{"gname":"University of Sydney","grp_id":"50","rels":[{"rel_title":"Type 2 Deiodinase in Cancer-Associated Fibroblasts: A Potential Therapeutic Target in Many Types of Cancer","rel_doi":"10.64898\/2026.09.14.26362848","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26362848","rel_abs":"Background: Cancer-associated fibroblasts (CAF) are major regulators of the tumor microenvironment (TME), yet the pathways governing CAF function remain incompletely understood. Type 2 deiodinase (DIO2, D2), which converts thyroxine (T4) to the active thyroid hormone triiodothyronine (T3), has not been systematically investigated in CAF across different solid tumors. Methods: We analyzed DIO2 expression using single-cell RNA sequencing (scRNA-seq) from primary thyroid tumors, a large integrated scRNASeq thyroid cancer atlas, and publicly available scRNA-seq datasets representing six additional solid tumor types. Bulk RNA sequencing data from the Oncology Research Information Exchange Network (ORIEN) database were used to examine correlations among DIO2, CAF subtype markers, and overall survival (OS). A genetically engineered TPO-CreERT2\/BrafV600E\/Trp53-deficient (TBP) mouse model was evaluated for CAF-specific Dio2 expression and pharmacologic inhibition of D2 activity. TBP mice were crossed with Dio2-\/- (Dio2 KO) mice to investigate the role of Dio2 in cancer development and progression. Results: DIO2 expression was highly restricted to CAF and was largely absent from epithelial-derived cancer, immune, and endothelial cells. Across thyroid cancer and six additional malignancies, DIO2 was consistently detected in CAF, demonstrating that CAF-specific DIO2 expression is a conserved feature of multiple tumor types. Within thyroid cancer, DIO2 was enriched in myofibroblastic CAF (myCAF) compared with inflammatory CAF (iCAF), and bulk transcriptomic analyses demonstrated stronger correlations between DIO2 expression and canonical myCAF markers than iCAF markers across numerous cancers. Elevated DIO2 expression was associated with worse OS in pancreatic and bladder cancers, paralleling the adverse prognostic impact of increased myCAF abundance. In contrast, thyroid cancer demonstrated an inverse association attributable to loss of epithelial DIO2 expression during tumor dedifferentiation. The TBP mouse model recapitulated human disease, with Dio2 expression restricted to CAF, robust stromal fibrosis, and measurable D2 enzymatic activity that was suppressed by cefuroxime and lenvatinib. Genetic loss of Dio2 in the TME resulted in significantly reduced tumor growth. Conclusions: DIO2 is a conserved marker of CAF, and myCAF, across multiple solid tumors and is associated with adverse clinical outcomes in some cancers. The TBP mouse provides a robust preclinical model to define the mechanistic role of DIO2 in CAF biology and to evaluate DIO2-directed therapeutic strategies targeting the tumor microenvironment.","rel_num_authors":32,"rel_authors":[{"author_name":"Mary Grace Carroll","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Noha Mukhtar","author_inst":"King Faisal Specialist Hospital and Research Centre"},{"author_name":"Jacob Calhoun","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Breaunna Garza","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Matthew A Loberg","author_inst":"Vanderbilt University"},{"author_name":"Hua-Chang Chen","author_inst":"Vanderbilt University"},{"author_name":"Quanhu Sheng","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alyse Staley","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Tatiana L Fonseca","author_inst":"University of Texas Medical Branch"},{"author_name":"Antonio C Bianco","author_inst":"University of Texas Medical Branch"},{"author_name":"Matthew D Ringel","author_inst":"The Ohio State University"},{"author_name":"Pamela Brock","author_inst":"The Ohio Satae University"},{"author_name":"Andrew J Gunderson","author_inst":"The Ohio State University"},{"author_name":"Ahamd A Tarhini","author_inst":"Moffitt Cancer Center"},{"author_name":"W Douglas Cress","author_inst":"Moffitt Cancer Center"},{"author_name":"Michael J Cavnar","author_inst":"University of Kentucky"},{"author_name":"Stephen Edge","author_inst":"Roswell Park Comprehensive Cancer Center"},{"author_name":"Varinder Kaur","author_inst":"University of Virginia"},{"author_name":"George J Weiner","author_inst":"University of Iowa"},{"author_name":"Janice L Farlow","author_inst":"Indiana University"},{"author_name":"Robert Dood","author_inst":"University of Utah"},{"author_name":"Roman Groisberg","author_inst":"Rutgers Cancer Institute of New Jersey"},{"author_name":"Abdul Rafeh Naquash","author_inst":"University of Oklahoma"},{"author_name":"Craig Shriver","author_inst":"Walter Reed National Military Medical Center"},{"author_name":"Dinesh Pal Mudaranthakam","author_inst":"University of Kansas Medical Center"},{"author_name":"Jose A Oliveras","author_inst":"Ponce Health Sciences University"},{"author_name":"Robert J Rounbehler","author_inst":"Aster Insights"},{"author_name":"Michelle L. Churchman","author_inst":"Aster Insights"},{"author_name":"Vivian L Weiss","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Rebecca E Schweppe","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Nikita Pozdeyev","author_inst":"University of Colorado Anschutz"},{"author_name":"Bryan R Haugen","author_inst":"Universtiy of Colorado Anschutz"}],"rel_date":"2026-09-23","rel_site":"medrxiv"},{"rel_title":"Type 2 Deiodinase in Cancer-Associated Fibroblasts: A Potential Therapeutic Target in Many Types of Cancer","rel_doi":"10.64898\/2026.09.14.26362848","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26362848","rel_abs":"Background: Cancer-associated fibroblasts (CAF) are major regulators of the tumor microenvironment (TME), yet the pathways governing CAF function remain incompletely understood. Type 2 deiodinase (DIO2, D2), which converts thyroxine (T4) to the active thyroid hormone triiodothyronine (T3), has not been systematically investigated in CAF across different solid tumors. Methods: We analyzed DIO2 expression using single-cell RNA sequencing (scRNA-seq) from primary thyroid tumors, a large integrated scRNASeq thyroid cancer atlas, and publicly available scRNA-seq datasets representing six additional solid tumor types. Bulk RNA sequencing data from the Oncology Research Information Exchange Network (ORIEN) database were used to examine correlations among DIO2, CAF subtype markers, and overall survival (OS). A genetically engineered TPO-CreERT2\/BrafV600E\/Trp53-deficient (TBP) mouse model was evaluated for CAF-specific Dio2 expression and pharmacologic inhibition of D2 activity. TBP mice were crossed with Dio2-\/- (Dio2 KO) mice to investigate the role of Dio2 in cancer development and progression. Results: DIO2 expression was highly restricted to CAF and was largely absent from epithelial-derived cancer, immune, and endothelial cells. Across thyroid cancer and six additional malignancies, DIO2 was consistently detected in CAF, demonstrating that CAF-specific DIO2 expression is a conserved feature of multiple tumor types. Within thyroid cancer, DIO2 was enriched in myofibroblastic CAF (myCAF) compared with inflammatory CAF (iCAF), and bulk transcriptomic analyses demonstrated stronger correlations between DIO2 expression and canonical myCAF markers than iCAF markers across numerous cancers. Elevated DIO2 expression was associated with worse OS in pancreatic and bladder cancers, paralleling the adverse prognostic impact of increased myCAF abundance. In contrast, thyroid cancer demonstrated an inverse association attributable to loss of epithelial DIO2 expression during tumor dedifferentiation. The TBP mouse model recapitulated human disease, with Dio2 expression restricted to CAF, robust stromal fibrosis, and measurable D2 enzymatic activity that was suppressed by cefuroxime and lenvatinib. Genetic loss of Dio2 in the TME resulted in significantly reduced tumor growth. Conclusions: DIO2 is a conserved marker of CAF, and myCAF, across multiple solid tumors and is associated with adverse clinical outcomes in some cancers. The TBP mouse provides a robust preclinical model to define the mechanistic role of DIO2 in CAF biology and to evaluate DIO2-directed therapeutic strategies targeting the tumor microenvironment.","rel_num_authors":32,"rel_authors":[{"author_name":"Mary Grace Carroll","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Noha Mukhtar","author_inst":"King Faisal Specialist Hospital and Research Centre"},{"author_name":"Jacob Calhoun","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Breaunna Garza","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Matthew A Loberg","author_inst":"Vanderbilt University"},{"author_name":"Hua-Chang Chen","author_inst":"Vanderbilt University"},{"author_name":"Quanhu Sheng","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alyse Staley","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Tatiana L Fonseca","author_inst":"University of Texas Medical Branch"},{"author_name":"Antonio C Bianco","author_inst":"University of Texas Medical Branch"},{"author_name":"Matthew D Ringel","author_inst":"The Ohio State University"},{"author_name":"Pamela Brock","author_inst":"The Ohio Satae University"},{"author_name":"Andrew J Gunderson","author_inst":"The Ohio State University"},{"author_name":"Ahamd A Tarhini","author_inst":"Moffitt Cancer Center"},{"author_name":"W Douglas Cress","author_inst":"Moffitt Cancer Center"},{"author_name":"Michael J Cavnar","author_inst":"University of Kentucky"},{"author_name":"Stephen Edge","author_inst":"Roswell Park Comprehensive Cancer Center"},{"author_name":"Varinder Kaur","author_inst":"University of Virginia"},{"author_name":"George J Weiner","author_inst":"University of Iowa"},{"author_name":"Janice L Farlow","author_inst":"Indiana University"},{"author_name":"Robert Dood","author_inst":"University of Utah"},{"author_name":"Roman Groisberg","author_inst":"Rutgers Cancer Institute of New Jersey"},{"author_name":"Abdul Rafeh Naquash","author_inst":"University of Oklahoma"},{"author_name":"Craig Shriver","author_inst":"Walter Reed National Military Medical Center"},{"author_name":"Dinesh Pal Mudaranthakam","author_inst":"University of Kansas Medical Center"},{"author_name":"Jose A Oliveras","author_inst":"Ponce Health Sciences University"},{"author_name":"Robert J Rounbehler","author_inst":"Aster Insights"},{"author_name":"Michelle L. Churchman","author_inst":"Aster Insights"},{"author_name":"Vivian L Weiss","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Rebecca E Schweppe","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Nikita Pozdeyev","author_inst":"University of Colorado Anschutz"},{"author_name":"Bryan R Haugen","author_inst":"Universtiy of Colorado Anschutz"}],"rel_date":"2026-09-23","rel_site":"medrxiv"},{"rel_title":"Type 2 Deiodinase in Cancer-Associated Fibroblasts: A Potential Therapeutic Target in Many Types of Cancer","rel_doi":"10.64898\/2026.09.14.26362848","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26362848","rel_abs":"Background: Cancer-associated fibroblasts (CAF) are major regulators of the tumor microenvironment (TME), yet the pathways governing CAF function remain incompletely understood. Type 2 deiodinase (DIO2, D2), which converts thyroxine (T4) to the active thyroid hormone triiodothyronine (T3), has not been systematically investigated in CAF across different solid tumors. Methods: We analyzed DIO2 expression using single-cell RNA sequencing (scRNA-seq) from primary thyroid tumors, a large integrated scRNASeq thyroid cancer atlas, and publicly available scRNA-seq datasets representing six additional solid tumor types. Bulk RNA sequencing data from the Oncology Research Information Exchange Network (ORIEN) database were used to examine correlations among DIO2, CAF subtype markers, and overall survival (OS). A genetically engineered TPO-CreERT2\/BrafV600E\/Trp53-deficient (TBP) mouse model was evaluated for CAF-specific Dio2 expression and pharmacologic inhibition of D2 activity. TBP mice were crossed with Dio2-\/- (Dio2 KO) mice to investigate the role of Dio2 in cancer development and progression. Results: DIO2 expression was highly restricted to CAF and was largely absent from epithelial-derived cancer, immune, and endothelial cells. Across thyroid cancer and six additional malignancies, DIO2 was consistently detected in CAF, demonstrating that CAF-specific DIO2 expression is a conserved feature of multiple tumor types. Within thyroid cancer, DIO2 was enriched in myofibroblastic CAF (myCAF) compared with inflammatory CAF (iCAF), and bulk transcriptomic analyses demonstrated stronger correlations between DIO2 expression and canonical myCAF markers than iCAF markers across numerous cancers. Elevated DIO2 expression was associated with worse OS in pancreatic and bladder cancers, paralleling the adverse prognostic impact of increased myCAF abundance. In contrast, thyroid cancer demonstrated an inverse association attributable to loss of epithelial DIO2 