{"gname":"Carnegie Mellon University","grp_id":"19","rels":[{"rel_title":"REM sleep EEG slowing signals basal forebrain integrity in older adults with subjective and mild cognitive impairment","rel_doi":"10.64898\/2026.09.30.26363850","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.30.26363850","rel_abs":"Introduction The basal forebrain is an early site of pathology in Alzheimer's disease (AD). Within this region, the nucleus basalis of Meynert (NbM) provides the primary cholinergic input to the neocortex and supports cortical activation during rapid eye movement (REM) sleep. REM electroencephalography (EEG) slowing is observed in older adults with AD and amnestic mild cognitive impairment (MCI). This study examined the relationship between REM EEG slowing and NbM volume, and whether it differed by cognitive status, sex, or sleep apnea severity. Methods Participants aged [&le;] 60 years with cognitive concerns underwent neuropsychological and medical assessments, polysomnography, and magnetic resonance imaging (MRI). REM EEG slowing was quantified as the ratio of delta and theta (<8Hz) to alpha, sigma, and beta (8-32Hz) power. Bilateral NbM and Ch1-3 volume were derived from T1-weighted MRI images. Multiple linear regression and moderation analyses adjusted for age, sex, and sleep apnea severity. Exploratory analyses examined associations between NbM volume, sleep macroarchitecture, and memory. Results The sample comprised 116 participants (59.5% female; mean age = 70.5 years, 64.7% MCI). Greater REM EEG slowing was associated with smaller NbM volume (all p < 0.05). Although moderation effects were not significant after FDR correction, within-group analyses suggested a stronger relationship in MCI. Smaller NbM volume was associated with longer sleep latency and poorer episodic memory (all p < 0.05). Discussion REM EEG slowing may reflect early NbM degeneration and provide a non-invasive biomarker of basal forebrain integrity in older adults with cognitive concerns. Longitudinal studies are required to establish its prognostic value.","rel_num_authors":12,"rel_authors":[{"author_name":"Aaron Lam","author_inst":"Healthy Brain Ageing Program, The Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia.; School of Psychology, Faculty of Science, University"},{"author_name":"Nicole Espinosa","author_inst":"Healthy Brain Ageing Program, The Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia.; School of Psychology, Faculty of Science, University"},{"author_name":"Elie Matar","author_inst":"Woolcock Institute of Medical Research, Macquarie University, Macquarie Park, NSW, Australia.; NHMRC Synergise, Integrate and Enhance Sleep Research to transfor"},{"author_name":"Nathan Cross","author_inst":"Healthy Brain Ageing Program, The Brain and Mind Centre, University of Sydney, Camperdown, NSW, Australia.; School of Psychology, Faculty of Science, University"},{"author_name":"Jurgen Fripp","author_inst":"NHMRC Synergise, Integrate and Enhance Sleep Research to transform Brain Ageing (SIESTA) Program; The Australian e-Health Research Centre, CSIRO Healthy and Bio"},{"author_name":"Ying Xia","author_inst":"The Australian e-Health Research Centre, CSIRO Healthy and Biosecurity, Herston, Queensland, Australia."},{"author_name":"Claire Andr\u00e9","author_inst":"Normandie Univ, UNICAEN, INSERM, UA20, NEUROPRESAGE, GIP Cyceron, 14000 Caen, France"},{"author_name":"Elizabeth Coulson","author_inst":"School of Anatomy and Physiology, Faculty of Medicine, Dentistry and Health Science, University of Melbourne, Melbourne, VIC, Australia"},{"author_name":"Renata Taranto","author_inst":"Woolcock Institute of Medical Research, Macquarie University, Macquarie Park, NSW, Australia."},{"author_name":"Ronald Grunstein","author_inst":"NHMRC Synergise, Integrate and Enhance Sleep Research to transform Brain Ageing (SIESTA) Program; Woolcock Institute of Medical Research, Macquarie University, "},{"author_name":"Angela L D'Rozario","author_inst":"NHMRC Synergise, Integrate and Enhance Sleep Research to transform Brain Ageing (SIESTA) Program; Woolcock Institute of Medical Research, Macquarie University, "},{"author_name":"Sharon L Naismith","author_inst":"NHMRC Synergise, Integrate and Enhance Sleep Research to transform Brain Ageing (SIESTA) Program; Healthy Brain Ageing Program, The Brain and Mind Centre, Unive"}],"rel_date":"2026-10-02","rel_site":"medrxiv"},{"rel_title":"AI-assisted nurse-led skin cancer screening in a teledermoscopy framework: a multi-site evaluation with one million lesions","rel_doi":"10.64898\/2026.10.01.26364543","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.01.26364543","rel_abs":"Nurse-led skin cancer screening extends specialist reach but depends on the nurse selecting which lesions to forward for diagnosis, and performance varies with experience. We evaluated whether real-time decision support using artificial intelligence (AI) improves malignancy detection in routine nurse-led teledermoscopy screening across MoleMap clinics in New Zealand and Australia (January 2024-July 2025). In this real-world study, clinics using AI decision support were compared with standard clinics. Nurses examined patients, captured dermoscopic images, and forwarded selected lesions to teledermatologists, who provided the reference diagnosis. The analytic cohort comprised 1,102,382 lesions from 98,422 patients across 577 sites. AI-assisted screening was associated with a higher malignancy detection rate than standard screening (25.5 vs 15.7 malignancies per 1,000 lesions; odds ratio adjusted for nurse experience 1.73, 95% CI 1.68-1.77), a finding consistent across all nurse-experience tiers and the three major malignant subtypes. AI assistance was also associated with a shift in recommended management: 21 additional intervention recommendations and 13 additional safety-netting recommendations (self-monitoring, short-term follow-up, or specialist referral) per 1,000 lesions, approximately balanced by 34 fewer no-action recommendations. The reference standard was teledermatologist diagnosis and allocation was not randomised; findings are therefore associational and require prospective, outcome-based confirmation.","rel_num_authors":8,"rel_authors":[{"author_name":"Noor E Karishma Shaik","author_inst":"The University of Melbourne"},{"author_name":"Nandakishor Desai","author_inst":"The University of Melbourne"},{"author_name":"Kyle Wang","author_inst":"MoleMap New Zealand"},{"author_name":"Lara Wild","author_inst":"MoleMap New Zealand"},{"author_name":"Adam G Dunn","author_inst":"The University of Sydney"},{"author_name":"Amanda Oakley","author_inst":"University of Auckland"},{"author_name":"Marimuthu Palaniswami","author_inst":"The University of Melbourne"},{"author_name":"Johan Vendrig","author_inst":"MoleMap New Zealand"}],"rel_date":"2026-10-02","rel_site":"medrxiv"},{"rel_title":"Subclinical hepatorenal biomarker alterations and urogenital indicators in Schistosoma haematobium-infected School-Aged Children in Sene West District, Ghana","rel_doi":"10.64898\/2026.09.30.26364430","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.30.26364430","rel_abs":"Urogenital schistosomiasis, caused by Schistosoma haematobium, remains a major public health challenge among school-aged children in rural Ghana. Although urogenital indicators are well-established, systemic hepatic biomarker alterations in post-mass drug administration pediatric settings remain poorly characterized. This cross-sectional study evaluated point-of-care urinalysis profiles alongside a panel of serum hepatic and renal biomarkers in 174 children (aged 3 to 16 years) from the Sene West District, Ghana. Active infection (urine microscopy egg detection) was identified in 84 participants (48.3%, median egg count = 4.50 eggs\/10 mL, IQR: 1.00 - 9.25). Active infection was strongly associated with microhematuria (57.1% vs. 11.1%, p < 0.001), proteinuria (42.9% vs. 22.2%, p = 0.004), and leukocyturia (27.4% vs. 4.4%, p < 0.001). Children with active infection also demonstrated a higher frequency of composite categorical hepatic biomarker alterations (60.7% vs. 37.8%, p = 0.002), whereas categorical renal alterations showed no significant difference (p = 0.332). Controlling for age and sex, multivariable logistic regression confirmed active infection as a significant independent predictor of composite hepatic biomarker alterations (aOR = 2.54, 95% CI: 1.37 - 4.69, p = 0.003), but not renal alterations (aOR = 1.40, p = 0.359). Continuous medians for individual serum biomarkers showed no significant differences between groups. Combining composite hepatic biomarker thresholds with routine dipstick screening improves the detection of subclinical morbidity in pediatric field settings.","rel_num_authors":9,"rel_authors":[{"author_name":"Dennis Kyei Ofori","author_inst":"UENR: University of Energy and Natural Resources"},{"author_name":"Anabel Acheampong","author_inst":"UENR: University of Energy and Natural Resources"},{"author_name":"Prince-Charles Kudzordzi","author_inst":"UENR: University of Energy and Natural Resources"},{"author_name":"Prince Nyarko","author_inst":"UENR: University of Energy and Natural Resources"},{"author_name":"Claudia Wubuareyasa Nseide","author_inst":"University of Energy and Natural Resources"},{"author_name":"Emmanuel Ansah Boateng","author_inst":"University of Energy and Natural Resources"},{"author_name":"Yahuza Sabit Tanko","author_inst":"Sene West District Health Directorate"},{"author_name":"Conor R. Caffrey","author_inst":"University of California San Diego"},{"author_name":"Kenneth Bentum Otabil","author_inst":"University of Energy and Natural Resources"}],"rel_date":"2026-10-02","rel_site":"medrxiv"},{"rel_title":"Safety-Relevant Biomedical Machine Learning Should Adopt Stability-First Reporting","rel_doi":"10.64898\/2026.09.30.26364447","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.30.26364447","rel_abs":"Biomedical Machine Learning (ML) is increasingly evaluated through Independent and Identically Distributed (IID) benchmarks, even when deployment involves irregular observation, missingness, distribution shift, and high failure costs. This position paper argues for a stability-oriented reporting standard for safety-relevant biomedical ML. The central requirement is not a specific model class or optimizer, but auditable evidence: performance should be reported under clinically plausible perturbations such as thinning, timestamp jitter, bursty missingness, channel dropout, and Signal-to-Noise Ratio (SNR) shift. When authors invoke training-stability diagnostics, those diagnostics should be hazard-linked: their assumptions, operational meaning, and relationship to stress-test degradation should be stated explicitly. We use controlled mechanism probes to illustrate two hazards that IID scores can hide: observation-process dependence under irregular sampling, and perturbation sensitivity associated with high-curvature training regimes such as Edge of Stability (EoS). We do not propose Neural ODEs, continuous-time models, Sharpness-Aware Minimization (SAM), or EoS metrics as default prescriptions. Instead, we propose a minimum reporting standard that makes robustness claims testable and supports escalation to more complex modelling or optimization only when stress tests justify the cost.","rel_num_authors":5,"rel_authors":[{"author_name":"Zayn Andre Zainal","author_inst":"The Universtiy of Sydney"},{"author_name":"Omid Kavehei","author_inst":"The University of Sydney"},{"author_name":"Isabelle Aguilar","author_inst":"The University of Sydney"},{"author_name":"Luis Fernando Herbozo Contreras","author_inst":"The University of Sydney"},{"author_name":"Zhaojing Huang","author_inst":"The University of Sydney"}],"rel_date":"2026-10-02","rel_site":"medrxiv"},{"rel_title":"Lanreotide for Advanced Pheochromocytoma and Paraganglioma: Results of a Multicenter Phase II Trial","rel_doi":"10.64898\/2026.10.01.26364504","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.01.26364504","rel_abs":"Background: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine neoplasms originating from chromaffin cells that express somatostatin receptors (SSTRs) and may therefore be susceptible to somatostatin analogue therapy. Despite this biological rationale, prospective evidence supporting the antiproliferative activity of somatostatin analogues in PPGL is limited. We conducted a multicenter phase 2 clinical trial to assess the efficacy and safety of lanreotide in patients with advanced or metastatic PPGL. [LAMPARA, NCT03946527] Methods: Patients with advanced or metastatic PPGL and evidence of recent disease progression received lanreotide depot\/autogel 120 mg subcutaneously every 4 weeks. Treatment was planned for 52 weeks with an option to continue for an additional 52 weeks. Endpoints included overall survival (OS), progression-free survival (PFS), and response according to RECIST. Serum chromogranin A (CgA) was evaluated as an exploratory biomarker. A tumor growth rate analysis was planned to allow comparison with data from the CLARINET trial in gastroenteropancreatic NETs. Results: Eighteen patients (median age 42 years; range 28-77) across three centers participated; 78% carried SDHx mutations. Lanreotide was well tolerated with predominantly grade 1-2 adverse events and no treatment discontinuations due to toxicity. The most common treatment-emergent adverse events were diarrhea (67%), injection-site reaction (44%), constipation (39%), fatigue (39%), and abdominal pain (39%). Serious adverse events were reported in four patients and were assessed as not related or unlikely related to lanreotide. All 18 patients had at least one recorded post-baseline tumor assessment. Two partial responses were recorded during extended follow-up. At approximately 1 year, disease stabilization was observed in 11 of 13 patients (85%) with an available assessment, while two patients (15%) had progressive disease. Biomarker analysis showed substantial variability in serum CgA values. Tumor growth rate analysis revealed a median growth rate of 0.00124\/day (tumor doubling time 559 days), comparable in order of magnitude to the rate of 0.00046\/day observed in 83 lanreotide-treated patients in CLARINET, and consistent with a median PFS [&ge;]2 years. Conclusions: Lanreotide exhibits promising antiproliferative activity in PPGL, with a favorable safety profile and extended periods of disease stabilization. These findings support the consideration of SSAs as an option in managing SSTR-positive PPGLs, delaying more aggressive treatments until disease progression mandates escalation.","rel_num_authors":6,"rel_authors":[{"author_name":"Jaydira Del Rivero","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Bahar Laderian","author_inst":"Montefiore\/Albert Einstein College of Medicine"},{"author_name":"Mengxi Zhou","author_inst":"Memorial Sloan Kettering Cancer Institute, Department of Radiology."},{"author_name":"Lyndon Luk","author_inst":"Columbia University Department of Radiology."},{"author_name":"Susan E Bates","author_inst":"Columbia University Department of Medicine."},{"author_name":"Tito Fojo","author_inst":"Columbia University Department of Medicine."}],"rel_date":"2026-10-02","rel_site":"medrxiv"},{"rel_title":"Lanreotide for Advanced Pheochromocytoma and Paraganglioma: Results of a Multicenter Phase II Trial","rel_doi":"10.64898\/2026.10.01.26364504","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.01.26364504","rel_abs":"Background: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine neoplasms originating from chromaffin cells that express somatostatin receptors (SSTRs) and may therefore be susceptible to somatostatin analogue therapy. Despite this biological rationale, prospective evidence supporting the antiproliferative activity of somatostatin analogues in PPGL is limited. We conducted a multicenter phase 2 clinical trial to assess the efficacy and safety of lanreotide in patients with advanced or metastatic PPGL. [LAMPARA, NCT03946527] Methods: Patients with advanced or metastatic PPGL and evidence of recent disease progression received lanreotide depot\/autogel 120 mg subcutaneously every 4 weeks. Treatment was planned for 52 weeks with an option to continue for an additional 52 weeks. Endpoints included overall survival (OS), progression-free survival (PFS), and response according to RECIST. Serum chromogranin A (CgA) was evaluated as an exploratory biomarker. A tumor growth rate analysis was planned to allow comparison with data from the CLARINET trial in gastroenteropancreatic NETs. Results: Eighteen patients (median age 42 years; range 28-77) across three centers participated; 78% carried SDHx mutations. Lanreotide was well tolerated with predominantly grade 1-2 adverse events and no treatment discontinuations due to toxicity. The most common treatment-emergent adverse events were diarrhea (67%), injection-site reaction (44%), constipation (39%), fatigue (39%), and abdominal pain (39%). Serious adverse events were reported in four patients and were assessed as not related or unlikely related to lanreotide. All 18 patients had at least one recorded post-baseline tumor assessment. Two partial responses were recorded during extended follow-up. At approximately 1 year, disease stabilization was observed in 11 of 13 patients (85%) with an available assessment, while two patients (15%) had progressive disease. Biomarker analysis showed substantial variability in serum CgA values. Tumor growth rate analysis revealed a median growth rate of 0.00124\/day (tumor doubling time 559 days), comparable in order of magnitude to the rate of 0.00046\/day observed in 83 lanreotide-treated patients in CLARINET, and consistent with a median PFS [&ge;]2 years. Conclusions: Lanreotide exhibits promising antiproliferative activity in PPGL, with a favorable safety profile and extended periods of disease stabilization. These findings support the consideration of SSAs as an option in managing SSTR-positive PPGLs, delaying more aggressive treatments until disease progression mandates escalation.","rel_num_authors":6,"rel_authors":[{"author_name":"Jaydira Del Rivero","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Bahar Laderian","author_inst":"Montefiore\/Albert Einstein College of Medicine"},{"author_name":"Mengxi Zhou","author_inst":"Memorial Sloan Kettering Cancer Institute, Department of Radiology."},{"author_name":"Lyndon Luk","author_inst":"Columbia University Department of Radiology."},{"author_name":"Susan E Bates","author_inst":"Columbia University Department of Medicine."},{"author_name":"Tito Fojo","author_inst":"Columbia University Department of Medicine."}],"rel_date":"2026-10-02","rel_site":"medrxiv"},{"rel_title":"Weakly Supervised Multiple-Instance Learning for Seizure Onset Zone Identification","rel_doi":"10.64898\/2026.09.30.26364032","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.30.26364032","rel_abs":"Accurate localization of the seizure onset zone (SOZ) is essential for planning resection or ablation in patients with focal drug-resistant epilepsy (DRE). However, the true SOZ cannot be directly observed during clinical evaluation, so precise electrode-level annotations are rarely available. To address this limitation, we developed a weakly supervised multiple-instance learning (MIL) framework in which labels were constructed from electrode resection status and postsurgical outcome. A shared gated recurrent unit (GRU) with temporal attention encoded each electrode's peri-onset neural fragility sequence. And attention-based pooling integrated information across variable numbers of electrodes to estimate whether each electrode group contained SOZ-related evidence. The cohort comprised 42 patients with DRE from three datasets, including 29 with successful and 13 with failed postsurgical outcomes. These patients contributed 136 seizure epochs. The cohort was divided at the patient level into training, validation and held-out test sets containing 25, 8 and 9 patients, respectively, with all data from each patient retained in the same subset. Predictions from non-resected regions were evaluated at the seizure-epoch and patient levels to assess postsurgical outcome discrimination for individual seizures and after aggregation across seizures from the same patient, respectively. At the seizure-epoch level, the proposed framework achieved an area under the receiver operating characteristic (ROC) curve (AUC) of 0.828, with a 95% confidence interval (CI) of 0.511-1.000, and performed comparably to Manifold Oblique Random Forests (MORF). At the patient level, the framework achieved an AUC of 0.944, with a 95% CI of 0.677-1.000, and yielded a numerically higher AUC than MORF. However, DeLong's test did not show a statistically significant difference between the methods, with a P value of 0.398. These findings support the feasibility of extracting clinically meaningful SOZ-related information from electrode-wise neural fragility sequences without precise electrode-level labels. Because the held-out test set included only nine patients and the CIs were wide, these preliminary findings require validation in larger independent cohorts.","rel_num_authors":7,"rel_authors":[{"author_name":"Junan Mao","author_inst":"University of Illinois Chicago"},{"author_name":"ANNE-CECILE LESAGE","author_inst":"University of Texas Medical Branch"},{"author_name":"Liliana Camarillo-Rodriguez","author_inst":"University of Texas Medical Branch"},{"author_name":"Diosely C Silveira","author_inst":"University of Texas Medical Branch"},{"author_name":"Yuanyi Zhang","author_inst":"University of Texas Medical Branch"},{"author_name":"Patrick J Karas","author_inst":"University of Texas Medical Branch"},{"author_name":"Jiefei Wang","author_inst":"University of Texas Medical Branch"}],"rel_date":"2026-10-02","rel_site":"medrxiv"},{"rel_title":"A vulnerable space: Health professions education scholars' reflections on AI-use disclosure","rel_doi":"10.64898\/2026.10.01.26364502","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.01.26364502","rel_abs":"Background AI use is growing by HPE scholars, and disclosure of that use is required by scientific ethics and journal policy. In spite of growing unease about the meaning, and meaningfulness, of AI-use disclosures in published manuscripts, little is known about how authors represent their AI use in published disclosure statements. Without such understanding, we are ill-equipped to redirect disclosure practices for increased sufficiency and sincerity, undermining efforts towards transparency in the era of AI-supported scholarship Methods In this descriptive qualitative study, 18 HPE researchers with experience disclosing generative AI use in publications from 2025-2026 were interviewed using Zoom. Data collection and thematic analysis proceeded iteratively, exploring participant experiences with AI use, their disclosure decisions, and evolving disclosure practices. Results Participants reported a wide range of experience writing AI-use disclosures (from 1-16 disclosures\/participant); in total 31 published disclosures were shared by participants and discussed during the interviews. Our analysis identified four themes: A spectrum of AI uses; Multi-factorial disclosure decisions; Discrepancies between actual and disclosed use; and Emotions around disclosure. Discussion AI-disclosure takes place at the intersection of shared ethical principles and situated pragmatic concerns. Disclosure is both an intellectual and an emotional practice, changing over time as AI use evolves and journal expectations develop. More generative uses may provoke divisive responses and are related to uncertainty about how to disclose, concern about disclosure penalties, and periodic use-disclosure discrepancies. Understanding how researchers are navigating these complexities may help the HPE community articulate clearer guidance for transparent and meaningful disclosure of AI-use in scholarly work. Reflective methodologies can help bring these issues to the surface of ongoing conversations about AI use.","rel_num_authors":4,"rel_authors":[{"author_name":"Lorelei A Lingard","author_inst":"Western University"},{"author_name":"Lauren A Maggio","author_inst":"University of Chicago at Illinois"},{"author_name":"Muhammad Ans","author_inst":"Western University"},{"author_name":"Erik Driessen","author_inst":"Maastricht University"}],"rel_date":"2026-10-02","rel_site":"medrxiv"},{"rel_title":"Comparative immunogenicity and relative vaccine efficacy of recombinant and cell culture-based influenza vaccines: Results from a randomized trial of adults in the United States, 2024-2025","rel_doi":"10.64898\/2026.10.01.26364413","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.01.26364413","rel_abs":"Background: Recombinant (RIV) and cell culture-based inactivated (ccIIV) influenza vaccines could improve seasonal influenza prevention; however, evidence is limited in how protection may differ among non-egg-based vaccines. Methods: We conducted a randomized trial of RIV versus ccIIV to compare vaccine immunogenicity in adults aged 18 to 64 years during the 2024-25 influenza season (ClinicalTrials.gov, NCT06518577). Active surveillance for influenza-like illness was conducted for six months post-vaccination and cumulative incidence of influenza by vaccine type was compared to estimate relative vaccine efficacy. Participants were tested for influenza by reverse-transcription polymerase chain reaction or rapid antigen tests. Immunogenicity was evaluated by hemagglutination inhibition (HAI), virus microneutralization (MN), and neuraminidase inhibition (NAI) assays in a subset of blood specimens collected pre-vaccination and one-month post-vaccination. Results: Among the 591 participants, 25 cases of influenza A were detected; 2.4% cumulative incidence among RIV recipients versus 6.1% among ccIIV recipients. The probability of influenza was 61% lower with RIV than ccIIV (95% confidence interval: 7 to 84). Among 151 participants, post-vaccination HAI and MN titers vaccine components were higher among RIV recipients while NAI titers were higher among ccIIV recipients. Conclusions: RIV provided better protection than ccIIV against influenza A illness in adults during the U.S. 2024-2025 season.","rel_num_authors":26,"rel_authors":[{"author_name":"Kelsey M Sumner","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Emma K Noble","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Lauren B Grant","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Jessica R Meeker","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Vel Murugan","author_inst":"Arizona State University"},{"author_name":"Lora Nordstrom","author_inst":"Valleywise Health"},{"author_name":"Stacey L House","author_inst":"Washington University School of Medicine, Department of Emergency Medicine"},{"author_name":"Rachel Presti","author_inst":"Wash U"},{"author_name":"Emmanuel B Walter","author_inst":"Duke University School of Medicine, Department of Pediatrics"},{"author_name":"Olivia L Williams","author_inst":"Duke University School of Medicine, Duke Human Vaccine Institute"},{"author_name":"Elie A Saade","author_inst":"University Hospitals Cleveland Medical Center"},{"author_name":"David H. Canaday","author_inst":"Case Western Reserve University"},{"author_name":"Katherine V Williams","author_inst":"University of Pittsburgh School of Medicine"},{"author_name":"Richard Zimmerman","author_inst":"University of Pittsburgh"},{"author_name":"F Liaini Gross","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Sara Valencia","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Brian M. Gurbaxani","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Nathaniel M Lewis","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Zhu-Nan Li","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Vasiliy Mishin","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Larisa Gubareva","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Bin Zhou","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Min Z Levine","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Brendan M Flannery","author_inst":"CDC"},{"author_name":"Sascha Ellington","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"- US Flu VE Network Collaborators","author_inst":"-"}],"rel_date":"2026-10-02","rel_site":"medrxiv"},{"rel_title":"Comparative immunogenicity and relative vaccine efficacy of recombinant and cell culture-based influenza vaccines: Results from a randomized trial of adults in the United States, 2024-2025","rel_doi":"10.64898\/2026.10.01.26364413","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.10.01.26364413","rel_abs":"Background: Recombinant (RIV) and cell culture-based inactivated (ccIIV) influenza vaccines could improve seasonal influenza prevention; however, evidence is limited in how protection may differ among non-egg-based vaccines. Methods: We conducted a randomized trial of RIV versus ccIIV to compare vaccine immunogenicity in adults aged 18 to 64 years during the 2024-25 influenza season (ClinicalTrials.gov, NCT06518577). Active surveillance for influenza-like illness was conducted for six months post-vaccination and cumulative incidence of influenza by vaccine type was compared to estimate relative vaccine efficacy. Participants were tested for influenza by reverse-transcription polymerase chain reaction or rapid antigen tests. Immunogenicity was evaluated by hemagglutination inhibition (HAI), virus microneutralization (MN), and neuraminidase inhibition (NAI) assays in a subset of blood specimens collected pre-vaccination and one-month post-vaccination. Results: Among the 591 participants, 25 cases of influenza A were detected; 2.4% cumulative incidence among RIV recipients versus 6.1% among ccIIV recipients. The probability of influenza was 61% lower with RIV than ccIIV (95% confidence interval: 7 to 84). Among 151 participants, post-vaccination HAI and MN titers vaccine components were higher among RIV recipients while NAI titers were higher among ccIIV recipients. Conclusions: RIV provided better protection than ccIIV against influenza A illness in adults during the U.S. 2024-2025 season.","rel_num_authors":26,"rel_authors":[{"author_name":"Kelsey M Sumner","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Emma K Noble","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Lauren B Grant","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Jessica R Meeker","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Vel Murugan","author_inst":"Arizona State University"},{"author_name":"Lora Nordstrom","author_inst":"Valleywise Health"},{"author_name":"Stacey L House","author_inst":"Washington University School of Medicine, Department of Emergency Medicine"},{"author_name":"Rachel Presti","author_inst":"Wash U"},{"author_name":"Emmanuel B Walter","author_inst":"Duke University School of Medicine, Department of Pediatrics"},{"author_name":"Olivia L Williams","author_inst":"Duke University School of Medicine, Duke Human Vaccine Institute"},{"author_name":"Elie A Saade","author_inst":"University Hospitals Cleveland Medical Center"},{"author_name":"David H. Canaday","author_inst":"Case Western Reserve University"},{"author_name":"Katherine V Williams","author_inst":"University of Pittsburgh School of Medicine"},{"author_name":"Richard Zimmerman","author_inst":"University of Pittsburgh"},{"author_name":"F Liaini Gross","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Sara Valencia","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Brian M. Gurbaxani","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Nathaniel M Lewis","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Zhu-Nan Li","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Vasiliy Mishin","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Larisa Gubareva","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Bin Zhou","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Min Z Levine","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Brendan M Flannery","author_inst":"CDC"},{"author_name":"Sascha Ellington","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"- US Flu VE Network Collaborators","author_inst":"-"}],"rel_date":"2026-10-02","rel_site":"medrxiv"},{"rel_title":"Multi-omics approach to map a clinically diverse large cohort with homozygous founder RAG1 p.C176F variant among Old Order Mennonites","rel_doi":"10.64898\/2026.09.29.26363255","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.29.26363255","rel_abs":"Partially preserved function of recombination-activating genes (RAG) 1 and 2 can be linked to divergent and hard-to-predict clinical and immunological phenotypes, even among close relatives. It is unclear how intrinsic RAG hypomorphism interacts with extrinsic environmental pressures to shape clinical trajectory. We dissect this phenomenon in a unique cohort of 18 Old Order Mennonite individuals with a novel missense founder RAG1 variant (p.C176F) with 25.8% recombinase activity of wild-type protein. After studying a myriad of markers, we demonstrate varying severity and progression of clinical disease (predominantly in females) that paralleled decline in CMV-specific immune competence, break in tolerance with hallmark presence of antibodies to IFN, a TH1\/IFN{gamma}-driven inflammatory milieu with elevated serum markers (CXCL9\/10), expansion of follicular helper T cells and clonal B cells enriched for autoreactive-prone VH4.34 B cell receptor. BCR and TCR repertoires carry the fingerprints of both extrinsic and RAG-driven intrinsic changes. Through this experiment of nature, our cohort demonstrated that partial RAG deficiency (pRD) is not a monolithic disease but the result of compounded RAG intrinsic and extrinsic events. Overall, this study uses multi-omics approaches to dissect the contribution of a hypomorphic RAG variant to variable severity of clinical disease and immunological dysregulation at cellular and molecular level. Emerging biomarkers of a multi-omic roadmap should allow monitoring of progression of clinical disease and guide who and when to treat with hematopoietic stem cell transplant in pRD.","rel_num_authors":62,"rel_authors":[{"author_name":"Evan Potts","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Marta Toth","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Karlla W. Brigatti","author_inst":"Clinic for Special Children, Gordonville, PA, USA"},{"author_name":"Erik G. Puffenberger","author_inst":"Clinic for Special Children, Gordonville, PA, USA"},{"author_name":"Paola R. Suhet","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Mustafa Talib","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Alanna E. Koehler","author_inst":"Clinic for Special Children, Gordonville, PA, USA"},{"author_name":"Zsuzsanna Gaal","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Kellie A. Larsen","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Rahim Z. Miller","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Daryl J. Gibson","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Philip Mendez","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA; Division of Allergy and I"},{"author_name":"Zixiao An","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Jeffrey J. Bednarski","author_inst":"Division of Hematology\/Oncology, Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Peter Blazso","author_inst":"Department of Pediatrics, University of Szeged, Szeged, Hungary"},{"author_name":"Marita Bosticardo","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Sharat Chandra","author_inst":"Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, Uni"},{"author_name":"Ivan K. Chinn","author_inst":"Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Joelle W. Clark","author_inst":"Clinic for Special Children, Gordonville, PA, USA"},{"author_name":"Antonio Condino-Neto","author_inst":"Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil"},{"author_name":"Ottavia M. Delmonte","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Dimana Dimitrova","author_inst":"Center for Immuno-Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Emily S. J. Edwards","author_inst":"Department of Immunology, School of Translational Medicine, Monash University, Melbourne, VIC, Australia"},{"author_name":"Ganesh V. Halade","author_inst":"Heart Institute, Division of Cardiovascular Sciences, Department of Internal Medicine, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Jennifer R. Heimall","author_inst":"Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, University of Pennsylvania, Philadelph"},{"author_name":"Ayal Hendel","author_inst":"Institute of Nanotechnology and Advanced Materials, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel"},{"author_name":"Sarah E. Henrickson","author_inst":"Division of Allergy and Immunology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Katherine E. Herman","author_inst":"Department of Medicine, Allergy\/Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, USA"},{"author_name":"Avni Joshi","author_inst":"Division of Allergy and Immunology, Mayo Clinic Children's, Rochester, MN, USA"},{"author_name":"Heather Kenney","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Maleewan Kitcharoensakkul","author_inst":"Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO, USA"},{"author_name":"Gloria Magro","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Eliza C. Martin","author_inst":"Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Edgar B. Oliveira-Junior","author_inst":"Immunogenic Laboratories, Sao Paulo, Brazil"},{"author_name":"Mei-Sing Ong","author_inst":"Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA"},{"author_name":"Oscar E. Ospina","author_inst":"Health Informatics, Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA"},{"author_name":"Francesca Pala","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Kady Palmer","author_inst":"Medical University of South Carolina, Charleston, SC, USA"},{"author_name":"Jason P. Raasch","author_inst":"Midwest Immunology Clinic, PLLC, Plymouth, MN, USA"},{"author_name":"Mathilde Salamon","author_inst":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA"},{"author_name":"Christopher D. Scharer","author_inst":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA"},{"author_name":"Christine M. Seroogy","author_inst":"Department of Pediatrics, Division of Allergy, Immunology, and Rheumatology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"},{"author_name":"Svetlana O. Sharapova","author_inst":"Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk Region, Belarus"},{"author_name":"Raz Somech","author_inst":"Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Michael Teng","author_inst":"Division of Allergy & Immunology, Department of Internal Medicine, University of South Florida, Tampa, FL, USA"},{"author_name":"Timothy J. Thauland","author_inst":"Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics, UCLA, Los Angeles, CA, USA"},{"author_name":"Boglarka Ujhazi","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"James W. Verbsky","author_inst":"Division of Rheumatology & Immunology, Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Brant R. Ward","author_inst":"Division of Allergy and Immunology, Children's National Hospital, Washington, DC, USA"},{"author_name":"Shengfeng Xu","author_inst":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Melis Yilmaz","author_inst":"Morsani College of Medicine, University of South Florida, Tampa, FL, USA"},{"author_name":"Yuhang Zhang","author_inst":"School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China"},{"author_name":"Wei Zhao","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, Virginia Commonwealth University, Richmond, VA, USA"},{"author_name":"Krisztian Csomos","author_inst":"Translational Genetics and Genomics Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD,"},{"author_name":"Yu Nee Lee","author_inst":"Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel"},{"author_name":"David G. Schatz","author_inst":"Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Manish Butte","author_inst":"Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics, UCLA, Los Angeles, CA, USA"},{"author_name":"Nicholas L. Rider","author_inst":"Virginia Tech Carilion School of Medicine, Department of Health Systems & Implementation Science, and Carilion Clinic, Department of Pediatrics, Section of Alle"},{"author_name":"Laura E. Poskitt","author_inst":"Clinic for Special Children, Gordonville, PA, USA"},{"author_name":"Luigi D. Notarangelo","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Kevin A. Strauss","author_inst":"Clinic for Special Children, Gordonville, PA, USA"},{"author_name":"Jolan E. Walter","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA; Division of Allergy and I"}],"rel_date":"2026-10-02","rel_site":"medrxiv"},{"rel_title":"Multi-omics approach to map a clinically diverse large cohort with homozygous founder RAG1 p.C176F variant among Old Order Mennonites","rel_doi":"10.64898\/2026.09.29.26363255","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.29.26363255","rel_abs":"Partially preserved function of recombination-activating genes (RAG) 1 and 2 can be linked to divergent and hard-to-predict clinical and immunological phenotypes, even among close relatives. It is unclear how intrinsic RAG hypomorphism interacts with extrinsic environmental pressures to shape clinical trajectory. We dissect this phenomenon in a unique cohort of 18 Old Order Mennonite individuals with a novel missense founder RAG1 variant (p.C176F) with 25.8% recombinase activity of wild-type protein. After studying a myriad of markers, we demonstrate varying severity and progression of clinical disease (predominantly in females) that paralleled decline in CMV-specific immune competence, break in tolerance with hallmark presence of antibodies to IFN, a TH1\/IFN{gamma}-driven inflammatory milieu with elevated serum markers (CXCL9\/10), expansion of follicular helper T cells and clonal B cells enriched for autoreactive-prone VH4.34 B cell receptor. BCR and TCR repertoires carry the fingerprints of both extrinsic and RAG-driven intrinsic changes. Through this experiment of nature, our cohort demonstrated that partial RAG deficiency (pRD) is not a monolithic disease but the result of compounded RAG intrinsic and extrinsic events. Overall, this study uses multi-omics approaches to dissect the contribution of a hypomorphic RAG variant to variable severity of clinical disease and immunological dysregulation at cellular and molecular level. Emerging biomarkers of a multi-omic roadmap should allow monitoring of progression of clinical disease and guide who and when to treat with hematopoietic stem cell transplant in pRD.","rel_num_authors":62,"rel_authors":[{"author_name":"Evan Potts","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Marta Toth","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Karlla W. Brigatti","author_inst":"Clinic for Special Children, Gordonville, PA, USA"},{"author_name":"Erik G. Puffenberger","author_inst":"Clinic for Special Children, Gordonville, PA, USA"},{"author_name":"Paola R. Suhet","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Mustafa Talib","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Alanna E. Koehler","author_inst":"Clinic for Special Children, Gordonville, PA, USA"},{"author_name":"Zsuzsanna Gaal","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Kellie A. Larsen","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Rahim Z. Miller","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Daryl J. Gibson","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Philip Mendez","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA; Division of Allergy and I"},{"author_name":"Zixiao An","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Jeffrey J. Bednarski","author_inst":"Division of Hematology\/Oncology, Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Peter Blazso","author_inst":"Department of Pediatrics, University of Szeged, Szeged, Hungary"},{"author_name":"Marita Bosticardo","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Sharat Chandra","author_inst":"Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, Uni"},{"author_name":"Ivan K. Chinn","author_inst":"Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Joelle W. Clark","author_inst":"Clinic for Special Children, Gordonville, PA, USA"},{"author_name":"Antonio Condino-Neto","author_inst":"Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil"},{"author_name":"Ottavia M. Delmonte","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Dimana Dimitrova","author_inst":"Center for Immuno-Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Emily S. J. Edwards","author_inst":"Department of Immunology, School of Translational Medicine, Monash University, Melbourne, VIC, Australia"},{"author_name":"Ganesh V. Halade","author_inst":"Heart Institute, Division of Cardiovascular Sciences, Department of Internal Medicine, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Jennifer R. Heimall","author_inst":"Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, University of Pennsylvania, Philadelph"},{"author_name":"Ayal Hendel","author_inst":"Institute of Nanotechnology and Advanced Materials, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel"},{"author_name":"Sarah