive linear association between ASB intake and liver-related adverse events (P-overall <0.001; P-nonlinearity = 0.72). In competing-risk analysis, the association for >1 serving\/day remained consistent after accounting for liver-related death as a competing event (sub-HR 1.40, 95% CI 1.02-1.93; P = 0.038; Gray test P = 0.006). The association was robust in sensitivity analyses. ASB intake was not significantly associated with liver-related death, and beverage substitution analyses showed no significant associations.\n\nConclusionAmong individuals with MASLD, high ASB intake, particularly >1 serving\/day, was associated with an increased risk of liver-related adverse events, but not liver-related death. This association was consistent across dose-response, competing-risk, and sensitivity analyses, suggesting that high ASB intake may represent a potential dietary risk marker for adverse liver outcomes in MASLD.","rel_num_authors":7,"rel_authors":[{"author_name":"ning xu","author_inst":"Soochow University Affiliated No 1 People's Hospital: First Affiliated Hospital of Soochow University"},{"author_name":"Jiaxi Lin","author_inst":"Soochow University Affiliated No 1 People's Hospital: First Affiliated Hospital of Soochow University"},{"author_name":"Lihe Liu","author_inst":"Soochow University Affiliated No 1 People's Hospital: First Affiliated Hospital of Soochow University"},{"author_name":"Shiqi Zhu","author_inst":"Soochow University Affiliated No 1 People\\'s Hospital: First Affiliated Hospital of Soochow University"},{"author_name":"Rui Li","author_inst":"Soochow University Affiliated No 1 People's Hospital: First Affiliated Hospital of Soochow University"},{"author_name":"Jinzhou Zhu","author_inst":"Soochow University Affiliated No 1 People's Hospital: First Affiliated Hospital of Soochow University"},{"author_name":"Chunfang Xu","author_inst":"Soochow University Affiliated No 1 People's Hospital: First Affiliated Hospital of Soochow University"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Exploring the Application of the Observational Medical Outcomes Partnership Common Data Model to Multi-site Stroke Rehabilitation Research Data","rel_doi":"10.64898\/2026.06.28.26356618","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.28.26356618","rel_abs":"BackgroundEmerging artificial intelligence and machine learning (AI\/ML) tools can help generate robust knowledge to support precision rehabilitation approaches for varied patient populations. There is a large amount of research-generated and clinical rehabilitation data available for this purpose; however, a pronounced lack of interoperability prevents large-scale data aggregation. Common data models (CDMs) such as Observational Medical Outcomes Partnership (OMOP) have improved data interoperability across healthcare settings, and more recently, for clinical rehabilitation data, specifically. However, the application of these CDMs to research-generated data has not yet been explored. Therefore, as a foundational step, our study evaluated the breadth and depth of OMOP CDM coverage for data in a multi-site repository of harmonized rehabilitation research data: the Enhancing NeuroImaging Genetics through Meta-Analysis Stroke Recovery (ENIGMA-SR) database.\n\nMethodsTwo raters independently mapped data elements representing 46 demographics and medical history (DMH) ENIGMA-SR variables and 95 distinct ENIGMA-SR rehabilitation assessments to OMOP standard concepts. Initial rater agreement was assessed for data element inclusion in OMOP and for specific OMOP concepts used (primary metric: Gwets agreement coefficient [AC]). Mapping differences were reconciled, and final mappings were descriptively analyzed to examine (1) overall OMOP inclusion, (2) inclusion of more granular levels (subscales, items) of complex assessments, and (3) mapped OMOP concept characteristics.\n\nResultsInitial rater agreement was good\/very good for overall OMOP inclusion of DMH and assessment data elements and for OMOP concepts mapped across almost all assessment data elements (Gwets AC: 0.79-0.89). Initial OMOP concept agreement was more variable for DMH data elements; however, all mapping differences were successfully reconciled to 100%. Overall, DMH data elements had higher OMOP inclusion than rehabilitation assessments: 84.8% (39\/46) vs. 58.9% (56\/95). OMOP coverage was particularly limited for complex assessment subscale- and item-level data elements (9.4% [3\/32]; 19.2% [14\/73]) and did not match the granularity level represented in ENIGMA-SR data for 56.2% (41\/73) of complex assessments. DMH and top-level assessment data elements were frequently mapped to multiple OMOP concepts (median: 6, 2; range: 1-23, 1-8), and for > 50% of these data elements the concepts spanned 2-3 different OMOP domains.\n\nConclusionFor ENIGMA-SR, the OMOP CDM has good coverage of DMH data, moderate top-level coverage of rehabilitation assessments, and very limited coverage of assessment subscales and items. This uneven coverage, combined with variability in OMOP concepts and domains mapped to equivalent data points, presents challenges for aggregating clinical and research-generated rehabilitation data into AI\/ML-ready datasets. Moreover, software tools currently available to facilitate the mapping process do not effectively accommodate content- and structure-related features inherent to research-generated data. Going forward, the utility of the OMOP CDM to aggregate multi-source rehabilitation data may be improved by expanding the catalogue of OMOP rehabilitation-related concepts, building cross-walks to research-oriented data standards, and adapting emerging computational tools to streamline the mapping process.","rel_num_authors":7,"rel_authors":[{"author_name":"Katherine J. Loomis","author_inst":"University of Southern California"},{"author_name":"Amisha Kumar","author_inst":"University of Southern California"},{"author_name":"Octavio