{"gname":"Georgia Institute of Technology","grp_id":"20","rels":[{"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":"Objectives To 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. Methods A 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. Results Biomarker-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). Conclusions Two 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":"DREAM 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. The 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":"DREAM 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. The 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":"Background: Recurrent 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. Methods: Genome-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). Results: The 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). Conclusions: Independent 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":"Background: Recurrent 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. Methods: Genome-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). Results: The 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). Conclusions: Independent 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":"Background Colorectal cancer (CRC) screening strategies such as colonoscopy and fecal immuno-chemical 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. Methods We 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. Results: Relative 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. Conclusions Currently 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":"Background Colorectal cancer (CRC) screening strategies such as colonoscopy and fecal immuno-chemical 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. Methods We 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. Results: Relative 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. Conclusions Currently 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":"Summary: The 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. Availability and Implementation: geneXplore 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":"Evidence for lanthanide and PQQ dependent dehydrogenases in Eukarya","rel_doi":"10.64898\/2026.07.14.738520","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.14.738520","rel_abs":"Lanthanides function as enzyme cofactors in bacteria, where they are widely distributed in pyrroloquinoline quinone-dependent 8-bladed beta-propeller dehydrogenases. No lanthanide-dependent enzymes, however, have been described outside prokaryotes. Here, we combined structural bioinformatics, phylogenetics, AlphaFold3 co-folding, coordination-sphere comparison, and quantum-mechanical cluster modeling to search for and rank putative lanthanide-coordinating 8-bladed beta-propeller enzymes in Eukarya. We identified candidate lanthanide-coordinating proteins in a diverse range of eukaryotes, predominantly plants and fungi, including species of clear industrial and agricultural relevance. A high-confidence subset matched validated bacterial Ln-binders based on both geometric similarity to canonical Ln-binding sites and on predicted Ln3+ versus Ca2+ selectivity. Our findings indicate that lanthanide biology likely extends beyond bacteria, with implications for plant, fungal, and broader eukaryotic metabolism, and warrant targeted biochemical investigation.","rel_num_authors":5,"rel_authors":[{"author_name":"Colin Michael Robinson","author_inst":"University of California, Berkeley"},{"author_name":"Norma Cecilia Martinez-Gomez","author_inst":"University of California, Berkeley"},{"author_name":"Jacob A West-Roberts","author_inst":"University of California, Berkeley"},{"author_name":"Marcos Yianis Voutsinos","author_inst":"Monash University"},{"author_name":"Jill Banfield","author_inst":"University of California, Berkeley"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"Protein tertiary packing is nearly achiral","rel_doi":"10.64898\/2026.07.13.737334","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.13.737334","rel_abs":"The chirality of proteins originates at the C stereocentre of each L-amino acid, and is expressed in secondary structure as the consistent twist of -helices and {beta}-sheets. How far does this handedness propagate as secondary-structure elements pack into a tertiary fold? This question is central to the development of neural networks for the design of heterochiral and mixed-chirality proteins containing mirror-image D-amino acids. Such networks are most effectively trained on the far more abundant structural data available for natural all-L proteins, yet in practice they must generate and evaluate the reflected, D-configured counterparts, which are not explicitly represented in the training set. Here, I develop a spatial tessellation-based parity-odd descriptor, the signed volume of Delaunay tetrahedra (VD), to measure how chirality is distributed in protein structure. Reflecting a structure only flips the sign of any parity-odd descriptor, so the asymmetry of the VD distribution quantifies the chirality of a given sequence-local or tertiary structural element. I find that the signed Delaunay volume distribution within individual secondary-structure elements is strongly asymmetric, but this handedness largely cancels once elements pack against one another. The resulting tertiary distribution is nearly symmetric across a broad range of structures, from monomers to protein-protein and protein-ligand complexes. Individual folds can nonetheless be strongly handed at the tertiary scale, solenoid and repeat proteins most of all, yet across a broad sample of the fold universe this handedness cancels, leaving the ensemble near-achiral. Tertiary packing is therefore only weakly chiral, with the small residual handedness greatest at binding interfaces and near-zero in the buried core. How much chirality a model perceives in a D-protein is thus largely a choice of representation, a trade-off between reflection symmetry and the richness of structural information the representation retains. Because VD reduces the parity-odd content of each structural element to a single scalar while capturing tertiary protein packing, it offers a natural representation for the design of heterochiral complexes and mixed-chirality proteins.","rel_num_authors":1,"rel_authors":[{"author_name":"Sagar D Khare","author_inst":"Rutgers University"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"Integrated pangenome and population genomics reveal selection on standing genetic variation driving fiber flax-linseed divergence","rel_doi":"10.64898\/2026.07.09.737549","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737549","rel_abs":"Flax (Linum usitatissimum L.) has been domesticated for dual end uses as linseed and fiber flax, yet the genomic basis of morphotype divergence remains unclear. Here, we constructed a morphotype-resolved pangenome by integrating three newly generated near telomere-to-telomere genome assemblies with 14 previously published ones. Despite substantial variation in assembly size, driven primarily by DNA transposons, gene content was highly conserved, with little evidence for significant morphotype-specific gene presence-absence variation. Population genomic analyses of 407 accessions revealed that fiber flax had reduced nucleotide diversity, extended linkage disequilibrium, and a more compact population structure relative to linseed, consistent with stronger selection and a narrower genetic base. Genome-wide differentiation was heterogeneous and concentrated in discrete regions. Integration of FST, nucleotide diversity ratios, Tajima's D, and genome-wide association signals identified morphotype-enriched genomic blocks distributed across the genome. Many candidate regions are primarily supported by directional shifts in nucleotide diversity rather than extreme differentiation, indicating selection on standing genetic variation. Genome-wide association analyses identified 1,712 unique quantitative trait nucleotides (QTNs), with predominantly small effect sizes and strong enrichment in gene-proximal regions, consistent with a polygenic architecture. Overall, fiber flax traits tend to be controlled by fewer loci with moderate-to-large effects, whereas linseed traits exhibit a more diffuse genetic architecture. Patterns of Tajima's D further support non-classical selection dynamics, with predominantly positive values in linseed and localized negative values in fiber flax, consistent with selection on standing genetic variation. Together, our results suggest that flax morphotype divergence is driven primarily by selection on pre-existing allelic variation within a conserved gene repertoire. This study provides a comprehensive framework linking genome structure, population genomics, and trait architecture, and highlights the importance of standing genetic variation as a key resource for flax breeding and improvement.","rel_num_authors":8,"rel_authors":[{"author_name":"Frank M. You","author_inst":"Ottawa Research and Development Centre, Agriculture and Agri-Food Canada"},{"author_name":"Chunfang Zheng","author_inst":"Ottawa Research and Development Centre, Agriculture and Agri-Food Canada"},{"author_name":"Tara Edwards","author_inst":"Ottawa Research and Development Centre, Agriculture and Agri-Food Canada"},{"author_name":"Pingchuan Li","author_inst":"Ottawa Research and Development Centre, Agriculture and Agri-Food Canada"},{"author_name":"Khalid Y. Rashid","author_inst":"Ottawa Research and Development Centre, Agriculture and Agri-Food Canada"},{"author_name":"Scott D. Duguid","author_inst":"Morden Research and Development Centre, Agriculture and Agri-Food Canada"},{"author_name":"Hellen Booker","author_inst":"Department of Plant Agriculture, University of Guelph"},{"author_name":"Sylvie Cloutier","author_inst":"Ottawa Research and Development Centre, Agriculture and Agri-Food Canada"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"Identification of a new mycobacterial peptide that controls the activity of the iron-dependent regulator, IdeR.","rel_doi":"10.64898\/2026.07.13.738276","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.13.738276","rel_abs":"ABSTRACT Mycobacterium tuberculosis (Mtb) must regulate intracellular iron to survive in the host and cause disease. IdeR (Iron-dependent Regulator) is an essential Mtb protein that governs intracellular iron levels by regulating the expression of genes involved in iron metabolism. IdeR expression, however, is iron independent, and the mechanisms that regulate IdeR's function are not fully understood. Here, we report the discovery of a previously unrecognized Mtb peptide (PRI) that regulates IdeR activity. PRI is induced under iron limitation; it binds to IdeR and restricts its activity. In addition, we demonstrate that altering the balance between PRI and IdeR impairs iron homeostasis and intracellular replication of Mtb in macrophages. The findings reveal a new paradigm in mycobacterial iron regulation and open new avenues for targeting iron homeostatic mechanisms in Mtb, which are crucial for virulence and antibiotic resistance.","rel_num_authors":8,"rel_authors":[{"author_name":"Gloria M Rodriguez","author_inst":"Rutgers University"},{"author_name":"Ashis Biswas","author_inst":"Rutgers University"},{"author_name":"Assirbad Behura","author_inst":"Rutgers University"},{"author_name":"Nishant Sharma","author_inst":"Rutgers University"},{"author_name":"Shamba Gupta","author_inst":"Rutgers University"},{"author_name":"Irene Perez","author_inst":"Universidad de Zaragoza, Spain"},{"author_name":"Jesus Gonzalo Asensio","author_inst":"University of Zaragoza"},{"author_name":"Jun Yong Choi","author_inst":"Queens College-CUNY"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"The UPRMT is a critical mediator of nutrient immunity","rel_doi":"10.64898\/2026.07.11.737880","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737880","rel_abs":"Mitochondria serve as critical signaling hubs that monitor the intracellular environment to orchestrate cellular stress responses during pathogen infection. The mitochondrial unfolded protein response (UPRMT), a key surveillance pathway, is widely considered to be activated by pathogen-derived toxins that directly damage host mitochondria. In contrast to this prevailing model, we demonstrate that E. faecalis, which lacks specialized mitochondrial toxins, activates the UPRMT in C. elegans via a combination of metabolic and oxidative stress. As both C. elegans and E. faecalis are heme auxotrophs, E. faecalis-ingested animals result in severe heme deficiency, leading to the disruption of the electron transport chain and activation of the UPRMT. During live infection, this primary mitochondrial stress is further amplified due to the Fenton reaction, driven by host NADPH oxidase BLI-3-generated hydrogen peroxide. Ultimately, our findings position the UPRMT as a fundamental homeostatic sensor that monitors metabolic and oxidative imbalances at the host-pathogen interface.","rel_num_authors":5,"rel_authors":[{"author_name":"Ayane Maruichi","author_inst":"University of California, Berkeley"},{"author_name":"Hanlin Zhang","author_inst":"University of California, Berkeley \/ Chinese Academy of Sciences, Shanghai"},{"author_name":"Alexandra May Viret","author_inst":"University of California, Berkeley"},{"author_name":"Larry K Joe","author_inst":"University of California, Berkeley"},{"author_name":"Andrew Dillin","author_inst":"University of California, Berkeley"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"Biophysical Characterization of ParBS Condensates suggests a physical mechanism for segregation","rel_doi":"10.64898\/2026.07.09.737391","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.737391","rel_abs":"The ParABS system orchestrates chromosome segregation in many bacterial species. The centromere-like parS sites serve as nucleation points for the initial binding of the ParB protein. Subsequent diffusion on adjacent, non-specific DNA regions (spreading) in the presence of CTP and binding of more ParB molecules along with DNA looping via ParB-ParB interactions bring distal parts of the chromosome into proximity. ParB interaction with the ParA-ATPase motor protein, then, drives genomic segregation. It has been shown that in some bacterial species, the ParB-parS complex undergoes phase separation into a condensate. However, the physico-chemical properties of such condensates and their response to forces, such as those they may face in the cell, have not yet been characterized. Performing turbidity measurements in the presence of CTP and various concentrations of DNA and physiologically relevant mono and divalent salt It was shown that Mg2+ facilitates, while K+ concentrations higher than ~20 mM disfavors, condensate formation. Microrheology measurements showed that condensates of ParB and DNA including parS sites (ParB-parS DNA) in the presence of CTP, are viscoelastic with a viscosity at Troom of ~5 Pa s and able to quickly respond to deformations with a network relaxation time of 0.1 s. Additionally, fluorescence combined with force spectroscopy showed that mechanical disruption of ParB-DNA condensates in the presence of CTP requires ~ 5-7.5 pN of tension in the DNA, which is lower than the force required to stall a molecular motor such as RNA polymerase, but higher than the force required for the relocation of chromosomes and plasmids during segregation. These results support the idea that ParB-parS condensates dynamically rearrange at the molecular level while maintaining the cohesion necessary to sustain the drag force of segregation without interfering with genomic transactions. This physical mechanism could be the basis for the critical role of ParB-parS condensates in organizing and partitioning bacterial chromosomes.","rel_num_authors":5,"rel_authors":[{"author_name":"Ritika Gupta","author_inst":"Clemson Unversity"},{"author_name":"Suleyman Ucuncuoglu","author_inst":"University of Iowa"},{"author_name":"William Seth Childers","author_inst":"University of Pittsburgh"},{"author_name":"David Dunlap","author_inst":"Clemson University"},{"author_name":"Laura Finzi","author_inst":"Clemson University"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"Large-scale automated detection reveals pervasive sex imbalance in biomedical research","rel_doi":"10.64898\/2026.07.13.738332","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.13.738332","rel_abs":"Sex is a critical biological variable that impacts disease risk, progression, and treatment response across virtually every organ system. However, decades of biomedical research have relied primarily on male study subjects, leaving large gaps in our understanding of female-specific disease biology. Quantifying the extent of this imbalance across thousands of disease areas and millions of publicly available biological samples has remained computationally intractable. Here, we present a multimodal computational framework that infers the biological sex of ~230,000 publicly available human transcriptome samples and links inferred sex labels to disease terms extracted from ~9,000 associated study records and ~5,000 publication abstracts to quantify sex imbalance at scale. Applying this approach revealed that the majority of disease terms with the largest research-derived sex imbalance are skewed toward male representation, including areas with no known biological justification for that imbalance. After adjusting for global sex-specific disease prevalence to isolate biologically unjustified imbalance, up to 58% of all disease terms showed male-leaning association. Diseases including glioblastoma, cirrhosis, idiopathic pulmonary fibrosis, and schizophrenia emerged as critically understudied in females despite affecting both sexes comparably. These findings provide a principled, data-driven basis for prioritizing compensatory research efforts and offer a reusable framework for ongoing monitoring of sex representation in the biomedical literature.","rel_num_authors":6,"rel_authors":[{"author_name":"Lydia E Valtadoros","author_inst":"University of Colorado Anschutz Medical Campus"},{"author_name":"Parker Hicks","author_inst":"University of Colorado Anschutz Medical Campus"},{"author_name":"Hao Yuan","author_inst":"Michigan State University"},{"author_name":"Mansooreh Ahmadian","author_inst":"University of Colorado Anschutz Medical Campus"},{"author_name":"Kayla A Johnson","author_inst":"University of Colorado Anschutz Medical Campus"},{"author_name":"Arjun Krishnan","author_inst":"University of Colorado Anschutz Medical Campus"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"Developmental signaling reveals functionally enriched human-specific gene regulation in telencephalic progenitors","rel_doi":"10.64898\/2026.07.13.738326","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.13.738326","rel_abs":"Comparative transcriptomic studies of neural progenitors implicated in human brain expansion have identified extensive baseline gene expression divergence, yet these differences are weakly enriched for functions relevant to development and disease. This suggests that functionally important regulatory divergence may emerge only under specific developmental signaling conditions. Here, we profiled morphogen-dependent gene expression responses in matched telencephalic neuroepithelial cells (telNECs) from human, chimpanzee, and orangutan at the onset of cortical neurogenesis. Baseline interspecies differences were extensive but functionally diffuse. In contrast, a distinct set of genes exhibited species-divergent responses to morphogen stimulation despite conserved baseline expression. These response genes were strongly enriched for regulators of progenitor proliferation and differentiation, neurodevelopmental disorder risk genes, and loci harboring human-lineage sequence changes. Together, these findings show that developmental signaling exposes a functionally enriched class of regulatory divergence beyond baseline comparisons and provide a framework for identifying evolutionarily relevant gene regulation during human brain development.","rel_num_authors":6,"rel_authors":[{"author_name":"Reed C McMullen","author_inst":"University of California San Francisco"},{"author_name":"Bryan J. Pavlovic","author_inst":"University of California San Francisco"},{"author_name":"Dani Swope","author_inst":"University of California San Francisco"},{"author_name":"David S Aley","author_inst":"University of California San Francisco"},{"author_name":"Nathan K Schaefer","author_inst":"University of California San Francisco"},{"author_name":"Alex Aaron Pollen","author_inst":"UCSF"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"Single-cell transcriptomic atlas of frontoinsular cortex reveals molecular correlates of selective neuronal vulnerability in FTD","rel_doi":"10.64898\/2026.07.13.738307","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.13.738307","rel_abs":"Frontotemporal dementia (FTD) is characterized by selective neuronal vulnerability, yet the features that predispose specific neuron types to degeneration remain unclear. We performed single-nucleus RNA sequencing of frontoinsular cortex, a region affected early in behavioral variant FTD, across individuals with C9orf72-associated and sporadic FTD-MND spectrum disease. By enriching for large projection neurons, we resolved molecular subtypes of layer 5 extratelencephalic neurons, including von Economo neurons, and identified selective depletion of specific layer 2\/3 and layer 5 neuron subtypes, convergent across genotypes. Despite selective neuronal loss, disease-associated transcriptional changes were convergent across excitatory neuron populations, suggesting that they reflect upstream pathophysiology or shared responses to local neurodegeneration. By relating neighborhood-level depletion in disease to gene expression in controls, we found that baseline cellular respiration and ATP synthesis predict neuronal vulnerability in disease. These findings define molecular correlates of selective neuronal vulnerability in FTD and provide a framework linking cell type and state to neurodegeneration.","rel_num_authors":19,"rel_authors":[{"author_name":"Arnar Breevoort","author_inst":"UCSF"},{"author_name":"Dimitar Ivanov","author_inst":"Harvard"},{"author_name":"Liam Horan-Portelance","author_inst":"UCSF"},{"author_name":"Alissa Nana","author_inst":"UCSF"},{"author_name":"Sarat Vatsavayai","author_inst":"UCSF"},{"author_name":"Alex Tudoras Miravet","author_inst":"UCSF"},{"author_name":"Jenelle L. Wallace","author_inst":"UCSF"},{"author_name":"Jingwen W. Ding","author_inst":"UCSF"},{"author_name":"Felipe L. Pereira","author_inst":"Mayo Clinic"},{"author_name":"Kristen Fernhoff","author_inst":"UCSF"},{"author_name":"Maria Luisa Gorno-Tempini","author_inst":"UCSF"},{"author_name":"Salvatore Spina","author_inst":"UCSF"},{"author_name":"Jennifer S. Yokoyama","author_inst":"UCSF"},{"author_name":"Howard J. Rosen","author_inst":"UCSF"},{"author_name":"Lea T. Grinberg","author_inst":"Mayo Clinic"},{"author_name":"Frank M. J. Jacobs","author_inst":"University of Amsterdam"},{"author_name":"Bruce L. Miller","author_inst":"UCSF"},{"author_name":"William W. Seeley","author_inst":"UCSF"},{"author_name":"Alex A. Pollen","author_inst":"UCSF"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"Forest degradation reshapes trophic functioning in vertebrate food webs across Amazonian forests","rel_doi":"10.64898\/2026.07.13.737465","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.13.737465","rel_abs":"The Amazon is a mosaic of ecosystems, accounting for 13% of all known species globally, and responsible for providing a variety of ecosystem services, including a key role in global climate regulation. However, 18% of the Amazon forest cover has been lost completely and a further 38% degraded, threatening biodiversity and millions of local livelihoods. Currently, little is known about how this impacts the functioning of ecological communities. Here, we combine an energetic approach with biodiversity metrics to quantify ecosystem functioning in mammal and bird food webs across Amazonia, along a gradient of forest degradation linked to road proximity. We show that even under relatively low disturbance, ecosystem functions shift: carnivory increases closer to roads, driven by generalist species that persist under these conditions, whereas herbivory declines mainly due to reduced herbivore biomass and species richness. This suggests that processes associated with forest degradation can alter energy flow even where biodiversity metrics remain relatively unchanged, highlighting energetic approaches as sensitive indicators of ecosystem disruption.","rel_num_authors":66,"rel_authors":[{"author_name":"Ana Carolina Antunes","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany"},{"author_name":"Ulrich Brose","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany; Friedrich-Schiller University Jena, Faculty of Biological Scien"},{"author_name":"Anelise Montanarin","author_inst":"Instituto Nacional de Pesquisas da Amazonia, Programa de Pos-Graduacao em Biologia (Ecologia), Manaus, Brazil; Grupo de Pesquisa de Ecologia e Conservacao de Fe"},{"author_name":"Benjamin Rosenbaum","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany"},{"author_name":"Carlos A. Peres","author_inst":"School of Environmental Sciences, University of East Anglia, Norwich, UK; Instituto Jurua, Manaus, Brazil"},{"author_name":"Carsten Meyer","author_inst":"Department of Biosciences, Durham University, Durham, UK; German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany"},{"author_name":"Henrique Miguel Pereira","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany; Martin Luther University Halle-Wittenberg, Halle (Saale), Germa"},{"author_name":"Jessica Hines","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany"},{"author_name":"Jingyi Li","author_inst":"Institute of Ecology, College of Urban and Environmental Sciences, and State Key Laboratory for Vegetation Structure, Function and Construction (VegLab), Peking"},{"author_name":"Tainara Sobroza","author_inst":"Universidade Federal do Oeste do Para (UFOPA), Santarem, Brazil"},{"author_name":"Emilio Berti","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany; Friedrich-Schiller University Jena, Faculty of Biological Scien"},{"author_name":"Adrian Barnett","author_inst":"Natural Resources Institute, University of Greenwich, Chatham, UK"},{"author_name":"Alexine Keuroghlian","author_inst":"Instituto Pro-Tapir, Campo Grande, Mato Grosso do Sul, Brazil"},{"author_name":"Antonio Carlos da Silva Zanzini","author_inst":"Laboratorio de Ecologia e Manejo da Vida Silvestre, Departamento de Ciencias Florestais, Universidade Federal de Lavras, Lavras, Brazil"},{"author_name":"Arlison B. Castro","author_inst":"Laboratorio de Ecologia e Conservacao, Universidade Federal do Oeste do Para, Santarem, Brazil; Instituto Nacional de Pesquisas da Amazonia, Programa de Pos-Gra"},{"author_name":"Benoit de Thoisy","author_inst":"Kwata NGO, Cayenne, French Guiana"},{"author_name":"Carlos Rodrigo Brocardo","author_inst":"Laboratorio de Ecologia e Conservacao da Biodiversidade Subtropical, Universidade Federal da Fronteira Sul (UFFS), Chapeco, Brazil; Programa de Pos-graduacao Co"},{"author_name":"Clarissa Rosa","author_inst":"Instituto Nacional de Pesquisas da Amazonia, Coordenacao de Dinamica Ambiental, Manaus, Brazil"},{"author_name":"Daniel da Silva Ferraz","author_inst":"Rede Eco-Diversa para Conservacao da Biodiversidade, Campo Grande, Brazil"},{"author_name":"Daniel Gomes da Rocha","author_inst":"Department of Biological & Biomedical Sciences, Southwestern Oklahoma State University, Weatherford, USA"},{"author_name":"Dian Carlos Pinheiro Rosa","author_inst":"Laboratorio de Ecologia e Conservacao, Universidade Federal do Oeste do Para, Santarem, Brazil"},{"author_name":"Diogo Maia Grabin","author_inst":"Grupo de Pesquisa de Ecologia e Conservacao de Felinos na Amazonia, Instituto de Desenvolvimento Mamiraua, Tefe, Brazil"},{"author_name":"Eduardo Nakano-Oliveira","author_inst":"Instituto de Pesquisas Cananeia (IPeC), Cananeia, Brazil"},{"author_name":"Elildo Alves Ribeiro de Carvalho Jr.","author_inst":"Centro Nacional de Pesquisa e Conservacao de Mamiferos Carnivoros, Instituto Chico Mendes de Conservacao da Biodiversidade, Atibaia, Brazil; Rede de Pesquisa em"},{"author_name":"Eloisa Neves Mendonca","author_inst":"Reserva Biologica do Gurupi, ICMBio, Maranhao, Brazil"},{"author_name":"Emerson M. Vieira","author_inst":"Laboratory of Vertebrate Ecology (Ecovert), Department of Ecology, Institute of Biological Sciences, University of Brasilia, Brasilia, Brazil"},{"author_name":"Emiliana Isasi-Catala","author_inst":"Wildlife Conservation Society, Lima, Peru"},{"author_name":"Emiliano Esterci Ramalho","author_inst":"Grupo de Pesquisa de Ecologia e Conservacao de Felinos na Amazonia, Instituto de Desenvolvimento Mamiraua, Tefe, Brazil; Instituto Pro-carnivoros, Atibaia, Braz"},{"author_name":"Fabricio Baccaro","author_inst":"Coordenacao de Tecnologia e Inovacao, Instituto Nacional de Pesquisas da Amazonia, Manaus, Brazil; INCT SinBiAm - Sintese da Biodiversidade Amazonica, Brazil"},{"author_name":"Fernanda Michalski","author_inst":"Postgraduate Programme in Tropical Biodiversity, Federal University of Amapa, Macapa, Brazil; Instituto Pro-carnivoros, Atibaia, Brazil"},{"author_name":"Fernanda Santos","author_inst":"Mastozoologia, Museu Paraense Emilio Goeldi, Belem, Brazil; Instituto Tecnologico Vale - DS, Belem, Brazil"},{"author_name":"Fernando Anaguano Yancha","author_inst":"Wildlife Conservation Society, Ecuador Program, Quito, Ecuador"},{"author_name":"Francesca Belem Lopes Palmeira","author_inst":"RLadies Ribeirao Preto, Ribeirao Preto, Brazil; rOpenSci, Berkeley, USA"},{"author_name":"Gabriel de Avila Batista","author_inst":"Independent researcher"},{"author_name":"Galo Zapata-Rios","author_inst":"Wildlife Conservation Society, Ecuador Program, Quito, Ecuador"},{"author_name":"Gilson de Souza Ferreira Neto","author_inst":"Universidade Federal do Amazonas (UFAM), Manaus, Brazil; Instituto Nacional de Pesquisas da Amazonia, Programa de Pos-Graduacao em Biologia (Ecologia), Manaus, "},{"author_name":"Guilherme Costa Alvarenga","author_inst":"WildCRU, Biology Department, University of Oxford, Oxford, UK; Grupo de Pesquisa de Ecologia e Conservacao de Felinos na Amazonia, Instituto de Desenvolvimento "},{"author_name":"Helena Alves do Prado","author_inst":"Graduate Program in Ecology and Evolution, Rio de Janeiro State University (UERJ), Rio de Janeiro, Brazil"},{"author_name":"Hugo C. M. Costa","author_inst":"Instituto Jurua, Manaus, Brazil"},{"author_name":"Joao Marcelo Deliberador Miranda","author_inst":"Departamento de Biologia, Universidade Estadual do Centro-Oeste - UNICENTRO, Guarapuava, Brazil"},{"author_name":"Julia Salvador Maldonado","author_inst":"Department of Ecosystem Science and Management, Ecology and Evolution Program, University of Wyoming, Wyoming, USA; Pontificia Universidad Catolica del Ecuador,"},{"author_name":"Karen Borges-Almeida","author_inst":"Instituto de Ciencias Biologicas, Universidade Federal de Goias, Goiania, Brazil"},{"author_name":"Leonardo Maracahipes-Santos","author_inst":"Instituto de Pesquisa Ambiental da Amazonia (IPAM), Canarana, Brazil"},{"author_name":"Lucas Paolucci","author_inst":"Departamento de Biologia Geral, Universidade Federal de Vicosa, Vicosa, Brazil"},{"author_name":"Luciana Zago da Silva","author_inst":"Departamento de Biologia, Universidade Estadual do Centro-Oeste - UNICENTRO, Guarapuava, Brazil"},{"author_name":"Maira Benchimol","author_inst":"Applied Ecology and Conservation Lab, Universidade Estadual de Santa Cruz (UESC), Ilheus, Brazil"},{"author_name":"Marcela Guimaraes Moreira Lima","author_inst":"Laboratorio de Biogeografia da Conservacao e Macroecologia, Universidade Federal do Para, Brazil"},{"author_name":"Paula Ribeiro Prist","author_inst":"Forests and Grasslands Team, International Union for Conservation of Nature (IUCN), Washington, USA; University of Sao Paulo (USP), Sao Paulo, Brazil"},{"author_name":"Paulo Monteiro Brando","author_inst":"Yale School of the Environment, Yale University, New Haven, USA; Instituto de Pesquisa Ambiental da Amazonia (IPAM), Canarana, Brazil"},{"author_name":"Raphael Foscarini","author_inst":"Universidade Federal de Ouro Preto (UFOP), Ouro Preto, Brazil"},{"author_name":"Renato Richard Hilario","author_inst":"Department of Environment and Development, Federal University of Amapa, Macapa, Brazil"},{"author_name":"Ricardo Sampaio","author_inst":"Centro Nacional de Pesquisa e Conservacao de Mamiferos Carnivoros, Instituto Chico Mendes de Conservacao da Biodiversidade, Atibaia, Brazil"},{"author_name":"Robert B. Wallace","author_inst":"Wildlife Conservation Society, Bolivia Program, La Paz, Bolivia"},{"author_name":"Rossano Marchetti Ramos","author_inst":"Centro Nacional de Monitoramento e Informacoes Ambientais (CENIMA), Instituto Brasileiro do Meio Ambiente e dos Recursos Naturais Renovaveis (IBAMA), Brasilia, "},{"author_name":"Rodolfo Vasquez Martinez","author_inst":"Jardin Botanico de Missouri-Peru, Oxapampa, Peru; Missouri Botanical Garden, St. Louis, Missouri, USA"},{"author_name":"Samir G. Rolim","author_inst":"Centro de Formacao em Ciencias Agroflorestais, Universidade Federal do Sul da Bahia, Ilheus, Brazil"},{"author_name":"Rocio del Pilar Rojas Gonzales","author_inst":"Jardin Botanico de Missouri-Peru, Oxapampa, Peru; Missouri Botanical Garden, St. Louis, Missouri, USA"},{"author_name":"Santiago Espinosa","author_inst":"Facultad de Ciencias, Universidad Autonoma de San Luis Potosi, Mexico; Facultad de Ciencias Exactas, Naturales y Ambientales, Pontificia Universidad Catolica de"},{"author_name":"Tony Enrique Noriega Pina","author_inst":"Department of Ecology and Fauna, National University of the Peruvian Amazon (UNAP), Iquitos, Peru"},{"author_name":"Wagner Tadeu Vieira Santiago","author_inst":"Centro de Estudos do Ambiente e do Mar (CESAM), Universidade de Aveiro, Aveiro, Portugal"},{"author_name":"Ana Yoko Ykeuti Meiga","author_inst":"School of Natural Resources and Environment, University of Florida, Gainesville, USA"},{"author_name":"Ana Paula de Almeida Correa","author_inst":"Universidade Federal de Ouro Preto (UFOP), Ouro Preto, Brazil"},{"author_name":"Andre Pinassi Antunes","author_inst":"Rede de Pesquisa em Conservacao, Uso e Manejo da Fauna da Amazonia (RedeFauna), Manaus, Brazil; Centro Nacional de Pesquisa e Conservacao de Mamiferos Carnivoro"},{"author_name":"Victor Lery Caetano-Andrade","author_inst":"Department of Coevolution of Land Use and Urbanisation, Max Planck Institute of Geoanthropology, Jena, Germany"},{"author_name":"Regison da Costa de Oliveira","author_inst":"Laboratorio de Manejo Florestal (LMF), Instituto Nacional de Pesquisas da Amazonia (INPA), Manaus, Brazil"},{"author_name":"Benoit Gauzens","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany; Friedrich-Schiller University Jena, Faculty of Biological Scien"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"Forest degradation reshapes trophic functioning in vertebrate food webs across Amazonian forests","rel_doi":"10.64898\/2026.07.13.737465","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.13.737465","rel_abs":"The Amazon is a mosaic of ecosystems, accounting for 13% of all known species globally, and responsible for providing a variety of ecosystem services, including a key role in global climate regulation. However, 18% of the Amazon forest cover has been lost completely and a further 38% degraded, threatening biodiversity and millions of local livelihoods. Currently, little is known about how this impacts the functioning of ecological communities. Here, we combine an energetic approach with biodiversity metrics to quantify ecosystem functioning in mammal and bird food webs across Amazonia, along a gradient of forest degradation linked to road proximity. We show that even under relatively low disturbance, ecosystem functions shift: carnivory increases closer to roads, driven by generalist species that persist under these conditions, whereas herbivory declines mainly due to reduced herbivore biomass and species richness. This suggests that processes associated with forest degradation can alter energy flow even where biodiversity metrics remain relatively unchanged, highlighting energetic approaches as sensitive indicators of ecosystem disruption.","rel_num_authors":66,"rel_authors":[{"author_name":"Ana Carolina Antunes","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany"},{"author_name":"Ulrich Brose","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany; Friedrich-Schiller University Jena, Faculty of Biological Scien"},{"author_name":"Anelise Montanarin","author_inst":"Instituto Nacional de Pesquisas da Amazonia, Programa de Pos-Graduacao em Biologia (Ecologia), Manaus, Brazil; Grupo de Pesquisa de Ecologia e Conservacao de Fe"},{"author_name":"Benjamin Rosenbaum","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany"},{"author_name":"Carlos A. Peres","author_inst":"School of Environmental Sciences, University of East Anglia, Norwich, UK; Instituto Jurua, Manaus, Brazil"},{"author_name":"Carsten Meyer","author_inst":"Department of Biosciences, Durham University, Durham, UK; German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany"},{"author_name":"Henrique