expression during tumor dedifferentiation. The TBP mouse model recapitulated human disease, with Dio2 expression restricted to CAF, robust stromal fibrosis, and measurable D2 enzymatic activity that was suppressed by cefuroxime and lenvatinib. Genetic loss of Dio2 in the TME resulted in significantly reduced tumor growth. Conclusions: DIO2 is a conserved marker of CAF, and myCAF, across multiple solid tumors and is associated with adverse clinical outcomes in some cancers. The TBP mouse provides a robust preclinical model to define the mechanistic role of DIO2 in CAF biology and to evaluate DIO2-directed therapeutic strategies targeting the tumor microenvironment.","rel_num_authors":32,"rel_authors":[{"author_name":"Mary Grace Carroll","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Noha Mukhtar","author_inst":"King Faisal Specialist Hospital and Research Centre"},{"author_name":"Jacob Calhoun","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Breaunna Garza","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Matthew A Loberg","author_inst":"Vanderbilt University"},{"author_name":"Hua-Chang Chen","author_inst":"Vanderbilt University"},{"author_name":"Quanhu Sheng","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alyse Staley","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Tatiana L Fonseca","author_inst":"University of Texas Medical Branch"},{"author_name":"Antonio C Bianco","author_inst":"University of Texas Medical Branch"},{"author_name":"Matthew D Ringel","author_inst":"The Ohio State University"},{"author_name":"Pamela Brock","author_inst":"The Ohio Satae University"},{"author_name":"Andrew J Gunderson","author_inst":"The Ohio State University"},{"author_name":"Ahamd A Tarhini","author_inst":"Moffitt Cancer Center"},{"author_name":"W Douglas Cress","author_inst":"Moffitt Cancer Center"},{"author_name":"Michael J Cavnar","author_inst":"University of Kentucky"},{"author_name":"Stephen Edge","author_inst":"Roswell Park Comprehensive Cancer Center"},{"author_name":"Varinder Kaur","author_inst":"University of Virginia"},{"author_name":"George J Weiner","author_inst":"University of Iowa"},{"author_name":"Janice L Farlow","author_inst":"Indiana University"},{"author_name":"Robert Dood","author_inst":"University of Utah"},{"author_name":"Roman Groisberg","author_inst":"Rutgers Cancer Institute of New Jersey"},{"author_name":"Abdul Rafeh Naquash","author_inst":"University of Oklahoma"},{"author_name":"Craig Shriver","author_inst":"Walter Reed National Military Medical Center"},{"author_name":"Dinesh Pal Mudaranthakam","author_inst":"University of Kansas Medical Center"},{"author_name":"Jose A Oliveras","author_inst":"Ponce Health Sciences University"},{"author_name":"Robert J Rounbehler","author_inst":"Aster Insights"},{"author_name":"Michelle L. Churchman","author_inst":"Aster Insights"},{"author_name":"Vivian L Weiss","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Rebecca E Schweppe","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Nikita Pozdeyev","author_inst":"University of Colorado Anschutz"},{"author_name":"Bryan R Haugen","author_inst":"Universtiy of Colorado Anschutz"}],"rel_date":"2026-09-23","rel_site":"medrxiv"},{"rel_title":"Type 2 Deiodinase in Cancer-Associated Fibroblasts: A Potential Therapeutic Target in Many Types of Cancer","rel_doi":"10.64898\/2026.09.14.26362848","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.14.26362848","rel_abs":"Background: Cancer-associated fibroblasts (CAF) are major regulators of the tumor microenvironment (TME), yet the pathways governing CAF function remain incompletely understood. Type 2 deiodinase (DIO2, D2), which converts thyroxine (T4) to the active thyroid hormone triiodothyronine (T3), has not been systematically investigated in CAF across different solid tumors. Methods: We analyzed DIO2 expression using single-cell RNA sequencing (scRNA-seq) from primary thyroid tumors, a large integrated scRNASeq thyroid cancer atlas, and publicly available scRNA-seq datasets representing six additional solid tumor types. Bulk RNA sequencing data from the Oncology Research Information Exchange Network (ORIEN) database were used to examine correlations among DIO2, CAF subtype markers, and overall survival (OS). A genetically engineered TPO-CreERT2\/BrafV600E\/Trp53-deficient (TBP) mouse model was evaluated for CAF-specific Dio2 expression and pharmacologic inhibition of D2 activity. TBP mice were crossed with Dio2-\/- (Dio2 KO) mice to investigate the role of Dio2 in cancer development and progression. Results: DIO2 expression was highly restricted to CAF and was largely absent from epithelial-derived cancer, immune, and endothelial cells. Across thyroid cancer and six additional malignancies, DIO2 was consistently detected in CAF, demonstrating that CAF-specific DIO2 expression is a conserved feature of multiple tumor types. Within thyroid cancer, DIO2 was enriched in myofibroblastic CAF (myCAF) compared with inflammatory CAF (iCAF), and bulk transcriptomic analyses demonstrated stronger correlations between DIO2 expression and canonical myCAF markers than iCAF markers across numerous cancers. Elevated DIO2 expression was associated with worse OS in pancreatic and bladder cancers, paralleling the adverse prognostic impact of increased myCAF abundance. In contrast, thyroid cancer demonstrated an inverse association attributable to loss of epithelial DIO2 expression during tumor dedifferentiation. The TBP mouse model recapitulated human disease, with Dio2 expression restricted to CAF, robust stromal fibrosis, and measurable D2 enzymatic activity that was suppressed by cefuroxime and lenvatinib. Genetic loss of Dio2 in the TME resulted in significantly reduced tumor growth. Conclusions: DIO2 is a conserved marker of CAF, and myCAF, across multiple solid tumors and is associated with adverse clinical outcomes in some cancers. The TBP mouse provides a robust preclinical model to define the mechanistic role of DIO2 in CAF biology and to evaluate DIO2-directed therapeutic strategies targeting the tumor microenvironment.","rel_num_authors":32,"rel_authors":[{"author_name":"Mary Grace Carroll","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Noha Mukhtar","author_inst":"King Faisal Specialist Hospital and Research Centre"},{"author_name":"Jacob Calhoun","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Breaunna Garza","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Matthew A Loberg","author_inst":"Vanderbilt University"},{"author_name":"Hua-Chang Chen","author_inst":"Vanderbilt University"},{"author_name":"Quanhu Sheng","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alyse Staley","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Tatiana L Fonseca","author_inst":"University of Texas Medical Branch"},{"author_name":"Antonio C Bianco","author_inst":"University of Texas Medical Branch"},{"author_name":"Matthew D Ringel","author_inst":"The Ohio State University"},{"author_name":"Pamela Brock","author_inst":"The Ohio Satae University"},{"author_name":"Andrew J Gunderson","author_inst":"The Ohio State University"},{"author_name":"Ahamd A Tarhini","author_inst":"Moffitt Cancer Center"},{"author_name":"W Douglas Cress","author_inst":"Moffitt Cancer Center"},{"author_name":"Michael J Cavnar","author_inst":"University of Kentucky"},{"author_name":"Stephen Edge","author_inst":"Roswell Park Comprehensive Cancer Center"},{"author_name":"Varinder Kaur","author_inst":"University of Virginia"},{"author_name":"George J Weiner","author_inst":"University of Iowa"},{"author_name":"Janice L Farlow","author_inst":"Indiana University"},{"author_name":"Robert Dood","author_inst":"University of Utah"},{"author_name":"Roman Groisberg","author_inst":"Rutgers Cancer Institute of New Jersey"},{"author_name":"Abdul Rafeh Naquash","author_inst":"University of Oklahoma"},{"author_name":"Craig Shriver","author_inst":"Walter Reed National Military Medical Center"},{"author_name":"Dinesh Pal Mudaranthakam","author_inst":"University of Kansas Medical Center"},{"author_name":"Jose A Oliveras","author_inst":"Ponce Health Sciences University"},{"author_name":"Robert J Rounbehler","author_inst":"Aster Insights"},{"author_name":"Michelle L. Churchman","author_inst":"Aster Insights"},{"author_name":"Vivian L Weiss","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Rebecca E Schweppe","author_inst":"Universtiy of Colorado Anschutz"},{"author_name":"Nikita Pozdeyev","author_inst":"University of Colorado Anschutz"},{"author_name":"Bryan R Haugen","author_inst":"Universtiy of Colorado Anschutz"}],"rel_date":"2026-09-23","rel_site":"medrxiv"},{"rel_title":"Caregiver knowledge and Attitudes toward Human Papillomavirus Vaccination among adolescent girls living with HIV in Sierra Leone: A health facility-based cross-sectional study","rel_doi":"10.64898\/2026.09.21.26363609","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363609","rel_abs":"Objective To assess the knowledge, willingness and barriers to human papillomavirus (HPV) vaccination among caregivers of adolescent girls living with HIV in Sierra Leone. Methods This cross-sectional study examined HPV vaccine knowledge, willingness, and barriers among 249 caregivers of adolescent girls living with HIV in Sierra Leone. Data were collected through structured questionnaires at public tertiary hospitals and high-volume HIV clinics, and associations were assessed using chi-square tests, logistic regression, and Kruskal-Wallis analyses. Results Only 32.1% (80\/249) of caregivers had heard of HPV, with even fewer aware of its link to cervical cancer (24.4%, 60\/246) or prevention methods of cervical cancer (31.9%, 79\/248). Misconceptions were prevalent; 16.3% (36\/221) erroneously linked oral contraceptives to cervical cancer, and 61.1% (44\/72) of caregivers unwilling to vaccinate cited distrust in vaccine efficacy. While tertiary-educated caregivers exhibited the highest level of knowledge (45.5%, p < 0.001), their willingness to vaccinate (50%, 33\/66) was comparable to that of less-educated groups, highlighting a knowledge-action gap. Structural barriers dominated, with 66.1% (154\/233) citing unawareness of the vaccine and 10.3% (24\/233) missing school-based vaccination days. Relationship dynamics significantly influenced willingness: extended family members showed the highest willingness (69.4%, p = 0.029), whereas grandparents were least willing (31%, 9\/29). Although systemic gaps such disrupted vaccination services, vaccines supplies and cold chain limited uptake, healthcare workers emerged as the most effective information source (rank sum = 889.5, p = 0.039). Conclusion The study highlights needs for culturally tailored education to dispel myths, community-driven strategies engaging trusted actors like healthcare workers and extended families.This study justifies the need for integration of HPV vaccination and cervical cancer screening into HIV care services.","rel_num_authors":16,"rel_authors":[{"author_name":"Darlinda  Fatmata Jiba","author_inst":"College of Medicine and Allied Health Sciences, University of Sierra Leone"},{"author_name":"Mamadu Baldeh","author_inst":"London School of Hygiene & Tropical Medicine"},{"author_name":"Patrick Turay","author_inst":"UNIMAK: University of Makeni"},{"author_name":"Saidu Kanu","author_inst":"University of Makeni"},{"author_name":"Matilda  N Kamara","author_inst":"Government of Sierra Leone"},{"author_name":"Lynda  M. L Farma-Grant","author_inst":"Government of Sierra Leone"},{"author_name":"Umu Barrie","author_inst":"Infectious Disease Research Network, Freetown, Sierra Leone"},{"author_name":"Waheed  O Awonuga","author_inst":"Government of Sierra Leone"},{"author_name":"Mary  M Baio","author_inst":"Government of Sierra Leone"},{"author_name":"Daniel Sesay","author_inst":"Government of Sierra Leone"},{"author_name":"Diana Shehab","author_inst":"Government of Sierra Leone"},{"author_name":"Rosaline Sinnah","author_inst":"Government of Sierra Leone"},{"author_name":"Enanga  S Namanga","author_inst":"Government of Sierra Leone"},{"author_name":"Phildys  M D Johnson","author_inst":"Government of Sierra Leone"},{"author_name":"Sulaiman Lakoh","author_inst":"University of Sierra Leone"},{"author_name":"J.  