Marin-Pardo","author_inst":"University of Southern California"},{"author_name":"Grace C. Bellinger","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Margaret A. French","author_inst":"University of Utah"},{"author_name":"Ryan T. Roemmich","author_inst":"Kennedy Krieger Institute\/Johns Hopkins University School of Medicine"},{"author_name":"Sook-Lei Liew","author_inst":"University of Southern California"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Genomic Evidence Links Inflammation to Residual Pulmonary Vascular Obstruction and Risk of Pulmonary Embolism Recurrence","rel_doi":"10.64898\/2026.06.26.26356642","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356642","rel_abs":"Background and AimsResidual pulmonary vascular obstruction (RPVO) defined as the persistence of thrombotic material within the pulmonary arteries several months after an acute pulmonary embolism (PE) is associated with an increased risk of severe complications, including recurrent events and chronic pulmonary hypertension. However, the genomic architecture underlying RPVO in unprovoked PE remains poorly understood, and this study aims to address this gap.\n\nMethodBy leveraging genetic and imaging RPVO data from three independent cohorts totaling 586 unprovoked PE patients, we conducted a meta-analysis of genome wide association study (GWAS) of RPVO using a dedicated statistical method to handle the semi-continuous distribution of RPVO. The meta-GWAS was complemented by haplotype association analyses and transcriptome wide association studies as well as Mendelian Randomization (MR) approaches based on plasma metabolites and proteins.\n\nResultsThrough meta-GWAS, we identified one locus, OSTN, associated with RPVO (lead variant rs59109356 associated with a [~]2-fold increase of RPVO, p=3.92x10-8). A second locus, CCN4, previously reported to associate with pulmonary fibrosis, was also identified, with evidence of association approaching genome-wide significance (p=6.7x10-). We also identified a common haplotype spanning over AHSG\/HRG\/KNG1 associated with a [~]3-fold increase of RPVO (p=2.96x10-8). Using plasma protein-based MR, we demonstrated that one unit increase in genetically determined plasma levels of IL-1 R AcP encoding IL1RAP was associated with a 28% (p=1.32x10-6) reduction in RPVO. We also observed statistical evidence that the CCN4 (p=0.06) and IL1RAP (p=0.02) loci associate with the risk of PE recurrence in a sample of 1,617 unprovoked PE patients.\n\nConclusionsaBy identifying novel molecular determinants of RPVO that map to loci involved in inflammatory pathways and vascular remodeling, our study provides evidence that inflammation is the predominant--and likely the key--mechanism underlying RPVO, whereas impaired fibrinolysis appears to play a more limited role.","rel_num_authors":22,"rel_authors":[{"author_name":"Floriane Samaria","author_inst":"Universite de Bordeaux"},{"author_name":"Gaelle Munsch","author_inst":"Universite de Brest"},{"author_name":"Ohanna C. L Bezerra","author_inst":"University of Toronto"},{"author_name":"Kerri L Wiggins","author_inst":"University of Washington"},{"author_name":"Lenaick Gourhant","author_inst":"Centre Hospitalier Univeristaire de Brest"},{"author_name":"Astrid van Hylckama Vlieg","author_inst":"Leids Universitair Medisch Centrum"},{"author_name":"Marine Germain","author_inst":"Universite de Bordeaux"},{"author_name":"Robert Olaso","author_inst":"Universite Paris-Saclay"},{"author_name":"Ilana Caro","author_inst":"Universite de Bordeaux"},{"author_name":"Noemie Saut","author_inst":"Aix-Marseille University"},{"author_name":"Delphine Bacq","author_inst":"Universite Paris-Saclay"},{"author_name":"Catherine A. Lemarie","author_inst":"Universite de Brest"},{"author_name":"Stephanie Debette","author_inst":"Universite de Bordeaux"},{"author_name":"Nicholas L. Smith","author_inst":"University of Washington"},{"author_name":"Frits Richard Rosendaal","author_inst":"Leiden Universitair Medisch Centrum"},{"author_name":"Pierre-Emmanuel Morange","author_inst":"Aix-Marseille University"},{"author_name":"Gregoire Le Gal","author_inst":"University of Ottawa"},{"author_name":"Jean-Fran\u00e7ois Deleuze","author_inst":"Universite Paris-Saclay"},{"author_name":"France Gagnon","author_inst":"University of Toronto Mississauga"},{"author_name":"Marc A. Rodger","author_inst":"McGill University"},{"author_name":"Francis Couturaud","author_inst":"Centre Hospitalier Universitaire de Brest"},{"author_name":"David-Alexandre Tregouet","author_inst":"Universite de Bordeaux"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Genomic Evidence Links Inflammation to Residual Pulmonary Vascular Obstruction and Risk of Pulmonary Embolism Recurrence","rel_doi":"10.64898\/2026.06.26.26356642","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356642","rel_abs":"Background and AimsResidual pulmonary vascular obstruction (RPVO) defined as the persistence of thrombotic material within the pulmonary arteries several months after an acute pulmonary embolism (PE) is associated with an increased risk of severe complications, including recurrent events and chronic pulmonary hypertension. However, the genomic architecture underlying RPVO in unprovoked PE remains poorly understood, and this study aims to address this gap.\n\nMethodBy leveraging genetic and imaging RPVO data from three independent cohorts totaling 586 unprovoked PE patients, we conducted a meta-analysis of genome wide association study (GWAS) of RPVO using a dedicated statistical method to handle the semi-continuous distribution of RPVO. The meta-GWAS was complemented by haplotype association analyses and transcriptome wide association studies as well as Mendelian Randomization (MR) approaches based on plasma metabolites and proteins.