E. Henrickson","author_inst":"Division of Allergy and Immunology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Katherine E. Herman","author_inst":"Department of Medicine, Allergy\/Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, USA"},{"author_name":"Avni Joshi","author_inst":"Division of Allergy and Immunology, Mayo Clinic Children's, Rochester, MN, USA"},{"author_name":"Heather Kenney","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Maleewan Kitcharoensakkul","author_inst":"Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO, USA"},{"author_name":"Gloria Magro","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Eliza C. Martin","author_inst":"Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Edgar B. Oliveira-Junior","author_inst":"Immunogenic Laboratories, Sao Paulo, Brazil"},{"author_name":"Mei-Sing Ong","author_inst":"Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA"},{"author_name":"Oscar E. Ospina","author_inst":"Health Informatics, Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA"},{"author_name":"Francesca Pala","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Kady Palmer","author_inst":"Medical University of South Carolina, Charleston, SC, USA"},{"author_name":"Jason P. Raasch","author_inst":"Midwest Immunology Clinic, PLLC, Plymouth, MN, USA"},{"author_name":"Mathilde Salamon","author_inst":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA"},{"author_name":"Christopher D. Scharer","author_inst":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA"},{"author_name":"Christine M. Seroogy","author_inst":"Department of Pediatrics, Division of Allergy, Immunology, and Rheumatology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"},{"author_name":"Svetlana O. Sharapova","author_inst":"Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk Region, Belarus"},{"author_name":"Raz Somech","author_inst":"Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Michael Teng","author_inst":"Division of Allergy & Immunology, Department of Internal Medicine, University of South Florida, Tampa, FL, USA"},{"author_name":"Timothy J. Thauland","author_inst":"Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics, UCLA, Los Angeles, CA, USA"},{"author_name":"Boglarka Ujhazi","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"James W. Verbsky","author_inst":"Division of Rheumatology & Immunology, Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Brant R. Ward","author_inst":"Division of Allergy and Immunology, Children's National Hospital, Washington, DC, USA"},{"author_name":"Shengfeng Xu","author_inst":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Melis Yilmaz","author_inst":"Morsani College of Medicine, University of South Florida, Tampa, FL, USA"},{"author_name":"Yuhang Zhang","author_inst":"School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China"},{"author_name":"Wei Zhao","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, Virginia Commonwealth University, Richmond, VA, USA"},{"author_name":"Krisztian Csomos","author_inst":"Translational Genetics and Genomics Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD,"},{"author_name":"Yu Nee Lee","author_inst":"Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel"},{"author_name":"David G. Schatz","author_inst":"Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Manish Butte","author_inst":"Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics, UCLA, Los Angeles, CA, USA"},{"author_name":"Nicholas L. Rider","author_inst":"Virginia Tech Carilion School of Medicine, Department of Health Systems & Implementation Science, and Carilion Clinic, Department of Pediatrics, Section of Alle"},{"author_name":"Laura E. Poskitt","author_inst":"Clinic for Special Children, Gordonville, PA, USA"},{"author_name":"Luigi D. Notarangelo","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Kevin A. Strauss","author_inst":"Clinic for Special Children, Gordonville, PA, USA"},{"author_name":"Jolan E. Walter","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA; Division of Allergy and I"}],"rel_date":"2026-10-02","rel_site":"medrxiv"},{"rel_title":"Multi-omics approach to map a clinically diverse large cohort with homozygous founder RAG1 p.C176F variant among Old Order Mennonites","rel_doi":"10.64898\/2026.09.29.26363255","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.29.26363255","rel_abs":"Partially preserved function of recombination-activating genes (RAG) 1 and 2 can be linked to divergent and hard-to-predict clinical and immunological phenotypes, even among close relatives. It is unclear how intrinsic RAG hypomorphism interacts with extrinsic environmental pressures to shape clinical trajectory. We dissect this phenomenon in a unique cohort of 18 Old Order Mennonite individuals with a novel missense founder RAG1 variant (p.C176F) with 25.8% recombinase activity of wild-type protein. After studying a myriad of markers, we demonstrate varying severity and progression of clinical disease (predominantly in females) that paralleled decline in CMV-specific immune competence, break in tolerance with hallmark presence of antibodies to IFN, a TH1\/IFN{gamma}-driven inflammatory milieu with elevated serum markers (CXCL9\/10), expansion of follicular helper T cells and clonal B cells enriched for autoreactive-prone VH4.34 B cell receptor. BCR and TCR repertoires carry the fingerprints of both extrinsic and RAG-driven intrinsic changes. Through this experiment of nature, our cohort demonstrated that partial RAG deficiency (pRD) is not a monolithic disease but the result of compounded RAG intrinsic and extrinsic events. Overall, this study uses multi-omics approaches to dissect the contribution of a hypomorphic RAG variant to variable severity of clinical disease and immunological dysregulation at cellular and molecular level. Emerging biomarkers of a multi-omic roadmap should allow monitoring of progression of clinical disease and guide who and when to treat with hematopoietic stem cell transplant in pRD.","rel_num_authors":62,"rel_authors":[{"author_name":"Evan Potts","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Marta Toth","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Karlla W. Brigatti","author_inst":"Clinic for Special Children, Gordonville, PA, USA"},{"author_name":"Erik G. Puffenberger","author_inst":"Clinic for Special Children, Gordonville, PA, USA"},{"author_name":"Paola R. Suhet","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Mustafa Talib","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Alanna E. Koehler","author_inst":"Clinic for Special Children, Gordonville, PA, USA"},{"author_name":"Zsuzsanna Gaal","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Kellie A. Larsen","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Rahim Z. Miller","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Daryl J. Gibson","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Philip Mendez","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA; Division of Allergy and I"},{"author_name":"Zixiao An","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Jeffrey J. Bednarski","author_inst":"Division of Hematology\/Oncology, Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Peter Blazso","author_inst":"Department of Pediatrics, University of Szeged, Szeged, Hungary"},{"author_name":"Marita Bosticardo","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Sharat Chandra","author_inst":"Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, Uni"},{"author_name":"Ivan K. Chinn","author_inst":"Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Joelle W. Clark","author_inst":"Clinic for Special Children, Gordonville, PA, USA"},{"author_name":"Antonio Condino-Neto","author_inst":"Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil"},{"author_name":"Ottavia M. Delmonte","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Dimana Dimitrova","author_inst":"Center for Immuno-Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Emily S. J. Edwards","author_inst":"Department of Immunology, School of Translational Medicine, Monash University, Melbourne, VIC, Australia"},{"author_name":"Ganesh V. Halade","author_inst":"Heart Institute, Division of Cardiovascular Sciences, Department of Internal Medicine, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Jennifer R. Heimall","author_inst":"Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, University of Pennsylvania, Philadelph"},{"author_name":"Ayal Hendel","author_inst":"Institute of Nanotechnology and Advanced Materials, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel"},{"author_name":"Sarah E. Henrickson","author_inst":"Division of Allergy and Immunology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Katherine E. Herman","author_inst":"Department of Medicine, Allergy\/Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, USA"},{"author_name":"Avni Joshi","author_inst":"Division of Allergy and Immunology, Mayo Clinic Children's, Rochester, MN, USA"},{"author_name":"Heather Kenney","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Maleewan Kitcharoensakkul","author_inst":"Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO, USA"},{"author_name":"Gloria Magro","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Eliza C. Martin","author_inst":"Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Edgar B. Oliveira-Junior","author_inst":"Immunogenic Laboratories, Sao Paulo, Brazil"},{"author_name":"Mei-Sing Ong","author_inst":"Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA"},{"author_name":"Oscar E. Ospina","author_inst":"Health Informatics, Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA"},{"author_name":"Francesca Pala","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Kady Palmer","author_inst":"Medical University of South Carolina, Charleston, SC, USA"},{"author_name":"Jason P. Raasch","author_inst":"Midwest Immunology Clinic, PLLC, Plymouth, MN, USA"},{"author_name":"Mathilde Salamon","author_inst":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA"},{"author_name":"Christopher D. Scharer","author_inst":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA"},{"author_name":"Christine M. Seroogy","author_inst":"Department of Pediatrics, Division of Allergy, Immunology, and Rheumatology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"},{"author_name":"Svetlana O. Sharapova","author_inst":"Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk Region, Belarus"},{"author_name":"Raz Somech","author_inst":"Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Michael Teng","author_inst":"Division of Allergy & Immunology, Department of Internal Medicine, University of South Florida, Tampa, FL, USA"},{"author_name":"Timothy J. Thauland","author_inst":"Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics, UCLA, Los Angeles, CA, USA"},{"author_name":"Boglarka Ujhazi","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"James W. Verbsky","author_inst":"Division of Rheumatology & Immunology, Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Brant R. Ward","author_inst":"Division of Allergy and Immunology, Children's National Hospital, Washington, DC, USA"},{"author_name":"Shengfeng Xu","author_inst":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Melis Yilmaz","author_inst":"Morsani College of Medicine, University of South Florida, Tampa, FL, USA"},{"author_name":"Yuhang Zhang","author_inst":"School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China"},{"author_name":"Wei Zhao","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, Virginia Commonwealth University, Richmond, VA, USA"},{"author_name":"Krisztian Csomos","author_inst":"Translational Genetics and Genomics Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD,"},{"author_name":"Yu Nee Lee","author_inst":"Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel"},{"author_name":"David G. Schatz","author_inst":"Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Manish Butte","author_inst":"Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics, UCLA, Los Angeles, CA, USA"},{"author_name":"Nicholas L. Rider","author_inst":"Virginia Tech Carilion School of Medicine, Department of Health Systems & Implementation Science, and Carilion Clinic, Department of Pediatrics, Section of Alle"},{"author_name":"Laura E. Poskitt","author_inst":"Clinic for Special Children, Gordonville, PA, USA"},{"author_name":"Luigi D. Notarangelo","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Kevin A. Strauss","author_inst":"Clinic for Special Children, Gordonville, PA, USA"},{"author_name":"Jolan E. Walter","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA; Division of Allergy and I"}],"rel_date":"2026-10-02","rel_site":"medrxiv"},{"rel_title":"Multi-omics approach to map a clinically diverse large cohort with homozygous founder RAG1 p.C176F variant among Old Order Mennonites","rel_doi":"10.64898\/2026.09.29.26363255","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.29.26363255","rel_abs":"Partially preserved function of recombination-activating genes (RAG) 1 and 2 can be linked to divergent and hard-to-predict clinical and immunological phenotypes, even among close relatives. It is unclear how intrinsic RAG hypomorphism interacts with extrinsic environmental pressures to shape clinical trajectory. We dissect this phenomenon in a unique cohort of 18 Old Order Mennonite individuals with a novel missense founder RAG1 variant (p.C176F) with 25.8% recombinase activity of wild-type protein. After studying a myriad of markers, we demonstrate varying severity and progression of clinical disease (predominantly in females) that paralleled decline in CMV-specific immune competence, break in tolerance with hallmark presence of antibodies to IFN, a TH1\/IFN{gamma}-driven inflammatory milieu with elevated serum markers (CXCL9\/10), expansion of follicular helper T cells and clonal B cells enriched for autoreactive-prone VH4.34 B cell receptor. BCR and TCR repertoires carry the fingerprints of both extrinsic and RAG-driven intrinsic changes. Through this experiment of nature, our cohort demonstrated that partial RAG deficiency (pRD) is not a monolithic disease but the result of compounded RAG intrinsic and extrinsic events. Overall, this study uses multi-omics approaches to dissect the contribution of a hypomorphic RAG variant to variable severity of clinical disease and immunological dysregulation at cellular and molecular level. Emerging biomarkers of a multi-omic roadmap should allow monitoring of progression of clinical disease and guide who and when to treat with hematopoietic stem cell transplant in pRD.","rel_num_authors":62,"rel_authors":[{"author_name":"Evan Potts","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Marta Toth","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Karlla W. Brigatti","author_inst":"Clinic for Special Children, Gordonville, PA, USA"},{"author_name":"Erik G. Puffenberger","author_inst":"Clinic for Special Children, Gordonville, PA, USA"},{"author_name":"Paola R. Suhet","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Mustafa Talib","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Alanna E. Koehler","author_inst":"Clinic for Special Children, Gordonville, PA, USA"},{"author_name":"Zsuzsanna Gaal","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Kellie A. Larsen","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Rahim Z. Miller","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Daryl J. Gibson","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Philip Mendez","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA; Division of Allergy and I"},{"author_name":"Zixiao An","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Jeffrey J. Bednarski","author_inst":"Division of Hematology\/Oncology, Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, USA"},{"author_name":"Peter Blazso","author_inst":"Department of Pediatrics, University of Szeged, Szeged, Hungary"},{"author_name":"Marita Bosticardo","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Sharat Chandra","author_inst":"Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, Uni"},{"author_name":"Ivan K. Chinn","author_inst":"Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Joelle W. Clark","author_inst":"Clinic for Special Children, Gordonville, PA, USA"},{"author_name":"Antonio Condino-Neto","author_inst":"Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil"},{"author_name":"Ottavia M. Delmonte","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Dimana Dimitrova","author_inst":"Center for Immuno-Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"},{"author_name":"Emily S. J. Edwards","author_inst":"Department of Immunology, School of Translational Medicine, Monash University, Melbourne, VIC, Australia"},{"author_name":"Ganesh V. Halade","author_inst":"Heart Institute, Division of Cardiovascular Sciences, Department of Internal Medicine, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"Jennifer R. Heimall","author_inst":"Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, University of Pennsylvania, Philadelph"},{"author_name":"Ayal Hendel","author_inst":"Institute of Nanotechnology and Advanced Materials, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel"},{"author_name":"Sarah E. Henrickson","author_inst":"Division of Allergy and Immunology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Katherine E. Herman","author_inst":"Department of Medicine, Allergy\/Immunology and Rheumatology, University of Rochester Medical Center, Rochester, NY, USA"},{"author_name":"Avni Joshi","author_inst":"Division of Allergy and Immunology, Mayo Clinic Children's, Rochester, MN, USA"},{"author_name":"Heather Kenney","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Maleewan Kitcharoensakkul","author_inst":"Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO, USA"},{"author_name":"Gloria Magro","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Eliza C. Martin","author_inst":"Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Edgar B. Oliveira-Junior","author_inst":"Immunogenic Laboratories, Sao Paulo, Brazil"},{"author_name":"Mei-Sing Ong","author_inst":"Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA"},{"author_name":"Oscar E. Ospina","author_inst":"Health Informatics, Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA"},{"author_name":"Francesca Pala","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Kady Palmer","author_inst":"Medical University of South Carolina, Charleston, SC, USA"},{"author_name":"Jason P. Raasch","author_inst":"Midwest Immunology Clinic, PLLC, Plymouth, MN, USA"},{"author_name":"Mathilde Salamon","author_inst":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA"},{"author_name":"Christopher D. Scharer","author_inst":"Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA"},{"author_name":"Christine M. Seroogy","author_inst":"Department of Pediatrics, Division of Allergy, Immunology, and Rheumatology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA"},{"author_name":"Svetlana O. Sharapova","author_inst":"Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk Region, Belarus"},{"author_name":"Raz Somech","author_inst":"Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel"},{"author_name":"Michael Teng","author_inst":"Division of Allergy & Immunology, Department of Internal Medicine, University of South Florida, Tampa, FL, USA"},{"author_name":"Timothy J. Thauland","author_inst":"Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics, UCLA, Los Angeles, CA, USA"},{"author_name":"Boglarka Ujhazi","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA"},{"author_name":"James W. Verbsky","author_inst":"Division of Rheumatology & Immunology, Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Brant R. Ward","author_inst":"Division of Allergy and Immunology, Children's National Hospital, Washington, DC, USA"},{"author_name":"Shengfeng Xu","author_inst":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Melis Yilmaz","author_inst":"Morsani College of Medicine, University of South Florida, Tampa, FL, USA"},{"author_name":"Yuhang Zhang","author_inst":"School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China"},{"author_name":"Wei Zhao","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, Virginia Commonwealth University, Richmond, VA, USA"},{"author_name":"Krisztian Csomos","author_inst":"Translational Genetics and Genomics Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD,"},{"author_name":"Yu Nee Lee","author_inst":"Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel"},{"author_name":"David G. Schatz","author_inst":"Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Manish Butte","author_inst":"Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics, UCLA, Los Angeles, CA, USA"},{"author_name":"Nicholas L. Rider","author_inst":"Virginia Tech Carilion School of Medicine, Department of Health Systems & Implementation Science, and Carilion Clinic, Department of Pediatrics, Section of Alle"},{"author_name":"Laura E. Poskitt","author_inst":"Clinic for Special Children, Gordonville, PA, USA"},{"author_name":"Luigi D. Notarangelo","author_inst":"Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes "},{"author_name":"Kevin A. Strauss","author_inst":"Clinic for Special Children, Gordonville, PA, USA"},{"author_name":"Jolan E. Walter","author_inst":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA; Division of Allergy and I"}],"rel_date":"2026-10-02","rel_site":"medrxiv"},{"rel_title":"Real-time situational assessment of respiratory virus epidemics in Australia over winter 2025 and an out-of-season influenza A H3N2 epidemic","rel_doi":"10.64898\/2026.09.30.26364449","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.30.26364449","rel_abs":"Introduction: In temperate regions, influenza and respiratory syncytial virus (RSV) typically exhibit seasonal epidemics during the winter months, often concurrently with SARS-CoV-2 epidemics. Monitoring past and real-time trends in infection dynamics is important for informing public health situational awareness, including identifying and characterising unusual epidemic activity. However, data used to monitor these trends can exhibit substantial noise including strong day-of-the-week variation in reporting. In addition, case data for influenza can obscure distinct trends in influenza subtypes if not combined with virological data. Aim: By quantifying trends in respiratory virus activity using statistical methods, the Australia-Aotearoa Consortium for Epidemic Forecasting and Analytics (ACEFA) aims to provide government partners with comprehensive epidemic intelligence. Methods: Analyses were performed on daily case time series data for SARS-CoV-2, RSV and influenza across Australia's eight jurisdictions. Past and real-time trends were inferred for each pathogen and each influenza subtype using Bayesian p-spline models. Results: The 2025 Winter Situational Assessment Program provided weekly reports throughout the winter season and during the out-of-season influenza A H3N2 epidemic, driven by the emergence of the novel influenza subclade ('subclade K'). Despite limited subtyping data, our analysis provided an early signal of increasing influenza A H3N2 during a period in which overall influenza cases were decreasing; increases in influenza A H3N2 activity were first detected in July, and by mid-August, increasing H3N2 activity was estimated across all jurisdictions. Discussion: Our analysis highlights the benefits of incorporating statistical methods into real-time epidemic situational assessment and in consolidating reporting across jurisdictions.","rel_num_authors":15,"rel_authors":[{"author_name":"Oliver Eales","author_inst":"The University of Melbourne"},{"author_name":"Alys R Young","author_inst":"University of Melbourne"},{"author_name":"Katharine L Senior","author_inst":"University of Melbourne"},{"author_name":"Ruarai Tobin","author_inst":"The University of Melbourne"},{"author_name":"Janaki Amin","author_inst":"Health Protection NSW"},{"author_name":"Brett N Archer","author_inst":"Queensland Health"},{"author_name":"Paul Armstrong","author_inst":"WA Department of Health"},{"author_name":"Sally Ellis","author_inst":"Health Protection NSW"},{"author_name":"Elizabeth J Robinson","author_inst":"Department of Health, Victoria"},{"author_name":"Janet Strachan","author_inst":"Department of Health, Victoria"},{"author_name":"Ashish C Shrestha","author_inst":"Queensland Health"},{"author_name":"Mark Veitch","author_inst":"Department of Health Tasmania"},{"author_name":"James Wood","author_inst":"University of New South Wales - Kensington Campus: University of New South Wales"},{"author_name":"James M McCaw","author_inst":"University of Melbourne"},{"author_name":"Freya M Shearer","author_inst":"The University of Melbourne"}],"rel_date":"2026-10-02","rel_site":"medrxiv"},{"rel_title":"Uncertainty-Aware Multiscale Treatment Response Forecasting in Advanced Non-Small Cell Lung Cancer Using Residual-Variance Conformal Prediction","rel_doi":"10.64898\/2026.09.30.26364431","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.30.26364431","rel_abs":"Voxel-level prediction of treatment response from longitudinal fluorodeoxyglucose (FDG) positron emission tomography\/computed tomography (PET\/CT) can enable spatially adaptive dose planning in advanced non-small cell lung cancer (NSCLC), but point predictions alone lack the uncertainty quantification needed for safe clinical decision-making. Standard conformal prediction (CP) provides distribution-free coverage but yields spatially uniform intervals and assumes exchangeability, an assumption violated by intra-tumoral spatial correlation. We propose a multiscale CP framework built on a re-optimized VoxelForecast generalized least squares model that explicitly captures voxel-level covariance. Variogram sensitivity analysis identified the Stable model as significantly superior to the previously used Matern family. The framework combines hierarchical nested leave-one-patient-out calibration, which restores exchangeability for valid voxel-level coverage, with residual-variance CP (VarCP), which learns a heteroscedastic, location-dependent scale to produce adaptive intervals while preserving finite-sample marginal coverage guarantees. On two prospective NSCLC trial cohorts, FLARE-RT (N=25 locally advanced, chemoradiotherapy; 11,100 voxels) and BRIGHT (N=19 metastatic, chemoimmunotherapy; 26,980 voxels), multiscale feature integration reduced voxel-level prediction error by 35% and 31%, respectively. VarCP maintained nominal coverage while producing 7-18% (FLARE-RT) and 4-8% (BRIGHT) narrower voxel-level intervals than a hierarchically calibrated standard CP baseline (paired Wilcoxon signed-rank, significant at most miscoverage levels), with comparable lesion-level gains (7-18% and 6-10%) via median-based aggregation of voxel residuals. VarCP delivers tighter yet mathematically guaranteed spatial uncertainty maps, supporting both voxel-level dose adjustment and whole-lesion treatment planning in advanced NSCLC.","rel_num_authors":7,"rel_authors":[{"author_name":"Shouyi Wang","author_inst":"The University of Texas at Arlington, Arlington, TX"},{"author_name":"Lei Deng","author_inst":"Fred Hutchinson Cancer Center, Seattle, WA"},{"author_name":"Ting Ye","author_inst":"Department of Biostatistics, University of Washington, Seattle, WA"},{"author_name":"Paul E. Kinahan","author_inst":"Department of Radiology, University of Washington, Seattle, WA"},{"author_name":"Jing Zeng","author_inst":"Department of Radiation Oncology, University of Washington, Seattle, WA"},{"author_name":"John H. Gennari","author_inst":"Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA"},{"author_name":"Stephen R. Bowen","author_inst":"Department of Radiation Oncology, University of Washington, Seattle, WA"}],"rel_date":"2026-10-02","rel_site":"medrxiv"},{"rel_title":"Prospective Bidirectional Associations Between Core Schemas, Attenuated Psychotic Symptoms, and Functioning in Youth at Clinical High Risk for Psychosis","rel_doi":"10.64898\/2026.09.30.26364206","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.30.26364206","rel_abs":"Objective: Cognitive models of psychosis implicate maladaptive core schemas in the development and emergence of psychotic symptoms, but no study has tested temporal dynamics between schemas and psychotic symptoms in a large sample of clinical high-risk (CHR) youth. Given their sizable role in cognitive behavioral therapies, the first-line treatment for CHR youth, core schemas may be key to both symptom development and treatment in this population. Methods: Participants were 578 CHR individuals from the second North American Prodrome Longitudinal Study (NAPLS-2) assessed across five timepoints. Time-lagged mixed-effects models tested forward and reverse paths for each Brief Core Schema Scales subscale with both psychotic symptom and functioning changes, controlling for autoregressive effects, time-varying depression, and linear time. Results: Twenty of 36 schema outcome pairs showed significant prospective associations. Negative-other schemas were prospectively associated with worsening across nearly all psychosis symptom and functioning domains. Suspiciousness exhibited bidirectional associations with all four schema subscales. Grandiose ideas were uniquely prospectively associated with positive-self and negative-other schemas. Positive schemas were prospectively associated with decreases in suspiciousness, negative symptoms, and improvements in functioning. Effects were largely independent of depressive symptoms and robust across sensitivity analyses, with partial attenuation of self-schema effects on suspiciousness. Conclusions: Core schemas were prospectively associated with psychosis symptom and functioning change in CHR youth, with symptom-domain specificity and bidirectionality. These findings extend cognitive models of psychosis into CHR syndromes and highlight schemas as potentially modifiable treatment targets to improve outcomes in this population.","rel_num_authors":15,"rel_authors":[{"author_name":"Alexander Broekhuijse","author_inst":"Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, USA"},{"author_name":"Abhishek Saxena","author_inst":"Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, USA"},{"author_name":"Catalina Mourgues-Codern","author_inst":"Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, USA"},{"author_name":"Hesham Mukhtar","author_inst":"Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, USA"},{"author_name":"Jean Addington","author_inst":"Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada"},{"author_name":"Carrie E. Bearden","author_inst":"Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA,"},{"author_name":"Kristin S. Cadenhead","author_inst":"Department of Psychiatry, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Daniel H. Mathalon","author_inst":"Department of Psychiatry and Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA; Mental Health Service, San Franc"},{"author_name":"Thomas H. McGlashan","author_inst":"Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, USA"},{"author_name":"Diana O. Perkins","author_inst":"Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Elaine F. Walker","author_inst":"Department of Psychology, Emory University, Atlanta, GA, USA"},{"author_name":"Tyrone D. Cannon","author_inst":"Department of Psychology, Yale University, New Haven, CT, USA"},{"author_name":"Scott W. Woods","author_inst":"Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, USA"},{"author_name":"Albert R. Powers III","author_inst":"Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, USA"},{"author_name":"Emily A. Farina","author_inst":"Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, USA"}],"rel_date":"2026-10-02","rel_site":"medrxiv"},{"rel_title":"Prospective Bidirectional Associations Between Core Schemas, Attenuated Psychotic Symptoms, and Functioning in Youth at Clinical High Risk for Psychosis","rel_doi":"10.64898\/2026.09.30.26364206","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.30.26364206","rel_abs":"Objective: Cognitive models of psychosis implicate maladaptive core schemas in the development and emergence of psychotic symptoms, but no study has tested temporal dynamics between schemas and psychotic symptoms in a large sample of clinical high-risk (CHR) youth. Given their sizable role in cognitive behavioral therapies, the first-line treatment for CHR youth, core schemas may be key to both symptom development and treatment in this population. Methods: Participants were 578 CHR individuals from the second North American Prodrome Longitudinal Study (NAPLS-2) assessed across five timepoints. Time-lagged mixed-effects models tested forward and reverse paths for each Brief Core Schema Scales subscale with both psychotic symptom and functioning changes, controlling for autoregressive effects, time-varying depression, and linear time. Results: Twenty of 36 schema outcome pairs showed significant prospective associations. Negative-other schemas were prospectively associated with worsening across nearly all psychosis symptom and functioning domains. Suspiciousness exhibited bidirectional associations with all four schema subscales. Grandiose ideas were uniquely prospectively associated with positive-self and negative-other schemas. Positive schemas were prospectively associated with decreases in suspiciousness, negative symptoms, and improvements in functioning. Effects were largely independent of depressive symptoms and robust across sensitivity analyses, with partial attenuation of self-schema effects on suspiciousness. Conclusions: Core schemas were prospectively associated with psychosis symptom and functioning change in CHR youth, with symptom-domain specificity and bidirectionality. These findings extend cognitive models of psychosis into CHR syndromes and highlight schemas as potentially modifiable treatment targets to improve outcomes in this population.","rel_num_authors":15,"rel_authors":[{"author_name":"Alexander Broekhuijse","author_inst":"Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, USA"},{"author_name":"Abhishek Saxena","author_inst":"Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, USA"},{"author_name":"Catalina Mourgues-Codern","author_inst":"Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, USA"},{"author_name":"Hesham Mukhtar","author_inst":"Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, USA"},{"author_name":"Jean Addington","author_inst":"Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada"},{"author_name":"Carrie E. Bearden","author_inst":"Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA,"},{"author_name":"Kristin S. Cadenhead","author_inst":"Department of Psychiatry, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Daniel H. Mathalon","author_inst":"Department of Psychiatry and Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA; Mental Health Service, San Franc"},{"author_name":"Thomas H. McGlashan","author_inst":"Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, USA"},{"author_name":"Diana O. Perkins","author_inst":"Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Elaine F. Walker","author_inst":"Department of Psychology, Emory University, Atlanta, GA, USA"},{"author_name":"Tyrone D. Cannon","author_inst":"Department of Psychology, Yale University, New Haven, CT, USA"},{"author_name":"Scott W. Woods","author_inst":"Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, USA"},{"author_name":"Albert R. Powers III","author_inst":"Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, USA"},{"author_name":"Emily A. Farina","author_inst":"Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, USA"}],"rel_date":"2026-10-02","rel_site":"medrxiv"},{"rel_title":"Prospective Bidirectional Associations Between Core Schemas, Attenuated Psychotic Symptoms, and Functioning in Youth at Clinical High Risk for Psychosis","rel_doi":"10.64898\/2026.09.30.26364206","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.30.26364206","rel_abs":"Objective: Cognitive models of psychosis implicate maladaptive core schemas in the development and emergence of psychotic symptoms, but no study has tested temporal dynamics between schemas and psychotic symptoms in a large sample of clinical high-risk (CHR) youth. Given their sizable role in cognitive behavioral therapies, the first-line treatment for CHR youth, core schemas may be key to both symptom development and treatment in this population. Methods: Participants were 578 CHR individuals from the second North American Prodrome Longitudinal Study (NAPLS-2) assessed across five timepoints. Time-lagged mixed-effects models tested forward and reverse paths for each Brief Core Schema Scales subscale with both psychotic symptom and functioning changes, controlling for autoregressive effects, time-varying depression, and linear time. Results: Twenty of 36 schema outcome pairs showed significant prospective associations. Negative-other schemas were prospectively associated with worsening across nearly all psychosis symptom and functioning domains. Suspiciousness exhibited bidirectional associations with all four schema subscales. Grandiose ideas were uniquely prospectively associated with positive-self and negative-other schemas. Positive schemas were prospectively associated with decreases in suspiciousness, negative symptoms, and improvements in functioning. Effects were largely independent of depressive symptoms and robust across sensitivity analyses, with partial attenuation of self-schema effects on suspiciousness. Conclusions: Core schemas were prospectively associated with psychosis symptom and functioning change in CHR youth, with symptom-domain specificity and bidirectionality. These findings extend cognitive models of psychosis into CHR syndromes and highlight schemas as potentially modifiable treatment targets to improve outcomes in this population.","rel_num_authors":15,"rel_authors":[{"author_name":"Alexander Broekhuijse","author_inst":"Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, USA"},{"author_name":"Abhishek Saxena","author_inst":"Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, USA"},{"author_name":"Catalina Mourgues-Codern","author_inst":"Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, USA"},{"author_name":"Hesham Mukhtar","author_inst":"Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, USA"},{"author_name":"Jean Addington","author_inst":"Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada"},{"author_name":"Carrie E. Bearden","author_inst":"Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA,"},{"author_name":"Kristin S. Cadenhead","author_inst":"Department of Psychiatry, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Daniel H. Mathalon","author_inst":"Department of Psychiatry and Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA; Mental Health Service, San Franc"},{"author_name":"Thomas H. McGlashan","author_inst":"Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, USA"},{"author_name":"Diana O. Perkins","author_inst":"Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Elaine F. Walker","author_inst":"Department of Psychology, Emory University, Atlanta, GA, USA"},{"author_name":"Tyrone D. Cannon","author_inst":"Department of Psychology, Yale University, New Haven, CT, USA"},{"author_name":"Scott W. Woods","author_inst":"Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, USA"},{"author_name":"Albert R. Powers III","author_inst":"Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, USA"},{"author_name":"Emily A. Farina","author_inst":"Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, USA"}],"rel_date":"2026-10-02","rel_site":"medrxiv"},{"rel_title":"Rare Germline Variants and Genetic Susceptibility to Pleural Mesothelioma: Moving Beyond DNA Repair","rel_doi":"10.64898\/2026.09.29.26364318","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.29.26364318","rel_abs":"A minority of asbestos-exposed individuals develop Pleural mesothelioma (PM), suggesting a role for inherited genetic factors. We performed germline whole-exome sequencing of blood from 127 EPIC participants who developed PM and controls. Rare pathogenic\/likely pathogenic variants were assessed in 193 cancer-associated genes and were evaluated for association with PM risk and overall survival. Exome-wide gene-based rare-variant aggregation analyses were performed using SKAT-O and Firth logistic regression. A PM polygenic risk score (PRS) was integrated with PTV status and asbestos exposure. Protein Truncating Variants (PTVs) were enriched in cases and associated with increased PM risk (OR=3.5, 95% CI 1.3-11.2, p-value = 0.01). PTV carriers had improved survival and lower mortality after adjustment for age at diagnosis and sex (HR=0.54, 95% CI 0.32-0.92, p-value = 0.023). PTV carriers had lower PRS values, and among individuals with low asbestos exposure, they were associated with increased PM risk (OR=5.75, 95% CI 1.09-58.2, p-value = 0.023). Gene-based analyses identified four novel loci. Rare variants and polygenic background may jointly influence PM risk, however validation in larger cohorts is warranted.","rel_num_authors":20,"rel_authors":[{"author_name":"Elton Jalis Herman","author_inst":"University of Turin"},{"author_name":"Carla Debernardi","author_inst":"University of Turin"},{"author_name":"Khadija Sana Hafeez","author_inst":"University of Turin"},{"author_name":"Sara Devito","author_inst":"University of Turin"},{"author_name":"Tze Y. Lim","author_inst":"Columbia University"},{"author_name":"Alessia Russo","author_inst":"University of Turin"},{"author_name":"Alessandra Allione","author_inst":"University of Turin"},{"author_name":"Elisabete Weiderpass","author_inst":"International Agency for Research on Cancer"},{"author_name":"Antonio Agudo","author_inst":"Catalan Institute of Oncology"},{"author_name":"Marta La Vecchia","author_inst":"University of Eastern Piedmont"},{"author_name":"Irma Dianzani","author_inst":"University of Eastern Piedmont"},{"author_name":"Natalia Cabrera Castro","author_inst":"Murcia Regional Health Council"},{"author_name":"Vittorio Simeon","author_inst":"University of Naples \"L. Vanvitelli\""},{"author_name":"Rosario Tumino","author_inst":"Hyblean Association for Epidemiology Research"},{"author_name":"Marcela Guevara","author_inst":"Navarra Institute for Health Research"},{"author_name":"Laia Peruchet Noray","author_inst":"Imperial College London"},{"author_name":"Ana Jim\u00e9nez Zabala","author_inst":"Biogipuzkoa Health Research Institute"},{"author_name":"Paolo Vineis","author_inst":"Imperial College London"},{"author_name":"Elisabetta Casalone","author_inst":"University of Turin"},{"author_name":"Giuseppe Matullo","author_inst":"University of Turin"}],"rel_date":"2026-10-02","rel_site":"medrxiv"},{"rel_title":"Spontaneous behavior predicts colony membership, individual identity, and rank in naked mole-rat societies","rel_doi":"10.64898\/2026.09.27.754730","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.27.754730","rel_abs":"Animal societies are organized across scales, from moment-to-moment actions of individuals to dynamic group structure. A central challenge in sociobiology is to understand how behaviors of individuals shape group structure. Here, using machine vision to map recurrent fine-scale behavioral modules in the eusocial naked mole-rat (Heterocephalus glaber), we show that spontaneous behavior in isolation predicts group-level social organization, including colony membership and individual identity. We determined dominance relationships and found highly linear hierarchies, with ranks stable over months to years. Remarkably, fine-scale behavioral profiles in isolation correctly predicted pairwise dominance relationships, allowing reconstruction of rank order within each colony. Models trained within one colony predicted rank poorly in others, suggesting that naked mole-rats express social position through behavioral patterns specific to each colony. Together, our results connect fine-scale behavior to social structure maintained over years and show that, even when an animal is alone, its behavior carries signatures of its identity, colony, and place within that society.","rel_num_authors":14,"rel_authors":[{"author_name":"Yuki Haba","author_inst":"Zuckerman Mind Brain Behavior Institute; Department of Biological Sciences and Howard Hughes Medical Institute, Columbia University"},{"author_name":"Ryan Schwark","author_inst":"Zuckerman Mind Brain Behavior Institute; Department of Biological Sciences and Howard Hughes Medical Institute, Columbia University"},{"author_name":"Caleb Weinreb","author_inst":"Department of Neurobiology, Harvard Medical School"},{"author_name":"Simon Ogundare","author_inst":"Zuckerman Mind Brain Behavior Institute; Department of Biological Sciences and Howard Hughes Medical Institute, Columbia University"},{"author_name":"William Foster","author_inst":"Zuckerman Mind Brain Behavior Institute; Department of Biological Sciences and Howard Hughes Medical Institute, Columbia University"},{"author_name":"Yu-Young Wesley Tsai","author_inst":"Zuckerman Mind Brain Behavior Institute; Department of Biological Sciences and Howard Hughes Medical Institute, Columbia University"},{"author_name":"Jerry Lyu","author_inst":"Zuckerman