Andrew Dykens","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-09-23","rel_site":"medrxiv"},{"rel_title":"Childhood and adolescent immunisation intentions post-COVID-19 in Lusaka, Zambia","rel_doi":"10.64898\/2026.09.21.26363608","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363608","rel_abs":"Background: Since the COVID-19 pandemic, parental delays and refusals of well-established, safe, and effective childhood vaccinations have contributed to the resurgence of infectious diseases. This raises concerns that COVID-19 vaccine hesitancy may also extend to novel vaccines for children when introduced in the future. This study examined caregivers, who included healthcare workers (HCWs), perceptions of novel vaccinations for children ages 0-17 years old and intentions to vaccinate children and adolescents ages 12-17 years against COVID-19. Methods: We conducted a secondary data analysis of a larger cross-sectional survey administered to parents\/caregivers of children ages 0-17 years in Lusaka, Zambia, between 13 November and 15 December 2023. Vaccination intention for COVID-19 was specifically focused on caregivers of adolescents ages 12-17 years, following COVID-19 vaccination guidelines during the study. Descriptive statistics were used to explore demographic characteristics, vaccination history, and caregivers COVID-19 vaccination status, along with their childrens routine childhood vaccine histories and perceptions of COVID-19 and novel vaccinations. Results: Among 277 caregivers (66.8% women, median age: 35 years), 93.1% reported that their child had received all recommended routine childhood vaccinations. COVID-19 vaccine uptake was higher among HCWs (68.2% with [&ge;]2 doses) than among community members (40.8%) and having [&ge;]2 doses was associated with higher COVID-19 vaccine uptake among their adolescents ages 12-17 years. 58.0% of caregivers indicated that their 12-17 years old adolescents had received at least one COVID-19 vaccine dose. Overall intention to further vaccinate children against COVID-19, especially among those already unvaccinated, remained low, with 24.7% of caregivers reporting no intent to vaccinate their children. Protection from hospitalization and death from malaria, TB, HIV, pneumonia, influenza, and diarrheal diseases were the most cited reason (79.1%) for intention to vaccinate children with novel vaccines for these diseases. The most prominent reasons for reluctance towards future vaccines were the fear of potential side effects (45.5%) and insufficient knowledge about vaccination benefits and risks (31.8%). Caregivers most trusted the Ministry of Health (86.6%) and healthcare professionals (66.8%) as sources of vaccine information. Conclusions: While routine childhood vaccine uptake remained high, acceptance of COVID-19 and future novel vaccines for children was lower and was influenced by caregivers own vaccination status. Targeted and transparent communication through trusted sources such as the Ministry of Health and healthcare professionals may be critical for addressing safety concerns and strengthening confidence in novel childhood vaccines.","rel_num_authors":11,"rel_authors":[{"author_name":"Mwiza Nyasa","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Anjali Sharma","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Andrew  D Kerkhoff","author_inst":"University of California San Francisco"},{"author_name":"Dennis Ngosa","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Bertha Shamoya","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Kombatende Sikombe","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Sandra Simbeza","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Nelly Zulu","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Elvin  H Geng","author_inst":"Washington University In Saint Louis: Washington University in St Louis"},{"author_name":"Jake  M Pry","author_inst":"UC Davis: University of California Davis"},{"author_name":"Noelle Tourneau","author_inst":"Zuckerberg San Francisco General Hospital and Trauma Center"}],"rel_date":"2026-09-23","rel_site":"medrxiv"},{"rel_title":"Childhood and adolescent immunisation intentions post-COVID-19 in Lusaka, Zambia","rel_doi":"10.64898\/2026.09.21.26363608","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363608","rel_abs":"Background: Since the COVID-19 pandemic, parental delays and refusals of well-established, safe, and effective childhood vaccinations have contributed to the resurgence of infectious diseases. This raises concerns that COVID-19 vaccine hesitancy may also extend to novel vaccines for children when introduced in the future. This study examined caregivers, who included healthcare workers (HCWs), perceptions of novel vaccinations for children ages 0-17 years old and intentions to vaccinate children and adolescents ages 12-17 years against COVID-19. Methods: We conducted a secondary data analysis of a larger cross-sectional survey administered to parents\/caregivers of children ages 0-17 years in Lusaka, Zambia, between 13 November and 15 December 2023. Vaccination intention for COVID-19 was specifically focused on caregivers of adolescents ages 12-17 years, following COVID-19 vaccination guidelines during the study. Descriptive statistics were used to explore demographic characteristics, vaccination history, and caregivers COVID-19 vaccination status, along with their childrens routine childhood vaccine histories and perceptions of COVID-19 and novel vaccinations. Results: Among 277 caregivers (66.8% women, median age: 35 years), 93.1% reported that their child had received all recommended routine childhood vaccinations. COVID-19 vaccine uptake was higher among HCWs (68.2% with [&ge;]2 doses) than among community members (40.8%) and having [&ge;]2 doses was associated with higher COVID-19 vaccine uptake among their adolescents ages 12-17 years. 58.0% of caregivers indicated that their 12-17 years old adolescents had received at least one COVID-19 vaccine dose. Overall intention to further vaccinate children against COVID-19, especially among those already unvaccinated, remained low, with 24.7% of caregivers reporting no intent to vaccinate their children. Protection from hospitalization and death from malaria, TB, HIV, pneumonia, influenza, and diarrheal diseases were the most cited reason (79.1%) for intention to vaccinate children with novel vaccines for these diseases. The most prominent reasons for reluctance towards future vaccines were the fear of potential side effects (45.5%) and insufficient knowledge about vaccination benefits and risks (31.8%). Caregivers most trusted the Ministry of Health (86.6%) and healthcare professionals (66.8%) as sources of vaccine information. Conclusions: While routine childhood vaccine uptake remained high, acceptance of COVID-19 and future novel vaccines for children was lower and was influenced by caregivers own vaccination status. Targeted and transparent communication through trusted sources such as the Ministry of Health and healthcare professionals may be critical for addressing safety concerns and strengthening confidence in novel childhood vaccines.","rel_num_authors":11,"rel_authors":[{"author_name":"Mwiza Nyasa","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Anjali Sharma","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Andrew  D Kerkhoff","author_inst":"University of California San Francisco"},{"author_name":"Dennis Ngosa","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Bertha Shamoya","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Kombatende Sikombe","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Sandra Simbeza","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Nelly Zulu","author_inst":"CIDRZ: Center for Infectious Disease Research in Zambia"},{"author_name":"Elvin  H Geng","author_inst":"Washington University In Saint Louis: Washington University in St Louis"},{"author_name":"Jake  M Pry","author_inst":"UC Davis: University of California Davis"},{"author_name":"Noelle Tourneau","author_inst":"Zuckerberg San Francisco General Hospital and Trauma Center"}],"rel_date":"2026-09-23","rel_site":"medrxiv"},{"rel_title":"Adaptation and Validation of Brief Tablet-Based Cognitive Assessment Tool in Uganda","rel_doi":"10.64898\/2026.09.21.26363152","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363152","rel_abs":"Background: Sub-Saharan Africa (sSA) faces accelerated growth in Alzheimer's disease and related dementias (ADRDs), including in older people living with HIV (PLWH). However, there are limited contextually relevant diagnostic tools to assess cognitive impairment in the region. The Tablet-based Cognitive Assessment Tool (TabCAT) is a digital platform hosting cognitive tests with automated scoring that can be administered by non-specialists and are designed for use across diverse cultures, languages, and education levels. We translated, adapted, and assessed the validity of a brief battery of TabCAT tests in the Uganda Aging and Dementia Cohort Study (UADCS), a prospective cohort of older PLWH and age- and sex-similar adults not living with HIV in southwestern Uganda. Methods: Four TabCAT tests were translated and culturally adapted through expert review and focus groups of adults at study sites. Psychometric validity was examined by assessing floor and ceiling effects, association with known demographic predictors, and concurrent and divergent validity against a reference-standard cognitive testing battery previously validated and employed in Uganda. Z-scores on all tests were derived using a regression-based normative approach to adjust for age, sex, education, urbanicity, and literacy. Receiver Operating Characteristic (ROC) curves were fit to assess the TabCAT Composite Score performance in discriminating objective cognitive impairment (defined using Jak\/Bondi criteria) in the total sample, then stratified by HIV serostatus. Results: TabCAT tests were reported by local experts and focus groups to have acceptable face and content validity. Participants (n=563, mean age 60{+\/-}6.4, 50% female, 51% did not complete primary school, 16% were not literate, 49% PLWH) completed the reference-standard and TabCAT battery. For TabCAT tests, there were no notable floor or ceiling effects, and test scores were associated with age and education as expected. Correlations between TabCAT and reference-standard tests were stronger in aligning cognitive domains (memory, executive function) than in non-aligning domains (motor). The TabCAT Composite Score discriminated cognitive impairment with good performance (c-statistic 0.77; 95% CI 0.72-0.81), including among PLWH. Discussion: TabCAT tests demonstrated face, content, construct, concurrent, and criterion validity for measuring cognition and detecting objective cognitive impairment among older adults in Uganda, including PLWH. These results support the potential of tablet-based brief cognitive assessment tools to measure cognitive performance and detect cognitive impairment in Uganda, including among older PLWH, and in populations with lower levels of education and literacy.","rel_num_authors":24,"rel_authors":[{"author_name":"Roslyn Valdespino","author_inst":"Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA"},{"author_name":"Gabrielle Hromas","author_inst":"Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA"},{"author_name":"Chen-Pin Wang","author_inst":"Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA"},{"author_name":"Robert Paul","author_inst":"University of Missouri- St Louis, St. Louis, MO, USA"},{"author_name":"Noeline Nakasujja","author_inst":"Makerere University, Kampala, Uganda"},{"author_name":"Zahra Reynolds","author_inst":"Massachusetts General Hospital (MGH), Boston, MA, USA"},{"author_name":"Flavia Atwiine","author_inst":"Mbarara University of Science & Technology, Mbarara, Uganda"},{"author_name":"Edna Tindimwebwa","author_inst":"Kabwohe Clinical Research Centre, Sheema, Uganda"},{"author_name":"Meredith Greene","author_inst":"Indiana University School of Medicine, Indianapolis, IN, US"},{"author_name":"Eliza Passell","author_inst":"Massachusetts General Hospital (MGH), Boston, MA, USA"},{"author_name":"Christine S. Ritchie","author_inst":"Massachusetts General Hospital (MGH), Boston, MA, USA"},{"author_name":"Susanne S. Hoeppner","author_inst":"Massachusetts General Hospital (MGH), Boston, MA, USA"},{"author_name":"Alexander C. Tsai","author_inst":"Massachusetts General Hospital (MGH), Boston, MA, USA"},{"author_name":"Janet Seeley","author_inst":"Department of Global Health and Development, London School of Hygiene & Tropical Medicine, London, UK"},{"author_name":"Amy Werry","author_inst":"Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA"},{"author_name":"Emi Varfaj","author_inst":"Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA"},{"author_name":"Sudha Seshadri","author_inst":"Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA"},{"author_name":"Samson Okello","author_inst":"University of North Carolina - Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Stephen Asiimwe","author_inst":"Massachusetts General Hospital (MGH), Boston, MA, USA"},{"author_name":"Deanna Saylor","author_inst":"University of North Carolina - Chapel Hill, Chapel Hill, NC, USA"},{"author_name":"Katherine L. Possin","author_inst":"Global Brain Health Institute (GBHI), University of California San Francisco (UCSF)"},{"author_name":"Elena Tsoy","author_inst":"Global Brain Health Institute (GBHI), University of California San Francisco (UCSF)"},{"author_name":"Mark J. Siedner","author_inst":"Massachusetts General Hospital (MGH), Boston, MA, USA"},{"author_name":"Jeremy A. Tanner","author_inst":"Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center, San Antonio, TX, USA"}],"rel_date":"2026-09-23","rel_site":"medrxiv"},{"rel_title":"A knockout screening platform for interferon-stimulated genes in respiratory