\n\nResultsThrough meta-GWAS, we identified one locus, OSTN, associated with RPVO (lead variant rs59109356 associated with a [~]2-fold increase of RPVO, p=3.92x10-8). A second locus, CCN4, previously reported to associate with pulmonary fibrosis, was also identified, with evidence of association approaching genome-wide significance (p=6.7x10-). We also identified a common haplotype spanning over AHSG\/HRG\/KNG1 associated with a [~]3-fold increase of RPVO (p=2.96x10-8). Using plasma protein-based MR, we demonstrated that one unit increase in genetically determined plasma levels of IL-1 R AcP encoding IL1RAP was associated with a 28% (p=1.32x10-6) reduction in RPVO. We also observed statistical evidence that the CCN4 (p=0.06) and IL1RAP (p=0.02) loci associate with the risk of PE recurrence in a sample of 1,617 unprovoked PE patients.\n\nConclusionsaBy identifying novel molecular determinants of RPVO that map to loci involved in inflammatory pathways and vascular remodeling, our study provides evidence that inflammation is the predominant--and likely the key--mechanism underlying RPVO, whereas impaired fibrinolysis appears to play a more limited role.","rel_num_authors":22,"rel_authors":[{"author_name":"Floriane Samaria","author_inst":"Universite de Bordeaux"},{"author_name":"Gaelle Munsch","author_inst":"Universite de Brest"},{"author_name":"Ohanna C. L Bezerra","author_inst":"University of Toronto"},{"author_name":"Kerri L Wiggins","author_inst":"University of Washington"},{"author_name":"Lenaick Gourhant","author_inst":"Centre Hospitalier Univeristaire de Brest"},{"author_name":"Astrid van Hylckama Vlieg","author_inst":"Leids Universitair Medisch Centrum"},{"author_name":"Marine Germain","author_inst":"Universite de Bordeaux"},{"author_name":"Robert Olaso","author_inst":"Universite Paris-Saclay"},{"author_name":"Ilana Caro","author_inst":"Universite de Bordeaux"},{"author_name":"Noemie Saut","author_inst":"Aix-Marseille University"},{"author_name":"Delphine Bacq","author_inst":"Universite Paris-Saclay"},{"author_name":"Catherine A. Lemarie","author_inst":"Universite de Brest"},{"author_name":"Stephanie Debette","author_inst":"Universite de Bordeaux"},{"author_name":"Nicholas L. Smith","author_inst":"University of Washington"},{"author_name":"Frits Richard Rosendaal","author_inst":"Leiden Universitair Medisch Centrum"},{"author_name":"Pierre-Emmanuel Morange","author_inst":"Aix-Marseille University"},{"author_name":"Gregoire Le Gal","author_inst":"University of Ottawa"},{"author_name":"Jean-Fran\u00e7ois Deleuze","author_inst":"Universite Paris-Saclay"},{"author_name":"France Gagnon","author_inst":"University of Toronto Mississauga"},{"author_name":"Marc A. Rodger","author_inst":"McGill University"},{"author_name":"Francis Couturaud","author_inst":"Centre Hospitalier Universitaire de Brest"},{"author_name":"David-Alexandre Tregouet","author_inst":"Universite de Bordeaux"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Effect of initiating an ARB- versus ACEI-based regimen on dementia risk, a target trial emulation of 2.5 million US Veterans","rel_doi":"10.64898\/2026.07.05.26357173","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.05.26357173","rel_abs":"BackgroundHypertension is a modifiable risk factor for dementia, yet the comparative effectiveness of angiotensin receptor blockers (ARBs) versus angiotensin converting enzyme inhibitors (ACEIs) on dementia risk remains uncertain.\n\nObjectiveTo compare the risk of dementia and dementia-free death of ARB versus ACEI initiation among US Veterans with incident hypertension.\n\nMethodsWe conducted a retrospective target trial emulation using a new-user, active-comparator design among Veterans with incident hypertension. We analyzed longitudinal electronic health records from 2,577,000 individuals who initiated ARBs or ACEIs between 1\/1\/2000-12\/31\/2017, with up to five years of follow-up. The exposure was initiation of an ARB-based versus ACEI-based antihypertensive regimen. Co-primary outcomes were dementia, identified using natural language processing of clinical notes, and dementia-free death. We used inverse probability of treatment weights based on 66 pretreatment covariates to estimate the cumulative incidence of the outcomes for each treatment group. Weighted risk ratios and absolute risk differences through five years were computed with bootstrapped 95% CIs. Secondary outcomes included all-cause death and a composite of dementia or death, evaluated using a weighted Kaplan-Meier approach.\n\nResultsAmong 2,577,000 Veterans (mean age, 63 years; 4.5% female; 65% White; 15% Black), 10% initiated ARBs and 90% initiated ACEIs. Over five years of follow up, 6% developed dementia, 12% died without dementia, and 13% died overall. ARB initiation yielded consistently lower risk of dementia (risk ratio, 0.88; 95% CI, 0.83-0.93 at 6 months to 0.92; 95% CI, 0.90-0.94 at 5 years) and dementia-free death (risk ratio, 0.90; 95% CI, 0.86-0.96 at 6 months to 1.00; 95% CI, 0.98-1.01 at 5 years) than ACEI initiation. Effects on secondary outcomes were similar to those for primary outcomes. Greater protective dementia effects were observed in older and male Veterans and non-statin users, with similar effects on dementia-free death.