{"gname":"University of California, Berkeley","grp_id":"13","rels":[{"rel_title":"Multimodal gene prioritization reveals nonlinear regulatory architecture in childhood-onset asthma","rel_doi":"10.64898\/2026.07.14.26357983","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.14.26357983","rel_abs":"Asthma is a heritable complex disease that disproportionately burdens minority and admixed populations in the US. However, the causal genes and regulatory mechanisms governing inherited risk remain largely unresolved. We performed a European-ancestry meta-analysis of 141,894 cases and 1,361,846 controls drawn from the Trans-national Asthma Genetic Consortium (TAGC) and Global Biobank Meta-analysis Initiative (GBMI), yielding an estimated h2SNP of 0.056 (SE = 0.0038) and 275 independently associated loci. To enhance mechanistic inference beyond variant-level associations, we developed a multimodal framework to predict asthma risk integrating GWAS summary statistics, bulk tissue expression quantitative trait loci (eQTL) data from the Genotype-Tissue Expression (GTEx) project, and single-cell gene eQTL data from the OneK1K Project. We performed transcriptome-wide association studies (TWAS) and subsequently applied probabilistic fine-mapping with FOCUS to prioritize putative causal genes expressed in bulk tissues and higher resolution immune cell populations. Fine-mapping asthma-associated genes implicated barrier-immune and metabolic-endocrine tissues alongside adaptive T-cell subsets as the primary mediators of asthma genetic risk, resolving canonical CD4+ Th2 effector genes including IL1RL1, TSLP, STAT6, and GATA3. Using these prioritized genes, we constructed a polygenic transcriptome risk score (PTRS) using random forest to integrate gene-level effects across critical tissues and cell types. Evaluated in two ancestrally distinct pediatric asthma cohorts, the Childhood Asthma Management Program (CAMP) and the Genetics of Asthma in Costa Rica Study (GACRS), our PTRS demonstrated improved transferability over the standard variant-level and gene-level baseline models. While modest common variant heritability limits the discriminative power of our models, we estimated a theoretical maximum achievable area under the receiver operating characteristic (AUROC) curve of 0.64. Our integrative nonlinear model of PRS-CSx and cross-modal (bulk tissue and single cell) FOCUS PTRS resulted in the best cross-cohort performance (CAMP AUC = 0.632, sd = 0.04, 3.55 case\/control odds ratio in top vs. bottom quartiles), representing an increase of +0.118 AUC over PRS-CSx, +0.067 AUC over tissue-specific TWAS pruning and thresholding, and +0.041 AUC over cell-type-specific FOCUS PTRS. Our results demonstrate that modeling nonlinear interactions between variant- and gene-level effects across both bulk tissue and single cell eQTL data improves our ability to determine high-risk individuals and to explain the likely mechanisms driving genetic susceptibility of childhood-onset asthma.","rel_num_authors":5,"rel_authors":[{"author_name":"Nan Huang","author_inst":"UC San Diego"},{"author_name":"Michelle F Ragsac","author_inst":"UC San Diego"},{"author_name":"Xiaoyu Gui","author_inst":"UC San Diego"},{"author_name":"Kelan  G. Tantisira","author_inst":"University of San Diego"},{"author_name":"Tiffany Amariuta","author_inst":"University of California San Diego"}],"rel_date":"2026-07-16","rel_site":"medrxiv"},{"rel_title":"Consecutive day effects between sleep quality and affective symptoms among youth in the Brazilian High-Risk Cohort study","rel_doi":"10.64898\/2026.07.14.26358099","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.14.26358099","rel_abs":"Background: Bidirectional next-day associations between sleep disturbances and affective symptoms have been shown in previous research, yet the consecutive day effects between these factors remains poorly understood. Methods: We analysed longitudinal ecological momentary assessment (EMA) data obtained from a subsample of young persons in the Brazilian High-Risk Cohort (BHRC) study collected in 2020-2021. Participants reported sleep quality each morning and rated affective symptoms relating to mood, anxiety, and energy four times daily for 28 days. We selected 88 individuals (17.83{+\/-}1.74 years, 56 [63.6%] female gender) with at least one instance where individuals were observed three-days in a row. Within-person bidirectional next-day effects between sleep quality and affective symptoms were estimated using mixed-effects regression analysis adjusting. We then applied g-estimation approaches to estimate the effect that lagged sleep quality and consecutive improvements in sleep quality had on affective symptoms. Results: Sleep quality and affective symptoms had bidirectional next-day effects, with sleep quality tending to have greater influence on affective symptoms than the reverse. Improved lagged sleep quality had positive effects on affective symptoms incrementally above the prior night's sleep quality. Also, improvement of sleep quality across consecutive days had incremental and approximately equal effects on affective symptoms. Conclusions: Sleep quality and affective symptoms exhibit a feedback loop, whereby poor sleep quality influences affective symptoms over consecutive days. Breaking these feedback loops, by improving sleep quality across several consecutive nights should improve affective symptoms. This supports interventions that target sustained improvement in sleep and possibly circadian regulation to improve affective symptoms.","rel_num_authors":12,"rel_authors":[{"author_name":"Mathew R Varidel","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Luke Borgnolo","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Victor An","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Joanne S Carpenter","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Ian B Hickie","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Pedro M Pan","author_inst":"National Institute of Developmental Psychiatry, Sao Paulo, Brazil"},{"author_name":"Francisco da Silva Jr.","author_inst":"National Institute of Developmental Psychiatry, Sao Paulo, Brazil"},{"author_name":"Jacob J Crouse","author_inst":"Brain and Mind Centre, The University of Sydney"},{"author_name":"Euripedes C Miguel","author_inst":"National Institute of Developmental Psychiatry, Sao Paulo, Brazil"},{"author_name":"Luis A Rohde","author_inst":"National Institute of Developmental Psychiatry, Sao Paulo, Brazil"},{"author_name":"Giovanni A Salum Jr.","author_inst":"National Institute of Developmental Psychiatry, Sao Paulo, Brazil"},{"author_name":"Frank Iorfino","author_inst":"Brain and Mind Centre, The University of Sydney"}],"rel_date":"2026-07-16","rel_site":"medrxiv"},{"rel_title":"Hospital and operator procedural volumes and one-year outcomes for TAVR in the United States: A STS\/ACC TVT Registry Analysis","rel_doi":"10.64898\/2026.07.13.26358001","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26358001","rel_abs":"Background: Prior analyses have demonstrated an inverse association between transcatheter aortic valve replacement (TAVR) procedural volume and short-term outcomes. However, less is known regarding the relationship between procedural volume and 1-year outcomes in the contemporary TAVR era. Objectives: To evaluate the association between annual hospital and operator TAVR procedural volumes and 1-year clinical outcomes in a contemporary national cohort. Methods: Clinical records from the Society of Thoracic Surgeons (STS)\/American College of Cardiology (ACC) Transcatheter Valve Therapies (TVT) Registry for patients undergoing commercial TAVR between January 2020 and December 2022 were linked to Centers for Medicare & Medicaid Services administrative claims. Annualized hospital and operator TAVR volumes were modeled continuously and categorized into tertiles. Primary outcomes included 1-year all-cause mortality, stroke, the composite of mortality or stroke, and all-cause readmissions. Hierarchical risk-adjusted models accounting for patient clustering within sites were used to evaluate associations between procedural volume and outcomes. Results: Among 215,335 patients undergoing TAVR at 788 hospitals by 3,444 operators between 2020 and 2022, median annual hospital and operator volumes were 74 (IQR: 43-115) and 16 (IQR: 10-32), respectively. Volume was then categorized into tertiles (low, medium and high). Compared with high-volume hospitals ([&ge;]102\/year), low-volume hospitals ([&le;]52\/year) had higher adjusted rates of 1-year all-cause mortality (Odds Ratio (OR): 1.10 [95% CI: 1.05-1.16]), stroke (OR: 1.10 [95% CI: 1.01-1.19]), mortality or stroke (OR: 1.10 [95% CI: 1.05-1.15]), and all-cause readmissions (OR: 1.05 [95% CI: 1.00-1.09]). Compared with high-volume operators ([&ge;]25\/year), low-volume operators ([&le;]11\/year) had higher adjusted rates of stroke (OR: 1.16 [95% CI: 1.05-1.28]) and mortality or stroke (OR: 1.09 [95% CI: 1.03-1.15]) but not other endpoints. Conclusions: In a large, contemporary national TAVR registry, lower annual hospital ([&le;] 52\/year) and operator ([&le;] 11\/year) procedural volumes were independently associated with worse 1-year clinical outcomes. These findings suggest that procedural experience continues to influence outcomes despite maturation of contemporary TAVR practice.","rel_num_authors":21,"rel_authors":[{"author_name":"Dharam J. Kumbhani","author_inst":"UT Southwestern"},{"author_name":"wayne batchelor","author_inst":"Inova Health"},{"author_name":"Joseph C Cleveland","author_inst":"University of Colorado"},{"author_name":"Pratik Manandhar","author_inst":"Duke Clinical Research Institute, Duke University Medical Center"},{"author_name":"Andrzej Kosinski","author_inst":"Duke University"},{"author_name":"Samir R. Kapadia","author_inst":"Cleveland Clinic"},{"author_name":"Gorav Ailawadi","author_inst":"University of Michigan"},{"author_name":"Gregory Fontana","author_inst":"HCA Healthcare Research Institute"},{"author_name":"Andrei M. Pop","author_inst":"Ascencion Health, Elk Grove, IL"},{"author_name":"Saket Girotra","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"James A de Lemos","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"John D. Carroll","author_inst":"University of Colorado"},{"author_name":"Ralph Brindis","author_inst":"Philip R. Lee Institute for Health Policy Studies and the Department of Medicine, University of California-San Francisco, San Francisco, CA"},{"author_name":"Tsuyoshi Kaneko","author_inst":"Washington University St. Louis"},{"author_name":"Vinod Thourani","author_inst":"Piedmont Heart Institute, Atlanta, GA"},{"author_name":"Robert W Yeh","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Amit N Vora","author_inst":"Yale University School of Medicine"},{"author_name":"Michael J. Mack","author_inst":"The Heart Hospital Baylor Plano"},{"author_name":"Vinay Badhwar","author_inst":"West Virginia University"},{"author_name":"Roxana Mehran","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Sreekanth Vemulapalli","author_inst":"Duke Clinical Research Institute"}],"rel_date":"2026-07-16","rel_site":"medrxiv"},{"rel_title":"Hospital and operator procedural volumes and one-year outcomes for TAVR in the United States: A STS\/ACC TVT Registry Analysis","rel_doi":"10.64898\/2026.07.13.26358001","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26358001","rel_abs":"Background: Prior analyses have demonstrated an inverse association between transcatheter aortic valve replacement (TAVR) procedural volume and short-term outcomes. However, less is known regarding the relationship between procedural volume and 1-year outcomes in the contemporary TAVR era. Objectives: To evaluate the association between annual hospital and operator TAVR procedural volumes and 1-year clinical outcomes in a contemporary national cohort. Methods: Clinical records from the Society of Thoracic Surgeons (STS)\/American College of Cardiology (ACC) Transcatheter Valve Therapies (TVT) Registry for patients undergoing commercial TAVR between January 2020 and December 2022 were linked to Centers for Medicare & Medicaid Services administrative claims. Annualized hospital and operator TAVR volumes were modeled continuously and categorized into tertiles. Primary outcomes included 1-year all-cause mortality, stroke, the composite of mortality or stroke, and all-cause readmissions. Hierarchical risk-adjusted models accounting for patient clustering within sites were used to evaluate associations between procedural volume and outcomes. Results: Among 215,335 patients undergoing TAVR at 788 hospitals by 3,444 operators between 2020 and 2022, median annual hospital and operator volumes were 74 (IQR: 43-115) and 16 (IQR: 10-32), respectively. Volume was then categorized into tertiles (low, medium and high). Compared with high-volume hospitals ([&ge;]102\/year), low-volume hospitals ([&le;]52\/year) had higher adjusted rates of 1-year all-cause mortality (Odds Ratio (OR): 1.10 [95% CI: 1.05-1.16]), stroke (OR: 1.10 [95% CI: 1.01-1.19]), mortality or stroke (OR: 1.10 [95% CI: 1.05-1.15]), and all-cause readmissions (OR: 1.05 [95% CI: 1.00-1.09]). Compared with high-volume operators ([&ge;]25\/year), low-volume operators ([&le;]11\/year) had higher adjusted rates of stroke (OR: 1.16 [95% CI: 1.05-1.28]) and mortality or stroke (OR: 1.09 [95% CI: 1.03-1.15]) but not other endpoints. Conclusions: In a large, contemporary national TAVR registry, lower annual hospital ([&le;] 52\/year) and operator ([&le;] 11\/year) procedural volumes were independently associated with worse 1-year clinical outcomes. These findings suggest that procedural experience continues to influence outcomes despite maturation of contemporary TAVR practice.","rel_num_authors":21,"rel_authors":[{"author_name":"Dharam J. Kumbhani","author_inst":"UT Southwestern"},{"author_name":"wayne batchelor","author_inst":"Inova Health"},{"author_name":"Joseph C Cleveland","author_inst":"University of Colorado"},{"author_name":"Pratik Manandhar","author_inst":"Duke Clinical Research Institute, Duke University Medical Center"},{"author_name":"Andrzej Kosinski","author_inst":"Duke University"},{"author_name":"Samir R. Kapadia","author_inst":"Cleveland Clinic"},{"author_name":"Gorav Ailawadi","author_inst":"University of Michigan"},{"author_name":"Gregory Fontana","author_inst":"HCA Healthcare Research Institute"},{"author_name":"Andrei M. Pop","author_inst":"Ascencion Health, Elk Grove, IL"},{"author_name":"Saket Girotra","author_inst":"The University of Texas Southwestern Medical Center"},{"author_name":"James A de Lemos","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"John D. Carroll","author_inst":"University of Colorado"},{"author_name":"Ralph Brindis","author_inst":"Philip R. Lee Institute for Health Policy Studies and the Department of Medicine, University of California-San Francisco, San Francisco, CA"},{"author_name":"Tsuyoshi Kaneko","author_inst":"Washington University St. Louis"},{"author_name":"Vinod Thourani","author_inst":"Piedmont Heart Institute, Atlanta, GA"},{"author_name":"Robert W Yeh","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Amit N Vora","author_inst":"Yale University School of Medicine"},{"author_name":"Michael J. Mack","author_inst":"The Heart Hospital Baylor Plano"},{"author_name":"Vinay Badhwar","author_inst":"West Virginia University"},{"author_name":"Roxana Mehran","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Sreekanth Vemulapalli","author_inst":"Duke Clinical Research Institute"}],"rel_date":"2026-07-16","rel_site":"medrxiv"},{"rel_title":"Comparative Effectiveness of Recommended and Delayed Dosing Schedules for Rotavirus Vaccine: Target Trial Emulation","rel_doi":"10.64898\/2026.07.13.26357904","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26357904","rel_abs":"Background: Live oral rotavirus vaccines were found to be less effective in low-income countries compared to high-income countries when using the same product and dosing schedule. We investigated whether altering dose timing may improve immune protection using a target trial emulation approach. Methods: We emulated a target trial with clone-censor weighting to compare the effectiveness of the recommended 2-dose rotavirus vaccine schedule with a delayed schedule among children under two years of age in Peru and Brazil. Secondary data from the Malnutrition and Enteric Disease Study (MAL-ED) birth cohort (2009-2014) were analyzed. Children were followed from the date of birth until the earliest occurrence of a rotavirus outcome (infection confirmed by PCR or enzyme immunoassay (EIA) or diarrhea confirmed by EIA), protocol nonadherence, loss to follow-up, or their second birthday. Results: We included 154 children in Brazil and 192 in Peru. At two years of follow-up, the risk ratio (RR) for PCR-confirmed infection, using the recommended schedule as the reference, was 1.00 (95% confidence interval [CI]: 0.73-1.37) in Peru and 0.85 (95% CI: 0.31-1.66) in Brazil. In Peru, the delayed schedule was associated with a higher cumulative risk of EIA-confirmed rotavirus diarrhea (RR at two years: 1.73; 95% CI: 1.02-2.77). Conclusions: Delaying the two-dose rotavirus vaccine schedule did not change the cumulative risk of rotavirus infection, but the delayed schedule was associated with a higher risk of rotavirus diarrhea in Peru, where rotavirus incidence was higher.","rel_num_authors":4,"rel_authors":[{"author_name":"Shae Gantt","author_inst":"Boston University School of Public Health"},{"author_name":"Toshiaki Komura","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Elizabeth  Rogawski McQuade","author_inst":"Emory University"},{"author_name":"Kayoko Shioda","author_inst":"Boston University School of Public Health"}],"rel_date":"2026-07-16","rel_site":"medrxiv"},{"rel_title":"Strategies to Reach Employees Nurturing Guidance and Trust in Healthcare (STRENGTH): Understanding Employee Drivers for Employer-Based Influenza Vaccination Programs","rel_doi":"10.64898\/2026.07.13.26357995","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26357995","rel_abs":"Background: Vaccine hesitancy and logistical barriers continue to limit influenza vaccination uptake among healthcare personnel. The STRENGTH initiative evaluated employee drivers of influenza vaccine acceptance in healthcare workgroups with lower vaccination compliance. Methods: This mixed-methods program evaluation used a custom Epic electronic medical record dashboard to identify workgroups with lower influenza vaccination rates, followed by focus groups, targeted worksite vaccination clinics, and an anonymous survey. Survey data from 73 respondents were analyzed using descriptive statistics, Mann-Whitney U tests, Kruskal-Wallis tests, chi-square or Fisher exact tests, and Spearman rank correlations. Results: Respondents had a mean age of 44.8 years (SD 11.3); 36 of 70 respondents reporting binary gender were male. Convenience of worksite vaccination received the highest importance ratings (mean 4.72\/5), followed by protection from influenza (mean 4.38\/5). Both were rated significantly above the neutral midpoint of 3 (Wilcoxon p<0.001). The strongest observed Spearman correlations were between peer pressure and leadership participation (rho=0.47) and between protection from influenza and willingness to receive a future combined influenza\/COVID-19 vaccine (rho=0.42). Conclusions: Convenience and perceived protection were the most important vaccination drivers. Employer-sponsored workplace vaccination programs can reduce logistical barriers while providing opportunities for targeted education and trust-building. Keywords: influenza vaccination; healthcare workers; vaccine hesitancy; occupational health; workplace vaccination; employer-sponsored vaccination","rel_num_authors":5,"rel_authors":[{"author_name":"Arthur P Sanchez","author_inst":"University of California San Diego Health"},{"author_name":"Kent Isakari","author_inst":"The Bishops School"},{"author_name":"Morgan Keefe","author_inst":"University of California San Diego Health"},{"author_name":"Marcia Isakari","author_inst":"University of California Davis"},{"author_name":"Amy Sitapati","author_inst":"University of California San Diego Health"}],"rel_date":"2026-07-16","rel_site":"medrxiv"},{"rel_title":"Genome-wide association study of susceptibility to pneumococcal carriage amongst children","rel_doi":"10.64898\/2026.07.13.26356474","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26356474","rel_abs":"Background Pneumococcal disease is a leading cause of paediatric pneumonia and meningitis. Pneumococcal colonisation is the fundamental step to pneumococcal disease causation. We aimed to identify genetic loci associated with pneumococcal colonisation amongst children. Methods We conducted a genome-wide association study on 2111 Nepalese children, comprising 1346 cases carrying pneumococcus and 765 controls. We tested 8.1 million imputed variants using logistic regression and ten principal components as covariates. Fine mapping and functional evidence were used to identify suspected causal variants and related genes of interest. Findings A cluster of 22 variants of genome-wide significance (p<5x10-8) were identified on chromosome 12q21.31, eight of which were within PPFIA2. Fine mapping of this region identified 5 variants within 0.1 Mb of the 5-prime region of PPFIA2 all of which are significant eQTLs for PPFIA2. We further describe three loci (10q23.31, 12q23.1, and 20p11.21) which had variants with highly suggestive associations (p<5x10-7)with pneumococcal carriage. Interpretation Our study demonstrate human susceptibility to pneumococcal carriage to be polygenic with genetic variations which regulate PPFIA2 expression playing a key role in the ability for pneumococcus to colonise children. Targeting these genetic factors and the associated pathways are a means for preventing pneumococcal disease. Funding This study was supported by funding from Gavi - the vaccine alliance, the European Unions Horizon 2020 research and innovation program under grant agreement number 668303 (PERFORM), and a Robert Austrian Research Award.","rel_num_authors":12,"rel_authors":[{"author_name":"Rama Kandasamy","author_inst":"Discipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Australia"},{"author_name":"Meeru Gurung","author_inst":"Paediatric Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal"},{"author_name":"Sonu Shrestha","author_inst":"Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom"},{"author_name":"Sagida Bibi","author_inst":"Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom"},{"author_name":"Stephen Thorson","author_inst":"Paediatric Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal"},{"author_name":"Michael Carter","author_inst":"Centre for Human Genetics, University of Oxford, Oxford, United Kingdom"},{"author_name":"Daniel O'Connor","author_inst":"Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom"},{"author_name":"David R Murdoch","author_inst":"Department of Pathology, University of Otago, Christchurch, New Zealand"},{"author_name":"Dominic F Kelly","author_inst":"Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom"},{"author_name":"Shrijana Shrestha","author_inst":"Paediatric Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal"},{"author_name":"Michael Levin","author_inst":"Department of Infectious Disease, Faculty of Medicine, Imperial College London, United Kingdom"},{"author_name":"Andrew J Pollard","author_inst":"Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, United Kingdom"}],"rel_date":"2026-07-16","rel_site":"medrxiv"},{"rel_title":"Clonal hematopoiesis is enriched in melanoma and associated with genotype-specific differences in tumor growth and survival","rel_doi":"10.64898\/2026.07.13.26357981","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26357981","rel_abs":"Background The clinical significance of clonal hematopoiesis of indeterminate potential (CHIP) in melanoma remains incompletely defined, particularly with respect to CHIP genotype, clone size, and somatic mutations (e.g BRAF mutations). We integrated human cohort data and a syngeneic melanoma mouse model to evaluate whether CHIP is associated with melanoma risk, tumor growth, and differential clinical outcomes. Methods We analyzed CHIP prevalence and survival in a large treatment-unselected melanoma cohort (n=2,480), evaluated tumor growth in a syngeneic BRAF-mutant (BRAFmut) melanoma murine model of TET2-CHIP and DNMT3A-CHIP, and assessed survival outcomes in an immune checkpoint inhibitor (ICI)-treated advanced melanoma cohort (n=361). Associations with progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier analyses and multivariable Cox proportional hazards models. Results CHIP was enriched among patients with treatment-unselected melanoma compared with age\/sex-matched healthy controls, and larger CHIP clone size showed an age-adjusted association with inferior OS. In a syngeneic BRAFmut melanoma murine model, TET2-CHIP, but not DNMT3A-CHIP, was associated with significantly increased primary melanoma tumor growth. Among patients with ICI-treated advanced melanoma, CHIP was associated with worse OS compared with patients without CHIP. TET2-CHIP had the strongest adverse association with survival, whereas DNMT3A-CHIP was not significantly associated with PFS or OS. Conclusions CHIP is enriched in melanoma and exploratory analyses demonstrate genotype-specific differences in melanoma tumor growth and clinical outcomes. These findings support further investigation of genotype-specific CHIP profiling as a potential biomarker for melanoma risk stratification and immunotherapy outcomes.","rel_num_authors":13,"rel_authors":[{"author_name":"Mason N Alford-Holloway","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Sarah C Reed","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Yash Pershad","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Joseph C Van Amburg","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Chad Potts","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Sanjay R Mohan","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Leo Y Luo","author_inst":"Vanderbilt University Medical Center"},{"author_name":"P. Brent Ferrell","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Michael R Savona","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Ben H Park","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Douglas B Johnson","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alexander G Bick","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Ashwin Kishtagari","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-07-16","rel_site":"medrxiv"},{"rel_title":"Curation of Mini Mental State Examination (MMSE) Scores in the VA Million Veteran Program (MVP): Applications for Cognitive Aging Research","rel_doi":"10.64898\/2026.07.14.26358064","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.14.26358064","rel_abs":"Background: Electronic health record (EHR)-linked biorepositories provide opportunities to advance epidemiological research in Alzheimer's disease (AD) and related dementias. Objective: Evaluate the extraction, curation, and associative validity of Mini Mental State Examination (MMSE) scores from the VA EHR for participants in the VA Million Veteran Program (MVP). Methods: The sample (N = 49,555; 7.4% women) included a multiethnic cohort (European [68.3%], African [20.4%], Hispanic [9.0%]) with EHR-extracted MMSE scores; 30.7% were apolipoprotein E (APOE) {epsilon}4 carriers, and 25.8% had multiple scores. Linear regressions examined cross-sectional associations between {epsilon}4 dosage (0, 1, 2) and first and lowest MMSE scores. MMSE scores were also evaluated against MVP dementia diagnostic algorithms in participants aged [&ge;]65 years. Results: Among participants of European ancestry, there was a significant {epsilon}4 dose-response relationship (ps < .001) with MMSE scores. Homozygote carriers scored lower than heterozygote carriers (Mdiff: first = -0.5; lowest = -0.9), who scored lower than non-carriers (Mdiff: first = -0.4; lowest = -0.6). Among Veterans of African and Hispanic ancestry, no dose-response relationship was observed, although {epsilon}4 carriers had lower scores than non-carriers (ps [&le;] .04). MMSE scores corresponded strongly with dementia case\/control status across phenotypes: mild impairment on the MMSE was strongly associated with AD (odds ratio [OR] = 11.48), with more severe MMSE impairment showing stronger associations (moderate OR = 17.95; severe OR = 27.83). Conclusion: This study demonstrated MMSE scores can be systematically extracted and curated from the VA EHR. Findings offer a scalable framework for future studies on risk stratification, highlighting the potential for harnessing MVP to explore genetic and clinical factors contributing to cognitive and dementia outcomes in diverse samples.","rel_num_authors":9,"rel_authors":[{"author_name":"Francesca V Lopez","author_inst":"VA San Diego Healthcare System, UC San Diego"},{"author_name":"Margaret Gillis","author_inst":"VA Boston Healthcare System"},{"author_name":"Sophia Lee","author_inst":"VA Boston Healthcare System"},{"author_name":"McKenna S Sakamoto","author_inst":"Penn State University"},{"author_name":"Rui Zhang","author_inst":"VA Boston Healthcare System"},{"author_name":"- VA Million Veteran Program","author_inst":""},{"author_name":"Richard Sherva","author_inst":"VA Boston Healthcare System; Boston University School of Medicine"},{"author_name":"Mark Logue","author_inst":"National Center for PTSD, VA Boston Healthcare System"},{"author_name":"Victoria C Merritt","author_inst":"VA San Diego Healthcare System\/UC San Diego"}],"rel_date":"2026-07-16","rel_site":"medrxiv"},{"rel_title":"From Genes to Neurochemistry: Excitation and Inhibition Mechanisms of Sensory Differences in Autism","rel_doi":"10.64898\/2026.07.14.26358047","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.14.26358047","rel_abs":"Sensory processing differences are a core feature of autism, affecting 60-95% of individuals, yet the associated neural mechanisms remain unclear. An excitation-inhibition (E\/I) imbalance in brain circuits has been proposed, but in vivo evidence linking genetic variation in E\/I pathways, regional neurochemistry, neural circuit function, and sensory behaviour has been lacking. Here we performed a multimodal investigation in 206 individuals (130 autistic), integrating gene-set polygenic scores for excitatory glutamatergic and inhibitory gamma-aminobutyric acid (GABA)-ergic pathways, magnetic resonance spectroscopy (MRS) measures of regional GABA and Glx (glutamate + glutamine) levels, vibrotactile psychophysical measures of tactile perception, and questionnaire measures of behavioural sensory reactivity. We found that glutamatergic polygenic scores predicted thalamic glutamate levels in neurotypical but not autistic individuals, suggesting altered genotype-neurochemistry coupling in autism. Thalamic Glx:GABA levels associated with tactile perception in both groups, but with opposing directions of effect, indicating that autistic and neurotypical individuals achieve similar perceptual outcomes with potentially differing thalamocortical circuit mechanisms. Within autistic individuals, tactile perceptual differences further related to behavioural sensory reactivity. Together, these findings suggest that autistic sensory processing potentially relies on distinct circuit mechanisms linking genetic variation, neurochemistry and perception. This work thus has important implications for how sensory differences are conceptualised, studied, and interpreted, and ultimately for how interventions and support are developed.","rel_num_authors":22,"rel_authors":[{"author_name":"Alice Rose Thomson","author_inst":"King's College London"},{"author_name":"Viola Hollestein","author_inst":"King's College London"},{"author_name":"Martina Arenella","author_inst":"King's College London"},{"author_name":"Helen Powell","author_inst":"King's College London"},{"author_name":"Jason He","author_inst":"King's College London"},{"author_name":"Beth Oakley","author_inst":"King's College London"},{"author_name":"Eva Loth","author_inst":"King's College London"},{"author_name":"Rosemary Holt","author_inst":"University of Cambridge"},{"author_name":"Jan K Buitelaar","author_inst":"Donders Institute for Brain, Cognition and Behaviour"},{"author_name":"Laura Colomar","author_inst":"King's College London"},{"author_name":"Natalie J Forde","author_inst":"Donders Institute for Brain, Cognition and Behaviour"},{"author_name":"Thomas Bourgeron","author_inst":"University de Paris"},{"author_name":"Terje Falck-Ytter","author_inst":"Uppsala University"},{"author_name":"Giorgia Bussu","author_inst":"Uppsala University"},{"author_name":"Tobia Banaschweski","author_inst":"German Center for Mental Health (DZPG)"},{"author_name":"Pascal M Aggensteiner","author_inst":"German Center for Mental Health (DZPG)"},{"author_name":"Richard Edden","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"Tony Charman","author_inst":"King's College London"},{"author_name":"Charlotte Pretzsch","author_inst":"King's College London"},{"author_name":"Declan Murphy","author_inst":"King's College London"},{"author_name":"Tomoki Arichi","author_inst":"King's College London"},{"author_name":"Nicolaas Puts","author_inst":"King's College London"}],"rel_date":"2026-07-16","rel_site":"medrxiv"},{"rel_title":"Associations of Trajectories of Loneliness and Neighborhood Stability with Depression, Alcohol and Substance Use, and Quality of Life among Women Living with HIV","rel_doi":"10.64898\/2026.07.14.26358061","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.14.26358061","rel_abs":"Social relationships are an important social determinant of health. Loneliness, the perceived gap between one's actual and desired relationships, has emerged as an important mechanism through which social relationships impact health. Like other intrapersonal-level factors associated with health, loneliness is influenced by broader social and structural factors, including characteristics of one's neighborhood social environment. Although neighborhood-level protective and risk factors for loneliness and for mental health have been identified, prior studies have often focused solely on self-reported perceptions of the neighborhood environment. Further, few have considered aspects of the neighborhood social environments, such as neighborhood stability (i.e., stability of the community with long or short-term residents), independent of neighborhood socioeconomic conditions. In the current analysis, we explored longitudinal patterns of loneliness in conjunction with neighborhood stability among women with HIV (WWH) enrolled into the MACS\/WIHS Combined Cohort Study (MWCCS) from 2014-2019 (N2019=1,394) to examine whether trajectories of loneliness and neighborhood stability were associated with depressive symptoms, non-prescription substance use, past-year cannabis use, number of alcoholic drinks per week, and several domains of quality of life. Loneliness at baseline (Betas = 0.24 - 0.54) and changes in loneliness over time (Betas = 0.11 - 0.26) were associated with each outcome, except for the association between changes in loneliness over time and drinks per week (Beta=0.13, p = 4.14x10-2), which did not persist after correcting for multiple comparisons. Neighborhood stability at baseline was associated with past year cannabis use (Beta=0.26, p = 1.00x10-2), depressive symptoms (Beta=-0.12, p = 1.54x10-3), and overall self-reported health (Beta=-0.08, p = 2.05x10-2). Changes in neighborhood stability across time were not associated with any outcome. Neighborhood stability moderated the association between changes in loneliness and general health perceptions. Our results demonstrate both overall loneliness and changes in loneliness over time have implications for current mental health in WWH, while changes in neighborhood stability did not.","rel_num_authors":21,"rel_authors":[{"author_name":"Peter B. Barr","author_inst":"VA New York Harbor Healthcare System, Brooklyn, NY Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY Ins"},{"author_name":"Andrew Edmonds","author_inst":"Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC"},{"author_name":"Bradley Aouizerat","author_inst":"Department of Oral and Maxillofacial Surgery, College of Dentistry, New York University, New York, NY Translational Research Center, College of Dentistry, New Y"},{"author_name":"Mardge Cohen","author_inst":"Department of Medicine, Stroger Hospital of Cook County Health and Hospitals System, Chicago, IL"},{"author_name":"Judith A Cook","author_inst":"Center on Mental Health Services Research and Policy, University of Illinois, Chicago, Chicago, IL"},{"author_name":"M. Reuel Friedman","author_inst":"Department of Urban-Global Public Health, Rutgers School of Public Health, Newark, NJ"},{"author_name":"Sabina Haberlen","author_inst":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD"},{"author_name":"Susan Holman","author_inst":"Department of Medicine, SUNY Downstate Health Sciences University, Brooklyn, NY"},{"author_name":"Mirjam-Colette Kempf","author_inst":"Schools of Nursing, Public Health and Medicine, University of Alabama at Birmingham, Birmingham, AL"},{"author_name":"Deborah Konkle-Parker","author_inst":"Schools of Nursing, Medicine and Population Health, University of Mississippi Medical Center, Jackson, MS"},{"author_name":"Jennafer L. Kwait","author_inst":"Whitman-Walker Institute, Washington, DC"},{"author_name":"David B. Hanna","author_inst":"Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY"},{"author_name":"Gayathri Pandey","author_inst":"Department of Community Health Sciences, School of Public Health, SUNY Downstate Health Sciences University, Brooklyn, NY"},{"author_name":"Michael Plankey","author_inst":"Department of Medicine, Division of General Internal Medicine, Georgetown University, Washington, DC"},{"author_name":"Leah H. Rubin","author_inst":"Departments of Neurology and Psychiatry and Behavioral Sciences, and Molecular and Cellular Pathobiology, Johns Hopkins University School of Medicine, Baltimore"},{"author_name":"Anna A. Rubtsova","author_inst":"Department of Behavioral, Social, and Health Education Sciences, Rollins School of Public Health, Emory University, Atlanta, GA"},{"author_name":"Rebecca M. Schwartz","author_inst":"Northwell Health, New Hyde Park, NY"},{"author_name":"Azure B. Thompson","author_inst":"Department of Community Health Sciences, School of Public Health, SUNY Downstate Health Sciences University, Brooklyn, NY"},{"author_name":"Deborah L. Jones","author_inst":"Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL"},{"author_name":"Jacquelyn