cells identifies LY6E as a dominant antiviral effector against coronaviruses","rel_doi":"10.64898\/2026.09.21.751853","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.751853","rel_abs":"Human coronaviruses (HCoVs) cause pathogenic outcomes ranging from mild illness to severe respiratory disease. Determining how respiratory cells coordinate an early antiviral response is necessary to understand successful control of HCoV replication. The Type I Interferon (IFN) response is a major component of innate viral immunity. IFN signaling leads to the upregulation of hundreds of interferon-stimulated genes (ISGs) that can have antiviral activity, though the individual ISGs that are responsible for restricting mildly pathogenic HCoVs in the respiratory epithelium are not clear. Here, we developed a targeted CRISPR-Cas9 knockout sgRNA library (termed the respISG library), focusing on ISGs that are upregulated across a panel of respiratory cells, to screen for innate host factors that restrict the mildly pathogenic human coronavirus, HCoV-OC43. We executed cell death-based screens in immortalized human small airway epithelial cells and identified lymphocyte antigen 6E (LY6E) as a top hit. We confirmed LY6E activity in validation studies and found it regulates entry of various SARS-CoV-2 Spike-pseudotyped lentiviruses. In addition to demonstrating a key role for LY6E in blocking a variety of HCoVs in small airway epithelial cells, this study establishes a loss-of-function CRISPR-Cas9 screening platform for identification of HCoV antiviral ISGs in respiratory cells.","rel_num_authors":10,"rel_authors":[{"author_name":"Caitlin I Stoddard","author_inst":"University of Pittsburgh"},{"author_name":"Morgan L Litchford","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Kevin Sung","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Rebecca L Hutcheson","author_inst":"University of Pittsburgh"},{"author_name":"Joshua Marceau","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Taylor Johnson","author_inst":"University of Minnesota"},{"author_name":"Akinobu Ota","author_inst":"Kinjo Gakuin University"},{"author_name":"Nell E Baumgarten","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Michael Gale Jr.","author_inst":"University of Minnesota"},{"author_name":"Julie Overbaugh","author_inst":"Fred Hutchinson Cancer Research Center"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"A microbiome-derived metabolite from Staphylococcus epidermidis inhibits Staphylococcus aureus biofilm formation and virulence","rel_doi":"10.64898\/2026.09.23.753553","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.23.753553","rel_abs":"Staphylococcus epidermidis is a common member of the healthy skin microbiome that contributes to barrier function and protection against pathogen colonization. In contrast, Staphylococcus aureus is a major human pathogen and the leading cause of skin and soft tissue infections, owing in part to its robust biofilm-forming capacity and increasing antimicrobial resistance. We previously demonstrated that S. epidermidis cell-free conditioned media (CFCM) inhibit S. aureus biofilm formation by altering bacterial gene expression without affecting growth. Here, we identify the metabolite responsible for this activity. Bioactivity-guided fractionation of S. epidermidis CFCM revealed pyroglutamic acid (PCA) as the active antibiofilm compound. Commercially sourced PCA inhibited S. aureus biofilm formation and reduced adhesion to epithelial cells. In a murine skin infection model, PCA treatment significantly attenuated disease severity, accelerated wound healing, and reduced bacterial burden. Analysis of S. epidermidis CFCM by chromatography, nuclear magnetic resonance spectroscopy, and mass spectrometry confirmed the presence of PCA and identified it as the bioactive constituent responsible for antibiofilm activity. Together, these findings uncover a previously unrecognized mechanism by which S. epidermidis suppresses S. aureus virulence and highlight the potential of microbiome-derived metabolites as therapeutics for the prevention and treatment of S. aureus skin infections.","rel_num_authors":6,"rel_authors":[{"author_name":"Ankur Sood","author_inst":"University of Kansas"},{"author_name":"Kiana Hajiarbabbi","author_inst":"University of Kansas"},{"author_name":"Willian Rodrigues Ribeiro","author_inst":"Universidade Federal do Rio de Janeiro"},{"author_name":"Ana Carolina Oliveira","author_inst":"Universidade Federal do Rio de Janeiro"},{"author_name":"L. Caetano M. Antunes","author_inst":"University of Kansas"},{"author_name":"Rosana B.R. Ferreira","author_inst":"University of Kansas"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"Dynamic belief representation and updating through learned attractor-like dynamics in the frontal cortex","rel_doi":"10.64898\/2026.09.17.752495","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752495","rel_abs":"To act adaptively, animals must infer hidden states of the world from incomplete sensory information and update beliefs as new observations accrue. While dopamine signals are well explained by reinforcement learning models that incorporate belief states, how the brain implements belief-state inference remains unknown. Prior modeling work showed that recurrent neural networks trained to predict value (Value-RNN) develop task-specific, attractor-like dynamics that mirror evolution of beliefs. Here we performed high-density electrophysiological recordings from orbitofrontal cortex (OFC) and other brain areas of mice performing two variants of a Pavlovian task that differ in reward probability, which produce different within-trial belief dynamics. We find that OFC population activity exhibits task-specific attractor-like dynamics that mirror the within-trial dynamics in the Value-RNN. These dynamics are absent in motor and olfactory regions, are not explained by behavioral differences, and emerge progressively with learning. Our findings indicate that the brain approximates belief-state inference through learned, task-specific attractor-like dynamics.","rel_num_authors":10,"rel_authors":[{"author_name":"Sandra A Romero Pinto","author_inst":"Columbia University"},{"author_name":"Jay A Hennig","author_inst":"Baylor College of Medicine"},{"author_name":"Mark Burrell","author_inst":"Harvard University"},{"author_name":"Daigo Okada","author_inst":"Max Planck Florida Institute for Neuroscience"},{"author_name":"Celia Benquet","author_inst":"Ecole Polytechnique Federale de Lausanne"},{"author_name":"Daniel Regester","author_inst":"Sainsbury Wellcome Centre for Neural Circuits and Behaviour, University College London"},{"author_name":"Yoh Isogai","author_inst":"Allen Institute for Neural Dynamics"},{"author_name":"Scott  W. Linderman","author_inst":"Stanford University"},{"author_name":"Samuel J Gershman","author_inst":"Harvard University"},{"author_name":"Naoshige Uchida","author_inst":"Harvard University"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"Impaired Peroxisome Import Drives Cellular Senescence through SCAF1-Dependent Suppression of Mitoribosome Biogenesis","rel_doi":"10.64898\/2026.09.19.752713","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.19.752713","rel_abs":"Communication between peroxisomes and mitochondria is essential for cellular metabolic homeostasis, yet how peroxisomal import stress impacts mitochondria function during aging and cellular senescence remains poorly defined. Using a genome-wide CRISPR screening in HEK293 cells under peroxisome import stress, we identified SCAF1 (SR-related CTD-associated factor 1) a known canonical nuclear pre-mRNA splicing factor, as an essential regulator of mitochondrial homeostasis. Under peroxisome stress SCAF1 undergoes proteolytic processing and translocates to the mitochondria, where its N-terminal region acts as an autonomous repressor module that blocks mitoribosomal subunit joining. Consequently, SCAF1 depletion accelerates subunit joining and elevates oxidative phosphorylation protein levels, whereas its overexpression in IMR90 fibroblast cells triggers robust cellular senescence characterized by increased senescence associated {beta} gal staining. Together, our findings uncover a stress-responsive peroxisome-to-mitochondria signaling axis mediated by SCAF1 translocation. This pathway directly modulates mitoribosome assembly to maintain translational homeostasis, providing a precise molecular mechanism for how upstream peroxisomal decline drives downstream mitochondrial dysfunction and cellular senescence.","rel_num_authors":3,"rel_authors":[{"author_name":"Jacinta Correia","author_inst":"Iowa State University"},{"author_name":"Jinoh Kim","author_inst":"Iowa State University"},{"author_name":"Hua Bai","author_inst":"Iowa State University"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"IFN-\u03ba directs antiviral immunity in human skin","rel_doi":"10.64898\/2026.09.19.752886","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.19.752886","rel_abs":"Inducible expression of type I IFNs is a well-established host innate defense mechanism to limit virus infection. Yet, many viruses have evolved strategies to suppress the induction of these cytokines to enhance replication, spread, and transmission between hosts. Whether additional antiviral mechanisms protect against infection when inducible responses are compromised is not well understood. Here, we demonstrate that human keratinocytes preemptively protect the skin against virus infection through constitutive production of IFN-kappa (IFN-{kappa}), a poorly studied type I IFN family member. We find that constitutive IFNK expression protects keratinocytes against skin tropic RNA and DNA viruses, including vesicular stomatitis virus (VSV) and herpes simplex virus-1 (HSV-1). Using a human skin organoid model, we further demonstrate that keratinocyte-derived IFN-{kappa} establishes an antiviral state in dermal fibroblasts. Genetic and chemical analysis of the type I IFN receptor (IFNAR) signaling pathway in monocultured keratinocytes and skin organoids revealed that distinct pathways control VSV and HSV-1 replication. While canonical JAK-STAT signaling provided protection against VSV, HSV-1 infection was controlled through a JAK-STAT-independent mechanism. Using transcriptomic analysis, we further identified an IFN-{kappa}-dependent gene signature in keratinocytes that is not similarly driven by other type I IFNs. Together, this work establishes constitutive IFN-{kappa} production by keratinocytes as a broadly antiviral tissue autonomous defense mechanism.","rel_num_authors":11,"rel_authors":[{"author_name":"Jafira M. Johnson","author_inst":"UMASS Chan Medical School"},{"author_name":"Laurellee Payne","author_inst":"UMASS Chan Medical School"},{"author_name":"Pooja Parameswaran","author_inst":"UMASS Chan Medical School"},{"author_name":"Yongzhi Chen","author_inst":"UMASS Chan Medical School"},{"author_name":"Mrinal K. Sarkar","author_inst":"University of Michigan"},{"author_name":"Anthony M. Coon","author_inst":"University of Michigan"},{"author_name":"J. Michelle Kahlenberg","author_inst":"University of Michigan"},{"author_name":"Johann E. Gudjonsson","author_inst":"University of Michigan"},{"author_name":"Katherine A. Fitzgerald","author_inst":"UMASS Chan Medical School"},{"author_name":"Mehdi Rashighi","author_inst":"Massachusetts General Hospital"},{"author_name":"Megan H. Orzalli","author_inst":"UMASS Chan Medical School"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"Dissociable Stimulus- and Response-Driven Serial Dependence Effects in Auditory, Visual, and Audiovisual Motion Judgments","rel_doi":"10.64898\/2026.09.17.752446","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752446","rel_abs":"Efficient motion perception requires integrating immediate sensory evidence with internal representations shaped by experience. This influence of recent history can produce serial dependence effects (SDEs), in which current judgments are biased toward or away from the source of previous information. We examined SDEs in auditory, visual, and cued audiovisual motion-direction discrimination using aggregate psychometric measures and trial-level generalized linear mixed-effects models (GLMMs), which estimated the independent contributions of the previous stimulus direction and the participant's previous response. Participants completed unisensory (n=57) and cued audiovisual (n=48) motion-discrimination tasks. Aggregate analyses indicated attractive SDEs in auditory conditions, repulsive SDEs in visual conditions, and no net SDE in the audiovisual-cued condition. Trial-level modeling revealed a more nuanced structure: previous stimulus direction produced repulsive effects in both unisensory conditions, with previous visual direction influencing judgments across all conditions containing visual motion, whereas previous response produced attractive effects only when visual information was task-relevant. In the audiovisual-cued condition, the absence of a net psychometric shift was consistent with the opposing influences