Mind Brain Behavior Institute; Department of Biological Sciences and Howard Hughes Medical Institute, Columbia University"},{"author_name":"Mayssam Mohamed","author_inst":"Zuckerman Mind Brain Behavior Institute; Department of Biological Sciences and Howard Hughes Medical Institute, Columbia University"},{"author_name":"Phalaen Chang","author_inst":"Zuckerman Mind Brain Behavior Institute; Department of Biological Sciences and Howard Hughes Medical Institute, Columbia University"},{"author_name":"Amanda Arnold","author_inst":"Zuckerman Mind Brain Behavior Institute; Department of Biological Sciences and Howard Hughes Medical Institute, Columbia University"},{"author_name":"Evan Schaffer","author_inst":"Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai"},{"author_name":"Kanaka Rajan","author_inst":"Department of Neurobiology, Harvard Medical School; Kempner Institute for the Study of Natural and Artificial Intelligence, Harvard University"},{"author_name":"Sandeep Robert Datta","author_inst":"Department of Neurobiology, Harvard Medical School"},{"author_name":"Ishmail Abdus-Saboor","author_inst":"Zuckerman Mind Brain Behavior Institute; Department of Biological Sciences and Howard Hughes Medical Institute, Columbia University"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"ALS\/FTD-linked TDP-43 alterations prevent HSV-1 infection by disrupting cell-adhesion pathways","rel_doi":"10.64898\/2026.09.28.755069","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.28.755069","rel_abs":"TAR DNA-binding protein-43 (TDP-43) alterations are a key hallmark of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative disorders. Increasing evidence links these conditions to viral infections, but it is not known if and how viral pathogens may be affected by disease-associated TDP-43. We found that ALS\/FTD-linked forms of human TDP-43 prevent infection by herpes simplex virus type-1 (HSV-1), a common neurotropic virus. This cell-autonomous protective effect was conserved across different TDP-43 mutations, sporadic ALS, and C9ORF72-ALS, in neural and non-neural cell types, and in patient-derived cells and animal models. In addition to restricting infection, TDP-43 mutation prevented inflammatory and cell stress-related responses to HSV-1 exposure. TDP-43 knockdown but not overexpression was sufficient to protect cells from HSV-1 infection, implicating a loss-of-function mechanism. Neurons with TDP-43 mutation had disruptions in adhesion-related pathways and, accordingly, had reduced early-stage viral binding and entry. Further analyses revealed alternative RNA splicing and impairment of focal adhesion kinase (FAK\/PTK2), a key mediator of cell-adhesion pathways. Inhibition of FAK was sufficient to decrease HSV-1 infection, and genetic enhancement of functional but not inactive FAK promoted infectivity in cells with TDP-43 mutation. Together, these data indicate that TDP-43 affects virus-host interactions by influencing adhesion pathways required for viral infection.","rel_num_authors":12,"rel_authors":[{"author_name":"Stephanie Jackvony Infurna","author_inst":"Weill Cornell Medicine"},{"author_name":"Laraib Ijaz","author_inst":"Weill Cornell Medicine"},{"author_name":"Evelyn J Hardin","author_inst":"Weill Cornell Medicine"},{"author_name":"Abulimiti Aikedan","author_inst":"Weill Cornell Medicine"},{"author_name":"Constance Zhou","author_inst":"Weill Cornell Medicine"},{"author_name":"Tejabhiram Yadavalli","author_inst":"University of Illinois Chicago"},{"author_name":"Minwoo Wendy Jang","author_inst":"Weill Cornell Medicine"},{"author_name":"Matthew Mahoney","author_inst":"Weill Cornell Medicine"},{"author_name":"Li Gan","author_inst":"Weill Cornell Cornell"},{"author_name":"Deepak Shukla","author_inst":"University of Illinois Chicago"},{"author_name":"Adam L Orr","author_inst":"Weill Cornell Medicine"},{"author_name":"Anna G Orr","author_inst":"Weill Cornell Medicine"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Efficacy profiling of structurally diverse cannabinoid receptor ligands across transducer-coupling assays","rel_doi":"10.64898\/2026.09.27.754774","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.27.754774","rel_abs":"The full efficacy range of ligands at CB1 and CB2 (i.e., inverse agonists, neutral agonists, partial agonists, full agonists, and high-efficacy agonists) has been reported collectively across numerous laboratories and assay platforms. Canonical Gi\/o and {beta}-arrestin signaling have each been suggested to shape physiological effects differently via different classes of cannabinoid ligands. These prior efficacy classifications, however, were obtained in multiple assay systems, often using indirect, amplified readouts and different reference agonists, making them difficult to compare across ligands. Here we profiled a structurally diverse panel of 22 cannabinoid ligands: synthetic cannabinoid receptor agonists (SCRAs), {Delta}-tetrahydrocannabinol ({Delta}-THC) analogues, endocannabinoid analogues, and antagonists\/inverse agonists at CB1 and CB2 receptors using bioluminescence resonance energy transfer (BRET) assays, measuring Gi1 engagement and {beta}-arrestin 2 recruitment and normalizing every response to the reference full agonist CP55,940. At CB1, SCRAs and {Delta}-THC analogues acted as high-efficacy agonists. At CB1, these high-efficacy agonists were also highly efficacious in {beta}-arrestin 2 recruitment. Across the panel, the most consistent trend was a loss of agonist efficacy from CB1 to CB2. Among antagonists, inverse agonists suppressed constitutive CB1 activity more than neutral antagonists. Together, these CP55,940-normalized measurements provide a common efficacy scale and a framework for interpreting pharmacodynamics of CB1 and CB2 cannabinoid receptors.","rel_num_authors":12,"rel_authors":[{"author_name":"Soo Jung Oh","author_inst":"Northeastern University"},{"author_name":"Christopher Lucaj","author_inst":"Northeastern University"},{"author_name":"Kiera Truong","author_inst":"Northeastern University"},{"author_name":"Ruiru Guo","author_inst":"Northeastern University"},{"author_name":"Hayato Umaoka","author_inst":"Northeastern University"},{"author_name":"Christos Iliopoulos-Tsoutsouvas","author_inst":"Northeastern University"},{"author_name":"Maria Gerasi","author_inst":"Northeastern University"},{"author_name":"Markos-Orestis Georgiadis","author_inst":"Northeastern University"},{"author_name":"Lipin Ji","author_inst":"Northeastern University"},{"author_name":"Spyros P Nikas","author_inst":"Northeastern University"},{"author_name":"Alexandros Makriyannis","author_inst":"Northeastern University"},{"author_name":"Hideaki Yano","author_inst":"Northeastern University"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"GGE: General-purpose deep meta-learning for classification of human transcriptomes with limited data","rel_doi":"10.64898\/2026.09.27.754054","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.27.754054","rel_abs":"Transcriptomic classification is often hindered by the small number of samples relative to the high dimensionality of gene expression data. We introduce General Gene Expression (GGE), a deep meta-learning framework designed to support robust classification in this limited-sample setting. By training across 5,220 distinct biomedical prediction objectives drawn from 1,779 different human datasets, GGE learns a model initialization that captures biological patterns shared across heterogeneous classification tasks. This learned initialization has two key advantages. First, it enables improved performance to new datasets using only a small number of labeled samples. Second, because it is learned across diverse prediction objectives, it can be applied to a broad range of biomedical problems. We show that GGE outperforms established classifiers in data-limited settings across a wide range of applications, including datasets generated using different RNA-seq platforms and preprocessing pipelines. In addition, attention-based analysis identifies recurrent genes that contribute to performance across multiple biological objectives, providing insight into shared determinants of human biological states. Together, these results establish GGE is a general-purpose framework for human transcriptome-based classification in biomedical settings where labeled data are scarce.","rel_num_authors":2,"rel_authors":[{"author_name":"Gal Yankovitz","author_inst":"Tel-Aviv University"},{"author_name":"Irit Gat-Viks","author_inst":"Tel-Aviv University"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"X-Y divergence of house fly (Musca domestica) proto-sex chromosomes follows distinct evolutionary trajectories despite residing in the same genome","rel_doi":"10.64898\/2026.09.26.754726","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.26.754726","rel_abs":"Sex determination systems and sex chromosomes frequently differ between species. One cause of these differences is new sex determining genes that drive evolutionary turnover of sex chromosomes. At the earliest stages of this turnover, X and Y (or Z and W) chromosomes start out as nearly identical homologs, and they can diverge via chromosomal rearrangements (e.g., inversions) that suppress X-Y recombination. However, multiple examples from across animals and plants provide exceptions to this canonical model of sex chromosome evolution. For example, some X-Y pairs remain undifferentiated for long evolutionary time periods, while other sex chromosomes become differentiated without chromosomal rearrangements. How or why these non-canonical trajectories occur remains elusive, despite increasing evidence of their pervasiveness. The house fly, Musca domestica, is a well-suited system to address this gap because all six chromosomes can be a Y, providing multiple replicates of a natural experiment within a single genomic environment. To test for canonical and non-canonical evolutionary trajectories, we generated haplotype-resolved chromosome-level assemblies from five strains of the house fly, each of which carries a different Y chromosome (IM, IIM, IIIM, VM, and YM). We identified an inversion on only one of the sex chromosomes (IIM), which was associated with elevated X-Y divergence but did not capture the male-determining locus. In contrast, there was X-Y divergence across almost the entire length of the IM, IIIM, and VM sex chromosomes, despite no detectable inversions. YM was the only sex chromosome to contain substantial Y-specific sequences, which were limited to a segment on one end of the chromosome containing the male-determining gene. This YM chromosome, and its corresponding X, were highly diverged from the X chromosome found in many other flies (Muller element F), despite a strong cytological resemblance. This study highlights how multiple different canonical and non-canonical modes of sex chromosome evolution can co-exist within a single genome.","rel_num_authors":10,"rel_authors":[{"author_name":"Jae Hak Son","author_inst":"Department of Genetics, Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, USA"},{"author_name":"David Luecke","author_inst":"USDA Agricultural Research Service, Veterinary Pest Genetics Research Unit, Kerrville, TX, USA"},{"author_name":"Basanta Bista","author_inst":"Department of Biology and Biochemistry, University of Houston, Houston, TX, USA"},{"author_name":"Yesbol Manat","author_inst":"Department of Biology and Biochemistry, University of Houston, Houston, TX, USA"},{"author_name":"Weihuan Cao","author_inst":"Department of Genetics, Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, USA"},{"author_name":"Leo Beukeboom","author_inst":"Groningen Institute for Evolutionary Life Sciences, University of Groningen, The Netherlands"},{"author_name":"Daniel Bopp","author_inst":"Institute of Molecular Life Sciences, University of Zurich, Switzerland"},{"author_name":"Christopher E Ellison","author_inst":"Department of Genetics, Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ, USA"},{"author_name":"Perot Saelao","author_inst":"USDA Agricultural Research Service, Veterinary Pest Genetics Research Unit, Kerrville, TX, USA"},{"author_name":"Richard P Meisel","author_inst":"Department of Biology and Biochemistry, University of Houston, Houston, TX, USA"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Method-dependent biases in cell type detection between single-cell and single-nucleus RNA sequencing in the photosymbiotic acoel Praesagittifera naikaiensis","rel_doi":"10.64898\/2026.09.27.754747","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.27.754747","rel_abs":"Background Comparisons of single-cell and single-nucleus RNA sequencing (scRNA-seq and snRNA-seq) data have been described in some mammalian tissues and, subsequently, in Drosophila, but remain unexplored in most invertebrate lineages. The xenacoelomorphs occupy key phylogenetic positions, yet they differ anatomically from mammals. They have a reduced extracellular matrix, high-salt body fluid, and no circulatory system. Despite these differences, they possess a well-developed nervous system. One of the xenacoelomorphs, the photosymbiotic acoel (Praesagittifera naikaiensis) also harbours symbiotic Tetraselmis algae, whose RNA can be co-captured with host RNA. Results We compared scRNA-seq and snRNA-seq data from whole P. naikaiensis specimens. Both methods yielded high-quality data with comparable gene detection but a larger share of scRNA-seq reads derived from symbiotic algae. Gene-level analyses revealed that neural genes were enriched in snRNA-seq relative to non-neural genes. Cross-method label transfer and integration-based validation identified six snRNA-seq clusters, including some neural populations, that lacked a clear scRNA-seq counterpart. In contrast, three cell populations, including muscle and metabolically active clusters, were reciprocally validated as captured by both methods. Conclusions Our results show that key snRNA-seq advantages, particularly the enhanced recovery of neural transcripts, are recapitulated in our dataset, which is consistent with previous reports in mammals. Furthermore, snRNA-seq reduces symbiont-derived reads and recovers several cell populations underrepresented in scRNA-seq. These findings provide practical guidance for cell atlas construction in non-model, symbiotic invertebrates.","rel_num_authors":10,"rel_authors":[{"author_name":"Ryo Nakamura","author_inst":"Okayama University"},{"author_name":"Mayuko Hamada","author_inst":"Okayama University"},{"author_name":"Kenji Kobayashi","author_inst":"Kyoto University"},{"author_name":"Satoshi Ansai","author_inst":"Okayama University"},{"author_name":"Mirco Dindo","author_inst":"University of Perugia"},{"author_name":"Tosuke Sakagami","author_inst":"Academia Sinica"},{"author_name":"Yi-Jyun Luo","author_inst":"Academia Sinica"},{"author_name":"Yutaka Satou","author_inst":"Kyoto University"},{"author_name":"Toshio Sekiguchi","author_inst":"Kanazawa University"},{"author_name":"Tatsuya Sakamoto","author_inst":"Okayama University"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Folate metabolism in tumor-associated macrophages drives immunosuppressive function to promote tumor growth","rel_doi":"10.64898\/2026.09.29.755523","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.29.755523","rel_abs":"Tumor-associated macrophages (TAMs) promote tumor growth, inhibit effector lymphocytes, and induce resistance to immune checkpoint inhibitors (ICI). Therapies designed to deplete TAMs have had little success in the clinic, and strategies aimed to repolarize immunosuppressive TAMs to pro-inflammatory states have struggled with systemic toxicity. We have identified that the combination of low folate in the tumor microenvironment and TAM dependency on the high affinity folate receptor beta (FR{beta}) for folate uptake results in a unique metabolic dependency of TAMs necessary for their immunosuppressive function. FR{beta} (encoded by Folr2) is uniquely expressed on myeloid cells and upregulated on TAMs. FR{beta}+ TAMs exhibit an immunosuppressive phenotype in melanoma and are associated with worse clinical outcomes and resistance to ICI in melanoma patients. We generated a novel Folr2-\/- mouse model to study why TAMs express a unique folate receptor and showed that tumor growth was slowed in the absence of Folr2 in a T-cell dependent manner. We observed a dramatic repolarization of Folr2-\/- TAMs in vivo to pro-inflammatory states, resulting in increased cytotoxic T cell and NK cell infiltration into tumors. Importantly, we show that folate is low in the tumor microenvironment by performing metabolomics on melanoma tumors and adjacent normal tissue from warm autopsy patient specimens, and that we could increase tumor growth in Folr2-\/- mice by increasing serum folate to supraphysiologic concentrations with a high folate diet. Integrated metabolomics and transcriptomic analysis demonstrated that Folr2-\/- macrophages have impaired folate uptake and 1C metabolism-based reduction of oxidized glutathione in low folate conditions, resulting in increased mitochondrial reactive oxygen species (ROS) in Folr2-\/- cells. Excess ROS results in leakage of mitochondrial DNA into the cytoplasm, activating cGAS-STING signaling and promoting pro-inflammatory macrophage polarization through TBK1 and NF-kB. Together, our data demonstrate that TAM expression of FR{beta} promotes their immunosuppressive functions by maintaining folate uptake in the low folate tumor microenvironment, suggesting that FR{beta} is a novel metabolic checkpoint on TAMs.","rel_num_authors":31,"rel_authors":[{"author_name":"Matthew P Zimmerman","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Vasyl Zhabotynsky","author_inst":"University of North Carolina"},{"author_name":"Haiyang Wang","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Emily K Cox","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Wan Lin Chong","author_inst":"UNC Chapel Hill"},{"author_name":"Alexander G. Bastian","author_inst":"High Point University"},{"author_name":"Andrew S. Kennedy","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Brian P. Fay","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Amy G. Reynolds","author_inst":"University of North Carolina at Chapel Hil"},{"author_name":"Anna Ebacher","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Jeremy A. Meier","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Katherine Vietor","author_inst":"Carbone Cancer Center, University of Wisconsin at Madison, Madison, WI and Cancer Biology Graduate Program, University of Wisconsin at Madison, Madison, WI, USA"},{"author_name":"Khalilah E. Taylor","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Pristine C. Onuoha","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Siddharth Maruvada","author_inst":"North Carolina State University"},{"author_name":"Katie E. Hurst","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Christopher Wong","author_inst":"University of California, Los Angeles"},{"author_name":"Carlton W. Anderson","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Nancy E. Thomas","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Rihe Liu","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Kirsten L. Bryant","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Albert S. Baldwin","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"David W. Ollila","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Jenny P-Y Ting","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Blake R. Rushing","author_inst":"University of North Carolina at Chapel Hill Gillings School of Global Public Health"},{"author_name":"Susan J. Sumner","author_inst":"University of North Carolina at Chapel Hill Gillings School of Global Public Health"},{"author_name":"Sergey A. Krupenko","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"WILLY HUGO","author_inst":"UCLA"},{"author_name":"Stergios J. Moschos","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Jessica E. Thaxton","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Brian C Miller","author_inst":"University of North Carolina at Chapel Hill"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"A kinetic-aware approach to infer metabolic variations and flux using transcriptomics and metabolomics data","rel_doi":"10.64898\/2026.09.27.754711","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.27.754711","rel_abs":"Assessing metabolic variations and flux quantities enable systematic understandings of metabolic shifts, reprogramming, adaptation and interactions in human diseases. However, omics-based estimation of metabolic flux and its variation remains challenging due to several fundamental limitations: the need for disease and tissue context specific metabolic model; nonlinear enzyme kinetic model that links enzyme and substrate changes to reaction flux; partial, unpaired, and snap-shot measurements across omics modalities; and uncertainty in computational prediction. Here, we present Michaelis-Menten model-based Flux Estimation Analysis (mmFEA), a Monte Carlo framework for estimating condition-specific flux changes by integrating paired or unpaired metabolomics and transcriptomics (or proteomics) data. mmFEA separates each reaction-rate change into enzyme- and substrate-associated components and assess reaction rate using Michaelis-Menten kinetics equation. A baseline metabolite saturation rate is introduced by integrating protein language model predicted kinetic parameters and human baseline level metabolic concentration to enable kinetic-aware integration of unpaired substrate and enzyme level measurements. Distribution of metabolic flux and variations between conditions are further computed using MCMC sampling by treating Michaelis-Menten-derived marginal flux distribution as prior and coherency in flux balance as likelihood. To benchmark mmFEA, we generated an in-house multi-omics data set including transcriptomics, metabolomics, metabolic activity functional assay, and CRISPR screening data using pancreatic cancer cell line system treated by APEX1 inhibitors. We demonstrated that mmFEA could accurately capture experimentally observed metabolic changes and achieved a better performance than all baseline methods. Our analysis revealed the necessity in using both substrate and enzyme modality and kinetic aware model in metabolic flux assessment. Further analysis using independent pancreatic cancer cohorts further validated the robustness of mmFEA, supporting integration of condition-linked unpaired data. Pan-cancer and spatial multi-omic applications demonstrated the use of mmFEA for resolving context-dependent metabolic variation when direct flux measurements are unavailable. Together, mmFEA provides a mechanistically grounded framework for estimating relative metabolic flux changes and their uncertainty from heterogeneous omics data.","rel_num_authors":17,"rel_authors":[{"author_name":"Haiqi Zhu","author_inst":"Department of Computer Science, Luddy School of Informatics, Computing, and Engineering, Indiana University Bloomington, Bloomington, IN 47408, USA"},{"author_name":"Changlin Wan","author_inst":"Department of Biomedical Engineering, Center for Biomedical Data Sciences, Knight Cancer Institute, and Brenden-Colson Center for Pancreatic Care, Oregon Health"},{"author_name":"Min Yang","author_inst":"Department of Biomedical Engineering, Center for Biomedical Data Sciences, Knight Cancer Institute, and Brenden-Colson Center for Pancreatic Care, Oregon Health"},{"author_name":"Yue Fang","author_inst":"Department of Biomedical Engineering, Center for Biomedical Data Sciences, Knight Cancer Institute, and Brenden-Colson Center for Pancreatic Care, Oregon Health"},{"author_name":"Zheng An","author_inst":"Department of Biomedical Engineering, Center for Biomedical Data Sciences, Knight Cancer Institute, and Brenden-Colson Center for Pancreatic Care, Oregon Health"},{"author_name":"Paveethran Swaminathan","author_inst":"Department of Biomedical Engineering, Center for Biomedical Data Sciences, Knight Cancer Institute, and Brenden-Colson Center for Pancreatic Care, Oregon Health"},{"author_name":"Pengtao Dang","author_inst":"Department of Biomedical Engineering, Center for Biomedical Data Sciences, Knight Cancer Institute, and Brenden-Colson Center for Pancreatic Care, Oregon Health"},{"author_name":"Zhi Li","author_inst":"Department of Biomedical Engineering, Center for Biomedical Data Sciences, Knight Cancer Institute, and Brenden-Colson Center for Pancreatic Care, Oregon Health"},{"author_name":"Jia Wang","author_inst":"Department of Computer Science, Luddy School of Informatics, Computing, and Engineering, Indiana University Bloomington, Bloomington, IN 47408, USA"},{"author_name":"Yijie Wang","author_inst":"Department of Computer Science, Luddy School of Informatics, Computing, and Engineering, Indiana University Bloomington, Bloomington, IN 47408, USA"},{"author_name":"Yabing Chen","author_inst":"Department of Pathology and Laboratory Medicine, School of Medicine, Oregon Health & Science University, Portland, OR 97239, USA"},{"author_name":"Anjun Ma","author_inst":"Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA"},{"author_name":"Qin Ma","author_inst":"Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA"},{"author_name":"Mark R. Kelley","author_inst":"Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Indiana Universit"},{"author_name":"Sha Cao","author_inst":"Department of Biomedical Engineering, Center for Biomedical Data Sciences, Knight Cancer Institute, and Brenden-Colson Center for Pancreatic Care, Oregon Health"},{"author_name":"Melissa L. Fishel","author_inst":"Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Indiana Universit"},{"author_name":"Chi Zhang","author_inst":"Department of Biomedical Engineering, Center for Biomedical Data Sciences, Knight Cancer Institute, and Brenden-Colson Center for Pancreatic Care, Oregon Health"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"A Natural qE- and qZ-Deficient Alga Retains Functional Plant-Like and Chlorophycean Violaxanthin De-Epoxidases","rel_doi":"10.64898\/2026.09.26.754548","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.26.754548","rel_abs":"Photosynthetic organisms protect themselves from excess light through non-photochemical quenching (NPQ), a process that safely dissipates excess light energy as heat. Current understanding of NPQ is largely drawn from a few model systems, leaving it unclear how universal NPQ mechanisms are across the green lineage. We characterize the slow, sustained NPQ of the green alga, Auxenochlorella protothecoides x symbiontica (UTEX 250-A). The Auxenochlorella genome lacks Light-Harvesting Complex Stress Related (LHCSR), one of the two proteins required for the fast energy-dependent quenching (qE) component of NPQ. Mutants lacking the Photosystem II Subunit S (PSBS)-like gene (psbsl1) in Auxenochlorella had no effect on NPQ, indicating this alga lacks canonical qE. We identified two candidate enzymes associated with zeaxanthin-dependent quenching (qZ), which has slower kinetics: a plant-type Violaxanthin De-Epoxidase (VDE) and an algal-type Chlorophycean Violaxanthin De-Epoxidase (CVDE). High light did not trigger the expected conversion of violaxanthin to zeaxanthin, a pigment change that is a hallmark of qZ. Mutants lacking VDE (vde1), CVDE (cvde1), or both enzymes (vde1 cvde1) still displayed slow, reversible NPQ. However, when the Auxenochlorella VDE1 and CVDE1 were expressed in a VDE-deficient mutant of Nicotiana benthamiana, both enzymes restored zeaxanthin production and NPQ, confirming they are catalytically functional de-epoxidases. Together, these results reveal an alga that retains two functional, evolutionarily distinct xanthophyll-cycle enzymes yet does not rely on typical xanthophyll pigment dynamics for photoprotection. This points to a biological function that is decoupled from de-epoxidase activity, highlighting unexplored diversity in green algal photoprotection.","rel_num_authors":11,"rel_authors":[{"author_name":"Karina W Cunningham","author_inst":"University of California, Berkeley"},{"author_name":"Setsuko Wakao","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Johanna L Hall","author_inst":"University of California, Berkeley"},{"author_name":"Crysten Blaby-Haas","author_inst":"Lawrence Berkeley National Laboratory"},{"author_name":"Rituparna Ivatury","author_inst":"University of California, Berkeley"},{"author_name":"Lucy Gleeson","author_inst":"University of California, Berkeley"},{"author_name":"Derrick Chuang","author_inst":"University of California, Berkeley"},{"author_name":"Jane J Kim","author_inst":"University of California, Berkeley"},{"author_name":"Jeffrey L Moseley","author_inst":"University of California, Berkeley"},{"author_name":"Graham R Fleming","author_inst":"University of California, Berkeley"},{"author_name":"Krishna K. Niyogi","author_inst":"HHMI, University of California"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Corallimorpharian genome supports the monophyly of Scleractinia and illuminates the cellular evolution of coral calcification","rel_doi":"10.64898\/2026.09.25.754439","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.25.754439","rel_abs":"The production of calcified skeletons by stony corals is the cornerstone of reef ecosystems and the persistence of marine biodiversity. Corallimorpharians, sometimes described as naked corals, resemble stony corals in many respects but lack hardened skeletons. However, whether they are stony corals that secondarily lost their skeletons has been a subject of much debate. Here, we present a chromosome-level genome of the corallimorpharian Ricordea yuma and show that macrosynteny and microsynteny analyses provide strong support for corallimorpharians as the sister group to stony corals. This phylogenetic placement indicates that corallimorpharians were not ancestrally skeletonized and therefore occupy a critical outgroup position for reconstructing the origin of coral calcification. Guided by this phylogenetic context, we sequenced whole-polyp single-cell transcriptomes from R. yuma and the complex coral Galaxea fascicularis and found that the scleractinian skeleton evolved through the emergence of a derived calicoblast cell state in stony corals. A combination of comparative genomics and regeneration experiments in G. fascicularis show that the emergence of the calicoblast cell state was accompanied by the evolution of a biomineralization toolkit assembled from lineage-specific innovations and co-opted ancestral components. Although corallimorpharians retain some ancestral genes later incorporated into coral biomineralization, they lack a detectable calicoblast-like transcriptional state and many core calcification genes. Together, our findings indicate that coral calcification arose through coordinated changes in genome architecture, gene repertoire, and cell identity, highlighting this process as a major evolutionary transition driven by the integration of genomic and cellular innovations.","rel_num_authors":15,"rel_authors":[{"author_name":"Thomas D. Lewin","author_inst":"Academia Sinica"},{"author_name":"Tosuke Sakagami","author_inst":"Academia Sinica"},{"author_name":"Victor M. Pinon-Gonzalez","author_inst":"Academia Sinica"},{"author_name":"Yuki Yoshioka","author_inst":"Academia Sinica"},{"author_name":"Li-Jung Kao","author_inst":"Academia Sinica"},{"author_name":"Yi-Ling Chiu","author_inst":"Academia Sinica"},{"author_name":"Kohsei Sasaki","author_inst":"National Taiwan Ocean University"},{"author_name":"Yi-Hua Chen","author_inst":"Academia Sinica"},{"author_name":"Jeng-Yi Li","author_inst":"Academia Sinica"},{"author_name":"Kai-Xuan Tin","author_inst":"Academia Sinica"},{"author_name":"Mei-Yeh Jade Lu","author_inst":"Academia Sinica"},{"author_name":"David J. Miller","author_inst":"James Cook University"},{"author_name":"Shinya Shikina","author_inst":"National Taiwan Ocean University"},{"author_name":"Mei-Fang Lin","author_inst":"National Sun Yat-sen University"},{"author_name":"Yi-Jyun Luo","author_inst":"Academia Sinica"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Engineered CTLA-4 targeting chimeras for targeted protein degradation and immune synapse reprogramming","rel_doi":"10.64898\/2026.09.29.755403","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.29.755403","rel_abs":"Despite the success of immune checkpoint blockade in cancer therapy, overcoming the immunosuppressive tumor microenvironment remains a major barrier to durable responses. Here, we introduce cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4)-targeting chimeras (cTACs), a class of synthetic molecules that harness CTLA-4-mediated trans-endocytosis (TE) for targeted protein degradation across cellular boundaries. The lead candidate, cTAC4.0, is composed of the extracellular domain of CD80 fused to an anti-programmed death-ligand 1 (PD-L1) fragment via a human immunoglobulin G4 (IgG4) heavy chain. Unlike existing protein degraders that function within cancer cells via house-keeping pathways, cTAC4.0 operates in trans between immune and tumor cells. It redirects the natural CD80-CTLA-4 internalization to capture and degrade PD-L1 from tumor cells into T cells, while simultaneously converting PD-L1-mediated suppression into CD28-driven co-stimulation, depending on the relative availability of CTLA-4 or CD28. Mechanistically, we demonstrate that cTAC4.0 promotes CTLA-4-dependent internalization and lysosomal degradation of both membrane-bound and soluble PD-L1, reduces surface PD-L1 levels on target cells, and activates T cells in a CD28-dependent manner. Functionally, cTAC4.0 enhances the cytotoxicity of both bispecific T cell engagers and T cell receptor (TCR)-engineered T cells in vitro, and when combined with these engineered T cells, it suppresses tumor growth in vivo in a glioblastoma xenograft model. By coupling immune checkpoint degradation with T cell activation in an immune synapse-enriched manner, cTACs establish a paradigm for intercellular protein degradation systems that simultaneously deplete suppressive ligands and enhance T cell function to overcome resistance in cancer immunotherapy.","rel_num_authors":13,"rel_authors":[{"author_name":"Ping Ren","author_inst":"1.\tDepartment of Genetics, Yale University School of Medicine, New Haven, CT, USA 2.\tSystem Biology Institute, Yale University, West Haven, CT, USA 3.\tCenter fo"},{"author_name":"Shao-Yu Fang","author_inst":"1.\tDepartment of Genetics, Yale University School of Medicine, New Haven, CT, USA 2.\tSystem Biology Institute, Yale University, West Haven, CT, USA 3.\tCenter fo"},{"author_name":"Shushu Zhao","author_inst":"11.\tVaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, USA 12.\tEllen and Ronald Caplan Cancer Center, The Wistar Institute, Philadelphia,"},{"author_name":"Hanbing Cao","author_inst":"1.\tDepartment of Genetics, Yale University School of Medicine, New Haven, CT, USA 2.\tSystem Biology Institute, Yale University, West Haven, CT, USA 3.\tCenter fo"},{"author_name":"Kaiyuan Tang","author_inst":"1.\tDepartment of Genetics, Yale University School of Medicine, New Haven, CT, USA 2.\tSystem Biology Institute, Yale University, West Haven, CT, USA 3.\tCenter fo"},{"author_name":"Xingbo Shang","author_inst":"2.\tSystem Biology Institute, Yale University, West Haven, CT, USA 3.\tCenter for Cancer Systems Biology, Yale University, West Haven, CT, USA 7.\tDepartment of Bi"},{"author_name":"Cole W. Christopher","author_inst":"11.\tVaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, USA 12.\tEllen and Ronald Caplan Cancer Center, The Wistar Institute, Philadelphia,"},{"author_name":"Yunfei Jiao","author_inst":"11.\tVaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, USA 12.\tEllen and Ronald Caplan Cancer Center, The Wistar Institute, Philadelphia,"},{"author_name":"Medha Majety","author_inst":"1.\tDepartment of Genetics, Yale University School of Medicine, New Haven, CT, USA 2.\tSystem Biology Institute, Yale University, West Haven, CT, USA 3.\tCenter fo"},{"author_name":"Andre Levchenko","author_inst":"2.\tSystem Biology Institute, Yale University, West Haven, CT, USA 3.\tCenter for Cancer Systems Biology, Yale University, West Haven, CT, USA 7.\tDepartment of Bi"},{"author_name":"David B. Weiner","author_inst":"11.\tVaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, USA 12.\tEllen and Ronald Caplan Cancer Center, The Wistar Institute, Philadelphia,"},{"author_name":"Sidi Chen","author_inst":"1.\tDepartment of Genetics, Yale University School of Medicine, New Haven, CT, USA 2.\tSystem Biology Institute, Yale University, West Haven, CT, USA 3.\tCenter fo"},{"author_name":"Xiaoyu Zhou","author_inst":"11.\tVaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, USA 12.\tEllen and Ronald Caplan Cancer Center, The Wistar Institute, Philadelphia,"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Evidence Accumulation in Synaptic Efficacy: Activity-Silent Decision-Making with Short-Term Plasticity","rel_doi":"10.64898\/2026.09.27.754756","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.27.754756","rel_abs":"Decision-making requires accumulation of evidence over time, yet exactly how neural circuits implement this computation remains debated. Classical models posit that evidence accumulation is realized by ramping neural activity, whereas recent experimental findings suggest an alternative mechanism in which neural activity remains largely silent before abruptly transitioning into an active decision state. This mechanism leaves a fundamental question unanswered: how is evidence accumulated during the neural activity-silent period? To address this question, we trained excitatory-inhibitory recurrent neural networks (RNNs) with short-term synaptic plasticity (STP) on a reaction-time decision task. We found that after training, the networks learned to leverage STP to make decisions in an activity-silent manner. Choice-tuning analysis revealed a clear functional organization of the network, and connection-pruning analysis uncovered the coupling between choice-selective excitatory and inhibitory neural groups. Guided by the architecture of trained RNNs, we constructed a minimal neural circuit model, in which evidence accumulates in facilitated synaptic efficacy that progressively reshapes the circuit's phase portrait, eventually driving the network state across the stability boundary and triggering a rapid transition to a choice state. We further compared activity before a choice between the theoretical STP and Static models to examine the potential energy benefit of activity-silent decision-making. Together, our results suggest STP as a mechanism for evidence accumulation in activity-silent decision-making and offer insights into the design of energy-efficient artificial neural networks.","rel_num_authors":5,"rel_authors":[{"author_name":"Tianhao Chu","author_inst":"School of Psychological and Cognitive Sciences, Peking University, China."