L. Meyers","author_inst":"Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY Institute for Genomics in Health (IGH), SUNY Downstate"},{"author_name":"Tracey Wilson","author_inst":"Department of Community Health Sciences, School of Public Health, SUNY Downstate Health Sciences University, Brooklyn, NY"}],"rel_date":"2026-07-16","rel_site":"medrxiv"},{"rel_title":"Associations of Trajectories of Loneliness and Neighborhood Stability with Depression, Alcohol and Substance Use, and Quality of Life among Women Living with HIV","rel_doi":"10.64898\/2026.07.14.26358061","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.14.26358061","rel_abs":"Social relationships are an important social determinant of health. Loneliness, the perceived gap between one's actual and desired relationships, has emerged as an important mechanism through which social relationships impact health. Like other intrapersonal-level factors associated with health, loneliness is influenced by broader social and structural factors, including characteristics of one's neighborhood social environment. Although neighborhood-level protective and risk factors for loneliness and for mental health have been identified, prior studies have often focused solely on self-reported perceptions of the neighborhood environment. Further, few have considered aspects of the neighborhood social environments, such as neighborhood stability (i.e., stability of the community with long or short-term residents), independent of neighborhood socioeconomic conditions. In the current analysis, we explored longitudinal patterns of loneliness in conjunction with neighborhood stability among women with HIV (WWH) enrolled into the MACS\/WIHS Combined Cohort Study (MWCCS) from 2014-2019 (N2019=1,394) to examine whether trajectories of loneliness and neighborhood stability were associated with depressive symptoms, non-prescription substance use, past-year cannabis use, number of alcoholic drinks per week, and several domains of quality of life. Loneliness at baseline (Betas = 0.24 - 0.54) and changes in loneliness over time (Betas = 0.11 - 0.26) were associated with each outcome, except for the association between changes in loneliness over time and drinks per week (Beta=0.13, p = 4.14x10-2), which did not persist after correcting for multiple comparisons. Neighborhood stability at baseline was associated with past year cannabis use (Beta=0.26, p = 1.00x10-2), depressive symptoms (Beta=-0.12, p = 1.54x10-3), and overall self-reported health (Beta=-0.08, p = 2.05x10-2). Changes in neighborhood stability across time were not associated with any outcome. Neighborhood stability moderated the association between changes in loneliness and general health perceptions. Our results demonstrate both overall loneliness and changes in loneliness over time have implications for current mental health in WWH, while changes in neighborhood stability did not.","rel_num_authors":21,"rel_authors":[{"author_name":"Peter B. Barr","author_inst":"VA New York Harbor Healthcare System, Brooklyn, NY Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY Ins"},{"author_name":"Andrew Edmonds","author_inst":"Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC"},{"author_name":"Bradley Aouizerat","author_inst":"Department of Oral and Maxillofacial Surgery, College of Dentistry, New York University, New York, NY Translational Research Center, College of Dentistry, New Y"},{"author_name":"Mardge Cohen","author_inst":"Department of Medicine, Stroger Hospital of Cook County Health and Hospitals System, Chicago, IL"},{"author_name":"Judith A Cook","author_inst":"Center on Mental Health Services Research and Policy, University of Illinois, Chicago, Chicago, IL"},{"author_name":"M. Reuel Friedman","author_inst":"Department of Urban-Global Public Health, Rutgers School of Public Health, Newark, NJ"},{"author_name":"Sabina Haberlen","author_inst":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD"},{"author_name":"Susan Holman","author_inst":"Department of Medicine, SUNY Downstate Health Sciences University, Brooklyn, NY"},{"author_name":"Mirjam-Colette Kempf","author_inst":"Schools of Nursing, Public Health and Medicine, University of Alabama at Birmingham, Birmingham, AL"},{"author_name":"Deborah Konkle-Parker","author_inst":"Schools of Nursing, Medicine and Population Health, University of Mississippi Medical Center, Jackson, MS"},{"author_name":"Jennafer L. Kwait","author_inst":"Whitman-Walker Institute, Washington, DC"},{"author_name":"David B. Hanna","author_inst":"Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY"},{"author_name":"Gayathri Pandey","author_inst":"Department of Community Health Sciences, School of Public Health, SUNY Downstate Health Sciences University, Brooklyn, NY"},{"author_name":"Michael Plankey","author_inst":"Department of Medicine, Division of General Internal Medicine, Georgetown University, Washington, DC"},{"author_name":"Leah H. Rubin","author_inst":"Departments of Neurology and Psychiatry and Behavioral Sciences, and Molecular and Cellular Pathobiology, Johns Hopkins University School of Medicine, Baltimore"},{"author_name":"Anna A. Rubtsova","author_inst":"Department of Behavioral, Social, and Health Education Sciences, Rollins School of Public Health, Emory University, Atlanta, GA"},{"author_name":"Rebecca M. Schwartz","author_inst":"Northwell Health, New Hyde Park, NY"},{"author_name":"Azure B. Thompson","author_inst":"Department of Community Health Sciences, School of Public Health, SUNY Downstate Health Sciences University, Brooklyn, NY"},{"author_name":"Deborah L. Jones","author_inst":"Department of Psychiatry & Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL"},{"author_name":"Jacquelyn L. Meyers","author_inst":"Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY Institute for Genomics in Health (IGH), SUNY Downstate"},{"author_name":"Tracey Wilson","author_inst":"Department of Community Health Sciences, School of Public Health, SUNY Downstate Health Sciences University, Brooklyn, NY"}],"rel_date":"2026-07-16","rel_site":"medrxiv"},{"rel_title":"Primitive GLMY Homology: An Algebraic Topology Approach for the Quantitative Characterization of Graph Pangenomes toward Population Genetic Analysis","rel_doi":"10.64898\/2026.07.10.737687","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737687","rel_abs":"A central task in population genetics is to identify genetic diversity in a population containing a number of individuals. In recent years, with the development of the third generation sequencing (TGS) technology, pan-genome research has become a hot topic. Although graphical representation has been a popular way to represent the pangenome, few works have attempted to describe it in a more mathematical way. In this paper, we used 79 high-quality assembly data of third-generation sequencing in yeast (including Saccharomyces cerevisiae and Saccharomyces paradoxus) to construct the graph pangenome, and introduced the Primitive GLMY ( Grigor'yan-Lin-Muranov-Yau) Homology in algebraic topology to quantitatively represent the pan-genome. We further made an intriguing attempt to conduct a population genetic analysis of this resulting dataset from the topological features of the graph pangenome. We found that there was good agreement between the obtained results and the biological context. We believe this study has developed a method for population genetic analysis of the genetic diversity of genome structural variation.","rel_num_authors":6,"rel_authors":[{"author_name":"Qi Wu","author_inst":"Beijing Institute of Mathematical Sciences and Applications (BIMSA), Beijing 100101, China."},{"author_name":"Jingyan Li","author_inst":"Beijing Institute of Mathematical Sciences and Applications (BIMSA), Beijing 100101, China."},{"author_name":"Guoqing Hu","author_inst":"Hetao Institute of Mathematics and Interdisciplinary Sciences (HIMIS), Shenzhen 518000, China."},{"author_name":"Piyu Zhou","author_inst":"University of Chinese Academy of Sciences, 101408, Beijing, China"},{"author_name":"Xin Zhao","author_inst":"Beijing Institute of Mathematical Sciences and Applications (BIMSA), Beijing 100101, China."},{"author_name":"Stephen S-T. Yau","author_inst":"Department of Mathematical Science, Tsinghua University, Beijing 100084, China."}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"Primitive GLMY Homology: An Algebraic Topology Approach for the Quantitative Characterization of Graph Pangenomes toward Population Genetic Analysis","rel_doi":"10.64898\/2026.07.10.737687","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737687","rel_abs":"A central task in population genetics is to identify genetic diversity in a population containing a number of individuals. In recent years, with the development of the third generation sequencing (TGS) technology, pan-genome research has become a hot topic. Although graphical representation has been a popular way to represent the pangenome, few works have attempted to describe it in a more mathematical way. In this paper, we used 79 high-quality assembly data of third-generation sequencing in yeast (including Saccharomyces cerevisiae and Saccharomyces paradoxus) to construct the graph pangenome, and introduced the Primitive GLMY ( Grigor'yan-Lin-Muranov-Yau) Homology in algebraic topology to quantitatively represent the pan-genome. We further made an intriguing attempt to conduct a population genetic analysis of this resulting dataset from the topological features of the graph pangenome. We found that there was good agreement between the obtained results and the biological context. We believe this study has developed a method for population genetic analysis of the genetic diversity of genome structural variation.","rel_num_authors":6,"rel_authors":[{"author_name":"Qi Wu","author_inst":"Beijing Institute of Mathematical Sciences and Applications (BIMSA), Beijing 100101, China."},{"author_name":"Jingyan Li","author_inst":"Beijing Institute of Mathematical Sciences and Applications (BIMSA), Beijing 100101, China."},{"author_name":"Guoqing Hu","author_inst":"Hetao Institute of Mathematics and Interdisciplinary Sciences (HIMIS), Shenzhen 518000, China."},{"author_name":"Piyu Zhou","author_inst":"University of Chinese Academy of Sciences, 101408, Beijing, China"},{"author_name":"Xin Zhao","author_inst":"Beijing Institute of Mathematical Sciences and Applications (BIMSA), Beijing 100101, China."},{"author_name":"Stephen S-T. Yau","author_inst":"Department of Mathematical Science, Tsinghua University, Beijing 100084, China."}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"Overlapping upstream ORFs repress translation and expand proteome diversity in Arabidopsis","rel_doi":"10.64898\/2026.07.14.738309","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.14.738309","rel_abs":"Upstream open reading frames (uORFs) are widespread cis-regulatory elements that modulate translation initiation of downstream main ORFs (mORFs). Among them, overlapping uORFs (ouORFs) that overlap with mORFs are predicted to exert the strongest translational repression, yet they remain largely unexplored because of the difficulty of their identification. Here, we developed complementary computational approaches to systematically identify translated ouORFs from super-resolution ribosome profiling data in Arabidopsis. We identified 965 translated ouORFs alongside 7,180 canonical non-overlapping uORFs (nuORFs). We found that ouORFs exert substantially stronger translational repression than nuORFs, and that this repression depends primarily on Kozak context rather than uORF length. In addition, genes containing ouORFs or nuORFs have weaker mORF Kozak contexts than genes without uORFs, which may further reduce mORF translation. Moreover, ouORF translation promotes initiation downstream of the annotated mORF start codon, generating N-terminally truncated protein isoforms with altered domain composition and subcellular localization. Using ATPS2 as an example, we demonstrate that ouORF translation regulates alternative translation initiation to control the balance between chloroplast and cytosolic protein isoforms. Together, our findings establish ouORFs as a versatile class of translational regulatory elements that coordinate both protein abundance and protein diversity, providing the first genome-wide characterization of translated ouORFs in plants.","rel_num_authors":5,"rel_authors":[{"author_name":"Hsin-Yen Larry Wu","author_inst":"Michigan State University"},{"author_name":"Yu-Hsuan Cheng","author_inst":"Michigan State University"},{"author_name":"Isaiah D. Kaufman","author_inst":"Michigan State University"},{"author_name":"Qiaoyun Ai","author_inst":"Michigans State University"},{"author_name":"Polly Yingshan Hsu","author_inst":"Michigan State University"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"An mRNA-Lipid Nanoparticle Platform Encoding the Conserved Outer Membrane Protein BamA Elicits Broadly Cross-Reactive Systemic and Mucosal Antibodies Against Antimicrobial-Resistant Neisseria gonorrhoeae","rel_doi":"10.64898\/2026.07.14.738439","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.14.738439","rel_abs":"Neisseria gonorrhoeae (Ng) is the causative agent of gonorrhea, and the global spread of antimicrobial-resistant strains makes vaccine development a public health priority. Although messenger RNA (mRNA) vaccines have transformed protection against viral diseases, the platform remains in its infancy against pathogenic bacteria. Here, we evaluated the immunogenicity and protective efficacy of an mRNA-lipid nanoparticle (LNP) vaccine encoding the highly conserved outer membrane antigen BamA in the female mouse model of lower genital tract infection. We delivered BamA mRNA-LNPs via intramuscular (IM) or intranasal (IN) routes, with or without CpG ODN 2395, and measured antigen-specific antibody responses in serum and vaginal lavage samples. Both routes elicited robust BamA-specific antibodies that recognized diverse Ng isolates, including ceftriaxone-resistant strains. However, neither route accelerated bacterial clearance nor reduced bioburden, nor did either generate serum bactericidal activity. These findings show that BamA mRNA-LNPs are immunogenic but, as formulated, are not protective, and they pave the way for modifications to the construct, adjuvant, and route. To our knowledge, this is the first evaluation of an mRNA vaccine against Ng, establishing the platform as an amenable approach for gonococcal antigen testing.","rel_num_authors":10,"rel_authors":[{"author_name":"Aleksandra E Sikora","author_inst":"Oregon State University"},{"author_name":"Natalie Wolske","author_inst":"Oregon State University"},{"author_name":"Namratha Turuvekere Vittala Murthy","author_inst":"Oregon State University"},{"author_name":"Abhishek Chanda","author_inst":"Oregon State University"},{"author_name":"Junaid Nazir","author_inst":"Oregon State University"},{"author_name":"Ryszard Aleksander Zielke","author_inst":"Oregon State University College of Pharmacy"},{"author_name":"Fabian G Martinez","author_inst":"Oregon State University"},{"author_name":"Jeonghwan Kim","author_inst":"Oregon State University"},{"author_name":"Ravi Kant","author_inst":"Shoolini University"},{"author_name":"Gaurav Sahay","author_inst":"Oregon State University"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"Host-secreted lactate during respiratory viral infection diminishes macrophage antibacterial activity through metabolic reprogramming","rel_doi":"10.64898\/2026.07.11.737940","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737940","rel_abs":"In polymicrobial infections, how the host recognizes and responds to pathogens influences which species will persist to cause chronic infections. The human respiratory tract is a common anatomical site for viral-bacterial co-infections, where primary viral infections predispose to secondary bacterial infections, leading to increased morbidity and mortality. Additionally, co-infections are disproportionately prevalent in people with chronic lung diseases, such as chronic obstructive pulmonary disease and cystic fibrosis. We previously reported that primary viral infections and antiviral interferon (IFN) signaling stimulate Pseudomonas aeruginosa (PA) biofilm formation on airway epithelial cells (AECs). IFN signaling induces aerobic glycolysis in AECs and generates lactate as a cellular byproduct. Given that innate immune systems play an integral role in co-infection dynamics, we investigated the role of host-secreted metabolites (i.e. lactate) on innate immune cell activity during respiratory co-infections. We found that exposure to the apical secretions from IFN{beta}-treated AECs significantly compromised macrophage antibacterial activity, with the soluble metabolite lactate playing an important role. Macrophages used monocarboxylate transporters and G-protein receptors to transport and\/or sense lactate, respectively, and this exposure to lactate diminished their bacterial-killing activity in a time-exposure dependent manner. Lactate exposure particularly reprogrammed macrophage cellular metabolism towards an anti-inflammatory state by increasing oxidative phosphorylation and fatty acid oxidation. Collectively, these findings provide insight into metabolites as complex regulators of trans-kingdom interactions and epithelial-macrophage crosstalk during respiratory co-infections.","rel_num_authors":3,"rel_authors":[{"author_name":"Sadia Sultana","author_inst":"Dartmouth College Geisel School of Medicine"},{"author_name":"Erin Walsh","author_inst":"Dartmouth College Geisel School of Medicine"},{"author_name":"Jennifer M. Bomberger","author_inst":"Dartmouth College"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"MInt-HDX: Leveraging Hydrogen-Deuterium Exchange Mass Spectrometry and Machine-Learning to Improve Protein-Ligand Docking.","rel_doi":"10.64898\/2026.07.14.738285","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.14.738285","rel_abs":"Understanding protein structural dynamics is central to elucidating biological function and guiding therapeutic discovery. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) typically offers peptide-level, and sometimes residue-level, time-dependent insights into protein structure, conformational dynamics and\/or ligand binding. Yet, translating HDX-MS data into atomic-resolution insights and deriving mechanistic understanding remains a key challenge. Integrative strategies which utilize HDX-MS to inform computational modeling or simulations, traditionally leverage HDX-MS data with physics-based approaches through the calculation of protection factors models. Here, we developed MInt-HDX, a hybrid physics-based, machine-learning framework trained on differential HDX-MS signatures across 11 protein-ligand systems or 1032 individual peptides, using eXtreme Gradient Boosting (XGBoost) to guide small-molecule ligand docking and pose selection. By leveraging XGBoost-predicted interacting residues with three-dimensional clustering and convex-hull geometric algorithms, MInt-HDX first generates HDX-guided candidate docking sites in 3D for physics-based molecular docking and then, following docking, employs HDX-MS-informed XGBoost filtering and scoring functions for ligand-pose ranking. MInt-HDX was validated across 3 protein-ligand systems, consistently resulting in Ligand-RMSD within 3 [A] of the crystallographic ligand conformation, individual steps of MInt-HDX were optimized and its overall performance was assessed against HDX-MS data quality factors and benchmarked against common physics-based and machine learning based docking approaches. Together, this work highlights how machine learning, informed by HDX-MS and aided by physics-based approaches, can bridge the gap between solution-phase HDX-MS data and structural modeling to accelerate protein-ligand discovery pipelines.","rel_num_authors":6,"rel_authors":[{"author_name":"Vincent Lowe","author_inst":"University of Maryland Baltimore"},{"author_name":"Ally K Smith","author_inst":"University of Maryland Baltimore"},{"author_name":"Rinky Parakra","author_inst":"University of Maryland Baltimore"},{"author_name":"Eucolona Toci","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Caren L Freel Meyers","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Daniel Deredge","author_inst":"University of Maryland Baltimore"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"Genomic foundation model embeddings encode higher-order viral genome architecture beyond sequence composition: a benchmark of Evo 2","rel_doi":"10.64898\/2026.07.14.738542","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.14.738542","rel_abs":"Genomic foundation models such as Evo 2 are increasingly applied to microbial genomics, yet how well their representations capture viral genome organisation, and how reliably they generate viral sequence, remain poorly characterised. We present a reproducible benchmark of Evo 2 on viral genomes. Using a pre-registered RefSeq viral corpus (19,429 genomes, organised by Baltimore class and host domain), we evaluated three axes: linear probes decoding Baltimore class, host domain and viral family from mean-pooled embeddings; ridge-regression probes recovering genomic features, including higher-order architectural properties such as gene density, coding fraction and gene overlap; and generative completion of fragmented genomes, scored on a leakage-safe set of eukaryote-infecting viruses (excluded from Evo 2's training corpus by design) against a bacteriophage comparator. All probes used cross-validation with sequence-identity clustered folds, benchmarked against both a GC-and-length control and a 6-mer composition representation. From its optimal intermediate layer, the 20B embedding classified Baltimore class at 0.96 accuracy and host domain at 0.99, exceeding both baselines; for viral family, however, 6-mer composition (0.89) matched the embedding (0.91. Most informatively, the embedding decoded coding fraction, gene density and gene overlap (R = 0.61, 0.77 and 0.64) far beyond 6-mer composition (0.10, 0.38 and 0.27), evidencing genuine encoding of genome architecture rather than nucleotide composition (p < 0.001). Performance scaled with model size. In generation, perplexity was lower for bacteriophages (1.18 bits\/nt) than for held-out eukaryotic viruses (1.80). Evo 2 encodes functional viral genome architecture beyond composition, while taxonomic and generative behaviour partly reflect composition and training exposure.","rel_num_authors":5,"rel_authors":[{"author_name":"Deyvid Amgarten","author_inst":"Faculdade Israelita de Ciencias da Saude Albert Einstein, Sao Paulo, Brazil"},{"author_name":"Anderson Schinaid","author_inst":"Hospital Israelita Albert Einstein, Sao Paulo, Brazil"},{"author_name":"Fernanda de Mello Malta","author_inst":"Hospital Albert Einstein"},{"author_name":"Alexandre R. Marra","author_inst":"Hospital Israelita Albert Einstein, Sao Paulo, Brazil"},{"author_name":"Joao Renato Rebello Pinho","author_inst":"Hospital Israelita Albert Einstein, Sao Paulo, Brazil"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"SHINE: Decoding transcriptional-metabolic microenvironments through higher-order spatial integration","rel_doi":"10.64898\/2026.07.10.737648","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737648","rel_abs":"Spatial omics technologies are expanding to co-profile transcriptomics and metabolomics on the same tissue slide, providing complementary views of gene expression and biochemical activity to reveal molecular programs within native tissue microenvironments. However, integrating the transcriptome and metabolome remains technically challenging due to spatial misalignment, resolution disparity, and higher-order cross-modality interactions. Here, we present SHINE, a hypergraph-based computational framework for the joint analysis of spatial gene expression and metabolic networks derived from the co-profiling slide, focusing on representation learning and cross-modality interaction. Across multiple datasets, SHINE consistently outperformed existing methods for domain segmentation and biomarker co-localization and provided interpretable insights into metabolic-transcriptional microenvironments. Specifically, in Parkinson's disease mouse models, SHINE accurately delineates dopaminergic neuron-depleted regions and reconstructs coherent dopamine-associated axes. In human lung and breast cancers, SHINE resolves tumor-associated spatial regions and identifies spatially organized gene-metabolite programs associated with the tumor microenvironment. SHINE enables scalable spatial multi-omics integration across diverse biological systems.","rel_num_authors":3,"rel_authors":[{"author_name":"Bingxue Du","author_inst":"Northwestern Polytechnical University"},{"author_name":"Jason W. H. Wong","author_inst":"The University of Hong Kong"},{"author_name":"Yuanhua Huang","author_inst":"The University of Hong Kong"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"Reconstructing sequence-grammar trajectories enables interpretable and tunable cis- regulatory element design","rel_doi":"10.64898\/2026.07.10.737719","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737719","rel_abs":"Designing synthetic cis-regulatory elements (CREs) with cell-type-specific activity is critical for precision gene and cell therapies, but remains challenging because optimization is often treated as a black box, obscuring how regulatory grammar emerges and how failed trajectories can be corrected. Here, we present GO-CRE (Guided Optimization of Cis-Regulatory Elements), a deep learning framework that integrates efficient sequence generation, predictor-guided reinforcement learning, and trajectory-level interpretation. GO-CRE reconstructs iterative sequence changes in a shared sequence-grammar landscape and identifies coordinated update programs corresponding to search, commitment, and optimization. In HepG2, GO-CRE revealed a low-complexity polyG trap and redirected optimization toward functional motif programs by introducing a polyG penalty. Final designs in HepG2 and K562 progressively acquired cell-type-associated grammar while retaining sequence diversity. Lentiviral massively parallel reporter assays validated cell-type-specific activity in K562 and HepG2 and showed higher average activity of HepG2 designs than endogenous CREs. Together, these findings establish sequence-grammar trajectory reconstruction as a basis for interpretable and tunable synthetic CRE design.","rel_num_authors":20,"rel_authors":[{"author_name":"Mingqian Ma","author_inst":"Carnegie Mellon University"},{"author_name":"Wanjuan Bu","author_inst":"Peking University"},{"author_name":"Guoqing Liu","author_inst":"Microsoft Research AI for Science"},{"author_name":"Yuxuan Liu","author_inst":"National Institute of Biological Sciences"},{"author_name":"Sizhen Liu","author_inst":"Peking University"},{"author_name":"Zhen Zhao","author_inst":"National Institute of Biological Sciences"},{"author_name":"Shijie Yao","author_inst":"Peking University"},{"author_name":"Qingru Hua","author_inst":"University of Rochester"},{"author_name":"Yujie Zhang","author_inst":"Peking University"},{"author_name":"Cuiting Zhong","author_inst":"Peking University"},{"author_name":"Haitao Huang","author_inst":"Hunan University"},{"author_name":"Pan Deng","author_inst":"Zhongguancun Academy"},{"author_name":"Peiran Jin","author_inst":"Zhongguancun Academy"},{"author_name":"Qijin Yin","author_inst":"Zhongguancun Academy"},{"author_name":"Chuan Cao","author_inst":"Zhongguancun Academy"},{"author_name":"Haiguang Liu","author_inst":"Zhongguancun Academy"},{"author_name":"Mo Xu","author_inst":"National Institute of Biological Sciences"},{"author_name":"Yuan He","author_inst":"Zhongguancun Academy"},{"author_name":"Tao Qin","author_inst":"Zhongguancun Academy"},{"author_name":"Zeyu Chen","author_inst":"Peking University"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"A claustro-cortical loop times state transitions for flexible behavior","rel_doi":"10.64898\/2026.07.10.737800","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737800","rel_abs":"Metastable dynamics, in which neural activity moves between transiently stable patterns, have been proposed to underlie the real-time coordination on which the brain's cognitive and behavioral functions depend. In the cortex, the simplest form of this regime is the alternation between active 'UP' states, in which neurons fire, and silent 'DOWN' states, in which firing is strongly reduced, a bistable architecture that shapes how afferent information is processed. Such metastable dynamics are ubiquitous across cortex, yet how their state transitions are timed and controlled, and how this timing shapes behavior, remain open questions. Here we show, in freely behaving mice performing a cue-guided switching task, that the metastable dynamics of frontal cortex are jointly shaped by its reciprocal loop with the claustrum, a small and widely connected subcortical structure, and that the loop's timing of these state transitions is required for efficient flexible behavior. Claustrum activity led the cortical UP-to-DOWN state transition, delivering to anterior cingulate cortex a low-dimensional drive aligned with the axis along which the cortical state switches. This drive was carried not by a rise in claustral firing but by transient coordination: population synchrony peaked at the transition even as mean rate fell. Silencing ACC-projecting claustrum terminals reduced directed claustro-cortical coupling, biased cortex away from the DOWN state by prolonging UP states and shortening DOWN states, and selectively impaired cue-driven switching while sparing exploratory foraging. These results place flexible behavior under the control of a defined cortico-subcortical loop that times cortical state transitions, offering a circuit-level entry point into the cognitive rigidity of many psychiatric and neurological conditions.","rel_num_authors":5,"rel_authors":[{"author_name":"Randall J Olson","author_inst":"Oregon Health & Science University"},{"author_name":"Alex Sonneborn","author_inst":"Oregon Health & Science University"},{"author_name":"Russell Milton","author_inst":"Oregon Health & Science University"},{"author_name":"Lowell Bartlett","author_inst":"Oregon Health & Science University"},{"author_name":"Atheir Abbas","author_inst":"VA Portland Health Care System"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"Dissociable Neural Responses to Conditioned Social Threats are Modulated by Spatial Proximity in PTSD and MDD","rel_doi":"10.64898\/2026.07.10.737814","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737814","rel_abs":"The brain's response to potential threats is shaped by the egocentric spatiotemporal distance to the threat. While distal threats recruit evaluative, cognitive-fear networks for strategic planning, proximal threats engage evolutionarily conserved reactive-fear circuitry to mount immediate defensive responses. Understanding this dual neural architecture is clinically relevant, as the spatial proximity to a traumatic event predicts subsequent psychiatric symptom severity and recovery. Despite the well-characterized disruptions to threat circuitry in posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), how these networks respond to threats at distinct spatial distances has yet to be investigated in these disorders. Utilizing 3D virtual reality technology, we implemented a spatially-modulated fear conditioning paradigm by presenting human avatars at proximal (peripersonal) and distal (extrapersonal) distances, paired with shock, to trauma-exposed participants (n = 50) during functional MRI (fMRI). We modeled associations between PTSD and MDD symptom severity and task-evoked hemodynamic responses within cognitive-fear and reactive-fear threat networks. Our results support a transdiagnostic disruption of thalamic responses to proximal threats, driven by heightened activation to the safety stimulus and stronger deactivation to the threat stimulus. MDD showed a disorder-specific effect of disrupted activity across cognitive-fear and social cognition regions in response to proximal social threats, and illness severity-by-proximity effects across motor regions. PTSD symptom severity was uniquely associated with hyperactivity of the amygdala to distal threats. Transdiagnostic disruption of connectivity between the dorsal precuneus and several subcortical structures followed a disorder-specific gradient across the anterior-posterior axis. While thalamic disruptions to threats represent a shared transdiagnostic effect, PTSD and MDD are distinguished by differences in amygdala hyperactivation and cognitive-fear network hypoactivation, respectively.","rel_num_authors":10,"rel_authors":[{"author_name":"Nick Steele","author_inst":"Duke University"},{"author_name":"Leonel Rangel-Jimenez","author_inst":"Duke University"},{"author_name":"Dash A. Watts","author_inst":"Yale University"},{"author_name":"LeeAnne Tunstall","author_inst":"Duke University"},{"author_name":"Jenna A. Beakas","author_inst":"Duke University"},{"author_name":"Ahmed Hussain","author_inst":"Duke University"},{"author_name":"Ashley Huggins","author_inst":"University of Arizona"},{"author_name":"Delin Sun","author_inst":"Duke University"},{"author_name":"Kevin S. LaBar","author_inst":"Duke University"},{"author_name":"Rajendra A. Morey","author_inst":"Duke University"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"Distinct and shared neural resources between processing of dynamic physical objects and spatial working memory","rel_doi":"10.64898\/2026.07.10.737787","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737787","rel_abs":"In human brains, portions of the frontoparietal cortex respond when people reason about the physical world (e.g. track objects, make predictions), and when people engage in a variety of demanding tasks (e.g. working memory, motor inhibition). Here, we use functional neuroimaging to address an open question about whether the same neural resources support both mental functions. Twenty-eight human adults (Mean age = 26.5y; 17 female; 26 right handed) were scanned using functional magnetic resonance imaging (fMRI) while they (i) tracked the dynamics of physical objects (vs social agents), and (ii) performed a hard (vs easy) spatial working memory task. For each participant, we identified functional regions of interest (fROIs) that were maximally engaged by each task (physical > social; hard > easy), and studied their engagement in the held out task. We report three pieces of evidence that physical > social fROIs are recruited during the spatial working memory task. First, fROIs maximally engaged during physical (vs social) processing responded just as strongly during hard (vs easy) spatial working memory. Second, people with strong hard > easy responses in one set of regions also tended to have strong physical > social responses in the other set. Third, people with strong hard > easy responses in physical > social fROIs, but not in hard > easy fROIs, performed more strongly at spatial working memory in the scanner. These findings suggest that portions of the frontoparietal cortex that preferentially respond to physical (vs social) stimuli are involved in functions beyond physical reasoning: either spatial processing specifically, or attentionally demanding tasks in general.","rel_num_authors":2,"rel_authors":[{"author_name":"Samuel M. Maione","author_inst":"Johns Hopkins University"},{"author_name":"Shari Liu","author_inst":"Johns Hopkins University"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"A Charge-Encoded Rheostat Permits Helix Nucleation but Limits Propagation in Skp1","rel_doi":"10.64898\/2026.07.13.737693","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.13.737693","rel_abs":"Molecular recognition by intrinsically disordered regions (IDRs) is widely thought to involve coupled folding and binding, yet the sequence features that regulate this transition remain underexplored. Here we show that helix 8 (H8), a disordered C-terminal segment of the SCF ubiquitin ligase adaptor Skp1, is intrinsically prevented from forming a stable helix by its own sequence grammar. Using an integrative approach to dissect its conformational dynamics, we find that H8 frequently nucleates helical structure but rarely propagates into a fully formed stable helix, populating instead a shallow metastable basin of helical intermediates. Contrary to conventional models of helix-coil exchange, where nucleation is rate limiting, helix initiation in H8 is readily accessible, while propagation is selectively suppressed by a glutamate-rich acidic patch. This acidic segment acts as a charge-sensitive conformational rheostat that limits helix extension and maintains H8 in a predominantly disordered state. As a result, H8 transiently samples partially helical conformations on the microsecond timescale without committing to a stable fold. We propose that this propagation-limited mechanism preserves conformational flexibility while maintaining recognition competence across a structurally diverse family of F-box binding partners. More broadly, our findings suggest that charged-hydrophobic-charged sequence patterning can encode conditional, context-dependent structure as a general organisational principle in intrinsically disordered proteomes.","rel_num_authors":9,"rel_authors":[{"author_name":"Debarghya Mitra","author_inst":"Indian Institute of Technology Bombay"},{"author_name":"Simran Tolani","author_inst":"Indian Institute of Technology Bombay, Powai, Mumbai"},{"author_name":"Amrita Bhattacharya","author_inst":"Aarhus University"},{"author_name":"Supriya Prathihar","author_inst":"Columbia University"},{"author_name":"Sagarjyoti Pathak","author_inst":"Indian Institute of Technology Bombay"},{"author_name":"Arpita Prasad","author_inst":"Indian Institute of Technology Bombay"},{"author_name":"Christian Griesinger","author_inst":"Max Planck Institute for Multidisciplinary Sciences"},{"author_name":"Ashutosh Kumar","author_inst":"Indian Institute of Technology Bombay"},{"author_name":"Sarath Chandra Dantu","author_inst":"Brunel University of London"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"Bacterial-driven development is mediated by Calcium-Dependent Intrinsic Apoptosis in the Squid-Vibrio Symbiosis","rel_doi":"10.64898\/2026.07.15.738745","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.738745","rel_abs":"The presence of beneficial microbes serves as a post-embryonic developmental cue in a wide array of metazoan species. However, the mechanisms through which mutualistic bacteria induce developmental processes such as apoptosis are poorly understood. A leading model system utilized to study bacteria-induced developmental apoptosis is the