of an attractive response-history effect and a repulsive visual stimulus-history effect rather than an absence of serial dependence. These findings suggest that serial dependence in motion perception reflects dissociable and concurrently operating processes, including a predominantly visual, adaptation-like stimulus-history effect and a task-dependent, decision-related response-history effect.","rel_num_authors":5,"rel_authors":[{"author_name":"Adam J Tiesman","author_inst":"Vanderbilt University"},{"author_name":"Kalina Stoyanova","author_inst":"Vanderbilt University"},{"author_name":"Hannah Bertisch","author_inst":"Vanderbilt University"},{"author_name":"Ramnarayan Ramachandran","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Mark T Wallace","author_inst":"Vanderbilt University"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"Spatial transcriptomics reveals epithelial-immune remodeling preceding malignant transformation of oral premalignant lesions","rel_doi":"10.64898\/2026.09.17.751597","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.751597","rel_abs":"Oral premalignant lesions (OPLs) are common; however, histopathological grading incompletely identifies lesions destined for cancer. To define tissue ecosystems that precede malignant transformation, we integrated single-cell-resolution Xenium spatial transcriptomics of 20 HPV-negative biospecimens from 16 patients, with independent single-cell RNA sequencing and immunofluorescence data from 38 patients with OPLs after quality control. Progressive OPLs exhibit a coordinated epithelial-immune program comprising MX1\/NOTCH3-high KRT14+\/KRT15+ basal epithelial states, S100A9-high inflammatory macrophages, TIGIT-high, exhaustion-associated T cells, and altered dendritic cell states. Spatial analyses showed that T cells and dendritic cells were displaced from the basal epithelial interface, and that epithelial neighborhoods were depleted of dendritic cells but enriched for TIGIT-high T cells, revealing immune reorganization not captured by cellular abundance alone. Independent single-cell and protein-level analyses reproduced basal epithelial interferon\/stress programs, S100A9-associated myeloid inflammation, TIGIT-high, exhaustion-associated T-cell programs, and dendritic cell redistribution. Ligand-receptor inference suggested convergent myeloid and lymphoid signals linked to epithelial stress, checkpoint regulation, and extracellular matrix remodeling. Functionally, recombinant S100A9 accelerated wound closure in oral epithelial and cancer cells, whereas S100A9 and S100A8\/S100A9 enhanced oral cancer cell proliferation. These responses were attenuated by pharmacologic inhibition of TLR4 or RAGE. Together, these data define a spatially organized, myeloid-skewed, checkpoint-enriched ecosystem present before invasion and suggest S100A9-TLR4\/RAGE signaling and epithelial-immune geometry as candidate mechanisms and biomarkers for oral cancer interception.","rel_num_authors":6,"rel_authors":[{"author_name":"Yuxiao Jarvan Jiang","author_inst":"University of California, San Francisco"},{"author_name":"Irshad Ali","author_inst":"University of California San Francisco"},{"author_name":"Jeanine M. Genkinger","author_inst":"Columbia University Mailman School of Public Health"},{"author_name":"Oliver D King","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Elizabeth Phillipone","author_inst":"Columbia University College of Dental Medicine"},{"author_name":"Fatemeh Momen-Heravi","author_inst":"University of California San Francisco"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"Spatial transcriptomics reveals epithelial-immune remodeling preceding malignant transformation of oral premalignant lesions","rel_doi":"10.64898\/2026.09.17.751597","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.751597","rel_abs":"Oral premalignant lesions (OPLs) are common; however, histopathological grading incompletely identifies lesions destined for cancer. To define tissue ecosystems that precede malignant transformation, we integrated single-cell-resolution Xenium spatial transcriptomics of 20 HPV-negative biospecimens from 16 patients, with independent single-cell RNA sequencing and immunofluorescence data from 38 patients with OPLs after quality control. Progressive OPLs exhibit a coordinated epithelial-immune program comprising MX1\/NOTCH3-high KRT14+\/KRT15+ basal epithelial states, S100A9-high inflammatory macrophages, TIGIT-high, exhaustion-associated T cells, and altered dendritic cell states. Spatial analyses showed that T cells and dendritic cells were displaced from the basal epithelial interface, and that epithelial neighborhoods were depleted of dendritic cells but enriched for TIGIT-high T cells, revealing immune reorganization not captured by cellular abundance alone. Independent single-cell and protein-level analyses reproduced basal epithelial interferon\/stress programs, S100A9-associated myeloid inflammation, TIGIT-high, exhaustion-associated T-cell programs, and dendritic cell redistribution. Ligand-receptor inference suggested convergent myeloid and lymphoid signals linked to epithelial stress, checkpoint regulation, and extracellular matrix remodeling. Functionally, recombinant S100A9 accelerated wound closure in oral epithelial and cancer cells, whereas S100A9 and S100A8\/S100A9 enhanced oral cancer cell proliferation. These responses were attenuated by pharmacologic inhibition of TLR4 or RAGE. Together, these data define a spatially organized, myeloid-skewed, checkpoint-enriched ecosystem present before invasion and suggest S100A9-TLR4\/RAGE signaling and epithelial-immune geometry as candidate mechanisms and biomarkers for oral cancer interception.","rel_num_authors":6,"rel_authors":[{"author_name":"Yuxiao Jarvan Jiang","author_inst":"University of California, San Francisco"},{"author_name":"Irshad Ali","author_inst":"University of California San Francisco"},{"author_name":"Jeanine M. Genkinger","author_inst":"Columbia University Mailman School of Public Health"},{"author_name":"Oliver D King","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Elizabeth Phillipone","author_inst":"Columbia University College of Dental Medicine"},{"author_name":"Fatemeh Momen-Heravi","author_inst":"University of California San Francisco"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"Spatial transcriptomics reveals epithelial-immune remodeling preceding malignant transformation of oral premalignant lesions","rel_doi":"10.64898\/2026.09.17.751597","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.751597","rel_abs":"Oral premalignant lesions (OPLs) are common; however, histopathological grading incompletely identifies lesions destined for cancer. To define tissue ecosystems that precede malignant transformation, we integrated single-cell-resolution Xenium spatial transcriptomics of 20 HPV-negative biospecimens from 16 patients, with independent single-cell RNA sequencing and immunofluorescence data from 38 patients with OPLs after quality control. Progressive OPLs exhibit a coordinated epithelial-immune program comprising MX1\/NOTCH3-high KRT14+\/KRT15+ basal epithelial states, S100A9-high inflammatory macrophages, TIGIT-high, exhaustion-associated T cells, and altered dendritic cell states. Spatial analyses showed that T cells and dendritic cells were displaced from the basal epithelial interface, and that epithelial neighborhoods were depleted of dendritic cells but enriched for TIGIT-high T cells, revealing immune reorganization not captured by cellular abundance alone. Independent single-cell and protein-level analyses reproduced basal epithelial interferon\/stress programs, S100A9-associated myeloid inflammation, TIGIT-high, exhaustion-associated T-cell programs, and dendritic cell redistribution. Ligand-receptor inference suggested convergent myeloid and lymphoid signals linked to epithelial stress, checkpoint regulation, and extracellular matrix remodeling. Functionally, recombinant S100A9 accelerated wound closure in oral epithelial and cancer cells, whereas S100A9 and S100A8\/S100A9 enhanced oral cancer cell proliferation. These responses were attenuated by pharmacologic inhibition of TLR4 or RAGE. Together, these data define a spatially organized, myeloid-skewed, checkpoint-enriched ecosystem present before invasion and suggest S100A9-TLR4\/RAGE signaling and epithelial-immune geometry as candidate mechanisms and biomarkers for oral cancer interception.","rel_num_authors":6,"rel_authors":[{"author_name":"Yuxiao Jarvan Jiang","author_inst":"University of California, San Francisco"},{"author_name":"Irshad Ali","author_inst":"University of California San Francisco"},{"author_name":"Jeanine M. Genkinger","author_inst":"Columbia University Mailman School of Public Health"},{"author_name":"Oliver D King","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Elizabeth Phillipone","author_inst":"Columbia University College of Dental Medicine"},{"author_name":"Fatemeh Momen-Heravi","author_inst":"University of California San Francisco"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"Dynamic social envirotypes demonstrate adolescent brain dysconnectivity is contextual","rel_doi":"10.64898\/2026.09.17.752338","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752338","rel_abs":"The adolescent social environment and dynamics therein have been linked to divergent brain organization and greater risk of psychopathology later in life, suggesting the neural underpinnings of mental health may depend on social context. To examine this, we leveraged longitudinal ABCD Study data to identify dynamic social envirotypes, or distinct trajectories of social environment change over four years. Dynamic social envirotypes differed in mental health outcomes, changes in mental health, and whole-brain functional connectivity, with each dynamic social envirotype exhibiting a characteristic pattern of brain network organization. Crucially, functional connectivity associations with internalizing and externalizing problems diverged across dynamic social envirotypes, with the highest and lowest social resource envirotypes showing largely opposing associations between connectivity and symptom severity. These findings suggest that dysconnectivity is contextual: there is no single brain connectivity pattern that is universally associated with better mental health. Rather, adolescent brain connectivity relates to mental health in context-specific ways, challenging normative narratives of the neural underpinnings of psychopathology and centering the role of context for understanding and treating mental health.","rel_num_authors":4,"rel_authors":[{"author_name":"Haily Merritt","author_inst":"Northeastern University London"},{"author_name":"Marlen Z Gonzalez","author_inst":"Cornell University"},{"author_name":"Stephanie Noble","author_inst":"Northeastern University"},{"author_name":"Andreia Sofia Teixeira","author_inst":"Northeastern University London"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"Novelty-seeking and directed exploration scale with dissociable social network outcomes and brain systems in older adults","rel_doi":"10.64898\/2026.09.21.753261","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.753261","rel_abs":"Social isolation and loneliness are major determinants of well-being in older adults. Shrinking social networks and age-related shifts in social behavior and decision-making may increase vulnerability to loneliness. These changes in social decision-making strategies can be conceptualized within an exploration-exploitation tradeoff framework, in which social options with known outcomes are prioritized over uncertain ones. Yet, no study has characterized how complementary decision-making strategies, undirected novelty seeking and goal-directed exploration, relate to social network constructs or are supported by distinct neural systems. These strategies capture distinct forms of decision-making: undirected novelty seeking is driven by the intrinsic salience of novel options independent of expected informational gain, whereas goal-directed exploration involves deliberately sampling uncertain options to reduce uncertainty and optimize future choices. Here, we used fMRI and a novel social bandit reinforcement task to identify dissociable social constructs and brain systems linked to undirected novelty seeking and goal-directed exploration in older adults. Undirected novelty seeking was associated with social network size and with activity of temporoparietal and mid-cingulate brain areas. Goal-directed exploration predicted subjective feelings of social connectedness and was associated with activity of anterior cingulate and prefrontal brain areas. Crucially, choice probabilities from a non-social version of the three-arm bandit task were not associated with social decision-making nor with social constructs. Our findings suggest that, in later life, dissociable social decision-making strategies, when faced with unknown options, rely on distinct neural systems supporting social network size as well as subjective