Miguel Pereira","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany; Martin Luther University Halle-Wittenberg, Halle (Saale), Germa"},{"author_name":"Jessica Hines","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany"},{"author_name":"Jingyi Li","author_inst":"Institute of Ecology, College of Urban and Environmental Sciences, and State Key Laboratory for Vegetation Structure, Function and Construction (VegLab), Peking"},{"author_name":"Tainara Sobroza","author_inst":"Universidade Federal do Oeste do Para (UFOPA), Santarem, Brazil"},{"author_name":"Emilio Berti","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany; Friedrich-Schiller University Jena, Faculty of Biological Scien"},{"author_name":"Adrian Barnett","author_inst":"Natural Resources Institute, University of Greenwich, Chatham, UK"},{"author_name":"Alexine Keuroghlian","author_inst":"Instituto Pro-Tapir, Campo Grande, Mato Grosso do Sul, Brazil"},{"author_name":"Antonio Carlos da Silva Zanzini","author_inst":"Laboratorio de Ecologia e Manejo da Vida Silvestre, Departamento de Ciencias Florestais, Universidade Federal de Lavras, Lavras, Brazil"},{"author_name":"Arlison B. Castro","author_inst":"Laboratorio de Ecologia e Conservacao, Universidade Federal do Oeste do Para, Santarem, Brazil; Instituto Nacional de Pesquisas da Amazonia, Programa de Pos-Gra"},{"author_name":"Benoit de Thoisy","author_inst":"Kwata NGO, Cayenne, French Guiana"},{"author_name":"Carlos Rodrigo Brocardo","author_inst":"Laboratorio de Ecologia e Conservacao da Biodiversidade Subtropical, Universidade Federal da Fronteira Sul (UFFS), Chapeco, Brazil; Programa de Pos-graduacao Co"},{"author_name":"Clarissa Rosa","author_inst":"Instituto Nacional de Pesquisas da Amazonia, Coordenacao de Dinamica Ambiental, Manaus, Brazil"},{"author_name":"Daniel da Silva Ferraz","author_inst":"Rede Eco-Diversa para Conservacao da Biodiversidade, Campo Grande, Brazil"},{"author_name":"Daniel Gomes da Rocha","author_inst":"Department of Biological & Biomedical Sciences, Southwestern Oklahoma State University, Weatherford, USA"},{"author_name":"Dian Carlos Pinheiro Rosa","author_inst":"Laboratorio de Ecologia e Conservacao, Universidade Federal do Oeste do Para, Santarem, Brazil"},{"author_name":"Diogo Maia Grabin","author_inst":"Grupo de Pesquisa de Ecologia e Conservacao de Felinos na Amazonia, Instituto de Desenvolvimento Mamiraua, Tefe, Brazil"},{"author_name":"Eduardo Nakano-Oliveira","author_inst":"Instituto de Pesquisas Cananeia (IPeC), Cananeia, Brazil"},{"author_name":"Elildo Alves Ribeiro de Carvalho Jr.","author_inst":"Centro Nacional de Pesquisa e Conservacao de Mamiferos Carnivoros, Instituto Chico Mendes de Conservacao da Biodiversidade, Atibaia, Brazil; Rede de Pesquisa em"},{"author_name":"Eloisa Neves Mendonca","author_inst":"Reserva Biologica do Gurupi, ICMBio, Maranhao, Brazil"},{"author_name":"Emerson M. Vieira","author_inst":"Laboratory of Vertebrate Ecology (Ecovert), Department of Ecology, Institute of Biological Sciences, University of Brasilia, Brasilia, Brazil"},{"author_name":"Emiliana Isasi-Catala","author_inst":"Wildlife Conservation Society, Lima, Peru"},{"author_name":"Emiliano Esterci Ramalho","author_inst":"Grupo de Pesquisa de Ecologia e Conservacao de Felinos na Amazonia, Instituto de Desenvolvimento Mamiraua, Tefe, Brazil; Instituto Pro-carnivoros, Atibaia, Braz"},{"author_name":"Fabricio Baccaro","author_inst":"Coordenacao de Tecnologia e Inovacao, Instituto Nacional de Pesquisas da Amazonia, Manaus, Brazil; INCT SinBiAm - Sintese da Biodiversidade Amazonica, Brazil"},{"author_name":"Fernanda Michalski","author_inst":"Postgraduate Programme in Tropical Biodiversity, Federal University of Amapa, Macapa, Brazil; Instituto Pro-carnivoros, Atibaia, Brazil"},{"author_name":"Fernanda Santos","author_inst":"Mastozoologia, Museu Paraense Emilio Goeldi, Belem, Brazil; Instituto Tecnologico Vale - DS, Belem, Brazil"},{"author_name":"Fernando Anaguano Yancha","author_inst":"Wildlife Conservation Society, Ecuador Program, Quito, Ecuador"},{"author_name":"Francesca Belem Lopes Palmeira","author_inst":"RLadies Ribeirao Preto, Ribeirao Preto, Brazil; rOpenSci, Berkeley, USA"},{"author_name":"Gabriel de Avila Batista","author_inst":"Independent researcher"},{"author_name":"Galo Zapata-Rios","author_inst":"Wildlife Conservation Society, Ecuador Program, Quito, Ecuador"},{"author_name":"Gilson de Souza Ferreira Neto","author_inst":"Universidade Federal do Amazonas (UFAM), Manaus, Brazil; Instituto Nacional de Pesquisas da Amazonia, Programa de Pos-Graduacao em Biologia (Ecologia), Manaus, "},{"author_name":"Guilherme Costa Alvarenga","author_inst":"WildCRU, Biology Department, University of Oxford, Oxford, UK; Grupo de Pesquisa de Ecologia e Conservacao de Felinos na Amazonia, Instituto de Desenvolvimento "},{"author_name":"Helena Alves do Prado","author_inst":"Graduate Program in Ecology and Evolution, Rio de Janeiro State University (UERJ), Rio de Janeiro, Brazil"},{"author_name":"Hugo C. M. Costa","author_inst":"Instituto Jurua, Manaus, Brazil"},{"author_name":"Joao Marcelo Deliberador Miranda","author_inst":"Departamento de Biologia, Universidade Estadual do Centro-Oeste - UNICENTRO, Guarapuava, Brazil"},{"author_name":"Julia Salvador Maldonado","author_inst":"Department of Ecosystem Science and Management, Ecology and Evolution Program, University of Wyoming, Wyoming, USA; Pontificia Universidad Catolica del Ecuador,"},{"author_name":"Karen Borges-Almeida","author_inst":"Instituto de Ciencias Biologicas, Universidade Federal de Goias, Goiania, Brazil"},{"author_name":"Leonardo Maracahipes-Santos","author_inst":"Instituto de Pesquisa Ambiental da Amazonia (IPAM), Canarana, Brazil"},{"author_name":"Lucas Paolucci","author_inst":"Departamento de Biologia Geral, Universidade Federal de Vicosa, Vicosa, Brazil"},{"author_name":"Luciana Zago da Silva","author_inst":"Departamento de Biologia, Universidade Estadual do Centro-Oeste - UNICENTRO, Guarapuava, Brazil"},{"author_name":"Maira Benchimol","author_inst":"Applied Ecology and Conservation Lab, Universidade Estadual de Santa Cruz (UESC), Ilheus, Brazil"},{"author_name":"Marcela Guimaraes Moreira Lima","author_inst":"Laboratorio de Biogeografia da Conservacao e Macroecologia, Universidade Federal do Para, Brazil"},{"author_name":"Paula Ribeiro Prist","author_inst":"Forests and Grasslands Team, International Union for Conservation of Nature (IUCN), Washington, USA; University of Sao Paulo (USP), Sao Paulo, Brazil"},{"author_name":"Paulo Monteiro Brando","author_inst":"Yale School of the Environment, Yale University, New Haven, USA; Instituto de Pesquisa Ambiental da Amazonia (IPAM), Canarana, Brazil"},{"author_name":"Raphael Foscarini","author_inst":"Universidade Federal de Ouro Preto (UFOP), Ouro Preto, Brazil"},{"author_name":"Renato Richard Hilario","author_inst":"Department of Environment and Development, Federal University of Amapa, Macapa, Brazil"},{"author_name":"Ricardo Sampaio","author_inst":"Centro Nacional de Pesquisa e Conservacao de Mamiferos Carnivoros, Instituto Chico Mendes de Conservacao da Biodiversidade, Atibaia, Brazil"},{"author_name":"Robert B. Wallace","author_inst":"Wildlife Conservation Society, Bolivia Program, La Paz, Bolivia"},{"author_name":"Rossano Marchetti Ramos","author_inst":"Centro Nacional de Monitoramento e Informacoes Ambientais (CENIMA), Instituto Brasileiro do Meio Ambiente e dos Recursos Naturais Renovaveis (IBAMA), Brasilia, "},{"author_name":"Rodolfo Vasquez Martinez","author_inst":"Jardin Botanico de Missouri-Peru, Oxapampa, Peru; Missouri Botanical Garden, St. Louis, Missouri, USA"},{"author_name":"Samir G. Rolim","author_inst":"Centro de Formacao em Ciencias Agroflorestais, Universidade Federal do Sul da Bahia, Ilheus, Brazil"},{"author_name":"Rocio del Pilar Rojas Gonzales","author_inst":"Jardin Botanico de Missouri-Peru, Oxapampa, Peru; Missouri Botanical Garden, St. Louis, Missouri, USA"},{"author_name":"Santiago Espinosa","author_inst":"Facultad de Ciencias, Universidad Autonoma de San Luis Potosi, Mexico; Facultad de Ciencias Exactas, Naturales y Ambientales, Pontificia Universidad Catolica de"},{"author_name":"Tony Enrique Noriega Pina","author_inst":"Department of Ecology and Fauna, National University of the Peruvian Amazon (UNAP), Iquitos, Peru"},{"author_name":"Wagner Tadeu Vieira Santiago","author_inst":"Centro de Estudos do Ambiente e do Mar (CESAM), Universidade de Aveiro, Aveiro, Portugal"},{"author_name":"Ana Yoko Ykeuti Meiga","author_inst":"School of Natural Resources and Environment, University of Florida, Gainesville, USA"},{"author_name":"Ana Paula de Almeida Correa","author_inst":"Universidade Federal de Ouro Preto (UFOP), Ouro Preto, Brazil"},{"author_name":"Andre Pinassi Antunes","author_inst":"Rede de Pesquisa em Conservacao, Uso e Manejo da Fauna da Amazonia (RedeFauna), Manaus, Brazil; Centro Nacional de Pesquisa e Conservacao de Mamiferos Carnivoro"},{"author_name":"Victor Lery Caetano-Andrade","author_inst":"Department of Coevolution of Land Use and Urbanisation, Max Planck Institute of Geoanthropology, Jena, Germany"},{"author_name":"Regison da Costa de Oliveira","author_inst":"Laboratorio de Manejo Florestal (LMF), Instituto Nacional de Pesquisas da Amazonia (INPA), Manaus, Brazil"},{"author_name":"Benoit Gauzens","author_inst":"German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany; Friedrich-Schiller University Jena, Faculty of Biological Scien"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"An integrated atlas of RNA to protein concordance across human tissues and cell types","rel_doi":"10.64898\/2026.07.13.738336","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.13.738336","rel_abs":"Differential expression studies, single-cell atlases, and target discovery pipelines measure RNA as a proxy for protein. Across human tissues, RNA explains only 40 to 60% of the variance in protein, and no framework resolves which genes reliably translate RNA into protein. We present an integrated atlas that matches single-cell transcriptomics from Tabula Sapiens and the Human Brain Cell Atlas to cell type-resolved immunohistochemistry from the Human Protein Atlas, comprising 488,190 observations across 11,154 genes, 24 tissues, and 53 cell types. For each gene we defined a suppression rate and separated genes into concordant, variable, and suppressed classes. The pooled correlation of {rho} {approx} 0.4 reflects the mixing of these classes, and concordance depends on the interaction between gene and tissue. Suppression is predictable from gene sequence alone and traces to reduced translational efficiency and assembly-dependent degradation rather than to mRNA decay. The suppressed class is enriched for drug targets nominated on clinical evidence but not those validated by compound activity. We implement these classifications in an R package, concordR, and audit proteins nominated as brain-derived targets in neurodegeneration, where almost none survive at the protein level. Our atlas establishes RNA to protein concordance as a measurable property of the individual gene.","rel_num_authors":2,"rel_authors":[{"author_name":"Caitlin A Finney","author_inst":"Westmead Institute for Medical Research"},{"author_name":"Artur Shvetcov","author_inst":"Westmead Institute for Medical Research"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"SparseSeg: Target-Conditioned Discovery Segmentation of Cryo-Volume Electron Microscopy Under Sparse Annotation","rel_doi":"10.64898\/2026.07.13.738355","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.13.738355","rel_abs":"Cryo-volume electron microscopy (cryo-vEM) enables near-native visualization of cellular ultrastructure, but its broad use is limited by low image contrast and the high cost of dense voxel-level annotation. Existing automated segmentation methods often generalize poorly across cell types, organelles, and imaging conditions. Here, we introduce SparseSeg, a target-conditioned, sparsity-driven segmentation framework that treats organelle segmentation as a discovery process rather than a closed-set classification task. SparseSeg uses a small number of context-specific exemplars to iteratively propagate reliable supervision through the volume. It combines sparse patch-based sampling, a multi-kernel U-Net, and geometry-consistent refinement to expand accurate segmentation while suppressing context-dependent false positives. Across serial cryo-FIB--SEM and conventional vEM datasets, SparseSeg achieves robust segmentation under extreme sparse annotation, including settings with less than 1% labeled slices. This framework reduces annotation burden while preserving morphological fidelity for quantitative cryo-vEM analysis.","rel_num_authors":4,"rel_authors":[{"author_name":"Bowen Shi","author_inst":"Zhejiang University"},{"author_name":"Yanjun Li","author_inst":"ZJU--Hangzhou Global Scientific and Technological Innovation Center"},{"author_name":"Qi Ouyang","author_inst":"Zhejiang University"},{"author_name":"Yanan Zhu","author_inst":"Zhejiang University"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"The activity, divergence, and evolutionary degradation of modern-day homing endonucleases and their reconstructed ancestors","rel_doi":"10.64898\/2026.07.13.738334","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.13.738334","rel_abs":"Homing endonucleases are selfish genetic elements that drive the mobilization of their own coding sequences, often in concert with surrounding introns. Homing endonuclease genes usually display life cycles in which they accumulate inactivating mutations after invading a host genomic target site, leading to eventual removal from the genome. We identified several hundred novel HEGs and determined the distribution of their behaviors and activities. Approximately ten percent are expressed as properly folded functional proteins that cleave predictable DNA target sites. Another approximately twenty percent display significant expression but little to no cleavage activity; the remainder display severely reduced expression. Despite the presence of debilitating mutations throughout most HEGs, ancestral reconstructions yielded endonucleases with improved expression and stability. One such reconstruction, at a hypothetical node preceding highly diverged HEs that cleave unique target sites, binds but does not cleave their individual targets. It instead cleaves a DNA sequence that represents a hybrid of those modern-day DNA targets while displaying a specificity profile that resembled those of previously characterized HEs. Its DNA-bound crystal structure adds detail to our understanding of how homing endonuclease DNA contacting surfaces and residues shift and rearrange during evolution, ultimately leading to their action at new target sites.","rel_num_authors":7,"rel_authors":[{"author_name":"Juliana C Young","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Abigail R. Lambert","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Janet M Young","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Lindsey A. Doyle","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Miriam Silverstein","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"David R. Edgell","author_inst":"University of Western Ontario"},{"author_name":"Barry L. Stoddard","author_inst":"Fred Hutchinson Cancer Center"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"Biochemical Indicators of Atlantification and Diapause Strategy in Arctic Copepods Point to a Decrease in Copepod-mediated Carbon Sequestration","rel_doi":"10.64898\/2026.07.13.738257","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.13.738257","rel_abs":"Arctic ecosystems are critically endangered by rising temperatures and changing hydrography, especially the intrusion of increasingly warm water from the Atlantic Ocean known as Atlantification. In addition to housing fragile biodiversity, Arctic copepods and their lipids play a crucial role in cycling carbon by transporting carbon into the deep ocean through their diapausing behaviors. Here, we explored the lipidomes of the Arctic copepod Calanus glacialis, collected from three fjords around Svalbard during November 2022 when C. glacialis are known to be in diapause. These three field sites provide a natural laboratory experiment, as they are influenced by different water masses with varying degrees of Atlantic water, and experience vast differences in sea ice coverage over the year. These environmental differences were clearly reflected in the lipidomic analysis, with stations influenced most by Atlantic Warm Water having the lowest total lipid concentrations and the lowest accumulation of storage lipids necessary for entering diapause. Membrane lipids were a significant proportion of the Svalbard copepod lipidomes, with the highest ratios observed at the Atlantified site. The high membrane lipid and high triacylglycerol concentrations were interpreted as signs of active feeding. This was further corroborated by fatty acid composition analysis, which revealed dietary biomarkers of carnivory at Atlantified sites. The copepods from the site most insulated from Atlantic influence had more than double the amount of storage lipids per individual and fatty acids associated with diatom biomass, indicating assimilation in the spring. Ultimately, the decrease in lipid content observed in association with Atlantification around Svalbard will impact diapause patterns, as Calanus species need 20-30% more WE to successfully complete diapause. In turn, this will impact the magnitude of carbon sequestration through the seasonal lipid pump, not to mention having radiating effects through the Arctic food web where Calanus glacialis plays an important role.","rel_num_authors":5,"rel_authors":[{"author_name":"Jiwoon Hwang","author_inst":"Department of Earth and Planetary Science, University of California, Berkeley Berkeley, CA; Carnegie Institution for Science, Stanford, CA"},{"author_name":"Mathieu Lutier","author_inst":"Department of Biosciences, University of Oslo, Norway"},{"author_name":"Khuong V Dinh","author_inst":"Department of Biosciences, University of Oslo, Norway"},{"author_name":"Katrine Borga","author_inst":"Department of Biosciences, University of Oslo, Norway"},{"author_name":"Bethanie R Edwards","author_inst":"Department of Earth and Planetary Science, University of California, Berkeley Berkeley, CA"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"Ependymomas are cancers of the pre-neural crest\/roof plate lineage","rel_doi":"10.64898\/2026.07.13.736818","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.13.736818","rel_abs":"Distinct molecular variants of the brain cancer ependymoma are distributed along the rostral-caudal extent of the central nervous system (CNS). Historically proposed to arise from ventricular ependyma, recent studies have suggested conflicting cellular origins, including the neural radial glia and the roof plate lineages. Using single-cell transcriptomics, immunohistochemistry, and lineage tracing, we demonstrate that ependymomas across all CNS compartments transcriptionally mirror MSX1+ve pre-neural crest\/roof plate (Pre-NC\/RP) lineage derivatives. Ependymoma subgroups recapitulate the spatial and molecular diversity of regional Pre-NC\/RP populations, while retaining conserved MSX1 expression. Expression of the oncogenic fusion ZFTA-RELA within the murine Pre-NC\/RP lineage generated tumors that faithfully resembled human ependymoma. These findings identify a common embryonic cellular origin for ependymomas and reconcile previously conflicting models of tumorigenesis.","rel_num_authors":69,"rel_authors":[{"author_name":"Polina Balin","author_inst":"Baylor College of Medicine"},{"author_name":"Sachin A Kumar","author_inst":"Boston Children's Hospital"},{"author_name":"Riley Galton","author_inst":"Stowers Institute for Medical Research"},{"author_name":"Alberto Delaidelli","author_inst":"Harvard Medical School"},{"author_name":"Wilda Orisme","author_inst":"St. Jude Children's Research Hospital"},{"author_name":"Parthiv Haldipur","author_inst":"Seattle Children's Research Institute"},{"author_name":"Ncedile Mankahla","author_inst":"The Hospital for Sick Children"},{"author_name":"Amr Saadeldin","author_inst":"Baylor College of Medicine"},{"author_name":"Nik von Krosigk","author_inst":"University of Toronto"},{"author_name":"Maria C Vladoiu","author_inst":"McMaster University"},{"author_name":"Anders W Erickson","author_inst":"University of Toronto"},{"author_name":"Meyer Barembaum","author_inst":"California Institute of Technology"},{"author_name":"Jake Millman","author_inst":"Seattle Children's Research Institute"},{"author_name":"Amy J Banks","author_inst":"University of Calgary"},{"author_name":"Jeffrey T Joseph","author_inst":"University of Calgary"},{"author_name":"Omar Khan","author_inst":"Seattle Children's Research Institute"},{"author_name":"Simon Du","author_inst":"Seattle Children's Research Institute"},{"author_name":"Olga Sirbu","author_inst":"University of Toronto"},{"author_name":"Winnie Ong","author_inst":"University of Toronto"},{"author_name":"Damien Faury","author_inst":"McGill University"},{"author_name":"Vicente Santa Maria Lopez","author_inst":"Baylor College of Medicine"},{"author_name":"Sigourney Bonner","author_inst":"CRUK Cambridge Institute"},{"author_name":"Jennifer C Coleman","author_inst":"University of Cambridge"},{"author_name":"Jason Eigenbrood","author_inst":"CRUK Cambridge Institute"},{"author_name":"Elizabeth Alexandra Cooper","author_inst":"University of Cambridge"},{"author_name":"Jonathan K Duh","author_inst":"Stanford University School of Medicine"},{"author_name":"Jiao Zhang","author_inst":"Baylor College of Medicine"},{"author_name":"John JY Lee","author_inst":"Massachusetts General Hospital"},{"author_name":"Alexandra Rasnitsyn","author_inst":"University of Toronto"},{"author_name":"Aidan E Cedillo","author_inst":"Baylor College of Medicine"},{"author_name":"Gabrielle Persad","author_inst":"University of Toronto"},{"author_name":"Liam D Hendrikse","author_inst":"Princess Margaret Cancer Centre"},{"author_name":"Olivier Saulnier","author_inst":"Institut Curie"},{"author_name":"Randy Van Ommeren","author_inst":"University of Toronto"},{"author_name":"David Przelicki","author_inst":"University of Toronto"},{"author_name":"Namal Abeysundara","author_inst":"The Hospital for Sick Children"},{"author_name":"Rachel Naomi Curry","author_inst":"Baylor College of Medicine"},{"author_name":"Hannah N Ahmed","author_inst":"Baylor College of Medicine"},{"author_name":"Raul A Suarez","author_inst":"The Hospital for Sick Children"},{"author_name":"Cory M Richman","author_inst":"The Hospital for Sick Children"},{"author_name":"Ning Huang","author_inst":"Baylor College of Medicine"},{"author_name":"Hao Wang","author_inst":"The Hospital for Sick Children"},{"author_name":"Haipend Su","author_inst":"Baylor College of Medicine"},{"author_name":"Jonelle Pallotta","author_inst":"The Hospital for Sick Children"},{"author_name":"Esta Mak","author_inst":"The Hospital for Sick Children"},{"author_name":"Andrew Bondoc","author_inst":"The Hospital for Sick Children"},{"author_name":"Adrian Levine","author_inst":"The Hospital for Sick Children"},{"author_name":"Baojin Yao","author_inst":"Baylor College of Medicine"},{"author_name":"Laura M Prolo","author_inst":"Stanford University"},{"author_name":"Craig Daniels","author_inst":"Baylor College of Medicine"},{"author_name":"Andrey Korshunov","author_inst":"German Cancer Research Center (DKFZ)"},{"author_name":"Kristen W Yeom","author_inst":"Phoenix Children's Hospital"},{"author_name":"Vijay Ramaswamy","author_inst":"Hospital for Sick Children"},{"author_name":"Livia Garzia","author_inst":"McGill University"},{"author_name":"Ana Nikolic","author_inst":"University of Calgary"},{"author_name":"Daniel Schramek","author_inst":"Lunenfeld-Tanenbaum Research Institute"},{"author_name":"Richard Lu","author_inst":"Cincinnati Children's Hospital"},{"author_name":"Jeremy N Rich","author_inst":"University of North Carolina"},{"author_name":"Kenneth Aldape","author_inst":"National Cancer Institute"},{"author_name":"Kathleen J Millen","author_inst":"Seattle Children's Research Institute"},{"author_name":"Poul Sorensen","author_inst":"University of British Columbia"},{"author_name":"Marco Gallo","author_inst":"Baylor College of Medicine"},{"author_name":"Richard J Gilbertson","author_inst":"CRUK Cambridge Institute"},{"author_name":"Nada Jabado","author_inst":"McGill University"},{"author_name":"Xiaochong Wu","author_inst":"Baylor College of Medicine"},{"author_name":"Lincoln D Stein","author_inst":"Ontario Institute for Cancer Research"},{"author_name":"David W Ellison","author_inst":"St. Jude Children's Research Hospital"},{"author_name":"Marianne E Bronner","author_inst":"Caltech: California Institute of Technology"},{"author_name":"Michael D Taylor","author_inst":"Baylor College of Medicine"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"Ependymomas are cancers of the pre-neural crest\/roof plate lineage","rel_doi":"10.64898\/2026.07.13.736818","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.13.736818","rel_abs":"Distinct molecular variants of the brain cancer ependymoma are distributed along the rostral-caudal extent of the central nervous system (CNS). Historically proposed to arise from ventricular ependyma, recent studies have suggested conflicting cellular origins, including the neural radial glia and the roof plate lineages. Using single-cell transcriptomics, immunohistochemistry, and lineage tracing, we demonstrate that ependymomas across all CNS compartments transcriptionally mirror MSX1+ve pre-neural crest\/roof plate (Pre-NC\/RP) lineage derivatives. Ependymoma subgroups recapitulate the spatial and molecular diversity of regional Pre-NC\/RP populations, while retaining conserved MSX1 expression. Expression of the oncogenic fusion ZFTA-RELA within the murine Pre-NC\/RP lineage generated tumors that faithfully resembled human ependymoma. These findings identify a common embryonic cellular origin for ependymomas and reconcile previously conflicting models of tumorigenesis.","rel_num_authors":69,"rel_authors":[{"author_name":"Polina Balin","author_inst":"Baylor College of Medicine"},{"author_name":"Sachin A Kumar","author_inst":"Boston Children's Hospital"},{"author_name":"Riley Galton","author_inst":"Stowers Institute for Medical Research"},{"author_name":"Alberto Delaidelli","author_inst":"Harvard Medical School"},{"author_name":"Wilda Orisme","author_inst":"St. Jude Children's Research Hospital"},{"author_name":"Parthiv Haldipur","author_inst":"Seattle Children's Research Institute"},{"author_name":"Ncedile Mankahla","author_inst":"The Hospital for Sick Children"},{"author_name":"Amr Saadeldin","author_inst":"Baylor College of Medicine"},{"author_name":"Nik von Krosigk","author_inst":"University of Toronto"},{"author_name":"Maria C Vladoiu","author_inst":"McMaster University"},{"author_name":"Anders W Erickson","author_inst":"University of Toronto"},{"author_name":"Meyer Barembaum","author_inst":"California Institute of Technology"},{"author_name":"Jake Millman","author_inst":"Seattle Children's Research Institute"},{"author_name":"Amy J Banks","author_inst":"University of Calgary"},{"author_name":"Jeffrey T Joseph","author_inst":"University of Calgary"},{"author_name":"Omar Khan","author_inst":"Seattle Children's Research Institute"},{"author_name":"Simon Du","author_inst":"Seattle Children's Research Institute"},{"author_name":"Olga Sirbu","author_inst":"University of Toronto"},{"author_name":"Winnie Ong","author_inst":"University of Toronto"},{"author_name":"Damien Faury","author_inst":"McGill University"},{"author_name":"Vicente Santa Maria Lopez","author_inst":"Baylor College of Medicine"},{"author_name":"Sigourney Bonner","author_inst":"CRUK Cambridge Institute"},{"author_name":"Jennifer C Coleman","author_inst":"University of Cambridge"},{"author_name":"Jason Eigenbrood","author_inst":"CRUK Cambridge Institute"},{"author_name":"Elizabeth Alexandra Cooper","author_inst":"University of Cambridge"},{"author_name":"Jonathan K Duh","author_inst":"Stanford University School of Medicine"},{"author_name":"Jiao Zhang","author_inst":"Baylor College of Medicine"},{"author_name":"John JY Lee","author_inst":"Massachusetts General Hospital"},{"author_name":"Alexandra Rasnitsyn","author_inst":"University of Toronto"},{"author_name":"Aidan E Cedillo","author_inst":"Baylor College of Medicine"},{"author_name":"Gabrielle Persad","author_inst":"University of Toronto"},{"author_name":"Liam D Hendrikse","author_inst":"Princess Margaret Cancer Centre"},{"author_name":"Olivier Saulnier","author_inst":"Institut Curie"},{"author_name":"Randy Van Ommeren","author_inst":"University of Toronto"},{"author_name":"David Przelicki","author_inst":"University of Toronto"},{"author_name":"Namal Abeysundara","author_inst":"The Hospital for Sick Children"},{"author_name":"Rachel Naomi Curry","author_inst":"Baylor College of Medicine"},{"author_name":"Hannah N Ahmed","author_inst":"Baylor College of Medicine"},{"author_name":"Raul A Suarez","author_inst":"The Hospital for Sick Children"},{"author_name":"Cory M Richman","author_inst":"The Hospital for Sick Children"},{"author_name":"Ning Huang","author_inst":"Baylor College of Medicine"},{"author_name":"Hao Wang","author_inst":"The Hospital for Sick Children"},{"author_name":"Haipend Su","author_inst":"Baylor College of Medicine"},{"author_name":"Jonelle Pallotta","author_inst":"The Hospital for Sick Children"},{"author_name":"Esta Mak","author_inst":"The Hospital for Sick Children"},{"author_name":"Andrew Bondoc","author_inst":"The Hospital for Sick Children"},{"author_name":"Adrian Levine","author_inst":"The Hospital for Sick Children"},{"author_name":"Baojin Yao","author_inst":"Baylor College of Medicine"},{"author_name":"Laura M Prolo","author_inst":"Stanford University"},{"author_name":"Craig Daniels","author_inst":"Baylor College of Medicine"},{"author_name":"Andrey Korshunov","author_inst":"German Cancer Research Center (DKFZ)"},{"author_name":"Kristen W Yeom","author_inst":"Phoenix Children's Hospital"},{"author_name":"Vijay Ramaswamy","author_inst":"Hospital for Sick Children"},{"author_name":"Livia Garzia","author_inst":"McGill University"},{"author_name":"Ana Nikolic","author_inst":"University of Calgary"},{"author_name":"Daniel Schramek","author_inst":"Lunenfeld-Tanenbaum Research Institute"},{"author_name":"Richard Lu","author_inst":"Cincinnati Children's Hospital"},{"author_name":"Jeremy N Rich","author_inst":"University of North Carolina"},{"author_name":"Kenneth Aldape","author_inst":"National Cancer Institute"},{"author_name":"Kathleen J Millen","author_inst":"Seattle Children's Research Institute"},{"author_name":"Poul Sorensen","author_inst":"University of British Columbia"},{"author_name":"Marco Gallo","author_inst":"Baylor College of Medicine"},{"author_name":"Richard J Gilbertson","author_inst":"CRUK Cambridge Institute"},{"author_name":"Nada Jabado","author_inst":"McGill University"},{"author_name":"Xiaochong Wu","author_inst":"Baylor College of Medicine"},{"author_name":"Lincoln D Stein","author_inst":"Ontario Institute for Cancer Research"},{"author_name":"David W Ellison","author_inst":"St. Jude Children's Research Hospital"},{"author_name":"Marianne E Bronner","author_inst":"Caltech: California Institute of Technology"},{"author_name":"Michael D Taylor","author_inst":"Baylor College of Medicine"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"Kinetochore-microtubule attachments are strengthened by Cnn1 stabilization of Stu2","rel_doi":"10.64898\/2026.07.13.738289","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.13.738289","rel_abs":"Accurate chromosome segregation requires kinetochores to form robust, load-bearing attachments to dynamic spindle microtubules, mediated primarily by the Ndc80 complex. Two receptors, Dsn1 and Cnn1 (CENP-T), recruit multiple copies of Ndc80c to the kinetochore, but whether they confer functional differences to Ndc80 behavior is unclear. We previously demonstrated that kinetochore components co-purifying with the yeast Dsn1 protein can maintain persistent load-bearing attachments that track with microtubule tip growth and shortening. Using an optical trapping-based assay, we show that Cnn1 purifications also sustain dynamic microtubule attachments under load. Mutation of a conserved region within the disordered N-terminal tail of Cnn1 weakened attachment strength in vitro and caused a growth defect when Dsn1 function was impaired. The Cnn1 mutation reduced Stu2 kinetochore levels without altering other kinetochore proteins. Restoring Stu2, either by direct addition in vitro or by tethering it to Ndc80c in vivo, rescued both attachment strength and cellular viability. These findings reveal a biophysical role for Cnn1 in enabling Stu2-dependent stabilization of kinetochore-microtubule attachments.","rel_num_authors":5,"rel_authors":[{"author_name":"Nairita Maitra","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Devin T Edwards","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Changkun Hu","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Charles L Asbury","author_inst":"University of Washington"},{"author_name":"Sue Biggins","author_inst":"Fred Hutchinson Cancer Research Center"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"Temporal decoding of blood flow derived mechanical cues driving liver regeneration","rel_doi":"10.64898\/2026.07.13.738320","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.13.738320","rel_abs":"Liver regeneration is initiated by rapid vascular changes, yet how blood flow-derived mechanical cues are decoded by liver sinusoidal endothelial cells (LSECs) remains unclear. Here, we found that partial hepatectomy generates temporally distinct mechanical cues in vivo, with a transient rise in shear stress followed by progressive sinusoidal dilation and endothelial stretch. To dissect these forces, we developed a liver regeneration chip that reconstructs sinusoidal architecture and enables independent or coupled manipulation of shear stress and mechanical stretch. Shear-dominant, stretch-dominant, and coupled mechanical modalities induce divergent LSEC regenerative programs involving extracellular matrix remodeling, cell-cycle regulation, cytoskeletal organization, and angiocrine signaling. Mechanistically, force-specific pathways, including Wnt, HIF-1, NF-{kappa}B, and Piezo1-associated signaling, mediate these outputs. Inhibition of these pathways after partial hepatectomy impairs hepatocyte proliferation and survival. These findings reveal that LSECs temporally decode blood flow-derived mechanical forces into distinct regenerative outputs, establishing endothelial mechanotransduction as an upstream regulator of liver regeneration.","rel_num_authors":7,"rel_authors":[{"author_name":"Xinyu Shu","author_inst":"Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construct"},{"author_name":"Guangyao Chen","author_inst":"Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construct"},{"author_name":"Chaoyang Song","author_inst":"Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construct"},{"author_name":"Yan Zhang","author_inst":"Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construct"},{"author_name":"Shouqin Lv","author_inst":"Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construct"},{"author_name":"Yu Du","author_inst":"Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construct"},{"author_name":"Mian Long","author_inst":"Center for Biomechanics and Bioengineering, Key Laboratory of Microgravity (National Microgravity Laboratory) and Beijing Key Laboratory of Engineered Construct"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"A pectin-based formulation protects milk fat globule membranes in stored human milk","rel_doi":"10.64898\/2026.07.13.734508","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.13.734508","rel_abs":"During household storage, expressed human milk can develop odor and flavor changes that trigger infant refusal and lead caregivers to discard their saved milk supply. We show that typical refrigeration and freezing conditions disrupt the milk fat globule membrane (MFGM), exposing milk lipids to lipases that catalyze hydrolysis and oxidation. A pectin-based formulation (PBF) maintains MFGM integrity during storage and following lipase challenge, suppressing production of glycerol, free fatty acid, and oxylipin byproducts without broadly affecting milk macronutrients, the proteome, and culturable microbial burden. Across an independent cohort of lactating individuals, lipase activity varied but tracked with maternal milk lipase gene expression, implicating endogenous lipolysis in stored-milk deterioration. In a blinded olfactory panel, PBF-treated, lipase-challenged milk smelled more like fresh milk than untreated controls. Together, these findings show that stabilizing the MFGM can protect stored human milk from lipase-driven deterioration, preserve sensory quality, and support use for infant feeding.","rel_num_authors":11,"rel_authors":[{"author_name":"Justin E Silpe","author_inst":"PumpKin Baby Inc., Princeton, NJ, USA"},{"author_name":"Hyesoo Kim","author_inst":"PumpKin Baby Inc., Princeton, NJ, USA; Department of Biochemistry and Molecular Biophysics, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Anjali ShahLyng","author_inst":"PumpKin Baby Inc., Princeton, NJ, USA"},{"author_name":"Yi-Ting Tsai","author_inst":"Department of Biochemistry and Molecular Biophysics, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Kelsey E Johnson","author_inst":"Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, C"},{"author_name":"Bum Jin Kim","author_inst":"Nutrition Program, School of Nutrition and Public Health, College of Health, Oregon State University, Corvallis, OR, USA"},{"author_name":"Carolyn M Slupsky","author_inst":"Departments of Nutrition and Food Science and Technology, University of California, Davis, Davis, CA, USA"},{"author_name":"Ameer Y Taha","author_inst":"Departments of Nutrition and Food Science and Technology, University of California, Davis, Davis, CA, USA"},{"author_name":"David C Dallas","author_inst":"Moore Family Center for Whole Grain Foods, Nutrition and Preventive Health, School of Nutrition and Public Health, College of Health, Oregon State University, C"},{"author_name":"Itay Budin","author_inst":"Department of Biochemistry and Molecular Biophysics, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Bonnie L Bassler","author_inst":"Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Princeton, NJ, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"VPS4 and CHMP7 release centromeres from the nuclear envelope for post-mitotic positioning in daughter nuclei","rel_doi":"10.64898\/2026.07.13.738224","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.13.738224","rel_abs":"Eukaryotic chromosomes occupy ordered configurations within the nucleus, an organization that must be re-established in daughter cells as the nuclear envelope reforms at the end of mitosis. The conserved enzyme VPS4 and ESCRT-III proteins mediate nuclear envelope reformation, yet their role in post-mitotic centromere positioning remains unclear. Here, we develop a chemical genetics approach to analyze the role of VPS4 in human cells. VPS4 inhibition prevents the clearance of CHMP7 from centromeres, which remain constrained in ring-like configurations established during mitosis. Without VPS4 activity, CHMP7, but not other ESCRT-III proteins, forms nuclear foci, nuclear envelope protein distribution is altered and inner nuclear membrane invaginations appear. Following these defects, DNA damage is observed in the vicinity of centromeres. Depletion of CHMP7, but not CHMP4B, suppresses this damage. We propose that VPS4-mediated turnover of CHMP7 releases centromeres from transient nuclear envelope contacts, ensuring their proper positioning after mitosis and maintaining genome integrity.","rel_num_authors":8,"rel_authors":[{"author_name":"Nikolay Kornakov","author_inst":"The Rockefeller University"},{"author_name":"Tyler Heiss","author_inst":"The Rockefeller University"},{"author_name":"Arielle Kolodzinski","author_inst":"The Rockefeller University"},{"author_name":"Rebecca Tam","author_inst":"The Rockefeller University"},{"author_name":"Megan E Kelley","author_inst":"The Rockefeller University"},{"author_name":"Natalie H Jones","author_inst":"The Rockefeller University"},{"author_name":"Amalia H Pasolli","author_inst":"The Rockefeller University"},{"author_name":"Tarun Kapoor","author_inst":"Rockefeller Univ."