Hawaiian bobtail squid, Euprymna scolopes , whose bacterial symbiont Vibrio fischeri induces several developmental events upon colonization of the squid's light organ. Upon hatching the light organ possesses ciliated epithelial fields (CEFs) and appendages that facilitate the collection of V. fischeri from the ambient seawater for symbiont colonization of the internal crypt spaces. To better understand the molecular pathways underpinning bacterial-induced development occurring in these appendages, we isolated appendages from hatchling (0-1h) and aposymbiotic and symbiotic E. scolopes light organs (18h) for RNA sequencing. Our analysis of this transcriptomic dataset indicated that symbiotic appendages undergo intrinsic apoptosis in response to excessive cytosolic calcium. Further experiments found that symbiotic appendages exhibited increased cytosolic calcium and mitochondrial membrane potential overload relative to their aposymbiotic counterparts. In comparing our appendage specific gene expression to previously published whole light organ transcriptomic dataset, we identified increased presence of apoptosis inducing factor (AIF) and decreased expression of transcripts related to protein folding in the appendages as potential mechanisms of apoptotic signal specificity to the CEF. Together, these data suggest a central role of cytosolic calcium in the developmental apoptotic signaling induced by V. fischeri colonization of the E. scolopes light organ.","rel_num_authors":4,"rel_authors":[{"author_name":"Madison A Emery","author_inst":"Michigan State University"},{"author_name":"Alice Breaux Walker","author_inst":"Michigan State University"},{"author_name":"Bethany A Rader","author_inst":"Southern Illinois University"},{"author_name":"Elizabeth A Heath-Heckman","author_inst":"Michigan State University"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"G4 DNA structures induced by UV radiation: a multi-omic approach","rel_doi":"10.64898\/2026.07.15.738736","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.738736","rel_abs":"DNA G quadruplexes (G4s) are secondary structures with critical roles in regulating genome function. G4s in regulatory regions like promoters and enhancers are important for controlling gene expression, while aberrant formation of G4s has been linked to genomic instability and human disease. Despite G4s importance and inherent danger, their dynamic formation remains incompletely understood. Here, we show that ultraviolet (UV) radiation uniquely induces widespread and persistent G4 formation in human cells, distinguishing it from other genotoxins. Through integrated genomic, transcriptomic, and proteomic analyses, we uncovered key features and functions of UV-induced G4s. Proteomic profiling identified RCOR3 as a factor associated with specific UV-induced G4s at late time points. Functional studies revealed that RCOR3 is essential for the formation and persistence of these structures. Furthermore, genes associated with UV G4s that are differentially expressed are enriched in pathways related to response to UV radiation, highlighting their biological relevance. These findings define the multi-omic landscape of UV-induced G4s and reveal new mechanistic insights into the interplay between genotoxic stress responses and the regulation of non-canonical DNA structures.","rel_num_authors":12,"rel_authors":[{"author_name":"Lindsay R. Julio","author_inst":"Department of Biology, Northeastern University, 360 Huntington Avenue, Boston, MA, USA 02115"},{"author_name":"Diana V. Turrieta Vejar","author_inst":"Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA 06510"},{"author_name":"Charlotte H. Walborsky","author_inst":"Department of Biology, Northeastern University, 360 Huntington Avenue, Boston, MA, USA 02115"},{"author_name":"Annika Salpukas","author_inst":"Department of Biology, Northeastern University, 360 Huntington Avenue, Boston, MA, USA 02115"},{"author_name":"Ella Chee","author_inst":"Department of Biology, Northeastern University, 360 Huntington Avenue, Boston, MA, USA 02115"},{"author_name":"Julianne C. Murthy","author_inst":"Department of Biology, Northeastern University, 360 Huntington Avenue, Boston, MA, USA 02115"},{"author_name":"Shannon G. MacLeod","author_inst":"Department of Biology, Northeastern University, 360 Huntington Avenue, Boston, MA, USA 02115"},{"author_name":"Adrianna L. Vandeuren","author_inst":"Department of Biology, University of Freiburg, Freiburg, Germany 79104"},{"author_name":"Mynaja Ferguson","author_inst":"Department of Chemistry, University of Massachusetts Boston, Boston, MA, USA 02125"},{"author_name":"Rachel E. Muriph","author_inst":"Department of Chemistry, University of Massachusetts Boston, Boston, MA, USA 02125"},{"author_name":"Jason J. Evans","author_inst":"Department of Chemistry, University of Massachusetts Boston, Boston, MA, USA 02125"},{"author_name":"Tovah A. Day","author_inst":"Department of Biology, Northeastern University, 360 Huntington Avenue, Boston, MA, USA 02115"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"G4 DNA structures induced by UV radiation: a multi-omic approach","rel_doi":"10.64898\/2026.07.15.738736","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.738736","rel_abs":"DNA G quadruplexes (G4s) are secondary structures with critical roles in regulating genome function. G4s in regulatory regions like promoters and enhancers are important for controlling gene expression, while aberrant formation of G4s has been linked to genomic instability and human disease. Despite G4s importance and inherent danger, their dynamic formation remains incompletely understood. Here, we show that ultraviolet (UV) radiation uniquely induces widespread and persistent G4 formation in human cells, distinguishing it from other genotoxins. Through integrated genomic, transcriptomic, and proteomic analyses, we uncovered key features and functions of UV-induced G4s. Proteomic profiling identified RCOR3 as a factor associated with specific UV-induced G4s at late time points. Functional studies revealed that RCOR3 is essential for the formation and persistence of these structures. Furthermore, genes associated with UV G4s that are differentially expressed are enriched in pathways related to response to UV radiation, highlighting their biological relevance. These findings define the multi-omic landscape of UV-induced G4s and reveal new mechanistic insights into the interplay between genotoxic stress responses and the regulation of non-canonical DNA structures.","rel_num_authors":12,"rel_authors":[{"author_name":"Lindsay R. Julio","author_inst":"Department of Biology, Northeastern University, 360 Huntington Avenue, Boston, MA, USA 02115"},{"author_name":"Diana V. Turrieta Vejar","author_inst":"Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA 06510"},{"author_name":"Charlotte H. Walborsky","author_inst":"Department of Biology, Northeastern University, 360 Huntington Avenue, Boston, MA, USA 02115"},{"author_name":"Annika Salpukas","author_inst":"Department of Biology, Northeastern University, 360 Huntington Avenue, Boston, MA, USA 02115"},{"author_name":"Ella Chee","author_inst":"Department of Biology, Northeastern University, 360 Huntington Avenue, Boston, MA, USA 02115"},{"author_name":"Julianne C. Murthy","author_inst":"Department of Biology, Northeastern University, 360 Huntington Avenue, Boston, MA, USA 02115"},{"author_name":"Shannon G. MacLeod","author_inst":"Department of Biology, Northeastern University, 360 Huntington Avenue, Boston, MA, USA 02115"},{"author_name":"Adrianna L. Vandeuren","author_inst":"Department of Biology, University of Freiburg, Freiburg, Germany 79104"},{"author_name":"Mynaja Ferguson","author_inst":"Department of Chemistry, University of Massachusetts Boston, Boston, MA, USA 02125"},{"author_name":"Rachel E. Muriph","author_inst":"Department of Chemistry, University of Massachusetts Boston, Boston, MA, USA 02125"},{"author_name":"Jason J. Evans","author_inst":"Department of Chemistry, University of Massachusetts Boston, Boston, MA, USA 02125"},{"author_name":"Tovah A. Day","author_inst":"Department of Biology, Northeastern University, 360 Huntington Avenue, Boston, MA, USA 02115"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"Predicting the protein interaction landscape of a mycobacterial pathogen","rel_doi":"10.64898\/2026.07.15.738315","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.738315","rel_abs":"High-dimensional phenotypic screens of bacterial loss-of-function mutant libraries have determined gene-gene connections and specific phenotypes for thousands of bacterial genes in many species, but deciphering the underlying mechanisms remains decidedly low-throughput. Here, we demonstrate the utility of proteome-wide AI-based protein-protein interaction (PPI) predictions for overcoming this gap by using pooled-AlphaFold3 to assess all ~1.3 million possible pairwise interactions in the proteome of Mycobacterium leprae. We identify ~2,000 strong and intermediate PPIs that underlie a significant fraction of phenotypes and gene-gene connections observed in large-scale chemical genomics screens from Mycobacterium tuberculosis, Mycobacterium smegmatis, and Corynebacterium glutamicum. This combined approach predicts specific functions for dozens of previously uncharacterized core, conserved, and essential mycobacterial proteins. We highlight new information derived from the study, including insights into mycobacterial envelope assembly, peptidoglycan remodeling, and new modulators of the central dogma enzymes RNA polymerase and DNA gyrase. These data establish combined pooled-AlphaFold3 PPI prediction and high-throughput genomics approach as the gold standard for large-scale characterization of protein function.","rel_num_authors":15,"rel_authors":[{"author_name":"Horia Todor","author_inst":"University of California - San Francisco"},{"author_name":"Lili M Kim","author_inst":"University of California - San Francisco"},{"author_name":"Evan Billings","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Anna E. Grzegorzewicz","author_inst":"Colorado State University"},{"author_name":"Hannah N. Burkhart","author_inst":"University of California - San Francisco"},{"author_name":"Michael DeJesus","author_inst":"The Rockefeller University"},{"author_name":"Allen Na","author_inst":"The Rockefeller University"},{"author_name":"Samuel Nitz","author_inst":"The Rockefeller University"},{"author_name":"Scarlet Shell","author_inst":"Worcester Polytechnic Institute"},{"author_name":"Mary Jackson","author_inst":"Colorado State University"},{"author_name":"Elizabeth A Campbell","author_inst":"The Rockefeller Univeristy"},{"author_name":"Filippo Mancia","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Jeremy M. Rock","author_inst":"The Rockefeller University"},{"author_name":"Carol A Gross","author_inst":"University of California - San Francisco"},{"author_name":"James Chen","author_inst":"University of California - San Francisco"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"Predicting the protein interaction landscape of a mycobacterial pathogen","rel_doi":"10.64898\/2026.07.15.738315","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.738315","rel_abs":"High-dimensional phenotypic screens of bacterial loss-of-function mutant libraries have determined gene-gene connections and specific phenotypes for thousands of bacterial genes in many species, but deciphering the underlying mechanisms remains decidedly low-throughput. Here, we demonstrate the utility of proteome-wide AI-based protein-protein interaction (PPI) predictions for overcoming this gap by using pooled-AlphaFold3 to assess all ~1.3 million possible pairwise interactions in the proteome of Mycobacterium leprae. We identify ~2,000 strong and intermediate PPIs that underlie a significant fraction of phenotypes and gene-gene connections observed in large-scale chemical genomics screens from Mycobacterium tuberculosis, Mycobacterium smegmatis, and Corynebacterium glutamicum. This combined approach predicts specific functions for dozens of previously uncharacterized core, conserved, and essential mycobacterial proteins. We highlight new information derived from the study, including insights into mycobacterial envelope assembly, peptidoglycan remodeling, and new modulators of the central dogma enzymes RNA polymerase and DNA gyrase. These data establish combined pooled-AlphaFold3 PPI prediction and high-throughput genomics approach as the gold standard for large-scale characterization of protein function.","rel_num_authors":15,"rel_authors":[{"author_name":"Horia Todor","author_inst":"University of California - San Francisco"},{"author_name":"Lili M Kim","author_inst":"University of California - San Francisco"},{"author_name":"Evan Billings","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Anna E. Grzegorzewicz","author_inst":"Colorado State University"},{"author_name":"Hannah N. Burkhart","author_inst":"University of California - San Francisco"},{"author_name":"Michael DeJesus","author_inst":"The Rockefeller University"},{"author_name":"Allen Na","author_inst":"The Rockefeller University"},{"author_name":"Samuel Nitz","author_inst":"The Rockefeller University"},{"author_name":"Scarlet Shell","author_inst":"Worcester Polytechnic Institute"},{"author_name":"Mary Jackson","author_inst":"Colorado State University"},{"author_name":"Elizabeth A Campbell","author_inst":"The Rockefeller Univeristy"},{"author_name":"Filippo Mancia","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Jeremy M. Rock","author_inst":"The Rockefeller University"},{"author_name":"Carol A Gross","author_inst":"University of California - San Francisco"},{"author_name":"James Chen","author_inst":"University of California - San Francisco"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"Predicting the protein interaction landscape of a mycobacterial pathogen","rel_doi":"10.64898\/2026.07.15.738315","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.738315","rel_abs":"High-dimensional phenotypic screens of bacterial loss-of-function mutant libraries have determined gene-gene connections and specific phenotypes for thousands of bacterial genes in many species, but deciphering the underlying mechanisms remains decidedly low-throughput. Here, we demonstrate the utility of proteome-wide AI-based protein-protein interaction (PPI) predictions for overcoming this gap by using pooled-AlphaFold3 to assess all ~1.3 million possible pairwise interactions in the proteome of Mycobacterium leprae. We identify ~2,000 strong and intermediate PPIs that underlie a significant fraction of phenotypes and gene-gene connections observed in large-scale chemical genomics screens from Mycobacterium tuberculosis, Mycobacterium smegmatis, and Corynebacterium glutamicum. This combined approach predicts specific functions for dozens of previously uncharacterized core, conserved, and essential mycobacterial proteins. We highlight new information derived from the study, including insights into mycobacterial envelope assembly, peptidoglycan remodeling, and new modulators of the central dogma enzymes RNA polymerase and DNA gyrase. These data establish combined pooled-AlphaFold3 PPI prediction and high-throughput genomics approach as the gold standard for large-scale characterization of protein function.","rel_num_authors":15,"rel_authors":[{"author_name":"Horia Todor","author_inst":"University of California - San Francisco"},{"author_name":"Lili M Kim","author_inst":"University of California - San Francisco"},{"author_name":"Evan Billings","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Anna E. Grzegorzewicz","author_inst":"Colorado State University"},{"author_name":"Hannah N. Burkhart","author_inst":"University of California - San Francisco"},{"author_name":"Michael DeJesus","author_inst":"The Rockefeller University"},{"author_name":"Allen Na","author_inst":"The Rockefeller University"},{"author_name":"Samuel Nitz","author_inst":"The Rockefeller University"},{"author_name":"Scarlet Shell","author_inst":"Worcester Polytechnic Institute"},{"author_name":"Mary Jackson","author_inst":"Colorado State University"},{"author_name":"Elizabeth A Campbell","author_inst":"The Rockefeller Univeristy"},{"author_name":"Filippo Mancia","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Jeremy M. Rock","author_inst":"The Rockefeller University"},{"author_name":"Carol A Gross","author_inst":"University of California - San Francisco"},{"author_name":"James Chen","author_inst":"University of California - San Francisco"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"A hierarchy of spatial confinements governs chromatin dynamics and genomic encounters","rel_doi":"10.64898\/2026.07.12.738087","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.12.738087","rel_abs":"Antibody diversity is generated through stochastic rearrangement of the immunoglobulin heavy chain locus (Igh) involving the recombination of variable (VH), diversity (DH) and joining (JH) gene segments. How coding elements within the Igh locus locate one another in the complex nuclear environment is not understood. Here, we sought to identify the molecular mechanisms and physical principles that govern VH-DHJH genomic encounters. We found that transcription imposed a local confinement that stabilized interactions between spatially proximal genomic elements. The loop anchor CTCF modestly constrained population-average chromatin motion, whereas cohesin-mediated loops established large-scale confinement and reinforced self-similarity of VH-DHJH motion across spatial and temporal scales. Quantitative scaling arguments for first-passage times revealed that encounter frequencies between remote VH-DHJH genomic regions are governed by the interplay of diffusivity and spatial proximity. Together, these findings show that the hierarchy of confinements imposed by transcription and loop extrusion provides the balance between stability and mobility required to regulate genomic encounter frequencies.","rel_num_authors":4,"rel_authors":[{"author_name":"Megan Aubrey","author_inst":"University of California, San Diego"},{"author_name":"Arpita Prusy","author_inst":"University of California, San Diego"},{"author_name":"Olga K. Dudko","author_inst":"University of California, San Diego"},{"author_name":"Cornelis Murre","author_inst":"University of California, San Diego"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"MSstatsBioNet: Integrating Statistical Analyses with Prior Knowledge Biomolecular Networks for Quantitative Proteomics and Phosphoproteomics","rel_doi":"10.64898\/2026.07.09.737605","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737605","rel_abs":"A common outcome of quantitative mass spectrometry-based proteomic and phosphoproteomic experiments is a list of proteins that are differentially abundant between conditions. However, biological interpretation requires evaluation in the context of prior knowledge of biological mechanisms and protein function. One approach to facilitate mechanistic biological interpretation is to integrate such lists with biological network databases, built from manually curated resources and text mining systems. This manuscript automates this process with MSstatsBioNet, a Bioconductor package that integrates MSstats, a family of open-source packages for detecting differentially abundant proteins, and INDRA, a system that extracts biomolecular networks from biomedical literature using text mining and merges those networks with the content of curated knowledge bases. Taking as input a list of differentially abundant proteins from MSstats, MSstatsBioNet retrieves a protein subnetwork from INDRA and overlays experimental fold changes onto the underlying subnetwork. Users can then interact with the network and overlaid data, interrogating primary literature evidence to construct granular mechanistic narratives for iterative hypothesis generation. We demonstrate the utility of this approach with three case studies, two measuring changes in protein abundance and one measuring changes in phosphorylation.","rel_num_authors":13,"rel_authors":[{"author_name":"Anthony Wu","author_inst":"Northeastern University"},{"author_name":"Devon Kohler","author_inst":"Northeastern University"},{"author_name":"Pruthvi Prakash Navada","author_inst":"Northeastern University"},{"author_name":"Julia E Robbins","author_inst":"Talus Bioscience Inc."},{"author_name":"Gabriel E Boyle","author_inst":"Seattle Children's Hospital"},{"author_name":"Alex Boshart","author_inst":"University of Toronto"},{"author_name":"Klas Karis","author_inst":"Northeastern University"},{"author_name":"Jacques Neefjes","author_inst":"Leiden University Medical Center"},{"author_name":"Ana Konvalinka","author_inst":"Toronto General Research Institute"},{"author_name":"Jay Sarthy","author_inst":"Seattle Children's Hospital"},{"author_name":"Lindsay Pino","author_inst":"Talus Bioscience Inc."},{"author_name":"Benjamin M Gyori","author_inst":"Northeastern University"},{"author_name":"Olga Vitek","author_inst":"Northeastern University"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"Conformational Basis of Functionally Selective Allosteric Modulation of the Angiotensin II type 1 Receptor by Small Molecules","rel_doi":"10.64898\/2026.07.15.736838","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.736838","rel_abs":"Blockade of signaling through the angiotensin II type 1 receptor (AT1R), a prototypical G protein-coupled receptor (GPCR), by angiotensin receptor blockers (ARBs) is a major therapeutic approach to treating a wide variety of cardiovascular and renal diseases. Like most GPCRs, the AT1R signals through two transducers, G proteins and beta-arrestins. Previous reports have described beta-arrestin-biased peptide orthosteric agonists for the AT1R with potential therapeutic advantages over currently available unbiased ARBs. Here we report the DNA-encoded library screening-guided isolation and pharmacological characterization of the first small molecule AT1R allosteric ligands. We use cryo-electron microscopy, double electron-electron resonance spectroscopy, molecular dynamics simulations, and targeted mutagenesis to determine their binding sites, binding modes and conformational mechanisms driving their unique and divergent modulatory effects on G protein and beta-arrestin pathways. Our findings uncover new mechanisms for precisely controlling the dynamic behavior of the AT1R with implications for drug development targeting this pathophysiologically important receptor family.","rel_num_authors":29,"rel_authors":[{"author_name":"Samuel Liu","author_inst":"Duke University School of Medicine"},{"author_name":"Peng Xiao","author_inst":"Shandong University"},{"author_name":"Matthias Elgeti","author_inst":"Leipzig University Medical School"},{"author_name":"Eve J. Fine","author_inst":"Stanford University"},{"author_name":"Emilio Y. Lucero","author_inst":"Duke University School of Medicine"},{"author_name":"Mikkel Vestergaard","author_inst":"Amgen Research Copenhagen"},{"author_name":"Junyan Wang","author_inst":"Duke University School of Medicine"},{"author_name":"Arun Jyothidasan","author_inst":"Duke University School of Medicine"},{"author_name":"Angus Li","author_inst":"Duke University School of Medicine"},{"author_name":"Changxiu Qu","author_inst":"Shandong University"},{"author_name":"Eva Olsen","author_inst":"Amgen Research Copenhagen"},{"author_name":"Georgios Mazis","author_inst":"Amgen Research Copenhagen"},{"author_name":"Josephine K. Madsen","author_inst":"Amgen Research Copenhagen"},{"author_name":"Carl-Mikael Suomivuori","author_inst":"Stanford University Stanford"},{"author_name":"Jihee Kim","author_inst":"Duke University School of Medicine"},{"author_name":"Natalia Pakharukova","author_inst":"Duke University School of Medicine"},{"author_name":"Rashad Rahman","author_inst":"Duke University School of Medicine"},{"author_name":"Stephanie M. Kereliuk","author_inst":"Duke University School of Medicine"},{"author_name":"Walter J. Koch","author_inst":"Duke University School of Medicine"},{"author_name":"Ryan T. Strachan","author_inst":"Septerna Inc."},{"author_name":"Dean P. Staus","author_inst":"Septerna Inc."},{"author_name":"Ali Masoudi","author_inst":"Septerna Inc."},{"author_name":"Wayne L. Hubbell","author_inst":"University of California, Los Angeles"},{"author_name":"Alem W. Kahsai","author_inst":"Duke University School of Medicine"},{"author_name":"Ron O. Dror","author_inst":"Stanford University"},{"author_name":"Howard A. Rockman","author_inst":"Duke University School of Medicine"},{"author_name":"JinPeng Sun","author_inst":"Shandong University"},{"author_name":"Seungkirl Ahn","author_inst":"Duke University School of Medicine"},{"author_name":"Robert J. Lefkowitz","author_inst":"Duke University School of Medicine"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"Deformability screening identifies NUDT5 as a mediator of cellular mechanobiology","rel_doi":"10.64898\/2026.07.15.734864","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.734864","rel_abs":"How cells deform, sense, and respond to mechanical cues drives physiological and disease processes ranging from development to cancer metastasis; however, unbiased approaches to identify mechanical mediators are lacking. We screened 1280 compounds to identify modulators of cancer cell deformability using a cellular filtration assay and identified 92 compounds that significantly reduced deformability of ovarian cancer cells; top hits also reduced migration and invasion. Connectivity mapping of the top 21 compounds identified NUDT5 (Nudix hydrolase 5) as a predicted mechanical mediator; transcriptomic analyses implicated NUDT5 in mechanobiology and metabolic processes. We confirmed that NUDT5 mediates intracellular ATP and cellular mechanical behaviors, including morphology and deformability. In ovarian cancer, increased NUDT5 levels were associated with higher tumor stage and worse patient survival; NUDT5 inhibition reduced migration and colony formation in vitro and peritoneal tumor burden in mice. These findings establish deformability-based screening as a platform for discovering mechanical mediators and identify NUDT5 as a therapeutic target in ovarian cancer.","rel_num_authors":19,"rel_authors":[{"author_name":"Angelina M. Flores","author_inst":"University of California, Los Angeles"},{"author_name":"Jennifer Soto","author_inst":"University of California, Los Angeles"},{"author_name":"Navjot Kaur Gill","author_inst":"University of California, Los Angeles"},{"author_name":"Ahmed Almunaifi","author_inst":"University of California, Los Angeles"},{"author_name":"Chau Ly","author_inst":"University of California, Los Angeles"},{"author_name":"Dongping Qi","author_inst":"University of California, Los Angeles"},{"author_name":"Ruchira Krishnamurthy","author_inst":"University of California, Los Angeles"},{"author_name":"Eleana Parajon","author_inst":"Johns Hopkins University"},{"author_name":"Bobby Tofig","author_inst":"University of California, Los Angeles"},{"author_name":"Valeria Garcia","author_inst":"The University of Texas at Austin"},{"author_name":"Maria Sol Recouvreux","author_inst":"University of California, Los Angeles"},{"author_name":"Song Li","author_inst":"University of California, Los Angeles"},{"author_name":"Yi Lu","author_inst":"The University of Texas at Austin"},{"author_name":"Beth Y. Karlan","author_inst":"University of California, Los Angeles"},{"author_name":"Douglas N. Robinson","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Junyoung O. Park","author_inst":"University of California, Los Angeles"},{"author_name":"Robert Damoiseaux","author_inst":"University of California, Los Angeles"},{"author_name":"Sandra Orsulic","author_inst":"University of California, Los Angeles"},{"author_name":"Amy C. Rowat","author_inst":"University of California, Los Angeles"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"A Multi-Institution Biobanking Pipeline for Primary Human Satellite Cells and Fibro-Adipogenic Progenitors","rel_doi":"10.64898\/2026.07.15.738758","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.738758","rel_abs":"Satellite Cells (SCs) and Fibro-Adipogenic Progenitors (FAPs) are muscle-resident cell populations crucial for maintaining skeletal muscle homeostasis and coordinating regeneration after injuries. However, primary human SCs and FAPs are difficult to co-isolate, and their broad use in translational research has been limited by a lack of standardized biobanking protocols. Recently, we published a protocol for efficient co-isolation of SCs and FAPs from human skeletal muscle. Here, we extend those efforts to establish a comprehensive pipeline for the cryopreservation, cold-chain transport, and independent-site utilization of human SCs and FAPs. Cells taken through this pipeline maintained lineage-specific markers, including Pax7, MyoD and CD56 for SCs, and PDGFR and TE7 for FAPs, indicating retention of their pre-biobanking phenotype. Furthermore, SCs demonstrate robust myogenic differentiation capacity, and FAPs demonstrate both fibrogenic and adipogenic differentiation capacity post-transport. Finally, previously biobanked SCs were incorporated into in vitro 3D muscle constructs, demonstrating their utility for human-based New Approach Methodologies (NAMs). This framework for multi-site collaboration facilitates broader access to human primary muscle cells, which will improve the scalability and translatability of human-based NAMs for skeletal muscle research.","rel_num_authors":10,"rel_authors":[{"author_name":"Frank S. Pittman","author_inst":"University of Oregon"},{"author_name":"Adam Rauff","author_inst":"University of Oregon"},{"author_name":"Grace E. Privett","author_inst":"University of Oregon"},{"author_name":"Alis Balayan","author_inst":"University of California San Diego"},{"author_name":"Severin Ruoss","author_inst":"University of California San Diego"},{"author_name":"Robert E. Guldberg","author_inst":"University of Oregon"},{"author_name":"Catherine M. Robertson","author_inst":"University of California San Diego"},{"author_name":"Adam J. Engler","author_inst":"University of California San Diego"},{"author_name":"Samuel R. Ward","author_inst":"University of California San Diego"},{"author_name":"Nick J. Willett","author_inst":"University of Oregon"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"Rab4 and Rab11 GTPases cooperate to reinforce adherens junctions at the leading edge to promote rapid embryonic wound healing","rel_doi":"10.64898\/2026.07.15.738337","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.738337","rel_abs":"Collective cell movements drive the formation and repair of tissues and contribute to the spread of metastatic disease. Cells must remodel their cell-cell adhesions and actomyosin cytoskeleton to enable migration, but the mechanisms that drive these molecular rearrangements are unclear. We used wound healing in the Drosophila embryonic epidermis to investigate these mechanisms. Upon wounding, a supracellular cable composed of actin and myosin assembles around the wound. In parallel, adherens junction proteins, including E-cadherin, are depleted from the wound edge via endocytosis and accumulate at former tricellular junctions around the wound (wTCJs) through unknown mechanisms. We found that the small GTPases Rab4 and Rab11, implicated in endosomal trafficking, are necessary for rapid wound repair. Manipulations of Rab4 and Rab11 activity reduced wound closure rates but did not have effects on tissue mechanics or myosin polarization that could explain the defect. Instead, Rab4 and Rab11 redistributed E-cadherin to accumulate at wTCJs in a process necessary for collective cell movement. Together, our results show that adherens junction reinforcement via endosomal recycling is a key step of coordinated cell migration that controls the rate of wound healing independent of cytoskeletal remodeling.","rel_num_authors":5,"rel_authors":[{"author_name":"Brianna D O'Donnell","author_inst":"University of Iowa"},{"author_name":"Sofia Mendez-Lopez","author_inst":"University of Toronto"},{"author_name":"Kate MacQuarrie","author_inst":"University of Toronto"},{"author_name":"Rodrigo Fernandez-Gonzalez","author_inst":"University of Toronto"},{"author_name":"Katheryn E Rothenberg","author_inst":"University of Iowa"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"Methodological assessment of PDMS passive sampling for skin VOC collection across body sites","rel_doi":"10.64898\/2026.07.15.738701","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.738701","rel_abs":"Background: Polydimethylsiloxane (PDMS) is a non-invasive and versatile material often used for non-invasive collection of skin-emitted volatile organic compounds (VOCs), with potential applicability in acute and pre-critical care settings. However, most existing PDMS-based methodologies rely on extensive sample preparation and environmental control, limiting their feasibility in time-sensitive clinical contexts. Methods: We conducted a proof-of-concept pilot study in four healthy volunteers to evaluate whether a simplified skin-contact PDMS sampling procedure can capture detectable VOCs and preserve individual-level variation. PDMS strips were applied directly to the skin with minimal preparation, and collected VOCs were analyzed using gas chromatography-mass spectrometry. Donor-associated variability was assessed using Bray-Curtis dissimilarity, and variability in VOC detection was evaluated across body sites. Results: Skin-contact PDMS sampling detected 160 VOCs across four participants. The mean within-donor Bray-Curtis dissimilarity was 0.308, compared with a mean between-donor dissimilarity of 0.347. Preliminary permutation testing showed distinguishable donor profiles (p-value = 0.004). VOC detection variability differed across body sites, with lower coefficients of variation at the forehead, neck, and wrist than at the ankle. Conclusions: Under simplified sampling conditions, skin-contact PDMS captured individual-associated VOC profiles with lower within-donor variability than between-donor variability. These findings support the feasibility of PDMS-based skin VOC sampling in minimally controlled settings. Further validation in larger and clinically relevant cohorts is warranted to assess the utility of PDMS-sampled skin VOCs as potential biomarkers for early disease detection.","rel_num_authors":11,"rel_authors":[{"author_name":"Seibi Kobara","author_inst":"Duke University School of Medicine"},{"author_name":"Min Huang","author_inst":"Duke University School of Medicine"},{"author_name":"Rizky Ilhamsyah","author_inst":"Georgia Institute of Technology"},{"author_name":"Daniel Struk","author_inst":"Georgia Institute of Technology"},{"author_name":"John Dimandja","author_inst":"Georgia Institute of Technology"},{"author_name":"Peter J. Hesketh","author_inst":"Georgia Institute of Technology"},{"author_name":"Daniela Chanci Arrubla","author_inst":"Duke University School of Medicine"},{"author_name":"Chase Fensore","author_inst":"Emory University"},{"author_name":"Carmen Polito","author_inst":"Emory University School of Medicine"},{"author_name":"Rishikesan Kamaleswaran","author_inst":"Duke University School of Medicine"},{"author_name":"Annette Esper","author_inst":"Emory University School of Medicine"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"Microbial mechanistic requirements for eliciting a topical and intranasal immune response","rel_doi":"10.64898\/2026.07.15.738787","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.738787","rel_abs":"The skin colonist Staphylococcus epidermidis elicits a potent antibody response that can be redirected against an antigen of interest, but this process relies on genetic engineering. Here, by adapting bioorthogonal chemistry methods to conjugate antigens to the cell surface, we make the process of generating a commensal vaccine rapid and efficient. A wide variety of bacteria displaying tetanus toxin fragment C (TTFC) elicit an antibody response when applied to mice topically, indicating that the inductive process is not limited to colonists. Colonization occurs at two different sites, the skin and nostril; by colonizing each with S. epidermidis-TTFC, we show that skin colonization yields a moderate IgG response, while nostril colonization elicits a highly potent systemic IgG response and an exuberant IgA response in the nostrils, lungs, and intestine. Two lines of evidence are consistent with the nasal-associated lymphoid tissue (NALT) as the inductive site for nostril colonization: imaging suggesting robust bacterial translocation, and the induction of commensal-specific B cells following colonization. On the skin, TTFC must be conjugated to live S. epidermidis to elicit an antibody response; in the nostrils, live S. epidermidis-TTFC and S. epidermidis mixed with TTFC are equally potent. Commensal vaccination yields a robust response in pet shop mice, and chemical conjugation facilitates antibody responses to a broad array of antigens, including a whole viral capsid and a rotavirus immunogen. Collectively, these findings provide compelling evidence of a translational path for commensal vaccines.","rel_num_authors":20,"rel_authors":[{"author_name":"Katherine D Bauman","author_inst":"Stanford University"},{"author_name":"Pranav V Lalgudi","author_inst":"Stanford University"},{"author_name":"Djenet Bousbaine","author_inst":"Stanford University"},{"author_name":"Anchaleena James","author_inst":"Stanford University"},{"author_name":"Miki L Chiang","author_inst":"Stanford University"},{"author_name":"Tam TD Nguyen","author_inst":"Stanford University"},{"author_name":"Joyce M Swenson","author_inst":"Microbiome Therapies Initiative"},{"author_name":"Eunice Tsang","author_inst":"Stanford University"},{"author_name":"Hyojin Kim","author_inst":"University of Washington"},{"author_name":"Felicitas Ruiz","author_inst":"University of Washington"},{"author_name":"Naveen Jasti","author_inst":"University of Washington"},{"author_name":"Zachary Jones","author_inst":"University of Washington"},{"author_name":"David B Li","author_inst":"Stanford University"},{"author_name":"Annie T Nguyen","author_inst":"Stanford University"},{"author_name":"Anne Trinh","author_inst":"Microbiome Therapies Initiative"},{"author_name":"Rathnamegha Lingamsetty","author_inst":"Stanford University"},{"author_name":"Aishan Zhao","author_inst":"Stanford University"},{"author_name":"Masahiko Terasaki","author_inst":"Stanford University"},{"author_name":"Neil P King","author_inst":"University of Washington"},{"author_name":"Michael A Fischbach","author_inst":"Stanford University"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"Carbohydrate-active enzymes of giant viruses: Molecular and biochemical characterization of