feelings of social connectedness.","rel_num_authors":14,"rel_authors":[{"author_name":"Christian Valtierra","author_inst":"University of California San Francisco"},{"author_name":"Jeremy Hogeveen","author_inst":"University of New Mexico"},{"author_name":"Gabriella Mace","author_inst":"University of California San Francisco"},{"author_name":"Samantha Moreno","author_inst":"University of California San Francisco"},{"author_name":"Avery Ostrand","author_inst":"University of California San Francisco"},{"author_name":"Sydney Griffith","author_inst":"University of California San Francisco"},{"author_name":"Maria Jose Auil","author_inst":"University of California San Francisco"},{"author_name":"Patrick McConnell","author_inst":"University of California San Francisco"},{"author_name":"Joseph C.C. Chen","author_inst":"University of California San Francisco"},{"author_name":"Jennifer Mitchell","author_inst":"University of California San Francisco"},{"author_name":"Gary R. Turner","author_inst":"York University"},{"author_name":"Nathan Spreng","author_inst":"McGill University"},{"author_name":"Adam Gazzaley","author_inst":"University of California San Francisco"},{"author_name":"Lorenzo Pasquini","author_inst":"University of California San Francisco"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"Novelty-seeking and directed exploration scale with dissociable social network outcomes and brain systems in older adults","rel_doi":"10.64898\/2026.09.21.753261","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.753261","rel_abs":"Social isolation and loneliness are major determinants of well-being in older adults. Shrinking social networks and age-related shifts in social behavior and decision-making may increase vulnerability to loneliness. These changes in social decision-making strategies can be conceptualized within an exploration-exploitation tradeoff framework, in which social options with known outcomes are prioritized over uncertain ones. Yet, no study has characterized how complementary decision-making strategies, undirected novelty seeking and goal-directed exploration, relate to social network constructs or are supported by distinct neural systems. These strategies capture distinct forms of decision-making: undirected novelty seeking is driven by the intrinsic salience of novel options independent of expected informational gain, whereas goal-directed exploration involves deliberately sampling uncertain options to reduce uncertainty and optimize future choices. Here, we used fMRI and a novel social bandit reinforcement task to identify dissociable social constructs and brain systems linked to undirected novelty seeking and goal-directed exploration in older adults. Undirected novelty seeking was associated with social network size and with activity of temporoparietal and mid-cingulate brain areas. Goal-directed exploration predicted subjective feelings of social connectedness and was associated with activity of anterior cingulate and prefrontal brain areas. Crucially, choice probabilities from a non-social version of the three-arm bandit task were not associated with social decision-making nor with social constructs. Our findings suggest that, in later life, dissociable social decision-making strategies, when faced with unknown options, rely on distinct neural systems supporting social network size as well as subjective feelings of social connectedness.","rel_num_authors":14,"rel_authors":[{"author_name":"Christian Valtierra","author_inst":"University of California San Francisco"},{"author_name":"Jeremy Hogeveen","author_inst":"University of New Mexico"},{"author_name":"Gabriella Mace","author_inst":"University of California San Francisco"},{"author_name":"Samantha Moreno","author_inst":"University of California San Francisco"},{"author_name":"Avery Ostrand","author_inst":"University of California San Francisco"},{"author_name":"Sydney Griffith","author_inst":"University of California San Francisco"},{"author_name":"Maria Jose Auil","author_inst":"University of California San Francisco"},{"author_name":"Patrick McConnell","author_inst":"University of California San Francisco"},{"author_name":"Joseph C.C. Chen","author_inst":"University of California San Francisco"},{"author_name":"Jennifer Mitchell","author_inst":"University of California San Francisco"},{"author_name":"Gary R. Turner","author_inst":"York University"},{"author_name":"Nathan Spreng","author_inst":"McGill University"},{"author_name":"Adam Gazzaley","author_inst":"University of California San Francisco"},{"author_name":"Lorenzo Pasquini","author_inst":"University of California San Francisco"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"Sleep spindle deficits in childhood absence epilepsy improve with antiseizure treatment and disease resolution","rel_doi":"10.64898\/2026.09.17.752393","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752393","rel_abs":"Childhood absence epilepsy (CAE), the most common childhood epilepsy syndrome, is associated with bursts of generalized thalamocortical spike-wave discharges and cognitive impairment, yet the physiological mechanisms linking disease activity, treatment, and cognition remain unclear. Sleep spindles, generated by thalamocortical circuits, are associated with cognitive function and may be disrupted by epileptic activity. Here, we retrospectively studied 87 EEGs from 53 children with active and resolved CAE and 87 age- and sex-matched controls to evaluate sleep spindle activity across disease states and its association with antiseizure medication (ASM) exposure. We found that children with active CAE had reduced spindle rates across all cortical regions compared to those with resolved CAE and controls, with the largest reduction in the frontal region, where epileptic spike activity was also most prominent. Spindle rate was inversely correlated with epileptic spike rate, consistent with a shared thalamocortical circuitry. The association between ASM exposure and spindle rate varied by disease state. In active CAE, treated children had higher spindle rates than untreated children. In resolved CAE, treated children had lower spindle rates than untreated children. In contrast, ASM-related differences in spike rate were more limited, although a medication-specific reduction was observed in active CAE. These findings support sleep spindle rate as a candidate physiological marker of disease state and ASM exposure in children with CAE. Given the established role of sleep spindles in memory consolidation, these findings support testing of whether spindle disruption provides a mechanistic link between epileptic thalamocortical activity and cognitive vulnerability in CAE.","rel_num_authors":6,"rel_authors":[{"author_name":"Skyler K Goodman","author_inst":"Massachusetts General Hospital"},{"author_name":"Sarah Yi","author_inst":"Johns Hopkins School of Medicine"},{"author_name":"Dhinakaran M Chinappen","author_inst":"Kennedy Krieger Institute \/ Johns Hopkins School of Medicine"},{"author_name":"Mark A Kramer","author_inst":"Johns Hopkins University"},{"author_name":"Catherine J Chu","author_inst":"Kennedy Krieger Institute \/ Johns Hopkins School of Medicine"},{"author_name":"Hunki Kwon","author_inst":"Kennedy Krieger Institute \/ Johns Hopkins School of Medicine"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"MIRCID: Inferred Hub-miRNAs Drive Cross-Task Improvements in Drug Mechanistic Modeling","rel_doi":"10.64898\/2026.09.17.752312","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752312","rel_abs":"Drug mechanism-of-action (MoA) modeling commonly relies on perturbational transcriptomes, but matched microRNA (miRNA) measurements are often unavailable. Inferred regulatory features offer a scalable way to reuse these data. Here, we present MIRCID, a framework comparing gene expression with inferred transcription factor (TF) activity and miRNA expression across pathway classification and similarity-based MoA retrieval. HubmiRNet infers 414 pan-cancer hub miRNAs (HubmiRs) from 977 L1000 landmark genes, achieving a Pearson correlation coefficient of 87.72\\%; its 1,298-output variant also outperformed SiCmiR on the full-miRNA task (71.21\\% versus 67.30\\%). In the evaluated comparisons, miRNA augmentation provided more consistent gains than TF activity. Generic embedding controls showed model-dependent utility, while complementarity analyses identified a distinct, partially linearly recoverable representation that retained gene-derived structure. Illustrative rescue cases linked improved classification to biologically plausible miRNA patterns in samples with weak transcriptional signatures. These findings support inferred HubmiRs as a biologically informed recoding of transcriptomic data for perturbational drug modeling, while leaving recovery of measured perturbational miRNA responses to further validation.","rel_num_authors":14,"rel_authors":[{"author_name":"Xin Cao","author_inst":"School of Medicine, The Chinese University of Hong Kong, Shenzhen, Longgang District, Shenzhen, Guangdong 518172, China; Warshel Institute for Computational Bio"},{"author_name":"Yigang Chen","author_inst":"School of Medicine, The Chinese University of Hong Kong, Shenzhen, Longgang District, Shenzhen, Guangdong 518172, China; Warshel Institute for Computational Bio"},{"author_name":"Jiatong Xu","author_inst":"School of Medicine, The Chinese University of Hong Kong, Shenzhen, Longgang District, Shenzhen, Guangdong 518172, China; Warshel Institute for Computational Bio"},{"author_name":"Ziyue Zhang","author_inst":"School of Medicine, The Chinese University of Hong Kong, Shenzhen, Longgang District, Shenzhen, Guangdong 518172, China; Warshel Institute for Computational Bio"},{"author_name":"Xiang Cheng","author_inst":"School of Medicine, The Chinese University of Hong Kong, Shenzhen, Longgang District, Shenzhen, Guangdong 518172, China"},{"author_name":"Shenyu Wang","author_inst":"School of Medicine, The Chinese University of Hong Kong, Shenzhen, Longgang District, Shenzhen, Guangdong 518172, China"},{"author_name":"Yangyi Zhang","author_inst":"School of Medicine, The Chinese University of Hong Kong, Shenzhen, Longgang District, Shenzhen, Guangdong 518172, China"},{"author_name":"Xiaoxuan Cai","author_inst":"School of Medicine, The Chinese University of Hong Kong, Shenzhen, Longgang District, Shenzhen, Guangdong 518172, China; Warshel Institute for Computational Bio"},{"author_name":"Shidong Cui","author_inst":"School of Medicine, The Chinese University of Hong Kong, Shenzhen, Longgang District, Shenzhen, Guangdong 518172, China; Warshel Institute for Computational Bio"},{"author_name":"Zihao Zhu","author_inst":"School of Medicine, The Chinese University of Hong Kong, Shenzhen, Longgang District, Shenzhen, Guangdong 518172, China; Warshel Institute for Computational Bio"},{"author_name":"Xiang Ji","author_inst":"School of Medicine, The Chinese University of Hong Kong, Shenzhen, Longgang District, Shenzhen, Guangdong 518172, China; Warshel Institute for Computational Bio"},{"author_name":"Hsi-Yuan Huang","author_inst":"School of Medicine, The Chinese University of Hong Kong, Shenzhen, Longgang District, Shenzhen, Guangdong 518172, China; Warshel Institute for Computational Bio"},{"author_name":"Yang-Chi-Dung Lin","author_inst":"School of Medicine, The Chinese University of Hong Kong, Shenzhen, Longgang District, Shenzhen, Guangdong 518172, China; Warshel Institute for Computational Bio"},{"author_name":"Hsien-Da Huang","author_inst":"School of Medicine, The Chinese University of Hong Kong, Shenzhen, Longgang District, Shenzhen, Guangdong 518172, China; Warshel Institute for Computational Bio"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"Priors for perceived speed combine supramodally for visual-tactile motion but not for audio-visual motion.","rel_doi":"10.64898\/2026.09.17.751718","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.751718","rel_abs":"Perception combines incoming sensory evidence with priors learned from preceding input. One example is the central tendency effect in which stimulus estimates regress towards a prior based on the mean of the stimulus distribution. Whether such priors are specific to each modality or shared across modalities remains unresolved. Here, we examined this question using speed perception in the visual, auditory and tactile modalities and used central tendency as a behavioral probe. By giving each modality its own speed range, clear predictions emerge when modalities are interleaved: if priors are modality specific, each modality should maintain its own central tendency bias whereas a supramodal prior would exhibit a different mean based on the pooled set of speeds. Moreover, a supra-modal prior should exhibit precision weighting, with the more reliable cue receiving more weight. For vision and touch, speed estimates converged when interleaved: both modalities shifted but the less reliable one shifted more, consistent with a precision-weighted supramodal prior. For vision and audition, the priors remained largely distinct: audition (the