}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"Sol-gel Transition Drives Hyper-fast Mixing in a Giant Cell","rel_doi":"10.64898\/2026.07.13.738335","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.13.738335","rel_abs":"The cytoplasm is a crowded and dynamic fluid within which cellular building blocks such as mRNA, proteins, or organelles undergo transport and mixing. Although small things like proteins can eventually mix through diffusion, the high viscosity of cytoplasm means that it should be difficult to obtain significant mixing for structures in the size range of mRNA, multi-protein complexes or organelles. In large amoeboid cells, the cytoplasm undergoes active streaming coupled to cell motility, but this streaming is laminar flow which should not be effective for mixing. In this work we used a combination of live cell tracking of injected beads and computational analysis of motion and mixing in giant amoeba Chaos carolinensis with the initial goal of testing the possibility that large-scale cellular deformations during pseudopod formation might implement chaotic mixing by a Baker-transform like process. Instead, we found that Chaos carolinensis accelerates cytoplasmic mixing using a novel cytoplasmic gel state capture and release strategy. While it was previously thought that the amoeba sol to gel state transitions only occur at the trailing and leading edge of the cell body, our work indicates that these transitions occur frequently throughout the mid-cell region, driving the cytoplasmic mixing of beads and organelles. These results indicate that amoeba achieves nearly complete mixing between 1 and 2 cytoplasmic stream\/flow cycle, effectively approximating the Bernoulli mixing regime and thus representing one of the theoretically fastest possible mixers.","rel_num_authors":11,"rel_authors":[{"author_name":"Ulises Diaz","author_inst":"UCSF"},{"author_name":"Moumita F Das","author_inst":"Rochester Institute of Technology"},{"author_name":"Sameer Thukral","author_inst":"Marine Biological Laboratory, Woods Hole"},{"author_name":"Judy Abuel","author_inst":"San Francisco State University"},{"author_name":"Mikesha Carter","author_inst":"San Francisco State University"},{"author_name":"Alba Marino","author_inst":"San Francisco State University"},{"author_name":"Laura Galvan","author_inst":"San Francisco State University"},{"author_name":"Austen Irungu","author_inst":"San Francisco State University"},{"author_name":"Jasmine Leiva","author_inst":"San Francisco State University"},{"author_name":"Alexander Ballor","author_inst":"San Francisco State University"},{"author_name":"Wallace F Marshall","author_inst":"UCSF"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"Minimal Data, Maximal Insight (MDMI): A Structure-guided Pipeline for Discovering Functional Alternatives in Peptide-Protein Interfaces","rel_doi":"10.64898\/2026.07.13.737974","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.13.737974","rel_abs":"Discovering functional peptides across vast sequence space remains a formidable challenge, particularly when experimental training data is scarce. We present Minimal Data Maximal Insight (MDMI), a two-stage structure-guided computational pipeline that designs functional peptide variants using only a small, annotated dataset. Rather than relying on sequence information alone, MDMI integrates three-dimensional structural features derived from predicted peptide-protein complexes into a machine learning model that captures interface geometry and binding energetics. This structure-aware predictor, paired with a genetic algorithm for sequence exploration, reduced false positives from 70% to close to zero in an all-negative benchmark panel compared with a sequence-only model in computational benchmarking, and produced approximately four-fold more high-confidence in silico binders than state-of-the-art peptide\/protein design baselines. Using the split-GFP system as a testbed, where fluorescence provides a direct functional readout of peptide-protein complementation, MDMI identified peptides with up to 38% sequence divergence from wild-type in Stage 1 while retaining measurable activity. In Stage 2, motif-guided recombination of successful Stage 1 variants produced highly divergent yet functional peptides bearing over 50% sequence difference from wild-type, revealing two distinct functional clusters in sequence space. As further validation, a top-performing candidate expressed as a full-length GFP fusion retained a GFP-like emission profile, supporting formation of a fluorescent GFP-like scaffold. These results demonstrate that structure-informed pipelines can uncover remote functional sequence space from minimal data, with broad implications for peptide and therapeutic analog discovery.","rel_num_authors":22,"rel_authors":[{"author_name":"Pouriya Bayat","author_inst":"University of Toronto"},{"author_name":"Spencer James Perkins","author_inst":"University of Toronto"},{"author_name":"Sebastian Clancy","author_inst":"University of Toronto"},{"author_name":"Sahil Swapnesh Patel","author_inst":"University of Toronto"},{"author_name":"Richard Fei Yin","author_inst":"University of Toronto"},{"author_name":"Kristof Bozovicar","author_inst":"University of Toronto"},{"author_name":"Serena Singh","author_inst":"University of Toronto"},{"author_name":"Suman Shrestha","author_inst":"University of Toronto"},{"author_name":"Zain Moustafa","author_inst":"University of Toronto"},{"author_name":"Riham Zayani","author_inst":"University of Toronto"},{"author_name":"Idorenyin IWE","author_inst":"University of Toronto"},{"author_name":"Sepehr Bayat","author_inst":"McMaster University"},{"author_name":"Paul Kelly","author_inst":"University of Toronto"},{"author_name":"Justin R.J Vigar","author_inst":"University of Toronto"},{"author_name":"Vivan Yuna White","author_inst":"University of Toronto"},{"author_name":"Matthew Xie","author_inst":"University of Toronto"},{"author_name":"Mohammad Simchi","author_inst":"University of Toronto"},{"author_name":"Sean Palter","author_inst":"University of Toronto"},{"author_name":"Jessica Nguyen","author_inst":"University of Toronto"},{"author_name":"Ilan Yaniv Zeisler","author_inst":"University of Toronto"},{"author_name":"Bonny Wu","author_inst":"University of Toronto"},{"author_name":"Keith Pardee","author_inst":"University of Toronto"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"rel_title":"Disrupting a Convergent Acetylation Circuit Collapses Leukemic Identity Across AML Subtypes","rel_doi":"10.64898\/2026.07.13.737885","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.13.737885","rel_abs":"Acute myeloid leukemia (AML) cells rely on an actively maintained, chromatin-encoded transcriptional program to sustain their malignant identity, offering a potential therapeutic vulnerability. Using genome-scale dependency data from over 1,000 cancer cell lines, we identify the SAGA histone acetyltransferase complex as a selective chromatin dependency in AML and hematological malignancies. We show that pharmacological degradation of the SAGA catalytic subunits KAT2A and KAT2B, using a cereblon-recruiting PROTAC (GSK983\/GSK699), drives potent, broad-spectrum antileukemic activity across genetically diverse AML cell lines, primary patient samples, and an isogenic KMT2A-rearranged model bearing cooperating oncogenic mutations. Mechanistically, KAT2A\/B degradation causes a genome-wide reduction in histone H3 lysine 9 acetylation (H3K9ac), with the most pronounced, asymmetric losses concentrated at core AML oncogene loci such as MYC, MYB, and the HOXA cluster. This targeted erasure of H3K9ac displaces the chromatin reader ENL from these loci, dissolving ENL-anchored transcriptional condensates and disrupting the Super Elongation Complex (SEC). Strikingly, our results show that KAT2A\/B licenses acetylation of the SEC itself, including ENL, AFF1, and AFF3, linking KAT2A\/B activity to both histone and non-histone regulation of transcriptional elongation machinery. Together, these findings establish KAT2A\/B degradation as a mechanism-based, pan-AML therapeutic strategy and identify a chromatin-to-condensate signaling axis with implications for transcriptional control beyond leukemia.","rel_num_authors":22,"rel_authors":[{"author_name":"Anagha Deshpande","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Cho-Ying Chiang","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Marlenne Perales Garcia","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Neha Niranjan","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Neelam Sinha","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Darren Finlay","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Alexandra M. Stevens","author_inst":"Texas Children's Hospital \/ Baylor College of Medicine"},{"author_name":"Emily Zahn","author_inst":"Washington University School of Medicine"},{"author_name":"Benjamin A. Garcia","author_inst":"Washington University School of Medicine"},{"author_name":"Irmela Jeremias","author_inst":"German Cancer Consortium (DKTK) \/ German Cancer Research Center (DKFZ)"},{"author_name":"Mark Wunderlich","author_inst":"Cincinnati Children's Hospital Medical Center"},{"author_name":"Kristen Jensen-Pergakes","author_inst":"Pfizer, Oncology Research & Development"},{"author_name":"Akshata Udyavar","author_inst":"Pfizer, Oncology Research & Development"},{"author_name":"Amy Carr","author_inst":"Pfizer, Oncology Research & Development"},{"author_name":"Andrew R. Nager","author_inst":"Pfizer, Oncology Research & Development"},{"author_name":"Yanling Yang","author_inst":"Pfizer, Oncology Research & Development"},{"author_name":"Rabi Murad","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Courtney Jones","author_inst":"Cincinnati Children's Hospital Medical Center"},{"author_name":"Shawn O'Connell","author_inst":"Pfizer, Oncology Research & Development"},{"author_name":"Thomas Paul","author_inst":"Pfizer, Oncology Research & Development"},{"author_name":"Kristiina Vuori","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Aniruddha J. Deshpande","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"}],"rel_date":"2026-07-14","rel_site":"biorxiv"},{"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":"Abstract: Background: Lacunar 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. Methods: Patients 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. Results: The 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. Conclusions: Lacunar 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.","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 \\emph{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 real-world comparative effectiveness research.","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 \\emph{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 real-world comparative effectiveness research.","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 \\emph{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 real-world comparative effectiveness research.","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":"Chlamydia trachomatis and Neisseria gonorrhoeae in newborns with and without neonatal conjunctivitis: cross-sectional study in Papua New Guinea","rel_doi":"10.64898\/2026.07.09.26357364","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357364","rel_abs":"In newborns seen a median of 11 days after birth, 97\/1699 (5.7%) had conjunctivitis, including 13\/97 (13.4%) with Chlamydia trachomatis or Neisseria gonorrhoeae detected. Among all babies, we estimated that 6.6% (95% confidence interval 3.8-9.9%) would have C. trachomatis or N. gonorrhoeae detected, of which 87.0% (74.8-93.8%) would be asymptomatic.","rel_num_authors":15,"rel_authors":[{"author_name":"Nicola Low","author_inst":"University of Bern: Universitat Bern"},{"author_name":"Alice Mengi","author_inst":"Papua New Guinea Institute of Medical Research"},{"author_name":"Lisa M Vallely","author_inst":"The Kirby Institute"},{"author_name":"Claire Descombes","author_inst":"University of Bern: Universitaet Bern"},{"author_name":"Lydia Braunack-Mayer","author_inst":"University of Bern: Universitaet Bern"},{"author_name":"Mitchell Starr","author_inst":"St. Vincent's Hospital, Sydney"},{"author_name":"Philip H Cunningham","author_inst":"St Vincent's Hospital, Sydney"},{"author_name":"Handan Wand","author_inst":"The Kirby Institute"},{"author_name":"Ben D Spycher","author_inst":"University of Bern: Universitaet Bern"},{"author_name":"Steven G Badman","author_inst":"The Kirby Institute"},{"author_name":"Moses Laman","author_inst":"Papua New Guinea Institute of Medical Research"},{"author_name":"William S Pomat","author_inst":"Papua New Guinea Institute of Medical Research"},{"author_name":"Andrew J Vallely","author_inst":"The Kirby Institute"},{"author_name":"Michaela A Riddell","author_inst":"The Kirby Institute"},{"author_name":"WANTAIM Trial Investigators Group","author_inst":"Papua New Guinea Institute of Medical Research"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Enteric pathogen burden and co-infection patterns across age and a rural-urban gradient: findings from the ECoMiD birth cohort, Northern Ecuador","rel_doi":"10.64898\/2026.07.08.26357325","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357325","rel_abs":"Enteric pathogen infections are a major global health challenge, influenced by a variety of host and environmental factors, and their clinical presentation and treatment can be complicated by the presence of co-infections. The prevalence of enteric infections and co-infections tend to vary between rural and urban contexts, likely driven by underlying environmental, geographic, and demographic characteristics. To improve understanding of urbanicity and age on enteric pathogen prevalence and on co-infection risk, we measured 22 enteric pathogens in fecal samples collected from children aged 6, 12, and 18 months across a rural-urban gradient within the ECoMiD birth cohort study (n=473). Enteric pathogen burden was high and increased with age, with at least one pathogen detected in 91% of children at 6 months, 97% at 12 months, and 98% at 18 months. However, prevalence of some pathogens-- notably Salmonella enterica, enterovirus, and rotavirus-- decreased with age. Co-infections were also common (88%), and children were infected with as many as 11 pathogens simultaneously. The most frequently observed co-infection profiles included enteroaggregative E. coli and atypical enteropathogenic E. coli, followed by combinations with diffusely adherent E. coli, enterovirus, enterotoxigenic E. coli, and\/or adenovirus. Enteric pathogen detection generally was higher in more rural settings, though patterns varied by pathogen. These results provide useful information for future examination of pathogen dynamics of co-occurrence. Given the ubiquity of enteric infections in high transmission settings, strategies that aim to reduce overall microbial exposure may be needed to supplement interventions targeting control of individual pathogens.","rel_num_authors":11,"rel_authors":[{"author_name":"Nicolette  Angela Zhou","author_inst":"University of Washington"},{"author_name":"Caitlin Hemlock","author_inst":"University of Washington"},{"author_name":"Kelsey  J. Jesser","author_inst":"University of Washington"},{"author_name":"Christine  S. Fagnant-Sperati","author_inst":"University of Washington"},{"author_name":"Jesse  D. Contreras","author_inst":"University of Michigan"},{"author_name":"Benjamin  F. Arnold","author_inst":"UCSF: University of California San Francisco"},{"author_name":"William Cevallos","author_inst":"Universidad Central del Ecuador"},{"author_name":"Gabriel Trueba","author_inst":"Universidad San Francisco de Quito"},{"author_name":"Gwenyth  O. Lee","author_inst":"Rutgers University Newark"},{"author_name":"Joseph  N.S. Eisenberg","author_inst":"University of Michigan"},{"author_name":"Karen Levy","author_inst":"University of Washington Seattle Campus: University of Washington"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Enteric pathogen burden and co-infection patterns across age and a rural-urban gradient: findings from the ECoMiD birth cohort, Northern Ecuador","rel_doi":"10.64898\/2026.07.08.26357325","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357325","rel_abs":"Enteric pathogen infections are a major global health challenge, influenced by a variety of host and environmental factors, and their clinical presentation and treatment can be complicated by the presence of co-infections. The prevalence of enteric infections and co-infections tend to vary between rural and urban contexts, likely driven by underlying environmental, geographic, and demographic characteristics. To improve understanding of urbanicity and age on enteric pathogen prevalence and on co-infection risk, we measured 22 enteric pathogens in fecal samples collected from children aged 6, 12, and 18 months across a rural-urban gradient within the ECoMiD birth cohort study (n=473). Enteric pathogen burden was high and increased with age, with at least one pathogen detected in 91% of children at 6 months, 97% at 12 months, and 98% at 18 months. However, prevalence of some pathogens-- notably Salmonella enterica, enterovirus, and rotavirus-- decreased with age. Co-infections were also common (88%), and children were infected with as many as 11 pathogens simultaneously. The most frequently observed co-infection profiles included enteroaggregative E. coli and atypical enteropathogenic E. coli, followed by combinations with diffusely adherent E. coli, enterovirus, enterotoxigenic E. coli, and\/or adenovirus. Enteric pathogen detection generally was higher in more rural settings, though patterns varied by pathogen. These results provide useful information for future examination of pathogen dynamics of co-occurrence. Given the ubiquity of enteric infections in high transmission settings, strategies that aim to reduce overall microbial exposure may be needed to supplement interventions targeting control of individual pathogens.","rel_num_authors":11,"rel_authors":[{"author_name":"Nicolette  Angela Zhou","author_inst":"University of Washington"},{"author_name":"Caitlin Hemlock","author_inst":"University of Washington"},{"author_name":"Kelsey  J. Jesser","author_inst":"University of Washington"},{"author_name":"Christine  S. Fagnant-Sperati","author_inst":"University of Washington"},{"author_name":"Jesse  D. Contreras","author_inst":"University of Michigan"},{"author_name":"Benjamin  F. Arnold","author_inst":"UCSF: University of California San Francisco"},{"author_name":"William Cevallos","author_inst":"Universidad Central del Ecuador"},{"author_name":"Gabriel Trueba","author_inst":"Universidad San Francisco de Quito"},{"author_name":"Gwenyth  O. Lee","author_inst":"Rutgers University Newark"},{"author_name":"Joseph  N.S. Eisenberg","author_inst":"University of Michigan"},{"author_name":"Karen Levy","author_inst":"University of Washington Seattle Campus: University of Washington"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Revealing Hidden Myocardial Infarction Signatures from Brief Single-Lead Electrocardiograms: A Novel Framework for Smart Wearable Applications","rel_doi":"10.64898\/2026.07.08.26357521","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357521","rel_abs":"The electrocardiogram (ECG) contains rich nonlinear and non-stationary dynamic information that is only partly captured by conventional ECG interpretation and beat-to-beat metrics, and is increasingly analyzed using black-box artificial intelligence models that often lack interpretability. Here, we introduce the ECG time-frequency \"eyeball\", an interpretable framework that transforms a brief single-lead ECG recording into a geometric signature and a set of low-dimensional rotational and geometrical features using empirical mode decomposition and Hilbert-based analytic signal mapping. In 30-second lead I-equivalent recordings from 170 healthy subjects and 80 patients with acute myocardial infarction (AMI), the proposed \"eyeball\" metrics significantly differentiated groups, with AMI associated with higher rotational frequency metrics, lower envelope metrics, and displaced centroid location. Representative examples revealed a coherent morphologic spectrum from normal patterns to geometries consistent with myocardial ischemia, injury, and infarction. The representation remained stable across recording windows from 30 seconds to 5 minutes, and individual \"eyeball\" features achieved areas under the receiver operating characteristic curve (AUCs) of up to 0.78 for AMI detection. These findings suggest that the ECG time-frequency \"eyeball\" condenses clinically relevant nonlinear ECG dynamics into an interpretable representation that may reveal hidden AMI signatures, complement conventional ECG interpretation, and provide a foundation for accessible single-lead cardiovascular screening using future smart wearables.","rel_num_authors":6,"rel_authors":[{"author_name":"Rashid Alavi","author_inst":"California Institute of Technology (Caltech)"},{"author_name":"Jiajun Li","author_inst":"University of Southern California"},{"author_name":"Ray V. Matthews","author_inst":"University of Southern California"},{"author_name":"Niema M. Pahlevan","author_inst":"University of Southern California"},{"author_name":"Robert A. Kloner","author_inst":"Huntington Medical Research Institutes"},{"author_name":"Morteza Gharib","author_inst":"California Institute of Technology (Caltech)"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Feasibility of Monkeypox virus sequencing from antigen rapid diagnostic tests as a potential tool to enhance genomic surveillance","rel_doi":"10.64898\/2026.07.09.26356424","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26356424","rel_abs":"Background Sequencing of monkeypox virus (MPXV) from antigen rapid diagnostic tests (Ag-RDTs) could expand genomic surveillance during outbreaks in decentralized settings where sequencing equipment and cold chain transportation are unavailable. We aimed to evaluate the efficacy of MPXV sequencing from MPXV antigen Ag-RDTs. Methods We tested MPXV Ag-RDTs from three different brands using serial dilutions of cultured MPXV subclade Ib. Positive Ag-RDTs with different intensities of the test band were stored for 19 days, either at room temperature or at +4 degree C, after which viral DNA was extracted from the pads of the test cassettes. Metagenomic and tiled amplicon-based Oxford Nanopore technology sequencing methods were then performed. Results Viral DNA extraction from MPXV Ag-RDTs showed a consistent decrease in viral load of 3 logs compared to the initial viral load of the applied viral dilution. Both sequencing methods were able to reach high coverage but the tiled amplicon-based demonstrated more consistent results with a coverage always above 85%. Conclusion This proof-of-concept supports the development of this approach in the field, with the aim of combining genomic surveillance with decentralized testing, including in remote areas.","rel_num_authors":8,"rel_authors":[{"author_name":"Charlotte Pronier PRONIER","author_inst":"Hopital Pontchaillou"},{"author_name":"Adriana Renzoni","author_inst":"University Hospitals of Geneva"},{"author_name":"Florian Laubscher","author_inst":"University Hospitals of Geneva"},{"author_name":"Valentin Chudzinski","author_inst":"University Hospitals of Geneva"},{"author_name":"Kenneth Adea","author_inst":"Universite de Geneve"},{"author_name":"Placide Mbala-Kingebeni","author_inst":"INRB: Institut National de Recherche Biomedicale"},{"author_name":"Camille Escadafal","author_inst":"University Hospitals of Geneva"},{"author_name":"Isabella Eckerle","author_inst":"University Hospitals of Geneva"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Population-scale molecular reconstruction of human circadian phase from blood biomarkers","rel_doi":"10.64898\/2026.07.08.26356418","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26356418","rel_abs":"Circadian timing influences human physiology and disease risk, yet scalable measures of molecular circadian phase are lacking. Here we infer circadian phase from circulating blood biomarkers in UK Biobank. Among 3,228 plasma biomarkers, 58% exhibit significant diurnal variation, with harmonic modeling identifying acrophase clustering consistent with canonical circadian patterns and independent constant-routine datasets. Machine-learning models trained on plasma proteomics predict sampling time (R2=0.68) and retain substantial accuracy with ~60 proteins. We define a novel construct, circadian acceleration (CA), as deviation from the population-average phase; CA is temporally stable, associates with chronotype and shift work, and responds to environmental perturbation. CA is heritable (h2SNP=0.10) and genetically correlated with chronotype and accelerometry-derived sleep traits. These results establish plasma proteomics as a scalable approach for population-level molecular circadian phenotyping.","rel_num_authors":18,"rel_authors":[{"author_name":"Clara Albinana","author_inst":"National Centre for Register-based Research, Aarhus University, Aarhus, Denmark, Department of Psychiatry, University of Oxford, Oxford, United Kingdom"},{"author_name":"Rebecca Richmond","author_inst":"Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom, MRC Integrative Epidemiology Unit, University of Bristol, Br"},{"author_name":"Baihan Wang","author_inst":"Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom"},{"author_name":"Lea Urpa","author_inst":"Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA, Center for Genomic Medicine, Massachusetts General Hospital, Bo"},{"author_name":"Jacob Crouse","author_inst":"Brain and Mind Centre, The University of Sydney, Sydney, Australia"},{"author_name":"Yanni Zeng","author_inst":"Department of forensic Psychiatry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China, Department of Psychiatry, University of Oxford, Oxfor"},{"author_name":"Daniel Rosoff","author_inst":"National Institute for Health and Care Research Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, United Kingdom, Oxford Centre for Diabetes, "},{"author_name":"Safia Abdi","author_inst":"Department of Psychiatry, University of Oxford, Oxford, United Kingdom"},{"author_name":"- FinnGen Consortium","author_inst":"-"},{"author_name":"Liming Li","author_inst":"Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China, Peking University Center for Public Health and Epidemi"},{"author_name":"Zhengming Chen","author_inst":"Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom"},{"author_name":"Iona Y. Millwood","author_inst":"Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom"},{"author_name":"Hanna M Ollila","author_inst":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, USA, Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsi"},{"author_name":"Ian Hickie","author_inst":"Brain and Mind Centre, The University of Sydney, Sydney, Australia"},{"author_name":"Frederic Gachon","author_inst":"Department of Biomedicine, Aarhus University, Aarhus, Denmark, Steno Diabetes Center Aarhus, Aarhus, Denmark"},{"author_name":"Achim Kramer","author_inst":"Division of Chronobiology, Charite Universitatsmedizin Berlin, Germany"},{"author_name":"David Ray","author_inst":"National Institute for Health and Care Research Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, United Kingdom, Oxford Centre for Diabetes, "},{"author_name":"Naomi Wray","author_inst":"Department of Psychiatry, University of Oxford, Oxford, United Kingdom, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia, B"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Minimal Residual Disease via circulating tumor DNA Predicts Exceptional Response in HER2-Positive Metastatic Breast Cancer","rel_doi":"10.64898\/2026.07.09.26357137","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357137","rel_abs":"PurposeExceptional responses are frequent in patients with HER2-positive (HER2+) metastatic breast cancer (MBC), but predictive biomarkers are lacking. We aimed to investigate the association between detection of minimal residual disease (MRD) via circulating tumor DNA (ctDNA) and exceptional response to first-line HER2 targeted therapy for MBC.\n\nPatients and MethodsWe identified exceptional (real-world progression-free survival [rwPFS] [&ge;]3 years) and conventional (rwPFS <3 years) responders treated with first-line HER2 targeted therapy for HER2+ MBC and plasma collected at landmark timepoints (e.g., baseline, year [Y] 1, Y2, Y3, at progression). We generated personalized, tissue-informed MRD assays using MAESTRO mutation enrichment sequencing in a pooled format. The primary endpoint was the association between MRD status at Y1 and rwPFS.\n\nResultsOf 70 patients, 63 (90%) (40 exceptional and 23 conventional responders) had sufficient samples and successful assay design; MAESTRO was run on 149 samples. A median of 1,823 (range 387-5,000) tumor-specific mutations were tracked per patient. MRD was detected in 49 (32%) samples (median tumor fraction [TFx] 936 ppm; range 3.8-164,068 ppm); 15 (31%) samples had TFx <100 ppm. MRD was associated with outcomes: 0\/27 [0%] exceptional versus 9\/12 [75%] conventional responders (p<0.001) had detectable MRD at Y1. Exceptional responders who remained progression-free were always MRD-negative (n=30) or cleared MRD by Y1 (n=3). Six exceptional responders experienced late progression, and four of them had a Y3 sample: MRD was detected in three patients (lead time range 2.77-13.47 years), one patient had breast-only progression and was MRD-negative.\n\nConclusionsMRD status at key timepoints is associated with exceptional response and late distant progression, supporting prospective clinical trials implementing MRD testing with highly sensitive tumor-informed assays to guide treatment de-escalation.","rel_num_authors":25,"rel_authors":[{"author_name":"Stefania Morganti","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Catherine Song","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Ningxuan Zhou","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Katherine Santos","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Pia Jain","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Laurel Walsh","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Rachel Li","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Justin Rhoades","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Katie Gilligan","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Gregory Kirkner","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Catherine Stever","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Ashka Patel","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Melissa E. Hughes","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Nolan Priedigkeit","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"G. Mike Makrigiorgios","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Ian Krop","author_inst":"Yale Cancer Center"},{"author_name":"Giuseppe Curigliano","author_inst":"European Institute of Oncology"},{"author_name":"Eric P. Winer","author_inst":"Yale Cancer Center"},{"author_name":"Sara M. Tolaney","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Nabihah Tayob","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Hillary Heiling","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Kan Xiong","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Nancy U. Lin","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Viktor A. Adalsteinsson","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Heather A. Parsons","author_inst":"Dana-Farber Cancer Institute"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Minimal Residual Disease via circulating tumor DNA Predicts Exceptional Response in HER2-Positive Metastatic Breast Cancer","rel_doi":"10.64898\/2026.07.09.26357137","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357137","rel_abs":"PurposeExceptional responses are frequent in patients with HER2-positive (HER2+) metastatic breast cancer (MBC), but predictive biomarkers are lacking. We aimed to investigate the association between detection of minimal residual disease (MRD) via circulating tumor DNA (ctDNA) and exceptional response to first-line HER2 targeted therapy for MBC.\n\nPatients and MethodsWe identified exceptional (real-world progression-free survival [rwPFS] [&ge;]3 years) and conventional (rwPFS <3 years) responders treated with first-line HER2 targeted therapy for HER2+ MBC and plasma collected at landmark timepoints (e.g., baseline, year [Y] 1, Y2, Y3, at progression). We generated personalized, tissue-informed MRD assays using MAESTRO mutation enrichment sequencing in a pooled format. The primary endpoint was the association between MRD status at Y1 and rwPFS.\n\nResultsOf 70 patients, 63 (90%) (40 exceptional and 23 conventional responders) had sufficient samples and successful assay design; MAESTRO was run on 149 samples. A median of 1,823 (range 387-5,000) tumor-specific mutations were tracked per patient. MRD was detected in 49 (32%) samples (median tumor fraction [TFx] 936 ppm; range 3.8-164,068 ppm); 15 (31%) samples had TFx <100 ppm. MRD was associated with outcomes: 0\/27 [0%] exceptional versus 9\/12 [75%] conventional responders (p<0.001) had detectable MRD at Y1. Exceptional responders who remained progression-free were always MRD-negative (n=30) or cleared MRD by Y1 (n=3). Six exceptional responders experienced late progression, and four of them had a Y3 sample: MRD was detected in three patients (lead time range 2.77-13.47 years), one patient had breast-only progression and was MRD-negative.