\n\nDiscussionAmong US Veterans with incident treated hypertension, initiation of ARB versus ACEI antihypertensive regimen conveyed a modestly lower risk of dementia. Given the high prevalence of hypertension, these modest effects may confer meaningful population-level benefits on brain health. Future research estimating per-protocol effects using a more generalizable population is needed to confirm our findings.","rel_num_authors":14,"rel_authors":[{"author_name":"Yizhe Xu","author_inst":"University of Utah"},{"author_name":"Jianlin Shi","author_inst":"University of Utah"},{"author_name":"Ryan Andrews","author_inst":"Columbia University"},{"author_name":"Catherine G. Derington","author_inst":"University of Utah School of Medicine"},{"author_name":"Tom Greene","author_inst":"University of Utah"},{"author_name":"Daniel Scharfstein","author_inst":"University of Utah"},{"author_name":"Ransmond Berchie","author_inst":"University of Utah"},{"author_name":"Mark Supiano","author_inst":"University of Utah"},{"author_name":"Jeff Williamson","author_inst":"Wake Forest University"},{"author_name":"Nicholas Pajewski","author_inst":"Wake Forest University"},{"author_name":"Jeremy Pruzin","author_inst":"Banner Alzheimer's Institute"},{"author_name":"Jaejin An","author_inst":"Kaiser Permanente Southern California"},{"author_name":"Jordana Cohen","author_inst":"University of Pennsylvania"},{"author_name":"Adam P. Bress","author_inst":"University of Utah, School of Medicine"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Artificial Intelligence-Enabled Detection of Vascular Perfusion Defects on Ventilation\/Perfusion (V\/Q) Scintigraphy for Pulmonary Embolism","rel_doi":"10.64898\/2026.06.25.26356599","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356599","rel_abs":"Accurate interpretation of planar ventilation-perfusion (V\/Q) scintigraphy, used for diagnosing pulmonary embolism (PE) based on PIOPED\/EANM guidelines, requires objective assessment of mismatched V\/Q defects. Manual delineation of V\/Q defects is time-consuming, subject to interobserver variability, and rarely performed in practice, limiting standardized reporting and quantification of disease burden. To address these challenges, we evaluated four modern AI models for automated segmentation of vascular perfusion defects in planar V\/Q scans and compared their performance to human annotators. We retrospectively identified 2,118 patients who underwent planar V\/Q scans at The Ottawa Hospital (June 2019-February 2023). Six standard projections (ANT, POST, LAO, RAO, LPO, RPO) were included. Four 2D neural networks (U-Net, nnU-Net, Swin UNETR, and a Bottleneck Transformer U-Net [BTU-Net]) were trained on 1,313 patients (7,878 projections) and validated on 329 (1,974 projections) using physician-annotated defects. A hold-out test set of 46 high probability patients was used to evaluate segmentation quality, and defect detection accuracy using free-response receiver operating characteristic (FROC) analysis, where BTU-Net was the only model performing on par with human readers, showing robust sensitivity across the entire range of segmentation probabilities. At 1.5 false positives per projection rate (FPPR), BTU-Net outperformed other models with sensitivity of 0.529 {+\/-} 0.026, On a separate hold-out set of low likelihood of disease patients (n=430), the lowest FPPR was 0.08 {+\/-} 0.01 for BTU-Net (P<0.0001). BTU-Net enables rapid, consistent, and accurate interpretation of planar V\/Q scans. Such tools may enhance diagnostic efficiency, standardize reporting, and support non-expert readers in evaluating PE.","rel_num_authors":16,"rel_authors":[{"author_name":"Amir Jabbarpour","author_inst":"Caleton University"},{"author_name":"Eric Moulton","author_inst":"Jubilant DraxImage"},{"author_name":"Sanaz Kaviani","author_inst":"The Ottawa Hospital"},{"author_name":"Wanzhen Zeng","author_inst":"The Ottawa Hospital"},{"author_name":"Siraj Ghassel","author_inst":"University of Ottawa"},{"author_name":"Ramin Akbarian","author_inst":"The Ottawa Hospital"},{"author_name":"Anne Couture","author_inst":"Hopital Maisonneuve-Rosemont"},{"author_name":"Aubert Roy","author_inst":"McGill University Faculty of Medicine"},{"author_name":"Richard Liu","author_inst":"Jewish General Hospital"},{"author_name":"Yousif Al-ali","author_inst":"Hopital Maisonneuve-Rosemont"},{"author_name":"Yasser Foufa","author_inst":"Montreal Heart Institute"},{"author_name":"Nuha Hejji","author_inst":"University of Ottawa"},{"author_name":"Sukainah AlSulaiman","author_inst":"The Ottawa Hospital, Ottawa"},{"author_name":"Zeinab Shirazi","author_inst":"zshir069@uottawa.ca"},{"author_name":"Eugene Leung","author_inst":"The Ottawa Hospital"},{"author_name":"Ran Klein","author_inst":"The Ottawa Hospital"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Artificial Intelligence-Enabled Detection of Vascular Perfusion Defects on Ventilation\/Perfusion (V\/Q) Scintigraphy for Pulmonary Embolism","rel_doi":"10.64898\/2026.06.25.26356599","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356599","rel_abs":"Accurate interpretation of planar ventilation-perfusion (V\/Q) scintigraphy, used for diagnosing pulmonary embolism (PE) based on PIOPED\/EANM guidelines, requires objective assessment of mismatched V\/Q defects. Manual delineation of V\/Q defects is time-consuming, subject to interobserver variability, and rarely performed in practice, limiting standardized reporting and quantification of disease burden. To address these challenges, we evaluated four modern AI models for automated segmentation of vascular perfusion defects in planar V\/Q scans and compared their performance to human annotators. We retrospectively identified 2,118 patients who underwent planar V\/Q scans at The Ottawa Hospital (June 2019-February 2023). Six standard projections (ANT, POST, LAO, RAO, LPO, RPO) were included. Four 2D neural networks (U-Net, nnU-Net, Swin UNETR, and a Bottleneck Transformer U-Net [BTU-Net]) were trained on 1,313 patients (7,878 projections) and validated on 329 (1,974 projections) using physician-annotated defects. A hold-out test set of 46 high probability patients was used to evaluate segmentation quality, and defect detection accuracy using free-response receiver operating characteristic (FROC) analysis, where BTU-Net was the only model performing on par with human readers, showing robust sensitivity across the entire range of segmentation probabilities. At 1.5 false positives per projection rate (FPPR), BTU-Net outperformed other models with sensitivity of 0.529 {+\/-} 0.026, On a separate hold-out set of low likelihood of disease patients (n=430), the lowest FPPR was 0.08 {+\/-} 0.01 for BTU-Net (P<0.0001). BTU-Net enables rapid, consistent, and accurate interpretation of planar V\/Q scans. Such tools may enhance