less reliable modality) showed a partial shift but did not converge on the precision weighted, supramodal mean. This was not explained by the large audiovisual reliability difference: it persisted when visual precision was reduced. These results show that in the motion domain, visual and tactile signals can combine crossmodally, but auditory and visual signals do not. Supramodal processing of motion therefore depends on which senses are involved and is likely explained by the lack of an early spatial mapping in audition.","rel_num_authors":3,"rel_authors":[{"author_name":"Alessia Tonelli","author_inst":"The University of Sydney"},{"author_name":"Cameron Phan","author_inst":"The University of Sydney"},{"author_name":"David Alais","author_inst":"The University of Sydney"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"A general method to develop excitation ratiometric neuropeptide sensors with enhanced sensitivity for in vivo applications","rel_doi":"10.64898\/2026.09.17.752296","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752296","rel_abs":"Neuropeptides regulate a wide range of physiological processes throughout the nervous and endocrine systems, yet their spatiotemporal dynamics in vivo remain poorly understood. While recently developed intensiometric sensors can detect neuropeptides, their use in vivo is often confounded by artifacts induced by hemodynamic changes, pH fluctuations, and motion. Here, we present a general strategy for engineering dual-excitation ratiometric (Ex-ratiometric) neuropeptide sensors by tuning the excited-state proton transfer properties of the fluorescent reporter. Dual excitation at 405 nm and 488 nm produces a ratiometric signal that intrinsically corrects fluorescence fluctuations unrelated to ligand binding. Using an AlphaFold3-guided in silico design approach combined with experimental validation, we developed a suite of Ex-ratiometric sensors. As a representative example, Ex-NTS2.0 enables robust detection of neurotensin (NTS) in vivo while remaining largely resistant to hemodynamics, pH, and motion-induced artifacts. Overall, these findings establish a scalable and mechanistically grounded platform for developing new Ex-ratiometric tools and provide a broadly applicable strategy for sensitive detection of neuropeptide dynamics in living systems.","rel_num_authors":6,"rel_authors":[{"author_name":"Huan Wang","author_inst":"Peking University School of Life Sciences"},{"author_name":"Yuqi Yan","author_inst":"Peking University School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies"},{"author_name":"Yulin Zhao","author_inst":"Peking University School of Life Sciences"},{"author_name":"Di Wang","author_inst":"Peking University School of Life Sciences"},{"author_name":"Changhao Huang","author_inst":"Peking University School of Life Sciences"},{"author_name":"Yulong Li","author_inst":"Peking University School of Life Sciences"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"An atlas of eukaryotic centromere architecture reveals recurrent evolutionary dynamics","rel_doi":"10.64898\/2026.09.17.752431","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.17.752431","rel_abs":"Centromeres evolved at the root of eukaryotes to segregate chromosomes during cell division. Despite their ancient origin, centromeric DNA sequences evolve rapidly and adopt diverse architectures, including point centromeres, satellite arrays, transposon clusters, and holocentrics. To analyse centromere evolution at a broad scale, we characterised architectures across 325 diverse Darwin Tree of Life genome assemblies. Centromere architecture is evolutionarily labile, and similar configurations arise independently across divergent lineages. In plants and animals, we modelled centromere evolution as a recurrent cycle, in which satellite- and transposon-based architectures interconvert, with independent origins of holocentricity. We curated >23 million satellite repeats comprising 263 families from 165 species. Despite sequence divergence between satellite families, higher order repeats are prevalent, indicating constraint on repeat architecture rather than primary sequence. Satellite arrays are heavily invaded by diverse transposon families, consistent with convergent adaptation to the centromeric niche. In 89 species, transposons themselves constitute the primary centromere structure. We observed centrophilic transposons forming tandem arrays, suggesting mechanisms for satellite regeneration. Our sample includes five independent origins of holocentricity in plants and animals, which vary in association with periodic satellite arrays. We propose that genetic instability, centrophilic transposition, and transmission distortion promote recurrent centromere architectural interconversions during evolution.","rel_num_authors":28,"rel_authors":[{"author_name":"Piotr Wlodzimierz","author_inst":"Polish Academy of Sciences"},{"author_name":"Estela Perez-Roman","author_inst":"University.of Sussex"},{"author_name":"Jacob Gonzalez Isa","author_inst":"University of Cambridge"},{"author_name":"Michael Hong","author_inst":"University of Cambridge"},{"author_name":"Meng Zhang","author_inst":"University of Cambridge"},{"author_name":"Ludmila Oliveira","author_inst":"Czech Academy of Sciences"},{"author_name":"Katharine Jenike","author_inst":"University of Cambridge"},{"author_name":"Robin Burns","author_inst":"University of Cambridge"},{"author_name":"Pio Sierra","author_inst":"University of Cambridge"},{"author_name":"Matthias Heuberger","author_inst":"University of Cambridge"},{"author_name":"Chenxi Zhou","author_inst":"University of Cambridge"},{"author_name":"Sagarika Koppera","author_inst":"University of Cambridge"},{"author_name":"Mia Becker","author_inst":"University of Cambridge"},{"author_name":"Nicola Gorringe","author_inst":"University of Cambridge"},{"author_name":"Petr Novak","author_inst":"Czech Academy of Sciences"},{"author_name":"Yennifer Mata-Sucre","author_inst":"Max Planck Institute for Plant Breeding Research"},{"author_name":"Giulio M Formenti","author_inst":"The Rockefeller University"},{"author_name":"Felipe Karam Teixeira","author_inst":"University of Cambridge"},{"author_name":"Ines Anna Drinnenberg","author_inst":"Institut Curie, UMR3664"},{"author_name":"Ioannis Kontoyiannis","author_inst":"University of Cambridge"},{"author_name":"Kamil S. Jaron","author_inst":"Wellcome Sanger Institute"},{"author_name":"Marcela Uliano da Silva","author_inst":"Wellcome Sanger Institute"},{"author_name":"Andre Marques","author_inst":"Max Planck Institute for Plant Breeding Research"},{"author_name":"Jiri Macas","author_inst":"Biology Centre of the Czech Academy of Sciences"},{"author_name":"Mark Blaxter","author_inst":"Wellcome Trust Sanger Institute"},{"author_name":"Richard Durbin","author_inst":"University of Cambridge"},{"author_name":"Alexandros Bousios","author_inst":"University of Sussex"},{"author_name":"Ian R Henderson","author_inst":"University of Cambridge"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"The gut-liver axis and the role of bacteria in severe dengue virus infection in mice","rel_doi":"10.64898\/2026.09.21.749971","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.749971","rel_abs":"Patients with severe dengue virus (DENV) infection can experience hemorrhage, shock and organ damage that coincides with defervescence and declining viremia. In addition to vascular leak, published work has shown that gut barrier permeability and elevated serum lipopolysaccharide (LPS) levels correlate with DENV disease severity. We previously described profound gut pathology in a mouse model of infection. This led to the hypothesis that a loss of gut epithelial barrier integrity and the influx of microbial products contribute to exacerbated inflammation and severe dengue disease. Consistent with this, here we demonstrated that DENV2 infection of AG129 mice compromised the gut epithelial barrier, promoted bacterial translocation, and induced microbial changes indicative of dysbiosis, including a reduced abundance of putatively beneficial microbial taxa and disrupted microbial circadian oscillations. Depleting gut bacteria with antibiotics from 1-day post-infection sharply reduced gut pathology as well as viral RNA in the proximal colon and liver, and the number of infected Kupffer cells in the liver. There was no evidence for systemic suppression of viral replication. We propose that viral infection of intestinal macrophages leads to inflammatory damage and mucosal barrier breakdown, dysbiosis and gut leak, with gut bacteria-dependent products promoting the susceptibility of Kupffer cells to DENV infection. Given the importance of liver damage in severe and fatal dengue disease, therapies that protect the gut barrier may help reduce disease severity.","rel_num_authors":14,"rel_authors":[{"author_name":"Adriana Pliego-Zamora","author_inst":"School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland 4072, Australia"},{"author_name":"Jaehyeon Kim","author_inst":"School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland 4072, Australia"},{"author_name":"Naphak Modhiran","author_inst":"School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland 4072, Australia"},{"author_name":"Karli Takizawa","author_inst":"School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland 4072, Australia"},{"author_name":"Ennae Gollasch-Miller","author_inst":"School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland 4072, Australia"},{"author_name":"Ran Wang","author_inst":"Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia"},{"author_name":"Paul R. Young","author_inst":"School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland 4072, Australia"},{"author_name":"Daniel Watterson","author_inst":"School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland 4072, Australia"},{"author_name":"Sumaira Z. Hasnain","author_inst":"Mater Research Institute - The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia"},{"author_name":"Parimala Vajjhala","author_inst":"School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland 4072, Australia"},{"author_name":"Yuji Sekiguchi","author_inst":"Molecular Biosystems Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan"},{"author_name":"Helle Bielefeldt-Ohmann","author_inst":"School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland 4072, Australia"},{"author_name":"Dieter M. Tourlousse","author_inst":"Molecular Biosystems Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan"},{"author_name":"Katryn J. Stacey","author_inst":"School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland 4072, Australia"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"High-Dimensional Multi-omic Mapping of Post-Mortem Human Brain Using Iterative Indirect Immunofluorescence Imaging on Xenium-Processed Tissues","rel_doi":"10.64898\/2026.09.16.751033","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.16.751033","rel_abs":"Spatial transcriptomics approaches provide crucial insights into gene expression distribution within intact tissue architecture, but they encounter limitations in detecting morphologically complex cell types, assessing their spatial associations with pathology, and accurately annotating cell types using RNA data alone. Therefore, we developed a robust post-processing workflow integrating Xenium spatial technology with iterative indirect immunofluorescence imaging (4i) on formalin-fixed paraffin-embedded (FFPE) human brain tissue. The post-Xenium 4i protocol presented here allows multi-omic tissue mapping, enabling deeper investigation of pathological microenvironments defined by the spatial distribution of neuropathological hallmarks and enrichment of specific cell populations. We applied this workflow on calcarine cortex tissue sections where cerebral amyloid angiopathy (CAA) burden is present, in addition to amyloid plaques and tau pathology, generating a 15-plex image that captures the complexity of the pathological microenvironment.","rel_num_authors":10,"rel_authors":[{"author_name":"Berke Karaahmet","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Tsering Lama","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Anqi Wang","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Wenqing Cao","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Vilas Menon","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Hans-Ulrich Klein","author_inst":"Columbia University Irving Medical Center"},{"author_name":"David  A Bennett","author_inst":"Rush University Medical Center"},{"author_name":"Philip De Jager","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Ya Zhang","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Mariko Taga","author_inst":"Columbia University Irving Medical Center"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"Disruption of a Structural Niche for Otoconia Maintenance May Underlie Common Vestibular Disorders","rel_doi":"10.64898\/2026.09.16.752180","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.16.752180","rel_abs":"Many falls and balance disorders