},{"author_name":"Yuling Wu","author_inst":"Peking University"},{"author_name":"Chenhao Zhang","author_inst":"Peking University"},{"author_name":"Fang Fang","author_inst":"Peking University"},{"author_name":"Si Wu","author_inst":"Peking University"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Distinct population dimensions separate sensory adaptation and expectation-related signals in visual cortex","rel_doi":"10.64898\/2026.09.30.755465","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.30.755465","rel_abs":"Mismatch negativity is conventionally quantified as a scalar response-amplitude difference between rare deviant and repeated standard stimuli, leaving its organization at the neuronal population level unresolved. We recorded population activity in mouse primary visual cortex (V1) during visual oddball and control paradigms while testing contributions from anterior cingulate cortex (ACC) input using optogenetic inhibition. Mismatch modulated firing rates bidirectionally and these changes largely canceled out on average, yet produced robustly separable population activity patterns. On the stimulus-encoding manifold, repeated standard exposure produced standard-specific response attenuation and a shared rotation of standard and deviant representations, revealing a component not isolated by conventional stimulus-specific adaptation and deviance-detection contrasts. Off the manifold, standards and deviants occupied opposing positions along an ACC-modulated axis consistent with expectation confirmation and violation. Thus, visual mismatch responses engage separable transformations of stimulus representations and expectation-related population activity, with ACC input selectively contributing to the latter while not significantly affecting stimulus encoding or on-manifold adaptation.","rel_num_authors":4,"rel_authors":[{"author_name":"Soyoun Kim","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Arenski Vazquez","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Renata Batista-Brito","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Lucas Sjulson","author_inst":"Albert Einstein College of Medicine"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Programming primary human T cells to deliver gene editing machinery","rel_doi":"10.64898\/2026.09.30.753584","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.30.753584","rel_abs":"Clinical applications of gene editors including CRISPR-Cas9 are limited by the cell-type specificity and tissue penetrance of current in vivo delivery options. Cell-mediated gene editor delivery could overcome these obstacles. To date, systems utilizing immortalized cell lines have demonstrated gene editor delivery in vitro. Because T cells traffic throughout the organism and engage in intercellular communication with individual target cells, we wondered whether they could be engineered to deliver gene editing machinery. Here, we demonstrate that primary human T cells can produce retroviral-based enveloped delivery vehicles (EDVs) packaging functional Cas9 ribonucleoproteins. When paired with fusogenic VSV-G, T cell-generated Cas9-EDVs edited a diverse array of target cells. We developed a miniaturized Moloney murine leukemia virus-based system that proved superior to existing architectures in this context and optimized both lentiviral and site-specific knock-in approaches for T cell engineering. These Enveloped Particle Information Courier- (EPIC-) T cells offer key advantages as delivery systems.","rel_num_authors":5,"rel_authors":[{"author_name":"James Meixiong","author_inst":"University of California, San Francisco"},{"author_name":"Oleksandr Zginnyk","author_inst":"University of California, San Francisco"},{"author_name":"Lauren Chow","author_inst":"University of California, San Francisco"},{"author_name":"Brian R Shy","author_inst":"University of California, San Francisco"},{"author_name":"Matthew H. Spitzer","author_inst":"University of California, San Francisco"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Hyperexcitable but seizure-free: hippocampal network dysfunction in a Wolfram syndrome model","rel_doi":"10.64898\/2026.09.27.754840","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.27.754840","rel_abs":"Wolfram syndrome (WS) is a rare, life-limiting progressive neurodegenerative disorder caused by pathogenic variants in the WFS1 gene. It is a prototype endoplasmic reticulum (ER) stress disorder, and the mechanisms underlying neurological phenotypes in WS remain incompletely understood. Although WFS1 protein is abundant in the hippocampus, the role of this region in WS remains relatively understudied. Here we characterize hippocampal function across scales in mice carrying a patient orthologous Wfs1 variant (p.W542*) on both alleles. Male mutants lose excitatory synapses, and dissociated hippocampal neurons are markedly hyperexcitable yet generate no increase in network bursting and no shift in network criticality, indicating that their additional firing is not recruited into coordinated population activity. This finding translates in vivo wherein intracranial electroencephalogram (EEG) recordings show no epileptiform activity or seizures in either sex, with no hippocampal astrogliosis, alongside a male-specific reduction in hippocampal low-gamma power. Additionally, EEG demonstrates a sex-specific disruption of sleep, which parallels a sex-divergent synaptic phenotype. Mutant male mice show impaired hippocampus-dependent fear memory and reduced voluntary motor activity. Taken together, we propose that cellular hyperexcitability in the WS hippocampus does not translate into increased network bursting, potentially due to disproportionate loss of excitatory synapses. This dissociation may provide a functional substrate for the neurological features of WS.","rel_num_authors":18,"rel_authors":[{"author_name":"Saumel Ahmadi","author_inst":"Washington University"},{"author_name":"Juan Gallardo Pinera","author_inst":"Washington University"},{"author_name":"Sophie Dokholyan","author_inst":"Washington University"},{"author_name":"Andrew D Sauerbeck","author_inst":"Washington University"},{"author_name":"Hong Nhung Phan","author_inst":"Washington University"},{"author_name":"Brianna Carman","author_inst":"Washington University"},{"author_name":"Avishek Debnath","author_inst":"Washington University"},{"author_name":"Samuel Brunwasser","author_inst":"University of California San Francisco"},{"author_name":"Gabriel Skinner","author_inst":"Washington University"},{"author_name":"Nicholas Rensing","author_inst":"Washington University School of Medicine"},{"author_name":"Michael Wong","author_inst":"Washington University School of Medicine"},{"author_name":"Cory Cearlock","author_inst":"Washington University"},{"author_name":"Susan E Maloney","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Terrance T Kummer","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Srikanth Singamaneni","author_inst":"Washington University in Saint Louis"},{"author_name":"John Cirrito","author_inst":"Washington University"},{"author_name":"Thomas Jonathan Foutz","author_inst":"Washingotn University in St. Louis"},{"author_name":"Fumihiko Urano","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Hyperexcitable but seizure-free: hippocampal network dysfunction in a Wolfram syndrome model","rel_doi":"10.64898\/2026.09.27.754840","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.27.754840","rel_abs":"Wolfram syndrome (WS) is a rare, life-limiting progressive neurodegenerative disorder caused by pathogenic variants in the WFS1 gene. It is a prototype endoplasmic reticulum (ER) stress disorder, and the mechanisms underlying neurological phenotypes in WS remain incompletely understood. Although WFS1 protein is abundant in the hippocampus, the role of this region in WS remains relatively understudied. Here we characterize hippocampal function across scales in mice carrying a patient orthologous Wfs1 variant (p.W542*) on both alleles. Male mutants lose excitatory synapses, and dissociated hippocampal neurons are markedly hyperexcitable yet generate no increase in network bursting and no shift in network criticality, indicating that their additional firing is not recruited into coordinated population activity. This finding translates in vivo wherein intracranial electroencephalogram (EEG) recordings show no epileptiform activity or seizures in either sex, with no hippocampal astrogliosis, alongside a male-specific reduction in hippocampal low-gamma power. Additionally, EEG demonstrates a sex-specific disruption of sleep, which parallels a sex-divergent synaptic phenotype. Mutant male mice show impaired hippocampus-dependent fear memory and reduced voluntary motor activity. Taken together, we propose that cellular hyperexcitability in the WS hippocampus does not translate into increased network bursting, potentially due to disproportionate loss of excitatory synapses. This dissociation may provide a functional substrate for the neurological features of WS.","rel_num_authors":18,"rel_authors":[{"author_name":"Saumel Ahmadi","author_inst":"Washington University"},{"author_name":"Juan Gallardo Pinera","author_inst":"Washington University"},{"author_name":"Sophie Dokholyan","author_inst":"Washington University"},{"author_name":"Andrew D Sauerbeck","author_inst":"Washington University"},{"author_name":"Hong Nhung Phan","author_inst":"Washington University"},{"author_name":"Brianna Carman","author_inst":"Washington University"},{"author_name":"Avishek Debnath","author_inst":"Washington University"},{"author_name":"Samuel Brunwasser","author_inst":"University of California San Francisco"},{"author_name":"Gabriel Skinner","author_inst":"Washington University"},{"author_name":"Nicholas Rensing","author_inst":"Washington University School of Medicine"},{"author_name":"Michael Wong","author_inst":"Washington University School of Medicine"},{"author_name":"Cory Cearlock","author_inst":"Washington University"},{"author_name":"Susan E Maloney","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Terrance T Kummer","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Srikanth Singamaneni","author_inst":"Washington University in Saint Louis"},{"author_name":"John Cirrito","author_inst":"Washington University"},{"author_name":"Thomas Jonathan Foutz","author_inst":"Washingotn University in St. Louis"},{"author_name":"Fumihiko Urano","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Structural streamlining of axonemal doublet microtubules in Plasmodium male gametes","rel_doi":"10.64898\/2026.10.01.755548","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.01.755548","rel_abs":"Male gametogenesis in malaria parasites produces up to eight flagellated gametes within approximately 15 min, requiring de novo construction of motile axonemes on an unusually short timescale. Here we combine cellular cryo-electron tomography, high-resolution cryo-EM, proteomics, and parasite genetics to define the molecular architecture and assembly states of the Plasmodium male gamete axoneme. The doublet microtubules retain the principal surface-associated motility modules but contain a markedly reduced luminal microtubule inner protein network. Their inner junction lacks PACRG and is instead organized by CFAP20 and CFAP52, whose combined loss disrupts doublet integrity and exflagellation. We further identify a calmodulin protein at the outer dynein arm docking region and show that outer dynein arms accumulate progressively during gametogenesis. These findings establish distinct form of axonemal remodeling in Plasmodium and reveal the ordered assembly of structural and motor modules during rapid male gamete formation.","rel_num_authors":12,"rel_authors":[{"author_name":"Zhixun Li","author_inst":"Peking University"},{"author_name":"Shuzhen Yang","author_inst":"Peking University"},{"author_name":"Yujin Huang","author_inst":"Xiamen University"},{"author_name":"Shanshan Ma","author_inst":"Peking University"},{"author_name":"Liping Luo","author_inst":"Peking University"},{"author_name":"Xiaoyang Hou","author_inst":"Xiamen University"},{"author_name":"Kunyue Deng","author_inst":"Peking University"},{"author_name":"Jinhua Wang","author_inst":"Capital Normal University"},{"author_name":"Guanbo Wang","author_inst":"Peking University"},{"author_name":"Miao Gui","author_inst":"Zhejiang University"},{"author_name":"Jing Yuan","author_inst":"Xiamen University"},{"author_name":"Qiang Guo","author_inst":"Peking University"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"The superior temporal asymmetrical pit remains asymmetric in autism spectrum disorder","rel_doi":"10.64898\/2026.10.01.755796","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.01.755796","rel_abs":"Neuroimaging studies identify the superior temporal sulcus (STS) as an anatomical and functional target in autism spectrum disorder (ASD). Yet, the STS is a heterogeneous structure containing unique subregions, such as the superior temporal asymmetrical pit (STAP), which is a recently identified human-specific landmark. To date, no study has compared the STAP between ASD individuals and neurotypical controls (NTs) in a large sample. Here, we analyzed the mean intra-hemispheric sulcal depth and inter-hemispheric laterality of the STAP, as well as the anterior and posterior portions of the STS (aSTS, pSTS), in 100 NTs and 100 ASD male individuals (ages 5-18) using a discovery-replication design. Across samples, the STAP and pSTS showed rightward asymmetry, while the aSTS showed leftward asymmetry within groups. All features of the STAP, aSTS, or pSTS did not differ significantly between groups. However, pSTS laterality related to individual differences in social cognition, which was further supported by a meta-analysis across over 200 studies showing that neurocognitive functional differences associated with social cognition and ASD are restricted to portions of the STS outside of the STAP. Together, these findings provide fine-grained insight into prior studies showing coarse morphological differences of the STS between individuals with ASD and NTs, as well as open up new questions and new neuroanatomical targets of the heterogeneous STS in future studies of brain structure, brain function, and cognition in ASD, as well as other neurodevelopmental disorders targeting the superior temporal cortex.","rel_num_authors":3,"rel_authors":[{"author_name":"Jake William Wirtjes","author_inst":"University of California, Berkeley"},{"author_name":"Ethan H Willbrand","author_inst":"University of Wisconsin School of Medicine and Public Health, Madison"},{"author_name":"Kevin S Weiner","author_inst":"University of California, Berkeley"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Multi-omic spatial mapping of the human habenula defines the molecular and anatomical organization of medial and lateral subregions","rel_doi":"10.64898\/2026.09.30.755667","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.30.755667","rel_abs":"The habenula (Hb) is a small epithalamic midline structure critical for reward processing and mood regulation that is implicated in many complex brain disorders, including depression and addiction. The molecular anatomy of the Hb has been well-characterized in model organisms, but little is known about its organization in the human brain, including the transcriptomic and epigenetic signatures of spatially-organized lateral (LHb) and medial (MHb) cell types. Here, we generated a high resolution spatiomolecular map of the human Hb using both multiomic single nucleus sequencing (snMultiome) and spatially-resolved transcriptomics. We measured gene expression and chromatin accessibility across 4 MHb and 5 LHb neuronal cell types as defined by transcriptomic conservation with rodents and zebrafish. We identified cell type-specific molecular specializations related to GABAergic and glutamatergic signaling as well as regulatory relationships between open chromatin regions, transcription factors, and target genes associated with depression and addiction. High resolution spatial transcriptomics identified the anatomical location of heterogeneous LHb subpopulations, including two putative inhibitory populations in the LHb. We further characterized cell-type relationships between Hb neurons and glial subtypes and predicted ligand-receptor interactions between LHb and MHb neurons. Finally, we delineated Hb cell types and spatial domains enriched in genes associated with genetic risk for psychiatric disorders, identifying the strongest enrichment in the MHb. Collectively, the generated data and analyses resolve the spatiomolecular organization of the human Hb and identify molecular-genetic associations with neuropsychiatric disease.","rel_num_authors":19,"rel_authors":[{"author_name":"Kelsey D. Montgomery","author_inst":"Lieber Institute for Brain Development"},{"author_name":"Jonathan M. Werner","author_inst":"Lieber Institute for Brain Development"},{"author_name":"Nicholas J. Eagles","author_inst":"Lieber Institute for Brain Development"},{"author_name":"Chunyu Liu","author_inst":"Johns Hopkins Bloomerg School of Public Health"},{"author_name":"Cynthia S. Cardinault","author_inst":"Lieber Institute for Brain Development"},{"author_name":"Svitlana V. Bach","author_inst":"Lieber Institute for Brain Development"},{"author_name":"Atharv Chandra","author_inst":"Lieber Institute for Brain Development"},{"author_name":"Ruth Zhang","author_inst":"Lieber Institute for Brain Development"},{"author_name":"Sarah E. Maguire","author_inst":"Lieber Institute for Brain Development"},{"author_name":"Heena R. Divecha","author_inst":"Lieber Institute for Brain Development"},{"author_name":"Amy Deep-Soboslay","author_inst":"Lieber Institute for Brain Development"},{"author_name":"Ryan A. Miller","author_inst":"Lieber Institute for Brain Development"},{"author_name":"Louise A. Huuki-Myers","author_inst":"Lieber Institute for Brain Development"},{"author_name":"Rahul A. Bharadwaj","author_inst":"Lieber Institute for Brain Development"},{"author_name":"Joel E. Kleinman","author_inst":"Lieber Institute for Brain Development"},{"author_name":"Thomas M. Hyde","author_inst":"Lieber Institute for Brain Development"},{"author_name":"Brion S. Maher","author_inst":"Johns Hopkins Bloomerg School of Public Health"},{"author_name":"Leonardo Collado-Torres","author_inst":"Lieber Institute for Brain Development"},{"author_name":"Kristen R. Maynard","author_inst":"Lieber Institute for Brain Development"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Integrating CSF and EV Proteomes Enhances Biomarker Discovery by Capturing Shared Variation Across Compartments","rel_doi":"10.64898\/2026.09.30.754912","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.30.754912","rel_abs":"Cerebrospinal fluid (CSF) contains brain derived proteins that can be leveraged as biomarkers for Alzheimer's disease (AD) and other neurodegenerative diseases. However, converting protein intensities to a disease signal remains a challenge because physiology driven changes to the localization of proteins across CSF subcompartments are obscured when CSF is analyzed alone. Where subcompartment data, such as that from extracellular vesicles (EVs), are also measured, separate but parallel analyses of EVs and CSF can obscure their shared disease signal. Here, we present an integrated matrix factorization approach that combines proteomic signals from matched CSF and phosphatidylserine exposed EVs and nanoparticles (EVps). In a ROS\/MAP cohort of 48 participants, integrating CSF and EVps signals improved biological concordance across compartments and increased the number of candidate proteins distinguishing participants with AD from controls. Notably, the joint signal identified as many brain related biomarker candidates as studies using substantially larger cohorts. By demonstrating that integration of CSF and EVps proteomes maximizes information from limited samples, this framework offers a path toward more efficient biomarker discovery across two compartments increasingly leveraged in neurodegenerative disease research.","rel_num_authors":5,"rel_authors":[{"author_name":"Bianca R. P. Brown","author_inst":"Yale University"},{"author_name":"Xiaoting Li","author_inst":"University of Cambridge"},{"author_name":"Monica R Grasty","author_inst":"Yale University"},{"author_name":"Andrew D Miranker","author_inst":"Yale University"},{"author_name":"Gamze Gursoy","author_inst":"University of Cambridge"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Divergence in wilt tolerance across the range of Mimulus guttatus in the absence of stomatal regulation","rel_doi":"10.64898\/2026.09.30.755782","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.30.755782","rel_abs":"Whether phenotypes and environments predict performance under stress is central to ecology and evolution and can reveal species' vulnerability to global change. We sampled Mimulus guttatus range-wide to test whether reproductive, morphological, and physiological traits predict drought responses. Surprisingly, we find that stomatal response, a key mediator of water balance, did not change as drought intensified. Climate, however, predicted survival after turgor loss: plants from regions with large daily relative to seasonal temperature ranges survived wilting longer. Stress responses also depended on life history: where summers are dry, perennials withstood lower water potentials, whereas annuals increased leaf cooling as they wilted. Known trait associations were not fixed: although many baseline traits tracked climate, none predicted drought responses. Drought performance therefore cannot be inferred from traits measured under well-watered conditions. Lacking stomatal regulation, riparian drought escapers like M. guttatus may be vulnerable if shorter growing seasons bring drought before reproduction.","rel_num_authors":14,"rel_authors":[{"author_name":"Haley A Branch","author_inst":"Connecticut College"},{"author_name":"Pauline Raimondeau","author_inst":"Yale University"},{"author_name":"Vanessa Tonet","author_inst":"Yale University"},{"author_name":"Henry Arenas Castro","author_inst":"Yale University"},{"author_name":"Andrew Fairclough","author_inst":"Michigan State University"},{"author_name":"Lily Hyde","author_inst":"Yale University"},{"author_name":"Dristen Lakes","author_inst":"North Carolina Agricultural and Technical State University"},{"author_name":"Alyssa Singletary","author_inst":"North Carolina Agricultural and Technical State University"},{"author_name":"Benjamin K Blackman","author_inst":"University of California, Berkeley"},{"author_name":"Katherine Toll","author_inst":"University of South Carolina"},{"author_name":"Mario Vallejo-Marin","author_inst":"Uppsala University"},{"author_name":"Craig R Brodersen","author_inst":"Yale University School of the Environment"},{"author_name":"Erika Edwards","author_inst":"Yale University"},{"author_name":"Jennifer M Coughlan","author_inst":"Yale University"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Divergence in wilt tolerance across the range of Mimulus guttatus in the absence of stomatal regulation","rel_doi":"10.64898\/2026.09.30.755782","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.30.755782","rel_abs":"Whether phenotypes and environments predict performance under stress is central to ecology and evolution and can reveal species' vulnerability to global change. We sampled Mimulus guttatus range-wide to test whether reproductive, morphological, and physiological traits predict drought responses. Surprisingly, we find that stomatal response, a key mediator of water balance, did not change as drought intensified. Climate, however, predicted survival after turgor loss: plants from regions with large daily relative to seasonal temperature ranges survived wilting longer. Stress responses also depended on life history: where summers are dry, perennials withstood lower water potentials, whereas annuals increased leaf cooling as they wilted. Known trait associations were not fixed: although many baseline traits tracked climate, none predicted drought responses. Drought performance therefore cannot be inferred from traits measured under well-watered conditions. Lacking stomatal regulation, riparian drought escapers like M. guttatus may be vulnerable if shorter growing seasons bring drought before reproduction.","rel_num_authors":14,"rel_authors":[{"author_name":"Haley A Branch","author_inst":"Connecticut College"},{"author_name":"Pauline Raimondeau","author_inst":"Yale University"},{"author_name":"Vanessa Tonet","author_inst":"Yale University"},{"author_name":"Henry Arenas Castro","author_inst":"Yale University"},{"author_name":"Andrew Fairclough","author_inst":"Michigan State University"},{"author_name":"Lily Hyde","author_inst":"Yale University"},{"author_name":"Dristen Lakes","author_inst":"North Carolina Agricultural and Technical State University"},{"author_name":"Alyssa Singletary","author_inst":"North Carolina Agricultural and Technical State University"},{"author_name":"Benjamin K Blackman","author_inst":"University of California, Berkeley"},{"author_name":"Katherine Toll","author_inst":"University of South Carolina"},{"author_name":"Mario Vallejo-Marin","author_inst":"Uppsala University"},{"author_name":"Craig R Brodersen","author_inst":"Yale University School of the Environment"},{"author_name":"Erika Edwards","author_inst":"Yale University"},{"author_name":"Jennifer M Coughlan","author_inst":"Yale University"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Divergence in wilt tolerance across the range of Mimulus guttatus in the absence of stomatal regulation","rel_doi":"10.64898\/2026.09.30.755782","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.30.755782","rel_abs":"Whether phenotypes and environments predict performance under stress is central to ecology and evolution and can reveal species' vulnerability to global change. We sampled Mimulus guttatus range-wide to test whether reproductive, morphological, and physiological traits predict drought responses. Surprisingly, we find that stomatal response, a key mediator of water balance, did not change as drought intensified. Climate, however, predicted survival after turgor loss: plants from regions with large daily relative to seasonal temperature ranges survived wilting longer. Stress responses also depended on life history: where summers are dry, perennials withstood lower water potentials, whereas annuals increased leaf cooling as they wilted. Known trait associations were not fixed: although many baseline traits tracked climate, none predicted drought responses. Drought performance therefore cannot be inferred from traits measured under well-watered conditions. Lacking stomatal regulation, riparian drought escapers like M. guttatus may be vulnerable if shorter growing seasons bring drought before reproduction.","rel_num_authors":14,"rel_authors":[{"author_name":"Haley A Branch","author_inst":"Connecticut College"},{"author_name":"Pauline Raimondeau","author_inst":"Yale University"},{"author_name":"Vanessa Tonet","author_inst":"Yale University"},{"author_name":"Henry Arenas Castro","author_inst":"Yale University"},{"author_name":"Andrew Fairclough","author_inst":"Michigan State University"},{"author_name":"Lily Hyde","author_inst":"Yale University"},{"author_name":"Dristen Lakes","author_inst":"North Carolina Agricultural and Technical State University"},{"author_name":"Alyssa Singletary","author_inst":"North Carolina Agricultural and Technical State University"},{"author_name":"Benjamin K Blackman","author_inst":"University of California, Berkeley"},{"author_name":"Katherine Toll","author_inst":"University of South Carolina"},{"author_name":"Mario Vallejo-Marin","author_inst":"Uppsala University"},{"author_name":"Craig R Brodersen","author_inst":"Yale University School of the Environment"},{"author_name":"Erika Edwards","author_inst":"Yale University"},{"author_name":"Jennifer M Coughlan","author_inst":"Yale University"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Divergence in wilt tolerance across the range of Mimulus guttatus in the absence of stomatal regulation","rel_doi":"10.64898\/2026.09.30.755782","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.30.755782","rel_abs":"Whether phenotypes and environments predict performance under stress is central to ecology and evolution and can reveal species' vulnerability to global change. We sampled Mimulus guttatus range-wide to test whether reproductive, morphological, and physiological traits predict drought responses. Surprisingly, we find that stomatal response, a key mediator of water balance, did not change as drought intensified. Climate, however, predicted survival after turgor loss: plants from regions with large daily relative to seasonal temperature ranges survived wilting longer. Stress responses also depended on life history: where summers are dry, perennials withstood lower water potentials, whereas annuals increased leaf cooling as they wilted. Known trait associations were not fixed: although many baseline traits tracked climate, none predicted drought responses. Drought performance therefore cannot be inferred from traits measured under well-watered conditions. Lacking stomatal regulation, riparian drought escapers like M. guttatus may be vulnerable if shorter growing seasons bring drought before reproduction.","rel_num_authors":14,"rel_authors":[{"author_name":"Haley A Branch","author_inst":"Connecticut College"},{"author_name":"Pauline Raimondeau","author_inst":"Yale University"},{"author_name":"Vanessa Tonet","author_inst":"Yale University"},{"author_name":"Henry Arenas Castro","author_inst":"Yale University"},{"author_name":"Andrew Fairclough","author_inst":"Michigan State University"},{"author_name":"Lily Hyde","author_inst":"Yale University"},{"author_name":"Dristen Lakes","author_inst":"North Carolina Agricultural and Technical State University"},{"author_name":"Alyssa Singletary","author_inst":"North Carolina Agricultural and Technical State University"},{"author_name":"Benjamin K Blackman","author_inst":"University of California, Berkeley"},{"author_name":"Katherine Toll","author_inst":"University of South Carolina"},{"author_name":"Mario Vallejo-Marin","author_inst":"Uppsala University"},{"author_name":"Craig R Brodersen","author_inst":"Yale University School of the Environment"},{"author_name":"Erika Edwards","author_inst":"Yale University"},{"author_name":"Jennifer M Coughlan","author_inst":"Yale University"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Jasmonate-induced expansion of the MYC2 cistrome occurs within a preconfigured chromatin landscape","rel_doi":"10.64898\/2026.10.01.755910","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.01.755910","rel_abs":"The transcription factor (TF) MYC2 is a central regulator of jasmonate (JA) signaling, yet its genome-wide occupancy has primarily been characterized using transgenic lines expressing tagged MYC2 proteins, leaving the dynamics of the native MYC2 cistrome unresolved. Here, using a MYC2-specific antibody, we define the wildtype MYC2 cistrome in Arabidopsis thaliana under basal and JA-induced conditions. Native MYC2 showed minimal genome-wide occupancy under control conditions but underwent a pronounced expansion following JA treatment, resulting in more than 3,000 binding sites enriched at core components of the JA signaling network. Cistrome expansion coincided with increased MYC2 protein abundance, while elevated basal MYC2 levels in a transgenic line were associated with extensive MYC2 occupancy even in the absence of JA, supporting a dosage-dependent relationship between MYC2 abundance and genome-wide binding. Despite this extensive cistrome expansion and transcriptional reprogramming, ATAC-seq revealed remarkably limited remodeling of chromatin accessibility following JA treatment. MYC2 recruitment occurred predominantly within pre-existing accessible chromatin regions that remained largely intact in myc2 myc3 myc4 mutants. Together, our findings reveal that JA-dependent expansion of the native MYC2 cistrome occurs within a largely pre-established accessome and identify MYC2 dosage as an important determinant of the extent of genome-wide occupancy.","rel_num_authors":7,"rel_authors":[{"author_name":"Linkan Dash","author_inst":"Waksman Institute of Microbiology, Department of Plant Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA"},{"author_name":"Moonia Ammari","author_inst":"Waksman Institute of Microbiology, Department of Plant Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA"},{"author_name":"Aanchal Choudhary","author_inst":"Department of Immunobiology, University of Lausanne, Epalinges, Switzerland"},{"author_name":"Kashif Maseh","author_inst":"Waksman Institute of Microbiology, Department of Plant Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA"},{"author_name":"Moorthy Gnanarajah","author_inst":"Waksman Institute of Microbiology, Department of Plant Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA"},{"author_name":"Jeevika Gupta","author_inst":"Waksman Institute of Microbiology, Department of Plant Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA"},{"author_name":"Mark Zander","author_inst":"Waksman Institute of Microbiology, Department of Plant Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Transcriptomic analysis reveals differential regulation of synaptic components in pediatric and adult brain tumors","rel_doi":"10.64898\/2026.09.30.755821","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.30.755821","rel_abs":"Neuronal-cancer cell interactions are a key component of brain tumor pathophysiology, yet many fundamental questions remain unanswered, with even more remaining unasked. Here, we present a comprehensive brain tumor reference map generated from bulk RNA-seq data of ~4,300 adult and pediatric brain tumors, including various glioma subtypes, medulloblastomas, ependymomas, and meningiomas, alongside ~1,400 healthy brain samples. By analyzing synaptic processes and synaptic gene expression across tumor types, we reveal the complexity of neuron-tumor crosstalk and its potential impact on patient survival. Our findings identify key synaptic signaling pathways and dysregulated patterns in brain tumors, including HNRNPH2 upregulation, a key factor in RNA processing and metabolism, in gliomas and medulloblastomas. Additionally, we highlight the role of cholinergic signaling, particularly CHRNA9, as a driver of glioma progression, which is also upregulated in WNT and Group 4 medulloblastomas, ependymomas, and meningiomas. Furthermore, P2 purinergic signaling emerges as a key player in glioma progression. These insights lay the groundwork for future studies exploring whether targeting these pathways could reprogram the tumor microenvironment toward an anti-tumor state, ultimately leading to novel therapeutic strategies and improved patient outcomes.","rel_num_authors":7,"rel_authors":[{"author_name":"Leyre Merino-Galan","author_inst":"Seattle Children's Research Institute"},{"author_name":"Sonali Arora","author_inst":"FHCRC"},{"author_name":"Greg Glatzer","author_inst":"FHCRH"},{"author_name":"Matt Jensen","author_inst":"FHCRH"},{"author_name":"Ashmitha Rajendran","author_inst":"Seattle Children's Research Institute"},{"author_name":"Eric C Holland","author_inst":"FHCRH"},{"author_name":"Siobhan S Pattwell","author_inst":"Seattle Children's; University of Washington School of Medicine; Fred Hutchinson Cancer Center"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Clonally expanded CD8 T cells in AML adopt an NK-like program distinct from canonical exhaustion","rel_doi":"10.64898\/2026.09.30.755147","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.30.755147","rel_abs":"CD8 T cells are key mediators of anti-tumor immunity, yet their differentiation states and clonal architecture within the acute myeloid leukemia (AML) bone marrow microenvironment remain incompletely defined. We performed high dimensional immune profiling of bone marrow samples from 46 newly diagnosed AML patients using mass cytometry to probe the microenvironment and T cell states. We used single-cell RNA and T cell receptor (TCR) sequencing to define CD8 T cell phenotypes, transcriptional states, and clonal architecture. AML-associated CD8 T cells were skewed toward terminally differentiated effector memory cells re-expressing CD45RA (TEMRAs), while canonically exhausted T cell populations were rare. Functional studies revealed that TEMRA CD8 T cells robustly produced IFN{gamma} and TNF upon in vitro stimulation. Clonal expansion was concentrated within the TEMRA compartment. Comparison of TCR sequences with known viral epitopes identified a small subset of expanded viral-specific clonotypes, while the majority of highly expanded clonotypes had unknown specificity and may include AML-specific T cells. Differential gene expression analysis revealed shared cytotoxic effector programs during clonal expansion but diverging activation signatures: viral-specific clones upregulated canonical T cell receptor signaling genes, whereas expanded clones of unknown specificity exhibited enrichment of natural killer (NK) receptor-associated genes. These genes comprised the leukemia-associated NK-immune (LaNKi) score which was elevated in an independent AML dataset compared to pan cancer tumor infiltrating lymphocytes. These findings define the CD8 T cell differentiation landscape and clonal architecture in AML marrow at diagnosis and suggest that T cell dysfunction in AML diverges from classical activation and exhaustion paradigms.","rel_num_authors":11,"rel_authors":[{"author_name":"Yunli E Chu","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Matthew A Cottam","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Chad R Potts","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Thomas Gracie","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Ciarra Polsley","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Justin A Cartailler","author_inst":"Northwestern University"},{"author_name":"Michael R Savona","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Rui Lu","author_inst":"The University of Alabama at Birmingham"},{"author_name":"Stanley C Lee","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Robert S Welner","author_inst":"The University of Alabama at Birmingham"},{"author_name":"P Brent Ferrell","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Clonally expanded CD8 T cells in AML adopt an NK-like program distinct from canonical exhaustion","rel_doi":"10.64898\/2026.09.30.755147","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.30.755147","rel_abs":"CD8 T cells are key mediators of anti-tumor immunity, yet their differentiation states and clonal architecture within the acute myeloid leukemia (AML) bone marrow microenvironment remain incompletely defined. We performed high dimensional immune profiling of bone marrow samples from 46 newly diagnosed AML patients using mass cytometry to probe the microenvironment and T cell states. We used single-cell RNA and T cell receptor (TCR) sequencing to define CD8 T cell phenotypes, transcriptional states, and clonal architecture. AML-associated CD8 T cells were skewed toward terminally differentiated effector memory cells re-expressing CD45RA (TEMRAs), while canonically exhausted T cell populations were rare. Functional studies revealed that TEMRA CD8 T cells robustly produced IFN{gamma} and TNF upon in vitro stimulation. Clonal expansion was concentrated within the TEMRA compartment. Comparison of TCR sequences with known viral epitopes identified a small subset of expanded viral-specific clonotypes, while the majority of highly expanded clonotypes had unknown specificity and may include AML-specific T cells. Differential gene expression analysis revealed shared cytotoxic effector programs during clonal expansion but diverging activation signatures: viral-specific clones upregulated canonical T cell receptor signaling genes, whereas expanded clones of unknown specificity exhibited enrichment of natural killer (NK) receptor-associated genes. These genes comprised the leukemia-associated NK-immune (LaNKi) score which was elevated in an independent AML dataset compared to pan cancer tumor infiltrating lymphocytes. These findings define the CD8 T cell differentiation landscape and clonal architecture in AML marrow at diagnosis and suggest that T cell dysfunction in AML diverges from classical activation and exhaustion paradigms.","rel_num_authors":11,"rel_authors":[{"author_name":"Yunli E Chu","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Matthew A Cottam","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Chad R Potts","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Thomas Gracie","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Ciarra Polsley","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Justin A Cartailler","author_inst":"Northwestern University"},{"author_name":"Michael R Savona","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Rui Lu","author_inst":"The University of Alabama at Birmingham"},{"author_name":"Stanley C Lee","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Robert S Welner","author_inst":"The University of Alabama at Birmingham"},{"author_name":"P Brent Ferrell","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"A bacteriophage split DNA polymerase incorporates a sliding clamp-derived processivity subunit","rel_doi":"10.64898\/2026.09.30.755723","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.30.755723","rel_abs":"Viruses that infect bacteria, termed bacteriophages or phages, typically encode their own DNA replication machinery that rapidly generates many copies of the phage genomic DNA in an infected cell. Nucleus-forming phages of the chimallivirus family possess a distinctive repertoire of predicted DNA replication proteins, with two proteins annotated as DNA polymerases plus a DnaB-like replicative helicase, but lacking an identified primase or sliding clamp protein. Here, we demonstrate that in the Pseudomonas aeruginosa-infecting chimallivirus PhiKZ, the core DNA polymerase comprises a stable 1:1 complex of two DNA polymerase subunits, termed DNAPN and DNAPC. A 2.1 A resolution cryoelectron microscopy structure of this core complex reveals homology to other phage and bacterial B-family DNA polymerases. Next, we identify a direct but transient interaction between the core DNA polymerase complex and a third protein termed Rhc, which possesses an N-terminal RNase H domain and a C-terminal domain related to DNA sliding clamp proteins. Cryoelectron microscopy structures of a stabilized DNA polymerase-Rhc complex, and of this complex bound to a primer-template DNA, reveal a single Rhc subunit that cooperates with the DNA polymerase thumb domain to bind double-stranded DNA emerging from the DNA polymerase active site. While the Rhc RNase H domain is not resolved in our structures, this domain is situated such that it could degrade RNA associated with an incoming template DNA strand. In vitro primer-extension assays show that Rhc strongly boosts DNA polymerase activity, and that this boost relies on the Rhc-DNA polymerase interface we observe in our structures. Overall, our findings reveal a distinctive chimallivirus-specific DNA replication machine with an integrated DNA-binding subunit related to sliding clamp proteins, and a flexibly-linked RNase H domain.","rel_num_authors":6,"rel_authors":[{"author_name":"Dwaipayan Basu","author_inst":"UC San Diego"},{"author_name":"Ryan K Min","author_inst":"University of California at San Diego (UCSD)"},{"author_name":"Koe Inlow","author_inst":"UC San Diego"},{"author_name":"Joe Pogliano","author_inst":"University of California, San Diego"},{"author_name":"Elizabeth Villa","author_inst":"University of California San Diego"},{"author_name":"Kevin D Corbett","author_inst":"University of California, San Diego"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"A bifunctional RNase H protein supports DNA replication and transcription in nucleus-forming Chimalliviridae phages","rel_doi":"10.64898\/2026.10.01.755736","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.01.755736","rel_abs":"Jumbo bacteriophages of the Chimalliviridae family replicate their genomes within a proteinaceous phage nucleus that spatially segregates viral DNA replication and transcription from translation. While the phage nucleus protects viral DNA from host defenses, it also imposes unique constraints on genome replication and gene expression. Here we identify the phage-encoded protein Rhc (RNase H-clamp) as a central mediator of genome transactions within the phage nucleus. Using the Escherichia coli infecting bacteriophage Goslar, we show that Rhc functions as an essential component of a non-canonical three-subunit DNA polymerase complex composed of DNAPN, DNAPC and Rhc. Rhc physically interacts with the DNAPC subunit, and both the catalytic activity of Rhc's N-terminal RNase H domain and its C-terminal sliding clamp-derived DNA binding domain are required for genome replication, nuclear maturation, and productive infection. Further, Goslar Rhc also supports transcription within the phage nucleus through a function that is separable from its DNA replication function. Rhc depletion results in reduced transcription of a subset of late genes, in a pattern that suggests a role for Rhc in resolving R-loops. Imaging and cryo-electron tomography reveal that loss of Rhc arrests phage development at a nascent nuclear stage, uncoupling nuclear assembly from maturation. Together, these findings identify Rhc as a multifunctional nuclear factor that mediates both DNA replication and transcription in nucleus-forming jumbo phages, revealing how viruses repurpose a conserved enzymatic activity to coordinate gene expression within a compartmentalized replication environment.","rel_num_authors":17,"rel_authors":[{"author_name":"Phoolwanti Rani","author_inst":"University of California San Diego; Howard Hughes Medical Institute"},{"author_name":"Niklas Klusch","author_inst":"University of California San Diego"},{"author_name":"Shannon Barret","author_inst":"University of California San Diego; Howard Hughes Medical Institute"},{"author_name":"Taylor Forman","author_inst":"University of California San Diego"},{"author_name":"Makaela Levine","author_inst":"University of California San Diego; Howard Hughes Medical Institute"},{"author_name":"Margot Riggi","author_inst":"Department of Cell and Virus Structure, Max Planck Institute of Biochemistry, Martinsried, Germany"},{"author_name":"Caroline Rees","author_inst":"University of California San Diego"},{"author_name":"Rui Liu","author_inst":"University of California San Diego"},{"author_name":"Lizbeth Hoffman","author_inst":"University of California San Diego; Howard Hughes Medical Institute"},{"author_name":"Meline Norquist","author_inst":"University of California San Diego"},{"author_name":"Dwaipayan Basu","author_inst":"University of California San Diego"},{"author_name":"Koe Inlow","author_inst":"University of California San Diego"},{"author_name":"Emily G Armbruster","author_inst":"University of California San Diego"},{"author_name":"Chase J Morgan","author_inst":"University of California San Diego"},{"author_name":"Joe Pogliano","author_inst":"University of California San Diego"},{"author_name":"Kevin D Corbett","author_inst":"University of California San Diego"},{"author_name":"Elizabeth Villa","author_inst":"University of California San Diego; Howard Hughes Medical Institute"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"A bifunctional RNase H protein supports DNA replication and transcription in nucleus-forming Chimalliviridae phages","rel_doi":"10.64898\/2026.10.01.755736","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.01.755736","rel_abs":"Jumbo bacteriophages of the Chimalliviridae family replicate their genomes within a proteinaceous phage nucleus that spatially segregates viral DNA replication and transcription from translation. While the phage nucleus protects viral DNA from host defenses, it also imposes unique constraints on genome replication and gene expression. Here we identify the phage-encoded protein Rhc (RNase H-clamp) as a central mediator of genome transactions within the phage nucleus. Using the Escherichia coli infecting bacteriophage Goslar, we show that Rhc functions as an essential component of a non-canonical three-subunit DNA polymerase complex composed of DNAPN, DNAPC and Rhc. Rhc physically interacts with the DNAPC subunit, and both the catalytic activity of Rhc's N-terminal RNase H domain and its C-terminal sliding clamp-derived DNA binding domain are required for genome replication, nuclear maturation, and productive infection. Further, Goslar Rhc also supports transcription within the phage nucleus through a function that is separable from its DNA replication function. Rhc depletion results in reduced transcription of a subset of late genes, in a pattern that suggests a role for Rhc in resolving R-loops. Imaging and cryo-electron tomography reveal that loss of Rhc arrests phage development at a nascent nuclear stage, uncoupling nuclear assembly from maturation. Together, these findings identify Rhc as a multifunctional nuclear factor that mediates both DNA replication and transcription in nucleus-forming jumbo phages, revealing how viruses repurpose a conserved enzymatic activity to coordinate gene expression within a compartmentalized replication environment.","rel_num_authors":17,"rel_authors":[{"author_name":"Phoolwanti Rani","author_inst":"University of California San Diego; Howard Hughes Medical Institute"},{"author_name":"Niklas Klusch","author_inst":"University of California San Diego"},{"author_name":"Shannon Barret","author_inst":"University of California San Diego; Howard Hughes Medical Institute"},{"author_name":"Taylor Forman","author_inst":"University of California San Diego"},{"author_name":"Makaela Levine","author_inst":"University of California San Diego; Howard Hughes Medical Institute"},{"author_name":"Margot Riggi","author_inst":"Department of Cell and Virus Structure, Max Planck Institute of Biochemistry, Martinsried, Germany"},{"author_name":"Caroline Rees","author_inst":"University of California San Diego"},{"author_name":"Rui Liu","author_inst":"University of California San Diego"},{"author_name":"Lizbeth Hoffman","author_inst":"University of California San Diego; Howard Hughes Medical Institute"},{"author_name":"Meline Norquist","author_inst":"University of California San Diego"},{"author_name":"Dwaipayan Basu","author_inst":"University of California San Diego"},{"author_name":"Koe Inlow","author_inst":"University of California San Diego"},{"author_name":"Emily G Armbruster","author_inst":"University of California San Diego"},{"author_name":"Chase J Morgan","author_inst":"University of California San Diego"},{"author_name":"Joe Pogliano","author_inst":"University of California San Diego"},{"author_name":"Kevin D Corbett","author_inst":"University of California San Diego"},{"author_name":"Elizabeth Villa","author_inst":"University of California San Diego; Howard Hughes Medical Institute"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Anatomical mapping of dopamine D1 and muscarinic M4 receptor","rel_doi":"10.64898\/2026.09.27.754786","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.27.754786","rel_abs":"Dopamine D1 receptors (D1R) and muscarinic M4 receptors (M4R) regulate overlapping functions in the cortex and the striatum, but the cellular relationship between D1R- and M4R-associated populations across brain regions remains incompletely defined. Using