diagnostic efficiency, standardize reporting, and support non-expert readers in evaluating PE.","rel_num_authors":16,"rel_authors":[{"author_name":"Amir Jabbarpour","author_inst":"Caleton University"},{"author_name":"Eric Moulton","author_inst":"Jubilant DraxImage"},{"author_name":"Sanaz Kaviani","author_inst":"The Ottawa Hospital"},{"author_name":"Wanzhen Zeng","author_inst":"The Ottawa Hospital"},{"author_name":"Siraj Ghassel","author_inst":"University of Ottawa"},{"author_name":"Ramin Akbarian","author_inst":"The Ottawa Hospital"},{"author_name":"Anne Couture","author_inst":"Hopital Maisonneuve-Rosemont"},{"author_name":"Aubert Roy","author_inst":"McGill University Faculty of Medicine"},{"author_name":"Richard Liu","author_inst":"Jewish General Hospital"},{"author_name":"Yousif Al-ali","author_inst":"Hopital Maisonneuve-Rosemont"},{"author_name":"Yasser Foufa","author_inst":"Montreal Heart Institute"},{"author_name":"Nuha Hejji","author_inst":"University of Ottawa"},{"author_name":"Sukainah AlSulaiman","author_inst":"The Ottawa Hospital, Ottawa"},{"author_name":"Zeinab Shirazi","author_inst":"zshir069@uottawa.ca"},{"author_name":"Eugene Leung","author_inst":"The Ottawa Hospital"},{"author_name":"Ran Klein","author_inst":"The Ottawa Hospital"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Retina-derived Quantitative Biomarkers of Brain Health","rel_doi":"10.64898\/2026.07.05.26357344","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.05.26357344","rel_abs":"Accurate and scalable assessment of quantitative neuroimaging biomarkers, such as white matter hyperintensities (WMH) and hippocampal (HIP) volumes, is essential for understanding and monitoring brain health, preventing neurological diseases and improving healthspan. However, population-level evaluation of these neuroimaging biomarkers relies on inaccessible, costly and time-consuming magnetic resonance imaging (MRI). Here we propose RetiBrain, a cross-modal deep learning framework that predicts these neuroimaging biomarkers from retinal color fundus photography (CFP) images. By distilling latent structural representations from MRI-based models into a CFP-based model, RetiBrain establishes biologically grounded eye-to-brain mapping. In a CFP-MRI paired cohort, RetiBrain accurately estimates six WMH- and HIP-related biomarkers and outperforms the state-of-the-art retinal foundation model RETFound, improving the mean Pearson correlation coefficient by 0.309 (from 0.240 to 0.549) and achieving a coefficient of 0.640 for periventricular WMH prediction. By integrating structural, topological and geometric feature analyses from CFP images, RetiBrain identifies interpretable retinal representations associated with neurodegeneration and cerebrovascular injury, hallmarks of major neurological diseases such as dementia and stroke. In a longitudinal cohort comprising 2,082 participants (4,164 CFP images with up to 15 years of follow-up), RetiBrain-predicted neuroimaging biomarkers robustly estimated neurological disease risk, as illustrated by dementia prediction (AUROC of 0.824, hazard ratio 2.500 per standard deviation increase, 95% CI: 2.201-2.840). RetiBrain provides a robust, scalable, cost-effective and convenient approach for the assessment of neuroimaging biomarkers, and has potential for long-term brain health monitoring in large-scale general population settings.","rel_num_authors":14,"rel_authors":[{"author_name":"Taizhangtian Ma","author_inst":"Department of Automation, Tsinghua University"},{"author_name":"Tao Yan","author_inst":"Department of Automation, Tsinghua University"},{"author_name":"Jing Sun","author_inst":"Department of Radiology, Beijing Friendship Hospital, Capital Medical University"},{"author_name":"Ning Wu","author_inst":"Department of Medical Imaging Technology, School of Medical Technology, Capital Medical University"},{"author_name":"Mingze Xu","author_inst":"Center for MRI Research, Academy for Advanced Interdisciplinary Studies, Peking University"},{"author_name":"Ruiheng Zhang","author_inst":"Beijing Tongren Hospital"},{"author_name":"Na Zeng","author_inst":"Department of Infection Control, Peking University First Hospital"},{"author_name":"Qi Sun","author_inst":"Precision and Intelligence Medical Imaging Lab, Beijing Friendship Hospital, Capital Medical University"},{"author_name":"Ying Hui","author_inst":"Kailuan General Hospital"},{"author_name":"Yuntao Wu","author_inst":"Kailuan General Hospital"},{"author_name":"Zhenchang Wang","author_inst":"Beijing Friendship Hospital, Capital Medical University"},{"author_name":"Tien Yin Wong","author_inst":"Tsinghua University"},{"author_name":"Han Lv","author_inst":"Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China"},{"author_name":"Hui Qiao","author_inst":"Department of Automation, Tsinghua University"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Retina-derived Quantitative Biomarkers of Brain Health","rel_doi":"10.64898\/2026.07.05.26357344","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.05.26357344","rel_abs":"Accurate and scalable assessment of quantitative neuroimaging biomarkers, such as white matter hyperintensities (WMH) and hippocampal (HIP) volumes, is essential for understanding and monitoring brain health, preventing neurological diseases and improving healthspan. However, population-level evaluation of these neuroimaging biomarkers relies on inaccessible, costly and time-consuming magnetic resonance imaging (MRI). Here we propose RetiBrain, a cross-modal deep learning framework that predicts these neuroimaging biomarkers from retinal color fundus photography (CFP) images. By distilling latent structural representations from MRI-based models into a CFP-based model, RetiBrain establishes biologically grounded eye-to-brain mapping. In a CFP-MRI paired cohort, RetiBrain accurately estimates six WMH- and HIP-related biomarkers and outperforms the state-of-the-art retinal foundation model RETFound, improving