\n\nConclusionsMRD status at key timepoints is associated with exceptional response and late distant progression, supporting prospective clinical trials implementing MRD testing with highly sensitive tumor-informed assays to guide treatment de-escalation.","rel_num_authors":25,"rel_authors":[{"author_name":"Stefania Morganti","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Catherine Song","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Ningxuan Zhou","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Katherine Santos","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Pia Jain","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Laurel Walsh","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Rachel Li","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Justin Rhoades","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Katie Gilligan","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Gregory Kirkner","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Catherine Stever","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Ashka Patel","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Melissa E. Hughes","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Nolan Priedigkeit","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"G. Mike Makrigiorgios","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Ian Krop","author_inst":"Yale Cancer Center"},{"author_name":"Giuseppe Curigliano","author_inst":"European Institute of Oncology"},{"author_name":"Eric P. Winer","author_inst":"Yale Cancer Center"},{"author_name":"Sara M. Tolaney","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Nabihah Tayob","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Hillary Heiling","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Kan Xiong","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Nancy U. Lin","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Viktor A. Adalsteinsson","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Heather A. Parsons","author_inst":"Dana-Farber Cancer Institute"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Psychometric validation of the Obstetric Quality of Recovery-10 scoring tool across the first month postpartum: a cross-sectional psychometric study","rel_doi":"10.64898\/2026.07.08.26357380","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357380","rel_abs":"Background: Postpartum recovery is a public health concern. The Obstetric Quality of Recovery-10 (ObsQoR-10) is a brief patient-reported outcome measure designed to assess early recovery after childbirth. Its validation is currently limited to the first three days postpartum. This study aimed to evaluate the psychometric properties of the ObsQoR-10 across the first 30 days postpartum. Methods:We conducted a cross-sectional psychometric evaluation of the ObsQoR-10 using baseline data from a national Swiss multilingual cohort (French, German, Italian, and English). Women were recruited within the first week postpartum and completed the ObsQoR-10 and the EuroQol 5-Dimensions 5-Levels (EQ-5D-5L) at a single time point within 30 days postpartum. Clinical data were extracted from medical records. Analyses were performed across three postpartum windows (0-2, 3-7, and 8-30 days). Structural validity, measurement invariance, reliability, and construct validity (convergent and known-groups) were assessed. Results:A total of 1935 women were included. Structural validity supported a stable four-factor structure with excellent model fit (CFI 0.995-0.997; RMSEA 0.055-0.059), and bifactor analysis supported essential unidimensionality. Measurement invariance was confirmed at metric and scalar levels across postpartum windows. Reliability was good (Cronbach's alpha 0.83-0.86). Convergent validity was supported by moderate correlations with the EQ-5D-5L (;0.51 to 0.30), decreasing over time. Known-groups validity was demonstrated by significantly lower scores in women with poorer health status, postpartum haemorrhage, and operative or caesarean birth (all p <0.001). Conclusions:The ObsQoR-10 demonstrates consistent, valid, and reliable psychometric properties for assessing postpartum recovery across the first 30 days.","rel_num_authors":11,"rel_authors":[{"author_name":"Emilienne Celetta","author_inst":"Geneva School of Health Sciences, HES-SO University of Applied Sciences and Arts Western Switzerland, Geneva, Switzerland"},{"author_name":"Elsa Lorthe","author_inst":"Geneva School of Health Sciences, HES-SO University of Applied Sciences and Arts Western Switzerland, Geneva, Switzerland"},{"author_name":"Gilles Cattani","author_inst":"Geneva School of Health Sciences, HES-SO University of Applied Sciences and Arts Western Switzerland, Geneva, Switzerland"},{"author_name":"Manuella Epiney","author_inst":"Division of Obstetrics, Department of Paediatrics, Gynaecology and Obstetrics, Geneva University Hospitals, Faculty of Medicine, University of Geneva, Geneva, S"},{"author_name":"Susanne Grylka-Baeschlin","author_inst":"Research Institute of Midwifery and Reproductive Health, Zurich University of Applied Sciences, Winterthur, Switzerland"},{"author_name":"Antonia Nathalie Mueller","author_inst":"Research Institute of Midwifery and Reproductive Health, Zurich University of Applied Sciences, Winterthur, Switzerland"},{"author_name":"Jessica Di Vincezo-Sormani","author_inst":"Geneva School of Health Sciences, HES-SO University of Applied Sciences and Arts Western Switzerland, Geneva, Switzerland"},{"author_name":"Melanie Suppan","author_inst":"Division of Anesthesiology, Department of Acute Medicine, Geneva University Hospitals, Geneva, Switzerland"},{"author_name":"Isabel Naya Widmer","author_inst":"Research Institute of Midwifery and Reproductive Health, Zurich University of Applied Sciences, Winterthur, Switzerland"},{"author_name":"Thomas Desplanches","author_inst":"Geneva School of Health Sciences, HES-SO University of Applied Sciences and Arts Western Switzerland, Geneva, Switzerland"},{"author_name":"Laurent Gaucher","author_inst":"Geneva School of Health Sciences, HES-SO University of Applied Sciences and Arts Western Switzerland, Geneva, Switzerland"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Amplitude Performance Subtypes in Parkinson's Disease","rel_doi":"10.64898\/2026.07.08.26357552","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357552","rel_abs":"Purpose: The purpose of this study was to identify subgroups of talkers with Parkinsons disease (PD) with shared tongue, lip, and jaw articulatory amplitude behaviors. The study also sought to identify demographic and clinical features that can distinguish the identified kinematic subgroups. Methods: 53 talkers with PD and 54 controls participated. Articulatory amplitudes of the tongue, lip, and jaw were measured during a paragraph reading task using three-dimensional electromagnetic articulography. Amplitude performance profiles of the tongue, lip, and jaw were established for each talker with PD by referencing their performance to that of controls. These profiles were submitted to a hierarchical cluster analysis to identify kinematic-based subgroups. Amplitude performances were compared across subgroups to determine between-group patterns. Demographic and clinical features (e.g., age, sex, disease duration, selected perceptual speech characteristics, dysarthria severity) were compared across the identified kinematic subgroups. Results: Four main kinematic subgroups with differing amplitude performance profiles were identified. One subgroup exhibited normal to mildly exaggerated or mildly reduced amplitudes and was labeled preclinical subgroup (n = 16). Three subgroups exhibited pronounced amplitude reductions of either the tongue (n = 10), the tongue and lips (n = 12), or the tongue, lips, and jaw (n = 10). In addition, there were five talkers with PD whose performance profiles did not align with the identified four subgroups. Their performance was characterized by either pronounced amplitude exaggerations or mildly reduced jaw and lip amplitudes and exaggerated tongue amplitudes. None of the demographic or clinical features differed significantly between the main four subgroups. Conclusion: Findings suggest that the extent to which hypokinesia manifests within the articulatory subsystem can vary in talkers with PD. Longitudinal studies are needed to determine if these subgroups represent different stages of disease progression or distinctly different manifestations of the disease within the articulatory subsystem.","rel_num_authors":4,"rel_authors":[{"author_name":"Antje Mefferd","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Kris Tjaden","author_inst":"University at Buffalo"},{"author_name":"Mary Dietrich","author_inst":"Vanderbilt University"},{"author_name":"Amy E Brown","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Randomized vibrotactile fingertip stimulation modulates beta band in Parkinson's Disease","rel_doi":"10.64898\/2026.07.09.26356470","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26356470","rel_abs":"There is growing interest and need for non-invasive stimulation approaches for the treatment of Parkinson's disease (PD) and other neurological conditions. Pilot studies indicate that vibrotactile stimulation on the fingertips may reduce PD motor symptoms (Pfeifer et al., 2021; Syrkin-Nikolau et al., 2018). PD motor symptoms (e.g., rigidity, bradykinesia) are correlated with exaggerated beta power in the subthalamic nucleus (STN), where neurons are excessively synchronized (Brown 2003; Kuhn et al., 2006; Neumann et al., 2016; Yin et al., 2021), but the effect of vibrotactile stimulation on the STN has not been determined. Here, in 12 PD participants in the OFF deep brain stimulation (DBS) and OFF medication state, we investigated how unilateral vibrotactile stimulation applied to the fingertips affects local field potential (LFP) power in STN. We used a within-participants design to expose each participant to a treatment stimulation pattern, termed randomized vibrotactile stimulation (RVS), and a control stimulation pattern, with the order randomized and with intermittent acquisition of STN LFP. RVS yielded a modest but statistically significant 12% (SEM 4.6%) reduction in mean normalized STN beta power and a 48% (SEM 19%) reduction in peak beta power compared to the DBS-off baseline condition and was significantly different when compared to our control stimulus. Furthermore, we identified a biomarker in STN beta power that predicts which participants may benefit from RVS. We observed that participants that exhibited prominent beta peaks had stronger reductions in mean beta power (17% reduction, SEM 6.1%) and peak beta power (55% reduction, SEM 10%). Regressing against the magnitude of the peak in beta provides a moderate prediction of change in mean and peak beta power due to RVS (R2 = 0.58 for mean and 0.52 for peak). We then used our observations to construct a computational model where beta peaks in a simulated STN varied from prominent to diminished. We found that the efficacy of randomized treatments was dependent on the magnitude of beta peaking, mirroring our clinical findings, and showing that RVS may act by reducing intra-neuronal synaptic strengths in STN. Despite robust changes in STN LFP in our study population, we did not observe a significant change in motor symptoms. These results suggest that peripheral vibrotactile stimulation can reduce STN beta power and motivate additional studies to investigate its long-term effects on motor symptoms across a large population of participants.","rel_num_authors":7,"rel_authors":[{"author_name":"Jesse I. Gilmer","author_inst":"University of Colorado Denver"},{"author_name":"Anthony Y Lee","author_inst":"University of Colorado Denver"},{"author_name":"Shahin Sharafi","author_inst":"University of Ottawa"},{"author_name":"Alexander J Baumgartner","author_inst":"University of Colorado School of Medicine"},{"author_name":"Thomas K Uchida","author_inst":"University of Ottawa"},{"author_name":"John A Thompson","author_inst":"University of Colorado School of Medicine"},{"author_name":"Mazen Al Borno","author_inst":"University of Colorado Denver"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Randomized vibrotactile fingertip stimulation modulates beta band in Parkinson's Disease","rel_doi":"10.64898\/2026.07.09.26356470","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26356470","rel_abs":"There is growing interest and need for non-invasive stimulation approaches for the treatment of Parkinson's disease (PD) and other neurological conditions. Pilot studies indicate that vibrotactile stimulation on the fingertips may reduce PD motor symptoms (Pfeifer et al., 2021; Syrkin-Nikolau et al., 2018). PD motor symptoms (e.g., rigidity, bradykinesia) are correlated with exaggerated beta power in the subthalamic nucleus (STN), where neurons are excessively synchronized (Brown 2003; Kuhn et al., 2006; Neumann et al., 2016; Yin et al., 2021), but the effect of vibrotactile stimulation on the STN has not been determined. Here, in 12 PD participants in the OFF deep brain stimulation (DBS) and OFF medication state, we investigated how unilateral vibrotactile stimulation applied to the fingertips affects local field potential (LFP) power in STN. We used a within-participants design to expose each participant to a treatment stimulation pattern, termed randomized vibrotactile stimulation (RVS), and a control stimulation pattern, with the order randomized and with intermittent acquisition of STN LFP. RVS yielded a modest but statistically significant 12% (SEM 4.6%) reduction in mean normalized STN beta power and a 48% (SEM 19%) reduction in peak beta power compared to the DBS-off baseline condition and was significantly different when compared to our control stimulus. Furthermore, we identified a biomarker in STN beta power that predicts which participants may benefit from RVS. We observed that participants that exhibited prominent beta peaks had stronger reductions in mean beta power (17% reduction, SEM 6.1%) and peak beta power (55% reduction, SEM 10%). Regressing against the magnitude of the peak in beta provides a moderate prediction of change in mean and peak beta power due to RVS (R2 = 0.58 for mean and 0.52 for peak). We then used our observations to construct a computational model where beta peaks in a simulated STN varied from prominent to diminished. We found that the efficacy of randomized treatments was dependent on the magnitude of beta peaking, mirroring our clinical findings, and showing that RVS may act by reducing intra-neuronal synaptic strengths in STN. Despite robust changes in STN LFP in our study population, we did not observe a significant change in motor symptoms. These results suggest that peripheral vibrotactile stimulation can reduce STN beta power and motivate additional studies to investigate its long-term effects on motor symptoms across a large population of participants.","rel_num_authors":7,"rel_authors":[{"author_name":"Jesse I. Gilmer","author_inst":"University of Colorado Denver"},{"author_name":"Anthony Y Lee","author_inst":"University of Colorado Denver"},{"author_name":"Shahin Sharafi","author_inst":"University of Ottawa"},{"author_name":"Alexander J Baumgartner","author_inst":"University of Colorado School of Medicine"},{"author_name":"Thomas K Uchida","author_inst":"University of Ottawa"},{"author_name":"John A Thompson","author_inst":"University of Colorado School of Medicine"},{"author_name":"Mazen Al Borno","author_inst":"University of Colorado Denver"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Feasibility of Patient-Uploaded Videos for Gait Assessment in Multiple Sclerosis","rel_doi":"10.64898\/2026.07.08.26356963","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26356963","rel_abs":"Background: Gait impairment is common among people with multiple sclerosis (PwMS) and is an important marker of disease progression. However, gait assessments typically require in-person evaluations. Objective: To describe the pose-estimation-based method for estimating spatiotemporal gait parameters from a single consumer-grade video, and evaluate the feasibility of home video collection by PwMS. Methods: In a single-center longitudinal digital phenotyping study, ambulatory adults with MS completed a standardized walking task recorded in the frontal plane. Pose estimation (MediaPipe Pose, Ultralytics) and custom scripts were used to estimate gait parameters from videos. Participants were invited to record walking videos at home using personal devices. Adoption and technical feasibility were evaluated across two home video data acquisition phases, with iterative protocol refinements. Results: The in-clinic study included 132 participants; 55 contributed home videos. In Phase I, while home video adoption was low (45% [30\/66]), 87% [26\/30] uploaded [&ge;]1 video of sufficient quality for gait analysis. After protocol refinements, 100% [25\/25] uploaded [&ge;]1 high-quality video. Overall, high-quality frontal-plane videos were obtained at similar rates at home (92% [97\/105]) and in-clinic (91% [423\/467]). Conclusions: Home walking videos can feasibly be collected by PwMS to estimate gait parameters, providing an accessible approach for remote gait monitoring.","rel_num_authors":12,"rel_authors":[{"author_name":"Megan McCune","author_inst":"University of California, San Francisco"},{"author_name":"Yoni Ackerman","author_inst":"University of California, San Francisco"},{"author_name":"Alexis Camacho","author_inst":"University of California, San Francisco"},{"author_name":"Nikki Sisodia","author_inst":"University of California, San Francisco"},{"author_name":"Jaeleene Wijangco","author_inst":"University of California, San Francisco"},{"author_name":"Kyra Henderson","author_inst":"University of California, San Francisco"},{"author_name":"Jeannine Bradsby","author_inst":"University of California, San Francisco"},{"author_name":"Shane Poole","author_inst":"University of California, San Francisco"},{"author_name":"Abel Torres Espin","author_inst":"University of Waterloo"},{"author_name":"Matthew J Miller","author_inst":"University of California, San Francisco"},{"author_name":"Valerie J Block","author_inst":"University of California, San Francisco"},{"author_name":"Riley Bove","author_inst":"University of California, San Francisco"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Drivers of Diagnostic Variation in a Digital Global Kidney Transplant Reader Study","rel_doi":"10.64898\/2026.07.09.26357318","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357318","rel_abs":"Background Diagnostic interpretation of kidney allograft biopsies using the Banff classification remains variable, but the determinants of this variability are not fully defined. We performed a global, fully digital multi-reader study to identify the principal drivers of disagreement in Banff-based assessment. Methods Thirty six kidney transplant biopsies were independently scored by 67 renal pathologists on a standardized digital platform. Readers assessed Banff lesions on hematoxylin and eosin, periodic acid Schiff, and Jones' silver stains; final diagnostic categories were assigned using prespecified Banff-based decision rules. Interobserver agreement was quantified with Gwet's agreement coefficient (AC) statistics. Determinants of diagnostic agreement were evaluated) using pairwise mixed-effects logistic regression, and reader similarity was examined by principal component analysis (PCA) with post hoc molecular annotation. Results Agreement for final diagnostic categories was moderate (Gwet's AC1, 0.55; 95% CI, 0.47 - 0.63). Lesion-level agreement varied substantially, with lowest agreement for selected threshold-dependent inflammatory or semi-quantitative lesions, including interstitial inflammation in areas of IFTA, peritubular capillaritis and arteriolar hyalinosis. Diagnostic concordance differed markedly across biopsies, indicating strong case-level heterogeneity. In pairwise models, differences in active inflammatory and vascular lesion scoring were the strongest correlates of diagnostic disagreement; reader experience and geography contributed minimally. Principal component analysis showed reader variation was organized along two dominant axes: a rejection-calling threshold axis linked mainly to tubulointerstitial inflammatory injury, and a T cell-mediated (TCMR\/TI) and antibody-mediated\/microvascular (AMR\/MVI) inflammation-oriented phenotypic classification axis. Conclusion Interobserver variation in Banff-based kidney transplant biopsy assessment is structured rather than random and driven mainly by how readers threshold and integrate key inflammatory lesion compartments rather than experience or geographic location.","rel_num_authors":77,"rel_authors":[{"author_name":"Rianne Hofstraat-Boersma","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Van 't Hoff Institute for Molecular Sciences, Uni"},{"author_name":"Romy du Long","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Pathology, University Medical Cente"},{"author_name":"Giorgio Buzzanca","author_inst":"Department of Pathology, Systems Pathology Research Group, Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Adeyemi A. Abiola","author_inst":"Department of Histopathology, African Medical Center of Excellence Hospital, Abuja, Nigeria"},{"author_name":"Sam Albadri","author_inst":"Department of Pathology, Mayo Clinic, Mayo Clinic School of Medicine, Rochester, United States"},{"author_name":"Zahabia Ali","author_inst":"Department of Cellular Pathology, Barts NHS Trust, London, United Kingdom"},{"author_name":"Ahmed Altaleb","author_inst":"Histopathology Unit, Mubarak Alkabeer Hospital, Jabriya, Kuwait"},{"author_name":"Andrea Angioi","author_inst":"S.C.D.U. Nefrologia, Dialisi e Trapianto, ARNAS Brotzu Hospital, Cagliari, Italy"},{"author_name":"Sultana G. Banu","author_inst":"Department of Pathology, Bangladesh Medical University, Dhaka, Bangladesh"},{"author_name":"Marc Barry","author_inst":"Department of Pathology, University of Utah, Salt Lake City, United States"},{"author_name":"Ami R. Bhalodia","author_inst":"The Pathology Laboratory, Lake Charles, United States"},{"author_name":"Paola Bianco","author_inst":"S.C. Anatomia Patologia, ARNAS Brotzu Hospital, Cagliari, Italy"},{"author_name":"Verena Broecker","author_inst":"Department of Pathology, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden"},{"author_name":"Roman Buelow","author_inst":"Institute for Pathology, RWTH Aachen University Hospital, Aachen, Germany"},{"author_name":"Bertrand Chauveau","author_inst":"Department of Pathology, Bordeaux University Hospital, Bordeaux, France"},{"author_name":"Guoli Chen","author_inst":"Department of Pathology, Penn State Health, Penn State College of Medicine, Hershey, United States"},{"author_name":"Boonyarit Cheunsuchon","author_inst":"Department of Pathology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand"},{"author_name":"Giovanna M. Crisi","author_inst":"Department of Pathology, UMASS-Chan School of Medical School - Baystate, Springfield, United States"},{"author_name":"Simin Daneshvar","author_inst":"Department of Anatomical Pathology, St. Vincent's Hospital, University of Melbourne, Melbourne, Australia"},{"author_name":"Amelie Dendooven","author_inst":"Department of Pathology, University Hospital of Ghent, Ghent University, Ghent, Belgium; Department of Pathology, Faculty of Medicine and Health Sciences, Unive"},{"author_name":"Pouneh Dokouhaki","author_inst":"Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada; Department of Pathology, St. Paul Hospital, Providence Healt"},{"author_name":"Cinthia B. Drachenberg","author_inst":"Department of Pathology, University of Maryland School of Medicine, Baltimore, United States"},{"author_name":"Alton B. Farris","author_inst":"Department of Pathology and laboratory Medicine, Emory University Hospital, Emory University, Atlanta, United States"},{"author_name":"Sophie Ferlicot","author_inst":"Department of Pathology, Le Kremlin-Bicetre Hospital, Paris-Saclay University, Paris, France"},{"author_name":"Sandrine Florquin","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands"},{"author_name":"Francesco Fontana","author_inst":"Nephrology, Dialysis and Kidney Transplant Unit, University Hospital of Modena, Modena, Italy"},{"author_name":"Jean-Baptiste Gibier","author_inst":"Institute of Pathology, Centre Hospitalier Universitaire de Lille, Lille, France"},{"author_name":"Ian W. Gibson","author_inst":"Department of Pathology, University of Manitoba, Winnipeg, Canada"},{"author_name":"Saurabh Gujarathi","author_inst":"Department of Pathology, Manipal Hospital, Pune, India"},{"author_name":"Allen R. Hendricks","author_inst":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States"},{"author_name":"Sufia Husain","author_inst":"Department of Pathology, College of Medicine, King Saud University - Medical City, Riyadh, Saudi Arabia"},{"author_name":"Jaynul Islam","author_inst":"Department of Pathology, BIRDEM General Hospital, Dhaka, Bangladesh"},{"author_name":"Wesam Ismail","author_inst":"Department of Pathology, Beni-Suef University, Beni-Suef, Egypt"},{"author_name":"Geetha Jagannathan","author_inst":"Department of Pathology and laboratory Medicine, Emory University Hospital, Emory University, Atlanta, United States"},{"author_name":"Johannes Klager","author_inst":"Department of Pathology, General Hospital of Vienna, Medical University of Vienna, Vienna, Austria"},{"author_name":"Nicolas Kozakowski","author_inst":"Department of Pathology, General Hospital of Vienna, Medical University of Vienna, Vienna, Austria"},{"author_name":"Adriana Krizova","author_inst":"Department of Laboratory Medicine, St. Michael's Hospital, University of Toronto, Toronto, Canada"},{"author_name":"Anila A. Kurien","author_inst":"Department of Pathology, Renopath, Center for Renal and Urological Pathology, Chennai, India"},{"author_name":"Boomi Kwon","author_inst":"Department of Pathology, Mater Hospital, Brisbane, Australia"},{"author_name":"Vincenzo L'Imperio","author_inst":"Department of Medicine and Surgery, Pathology, Fondazione IRCCS San Gerardo dei Tintori, University of Milano-Bicocca, Monza, Italy"},{"author_name":"Felipe L. Ledesma","author_inst":"Department of Pathology, University of Sao Paulo Medicine School, Sao Paulo, Brazil"},{"author_name":"Julia P. Low","author_inst":"Department of Anatomical Pathology, Sydpath, St. Vincent's Hospital, Sydney, University of South Wales, Australia"},{"author_name":"Jonne Martin","author_inst":"Department of Cellular Pathology, The Royal London Hospital, Queen Mary University of London, London, United Kingdom"},{"author_name":"Shweta S. Mehta","author_inst":"Department of Pathology, Kauvery Hospital, Bengaluru, India"},{"author_name":"Nidia Messias","author_inst":"Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, United States"},{"author_name":"Salvatore E. Mignano","author_inst":"Department of Pathology & Genomic Medicine, Thomas Jefferson University Hospital, Philadelphia, United States"},{"author_name":"Monik E. Miranda","author_inst":"Department of Anatomical Pathology, Cipto Mangunkusumo Hospital, Universitas Indonesia, Jakarta, Indonesia"},{"author_name":"Gilbert Moeckel","author_inst":"Department of Pathology, Yale New Haven Hospital, Yale University, New Haven, United States"},{"author_name":"Chiara Pala","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Medicine and Surgery, Nephrology Un"},{"author_name":"Brendon Price","author_inst":"Division of Anatomical Pathology, Department of Pathology, NHLS.Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa"},{"author_name":"Marc A. Ranson","author_inst":"Department of Pathology, University of Manitoba, Winnipeg, Canada"},{"author_name":"Andrea N. Rodriguez","author_inst":"Department of Pathology, Hospital Nacional Professor Alejandro Posadas, Buenos Aires, Argentina; Department of Pathology, The Favaloro Foundation University Hos"},{"author_name":"Joris J.T.H. Roelofs","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands"},{"author_name":"Avi Rosenberg","author_inst":"Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States"},{"author_name":"Alireza Sadeghipour","author_inst":"Department of Pathology, Rasoul-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran"},{"author_name":"Miroslav Sekulic","author_inst":"Department of Pathology and Cell Biology, Columbia University Medical Center, Columbia University, New York, United States"},{"author_name":"Suman Setty","author_inst":"Department of Pathology, University of Illinois Hospital and Health Sciences System, University of Illinois at Chicago, Chicago, United States"},{"author_name":"Michael Sheaff","author_inst":"Department of Cellular Pathology, Barts NHS Trust, London, United Kingdom"},{"author_name":"Maria F.S. Soares","author_inst":"Department of Cellular Pathology, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom"},{"author_name":"Jerasit Surintrspanont","author_inst":"Department of Pathology, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand"},{"author_name":"George Terinte-Balcan","author_inst":"Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique-Hopitaux de Paris, Paris, France"},{"author_name":"Francesca Testa","author_inst":"Nephrology, Dialysis and Kidney Transplant Unit, University Hospital of Modena, Modena, Italy"},{"author_name":"David O. Hendriquez Ticas","author_inst":"Department of Pathology, Northwestern Memorial Hospital, Feinberg School of Medicine Northwestern University, Chicago, United States"},{"author_name":"Maria F. Toniolo","author_inst":"Department of Pathology, Instituto de Transplantes y Alta Complejidad, Buenos Aires, Argentina"},{"author_name":"Dominique van Midden","author_inst":"Department of Pathology, Radboud University Medical Center, Radboud University, Nijmegen, Netherlands"},{"author_name":"Ramya K. Velagapudi","author_inst":"Department of Pathology, University of Mississippi Medical Center, Jackson, United States"},{"author_name":"Seethalakshmi Viswanathan","author_inst":"Department of Tissue Pathology, Westmead Hospital, Westmead Clinical School, University of Sydney, Sydney, Australia"},{"author_name":"Saskia von Stillfried","author_inst":"Institute for Pathology, RWTH Aachen University Hospital, Aachen, Germany"},{"author_name":"Chih-Ying Wu","author_inst":"Department of Pathology and laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Institute of Biomedical Sciences, National Chung Hsing Un"},{"author_name":"Nienke Kalverboer","author_inst":"Department of Pathology, Systems Pathology Research Group, Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Imke B. Bruns","author_inst":"Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands"},{"author_name":"Giulia Callegaro","author_inst":"Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands"},{"author_name":"Bob van de Water","author_inst":"Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands"},{"author_name":"Danny van der Helm","author_inst":"Division of Nephrology, Department Internal Medicine; Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Aiko P.J. de Vries","author_inst":"Division of Nephrology, Department Internal Medicine; Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Hessel Peters-Sengers","author_inst":"Center for Infection and Molecular Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands"},{"author_name":"Jesper Kers","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Pathology, Systems Pathology Resear"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Drivers of Diagnostic Variation in a Digital Global Kidney Transplant Reader Study","rel_doi":"10.64898\/2026.07.09.26357318","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357318","rel_abs":"Background Diagnostic interpretation of kidney allograft biopsies using the Banff classification remains variable, but the determinants of this variability are not fully defined. We performed a global, fully digital multi-reader study to identify the principal drivers of disagreement in Banff-based assessment. Methods Thirty six kidney transplant biopsies were independently scored by 67 renal pathologists on a standardized digital platform. Readers assessed Banff lesions on hematoxylin and eosin, periodic acid Schiff, and Jones' silver stains; final diagnostic categories were assigned using prespecified Banff-based decision rules. Interobserver agreement was quantified with Gwet's agreement coefficient (AC) statistics. Determinants of diagnostic agreement were evaluated) using pairwise mixed-effects logistic regression, and reader similarity was examined by principal component analysis (PCA) with post hoc molecular annotation. Results Agreement for final diagnostic categories was moderate (Gwet's AC1, 0.55; 95% CI, 0.47 - 0.63). Lesion-level agreement varied substantially, with lowest agreement for selected threshold-dependent inflammatory or semi-quantitative lesions, including interstitial inflammation in areas of IFTA, peritubular capillaritis and arteriolar hyalinosis. Diagnostic concordance differed markedly across biopsies, indicating strong case-level heterogeneity. In pairwise models, differences in active inflammatory and vascular lesion scoring were the strongest correlates of diagnostic disagreement; reader experience and geography contributed minimally. Principal component analysis showed reader variation was organized along two dominant axes: a rejection-calling threshold axis linked mainly to tubulointerstitial inflammatory injury, and a T cell-mediated (TCMR\/TI) and antibody-mediated\/microvascular (AMR\/MVI) inflammation-oriented phenotypic classification axis. Conclusion Interobserver variation in Banff-based kidney transplant biopsy assessment is structured rather than random and driven mainly by how readers threshold and integrate key inflammatory lesion compartments rather than experience or geographic location.","rel_num_authors":77,"rel_authors":[{"author_name":"Rianne Hofstraat-Boersma","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Van 't Hoff Institute for Molecular Sciences, Uni"},{"author_name":"Romy du Long","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Pathology, University Medical Cente"},{"author_name":"Giorgio Buzzanca","author_inst":"Department of Pathology, Systems Pathology Research Group, Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Adeyemi A. Abiola","author_inst":"Department of Histopathology, African Medical Center of Excellence Hospital, Abuja, Nigeria"},{"author_name":"Sam Albadri","author_inst":"Department of Pathology, Mayo Clinic, Mayo Clinic School of Medicine, Rochester, United States"},{"author_name":"Zahabia Ali","author_inst":"Department of Cellular Pathology, Barts NHS Trust, London, United Kingdom"},{"author_name":"Ahmed Altaleb","author_inst":"Histopathology Unit, Mubarak Alkabeer Hospital, Jabriya, Kuwait"},{"author_name":"Andrea Angioi","author_inst":"S.C.D.U. Nefrologia, Dialisi e Trapianto, ARNAS Brotzu Hospital, Cagliari, Italy"},{"author_name":"Sultana G. Banu","author_inst":"Department of Pathology, Bangladesh Medical University, Dhaka, Bangladesh"},{"author_name":"Marc Barry","author_inst":"Department of Pathology, University of Utah, Salt Lake City, United States"},{"author_name":"Ami R. Bhalodia","author_inst":"The Pathology Laboratory, Lake Charles, United States"},{"author_name":"Paola Bianco","author_inst":"S.C. Anatomia Patologia, ARNAS Brotzu Hospital, Cagliari, Italy"},{"author_name":"Verena Broecker","author_inst":"Department of Pathology, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden"},{"author_name":"Roman Buelow","author_inst":"Institute for Pathology, RWTH Aachen University Hospital, Aachen, Germany"},{"author_name":"Bertrand Chauveau","author_inst":"Department of Pathology, Bordeaux University Hospital, Bordeaux, France"},{"author_name":"Guoli Chen","author_inst":"Department of Pathology, Penn State Health, Penn State College of Medicine, Hershey, United States"},{"author_name":"Boonyarit Cheunsuchon","author_inst":"Department of Pathology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand"},{"author_name":"Giovanna M. Crisi","author_inst":"Department of Pathology, UMASS-Chan School of Medical School - Baystate, Springfield, United States"},{"author_name":"Simin Daneshvar","author_inst":"Department of Anatomical Pathology, St. Vincent's Hospital, University of Melbourne, Melbourne, Australia"},{"author_name":"Amelie Dendooven","author_inst":"Department of Pathology, University Hospital of Ghent, Ghent University, Ghent, Belgium; Department of Pathology, Faculty of Medicine and Health Sciences, Unive"},{"author_name":"Pouneh Dokouhaki","author_inst":"Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada; Department of Pathology, St. Paul Hospital, Providence Healt"},{"author_name":"Cinthia B. Drachenberg","author_inst":"Department of Pathology, University of Maryland School of Medicine, Baltimore, United States"},{"author_name":"Alton B. Farris","author_inst":"Department of Pathology and laboratory Medicine, Emory University Hospital, Emory University, Atlanta, United States"},{"author_name":"Sophie Ferlicot","author_inst":"Department of Pathology, Le Kremlin-Bicetre Hospital, Paris-Saclay University, Paris, France"},{"author_name":"Sandrine Florquin","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands"},{"author_name":"Francesco Fontana","author_inst":"Nephrology, Dialysis and Kidney Transplant Unit, University Hospital of Modena, Modena, Italy"},{"author_name":"Jean-Baptiste Gibier","author_inst":"Institute of Pathology, Centre Hospitalier Universitaire de Lille, Lille, France"},{"author_name":"Ian W. Gibson","author_inst":"Department of Pathology, University of Manitoba, Winnipeg, Canada"},{"author_name":"Saurabh Gujarathi","author_inst":"Department of Pathology, Manipal Hospital, Pune, India"},{"author_name":"Allen R. Hendricks","author_inst":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States"},{"author_name":"Sufia Husain","author_inst":"Department of Pathology, College of Medicine, King Saud University - Medical City, Riyadh, Saudi Arabia"},{"author_name":"Jaynul Islam","author_inst":"Department of Pathology, BIRDEM General Hospital, Dhaka, Bangladesh"},{"author_name":"Wesam Ismail","author_inst":"Department of Pathology, Beni-Suef University, Beni-Suef, Egypt"},{"author_name":"Geetha Jagannathan","author_inst":"Department of Pathology and laboratory Medicine, Emory University Hospital, Emory University, Atlanta, United States"},{"author_name":"Johannes Klager","author_inst":"Department of Pathology, General Hospital of Vienna, Medical University of Vienna, Vienna, Austria"},{"author_name":"Nicolas Kozakowski","author_inst":"Department of Pathology, General Hospital of Vienna, Medical University of Vienna, Vienna, Austria"},{"author_name":"Adriana Krizova","author_inst":"Department of Laboratory Medicine, St. Michael's Hospital, University of Toronto, Toronto, Canada"},{"author_name":"Anila A. Kurien","author_inst":"Department of Pathology, Renopath, Center for Renal and Urological Pathology, Chennai, India"},{"author_name":"Boomi Kwon","author_inst":"Department of Pathology, Mater Hospital, Brisbane, Australia"},{"author_name":"Vincenzo L'Imperio","author_inst":"Department of Medicine and Surgery, Pathology, Fondazione IRCCS San Gerardo dei Tintori, University of Milano-Bicocca, Monza, Italy"},{"author_name":"Felipe L. Ledesma","author_inst":"Department of Pathology, University of Sao Paulo Medicine School, Sao Paulo, Brazil"},{"author_name":"Julia P. Low","author_inst":"Department of Anatomical Pathology, Sydpath, St. Vincent's Hospital, Sydney, University of South Wales, Australia"},{"author_name":"Jonne Martin","author_inst":"Department of Cellular Pathology, The Royal London Hospital, Queen Mary University of London, London, United Kingdom"},{"author_name":"Shweta S. Mehta","author_inst":"Department of Pathology, Kauvery Hospital, Bengaluru, India"},{"author_name":"Nidia Messias","author_inst":"Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, United States"},{"author_name":"Salvatore E. Mignano","author_inst":"Department of Pathology & Genomic Medicine, Thomas Jefferson University Hospital, Philadelphia, United States"},{"author_name":"Monik E. Miranda","author_inst":"Department of Anatomical Pathology, Cipto Mangunkusumo Hospital, Universitas Indonesia, Jakarta, Indonesia"},{"author_name":"Gilbert Moeckel","author_inst":"Department of Pathology, Yale New Haven Hospital, Yale University, New Haven, United States"},{"author_name":"Chiara Pala","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Medicine and Surgery, Nephrology Un"},{"author_name":"Brendon Price","author_inst":"Division of Anatomical Pathology, Department of Pathology, NHLS.Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa"},{"author_name":"Marc A. Ranson","author_inst":"Department of Pathology, University of Manitoba, Winnipeg, Canada"},{"author_name":"Andrea N. Rodriguez","author_inst":"Department of Pathology, Hospital Nacional Professor Alejandro Posadas, Buenos Aires, Argentina; Department of Pathology, The Favaloro Foundation University Hos"},{"author_name":"Joris J.T.H. Roelofs","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands"},{"author_name":"Avi Rosenberg","author_inst":"Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States"},{"author_name":"Alireza Sadeghipour","author_inst":"Department of Pathology, Rasoul-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran"},{"author_name":"Miroslav Sekulic","author_inst":"Department of Pathology and Cell Biology, Columbia University Medical Center, Columbia University, New York, United States"},{"author_name":"Suman Setty","author_inst":"Department of Pathology, University of Illinois Hospital and Health Sciences System, University of Illinois at Chicago, Chicago, United States"},{"author_name":"Michael Sheaff","author_inst":"Department of Cellular Pathology, Barts NHS Trust, London, United Kingdom"},{"author_name":"Maria F.S. Soares","author_inst":"Department of Cellular Pathology, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom"},{"author_name":"Jerasit Surintrspanont","author_inst":"Department of Pathology, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand"},{"author_name":"George Terinte-Balcan","author_inst":"Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique-Hopitaux de Paris, Paris, France"},{"author_name":"Francesca Testa","author_inst":"Nephrology, Dialysis and Kidney Transplant Unit, University Hospital of Modena, Modena, Italy"},{"author_name":"David O. Hendriquez Ticas","author_inst":"Department of Pathology, Northwestern Memorial Hospital, Feinberg School of Medicine Northwestern University, Chicago, United States"},{"author_name":"Maria F. Toniolo","author_inst":"Department of Pathology, Instituto de Transplantes y Alta Complejidad, Buenos Aires, Argentina"},{"author_name":"Dominique van Midden","author_inst":"Department of Pathology, Radboud University Medical Center, Radboud University, Nijmegen, Netherlands"},{"author_name":"Ramya K. Velagapudi","author_inst":"Department of Pathology, University of Mississippi Medical Center, Jackson, United States"},{"author_name":"Seethalakshmi Viswanathan","author_inst":"Department of Tissue Pathology, Westmead Hospital, Westmead Clinical School, University of Sydney, Sydney, Australia"},{"author_name":"Saskia von Stillfried","author_inst":"Institute for Pathology, RWTH Aachen University Hospital, Aachen, Germany"},{"author_name":"Chih-Ying Wu","author_inst":"Department of Pathology and laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Institute of Biomedical Sciences, National Chung Hsing Un"},{"author_name":"Nienke Kalverboer","author_inst":"Department of Pathology, Systems Pathology Research Group, Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Imke B. Bruns","author_inst":"Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands"},{"author_name":"Giulia Callegaro","author_inst":"Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands"},{"author_name":"Bob van de Water","author_inst":"Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands"},{"author_name":"Danny van der Helm","author_inst":"Division of Nephrology, Department Internal Medicine; Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Aiko P.J. de Vries","author_inst":"Division of Nephrology, Department Internal Medicine; Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Hessel Peters-Sengers","author_inst":"Center for Infection and Molecular Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands"},{"author_name":"Jesper Kers","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Pathology, Systems Pathology Resear"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Drivers of Diagnostic Variation in a Digital Global Kidney Transplant Reader Study","rel_doi":"10.64898\/2026.07.09.26357318","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357318","rel_abs":"Background Diagnostic interpretation of kidney allograft biopsies using the Banff classification remains variable, but the determinants of this variability are not fully defined. We performed a global, fully digital multi-reader study to identify the principal drivers of disagreement in Banff-based assessment. Methods Thirty six kidney transplant biopsies were independently scored by 67 renal pathologists on a standardized digital platform. Readers assessed Banff lesions on hematoxylin and eosin, periodic acid Schiff, and Jones' silver stains; final diagnostic categories were assigned using prespecified Banff-based decision rules. Interobserver agreement was quantified with Gwet's agreement coefficient (AC) statistics. Determinants of diagnostic agreement were evaluated) using pairwise mixed-effects logistic regression, and reader similarity was examined by principal component analysis (PCA) with post hoc molecular annotation. Results Agreement for final diagnostic categories was moderate (Gwet's AC1, 0.55; 95% CI, 0.47 - 0.63). Lesion-level agreement varied substantially, with lowest agreement for selected threshold-dependent inflammatory or semi-quantitative lesions, including interstitial inflammation in areas of IFTA, peritubular capillaritis and arteriolar hyalinosis. Diagnostic concordance differed markedly across biopsies, indicating strong case-level heterogeneity. In pairwise models, differences in active inflammatory and vascular lesion scoring were the strongest correlates of diagnostic disagreement; reader experience and geography contributed minimally. Principal component analysis showed reader variation was organized along two dominant axes: a rejection-calling threshold axis linked mainly to tubulointerstitial inflammatory injury, and a T cell-mediated (TCMR\/TI) and antibody-mediated\/microvascular (AMR\/MVI) inflammation-oriented phenotypic classification axis. Conclusion Interobserver variation in Banff-based kidney transplant biopsy assessment is structured rather than random and driven mainly by how readers threshold and integrate key inflammatory lesion compartments rather than experience or geographic location.","rel_num_authors":77,"rel_authors":[{"author_name":"Rianne Hofstraat-Boersma","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Van 't Hoff Institute for Molecular Sciences, Uni"},{"author_name":"Romy du Long","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Pathology, University Medical Cente"},{"author_name":"Giorgio Buzzanca","author_inst":"Department of Pathology, Systems Pathology Research Group, Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Adeyemi A. Abiola","author_inst":"Department of Histopathology, African Medical Center of Excellence Hospital, Abuja, Nigeria"},{"author_name":"Sam Albadri","author_inst":"Department of Pathology, Mayo Clinic, Mayo Clinic School of Medicine, Rochester, United States"},{"author_name":"Zahabia Ali","author_inst":"Department of Cellular Pathology, Barts NHS Trust, London, United Kingdom"},{"author_name":"Ahmed Altaleb","author_inst":"Histopathology Unit, Mubarak Alkabeer Hospital, Jabriya, Kuwait"},{"author_name":"Andrea Angioi","author_inst":"S.C.D.U. Nefrologia, Dialisi e Trapianto, ARNAS Brotzu Hospital, Cagliari, Italy"},{"author_name":"Sultana G. Banu","author_inst":"Department of Pathology, Bangladesh Medical University, Dhaka, Bangladesh"},{"author_name":"Marc Barry","author_inst":"Department of Pathology, University of Utah, Salt Lake City, United States"},{"author_name":"Ami R. Bhalodia","author_inst":"The Pathology Laboratory, Lake Charles, United States"},{"author_name":"Paola Bianco","author_inst":"S.C. Anatomia Patologia, ARNAS Brotzu Hospital, Cagliari, Italy"},{"author_name":"Verena Broecker","author_inst":"Department of Pathology, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden"},{"author_name":"Roman Buelow","author_inst":"Institute for Pathology, RWTH Aachen University Hospital, Aachen, Germany"},{"author_name":"Bertrand Chauveau","author_inst":"Department of Pathology, Bordeaux University Hospital, Bordeaux, France"},{"author_name":"Guoli Chen","author_inst":"Department of Pathology, Penn State Health, Penn State College of Medicine, Hershey, United States"},{"author_name":"Boonyarit Cheunsuchon","author_inst":"Department of Pathology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand"},{"author_name":"Giovanna M. Crisi","author_inst":"Department of Pathology, UMASS-Chan School of Medical School - Baystate, Springfield, United States"},{"author_name":"Simin Daneshvar","author_inst":"Department of Anatomical Pathology, St. Vincent's Hospital, University of Melbourne, Melbourne, Australia"},{"author_name":"Amelie Dendooven","author_inst":"Department of Pathology, University Hospital of Ghent, Ghent University, Ghent, Belgium; Department of Pathology, Faculty of Medicine and Health Sciences, Unive"},{"author_name":"Pouneh Dokouhaki","author_inst":"Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada; Department of Pathology, St. Paul Hospital, Providence Healt"},{"author_name":"Cinthia B. Drachenberg","author_inst":"Department of Pathology, University of Maryland School of Medicine, Baltimore, United States"},{"author_name":"Alton B. Farris","author_inst":"Department of Pathology and laboratory Medicine, Emory University Hospital, Emory University, Atlanta, United States"},{"author_name":"Sophie Ferlicot","author_inst":"Department of Pathology, Le Kremlin-Bicetre Hospital, Paris-Saclay University, Paris, France"},{"author_name":"Sandrine Florquin","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands"},{"author_name":"Francesco Fontana","author_inst":"Nephrology, Dialysis and Kidney Transplant Unit, University Hospital of Modena, Modena, Italy"},{"author_name":"Jean-Baptiste Gibier","author_inst":"Institute of Pathology, Centre Hospitalier Universitaire de Lille, Lille, France"},{"author_name":"Ian W. Gibson","author_inst":"Department of Pathology, University of Manitoba, Winnipeg, Canada"},{"author_name":"Saurabh Gujarathi","author_inst":"Department of Pathology, Manipal Hospital, Pune, India"},{"author_name":"Allen R. Hendricks","author_inst":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States"},{"author_name":"Sufia Husain","author_inst":"Department of Pathology, College of Medicine, King Saud University - Medical City, Riyadh, Saudi Arabia"},{"author_name":"Jaynul Islam","author_inst":"Department of Pathology, BIRDEM General Hospital, Dhaka, Bangladesh"},{"author_name":"Wesam Ismail","author_inst":"Department of Pathology, Beni-Suef University, Beni-Suef, Egypt"},{"author_name":"Geetha Jagannathan","author_inst":"Department of Pathology and laboratory Medicine, Emory University Hospital, Emory University, Atlanta, United States"},{"author_name":"Johannes Klager","author_inst":"Department of Pathology, General Hospital of Vienna, Medical University of Vienna, Vienna, Austria"},{"author_name":"Nicolas Kozakowski","author_inst":"Department of Pathology, General Hospital of Vienna, Medical University of Vienna, Vienna, Austria"},{"author_name":"Adriana Krizova","author_inst":"Department of Laboratory Medicine, St. Michael's Hospital, University of Toronto, Toronto, Canada"},{"author_name":"Anila A. Kurien","author_inst":"Department of Pathology, Renopath, Center for Renal and Urological Pathology, Chennai, India"},{"author_name":"Boomi Kwon","author_inst":"Department of Pathology, Mater Hospital, Brisbane, Australia"},{"author_name":"Vincenzo L'Imperio","author_inst":"Department of Medicine and Surgery, Pathology, Fondazione IRCCS San Gerardo dei Tintori, University of Milano-Bicocca, Monza, Italy"},{"author_name":"Felipe L. Ledesma","author_inst":"Department of Pathology, University of Sao Paulo Medicine School, Sao Paulo, Brazil"},{"author_name":"Julia P. Low","author_inst":"Department of Anatomical Pathology, Sydpath, St. Vincent's Hospital, Sydney, University of South Wales, Australia"},{"author_name":"Jonne Martin","author_inst":"Department of Cellular Pathology, The Royal London Hospital, Queen Mary University of London, London, United Kingdom"},{"author_name":"Shweta S. Mehta","author_inst":"Department of Pathology, Kauvery Hospital, Bengaluru, India"},{"author_name":"Nidia Messias","author_inst":"Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, United States"},{"author_name":"Salvatore E. Mignano","author_inst":"Department of Pathology & Genomic Medicine, Thomas Jefferson University Hospital, Philadelphia, United States"},{"author_name":"Monik E. Miranda","author_inst":"Department of Anatomical Pathology, Cipto Mangunkusumo Hospital, Universitas Indonesia, Jakarta, Indonesia"},{"author_name":"Gilbert Moeckel","author_inst":"Department of Pathology, Yale New Haven Hospital, Yale University, New Haven, United States"},{"author_name":"Chiara Pala","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Medicine and Surgery, Nephrology Un"},{"author_name":"Brendon Price","author_inst":"Division of Anatomical Pathology, Department of Pathology, NHLS.Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa"},{"author_name":"Marc A. Ranson","author_inst":"Department of Pathology, University of Manitoba, Winnipeg, Canada"},{"author_name":"Andrea N. Rodriguez","author_inst":"Department of Pathology, Hospital Nacional Professor Alejandro Posadas, Buenos Aires, Argentina; Department of Pathology, The Favaloro Foundation University Hos"},{"author_name":"Joris J.T.H. Roelofs","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands"},{"author_name":"Avi Rosenberg","author_inst":"Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States"},{"author_name":"Alireza Sadeghipour","author_inst":"Department of Pathology, Rasoul-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran"},{"author_name":"Miroslav Sekulic","author_inst":"Department of Pathology and Cell Biology, Columbia University Medical Center, Columbia University, New York, United States"},{"author_name":"Suman Setty","author_inst":"Department of Pathology, University of Illinois Hospital and Health Sciences System, University of Illinois at Chicago, Chicago, United States"},{"author_name":"Michael Sheaff","author_inst":"Department of Cellular Pathology, Barts NHS Trust, London, United Kingdom"},{"author_name":"Maria F.S. Soares","author_inst":"Department of Cellular Pathology, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom"},{"author_name":"Jerasit Surintrspanont","author_inst":"Department of Pathology, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand"},{"author_name":"George Terinte-Balcan","author_inst":"Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique-Hopitaux de Paris, Paris, France"},{"author_name":"Francesca Testa","author_inst":"Nephrology, Dialysis and Kidney Transplant Unit, University Hospital of Modena, Modena, Italy"},{"author_name":"David O. Hendriquez Ticas","author_inst":"Department of Pathology, Northwestern Memorial Hospital, Feinberg School of Medicine Northwestern University, Chicago, United States"},{"author_name":"Maria F. Toniolo","author_inst":"Department of Pathology, Instituto de Transplantes y Alta Complejidad, Buenos Aires, Argentina"},{"author_name":"Dominique van Midden","author_inst":"Department of Pathology, Radboud University Medical Center, Radboud University, Nijmegen, Netherlands"},{"author_name":"Ramya K. Velagapudi","author_inst":"Department of Pathology, University of Mississippi Medical Center, Jackson, United States"},{"author_name":"Seethalakshmi Viswanathan","author_inst":"Department of Tissue Pathology, Westmead Hospital, Westmead Clinical School, University of Sydney, Sydney, Australia"},{"author_name":"Saskia von Stillfried","author_inst":"Institute for Pathology, RWTH Aachen University Hospital, Aachen, Germany"},{"author_name":"Chih-Ying Wu","author_inst":"Department of Pathology and laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Institute of Biomedical Sciences, National Chung Hsing Un"},{"author_name":"Nienke Kalverboer","author_inst":"Department of Pathology, Systems Pathology Research Group, Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Imke B. Bruns","author_inst":"Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands"},{"author_name":"Giulia Callegaro","author_inst":"Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands"},{"author_name":"Bob van de Water","author_inst":"Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands"},{"author_name":"Danny van der Helm","author_inst":"Division of Nephrology, Department Internal Medicine; Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Aiko P.J. de Vries","author_inst":"Division of Nephrology, Department Internal Medicine; Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Hessel Peters-Sengers","author_inst":"Center for Infection and Molecular Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands"},{"author_name":"Jesper Kers","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Pathology, Systems Pathology Resear"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Drivers of Diagnostic Variation in a Digital Global Kidney Transplant Reader Study","rel_doi":"10.64898\/2026.07.09.26357318","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357318","rel_abs":"Background Diagnostic interpretation of kidney allograft biopsies using the Banff classification remains variable, but the determinants of this variability are not fully defined. We performed a global, fully digital multi-reader study to identify the principal drivers of disagreement in Banff-based assessment. Methods Thirty six kidney transplant biopsies were independently scored by 67 renal pathologists on a standardized digital platform. Readers assessed Banff lesions on hematoxylin and eosin, periodic acid Schiff, and Jones' silver stains; final diagnostic categories were assigned using prespecified Banff-based decision rules. Interobserver agreement was quantified with Gwet's agreement coefficient (AC) statistics. Determinants of diagnostic agreement were evaluated) using pairwise mixed-effects logistic regression, and reader similarity was examined by principal component analysis (PCA) with post hoc molecular annotation. Results Agreement for final diagnostic categories was moderate (Gwet's AC1, 0.55; 95% CI, 0.47 - 0.63). Lesion-level agreement varied substantially, with lowest agreement for selected threshold-dependent inflammatory or semi-quantitative lesions, including interstitial inflammation in areas of IFTA, peritubular capillaritis and arteriolar hyalinosis. Diagnostic concordance differed markedly across biopsies, indicating strong case-level heterogeneity. In pairwise models, differences in active inflammatory and vascular lesion scoring were the strongest correlates of diagnostic disagreement; reader experience and geography contributed minimally. Principal component analysis showed reader variation was organized along two dominant axes: a rejection-calling threshold axis linked mainly to tubulointerstitial inflammatory injury, and a T cell-mediated (TCMR\/TI) and antibody-mediated\/microvascular (AMR\/MVI) inflammation-oriented phenotypic classification axis. Conclusion Interobserver variation in Banff-based kidney transplant biopsy assessment is structured rather than random and driven mainly by how readers threshold and integrate key inflammatory lesion compartments rather than experience or geographic location.","rel_num_authors":77,"rel_authors":[{"author_name":"Rianne Hofstraat-Boersma","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Van 't Hoff Institute for Molecular Sciences, Uni"},{"author_name":"Romy du Long","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Pathology, University Medical Cente"},{"author_name":"Giorgio Buzzanca","author_inst":"Department of Pathology, Systems Pathology Research Group, Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Adeyemi A. Abiola","author_inst":"Department of Histopathology, African Medical Center of Excellence Hospital, Abuja, Nigeria"},{"author_name":"Sam Albadri","author_inst":"Department of Pathology, Mayo Clinic, Mayo Clinic School of Medicine, Rochester, United States"},{"author_name":"Zahabia Ali","author_inst":"Department of Cellular Pathology, Barts NHS Trust, London, United Kingdom"},{"author_name":"Ahmed Altaleb","author_inst":"Histopathology Unit, Mubarak Alkabeer Hospital, Jabriya, Kuwait"},{"author_name":"Andrea Angioi","author_inst":"S.C.D.U. Nefrologia, Dialisi e Trapianto, ARNAS Brotzu Hospital, Cagliari, Italy"},{"author_name":"Sultana G. Banu","author_inst":"Department of Pathology, Bangladesh Medical University, Dhaka, Bangladesh"},{"author_name":"Marc Barry","author_inst":"Department of Pathology, University of Utah, Salt Lake City, United States"},{"author_name":"Ami R. Bhalodia","author_inst":"The Pathology Laboratory, Lake Charles, United States"},{"author_name":"Paola Bianco","author_inst":"S.C. Anatomia Patologia, ARNAS Brotzu Hospital, Cagliari, Italy"},{"author_name":"Verena Broecker","author_inst":"Department of Pathology, Sahlgrenska University Hospital, Gothenburg University, Gothenburg, Sweden"},{"author_name":"Roman Buelow","author_inst":"Institute for Pathology, RWTH Aachen University Hospital, Aachen, Germany"},{"author_name":"Bertrand Chauveau","author_inst":"Department of Pathology, Bordeaux University Hospital, Bordeaux, France"},{"author_name":"Guoli Chen","author_inst":"Department of Pathology, Penn State Health, Penn State College of Medicine, Hershey, United States"},{"author_name":"Boonyarit Cheunsuchon","author_inst":"Department of Pathology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand"},{"author_name":"Giovanna M. Crisi","author_inst":"Department of Pathology, UMASS-Chan School of Medical School - Baystate, Springfield, United States"},{"author_name":"Simin Daneshvar","author_inst":"Department of Anatomical Pathology, St. Vincent's Hospital, University of Melbourne, Melbourne, Australia"},{"author_name":"Amelie Dendooven","author_inst":"Department of Pathology, University Hospital of Ghent, Ghent University, Ghent, Belgium; Department of Pathology, Faculty of Medicine and Health Sciences, Unive"},{"author_name":"Pouneh Dokouhaki","author_inst":"Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada; Department of Pathology, St. Paul Hospital, Providence Healt"},{"author_name":"Cinthia B. Drachenberg","author_inst":"Department of Pathology, University of Maryland School of Medicine, Baltimore, United States"},{"author_name":"Alton B. Farris","author_inst":"Department of Pathology and laboratory Medicine, Emory University Hospital, Emory University, Atlanta, United States"},{"author_name":"Sophie Ferlicot","author_inst":"Department of Pathology, Le Kremlin-Bicetre Hospital, Paris-Saclay University, Paris, France"},{"author_name":"Sandrine Florquin","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands"},{"author_name":"Francesco Fontana","author_inst":"Nephrology, Dialysis and Kidney Transplant Unit, University Hospital of Modena, Modena, Italy"},{"author_name":"Jean-Baptiste Gibier","author_inst":"Institute of Pathology, Centre Hospitalier Universitaire de Lille, Lille, France"},{"author_name":"Ian W. Gibson","author_inst":"Department of Pathology, University of Manitoba, Winnipeg, Canada"},{"author_name":"Saurabh Gujarathi","author_inst":"Department of Pathology, Manipal Hospital, Pune, India"},{"author_name":"Allen R. Hendricks","author_inst":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, United States"},{"author_name":"Sufia Husain","author_inst":"Department of Pathology, College of Medicine, King Saud University - Medical City, Riyadh, Saudi Arabia"},{"author_name":"Jaynul Islam","author_inst":"Department of Pathology, BIRDEM General Hospital, Dhaka, Bangladesh"},{"author_name":"Wesam Ismail","author_inst":"Department of Pathology, Beni-Suef University, Beni-Suef, Egypt"},{"author_name":"Geetha Jagannathan","author_inst":"Department of Pathology and laboratory Medicine, Emory University Hospital, Emory University, Atlanta, United States"},{"author_name":"Johannes Klager","author_inst":"Department of Pathology, General Hospital of Vienna, Medical University of Vienna, Vienna, Austria"},{"author_name":"Nicolas Kozakowski","author_inst":"Department of Pathology, General Hospital of Vienna, Medical University of Vienna, Vienna, Austria"},{"author_name":"Adriana Krizova","author_inst":"Department of Laboratory Medicine, St. Michael's Hospital, University of Toronto, Toronto, Canada"},{"author_name":"Anila A. Kurien","author_inst":"Department of Pathology, Renopath, Center for Renal and Urological Pathology, Chennai, India"},{"author_name":"Boomi Kwon","author_inst":"Department of Pathology, Mater Hospital, Brisbane, Australia"},{"author_name":"Vincenzo L'Imperio","author_inst":"Department of Medicine and Surgery, Pathology, Fondazione IRCCS San Gerardo dei Tintori, University of Milano-Bicocca, Monza, Italy"},{"author_name":"Felipe L. Ledesma","author_inst":"Department of Pathology, University of Sao Paulo Medicine School, Sao Paulo, Brazil"},{"author_name":"Julia P. Low","author_inst":"Department of Anatomical Pathology, Sydpath, St. Vincent's Hospital, Sydney, University of South Wales, Australia"},{"author_name":"Jonne Martin","author_inst":"Department of Cellular Pathology, The Royal London Hospital, Queen Mary University of London, London, United Kingdom"},{"author_name":"Shweta S. Mehta","author_inst":"Department of Pathology, Kauvery Hospital, Bengaluru, India"},{"author_name":"Nidia Messias","author_inst":"Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, United States"},{"author_name":"Salvatore E. Mignano","author_inst":"Department of Pathology & Genomic Medicine, Thomas Jefferson University Hospital, Philadelphia, United States"},{"author_name":"Monik E. Miranda","author_inst":"Department of Anatomical Pathology, Cipto Mangunkusumo Hospital, Universitas Indonesia, Jakarta, Indonesia"},{"author_name":"Gilbert Moeckel","author_inst":"Department of Pathology, Yale New Haven Hospital, Yale University, New Haven, United States"},{"author_name":"Chiara Pala","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Medicine and Surgery, Nephrology Un"},{"author_name":"Brendon Price","author_inst":"Division of Anatomical Pathology, Department of Pathology, NHLS.Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa"},{"author_name":"Marc A. Ranson","author_inst":"Department of Pathology, University of Manitoba, Winnipeg, Canada"},{"author_name":"Andrea N. Rodriguez","author_inst":"Department of Pathology, Hospital Nacional Professor Alejandro Posadas, Buenos Aires, Argentina; Department of Pathology, The Favaloro Foundation University Hos"},{"author_name":"Joris J.T.H. Roelofs","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands"},{"author_name":"Avi Rosenberg","author_inst":"Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States"},{"author_name":"Alireza Sadeghipour","author_inst":"Department of Pathology, Rasoul-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran"},{"author_name":"Miroslav Sekulic","author_inst":"Department of Pathology and Cell Biology, Columbia University Medical Center, Columbia University, New York, United States"},{"author_name":"Suman Setty","author_inst":"Department of Pathology, University of Illinois Hospital and Health Sciences System, University of Illinois at Chicago, Chicago, United States"},{"author_name":"Michael Sheaff","author_inst":"Department of Cellular Pathology, Barts NHS Trust, London, United Kingdom"},{"author_name":"Maria F.S. Soares","author_inst":"Department of Cellular Pathology, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom"},{"author_name":"Jerasit Surintrspanont","author_inst":"Department of Pathology, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand"},{"author_name":"George Terinte-Balcan","author_inst":"Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique-Hopitaux de Paris, Paris, France"},{"author_name":"Francesca Testa","author_inst":"Nephrology, Dialysis and Kidney Transplant Unit, University Hospital of Modena, Modena, Italy"},{"author_name":"David O. Hendriquez Ticas","author_inst":"Department of Pathology, Northwestern Memorial Hospital, Feinberg School of Medicine Northwestern University, Chicago, United States"},{"author_name":"Maria F. Toniolo","author_inst":"Department of Pathology, Instituto de Transplantes y Alta Complejidad, Buenos Aires, Argentina"},{"author_name":"Dominique van Midden","author_inst":"Department of Pathology, Radboud University Medical Center, Radboud University, Nijmegen, Netherlands"},{"author_name":"Ramya K. Velagapudi","author_inst":"Department of Pathology, University of Mississippi Medical Center, Jackson, United States"},{"author_name":"Seethalakshmi Viswanathan","author_inst":"Department of Tissue Pathology, Westmead Hospital, Westmead Clinical School, University of Sydney, Sydney, Australia"},{"author_name":"Saskia von Stillfried","author_inst":"Institute for Pathology, RWTH Aachen University Hospital, Aachen, Germany"},{"author_name":"Chih-Ying Wu","author_inst":"Department of Pathology and laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; Institute of Biomedical Sciences, National Chung Hsing Un"},{"author_name":"Nienke Kalverboer","author_inst":"Department of Pathology, Systems Pathology Research Group, Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Imke B. Bruns","author_inst":"Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands"},{"author_name":"Giulia Callegaro","author_inst":"Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands"},{"author_name":"Bob van de Water","author_inst":"Cell Systems and Drug Safety, Leiden Academic Center for Drug Research, Leiden University, Leiden, Netherlands"},{"author_name":"Danny van der Helm","author_inst":"Division of Nephrology, Department Internal Medicine; Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Aiko P.J. de Vries","author_inst":"Division of Nephrology, Department Internal Medicine; Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands"},{"author_name":"Hessel Peters-Sengers","author_inst":"Center for Infection and Molecular Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands"},{"author_name":"Jesper Kers","author_inst":"Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Pathology, Systems Pathology Resear"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Blood DNA Methylation Predicts Long-Term Risk of Dementia in Prospective Cohorts","rel_doi":"10.64898\/2026.07.08.26357554","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357554","rel_abs":"Blood-based DNA methylation may help identify biological changes related to dementia risk before clinical symptoms appear. We conducted an epigenome-wide association study of incident all-cause dementia in 5,999 cognitively healthy women from the Women's Health Initiative Memory Study, 777 of whom developed dementia over up to 25 years of follow-up. Baseline blood DNA methylation was tested for association with time to dementia. One CpG site, cg05917797, was significantly associated with dementia risk, with higher methylation linked to lower risk. This association was only minimally changed after accounting for APOE {varepsilon}4 carrier status, plasma p-tau217, and epigenetic aging measures. cg05917797 also replicated in meta-analysis of four independent prospective cohorts including 10,916 participants and 413 incident dementia cases. In post-mortem brain methylation datasets, higher methylation at cg05917797 was associated with lower Braak stage in temporal gyrus and cerebellum. In meta-analysis of all five prospective cohorts, including 16,915 participants and 1,190 dementia cases, cg05917797 remained the leading association, and three additional CpGs were identified for further study. These findings support cg05917797 as a reproducible blood-based epigenetic marker of long-term dementia risk.","rel_num_authors":19,"rel_authors":[{"author_name":"Adam X Maihofer","author_inst":"UC San Diego"},{"author_name":"Caroline E. Mackey","author_inst":"University of California San Diego"},{"author_name":"Josephine A. Robertson","author_inst":"University of Edinburgh"},{"author_name":"Riccardo E. Marioni","author_inst":"University of Edinburgh"},{"author_name":"Steve Nguyen","author_inst":"UCSD HWSPH"},{"author_name":"Linda K. McEvoy","author_inst":"Wake Forest University School of Medicine"},{"author_name":"Andrea Z. LaCroix","author_inst":"University of California San Diego"},{"author_name":"Mark  Espeland A. Espeland","author_inst":"Wake Forest University School of Medicine"},{"author_name":"Stephen R. Rapp","author_inst":"Wake Forest University School of Medicine"},{"author_name":"Susan M. Resnick","author_inst":"National Institutes of Health"},{"author_name":"Bowei Zhang","author_inst":"University of California - San Diego"},{"author_name":"Steve Horvath","author_inst":"University of California, Los Angeles"},{"author_name":"Kenneth B Beckman","author_inst":"University of Minnesota"},{"author_name":"Towia A. Libermann","author_inst":"Beth Israel Deaconess Medical Center"},{"author_name":"Tom C Russ","author_inst":"University of Edinburgh"},{"author_name":"Simon R Cox","author_inst":"University of Edinburgh"},{"author_name":"Sarah E Harris","author_inst":"University of Edinburgh"},{"author_name":"Maira Pyrgioti","author_inst":"University of Edinburgh"},{"author_name":"Aladdin H Shadyab","author_inst":"University of California San Diego"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"CFD-derived biomarkers in intermediate risk pulmonary embolism patients treated with mechanical thrombectomy","rel_doi":"10.64898\/2026.07.09.26357404","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357404","rel_abs":"Background: Acute pulmonary embolism (PE) is a leading cause of morbidity and mortality with persistent difficulties in choosing interventions and predicting outcomes for patients defined clinically as intermediate risk. Computational fluid dynamics (CFD) tools have been used to understand the hemodynamic environment and plan interventions in the pulmonary arteries across a variety of disease conditions. Several biomechanical metrics have been used to evaluate risk in narrowed vessels, including hemodynamic resistance, power dissipation, and fractional flow reserve (FFR). In this study, we evaluate differences in these CFD-derived biomarkers between healthy controls (HC) and intermediate risk, acute PE patients. Additionally, we examine the response of patient hemodynamics to mechanical thrombectomy and compare values of these biomarkers across post-intervention pressure status. Methods: A CFD framework was developed