D1R-tdTomato\/M4R-EGFP double-reporter mice, we quantified tdTomato-only, EGFP-only, and coexpressing cellular populations across the dorsal striatum, nucleus accumbens, and medial prefrontal cortex in 18 animals. Reporter composition differed strongly by anatomical region. Coexpression was prominent throughout the dorsal striatum and greatest in the dorsomedial striatum, whereas the nucleus accumbens shifted toward greater tdTomato-only and reduced EGFP-only representation, particularly in the core. In contrast, the medial prefrontal cortex was dominated by EGFP-only cells. These regional patterns were broadly retained across sex and age. HCR-FISH further supported spatial correspondence between endogenous Drd1 and Chrm4 transcript signal and the respective fluorescent reporters. Together, these findings demonstrate region-dependent organization of D1R- and M4R-associated cellular populations across the cortex and striatum and define distinct anatomical contexts in which M4R-directed signaling may influence D1R-associated neurons.","rel_num_authors":8,"rel_authors":[{"author_name":"Rian Garland","author_inst":"Northeastern University"},{"author_name":"Maya Dickson","author_inst":"Northeastern University"},{"author_name":"Alice Lee","author_inst":"Northeastern University"},{"author_name":"Ali Noorouzi","author_inst":"Northeastern University"},{"author_name":"Hayato Umaoka","author_inst":"Northeastern University"},{"author_name":"Ana Semeano","author_inst":"Northeastern University"},{"author_name":"James R Monaghan","author_inst":"Northeastern University"},{"author_name":"Hideaki Yano","author_inst":"Northeastern University"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Spatially coordinated RTK-ERK signaling dynamics shape osteosarcoma single-cell drug response in the lung microenvironment","rel_doi":"10.64898\/2026.09.30.755770","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.30.755770","rel_abs":"Purpose: Lung metastases are the primary cause of death in osteosarcoma patients and treatment response often vary due to convergence of genetic and phenotypic influences in the context of a dynamic tumor-host tissue environment. The purpose of this study was to determine how dynamic tumor- and host-driven receptor tyrosine kinase (RTK)-ERK signaling interactions contribute to phenotypic drug response heterogeneity. Experimental Design: Live-cell time-lapse microscopy and data-driven dynamical modeling was used to resolve ERK activity, FOSL1\/Fra-1 reporter expression, and spatiotemporal cell fate in living, biosensor-expressing osteosarcoma lung metastases ex vivo following MCL1 inhibitor exposure. RTK inhibitors were then evaluated for their ability to suppress adaptive signaling and enhance MCL1 inhibitor efficacy ex vivo and in vivo. Results: MCL1 inhibition induced extensive tumor-cell death; however, persistent ERKhigh\/Fra-1high reporter cells emerged and were enriched at the tumor-lung interface, consistent with adaptive resistance. Experimental and computational approaches revealed that tumor-cell lysis amplified fibroblast growth factor receptor (FGFR)-mediated ERK signaling in neighboring cells, promoting a targetable drug-resistant state marked by adaptive ERK induction, FOSL1\/Fra-1 expression, and correlated with upregulation of known drug resistance pathways Nrf2 and HMOX1. Combinatorial inhibition of FGFR with fexagratinib, or broad-spectrum RTK inhibitor, pazopanib, suppressed adaptive ERK activation and enhanced MCL1 inhibitor response resulting in greater efficacy ex vivo and in vivo. Conclusions: Tumor-host and tumor-cell-lysis-induced FGFR-ERK signaling contribute to spatiotemporally heterogeneous adaptive resistance in metastatic osteosarcoma. These data support combinatorial targeting of RTK signaling with cytotoxic or targeted agents as a strategy to block adaptive resistance and improve treatment efficacy.","rel_num_authors":14,"rel_authors":[{"author_name":"Rawan Makkawi","author_inst":"Oregon Health and Science University"},{"author_name":"Carol Halsey","author_inst":"Oregon Health and Science University"},{"author_name":"Vaibhav Murthy","author_inst":"Oregon Health and Science University"},{"author_name":"Elise C Manalo","author_inst":"Oregon Health and Science University"},{"author_name":"Hugo Cros","author_inst":"Oregon Health and Science University"},{"author_name":"Xin Yi","author_inst":"Oregon Health and Science University"},{"author_name":"Jessie May Cartier","author_inst":"Oregon Health and Science University"},{"author_name":"Matthew Chang","author_inst":"Oregon Health and Science University"},{"author_name":"Mark Flory","author_inst":"Oregon Health and Science University"},{"author_name":"Kelly Guptell","author_inst":"Nationwide Children's Hospital"},{"author_name":"Amy Gross","author_inst":"Nationwide Children's Hospital"},{"author_name":"Ryan D Roberts","author_inst":"Nationwide Children's Hospital"},{"author_name":"Jeremy Copperman","author_inst":"Oregon Health and Science University"},{"author_name":"Alexander E Davies","author_inst":"Oregon Health and Science University"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Epithelial to mesenchymal transition and M2 macrophages drive aggressiveness in murine and human sarcomatoid urothelial carcinoma.","rel_doi":"10.64898\/2026.09.30.755727","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.30.755727","rel_abs":"Patients with majority variant subtype histology including sarcomatoid urothelial carcinoma (SUC) have poor outcomes and limited treatment options, and there are few preclinical resources to investigate rare histologic subtypes. We developed three novel variant subtype histology bladder cancer (BC) cell lines by finding that basal BC tumor cells derived from mice treated with N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) were initially not competent to grow in immune competent mice, but then acquired tumorigenicity following passaging (recycling) in mice lacking mature B and T cells. Three genitourinary oncology pathologists identified BBN966 as SUC, BBN964 as a hybrid between SUC and squamous, and BBN975 as squamous, and each had unique growth characteristics. Using a publicly available dataset and our spatial transcriptomics analysis of a cohort of human tumors with mixed SUC and UC as comparators, we found that consistent with human SUC, BBN966 lack expression of basal and luminal genes. Consistent with human SUC and spatial transcriptomics analysis of canine SUC, BBN966 had the highest epithelial to mesenchymal transition (EMT) upregulation, and all three recycled tumor cells had increased EMT pathway expression in recycled tumor cells. Moreover, increased expression of genes upregulated in all three recycled tumor cells associated with worse overall survival in patients with muscle invasive UC. Similar to human SUC, BBN966 tumors had higher proportion of M2 macrophage gene expression. Finally, we found in the largest cohort of PD-L1 IHC to date that 20 of 38 (52.6%) human SUC had CPS > 50, which was driven mostly by tumor proportion score. Consistent with this, we found anti-PD1 immune checkpoint inhibitor (ICI) significantly inhibited BBN966 tumor growth, while the hybrid BBN964 tumors had mixed response to ICI. Thus, the murine BBN966 tumors exhibited similarities to human SUC, and can be used to examine novel therapies for translation into future SUC clinical studies.","rel_num_authors":30,"rel_authors":[{"author_name":"Yujiro Hayashi","author_inst":"Johns Hopkins University"},{"author_name":"Roy Elias","author_inst":"Johns Hopkins University"},{"author_name":"Eugene Douglass","author_inst":"University of Georgia"},{"author_name":"Akinaru Yamamoto","author_inst":"Johns Hopkins University"},{"author_name":"Matthew Schuler","author_inst":"Johns Hopkins University"},{"author_name":"Mingxiao Feng","author_inst":"Johns Hopkins University"},{"author_name":"Ekatherina Y. Batourina","author_inst":"Columbia University"},{"author_name":"Anne E. Geller","author_inst":"Johns Hopkins University"},{"author_name":"Woonyoung Choi","author_inst":"Johns Hopkins University"},{"author_name":"Gabriela Colocho","author_inst":"Johns Hopkins University"},{"author_name":"Alyssa Arbuiso","author_inst":"Johns Hopkins University"},{"author_name":"Samuel Jin","author_inst":"Johns Hopkins University"},{"author_name":"Adam K. Aragaki","author_inst":"Johns Hopkins University"},{"author_name":"Charles Ruland","author_inst":"Johns Hopkins University"},{"author_name":"Stanley Rapiey","author_inst":"Johns Hopkins University"},{"author_name":"Jean Hoffman-Censits","author_inst":"Johns Hopkins University"},{"author_name":"Max Kates","author_inst":"Johns Hopkins University"},{"author_name":"Sunil Patel","author_inst":"Johns Hopkins University"},{"author_name":"Nirmish Singla","author_inst":"Johns Hopkins University"},{"author_name":"Armine Smith","author_inst":"Johns Hopkins University"},{"author_name":"Stephanie Russell","author_inst":"Johns Hopkins University"},{"author_name":"Huili Li","author_inst":"Johns Hopkins University"},{"author_name":"Joshua I. Warrick","author_inst":"Yale University"},{"author_name":"Ezra Baraban","author_inst":"Johns Hopkins University"},{"author_name":"Karin Allenspach","author_inst":"University of Georgia"},{"author_name":"Cathy Lee Mendelsohn","author_inst":"Columbia University"},{"author_name":"Andres Matoso","author_inst":"Johns Hopkins University"},{"author_name":"Noah M. Hahn","author_inst":"Johns Hopkins University"},{"author_name":"David J. McConkey","author_inst":"Johns Hopkins University"},{"author_name":"Burles Avner Johnson III","author_inst":"Johns Hopkins University"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Epithelial to mesenchymal transition and M2 macrophages drive aggressiveness in murine and human sarcomatoid urothelial carcinoma.","rel_doi":"10.64898\/2026.09.30.755727","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.30.755727","rel_abs":"Patients with majority variant subtype histology including sarcomatoid urothelial carcinoma (SUC) have poor outcomes and limited treatment options, and there are few preclinical resources to investigate rare histologic subtypes. We developed three novel variant subtype histology bladder cancer (BC) cell lines by finding that basal BC tumor cells derived from mice treated with N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) were initially not competent to grow in immune competent mice, but then acquired tumorigenicity following passaging (recycling) in mice lacking mature B and T cells. Three genitourinary oncology pathologists identified BBN966 as SUC, BBN964 as a hybrid between SUC and squamous, and BBN975 as squamous, and each had unique growth characteristics. Using a publicly available dataset and our spatial transcriptomics analysis of a cohort of human tumors with mixed SUC and UC as comparators, we found that consistent with human SUC, BBN966 lack expression of basal and luminal genes. Consistent with human SUC and spatial transcriptomics analysis of canine SUC, BBN966 had the highest epithelial to mesenchymal transition (EMT) upregulation, and all three recycled tumor cells had increased EMT pathway expression in recycled tumor cells. Moreover, increased expression of genes upregulated in all three recycled tumor cells associated with worse overall survival in patients with muscle invasive UC. Similar to human SUC, BBN966 tumors had higher proportion of M2 macrophage gene expression. Finally, we found in the largest cohort of PD-L1 IHC to date that 20 of 38 (52.6%) human SUC had CPS > 50, which was driven mostly by tumor proportion score. Consistent with this, we found anti-PD1 immune checkpoint inhibitor (ICI) significantly inhibited BBN966 tumor growth, while the hybrid BBN964 tumors had mixed response to ICI. Thus, the murine BBN966 tumors exhibited similarities to human SUC, and can be used to examine novel therapies for translation into future SUC clinical studies.","rel_num_authors":30,"rel_authors":[{"author_name":"Yujiro Hayashi","author_inst":"Johns Hopkins University"},{"author_name":"Roy Elias","author_inst":"Johns Hopkins University"},{"author_name":"Eugene Douglass","author_inst":"University of Georgia"},{"author_name":"Akinaru Yamamoto","author_inst":"Johns Hopkins University"},{"author_name":"Matthew Schuler","author_inst":"Johns Hopkins University"},{"author_name":"Mingxiao Feng","author_inst":"Johns Hopkins University"},{"author_name":"Ekatherina Y. Batourina","author_inst":"Columbia University"},{"author_name":"Anne E. Geller","author_inst":"Johns Hopkins University"},{"author_name":"Woonyoung Choi","author_inst":"Johns Hopkins University"},{"author_name":"Gabriela Colocho","author_inst":"Johns Hopkins University"},{"author_name":"Alyssa Arbuiso","author_inst":"Johns Hopkins University"},{"author_name":"Samuel Jin","author_inst":"Johns Hopkins University"},{"author_name":"Adam K. Aragaki","author_inst":"Johns Hopkins University"},{"author_name":"Charles Ruland","author_inst":"Johns Hopkins University"},{"author_name":"Stanley Rapiey","author_inst":"Johns Hopkins University"},{"author_name":"Jean Hoffman-Censits","author_inst":"Johns Hopkins University"},{"author_name":"Max Kates","author_inst":"Johns Hopkins University"},{"author_name":"Sunil Patel","author_inst":"Johns Hopkins University"},{"author_name":"Nirmish Singla","author_inst":"Johns Hopkins University"},{"author_name":"Armine Smith","author_inst":"Johns Hopkins University"},{"author_name":"Stephanie Russell","author_inst":"Johns Hopkins University"},{"author_name":"Huili Li","author_inst":"Johns Hopkins University"},{"author_name":"Joshua I. Warrick","author_inst":"Yale University"},{"author_name":"Ezra Baraban","author_inst":"Johns Hopkins University"},{"author_name":"Karin Allenspach","author_inst":"University of Georgia"},{"author_name":"Cathy Lee Mendelsohn","author_inst":"Columbia University"},{"author_name":"Andres Matoso","author_inst":"Johns Hopkins University"},{"author_name":"Noah M. Hahn","author_inst":"Johns Hopkins University"},{"author_name":"David J. McConkey","author_inst":"Johns Hopkins University"},{"author_name":"Burles Avner Johnson III","author_inst":"Johns Hopkins University"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Epithelial to mesenchymal transition and M2 macrophages drive aggressiveness in murine and human sarcomatoid urothelial carcinoma.","rel_doi":"10.64898\/2026.09.30.755727","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.30.755727","rel_abs":"Patients with majority variant subtype histology including sarcomatoid urothelial carcinoma (SUC) have poor outcomes and limited treatment options, and there are few preclinical resources to investigate rare histologic subtypes. We developed three novel variant subtype histology bladder cancer (BC) cell lines by finding that basal BC tumor cells derived from mice treated with N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) were initially not competent to grow in immune competent mice, but then acquired tumorigenicity following passaging (recycling) in mice lacking mature B and T cells. Three genitourinary oncology pathologists identified BBN966 as SUC, BBN964 as a hybrid between SUC and squamous, and BBN975 as squamous, and each had unique growth characteristics. Using a publicly available dataset and our spatial transcriptomics analysis of a cohort of human tumors with mixed SUC and UC as comparators, we found that consistent with human SUC, BBN966 lack expression of basal and luminal genes. Consistent with human SUC and spatial transcriptomics analysis of canine SUC, BBN966 had the highest epithelial to mesenchymal transition (EMT) upregulation, and all three recycled tumor cells had increased EMT pathway expression in recycled tumor cells. Moreover, increased expression of genes upregulated in all three recycled tumor cells associated with worse overall survival in patients with muscle invasive UC. Similar to human SUC, BBN966 tumors had higher proportion of M2 macrophage gene expression. Finally, we found in the largest cohort of PD-L1 IHC to date that 20 of 38 (52.6%) human SUC had CPS > 50, which was driven mostly by tumor proportion score. Consistent with this, we found anti-PD1 immune checkpoint inhibitor (ICI) significantly inhibited BBN966 tumor growth, while the hybrid BBN964 tumors had mixed response to ICI. Thus, the murine BBN966 tumors exhibited similarities to human SUC, and can be used to examine novel therapies for translation into future SUC clinical studies.","rel_num_authors":30,"rel_authors":[{"author_name":"Yujiro Hayashi","author_inst":"Johns Hopkins University"},{"author_name":"Roy Elias","author_inst":"Johns Hopkins University"},{"author_name":"Eugene Douglass","author_inst":"University of Georgia"},{"author_name":"Akinaru Yamamoto","author_inst":"Johns Hopkins University"},{"author_name":"Matthew Schuler","author_inst":"Johns Hopkins University"},{"author_name":"Mingxiao Feng","author_inst":"Johns Hopkins University"},{"author_name":"Ekatherina Y. Batourina","author_inst":"Columbia University"},{"author_name":"Anne E. Geller","author_inst":"Johns Hopkins University"},{"author_name":"Woonyoung Choi","author_inst":"Johns Hopkins University"},{"author_name":"Gabriela Colocho","author_inst":"Johns Hopkins University"},{"author_name":"Alyssa Arbuiso","author_inst":"Johns Hopkins University"},{"author_name":"Samuel Jin","author_inst":"Johns Hopkins University"},{"author_name":"Adam K. Aragaki","author_inst":"Johns Hopkins University"},{"author_name":"Charles Ruland","author_inst":"Johns Hopkins University"},{"author_name":"Stanley Rapiey","author_inst":"Johns Hopkins University"},{"author_name":"Jean Hoffman-Censits","author_inst":"Johns Hopkins University"},{"author_name":"Max Kates","author_inst":"Johns Hopkins University"},{"author_name":"Sunil Patel","author_inst":"Johns Hopkins University"},{"author_name":"Nirmish Singla","author_inst":"Johns Hopkins University"},{"author_name":"Armine Smith","author_inst":"Johns Hopkins University"},{"author_name":"Stephanie Russell","author_inst":"Johns Hopkins University"},{"author_name":"Huili Li","author_inst":"Johns Hopkins University"},{"author_name":"Joshua I. Warrick","author_inst":"Yale University"},{"author_name":"Ezra Baraban","author_inst":"Johns Hopkins University"},{"author_name":"Karin Allenspach","author_inst":"University of Georgia"},{"author_name":"Cathy Lee Mendelsohn","author_inst":"Columbia University"},{"author_name":"Andres Matoso","author_inst":"Johns Hopkins University"},{"author_name":"Noah M. Hahn","author_inst":"Johns Hopkins University"},{"author_name":"David J. McConkey","author_inst":"Johns Hopkins University"},{"author_name":"Burles Avner Johnson III","author_inst":"Johns Hopkins University"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Creation of a High-Resolution, Continually Evolvable Lineage Tracer","rel_doi":"10.64898\/2026.09.30.754670","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.30.754670","rel_abs":"Cellular diversity is required for the proper function of many tissues, including the retina, with its ~130 cell types.1-3 Previous lineage studies suggested that retinal progenitor cells (RPCs) generate cell diversity through biased cell divisions.4-9 However, the extent to which each progenitor cell contributes to diversity, and the overarching rules governing the lineages of the collection of progenitor cells, are unknown. While classic lineage tracing approaches including retroviral labeling4,6,10, dye injection11,12, and time-lapse microscopy13,14 were used to make the foundational insights regarding retinal lineages, they cannot be used to interrogate multigenerational lineages at scale. Here we describe the creation of an evolvable lineage tracing tool, \"SCRIBBLE\" for Sequential Combinatorial Recorder for Iterative Barcode-Based Lineage Evolution. SCRIBBLE uses prime editor to iteratively edit a barcode sequence while preserving the order of genesis of clonally related progeny. Through a series of rationally designed high-throughput screens and design optimizations, we identified novel sequences that support a high level of barcode editing and information content. Evaluation of SCRIBBLE in embryonic mouse retina recapitulated known lineages in retinal development, demonstrating that SCRIBBLE is capable of high-resolution lineage tracing in a complex tissue.","rel_num_authors":12,"rel_authors":[{"author_name":"Ryan N Delgado","author_inst":"Harvard Medical School"},{"author_name":"Yichen Si","author_inst":"Harvard Medical School"},{"author_name":"Rebecca E Andersen","author_inst":"Boston Children's Hospital"},{"author_name":"ChangHee Lee","author_inst":"Harvard Medical School"},{"author_name":"Henry L Bushnell","author_inst":"Harvard Medical School"},{"author_name":"Jordan L Doman","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Smriti Pandey","author_inst":"The Broad Institute of MIT and Harvard"},{"author_name":"Alexander A Sousa","author_inst":"The Broad Institute of MIT and Harvard"},{"author_name":"Emma R West","author_inst":"Harvard Medical School"},{"author_name":"Carina E Dagotto","author_inst":"Harvard Medical School"},{"author_name":"David R Liu","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Constance L Cepko","author_inst":"Harvard Medical School"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"RasGRP1 promotes efficient intestinal tuft cell differentiation","rel_doi":"10.64898\/2026.09.30.755407","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.30.755407","rel_abs":"Intestinal stem and progenitor cells balance proliferation and lineage commitment to maintain epithelial homeostasis and adapt to environmental challenges. Tuft cells are a rare chemosensory lineage that rapidly expands in response to the cytokine IL-13 during helminth infection, yet how epithelial progenitor states influence this response remains incompletely understood. Using genetic mouse models, intestinal organoids, and single-cell approaches, we identify the Ras guanine nucleotide exchange factor RasGRP1 as an epithelial-intrinsic promoter of efficient tuft cell differentiation. Rasgrp1 is expressed in rare crypt epithelial cells distinct from Lgr5-positive stem cells. Once cells entered the tuft cell differentiation trajectory, Rasgrp1 deficiency has little impact on tuft cell maturation, including expression of the Pou2f3 tuft cell transcription factor. Instead, RasGRP1 acts at the progenitor stage, where it restrains EGFR-driven proliferation and supports a transcriptionally heterogeneous transit-amplifying state, including a subset of cells expressing Pou2f3, that is largely lost upon Rasgrp1 deficiency. Consistent with this model, EGFR inhibition restores tuft cell numbers in Rasgrp1-deficient organoids and cooperates with IL-13 to enhance tuft cell differentiation. Rasgrp1-deficient mice exhibit delayed tuft cell hyperplasia and inefficient helminth clearance. Conversely, constitutive epithelial RasGRP1 overexpression, uncoupled from its endogenous regulation, drives spontaneous tuft cell hyperplasia and accelerates parasite clearance, but alters the balance of intestinal epithelial lineages. Together, our findings identify RasGRP1 as a cell-intrinsic regulator that restrains progenitor proliferation and promotes responsiveness to IL-13, thereby coupling growth factor signaling, cell cycle control, and immune-driven epithelial lineage specification.","rel_num_authors":15,"rel_authors":[{"author_name":"Lauren A Shechtman","author_inst":"University of California, San Francisco"},{"author_name":"Philippe Depeille","author_inst":"Department of Anatomy, University of California, San Francisco; CA, U.S.A."},{"author_name":"Eric Smith","author_inst":"Department of Anatomy, University of California, San Francisco; CA, U.S.A."},{"author_name":"Hong-Erh Liang","author_inst":"Department of Medicine, University of California, San Francisco; CA, U.S.A."},{"author_name":"Tammie S. Y. Tam","author_inst":"CoLabs, University of California, San Francisco; CA, U.S.A."},{"author_name":"Annabelle Duflock","author_inst":"Department of Anatomy, University of California, San Francisco; CA, U.S.A."},{"author_name":"Victor S. Cortez","author_inst":"Department of Medicine, University of California, San Francisco; CA, U.S.A."},{"author_name":"Claire E. O'Leary","author_inst":"Department of Medicine, University of California, San Francisco; CA, U.S.A."},{"author_name":"Alan Shen","author_inst":"Department of Anatomy, University of California, San Francisco; CA, U.S.A."},{"author_name":"Wouter Bos","author_inst":"Department of Anatomy, University of California, San Francisco; CA, U.S.A."},{"author_name":"Gabriela K Fragiadakis","author_inst":"University of California, San Francisco"},{"author_name":"alexis K combes","author_inst":"UCSF"},{"author_name":"Hugo Gonzalez","author_inst":"Facultad de Ciencias para el Cuidado de la Salud, Universidad San Sebastian; Santiago, Chile"},{"author_name":"Richard M Locksley","author_inst":"UCSF"},{"author_name":"Jeroen P Roose","author_inst":"UCSF"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"RasGRP1 promotes efficient intestinal tuft cell differentiation","rel_doi":"10.64898\/2026.09.30.755407","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.30.755407","rel_abs":"Intestinal stem and progenitor cells balance proliferation and lineage commitment to maintain epithelial homeostasis and adapt to environmental challenges. Tuft cells are a rare chemosensory lineage that rapidly expands in response to the cytokine IL-13 during helminth infection, yet how epithelial progenitor states influence this response remains incompletely understood. Using genetic mouse models, intestinal organoids, and single-cell approaches, we identify the Ras guanine nucleotide exchange factor RasGRP1 as an epithelial-intrinsic promoter of efficient tuft cell differentiation. Rasgrp1 is expressed in rare crypt epithelial cells distinct from Lgr5-positive stem cells. Once cells entered the tuft cell differentiation trajectory, Rasgrp1 deficiency has little impact on tuft cell maturation, including expression of the Pou2f3 tuft cell transcription factor. Instead, RasGRP1 acts at the progenitor stage, where it restrains EGFR-driven proliferation and supports a transcriptionally heterogeneous transit-amplifying state, including a subset of cells expressing Pou2f3, that is largely lost upon Rasgrp1 deficiency. Consistent with this model, EGFR inhibition restores tuft cell numbers in Rasgrp1-deficient organoids and cooperates with IL-13 to enhance tuft cell differentiation. Rasgrp1-deficient mice exhibit delayed tuft cell hyperplasia and inefficient helminth clearance. Conversely, constitutive epithelial RasGRP1 overexpression, uncoupled from its endogenous regulation, drives spontaneous tuft cell hyperplasia and accelerates parasite clearance, but alters the balance of intestinal epithelial lineages. Together, our findings identify RasGRP1 as a cell-intrinsic regulator that restrains progenitor proliferation and promotes responsiveness to IL-13, thereby coupling growth factor signaling, cell cycle control, and immune-driven epithelial lineage specification.","rel_num_authors":15,"rel_authors":[{"author_name":"Lauren A Shechtman","author_inst":"University of California, San Francisco"},{"author_name":"Philippe Depeille","author_inst":"Department of Anatomy, University of California, San Francisco; CA, U.S.A."},{"author_name":"Eric Smith","author_inst":"Department of Anatomy, University of California, San Francisco; CA, U.S.A."},{"author_name":"Hong-Erh Liang","author_inst":"Department of Medicine, University of California, San Francisco; CA, U.S.A."},{"author_name":"Tammie S. Y. Tam","author_inst":"CoLabs, University of California, San Francisco; CA, U.S.A."},{"author_name":"Annabelle Duflock","author_inst":"Department of Anatomy, University of California, San Francisco; CA, U.S.A."},{"author_name":"Victor S. Cortez","author_inst":"Department of Medicine, University of California, San Francisco; CA, U.S.A."},{"author_name":"Claire E. O'Leary","author_inst":"Department of Medicine, University of California, San Francisco; CA, U.S.A."},{"author_name":"Alan Shen","author_inst":"Department of Anatomy, University of California, San Francisco; CA, U.S.A."},{"author_name":"Wouter Bos","author_inst":"Department of Anatomy, University of California, San Francisco; CA, U.S.A."},{"author_name":"Gabriela K Fragiadakis","author_inst":"University of California, San Francisco"},{"author_name":"alexis K combes","author_inst":"UCSF"},{"author_name":"Hugo Gonzalez","author_inst":"Facultad de Ciencias para el Cuidado de la Salud, Universidad San Sebastian; Santiago, Chile"},{"author_name":"Richard M Locksley","author_inst":"UCSF"},{"author_name":"Jeroen P Roose","author_inst":"UCSF"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Serum IgM crosslinks hepatitis B subviral particles into supramolecular immune complexes","rel_doi":"10.64898\/2026.09.30.755772","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.30.755772","rel_abs":"Hepatitis B virus (HBV)-infected cells release hepatitis B surface antigen (HBsAg)-rich subviral particles (SVPs) in large excess over infectious virions. SVPs bind antibodies against HBsAg (anti-HBs), including neutralizing antibodies, but the physical products of antibody capture in human blood are uncharacterized. Here we used cryo-electron tomography (cryo-ET) to image HBsAg-enriched serum from a patient with severe acute Hepatitis B and observed three-dimensional assemblies of intact IgM-SVP immune complexes. These associations persisted at a lower particle density and were validated by a spatial-randomization null model. Subtomogram averaging and single-particle cryo-electron microscopy (cryo-EM) identified three serum IgM Fc-core assemblies, IgM-J-CD5L, IgM-J and IgM-J-SC, with cryo-EM maps reaching 2.8 angstrom resolution. Mapping these Fc core assemblies into tomograms revealed full-length IgM engaging individual SVPs through several Fab arms and bridging neighboring particles into immune complex networks containing multiple IgM molecules and SVPs. Thus, serum IgM uses multivalent Fab interactions to crosslink HBsAg-rich SVPs into supramolecular immune complexes. This observation extends the SVP decoy model from passive antibody sequestration to higher-order particle organization.","rel_num_authors":15,"rel_authors":[{"author_name":"Chang Liu","author_inst":"The University of Texas at Austin"},{"author_name":"Aditi Dhawan","author_inst":"German Cancer Research Center (DKFZ)"},{"author_name":"Xinyi Yao","author_inst":"The University of Texas at Austin"},{"author_name":"Juyeon Park","author_inst":"The University of Texas at Austin"},{"author_name":"Gautam Penna","author_inst":"The University of Texas at Austin"},{"author_name":"Sean Mulligan","author_inst":"Oregon Health & Science University"},{"author_name":"Alexandra Beaver","author_inst":"The University of Texas at Austin"},{"author_name":"Helen Chen","author_inst":"The University of Texas at Austin"},{"author_name":"Flora Donati","author_inst":"German Cancer Research Center (DKFZ)"},{"author_name":"Stephan Urban","author_inst":"German Cancer Research Center (DKFZ)"},{"author_name":"Ralf Bartenschlager","author_inst":"German Cancer Research Center (DKFZ)"},{"author_name":"George Georgiou","author_inst":"The University of Texas at Austin"},{"author_name":"Shirin Nkongolo","author_inst":"University Health Network"},{"author_name":"Stefan Seitz","author_inst":"German Cancer Research Center (DKFZ)"},{"author_name":"Zunlong Ke","author_inst":"The University of Texas at Austin"}],"rel_date":"2026-10-02","rel_site":"biorxiv"},{"rel_title":"Time-aware machine learning enables early intrapartum identification of fetuses at risk of hypoxic-ischemic encephalopathy from cardiotocography","rel_doi":"10.64898\/2026.09.28.26364144","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.28.26364144","rel_abs":"Cardiotocography (CTG) is the standard of care for intrapartum fetal monitoring, yet its poor specificity drives unnecessary intervention without reducing hypoxic-ischemic encephalopathy (HIE). Most artificial intelligence (AI) models are trained exclusively on the final hour before delivery, a window only identifiable retrospectively. We hypothesized that this framework prevents models from learning the early evolving signs of HIE. We analyzed 174,186 deliveries, with gestational age GA[&ge;]35 weeks, from Kaiser Permanente Northern California. Forty CTG features were extracted from 20-minute epochs to train Random Forest classifiers targeting severe acidosis (N=2,636) and clinically validated HIE (N=304). The training window was progressively extended from the final hour to the full duration of labor, and time from labor onset (TLO) was added as a feature. Models were evaluated continuously throughout labor at a fixed 15% false positive rate. Our results showed that the early identification of fetuses at risk of HIE improved as the training window was extended, plateauing at 18 hours. Adding TLO gave the highest early-warning performance: 40.3% of HIE cases identified at least 3 hours and 27.3% at least 6 hours before delivery, absolute gains of 8.4% and 10.7% over the last-hour classifier. Finally, 55.7% of HIE cases were identified at least 40 minutes before delivery. In conclusion, classifiers trained only on the last hour may identify HIE patterns that occur near delivery; time-aware models trained across labor map the temporal evolution of these patterns and provide actionable early warnings. Thus, AI systems for intrapartum monitoring must account for the temporal evolution of labor to shift from end-of-labor diagnosis to early-warning decision support.","rel_num_authors":9,"rel_authors":[{"author_name":"Johann Vargas-Calixto","author_inst":"Emory University School of Medicine"},{"author_name":"Michael  W. Kuzniewicz","author_inst":"Kaiser Permanente Northern California"},{"author_name":"Marie-Coralie Cornet","author_inst":"University of California San Francisco"},{"author_name":"Yvonne  W. Wu","author_inst":"University of California San Francisco"},{"author_name":"Aditi Lahiri","author_inst":"Kaiser Permanente Northern California"},{"author_name":"Lawrence Gerstley","author_inst":"Kaiser Permanente Northern California"},{"author_name":"John Parker","author_inst":"PeriGen Inc."},{"author_name":"Philip  A. Warrick","author_inst":"PeriGen Inc."},{"author_name":"Robert  E. Kearney","author_inst":"McGill University"}],"rel_date":"2026-10-01","rel_site":"medrxiv"},{"rel_title":"Modelling the influence of the duration of effectiveness and time taken to implement vector control interventions for vector-borne diseases.","rel_doi":"10.64898\/2026.09.30.26364329","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.30.26364329","rel_abs":"Implementing vector control interventions against infectious diseases is operationally challenging, with delivery and population uptake taking considerable time within a community. Studies have suggested that the slow mass drug administration (MDA) of the endectocide, ivermectin, may have contributed to the lower epidemiological impact against malaria observed in recent cluster-randomised controlled trials, although evidence supporting this hypothesis is lacking. It is unclear whether interventions which have short but highly effective durations of entomological impact are more impactful than tools which kill the same number of mosquitoes but over a longer period. Transmission dynamics mathematical models can be used to explore the trade-offs between product profiles and investigate how different implementation periods could influence disease control. First, we use a simple vector-borne disease compartmental model to explore the epidemiological impact of killing the same number of mosquitoes over 10, 30 or 90 days. We find that for different mosquito-killing periods, the total number of cases averted is similar, although the observable impact may depend on when efficacy is assessed. Secondly, we adapted an existing malaria transmission model and simulated the fast and slow deployment of an effective endectocide MDA campaign in different seasonal settings. In perennial and seasonal settings and for a given coverage, slow MDA deployment averts more clinical cases of malaria than a fast synchronised distribution (completed in a single day, although the difference was modest). The benefits of the intervention depend on how well-timed a deployment is relative to the peak of the transmission season, with the efficacy of an ivermectin-like endectocide MDA being up to approximately 42% lower if started late. The work indicates that the time taken to complete MDA campaigns is unlikely to drive major differences in the effectiveness of short-lived endectocides and showcases how transmission dynamics models can be used to support epidemiological trial interpretation.","rel_num_authors":8,"rel_authors":[{"author_name":"Nilani Chandradeva","author_inst":"University of Glasgow"},{"author_name":"Andrew C. Glover","author_inst":"Imperial College London"},{"author_name":"Charles Whittaker","author_inst":"University of California, Berkeley"},{"author_name":"Tom Brewer","author_inst":"Imperial College London"},{"author_name":"Joseph  D. Challenger","author_inst":"Imperial College London"},{"author_name":"Hannah  C. Slater","author_inst":"PATH, Seattle, USA"},{"author_name":"Ellie Sherrard-Smith","author_inst":"Liverpool School of Tropical Medicine"},{"author_name":"Thomas  S. Churcher","author_inst":"Imperial College London"}],"rel_date":"2026-10-01","rel_site":"medrxiv"},{"rel_title":"The Effects of a Digital Exercise Therapy Application for Patients with Shoulder and Knee Pain During the COVID-19 Pandemic","rel_doi":"10.64898\/2026.09.25.26364013","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.25.26364013","rel_abs":"Objective: To examine changes in function and pain interference among patients utilizing a digital exercise therapy application (DETA) for knee and shoulder pain. Methods: We conducted a retrospective analysis of data from patients utilizing a DETA for non-operative knee and shoulder pain. Primary outcomes for the study were 8-week changes in physical function, measured using the PROMIS-Physical Function (knee pain) and PROMIS-Upper Extremity Function (shoulder pain); and pain interference, measured using the PROMIS-Pain Interference. Data on patient characteristics was used to examine outcomes among specific patient subgroups. Results: We observed a 3.5 point (SD: 7.8) increase in function and a 3.9 point (SD: 7.5) decrease in pain interference overall (p<0.001), with changes in function and pain interference surpassing the minimal clinically important difference for patients with knee and shoulder pain. Patients with knee pain experienced greater improvements in function than those with shoulder pain (p=0.02), as did patients who report moderate-high levels of exertion during exercise compared to those reporting low levels of exertion (p=0.05). We saw greater reductions in pain interference among those with higher education (p=0.03), those with more acute symptoms (p=0.01) and those reporting moderate-high levels of exercise exertion (p=0.02). Conclusion: We observed a clinically meaningful improvement in pain interference and function among patients utilizing a DETA for knee and shoulder pain. Patients with knee pain, higher levels of education, more acute symptoms, and those who reported higher levels of exertion with exercise experienced the greatest changes in function and pain. Impact Statement: This study indicates that self-guided interventions, such as those delivered through a DETA, may be beneficial for patients with knee and shoulder pain. These results may also inform the development of patient profiles that can be used to identify patients most appropriate to receive care through a mobile application.","rel_num_authors":6,"rel_authors":[{"author_name":"Kevin H McLaughlin","author_inst":"Johns Hopkins University"},{"author_name":"Marc Gruner","author_inst":"Limber Health"},{"author_name":"Negar Ahmadian","author_inst":"Limber Health"},{"author_name":"Tiffany Patch","author_inst":"Emory University"},{"author_name":"Bashir Zakria","author_inst":"Johns Hopkins University"},{"author_name":"Richard L Skolasky","author_inst":"Johns Hopkins University"}],"rel_date":"2026-10-01","rel_site":"medrxiv"},{"rel_title":"Triangulating population, individual, and genetic evidence for priority setting in structurally heterogeneous blocs: metabolic risk factors for stroke in the Shanghai Cooperation Organisation","rel_doi":"10.64898\/2026.09.30.26364374","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.30.26364374","rel_abs":"BACKGROUND: Regional stroke-prevention priorities usually rest on what a bloc's members share. Where members span multiple Global Burden of Disease (GBD) super-regions and genetic ancestry groups, population, individual, and genetic evidence face different transportability limits, and earlier combined studies did not prespecify what counts as disagreement. METHODS: We studied the Shanghai Cooperation Organisation, which spans four super-regions and five ancestry groups and is land-contiguous. For five metabolic risk factors we triangulated GBD 2023 attributable fractions of stroke DALYs in ten states, incident stroke among 7896 adults in the China Health and Retirement Longitudinal Study (2011-18; SHRs per 1 SD), and subtype-specific Mendelian randomisation in three ancestries. An explicit rule set, with one pre-submission amendment, classified convergence and divergence by whether a listed mechanism accounted for it. FINDINGS: High systolic blood pressure converged: 53-71% of attributable DALYs, the strongest cohort exposure (SHR 1.37, 95% CI 1.26-1.48), and genetically supported in both ancestries. LDL cholesterol (GBD attribution restricted to ischaemic stroke; European genetic evidence for that subtype; no cohort association) and body-mass index (last in attribution but second in the cohort, with a 1.80-fold [1.48-2.18] gradient inside the 20-25 kg\/m2 minimum-risk window) showed structural discordance. The cohort lacked subtype data to establish LDL dilution. Fasting glucose and kidney dysfunction diverged without such a mechanism. INTERPRETATION: Systolic blood pressure had the strongest cross-stream support. LDL cholesterol and body-mass index require qualified interpretation; fasting glucose and kidney dysfunction could not be ranked reliably. The framework identifies where priorities require scrutiny. FUNDING: None.","rel_num_authors":5,"rel_authors":[{"author_name":"Xinyu Wang","author_inst":"Department of Neurosurgery, Xuanwu Hospital, Capital Medical University"},{"author_name":"Mu Li","author_inst":"School of Economics, Beijing Technology and Business University"},{"author_name":"Junzhao Zhang","author_inst":"School of Basic Medical Sciences, Capital Medical University"},{"author_name":"Hongqi Zhang","author_inst":"Department of Neurosurgery, Xuanwu Hospital, Capital Medical University"},{"author_name":"Yongjie Ma","author_inst":"Xuanwu hospital, Capital Medical University"}],"rel_date":"2026-10-01","rel_site":"medrxiv"},{"rel_title":"Real-World Implementation and Clinical Outcomes of Mavacamten in an Underserved Urban Cohort With Obstructive Hypertrophic Cardiomyopathy","rel_doi":"10.64898\/2026.09.29.26364363","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.29.26364363","rel_abs":"Background Real-world data regarding mavacamten use in underserved and racially diverse populations remain limited, particularly for long-term therapy implementation. Structural barriers such as financial instability, fragmented healthcare access, and challenges adhering to REMS-related monitoring requirements may affect longitudinal therapy implementation. Methods We performed a retrospective observational study of consecutive patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) evaluated for mavacamten therapy at a tertiary HCM center in Bronx, NY, between 6\/2022-10\/2025. Patients were followed for up to 48 weeks after treatment initiation. Clinical characteristics, treatment interruptions, adverse events, echocardiographic and functional outcomes, and implementation barriers were assessed descriptively. Results Seventy-two patients with symptomatic oHCM were evaluated for mavacamten; sixty-seven initiated treatment. Mean age was 66.9{+\/-}15.3 years, 72% were female, and 61% identified as Black or Hispanic. Median resting left ventricular outflow tract (LVOT) gradient decreased from 51mmHg (IQR30-88) at baseline to 7mmHg (IQR5-10) at 48 weeks. Median Valsalva LVOT gradient decreased from 74mmHg (IQR50-104) to 20mmHg (IQR10-29). At final follow-up, 80% of patients improved by [&ge;]1 NYHA functional class. LVEF declined below 50% in five patients and recovered in all cases. Approximately one-quarter experienced treatment interruption or discontinuation, nearly half related to insurance instability, non-adherence, and REMS-related monitoring barriers. Conclusions Mavacamten demonstrated efficacy and safety outcomes comparable to those reported in clinical trials and prior registries in this predominantly underserved minority urban cohort. However, structural and healthcare-access barriers substantially affected long-term treatment implementation. These findings highlight the need to address healthcare-system