the mean Pearson correlation coefficient by 0.309 (from 0.240 to 0.549) and achieving a coefficient of 0.640 for periventricular WMH prediction. By integrating structural, topological and geometric feature analyses from CFP images, RetiBrain identifies interpretable retinal representations associated with neurodegeneration and cerebrovascular injury, hallmarks of major neurological diseases such as dementia and stroke. In a longitudinal cohort comprising 2,082 participants (4,164 CFP images with up to 15 years of follow-up), RetiBrain-predicted neuroimaging biomarkers robustly estimated neurological disease risk, as illustrated by dementia prediction (AUROC of 0.824, hazard ratio 2.500 per standard deviation increase, 95% CI: 2.201-2.840). RetiBrain provides a robust, scalable, cost-effective and convenient approach for the assessment of neuroimaging biomarkers, and has potential for long-term brain health monitoring in large-scale general population settings.","rel_num_authors":14,"rel_authors":[{"author_name":"Taizhangtian Ma","author_inst":"Department of Automation, Tsinghua University"},{"author_name":"Tao Yan","author_inst":"Department of Automation, Tsinghua University"},{"author_name":"Jing Sun","author_inst":"Department of Radiology, Beijing Friendship Hospital, Capital Medical University"},{"author_name":"Ning Wu","author_inst":"Department of Medical Imaging Technology, School of Medical Technology, Capital Medical University"},{"author_name":"Mingze Xu","author_inst":"Center for MRI Research, Academy for Advanced Interdisciplinary Studies, Peking University"},{"author_name":"Ruiheng Zhang","author_inst":"Beijing Tongren Hospital"},{"author_name":"Na Zeng","author_inst":"Department of Infection Control, Peking University First Hospital"},{"author_name":"Qi Sun","author_inst":"Precision and Intelligence Medical Imaging Lab, Beijing Friendship Hospital, Capital Medical University"},{"author_name":"Ying Hui","author_inst":"Kailuan General Hospital"},{"author_name":"Yuntao Wu","author_inst":"Kailuan General Hospital"},{"author_name":"Zhenchang Wang","author_inst":"Beijing Friendship Hospital, Capital Medical University"},{"author_name":"Tien Yin Wong","author_inst":"Tsinghua University"},{"author_name":"Han Lv","author_inst":"Department of Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China"},{"author_name":"Hui Qiao","author_inst":"Department of Automation, Tsinghua University"}],"rel_date":"2026-07-08","rel_site":"medrxiv"},{"rel_title":"Fine-Tuned Large Language Models for Detecting Social Isolation from Unstructured Clinical Notes","rel_doi":"10.64898\/2026.07.05.26357334","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.05.26357334","rel_abs":"ObjectivesThis study aimed to leverage FLAN-T5-Large, BERT, RoBERTa, and Gemma-2-2B, with fine-tuning, to identify instances of social isolation and social support within unstructured clinical notes.\n\nMaterials and MethodsAnnotated clinical note spans containing social context cues were used to fine-tune each model. Performance was evaluated using Accuracy, Precision, Recall, and Macro-F1 score. A structured prompt was used to instruct the model to perform classification task and mitigate overgeneralization. Performance comparisons across the models assessed sensitivity, robustness, and false positive reduction.\n\nResultsFLAN-T5-Large achieved highest performance, with Macro-F1 of 0.92{+\/-}0.04, demonstrating balanced results across classes: social isolation (F1 = 0.91{+\/-}0.03), no social isolation (F1 = 0.94{+\/-}0.05), and social support (F1 = 0.90{+\/-}0.04). Gemma-2-2B produced comparable results, with Macro-F1 score of 0.89{+\/-}0.10. BERT and RoBERTa achieved lower Macro-F1 scores of 0.77{+\/-}0.17 and 0.80{+\/-}0.21 respectively, with variability across categories.\n\nDiscussionA major contribution of this work is precise identification of multiple concepts related to social connectedness. By integrating annotated examples of both true and false positives, including negations and contextually ambiguous terms, the model better distinguished relevant social context cues from noise. Training on both social isolation and support provided a dual framework for comparative analyses and patient stratification.\n\nConclusionTransformer-based NLP models, particularly FLAN-T5-Large, demonstrated potential for identifying social isolation and social support in clinical text. These findings support the use of generative AI techniques to enhance detection of social isolation from EHRs, advancing context-aware healthcare analytics.\n\nLay SummaryHaving strong social connections can help people live longer, while feeling isolated can increase the risk of serious health problems. The signals about if someone is socially isolated are not captured in their Electronic Health Records but are hidden inside clinical notes that are created as part of healthcare visits. Since these notes are long and complex, it is not possible to manually review them for social connections. Hence, advanced Artificial Intelligence models called large language models - LLMs are used to automatically find the signals of social isolation or social support in clinical notes. To train the LLMs in detecting these signals, we first created a large set of examples for three scenarios: social isolation, social support, and situations where the example contained word \"isolation\" but not related to social connection. These examples helped the LLMs to understand the patterns in the examples for each scenario. We trained three LLMs, FLAN-T5, BERT, and Gemma. Among them, FLAN-T5-Large performed better with accurate and consistent results across different patient groups. This automated approach can help healthcare systems identify patients who may lack social support, update their health records and direct them to services that can help them, ultimately improving patient care.","rel_num_authors":7,"rel_authors":[{"author_name":"Lokesh K