glycosyl hydrolases from algae-infecting chloroviruses","rel_doi":"10.64898\/2026.07.15.738767","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.738767","rel_abs":"Microbial hydrolases are considered to be promising enzymes for pathogen control. Bacterial and viral chitinases of the glycosyl hydrolase (GH) 18 family are important biological macromolecules with antifungal and anti-insect activity. Chloroviruses, nucleocytoplasmic large DNA viruses (NCLDVs) that infect unicellular green algae have a considerable number of genes involved in carbohydrate metabolism, including the chitinase GH18 family. In this study, we investigated the abundance and diversity of chitinases in chlorovirus genomes using a combination of silico and in vitro strategies, and characterized these enzymes at a molecular and biochemical level. Different enzymatic profiles were observed in Chlorovirus subgenera revealing the different viral machinery related to host species. We performed a comprehensive biochemical characterization of three heterologous expressed GH18 domains, which revealed their endo and exochitinase activity and thermostability. Crystallographic analysis of the GH18 domain by X-ray diffraction yielded a structure at 1.0 angstrom resolution, representing the highest-resolution structure reported to date for a giant viral protein and showing lower predominancy of residue coevolution compared GH18 chitinases from other organisms. Additionally, our binding site characterization predicted high conservation in betachloroviruses and gammachloroviruses, and less so in alphachloroviruses. Lastly, these enzymes did not inhibit fungal growth of medical and agricultural importance species in vitro but exhibited high inhibitory activity against different algae at nanogram\/mL range. Together, our experimental and computational data show that evolutionary events may contribute to maintaining viral chitinases enzymatic activity and specificity. These findings highlight the potential of virus-derived enzymes as promising new biotechnological tools for microbial control against different algal strains.","rel_num_authors":13,"rel_authors":[{"author_name":"Ellen Oliveira","author_inst":"Federal University of Minas Gerais"},{"author_name":"Pavla A. L. Fajtova","author_inst":"University of California San Diego"},{"author_name":"Mateus Sa Magalhaes Serafim","author_inst":"Federal University of Minas Gerais"},{"author_name":"Sara Souza","author_inst":"Federal University of Minas Gerais"},{"author_name":"Clecio Filho","author_inst":"Federal University of Minas Gerais"},{"author_name":"Joao Victor Carvalho","author_inst":"Federal University of Minas Gerais"},{"author_name":"Alan Gomes","author_inst":"Federal University of Minas Gerais"},{"author_name":"Daniel Santos","author_inst":"Federal University of Minas Gerais"},{"author_name":"Matheus Motta","author_inst":"Federal University of Minas Gerais"},{"author_name":"Lucas Bleicher","author_inst":"Federal University of Minas Gerais"},{"author_name":"Ronaldo Nagem","author_inst":"Federal University of Minas Gerais"},{"author_name":"Anthony O Donoghue","author_inst":"University of California San Diego"},{"author_name":"Rodrigo Rodrigues","author_inst":"Federal University of Minas Gerais"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"The secreted elastase SjCE2b drives host skin penetration by Schistosoma japonicum","rel_doi":"10.64898\/2026.07.12.738118","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.12.738118","rel_abs":"Cercarial elastase is the most abundant protease secreted by Schistosoma mansoni and plays a critical role in cercarial invasion. Although Schistosoma japonicum encodes only a single elastase, SjCE2b, its secretion by cercariae and its specific function in skin penetration have remained elusive. Here, we report the first proteomic analysis of S. japonicum cercarial excretory-secretory products (ESPs) induced by linoleic acid or mouse skin, confirming the presence of SjCE2b in both ESPs preparations. Recombinant SjCE2b expressed in Pichia pastoris was characterized as a trypsin-like serine protease whose activity is entirely abolished by the elastase inhibitor MeoSuc-AAPF-CMK. Furthermore, SjCE2b expression was detected exclusively in cercarial extracts and localized specifically to the cercarial acetabular glands and ducts. Subsequent proteomic analysis indicates that SjCE2b can degrade numerous human epidermal proteins, including ten isoforms of type I and type II keratins. In vitro digestion assays further demonstrated that SjCE2b can digest key structural components of the dermis, including elastin, collogen, and fibronectin. Additionally, the cleavage of complement component C3 and immunoglobulins (IgA and IgG) suggests that SjCE2b may facilitate immune evasion by newly transformed schistosomula. Critically, the incubation of cercariae with anti-rSjCE2b antibody reduced the worm burden by 80.85%, confirming the essential role of SjCE2b in the skin penetration of S. japonicum cercariae and highlighting it as a compelling candidate for vaccine or therapeutic development.","rel_num_authors":7,"rel_authors":[{"author_name":"Bingkuan Zhu","author_inst":"Fudan University School of Life Sciences"},{"author_name":"Yi Shen","author_inst":"Fudan University School of Life Sciences"},{"author_name":"Fang Luo","author_inst":"Fudan University School of Life Sciences"},{"author_name":"Chuan Su","author_inst":"Nanjing Medical University School of Basic Medical Sciences"},{"author_name":"Hong You","author_inst":"QIMR Berghofer Medical Research Institute"},{"author_name":"Xumin Zhang","author_inst":"Fudan University School of Life Sciences"},{"author_name":"Wei Hu","author_inst":"Fudan University School of Life Sciences"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"Heteroresistance in Enterococcus faecalis is prevalent for key antibiotics and mainly caused by mutations","rel_doi":"10.64898\/2026.07.14.738184","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.14.738184","rel_abs":"Heteroresistance (HR), the coexistence of a rare resistant subpopulation within a predominantly susceptible bacterial population, is a clinically relevant problem. The resistant subpopulation often escapes detection by standard susceptibility testing, which can lead to treatment failure. To investigate HR in Enterococcus faecalis, we performed population analysis profiling (PAP) on 40 clinical isolates against five clinically important antibiotics and whole-genome sequenced (WGS) the resistant subpopulations. HR was identified for daptomycin (20.0%), gentamicin (13.2%), and tigecycline (35.9%), but not for linezolid, and vancomycin. Genomic analysis revealed that daptomycin resistance was primarily caused by mutations affecting cell envelope integrity and stress-response pathways. Gentamicin resistance was linked to alterations in efflux regulation, ribosomal proteins synthesis, and transcriptional control. Tigecycline resistance involved deletions in the tet(M) leader peptide, resulting in a 25-fold increased tet(M) expression, as well as transposition of the transposon Tn916 carrying tet(M) to multiple chromosomal sites, causing an increased gene dosage of tet(M). These findings highlight the role of chromosomal mutations and mobile genetic elements in causing HR in E. faecalis Keywords: Enterococcus faecalis, antibiotic, heteroresistance, population analysis profile, point mutations, tet(M).","rel_num_authors":7,"rel_authors":[{"author_name":"Sheida Heidarian","author_inst":"Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden"},{"author_name":"Sarah Lohsen","author_inst":"Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA."},{"author_name":"Andrei Guliaev","author_inst":"Clinical Genomics Uppsala, Science for Life Laboratory, Uppsala University, Uppsala, Sweden"},{"author_name":"Herve Nicoloff","author_inst":"Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden"},{"author_name":"Sarah W Satola","author_inst":"Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA."},{"author_name":"Dan I Andersson","author_inst":"Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden"},{"author_name":"Karin Hjort","author_inst":"Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"Enhanced BCMA Antigen Density Increases Trogocytosis and Attenuates CAR T cell Function","rel_doi":"10.64898\/2026.07.15.738803","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.738803","rel_abs":"Background: Chimeric Antigen Receptor (CAR) T cell therapy targeting B-cell maturation antigen (BCMA) has demonstrated impressive clinical efficacy in relapsed\/refractory multiple myeloma (MM). Nonetheless, disease relapse limits durable response for most patients. Trogocytosis of target antigen by effector cells has emerged as a potential contributor to reduced surface antigen density, CAR T cell dysfunction, and fratricide. Although gamma-secretase inhibitors (GSI) significantly increase cell surface BCMA density and decrease soluble BCMA (sBCMA), their effects on BCMA trogocytosis and the resulting impact on CAR T-cell function remain incompletely understood. Methods: We investigated the effects of GSI on BCMA-directed CAR T cell function and trogocytosis using in vitro co-culture systems with MM cell lines across a spectrum of BCMA expression. We validated findings using confocal microscopy and cytotoxicity assays. Trogocytosis and fratricide were assessed in time-resolved functional studies. Phenotypic and functional differences between trogocytosis-positive (CAR T Trogo+) and trogocytosis-negative (CAR T) cells were evaluated using multiparametric flow cytometry, proteomic profiling, single-cell RNA sequencing (scRNA-seq), T-cell receptor (TCR) sequencing, and in vitro rechallenge assays. We also interrogated clinical samples from two Phase I trials (NCT03338972 and NCT03502577) which employed the identical CAR T cell construct with or without GSI respectively, to evaluate the relationship between trogocytosis, CAR T cell persistence, and treatment outcome. Results: GSI driven increases in BCMA density on MM cell lines enhanced CAR T cell cytotoxicity but concomitantly increased trogocytosis, particularly in high-antigen-density cell lines (H929+GSI vs H929; 30 min (P<0.0001), 1 h (P<0.0001), 2 h (P<0.0001), 6 h (P<0.0001), and 24 h (P<0.0001) and in CD4+ CAR T cells (K562mCherry+GSI, CD4 vs CD8 CAR T cells;10 min (P=0.01), 2 h (P=0.01), and 6 h (P=0.004). Following BCMA acquisition, CAR T cells (CAR T Trogo+) exhibited reduced proliferative capacity, diminished cytotoxic function (CAR T Trogo+ vs CAR T; (P=0.01), and an increase in markers of exhaustion\/activation (CD4+ CAR T Trogo+ vs CD4 CAR T and CD8+ CAR T Trogo+ vs CAR T; PD-1+LAG-3+, PD-1+TIM-3+, and TOX+TIM-3 co-expression, (P=0.007, P<0.0001, P=0.006 and P=0.004, P=0.03, P=0.006). In fratricide assays, CAR T Trogo+ cells were susceptible to killing by naive CAR T cells. Single cell RNA-seq supports the phenotypic findings revealing transcriptional features of heightened activation and accelerated exhaustion in CAR T Trogo+ cells. Clinical phase I trial data confirm BCMA trogocytosis in patient samples. Conclusions: Our findings highlight the paradoxical effects of increased BCMA density on BCMA CAR T cell therapy: enhancement of initial tumor targeting and promotion of trogocytosis-associated dysfunction. Trogocytosis may contribute to antigen modulation, CAR T cell exhaustion, and fratricide, potentially muting the therapeutic benefits of enhanced antigen density. To optimize GSI and mitigate trogocytosis-associated resistance mechanism, future clinical trial designs should incorporate early time-point sampling, a sample size providing sufficient statistical power to determine an impact on CAR T cell persistence and treatment response, and mechanistic assessments.","rel_num_authors":14,"rel_authors":[{"author_name":"Pinar Ataca Atilla","author_inst":"University of Miami, Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center"},{"author_name":"Sylvain Simon","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Erden Atilla","author_inst":"University of Miami, Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center"},{"author_name":"David  G Coffey","author_inst":"University of Miami Hospitals and Clinics: Sylvester Comprehensive Cancer Center"},{"author_name":"Andrew J Cowan","author_inst":"Division of Medical Oncology, Department of Medicine, University of British Columbia and BC Cancer Agency"},{"author_name":"Grace Bugos","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Thomas J Diefenbach","author_inst":"University of Miami\/Sylvester Comprehensive Cancer Center"},{"author_name":"Janice J Huang","author_inst":"University of Miami"},{"author_name":"Efe Karaca","author_inst":"University of Miami School of Medicine"},{"author_name":"Zhiqun Zhou","author_inst":"University of Miami\/Sylvester Comprehensive Cancer Center"},{"author_name":"Melissa L Comstock","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Geoffrey R Hill","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Stanley R Riddell","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Damian J Green","author_inst":"University of Miami, Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"CRISPR-Associated Transposases Enable Programmable DNA Integration in Plants","rel_doi":"10.64898\/2026.07.15.738807","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.738807","rel_abs":"Programmable DNA integration is a major challenge in plant genome engineering. CRISPR-associated transposases (CAST) catalyze efficient RNA-guided DNA integration without double-strand breaks, yet their activity has not been established in plants. Here, we reconstituted and engineered a Type I-F CAST for programmable DNA integration in plant cells. We validated expression of the wild-type Pseudoalteromonas CAST (PseCAST) machinery in plants and established targeted episomal integration in Arabidopsis thaliana protoplasts and chromosomal integration at a transgenic locus in Nicotiana benthamiana. The evolved PseCAST system, evoCAST, showed chromosomal integration efficiencies of 2.7%, representing a 6-fold improvement over wild-type PseCAST. evoCAST also enabled the insertion of cis-regulatory elements into a synthetic landing pad with 8% efficiency. evoCAST was subsequently retargeted to six endogenous genomic loci, demonstrating programmable integration across diverse chromosomal contexts. Finally, a cofactor screen identified the chromatin-associated factor AtHMGB2 as an enhancer of evoCAST-mediated integration activity in plants. These results establish CAST as a functional platform for programmable DNA insertion in plants and provide a foundation for developing targeted genome-engineering technologies for crop biotechnology.","rel_num_authors":6,"rel_authors":[{"author_name":"Yunqing Wang","author_inst":"California Institute of Technology"},{"author_name":"Kimberley Muchenje","author_inst":"California Institute of Technology"},{"author_name":"Ashot Papikian","author_inst":"California Institute of Technology"},{"author_name":"Mark Legendre","author_inst":"California Institute of Technology"},{"author_name":"Esther Leem","author_inst":"California Institute of Technology"},{"author_name":"Gozde S Demirer","author_inst":"California Institute of Technology"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"Development and Validation of Thalia: A High-ResolutionPediatric Computational Model of a 10-Month-Old Infant","rel_doi":"10.64898\/2026.07.09.737638","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737638","rel_abs":"Numerical human models are essential to advance medical device design, safety assessment, and study how anatomical development influences physiological processes. Despite increasing availability of pediatric models, a critical gap remains in high-resolution, non-morphed whole-body models representing children around one year of age. Existing pediatric models are often derived from morphing older anatomies or lack sufficient tissue segmentation to accurately capture early developmental anatomy. This study introduces Thalia, a non-morphed, high-resolution numerical model of a healthy 10-month-old female. The model was constructed by segmenting 442 tissues from Magnetic Resonance Imaging data. Brain tissues were automatically segmented using an infant-specific FreeSurfer framework, followed by semi-automated and manual refinement in 3DSlicer. The model was validated by expert review and quantitative comparison with age-matched anatomical values reported in the literature. The resulting whole-body model provides detailed anatomical representation across the brain, musculoskeletal system, vasculature, and internal organs, enabling realistic assignment of tissue-specific properties for computational studies. It provides a versatile platform for pediatric medical device development, dosimetry, safety assessment, and bioelectromagnetic simulations. This pediatric numerical anatomical model is openly available as an open-source resource.","rel_num_authors":8,"rel_authors":[{"author_name":"Alice Albrecht","author_inst":"UCSF"},{"author_name":"Georgios Ntolkeras","author_inst":"Boston Children Hospital"},{"author_name":"Lilla Zollei","author_inst":"Harvard Medical School"},{"author_name":"Georgios Sideris","author_inst":"Boston Children Hospital"},{"author_name":"Francesca Marturano","author_inst":"Harvard Medical School"},{"author_name":"Michael H Lev","author_inst":"Mass General Brigham"},{"author_name":"Ellen Grant","author_inst":"Boston Children Hospital"},{"author_name":"Giorgio Bonmassar","author_inst":"Harvard Medical School"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"Site-specific cholesterol depletion therapy for gastric cancer","rel_doi":"10.64898\/2026.07.15.738777","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.738777","rel_abs":"Altered cholesterol metabolism is a recognized hallmark of cancer, but systemic modulation has not yet delivered significant clinical results. Accumulating evidence shows that cholesterol plays distinct roles across diverse cellular membranes, suggesting that site-specific modulation may produce superior therapeutic outcomes. Cholesterol is associated with gastric cancer (GC), but the mechanistic link is complex and no effective cholesterol-targeted therapy has been developed. Here, we report that cholesterol levels in GC cells are site-specifically elevated in the inner leaflet of the plasma membrane (IPM). This elevated IPM cholesterol constitutively activates Wnt-{beta}-catenin signaling to drive cell survival and proliferation. Mechanistically, Niemann-Pick C1-like 1 (NPC1L1), which is highly expressed in GC patient tissues and cell lines, acts as a cholesterol flippase to raise IPM cholesterol levels, facilitating ligand-independent {beta}-catenin signalosome formation. Ezetimibe, a clinically approved NPC1L1 inhibitor, blocks this flippase activity, lowers IPM cholesterol levels, and suppresses {beta}-catenin signaling. Ezetimibe treatment induces apoptosis in GC cells while sparing normal primary gastric epithelial cells, which exhibit low levels of NPC1L1 and IPM cholesterol. Collectively, these results suggest that site-specific modulation of cellular cholesterol is a viable approach to developing safe and effective therapies for cancers linked to local cholesterol elevation.","rel_num_authors":6,"rel_authors":[{"author_name":"Simona Kavrakova","author_inst":"University of Illinois Chicago"},{"author_name":"Ashutosh Sharma","author_inst":"University of Illinois Chicago"},{"author_name":"Elena Ristevska","author_inst":"University of Illinois Chicago"},{"author_name":"Xingyu Guo","author_inst":"University of Illinois Chicago"},{"author_name":"Julian Zalejski","author_inst":"University of Illinois Chicago"},{"author_name":"Wonhwa Cho","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"A dominant coral parasite, Candidatus Aquirickettsia rohweri, resists antibiotic exposure and thermal challenge below the bleaching threshold in disease-susceptible Acropora cervicornis","rel_doi":"10.64898\/2026.07.15.738557","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.738557","rel_abs":"The critically endangered Caribbean staghorn coral Acropora cervicornis hosts microbiomes frequently dominated by the putatively parasitic intracellular bacterium Candidatus Aquirickettsia rohweri, which is associated with reduced coral growth and heightened disease susceptibility. Whether this dominance can be disrupted through antibiotic treatment and a sequential disturbance of thermal stress, remains unknown. In this study, we exposed disease-susceptible A. cervicornis fragments to broad-spectrum antibiotics, sub-bleaching thermal stress, or the combination of an antibiotic pre-treatment followed by thermal stress, and tracked changes in microbiome composition and diversity across all experimental phases using 16S rRNA amplicon sequencing and quantitative PCR (qPCR). We find that while the minor microbial fraction exhibits sustained compositional shifts in response to treatment, Ca. Aquirickettsia rohweri is resilient to antibiotic and thermal perturbation and may in fact increase in abundance following antibiotic exposure, suggesting that its dominance is actively maintained and not readily displaced by current disease mitigation strategies.These results indicate that antibiotic intervention is unlikely to be a viable strategy for disrupting Ca. A. rohweri dominance in disease-susceptible A. cervicornis, underscoring the urgency of understanding its transmission routes to inform microbiome rescue efforts.","rel_num_authors":6,"rel_authors":[{"author_name":"Sunni Patton","author_inst":"University of California, Santa Barbara"},{"author_name":"Eddie Fuques","author_inst":"University of California, Santa Barbara"},{"author_name":"Lauren Speare","author_inst":"Georgia Institute of Technology"},{"author_name":"J. Grace Klinges","author_inst":"Island Conservation"},{"author_name":"Erinn M Muller","author_inst":"Mote Marine Laboratory"},{"author_name":"Rebecca L Vega Thurber","author_inst":"University of California, Santa Barbara"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"Systematic identification of cell division proteins in haloarchaea and the discovery of a membrane anchor for the Z ring","rel_doi":"10.64898\/2026.07.16.738847","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.16.738847","rel_abs":"Most archaea rely on the tubulin-like protein FtsZ for division. In the last decade, several novel cell division proteins have been discovered in the model haloarchaeon Haloferax volcanii which contains two FtsZ proteins, FtsZ1 and FtsZ2. However, the composition of this FtsZ-based archaeal divisome is largely uncharacterized. Here, using in vivo crosslinking coupled with immunoprecipitation and mass spectrometry (CLIP-MS), we identified ten proteins that localize to the division site, including wide-spread proteins predicted to be involved in DNA binding and energy metabolism. Deletion analysis indicate that most of these proteins have a modest or minor impact on cell division, but HVO_0399, renamed as Cell Division Protein C (CdpC), is important for cell division and functions as a membrane anchor for FtsZ1. CdpC consists of three domains, an N-terminal domain (NTD) containing an amphipathic helix critical for membrane binding, a long intrinsically disordered linker, and a C-terminal domain (CTD) that binds FtsZ1 with high affinity and likely promotes its polymerization. Notably, both the NTD and CTD of CdpC harbor a zinc finger that is indispensable for its function. Phylogenetic analysis indicates that CdpC sequences evolved fast across haloarchaea, but exhibited high conservation in domain structure and critical residues found in this study. Overall, our study expands the repertoire of candidate division proteins and establishes CdpC as a membrane anchor for FtsZ1 in haloarchaea. These findings pave the way for in-depth studies of arcaheal cell division and broaden the function of zinc finger proteins in archaea.","rel_num_authors":12,"rel_authors":[{"author_name":"Shishen Du","author_inst":"Wuhan University"},{"author_name":"Wenchao Zheng","author_inst":"Wuhan University"},{"author_name":"Shan Zhao","author_inst":"Wuhan University"},{"author_name":"Yafei Liu","author_inst":"Wuhan University"},{"author_name":"Jiayao Cui","author_inst":"Eastern Institute of Technology"},{"author_name":"Jiarong Wu","author_inst":"Wuhan University"},{"author_name":"Xiaoyao Zou","author_inst":"Wuhan University"},{"author_name":"Ying Li","author_inst":"Wuhan Univeristy"},{"author_name":"Han Gong","author_inst":"Wuhan University"},{"author_name":"Xiangdong Chen","author_inst":"College of Life Sciences, Wuhan University"},{"author_name":"Joseph Lutkenhaus","author_inst":"University of Kansas Medical Center"},{"author_name":"Fabai Wu","author_inst":"Eastern Institute of Technology"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"A single glycosaminoglycan-linked residual-straincoefficient explains regional opening angle changes afterdepletion in the porcine thoracic aorta","rel_doi":"10.64898\/2026.07.15.738269","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.738269","rel_abs":"Residual stresses in arteries are commonly revealed by the opening of a ring after a radial cut. Glycosaminoglycans (GAGs) contribute to this response, but fixed-chargedensity (FCD)-driven Donnan swelling alone does not fully explain the opening-angle reduction measured after enzymatic GAG depletion. We therefore tested whether the transmural FCD profile defines a removable preferred-stretch field superposed on a structural field retained after GAG depletion. A reduced analytical-computational axisymmetric closure framework was applied to regional-average measurements from the ascending aorta, arch, and descending porcine thoracic aorta. Each control state was fitted using its measured circumferential opening angle, geometry, material properties, and through-wall FCD profile. GAG depletion was represented by removing the FCD-linked preferred-stretch component. One coefficient governing this removable component was selected jointly from the three measured regional post-depletion angles. A one-layer wall was the primary parsimonious model; a two-layer wall tested anatomical robustness. The one-layer model fitted a shared coefficient of -1.4226 x 10-3 (mEq\/L)-1 and predicted depleted angles of 82.639{degrees}, 44.032{degrees}, and 19.979{degrees}, compared with measured values of 85{degrees}, 41{degrees}, and 18{degrees} (three-region RMSE 2.50{degrees}). The two-layer model fitted -1.51746 x 10-3 (mEq\/L)-1 and predicted 82.972{degrees}, 44.273{degrees}, and 18.534{degrees} (RMSE 2.24{degrees}). Thus, layer differentiation improved aggregate fit only modestly. These findings support a parsimonious mechanism in which GAG depletion removes an FCD-shaped circumferential preferred-stretch component while most residual-stress architecture remains in a structural field retained after depletion. Donnan swelling remains mechanically relevant, but it is insufficient alone to explain the measured regional response.","rel_num_authors":4,"rel_authors":[{"author_name":"Michel R. Labrosse","author_inst":"University of Ottawa"},{"author_name":"Noor Ghadie","author_inst":"University of Ottawa Heart Institute"},{"author_name":"Jean-Philippe St-Pierre","author_inst":"University of Ottawa"},{"author_name":"Munir Boodhwani","author_inst":"University of Ottawa Heart Institute"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"A single glycosaminoglycan-linked residual-straincoefficient explains regional opening angle changes afterdepletion in the porcine thoracic aorta","rel_doi":"10.64898\/2026.07.15.738269","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.738269","rel_abs":"Residual stresses in arteries are commonly revealed by the opening of a ring after a radial cut. Glycosaminoglycans (GAGs) contribute to this response, but fixed-chargedensity (FCD)-driven Donnan swelling alone does not fully explain the opening-angle reduction measured after enzymatic GAG depletion. We therefore tested whether the transmural FCD profile defines a removable preferred-stretch field superposed on a structural field retained after GAG depletion. A reduced analytical-computational axisymmetric closure framework was applied to regional-average measurements from the ascending aorta, arch, and descending porcine thoracic aorta. Each control state was fitted using its measured circumferential opening angle, geometry, material properties, and through-wall FCD profile. GAG depletion was represented by removing the FCD-linked preferred-stretch component. One coefficient governing this removable component was selected jointly from the three measured regional post-depletion angles. A one-layer wall was the primary parsimonious model; a two-layer wall tested anatomical robustness. The one-layer model fitted a shared coefficient of -1.4226 x 10-3 (mEq\/L)-1 and predicted depleted angles of 82.639{degrees}, 44.032{degrees}, and 19.979{degrees}, compared with measured values of 85{degrees}, 41{degrees}, and 18{degrees} (three-region RMSE 2.50{degrees}). The two-layer model fitted -1.51746 x 10-3 (mEq\/L)-1 and predicted 82.972{degrees}, 44.273{degrees}, and 18.534{degrees} (RMSE 2.24{degrees}). Thus, layer differentiation improved aggregate fit only modestly. These findings support a parsimonious mechanism in which GAG depletion removes an FCD-shaped circumferential preferred-stretch component while most residual-stress architecture remains in a structural field retained after depletion. Donnan swelling remains mechanically relevant, but it is insufficient alone to explain the measured regional response.","rel_num_authors":4,"rel_authors":[{"author_name":"Michel R. Labrosse","author_inst":"University of Ottawa"},{"author_name":"Noor Ghadie","author_inst":"University of Ottawa Heart Institute"},{"author_name":"Jean-Philippe St-Pierre","author_inst":"University of Ottawa"},{"author_name":"Munir Boodhwani","author_inst":"University of Ottawa Heart Institute"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"Neuroanatomical Subtypes of Callous-Unemotional Traits in a Community Sample of Youth","rel_doi":"10.64898\/2026.07.14.738524","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.14.738524","rel_abs":"Importance. Callous Unemotional (CU) traits are associated with significant clinical and neurophysiological heterogeneity that may affect treatment effectiveness. Objective. To uncover neuroanatomical subtypes of CU traits using weakly-supervised machine learning and assess whether emerging subtypes differ on relevant clinical, temperamental, and environmental constructs. Design, Setting, and Participants. Imaging data was from the longitudinal Adolescent, Brain, Cognitive Development (ABCD) Study. Participants were 9-10 years old at baseline (M=9.925, 69.9% male) and included 222 children with CU traits and 234 typically developing controls matched on age, sex and income. Main Outcomes and Measures. The weakly-supervised heterogeneity through discriminative analysis (HYDRA) model was trained on grey matter (GM) volumes from 84 regions of interest (ROIs) and tested for reproducibility using cross-validation and permutation testing. Derived subtypes were compared cross-sectionally and prospectively on relevant clinical, temperamental, and environmental measures and subsequent GM volume at 2-year follow up. Results. HYDRA revealed an optimal 2-subtype solution within children with CU traits. Subtypes showed comparable levels of aggression that were significantly higher than typically developing controls. At the same time, subtype 1 had larger GM volume, fewer internalizing symptoms, and less adversity exposure, while subtype 2 was characterized by smaller GM volume, more internalizing symptoms, and more adversity exposure. Conclusions and Relevance. This study provides evidence of neuroanatomically distinct subtypes of CU traits characterized by different clinical and etiological profiles, with implications for diagnosis and treatment.","rel_num_authors":10,"rel_authors":[{"author_name":"Kristin Murtha","author_inst":"University of Pennsylvania"},{"author_name":"Mathilde Antoniades","author_inst":"University of Pennsylvania"},{"author_name":"Jakob Seidlitz","author_inst":"University of Pennsylvania"},{"author_name":"Ran Barzilay","author_inst":"Children's Hospital of Pennsylvania"},{"author_name":"Tyler M. Moore","author_inst":"University of Pennsylvania"},{"author_name":"Russell Shinohara","author_inst":"University of Pennsylvania"},{"author_name":"Theodore D. Satterthwaite","author_inst":"University of Pennsylvania"},{"author_name":"Eva Kimonis","author_inst":"University of New South Whales"},{"author_name":"Christos Davatzikos","author_inst":"University of Pennsylvania"},{"author_name":"Rebecca Waller","author_inst":"University of Pennsylvania"}],"rel_date":"2026-07-16","rel_site":"biorxiv"},{"rel_title":"Early Feasibility of NIVA Score Decongestion Responsiveness: A Pilot Clinical and Preclinical Study","rel_doi":"10.64898\/2026.07.13.26357910","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26357910","rel_abs":"Residual congestion is the principal driver of heart failure readmission, and reliable serial assessment of volume status remains an unmet clinical need. This study asked whether a wrist-worn, machine-learning-based device for non-invasive venous waveform analysis in heart failure (the NIVAHF device), which produces an integer-scaled estimate of pulmonary capillary wedge pressure termed the NIVA Score, responds to acute changes in volume status. Agreement between the NIVA Score and invasively measured pulmonary capillary wedge pressure at single time points has been established in a separate prospective, multi-site study; however, such static agreement does not establish whether the measure tracks dynamic decongestion. We therefore evaluated the directional responsiveness of the locked NIVA Score in two prespecified cohorts: hospitalized adults with acute decompensated heart failure undergoing routine intravenous diuresis, and a controlled porcine model of volume overload followed by diuresis. In eleven patients contributing thirteen paired measurements (mean net fluid balance -2.1 {+\/-} 1.0 L), NIVA Scores decreased significantly after diuresis (paired t-test, P = 0.04). In five pigs contributing twenty-four paired measurements, NIVA Scores decreased significantly after intravenous furosemide following crystalloid loading (P < 0.01), and the direction of change was concordant with measured urine output in every animal. Statistical significance was reached in both cohorts despite modest sample sizes, indicating a measurable NIVA Score reduction with volume removal. In an exploratory analysis, the discharge NIVA Score yielded an area under the receiver-operating-characteristic curve of 0.85 (95% confidence interval 0.575-1.00; P = 0.04) for thirty-day readmission. Together, the significant, directionally concordant NIVA Score reductions across independent clinical and preclinical cohorts demonstrate that the device tracks acute decongestion and support its use for serial, non-invasive congestion monitoring; an adequately powered prospective study is the planned next step.","rel_num_authors":21,"rel_authors":[{"author_name":"Bret D. Alvis","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jeffrey Schmeckpeper","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Aniket  S Rali","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jessica Huston","author_inst":"University of Pittsburgh Medical Center"},{"author_name":"Stacy Tsai","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Kaushik Amancherla","author_inst":"Vanderbilt University Medical Center"},{"author_name":"David Armstrong","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Richa Gupta","author_inst":"MedStar Health"},{"author_name":"Jonathan  S. Whitfield","author_inst":"VoluMetrix, Inc."},{"author_name":"Rene Harder","author_inst":"VoluMetrix, Inc."},{"author_name":"Katharine Miller","author_inst":"VoluMetrix, Inc."},{"author_name":"Mackenzie Horne","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Dawson Wervey","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Romy Pein","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Tara Isanaka","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Marisa Case","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Eric Wise","author_inst":"University of Minnesota Medical Center Fairview: M Health Fairview University of Minnesota Medical Center East Bank"},{"author_name":"Bryce Perrien","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Colleen Brophy","author_inst":"Vanderbilt University Medical Center"},{"author_name":"JoAnn Lindenfeld","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Kyle Hocking","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"West Nile virus in Italy: history and evolving transmission patterns","rel_doi":"10.64898\/2026.07.12.26357540","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.12.26357540","rel_abs":"West Nile virus (WNV) has become an important public health concern in Europe. Italy is one of the most affected countries, yet our understanding of WNV epidemiology, genomics, and dispersal across hosts and geographic regions is incomplete. AIM: To reveal the history of WNV in Italy by integrating epidemiological, genomic, and environmental data into descriptive and quantitative assessments of its past spatio-temporal surveillance and expansion. We collated vertebrate and mosquito WNV records from national surveillance and the scientific literature spanning multiple decades. Historical serological and molecular data were summarized by host and region, climatic associations with case trends were assessed using regression models, and phylodynamic and phylogeographic analyses reconstructed viral introductions and dispersal within Italy.WNV circulation in Italy has changed markedly over time, with increasing human case reporting and expansion beyond historically affected northern regions. Climate-informed regression models explained recent reporting trends, supporting an environmental contribution to transmission. Phylodynamic analyses identified multiple independent introductions and sustained local transmission with increasing regional connectivity. Wavefront analyses revealed lineage-specific dispersal patterns associated with seasonal climatic gradients. Discrepancies between epidemiological records and genomic sampling highlighted uneven surveillance across regions and host species.WNV emergence in Italy reflects repeated viral introductions, local persistence, heterogeneous surveillance, and environmentally associated dispersal dynamics. Strengthening integrated surveillance combining epidemiological, environmental, and genomic data will improve early detection, the monitoring of transmission dynamics, and public health preparedness under ongoing environmental change.","rel_num_authors":25,"rel_authors":[{"author_name":"Marta Giovanetti","author_inst":"Fundacao Oswaldo Cruz"},{"author_name":"Eleonora Cella","author_inst":"University of Central Florida"},{"author_name":"Vagner Fonseca","author_inst":"Departamento de Ciencias Exatas e da Terra, Campis I, Universidade do Estado da Bahia (UNEB), Salvador, Brasil; Centre for Epidemic Response and Innovation (CER"},{"author_name":"Monika Moir","author_inst":"Stellenbosch University"},{"author_name":"Bas Oude Munnink","author_inst":"ErasmusMC"},{"author_name":"Claudio de Martinis","author_inst":"Department of Animal Health, Istituto Zooprofilattico Sperimentale del Mezzogiorno, Via Salute, 2, Portici, Naples, 80055, Italy"},{"author_name":"Ana Moreno","author_inst":"Istituto Zooprofilattico Sperimentale della Lombardia e dell Emilia-Romagna Bruno Ubertini"},{"author_name":"Alberto Rizzo","author_inst":"Laboratory of Clinical Microbiology, Virology and Bioemergencies, Luigi Sacco Hospital, Regional Center for Infectious Diseases (CEREMI), Lombardy Region, Milan"},{"author_name":"Davide Mileto","author_inst":"Laboratory of Clinical Microbiology, Virology and Bioemergencies, Luigi Sacco Hospital, Regional Center for Infectious Diseases (CEREMI), Lombardy Region, Milan"},{"author_name":"Francesca Caccuri","author_inst":"University of Brescia: Universita degli Studi di Brescia"},{"author_name":"Arnaldo Caruso","author_inst":"Universita degli Studi di Brescia"},{"author_name":"Enzo Tramontano Prof.","author_inst":"University of Cagliari"},{"author_name":"Svetoslav Nanev Slavov","author_inst":"Butantan Institute, Sao Paulo, Brazil"},{"author_name":"Ana Maria Bispo de Filippis","author_inst":"Laboratorio de Arbovirus e Virus Hemorragicos, Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil."},{"author_name":"Tulio de Oliveira","author_inst":"University of KwaZulu-Natal"},{"author_name":"Luiz  C. J. Alcantara","author_inst":"FIOCRUZ"},{"author_name":"Alessandro Marcello","author_inst":"International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy"},{"author_name":"Vittorio Colizzi","author_inst":"Faculty of Medicine, University Hospital Complex Le Bon Samaritain, NDjamena, Chad"},{"author_name":"Giovanni Rezza","author_inst":"Faculty of Medicine, Vita-Salute San Raffaele University, Milan, Italy"},{"author_name":"Massimo Ciccozzi","author_inst":"University Campus Bio-Medico of Rome"},{"author_name":"Concetta Castilletti","author_inst":"IRCCS Sacro Cuore Don Calabria Hospital, Negrar, Italy"},{"author_name":"Edward C Holmes","author_inst":"University of Sydney"},{"author_name":"Fabrizio Maggi","author_inst":"Laboratory ofVirology and Laboratories of Biosafety, National Institute for infectious Diseases Lazzaro Spallanzani, IRCCS, Rome, Italy"},{"author_name":"Luisa Barzon","author_inst":"Department of Molecular Medicine, University of Padova, Padova, Italy"},{"author_name":"Jose Lourenco","author_inst":"Universidade Catolica Portuguesa"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"Data-driven calibration of low-cost wearable motion trackers for gait and dynamic stability measurement","rel_doi":"10.64898\/2026.07.13.26357919","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26357919","rel_abs":"Low cost inside out wearable trackers can be deployed at scale to measure body motion, but errors in estimated sensor position propagate through coordinate transformations into derived gait and dynamic-stability metrics. Healthy adults walked on a treadmill at 0.5 to 2.0 m\/s while VIVE Ultimate Tracker (VUT) and Vicon data were recorded. Data-driven calibration models were developed to correct tracker coordinates and to estimate full body centre of mass (CoM) from a sacrum-only configuration. Agreement with Vicon was assessed using RMSE, mixed-effects Bland-Altman limits of agreement, MAE, and intraclass correlation coefficients. Calibration improved coordinate-level agreement. For gait parameters, model-corrected VUT showed small errors against Vicon (MAE: 0.24 to 0.71 mm step height, 1.73 to 4.63 mm step length, 0.15 to 0.95 mm step width, 0.26 to 0.88 mm foot clearance). Proxy CoM-derived margin of stability (MoS) agreed excellently with Vicon. For the sacrum-only pipeline, calibration reduced CoM RMSE from 103.65 to 104.04 mm to 7.55 to 8.95 mm, and markedly reduced systematic error in stability outcomes, with extrapolated CoM bias decreasing from 172.92 to 0.29 mm and MoS bias from -75.09 to -3.54 mm. Data-driven calibration improved the measurement utility of low-cost VUTs, enabling inexpensive, relatively simple gait and stability measurement from a sacrum-only setup in controlled settings.","rel_num_authors":6,"rel_authors":[{"author_name":"Yixuan He","author_inst":"Neuroscience Research Australia"},{"author_name":"Yuxin Dong","author_inst":"University of New South Wales"},{"author_name":"Matthew Andrew Brodie","author_inst":"University of New South Wales"},{"author_name":"Juno Kim","author_inst":"University of New South Wales"},{"author_name":"Stephen R. Lord","author_inst":"Neuroscience Research Australia"},{"author_name":"Yoshiro Okubo","author_inst":"Neuroscience Research Australia"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"A Multimodal Benchmark for Evaluating Cause-of-Death Inference Using Child Health and Mortality Data","rel_doi":"10.64898\/2026.07.13.26357980","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26357980","rel_abs":"Accurately attributing causes of death is vital for global health, yet fewer than 5% of deaths in resource-constrained regions are medically certified. To assign causes to these unlabeled deaths at scale, practitioners traditionally rely on verbal autopsy, using supervised statistical models to classify based on structured survey data. However, modern mortality surveillance increasingly collects rich, unstructured multimodal data, such as free-text caregiver narratives and postmortem diagnostics, which traditional supervised statistical models struggle to seamlessly integrate. In this paper, we present a comprehensive, multimodal benchmark for cause-of-death classification using data from the Child Health and Mortality Prevention Surveillance (CHAMPS) network, a unique surveillance platform spanning nine countries across South Asia and Sub-Saharan Africa. Using this dataset, we introduce an evaluation framework designed to rigorously assess diagnostic reasoning, moving beyond traditional metrics that fail to capture complex clinical realities. We demonstrate the utility of this benchmark by evaluating zero-shot large language models against supervised baselines across various data modalities. Our results reveal distinct differences in how these modeling approaches synthesize unstructured medical evidence. This benchmark provide a rigorously defined resource for assessing clinical reasoning in next-generation mortality surveillance.","rel_num_authors":21,"rel_authors":[{"author_name":"Junhe Yang","author_inst":"University of Washington"},{"author_name":"Soumyakanti Pan","author_inst":"University of Washington"},{"author_name":"Hyun Seung Lim","author_inst":"Northeastern University"},{"author_name":"Yue Chu","author_inst":"Ohio State University"},{"author_name":"Yuting Guo","author_inst":"Emory University School of Medicine"},{"author_name":"Nishtha Agarwal","author_inst":"University of Washington"},{"author_name":"Varun Babbar","author_inst":"Duke University"},{"author_name":"Gaurav Rajesh Parikh","author_inst":"Duke University"},{"author_name":"Yiqun T. Chen","author_inst":"Johns Hopkins University"},{"author_name":"Chris  A Rees","author_inst":"Emory University School of Medicine"},{"author_name":"Ziyaad Dangor","author_inst":"University of the Witwatersrand"},{"author_name":"Sanjay G. Lala","author_inst":"University of the Witwatersrand"},{"author_name":"Zehang Richard Li","author_inst":"University of California, Santa Cruz"},{"author_name":"Samuel J. Clark","author_inst":"Ohio State University"},{"author_name":"Zhenke Wu","author_inst":"University of Michigan"},{"author_name":"Abhirup Datta","author_inst":"Johns Hopkins University"},{"author_name":"Li Liu","author_inst":"Johns Hopkins University"},{"author_name":"Cynthia Rudin","author_inst":"Duke University"},{"author_name":"Samuel V. Scarpino","author_inst":"Northeastern University"},{"author_name":"Benjamin M. Gyori","author_inst":"Northeastern University"},{"author_name":"Tyler H. McCormick","author_inst":"University of Washington"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"A Multimodal Benchmark for Evaluating Cause-of-Death Inference Using Child Health and Mortality Data","rel_doi":"10.64898\/2026.07.13.26357980","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26357980","rel_abs":"Accurately attributing causes of death is vital for global health, yet fewer than 5% of deaths in resource-constrained regions are medically certified. To assign causes to these unlabeled deaths at scale, practitioners traditionally rely on verbal autopsy, using supervised statistical models to classify based on structured survey data. However, modern mortality surveillance increasingly collects rich, unstructured multimodal data, such as free-text caregiver narratives and postmortem diagnostics, which traditional supervised statistical models struggle to seamlessly integrate. In this paper, we present a comprehensive, multimodal benchmark for cause-of-death classification using data from the Child Health and Mortality Prevention Surveillance (CHAMPS) network, a unique surveillance platform spanning nine countries across South Asia and Sub-Saharan Africa. Using this dataset, we introduce an evaluation framework designed to rigorously assess diagnostic reasoning, moving beyond traditional metrics that fail to capture complex clinical realities. We demonstrate the utility of this benchmark by evaluating zero-shot large language models against supervised baselines across various data modalities. Our results reveal distinct differences in how these modeling approaches synthesize unstructured medical evidence. This benchmark provide a rigorously defined resource for assessing clinical reasoning in next-generation mortality surveillance.","rel_num_authors":21,"rel_authors":[{"author_name":"Junhe Yang","author_inst":"University of Washington"},{"author_name":"Soumyakanti Pan","author_inst":"University of Washington"},{"author_name":"Hyun Seung Lim","author_inst":"Northeastern University"},{"author_name":"Yue Chu","author_inst":"Ohio State University"},{"author_name":"Yuting Guo","author_inst":"Emory University School of Medicine"},{"author_name":"Nishtha Agarwal","author_inst":"University of Washington"},{"author_name":"Varun Babbar","author_inst":"Duke University"},{"author_name":"Gaurav Rajesh Parikh","author_inst":"Duke University"},{"author_name":"Yiqun T. Chen","author_inst":"Johns Hopkins University"},{"author_name":"Chris  A Rees","author_inst":"Emory University School of Medicine"},{"author_name":"Ziyaad Dangor","author_inst":"University of the Witwatersrand"},{"author_name":"Sanjay G. Lala","author_inst":"University of the Witwatersrand"},{"author_name":"Zehang Richard Li","author_inst":"University of California, Santa Cruz"},{"author_name":"Samuel J. Clark","author_inst":"Ohio State University"},{"author_name":"Zhenke Wu","author_inst":"University of Michigan"},{"author_name":"Abhirup Datta","author_inst":"Johns Hopkins University"},{"author_name":"Li Liu","author_inst":"Johns Hopkins University"},{"author_name":"Cynthia Rudin","author_inst":"Duke University"},{"author_name":"Samuel V. Scarpino","author_inst":"Northeastern University"},{"author_name":"Benjamin M. Gyori","author_inst":"Northeastern University"},{"author_name":"Tyler H. McCormick","author_inst":"University of Washington"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"The topology of adolescent mental health","rel_doi":"10.64898\/2026.07.13.26357465","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26357465","rel_abs":"The increased vulnerability to mental health problems in adolescence is frequently reported but poorly understood, hampered by a rigid diagnostic system which fails to capture intertwining symptoms and only loosely aligns with biological axes of variability. Here, we reconceptualised the mental health symptoms of young adolescents in the ABCD cohort (N=11862) as a latent topology of overlapping symptom dimensions, using an unsupervised machine learning algorithm to establish how transdiagnostic dimensions co-occur and overlap within individuals. Combining this with a novel classification approach, we delineated zones within this landscape, within which specific profiles of symptoms were robustly represented. These data-driven profiles were leveraged to establish associated resting-state functional connectivity and genetic characteristics. In doing so we recaptured the commonly reported p-factor axis as well as further symptom-subtype dimensions. Gene ontology analysis revealed that shared neurobiological and cellular mechanisms embedded in both the genome and transcriptome may confer risk for psychopathology.","rel_num_authors":11,"rel_authors":[{"author_name":"Maria Barbara Jelen","author_inst":"University of Cambridge"},{"author_name":"Alexa Mousley","author_inst":"University of Cambridge"},{"author_name":"Kayson Fakhar","author_inst":"University of Cambridge"},{"author_name":"Estherina Trachtenberg","author_inst":"University of Cambridge"},{"author_name":"Yuankai He","author_inst":"University of Cambridge"},{"author_name":"Robert Kohler","author_inst":"Yale University"},{"author_name":"Shambhavi Aggarwal","author_inst":"McGill University"},{"author_name":"Varun Warrier","author_inst":"University of Cambridge"},{"author_name":"Danilo Bzdok","author_inst":"McGill University"},{"author_name":"Sarah W. Yip","author_inst":"Yale University"},{"author_name":"Duncan E. Astle","author_inst":"University of Cambridge"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"Serious Illness Conversations in Older Patients at High Risk of Mortality in Primary Care During the COVID-19 Pandemic: A Quasi-Experimental Study","rel_doi":"10.64898\/2026.07.12.26357462","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.12.26357462","rel_abs":"Purpose: Serious Illness Conversations (SICs) are essential to delivering person-centered care for older adults with chronic conditions, but are rarely integrated into routine primary care. To address this gap, we compared the effectiveness of a structured training strategy versus passive dissemination of educational materials on SIC documentation rates during the COVID-19 pandemic. Methods: A quasi-experimental study across 13 primary care clinics in Quebec, Canada. Five clinics received structured team-based Serious Illness Care Program training (intervention group) with a provincially disseminated SIC toolkit and eight received the toolkit only (control group). The primary outcome was the proportion of patients with a documented SIC across three time periods (Period 1, pre pandemic; Period 2, pandemic initial wave; and Period 3, post dissemination of SIC toolkit). We used generalized estimating equations (GEE). Results: Across 13 clinics, 2,368 eligible patients (mean age 75.8 years (SD = 7.5), 54% female, with a mean Charlson Comorbidity Index of 4.88 (SD = 2)) accounted for 19,134 clinical visits, 49.5% in person and 49.6% virtually. SIC documentation rates were 3.3% (control) and 3.4% (intervention) in Period 1, 9.3% and 4.3% in Period 2, and 6.4% and 4.8% in Period 3, respectively. There was no statistically significant improvement to SIC documentation in the intervention group at Period 2 nor Period 3. Conclusion: Structured training was not more effective than passive dissemination for SIC documentation. Educational interventions must be supported by structural changes, workflow integration, and organizational leadership. Multi-level implementation strategies are needed to embed SICs sustainably into primary care.","rel_num_authors":11,"rel_authors":[{"author_name":"Gabrielle Chicoine","author_inst":"Knowledge Translation Program, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada"},{"author_name":"Nathalie Germain","author_inst":"Centre de recherche du CISSS de Chaudi\u00e8re-Appalaches, L\u00e9vis, QC, Canada"},{"author_name":"St\u00e9phane Turcotte","author_inst":"Centre de recherche du CISSS de Chaudi\u00e8re-Appalaches, L\u00e9vis, QC, Canada"},{"author_name":"\u00c9milie C\u00f4t\u00e9","author_inst":"Centre de recherche du CISSS de Chaudi\u00e8re-Appalaches, L\u00e9vis, QC, Canada"},{"author_name":"V\u00e9ronique G\u00e9linas","author_inst":"Centre de recherche du CISSS de Chaudi\u00e8re-Appalaches, L\u00e9vis, QC, Canada"},{"author_name":"France L\u00e9gar\u00e9","author_inst":"VITAM - Centre de recherche en sant\u00e9 durable; CIUSSS de la Capitale-Nationale, Quebec City, QC, Canada; Department of Family and Emergency Medicine, Universit\u00e9 "},{"author_name":"Jean-S\u00e9bastien Paquette","author_inst":"CSSS du Nord de Lanaudi\u00e8re, Saint-Charles-Borrom\u00e9e, QC, Canada; Department of Family and Emergency Medicine, Universit\u00e9 Laval, Quebec City, QC, Canada; VITAM - "},{"author_name":"Annette M Totten","author_inst":"Department of Medical Informatics and Clinical Epidemiology, School of Medicine, Oregon Health and Science University, Portland, OR, USA"},{"author_name":"Mich\u00e8le Morin","author_inst":"Centre de recherche du CISSS de Chaudi\u00e8re-Appalaches, L\u00e9vis, QC, Canada"},{"author_name":"Sharon E Straus","author_inst":"Knowledge Translation Program, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada"},{"author_name":"Patrick M Archambault","author_inst":"Centre de recherche du CISSS de Chaudi\u00e8re-Appalaches, L\u00e9vis, QC, Canada; Department of Family and Emergency Medicine, Universit\u00e9 Laval, VITAM - Centre de recher"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"Description of the Intervention for Virological Suppression in Youth with HIV (iVY): A telehealth behavioral intervention focused on mental health, substance use, and HIV care engagement among youth living with HIV","rel_doi":"10.64898\/2026.07.13.26357907","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26357907","rel_abs":"Objective: Youth with HIV experience persistent disparities across the HIV care continuum, including low rates of engagement in care and viral suppression. In a recent national survey, youth and young adults, defined by the CDC as ages 13-34, accounted for approximately 20-40% of new HIV diagnoses in the United States. We describe the Intervention for Virological Suppression in Youth with HIV (iVY), a youth-friendly, tailored approach that integrates mental health and substance use support with HIV treatment engagement. Design: This paper describes the development of the intervention used in iVY, which is currently being evaluated in a randomized clinical trial (RCT) using an adaptive treatment strategy. HIV virological suppression is measured via dried blood spot at 16 weeks. Setting: The intervention is delivered fully remotely across California and Florida. Participants: YWH aged 18-29 who are not durably virally suppressed are enrolled and randomized to the intervention or usual care. The RCT will enroll and randomize 200 participants to the intervention (n = 100) versus usual care (n = 100). Intervention Description: iVY includes: (1) tailored brief, weekly video-counseling sessions focused on HIV treatment adherence and engagement, mental health, substance use, and related barriers; and (2) a mobile health application designed to support adherence, resource access, and peer connection. Participants who are not virally suppressed receive an additional 16 weeks of intensified intervention, while responders continue with app-based support. Conclusion: This paper provides a detailed description of a telehealth-based behavioral intervention tailored to the needs of youth with HIV. The intervention offers a scalable model for integrating behavioral health and HIV care to address barriers to treatment engagement in this priority population.","rel_num_authors":6,"rel_authors":[{"author_name":"Celeste Balaban","author_inst":"University of California San Francisco"},{"author_name":"Caravella McCuistian","author_inst":"UCSF: University of California San Francisco"},{"author_name":"Hiromi Ortega Roque","author_inst":"UCSF: University of California San Francisco"},{"author_name":"Valerie  A. Gruber","author_inst":"UCSF: University of California San Francisco"},{"author_name":"Mallory  O. Johnson","author_inst":"UCSF: University of California San Francisco"},{"author_name":"Parya Saberi","author_inst":"UCSF: University of California San Francisco"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"Multi-tissue analyses of allele-specific chromatin accessibility nominate likely functional variants for type 2 diabetes","rel_doi":"10.64898\/2026.07.14.26358094","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.14.26358094","rel_abs":"Genome-wide association studies (GWAS) have identified >1,200 signals associated with type 2 diabetes (T2D), yet identifying functional variants remains challenging because the majority of them lie in noncoding regions of the genome and are in areas of high linkage disequilibrium (LD). While chromatin accessibility QTL (caQTL) and expression QTL (eQTL) analyses are useful for nominating regulatory mechanisms underlying GWAS signals, limitations still exist in pinpointing functional variants within regions of high LD. A complementary approach that has been less frequently applied is to focus on the allele-specific effect on chromatin accessibility at heterozygous single-nucleotide polymorphisms (SNPs), hereafter referred to as allelic imbalance. We analyzed the allelic imbalance of reads generated from an assay for transposase-accessible chromatin with sequencing (ATAC-seq) across genotyped samples from 490 donors in T2D-relevant tissues: skeletal muscle, liver, pancreatic islets, adipose tissue, and relevant cell types. We identified 119,949 allelically imbalanced SNPs (FDR<0.05) across the genome. The allelic imbalance was often most prominent in one tissue and showed an enrichment overlapping with tissue-specific transcription factor (TF) binding footprints. Focusing on the 8,581 SNPs in previously published 99% credible sets from 338 T2D GWAS signals, we identified 256 imbalanced SNPs across 123 (36.4% of) signals, each showing allelic imbalance in at least one tissue or cell type. Of these, 71 signals contained only a single imbalanced SNP, representing excellent candidate causative variants. As a proof-of-concept, we showed that 23 of the 256 imbalanced SNPs were supported by allelic assays from previous studies. Further, we experimentally validated two imbalanced SNPs as likely functional variants: rs34584161 among a seven-SNP T2D credible set at the RNF6 signal in islets and rs849134 among a 13-SNP credible set at the JAZF1 signal in liver. This study demonstrates the power of integrating ATAC-seq allelic imbalance (ASAI) with GWAS statistical fine-mapping to identify candidate functional regulatory variants from among tightly linked GWAS variants in disease-relevant tissues. While applied here in T2D, this approach represents a widely applicable high-throughput framework for refining the genetic architecture of complex traits.","rel_num_authors":35,"rel_authors":[{"author_name":"Narisu Narisu","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Hannah X Li","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Caleb J M Rathbun","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Arushi Varshney","author_inst":"Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA"},{"author_name":"Amy J Swift","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Tingfen Yan","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Neelam Sinha","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Kevin W Currin","author_inst":"Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA"},{"author_name":"Dongxiang Xue","author_inst":"Department of Surgery, Center for Genomic Health, Weill Cornell Medicine, New York, NY 10065, USA"},{"author_name":"Catherine C Robertson","author_inst":"Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA"},{"author_name":"D Leland Taylor","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Henry J Taylor","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Aimee Beck","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Brian N Lee","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Li Wang","author_inst":"Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA"},{"author_name":"K Alaine Broadaway","author_inst":"Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA"},{"author_name":"Emma P Wilson","author_inst":"Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA"},{"author_name":"Heather Stringham","author_inst":"Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Jouko Saramies","author_inst":"South Karelia Social and Health Care District, Wellbeing Services County of South Karelia, Finland"},{"author_name":"Timo A Lakka","author_inst":"Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland"},{"author_name":"Cassandra N Spracklen","author_inst":"Department of Biostatistics and Epidemiology, University of Massachusetts Amherst, Amherst, MA 01003, USA"},{"author_name":"Laura J Scott","author_inst":"Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"Michael L Stitzel","author_inst":"The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA"},{"author_name":"Jaakko Tuomilehto","author_inst":"Finnish Institute for Health and Welfare, Helsinki, Finland"},{"author_name":"Markku Laakso","author_inst":"Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland"},{"author_name":"Heikki A Koistinen","author_inst":"Finnish Institute for Health and Welfare, Helsinki, Finland"},{"author_name":"Michael Boehnke","author_inst":"Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA"},{"author_name":"H Efsun Arda","author_inst":"Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, US"},{"author_name":"Shuibing Chen","author_inst":"Department of Surgery, Center for Genomic Health, Weill Cornell Medicine, New York, NY 10065, USA"},{"author_name":"Leslie G Biesecker","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Lori L Bonnycastle","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Michael R Erdos","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"},{"author_name":"Karen L Mohlke","author_inst":"Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA"},{"author_name":"Stephen C J Parker","author_inst":"Gilbert S. Omenn Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA"},{"author_name":"Francis S Collins","author_inst":"Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"Quantifying the contribution of genetic variation to healthcare expenditure across diverse healthcare systems","rel_doi":"10.64898\/2026.07.14.26358031","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.14.26358031","rel_abs":"Healthcare systems must balance rising costs with the delivery of effective care, yet the factors underlying large inter-individual differences in healthcare expenditure remain incompletely understood. Here we examine how genome-wide genetic variation contributes to healthcare costs, analysing inpatient, outpatient, primary care and prescription drug expenditure in up to 1,429,889 individuals from 11 studies across 7 countries. We identify hundreds of common genetic variants robustly associated with healthcare costs, revealing a reproducible polygenic architecture shared across healthcare systems. Individual common variants have modest effects, typically altering annual costs by ~1-2% per allele, with the strongest signals arising from the HLA region, consistent with pleiotropic effects across autoimmune and inflammatory diseases. In contrast, putative loss-of-function (pLOF) variants (ClinVar\/ENIGMA pathogenic variants or LOFTEE high-confidence pLOF) in clinically actionable genes, studied in UK Biobank, have large individual-level consequences: carriers of such variants in BRCA1, BRCA2, MSH2 and APC experience more than a two-fold increase in annual inpatient costs. Cost-associated signals colocalize extensively with autoimmune disorders, cardiometabolic risk factors, pain sensitivity, and depression amongst others. Polygenic scores derived for healthcare costs can predict up to 1.4% of drug-related healthcare expenditure in independent cohorts and retain their effects in within-family analyses, indicating largely direct genetic influences. By linking genetic risk to healthcare expenditure, this work provides a foundation for integrating human genetics into health economics, preventive strategies and population-level screening.","rel_num_authors":57,"rel_authors":[{"author_name":"Sebastian May-Wilson","author_inst":"University of Helsinki"},{"author_name":"Jiwoo Lee","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Tomoko Nakanishi","author_inst":"University of Helsinki"},{"author_name":"Camiel M van der Laan","author_inst":"Vrije Universiteit Amsterdam"},{"author_name":"Ioannis Louloudis","author_inst":"Novo Nordisk Foundation Center for Protein Research"},{"author_name":"Kuang Lin","author_inst":"University of Oxford"},{"author_name":"Stavroula Kanoni","author_inst":"Queen Mary University London"},{"author_name":"Patrick Fahr","author_inst":"University of Oxford"},{"author_name":"Anne Richmond","author_inst":"The University of Edinburgh"},{"author_name":"Chadi Saad","author_inst":"Qatar Precision Health Institute"},{"author_name":"Penelope Lind","author_inst":"QIMR Berghofer"},{"author_name":"Zaina Al-Kanaani","author_inst":"Hamad Medical Corporation"},{"author_name":"Mykyta Artomov","author_inst":"Nationwide Children's Hospital"},{"author_name":"Karina Banasik","author_inst":"Copenhagen University Hospital"},{"author_name":"Enda M Byrne","author_inst":"University of Queensland"},{"author_name":"Zhengming Chen","author_inst":"Oxford University"},{"author_name":"Christian Erikstrup","author_inst":"Aarhus University Hospital"},{"author_name":"Erik Sorensen","author_inst":"Rigshospitalet"},{"author_name":"Jakob German","author_inst":"Institute for Molecular Medicine Finland \/ Broad Institute of MIT and Harvard"},{"author_name":"Giulia Brunelli","author_inst":"University of Helsinki"},{"author_name":"Daniel F. Gudbjartsson","author_inst":"deCODE Genetics\/Amgen"},{"author_name":"Unnur Thorsteinsdottir","author_inst":"deCODE Genetics\/Amgen"},{"author_name":"Ian B. Hickie","author_inst":"University of Sydney"},{"author_name":"Nikita Kolosov","author_inst":"University of Helsinki"},{"author_name":"Satoshi Koyama","author_inst":"The Broad Institute of MIT And Harvard"},{"author_name":"Arne Kukkonen","author_inst":"University of Tartu"},{"author_name":"Liming Li","author_inst":"Peking University Health Science Center"},{"author_name":"Daniel L. McCartney","author_inst":"University of Edinburgh"},{"author_name":"Laust Hvas Mortensen","author_inst":"University of Copenhagen"},{"author_name":"Sisse R. Ostrowski","author_inst":"Rigshospitalet"},{"author_name":"Ole Birger Pedersen","author_inst":"Naestved Hospital"},{"author_name":"Henning Bundgaard","author_inst":"Copenhagen University Hospital (Rigshospitalet)"},{"author_name":"Dan J. Siskind","author_inst":"The University of Queensland"},{"author_name":"Doug Speed","author_inst":"Aarhus University"},{"author_name":"Patrick Sulem","author_inst":"deCODE Genetics\/Amgen"},{"author_name":"Andres Vork","author_inst":"University of Tartu"},{"author_name":"Sarah Wordsworth","author_inst":"Broad Institute of Harvard and MIT"},{"author_name":"Zhiyu Yang","author_inst":"University of Helsinki"},{"author_name":"Kristina Zguro","author_inst":"University of Helsinki"},{"author_name":"- Genes & Health Research Team","author_inst":"-"},{"author_name":"- FinnGen","author_inst":"-"},{"author_name":"Sarah Medland","author_inst":"QIMR"},{"author_name":"Nicholas G. Martin","author_inst":"QIMR Berghofer"},{"author_name":"Hamdi Mbarek","author_inst":"Qatar Genome"},{"author_name":"Dorret I. Boomsma","author_inst":"Vrije Universiteit Amsterdam"},{"author_name":"Riccardo Marioni","author_inst":"University of Edinburgh"},{"author_name":"James Buchanan","author_inst":"Wolfson Institute of Population Health"},{"author_name":"Pradeep Natarajan","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Sarah Finer","author_inst":"Queen Mary University of London"},{"author_name":"David A van Heel","author_inst":"Queen Mary University of London"},{"author_name":"Robin Walters","author_inst":"Oxford University"},{"author_name":"Erik Abner","author_inst":"Estonian Genome Center, University of Tartu, Tartu, 51010, Estonia"},{"author_name":"Soren Brunak","author_inst":"Novo Nordisk Foundation Center for Protein Research"},{"author_name":"Neil Martin Davies","author_inst":"University College London"},{"author_name":"Tatiana Cajuso Pons","author_inst":"University of Helsinki"},{"author_name":"Padraig Dixon","author_inst":"University of Oxford"},{"author_name":"Andrea Ganna","author_inst":"University of Helsinki"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"Local ancestry-informed rare variant burden testing improves gene discovery in admixed populations","rel_doi":"10.64898\/2026.07.13.26357993","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26357993","rel_abs":"Rare-variant association studies enable the discovery of high-impact genetic contributors often missed by conventional genome-wide association studies focused on common variation. However, standard burden tests aggregate variants without accounting for local ancestry in admixed genomes, reducing power when rare variant frequencies or genetic effects differ across ancestral backgrounds. Here, we introduce Tractor-Burden, an ancestry-aware gene-based association method that partitions rare-variant burden by inferred local ancestry and estimates ancestry-specific effects within a unified regression. In simulations, Tractor-Burden is well calibrated and improves power over standard burden tests under effect heterogeneity. Applied to whole-genome sequencing data from 47,152 admixed African-European individuals in the All of Us Research Program, Tractor-Burden recapitulates known associations, including ancestry-enriched effects at LDLR, and identifies additional suggestive genes and pathways for type 2 diabetes. Tractor-Burden extends rare-variant association testing to admixed genomes and provides a scalable framework for detecting and interpreting gene-level effects across local ancestry backgrounds.","rel_num_authors":9,"rel_authors":[{"author_name":"Pragati Kore","author_inst":"Baylor College of Medicine"},{"author_name":"Taotao Tan","author_inst":"Baylor College of Medicine"},{"author_name":"Wenxuan Lu","author_inst":"Johns Hopkins University"},{"author_name":"Astrid Manuel-Friedman","author_inst":"Baylor College of Medicine"},{"author_name":"Linfeng Hu","author_inst":"The Broad Institute of MIT and Harvard"},{"author_name":"Nilanjan Chatterjee","author_inst":"Johns Hopkins University"},{"author_name":"Wei Zhou","author_inst":"The Broad Institute of MIT and Harvard"},{"author_name":"Ryan S. Dhindsa","author_inst":"Baylor College of Medicine"},{"author_name":"Elizabeth G. Atkinson","author_inst":"Baylor College of Medicine"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"Concerns, Priorities, and Pathways: Healthcare Provider Perspectives on Implementing Tuberculosis Preventive Treatment for People with HIV in Indonesia and the Philippines","rel_doi":"10.64898\/2026.07.13.26357999","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26357999","rel_abs":"Background Tuberculosis preventive therapy (TPT) is a cornerstone intervention for reducing TB incidence among people living with HIV, yet its integration into routine care remains inconsistent in high-burden settings. While policy frameworks are well established, less is known about how frontline healthcare workers (HCWs) operationalize TPT within constraint health systems. This study explores healthcare workers (HCWs) perspectives on TPT implementation in Indonesia and the Philippines using normalization process theory (NPT), to understand how TPT is (or fails to be) embedded in everyday clinical practice. Methods We conducted ten focus group discussions and four in-depth interviews with HCWs across major TB\/HIV treatment centers in Manila, Philippines and Jakarta, Indonesia between June to December 2023. Data were analyzed using reflexive thematic analysis, followed by interpretative mapping onto four NPT constructs: coherence, cognitive participation, collective action and reflexive monitoring. Results TPT implementation was characterized by a persistent gap between policy intent and routine practice. Under coherence, HCWs described fragmented knowledge and limited exposure to standardized protocols, undermining confidence in TPT delivery. Cognitive participation was constrained by a doctor-centric model and high staff turnover, weakening shared ownership of TPT. In collective action, operational fragilities, including weak documentation systems, supply interruptions, and poor inter-level coordination, resulted in inconsistent delivery. Through reflexive monitoring, HCWs identified patient concerns around side effects and pill burden, alongside provider concerns regarding diagnostic uncertainty and fears of missing active TB. Across settings, HCWs actively proposed system-oriented solutions, including SOP standardization, team-based training, digital reminders, and strengthened care continuity mechanisms. Conclusions TPT implementation is not limited by awareness alone but by the absence of routinized systems that support consistent practice. Strengthening implementation requires shifting from individual-dependent delivery toward system-enabled integration, through standardized protocols, distributed workforce engagement, embedded monitoring mechanisms, and uninterrupted drug supply systems. Interventions that align with everyday clinical workflows and reinforce collective responsibility across cadres are critical to closing policy and practice gap.","rel_num_authors":17,"rel_authors":[{"author_name":"Prashant Kulkarni","author_inst":"Johns Hopkins: Johns Hopkins University"},{"author_name":"Laura Steiner","author_inst":"Johns Hopkins School of Medicine: The Johns Hopkins University School of Medicine"},{"author_name":"Alieen Gianan-Gascon","author_inst":"RITM: Research Institute for Tropical Medicine"},{"author_name":"Candice  Eula Lamigo","author_inst":"RITM: Research Institute for Tropical Medicine"},{"author_name":"Bianca  Joyce