barriers to ensure equitable implementation of contemporary HCM therapies.","rel_num_authors":4,"rel_authors":[{"author_name":"Joshua Bock","author_inst":"New York City Health and Hospitals Jacobi"},{"author_name":"Sandhya Murthy","author_inst":"Montefiore Medical Center, Albert Einstein College of Medicine"},{"author_name":"Aldo L Schenone","author_inst":"'Montefiore Medical Center\/Albert Einstein College of Medicine"},{"author_name":"Adaya Weissler-Snir","author_inst":"Morristown Medical Center"}],"rel_date":"2026-10-01","rel_site":"medrxiv"},{"rel_title":"Effects of 2025-2026 U.S. health and science policy changes on academic pulmonary and critical care medicine: an ASPIRE-PCCM prospective survey study","rel_doi":"10.64898\/2026.09.25.26364007","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.25.26364007","rel_abs":"Background: The rapidly evolving United States (U.S.) health and science policy landscape in 2025 may have heterogeneous effects on academic medicine, biomedical research, physician workforce development and patient care. Research Question: How do academic pulmonary and critical care medicine (PCCM) physicians perceive U.S. health and science policy changes and which changes do they consider most influential on research, trainee education and clinical care? Study Design and Methods: We conducted a prospective survey from March 27, 2026 through April 29, 2026 among selected faculty at U.S. academic PCCM programs as part of the Alliance of Scholars and Professionals for Innovation, Research, and Education in Pulmonary and Critical Care Medicine (ASPIRE-PCCM). Results: Ninety-four of 99 ASPIRE-PCCM panel members completed the survey (response rate 95%), representing 18 of 19 ASPIRE-PCCM wave 1 institutions. All respondents reported the rate of changes in U.S. federal health and science policy in the first half of 2025 as 6 or higher on a scale of 1 (\"typical pace of change\") to 10 (\"most change in my lifetime\"), with 89 (96%) evaluating the changes as harmful or very harmful. Respondents identified cancellation of research grants, disruptions and changes to NIH scientific review processes, and changes to visa and immigration policies as key factors affecting early career recruitment. Reported negative effects on quality of care included increased vaccine hesitancy, changing reimbursement structures, and diminished research capacity. State-level and non-governmental efforts, including professional society advocacy, institutional bridge funding and personal advocacy efforts were identified as partially mitigating harms. Despite these concerns, 72% of respondents reported that would still pursue careers in PCCM. Interpretation: Academic pulmonary and critical care physicians reported challenges following recent U.S. health and science policy changes that may be mitigated, but not neutralized, by institutional, professional-society, and individual actions.","rel_num_authors":6,"rel_authors":[{"author_name":"Theodore J Iwashyna","author_inst":"Johns Hopkins"},{"author_name":"Yvette Shu","author_inst":"Johns Hopkins"},{"author_name":"Catherine Ettman","author_inst":"Johns Hopkins"},{"author_name":"Elizabeth Viglianti","author_inst":"University of Michigan"},{"author_name":"David Furfaro","author_inst":"Beth Israel Deaconess Hospital"},{"author_name":"Kristina Montemayor","author_inst":"Johns Hopkins"}],"rel_date":"2026-10-01","rel_site":"medrxiv"},{"rel_title":"Correlates of Protection and Response Durability of the RTS,S Vaccine in Four Malaria Challenge Studies","rel_doi":"10.64898\/2026.09.30.26364316","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.30.26364316","rel_abs":"RTS,S\/AS01 (RTS,S) is one of two WHO-recommended malaria vaccines for children in moderate-to-high transmission settings. Yet, no validated immune correlate of protection (CoP) has been established for this vaccine. We selected 16 biomarkers to further assess as candidate CoPs, based largely on their ability to well-predict post-challenge outcomes in a previous integrative correlates analysis of two phase 2a controlled human malaria infection (CHMI) studies, Malaria-068 and Malaria-071. We evaluated the predictive power of these 16 biomarkers in two additional phase 2a CHMI studies, Malaria-092 and Malaria-102, to confirm these candidate CoPs in new malaria vaccine trials. In MAL092, malaria-naive volunteers were challenged three months after a series of two or three doses of RTS,S\/AS01, and in MAL102, a subset were boosted nine months later and re-challenged after three weeks. The 16 biomarkers included Plasmodium falciparum circumsporozoite protein (CSP)-specific IgG antibodies targeting the CSP NANP-repeat region (CSP IgG ELISA), NANP repeat-specific antibody binding to human Fc gamma receptors (FcgRs), CSP-specific antibody Fc effector functions, total NANP6-specific serum Ig measured by biolayer interferometry (BLI), and NANP6-specific IgG1 antibodies measured by binding antibody multiplex assay. Immunogenicity analyses confirmed that the vaccine regimens elicited robust immune responses, including multiple biomarkers not previously reported on, in both trials. In MAL092, participants clustered into two distinct immunogenicity profiles that overlapped with malaria protection status. In univariate logistic regression analyses, most biomarkers were significantly associated with protection when measured on the day of challenge in both trials. Notably, the same three biomarkers ranked as top correlates in both trials (FCGR2AH NANP6, FCGR2AR NANP6, and FCGR2B NANP6; all adjusted p-values <0.001), with similar effect sizes across studies. Despite these strong associations, no biomarker demonstrated significantly better individual-level predictive performance than CSP IgG ELISA. In MAL092, CSP IgG ELISA achieved an area under the curve (AUC) [95% confidence interval (CI)] of 0.74 (0.63, 0.84), compared with AUCs of 0.76 - 0.78 for the top five biomarkers, all of which reflected NANP6-specific Fc{gamma}R binding (all adjusted p-values > 0.37 versus CSP IgG ELISA). Predictive models trained on data from two prior CHMI studies and applied to MAL092 and MAL102 identified a model based on FCGR2B NANP6 (validation AUC = 0.77 in MAL092; 0.80 in MAL102) as the best-performing univariate model for both studies. The best-performing multivariate predictive model for MAL092 was based on BLI NANP6 Dissociation AUC and ADCP NANP6 (validation AUC = 0.76), and in MAL102, it was based on CSP IgG ELISA, BLI NANP6 Dissociation AUC, and ADCP NANP6 (validation AUC = 0.82). The next approximately 10 highest-ranked models, however, had comparable performance with overlapping 95% CIs, and none were clearly superior to CSP IgG ELISA (validation AUCs 0.74 and 0.71 in MAL092 and MAL102, respectively). Collectively, these findings suggest that the majority of the previously identified candidate CoPs also hold up well in two additional malaria vaccine CHMI trials and underscore the continued utility of the CSP IgG ELISA readout as a robust marker of protection. Further studies are needed to determine whether these candidate CoPs hold in malaria-endemic field settings. Identifying validated CoPs that predict malaria vaccine efficacy would promote the development and approval of more effective and durable next-generation vaccines. These advances could also inform vaccine strategies for other infectious diseases.","rel_num_authors":24,"rel_authors":[{"author_name":"Soo-Young Kim","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Thomas Linnekin","author_inst":"SeromYx Systems"},{"author_name":"Lindsay Nicole Carpp","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Cynthia K. Lee","author_inst":"PATHs Center for Vaccine Innovation and Access"},{"author_name":"Christian F. Ockenhouse","author_inst":"PATHs Center for Vaccine Innovation and Access"},{"author_name":"Laina D. Mercer","author_inst":"PATHs Center for Vaccine Innovation and Access"},{"author_name":"Scott Gregory","author_inst":"PATHs Center for Vaccine Innovation and Access"},{"author_name":"Caitlyn Linde","author_inst":"SeromYx Systems"},{"author_name":"Todd Suscovich","author_inst":"SeromYx Systems"},{"author_name":"Tom Shneer","author_inst":"SeromYx Systems"},{"author_name":"Kelly E. Seaton","author_inst":"Duke University"},{"author_name":"S. Moses Dennison","author_inst":"Duke University"},{"author_name":"Rachel L. Spreng","author_inst":"Duke University"},{"author_name":"Sarah V. Mudrak","author_inst":"Duke University"},{"author_name":"Laura Fontana","author_inst":"Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard"},{"author_name":"Drienna Holman","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Solmaz Shotorbani","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Jishnu Das","author_inst":"SeromYx Systems"},{"author_name":"James E. Moon","author_inst":"Walter Reed Army Institute of Research"},{"author_name":"Neville Kisalu","author_inst":"PATHs Center for Vaccine Innovation and Access"},{"author_name":"Lenny Moise","author_inst":"SeromYx Systems"},{"author_name":"Galit Alter","author_inst":"Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard"},{"author_name":"Georgia Tomaras","author_inst":"Duke University"},{"author_name":"Ollivier Hyrien","author_inst":"Fred Hutchinson Cancer Center"}],"rel_date":"2026-10-01","rel_site":"medrxiv"},{"rel_title":"Clonal Hematopoiesis Accelerates Frailty and Functional Decline","rel_doi":"10.64898\/2026.09.24.26363888","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.24.26363888","rel_abs":"Frailty reflects declining physiological reserve across multiple organ systems with aging, yet the underlying biological mechanisms contributing to frailty remain poorly understood. We tested whether somatic mutations in the blood were associated with incident frailty and faster progression in 730,088 participants from UK Biobank, All of Us, BioVU and the Womens Health Initiative. We found that clonal hematopoiesis of indeterminate potential (CHIP) and autosomal mosaic chromosomal alterations showed strong associations with frailty, whereas mosaic loss of chromosome X or Y did not. Findings were consistent across survey-based, directly measured and clinically assessed frailty, as well as healthspan phenotypes. A Tet2 mouse model demonstrated multisystem frailty-like functional decline and T-cell remodeling. In humans, T-cell activation-related proteins directly mediated the association between clonal hematopoiesis and frailty. Collectively, these findings support a model in which clonal hematopoiesis accelerates biological aging through immunosenescence.","rel_num_authors":25,"rel_authors":[{"author_name":"Kun Zhao","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Candice Quin","author_inst":"School of Biological Sciences, Victoria University of Wellington"},{"author_name":"Yash Pershad","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Liying Xue","author_inst":"Vanderbilt University"},{"author_name":"Weizhi Cao","author_inst":"Vanderbilt University"},{"author_name":"Grace I Bowman","author_inst":"University of Colorado Boulder, Boulder"},{"author_name":"Caitlyn Vlasschaert","author_inst":"Queen's University"},{"author_name":"Robert W Corty","author_inst":"Vanderbilt University Medical Center"},{"author_name":"J. Brett Heimlich","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Erica N DeJong","author_inst":"McMaster University"},{"author_name":"Caitlin Lee","author_inst":"Queens University"},{"author_name":"Zil Patel","author_inst":"Queens University"},{"author_name":"Marco M Buttigieg","author_inst":"Queens University"},{"author_name":"Chris P Verschoor","author_inst":"McMaster University"},{"author_name":"Calum A Bane","author_inst":"University of Aberdeen"},{"author_name":"Amy J.M. McNaughton","author_inst":"Queens University"},{"author_name":"Dawn M.E. Bowdish","author_inst":"McMaster University"},{"author_name":"George A Kuchel","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Eric A. Whitsel","author_inst":"Department of Epidemiology, Gillings School of Public Health and Department of Medicine, University of North Carolina - Chapel Hill, NC"},{"author_name":"Aladdin H Shadyab","author_inst":"University of California San Diego"},{"author_name":"Charles Kooperberg","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Andrea Z LaCroix","author_inst":"University of California San Diego"},{"author_name":"Alexander P. Reiner","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Michael J Rauh","author_inst":"Queens University"},{"author_name":"Alexander G Bick","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-10-01","rel_site":"medrxiv"},{"rel_title":"Clonal Hematopoiesis Accelerates Frailty and Functional Decline","rel_doi":"10.64898\/2026.09.24.26363888","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.24.26363888","rel_abs":"Frailty reflects declining physiological reserve across multiple organ systems with aging, yet the underlying biological mechanisms contributing to frailty remain poorly understood. We tested whether somatic mutations in the blood were associated with incident frailty and faster progression in 730,088 participants from UK Biobank, All of Us, BioVU and the Womens Health Initiative. We found that clonal hematopoiesis of indeterminate potential (CHIP) and autosomal mosaic chromosomal alterations showed strong associations with frailty, whereas mosaic loss of chromosome X or Y did not. Findings were consistent across survey-based, directly measured and clinically assessed frailty, as well as healthspan phenotypes. A Tet2 mouse model demonstrated multisystem frailty-like functional decline and T-cell remodeling. In humans, T-cell activation-related proteins directly mediated the association between clonal hematopoiesis and frailty. Collectively, these findings support a model in which clonal hematopoiesis accelerates biological aging through immunosenescence.","rel_num_authors":25,"rel_authors":[{"author_name":"Kun Zhao","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Candice Quin","author_inst":"School of Biological Sciences, Victoria University of Wellington"},{"author_name":"Yash Pershad","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Liying Xue","author_inst":"Vanderbilt University"},{"author_name":"Weizhi Cao","author_inst":"Vanderbilt University"},{"author_name":"Grace I Bowman","author_inst":"University of Colorado Boulder, Boulder"},{"author_name":"Caitlyn Vlasschaert","author_inst":"Queen's University"},{"author_name":"Robert W Corty","author_inst":"Vanderbilt University Medical Center"},{"author_name":"J. Brett Heimlich","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Erica N DeJong","author_inst":"McMaster University"},{"author_name":"Caitlin Lee","author_inst":"Queens University"},{"author_name":"Zil Patel","author_inst":"Queens University"},{"author_name":"Marco M Buttigieg","author_inst":"Queens University"},{"author_name":"Chris P Verschoor","author_inst":"McMaster University"},{"author_name":"Calum A Bane","author_inst":"University of Aberdeen"},{"author_name":"Amy J.M. McNaughton","author_inst":"Queens University"},{"author_name":"Dawn M.E. Bowdish","author_inst":"McMaster University"},{"author_name":"George A Kuchel","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Eric A. Whitsel","author_inst":"Department of Epidemiology, Gillings School of Public Health and Department of Medicine, University of North Carolina - Chapel Hill, NC"},{"author_name":"Aladdin H Shadyab","author_inst":"University of California San Diego"},{"author_name":"Charles Kooperberg","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Andrea Z LaCroix","author_inst":"University of California San Diego"},{"author_name":"Alexander P. Reiner","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Michael J Rauh","author_inst":"Queens University"},{"author_name":"Alexander G Bick","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-10-01","rel_site":"medrxiv"},{"rel_title":"Clonal Hematopoiesis Accelerates Frailty and Functional Decline","rel_doi":"10.64898\/2026.09.24.26363888","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.24.26363888","rel_abs":"Frailty reflects declining physiological reserve across multiple organ systems with aging, yet the underlying biological mechanisms contributing to frailty remain poorly understood. We tested whether somatic mutations in the blood were associated with incident frailty and faster progression in 730,088 participants from UK Biobank, All of Us, BioVU and the Womens Health Initiative. We found that clonal hematopoiesis of indeterminate potential (CHIP) and autosomal mosaic chromosomal alterations showed strong associations with frailty, whereas mosaic loss of chromosome X or Y did not. Findings were consistent across survey-based, directly measured and clinically assessed frailty, as well as healthspan phenotypes. A Tet2 mouse model demonstrated multisystem frailty-like functional decline and T-cell remodeling. In humans, T-cell activation-related proteins directly mediated the association between clonal hematopoiesis and frailty. Collectively, these findings support a model in which clonal hematopoiesis accelerates biological aging through immunosenescence.","rel_num_authors":25,"rel_authors":[{"author_name":"Kun Zhao","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Candice Quin","author_inst":"School of Biological Sciences, Victoria University of Wellington"},{"author_name":"Yash Pershad","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Liying Xue","author_inst":"Vanderbilt University"},{"author_name":"Weizhi Cao","author_inst":"Vanderbilt University"},{"author_name":"Grace I Bowman","author_inst":"University of Colorado Boulder, Boulder"},{"author_name":"Caitlyn Vlasschaert","author_inst":"Queen's University"},{"author_name":"Robert W Corty","author_inst":"Vanderbilt University Medical Center"},{"author_name":"J. Brett Heimlich","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Erica N DeJong","author_inst":"McMaster University"},{"author_name":"Caitlin Lee","author_inst":"Queens University"},{"author_name":"Zil Patel","author_inst":"Queens University"},{"author_name":"Marco M Buttigieg","author_inst":"Queens University"},{"author_name":"Chris P Verschoor","author_inst":"McMaster University"},{"author_name":"Calum A Bane","author_inst":"University of Aberdeen"},{"author_name":"Amy J.M. McNaughton","author_inst":"Queens University"},{"author_name":"Dawn M.E. Bowdish","author_inst":"McMaster University"},{"author_name":"George A Kuchel","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Eric A. Whitsel","author_inst":"Department of Epidemiology, Gillings School of Public Health and Department of Medicine, University of North Carolina - Chapel Hill, NC"},{"author_name":"Aladdin H Shadyab","author_inst":"University of California San Diego"},{"author_name":"Charles Kooperberg","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Andrea Z LaCroix","author_inst":"University of California San Diego"},{"author_name":"Alexander P. Reiner","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Michael J Rauh","author_inst":"Queens University"},{"author_name":"Alexander G Bick","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-10-01","rel_site":"medrxiv"},{"rel_title":"Clonal Hematopoiesis Accelerates Frailty and Functional Decline","rel_doi":"10.64898\/2026.09.24.26363888","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.24.26363888","rel_abs":"Frailty reflects declining physiological reserve across multiple organ systems with aging, yet the underlying biological mechanisms contributing to frailty remain poorly understood. We tested whether somatic mutations in the blood were associated with incident frailty and faster progression in 730,088 participants from UK Biobank, All of Us, BioVU and the Womens Health Initiative. We found that clonal hematopoiesis of indeterminate potential (CHIP) and autosomal mosaic chromosomal alterations showed strong associations with frailty, whereas mosaic loss of chromosome X or Y did not. Findings were consistent across survey-based, directly measured and clinically assessed frailty, as well as healthspan phenotypes. A Tet2 mouse model demonstrated multisystem frailty-like functional decline and T-cell remodeling. In humans, T-cell activation-related proteins directly mediated the association between clonal hematopoiesis and frailty. Collectively, these findings support a model in which clonal hematopoiesis accelerates biological aging through immunosenescence.","rel_num_authors":25,"rel_authors":[{"author_name":"Kun Zhao","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Candice Quin","author_inst":"School of Biological Sciences, Victoria University of Wellington"},{"author_name":"Yash Pershad","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Liying Xue","author_inst":"Vanderbilt University"},{"author_name":"Weizhi Cao","author_inst":"Vanderbilt University"},{"author_name":"Grace I Bowman","author_inst":"University of Colorado Boulder, Boulder"},{"author_name":"Caitlyn Vlasschaert","author_inst":"Queen's University"},{"author_name":"Robert W Corty","author_inst":"Vanderbilt University Medical Center"},{"author_name":"J. Brett Heimlich","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Erica N DeJong","author_inst":"McMaster University"},{"author_name":"Caitlin Lee","author_inst":"Queens University"},{"author_name":"Zil Patel","author_inst":"Queens University"},{"author_name":"Marco M Buttigieg","author_inst":"Queens University"},{"author_name":"Chris P Verschoor","author_inst":"McMaster University"},{"author_name":"Calum A Bane","author_inst":"University of Aberdeen"},{"author_name":"Amy J.M. McNaughton","author_inst":"Queens University"},{"author_name":"Dawn M.E. Bowdish","author_inst":"McMaster University"},{"author_name":"George A Kuchel","author_inst":"University of Connecticut School of Medicine"},{"author_name":"Eric A. Whitsel","author_inst":"Department of Epidemiology, Gillings School of Public Health and Department of Medicine, University of North Carolina - Chapel Hill, NC"},{"author_name":"Aladdin H Shadyab","author_inst":"University of California San Diego"},{"author_name":"Charles Kooperberg","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Andrea Z LaCroix","author_inst":"University of California San Diego"},{"author_name":"Alexander P. Reiner","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Michael J Rauh","author_inst":"Queens University"},{"author_name":"Alexander G Bick","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-10-01","rel_site":"medrxiv"},{"rel_title":"PROTEOMIC IDENTIFICATION OF NOVEL AUTOANTIBODY TARGETS IN RHEUMATOID ARTHRITIS AND DIAGNOSTIC PERFORMANCE OF TGF-BETA-1-INDUCED PROTEIN AND SERUM AMYLOID A AUTOANTIBODIES","rel_doi":"10.64898\/2026.09.25.26361099","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.25.26361099","rel_abs":"Objective: The principal diagnostic test for rheumatoid arthritis (RA) relies on the detection of anti-cyclic citrullinated peptide (CCP) antibodies. The CCP test exhibits moderate sensitivity and specificity but does not adequately detect a high proportion of cases or effectively distinguish RA from related conditions such as systemic lupus erythematosus (SLE). To discover improved diagnostic biomarkers for RA, we performed a comprehensive proteomic analysis of antibody-bound antigens present in RA, SLE, and healthy control (HC) sera and identified proteins associated with transforming growth factor-beta-1 (TGF-beta-1) signaling and assessed the sensitivity and specificity of antibodies against these antigens in comparison to CCP. Methods: Total antibodies were immunoprecipitated from pooled sera of HC individuals (n=3) and patients with clinically diagnosed RA (n=3) or SLE (n=3). Antibody-bound antigens were identified using multidimensional protein identification technology (MudPIT) shotgun proteomics. Candidate antigens associated with TGF-beta-1 signaling were selected for evaluation, and corresponding serum autoantibodies were assessed for their ability to classify RA using a POC lateral-flow immunochromatographic format. Results: Proteins present in antibody immunoprecipitations included TGF-beta-1-induced protein (TGFBI), thrombospondin 1 (TSP1), serum amyloid A1 (SAA), and fibronectin (FN). POC assays using these candidates, as well as TGF-beta-1 itself, as capture antigens were used to detect corresponding serum autoantibodies in 107 subjects with clinically diagnosed RA, 42 subjects with other rheumatic diseases (non-RA), and 121 HC subjects. Receiver operating characteristic curves were constructed using RA and HC groups to assess diagnostic performance, and optimal cutpoints identified using the Youden Index (maximizing the sum of sensitivity and specificity). CCP test results were determined using previously established thresholds. Using an analysis et of 169 subjects in the HC and RA groups who had values for TGFBI, SAA, and CCP, TGFBI autoantibodies achieved a sensitivity of 82%, specificity of 98.8%, positive likelihood ratio (PLR) of 65.6, and NLR of 0.2. SAA autoantibodies achieved a sensitivity of 92.1%, specificity of 85%, PLR of 6.1, and NLR of 0.1. Both outperformed CCP (sensitivity of 68.5%, specificity of 95%, PLR of 13.7, and NLR of 0.3). Using an analysis set of 120 subjects in the RA and non-RA groups who had values for TGFBI, SAA, and CCP, TGFBI and SAA autoantibodies exhibited sensitivities and specificities of 82 and 92.1% and 74.2 and 45.2%, respectively, compared to 68.5 and 74.2% for CCP. Autoantibodies to TGF-beta-1, TSP1, and FN exhibited only modest diagnostic performance. Conclusion: RA sera contain autoantibodies targeting multiple proteins associated with the TGF-beta-1 signaling pathway that is implicated in inflammatory processes in RA. Among the candidates tested, TGFBI and SAA autoantibodies exhibited the highest diagnostic performance in a POC lateral-flow format, supporting their potential utility as biomarkers for RA diagnosis. These findings also support further investigation of the TGF-beta-1 signaling pathway as a potential therapeutic target in RA.","rel_num_authors":12,"rel_authors":[{"author_name":"Melissa Frenchmeyer","author_inst":"ModalityDx"},{"author_name":"Michael Moleski","author_inst":"ModalityDx"},{"author_name":"Stephanie Fernandez","author_inst":"ModalityDx"},{"author_name":"Allison Keilman","author_inst":"ModalityDx"},{"author_name":"Kilsun Kim","author_inst":"Oregon Health & Science University"},{"author_name":"Keith Zientek","author_inst":"Oregon Health & Science University"},{"author_name":"Philip Wilmarth","author_inst":"Oregon Health & Science University"},{"author_name":"Ashok Reddy","author_inst":"Oregon Health & Science University"},{"author_name":"Lina Gao","author_inst":"Oregon Health & Science University"},{"author_name":"Vishnupriya R Paturi","author_inst":"ModalityDx"},{"author_name":"Charles T Roberts","author_inst":"Diabetomics, Inc."},{"author_name":"Srinivasa R Nagalla","author_inst":"ModalityDx"}],"rel_date":"2026-10-01","rel_site":"medrxiv"},{"rel_title":"Quantifying advances in infectious disease forecast skill across seasons and pathogens","rel_doi":"10.64898\/2026.09.29.26364307","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.29.26364307","rel_abs":"Infectious disease forecasting supports public health preparedness and response by informing resource allocation, intervention planning, and situational awareness. Infectious disease forecasting capabilities in the United States have grown over the past decade yet whether forecast quality has improved over this time remains unclear. Current evaluation metrics describe relative performance for a common set of forecast targets but cannot evaluate performance across different outcomes, seasons, and pathogens. We addressed this challenge by developing a novel skill score metric to assess forecasts based on performance relative to two benchmark models: a hindcast as an idealized upper bound of performance and a baseline model as a minimal performance standard. To study the impact of the baseline choice, we considered three types of baseline models with varying levels of complexity. Using this skill score framework, we retrospectively evaluated short-term influenza (influenza-like illness and hospitalization) and COVID-19 (case, death, and hospitalization) forecasts, focusing on how the performance of team and multi-model ensemble forecasts changed over time. The ensemble outperformed 99% of forecasts from a simplistic, naive baseline, and 84-91% of forecasts from more complex baseline models that incorporate recent data. We found consistent improvements in ensemble and team forecast skill over time for both influenza forecast targets, with 4-week horizon forecasts in the most recent year having higher skill scores than 1-week horizon forecasts in the first year of each challenge. Results were mixed for COVID-19 forecasts. This framework provides a comprehensive picture of progress in infectious disease forecasting over the past decade enabled by improved standardization, data, models, and collaboration.","rel_num_authors":7,"rel_authors":[{"author_name":"Clara Bay","author_inst":"Northeastern University"},{"author_name":"Nima R. Moghaddas","author_inst":"Northeastern University"},{"author_name":"Jessica T Davis","author_inst":"Northeastern University"},{"author_name":"Rebecca Borchering","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Matthew Biggerstaff","author_inst":"Centers for Disease Control & Prevention"},{"author_name":"Alessandro Vespignani","author_inst":"Northeastern University"},{"author_name":"Michael A. Johansson","author_inst":"Northeastern University"}],"rel_date":"2026-10-01","rel_site":"medrxiv"},{"rel_title":"Environmental exposures associated with behavioral outcomes and their link to endogenous metabolites in children born very preterm","rel_doi":"10.64898\/2026.09.25.26364017","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.25.26364017","rel_abs":"Abstract: Background: Children born very preterm (VPT) are at elevated risk for adverse neurobehavioral outcomes and are vulnerable to environmental exposures. We used untargeted metabolomics analysis to identify environmentally relevant metabolites associated with childhood behavioral problems and to characterize related endogenous metabolic pathways. Methods: We studied 226 children born <30 weeks gestation in a multi-site cohort study. Urine collected at age 4 was profiled using untargeted ultra-high-performance liquid chromatography high-resolution mass spectrometry (UHPLC-HRMS). Associations between 30 exogenous environmental metabolites and behavioral problems score at age 4 were evaluated cross-sectionally using multivariable linear regression, followed by metabolome-wide association and pathway enrichment analyses. Results: Three exogenous metabolites were nominally associated with child behavior problems. Specifically, 2-(Acetylamino)-3-( henylthiol)propanoic acid was positively associated with overall ({beta}=1.42, p=0.006), externalizing ({beta}=1.50, p=0.006), and internalizing ({beta}=1.34, p=0.021) behavior problems. Diethofencarb was positively associated with overall ({beta}=0.34, p=0.018) and externalizing ({beta}=0.39, p=0.010) behavior problems, while protocatechuic acid was inversely associated with internalizing problems ({beta}=-0.68, p=0.027). No associations remained significant after false discovery rate (FDR) correction. Nevertheless, these metabolites were associated with 151, 131, and 530 endogenous metabolic features, respectively, at FDR<0.05, highlighting perturbations in lipid metabolism, mitochondrial energetics, inflammatory signaling, amino acid metabolism, and neuroactive pathways. Conclusions: Environmental metabolites associated with behavior problems were linked to broad endogenous metabolic differences relevant to neurodevelopment. These findings highlight potentially modifiable environmental influences, including exposures related to combustion-derived pollutants, pesticides, and dietary sources, that may contribute to behavioral vulnerability among children born very preterm","rel_num_authors":7,"rel_authors":[{"author_name":"Priyadarshni Patel","author_inst":"Emory Rollins School of Public Health"},{"author_name":"Youran Tan","author_inst":"Emory Rollins School of Public Health"},{"author_name":"Donghai Liang","author_inst":"Emory Rollins School of Public Health"},{"author_name":"Marie Camerota","author_inst":"Alpert Medical School of Brown University"},{"author_name":"Carmen Marsit","author_inst":"Emory University Rollins School of Public Health"},{"author_name":"Barry M Lester","author_inst":"Women & Infants Hospital \/ Brown University"},{"author_name":"Todd Everson","author_inst":"Emory Rollins School of Public Health"}],"rel_date":"2026-10-01","rel_site":"medrxiv"},{"rel_title":"Occupational endotoxin exposure, DNA methylation changes, and immune-cell remodeling: an epigenome-wide association study in two cohorts","rel_doi":"10.64898\/2026.09.29.26364351","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.29.26364351","rel_abs":"Background: Millions of textile and agricultural workers inhale organic dust containing endotoxin, an exposure associated with impaired respiratory function. However, the underlying biological pathways remain unclear. We conducted a two-cohort epigenome-wide association study (EWAS) to identify airborne endotoxin-associated DNA methylation (DNAm) alterations and pathways. Methods: In the discovery phase, we compared blood DNAm in 281 endotoxin-exposed cotton workers and 253 unexposed silk-workers from the Shanghai Textile Worker Study (STWS) measured using Illumina MethylationEPICv2 arrays. STWS endotoxin assessment combined detailed work histories and onsite measurements. For targeted parallel validation, we tested STWS signals in 686 incident lung cancer cases and 683 matched controls from the Shanghai Women's Health Study (SWHS), using occupation-derived low, medium, or high exposure-intensity ranks based on published evidence. To gain biological insight, we analyzed pathway enrichment, immune-cell composition, DNAm inflammation risk scores (IRSs), and respiratory phenotype associations in STWS. Results: In STWS, we identified 36 epigenome-wide significant DNAm sites (P<5e-8), of which, 35 were hypomethylated. Among 30 sites testable in SWHS, 18 had concordant effect directions, and four were nominally significant: cg11869499 (POLG; P=0.041), cg16290931 (TSKS; P=0.044), cg05019530 (EPIC1; P=0.042), and cg26033526 (PSMB9\/TAP1; P=0.013). Enrichment implicated immune and signal-transduction pathways, including IgSF cell-adhesion-molecule signaling (FDR=8.2e-6;). Neutrophil were higher in cotton workers than in silk workers (63.5% vs 58.9%, p=7.52e-10). Cumulative endotoxin was associated with higher CRP-based IRSs, which showed the most consistent associations with lower lung function and airflow obstruction. Conclusions: Our EWAS findings suggest that occupational endotoxin may operate partly through immune-cell composition and inflammatory pathways.","rel_num_authors":19,"rel_authors":[{"author_name":"Hantao Wang","author_inst":"National Institutes of Health"},{"author_name":"Mohammad L Rahman","author_inst":"National Cancer Institute"},{"author_name":"Charles E Breeze","author_inst":"Colorado State University"},{"author_name":"Jungeun Lim","author_inst":"National Heart Lung and Blood Institute"},{"author_name":"Wei Hu","author_inst":"National Cancer Institute"},{"author_name":"Fengying Zhang","author_inst":"Shanghai Putuo District People's Hospital"},{"author_name":"Qiuyin Cai","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Gong Yang","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jirong Long","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Li Su","author_inst":"Harvard T.H. Chan School of Public Health"},{"author_name":"Yu-Tang Gao","author_inst":"Shanghai Cancer Institute"},{"author_name":"Xiao-ou Shu","author_inst":"Vanderbilt"},{"author_name":"Batel Blechter","author_inst":"National Cancer Institute"},{"author_name":"Jianxin Shi","author_inst":"National Cancer Insititute"},{"author_name":"Nathaniel Rothman","author_inst":"National Cancer Institute"},{"author_name":"Wei Zheng","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Qing Lan","author_inst":"National Cancer Institute"},{"author_name":"David  C Christiani","author_inst":"Harvard University T H Chan School of Public Health"},{"author_name":"Jason Wong","author_inst":"National Heart Lung and Blood Institute"}],"rel_date":"2026-10-01","rel_site":"medrxiv"},{"rel_title":"Widespread 3-Base Periodicity in Complex DNA Mixtures and an Alignment-Free Algorithm to Uncover its Source","rel_doi":"10.64898\/2026.09.26.754620","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.26.754620","rel_abs":"Background: Protein-coding DNA exhibits characteristic three-base periodicity. In unaligned DNA libraries, however, this signal should cancel if fragment boundaries are uniformly distributed across codon phases. Yet, we find that in multiple metagenomic libraries, base frequencies depended systematically on distance from fragment boundaries, producing a period-3 pattern. We investigated the origin of this unexpected signal. Results: The signal was observed in modern metagenomic datasets and widely across ancient-DNA datasets. We developed a new alignment-free algorithm to infer latent triplet-phase structure from nucleotide composition. The inferred shifts were strongly nonuniform at fragment boundaries, explaining the read-coordinate periodicity. We initially suspected a protocol artifact. To test an alternative, we derived a probabilistic framework linking nucleotide-dependent boundary selection to codon-phase frequencies. The framework showed that, because nucleotide composition differs among codon positions, preferential breakage at particular nucleotides biases the phases represented at fragment boundaries. Simulations confirmed this mechanism: purine-associated fragmentation produced strong period-3 coherence in a coding-dense bacterial genome, whereas no comparable genome-wide effect appeared in the human reference genome. Conclusions: The observed read-coordinate three-base periodicity does not require an intrinsic phase bias in the source DNA. Instead, sequence-dependent fragment formation or recovery can couple boundaries to codon phase. Purine-associated post-mortem fragmentation plausibly explains the widespread phenomenon in ancient-DNA libraries, although PCR- or library-specific mechanisms may contribute to it in modern datasets. Our alignment-free algorithm provides a practical method for estimating and normalizing phase shifts before searching for positional nucleotide patterns, preventing boundary-associated bias from being mistaken for an intrinsic biological pattern.","rel_num_authors":6,"rel_authors":[{"author_name":"noam hecht","author_inst":"tel aviv university"},{"author_name":"Nicolas Duek","author_inst":"tel aviv university"},{"author_name":"Yuval Dotan","author_inst":"tel aviv university"},{"author_name":"Saharon Rosset","author_inst":"tel aviv university"},{"author_name":"Viviane Slon","author_inst":"Tel Aviv University"},{"author_name":"Muli Safra","author_inst":"tel aviv university"}],"rel_date":"2026-10-01","rel_site":"biorxiv"},{"rel_title":"Evaluation of Human Norovirus Replication in Salivary Gland Cells","rel_doi":"10.64898\/2026.09.29.755260","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.29.755260","rel_abs":"Human noroviruses (HuNoVs) are the most common cause of non-bacterial foodborne illnesses worldwide. HuNoVs are notoriously difficult to culture, and current cell culture systems, such as human intestinal enteroids have limitations in efficiency and scalability, which has limited their applications in food safety studies. Recently, it has been shown that transformed salivary gland cell lines (including NS-SV-TT-DC) allow for replication and passaging of norovirus GII.4. Herein, we examined whether we can independently observe viral replication in salivary gland cells and if other strains of human norovirus can replicate in these cells. For this purpose, we first evaluated the replication of several norovirus strains in NS-SV-TT-DC cells by either infecting them with vesicle-cloaked viruses or total viruses in stool filtrates. Low levels of viral replication was observed and vesicle isolation did not improve viral replication. Next, we screened for replication of 50 norovirus samples from 9 genotypes, and 14 isolates demonstrated over a two-fold viral replication. We observed that the initial viral load in the samples does not have a significant effect on replication efficiency. We were also able to passage several isolates. Subsequently, we examined whether interferon inhibitors such as Ruxolitinib, TPCA-1, and BX795 would improve viral replication and observed negligible effects. Finally we tested multiple supplements including MgCl2, bile salt, ceramide, and TAK-779. Most supplements had little or no effect on HuNoV replication in NS-SV-TT-DC cells. Bile salt and TAK-779 showed limited, genotype-specific benefits. Altogether these results indicate that salivary gland cells allow limited replication of certain HuNoV isolates.","rel_num_authors":5,"rel_authors":[{"author_name":"Jennifer Harlow","author_inst":"Health Canada"},{"author_name":"Simon Briggs","author_inst":"Health Canada"},{"author_name":"Emma Pothier","author_inst":"Health Canada"},{"author_name":"Katheryn Pham","author_inst":"University of Ottawa"},{"author_name":"Neda Nasheri","author_inst":"Health Canada"}],"rel_date":"2026-10-01","rel_site":"biorxiv"},{"rel_title":"Evaluation of Human Norovirus Replication in Salivary Gland Cells","rel_doi":"10.64898\/2026.09.29.755260","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.29.755260","rel_abs":"Human noroviruses (HuNoVs) are the most common cause of non-bacterial foodborne illnesses worldwide. HuNoVs are notoriously difficult to culture, and current cell culture systems, such as human intestinal enteroids have limitations in efficiency and scalability, which has limited their applications in food safety studies. Recently, it has been shown that transformed salivary gland cell lines (including NS-SV-TT-DC) allow for replication and passaging of norovirus GII.4. Herein, we examined whether we can independently observe viral replication in salivary gland cells and if other strains of human norovirus can replicate in these cells. For this purpose, we first evaluated the replication of several norovirus strains in NS-SV-TT-DC cells by either infecting them with vesicle-cloaked viruses or total viruses in stool filtrates. Low levels of viral replication was observed and vesicle isolation did not improve viral replication. Next, we screened for replication of 50 norovirus samples from 9 genotypes, and 14 isolates demonstrated over a two-fold viral replication. We observed that the initial viral load in the samples does not have a significant effect on replication efficiency. We were also able to passage several isolates. Subsequently, we examined whether interferon inhibitors such as Ruxolitinib, TPCA-1, and BX795 would improve viral replication and observed negligible effects. Finally we tested multiple supplements including MgCl2, bile salt, ceramide, and TAK-779. Most supplements had little or no effect on HuNoV replication in NS-SV-TT-DC cells. Bile salt and TAK-779 showed limited, genotype-specific benefits. Altogether these results indicate that salivary gland cells allow limited replication of certain HuNoV isolates.","rel_num_authors":5,"rel_authors":[{"author_name":"Jennifer Harlow","author_inst":"Health Canada"},{"author_name":"Simon Briggs","author_inst":"Health Canada"},{"author_name":"Emma Pothier","author_inst":"Health Canada"},{"author_name":"Katheryn Pham","author_inst":"University of Ottawa"},{"author_name":"Neda Nasheri","author_inst":"Health Canada"}],"rel_date":"2026-10-01","rel_site":"biorxiv"},{"rel_title":"Non-coding RNAs drive transcriptional network rewiring underlying thermal dimorphism in a human pathogenic fungus","rel_doi":"10.64898\/2026.09.29.755541","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.29.755541","rel_abs":"As fungal pathogens pose mounting global challenges, decoding their complex adaptive traits remains a paramount academic priority. While previous studies have provided foundational insights into protein-coding variations and orphan genes, fully understanding such traits requires exploring upstream non-coding regulatory networks. Here, we present a high-resolution, rRNA-depleted temporal transcriptomic framework across reciprocal dimorphic transitions to decode how non-coding network rewiring involving in fungal adaption. Integrating temporal profiling with comparative genomics reveals that early ATP-related metabolic reprogramming and melanin biosynthesis direct morphogenesis via species-specific motifs. Further temporal network modeling uncovers a functional stratification where long non-coding RNAs orchestrate early stress responses, whereas circular RNAs drive morphological conversion. Functional validation confirms that hub non-coding transcripts mediate stress adaptation, with cross-species perturbation in the closest non-pathogen species altering phenotypic outcomes. Together, these findings demonstrate how system-level non-coding dynamics underlie the evolutionary innovation of thermal dimorphism, establishing a robust paradigm for understanding specialized fungal pathogenicity and evolution adaption.","rel_num_authors":3,"rel_authors":[{"author_name":"Xueyan Hu","author_inst":"Peking University"},{"author_name":"Juan Wang","author_inst":"Peking University"},{"author_name":"Ence Yang","author_inst":"Peking University"}],"rel_date":"2026-10-01","rel_site":"biorxiv"},{"rel_title":"Adaptive respiratory bypass restores oxidative metabolism in NADH dehydrogenase-deficient Escherichia coli","rel_doi":"10.64898\/2026.10.01.755914","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.10.01.755914","rel_abs":"Nicotinamide adenine dinucleotide is central to the cellular redox network and continuously cycles between its oxidized (NAD) and reduced (NADH) forms. Membrane-bound NADH dehydrogenases are the primary NADH-oxidizing enzymes and principal entry point for reducing equivalents into the bacterial respiratory chain. While maintaining optimal balance of this redox cofactor is among the most fundamental biochemical constraints on living systems, how cells adapt when the primary NADH oxidation route is lost remains poorly understood. Here we show that Escherichia coli lacking both NADH dehydrogenases initially compensates through costly fermentative lactate secretion, potentially to maintain redox and energy homeostasis, but at the cost of impaired growth and oxidative metabolism. Using adaptive laboratory evolution across four independent lineages, we found that all evolved populations derepressed malate:quinone oxidoreductase by disrupting an ArcA-binding site. This gain-of-function mutation establishes an alternative pathway that funnels electrons directly into the quinone pool, restoring respiratory oxygen consumption to wild-type level. Multi-omics and genome-scale metabolic modeling reveal that this bypass drives broad reorganization of central carbon metabolism, reinstates tricarboxylic acid cycle flux, and shifts cells toward a higher, more oxidative aero-type. These findings uncover a previously unrecognized metabolic buffering capacity that enables bacteria to circumvent loss of canonical respiratory entry points.","rel_num_authors":5,"rel_authors":[{"author_name":"Arpita Biswas","author_inst":"Tata Institute of Fundamental Research, Mumbai, India"},{"author_name":"Arjun Patel","author_inst":"Department of Biology, San Diego State University, San Diego, CA, USA."