Chinthala","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Cindy Lemon","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Arash Shaban-Nejad","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Gregory Farage","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Robert L Davis","author_inst":"The University of Tennessee Health Science Center"},{"author_name":"Hua Xu","author_inst":"Yale University"},{"author_name":"Charisse Madlock-Brown","author_inst":"University of Iowa"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Fine-Tuned Large Language Models for Detecting Social Isolation from Unstructured Clinical Notes","rel_doi":"10.64898\/2026.07.05.26357334","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.05.26357334","rel_abs":"ObjectivesThis study aimed to leverage FLAN-T5-Large, BERT, RoBERTa, and Gemma-2-2B, with fine-tuning, to identify instances of social isolation and social support within unstructured clinical notes.\n\nMaterials and MethodsAnnotated clinical note spans containing social context cues were used to fine-tune each model. Performance was evaluated using Accuracy, Precision, Recall, and Macro-F1 score. A structured prompt was used to instruct the model to perform classification task and mitigate overgeneralization. Performance comparisons across the models assessed sensitivity, robustness, and false positive reduction.\n\nResultsFLAN-T5-Large achieved highest performance, with Macro-F1 of 0.92{+\/-}0.04, demonstrating balanced results across classes: social isolation (F1 = 0.91{+\/-}0.03), no social isolation (F1 = 0.94{+\/-}0.05), and social support (F1 = 0.90{+\/-}0.04). Gemma-2-2B produced comparable results, with Macro-F1 score of 0.89{+\/-}0.10. BERT and RoBERTa achieved lower Macro-F1 scores of 0.77{+\/-}0.17 and 0.80{+\/-}0.21 respectively, with variability across categories.\n\nDiscussionA major contribution of this work is precise identification of multiple concepts related to social connectedness. By integrating annotated examples of both true and false positives, including negations and contextually ambiguous terms, the model better distinguished relevant social context cues from noise. Training on both social isolation and support provided a dual framework for comparative analyses and patient stratification.\n\nConclusionTransformer-based NLP models, particularly FLAN-T5-Large, demonstrated potential for identifying social isolation and social support in clinical text. These findings support the use of generative AI techniques to enhance detection of social isolation from EHRs, advancing context-aware healthcare analytics.\n\nLay SummaryHaving strong social connections can help people live longer, while feeling isolated can increase the risk of serious health problems. The signals about if someone is socially isolated are not captured in their Electronic Health Records but are hidden inside clinical notes that are created as part of healthcare visits. Since these notes are long and complex, it is not possible to manually review them for social connections. Hence, advanced Artificial Intelligence models called large language models - LLMs are used to automatically find the signals of social isolation or social support in clinical notes. To train the LLMs in detecting these signals, we first created a large set of examples for three scenarios: social isolation, social support, and situations where the example contained word \"isolation\" but not related to social connection. These examples helped the LLMs to understand the patterns in the examples for each scenario. We trained three LLMs, FLAN-T5, BERT, and Gemma. Among them, FLAN-T5-Large performed better with accurate and consistent results across different patient groups. This automated approach can help healthcare systems identify patients who may lack social support, update their health records and direct them to services that can help them, ultimately improving patient care.","rel_num_authors":7,"rel_authors":[{"author_name":"Lokesh K Chinthala","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Cindy Lemon","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Arash Shaban-Nejad","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Gregory Farage","author_inst":"University of Tennessee Health Science Center"},{"author_name":"Robert L Davis","author_inst":"The University of Tennessee Health Science Center"},{"author_name":"Hua Xu","author_inst":"Yale University"},{"author_name":"Charisse Madlock-Brown","author_inst":"University of Iowa"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"In-clinic validation of a smartphone-based finger tapping test for use in neurodegenerative and neurological populations.","rel_doi":"10.64898\/2026.06.25.26356467","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.25.26356467","rel_abs":"BackgroundMotor disturbances are common in neurologic and neurodegenerative syndromes. A standard motor speed and dexterity measure is the finger tapping test (FTT). The FTT has traditionally been administered in clinic using a mechanical FTT, limiting accessibility and early motor change quantification. This study assessed the validity of a smartphone app-based FTT, which may expand access and enable more frequent testing.\n\nMethodsThe cohort was diagnostically diverse, including participants with frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal syndrome, primary progressive aphasia, multiple sclerosis, and clinically unimpaired controls. Participants completed a 20-second ALLFTD Mobile App (mApp)-FTT with each hand. Tapping speed metrics were extracted. Participants completed the gold-standard mechanical FTT, a neurologist-administered finger tapping exam, the PSP Rating Scale (PSPRS) and the Unified Parkinsons Disease Rating Scale (UPDRS). Correlations assessed mApp-FTT and mechanical FTT relationships; regressions evaluated associations with neurologist-rated finger tapping impairment, PSPRS and UPDRS, adjusting for age and sex.