to simulate patient-specific hemodynamics within the pulmonary vasculature identifiable from clinical imaging. The pipeline involved reconstructing three-dimensional (3D) structures of the pulmonary arteries and modeling blood flow with the finite element method. Patient-specific boundary conditions were derived from matching pre-intervention inlet mPAP to the patient's measured value given their measured CO as steady inflow. Converged simulations allowed for precise quantification of primary hemodynamic characteristics (flow and pressure) as well as secondary flow phenomena, primarily wall shear stress (WSS) and simulated pressure metrics such as fractional flow reserve (FFR). Results: Our simulations revealed significant elevations in resistance, power dissipation, and the number of vessels with low FFR in those patients with acute PE (n=6) compared to HC (n=3). Occlusions of hemodynamic significance were generally found in segmental pulmonary arteries. For patients with normalized pulmonary pressures post-thrombectomy (n=3), we found significantly higher proximal power dissipation and counts of low FFR vessels in comparison to those with elevated pressures after intervention (n=3). Distal resistance, which was derived from the portion of resistance attributed to the outflow boundary conditions, was significantly higher in patients with elevated pressures post-intervention. Across all PE patients, FFR count was significantly correlated with post-thrombectomy pulmonary pressure and cardiac index. Discussion: CFD-derived biomarkers offer a promising tool for understanding disease severity in acute PE. Differences between HCs and acute PE patients reveal expected increases in metrics associated with proximal disease burden. Yet, in examining acute PE patients with varying post-intervention hemodynamics, we found that these metrics of proximal disease burden could also be useful to predict the efficacy of mechanical thrombectomy. Those patients with normalized pressures had higher values for proximal disease metrics and lower values for distal disease metrics than those with continued elevations in pressure. This suggests that accessibility of hemodynamically-significant emboli to thrombectomy may be useful as a predictor for outcomes.","rel_num_authors":4,"rel_authors":[{"author_name":"Mehul Gilani","author_inst":"Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh Medical Center"},{"author_name":"Alexander Barr","author_inst":"Department of Biomedical Engineering, Carnegie Mellon University"},{"author_name":"Mazen O Al-Qadi","author_inst":"Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh Medical Center"},{"author_name":"Jason M Szafron","author_inst":"Department of Biomedical Engineering, Carnegie Mellon University"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Engagement with a Chatbot-based Intervention for the delivery of mailed at-home COVID-19 Testing: a Descriptive Log Analysis Study from the SCALE-UP II Trial","rel_doi":"10.64898\/2026.07.08.26357530","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357530","rel_abs":"Background Promoting at-home tests (e.g., for COVID-19) using chatbots may be a novel and scalable way to improve uptake across underserved populations. Objective The objective of this study was to assess the navigational patterns (i.e., sequence of interactions) of underserved populations when using a chatbot designed to provide education on COVID-19 testing and free order access for at-home COVID-19 test kits. Methods The study was a descriptive analysis of the original data of the chatbot intervention of the SCALE-UP II trial, which compared different digital health modalities (i.e., chatbots versus simple text messages) to deliver free at-home COVID-19 test kits to minority populations in Utah. SCALE-UP II (registration numbers NCT05533918; NCT05533359) was a multisite, pragmatic clinical trial with patients randomized in a 2x2x2 factorial design (smartphone study) to receive (1) chatbot or text messaging, (2) the option to request patient navigation, and (3) intervention frequency every 10 or 30 days. All other participants were randomized in a 2x2 factorial design (nonsmartphone study) to receive the option to request patient navigation and intervention frequency every 10 or 30 days. Eligible patients (1) had an appointment at one of the participating community health centers (CHC) in the last 3 years, (2) were 18 years and older, and (3) had a valid cellphone number recorded in the CHC electronic health record (EHR). The trial enrolled 2117 in the smartphone study and 31,439 in the nonsmartphone study. In the smartphone study, the proportion of participants who requested test kits in the Chatbot arm was lower than in SMS text messaging. In the nonsmartphone study, test kits was higher if they were messaged every 10 days. Sources of funding included the National Institute on Minority Health and Health Disparities (NIMHD) of the US National Institutes of Health (NIH) grant number 5U01MD017421 and by awards from the National Cancer Institute of the NIH (P30CA042014) and the Huntsman Cancer Foundation. Results: Of 1,051 patients randomized to the chatbot intervention, 309 (29%) launched the chatbot, 196 (63%) interacted with it, and 186 (60%) started the COVID-19 test kit ordering process. Among those who launched the chatbot, 170 (55%) completed a test kit order. One patient (0.3%) accessed the chatbot educational content. The median age was 51, with 66% female, 54% Latino\/a, 55% uninsured, and 86% located in an urban area. Conclusion: Ordering of COVID-19 test kits among underserved patients who interacted with the chatbot was high. Thus, chatbots may represent a viable approach to reach underserved populations as a part of public health response in a pandemic. All patients except one placed orders without reviewing educational content. Chatbot design should identify and minimize the number of steps for patients to achieve a specific goal.","rel_num_authors":26,"rel_authors":[{"author_name":"Joni  H Pierce","author_inst":"University of Utah"},{"author_name":"Jiantao Bian","author_inst":"University of Utah"},{"author_name":"Tatyana  V. Kuzmenko","author_inst":"University of Utah"},{"author_name":"Kimberly  A. Kaphingst","author_inst":"University of Utah"},{"author_name":"Leticia Stevens","author_inst":"University of Utah"},{"author_name":"Adriana Rush","author_inst":"University of Utah"},{"author_name":"Ryzen Benson","author_inst":"University of California San Francisco"},{"author_name":"Emerson  P. Borsato","author_inst":"University of Utah"},{"author_name":"Bryan Gibson","author_inst":"University of Utah Health Clinical Neurosciences Center"},{"author_name":"Kensaku Kawamoto","author_inst":"University of Utah"},{"author_name":"Andy  J. King","author_inst":"University of Utah"},{"author_name":"Brian Orleans","author_inst":"University of Utah"},{"author_name":"Jonathan Chipman","author_inst":"University of Utah"},{"author_name":"Tom Greene","author_inst":"University of Utah"},{"author_name":"Ray Meads","author_inst":"University of Utah"},{"author_name":"Tracey Siaperas","author_inst":"AUCH: Association for Utah Community Health"},{"author_name":"Shlisa Hughes","author_inst":"AUCH: Association for Utah Community Health"},{"author_name":"Alan Pruhs","author_inst":"AUCH: Association for Utah Community Health"},{"author_name":"Courtney  Pariera Dinkins","author_inst":"AUCH: Association for Utah Community Health"},{"author_name":"Cho  Y. Lam","author_inst":"Huntsman Cancer Institute Cancer Hospital: University of Utah Health Huntsman Cancer Institute"},{"author_name":"Ryan  C. Cornia","author_inst":"University of Utah"},{"author_name":"Richard  L. Bradshaw","author_inst":"University of Utah"},{"author_name":"Jorie Butler","author_inst":"University of Utah"},{"author_name":"Chelsey  R. Schlechter","author_inst":"University of Utah"},{"author_name":"David  W. Wetter","author_inst":"University of Utah Health Huntsman Cancer Institute"},{"author_name":"Guilherme Del Fiol","author_inst":"University of Utah"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Automatic Classification of Medical Artificial Intelligence Articles by Their Level of Translational Maturity: An Interpretable Supervised Text-Classification Approach","rel_doi":"10.64898\/2026.07.09.26357253","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357253","rel_abs":"The rapid expansion of the medical artificial intelligence (AI) literature has outpaced our ability to judge how far published models have progressed towards clinical use. We investigated whether the translational maturity of a study can be estimated automatically from its abstract. Using PubMed, we assembled a corpus of 11,024 candidate articles, reduced it to 1,816 AI-related articles by heuristic filtering, and manually double-annotated a balanced sample of 524 articles across five maturity classes (internal validation, external validation, prospective evaluation, implementation or governance, and not applicable). Abstracts were represented as TF-IDF features and classified using multinomial logistic regression with a Lasso penalty, chosen for interpretability and suitability for a small, imbalanced dataset. On a stratified held-out test set (n = 104), the model achieved 69.2% accuracy, Cohen's kappa of 0.495, macro-F1 of 0.458 and a weighted AUC of 0.820. Performance was strong for the frequent classes but poor for the rare implementation or governance class, which the model failed to recover. A balanced manual verification of 200 large-corpus predictions confirmed this pattern, with per-class precision ranging from 82.5% (internal validation) to 5.0% (implementation or governance). An interpretable, low-resource classifier can support literature mapping but requires human oversight for advanced maturity levels.","rel_num_authors":2,"rel_authors":[{"author_name":"Sandeep Reddy","author_inst":"Queensland University of Technology"},{"author_name":"Alix Heritier","author_inst":"ENSAI"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Aficamten Reduces Eligibility for Septal Reduction Therapy in Obstructive Hypertrophic Cardiomyopathy: Long-Term Outcomes from FOREST-HCM","rel_doi":"10.64898\/2026.07.08.26357594","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357594","rel_abs":"BackgroundSeptal reduction therapy (SRT) is recommended in drug-refractory, symptomatic obstructive hypertrophic cardiomyopathy (oHCM). We evaluated whether aficamten, a novel cardiac myosin inhibitor, can reliably transition guideline-eligible SRT candidates to ineligibility, and the associated safety profile of aficamten in this group.\n\nMethodsWe analyzed participants with oHCM enrolled in FOREST-HCM (NCT04848506), the long-term open-label extension study of aficamten, from 28 May 2021 to 9 May 2025.\n\nResultsThree hundred and fifteen patients were included, of whom 104 met 2024 ACC\/AHA guideline criteria for SRT eligibility at baseline. The SRT-eligible cohort was predominantly female (57%), with mean resting and Valsalva left ventricular outflow tract (LVOT) gradients of 63 {+\/-} 39 and 109 {+\/-} 42 mmHg, and all were in New York Heart Association (NYHA) class III. All baseline SRT-eligible patients became SRT-ineligible with aficamten therapy during study follow-up over a median of 42 days (IQR: 17, 49), except for one participant who withdrew from the study to pursue SRT (total of 3 participants withdrew). After dose titration, 3\/104 (2.9%) remained guideline-eligible; by week 72 no patients met eligibility criteria. At maintenance, resting and Valsalva LVOT gradients improved by a least-squares mean of -41 mmHg ([95% CI -44 to -37]; P<0.0001) and -56 mmHg ([95% CI -62 to -51]; P<0.0001), respectively. Relative to baseline, NT-proBNP improved by 77% (95% CI 74 - 80%), high-sensitivity cardiac troponin I decreased by 38% (95% CI 30 - 46%), KCCQ-CSS improved by a mean of 20.2 (SD 19.3) points, and 95.2% of SRT-eligible patients had improved by [&ge;]1 NYHA class. Overall, the safety profile was favorable, with 2 occurrences of left ventricular ejection fraction (LVEF) < 50% over 193.7 patient-years of follow-up (1 event per 100 patient-years), managed by down-titration. There were no baseline SRT-eligible patients who died or developed LVEF <40%.\n\nConclusionsAficamten resolved guideline eligibility for SRT in nearly all baseline-eligible patients, with rapid and durable improvements in hemodynamics, symptoms, biomarkers and health status sustained for up to 3.5 years. Instances of LVEF <50% were rare and without clinical sequelae. These data support aficamten as a safe and effective alternative to SRT in oHCM.\n\nRegistrationClinicalTrials.gov, NCT04848506 (https:\/\/clinicaltrials.gov\/study\/NCT04848506); Date of registration: April 19, 2021\n\nClinical PerspectiveO_ST_ABSWhat is new?C_ST_ABS- Aficamten is a cardiac myosin inhibitor that improved symptoms and left ventricular outflow tract gradients in almost all patients who were eligible for septal reduction therapy (SRT) in the FOREST-HCM trial.\n- Aficamten was safe with rare reduction in systolic function and no heart failure events.\n\n\nWhat are the clinical implications?- Aficamten can be used as an alternative to patients who are eligible for SRT.","rel_num_authors":27,"rel_authors":[{"author_name":"Ahmad Masri","author_inst":"Oregon Health & Science University"},{"author_name":"- FOREST-HCM Investigators","author_inst":"-"},{"author_name":"Benjamin Meder","author_inst":"University of Heidelberg"},{"author_name":"Lubna Choudhury","author_inst":"Northwestern University"},{"author_name":"Pablo Garcia-Pavia","author_inst":"Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain"},{"author_name":"Theodore P. Abraham","author_inst":"University of California San Francisco Division of Cardiology"},{"author_name":"Roberto Barriales-Villa","author_inst":"Complexo Hospitalario Universitario A Coru\u00f1a, Universidade da Coru\u00f1a, SERGAS, Instituto de Investigaci\u00f3n Biom\u00e9dica A Coru\u00f1a (INIBIC), CIBERCV"},{"author_name":"Ozlem Bilen","author_inst":"Emory University"},{"author_name":"Perry M. Elliott","author_inst":"University College London"},{"author_name":"Albert Hagege","author_inst":"Hopital Europeen Georges Pompidou Cancerologie"},{"author_name":"Sherif F Nagueh","author_inst":"Methodist DeBakey Heart and Vascular Center"},{"author_name":"Srihari S. Naidu","author_inst":"Westchester Medical Center Foundation"},{"author_name":"Michael E Nassif","author_inst":"University of Missouri Extension"},{"author_name":"Iacopo Olivotto","author_inst":"Meyer Children?s Hospital"},{"author_name":"Artur Oreziak","author_inst":"Institute of Cardiology"},{"author_name":"Anjali T. Owens","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"Omar Wever-Pinzon","author_inst":"University of Miami Health System"},{"author_name":"Florian Rader","author_inst":"Cedars-Sinai Smidt Heart Institute"},{"author_name":"Albree Tower-Rader","author_inst":"Massachusetts General Hospital"},{"author_name":"Justin Godown","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Stephen B. Heitner","author_inst":"Cytokinetics Inc"},{"author_name":"Daniel L Jacoby","author_inst":"Cytokinetics, Incorporated"},{"author_name":"Stuart Kupfer","author_inst":"Cytokinetics"},{"author_name":"Fady I. Malik","author_inst":"Cytokinetics Inc"},{"author_name":"Regina Sohn","author_inst":"Cytokinetics, Incorporated"},{"author_name":"Jenny Wei","author_inst":"Cytokinetics, Inc."},{"author_name":"Sara Saberi","author_inst":"University of Michigan Herbarium"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Aficamten Reduces Eligibility for Septal Reduction Therapy in Obstructive Hypertrophic Cardiomyopathy: Long-Term Outcomes from FOREST-HCM","rel_doi":"10.64898\/2026.07.08.26357594","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357594","rel_abs":"BackgroundSeptal reduction therapy (SRT) is recommended in drug-refractory, symptomatic obstructive hypertrophic cardiomyopathy (oHCM). We evaluated whether aficamten, a novel cardiac myosin inhibitor, can reliably transition guideline-eligible SRT candidates to ineligibility, and the associated safety profile of aficamten in this group.\n\nMethodsWe analyzed participants with oHCM enrolled in FOREST-HCM (NCT04848506), the long-term open-label extension study of aficamten, from 28 May 2021 to 9 May 2025.\n\nResultsThree hundred and fifteen patients were included, of whom 104 met 2024 ACC\/AHA guideline criteria for SRT eligibility at baseline. The SRT-eligible cohort was predominantly female (57%), with mean resting and Valsalva left ventricular outflow tract (LVOT) gradients of 63 {+\/-} 39 and 109 {+\/-} 42 mmHg, and all were in New York Heart Association (NYHA) class III. All baseline SRT-eligible patients became SRT-ineligible with aficamten therapy during study follow-up over a median of 42 days (IQR: 17, 49), except for one participant who withdrew from the study to pursue SRT (total of 3 participants withdrew). After dose titration, 3\/104 (2.9%) remained guideline-eligible; by week 72 no patients met eligibility criteria. At maintenance, resting and Valsalva LVOT gradients improved by a least-squares mean of -41 mmHg ([95% CI -44 to -37]; P<0.0001) and -56 mmHg ([95% CI -62 to -51]; P<0.0001), respectively. Relative to baseline, NT-proBNP improved by 77% (95% CI 74 - 80%), high-sensitivity cardiac troponin I decreased by 38% (95% CI 30 - 46%), KCCQ-CSS improved by a mean of 20.2 (SD 19.3) points, and 95.2% of SRT-eligible patients had improved by [&ge;]1 NYHA class. Overall, the safety profile was favorable, with 2 occurrences of left ventricular ejection fraction (LVEF) < 50% over 193.7 patient-years of follow-up (1 event per 100 patient-years), managed by down-titration. There were no baseline SRT-eligible patients who died or developed LVEF <40%.\n\nConclusionsAficamten resolved guideline eligibility for SRT in nearly all baseline-eligible patients, with rapid and durable improvements in hemodynamics, symptoms, biomarkers and health status sustained for up to 3.5 years. Instances of LVEF <50% were rare and without clinical sequelae. These data support aficamten as a safe and effective alternative to SRT in oHCM.\n\nRegistrationClinicalTrials.gov, NCT04848506 (https:\/\/clinicaltrials.gov\/study\/NCT04848506); Date of registration: April 19, 2021\n\nClinical PerspectiveO_ST_ABSWhat is new?C_ST_ABS- Aficamten is a cardiac myosin inhibitor that improved symptoms and left ventricular outflow tract gradients in almost all patients who were eligible for septal reduction therapy (SRT) in the FOREST-HCM trial.\n- Aficamten was safe with rare reduction in systolic function and no heart failure events.\n\n\nWhat are the clinical implications?- Aficamten can be used as an alternative to patients who are eligible for SRT.","rel_num_authors":27,"rel_authors":[{"author_name":"Ahmad Masri","author_inst":"Oregon Health & Science University"},{"author_name":"- FOREST-HCM Investigators","author_inst":"-"},{"author_name":"Benjamin Meder","author_inst":"University of Heidelberg"},{"author_name":"Lubna Choudhury","author_inst":"Northwestern University"},{"author_name":"Pablo Garcia-Pavia","author_inst":"Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain"},{"author_name":"Theodore P. Abraham","author_inst":"University of California San Francisco Division of Cardiology"},{"author_name":"Roberto Barriales-Villa","author_inst":"Complexo Hospitalario Universitario A Coru\u00f1a, Universidade da Coru\u00f1a, SERGAS, Instituto de Investigaci\u00f3n Biom\u00e9dica A Coru\u00f1a (INIBIC), CIBERCV"},{"author_name":"Ozlem Bilen","author_inst":"Emory University"},{"author_name":"Perry M. Elliott","author_inst":"University College London"},{"author_name":"Albert Hagege","author_inst":"Hopital Europeen Georges Pompidou Cancerologie"},{"author_name":"Sherif F Nagueh","author_inst":"Methodist DeBakey Heart and Vascular Center"},{"author_name":"Srihari S. Naidu","author_inst":"Westchester Medical Center Foundation"},{"author_name":"Michael E Nassif","author_inst":"University of Missouri Extension"},{"author_name":"Iacopo Olivotto","author_inst":"Meyer Children?s Hospital"},{"author_name":"Artur Oreziak","author_inst":"Institute of Cardiology"},{"author_name":"Anjali T. Owens","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"Omar Wever-Pinzon","author_inst":"University of Miami Health System"},{"author_name":"Florian Rader","author_inst":"Cedars-Sinai Smidt Heart Institute"},{"author_name":"Albree Tower-Rader","author_inst":"Massachusetts General Hospital"},{"author_name":"Justin Godown","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Stephen B. Heitner","author_inst":"Cytokinetics Inc"},{"author_name":"Daniel L Jacoby","author_inst":"Cytokinetics, Incorporated"},{"author_name":"Stuart Kupfer","author_inst":"Cytokinetics"},{"author_name":"Fady I. Malik","author_inst":"Cytokinetics Inc"},{"author_name":"Regina Sohn","author_inst":"Cytokinetics, Incorporated"},{"author_name":"Jenny Wei","author_inst":"Cytokinetics, Inc."},{"author_name":"Sara Saberi","author_inst":"University of Michigan Herbarium"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Aficamten Reduces Eligibility for Septal Reduction Therapy in Obstructive Hypertrophic Cardiomyopathy: Long-Term Outcomes from FOREST-HCM","rel_doi":"10.64898\/2026.07.08.26357594","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357594","rel_abs":"BackgroundSeptal reduction therapy (SRT) is recommended in drug-refractory, symptomatic obstructive hypertrophic cardiomyopathy (oHCM). We evaluated whether aficamten, a novel cardiac myosin inhibitor, can reliably transition guideline-eligible SRT candidates to ineligibility, and the associated safety profile of aficamten in this group.\n\nMethodsWe analyzed participants with oHCM enrolled in FOREST-HCM (NCT04848506), the long-term open-label extension study of aficamten, from 28 May 2021 to 9 May 2025.\n\nResultsThree hundred and fifteen patients were included, of whom 104 met 2024 ACC\/AHA guideline criteria for SRT eligibility at baseline. The SRT-eligible cohort was predominantly female (57%), with mean resting and Valsalva left ventricular outflow tract (LVOT) gradients of 63 {+\/-} 39 and 109 {+\/-} 42 mmHg, and all were in New York Heart Association (NYHA) class III. All baseline SRT-eligible patients became SRT-ineligible with aficamten therapy during study follow-up over a median of 42 days (IQR: 17, 49), except for one participant who withdrew from the study to pursue SRT (total of 3 participants withdrew). After dose titration, 3\/104 (2.9%) remained guideline-eligible; by week 72 no patients met eligibility criteria. At maintenance, resting and Valsalva LVOT gradients improved by a least-squares mean of -41 mmHg ([95% CI -44 to -37]; P<0.0001) and -56 mmHg ([95% CI -62 to -51]; P<0.0001), respectively. Relative to baseline, NT-proBNP improved by 77% (95% CI 74 - 80%), high-sensitivity cardiac troponin I decreased by 38% (95% CI 30 - 46%), KCCQ-CSS improved by a mean of 20.2 (SD 19.3) points, and 95.2% of SRT-eligible patients had improved by [&ge;]1 NYHA class. Overall, the safety profile was favorable, with 2 occurrences of left ventricular ejection fraction (LVEF) < 50% over 193.7 patient-years of follow-up (1 event per 100 patient-years), managed by down-titration. There were no baseline SRT-eligible patients who died or developed LVEF <40%.\n\nConclusionsAficamten resolved guideline eligibility for SRT in nearly all baseline-eligible patients, with rapid and durable improvements in hemodynamics, symptoms, biomarkers and health status sustained for up to 3.5 years. Instances of LVEF <50% were rare and without clinical sequelae. These data support aficamten as a safe and effective alternative to SRT in oHCM.\n\nRegistrationClinicalTrials.gov, NCT04848506 (https:\/\/clinicaltrials.gov\/study\/NCT04848506); Date of registration: April 19, 2021\n\nClinical PerspectiveO_ST_ABSWhat is new?C_ST_ABS- Aficamten is a cardiac myosin inhibitor that improved symptoms and left ventricular outflow tract gradients in almost all patients who were eligible for septal reduction therapy (SRT) in the FOREST-HCM trial.\n- Aficamten was safe with rare reduction in systolic function and no heart failure events.\n\n\nWhat are the clinical implications?- Aficamten can be used as an alternative to patients who are eligible for SRT.","rel_num_authors":27,"rel_authors":[{"author_name":"Ahmad Masri","author_inst":"Oregon Health & Science University"},{"author_name":"- FOREST-HCM Investigators","author_inst":"-"},{"author_name":"Benjamin Meder","author_inst":"University of Heidelberg"},{"author_name":"Lubna Choudhury","author_inst":"Northwestern University"},{"author_name":"Pablo Garcia-Pavia","author_inst":"Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain"},{"author_name":"Theodore P. Abraham","author_inst":"University of California San Francisco Division of Cardiology"},{"author_name":"Roberto Barriales-Villa","author_inst":"Complexo Hospitalario Universitario A Coru\u00f1a, Universidade da Coru\u00f1a, SERGAS, Instituto de Investigaci\u00f3n Biom\u00e9dica A Coru\u00f1a (INIBIC), CIBERCV"},{"author_name":"Ozlem Bilen","author_inst":"Emory University"},{"author_name":"Perry M. Elliott","author_inst":"University College London"},{"author_name":"Albert Hagege","author_inst":"Hopital Europeen Georges Pompidou Cancerologie"},{"author_name":"Sherif F Nagueh","author_inst":"Methodist DeBakey Heart and Vascular Center"},{"author_name":"Srihari S. Naidu","author_inst":"Westchester Medical Center Foundation"},{"author_name":"Michael E Nassif","author_inst":"University of Missouri Extension"},{"author_name":"Iacopo Olivotto","author_inst":"Meyer Children?s Hospital"},{"author_name":"Artur Oreziak","author_inst":"Institute of Cardiology"},{"author_name":"Anjali T. Owens","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"Omar Wever-Pinzon","author_inst":"University of Miami Health System"},{"author_name":"Florian Rader","author_inst":"Cedars-Sinai Smidt Heart Institute"},{"author_name":"Albree Tower-Rader","author_inst":"Massachusetts General Hospital"},{"author_name":"Justin Godown","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Stephen B. Heitner","author_inst":"Cytokinetics Inc"},{"author_name":"Daniel L Jacoby","author_inst":"Cytokinetics, Incorporated"},{"author_name":"Stuart Kupfer","author_inst":"Cytokinetics"},{"author_name":"Fady I. Malik","author_inst":"Cytokinetics Inc"},{"author_name":"Regina Sohn","author_inst":"Cytokinetics, Incorporated"},{"author_name":"Jenny Wei","author_inst":"Cytokinetics, Inc."},{"author_name":"Sara Saberi","author_inst":"University of Michigan Herbarium"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Protocol for Implementation and Evaluation of a Reserve-Stress-Rescue Pathway for High-Risk Preoperative Triage.","rel_doi":"10.64898\/2026.07.09.26357629","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357629","rel_abs":"Background High-risk preoperative triage remains fragmented: existing tools often estimate risk without identifying modifiable mechanisms or linking classification to postoperative monitoring, destination planning, and rescue resources. This protocol describes implementation and evaluation of a Reserve-Stress-Rescue (RSR Framework), pathway that operationalizes perioperative high risk as a mismatch among patient physiologic reserve, procedural stress, and system rescue capacity. Approach RSR is a proposed clinician-facing, modular scoring framework for adults undergoing major surgery, especially patients with frailty, multimorbidity, poor functional capacity, anemia or malnutrition, cardiopulmonary disease, or limited postoperative support. Each domain, Reserve, Stress, and Rescue, is scored from 0 to 4 and recorded as both a three-part profile and a total score from 0 to 12. Scores map to Green, Amber, Red, and Crimson triage bands that trigger escalating actions, including targeted optimization, multidisciplinary review, anesthesia and surgical planning, postoperative destination selection, monitoring intensity, and predefined escalation criteria. Validation Plan The initial phase of this study received an exemption determination from the Yale University Institutional Review Board on June 3, 2026, under IRB Protocol ID 2000042729, with exempt categories 2(ii) and 4(iii), including a waiver of HIPAA authorization for access to and use of protected health information as described in the approved protocol. Evaluation will proceed in stages, assessing feasibility, interrater reliability, completeness, acceptability, discrimination, calibration, and clinical utility. Key outcomes include postoperative complications, unplanned escalation of care, intensive care utilization, failure to rescue, mortality, length of stay, triage burden, low-yield testing cascades, and management-changing pathway activation. Conclusion The RSR pathway reframes high-risk status as a modifiable interaction between vulnerability, operative insult, and rescue capacity rather than a fixed patient label. If feasible and valid, RSR may standardize high-risk identification, align perioperative resources with anticipated physiology, improve communication, and support safer, actionable shared decision-making.","rel_num_authors":3,"rel_authors":[{"author_name":"Inwoo Sohn","author_inst":"University of California San Diego"},{"author_name":"Tanush Singh","author_inst":"Philadelphia College of Osteopathic Medicine"},{"author_name":"Zyad  J. Carr","author_inst":"Yale School of Medicine: Yale University School of Medicine"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Protocol for Implementation and Evaluation of a Reserve-Stress-Rescue Pathway for High-Risk Preoperative Triage.","rel_doi":"10.64898\/2026.07.09.26357629","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357629","rel_abs":"Background High-risk preoperative triage remains fragmented: existing tools often estimate risk without identifying modifiable mechanisms or linking classification to postoperative monitoring, destination planning, and rescue resources. This protocol describes implementation and evaluation of a Reserve-Stress-Rescue (RSR Framework), pathway that operationalizes perioperative high risk as a mismatch among patient physiologic reserve, procedural stress, and system rescue capacity. Approach RSR is a proposed clinician-facing, modular scoring framework for adults undergoing major surgery, especially patients with frailty, multimorbidity, poor functional capacity, anemia or malnutrition, cardiopulmonary disease, or limited postoperative support. Each domain, Reserve, Stress, and Rescue, is scored from 0 to 4 and recorded as both a three-part profile and a total score from 0 to 12. Scores map to Green, Amber, Red, and Crimson triage bands that trigger escalating actions, including targeted optimization, multidisciplinary review, anesthesia and surgical planning, postoperative destination selection, monitoring intensity, and predefined escalation criteria. Validation Plan The initial phase of this study received an exemption determination from the Yale University Institutional Review Board on June 3, 2026, under IRB Protocol ID 2000042729, with exempt categories 2(ii) and 4(iii), including a waiver of HIPAA authorization for access to and use of protected health information as described in the approved protocol. Evaluation will proceed in stages, assessing feasibility, interrater reliability, completeness, acceptability, discrimination, calibration, and clinical utility. Key outcomes include postoperative complications, unplanned escalation of care, intensive care utilization, failure to rescue, mortality, length of stay, triage burden, low-yield testing cascades, and management-changing pathway activation. Conclusion The RSR pathway reframes high-risk status as a modifiable interaction between vulnerability, operative insult, and rescue capacity rather than a fixed patient label. If feasible and valid, RSR may standardize high-risk identification, align perioperative resources with anticipated physiology, improve communication, and support safer, actionable shared decision-making.","rel_num_authors":3,"rel_authors":[{"author_name":"Inwoo Sohn","author_inst":"University of California San Diego"},{"author_name":"Tanush Singh","author_inst":"Philadelphia College of Osteopathic Medicine"},{"author_name":"Zyad  J. Carr","author_inst":"Yale School of Medicine: Yale University School of Medicine"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Distinct Patterns of Mobility Recovery After Stroke Using Routine Clinical Data","rel_doi":"10.64898\/2026.07.08.26357600","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.08.26357600","rel_abs":"Background: Mobility recovery after stroke is highly variable, yet is typically described using average patterns that obscure meaningful differences between individuals. Identifying distinct recovery trajectories may improve prognostication and guide rehabilitation strategies. Methods: We conducted a retrospective cohort study of adults admitted for stroke to a large health system between 2016 and 2024. Mobility was assessed using Activity Measure for Post-Acute Care (AM-PAC) Basic Mobility, which was collected during routine clinical care. Growth mixture modeling was used to identify subgroups with distinct mobility recovery trajectories during the first 180 days after stroke. Subgroups were then characterized with baseline personal and clinical characteristics. Results: Seven hundred and fifty individuals contributed 3,389 mobility observations (median 4 per person). A five-class solution was selected based on model fit and classification quality. Distinct trajectories were identified: low stable (n=127), low rapidly improving (n=29), mid declining (n=169), mid improving (n=365), and high stable (n=60). Subgroups differed in both baseline mobility and patterns of change over time, with some demonstrating improvement, others remaining stable, and one declining. Individuals in improving subgroups were generally younger, more likely to be independent before stroke, received physical therapy on a greater proportion of hospital days, and were more frequently discharged to inpatient rehabilitation. In contrast, those in low or declining trajectories had lower baseline function, longer hospital stays, and were more likely to be discharged to skilled nursing facilities. Conclusions: The distinct mobility recovery trajectories identified in this work reflect the heterogeneity present in routine clinical practice. Subgroups differed in both recovery patterns and characteristics. Early identification of trajectory membership may improve prognostication and inform more targeted rehabilitation strategies.","rel_num_authors":4,"rel_authors":[{"author_name":"Margaret A. French","author_inst":"University of Utah Health"},{"author_name":"Elisabeth Breese Marsh","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Ryan Thomas Roemmich","author_inst":"Kennedy Krieger Institute"},{"author_name":"Preeti Raghavan","author_inst":"Johns Hopkins"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Glutamine and NAA dissociate in ALS across somatotopically defined motor regions using 7T MRSI","rel_doi":"10.64898\/2026.07.09.26357702","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357702","rel_abs":"Amyotrophic lateral sclerosis (ALS) is increasingly understood as a progressive neurodegenerative disorder with distributed cortical and subcortical involvement, but in vivo metabolic mapping has been limited by the spatial coverage of single-voxel proton magnetic resonance spectroscopy (MRS). We acquired high-resolution whole-brain 7T 3D-CRT-FID-MRSI alongside motor-cortex single-voxel sLASER in five rapidly progressing people living with ALS (plALS) and seven non-neurodegenerative controls (NCs), with up to three sessions per participant. Regional metabolite ratios (N-Acetylaspartate [tNAA], glutamate [Glu], glutamine [Gln] to creatine [tCr], and Glu+Gln [Glx] to tNAA) were modelled with Bayesian hierarchical mixed-effects models, and the primary motor cortex was subdivided along its dorsoventral somatotopic axis (bulbar\/face, hand\/upper-limb, foot\/lower-limb). At baseline, plALS showed a motor-cortex-selective tNAA\/tCr deficit (motor composite -8.7%, 95% credible Interval [CrI] -16.1 to -1.1, posterior probability=0.99) accompanied by cortically diffuse glutamatergic elevation (Gln\/tCr +25.6%, posterior probability=0.96; Glx\/tNAA +10.4%, posterior probability=0.95). Reliable separation of the J-coupled glutamine and glutamate resonances at 7T revealed Gln\/tCr as a more sensitive marker of glutamatergic dysregulation than Glu\/tCr alone in this cohort. Within the somatotopic subdivision, all five plALS showed their peak Gln\/tCr increase in the bulbar\/face zone irrespective of clinical onset, including three lower-limb-onset patients. Annualised metabolite slope by zone correlated with the matched ALSFRS-R domain decline (Glx\/tNAA r=0.82, p<0.001). Group-level longitudinal interactions were modest. Bayesian assurance simulations indicated Glx\/tNAA as the most efficient candidate primary endpoint for a confirmatory cross-sectional study. These findings demonstrate that 7T whole-brain MRSI can resolve a metabolic dissociation between motor-selective neuronal compromised and somatotopically patterned glutamatergic dysregulation in ALS and provide design-ready endpoint and sample-size guidance for utility as a structural