Sornillo","author_inst":"RITM: Research Institute for Tropical Medicine"},{"author_name":"Ruth  Anne Hechanova-Cruz","author_inst":"RITM: Research Institute for Tropical Medicine"},{"author_name":"Anna  Maureen Dungca-Lorilla","author_inst":"RITM: Research Institute for Tropical Medicine"},{"author_name":"Aljira  Fitya Hapsari","author_inst":"Universitas Indonesia"},{"author_name":"Retnosari Hardaningsih","author_inst":"Hospital Dr Cipto Mangunkusumo: Rumah Sakit Dr Cipto Mangunkusumo"},{"author_name":"Mira Yulianti","author_inst":"Hospital Dr Cipto Mangunkusumo: Rumah Sakit Dr Cipto Mangunkusumo"},{"author_name":"Anshari  Saifuddin Hasibuan","author_inst":"Hospital Dr Cipto Mangunkusumo: Rumah Sakit Dr Cipto Mangunkusumo"},{"author_name":"Evy Yunihastuti","author_inst":"Hospital Dr Cipto Mangunkusumo: Rumah Sakit Dr Cipto Mangunkusumo"},{"author_name":"Priyanka Raichur","author_inst":"Johns Hopkins University"},{"author_name":"Rossana Ditangco","author_inst":"RITM: Research Institute for Tropical Medicine"},{"author_name":"Jonathan  E Golub","author_inst":"Johns Hopkins: Johns Hopkins University"},{"author_name":"Christopher  J Hoffmann","author_inst":"Johns Hopkins University"},{"author_name":"Mark  Donald C. Re\u00f1osa","author_inst":"RITM: Research Institute for Tropical Medicine"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"Mortality in Eastern Democratic Republic of the Congo: A Population-Based Survey Following the 2025 M23 Offensive and Humanitarian Funding Withdrawal","rel_doi":"10.64898\/2026.07.10.26357778","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.10.26357778","rel_abs":"Introduction: In early 2025, North and South Kivu Provinces in the Democratic Republic of the Congo (DRC) underwent a major geopolitical shift marked by the concurrent abrupt withdrawal of humanitarian support and large-scale military takeover by the M23 armed group. This study sought to quantify mortality before and after the humanitarian and security collapse. Methods: We conducted a retrospective, two-stage cluster household survey comparing mortality in the pre- and post-crisis periods. Difference-in-differences were analyzed using survey-weighted Poisson regression with a log-link and person-time offset to estimate adjusted incident rate ratios for crude, under-five, and sex-specific mortality. We interviewed community leaders and health facility staff as key informants to provide qualitative data. Results: The adjusted risk of death was 2.02 times higher in the post-crisis than the pre-crisis period (95% CI 1.07, 3.80; p=0.03). Crude mortality rose from a pre-crisis adjusted marginal mean of 0.38 (95% CI 0.22, 0.53) to 0.74 (95% CI 0.56, 0.92) deaths\/10,000\/day. The increase in mortality was consistent across DRC-Government and M23 controlled areas. Results indicate that 165,391 (95%CI: 63,557, 267,225) excess deaths occurred in the post-crisis period, equating to 245,397 annual excess deaths. Conclusion: The crisis in DRC is driven by the convergence of humanitarian funding withdrawals and escalating conflict. Averting further preventable deaths requires large-scale restoration of humanitarian assistance. The resources needed to do so represent a small fraction of global economic capacity.","rel_num_authors":3,"rel_authors":[{"author_name":"Jennifer OKeeffe","author_inst":"Rebuild Hope for Africa"},{"author_name":"Augustin Gang Baderha Karume","author_inst":"Rebuild Hope for Africa"},{"author_name":"Les Roberts","author_inst":"Rebuild Hope for Africa"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"Intermittent theta burst stimulation modulates working memory-related theta-gamma coupling in adolescents with ADHD","rel_doi":"10.64898\/2026.07.13.26357958","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26357958","rel_abs":"Objective: Working memory (WM) deficits are a co-occurring feature to numerous neuropsychiatric disorders, particularly attention-deficit\/hyperactivity disorder (ADHD), and there remain no treatments that directly target WM. The coupling between the phase of theta band activity and amplitude of gamma band activity (i.e., TGC) is an established neural correlate of WM. However, no studies have examined WM-related TGC in ADHD or whether neuromodulation can modulate these oscillatory dynamics in youth. This set of studies examined the effects of intermittent theta burst stimulation (iTBS) to the left dorsolateral prefrontal cortex (DLPFC) and left posterior parietal cortex (PPC) on TGC in youth with ADHD. Methods: In two randomized, double-blind, sham-controlled crossover trials, adolescents with ADHD and clinically significant parent-reported WM symptoms first completed a single-session study comparing DLPFC versus PPC iTBS targeting (n = 47) and then a multi-session clinical trial comparing 10 sessions of active versus sham left DLPFC iTBS (n = 29). Participants completed a computerized visuospatial Sternberg WM task with concurrent electroencephalography (EEG) before and after the single sessions, as well as at baseline, midway through treatment, and approximately 24 hours after the final session within the multi-session trial. Phase-amplitude coupling between theta phase and gamma amplitude was quantified using the Kullback Leibler modulation index at frontoparietal electrodes. Linear mixed-effects models examined treatment effects and associations between change in TGC and WM status (including accuracy, reaction time, and clinical symptoms). Results: Across participants, lower TGC was associated with lower symptoms and better WM performance, including higher accuracy, faster and more consistent RT. Active iTBS increased frontoparietal TGC relative to sham stimulation, with effects observed both acutely after a single session and ~24 hours after multiple sessions. DLPFC-targeted iTBS increased TGC, whereas PPC-iTBS had no measurable effect. Change in TGC was associated with change in WM, such that a decrease in TGC was associated with faster RT and decreased RT variability. Higher baseline TGC was associated with greater improvement in WM. Active iTBS decoupled the TGC-WM association observed during sham iTBS, and greater electric field intensity of iTBS was associated with greater improvement in WM accuracy and greater decrease in TGC. Conclusions: Active iTBS to the left DLPFC modulated WM-related TGC in youth with ADHD. These findings provide preliminary evidence that neuromodulation may improve WW by modifying oscillatory dynamics within frontoparietal networks. Larger clinical trials with higher stimulation doses are needed to determine whether targeting oscillatory coupling represents a potential therapeutic strategy for WM deficits.","rel_num_authors":14,"rel_authors":[{"author_name":"Brian Kavanaugh","author_inst":"Brown University Health\/Bradley Hospital"},{"author_name":"Megan Vigne","author_inst":"Butler Hospital"},{"author_name":"Christopher Legere","author_inst":"Bradley Hospital"},{"author_name":"Zachary Borden","author_inst":"Butler Hospital"},{"author_name":"Elena Lynott","author_inst":"Brown University"},{"author_name":"Daniel Cheong","author_inst":"Brown University"},{"author_name":"Alexa Warren","author_inst":"Connecticut College"},{"author_name":"W Luke Acuff","author_inst":"Butler Hospital"},{"author_name":"Eric Tirrell","author_inst":"Butler Hospital"},{"author_name":"Elena Festa","author_inst":"Brown University"},{"author_name":"Stephanie Jones","author_inst":"Brown University"},{"author_name":"Richard Jones","author_inst":"Brown University"},{"author_name":"Anthony Spirito","author_inst":"Brown University"},{"author_name":"Linda Carpenter","author_inst":"Butler Hospital"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"Platform-Specific Safety of Pulsed Field Ablation for Atrial Fibrillation: A MAUDE Analysis","rel_doi":"10.64898\/2026.07.13.26358008","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.13.26358008","rel_abs":"Background: Three pulsed-field ablation (PFA) systems are FDA-approved for atrial fibrillation (AF), yet whether their safety profiles differ from each other and from radiofrequency (RF) ablation has not been systematically characterized using real-world adverse event data. We compared platform-specific complication profiles across three FDA-approved PFA systems and contemporary RF catheters in MAUDE. Methods: We analyzed 2,262 manually adjudicated MAUDE adverse event reports (760 PFA, 1,502 RF) through July 2025. Neurologic events underwent independent adjudication into five tiers by three auditors. Disproportionality was assessed using Reporting Odds Ratios (ROR) with Benjamini-Hochberg (BH) correction. Results: Pooled PFA had significantly lower BH-adjusted ROR for tamponade (0.52, 95% CI 0.41-0.67) and esophageal injury (0.09, 0.01-0.66), consistent with a tissue-selective reporting profile across platforms. Platform-level analysis, however, revealed substantial heterogeneity: the stroke signal was driven by Varipulse (ROR 16.41, 8.61-31.28) and was not observed with Farapulse (ROR 1.26, NS). Pooled PFA had higher ROR for imaging-confirmed stroke (3.84, 2.27-6.49) and arrhythmia (2.57, 1.91-3.45). Coronary vasospasm (24 vs. 0 events) and hemolysis (15 vs. 1 events) were PFA-specific. Composite serious adverse events were similar. In a pre-specified extension period analysis (August-December 2025), the pooled PFA stroke signal attenuated to non-significance (ROR 1.60, 0.89-2.85), consistent with notoriety bias following the FDA Safety Communication. Conclusions: PFA adverse-event reporting shows substantial platform heterogeneity across approved systems. Varipulse was associated with a disproportionate neurologic reporting signal, while all PFA platforms show tissue-selective reporting patterns relative to RF. These findings support platform-aware clinical decision-making and post-market surveillance.","rel_num_authors":4,"rel_authors":[{"author_name":"Ahsan Ullah","author_inst":"Rutgers New Jersey Medical School Division of Cardiology"},{"author_name":"Jose Fossas-Espinosa","author_inst":"Rutgers New Jersey Medical School Division of Cardiology"},{"author_name":"Luka Petrovic","author_inst":"Rutgers New Jersey Medical School Division of Cardiology"},{"author_name":"Emad Aziz","author_inst":"Rutgers University, New Jersey Medical School"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"Orthogonal Contributions of Genetic, Clinical, and Social Determinants of Health Risk Burdens on Alzheimer's Disease Pathophysiology","rel_doi":"10.64898\/2026.07.07.26357509","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.07.26357509","rel_abs":"Importance: Alzheimer's disease (AD) arises from complex interactions among genetic, clinical, and social determinants of health (SDoH) risk factors, yet their independent contributions to underlying AD pathophysiology remain elusive. Objective: To quantify the effects of risk factors across amyloid (A{beta})\/tau, neurodegeneration, and cognition. Design: Cross-sectional analysis using structural equation modeling (SEM). Setting: Health and Aging Brain Study-Health Disparities (HABS-HD), a community-based cohort study. Participants: A total of 2,276 participants with demographics, genetic, clinical, and biomarker data from the baseline visit. Exposures: APOE e4 carrier status, AD polygenic risk score (AD-PRS), clinical risk score (CogDRisk), and a social determinants of health (SDoH) latent score derived using factor analysis. Main Outcomes and Measures: Latent variables representing A{beta}\/tau pathology (plasma pTau181, plasma pTau217\/A{beta}42, amyloid PET positivity, and global standardized uptake value ratio), neurodegeneration (plasma neurofilament light, cortical thickness, hippocampal volume), and cognition (memory, executive, and language tests) were modeled and regressed on AD latent variables using SEM adjusted for age, sex, genetic principal components, and spoken language. Results: The total analytic sample included 2,276 participants (mean age: 65.3 {+\/-} 8.7; non-Hispanic White: 43.0%, non-Hispanic Black: 16.2%, and Latinx\/Hispanic adults: 40.8%). APOE e4 was strongly associated with worse A{beta}\/tau latent variable ({beta}=0.31; p<0.001), with smaller but significant associations with neurodegeneration ({beta}=0.085; p<0.001) and cognition ({beta}=0.083; p<0.001). Higher AD-PRS was modestly associated with worse A{beta}\/tau ({beta}=0.075; p<0.01) but was not associated with neurodegeneration or cognition. A higher clinical risk score was significantly associated with worse neurodegeneration ({beta}=0.16; p<0.001) but not with A{beta}\/tau or cognition. Adverse SDoH was associated with worse neurodegeneration ({beta}=0.071; p<0.05) and strongly associated with worse cognition ({beta}=0.22; p<0.001), with no associations with A{beta}\/tau. Conclusion and Relevance: Genetic risks were primarily associated with A{beta} and tau pathology, clinical risks with neurodegeneration, and SDoH risks with cognition, suggesting that risk factors exert differential effects on AD pathophysiology. Future studies investigating additional risk factors and their longitudinal associations with AD pathophysiological changes are warranted.","rel_num_authors":8,"rel_authors":[{"author_name":"Meri S. Okorie","author_inst":"University of California, San Francisco"},{"author_name":"Xiaqing Jiang","author_inst":"University of California, San Francisco"},{"author_name":"Paulina Tolosa-Tort","author_inst":"University of California, San Francisco"},{"author_name":"Rakshya U Sharma","author_inst":"University of California, San Francisco"},{"author_name":"Alexandra L. Clark","author_inst":"University of Texas at Austin"},{"author_name":"Kristine Yaffe","author_inst":"University of California San Francisco"},{"author_name":"Jennifer S. Yokoyama","author_inst":"University of California, San Francisco"},{"author_name":"Shea J Andrews","author_inst":"University of California San Francisco"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"PRANA: A Deep Learning Method for Adapting Polygenic Risk Scores to Diverse Ethnic Groups","rel_doi":"10.64898\/2026.07.12.26357860","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.12.26357860","rel_abs":"Polygenic risk scores (PRSs), which quantify inherited susceptibility to complex traits and diseases, have emerged as valuable tools for risk stratification and precision medicine. Despite their promise, PRS developed on European cohorts often demonstrate substantially reduced predictive accuracy in non-European populations, due to differences in genetic architecture. The disproportionate representation of European ancestry cohorts in genome-wide association studies (GWAS) leads to inequitable deployment of PRS technologies across diverse populations. Here, we introduce PRANA (Polygenic Risk Adaptation via Neural-network Architecture), a deep learning framework that adapts an existing PRS developed on one population to other ancestries. Unlike methods that require large-scale GWAS in the target population, PRANA leverages pre-trained PRS models derived from European cohorts and adapts them using modestly sized cohorts from the target population. We evaluated PRANA on seven complex traits in South Asian, East Asian and Ashkenazi Jewish populations, as well as in selected smaller East Asian subpopulations where the scarcity of training data poses a particular challenge. PRANA mostly improved predictive performance of the baseline PRS models by 5%-20% in terms of effect size and Nagelkerke's R^2, and, in most cases, outperformed existing cross-ancestry multi-PRS approaches. These results highlight PRANA as a scalable and practical strategy to reduce disparities in genomic risk prediction and advance the equitable application of PRS in diverse populations.","rel_num_authors":5,"rel_authors":[{"author_name":"Hagai Levi","author_inst":"Tel Aviv University"},{"author_name":"- The Breast Cancer Association Consortium","author_inst":""},{"author_name":"Kyriaki Michailidou","author_inst":"The Cyprus Institute of Neurology and Genetics"},{"author_name":"Ran Elkon","author_inst":"Tel Aviv University"},{"author_name":"Ron Shamir","author_inst":"Tel Aviv University"}],"rel_date":"2026-07-15","rel_site":"medrxiv"},{"rel_title":"COB: a comprehensive database of chloroplast outer envelope beta-barrel proteins","rel_doi":"10.64898\/2026.07.15.738633","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.738633","rel_abs":"Despite their central role in metabolite exchange, lipid trafficking, and protein import, chloroplast outer envelope beta-barrel proteins lack a dedicated comprehensive sequence database spanning many plant proteomes. Here we present COB (chloroplast outer-envelope beta-barrel), comprising 16,586 sequences organized across ten protein categories and an uncharacterized group, constructed using a machine learning classifier that identifies chloroplast beta-barrels from features of evolutionary protein contact maps. COB reveals that Streptophyta have more barrels overall and a greater variety of solute transporters than Chlorophyta. COB shows considerable structural diversity across categories, including variable beta-strand counts and a high prevalence of open barrel conformations not seen in bacterial outer membrane proteins. Structure predictions for Arabidopsis thaliana outer envelope proteins identify candidate hybrid barrel assemblies, with TOC159 family members as universal interaction partners, and single-chain multi-barrel architectures previously described only in Gram-negative bacteria. Chloroplast barrels also have more open topologies and shorter strands than bacterial barrels. COB provides a comprehensive sequence resource for chloroplast outer envelope beta-barrels, establishing a foundation for investigating the evolution, structure, and functions of this essential protein-fold.","rel_num_authors":4,"rel_authors":[{"author_name":"Emily Proctor","author_inst":"University of Kansas"},{"author_name":"Daniel Montezano","author_inst":"University of Kansas"},{"author_name":"Matthew M. Copeland","author_inst":"University of Kansas"},{"author_name":"Joanna S.G. Slusky","author_inst":"University of Kansas"}],"rel_date":"2026-07-15","rel_site":"biorxiv"},{"rel_title":"Prototype-based AI triage for 3D pathology","rel_doi":"10.64898\/2026.07.09.737559","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737559","rel_abs":"Non-destructive 3D pathology enables high-resolution slide-free imaging of intact clinical specimens, providing comprehensive visualization of tissue structures beyond what conventional slide-based 2D histopathology can provide. However, the scale and complexity of volumetric datasets make exhaustive manual review impractical, motivating AI-assisted triage methods to select a small number of high-risk 2D slices for pathologist review. While prior triage models have shown promise, interpretability is poor and performance can be suboptimal, especially in the nascent field of 3D pathology in which labeled data is limited. We present SCOPE, a Segmentation-guided CrOss-slice PrototypE learning framework for comprehensive risk assessment of 2D levels within 3D pathology datasets. SCOPE combines (i) clustering-based pretraining on large-scale unlabeled volumetric data to initialize morphology-aware prototypes, (ii) segmentation-derived structural priors from publicly available models to guide prototype learning, and (iii) cross-slice (2.5D) prototype aggregation across neighboring slices to generate slice-level risk predictions. In prostate and esophageal data cohorts, SCOPE consistently outperforms attention-based and prototype-based multiple instance learning baselines for both binary and multiclass prediction tasks, enabling depth-resolved risk profiling for 3D triage based on morphological prototypes that are interpretable to pathologists.","rel_num_authors":15,"rel_authors":[{"author_name":"Renao Yan","author_inst":"Department of Mechanical Engineering, University of Washington, Seattle, WA, USA"},{"author_name":"Gan Gao","author_inst":"Department of Mechanical Engineering, University of Washington, Seattle, WA, USA"},{"author_name":"Andrew H. Song","author_inst":"Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"author_name":"Huai-Ching Hsieh","author_inst":"Department of Bioengineering, Stanford University, Stanford, WA, USA"},{"author_name":"Yujie Zhao","author_inst":"Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA, USA"},{"author_name":"Cristina Almagro-Perez","author_inst":"Department of Pathology, Mass General Brigham, Harvard Medical School, Boston, MA, USA"},{"author_name":"David Brenes","author_inst":"Department of Pathology, Stanford University, Stanford, CA, USA"},{"author_name":"Sarah S.L. Chow","author_inst":"Department of Mechanical Engineering, University of Washington, Seattle, WA, USA"},{"author_name":"Jeanne Shen","author_inst":"Department of Pathology, Stanford University, Stanford, CA, USA"},{"author_name":"Deepti M. Reddi","author_inst":"Department of Laboratory Medicine & Pathology, University of Washington, Seattle, WA, USA"},{"author_name":"Lawrence D. True","author_inst":"Department of Laboratory Medicine & Pathology, University of Washington, Seattle, WA, USA"},{"author_name":"Priti Lal","author_inst":"Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Anant Madabhushi","author_inst":"Wallace H. Coulter Department of Biomedical Engineering, Emory University & Georgia Institute of Technology, Atlanta, GA, USA"},{"author_name":"Faisal Mahmood","author_inst":"Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA, USA"},{"author_name":"Jonathan T.C. Liu","author_inst":"Department of Pathology, Stanford University, Stanford, CA, USA"}],"rel_date":"2026-07-15","rel_site":"biorxiv"},{"rel_title":"Trait Resilience Modulates the Association Between Cortisol and Aperiodic Neural Dynamics","rel_doi":"10.64898\/2026.07.09.737399","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737399","rel_abs":"Cortisol, our stress hormone, exerts widespread influence on neural activity. However, its influence on the aperiodic component of the electroencephalography power spectrum remains to be investigated. Given individual differences in the capacity to cope with stress and adversity, it also remains unclear whether trait resilience moderates this relationship. Hence, the present study examined whether individual differences in trait resilience moderates the association between resting cortisol and aperiodic activity. Participants (N=145) completed various self-report questionnaires (e.g., trait resilience). Electroencephalography was recorded over a 20-minute baseline period, followed by salivary cortisol collection. The results revealed a significant moderating effect of trait resilience in the occipital scalp region. Specifically, higher cortisol concentration was associated with flatter 1\/f slopes amongst individuals with low trait resilience, whereas this association was reversed amongst those with high trait resilience. Overall, our findings highlight the role of individual differences in trait resilience in shaping hypothalamic-pituitary-adrenal axis-related neural dynamics.","rel_num_authors":4,"rel_authors":[{"author_name":"Kar Fye Alvin Lee","author_inst":"The University of Hong Kong"},{"author_name":"Suhail T. Asharaf","author_inst":"The University of Hong Kong"},{"author_name":"Li Liang","author_inst":"The University of Hong Kong"},{"author_name":"Tatia M.C. Lee","author_inst":"The University of Hong Kong"}],"rel_date":"2026-07-15","rel_site":"biorxiv"},{"rel_title":"Coordination Failures Generate Selection Gradients in Animal Collectives","rel_doi":"10.64898\/2026.07.09.737300","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737300","rel_abs":"Collective animal behavior occurs in high-stakes contexts where failing to coordinate effectively with group-mates can spell disaster for individuals. Yet, identifying instances of coordination failure is challenging, meaning their evolutionary effects remain mysterious. Synchronous calls in alternating frog choruses (i.e., inadvertent signal collisions) are unambiguous failure events that impose steep attractiveness costs. We modeled tungara frog chorusing dynamics to reveal the sensorimotor and social mechanisms underpinning synchrony. Ultimately, inter-male variation in two key sensorimotor attributes, the periods of male calling rhythms and call latencies, generated divergent synchrony engagement patterns. Modeling female preferences revealed that these varied behavioral outcomes then yielded disparate attractiveness consequences. By mechanistically linking the causes and consequences of coordination failure, we demonstrate that non-random failure patterns in collectives generate selection gradients that refine sensorimotor tuning.","rel_num_authors":3,"rel_authors":[{"author_name":"Luke Cullen Larter","author_inst":"Brown University"},{"author_name":"Michael J Ryan","author_inst":"University of Texas at Austin"},{"author_name":"Matthew J Fuxjager","author_inst":"Brown University"}],"rel_date":"2026-07-15","rel_site":"biorxiv"},{"rel_title":"A geometric and dynamical theory of latent computations in biological neural networks","rel_doi":"10.64898\/2026.07.10.737763","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737763","rel_abs":"Many neural recordings have revealed low-dimensional sets of behaviorally relevant variables encoded within large-scale neural activity patterns. However, dimensionality reduction analyses alone cannot yield causal explanations for how networks stably implement computations that are resilient to the substantial variability of single neuron dynamics. Further, existing methods for dimensionality reduction often rely on simplifying assumptions about network structure that limit their applicability and explanatory power. To provide a theoretical framework describing the dynamics of low-dimensional computation in high-dimensional neural networks, here we introduce the concept of latent processing units (LPUs), which are architecture-agnostic computational elements operating within biological neural circuitry. Six theorems governing coding and computation by LPUs collectively provide explanations for a range of common biological findings: low-dimensional sets of coding variables can generate high-dimensional neural dynamics; many neurons have activity patterns that represent behaviorally relevant variables but exert little influence on downstream circuits; linear readouts of neural population activity commonly permit near-optimal decoding; the drift of neural representations is often substantial even while network computations remain intact. Overall, our treatment of LPUs, as enacted in network dynamics, unifies the geometric and dynamical views of neural computation under a joint framework and provides systems neuroscience with a causal account of how the brain executes reliable computations.","rel_num_authors":12,"rel_authors":[{"author_name":"Fatih Dinc","author_inst":"Stanford University"},{"author_name":"Marta Blanco-Pozo","author_inst":"University of Oxford"},{"author_name":"David Klindt","author_inst":"Cold Spring Harbor Laboratory"},{"author_name":"Francisco Acosta","author_inst":"UC Santa Barbara"},{"author_name":"Cameron Sylber","author_inst":"Stanford University"},{"author_name":"Yiqi Jiang","author_inst":"Stanford University"},{"author_name":"Sadegh Ebrahimi","author_inst":"Stanford University"},{"author_name":"Adam Shai","author_inst":"Stanford University"},{"author_name":"Hidenori Tanaka","author_inst":"NTT Research"},{"author_name":"Paul Yuan","author_inst":"Fudan University"},{"author_name":"Nina Miolane","author_inst":"UC Santa Barbara"},{"author_name":"Mark J Schnitzer","author_inst":"Stanford University"}],"rel_date":"2026-07-15","rel_site":"biorxiv"},{"rel_title":"An IL-34-IGF-1 inflammatory axis fuels KRAS-mutant lung cancer progression","rel_doi":"10.64898\/2026.07.14.738492","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.14.738492","rel_abs":"Macrophages are innate immune cells of embryonic or adult origin with tissue specific roles in homeostasis, disease surveillance, and wound repair that can be co-opted to promote tumor growth and spread (1-11). An understanding of the specific roles of macrophage subsets in lung tumor initiation and progression could promote new therapeutic approaches for this deadly disease. Here, we show that KRASG12D mutations in lung epithelium drive proliferation of resident, embryonically-derived alveolar macrophages, which then promote tumor cell proliferation and protection from ferroptosis, leading to tumor progression. Using genetically engineered mouse models of mutant KRASG12D non-small cell lung cancer (12,13), we found that alveolar macrophages accumulate by proliferation in response to tumor cell-secreted IL-34, recapitulating events observed in late embryonic lung development. Tumor alveolar macrophages in turn drive IGF-1-dependent tumor cell proliferation. Neutralization or deletion of IL-34 suppresses IGF-1 expression, reduces macrophage and tumor cell proliferation and inhibits tumor progression. High IL34 and IGF1 correlate with poor survival in KRASG12D\/V lung adenocarcinomas and in other solid tumors, indicating that bi-directional proliferative signaling between resident macrophages and tumor cells can drive human lung tumor progression. These studies identify resident macrophage-tumor cell interactions as key interception points for lung cancer therapy.","rel_num_authors":22,"rel_authors":[{"author_name":"Jaroslav Zak","author_inst":"Huntsman Cancer Institute, University of Utah"},{"author_name":"Hui Chen","author_inst":"University of California, San Diego"},{"author_name":"Erpei Wang","author_inst":"University of California, San Diego"},{"author_name":"Patrick Ozark","author_inst":"Huntsman Cancer Institute, University of Utah"},{"author_name":"Giuliana Mognol","author_inst":"University of California, San Diego"},{"author_name":"MATTHEW Dae-Young PARK","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Nadine Fournier","author_inst":"Swiss Federal Institute of Technology in Lausanne"},{"author_name":"Priyanka Chaudary","author_inst":"University of California, San Diego"},{"author_name":"Jingjing Hu","author_inst":"University of California, San Diego"},{"author_name":"Ryan Shepard","author_inst":"University of California, San Diego"},{"author_name":"Anghesom Ghebremedin","author_inst":"University of California, San Diego"},{"author_name":"Marc Paradise","author_inst":"University of California, San Diego"},{"author_name":"Jason Rivera","author_inst":"University of California, San Diego"},{"author_name":"William J Harris","author_inst":"University of California, San Diego"},{"author_name":"Zihan Xu","author_inst":"University of California, San Diego"},{"author_name":"Adam Ramadan","author_inst":"University of California, San Diego"},{"author_name":"Birkley Lim","author_inst":"University of California, San Diego"},{"author_name":"Marco Colonna","author_inst":"Washington University"},{"author_name":"Miriam Merad","author_inst":"icahn School of medicine"},{"author_name":"Michele De Palma","author_inst":"Swiss Federal Institute of Technology in Lausanne"},{"author_name":"Mark Onaitis","author_inst":"University of California, San Diego"},{"author_name":"Judith A Varner","author_inst":"University of California, San Diego"}],"rel_date":"2026-07-15","rel_site":"biorxiv"},{"rel_title":"An IL-34-IGF-1 inflammatory axis fuels KRAS-mutant lung cancer progression","rel_doi":"10.64898\/2026.07.14.738492","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.14.738492","rel_abs":"Macrophages are innate immune cells of embryonic or adult origin with tissue specific roles in homeostasis, disease surveillance, and wound repair that can be co-opted to promote tumor growth and spread (1-11). An understanding of the specific roles of macrophage subsets in lung tumor initiation and progression could promote new therapeutic approaches for this deadly disease. Here, we show that KRASG12D mutations in lung epithelium drive proliferation of resident, embryonically-derived alveolar macrophages, which then promote tumor cell proliferation and protection from ferroptosis, leading to tumor progression. Using genetically engineered mouse models of mutant KRASG12D non-small cell lung cancer (12,13), we found that alveolar macrophages accumulate by proliferation in response to tumor cell-secreted IL-34, recapitulating events observed in late embryonic lung development. Tumor alveolar macrophages in turn drive IGF-1-dependent tumor cell proliferation. Neutralization or deletion of IL-34 suppresses IGF-1 expression, reduces macrophage and tumor cell proliferation and inhibits tumor progression. High IL34 and IGF1 correlate with poor survival in KRASG12D\/V lung adenocarcinomas and in other solid tumors, indicating that bi-directional proliferative signaling between resident macrophages and tumor cells can drive human lung tumor progression. These studies identify resident macrophage-tumor cell interactions as key interception points for lung cancer therapy.","rel_num_authors":22,"rel_authors":[{"author_name":"Jaroslav Zak","author_inst":"Huntsman Cancer Institute, University of Utah"},{"author_name":"Hui Chen","author_inst":"University of California, San Diego"},{"author_name":"Erpei Wang","author_inst":"University of California, San Diego"},{"author_name":"Patrick Ozark","author_inst":"Huntsman Cancer Institute, University of Utah"},{"author_name":"Giuliana Mognol","author_inst":"University of California, San Diego"},{"author_name":"MATTHEW Dae-Young PARK","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Nadine Fournier","author_inst":"Swiss Federal Institute of Technology in Lausanne"},{"author_name":"Priyanka Chaudary","author_inst":"University of California, San Diego"},{"author_name":"Jingjing Hu","author_inst":"University of California, San Diego"},{"author_name":"Ryan Shepard","author_inst":"University of California, San Diego"},{"author_name":"Anghesom Ghebremedin","author_inst":"University of California, San Diego"},{"author_name":"Marc Paradise","author_inst":"University of California, San Diego"},{"author_name":"Jason Rivera","author_inst":"University of California, San Diego"},{"author_name":"William J Harris","author_inst":"University of California, San Diego"},{"author_name":"Zihan Xu","author_inst":"University of California, San Diego"},{"author_name":"Adam Ramadan","author_inst":"University of California, San Diego"},{"author_name":"Birkley Lim","author_inst":"University of California, San Diego"},{"author_name":"Marco Colonna","author_inst":"Washington University"},{"author_name":"Miriam Merad","author_inst":"icahn School of medicine"},{"author_name":"Michele De Palma","author_inst":"Swiss Federal Institute of Technology in Lausanne"},{"author_name":"Mark Onaitis","author_inst":"University of California, San Diego"},{"author_name":"Judith A Varner","author_inst":"University of California, San Diego"}],"rel_date":"2026-07-15","rel_site":"biorxiv"},{"rel_title":"Structural Composition Enables Very Fast Learning","rel_doi":"10.64898\/2026.07.14.738142","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.14.738142","rel_abs":"There is a gap between neuroscientific theories of learning and the speed of learning observed in many experiments. Since the Cognitive Revolution of the 1950s, compositionality has played a central role in efforts to bridge this gap. Roughly, a compositional system is one where distinct modules are combined according to a set of rules in order to accomplish complex tasks. Recently, significant progress has been made in understanding the emergence of modules in both biological and artificial neural systems. How, and under what conditions, the rules of module recombination are represented in these systems remains an open question. Here we present a neural model that can leverage these rules to dramatically speed up learning. We first show that when faced with multiple tasks which share subcomponents, models learn a low-dimensional representation that captures how subcomponents are reused across the task set. These low-dimensional spaces encode the structure that governs how modules should be recombined. Restricting learning to these subspaces greatly reduces the amount of experience needed to acquire a novel task, even when learning from reinforcement on single trials. In some cases, we can leverage the geometric regularities of these representations to reduce learning to a form of hypothesis testing over a small set of discrete points. Finally, we use this theory to model both behavioral and neural data from non-human primates performing a compositional task, and show that key features in this data are consistent with a model in which exploration during learning is restricted to these low-dimensional spaces. Overall, this work shows that the advantages of modularity in neural systems can be greatly improved upon when models represent the structure of module reuse. Both these features working in tandem lead to learning on timescales similar to biological intelligences, and hence provide a model for how such fast, adaptable behavior can emerge from systems of neurons.","rel_num_authors":3,"rel_authors":[{"author_name":"Reidar Riveland","author_inst":"Gatsby Computational Neuroscience Unit, UCL"},{"author_name":"Alexandre Pouget","author_inst":"University of Geneva"},{"author_name":"Peter Latham","author_inst":"Gatsby Computational Neuroscience Unit, UCL"}],"rel_date":"2026-07-15","rel_site":"biorxiv"},{"rel_title":"Epithelial Stem Cell Fate Determines Chemoradiotherapy Response in Rectal Cancer","rel_doi":"10.64898\/2026.07.15.736775","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.15.736775","rel_abs":"Rectal cancers are often treated with neoadjuvant chemoradiotherapy (CRT), yet 85% of patients do not achieve a pathological complete response. To identify the molecular determinants of CRT response, we profiled the single-cell signalling, DNA-damage, cell-cycle, apoptotic, and cell-fate responses of 2,769 patient-derived organoid cultures treated with CRT, cancer-associated fibroblasts (CAFs), and signal-rewiring agents. We find that CRT response is determined by stem cell-fate. CRT triggers comparable DNA-damage in isogenic proliferative (proCSC) and revival (revCSC) colonic stem cells, but proCSC retain damage and die whereas revCSC resolve damage and persist. Both CRT and CAFs drive proCSC to a common treatment-resistant revCSC fate and high revCSC predicts worse survival in patients. Pharmacologically constraining stem-cell plasticity increases CRT sensitivity, and Spatial Perturbation of ARrayed Tumour Assembloids (SPARTA) confirms YAP\/TEAD inhibition improves chemotherapy responses in human stromal-tumour models. These results suggest that cancer cell-fate, not genotoxic damage itself, ultimately