},{"author_name":"Nikita Goel","author_inst":"TIFR, Mumbai, India"},{"author_name":"Snehal V. Khairnar","author_inst":"TIFR, Mumbai, India"},{"author_name":"Amitesh Anand","author_inst":"Tata Institute of Fundamental Research"}],"rel_date":"2026-10-01","rel_site":"biorxiv"},{"rel_title":"Stressor Identity Shapes Reactivity To Subsequent Stress","rel_doi":"10.64898\/2026.09.26.754453","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.26.754453","rel_abs":"Extensive work has established that exposure to a single acute stressor can have profound impacts on future reactivity to new stressors, including enhanced acquisition of new fear. The impact of stressor type on development of stress sensitization, however, remains unclear. We investigated whether fundamentally different acute stressors (shock, social defeat, or restraint stress) differ in ability to sensitize acquisition of a new, contextually distinct fear memory in adult male mice two weeks following stress exposure. Stressor subtype differentially sensitized new fear learning; specifically, shock and social defeat - but not restraint stress - led to enhanced recall of a new shock-paired fear memory. We also compared how stressor subtypes differentially engage the brain-periphery interactions that regulate stress responsivity. Notably, restraint stress, which did not lead to fear sensitization to foot shock, drove similar or even greater corticosterone release than other stressors, suggesting that the neuroendocrine response to the original stressor is dissociable from development of a behavioural fear sensitization response. Using the immediate-early gene FOS as a marker of neural activity, all conditions - including the context-only control condition - activated a similar number of neurons in the basolateral amygdala. In contrast, only stressful conditions activated the paraventricular nucleus of the hypothalamus, and restraint stress selectively spared activation of the dorsal hippocampus. These data collectively suggest that future responses to stress depend critically on the identity of previously experienced stressors, rather than simply on prior exposure to stress, establishing a powerful comparative model for investigating the specific mechanisms underlying stress-enhanced fear learning.","rel_num_authors":11,"rel_authors":[{"author_name":"Robert J Aukema","author_inst":"McLean Hospital, Harvard Medical School"},{"author_name":"Lauren T Seabrook","author_inst":"McLean Hospital, Harvard Medical School"},{"author_name":"Byung Kwon Moon","author_inst":"McLean Hospital"},{"author_name":"Paloma Martinez","author_inst":"McLean Hospital"},{"author_name":"Claudia Klengel","author_inst":"McLean Hospital"},{"author_name":"Bettina Ventura","author_inst":"McLean Hospital"},{"author_name":"Olga Ponomareva","author_inst":"McLean Hospital, Harvard Medical School"},{"author_name":"Jakob Hartmann","author_inst":"McLean Hospital, Harvard Medical School"},{"author_name":"William A. Carlezon Jr.","author_inst":"McLean Hospital, Harvard Medical School"},{"author_name":"Junghyup Suh","author_inst":"McLean Hospital, Harvard Medical School"},{"author_name":"Kerry J Ressler","author_inst":"McLean Hospital, Harvard Medical School"}],"rel_date":"2026-10-01","rel_site":"biorxiv"},{"rel_title":"Decoding brain anatomy from neuronal neighborhoods with MYCEL","rel_doi":"10.64898\/2026.09.26.754562","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.26.754562","rel_abs":"Extracellular recordings carry information about neuronal location, and pooling per-unit predictions across neighboring electrodes improves its readout, but whether this local pooling should be learned is untested. We present MYCEL (Message-passing Yields Cellular Embeddings of Location), a graph neural network whose nodes are spike-sorted units carrying waveform and spike-timing features selected on cell-type ground truth, and whose edges encode recording geometry. On the Allen Brain Observatory Visual Coding Neuropixels dataset, learned message passing outperforms fixed aggregation, with the largest gains where single units are least informative. On the International Brain Laboratory Brain Wide Map, MYCEL matches the strongest population model at one-tenth the pairwise interactions. On held-out animals, the embeddings recover laminar depth within visual cortex. Retrained with only the edge geometry changed, the same framework decodes anatomy in macaque visual cortex and human medial temporal lobe. Thus, how neighboring neurons are combined matters as much as the features that describe them.","rel_num_authors":7,"rel_authors":[{"author_name":"Jesus Gonzalez-Ferrer","author_inst":"University of California Santa Cruz"},{"author_name":"Avelina Moreno-Ochando","author_inst":"University of California Santa Cruz"},{"author_name":"John R Minnick","author_inst":"University of California Santa Cruz"},{"author_name":"Aidan Schneider","author_inst":"Yale University"},{"author_name":"Mircea Teodorescu","author_inst":"University of California Santa Cruz"},{"author_name":"David Haussler","author_inst":"University of California Santa Cruz"},{"author_name":"Mohammed A Mostajo-Radji","author_inst":"University of California Santa Cruz"}],"rel_date":"2026-10-01","rel_site":"biorxiv"},{"rel_title":"Challenges and opportunities for integrating genetic diversity monitoring in megadiverse countries: reflections from Mexico","rel_doi":"10.64898\/2026.09.26.754592","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.26.754592","rel_abs":"Megadiverse countries concentrate most of the World's biodiversity. These countries encompass different levels of research infrastructure, and nearly all of them have been historically committed to the Convention of Biological Diversity, often setting precedents and leading new approaches. Here, we ask whether the assessment of genetic diversity indicators provide novel insights for biodiversity management and conservation in one of those countries, Mexico. We evaluated the first national application of the Kunming-Montreal Global Biodiversity Framework (GBF), genetic diversity indicators in Mexico. The data covered 97 taxa across diverse ecosystem types and taxonomic groups, including crop wild relatives, to assess the capacity of genetic diversity indicators to provide novel insights, as well as their relevance for strengthening national conservation strategies. We calculated two indicators: the proportion of populations with an effective population size greater than 500 (Ne 500) and the proportion of populations maintained (PM). Data were sufficient to estimate the Ne 500 indicator for 47 taxa and the PM for 28 taxa, with mean indicator values of 0.217 and 0.936, respectively. Species' geographic range was positively associated with Ne 500, whereas national endemicity had no significant effect. Comparisons with the IUCN Red List and Mexico's national extinction-risk legislation revealed that genetic vulnerability occurs even among taxa not currently recognized as threatened. Our findings highlight a gap in legal recognition of genetic diversity protection that could be strengthened by incorporating population-level assessments focused on maintaining adaptive potential in the long-term. Additionally, the indicators allowed to highlight conservation concerns within crop wild relatives, though fully realizing their potential requires integrating the entire wild-to-domesticated complex. The Mexican experience highlights that the main challenge for scaling the monitoring of genetic diversity is not only generating new data, but integrating existing information into systems that strengthen collaboration and communication among researchers, local communities, and government institutions.","rel_num_authors":24,"rel_authors":[{"author_name":"Alicia Mastretta-Yanes","author_inst":"Royal Botanic Gardens, Kew, Richmond, Surrey, United Kingdom"},{"author_name":"Libertad Arredondo Amezcua","author_inst":"Investigadora independiente, Michoacan, Mexico"},{"author_name":"Alexander Llanes-Quevedo","author_inst":"Museo de Zoologia \"Alfonso L. Herrera\" Facultad de Ciencias, UNAM, Avenida Universidad 3000, Circuito Exterior s\/n, Ciudad Universitaria, Alcaldia Coyoacan, C.P"},{"author_name":"Maria Camila Latorre-Cardenas","author_inst":"Instituto de Investigaciones en Ecosistemas y Sustentabilidad, Universidad Nacional Autonoma de Mexico, Antigua carretera a Patzuaro 8701, Morelia, Michoacan, 5"},{"author_name":"Juan Francisco Ornelas","author_inst":"Red de Biologia Evolutiva, Instituto de Ecologia, A.C. (INECOL), Carretera Antigua a Coatepec No. 351, El Haya, Xalapa, Veracruz 91073, Mexico"},{"author_name":"Santiago Ramirez Barahona","author_inst":"Departamento de Botanica, Instituto de Biologia, Universidad Nacional Autonoma de Mexico, Tercer Circuito Exterior s\/n, Ciudad Universitaria, C.P. 04510, Ciudad"},{"author_name":"Eugenia Zarza","author_inst":"Departamento de Ciencias de la Sustentabilidad, El Colegio de la Frontera Sur, Tapachula, Chiapas, Mexico -- Investigadora por Mexico, Secretaria de Ciencia, Hu"},{"author_name":"Rossana Amaro-Garcia","author_inst":"Genetica de la Conservacion, Jardin Botanico, Instituto de Biologia, Universidad Nacional Autonoma de Mexico, Tercer Circuito Exterior s\/n, Ciudad Universitaria"},{"author_name":"Francisca Acevedo Gasman","author_inst":"Comision Nacional para el Conocimiento y Uso de la Biodiversidad (CONABIO), Liga Periferico-Insurgentes Sur No. 4903, Colonia Parques del Pedregal, Alcaldia Tla"},{"author_name":"Valeria Alavez","author_inst":"Genetica de la Conservacion, Jardin Botanico, Instituto de Biologia, Universidad Nacional Autonoma de Mexico, Tercer Circuito Exterior s\/n, Ciudad Universitaria"},{"author_name":"Caroline Burgeff","author_inst":"Comision Nacional para el Conocimiento y Uso de la Biodiversidad (CONABIO), Liga Periferico-Insurgentes Sur No. 4903, Colonia Parques del Pedregal, Alcaldia Tla"},{"author_name":"Andrea Cruz-Angon","author_inst":"NBSAP-Accelerator Partnership, UN Environment Programme, United Nations Avenue, Gigiri Nairobi, Kenya, P.O. Box 30552, 00100, Nairobi, Kenya"},{"author_name":"Rusby G. Contreras-Diaz","author_inst":"Escuela Nacional de Estudios Superiores, Unidad Merida, Universidad Nacional Autonoma de Mexico, Merida, Yucatan, Mexico"},{"author_name":"Maria Andrea Orjuela Restrepo","author_inst":"Comision Nacional para el Conocimiento y Uso de la Biodiversidad (CONABIO), Liga Periferico-Insurgentes Sur No. 4903, Colonia Parques del Pedregal, Alcaldia Tla"},{"author_name":"Oswaldo Oliveros-Galindo","author_inst":"Comision Nacional para el Conocimiento y Uso de la Biodiversidad (CONABIO), Liga Periferico-Insurgentes Sur No. 4903, Colonia Parques del Pedregal, Alcaldia Tla"},{"author_name":"Melissa Rios-Lopez","author_inst":"Genetica de la Conservacion, Jardin Botanico, Instituto de Biologia, Universidad Nacional Autonoma de Mexico, Tercer Circuito Exterior s\/n, Ciudad Universitaria"},{"author_name":"Diana Maria Rivera-Rodriguez","author_inst":"Instituto Tecnologico de Tlajomulco, Tecnologico Nacional de Mexico, Carretera Tlajomulco-San Miguel Cuyutlan Km. 10. C.P. 45640, Tlajomulco de Zuniga, Jalisco,"},{"author_name":"Jose de Jesus Sanchez-Gonzalez","author_inst":"Universidad de Guadalajara (Jubilado), Av. Juarez No. 976, Colonia Centro, C.P. 44100, Guadalajara, Jalisco, Mexico"},{"author_name":"Sofia Suarez-Acuna","author_inst":"Facultad de Ciencias, UNAM, Avenida Universidad 3000, Circuito Exterior s\/n, Ciudad Universitaria, Alcaldia Coyoacan, C.P. 04510, Ciudad de Mexico, Mexico"},{"author_name":"Jessica M. da Silva","author_inst":"University of Johannesburg, Department of Zoology. Centre for Ecological Genomics and Wildlife Conservation, Auckland Park Campus, Johannesburg 2006, South Afri"},{"author_name":"Sean Hoban","author_inst":"The Morton Arboretum, Center for Tree Science, Lisle, USA"},{"author_name":"Viktoria Koppa","author_inst":"Department of Zoology, Stockholm University, Stockholm, Sweden"},{"author_name":"Linda Laikre","author_inst":"Department of Zoology, Stockholm University, Stockholm, Sweden"},{"author_name":"Ana Wegier","author_inst":"Genetica de la Conservacion, Jardin Botanico, Instituto de Biologia, Universidad Nacional Autonoma de Mexico, Tercer Circuito Exterior s\/n, Ciudad Universitaria"}],"rel_date":"2026-10-01","rel_site":"biorxiv"},{"rel_title":"Humoral Immune Dysregulation Defines High-Risk Cirrhotic Ascites","rel_doi":"10.64898\/2026.09.25.754574","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.25.754574","rel_abs":"Fluid accumulates within serosal cavities in diverse disease states, where it creates biologically active and potentially pathologic niches. How these expanded microenvironments reflect and shape disease biology remains incompletely resolved. Here, we investigated human ascites fluid (n = 118), a hallmark of decompensated cirrhosis, to determine whether signatures of microbial exposure and local host response distinguish outcomes. Cirrhotic ascites was characterized by barrier remodeling, depletion of plasma cell-associated programs, and enrichment of oropharyngeal microbes. Surprisingly, detection of oropharyngeal microbes in ascites was not associated with adverse outcomes. Instead, the ascites of cirrhotic patients with poor outcomes was marked by profound plasma cell depletion and significantly reduced dimeric IgA, despite the presence of antigen-experienced B cells. Together, these findings identify local B cell dysregulation as a previously underappreciated component of cirrhosis-associated immune dysfunction. Impaired local humoral immunity, rather than microbial translocation alone, emerges as a feature of high-risk decompensated cirrhosis.","rel_num_authors":17,"rel_authors":[{"author_name":"Arielle Klepper","author_inst":"University of California, San Francisco"},{"author_name":"Matt S Zinter","author_inst":"University of California, San Francisco"},{"author_name":"Tamara Roach","author_inst":"University of California, San Francisco"},{"author_name":"Sukhman Sidhu","author_inst":"University of California, San Francisco"},{"author_name":"Zoe Berman","author_inst":"University of California, San Francisco"},{"author_name":"Ishaan Dureja","author_inst":"University of California, San Francisco"},{"author_name":"Ravi Dandekar","author_inst":"University of California San Francisco"},{"author_name":"Sammer Ganem","author_inst":"University of California, San Francisco"},{"author_name":"Karina Perlaza","author_inst":"University of California, San Francisco"},{"author_name":"Bryan Castillo-Rojas","author_inst":"University of California, San Francisco"},{"author_name":"Kelsey Zorn","author_inst":"University of California, San Francisco"},{"author_name":"Jacquelyn J Maher","author_inst":"University of California San Francisco"},{"author_name":"Jody L Baron","author_inst":"University of California, San Francisco"},{"author_name":"Matthew Yocum","author_inst":"University of California, San Francisco"},{"author_name":"Andrew R Lai","author_inst":"University of California, San Francisco"},{"author_name":"Jennifer Lai","author_inst":"University of California, San Francisco"},{"author_name":"Joseph L DeRisi","author_inst":"University of California, San Francisco"}],"rel_date":"2026-10-01","rel_site":"biorxiv"},{"rel_title":"SEEKER: A genome-scale library-on-library screening platform for deciphering T cell recognition of antigen","rel_doi":"10.64898\/2026.09.25.753432","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.25.753432","rel_abs":"Decoding which antigens activate a given T cell receptor (TCR) is a central challenge in immunology. We present SEEKER, a functional genome-scale library-on-library screening platform built on three elements: a Jurkat-derived T-APC cell (TAPCell) that combinatorially expresses one TCR and one peptide-MHC drawn from separate libraries together with an NFAT activation reporter; encapsulation of single TAPCells in a thermos-reversible hydrogel for isolated clonal expansion, so recognition is read out as intraclonal activation; and dual-asymmetric PCR that links TCR- and pMHC-encoding sequences into a heritable unit, enabling progressive hit enrichment over screening rounds. SEEKER interrogates ~10^8 TCR-pMHC combinations per run without prior knowledge. Screening joint-infiltrating CD8+ T cells from HLA-B*27+ ankylosing spondylitis patients against proteome-wide libraries validated 53 TCR-peptide pairs, uncovered extensive cross-recognition of self and common viral epitopes, and revealed highly polyreactive T cells recognizing up to 80 autoantigens, implicating virus-triggered poly-autoreactivity in multi-organ autoimmune diseases.","rel_num_authors":13,"rel_authors":[{"author_name":"Sicheng Li","author_inst":"School of Basic Medical Sciences, Tsinghua Medicine, Tsinghua University, Beijing, China"},{"author_name":"Li Lin","author_inst":"National Key Laboratory for Immunity and Inflammation, Changzheng Hospital, Shanghai, China"},{"author_name":"Wenxu Wu","author_inst":"Department of Automation, Tsinghua University, Beijing, China"},{"author_name":"Binwen Liu","author_inst":"School of Basic Medical Sciences, Tsinghua Medicine, Tsinghua University, Beijing, China"},{"author_name":"Huihui Ji","author_inst":"SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Shanxi Medical University, Taiyuan, Shanxi Province, China"},{"author_name":"Zongyu Guo","author_inst":"Changping Laboratory, Beijing, China"},{"author_name":"Yaqiong Liu","author_inst":"Changping Laboratory, Beijing, China"},{"author_name":"Juncheng Wu","author_inst":"Department of Automation, Tsinghua University, Beijing, China"},{"author_name":"Bo Liu","author_inst":"Changping Laboratory, Beijing, China"},{"author_name":"Lisang Zhong","author_inst":"School of Basic Medical Sciences, Tsinghua Medicine, Tsinghua University, Beijing, China"},{"author_name":"Xiaowo Wang","author_inst":"Tsinghua University"},{"author_name":"Huji Xu","author_inst":"School of Basic Medical Sciences, Tsinghua Medicine, Tsinghua University, Beijing, China"},{"author_name":"Hai Qi","author_inst":"School of Basic Medical Sciences, Tsinghua Medicine, Tsinghua University"}],"rel_date":"2026-10-01","rel_site":"biorxiv"},{"rel_title":"Associations of Outdoor Air Pollution With Cause-specific Mortality in Metastatic Prostate Cancer: A cohort study","rel_doi":"10.64898\/2026.09.29.26364034","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.29.26364034","rel_abs":"Background: Cardiovascular disease is an important competing cause of death in men with metastatic prostate cancer, and ambient air pollution may increase cardiovascular vulnerability. We evaluated associations of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) with all-cause, cardiovascular, and prostate cancer-specific mortality, including joint associations with androgen deprivation therapy (ADT). Methods: We analyzed 33,384 men from 11 US state registries diagnosed with metastatic prostate cancer during 2000-2015 and followed through 2018. Residential PM2.5 and NO2 concentrations at diagnosis were assigned using 1-km exposure models. Multivariable Cox models estimated all-cause mortality, and inverse-probability-weighted Cox models assessed cause-specific mortality. Results: Each interquartile-range increase in PM2.5 was associated with higher cardiovascular mortality (HR 1.04, 95% CI 1.02-1.07; p-trend=0.008). Cardiovascular mortality was also higher in the fourth and fifth PM2.5 quintiles versus the first (HR 1.18 and 1.21, respectively). Higher NO2 was associated with prostate cancer-specific mortality in the highest quintile (HR 1.07, 95% CI 1.01-1.13). In joint analyses, ADT-treated men with high versus low PM2.5 exposure had higher cardiovascular mortality (HR 1.19, 95% CI 1.05-1.34), without clear evidence of effect modification (p-interaction=0.051). Conclusions: In men with metastatic prostate cancer, higher PM2.5 exposure was associated with cardiovascular mortality, particularly among ADT-treated patients, supporting further study of environmental exposures and systemic therapy in cardio-oncology.","rel_num_authors":12,"rel_authors":[{"author_name":"Andrea Cosenza","author_inst":"Division of Health Services Research, Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, PA"},{"author_name":"David-Dan Nguyen","author_inst":"University of Toronto"},{"author_name":"Zhiyu Qian","author_inst":"Department of Urology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Vincenzo Striano","author_inst":"Department of Urology, Humanitas Research Hospital, 20089 Pieve Emanuele (Mi), Lombardy, Italy"},{"author_name":"Leonard Appleman","author_inst":"Department of Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA"},{"author_name":"Francesco Montorsi","author_inst":"Division of Experimental Oncology\/Unit of Urology, URI, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy"},{"author_name":"Alberto Briganti","author_inst":"Division of Experimental Oncology\/Unit of Urology, URI, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy"},{"author_name":"Giorgio Gandaglia","author_inst":"Division of Experimental Oncology\/Unit of Urology, URI, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy"},{"author_name":"Benjamin J. Davies","author_inst":"Division of Health Services Research, Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, PA"},{"author_name":"Bruce L. Jacobs","author_inst":"Division of Health Services Research, Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, PA"},{"author_name":"Quoc-Dien Trinh","author_inst":"Division of Health Services Research, Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, PA"},{"author_name":"Hari S Iyer","author_inst":"Rutgers Cancer Institute"}],"rel_date":"2026-09-30","rel_site":"medrxiv"},{"rel_title":"Health Insurance and Maternal Healthcare Utilisation in Nepal: Evidence from the Nepal Demographic and Health Survey 2022","rel_doi":"10.64898\/2026.09.29.26364291","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.29.26364291","rel_abs":"Background: Access to maternal healthcare services is essential for improving maternal and neonatal health outcomes. Health insurance can reduce financial barriers to healthcare access and may facilitate utilisation of maternal health services, and contextualized evidence can further support policy development and implementation. This study assessed the association between health insurance coverage and utilisation of antenatal care (ANC), institutional delivery, skilled birth attendance and postnatal care (PNC) services among women in Nepal. Methods: This study used data from the 2022 Nepal Demographic and Health Survey (NDHS), a nationally representative cross-sectional survey. The analysis included women aged 15-49 years who had a live birth within the 24 months preceding the survey. Inverse probability of treatment weighting (IPTW) based on propensity scores was applied to balance measured socioeconomic and demographic characteristics between insured and uninsured women. Weighted marginal structural models were used to estimate the association between health insurance coverage and maternal healthcare utilisation outcomes. Robustness was assessed using alternative propensity score specifications and E-values for unmeasured confounding. Results: Among 14,845 women interviewed, 2,078 reported a recent live birth and were included in the analysis (unweighted; 1,998 when survey-weighted). Of these, 201 (9.7%) had health insurance coverage and 1,877 (90.3%) were uninsured. After adjustment using IPTW, health insurance coverage was associated with significantly higher utilisation of maternal healthcare services. Insured women had more than twice the odds of attending at least four ANC visits compared with uninsured women (AOR 2.14; 95% CI 1.15-3.98). Similarly, insured women had higher odds of receiving a PNC check-up within two days of delivery (AOR 2.05; 95% CI 1.28-3.27) and receiving PNC from a skilled provider (AOR 1.94; 95% CI 1.23-3.06). Although insurance coverage was positively associated with institutional delivery (AOR 1.55; 95% CI 0.91-2.62) and skilled birth attendance (AOR 1.57; 95% CI 0.90-2.72), these associations did not reach statistical significance. Conclusion: Health insurance coverage was associated with greater utilisation of antenatal and postnatal healthcare services among women in Nepal. However, no significant association was observed for institutional delivery or skilled birth attendance. Expanding health insurance coverage, particularly among underserved populations, may help improve maternal healthcare utilisation and support progress towards universal health coverage and maternal health-related Sustainable Development Goals.","rel_num_authors":4,"rel_authors":[{"author_name":"Yash Raj Lamsal","author_inst":"Kathmandu University"},{"author_name":"Abdulaziz Mohammed Hussen","author_inst":"Department of Global Public Health and Bioethics, Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, Utr"},{"author_name":"Joyce L. Browne","author_inst":"Department of Global Public Health and Bioethics, Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, Utr"},{"author_name":"Reshu Agrawal Sagtani","author_inst":"School of Public Health, Patan Academy of Health Sciences, Nepal"}],"rel_date":"2026-09-30","rel_site":"medrxiv"},{"rel_title":"Age-Standardized Comorbidity Prevalence of Cardiometabolic Conditions and Socioeconomic Inequalities in Hong Kong: A District Comparison","rel_doi":"10.64898\/2026.09.24.26363851","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.24.26363851","rel_abs":"Background: Hypertension (HTN) and Type 2 diabetes mellitus (T2DM) are leading drivers of the global cardiometabolic disease burden and major contributors to preventable morbidity and mortality. In Hong Kong, where population ageing and lifestyle-related risk factors are increasingly prevalent, both conditions and their complications pose substantial challenges to the healthcare system. Although territory-wide prevalence figures are available, small area district-level evidence on the burden of these diseases and their associated complications remains limited. Disparities are likely due to heterogeneity in demographic composition, socioeconomic status, and primary care accessibility across Hong Kong's eighteen administrative districts. There is also a lack of accessible, age-adjusted, district-level disease visualization in Hong Kong. Objectives: This study estimates the age-standardized prevalence rates (ASPR) of HTN, T2DM, and their associated complications across the eighteen districts of Hong Kong, formally evaluate the statistical significance of inter-district disparities, and rank the districts according to disease burden to inform place-based health planning. Methods: This study analyzed the prevalence of chronic diseases from 2014 to 2023 in 18 districts among an adult cohort aged equal or above 35 years using data collected from the Hong Kong Hospital Authority (HA) electronic health records, using the International Classification of Diseases, Ninth Revision (ICD-9) diagnostic codes, the International Classification of Primary Care (ICPC) codes, and the disease flags to identify diseases. Sample weights are used to reflect the total population. HTN, T2DM, and their major complications were identified according to standardized diagnostic criteria. ASPR were calculated for each district with the WHO World Standard Population as the standard. Inter-district disparities in disease prevalence were assessed using Cochran's Q test, with statistical significance set at P <0.05. The slope index of inequality (SII) was also used to analyze the socioeconomic inequality between districts. Districts were subsequently ranked according to their ASPR for each condition to identify high-burden and low-burden areas. Results: 1,756,521 patients (52.71% females) contribute 9,906,729 patient-years from 2014 to 2023. Substantial inter-district variation and increasing trend were observed in the ASPR of HTN, T2DM, and their complications. The weighted ASPR of HTN varied by 27.3% from 46,701 (95% CI: 45,691-47,711) per 100,000 population in Tsuen Wan district to 59,445 (95% CI: 58,759-60,130) per 100,000 population in Yuen Long district, and the weighted ASPR of T2DM ranged from 20,464 (Tsuen Wan, 95% CI: 19,803-21,124) per 100,000 population to 28,275 (Yuen Long, 95% CI: 27,792-28,758) per 100,000 population across the districts in 2023. All diseases showed district disparities (all P <0.05). Cochran's Q test demonstrated statistically significant disparities across districts and showed no convergence through the period. The SII test also showed the most serious inequality exists in HTN, with the lower socioeconomic position districts have more burden. Conclusion: Significant geographic disparities exist in the prevalence of HTN, T2DM, and their complications across Hong Kong's eighteen districts. These findings highlight the need for district-specific public health strategies, equitable allocation of primary care resources, and targeted chronic disease prevention and management programs in high-burden areas.","rel_num_authors":5,"rel_authors":[{"author_name":"Jingjing Zhou","author_inst":"The University of Hong Kong"},{"author_name":"Zhenyuan Liu","author_inst":"The University of Hong Kong"},{"author_name":"Yuchen Cai","author_inst":"The University of Hong Kong"},{"author_name":"Qiaohui Wu","author_inst":"The University of Hong Kong"},{"author_name":"David  Makram Bishai","author_inst":"The University of Hong Kong"}],"rel_date":"2026-09-30","rel_site":"medrxiv"},{"rel_title":"Haploinsufficiency, de novo and biallelic missense variants in CSMD2 are associated with neurodevelopmental disorders","rel_doi":"10.64898\/2026.09.24.26361611","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.24.26361611","rel_abs":"CUB and Sushi domains-containing CSMD proteins are involved in neuron development. Variants in the CSMD1-3 paralogs were GWAS-associated with cognition, attention-deficit hyperactivity disorder (ADHD), schizophrenia and brain structure, suggesting that these genes could be linked to neurodevelopmental disorders (NDD). Indeed, rare biallelic variants in all three CSMD paralogs were recently associated with epilepsy, while rare biallelic variants in CSMD1 were also linked with intellectual disability and cortical malformations. We identified nine individuals from eight families carrying CSMD2 biallelic missense variants in developmental delay\/intellectual disability cohorts. Affected individuals presented with autism spectrum disorder (ASD), ADHD and brain anomalies. Consistent with gnomAD metrics that suggest CSMD2 haploinsufficiency, we also report two families segregating monoallelic CSMD2 frameshift variants, which complement a described de novo truncation variant in an ASD proband. We concomitantly report two phenotypically overlapping individuals with de novo CSMD2 missense variants and compare them to twelve de novo CSMD2 cases identified in published trio analyses. UK Biobank analyses showed nominally significant enrichment of ADHD, ASD and neuroticism in volunteers carrying at least one rare CSMD2 variant. In silico modelling and immunofluorescence assays showed that mutated residues in affected individuals with biallelic and de novo missense variants are clustering in two regions and that the encoded proteins showed impaired membrane localization and an increased cytoplasmic aggregation. Zebrafish crispant larvae for the orthologous csmd2 presented with microcephaly, smaller cerebellum, and reduced Purkinje cell size. Larvae also displayed decreased swimming velocity, diminished connectivity between the optic tecta, and abnormal peripheral neuronal branching. We demonstrate that rare, likely pathogenic variants in CSMD2 are associated with both autosomal recessive and dominant forms of NDD further substantiating the functional significance of CSMD paralogs in neurogenesis\/synapse formation.","rel_num_authors":55,"rel_authors":[{"author_name":"Clara Pailler-Pradeau","author_inst":"University of Lausanne"},{"author_name":"Marianne Victoria Lem\u0117e","author_inst":"Universit\u0117 de Strasbourg"},{"author_name":"Caterina Cevallos","author_inst":"University of Lausanne"},{"author_name":"Francesca Mattioli","author_inst":"University of Lausanne"},{"author_name":"Jacqueline Chrast","author_inst":"University of Lausanne"},{"author_name":"Sissy Bassani","author_inst":"University of Lausanne"},{"author_name":"Hossein Darvish","author_inst":"Nikagene Genetic Diagnostic Laboratory"},{"author_name":"Ginevra Zanni","author_inst":"Bambino Ges\u00fa Children's Hospital"},{"author_name":"Giovanna Stefania Colafati","author_inst":"Bambino Ges\u00fa Children's Hospital"},{"author_name":"Lorena Travaglini","author_inst":"Bambino Ges\u00fa Children's Hospital"},{"author_name":"Francesco Nicita","author_inst":"Bambino Ges\u00fa Children's Hospital"},{"author_name":"Shivarajan M. Amudhavalli","author_inst":"Children's Mercy Hospital"},{"author_name":"Caitlin Lawson","author_inst":"Children's Mercy Hospital"},{"author_name":"Joseph G. Gleeson","author_inst":"University of California"},{"author_name":"Isabella Stuewe","author_inst":"University of California"},{"author_name":"Liana Friedman","author_inst":"University of California"},{"author_name":"Maha S. Zaki","author_inst":"National Research Centre Egypt"},{"author_name":"Lauren Bell","author_inst":"University of Illinois"},{"author_name":"Elise Boucher Brischoux","author_inst":"Universit\u00e9 Marie et Louis Pasteur"},{"author_name":"Paul Kuentz","author_inst":"Universit\u00e9 Marie et Louis Pasteur"},{"author_name":"Nico Fuhrmann","author_inst":"University of Cologne"},{"author_name":"Victoria Lampkemeyer","author_inst":"University of Cologne"},{"author_name":"Christian Netzer","author_inst":"University of Cologne"},{"author_name":"Thomas Smol","author_inst":"Universit\u00e9 de Lille, CHU de Lille"},{"author_name":"Catherine Vincent-Delorme","author_inst":"Universit\u00e9 de Lille"},{"author_name":"Zafar Iqbal","author_inst":"Oslo University Hospital"},{"author_name":"Mathias Toft","author_inst":"Oslo University Hospital"},{"author_name":"Tarab Zehra","author_inst":"Aga Khan University"},{"author_name":"Sidra Kaleem Jafri","author_inst":"Aga Khan University"},{"author_name":"Ambrin Fatima","author_inst":"Aga Khan University"},{"author_name":"Mukhtar Ullah","author_inst":"University of Lausanne"},{"author_name":"Zainab Akhtar","author_inst":"University of Lausanne"},{"author_name":"Tayyaba Shan","author_inst":"Quaid-i-Azam University"},{"author_name":"Sabika Firasat","author_inst":"Quaid-i-Azam University"},{"author_name":"Saghar Ghasemi Firouzabadi","author_inst":"Nikagene Genetic Diagnostic Laboratory"},{"author_name":"Abbas Tafakhori","author_inst":"Tehran University of Medical Sciences"},{"author_name":"Sarina Sharbatkhori","author_inst":"Nikagene Genetic Diagnostic Laboratory"},{"author_name":"Faezeh Jamali","author_inst":"North Khorasan University of Medical Sciences"},{"author_name":"Maximilian Balbach","author_inst":"Harvard Medical School"},{"author_name":"Friedhelm Hildebrandt","author_inst":"Harvard Medical School"},{"author_name":"Emily O'Heir","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Lynn Pais","author_inst":"Broad Institute"},{"author_name":"Alba Sanchis-Juan","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Michael Talkowski","author_inst":"Massachusetts General Hospital"},{"author_name":"- Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium","author_inst":""},{"author_name":"Quinten Waisfisz","author_inst":"Amsterdam University Medical Center"},{"author_name":"Lotte Kleinendorst","author_inst":"Amsterdam University Medical Center"},{"author_name":"Giovanna Ambrosini","author_inst":"University of Lausanne"},{"author_name":"Trisha Kuchta","author_inst":"Indiana University Health Medical Group"},{"author_name":"Zoltan Kutalik","author_inst":"University Hospital of Lausanne"},{"author_name":"Nicolas Guex","author_inst":"University of Lausanne"},{"author_name":"Stylianos E. Antonarakis","author_inst":"Univ. of Geneva Medical School"},{"author_name":"Muhammad E. Ansar","author_inst":"University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles"},{"author_name":"Christelle Golzio","author_inst":"Universit\u00e9 de Strasbourg"},{"author_name":"Alexandre Reymond","author_inst":"University of Lausanne"}],"rel_date":"2026-09-30","rel_site":"medrxiv"},{"rel_title":"Haploinsufficiency, de novo and biallelic missense variants in CSMD2 are associated with neurodevelopmental disorders","rel_doi":"10.64898\/2026.09.24.26361611","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.24.26361611","rel_abs":"CUB and Sushi domains-containing CSMD proteins are involved in neuron development. Variants in the CSMD1-3 paralogs were GWAS-associated with cognition, attention-deficit hyperactivity disorder (ADHD), schizophrenia and brain structure, suggesting that these genes could be linked to neurodevelopmental disorders (NDD). Indeed, rare biallelic variants in all three CSMD paralogs were recently associated with epilepsy, while rare biallelic variants in CSMD1 were also linked with intellectual disability and cortical malformations. We identified nine individuals from eight families carrying CSMD2 biallelic missense variants in developmental delay\/intellectual disability cohorts. Affected individuals presented with autism spectrum disorder (ASD), ADHD and brain anomalies. Consistent with gnomAD metrics that suggest CSMD2 haploinsufficiency, we also report two families segregating monoallelic CSMD2 frameshift variants, which complement a described de novo truncation variant in an ASD proband. We concomitantly report two phenotypically overlapping individuals with de novo CSMD2 missense variants and compare them to twelve de novo CSMD2 cases identified in published trio analyses. UK Biobank analyses showed nominally significant enrichment of ADHD, ASD and neuroticism in volunteers carrying at least one rare CSMD2 variant. In silico modelling and immunofluorescence assays showed that mutated residues in affected individuals with biallelic and de novo missense variants are clustering in two regions and that the encoded proteins showed impaired membrane localization and an increased cytoplasmic aggregation. Zebrafish crispant larvae for the orthologous csmd2 presented with microcephaly, smaller cerebellum, and reduced Purkinje cell size. Larvae also displayed decreased swimming velocity, diminished connectivity between the optic tecta, and abnormal peripheral neuronal branching. We demonstrate that rare, likely pathogenic variants in CSMD2 are associated with both autosomal recessive and dominant forms of NDD further substantiating the functional significance of CSMD paralogs in neurogenesis\/synapse formation.","rel_num_authors":55,"rel_authors":[{"author_name":"Clara Pailler-Pradeau","author_inst":"University of Lausanne"},{"author_name":"Marianne Victoria Lem\u0117e","author_inst":"Universit\u0117 de Strasbourg"},{"author_name":"Caterina Cevallos","author_inst":"University of Lausanne"},{"author_name":"Francesca Mattioli","author_inst":"University of Lausanne"},{"author_name":"Jacqueline Chrast","author_inst":"University of Lausanne"},{"author_name":"Sissy Bassani","author_inst":"University of Lausanne"},{"author_name":"Hossein Darvish","author_inst":"Nikagene Genetic Diagnostic Laboratory"},{"author_name":"Ginevra Zanni","author_inst":"Bambino Ges\u00fa Children's Hospital"},{"author_name":"Giovanna Stefania Colafati","author_inst":"Bambino Ges\u00fa Children's Hospital"},{"author_name":"Lorena Travaglini","author_inst":"Bambino Ges\u00fa Children's Hospital"},{"author_name":"Francesco Nicita","author_inst":"Bambino Ges\u00fa Children's Hospital"},{"author_name":"Shivarajan M. Amudhavalli","author_inst":"Children's Mercy Hospital"},{"author_name":"Caitlin Lawson","author_inst":"Children's Mercy Hospital"},{"author_name":"Joseph G. Gleeson","author_inst":"University of California"},{"author_name":"Isabella Stuewe","author_inst":"University of California"},{"author_name":"Liana Friedman","author_inst":"University of California"},{"author_name":"Maha S. Zaki","author_inst":"National Research Centre Egypt"},{"author_name":"Lauren Bell","author_inst":"University of Illinois"},{"author_name":"Elise Boucher Brischoux","author_inst":"Universit\u00e9 Marie et Louis Pasteur"},{"author_name":"Paul Kuentz","author_inst":"Universit\u00e9 Marie et Louis Pasteur"},{"author_name":"Nico Fuhrmann","author_inst":"University of Cologne"},{"author_name":"Victoria Lampkemeyer","author_inst":"University of Cologne"},{"author_name":"Christian Netzer","author_inst":"University of Cologne"},{"author_name":"Thomas Smol","author_inst":"Universit\u00e9 de Lille, CHU de Lille"},{"author_name":"Catherine Vincent-Delorme","author_inst":"Universit\u00e9 de Lille"},{"author_name":"Zafar Iqbal","author_inst":"Oslo University Hospital"},{"author_name":"Mathias Toft","author_inst":"Oslo University Hospital"},{"author_name":"Tarab Zehra","author_inst":"Aga Khan University"},{"author_name":"Sidra Kaleem Jafri","author_inst":"Aga Khan University"},{"author_name":"Ambrin Fatima","author_inst":"Aga Khan University"},{"author_name":"Mukhtar Ullah","author_inst":"University of Lausanne"},{"author_name":"Zainab Akhtar","author_inst":"University of Lausanne"},{"author_name":"Tayyaba Shan","author_inst":"Quaid-i-Azam University"},{"author_name":"Sabika Firasat","author_inst":"Quaid-i-Azam University"},{"author_name":"Saghar Ghasemi Firouzabadi","author_inst":"Nikagene Genetic Diagnostic Laboratory"},{"author_name":"Abbas Tafakhori","author_inst":"Tehran University of Medical Sciences"},{"author_name":"Sarina Sharbatkhori","author_inst":"Nikagene Genetic Diagnostic Laboratory"},{"author_name":"Faezeh Jamali","author_inst":"North Khorasan University of Medical Sciences"},{"author_name":"Maximilian Balbach","author_inst":"Harvard Medical School"},{"author_name":"Friedhelm Hildebrandt","author_inst":"Harvard Medical School"},{"author_name":"Emily O'Heir","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Lynn Pais","author_inst":"Broad Institute"},{"author_name":"Alba Sanchis-Juan","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Michael Talkowski","author_inst":"Massachusetts General Hospital"},{"author_name":"- Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium","author_inst":""},{"author_name":"Quinten Waisfisz","author_inst":"Amsterdam University Medical Center"},{"author_name":"Lotte Kleinendorst","author_inst":"Amsterdam University Medical Center"},{"author_name":"Giovanna Ambrosini","author_inst":"University of Lausanne"},{"author_name":"Trisha Kuchta","author_inst":"Indiana University Health Medical Group"},{"author_name":"Zoltan Kutalik","author_inst":"University Hospital of Lausanne"},{"author_name":"Nicolas Guex","author_inst":"University of Lausanne"},{"author_name":"Stylianos