biomarker of brain function in clinical trials.","rel_num_authors":12,"rel_authors":[{"author_name":"Zeinab Eftekhari","author_inst":"The University of Queensland"},{"author_name":"Sicong Tu","author_inst":"The University of Sydney"},{"author_name":"Timothy Ballard","author_inst":"The University of Queensland"},{"author_name":"Korbinian Eckstein","author_inst":"Medical University of Vienna"},{"author_name":"Bernhard Strasser","author_inst":"Medical University of Vienna"},{"author_name":"Fabian Niess","author_inst":"Medical University of Vienna"},{"author_name":"Lukas Hingerl","author_inst":"Medical University of Vienna"},{"author_name":"Wolfgang Bogner","author_inst":"Medical University of Vienna"},{"author_name":"Matthew C Kiernan","author_inst":"The University of Sydney"},{"author_name":"Robert D Henderson","author_inst":"The University of Queensland"},{"author_name":"Markus Barth","author_inst":"The University of Queensland"},{"author_name":"Thomas B Shaw","author_inst":"The University of Queensland"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Childhood Sexual Abuse and Long-Term Risk of Self-Harm, Overdose, and Cardiovascular Disease","rel_doi":"10.64898\/2026.07.09.26357627","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.09.26357627","rel_abs":"Importance Childhood sexual abuse (CSA) is linked to adverse psychiatric outcomes in adulthood, but evidence on its association with cardiovascular disease and mortality from large, diagnostically ascertained cohorts remains limited. Objective To assess the 10-year risk of all-cause mortality, suicide or self-harm, drug overdose or poisoning, and cardiovascular disease among patients with a diagnosed history of CSA compared with a matched unexposed cohort. Methods In this retrospective cohort study, we used deidentified electronic health record data from 68 health care organizations in the TriNetX US Collaborative Network. Patients diagnosed with confirmed or suspected childhood sexual abuse (CSA) before age 18 between January 1, 2003, and December 31, 2015, who had a subsequent adult encounter, were propensity score matched 1:1 with unexposed patients on age, sex, race and ethnicity, and baseline psychiatric and medical comorbidities (n = 9,083 per cohort). Outcomes--all-cause mortality, suicide or self-harm, drug overdose or poisoning, and cardiovascular disease--were assessed over 10 years from the index adult encounter using risk and time-to-event analyses to estimate risks, risk ratios, and hazard ratios. Results Among 18,166 matched patients (mean [SD] age, 19.0 [2.0] years; 14,813 [81.6%] female), CSA was associated with significantly elevated risk of suicide or self-harm (5.1% vs 2.8%; risk ratio [RR], 1.84; 95% CI, 1.57-2.16), drug overdose or poisoning (5.5% vs 3.7%; RR, 1.47; 95% CI, 1.28-1.69), and cardiovascular disease (12.3% vs 9.3%; RR, 1.31; 95% CI, 1.20-1.44), with concordant hazard ratios (all P < .001). All-cause mortality was numerically higher but not statistically significant (0.5% vs 0.4%; RR, 1.16; 95% CI, 0.75-1.79; P = .51). Conclusions and Relevance A diagnostically confirmed history of CSA was associated with substantially elevated 10-year risk of self-harm, overdose, and cardiovascular disease, independent of baseline demographic and psychiatric comorbidity. These findings support integrated psychiatric and cardiovascular screening for adult survivors of CSA and trauma-informed care extending beyond mental health services alone.","rel_num_authors":12,"rel_authors":[{"author_name":"Oluwasegun Akinyemi","author_inst":"Howard University College of Medicine"},{"author_name":"Olububechukwu Eze","author_inst":"Howard University College of Medicine"},{"author_name":"Mojisola Fasokun","author_inst":"University of Alabama at Birmingham"},{"author_name":"Isaac Olaosebikan","author_inst":"Towson University"},{"author_name":"Temitayo Ogundipe","author_inst":"Sentara Williamsburg Regional Medical Center"},{"author_name":"Delia Singleton","author_inst":"Howard University College of Medicine"},{"author_name":"Ayomide Ogunsakin","author_inst":"Howard University College of Medicine"},{"author_name":"Samar Khalil","author_inst":"Howard University College of Medicine"},{"author_name":"Kaelyn Gordon","author_inst":"Howard University College of Medicine"},{"author_name":"Miriam Micheal","author_inst":"Howard University College of Medicine"},{"author_name":"Kakra Hughes","author_inst":"Howard University College of Medicine"},{"author_name":"Temitope Ogundare","author_inst":"NewYork-Presbyterian Hospital: NewYork-Presbyterian Columbia University Medical Center"}],"rel_date":"2026-07-13","rel_site":"medrxiv"},{"rel_title":"Single-nuclear RNA sequencing reveals an ATF3-independent sensory-neuron program after surgical incision","rel_doi":"10.64898\/2026.07.08.737350","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737350","rel_abs":"Background. Acute postoperative pain is common and often treated with opioids, but which sensory-neuron changes are responsible for the peripheral drive of pain is poorly defined. Skin incision induces activating transcription factor 3 (ATF3), the canonical marker of nerve injury, in dorsal root ganglion (DRG) neurons, and ATF3 marks the neurons that remain hyperexcitable. Whether ATF3 is required for postoperative pain is unknown. Methods. Adult mice of both sexes underwent hind-paw plantar incision. Postoperative nociceptive behavior was compared between sensory-neuron-specific ATF3 conditional-knockout mice (Avil^Cre\/+; Atf3^fl\/fl) and littermate controls using assays that probe distinct primary-afferent modalities (von Frey; Hargreaves; dynamic light touch) together with an operator-independent index of spontaneous injury behavior. Single-nucleus RNA sequencing of wild-type and ATF3-null DRG sensory neurons (naive and postoperative day 1) characterized the initiating injury program; transcription-factor-activity inference, RNAscope, and phospho-c-Jun immunostaining examined c-Jun; and the oral dual leucine zipper kinase (DLK) inhibitor GNE-3511, given at the time of incision, was tested behaviorally. Results. Incision transiently induced ATF3 in a subset of DRG neurons, returning to baseline by day 14, in parallel with the two-week course of nociceptive behavior. Deleting ATF3 in sensory neurons did not change the onset or resolution of nociceptive behavior on any readout, in either sex, across mechanical, thermal, and tactile modalities. Single-nucleus profiling showed a broad surgery-responsive nociceptor program in which ATF3 was the most strongly induced gene, yet only 23% of surgery-responsive neurons expressed it. Without ATF3, the program was remodeled but not abolished, and transcription-factor-activity inference nominated c-Jun as a candidate ATF3-independent factor; incision induced c-Jun in vivo. Systemic inhibition of DLK, which activates c-Jun pathway, lowered c-Jun phosphorylation and reduced evoked nociceptive hypersensitivity. Conclusions. Our results indicate that ATF3 marks part of the injured sensory neuron but does not drive acute post-surgical nociceptive behavior, and that it is not required for the postsurgical pain behaviors across afferent modalities carried by molecularly distinct nociceptor classes. The underlying injury program is broader than ATF3 and is nominated to depend on c-Jun. Because DLK inhibition, given at the time of incision, reduced evoked hypersensitivity, we propose the DLK-JNK-c-Jun axis as a candidate perioperative non-opioid target, which will require further genetic validation.","rel_num_authors":6,"rel_authors":[{"author_name":"Po-Yi Paul Su","author_inst":"University of California San Francisco"},{"author_name":"Jessica Yu","author_inst":"University of California San Francisco"},{"author_name":"Jarret AP Weinrich","author_inst":"University of California San Francisco"},{"author_name":"Fang Ye","author_inst":"First Affiliated Hospital, Sun Yat-Sen University"},{"author_name":"Lingyi Zhang","author_inst":"First Affiliated Hospital, Sun Yat-Sen University"},{"author_name":"Zhonghui Guan","author_inst":"University of California San Francisco"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Charge Imbalance Drives Salt-Optimized Nucleosome Phase Separation under Physiological Conditions","rel_doi":"10.64898\/2026.07.08.737367","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737367","rel_abs":"Liquid-liquid phase separation (LLPS) of chromatin contributes to genome organization and regulates genome accessibility to control gene expression. Despite advances in identifying the environmental conditions that promote chromatin condensation, the specific molecular interactions that initiate condensate formation, as well as the physical mechanisms by which DNA mechanics and epigenetic modifications modulate the resulting interaction network, remain unclear. Here, we utilize a residue-resolution, coarse-grained protein-DNA model to simulate nucleosome interactions across diverse ionic and structural conditions. Our simulations reveal non-monotonic salt-dependent phase-separation behavior, with optimal nucleosome condensation occurring under physiological salt conditions. Such a behavior was caused by the charge-imbalanced polyampholytic nature of nucleosomes, which drives competition between local protein-DNA attractions and global DNA-DNA repulsion. We further demonstrate that the conformational flexibility of nucleosomal DNA promotes unwrapping of DNA from the histone core, thereby strengthening histone-DNA interactions and enhancing condensate formation. Finally, we show that acetylation of histone H3 and H4 tails significantly reduces inter-nucleosomal interactions and increases nucleosome dynamics within condensates. Together, our study establishes a quantitative link between microscopic molecular interactions and macroscopic material properties, providing new insights into how mechanical constraints and epigenetic modifications could cooperatively tune genome architecture.","rel_num_authors":4,"rel_authors":[{"author_name":"Irene Silvernail","author_inst":"North Carolina State University"},{"author_name":"Yang Zhang","author_inst":"North Carolina State University"},{"author_name":"Xun Chen","author_inst":"Rice University"},{"author_name":"Xingcheng Lin","author_inst":"North Carolina State University"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Generation of hypoimmunogenic gastric insulin-secreting organoids","rel_doi":"10.64898\/2026.07.08.736836","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.736836","rel_abs":"Gastric insulin-secreting organoids (GINS) represent a promising source of {beta}-like cells for type 1 diabetes (T1D) therapy. In same-donor comparisons with induced pluripotent stem cell-derived islets (iPSC-islets), GINS displayed robust glucose responsiveness and reduced expression of key T1D autoantigens. Importantly, GINS exhibited decreased susceptibility to cytotoxicity mediated by engineered HLA-matched preproinsulin-specific effector T cells (Avatar Teffs) and a distinct transcriptional profile enriched for immune-modulatory and stress-adaptive gene programs. To enhance immune evasion, we engineered gastric stem cells to overexpress Programmed Death Ligand 1 (PD-L1) in an inducible manner. PD-L1+ GINS maintained normal functionality, while exhibiting improved survival under allogeneic Avatar Teff challenge in a MHC class I-independent fashion. We evaluated PD-L1-mediated protection against autologous Avatar Teff attack using an endothelialized microfluidic platform recapitulating physiologic immune interactions. T cells show reduced infiltration into PD-L1 GINS, resulting in significantly higher organoid viability compared to control GINS. Together, these findings identify GINS as a functional and engineerable {beta}-like cell platform with intrinsic hypoimmunogenic features, and support PD-L1 engineering as a strategy to enhance immune protection for both allogeneic and autologous transplantation in T1D.","rel_num_authors":14,"rel_authors":[{"author_name":"Anna Ada Dattoli","author_inst":"Weill Cornell Medicine"},{"author_name":"Matthew E Brown","author_inst":"University of Florida"},{"author_name":"Zachary Feinsten","author_inst":"Weill Cornell Medicine"},{"author_name":"Bradley Pearson","author_inst":"Weill Cornell Medicine"},{"author_name":"Ying Lang","author_inst":"Weill Cornell Medicine"},{"author_name":"Vasumati Polavarapu","author_inst":"Weill Cornell Medicine"},{"author_name":"Max Zhou","author_inst":"Weill Cornell Medicine"},{"author_name":"Ryan Nachman","author_inst":"Weill Cornell Medicine"},{"author_name":"Yosip Kelemen","author_inst":"Weill Cornell Medicine"},{"author_name":"Shahin Rafii","author_inst":"Weill Cornell Medicine"},{"author_name":"Remi J. Creusot","author_inst":"Columbia University"},{"author_name":"Todd Brusko","author_inst":"University of Florida"},{"author_name":"Joe Zhou","author_inst":"Weill Cornell Medicine"},{"author_name":"Xiaofeng Huang","author_inst":"Weill Cornell Medical College"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Activation of mu-opioid receptors slows pacemaking in hypothalamic A11 dopamine neurons","rel_doi":"10.64898\/2026.07.08.737263","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737263","rel_abs":"Hypothalamic A11 dopamine neurons provide the only known source of spinal dopamine and critically modulate pain and motor systems. Yet, the electrophysiological properties of A11 neurons were unknown. Here, we characterized A11 dopamine neurons in mice using brain slice immunohistochemistry, and fluorescence-guided whole-cell patch-clamp and cell-attached electrophysiology. A11 dopamine neurons contained the enzymes necessary to synthesize dopamine, projected to the spinal cord, and were small, morphologically simple, and high resistance. Additionally, they received excitatory glutamatergic and inhibitory GABAergic synaptic input. Most A11 dopamine neurons fired action potentials spontaneously in a rhythmic pacemaker manner at ~5 Hz, while the remainder were quiescent at rest, but fired readily with somatic current injection. Pacemaking A11 dopamine neurons were differentiated from quiescent neurons by a net inward current at subthreshold potentials. Activation of mu-opioid receptors reduced the net inward current at subthreshold potentials via activation of potassium current but also decreased GABAergic synaptic currents onto A11 dopamine neurons. Using cell-attached recording to preserve the natural chloride gradient, we found mu-opioid receptor agonism reduced spontaneous action potential firing of A11 dopamine neurons. The results lay the necessary framework for future studies investigating synaptic and ion channel mechanisms underlying the excitability in A11 dopamine neurons in physiological and pathological conditions.","rel_num_authors":4,"rel_authors":[{"author_name":"Angela F. Smith","author_inst":"University of Iowa"},{"author_name":"Hannah N. Rust","author_inst":"University of Iowa"},{"author_name":"Kathleen A. Sluka","author_inst":"University of Iowa"},{"author_name":"Stephanie C. Gantz","author_inst":"University of Iowa"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"PolliCrop: A high-throughput computer vision pipeline for pollinator monitoring in agroecosystems","rel_doi":"10.64898\/2026.07.08.737348","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737348","rel_abs":"Flower-visiting insect populations are declining since the 1990s, especially because of the decrease of floral resources in agricultural settings. Mass flowering crops can help increase resource availability, and plant breeding can be directed towards selecting varieties attracting more flower-visiting insects. This requires the implementation of an automated high-throughput phenotyping tool for assessing the attractiveness of plant genotypes to flower-visiting insects. In this study, (i) we present a procedure to take standardized images of sunflower heads with camera traps continuously at day and night in the field; (ii) we trained two versions of a deep learning model, named PolliCrop, to automatically detect and identify three classes of the main insects visiting sunflower on these images (non-Bombus bees, bumble bees, lepidopterans); (iii) we assessed and validated the ability of PolliCrop to correctly predict the true visitation frequencies of the insect classes on three sunflower genotypes; (iv) we presented two statistical approaches to compare the insect visitation frequencies between plant genotypes, one including weather variables, and the other one without. One PolliCrop version yielded satisfying performance to correctly detect the three insect classes. In particular, it correctly predicted the insect visitation frequencies on two sunflower genotypes in a range of {+\/-}10%. The other PolliCrop version can be useful in certain contexts of images and objectives. PolliCrop can be extended in the future to other crop species by training PolliCrop on new images captured in these crops. The field experimental design to set up for comparing the attractiveness between genotypes is also discussed.","rel_num_authors":12,"rel_authors":[{"author_name":"Stan Chabert","author_inst":"INRAE"},{"author_name":"Jordan Bernigaud-Samatan","author_inst":"INRAE"},{"author_name":"Benjamin K Blackman","author_inst":"University of California"},{"author_name":"Nicolas Blanchet","author_inst":"INRAE"},{"author_name":"Olivier Catrice","author_inst":"INRAE"},{"author_name":"Cecile Donnadieu","author_inst":"INRAE"},{"author_name":"Marianne Gani","author_inst":"INRAE"},{"author_name":"Remi Grousset","author_inst":"INRAE"},{"author_name":"Salena Husband","author_inst":"Julius Kuhn Institute"},{"author_name":"Guillaume Tueux","author_inst":"INRAE"},{"author_name":"Silvio Erler","author_inst":"Julius Kuhn Institute"},{"author_name":"Nicolas B Langlade","author_inst":"INRAE"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Glutamine Metabolism Supports \u03b1 cell Mass and Glucagon Secretion","rel_doi":"10.64898\/2026.07.09.735845","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.735845","rel_abs":"The liver- cell axis is a finely tuned biological rheostat that regulates whole body amino acid availability. Pancreatic  cells secrete glucagon that regulates amino acid catabolism through gluconeogenesis and ureagenesis, yet the mechanisms linking amino acid levels to  cell growth and function are not fully understood. Here, we identify glutaminase, the enzyme that catalyzes glutamine catabolism, as a critical  cell regulator. Glutaminase is highly enriched in  cells across species.  cell expression of glutaminase is required for nutrient-dependent mTORC1 activation, suppression of AMPK signaling, and sustained expression of the glutamine transporter SLC38A5. This establishes a feed-forward loop linking glutamine metabolism to amino acid sensing and growth. Reduced glutaminase activity impairs dynamic glucagon secretion in response to low glucose and amino acids. Together, these findings highlight the importance of glutamine metabolism in  cell growth and hormone secretion and suggest it may play a role in  cell adaptation to hyperaminoacidemia.","rel_num_authors":29,"rel_authors":[{"author_name":"Anna Marie R Schornack","author_inst":"Vanderbilt University"},{"author_name":"Tyler J Rodgers","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Matthew Shou","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Walter A Siv","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Linlin Yin","author_inst":"Vanderbilt University"},{"author_name":"Katelyn Sellick","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Varsha Chigurupati","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Joshua Debo","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Soham Saraf","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Paula G Nickles","author_inst":"Vanderbilt University"},{"author_name":"Selina Park","author_inst":"Creighton University School of Medicine"},{"author_name":"Shannon E Gibson","author_inst":"Vanderbilt University"},{"author_name":"Nitin Shankar","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jordyn R Dobson","author_inst":"Vanderbilt University"},{"author_name":"Soma Behara","author_inst":"Vanderbilt University"},{"author_name":"Jade E Stanley","author_inst":"Vanderbilt University"},{"author_name":"Angelina Ehara","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Madushika Wimalarathne","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Amber Crabtree","author_inst":"Vanderbilt University"},{"author_name":"Austin Reuter","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alan D. Attie","author_inst":"University of Wisconsin-Madison"},{"author_name":"Elma Zaganjor","author_inst":"Vanderbilt University"},{"author_name":"Katie C Coate","author_inst":"Vanderbilt University"},{"author_name":"Yan Li","author_inst":"Case Western Reserve University"},{"author_name":"Jeffrey C Rathmell","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Mark P Keller","author_inst":"University of Wisconsin Madison"},{"author_name":"David A Jacobson","author_inst":"Vanderbilt University"},{"author_name":"Wenbiao Chen","author_inst":"Vanderbilt University"},{"author_name":"E. Danielle Dean","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Glutamine Metabolism Supports \u03b1 cell Mass and Glucagon Secretion","rel_doi":"10.64898\/2026.07.09.735845","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.735845","rel_abs":"The liver- cell axis is a finely tuned biological rheostat that regulates whole body amino acid availability. Pancreatic  cells secrete glucagon that regulates amino acid catabolism through gluconeogenesis and ureagenesis, yet the mechanisms linking amino acid levels to  cell growth and function are not fully understood. Here, we identify glutaminase, the enzyme that catalyzes glutamine catabolism, as a critical  cell regulator. Glutaminase is highly enriched in  cells across species.  cell expression of glutaminase is required for nutrient-dependent mTORC1 activation, suppression of AMPK signaling, and sustained expression of the glutamine transporter SLC38A5. This establishes a feed-forward loop linking glutamine metabolism to amino acid sensing and growth. Reduced glutaminase activity impairs dynamic glucagon secretion in response to low glucose and amino acids. Together, these findings highlight the importance of glutamine metabolism in  cell growth and hormone secretion and suggest it may play a role in  cell adaptation to hyperaminoacidemia.","rel_num_authors":29,"rel_authors":[{"author_name":"Anna Marie R Schornack","author_inst":"Vanderbilt University"},{"author_name":"Tyler J Rodgers","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Matthew Shou","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Walter A Siv","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Linlin Yin","author_inst":"Vanderbilt University"},{"author_name":"Katelyn Sellick","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Varsha Chigurupati","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Joshua Debo","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Soham Saraf","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Paula G Nickles","author_inst":"Vanderbilt University"},{"author_name":"Selina Park","author_inst":"Creighton University School of Medicine"},{"author_name":"Shannon E Gibson","author_inst":"Vanderbilt University"},{"author_name":"Nitin Shankar","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jordyn R Dobson","author_inst":"Vanderbilt University"},{"author_name":"Soma Behara","author_inst":"Vanderbilt University"},{"author_name":"Jade E Stanley","author_inst":"Vanderbilt University"},{"author_name":"Angelina Ehara","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Madushika Wimalarathne","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Amber Crabtree","author_inst":"Vanderbilt University"},{"author_name":"Austin Reuter","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alan D. Attie","author_inst":"University of Wisconsin-Madison"},{"author_name":"Elma Zaganjor","author_inst":"Vanderbilt University"},{"author_name":"Katie C Coate","author_inst":"Vanderbilt University"},{"author_name":"Yan Li","author_inst":"Case Western Reserve University"},{"author_name":"Jeffrey C Rathmell","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Mark P Keller","author_inst":"University of Wisconsin Madison"},{"author_name":"David A Jacobson","author_inst":"Vanderbilt University"},{"author_name":"Wenbiao Chen","author_inst":"Vanderbilt University"},{"author_name":"E. Danielle Dean","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Glutamine Metabolism Supports \u03b1 cell Mass and Glucagon Secretion","rel_doi":"10.64898\/2026.07.09.735845","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.09.735845","rel_abs":"The liver- cell axis is a finely tuned biological rheostat that regulates whole body amino acid availability. Pancreatic  cells secrete glucagon that regulates amino acid catabolism through gluconeogenesis and ureagenesis, yet the mechanisms linking amino acid levels to  cell growth and function are not fully understood. Here, we identify glutaminase, the enzyme that catalyzes glutamine catabolism, as a critical  cell regulator. Glutaminase is highly enriched in  cells across species.  cell expression of glutaminase is required for nutrient-dependent mTORC1 activation, suppression of AMPK signaling, and sustained expression of the glutamine transporter SLC38A5. This establishes a feed-forward loop linking glutamine metabolism to amino acid sensing and growth. Reduced glutaminase activity impairs dynamic glucagon secretion in response to low glucose and amino acids. Together, these findings highlight the importance of glutamine metabolism in  cell growth and hormone secretion and suggest it may play a role in  cell adaptation to hyperaminoacidemia.","rel_num_authors":29,"rel_authors":[{"author_name":"Anna Marie R Schornack","author_inst":"Vanderbilt University"},{"author_name":"Tyler J Rodgers","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Matthew Shou","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Walter A Siv","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Linlin Yin","author_inst":"Vanderbilt University"},{"author_name":"Katelyn Sellick","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Varsha Chigurupati","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Joshua Debo","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Soham Saraf","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Paula G Nickles","author_inst":"Vanderbilt University"},{"author_name":"Selina Park","author_inst":"Creighton University School of Medicine"},{"author_name":"Shannon E Gibson","author_inst":"Vanderbilt University"},{"author_name":"Nitin Shankar","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jordyn R Dobson","author_inst":"Vanderbilt University"},{"author_name":"Soma Behara","author_inst":"Vanderbilt University"},{"author_name":"Jade E Stanley","author_inst":"Vanderbilt University"},{"author_name":"Angelina Ehara","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Madushika Wimalarathne","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Amber Crabtree","author_inst":"Vanderbilt University"},{"author_name":"Austin Reuter","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alan D. Attie","author_inst":"University of Wisconsin-Madison"},{"author_name":"Elma Zaganjor","author_inst":"Vanderbilt University"},{"author_name":"Katie C Coate","author_inst":"Vanderbilt University"},{"author_name":"Yan Li","author_inst":"Case Western Reserve University"},{"author_name":"Jeffrey C Rathmell","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Mark P Keller","author_inst":"University of Wisconsin Madison"},{"author_name":"David A Jacobson","author_inst":"Vanderbilt University"},{"author_name":"Wenbiao Chen","author_inst":"Vanderbilt University"},{"author_name":"E. Danielle Dean","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Isolation and characterization of novel filamentous phages from Swiss-type cheeses infecting the Gram-positive bacterium Propionibacterium freudenreichii","rel_doi":"10.64898\/2026.07.11.737922","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737922","rel_abs":"Filamentous phages infecting Gram-positive bacteria remain largely unexplored. Notably, only two filamentous phages, B5 and Philemon infecting Propionibacterium freudenreichii, have been described to date in the phage-rich dairy ecosystem. Although both were genomically characterized, only B5 was confirmed to be an infective filamentous single-stranded DNA phage. The aim of this study was to isolate and characterize new filamentous phages from Swiss-type cheese to investigate their diversity, structural features, host specificity, and potential adaptation to the dairy environment. Thirty raw and pasteurized milk cheeses from France were screened for phages infecting P. freudenreichii strains. Eleven phages were isolated, nine of which displayed a filamentous morphology. Named MINOG1 to MINOG9, these filamentous phages exhibited genomic features typical of this morphotype, including small single-stranded DNA genomes with collinear genes organized into functional modules. Comparison with B5 and Philemon revealed sequence divergence ranging from 0.1% to 7%. These phages also exhibited a diverse host range. To further explore phage-P. freudenreichii interactions, we screened the genomes of the strains used in this study, as well as additional genomes retrieved from the NCBI database, for CRISPR spacers predicted to target these filamentous phages. Numerous strains contained CRISPR spacers showing 79 to 100% identity to genomic regions of these phages. Two P. freudenreichii strains displayed markedly different phage resistance levels despite exact spacer-protospacer matches with phages B5, MINOG1, MINOG2, and MINOG8. Conversely, several strains were resistant to nearly all tested phages despite lacking CRISPR spacers targeting them suggesting the presence of additional defense systems in P. freudenreichii.","rel_num_authors":8,"rel_authors":[{"author_name":"Noel Grosset","author_inst":"Agrocampus-ouest\/INRA UMR STLO"},{"author_name":"Aur\u00e9lie Nicolas","author_inst":"INRAE, Institut Agro"},{"author_name":"Julien Jardin","author_inst":"INRAE, Institut Agro"},{"author_name":"Frank Oechslin","author_inst":"University of Ottawa"},{"author_name":"Antoine Culot","author_inst":"Rime Bioinformatics SAS"},{"author_name":"Sylvain Moineau","author_inst":"Universite Laval"},{"author_name":"Michel Gautier","author_inst":"Agrocampus Ouest"},{"author_name":"\u00c9ric GU\u00c9DON","author_inst":"Science et Technologie du Lait et de l'Oeuf"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Isolation and characterization of novel filamentous phages from Swiss-type cheeses infecting the Gram-positive bacterium Propionibacterium freudenreichii","rel_doi":"10.64898\/2026.07.11.737922","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737922","rel_abs":"Filamentous phages infecting Gram-positive bacteria remain largely unexplored. Notably, only two filamentous phages, B5 and Philemon infecting Propionibacterium freudenreichii, have been described to date in the phage-rich dairy ecosystem. Although both were genomically characterized, only B5 was confirmed to be an infective filamentous single-stranded DNA phage. The aim of this study was to isolate and characterize new filamentous phages from Swiss-type cheese to investigate their diversity, structural features, host specificity, and potential adaptation to the dairy environment. Thirty raw and pasteurized milk cheeses from France were screened for phages infecting P. freudenreichii strains. Eleven phages were isolated, nine of which displayed a filamentous morphology. Named MINOG1 to MINOG9, these filamentous phages exhibited genomic features typical of this morphotype, including small single-stranded DNA genomes with collinear genes organized into functional modules. Comparison with B5 and Philemon revealed sequence divergence ranging from 0.1% to 7%. These phages also exhibited a diverse host range. To further explore phage-P. freudenreichii interactions, we screened the genomes of the strains used in this study, as well as additional genomes retrieved from the NCBI database, for CRISPR spacers predicted to target these filamentous phages. Numerous strains contained CRISPR spacers showing 79 to 100% identity to genomic regions of these phages. Two P. freudenreichii strains displayed markedly different phage resistance levels despite exact spacer-protospacer matches with phages B5, MINOG1, MINOG2, and MINOG8. Conversely, several strains were resistant to nearly all tested phages despite lacking CRISPR spacers targeting them suggesting the presence of additional defense systems in P. freudenreichii.","rel_num_authors":8,"rel_authors":[{"author_name":"Noel Grosset","author_inst":"Agrocampus-ouest\/INRA UMR STLO"},{"author_name":"Aur\u00e9lie Nicolas","author_inst":"INRAE, Institut Agro"},{"author_name":"Julien Jardin","author_inst":"INRAE, Institut Agro"},{"author_name":"Frank Oechslin","author_inst":"University of Ottawa"},{"author_name":"Antoine Culot","author_inst":"Rime Bioinformatics SAS"},{"author_name":"Sylvain Moineau","author_inst":"Universite Laval"},{"author_name":"Michel Gautier","author_inst":"Agrocampus Ouest"},{"author_name":"\u00c9ric GU\u00c9DON","author_inst":"Science et Technologie du Lait et de l'Oeuf"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"White-Matter BOLD Encoding Beyond Marginal Connectivity","rel_doi":"10.64898\/2026.07.08.737282","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737282","rel_abs":"Functional MRI studies have traditionally focused on gray matter, whereas white-matter BOLD signals have often been treated as weak or artifactual. Recent work suggests that white-matter BOLD fluctuations contain reproducible functional information, but most gray-to-white matter analyses rely on marginal functional connectivity, which cannot separate pairwise coupling from shared variance among distributed cortical systems. Here, we used a multivariate cortical encoding framework to test whether spontaneous white-matter BOLD activity can be predicted from distributed cortical gray-matter activity and whether this predictive structure reveals organization beyond marginal connectivity. Resting-state fMRI data from 81 Human Connectome Project young adult participants were analyzed using a strict white-matter mask with no overlap with cortical predictors. For each white-matter voxel, time series from 400 Schaefer cortical parcels were used to predict held-out white-matter BOLD signals with nested leave-one-run-out ridge regression. Cortical activity modestly but reliably predicted white-matter BOLD dynamics, demonstrating consistent cross-validated prediction accuracy across a broad spatial extent of the white matter. Ridge beta fingerprints strongly recapitulated marginal functional connectivity fingerprints, indicating a shared functional backbone, but their first gradients diverged reproducibly. This beta-FC divergence axis organized FC-adjusted prediction residuals and remained robust after controlling for gray-matter proximity, mask-boundary distance, white-matter prevalence, temporal signal variability, spatial coordinates, and spatial autocorrelation. The high-divergence end showed relatively low marginal FC but high FC-adjusted prediction residuals and was enriched for posterior thalamic\/optic-radiation and posterior corona-radiata anatomy. These findings suggest that multivariate cortical encoding reveals a tract-organized dimension of white-matter functional coupling not captured by pairwise connectivity alone.","rel_num_authors":3,"rel_authors":[{"author_name":"Muwei Li","author_inst":"Vanderbilt University Institute of Imaging Science"},{"author_name":"Zhaohua Ding","author_inst":"Vanderbilt University Institute of Imaging Science"},{"author_name":"John C Gore","author_inst":"Vanderbilt University Institute of Imaging Science"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Associative Visual Memory in Aphantasia: Evidence for Intact Object and Spatial Memory, Metacognitive Awareness, but Different Strategies","rel_doi":"10.64898\/2026.07.08.736656","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.736656","rel_abs":"Many forms of memory are thought to rely on visual imagery, but individuals who report lacking visual imagery (aphantasia) can still perform various memory tasks. There is, however, evidence that aphantasia may lead to less detailed autobiographical memories, suggesting there may be deficits in the underlying cognitive processes that support personal memories. One such process is associative memory, which requires binding of different types of information. Here, we tested whether associative visual memory is intact in aphantasia. We assessed 72 self-identified individuals with aphantasia and 77 controls who reported having visual imagery. Participants completed an associative memory task which involved memorising displays where a unique object in a specific location was associated with a particular colour fixation point. Individuals with aphantasia performed equivalently to controls for object locations and outperformed controls on the associated object-identity. In addition, whereas controls were significantly worse at remembering associated object-identity than