governs response to standard-of-care chemoradiotherapy.","rel_num_authors":18,"rel_authors":[{"author_name":"Nick Li","author_inst":"Cell Communication Laboratory, Department of Oncology, University College London Cancer Institute, 72 Huntley Street, London, UK"},{"author_name":"Fiza Ishaqwala","author_inst":"School of Cancer Sciences, University of Glasgow, Glasgow, UK"},{"author_name":"Thomas A. Wright","author_inst":"School of Cancer Sciences, University of Glasgow, Glasgow, UK"},{"author_name":"Alistair Wilkinson","author_inst":"Cell Communication Laboratory, Department of Oncology, University College London Cancer Institute, 72 Huntley Street, London, UK; Department of Computer Science"},{"author_name":"Petra Vlckova","author_inst":"Cell Communication Laboratory, Department of Oncology, University College London Cancer Institute, 72 Huntley Street, London, UK; Cancer Research UK City of Lon"},{"author_name":"Katherine Trevers","author_inst":"Cancer Research UK City of London Centre Pathology Translational Technology Platform, University College London Cancer Institute, London, UK"},{"author_name":"Rhianna O'Sullivan","author_inst":"Cell Communication Laboratory, Department of Oncology, University College London Cancer Institute, 72 Huntley Street, London, UK"},{"author_name":"Shauna Crampsie","author_inst":"Cell Communication Laboratory, Department of Oncology, University College London Cancer Institute, 72 Huntley Street, London, UK"},{"author_name":"Ewa Basiarz","author_inst":"Cell Communication Laboratory, Department of Oncology, University College London Cancer Institute, 72 Huntley Street, London, UK; Cancer Research UK City of Lon"},{"author_name":"Sierra Vanderkamp","author_inst":"Cell Communication Laboratory, Department of Oncology, University College London Cancer Institute, 72 Huntley Street, London, UK; Cancer Research UK City of Lon"},{"author_name":"Ashley K McCulloch","author_inst":"School of Cancer Sciences, University of Glasgow, Glasgow, UK"},{"author_name":"Aurelie Dobric","author_inst":"Cell Communication Laboratory, Department of Oncology, University College London Cancer Institute, 72 Huntley Street, London, UK"},{"author_name":"Smita Krishnaswamy","author_inst":"Department of Computer Science, Yale University, New Haven, CT, USA"},{"author_name":"Bart Vanhaesebroeck","author_inst":"Cell Signalling Laboratory, Department of Oncology, University College London Cancer Institute, London, UK"},{"author_name":"- Glasgow Serial Sampling Consortium","author_inst":""},{"author_name":"Campbell S. D. Roxburgh","author_inst":"School of Cancer Sciences, University of Glasgow, Glasgow, UK; Academic Unit of Surgery, Glasgow Royal Infirmary, Glasgow, UK"},{"author_name":"Maria Hawkins","author_inst":"Department of Physics and Biomedical Engineering, University College London, London, UK"},{"author_name":"Christopher J. Tape","author_inst":"Cell Communication Laboratory, Department of Oncology, University College London Cancer Institute, 72 Huntley Street, London, UK; Cell Signalling Laboratory, De"}],"rel_date":"2026-07-15","rel_site":"biorxiv"},{"rel_title":"The hidden multiverse of ecological roles in Fungi","rel_doi":"10.64898\/2026.07.14.738353","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.14.738353","rel_abs":"Ecological roles are treated as discrete, bounded units of biological organization, even as evidence shows that many taxa are versatile, performing more than one of them. Each record of versatility represents a boundary crossing, yet current categorical paradigms prevent this cumulative evidence from reshaping the roles themselves. We solve this by introducing the ecological multiverse, a self-correcting framework that turns boundary crossings into a network of role connectivity. Applied to Fungi, the multiverse recasts the major form of plant pathogenicity from an isolated disease role into a central hub linking much of fungal functional space, especially benign plant symbioses and decomposition. By exposing this topology, the multiverse transforms categorical views of ecological function into a dynamic map, revealing pathways of role change as organisms and knowledge evolve.","rel_num_authors":9,"rel_authors":[{"author_name":"Carlos A Aguilar-Trigueros","author_inst":"Univeristy of Jyvaskyla"},{"author_name":"Adam Frew","author_inst":"Umea University"},{"author_name":"Adriana Romero-Olivares","author_inst":"University of California, Riverside"},{"author_name":"Joseph A Edwards","author_inst":"University of Tennessee - Knoxville"},{"author_name":"Amy Zanne","author_inst":"Cary Institute of Ecosystem Studies"},{"author_name":"Nerea Abrego","author_inst":"University Jyvaskyla"},{"author_name":"Tessa Camenzind","author_inst":"University of Hohenheim"},{"author_name":"Sten Anslan","author_inst":"University of Jyvaskyla"},{"author_name":"Jeff Powell","author_inst":"Western Sydney University"}],"rel_date":"2026-07-15","rel_site":"biorxiv"},{"rel_title":"OTTR-CLASH: improved biochemical and bioinformatic identification of Argonaute 2-mediated microRNA-target RNA interactions","rel_doi":"10.64898\/2026.07.14.738487","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.14.738487","rel_abs":"Various methods have detected miRNA-target interactions via immunoprecipitation of UV-crosslinked Argonaute ribonucleoprotein complexes, followed by intermolecular ligation of bound miRNAs to target strands, forming chimeric RNAs. To date, these methods have relied on conventional viral reverse transcriptases (RTs) to generate cDNAs for sequencing. However, crosslinked RNAs often retain adducts after purification, which can make them poor templates for viral RTs. Here, we adapted OTTR (Ordered Two-Template Relay) techniques to generate cDNAs from Ago2-bound RNAs. OTTR makes use of a modified retroelement-encoded RT, which is strongly processive even on templates with modifications or adducts. We show that this OTTR-CLASH method increases the frequency of generating chimeric RNAs compared to previous methods. We also developed an improved bioinformatic pipeline for analysis of these data, and we use this to catalog miRNA-target interactions not previously described in the literature.","rel_num_authors":7,"rel_authors":[{"author_name":"Paul D. Kaufman","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Haibo Liu","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Kai Hu","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Lucas Ferguson","author_inst":"University of California, Berkeley"},{"author_name":"Kathleen Collins","author_inst":"Univ of California, Berkeley"},{"author_name":"Lihua Julie Zhu","author_inst":"University of Massachusetts Medical School"},{"author_name":"Thoru Pederson","author_inst":"UMASS Medical School"}],"rel_date":"2026-07-15","rel_site":"biorxiv"},{"rel_title":"Two-Year Evolution of a Prospective Audit and Feedback of an Antimicrobial Stewardship Program in a quaternary Intensive Care Unit in Ghana","rel_doi":"10.64898\/2026.07.11.26357812","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.11.26357812","rel_abs":"ObjectivesTo evaluate two-year, side-by-side outcomes of a prospective audit and feedback (PAF)-based antimicrobial stewardship program (ASP) in a quaternary ICU in Ghana, comparing diagnostic stewardship, antimicrobial prescribing patterns, and clinician adherence to stewardship recommendations between 2024 and 2025. Longitudinal PAF data from low- and middle-income countries (LMIC) quaternary ICUs are scarce; this study addresses that evidence gap.\n\nMethodsA retrospective comparative analysis of routine Antimicrobial Stewardship (AMS) surveillance data was conducted at the University of Ghana Medical Centre ICU: 102 visits in 2024 and 63 in 2025. Proportions were compared by chi-square or Fishers exact test; continuous variables by Mann-Whitney U. Wilson score 95% confidence intervals (CIs) were computed for primary proportions.\n\nResultsBiomarker-guided prescribing rose from 86.3% to 100% of visits (p=0.005) and culture and sensitivity testing from 74.5% to 90.5% (p=0.02). Targeted (culture-guided) therapy increased significantly from 23.5% to 41.7% of antibiotic recipients (p=0.03), while empiric prescribing declined correspondingly. Overall antibiotic utilization remained high in both years (96.1% vs 95.2%; p=1.00), and meropenem use rose from 42.9% to 56.7% (p=0.13). AMS interventions were recommended in 67.6% and 63.5% of visits, respectively. Clinician acceptance improved markedly from 40.6% (95% CI: 29.8-52.4%) to 67.5% (95% CI: 52.0-79.9%) (p=0.01).\n\nConclusionsTwo years of PAF in a Ghanaian quaternary ICU demonstrated progressive program maturation: universal biomarker adoption, a significant shift toward targeted prescribing, and markedly enhanced clinician acceptance. Persistently high antibiotic utilization and rising carbapenem dependence underscore the need for sustained surveillance and carbapenem-sparing strategies in LMIC critical care.","rel_num_authors":9,"rel_authors":[{"author_name":"Peter  Kwamina McCarthy","author_inst":"University of Ghana Medical Centre"},{"author_name":"Nana  Ama Buadiba Osei","author_inst":"University of Ghana Medical Centre"},{"author_name":"Daniel  Freeman Owusu Ansah","author_inst":"University of Ghana Medical Centre"},{"author_name":"Josephine Mensah","author_inst":"University of Ghana Medical Centre"},{"author_name":"Salomey  Asaah Denkyira","author_inst":"University of Ghana Medical Centre"},{"author_name":"Fareeda  Serwaa Brobbey","author_inst":"University of Ghana Medical Centre"},{"author_name":"Glennsa  Nana Abena Ohene","author_inst":"University of Ghana Medical Centre"},{"author_name":"Blessing  Boakye Yiadom","author_inst":"Greater Accra Regional Hospital"},{"author_name":"George  Boateng Kyei","author_inst":"Washington University In St Louis: Washington University in St Louis"}],"rel_date":"2026-07-14","rel_site":"medrxiv"},{"rel_title":"Comparing a trial of labour with planned caesarean after one previous caesarean delivery: a protocol for a population-based cohort study","rel_doi":"10.64898\/2026.07.12.26357849","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.12.26357849","rel_abs":"The caesarean section rate has risen. An increasing number of women who have had one previous caesarean section need to consider mode of delivery in a subsequent pregnancy. Both trial of labour after caesarean (TOLAC) and planned repeat caesarean section are associated with maternal and perinatal risks. We will undertake a retrospective cohort study of recorded livebirths for women who have had one previous caesarean section in the United States from 2011 to 2024. Using multivariable logistic regression, we will examine the relationship between the intended mode of delivery at 39 weeks gestational age (TOLAC at 39 weeks or any mode of delivery at 39 to 43 weeks versus caesarean section without trial of labour at 39 weeks) and important maternal and neonatal outcomes. We will also examine the relationship between TOLAC and caesarean section without a trial of labour for maternal outcomes at 20 to 43 weeks and for perinatal outcomes at 37 to 43 weeks. Due to the large data size, this study will be able to report on rare maternal and perinatal outcomes and contribute to evidence that influences important decisions about mode of delivery after one caesarean section.","rel_num_authors":9,"rel_authors":[{"author_name":"Romy Ehrlich","author_inst":"Royal Prince Alfred Hospital"},{"author_name":"Pejman Adily","author_inst":"Sydney Institute for Women, Children and their Families"},{"author_name":"Mark Lauer","author_inst":"Sydney Institute for Women, Children and their Families"},{"author_name":"Rajit Narayan","author_inst":"Royal Prince Alfred Hospital"},{"author_name":"Hala Phipps","author_inst":"Sydney Institute for Women, Children and their Families"},{"author_name":"Adam Mackie","author_inst":"Royal Prince Alfred Hospital"},{"author_name":"Vincenzo Berghella","author_inst":"Sydney Kimmel Medical College of Thomas Jefferson University"},{"author_name":"Adrienne Gordon","author_inst":"Reproduction and Perinatal Centre, Faculty of Medicine and Health, University of Sydney"},{"author_name":"Bradley de Vries","author_inst":"Royal Prince Alfred Hospital"}],"rel_date":"2026-07-14","rel_site":"medrxiv"},{"rel_title":"Statistical Analysis Plan (SAP) - DREAM: an adaptive, randomised, placebo-controlled trial of duloxetine for reducing leg pain in people with chronic sciatica","rel_doi":"10.64898\/2026.07.12.26357883","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.12.26357883","rel_abs":"2DREAM is a randomised, superiority, parallel-group, placebo-controlled, participant, clinician, and assessor blinded trial with an adaptive group sequential design that allows early stopping for efficacy or futility. The purpose is to investigate whether taking 60 mg of duloxetine daily for 12 weeks in addition to guideline-recommended advice, compared with placebo in addition to guideline-recommended advice, can reduce leg pain intensity in individuals with chronic sciatica.\n\nThe primary outcome is leg pain intensity measured on a 0-10 numerical pain rating scale. It will be analysed using a repeated-measures linear mixed model. This statistical analysis plan pre-specifies the methods of analysis to be used in the interim analysis and the final analysis for the outcomes and key variables collected in the trial. It includes planned sensitivity analyses for the final analysis, including covariate adjustments and subgroup analyses, as well as the health economics analysis plan.","rel_num_authors":18,"rel_authors":[{"author_name":"Xiaoqiu Liu","author_inst":"The George Institute for Global Health"},{"author_name":"Laurent Billot","author_inst":"The George Institute for Global Health"},{"author_name":"Anthony Devaux","author_inst":"The George Institute for Global Health"},{"author_name":"Christopher Maher","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District and The University of Sydney"},{"author_name":"Christine Lin","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District and The University of Sydney"},{"author_name":"Richard Day","author_inst":"St Vincent's Clinical School, Faculty of Medicine, University of New South Wales"},{"author_name":"Rowena Ivers","author_inst":"Graduate School of Medicine, Faculty of Science, Medicine and Health, University of Wollongong"},{"author_name":"Martin Underwood","author_inst":"Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick"},{"author_name":"Andrew McLachlan","author_inst":"Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney"},{"author_name":"Bethan Richards","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District and The University of Sydney"},{"author_name":"Nanna Finnerup","author_inst":"Danish Pain Research Centre, Department of Clinical Medicine, Aarhus University"},{"author_name":"Cecilia Taing","author_inst":"The University of Sydney Sydney Musculoskeletal Health, Sydney School of Public Health"},{"author_name":"Kate Tong","author_inst":"The University of Sydney Sydney Musculoskeletal Health, Sydney School of Public Health"},{"author_name":"Masoud Jamshidi","author_inst":"The University of Sydney Sydney Musculoskeletal Health, Sydney School of Public Health"},{"author_name":"Maliha Hassan","author_inst":"The University of Sydney Sydney Musculoskeletal Health, Sydney School of Public Health"},{"author_name":"Melanie Hamilton","author_inst":"The University of Sydney Sydney Musculoskeletal Health, Sydney School of Public Health"},{"author_name":"Emily Atkins","author_inst":"The George Institute for Global Health"},{"author_name":"Giovanni Ferreira","author_inst":"The University of Sydney"}],"rel_date":"2026-07-14","rel_site":"medrxiv"},{"rel_title":"Statistical Analysis Plan (SAP) - DREAM: an adaptive, randomised, placebo-controlled trial of duloxetine for reducing leg pain in people with chronic sciatica","rel_doi":"10.64898\/2026.07.12.26357883","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.12.26357883","rel_abs":"2DREAM is a randomised, superiority, parallel-group, placebo-controlled, participant, clinician, and assessor blinded trial with an adaptive group sequential design that allows early stopping for efficacy or futility. The purpose is to investigate whether taking 60 mg of duloxetine daily for 12 weeks in addition to guideline-recommended advice, compared with placebo in addition to guideline-recommended advice, can reduce leg pain intensity in individuals with chronic sciatica.\n\nThe primary outcome is leg pain intensity measured on a 0-10 numerical pain rating scale. It will be analysed using a repeated-measures linear mixed model. This statistical analysis plan pre-specifies the methods of analysis to be used in the interim analysis and the final analysis for the outcomes and key variables collected in the trial. It includes planned sensitivity analyses for the final analysis, including covariate adjustments and subgroup analyses, as well as the health economics analysis plan.","rel_num_authors":18,"rel_authors":[{"author_name":"Xiaoqiu Liu","author_inst":"The George Institute for Global Health"},{"author_name":"Laurent Billot","author_inst":"The George Institute for Global Health"},{"author_name":"Anthony Devaux","author_inst":"The George Institute for Global Health"},{"author_name":"Christopher Maher","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District and The University of Sydney"},{"author_name":"Christine Lin","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District and The University of Sydney"},{"author_name":"Richard Day","author_inst":"St Vincent's Clinical School, Faculty of Medicine, University of New South Wales"},{"author_name":"Rowena Ivers","author_inst":"Graduate School of Medicine, Faculty of Science, Medicine and Health, University of Wollongong"},{"author_name":"Martin Underwood","author_inst":"Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick"},{"author_name":"Andrew McLachlan","author_inst":"Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney"},{"author_name":"Bethan Richards","author_inst":"Institute for Musculoskeletal Health, Sydney Local Health District and The University of Sydney"},{"author_name":"Nanna Finnerup","author_inst":"Danish Pain Research Centre, Department of Clinical Medicine, Aarhus University"},{"author_name":"Cecilia Taing","author_inst":"The University of Sydney Sydney Musculoskeletal Health, Sydney School of Public Health"},{"author_name":"Kate Tong","author_inst":"The University of Sydney Sydney Musculoskeletal Health, Sydney School of Public Health"},{"author_name":"Masoud Jamshidi","author_inst":"The University of Sydney Sydney Musculoskeletal Health, Sydney School of Public Health"},{"author_name":"Maliha Hassan","author_inst":"The University of Sydney Sydney Musculoskeletal Health, Sydney School of Public Health"},{"author_name":"Melanie Hamilton","author_inst":"The University of Sydney Sydney Musculoskeletal Health, Sydney School of Public Health"},{"author_name":"Emily Atkins","author_inst":"The George Institute for Global Health"},{"author_name":"Giovanni Ferreira","author_inst":"The University of Sydney"}],"rel_date":"2026-07-14","rel_site":"medrxiv"},{"rel_title":"Multi-omic Profiling of Recurrence Risk Across Breast Cancer Subtypes","rel_doi":"10.64898\/2026.07.10.26357777","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.10.26357777","rel_abs":"Recurrence risk greatly varies across intrinsic subtypes in breast cancer, yet the molecular and immune programs within primary tumors that go on to develop recurrence remains poorly understood. We performed multi-omic analysis of 340 breast cancer tumors across Basal-like, Luminal A, and Luminal B subtypes to identify tumor-intrinsic and microenvironmental features associated with recurrence. Within each intrinsic subtype, we compared recurrent and non-recurrent tumors across RNA, copy-number, and pathway-level mutational features. Basal-like tumors in patients who developed recurrence were characterized by reduced lymphocytes and pro-inflammatory M1 macrophages, enrichment of TGF-{beta}\/EMT activity, copy number gains within 5p\/7p\/7q, 4q losses, and increased pathway tumor mutational burden (pTMB) in growth-factor, inflammatory, and motility-associated signaling pathways, each of which was associated with increased recurrence risk. In Luminal A tumors, recurrent cases showed higher lymphocytes and pro-inflammatory M1 macrophages, enrichment of metabolic, stress-response, and stemness\/plasticity associated pathways, and higher pTMB in growth-factor, inflammatory, motility-associated, DNA repair and apoptosis signaling pathways all associated with recurrence risk. Among Luminal B tumors, recurrent cases were enriched for proliferation, genomic instability, DNA repair, and stress-response pathways, showed a prominent 1q copy number amplification, and exhibited increased pTMB in Hedgehog signaling which increased recurrence risk. Subtype-specific prediction models were developed to generate recurrence-risk scores and validated using an external cohort (METABRIC; 1,170 total cases). The performance of our recurrence risk scores in METABRIC were associated with recurrence free survival (RFS) across subtypes (Basal: HR=1.27, 95% CI [1.07-1.50], p=0.006, Luminal A: HR=1.18, 95% CI [1.06-1.31], p=0.002, Luminal B: HR=1.41, 95% CI [1.03-1.93], p=0.03). Together, these findings demonstrate that primary tumors in patients who develop recurrence harbor distinct subtype-specific biological programs detectable at diagnosis and support a subtype-informed multi-omic modeling as a framework for recurrence-risk stratification.","rel_num_authors":4,"rel_authors":[{"author_name":"A. Eden Cruikshank","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Pooja Chandra","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Chistopher I Li","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Gavin Ha","author_inst":"Fred Hutchinson Cancer Research Center"}],"rel_date":"2026-07-14","rel_site":"medrxiv"},{"rel_title":"Comorbidity Exposure-Window Definitions and Multidimensional Disparities in Long COVID Risk: Evidence from a U.S. National Cohort (2020-2024)","rel_doi":"10.64898\/2026.07.11.26357794","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.11.26357794","rel_abs":"Long COVID (LC) affects millions of individuals worldwide, particularly those with preexisting comorbidities. However, whether these comorbidities should be defined before SARS-CoV-2 infection or before LC diagnosis remains unresolved, and this methodological choice may substantially bias estimates of comorbidity-associated LC risk. In addition, most previous studies were conducted during earlier phases of the pandemic and relied on relatively small or geographically restricted cohorts, limiting understanding of temporal trends and population disparities in LC risk. Leveraging Electronic Health Records (EHR) from 6,130,413 adults with documented COVID-19 across 49 U.S. states in the National COVID Cohort Collaborative (N3C) from 2020 to 2024, we evaluated the impact of different comorbidity exposure-window definitions on LC risk estimation. We utilized ensemble cross-fitted double\/debiased machine learning to adjust for complex individual- and county-level confounders. Across the 16 major comorbidities evaluated, defining conditions before SARS-CoV-2 infection, rather than before LC diagnosis, yielded 23%-115% higher adjusted attributable risks and 6%-37% higher adjusted relative risks. Additionally, comorbidity-associated risks generally declined from 2020 to 2024, with substantial demographic, socioeconomic, geographic, and multimorbidity-related disparities persisting throughout the study period. These findings identify temporal exposure-window specification as a major source of bias in LC epidemiology. Failure to distinguish preexisting comorbidities from conditions identified during postinfection follow-up can substantially alter estimates of disease burden, the identification of high-risk populations, and the interpretation of temporal and geographic disparities. More broadly, our results highlight how temporal misclassification of exposures in longitudinal EHR studies can distort risk attribution and population-level inference.","rel_num_authors":12,"rel_authors":[{"author_name":"Yewen Chen PhD","author_inst":"Epidemiology & Biostatistics, College of Public Health, University of Georgia, Athens, GA, USA"},{"author_name":"Zhetao Chen MS","author_inst":"Epidemiology & Biostatistics, College of Public Health, University of Georgia, Athens, GA, USA"},{"author_name":"Ge Yang PhD","author_inst":"Epidemiology & Biostatistics, College of Public Health, University of Georgia, Athens, GA, USA"},{"author_name":"Bingnan Li MS","author_inst":"Department of Statistics, Franklin College of Arts and Science, University of Georgia, Athens, GA, USA"},{"author_name":"Kehinde Olawale Ogunyemi MD","author_inst":"Epidemiology & Biostatistics, College of Public Health, University of Georgia, Athens, GA, USA"},{"author_name":"Jialing Liu MS","author_inst":"Epidemiology & Biostatistics, College of Public Health, University of Georgia, Athens, GA, USA"},{"author_name":"Fangzhi Luo MS","author_inst":"Epidemiology & Biostatistics, College of Public Health, University of Georgia, Athens, GA, USA"},{"author_name":"Yuan Ke PhD","author_inst":"Department of Statistics, Franklin College of Arts and Science, University of Georgia, Athens, GA, USA"},{"author_name":"Leonardo Martinez PhD","author_inst":"Division of Epidemiology, School of Public Health, University of California, Berkeley, USA"},{"author_name":"Xianyan Chen PhD","author_inst":"Epidemiology & Biostatistics, College of Public Health, University of Georgia, Athens, GA, USA"},{"author_name":"Janani Rajbhandari PhD","author_inst":"Epidemiology & Biostatistics, College of Public Health, University of Georgia, Athens, GA, USA"},{"author_name":"Ye Shen PhD","author_inst":"Epidemiology & Biostatistics, College of Public Health, University of Georgia, Athens, GA, USA"}],"rel_date":"2026-07-14","rel_site":"medrxiv"},{"rel_title":"PAUSE-Agents: A Clinician-in-the-Loop Multi-Agent AI Pipeline for ICU-to-Ward Handoff Briefs","rel_doi":"10.64898\/2026.07.10.26357759","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.10.26357759","rel_abs":"ICU-to-ward transfers are high-risk transitions marked by information loss and burdensome handoff preparation. We developed PAUSE-Agents, a clinician-in-the-loop multi-agent LLM pipeline that drafts source-attributed handoff briefs from structured ICU data and clinical notes using the clinician-developed ICU-PAUSE template. Mirroring ICU team structure, PAUSE-Agents routes each record through a scribe extractor, 6 role-specialized agents, explicit conflict surfacing, and deterministic safety checks before synthesis, producing an editable first draft rather than an autonomous note. In a single-center medical ICU cohort, 5 physicians completed 100 reviews of 84 agent-drafted briefs. Among adjudicable claims, 98.8% were verified and 1.2% were incorrect; 88% of briefs had no pertinent omission, and mean PDSQI-9 quality was 4.20\/5. PAUSE-Agents surfaced 118 conflict warnings and 421 safety flags, making documentation inconsistencies visible before handoff. An o4-mini PDSQI-9 judge showed limited case-level discrimination but supported aggregate monitoring. We release PAUSE-Agents and its clinician evaluation application.","rel_num_authors":15,"rel_authors":[{"author_name":"Saki Amagai","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Wan-Ting Liao","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Caleb Murphy","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Courtney Reamer","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Yupeng Liu","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Bhavana Ambil","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Glenn Fernandes","author_inst":"Northwestern University"},{"author_name":"Lekshmi Santhosh","author_inst":"University of California, San Francisco"},{"author_name":"Patrick Lyons","author_inst":"Oregon Health & Science University School of Medicine"},{"author_name":"Neil Jordan","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"David Liebovitz","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Adrienne Kline","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Juan C Rojas","author_inst":"Rush University"},{"author_name":"Yuan Luo","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Catherine Gao","author_inst":"Northwestern University Feinberg School of Medicine"}],"rel_date":"2026-07-14","rel_site":"medrxiv"},{"rel_title":"PAUSE-Agents: A Clinician-in-the-Loop Multi-Agent AI Pipeline for ICU-to-Ward Handoff Briefs","rel_doi":"10.64898\/2026.07.10.26357759","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.10.26357759","rel_abs":"ICU-to-ward transfers are high-risk transitions marked by information loss and burdensome handoff preparation. We developed PAUSE-Agents, a clinician-in-the-loop multi-agent LLM pipeline that drafts source-attributed handoff briefs from structured ICU data and clinical notes using the clinician-developed ICU-PAUSE template. Mirroring ICU team structure, PAUSE-Agents routes each record through a scribe extractor, 6 role-specialized agents, explicit conflict surfacing, and deterministic safety checks before synthesis, producing an editable first draft rather than an autonomous note. In a single-center medical ICU cohort, 5 physicians completed 100 reviews of 84 agent-drafted briefs. Among adjudicable claims, 98.8% were verified and 1.2% were incorrect; 88% of briefs had no pertinent omission, and mean PDSQI-9 quality was 4.20\/5. PAUSE-Agents surfaced 118 conflict warnings and 421 safety flags, making documentation inconsistencies visible before handoff. An o4-mini PDSQI-9 judge showed limited case-level discrimination but supported aggregate monitoring. We release PAUSE-Agents and its clinician evaluation application.","rel_num_authors":15,"rel_authors":[{"author_name":"Saki Amagai","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Wan-Ting Liao","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Caleb Murphy","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Courtney Reamer","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Yupeng Liu","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Bhavana Ambil","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Glenn Fernandes","author_inst":"Northwestern University"},{"author_name":"Lekshmi Santhosh","author_inst":"University of California, San Francisco"},{"author_name":"Patrick Lyons","author_inst":"Oregon Health & Science University School of Medicine"},{"author_name":"Neil Jordan","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"David Liebovitz","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Adrienne Kline","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Juan C Rojas","author_inst":"Rush University"},{"author_name":"Yuan Luo","author_inst":"Northwestern University Feinberg School of Medicine"},{"author_name":"Catherine Gao","author_inst":"Northwestern University Feinberg School of Medicine"}],"rel_date":"2026-07-14","rel_site":"medrxiv"},{"rel_title":"Autonomous Agents for Auditable Cardiovascular Artificial Intelligence Development","rel_doi":"10.64898\/2026.07.10.26357656","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.10.26357656","rel_abs":"Clinical artificial intelligence (AI) models are usually reported as finished artifacts, but each model reflects a limited human search across a much larger space of architectures, inputs, losses, optimizers, and training recipes. We tested whether autonomous code-writing agents could perform a controlled model-development experiment: proposing and evaluating code changes, and seeking performance gains without new data or human-guided edits. We built two such agents: an Iteration Agent that searches sequentially, keeping the best variant at each step, and an Evolution Agent that searches for variations in parallel using multiple large language models and prioritizes high-performing lineages across generations. In two architecturally distinct AI-enhanced electrocardiography (AI-ECG) models for structural heart disease, agent-optimized variants improved rank discrimination across held-out, external, and cross-institution evaluations, with area under the receiver operating characteristic curve gains of +0.006 to +0.039 (paired p < 0.05). At a fixed 90% sensitivity, specificity rose by up to 7.1 percentage points and positive predictive value by up to 4.8 percentage points. The selected code changes were substantive, spanning architecture, representation, and training recipe variations. These findings position autonomous agents as an auditable layer for clinical AI model improvement, provided that candidate selection, external validation, and post-update governance are explicit. We release these agents as an open, reusable toolkit.","rel_num_authors":6,"rel_authors":[{"author_name":"Lovedeep Singh Dhingra","author_inst":"Yale School of Medicine"},{"author_name":"Bruno Batinica","author_inst":"Yale University"},{"author_name":"Ryan B Choi","author_inst":"Yale School of Medicine"},{"author_name":"Philip M Croon","author_inst":"Yale School of Medicine"},{"author_name":"Evangelos K Oikonomou","author_inst":"Yale School of Medicine"},{"author_name":"Rohan Khera","author_inst":"Yale School of Medicine"}],"rel_date":"2026-07-14","rel_site":"medrxiv"},{"rel_title":"Validation of the VACTERL Episignature and Evidence for Epigenomic Convergence Across Recurrent Constellations of Embryonic Malformations","rel_doi":"10.64898\/2026.07.10.26357391","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.10.26357391","rel_abs":"BackgroundRecurrent constellations of embryonic malformations (RCEMs) comprise multiple malformation conditions with largely unexplained etiologies and no established molecular biomarkers. A shared DNA methylation episignature was recently identified in VACTERL association and oculoauriculovertebral spectrum (OAVS). We sought to validate this episignature in an independent, deeply phenotyped cohort and evaluate its detection across related RCEMs.\n\nMethodsGenome-wide DNA methylation profiling was performed on peripheral blood from 38 participants with clinically diagnosed RCEMs, including VACTERL (n=21), partial VACTERL (n=3), OAVS (n=3), and other RCEM-related conditions (n=11).\n\nResultsThe Episign V5 RCEM episignature demonstrated robust sensitivity for VACTERL (18\/21, 85.7% positive), while the remaining three participants showed intermediate positivity. Of three participants with partial VACTERL, one with tracheoesophageal fistula demonstrated intermediate positivity, whereas the other two were negative. Episignature positivity was also identified in oculoauriculofrontonasal dysplasia (1\/1, robust) and rhomboencephalosynapsis (1\/2, robust) but was limited in OAVS (1\/3, intermediate) and absent in frontonasal dysplasia (0\/4).\n\nConclusionsIndependent validation establishes the Episign V5 RCEM episignature as a reproducible molecular biomarker for VACTERL, a condition that remains a diagnosis of exclusion. Variable detection across related malformation conditions suggests etiologic heterogeneity, whereas overlap among selected phenotypes supports epigenomic convergence across the RCEM spectrum.","rel_num_authors":23,"rel_authors":[{"author_name":"Julianne K Postma","author_inst":"Department of Medical Genetics, Children's Hospital of Eastern Ontario, University of Ottawa"},{"author_name":"Sadegheh Haghshenas","author_inst":"Verspeeten Clinical Genome Centre, London Health Sciences Centre"},{"author_name":"Teija MI Bily","author_inst":"Schulich School of Medicine and Dentistry"},{"author_name":"Majdina Isovic","author_inst":"Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre, Division of Genetics and Development, Child Health Research Institute"},{"author_name":"Alexandre White-Brown","author_inst":"Department of Medical Genetics, Children's Hospital of Eastern Ontario, Children's Hospital of Eastern Ontario Research Institute"},{"author_name":"Haley McConkey","author_inst":"Verspeeten Clinical Genome Centre, London Health Sciences Centre, Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, We"},{"author_name":"Jennifer Kerkhof","author_inst":"Verspeeten Clinical Genome Centre, London Health Sciences Centre,"},{"author_name":"Jessica Rzasa","author_inst":"Verspeeten Clinical Genome Centre, London Health Sciences Centre,"},{"author_name":"Maha Saleh","author_inst":"Division of Medical Genetics, Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, Medical Genetics Program of Southwestern"},{"author_name":"Chitra Prasad","author_inst":"Division of Medical Genetics, Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, Medical Genetics Program of Southwestern"},{"author_name":"Victoria M Siu","author_inst":"Division of Medical Genetics, Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, Medical Genetics Program of Southwestern"},{"author_name":"Melissa T Carter","author_inst":"Department of Medical Genetics, Children's Hospital of Eastern Ontario, Department of Pediatrics, University of Ottawa, Children's Hospital of Eastern Ontario R"},{"author_name":"David A Dyment","author_inst":"Department of Medical Genetics, Children's Hospital of Eastern Ontario, Department of Pediatrics, University of Ottawa, Children's Hospital of Eastern Ontario R"},{"author_name":"Joanna Lazier","author_inst":"Children's Hospital of Eastern Ontario"},{"author_name":"Sarah L Sawyer","author_inst":"Department of Medical Genetics, Children's Hospital of Eastern Ontario, Department of Pediatrics, University of Ottawa, Children's Hospital of Eastern Ontario R"},{"author_name":"Angelica A Moresco","author_inst":"Division of Medical Genetics, Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, Medical Genetics Program of Southwestern"},{"author_name":"Maria Jimena Diaz","author_inst":"Department of Medical Genetics, National Pediatric Hospital J. P. Garrahan"},{"author_name":"Silvina L Abbate","author_inst":"Department of Medical Genetics, National Pediatric Hospital J. P. Garrahan"},{"author_name":"Philippe M Campeau","author_inst":"CHU Sainte-Justine Research Center"},{"author_name":"A. Micheil Innes","author_inst":"Departments of Medical Genetics and Pediatrics and Alberta Children's Hospital Research Institute, Cumming School of Medicine"},{"author_name":"Kym M Boycott","author_inst":"Department of Medical Genetics, Children's Hospital of Eastern Ontario, Department of Pediatrics, University of Ottawa, Children's Hospital of Eastern Ontario R"},{"author_name":"Bekim Sadikovic","author_inst":"Verspeeten Clinical Genome Centre, London Health Sciences Centre, Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, We"},{"author_name":"Tugce B Balci","author_inst":"Division of Medical Genetics, Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, Medical Genetics Program of Southwestern"}],"rel_date":"2026-07-14","rel_site":"medrxiv"},{"rel_title":"Validation of the VACTERL Episignature and Evidence for Epigenomic Convergence Across Recurrent Constellations of Embryonic Malformations","rel_doi":"10.64898\/2026.07.10.26357391","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.10.26357391","rel_abs":"BackgroundRecurrent constellations of embryonic malformations (RCEMs) comprise multiple malformation conditions with largely unexplained etiologies and no established molecular biomarkers. A shared DNA methylation episignature was recently identified in VACTERL association and oculoauriculovertebral spectrum (OAVS). We sought to validate this episignature in an independent, deeply phenotyped cohort and evaluate its detection across related RCEMs.