E. Antonarakis","author_inst":"Univ. of Geneva Medical School"},{"author_name":"Muhammad E. Ansar","author_inst":"University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles"},{"author_name":"Christelle Golzio","author_inst":"Universit\u00e9 de Strasbourg"},{"author_name":"Alexandre Reymond","author_inst":"University of Lausanne"}],"rel_date":"2026-09-30","rel_site":"medrxiv"},{"rel_title":"Haploinsufficiency, de novo and biallelic missense variants in CSMD2 are associated with neurodevelopmental disorders","rel_doi":"10.64898\/2026.09.24.26361611","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.24.26361611","rel_abs":"CUB and Sushi domains-containing CSMD proteins are involved in neuron development. Variants in the CSMD1-3 paralogs were GWAS-associated with cognition, attention-deficit hyperactivity disorder (ADHD), schizophrenia and brain structure, suggesting that these genes could be linked to neurodevelopmental disorders (NDD). Indeed, rare biallelic variants in all three CSMD paralogs were recently associated with epilepsy, while rare biallelic variants in CSMD1 were also linked with intellectual disability and cortical malformations. We identified nine individuals from eight families carrying CSMD2 biallelic missense variants in developmental delay\/intellectual disability cohorts. Affected individuals presented with autism spectrum disorder (ASD), ADHD and brain anomalies. Consistent with gnomAD metrics that suggest CSMD2 haploinsufficiency, we also report two families segregating monoallelic CSMD2 frameshift variants, which complement a described de novo truncation variant in an ASD proband. We concomitantly report two phenotypically overlapping individuals with de novo CSMD2 missense variants and compare them to twelve de novo CSMD2 cases identified in published trio analyses. UK Biobank analyses showed nominally significant enrichment of ADHD, ASD and neuroticism in volunteers carrying at least one rare CSMD2 variant. In silico modelling and immunofluorescence assays showed that mutated residues in affected individuals with biallelic and de novo missense variants are clustering in two regions and that the encoded proteins showed impaired membrane localization and an increased cytoplasmic aggregation. Zebrafish crispant larvae for the orthologous csmd2 presented with microcephaly, smaller cerebellum, and reduced Purkinje cell size. Larvae also displayed decreased swimming velocity, diminished connectivity between the optic tecta, and abnormal peripheral neuronal branching. We demonstrate that rare, likely pathogenic variants in CSMD2 are associated with both autosomal recessive and dominant forms of NDD further substantiating the functional significance of CSMD paralogs in neurogenesis\/synapse formation.","rel_num_authors":55,"rel_authors":[{"author_name":"Clara Pailler-Pradeau","author_inst":"University of Lausanne"},{"author_name":"Marianne Victoria Lem\u0117e","author_inst":"Universit\u0117 de Strasbourg"},{"author_name":"Caterina Cevallos","author_inst":"University of Lausanne"},{"author_name":"Francesca Mattioli","author_inst":"University of Lausanne"},{"author_name":"Jacqueline Chrast","author_inst":"University of Lausanne"},{"author_name":"Sissy Bassani","author_inst":"University of Lausanne"},{"author_name":"Hossein Darvish","author_inst":"Nikagene Genetic Diagnostic Laboratory"},{"author_name":"Ginevra Zanni","author_inst":"Bambino Ges\u00fa Children's Hospital"},{"author_name":"Giovanna Stefania Colafati","author_inst":"Bambino Ges\u00fa Children's Hospital"},{"author_name":"Lorena Travaglini","author_inst":"Bambino Ges\u00fa Children's Hospital"},{"author_name":"Francesco Nicita","author_inst":"Bambino Ges\u00fa Children's Hospital"},{"author_name":"Shivarajan M. Amudhavalli","author_inst":"Children's Mercy Hospital"},{"author_name":"Caitlin Lawson","author_inst":"Children's Mercy Hospital"},{"author_name":"Joseph G. Gleeson","author_inst":"University of California"},{"author_name":"Isabella Stuewe","author_inst":"University of California"},{"author_name":"Liana Friedman","author_inst":"University of California"},{"author_name":"Maha S. Zaki","author_inst":"National Research Centre Egypt"},{"author_name":"Lauren Bell","author_inst":"University of Illinois"},{"author_name":"Elise Boucher Brischoux","author_inst":"Universit\u00e9 Marie et Louis Pasteur"},{"author_name":"Paul Kuentz","author_inst":"Universit\u00e9 Marie et Louis Pasteur"},{"author_name":"Nico Fuhrmann","author_inst":"University of Cologne"},{"author_name":"Victoria Lampkemeyer","author_inst":"University of Cologne"},{"author_name":"Christian Netzer","author_inst":"University of Cologne"},{"author_name":"Thomas Smol","author_inst":"Universit\u00e9 de Lille, CHU de Lille"},{"author_name":"Catherine Vincent-Delorme","author_inst":"Universit\u00e9 de Lille"},{"author_name":"Zafar Iqbal","author_inst":"Oslo University Hospital"},{"author_name":"Mathias Toft","author_inst":"Oslo University Hospital"},{"author_name":"Tarab Zehra","author_inst":"Aga Khan University"},{"author_name":"Sidra Kaleem Jafri","author_inst":"Aga Khan University"},{"author_name":"Ambrin Fatima","author_inst":"Aga Khan University"},{"author_name":"Mukhtar Ullah","author_inst":"University of Lausanne"},{"author_name":"Zainab Akhtar","author_inst":"University of Lausanne"},{"author_name":"Tayyaba Shan","author_inst":"Quaid-i-Azam University"},{"author_name":"Sabika Firasat","author_inst":"Quaid-i-Azam University"},{"author_name":"Saghar Ghasemi Firouzabadi","author_inst":"Nikagene Genetic Diagnostic Laboratory"},{"author_name":"Abbas Tafakhori","author_inst":"Tehran University of Medical Sciences"},{"author_name":"Sarina Sharbatkhori","author_inst":"Nikagene Genetic Diagnostic Laboratory"},{"author_name":"Faezeh Jamali","author_inst":"North Khorasan University of Medical Sciences"},{"author_name":"Maximilian Balbach","author_inst":"Harvard Medical School"},{"author_name":"Friedhelm Hildebrandt","author_inst":"Harvard Medical School"},{"author_name":"Emily O'Heir","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Lynn Pais","author_inst":"Broad Institute"},{"author_name":"Alba Sanchis-Juan","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Michael Talkowski","author_inst":"Massachusetts General Hospital"},{"author_name":"- Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium","author_inst":""},{"author_name":"Quinten Waisfisz","author_inst":"Amsterdam University Medical Center"},{"author_name":"Lotte Kleinendorst","author_inst":"Amsterdam University Medical Center"},{"author_name":"Giovanna Ambrosini","author_inst":"University of Lausanne"},{"author_name":"Trisha Kuchta","author_inst":"Indiana University Health Medical Group"},{"author_name":"Zoltan Kutalik","author_inst":"University Hospital of Lausanne"},{"author_name":"Nicolas Guex","author_inst":"University of Lausanne"},{"author_name":"Stylianos E. Antonarakis","author_inst":"Univ. of Geneva Medical School"},{"author_name":"Muhammad E. Ansar","author_inst":"University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles"},{"author_name":"Christelle Golzio","author_inst":"Universit\u00e9 de Strasbourg"},{"author_name":"Alexandre Reymond","author_inst":"University of Lausanne"}],"rel_date":"2026-09-30","rel_site":"medrxiv"},{"rel_title":"Haploinsufficiency, de novo and biallelic missense variants in CSMD2 are associated with neurodevelopmental disorders","rel_doi":"10.64898\/2026.09.24.26361611","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.24.26361611","rel_abs":"CUB and Sushi domains-containing CSMD proteins are involved in neuron development. Variants in the CSMD1-3 paralogs were GWAS-associated with cognition, attention-deficit hyperactivity disorder (ADHD), schizophrenia and brain structure, suggesting that these genes could be linked to neurodevelopmental disorders (NDD). Indeed, rare biallelic variants in all three CSMD paralogs were recently associated with epilepsy, while rare biallelic variants in CSMD1 were also linked with intellectual disability and cortical malformations. We identified nine individuals from eight families carrying CSMD2 biallelic missense variants in developmental delay\/intellectual disability cohorts. Affected individuals presented with autism spectrum disorder (ASD), ADHD and brain anomalies. Consistent with gnomAD metrics that suggest CSMD2 haploinsufficiency, we also report two families segregating monoallelic CSMD2 frameshift variants, which complement a described de novo truncation variant in an ASD proband. We concomitantly report two phenotypically overlapping individuals with de novo CSMD2 missense variants and compare them to twelve de novo CSMD2 cases identified in published trio analyses. UK Biobank analyses showed nominally significant enrichment of ADHD, ASD and neuroticism in volunteers carrying at least one rare CSMD2 variant. In silico modelling and immunofluorescence assays showed that mutated residues in affected individuals with biallelic and de novo missense variants are clustering in two regions and that the encoded proteins showed impaired membrane localization and an increased cytoplasmic aggregation. Zebrafish crispant larvae for the orthologous csmd2 presented with microcephaly, smaller cerebellum, and reduced Purkinje cell size. Larvae also displayed decreased swimming velocity, diminished connectivity between the optic tecta, and abnormal peripheral neuronal branching. We demonstrate that rare, likely pathogenic variants in CSMD2 are associated with both autosomal recessive and dominant forms of NDD further substantiating the functional significance of CSMD paralogs in neurogenesis\/synapse formation.","rel_num_authors":55,"rel_authors":[{"author_name":"Clara Pailler-Pradeau","author_inst":"University of Lausanne"},{"author_name":"Marianne Victoria Lem\u0117e","author_inst":"Universit\u0117 de Strasbourg"},{"author_name":"Caterina Cevallos","author_inst":"University of Lausanne"},{"author_name":"Francesca Mattioli","author_inst":"University of Lausanne"},{"author_name":"Jacqueline Chrast","author_inst":"University of Lausanne"},{"author_name":"Sissy Bassani","author_inst":"University of Lausanne"},{"author_name":"Hossein Darvish","author_inst":"Nikagene Genetic Diagnostic Laboratory"},{"author_name":"Ginevra Zanni","author_inst":"Bambino Ges\u00fa Children's Hospital"},{"author_name":"Giovanna Stefania Colafati","author_inst":"Bambino Ges\u00fa Children's Hospital"},{"author_name":"Lorena Travaglini","author_inst":"Bambino Ges\u00fa Children's Hospital"},{"author_name":"Francesco Nicita","author_inst":"Bambino Ges\u00fa Children's Hospital"},{"author_name":"Shivarajan M. Amudhavalli","author_inst":"Children's Mercy Hospital"},{"author_name":"Caitlin Lawson","author_inst":"Children's Mercy Hospital"},{"author_name":"Joseph G. Gleeson","author_inst":"University of California"},{"author_name":"Isabella Stuewe","author_inst":"University of California"},{"author_name":"Liana Friedman","author_inst":"University of California"},{"author_name":"Maha S. Zaki","author_inst":"National Research Centre Egypt"},{"author_name":"Lauren Bell","author_inst":"University of Illinois"},{"author_name":"Elise Boucher Brischoux","author_inst":"Universit\u00e9 Marie et Louis Pasteur"},{"author_name":"Paul Kuentz","author_inst":"Universit\u00e9 Marie et Louis Pasteur"},{"author_name":"Nico Fuhrmann","author_inst":"University of Cologne"},{"author_name":"Victoria Lampkemeyer","author_inst":"University of Cologne"},{"author_name":"Christian Netzer","author_inst":"University of Cologne"},{"author_name":"Thomas Smol","author_inst":"Universit\u00e9 de Lille, CHU de Lille"},{"author_name":"Catherine Vincent-Delorme","author_inst":"Universit\u00e9 de Lille"},{"author_name":"Zafar Iqbal","author_inst":"Oslo University Hospital"},{"author_name":"Mathias Toft","author_inst":"Oslo University Hospital"},{"author_name":"Tarab Zehra","author_inst":"Aga Khan University"},{"author_name":"Sidra Kaleem Jafri","author_inst":"Aga Khan University"},{"author_name":"Ambrin Fatima","author_inst":"Aga Khan University"},{"author_name":"Mukhtar Ullah","author_inst":"University of Lausanne"},{"author_name":"Zainab Akhtar","author_inst":"University of Lausanne"},{"author_name":"Tayyaba Shan","author_inst":"Quaid-i-Azam University"},{"author_name":"Sabika Firasat","author_inst":"Quaid-i-Azam University"},{"author_name":"Saghar Ghasemi Firouzabadi","author_inst":"Nikagene Genetic Diagnostic Laboratory"},{"author_name":"Abbas Tafakhori","author_inst":"Tehran University of Medical Sciences"},{"author_name":"Sarina Sharbatkhori","author_inst":"Nikagene Genetic Diagnostic Laboratory"},{"author_name":"Faezeh Jamali","author_inst":"North Khorasan University of Medical Sciences"},{"author_name":"Maximilian Balbach","author_inst":"Harvard Medical School"},{"author_name":"Friedhelm Hildebrandt","author_inst":"Harvard Medical School"},{"author_name":"Emily O'Heir","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Lynn Pais","author_inst":"Broad Institute"},{"author_name":"Alba Sanchis-Juan","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Michael Talkowski","author_inst":"Massachusetts General Hospital"},{"author_name":"- Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium","author_inst":""},{"author_name":"Quinten Waisfisz","author_inst":"Amsterdam University Medical Center"},{"author_name":"Lotte Kleinendorst","author_inst":"Amsterdam University Medical Center"},{"author_name":"Giovanna Ambrosini","author_inst":"University of Lausanne"},{"author_name":"Trisha Kuchta","author_inst":"Indiana University Health Medical Group"},{"author_name":"Zoltan Kutalik","author_inst":"University Hospital of Lausanne"},{"author_name":"Nicolas Guex","author_inst":"University of Lausanne"},{"author_name":"Stylianos E. Antonarakis","author_inst":"Univ. of Geneva Medical School"},{"author_name":"Muhammad E. Ansar","author_inst":"University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles"},{"author_name":"Christelle Golzio","author_inst":"Universit\u00e9 de Strasbourg"},{"author_name":"Alexandre Reymond","author_inst":"University of Lausanne"}],"rel_date":"2026-09-30","rel_site":"medrxiv"},{"rel_title":"Relevance-Based Prediction: A Transparent, Patient-SpecificApproach to Predicting Medical Outcomes","rel_doi":"10.64898\/2026.09.28.26364225","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.28.26364225","rel_abs":"Accurate prediction of individual medical outcomes is essential for optimizing treatment allocation amid rising costs, coverage denials, and limited clinical resources. Traditional predictive models, including linear regression and neural networks, rely on average effects and cannot tailor predictions to the specific circumstances of individual cases. We present relevance-based prediction (RBP), a model-free and task-specific method that predicts outcomes as weighted averages of observed cases, with weights determined by a rigorously defined and theoretically justified measure of relevance. Unlike model-based methods that rely on fixed calibrated parameters, relevance-based prediction revisits the original data for each prediction and customizes both the cases and variables used. We illustrate RBP by applying it to predict opioid treatment outcomes and demonstrate that it provides case-specific insights unavailable from conventional models, including how each prior case informs a prediction, how each variable affects each predictions reliability and value, and how reliable each prediction is before it is made. These individualized insights may prevent misleading average-based decisions and reduce harmful or suboptimal treatment.","rel_num_authors":5,"rel_authors":[{"author_name":"Christopher L Robinson","author_inst":"The Johns Hopkins University School of Medicine"},{"author_name":"David Turkington","author_inst":"Cambridge Prediction Analytics"},{"author_name":"Linda Lee","author_inst":"Harvard Medical School, Massachusetts Eye and Ear"},{"author_name":"Mark Kritzman","author_inst":"Cambridge Prediction Analytics"},{"author_name":"R. Jason Yong","author_inst":"Brigham and Women's Hospital"}],"rel_date":"2026-09-30","rel_site":"medrxiv"},{"rel_title":"Axitinib in Progressive Metastatic Pheochromocytoma and Paraganglioma: Results of a Phase II Study","rel_doi":"10.64898\/2026.09.28.26364204","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.28.26364204","rel_abs":"Purpose: Metastatic pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine malignancies with limited systemic treatment options. Although inhibition of vascular endothelial growth factor (VEGF) signaling has demonstrated clinical benefit in metastatic PPGL, prospective data evaluating selective VEGF receptor inhibition remain limited. Axitinib is a potent and selective inhibitor of VEGFR-1, -2, and -3 with established activity in several solid tumors. We evaluated the efficacy and safety of axitinib in patients with progressive metastatic PPGL. Methods: Patients with progressive metastatic or unresectable PPGL were enrolled in a prospective, open-label, single-arm, phase II study (NCT03839498). Eligible patients had measurable disease according to RECIST version 1.1 and no prior treatment with a tyrosine kinase inhibitor. Axitinib was administered orally at an initial dose of 5 mg twice daily with protocol-defined dose modifications based on tolerability. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Safety was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). Results: Nineteen patients were enrolled, and 17 received study treatment. A confirmed partial response was achieved in 35.3% of treated patients. Median progression-free survival was 7.9 months (95% CI, 6.1-16.8 months), median duration of response was 7.4 months, median duration of treatment was 9.5 months, and median overall survival was 29 months. Hypertension, the most common treatment-related adverse event, occurring in 79% of patients, was effectively managed with antihypertensive therapy and dose modification. Other common treatment-related adverse events included fatigue, diarrhea, oral mucositis, and palmar-plantar erythrodysesthesia. No patient permanently discontinued treatment because of treatment-related toxicity. Conclusions: In patients with progressive metastatic PPGL, single-agent axitinib demonstrated clinically meaningful antitumor activity with a manageable safety profile. The observed efficacy compares favorably with sunitinib in this rare disease. The ability to maintain treatment despite predictable VEGF-associated toxicities suggests that axitinib represents a viable therapeutic option for patients with metastatic PPGL.","rel_num_authors":9,"rel_authors":[{"author_name":"Jaydira Del Rivero","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Andrea Apolo","author_inst":"National Cancer Institute, NIH"},{"author_name":"Maureen Edgerly","author_inst":"National Cancer Institute, National Institutes of Health."},{"author_name":"William Douglas Figg Sr.","author_inst":"National Institutes of Health"},{"author_name":"James Lee","author_inst":"Genitourinary Malignancy Branch, National Cancer Institute, NIH"},{"author_name":"John Ausiello","author_inst":"Department of Medicine, Columbia University, New York, NY"},{"author_name":"Karel Pacak","author_inst":"NICHD, NIH"},{"author_name":"Susan E Bates","author_inst":"Department of Surgery, Columbia University, New York, NY,  Department of Medicine, Columbia University, New York, NY"},{"author_name":"Tito Fojo","author_inst":"Department of Surgery, Columbia University, New York, NY, Department of Medicine, Columbia University, New York, NY"}],"rel_date":"2026-09-30","rel_site":"medrxiv"},{"rel_title":"Neuropsychiatric Symptom Associations with NOTCH3 Genotype in the United States CADASIL Consortium","rel_doi":"10.64898\/2026.09.24.26363718","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.24.26363718","rel_abs":"Background and objectives: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the most common monogenic cerebral small vessel disease. Though neuropsychiatric symptoms (NPS) of CADASIL profoundly impact function and quality of life, these symptoms remain understudied. This analysis characterizes the prevalence, severity, and profile of NPS among individuals with CADASIL-causing NOTCH3 variants and non-carrier biological family controls in the United States CADASIL Consortium (USCC). Methods: This cross-sectional analysis used multimodal baseline data from 12 enrollment sites across the country. Statistical analyses used nonparametric tests and regression models to compare clinical and neuropsychiatric outcomes across CADASIL risk tiers and controls, adjusting for age, sex, race, and education where appropriate. The primary outcome measure was the Neuropsychiatric Inventory Questionnaire (NPI-Q), an informant-reported measure which assesses 12 categories of NPS. NPI-Q item severity and distress were evaluated for individuals with confirmed cysteine-altering NOTCH3 variants and compared with controls. Results: Four hundred fifty-nine USCC participants were included in the analytic cohort: 343 cases [256 high-risk (HR); 63 medium-risk (MR); 24 low-risk (LR)]; and 116 controls. Among participants with available NPI-Q data, at least one neuropsychiatric symptom was reported by 72.6% (n = 228\/314) of cases compared with 53.2% (n = 58\/109) of controls. Reported symptoms were more common among CADASIL cases than controls, occurring in 75.0%, 71.2%, and 72.7% of participants in the LR, MR, and HR groups, respectively, compared with 53.2% of controls. Compared with controls, participants in the MR group and HR group had higher NPI-Q severity scores. HR participants also had higher NPI-Q distress scores than controls. Discussion: Our findings support the notion that NPS are an important clinical manifestation of CADASIL. Beyond previously reported symptoms, additional neuropsychiatric manifestations were identified. Given the higher burden and variability in the neuropsychiatric presentation of CADASIL, the relationships among neuropsychiatric, neurological, and patient-reported outcomes merit further investigation. The NPS profile may enhance the evaluation of the safety and efficacy of different treatments to target these symptoms for CADASIL patients. Trial Registration Information: The study is registered at ClinicalTrials.gov (NCT05677880, 12\/12\/2022).","rel_num_authors":25,"rel_authors":[{"author_name":"Megan R. Caruso","author_inst":"Butler Hospital"},{"author_name":"Barbara L. Fischer","author_inst":"University of Wisconsin-Madison"},{"author_name":"William H. Adams","author_inst":"Loyola University Chicago"},{"author_name":"Deven K. Burks","author_inst":"University of Wisconsin-Madison"},{"author_name":"Bianca Le","author_inst":"University of Washington"},{"author_name":"Arash Salardini","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Jennifer J. Majersik","author_inst":"The University of Utah"},{"author_name":"Stephen P. Salloway","author_inst":"Butler Hospital"},{"author_name":"Jamie L. Elliott","author_inst":"University of Wisconsin-Madison"},{"author_name":"H. Jeremy Bockholt","author_inst":"Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology, Emory Universit"},{"author_name":"Suman Jayadev","author_inst":"University of Washington"},{"author_name":"Michael D. Geschwind","author_inst":"University of California, San Francisco"},{"author_name":"Jose Biller","author_inst":"Loyola University Chicago"},{"author_name":"Helmi L. Lutsep","author_inst":"Oregon Health & Science University"},{"author_name":"Sara J. Doyle","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Jason D. Hinman","author_inst":"David Geffen School of Medicine, University of California, Los Angeles"},{"author_name":"David S. Liebeskind","author_inst":"University of Southern California"},{"author_name":"Imama A. Naqvi","author_inst":"Columbia University"},{"author_name":"Kelsey Eklund","author_inst":"University of Colorado, Anschutz"},{"author_name":"Sudha Seshadri","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Lisa C. Krishnamurthy","author_inst":"Emory University"},{"author_name":"Myriam Fornage","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Jane S. Paulsen","author_inst":"University of Wisconsin-Madison"},{"author_name":"Edward D. Huey","author_inst":"Butler Hospital"},{"author_name":"- The United States CADASIL Consortium","author_inst":""}],"rel_date":"2026-09-30","rel_site":"medrxiv"},{"rel_title":"Neuropsychiatric Symptom Associations with NOTCH3 Genotype in the United States CADASIL Consortium","rel_doi":"10.64898\/2026.09.24.26363718","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.24.26363718","rel_abs":"Background and objectives: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the most common monogenic cerebral small vessel disease. Though neuropsychiatric symptoms (NPS) of CADASIL profoundly impact function and quality of life, these symptoms remain understudied. This analysis characterizes the prevalence, severity, and profile of NPS among individuals with CADASIL-causing NOTCH3 variants and non-carrier biological family controls in the United States CADASIL Consortium (USCC). Methods: This cross-sectional analysis used multimodal baseline data from 12 enrollment sites across the country. Statistical analyses used nonparametric tests and regression models to compare clinical and neuropsychiatric outcomes across CADASIL risk tiers and controls, adjusting for age, sex, race, and education where appropriate. The primary outcome measure was the Neuropsychiatric Inventory Questionnaire (NPI-Q), an informant-reported measure which assesses 12 categories of NPS. NPI-Q item severity and distress were evaluated for individuals with confirmed cysteine-altering NOTCH3 variants and compared with controls. Results: Four hundred fifty-nine USCC participants were included in the analytic cohort: 343 cases [256 high-risk (HR); 63 medium-risk (MR); 24 low-risk (LR)]; and 116 controls. Among participants with available NPI-Q data, at least one neuropsychiatric symptom was reported by 72.6% (n = 228\/314) of cases compared with 53.2% (n = 58\/109) of controls. Reported symptoms were more common among CADASIL cases than controls, occurring in 75.0%, 71.2%, and 72.7% of participants in the LR, MR, and HR groups, respectively, compared with 53.2% of controls. Compared with controls, participants in the MR group and HR group had higher NPI-Q severity scores. HR participants also had higher NPI-Q distress scores than controls. Discussion: Our findings support the notion that NPS are an important clinical manifestation of CADASIL. Beyond previously reported symptoms, additional neuropsychiatric manifestations were identified. Given the higher burden and variability in the neuropsychiatric presentation of CADASIL, the relationships among neuropsychiatric, neurological, and patient-reported outcomes merit further investigation. The NPS profile may enhance the evaluation of the safety and efficacy of different treatments to target these symptoms for CADASIL patients. Trial Registration Information: The study is registered at ClinicalTrials.gov (NCT05677880, 12\/12\/2022).","rel_num_authors":25,"rel_authors":[{"author_name":"Megan R. Caruso","author_inst":"Butler Hospital"},{"author_name":"Barbara L. Fischer","author_inst":"University of Wisconsin-Madison"},{"author_name":"William H. Adams","author_inst":"Loyola University Chicago"},{"author_name":"Deven K. Burks","author_inst":"University of Wisconsin-Madison"},{"author_name":"Bianca Le","author_inst":"University of Washington"},{"author_name":"Arash Salardini","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Jennifer J. Majersik","author_inst":"The University of Utah"},{"author_name":"Stephen P. Salloway","author_inst":"Butler Hospital"},{"author_name":"Jamie L. Elliott","author_inst":"University of Wisconsin-Madison"},{"author_name":"H. Jeremy Bockholt","author_inst":"Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology, Emory Universit"},{"author_name":"Suman Jayadev","author_inst":"University of Washington"},{"author_name":"Michael D. Geschwind","author_inst":"University of California, San Francisco"},{"author_name":"Jose Biller","author_inst":"Loyola University Chicago"},{"author_name":"Helmi L. Lutsep","author_inst":"Oregon Health & Science University"},{"author_name":"Sara J. Doyle","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Jason D. Hinman","author_inst":"David Geffen School of Medicine, University of California, Los Angeles"},{"author_name":"David S. Liebeskind","author_inst":"University of Southern California"},{"author_name":"Imama A. Naqvi","author_inst":"Columbia University"},{"author_name":"Kelsey Eklund","author_inst":"University of Colorado, Anschutz"},{"author_name":"Sudha Seshadri","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Lisa C. Krishnamurthy","author_inst":"Emory University"},{"author_name":"Myriam Fornage","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Jane S. Paulsen","author_inst":"University of Wisconsin-Madison"},{"author_name":"Edward D. Huey","author_inst":"Butler Hospital"},{"author_name":"- The United States CADASIL Consortium","author_inst":""}],"rel_date":"2026-09-30","rel_site":"medrxiv"},{"rel_title":"Neuropsychiatric Symptom Associations with NOTCH3 Genotype in the United States CADASIL Consortium","rel_doi":"10.64898\/2026.09.24.26363718","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.24.26363718","rel_abs":"Background and objectives: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the most common monogenic cerebral small vessel disease. Though neuropsychiatric symptoms (NPS) of CADASIL profoundly impact function and quality of life, these symptoms remain understudied. This analysis characterizes the prevalence, severity, and profile of NPS among individuals with CADASIL-causing NOTCH3 variants and non-carrier biological family controls in the United States CADASIL Consortium (USCC). Methods: This cross-sectional analysis used multimodal baseline data from 12 enrollment sites across the country. Statistical analyses used nonparametric tests and regression models to compare clinical and neuropsychiatric outcomes across CADASIL risk tiers and controls, adjusting for age, sex, race, and education where appropriate. The primary outcome measure was the Neuropsychiatric Inventory Questionnaire (NPI-Q), an informant-reported measure which assesses 12 categories of NPS. NPI-Q item severity and distress were evaluated for individuals with confirmed cysteine-altering NOTCH3 variants and compared with controls. Results: Four hundred fifty-nine USCC participants were included in the analytic cohort: 343 cases [256 high-risk (HR); 63 medium-risk (MR); 24 low-risk (LR)]; and 116 controls. Among participants with available NPI-Q data, at least one neuropsychiatric symptom was reported by 72.6% (n = 228\/314) of cases compared with 53.2% (n = 58\/109) of controls. Reported symptoms were more common among CADASIL cases than controls, occurring in 75.0%, 71.2%, and 72.7% of participants in the LR, MR, and HR groups, respectively, compared with 53.2% of controls. Compared with controls, participants in the MR group and HR group had higher NPI-Q severity scores. HR participants also had higher NPI-Q distress scores than controls. Discussion: Our findings support the notion that NPS are an important clinical manifestation of CADASIL. Beyond previously reported symptoms, additional neuropsychiatric manifestations were identified. Given the higher burden and variability in the neuropsychiatric presentation of CADASIL, the relationships among neuropsychiatric, neurological, and patient-reported outcomes merit further investigation. The NPS profile may enhance the evaluation of the safety and efficacy of different treatments to target these symptoms for CADASIL patients. Trial Registration Information: The study is registered at ClinicalTrials.gov (NCT05677880, 12\/12\/2022).","rel_num_authors":25,"rel_authors":[{"author_name":"Megan R. Caruso","author_inst":"Butler Hospital"},{"author_name":"Barbara L. Fischer","author_inst":"University of Wisconsin-Madison"},{"author_name":"William H. Adams","author_inst":"Loyola University Chicago"},{"author_name":"Deven K. Burks","author_inst":"University of Wisconsin-Madison"},{"author_name":"Bianca Le","author_inst":"University of Washington"},{"author_name":"Arash Salardini","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Jennifer J. Majersik","author_inst":"The University of Utah"},{"author_name":"Stephen P. Salloway","author_inst":"Butler Hospital"},{"author_name":"Jamie L. Elliott","author_inst":"University of Wisconsin-Madison"},{"author_name":"H. Jeremy Bockholt","author_inst":"Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology, Emory Universit"},{"author_name":"Suman Jayadev","author_inst":"University of Washington"},{"author_name":"Michael D. Geschwind","author_inst":"University of California, San Francisco"},{"author_name":"Jose Biller","author_inst":"Loyola University Chicago"},{"author_name":"Helmi L. Lutsep","author_inst":"Oregon Health & Science University"},{"author_name":"Sara J. Doyle","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Jason D. Hinman","author_inst":"David Geffen School of Medicine, University of California, Los Angeles"},{"author_name":"David S. Liebeskind","author_inst":"University of Southern California"},{"author_name":"Imama A. Naqvi","author_inst":"Columbia University"},{"author_name":"Kelsey Eklund","author_inst":"University of Colorado, Anschutz"},{"author_name":"Sudha Seshadri","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Lisa C. Krishnamurthy","author_inst":"Emory University"},{"author_name":"Myriam Fornage","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Jane S. Paulsen","author_inst":"University of Wisconsin-Madison"},{"author_name":"Edward D. Huey","author_inst":"Butler Hospital"},{"author_name":"- The United States CADASIL Consortium","author_inst":""}],"rel_date":"2026-09-30","rel_site":"medrxiv"},{"rel_title":"Neuropsychiatric Symptom Associations with NOTCH3 Genotype in the United States CADASIL Consortium","rel_doi":"10.64898\/2026.09.24.26363718","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.24.26363718","rel_abs":"Background and objectives: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the most common monogenic cerebral small vessel disease. Though neuropsychiatric symptoms (NPS) of CADASIL profoundly impact function and quality of life, these symptoms remain understudied. This analysis characterizes the prevalence, severity, and profile of NPS among individuals with CADASIL-causing NOTCH3 variants and non-carrier biological family controls in the United States CADASIL Consortium (USCC). Methods: This cross-sectional analysis used multimodal baseline data from 12 enrollment sites across the country. Statistical analyses used nonparametric tests and regression models to compare clinical and neuropsychiatric outcomes across CADASIL risk tiers and controls, adjusting for age, sex, race, and education where appropriate. The primary outcome measure was the Neuropsychiatric Inventory Questionnaire (NPI-Q), an informant-reported measure which assesses 12 categories of NPS. NPI-Q item severity and distress were evaluated for individuals with confirmed cysteine-altering NOTCH3 variants and compared with controls. Results: Four hundred fifty-nine USCC participants were included in the analytic cohort: 343 cases [256 high-risk (HR); 63 medium-risk (MR); 24 low-risk (LR)]; and 116 controls. Among participants with available NPI-Q data, at least one neuropsychiatric symptom was reported by 72.6% (n = 228\/314) of cases compared with 53.2% (n = 58\/109) of controls. Reported symptoms were more common among CADASIL cases than controls, occurring in 75.0%, 71.2%, and 72.7% of participants in the LR, MR, and HR groups, respectively, compared with 53.2% of controls. Compared with controls, participants in the MR group and HR group had higher NPI-Q severity scores. HR participants also had higher NPI-Q distress scores than controls. Discussion: Our findings support the notion that NPS are an important clinical manifestation of CADASIL. Beyond previously reported symptoms, additional neuropsychiatric manifestations were identified. Given the higher burden and variability in the neuropsychiatric presentation of CADASIL, the relationships among neuropsychiatric, neurological, and patient-reported outcomes merit further investigation. The NPS profile may enhance the evaluation of the safety and efficacy of different treatments to target these symptoms for CADASIL patients. Trial Registration Information: The study is registered at ClinicalTrials.gov (NCT05677880, 12\/12\/2022).","rel_num_authors":25,"rel_authors":[{"author_name":"Megan R. Caruso","author_inst":"Butler Hospital"},{"author_name":"Barbara L. Fischer","author_inst":"University of Wisconsin-Madison"},{"author_name":"William H. Adams","author_inst":"Loyola University Chicago"},{"author_name":"Deven K. Burks","author_inst":"University of Wisconsin-Madison"},{"author_name":"Bianca Le","author_inst":"University of Washington"},{"author_name":"Arash Salardini","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Jennifer J. Majersik","author_inst":"The University of Utah"},{"author_name":"Stephen P. Salloway","author_inst":"Butler Hospital"},{"author_name":"Jamie L. Elliott","author_inst":"University of Wisconsin-Madison"},{"author_name":"H. Jeremy Bockholt","author_inst":"Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology, Emory Universit"},{"author_name":"Suman Jayadev","author_inst":"University of Washington"},{"author_name":"Michael D. Geschwind","author_inst":"University of California, San Francisco"},{"author_name":"Jose Biller","author_inst":"Loyola University Chicago"},{"author_name":"Helmi L. Lutsep","author_inst":"Oregon Health & Science University"},{"author_name":"Sara J. Doyle","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Jason D. Hinman","author_inst":"David Geffen School of Medicine, University of California, Los Angeles"},{"author_name":"David S. Liebeskind","author_inst":"University of Southern California"},{"author_name":"Imama A. Naqvi","author_inst":"Columbia University"},{"author_name":"Kelsey Eklund","author_inst":"University of Colorado, Anschutz"},{"author_name":"Sudha Seshadri","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Lisa C. Krishnamurthy","author_inst":"Emory University"},{"author_name":"Myriam Fornage","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Jane S. Paulsen","author_inst":"University of Wisconsin-Madison"},{"author_name":"Edward D. Huey","author_inst":"Butler Hospital"},{"author_name":"- The United States CADASIL Consortium","author_inst":""}],"rel_date":"2026-09-30","rel_site":"medrxiv"},{"rel_title":"DNA Methylation of Neurodevelopmental, Stress-Response, Reward, and Opioid Pathway Genes: Sex Differences in Infants with Neonatal Opioid Exposure","rel_doi":"10.64898\/2026.09.28.26364198","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.28.26364198","rel_abs":"Objective: To investigate sex-specific associations between DNA methylation (DNAm) of neurodevelopmental, stress-response, and dopaminergic pathway genes and need for pharmacological treatment for Neonatal Opioid Withdrawal Syndrome (NOWS) among opioid-exposed newborns. Study Design: Buccal swabs were collected at birth from 181 infants in the multi-site Child and Family Study (CAFS). DNAm was measured via pyrosequencing at CpG sites within promoter regions of neurodevelopmental (BDNF), stress-response (AVP, NR3C1, OXTR, FKBP5, SLC6A4), dopaminergic (DRD2, DRD4), and opioid signaling (OPRM1) genes. Need for pharmacological treatment for NOWS was obtained from medical records. We estimated robust linear regression models to investigate sex-specific associations of DNAm and need for NOWS treatment. Estimated marginal means quantified sex-specific DNAm differences by treatment status. Results: After correction for multiple testing, five CpG sites within DRD4 were significantly associated with need for pharmacological treatment, with four sites showing higher DNAm in treated infants and one showing lower DNAm. Significant sex-specific associations were identified within DRD4 and AVP. Conclusions: Epigenetic variation across multiple biological pathways contributes to variability in NOWS severity among infants with prenatal opioid exposure. The relationship between epigenetic variation and need for NOWS treatment may vary depending on infant sex.","rel_num_authors":5,"rel_authors":[{"author_name":"Angelica Aragon Vasquez","author_inst":"Women & Infants Hospital"},{"author_name":"Marie Camerota","author_inst":"Women & Infants Hospital \/ Brown University"},{"author_name":"Mara G Coyle","author_inst":"The Warren Alpert Medical School of Brown University"},{"author_name":"Elisabeth D Conradt","author_inst":"Duke University"},{"author_name":"Barry M Lester","author_inst":"Women & Infants Hospital \/ Brown University"}],"rel_date":"2026-09-29","rel_site":"medrxiv"},{"rel_title":"ASXL1-Mutant Clonal Hematopoiesis is Associated with Calcific Aortic Valve Disease and Promotes Valvular Calcification In Vitro","rel_doi":"10.64898\/2026.09.23.26363798","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.23.26363798","rel_abs":"Background and AimsCalcific aortic valve disease (CAVD) is a common valvular heart condition and has no effective medical therapy. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the acquisition of somatic mutations in hematopoietic stem cells which provides a selection advantage, has been associated with incident aortic stenosis (AS), particularly when driven by TET2 mutations.\n\nMethodsWe evaluated the association of CHIP and gene-specific CHIP subtypes with AS in the UK Biobank (UKB) and with aortic valve hemodynamics in the Atherosclerosis Risk in Communities (ARIC) study to prioritize gene driver mutations for mechanistic study. We then generated human ASXL1-mutant THP-1 derived macrophage like cells and evaluated the ability of THP-1 conditioned media to promote a calcific response in human valvular interstitial cells (VICs). We additionally performed mass spectrometry proteomics to characterize the ASXL1-mutant THP-1 macrophage secretome. Therapeutically relevant inflammatory pathways were inhibited with anakinra (interleukin [IL]-1) or tocilizumab (IL-6).\n\nResultsAmong 449,109 individuals in the UKB with whole exome sequencing, large CHIP clones and non-DNMT3A CHIP subtypes (e.g., TET2, ASXL1, and JAK2 CHIP) were independently associated with risk of incident AS. Among 1,963 individuals in ARIC with CHIP sequencing and echocardiographic data, only ASXL1 CHIP was associated with worse aortic valve hemodynamics. In vitro, ASXL1-mutant human THP-1-derived macrophage-like cells had increased AIM2 inflammasome activation. THP-1 media promoted VIC calcification, which was accelerated in ASXL1 mutant macrophages. Proteomic profiling identified inflammatory proteins linked to valvular calcification. Accelerated VIC calcification was reduced by IL-1 inhibition by anakinra or IL-6 inhibition by tocilizumab.\n\nConclusionsIntegrating human cohort data with experimental evidence using ASXL1-mutant human macrophage-like cells and human valve cells, these findings identify ASXL1-mutant CHIP as a distinct inflammatory subtype associated with valvular calcification and support IL-1 and IL-6 signaling as candidate therapeutic pathways for future investigation in CAVD.","rel_num_authors":25,"rel_authors":[{"author_name":"Aeron Small","author_inst":"Brigham and Women's Hospital"},{"author_name":"Liying Xue","author_inst":"Mass General Brigham"},{"author_name":"Shinsuke Ito","author_inst":"Mass General Brigham"},{"author_name":"Cesar De Jeronimo Diaz","author_inst":"UCSF"},{"author_name":"Yuto Nakamura","author_inst":"Mass General Brigham"},{"author_name":"Niekbachsh Mohammadnia","author_inst":"Mass General Brigham"},{"author_name":"Huajun Liao","author_inst":"UCSF"},{"author_name":"Yota Maekawa","author_inst":"Mass General Brigham"},{"author_name":"Linke Li","author_inst":"Massachusetts General Hospital"},{"author_name":"Sasha A Singh","author_inst":"Brigham and Women's Hospital\/Harvard Medical School"},{"author_name":"Taku Kasai","author_inst":"Brigham and Women's Hospital"},{"author_name":"Luisa Weiss","author_inst":"Mass General Brigham"},{"author_name":"Md Mesbah Uddin","author_inst":"Broad Institute"},{"author_name":"Art Schuermans","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Spencer Flynn","author_inst":"Mass General Brigham"},{"author_name":"Elby Mackenzie","author_inst":"McGill University"},{"author_name":"James C Engert","author_inst":"Research Institute of McGill University Health Centre"},{"author_name":"George Thanassoulis","author_inst":"McGill University"},{"author_name":"Peter Libby","author_inst":"Mass General Brigham Inc"},{"author_name":"Amil Shah","author_inst":"UT Southwestern"},{"author_name":"Christie M. Ballantyne","author_inst":"Baylor College of Medicine"},{"author_name":"Pradeep Natarajan","author_inst":"Mass General Brigham"},{"author_name":"Trevor Fidler","author_inst":"UCSF"},{"author_name":"Elena Aikawa","author_inst":"Brigham and Women's Hospital, Harvard Medical School"},{"author_name":"Michael C. Honigberg","author_inst":"Massachusetts General Hospital"}],"rel_date":"2026-09-29","rel_site":"medrxiv"}]}