\n\nResultsThe mApp-FTT showed moderate-to-strong correlations with the mechanical FTT (dominant: r=0.63, p<0.001; non-dominant: r=0.55, p<0.001). Taps per second were associated with PSPRS motor severity (dominant hand: std. {beta}=-0.59, 95% CI [-0.91, -0.27], p<0.001) and the UPDRS (dominant hand: std. {beta}=-0.41, 95% CI [-0.82, 0.00], p=0.049). Flight time was modestly associated with neurologist-rated finger tapping impairment (dominant hand: std. {beta}=0.15, 95% CI [0.00, 0.29], p=0.044).\n\nConclusionThese findings support mApp-FTT validity as a measure of motor function across neurodegenerative conditions. Validation in longitudinal and unsupervised remote settings is warranted to understand scalability and evaluate change over time.","rel_num_authors":24,"rel_authors":[{"author_name":"Morgan O'Connor","author_inst":"Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA"},{"author_name":"Mark Sanderson-Cimino","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Zi Li","author_inst":"Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA"},{"author_name":"Sreya Dhanam","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Anjali Sadarangani","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Joshua Downer","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Ray Fregly","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Jack Taylor","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Amy B. Wise","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Kaitlin B. Casaletto","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Leah K. Forsberg","author_inst":"Department of Neurology, Mayo Clinic, Rochester, MN, USA"},{"author_name":"Maria Luisa Gorno-Tempini","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Hilary W. Heuer","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Joel H. Kramer","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"John Kornak","author_inst":"Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA"},{"author_name":"Bruce L Miller","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Emily W Paolillo","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Riley Bove","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Gil Rabinovici","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"William W. Seeley","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Brad F. Boeve","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Howie J. Rosen","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Adam L. Boxer","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"},{"author_name":"Adam M. Staffaroni","author_inst":"Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA"}],"rel_date":"2026-07-07","rel_site":"medrxiv"},{"rel_title":"Association Between Area Deprivation and Dental Provider Density in California: A Cross-Sectional Ecological Study","rel_doi":"10.64898\/2026.07.04.26357261","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.04.26357261","rel_abs":"BackgroundNeighborhood socioeconomic disadvantage may contribute to inequities in access to dental care by influencing the geographic distribution of providers. The Area Deprivation Index (ADI) is a validated measure of neighborhood deprivation, but its association with dental workforce availability has not been examined statewide in California. This study evaluated the relationship between neighborhood deprivation and dental provider density across California ZIP Code Tabulation Areas (ZCTAs).\n\nMethodsWe conducted a cross-sectional ecological study of California ZCTAs using publicly available data from the National Plan and Provider Enumeration System (April 2026), the Neighborhood Atlas 2023 ADI, and 2024 U.S. Census population estimates. Active dental providers were linked to ZCTAs and provider density was calculated per 10,000 residents. ADI was aggregated to the ZCTA level using the median ADI national percentile. Negative binomial regression was used to assess the association between ADI and dental provider density, with population included as an offset. Secondary analyses examined California-specific ADI quartiles, dental deserts, and specialist versus general dentist availability.\n\nResultsThe final analytic sample included 1,426 California ZCTAs representing 39,016,384 residents and 37,945 active dental providers. Greater neighborhood deprivation was significantly associated with lower dental provider density. Each one-percentile increase in ADI corresponded to a 1.8% reduction in provider density (incidence rate ratio [RR] 0.9823, 95% confidence interval [CI] 0.9799-0.9847; p < 0.001). Compared with the least deprived quartile, the most deprived quartile had 61% fewer dental providers (RR 0.39, 95% CI 0.34-0.45; p < 0.001). Overall, 15.9% of ZCTAs contained no active dental providers, increasing from 6.8% in the least deprived quartile to 31.1% in the most deprived quartile. Specialist availability demonstrated an even steeper deprivation gradient, with specialist density declining by 86% between the least and most deprived quartiles.\n\nConclusionsNeighborhood deprivation was strongly associated with reduced dental provider availability across California. Highly deprived communities had substantially lower provider density, were more likely to be dental deserts, and experienced particularly pronounced shortages of dental specialists. ADI may be a useful tool for identifying communities where workforce shortages and socioeconomic disadvantage intersect and for informing equitable workforce planning and policy interventions.\n\nTrial registrationNot applicable. This study used publicly available, de-identified data and did not involve human participants.","rel_num_authors":2,"rel_authors":[{"author_name":"Anna-Lena Asiedu","author_inst":"University of California San Francisco, School of Dentistry"},{"author_name":"Collins Gaba","author_inst":"Boston University School of Social Work"}],"rel_date":"2026-07-07","rel_site":"medrxiv"}]}