object-location, individuals with aphantasia showed no such difference. Both groups showed good metacognitive performance evidenced by a positive correlation between confidence and accuracy; there were no significant differences in confidence between the groups. Reported strategies varied between groups: a large proportion of control participants reported using visual imagery and self-reported use of imagery positively correlated with performance. Conversely, individuals with aphantasia mostly reported using nonvisual strategies to remember the associations. Overall, the findings suggest that individuals with aphantasia can form associative memories using nonvisual strategies. Thus, difficulties with autobiographical memory in aphantasia seem unlikely to be due to fundamental issues with associative memory.","rel_num_authors":3,"rel_authors":[{"author_name":"Rebecca Keogh","author_inst":"Macquarie University"},{"author_name":"Zoey Isherwood","author_inst":"University of New South Wales"},{"author_name":"Anina  N Rich","author_inst":"Macquarie University"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Biomarker Variability Limits Individualized Amyloid Time Estimation in Alzheimer Disease","rel_doi":"10.64898\/2026.07.08.737258","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737258","rel_abs":"Objective: Disease progression modeling (DPM) or \"amyloid time\" is increasingly used to stage Alzheimer disease (AD). DPM performance depends on within-individual heterogeneity in rates of pathological accumulation as well as test-retest reliability of the biomarker. The relative contributions of these variabilities have not been systematically assessed. This would be particularly relevant if extrapolations from DPM were to be used to make individual-level predictions for research, clinical trials, or potentially future clinical practice. Methods: We conducted simulation studies incorporating empirically-derived noise properties from amyloid biomarkers to assess the contributions of inter- and intra-individual variability. Findings generalized in an autosomal dominant AD cohort with amyloid positron emission tomography (PET), cerebrospinal fluid (CSF), and plasma biomarkers and in a sporadic AD cohort with both amyloid PET and plasma biomarkers. We assessed group level DPM performance via mean average error (MAE) and root mean squared error (RMSE). At the individual level, we evaluated distinctness of distributions of biomarker levels associated with specific disease timings. Results: Inter-individual variability was the dominant source of error in temporal estimates. Intra-individual variability reduced estimate stability. Optimal performance occurred in biomarkers with positive average accumulation rates where a subset of individuals had exceptionally high levels of accumulation. In research study data, amyloid PET outperformed CSF and plasma biomarkers. Interpretation: DPM is fundamentally constrained by dynamic range, variability, and test-retest reliability of the biomarker of interest. Current DPM approaches are more robust at the group level, particularly when applied to biomarkers with more than 10-15% variability like fluid biomarkers. Funding: National Institute on Aging, Alzheimer's Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Korean Ministry of Health & Welfare and Ministry of Science and ICT, Spanish Institute of Health.","rel_num_authors":25,"rel_authors":[{"author_name":"Julie K Wisch","author_inst":"Washington University Medical School"},{"author_name":"Ziqiao Jiao","author_inst":"Washington University School of Medicine"},{"author_name":"Peter R Millar","author_inst":"Washington University in St. Louis"},{"author_name":"Nicole S McKay","author_inst":"Washington University School of Medicine"},{"author_name":"Aleksandra Beric","author_inst":"Washington University in St. Louis"},{"author_name":"Wenjing Lin","author_inst":"Washington University School of Medicine"},{"author_name":"Bryce Baker","author_inst":"Washington University School of Medicine"},{"author_name":"Jennifer Stauber","author_inst":"Washington University School of Medicine"},{"author_name":"Sam Preminger","author_inst":"Washington University School of Medicine"},{"author_name":"Mathias Jucker","author_inst":"University of Tubingen"},{"author_name":"Nicolas R Barthelemy","author_inst":"Washington University School of Medicine"},{"author_name":"Jasmeer Chhatwal","author_inst":"BWH\/MGH\/Harvard Medical School"},{"author_name":"Natalie S. Ryan","author_inst":"University College London Queen Square"},{"author_name":"Suzanne E Schindler","author_inst":"Washington University in St. Louis"},{"author_name":"Carlos Cruchaga","author_inst":"Washington University"},{"author_name":"Tammie Lee Smith Benzinger","author_inst":"Washington University in Saint Louis"},{"author_name":"Celeste Karch","author_inst":"Washington University in St Louis"},{"author_name":"RJ Bateman","author_inst":"Washington University School of Medicine, Department of Neurology,"},{"author_name":"Eric McDade","author_inst":"Washington University in St. Louis"},{"author_name":"Jorge Llibre-Guerra","author_inst":"Washington University in St. Louis"},{"author_name":"- The Dominantly Inherited Alzheimer Network","author_inst":""},{"author_name":"- The Alzheimer Disease Neuroimaging Initiative","author_inst":""},{"author_name":"Brian A Gordon","author_inst":"Washington University School of Medicine"},{"author_name":"Beau Ances","author_inst":"Washington University in St. Louis"},{"author_name":"Laura Ibanez","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Development of Shelf-Stable Reagents and Assay Kits for Bioluminescence Applications using the Capillary-Assisted Vitrification Platform Stabilization Technology","rel_doi":"10.64898\/2026.07.11.737891","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737891","rel_abs":"Luminescence is a powerful method for detecting trace analytes and monitoring biological processes. However, most bioluminescence reagents, including luciferase and its substrates, are sensitive to temperature, limiting their useable shelf lives, and resulting in inconsistent performance. Enhancing the stability of these reagents could improve data quality, simplify workflows, and address cold chain storage issues. In this study, we demonstrate the application of the platform stabilization technology, capillary-assisted vitrification (CAV), as a tool to stabilize different luciferases and their substrates, and the application of the stabilized reagents in both in vitro and in vivo bioluminescent assays. We demonstrate that CAV-stabilized reagents can be stored and shipped ambiently, maintain consistent performance over time, and are suitable for use in cell viability quantification, tumor monitoring, in vivo imaging, microbial detection, and immunoassays. Additionally, different reagents can be co-formulated to make ready-to-use assay kits that can also be shipped and stored ambiently. Our results demonstrate that CAV stabilization is a viable alternative to traditional storage methods, with broad potential to improve bioluminescence workflows.","rel_num_authors":15,"rel_authors":[{"author_name":"Mary Shank-Retzlaff","author_inst":"Ambient Biosciences"},{"author_name":"Shari Radford","author_inst":"Ambient Biosciences"},{"author_name":"Yolanda Peris-Taverner","author_inst":"Ambient Biosciences"},{"author_name":"Michael Dibble","author_inst":"Promega Corporation"},{"author_name":"Kevin Corn","author_inst":"Vanderbilt University"},{"author_name":"Tian Zhu","author_inst":"Vanderbilt University"},{"author_name":"Shannon Martello","author_inst":"Vanderbilt University"},{"author_name":"McKenzie Mayeau","author_inst":"Vanderbilt University"},{"author_name":"Amanda Ladd","author_inst":"Ambient Biosciences"},{"author_name":"Sankar Renu","author_inst":"Ambient Biosciences"},{"author_name":"Tejasvi Chunduri","author_inst":"Ambient Biosciences"},{"author_name":"Aniket Jadhav","author_inst":"Ambient Biosciences"},{"author_name":"Melanie Dart","author_inst":"Promega Corporation"},{"author_name":"Marjan Rafat","author_inst":"Vanderbilt University"},{"author_name":"Laura Bronsart","author_inst":"Ambient Biosciences"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Prior Context Scaffolds Sentential Semantic Integration during Noisy Speech Comprehension","rel_doi":"10.64898\/2026.07.11.737996","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737996","rel_abs":"Understanding speech in noise is a central challenge of everyday communication, yet listeners often succeed by using prior context. How the brain uses such context remains debated: it may refine predictions about upcoming words, or it may provide a higher-level framework that helps degraded speech cohere into meaning. Here we combined simultaneous EEG-fNIRS recording with hierarchical multivariate encoding models to track how prior context shapes speech processing from acoustics to words and sentential meaning. Participants listened to natural spoken narratives under clear speech, noisy speech, and context-supported noisy speech conditions. Context brought comprehension of noisy speech close to clear-speech levels. EEG revealed that contextual support reduced neural encoding of lexical surprisal and entropy, indicating weaker tracking of local word-level prediction demands. In contrast, when context was available, fNIRS showed enhanced encoding of sentence-level semantic integration across frontal regions and the right angular gyrus, and stronger angular gyrus encoding predicted better comprehension. By combining EEG and fNIRS to capture complementary electrophysiological and hemodynamic signals, this multimodal approach reveals a hierarchical shift in degraded speech comprehension: prior context does not simply improve word-by-word prediction, but scaffolds the integration of noisy input into coherent discourse.","rel_num_authors":3,"rel_authors":[{"author_name":"Xinmiao Zhang","author_inst":"Tsinghua University"},{"author_name":"Zhuoran Li","author_inst":"University of Iowa"},{"author_name":"Dan Zhang","author_inst":"Tsinghua University"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"amR: an R package suite to predict antimicrobial resistance in bacterial pathogens","rel_doi":"10.64898\/2026.07.10.734579","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.734579","rel_abs":"Motivation: Identifying bacterial antimicrobial resistance (AMR) is critical for diagnostics and treatment, but resistance is a complex trait arising from myriad mechanisms spanning multiple molecular scales. Existing computational approaches often function as black boxes and rarely explore cross-species or multi-drug patterns. We developed amR, an integrated R package suite that provides a complete framework from bacterial genome data curation to interpretable AMR predictions, enabling identification of resistance mechanisms across species and drugs. Results: The amR R package suite contains three modular packages. amRdata downloads genomes and paired antimicrobial susceptibility testing data from BV-BRC and processes them, constructs pangenomes, and extracts features at gene\/protein cluster, protein domain, annotated Clusters of Orthologous Groups and ResFinder AMR-associated features, and structural variant scales; data are stored in memory-efficient formats (Parquet, DuckDB). amRml trains interpretable machine learning models per species-drug combination, calculates feature importance and performance metrics, and provides rich ground for hypothesis generation and mechanism discovery. amRviz provides an interactive Shiny dashboard to explore metadata distributions and model performance across species and drugs, visualize top predictive AMR features, and analyze cross-model patterns across geographic\/temporal strata. We apply the suite to Shigella sonnei, achieving a median Matthews Correlation Coefficient of 0.89 across 23 drugs and drug classes. With thousands of genomes, multi-scale features, and interpretable models, amR provides an accessible, comprehensive framework for AMR research. The amR package suite is installable via GitHub (https:\/\/github.com\/JRaviLab\/amR; BSD-3-Clause license).","rel_num_authors":9,"rel_authors":[{"author_name":"Abhirupa Ghosh","author_inst":"University of Colorado Anschutz"},{"author_name":"Evan P Brenner","author_inst":"University of Colorado Anschutz"},{"author_name":"Emily A Boyer","author_inst":"University of Colorado Anschutz"},{"author_name":"Alexander P McKim","author_inst":"University of Colorado Anschutz"},{"author_name":"Charmie K Vang","author_inst":"University of Colorado Anschutz"},{"author_name":"Ethan P Wolfe","author_inst":"University of Colorado Anschutz"},{"author_name":"David A Mayer","author_inst":"University of Colorado Anschutz"},{"author_name":"Raymond L Lesiyon","author_inst":"University of Colorado Anschutz"},{"author_name":"Janani Ravi","author_inst":"University of Colorado Anschutz"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Regulatory T cells establish an IL-10-IL10R immunometabolic checkpoint that limits HSL activation and lipolysis","rel_doi":"10.64898\/2026.07.12.738050","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.12.738050","rel_abs":"Adipose tissue harbors a significant population of regulatory T (Treg) cells that enforce immune homeostasis, yet whether Tregs function as an immunometabolic checkpoint to directly regulate core adipocyte signaling programs remains incompletely defined. Here we show that adipose Tregs function as a dominant, time-dependent checkpoint on {beta}-adrenergic signal-driven lipolytic program and signal transduction in adipocytes. Our integrated scRNA-seq, flow cytometry, and phosphoproteomics data show that prolonged adrenergic stimulation induces a progressive attenuation of activation of key lipase hormone-sensitive lipase (HSL) that coincides with Treg depletion in circulation and accumulation within white adipose tissue. Genetic perturbations establish Treg-derived interleukin-10 (IL-10) as the key mediator of this brake. IL-10 signaling through adipocyte IL-10R suppresses adrenergic HSL activation and rewires downstream signaling nodes that govern catecholamine responsiveness, lipolysis, and systemic energy homeostasis. Mechanistically, IL-10R engages a STAT3-dependent transcriptional program that induces the G-protein regulators RGS2 and RGS3, diminished PKA flux to HSL that reinforces suppression of the HSL activation state and lipolysis. Together, these findings define an adrenergic-immune feedback circuit in which Tregs fine tune the amplitude and duration of catecholamine responsiveness in adipocytes, establishing immune control of a core lipolytic pathway with implications for obesity-associated adipose dysfunction.","rel_num_authors":12,"rel_authors":[{"author_name":"Ramazan Yildiz","author_inst":"Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029"},{"author_name":"Kajal Davi","author_inst":"Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029"},{"author_name":"Niki F. Brisnovali","author_inst":"Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029; Cardiovascular Research Institute, Icahn School "},{"author_name":"James W.R. McMullen","author_inst":"Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029"},{"author_name":"Chung Hwan Cho","author_inst":"Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029"},{"author_name":"Khatanzul Ganbold","author_inst":"Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029"},{"author_name":"YoungUk Jang","author_inst":"Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029"},{"author_name":"Njeri Z.R. Sparman","author_inst":"Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029"},{"author_name":"Aidan Warnock","author_inst":"Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029"},{"author_name":"Gabriel Deards","author_inst":"Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029"},{"author_name":"Leigh Goedeke","author_inst":"Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029; Cardiovascular Research Institute, Icahn School "},{"author_name":"Prashant Rajbhandari","author_inst":"Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Phasis: a software tool for register-resolved discovery of plant phased small RNA loci","rel_doi":"10.64898\/2026.07.11.737977","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737977","rel_abs":"Plant PHAS locus discovery remains challenging because phasiRNA-producing loci must be distinguished from other sRNA-producing regions with high abundance or apparent periodicity. This problem is especially acute for reproductive 24-PHAS loci, which occur within genomes that also produce abundant 24-nt siRNAs from non-PHAS regions. We present Phasis, an open-source Python software tool for plant PHAS-locus discovery from small RNA sequencing data. Phasis combines statistical evidence for phased accumulation with locus-level features and a Register-Resolved Locus Interpretation Layer that evaluates whether candidate loci show coherent phased architecture. Across diverse plant datasets, Phasis recovered validated or annotated 21- and 24-PHAS loci with a strong balance between call-level precision and reference-locus recall, and generally outperformed PhaseTank and ShortStack in matched benchmark analyses. The register-resolved interpretation layer reduced unsupported calls by separating coherent phased loci from ambiguous sRNA-producing regions. In maize dcl5 mutant libraries, Phasis showed strong depletion of 24-PHAS recovery, supporting DCL5-dependent recovery of reproductive 24-PHAS signal. Together, these results support Phasis as a biologically interpretable tool for large-scale discovery of plant DCL-dependent phasiRNA loci.","rel_num_authors":5,"rel_authors":[{"author_name":"Thales Henrique Cherubino Ribeiro","author_inst":"University of California - Davis"},{"author_name":"Atul Kakrana","author_inst":"University of Delaware"},{"author_name":"Vinicius Andrade Maia","author_inst":"Federal University of Lavras"},{"author_name":"Scott Lewis","author_inst":"Washington University in St. Louis"},{"author_name":"Blake C. Meyers","author_inst":"University of California - Davis"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Single cell multi-omics enables high-resolution identification and functionalpurification of human acute myeloid leukemia stem cells","rel_doi":"10.64898\/2026.07.12.737989","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.12.737989","rel_abs":"In human acute myeloid leukemia (AML), a sub-population of leukemia stem cells (LSCs) drive disease initiation, therapeutic resistance, and relapse. However, the lack of reliable markers to distinguish LSCs from bulk leukemia cells has impeded progress in studying LSC pathogenesis and developing meaningful LSC-specific diagnostics and therapeutics. Existing LSC gene signatures, derived from bulk populations, cannot definitively identify LSCs at single-cell resolution. To address this, we analyzed large patient cohorts with bulk gene expression data and single-cell multi-omic assays to identify a prognostic gene signature that is specifically enriched in a clinically adverse AML sub-population. Using this signature, we defined and prospectively isolated CD34+CD90-CLL1-CD69+CD53- immunophenotypic LSCs that are significantly enriched for LSC content based on limiting dilution xenotransplantation assays. Our findings demonstrate the power of single-cell multi-omics to precisely identify a clinically relevant LSC population and establish a clear framework for future translational research in AML.","rel_num_authors":11,"rel_authors":[{"author_name":"Asiri Ediriwickrema","author_inst":"Stanford University"},{"author_name":"Yusuke Nakauchi","author_inst":"Stanford University"},{"author_name":"Thomas Kohnke","author_inst":"Stanford University"},{"author_name":"Amy C. Fan","author_inst":"Stanford University"},{"author_name":"Xiaoyi Hu","author_inst":"Stanford University"},{"author_name":"Brooks A. Benard","author_inst":"Stanford University"},{"author_name":"Daiki Karigane","author_inst":"Stanford University"},{"author_name":"Miles H. Linde","author_inst":"Stanford University"},{"author_name":"Aaron M. Newman","author_inst":"Stanford University"},{"author_name":"Andrew J. Gentles","author_inst":"Stanford University"},{"author_name":"Ravindra Majeti","author_inst":"Stanford University"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Single cell multi-omics enables high-resolution identification and functionalpurification of human acute myeloid leukemia stem cells","rel_doi":"10.64898\/2026.07.12.737989","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.12.737989","rel_abs":"In human acute myeloid leukemia (AML), a sub-population of leukemia stem cells (LSCs) drive disease initiation, therapeutic resistance, and relapse. However, the lack of reliable markers to distinguish LSCs from bulk leukemia cells has impeded progress in studying LSC pathogenesis and developing meaningful LSC-specific diagnostics and therapeutics. Existing LSC gene signatures, derived from bulk populations, cannot definitively identify LSCs at single-cell resolution. To address this, we analyzed large patient cohorts with bulk gene expression data and single-cell multi-omic assays to identify a prognostic gene signature that is specifically enriched in a clinically adverse AML sub-population. Using this signature, we defined and prospectively isolated CD34+CD90-CLL1-CD69+CD53- immunophenotypic LSCs that are significantly enriched for LSC content based on limiting dilution xenotransplantation assays. Our findings demonstrate the power of single-cell multi-omics to precisely identify a clinically relevant LSC population and establish a clear framework for future translational research in AML.","rel_num_authors":11,"rel_authors":[{"author_name":"Asiri Ediriwickrema","author_inst":"Stanford University"},{"author_name":"Yusuke Nakauchi","author_inst":"Stanford University"},{"author_name":"Thomas Kohnke","author_inst":"Stanford University"},{"author_name":"Amy C. Fan","author_inst":"Stanford University"},{"author_name":"Xiaoyi Hu","author_inst":"Stanford University"},{"author_name":"Brooks A. Benard","author_inst":"Stanford University"},{"author_name":"Daiki Karigane","author_inst":"Stanford University"},{"author_name":"Miles H. Linde","author_inst":"Stanford University"},{"author_name":"Aaron M. Newman","author_inst":"Stanford University"},{"author_name":"Andrew J. Gentles","author_inst":"Stanford University"},{"author_name":"Ravindra Majeti","author_inst":"Stanford University"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"A Method for Image-Based Modeling of Uterine Passive Mechanics During Late Pregnancy","rel_doi":"10.64898\/2026.07.10.737823","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737823","rel_abs":"Purpose: Computational models of the uterus during pregnancy enable analysis of electro-chemo-mechanical pathways to predict labor timing and guide treatment planning. We aim to develop a robust image-based modeling pipeline to investigate uterine passive mechanics during late pregnancy. Methods: A parametric model of the uterus and cervix was created using a patient's MRI measurements at 38 weeks of gestation. Inspired by advances in cardiac mechanics models, we created Laplace-Dirichlet solutions to inform tissue domains, fiber structure within the uterus and cervix, and spatially varying Robin boundary conditions. Prior imaging and mechanical testing data were used to fit material parameters. Boundary condition parameters were tuned to match the displacements of a previously established approach that employed contact with surrounding tissue. The tissue mechanical response to a physiologic load was assessed across varying material properties and fiber architectures. Results: Discrepancies in nodal displacements between the current approach and the contact-based model were limited to 3.4{+\/-}1.8 mm, yielding nearly 90% computational savings. Uterine tensile strains were more sensitive to ground substance elastic modulus (E) compared to fiber properties. Reduced (E) and fiber stiffness increased cervical strains and compression. Fiber dispersion and architecture modulated the opening of the cervical internal ostium but had a reduced impact on compression. Conclusion: We developed a novel workflow for modeling passive uterine mechanics, informed by patient-specific measurements and in vitro mechanical tests. The robust workflow may prove useful for studying labor progression and conducting longitudinal studies to enhance our understanding of normal and pathological pregnancies.","rel_num_authors":6,"rel_authors":[{"author_name":"Olivia Mergler","author_inst":"Columbia University"},{"author_name":"Abigail Laughlin","author_inst":"Columbia University"},{"author_name":"Erin Marie Louwagie","author_inst":"Columbia University"},{"author_name":"Lei Shi","author_inst":"Kennesaw State University"},{"author_name":"Kristin Marie Myers","author_inst":"Columbia University"},{"author_name":"Vijay Vedula","author_inst":"Columbia University"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Retrograde trafficking inhibitors allosterically trap Get3 to block tail-anchored protein biogenesis","rel_doi":"10.64898\/2026.07.11.737968","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737968","rel_abs":"Retro-1 and Retro-2 are structurally distinct small molecules that protect cells from diverse toxins and viruses by disrupting retrograde trafficking, yet their mechanism of action has remained elusive. We show that both compounds target Get3, the ATPase chaperone of the guided entry of tail-anchored proteins (GET) pathway, which mediates biogenesis of tail-anchored SNARE proteins required for retrograde transport to the ER membrane. Cryo-electron microscopy reveals that Retro compounds bind a cryptic pocket in Get3, allosterically stabilizing Get3 in a stalled complex with upstream pathway components. Our work uncovers the GET pathway as an unsuspected vulnerability in pathogen entry, provides clear routes toward compound optimization, and establishes stabilization of dynamic protein complexes as a therapeutic strategy.","rel_num_authors":11,"rel_authors":[{"author_name":"Juliet A Lee","author_inst":"California Institute of Technology"},{"author_name":"Xilin Gu","author_inst":"University of California San Francisco"},{"author_name":"Charlene Chan","author_inst":"Harvard Medical School"},{"author_name":"Vida Storm Robertson","author_inst":"California Institute of Technology"},{"author_name":"Victor Garcia-Ruiz","author_inst":"California Institute of Technology"},{"author_name":"Yancheng E Li","author_inst":"California Institute ofTechnology"},{"author_name":"Anna Huyen Ngo","author_inst":"California Institute of Technology"},{"author_name":"Philip Alabi","author_inst":"University of California San Francisco"},{"author_name":"Vladimir Denic","author_inst":"Harvard University"},{"author_name":"Jason K Sello","author_inst":"University of Californai San Francisco"},{"author_name":"William Clemons","author_inst":"Caltech"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Retrograde trafficking inhibitors allosterically trap Get3 to block tail-anchored protein biogenesis","rel_doi":"10.64898\/2026.07.11.737968","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.11.737968","rel_abs":"Retro-1 and Retro-2 are structurally distinct small molecules that protect cells from diverse toxins and viruses by disrupting retrograde trafficking, yet their mechanism of action has remained elusive. We show that both compounds target Get3, the ATPase chaperone of the guided entry of tail-anchored proteins (GET) pathway, which mediates biogenesis of tail-anchored SNARE proteins required for retrograde transport to the ER membrane. Cryo-electron microscopy reveals that Retro compounds bind a cryptic pocket in Get3, allosterically stabilizing Get3 in a stalled complex with upstream pathway components. Our work uncovers the GET pathway as an unsuspected vulnerability in pathogen entry, provides clear routes toward compound optimization, and establishes stabilization of dynamic protein complexes as a therapeutic strategy.","rel_num_authors":11,"rel_authors":[{"author_name":"Juliet A Lee","author_inst":"California Institute of Technology"},{"author_name":"Xilin Gu","author_inst":"University of California San Francisco"},{"author_name":"Charlene Chan","author_inst":"Harvard Medical School"},{"author_name":"Vida Storm Robertson","author_inst":"California Institute of Technology"},{"author_name":"Victor Garcia-Ruiz","author_inst":"California Institute of Technology"},{"author_name":"Yancheng E Li","author_inst":"California Institute ofTechnology"},{"author_name":"Anna Huyen Ngo","author_inst":"California Institute of Technology"},{"author_name":"Philip Alabi","author_inst":"University of California San Francisco"},{"author_name":"Vladimir Denic","author_inst":"Harvard University"},{"author_name":"Jason K Sello","author_inst":"University of Californai San Francisco"},{"author_name":"William Clemons","author_inst":"Caltech"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Influence of Primary Coordination Sphere on Anion Rebound Selectivity in Nonheme Fe Enzyme-Catalyzed C(sp3)-H Functionalization: A Comparative Experimental and Computational Study of EgtB and ACCO","rel_doi":"10.64898\/2026.07.10.737789","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737789","rel_abs":"Developing enzymatic mechanisms for C-F bond formation remains a long-standing challenge. Here, we repurposed the biosynthetic nonheme Fe enzyme EgtB, which features a three-histidine facial triad, to catalyze C(sp3)-H fluorination reactions. Directed evolution of EgtB afforded two new-to-nature fluorine atom transferases with opposite enantiopreference, EgtBCHF1 and EgtBCHF2, with up to 28-fold improved total activity. In contrast to our previously evolved nonheme Fe fluorine atom transfer biocatalyst ACCOCHF, which contains a two-histidine-one-carboxylate facial triad, the evolved EgtBCHF variants displayed unexpected hydroxylation activity. 18O-labeling experiments showed that the hydroxy group originated from water rather than residual O2. Computational studies suggested that the three-histidine-supported Fe(III) center exhibits enhanced Lewis acidity compared to the two-histidine-one-carboxylate system, allowing deprotonation of Fe(III)-bound water to form a Fe(III)-OH species to catalyze radical hydroxylation. Primary coordination-sphere mutagenesis in EgtB and ACCO further supported the critical role of Fe coordination chemistry in controlling radical rebound reactivity and selectivity. Computational studies revealed that Fe coordination chemistry strongly influences both fluorine atom abstraction and radical rebound, with the intrinsic C-X (X = F, OH, and N3) bond forming radical rebound preference following the order N3 > OH > F. Furthermore, multivariate linear regression analysis revealed that fluorine atom abstraction is primarily governed by the intrinsic Fe-F bond strength, whereas fluorine rebound is predominantly controlled by the electronic structure of the Fe(III) intermediate. Together, these findings provide mechanistic insights into nonheme Fe enzymology and reprogramming toward selective radical rebound reactions, including challenging C-H fluorination.","rel_num_authors":6,"rel_authors":[{"author_name":"Yang Yang","author_inst":"Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, California 93106, United States"},{"author_name":"Liupeng Zhao","author_inst":"Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, California 93106, United States"},{"author_name":"Rui Guo","author_inst":"Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, California 93106, United States"},{"author_name":"Binh Khanh Mai","author_inst":"Department of Chemistry, University of Pittsburgh, Pennsylvania 15260, United States"},{"author_name":"Heyu Chen","author_inst":"Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, California 93106, United States"},{"author_name":"Peng Liu","author_inst":"Department of Chemistry, University of Pittsburgh, Pennsylvania 15260, United States"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"APOBEC3G expression marks a TMB-high, T cell-inflamed tumor state and is associated with response to immune checkpoint blockade in multiple cancer cohorts","rel_doi":"10.64898\/2026.07.08.737369","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.08.737369","rel_abs":"Immune checkpoint therapies have transformed clinical practice; however, reliable biomarkers to predict response remain limited. Tumor mutational burden (TMB) has emerged as an important biomarker because it is thought to reflect neoantigen load, yet its predictive utility has been inconsistent. This limitation may partly arise because TMB primarily captures tumor-intrinsic immunogenicity, which is heterogeneous and does not fully reflect the state of antitumor immunity. To identify transcriptomic surrogates that capture both high mutational burden and antitumor immune activation, we investigated whether mRNA expression of mutagenic APOBEC3 family members could identify tumors with high TMB and T cell-rich immune states. Using a pan-cancer computational framework, we evaluated the association of four APOBEC3 genes with mutational burden, neoantigen load, immune infiltration, and immune checkpoint blockade response. Among APOBEC3A, APOBEC3B, APOBEC3G, and APOBEC3H, APOBEC3G emerged as the strongest and most consistent marker of TMB-high\/CD8-high and neoantigen-high\/CD8-high tumor phenotypes. Single-cell analyses further demonstrated that APOBEC3G is enriched in both malignant cells and T cells compared with other APOBEC3 family members, with APOBEC3G-positive CD8 T cells exhibiting elevated activation markers, including GZMB and IFNG. Importantly, retrospective analyses of 50 immune checkpoint blockade cohorts showed that APOBEC3G had the most consistent association among APOBEC3 family members with treatment response and clinical outcomes. Together, these findings identify APOBEC3G as a candidate transcriptomic marker of a TMB-associated, T cell-inflamed tumor state linked to immune checkpoint blockade benefit, warranting further prospective validation.","rel_num_authors":4,"rel_authors":[{"author_name":"Kelly Butler","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Dhanusha Yesudhas","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Bilal Lone","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"A. Rouf Banday","author_inst":"National Cancer Institute, National Institutes of Health"}],"rel_date":"2026-07-13","rel_site":"biorxiv"},{"rel_title":"Drought degrades riparian subsidy quality and constrains aquatic ecosystem functioning","rel_doi":"10.64898\/2026.07.10.737855","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.10.737855","rel_abs":"The exchange of energy and organisms across habitat boundaries links aquatic and terrestrial ecosystems and sustains ecosystem functioning. Although disturbance may disrupt these linkages, the mechanisms at play remain poorly understood. Here, we investigated the extent to which flow intermittency may disrupt riparian-aquatic ecosystem linkages by altering consumer communities in the recipient ecosystem or by altering resource quality in the donor ecosystem. We ran an experiment in an intermittent river network in California, focusing on a critical forest-to-river subsidy (organic matter in the form of leaf litter), its transformation, and its reciprocal benefit (aquatic insect production). Using three riparian species (willow, cottonwood, and oak) at sites spanning a gradient of flow permanence, we quantified intraspecific plasticity in leaf traits (specific leaf area, nitrogen and phosphorus concentrations, and d13C), measured decomposition rates, and estimated the secondary production of aquatic shredders (Plecoptera). Across all leaf species, decomposition rates were 16-36% lower at intermittent than perennial sites, an effect largely driven by intraspecific leaf trait plasticity rather than changes in consumer abundance. At high flow intermittency, willow experienced water stress (enriched d13C) and reduced specific leaf area, while cottonwood showed primarily stoichiometric responses (reduced leaf nitrogen and phosphorus). Despite these divergent strategies, all species produced lower-quality litter at intermittent sites. Variance partitioning confirmed that initial litter quality uniquely explained 51.5% of variation in decomposition rates, more than double the contribution of invertebrate community metrics; and structural equation modeling revealed that both leaf traits and stonefly (Plecoptera) secondary production significantly predicted decomposition rates, with leaf traits exerting the stronger effect. Notably, stonefly secondary production was 37-98% lower at intermittent sites across leaf species. Because these insects later emerge as terrestrial adults, they provide a significant energy flux to riparian predators, and, thus, impoverished litter quality suppresses the reciprocal transfer of energy back to terrestrial food webs. As drought intensifies globally, the decoupling of terrestrial-aquatic linkages may begin in the riparian canopy.","rel_num_authors":2,"rel_authors":[{"author_name":"Rose Marie Mohammadi","author_inst":"University of California, Berkeley"},{"author_name":"Albert Ruh\u00ed","author_inst":"University of California, Berkeley"}],"rel_date":"2026-07-13","rel_site":"biorxiv"}]}