\n\nMethodsGenome-wide DNA methylation profiling was performed on peripheral blood from 38 participants with clinically diagnosed RCEMs, including VACTERL (n=21), partial VACTERL (n=3), OAVS (n=3), and other RCEM-related conditions (n=11).\n\nResultsThe Episign V5 RCEM episignature demonstrated robust sensitivity for VACTERL (18\/21, 85.7% positive), while the remaining three participants showed intermediate positivity. Of three participants with partial VACTERL, one with tracheoesophageal fistula demonstrated intermediate positivity, whereas the other two were negative. Episignature positivity was also identified in oculoauriculofrontonasal dysplasia (1\/1, robust) and rhomboencephalosynapsis (1\/2, robust) but was limited in OAVS (1\/3, intermediate) and absent in frontonasal dysplasia (0\/4).\n\nConclusionsIndependent validation establishes the Episign V5 RCEM episignature as a reproducible molecular biomarker for VACTERL, a condition that remains a diagnosis of exclusion. Variable detection across related malformation conditions suggests etiologic heterogeneity, whereas overlap among selected phenotypes supports epigenomic convergence across the RCEM spectrum.","rel_num_authors":23,"rel_authors":[{"author_name":"Julianne K Postma","author_inst":"Department of Medical Genetics, Children's Hospital of Eastern Ontario, University of Ottawa"},{"author_name":"Sadegheh Haghshenas","author_inst":"Verspeeten Clinical Genome Centre, London Health Sciences Centre"},{"author_name":"Teija MI Bily","author_inst":"Schulich School of Medicine and Dentistry"},{"author_name":"Majdina Isovic","author_inst":"Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre, Division of Genetics and Development, Child Health Research Institute"},{"author_name":"Alexandre White-Brown","author_inst":"Department of Medical Genetics, Children's Hospital of Eastern Ontario, Children's Hospital of Eastern Ontario Research Institute"},{"author_name":"Haley McConkey","author_inst":"Verspeeten Clinical Genome Centre, London Health Sciences Centre, Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, We"},{"author_name":"Jennifer Kerkhof","author_inst":"Verspeeten Clinical Genome Centre, London Health Sciences Centre,"},{"author_name":"Jessica Rzasa","author_inst":"Verspeeten Clinical Genome Centre, London Health Sciences Centre,"},{"author_name":"Maha Saleh","author_inst":"Division of Medical Genetics, Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, Medical Genetics Program of Southwestern"},{"author_name":"Chitra Prasad","author_inst":"Division of Medical Genetics, Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, Medical Genetics Program of Southwestern"},{"author_name":"Victoria M Siu","author_inst":"Division of Medical Genetics, Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, Medical Genetics Program of Southwestern"},{"author_name":"Melissa T Carter","author_inst":"Department of Medical Genetics, Children's Hospital of Eastern Ontario, Department of Pediatrics, University of Ottawa, Children's Hospital of Eastern Ontario R"},{"author_name":"David A Dyment","author_inst":"Department of Medical Genetics, Children's Hospital of Eastern Ontario, Department of Pediatrics, University of Ottawa, Children's Hospital of Eastern Ontario R"},{"author_name":"Joanna Lazier","author_inst":"Children's Hospital of Eastern Ontario"},{"author_name":"Sarah L Sawyer","author_inst":"Department of Medical Genetics, Children's Hospital of Eastern Ontario, Department of Pediatrics, University of Ottawa, Children's Hospital of Eastern Ontario R"},{"author_name":"Angelica A Moresco","author_inst":"Division of Medical Genetics, Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, Medical Genetics Program of Southwestern"},{"author_name":"Maria Jimena Diaz","author_inst":"Department of Medical Genetics, National Pediatric Hospital J. P. Garrahan"},{"author_name":"Silvina L Abbate","author_inst":"Department of Medical Genetics, National Pediatric Hospital J. P. Garrahan"},{"author_name":"Philippe M Campeau","author_inst":"CHU Sainte-Justine Research Center"},{"author_name":"A. Micheil Innes","author_inst":"Departments of Medical Genetics and Pediatrics and Alberta Children's Hospital Research Institute, Cumming School of Medicine"},{"author_name":"Kym M Boycott","author_inst":"Department of Medical Genetics, Children's Hospital of Eastern Ontario, Department of Pediatrics, University of Ottawa, Children's Hospital of Eastern Ontario R"},{"author_name":"Bekim Sadikovic","author_inst":"Verspeeten Clinical Genome Centre, London Health Sciences Centre, Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, We"},{"author_name":"Tugce B Balci","author_inst":"Division of Medical Genetics, Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, Medical Genetics Program of Southwestern"}],"rel_date":"2026-07-14","rel_site":"medrxiv"},{"rel_title":"Genome-wide association study highlights 44 loci for transient ischemic attack and shared genetic architecture with stroke","rel_doi":"10.64898\/2026.07.10.26357754","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.10.26357754","rel_abs":"Transient ischemic attack (TIA) is a critical harbinger of subsequent stroke, and most genetic risk remains uncharacterized. Here we firstly performed the largest TIA genome-wide association study (GWAS) meta analysis in 1,332,453 European individuals (58,976 cases and 1,273,477 controls), followed by an independent replication in 610,409 non-European individuals (23,557 TIA and 586,852 controls), a multi-ancestry GWAS meta analysis in 1,942,862 individuals (82,533 cases and 1,860,329 controls), and a cross-trait GWAS meta-analysis of TIA with stroke and its subtypes. We identified 44 loci including 25 known stroke loci and 19 TIA specific loci (CELSR2, SLC4A7, CASC15, SRRM3, SLC44A1, LOC107984361, GSE1, LOC105372530, HCG20, OXR1, SLC4A1, RBBP8, TUSC3, DCC, PALMD, ZNF475, CTAGE1, FUT2 and MRPS6). Post-GWAS pinpointed 51 high confidence genes (24 are potential therapeutic targets) and 13 statistically significant pathways including protein-lipid complex, neurofibrillary tangle, high-density lipoprotein particle. These findings provide critical insights into the genetic basis of TIA.","rel_num_authors":15,"rel_authors":[{"author_name":"Shuyuan Hu","author_inst":"Capital Medical University"},{"author_name":"Ping Zhu","author_inst":"Capital Medical University"},{"author_name":"Shiyang Wu","author_inst":"Capital Medical University"},{"author_name":"Shan Gao","author_inst":"Capital Medical University"},{"author_name":"Ruibai Wang","author_inst":"Capital Medical University"},{"author_name":"Fengzhen Liu","author_inst":"Capital Medical University"},{"author_name":"Yijie He","author_inst":"Capital Medical University"},{"author_name":"Zhifa Han","author_inst":"Capital Medical University"},{"author_name":"Tao Wang","author_inst":"Capital Medical University"},{"author_name":"Mingxin Wang","author_inst":"Shengli Oilfield Central Hospital"},{"author_name":"Changhong Ren","author_inst":"Xuanwu Hospital, Capital Medical University"},{"author_name":"Xunming Ji","author_inst":"Capital Medical University"},{"author_name":"Wenbo Zhao","author_inst":"Xuanwu Hospital, Capital Medical University"},{"author_name":"Sijie Li","author_inst":"Xuanwu Hospital, Capital Medical University"},{"author_name":"Guiyou Liu","author_inst":"Capital Medical University"}],"rel_date":"2026-07-14","rel_site":"medrxiv"},{"rel_title":"Genome-wide association study highlights 44 loci for transient ischemic attack and shared genetic architecture with stroke","rel_doi":"10.64898\/2026.07.10.26357754","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.10.26357754","rel_abs":"Transient ischemic attack (TIA) is a critical harbinger of subsequent stroke, and most genetic risk remains uncharacterized. Here we firstly performed the largest TIA genome-wide association study (GWAS) meta analysis in 1,332,453 European individuals (58,976 cases and 1,273,477 controls), followed by an independent replication in 610,409 non-European individuals (23,557 TIA and 586,852 controls), a multi-ancestry GWAS meta analysis in 1,942,862 individuals (82,533 cases and 1,860,329 controls), and a cross-trait GWAS meta-analysis of TIA with stroke and its subtypes. We identified 44 loci including 25 known stroke loci and 19 TIA specific loci (CELSR2, SLC4A7, CASC15, SRRM3, SLC44A1, LOC107984361, GSE1, LOC105372530, HCG20, OXR1, SLC4A1, RBBP8, TUSC3, DCC, PALMD, ZNF475, CTAGE1, FUT2 and MRPS6). Post-GWAS pinpointed 51 high confidence genes (24 are potential therapeutic targets) and 13 statistically significant pathways including protein-lipid complex, neurofibrillary tangle, high-density lipoprotein particle. These findings provide critical insights into the genetic basis of TIA.","rel_num_authors":15,"rel_authors":[{"author_name":"Shuyuan Hu","author_inst":"Capital Medical University"},{"author_name":"Ping Zhu","author_inst":"Capital Medical University"},{"author_name":"Shiyang Wu","author_inst":"Capital Medical University"},{"author_name":"Shan Gao","author_inst":"Capital Medical University"},{"author_name":"Ruibai Wang","author_inst":"Capital Medical University"},{"author_name":"Fengzhen Liu","author_inst":"Capital Medical University"},{"author_name":"Yijie He","author_inst":"Capital Medical University"},{"author_name":"Zhifa Han","author_inst":"Capital Medical University"},{"author_name":"Tao Wang","author_inst":"Capital Medical University"},{"author_name":"Mingxin Wang","author_inst":"Shengli Oilfield Central Hospital"},{"author_name":"Changhong Ren","author_inst":"Xuanwu Hospital, Capital Medical University"},{"author_name":"Xunming Ji","author_inst":"Capital Medical University"},{"author_name":"Wenbo Zhao","author_inst":"Xuanwu Hospital, Capital Medical University"},{"author_name":"Sijie Li","author_inst":"Xuanwu Hospital, Capital Medical University"},{"author_name":"Guiyou Liu","author_inst":"Capital Medical University"}],"rel_date":"2026-07-14","rel_site":"medrxiv"},{"rel_title":"Should Multi-Cancer Early Detection Testing Replace Guideline-Recommended Colorectal Cancer Screening? A Comparative Modeling Analysis","rel_doi":"10.64898\/2026.07.10.26357782","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.10.26357782","rel_abs":"BackgroundColorectal cancer (CRC) screening strategies such as colonoscopy and fecal immunochemical testing (FIT) reduce CRC mortality through both early detection and prevention via precursor lesion removal. Multicancer early detection (MCED) blood tests offer the potential to detect multiple cancers with a single assay but provide little opportunity for cancer prevention. Whether the ability to detect multiple cancers can offset the loss of CRC prevention remains unclear.\n\nMethodsWe used microsimulation to compare MCED and guideline-recommended CRC screening strategies. CRC outcomes were simulated using CRC-SPIN v3.0 and non-CRC cancers using MCEDsim, calibrated to SEER incidence data. Assuming optimistic MCED preclinical sensitivity equal to published case-control estimates, we compared life-years gained and late-stage disease outcomes for annual FIT, decennial colonoscopy, and MCED-only strategies across a range of preclinical durations and survival benefit assumptions.\n\nResultsRelative to no screening, colonoscopy and FIT reduced late-stage diagnoses by 26% and 25%, respectively, versus 20%-32% for annual MCED screening. Across assumptions, MCED-only strategies generated 33%-51% as many life-years gained as colonoscopy.\n\nConclusionsCurrently available MCED tests are unlikely to be effective replacements for guideline-recommended CRC screening, which derives substantial benefit from the detection and removal of precursor lesions. MCED screening may provide additional benefit as a supplement to recommended CRC screening.","rel_num_authors":6,"rel_authors":[{"author_name":"Ishfaq Ahmad","author_inst":"Oregon Health & Science University"},{"author_name":"Carolyn M Rutter","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Chris E Maerzluft","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Isabel Dengos","author_inst":"Oregon Health & Science University"},{"author_name":"Kemal C Gogebakan","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Jane M Lange","author_inst":"Oregon Health & Science University"}],"rel_date":"2026-07-14","rel_site":"medrxiv"},{"rel_title":"Should Multi-Cancer Early Detection Testing Replace Guideline-Recommended Colorectal Cancer Screening? A Comparative Modeling Analysis","rel_doi":"10.64898\/2026.07.10.26357782","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.10.26357782","rel_abs":"BackgroundColorectal cancer (CRC) screening strategies such as colonoscopy and fecal immunochemical testing (FIT) reduce CRC mortality through both early detection and prevention via precursor lesion removal. Multicancer early detection (MCED) blood tests offer the potential to detect multiple cancers with a single assay but provide little opportunity for cancer prevention. Whether the ability to detect multiple cancers can offset the loss of CRC prevention remains unclear.\n\nMethodsWe used microsimulation to compare MCED and guideline-recommended CRC screening strategies. CRC outcomes were simulated using CRC-SPIN v3.0 and non-CRC cancers using MCEDsim, calibrated to SEER incidence data. Assuming optimistic MCED preclinical sensitivity equal to published case-control estimates, we compared life-years gained and late-stage disease outcomes for annual FIT, decennial colonoscopy, and MCED-only strategies across a range of preclinical durations and survival benefit assumptions.\n\nResultsRelative to no screening, colonoscopy and FIT reduced late-stage diagnoses by 26% and 25%, respectively, versus 20%-32% for annual MCED screening. Across assumptions, MCED-only strategies generated 33%-51% as many life-years gained as colonoscopy.\n\nConclusionsCurrently available MCED tests are unlikely to be effective replacements for guideline-recommended CRC screening, which derives substantial benefit from the detection and removal of precursor lesions. MCED screening may provide additional benefit as a supplement to recommended CRC screening.","rel_num_authors":6,"rel_authors":[{"author_name":"Ishfaq Ahmad","author_inst":"Oregon Health & Science University"},{"author_name":"Carolyn M Rutter","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Chris E Maerzluft","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Isabel Dengos","author_inst":"Oregon Health & Science University"},{"author_name":"Kemal C Gogebakan","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Jane M Lange","author_inst":"Oregon Health & Science University"}],"rel_date":"2026-07-14","rel_site":"medrxiv"},{"rel_title":"geneXplore: An Interactive Browser for X Chromosome-Wide Association Study Results","rel_doi":"10.64898\/2026.07.14.26357489","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.14.26357489","rel_abs":"SummaryThe X chromosome comprises approximately 5% of the human genome and encodes over 800 protein-coding genes, many of which exhibit sex-differentiated expression patterns due to escape from X chromosome inactivation (XCI) mechanisms. Despite its relevance to sex differences in complex traits, the X chromosome is routinely excluded from genome-wide association studies due to analytical challenges, and when analyzed, the impact of escape from XCI or sex is limitedly explored. No dedicated, publicly accessible browser for X chromosome-wide association study (XWAS) summary statistics currently exists, creating a barrier to systematic investigation of X-linked contributions to human traits. Here, we present geneXplore, an interactive web browser based on the PheWeb2 implementation, tailored for XWAS summary statistics across 1,944 phenotypes while distinguishing random XCI (rXCI), escape from XCI (eXCI), and sex-stratified analyses. Users can explore results via interactive plots (Manhattan and Miami, PheWAS and LocusZoom), searchable tables and access to cross-database lookup, with full summary statistics available for download.\n\nAvailability and ImplementationgeneXplore is freely available at https:\/\/genexplore.wustl.edu\/ with no registration required and will be maintained for a minimum of two years following publication. Source code is available at https:\/\/github.com\/Belloy-Lab\/geneXplore_XWAS_Browser under an MIT license.","rel_num_authors":9,"rel_authors":[{"author_name":"Noah Cook","author_inst":"Washington University in St. Louis"},{"author_name":"Jordan Boulais-Richard","author_inst":"Universite de Montreal"},{"author_name":"Youjie Zeng","author_inst":"Washington University in St. Louis"},{"author_name":"Chenyu Yang","author_inst":"Washington University in St. Louis"},{"author_name":"John Budde","author_inst":"Washington University in St. Louis"},{"author_name":"Daniel Taliun","author_inst":"McGill University"},{"author_name":"Sarah A Gagliano Taliun","author_inst":"Universite de Montreal"},{"author_name":"Carlos Cruchaga","author_inst":"Washington University in St. Louis"},{"author_name":"Michael E Belloy","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-07-14","rel_site":"medrxiv"},{"rel_title":"Vasculopathy of the small vessels is common in lacunar stroke - a 7T MRI study","rel_doi":"10.64898\/2026.07.09.26357711","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357711","rel_abs":"BackgroundLacunar stroke is a common and disabling cerebrovascular disease. Small-vessel vasculopathy is thought to be the most common underlying cause, but this has only been identified on histopathology. 7T MRI allows small vessels to be seen in vivo. This study aimed to investigate rates of small vessel vasculopathy in lacunar stroke using 7T MRI.\n\nMethodsPatients with lacunar stroke at an Australian tertiary stroke centre were prospectively screened and recruited to the study. Patients underwent 7T MRI with T1, T2, time-of-flight (TOF), diffusion-weighted imaging (DWI) and susceptibility-weighted imaging (SWI) sequences. Images were interpreted by two blinded neuroradiologists.\n\nResultsThe likely symptomatic perforator could be identified in 16\/19 (84%) of cases. Amongst cases where the symptomatic perforator was observed, 14\/16 (88%) of the symptomatic perforator vessels had focal stenosis consistent with steno-occlusive vasculopathy. There were 3\/19 (16%) of cases with associated large artery vasculopathy. There were 7\/16 (44%) cases where an occluded perforator was seen. The majority of patients had at least one vascular risk factor (15\/19, 79%) and there were no cases where non-atherosclerotic vasculopathy was suspected.\n\nConclusionsLacunar stroke is commonly associated with small vessel vasculopathy, likely due to atherosclerosis, which can be identified in vivo with 7T MRI time-of-flight imaging.","rel_num_authors":14,"rel_authors":[{"author_name":"Davor Pavlin-Premrl","author_inst":"Austin Hospital"},{"author_name":"Bradford Moffat","author_inst":"Melbourne Brain Centre - Royal Melbourne Hospital Campus"},{"author_name":"Rebecca Glarin","author_inst":"Melbourne Brain Centre - Royal Melbourne Hospital Campus"},{"author_name":"Vincent S Thijs","author_inst":"Florey"},{"author_name":"Nawaf Yassi","author_inst":"University of Melbourne"},{"author_name":"Mark W Parsons","author_inst":"University of New South Wales South Western Sydney Clinical School, Ingham Institute for Applied Medical Research"},{"author_name":"Peter J Mitchell","author_inst":"The Royal Melbourne Hospital"},{"author_name":"Julian Maingard","author_inst":"Austin Health \/ University of Melbourne"},{"author_name":"Hamed Asadi","author_inst":"Monash Medical Centre\/Austin Hospital\/Deakin University"},{"author_name":"Ashu Jhamb","author_inst":"St. Vincent's Hospital"},{"author_name":"Mark Schembri","author_inst":"Beaumont Hospital"},{"author_name":"Ali Khabaza","author_inst":"Austin Hospital"},{"author_name":"Anna H. Balabanski","author_inst":"The University of Melbourne"},{"author_name":"Bruce C V Campbell","author_inst":"The University of Melbourne Faculty of Medicine Dentistry and Health Sciences"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"MAGIC Composite Score Predicts Outcomes of Second-Line Therapy for Acute GVHD","rel_doi":"10.64898\/2026.07.09.26357664","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357664","rel_abs":"Approximately 30% of patients with acute graft-versus-host disease (GVHD) develop steroid-refractory disease and have very poor outcomes. Ruxolitinib has become the standard of care for steroid-refractory acute GVHD, but it is unclear which patients derive benefit. The MAGIC Composite Score (MCS), an algorithm that combines clinical symptoms and biomarkers, has been validated to predict outcomes at the start of primary GVHD treatment. Here, we evaluated its performance at the initiation of second-line treatment in 278 patients. MCS stratified patients into three risk groups (MCS1-3), with the majority (88%) classified as intermediate or high risk. Increasing MCS score was associated with progressively higher 1-year non-relapse mortality (NRM) rates (16%, 41%, and 73%; p<0.001), lower 1-year survival (77%, 56%, and 24%; p<0.001), and lower complete response (CR) rates at day 28 (47%, 38%, and 20%, respectively; p<0.01). The area under the receiver operating characteristic curve (AUROC) for 1-year NRM was significantly higher with MCS compared to clinical symptoms alone (0.70 vs. 0.63; p=0.023). Among patients treated with ruxolitinib, higher MCS similarly predicted higher NRM and lower survival and CR rates. Patients classified as MCS2\/3 had poor outcomes despite ruxolitinib, underscoring the need for novel therapies in this patient population. In conclusion the MCS is an accurate predictor of outcomes for patients who require second-line treatment and may be of use as an eligibility criterion for future clinical trials in this high-risk population.\n\nKey PointsO_LIMAGIC Composite Scores that integrate clinical symptoms and biomarker scores predict outcomes of second-line therapy for acute GVHD more accurately than clinical symptoms alone.\nC_LIO_LIMCS identifies patients with high NRM despite treatment with ruxolitinib.\nC_LI","rel_num_authors":35,"rel_authors":[{"author_name":"Tara Sebastian","author_inst":"Division of Hematology\/Medical Oncology, The Tisch Cancer Center, Icahn School of Medicine at Mount Sinai"},{"author_name":"Daniela Weber","author_inst":"Department of Hematology and Oncology, Internal Medicine III, University of Regensburg"},{"author_name":"Aaron M. Etra","author_inst":"Division of Hematology\/Medical Oncology, The Tisch Cancer Center, Icahn School of Medicine at Mount Sinai"},{"author_name":"Ingrid Vasova","author_inst":"Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universitat Erlangen-Nurnberg and University Hospital Erlangen"},{"author_name":"Francis Ayuk","author_inst":"Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf"},{"author_name":"Hannah K. Choe","author_inst":"Division of Hematology, Blood and Marrow Transplantation Program, The Ohio State University Comprehensive Cancer Center"},{"author_name":"Zachariah DeFilipp","author_inst":"Hematopoietic Cell Transplant and Cellular Therapy Program, Massachusetts General Hospital"},{"author_name":"Francesco Quagliarella","author_inst":"Department of Pediatric Hematology\/Oncology and of Cell and Gene Therapy, Bambino Gesu Children's Hospital, Istituto di Ricovero e Cura a Carattere Scientifico"},{"author_name":"Karni Bedirian","author_inst":"Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai"},{"author_name":"Marcio Augusto Diniz","author_inst":"Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai"},{"author_name":"Paibel Aguayo-Hiraldo","author_inst":"Division of Bone Marrow Transplantation, Children's Hospital Los Angeles, University of Southern California"},{"author_name":"Peter Bader","author_inst":"Division of Stem Cell Transplantation and Immunology, Department of Pediatrics, Goethe University Frankfurt"},{"author_name":"Janna Baez","author_inst":"Division of Hematology\/Medical Oncology, The Tisch Cancer Center, Icahn School of Medicine at Mount Sinai"},{"author_name":"Chantiya Chanswangphuwana","author_inst":"Division of Hematology and Center of Excellence in Translational Hematology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospi"},{"author_name":"Gilbert Eng","author_inst":"Division of Hematology\/Medical Oncology, The Tisch Cancer Center, Icahn School of Medicine at Mount Sinai"},{"author_name":"Thomas Francke","author_inst":"Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School"},{"author_name":"Elizabeth O. Hexner","author_inst":"Department of Medicine and Abramson Cancer Center, Perelman School of Medicine"},{"author_name":"Nikolaos Katsivelos","author_inst":"Division of Hematology\/Medical Oncology, The Tisch Cancer Center, Icahn School of Medicine at Mount Sinai"},{"author_name":"Carrie L. Kitko","author_inst":"Pediatric Hematology\/Oncology Division, Vanderbilt University Medical Center"},{"author_name":"Sabrina Kraus","author_inst":"Department of Internal Medicine II, University Hospital of Wurzburg"},{"author_name":"Ioannis E. Louloudis","author_inst":"Division of Hematology\/Medical Oncology, The Tisch Cancer Center, Icahn School of Medicine at Mount Sinai"},{"author_name":"George Morales","author_inst":"Division of Hematology\/Medical Oncology, The Tisch Cancer Center, Icahn School of Medicine at Mount Sinai"},{"author_name":"Ryotaro Nakamura","author_inst":"Department of Hematology\/Hematopoietic Cell Transplantation, City of Hope"},{"author_name":"Timothy S. Olson","author_inst":"Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia"},{"author_name":"Muna Qayed","author_inst":"Department of Pediatrics, Emory University School of Medicine"},{"author_name":"Pavan Reddy","author_inst":"Dan Duncan Cancer Center, Baylor College of Medicine"},{"author_name":"Ran Reshef","author_inst":"Division of Hematology\/Oncology and Columbia Center for Translational Immunology"},{"author_name":"Tal Schechter","author_inst":"Division of Hematology\/Oncology\/Blood and Marrow Transplant, The Hospital for Sick Children, University of Toronto"},{"author_name":"Tingyu Wang","author_inst":"Division of Hematology\/Medical Oncology, The Tisch Cancer Center, Icahn School of Medicine at Mount Sinai"},{"author_name":"Matthias Wolf","author_inst":"Department of Medicine I, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg"},{"author_name":"Rachel Young","author_inst":"Division of Hematology\/Medical Oncology, The Tisch Cancer Center, Icahn School of Medicine at Mount Sinai"},{"author_name":"Robert Zeiser","author_inst":"Department of Medicine I, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg"},{"author_name":"William J. Hogan","author_inst":"Division of Hematology, Mayo Clinic"},{"author_name":"John E. Levine","author_inst":"Division of Hematology\/Medical Oncology, The Tisch Cancer Center, Icahn School of Medicine at Mount Sinai"},{"author_name":"James L.M. Ferrara","author_inst":"Division of Hematology\/Medical Oncology, The Tisch Cancer Center, Icahn School of Medicine at Mount Sinai"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"From Bias Detection to Distributional Calibration: Negative Controls for Shared Systematic Error in Real-world Evidence Pipelines","rel_doi":"10.64898\/2026.07.08.26357550","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357550","rel_abs":"Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been linked to heterogeneous, potentially pleiotropic effects across organ systems, motivating outcome-wide comparative risk profiling in real-world data. A central challenge in such analyses is residual bias that remains after adjustment for observed confounders, which can distort effect estimates and mis-calibrate uncertainty. We present distributional diagnosis and calibration (DC), which uses panels of negative control outcomes (NCOs) to diagnose residual bias and calibrate uncertainty. DC evaluates null behavior via p-value uniformity and empirical coverage across NCOs, and uses the empirical distribution of NCO effect estimates to calibrate confidence intervals for prespecified primary outcomes. DC is modular: it can wrap around commonly used causal inference methods and operates directly on summary statistics, supporting collaborative research under data-sharing constraints. Using electronic health records from a large U.S. clinical research network (152.7 million patients), we compared GLP-1RAs with sodium-glucose cotransporter 2 inhibitors across 15 prespecified outcomes spanning cardiovascular, mental health, and genitourinary domains using four causal estimators. Across outcomes and methods, DC diagnostics revealed substantial and method-dependent residual systematic error. DC calibration attenuated systematic error signals observed in negative controls and yielded more stable, better-calibrated estimates for clinical outcomes, supporting DC as a practical strategy to strengthen the credibility of outcome-wide real-world CER.\n\nDisclaimerThe contents are solely the responsibility of the authors and do not necessarily represent the official views of, or an endorsement by, Food and Drug Administration (FDA)\/Department of Health and Human Services (HHS) or the U.S. Government.","rel_num_authors":19,"rel_authors":[{"author_name":"Huiyuan Wang","author_inst":"University of Pennsylvania"},{"author_name":"Bingyu Zhang","author_inst":"University of Pennsylvania"},{"author_name":"Yuqing Lei","author_inst":"University of Pennsylvania"},{"author_name":"Yiwen Lu","author_inst":"University of Pennsylvania"},{"author_name":"Dazheng Zhang","author_inst":"University of Pennsylvania"},{"author_name":"Xinyao Jian","author_inst":"University of Pennsylvania"},{"author_name":"Yuru Zhu","author_inst":"University of Pennsylvania"},{"author_name":"Wenjie Hu","author_inst":"University of Pennsylvania"},{"author_name":"Haitao Chu","author_inst":"Pfizer"},{"author_name":"Yong Chen","author_inst":"Pfizer"},{"author_name":"Marc A Suchard","author_inst":"University of California, Los Angeles"},{"author_name":"Patrick B Ryan","author_inst":"Janssen Research and Development"},{"author_name":"George Hripcsak","author_inst":"Columbia University Irving Medical Center"},{"author_name":"David A Asch","author_inst":"University of Pennsylvania"},{"author_name":"Yun Lu","author_inst":"Food and Drug Administration"},{"author_name":"Yu Bin","author_inst":"University of California Berkeley"},{"author_name":"Martijn J Schuemie","author_inst":"University of California, Los Angeles"},{"author_name":"Yumou Qiu","author_inst":"Peking University"},{"author_name":"Yong Chen","author_inst":"University of Pennsylvania"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"From Bias Detection to Distributional Calibration: Negative Controls for Shared Systematic Error in Real-world Evidence Pipelines","rel_doi":"10.64898\/2026.07.08.26357550","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357550","rel_abs":"Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been linked to heterogeneous, potentially pleiotropic effects across organ systems, motivating outcome-wide comparative risk profiling in real-world data. A central challenge in such analyses is residual bias that remains after adjustment for observed confounders, which can distort effect estimates and mis-calibrate uncertainty. We present distributional diagnosis and calibration (DC), which uses panels of negative control outcomes (NCOs) to diagnose residual bias and calibrate uncertainty. DC evaluates null behavior via p-value uniformity and empirical coverage across NCOs, and uses the empirical distribution of NCO effect estimates to calibrate confidence intervals for prespecified primary outcomes. DC is modular: it can wrap around commonly used causal inference methods and operates directly on summary statistics, supporting collaborative research under data-sharing constraints. Using electronic health records from a large U.S. clinical research network (152.7 million patients), we compared GLP-1RAs with sodium-glucose cotransporter 2 inhibitors across 15 prespecified outcomes spanning cardiovascular, mental health, and genitourinary domains using four causal estimators. Across outcomes and methods, DC diagnostics revealed substantial and method-dependent residual systematic error. DC calibration attenuated systematic error signals observed in negative controls and yielded more stable, better-calibrated estimates for clinical outcomes, supporting DC as a practical strategy to strengthen the credibility of outcome-wide real-world CER.\n\nDisclaimerThe contents are solely the responsibility of the authors and do not necessarily represent the official views of, or an endorsement by, Food and Drug Administration (FDA)\/Department of Health and Human Services (HHS) or the U.S. Government.","rel_num_authors":19,"rel_authors":[{"author_name":"Huiyuan Wang","author_inst":"University of Pennsylvania"},{"author_name":"Bingyu Zhang","author_inst":"University of Pennsylvania"},{"author_name":"Yuqing Lei","author_inst":"University of Pennsylvania"},{"author_name":"Yiwen Lu","author_inst":"University of Pennsylvania"},{"author_name":"Dazheng Zhang","author_inst":"University of Pennsylvania"},{"author_name":"Xinyao Jian","author_inst":"University of Pennsylvania"},{"author_name":"Yuru Zhu","author_inst":"University of Pennsylvania"},{"author_name":"Wenjie Hu","author_inst":"University of Pennsylvania"},{"author_name":"Haitao Chu","author_inst":"Pfizer"},{"author_name":"Yong Chen","author_inst":"Pfizer"},{"author_name":"Marc A Suchard","author_inst":"University of California, Los Angeles"},{"author_name":"Patrick B Ryan","author_inst":"Janssen Research and Development"},{"author_name":"George Hripcsak","author_inst":"Columbia University Irving Medical Center"},{"author_name":"David A Asch","author_inst":"University of Pennsylvania"},{"author_name":"Yun Lu","author_inst":"Food and Drug Administration"},{"author_name":"Yu Bin","author_inst":"University of California Berkeley"},{"author_name":"Martijn J Schuemie","author_inst":"University of California, Los Angeles"},{"author_name":"Yumou Qiu","author_inst":"Peking University"},{"author_name":"Yong Chen","author_inst":"University of Pennsylvania"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"From Bias Detection to Distributional Calibration: Negative Controls for Shared Systematic Error in Real-world Evidence Pipelines","rel_doi":"10.64898\/2026.07.08.26357550","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357550","rel_abs":"Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been linked to heterogeneous, potentially pleiotropic effects across organ systems, motivating outcome-wide comparative risk profiling in real-world data. A central challenge in such analyses is residual bias that remains after adjustment for observed confounders, which can distort effect estimates and mis-calibrate uncertainty. We present distributional diagnosis and calibration (DC), which uses panels of negative control outcomes (NCOs) to diagnose residual bias and calibrate uncertainty. DC evaluates null behavior via p-value uniformity and empirical coverage across NCOs, and uses the empirical distribution of NCO effect estimates to calibrate confidence intervals for prespecified primary outcomes. DC is modular: it can wrap around commonly used causal inference methods and operates directly on summary statistics, supporting collaborative research under data-sharing constraints. Using electronic health records from a large U.S. clinical research network (152.7 million patients), we compared GLP-1RAs with sodium-glucose cotransporter 2 inhibitors across 15 prespecified outcomes spanning cardiovascular, mental health, and genitourinary domains using four causal estimators. Across outcomes and methods, DC diagnostics revealed substantial and method-dependent residual systematic error. DC calibration attenuated systematic error signals observed in negative controls and yielded more stable, better-calibrated estimates for clinical outcomes, supporting DC as a practical strategy to strengthen the credibility of outcome-wide real-world CER.\n\nDisclaimerThe contents are solely the responsibility of the authors and do not necessarily represent the official views of, or an endorsement by, Food and Drug Administration (FDA)\/Department of Health and Human Services (HHS) or the U.S. Government.","rel_num_authors":19,"rel_authors":[{"author_name":"Huiyuan Wang","author_inst":"University of Pennsylvania"},{"author_name":"Bingyu Zhang","author_inst":"University of Pennsylvania"},{"author_name":"Yuqing Lei","author_inst":"University of Pennsylvania"},{"author_name":"Yiwen Lu","author_inst":"University of Pennsylvania"},{"author_name":"Dazheng Zhang","author_inst":"University of Pennsylvania"},{"author_name":"Xinyao Jian","author_inst":"University of Pennsylvania"},{"author_name":"Yuru Zhu","author_inst":"University of Pennsylvania"},{"author_name":"Wenjie Hu","author_inst":"University of Pennsylvania"},{"author_name":"Haitao Chu","author_inst":"Pfizer"},{"author_name":"Yong Chen","author_inst":"Pfizer"},{"author_name":"Marc A Suchard","author_inst":"University of California, Los Angeles"},{"author_name":"Patrick B Ryan","author_inst":"Janssen Research and Development"},{"author_name":"George Hripcsak","author_inst":"Columbia University Irving Medical Center"},{"author_name":"David A Asch","author_inst":"University of Pennsylvania"},{"author_name":"Yun Lu","author_inst":"Food and Drug Administration"},{"author_name":"Yu Bin","author_inst":"University of California Berkeley"},{"author_name":"Martijn J Schuemie","author_inst":"University of California, Los Angeles"},{"author_name":"Yumou Qiu","author_inst":"Peking University"},{"author_name":"Yong Chen","author_inst":"University of Pennsylvania"}],"rel_date":"2026-07-13","rel_site":"medrxiv"}]}