in older adults originate in the otolith organs, the gravity sensors of the inner ear. These sensors maintain upright posture through otoconia, calcium carbonate crystals that mass-load the sensory maculae. Otoconia dislodgement causes the most common form of vertigo, and their age-related loss reduces gravity sensation and undermines balance. Yet the cellular mechanisms of otoconia formation and maintenance -and how they fail in disease- remain unknown. Using mineral-preserving histology, crystal-sensitive imaging, volume electron microscopy, and immunolabeling in human and animal otolith organs, we found otoconia biogenesis-related proteins and early crystallization at the pole opposing the macula, the roof domain. We discovered filigree extracellular matrix scaffolds bridging roof and macula, loaded with nascent otoconia, suggesting scaffold-guided transport across the organ. Single-cell transcriptomics nominated a specialized roof mesenchyme, signaling to the roof epithelium, as a driver of otoconia and scaffold production. In guinea pigs with endolymphatic hydrops, fluid expansion of the organs ruptured the otoconia-trafficking scaffolds as roof and macula separated, followed by a decline in macular otoconial mass. We propose a new disease model for common vertigo and balance disorders in which disruption of the otoconia-generating and -trafficking epithelial-mesenchymal roof niche leads to displacement and depletion of otoconia.","rel_num_authors":8,"rel_authors":[{"author_name":"Diana M. Correa","author_inst":"Otopathology Laboratory, Eaton-Peabody Laboratories, Laboratory Mass Eye and Ear - Department of Otolaryngology-Head and Neck Surgery, Harvard Medical School"},{"author_name":"Abel P. David","author_inst":"Department of Otolaryngology-Head and Neck Surgery, Northwestern Medicine - Feinberg School of Medicine, Northwestern University"},{"author_name":"Ruiqi Zhou","author_inst":"Department of Otolaryngology-Head and Neck Surgery, Epithelial Biology Center, Vanderbilt Center for Stem Cell Biology, Center for Computational Systems Biology"},{"author_name":"Richard Osgood","author_inst":"Eaton-Peabody Laboratories, Mass Eye and Ear - Department of Otolaryngology-Head and Neck Surgery, Harvard Medical School"},{"author_name":"Artur A. Indzhykulian","author_inst":"Eaton-Peabody Laboratories, Mass Eye and Ear - Department of Otolaryngology-Head and Neck Surgery, Harvard Medical School"},{"author_name":"Stephan Kraemer","author_inst":"Center for Nanoscale Systems, Harvard University"},{"author_name":"Taha A Jan","author_inst":"Vanderbilt University Medical CenterDepartment of Otolaryngology-Head and Neck Surgery, Epithelial Biology Center, Vanderbilt Center for Stem Cell Biology, Cent"},{"author_name":"Andreas H Eckhard","author_inst":"Otopathology Laboratory, Eaton-Peabody Laboratories, Laboratory Mass Eye and Ear - Department of Otolaryngology-Head and Neck Surgery, Harvard Medical School"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"Marine sulfated glycans inhibit the binding of Borrelia burgdorferi adhesins to heparin\/GAGs","rel_doi":"10.64898\/2026.09.22.753655","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.753655","rel_abs":"Recognition of host glycosaminoglycans (GAGs) is critical for the adhesion and colonization of Borrelia burgdorferi, but the structural requirements for these interactions remain incompletely understood. Using surface plasmon resonance (SPR), we characterized the heparin-binding properties of three Borrelia adhesins, i.e. Bgp, DbpA-A9, and DbpB-B31 and evaluated inhibitors comprising heparin oligosaccharides, selectively desulfated heparins, mammalian GAGs, marine sulfated glycans, pentosan polysulfate (PPS), and mucopolysaccharide polysulfate (MPS). All three adhesins bound directly to heparin, with equilibrium dissociation constants (KD) of 2.18 nM for Bgp and 36.4 nM for DbpB-B31. Competition assays identified N-sulfation and 6-O-sulfation as major determinants of binding, whereas 2-O-sulfation had a lower effect. Bgp showed chain-length dependence over dp4-dp20, whereas DbpB-B31 preferentially recognized longer oligosaccharides, particularly those of dp12 or greater. Chondroitin sulfate E also exhibited strong inhibitory activity, indicating that recognition was not restricted to heparin\/heparan sulfate backbones. Among the tested sulfated glycans, fucosylated chondroitin sulfate (HfFucCS) from Holothuria floridana was the most potent inhibitor of Bgp, with an IC50 of approximately 4 ng\/mL, whereas PPS was the strongest inhibitor of DbpB-B31, followed by MPS. These findings reveal protein-specific sulfated-glycan recognition and identify promising candidates for disrupting B. burgdorferi-host GAG interactions.","rel_num_authors":9,"rel_authors":[{"author_name":"Changkai Bu","author_inst":"Rensselaer Polytechnic Institute"},{"author_name":"Ke Xia","author_inst":"Rensselaer Polytechnic Institute"},{"author_name":"Carly Fernandes","author_inst":"Tufts University"},{"author_name":"Yi-Pin Lin","author_inst":"Cummings School of Veterinary Medicine, Tufts University"},{"author_name":"Nikhat Parveen","author_inst":"Rutgers New Jersey Medical School"},{"author_name":"Vitor H. Pomin","author_inst":"The University of Mississippi"},{"author_name":"Jonathan S. Dordick","author_inst":"Rensselaer Polytechnic Institute"},{"author_name":"Lianli Chi","author_inst":"Shandong University"},{"author_name":"Fuming Zhang","author_inst":"Rensselaer Polytechnic Institute"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"A general route to volumetric segmentation under annotation scarcity","rel_doi":"10.64898\/2026.09.16.752170","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.16.752170","rel_abs":"Volumetric cell segmentation is limited by the scarcity of labelled data, because manual curation of three-dimensional datasets is prohibitively laborious. We find that this gap can be bridged with volumes in which synthetic 3D objects mirror the properties of real cells and of image formation, notably the axial spread of the point-spread function. Such volumes provide unlimited labelled training data, and we show that a model trained on them produces accurate segmentations of real biological data.","rel_num_authors":6,"rel_authors":[{"author_name":"samhita radhakrishnan","author_inst":"University of Geneva"},{"author_name":"saurabh mathur","author_inst":"University of Geneva"},{"author_name":"aleksandr aleksandrov","author_inst":"University of Geneva"},{"author_name":"hugo schweke","author_inst":"University of Geneva"},{"author_name":"geraldine silvano","author_inst":"University of Geneva"},{"author_name":"emmanuel d levy","author_inst":"University of Geneva"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"Autism genes converge on three functional programs organized by neuronal subclass, developmental timing, and cortical patterning","rel_doi":"10.64898\/2026.09.22.753508","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.753508","rel_abs":"Our companion sequencing study uncovered 253 genes robustly associated with autism spectrum disorder (ASD), yet the biological programs they impact, and the cellular, developmental, and spatial contexts in which they converge, remain unresolved. Here we systematically contextualize genes associated with ASD across neurodevelopment and cortical areas, integrating developmental single-cell and spatial atlases with gene- and isoform co-expression, regulatory, proteomic, and synaptic networks. Genetic burden concentrates within temporally-resolved neuronal subclasses: newborn excitatory neurons, immature interneurons, and maturing intratelencephalic lineages. Genes associated with ASD converge on three functional programs--gene regulation, neuronal morphogenesis, and synaptic transmembrane signaling machinery--resolved from 28 ASD-associated networks, several of which are directly regulated by ASD genes including MEF2C, SOX11, and FOXP2. These programs are spatially patterned, with risk genes exhibiting an increasing anterior-to-posterior cortical expression gradient, anchored in the primary visual cortex and driven by excitatory neuron gene-regulatory programs. Finally, ASD risk genes associated with more severe developmental phenotypes show broader excitatory neuron enrichment and less interneuron involvement. Together, these findings anchor ASD genetic vulnerability to specific neurodevelopmental lineages, epochs, and molecular substrates, and delineate the features that distinguish ASD from comorbidities with broader developmental impacts.","rel_num_authors":18,"rel_authors":[{"author_name":"Rachel L. Smith","author_inst":"University of Pennsylvania"},{"author_name":"Yundan Liao","author_inst":"University of Pennsylvania"},{"author_name":"Lambertus Klei","author_inst":"University of Pittsburgh"},{"author_name":"Lujing Zhang","author_inst":"Carnegie Mellon University"},{"author_name":"Yunlong Ma","author_inst":"University of Pennsylvania"},{"author_name":"Miao Tang","author_inst":"University of Pennsylvania"},{"author_name":"F. Kyle Satterstrom","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Chiara Auwerx","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Jack M. Fu","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Joseph D. Buxbaum","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Mark J. Daly","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Michael E. Talkowski","author_inst":"Broad Institute of MIT and Harvard"},{"author_name":"Luis de la Torre-Ubieta","author_inst":"University of California Los Angeles"},{"author_name":"Yevgenia Kozorovitskiy","author_inst":"Northwestern University"},{"author_name":"Matthew L. MacDonald","author_inst":"University of Pittsburgh"},{"author_name":"Kathryn Roeder","author_inst":"Carnegie Mellon University"},{"author_name":"Bernie Devlin","author_inst":"University of Pittsburgh"},{"author_name":"Michael J. Gandal","author_inst":"University of Pennsylvania"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"Longitudinal, Non-Invasive Imaging of the Developing Chick Heart, Vasculature, and Chorioallantoic Membrane (CAM)","rel_doi":"10.64898\/2026.09.22.753481","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.753481","rel_abs":"The chick embryo is a widely used vertebrate model for developmental biology, cardiovascular, and bioengineering research. We present an automated laser speckle contrast imaging (LSCI) platform for non-invasive, longitudinal, label-free imaging of the developing heart and extraembryonic vasculature of the chick embryo through the intact eggshell. The platform can detect blood vessels as small as 70 +\/- 17 um in diameter and enable repeated imaging from day 0 to day 8 of incubation without disturbing normal embryonic development. It provides both structural (a map of growing extraembryonic blood vessels) and functional (blood flow dynamics and heart rate) information. Using this system, we generated the first continuous, non-invasive, time-lapse recordings of the early functioning chick heart and its extraembryonic vessels. Longitudinal imaging was performed on 15 embryos from different chicken breeds with eggshell colors white, brown and green. Analysis revealed slight variability in early cardiac and vascular morphogenesis across breeds and shell types and shows its potential for automated developmental staging. Finally, for the first time, the growing vasculature of the yolk sac and the chorioallantoic (CAM) membrane was imaged from day 4 to 8. The heart rate and growth of the extraembryonic blood vessels were quantified automatically during imaging.","rel_num_authors":6,"rel_authors":[{"author_name":"Zijia Jin","author_inst":"Stevens Institute of Technology"},{"author_name":"Sudhanshu Kakkar","author_inst":"Stevens Institute of Technology"},{"author_name":"Dhaivik Chenemilla","author_inst":"Stevens Institute of Technology"},{"author_name":"Carol Readhead","author_inst":"California Institute of Technology"},{"author_name":"Marianne E Bronner","author_inst":"Caltech: California Institute of Technology"},{"author_name":"Simon Mahler","author_inst":"Stevens Institute of Technology"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"Estrogen is Coupled to the Calcium Release Machinery in HumanLeiomyoma Cells","rel_doi":"10.64898\/2026.09.22.753480","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.753480","rel_abs":"Uterine leiomyomas, commonly known as fibroids, are benign tumors of the female reproductive tract. They are the most common tumor of the female reproductive system and the leading cause of hysterectomy in the United States. Progesterone, estrogen, and their receptors are important drivers for the development and growth of leiomyomas. How estrogen drives leiomyoma growth remains unclear. We have previously shown that simvastatin can inhibit leiomyoma growth by modulating intracellular calcium. This suggests that calcium signaling is important for leiomyoma growth. We therefore hypothesized that estrogen may drive leiomyoma growth by stimulating calcium release through the membrane estrogen receptor GPR30 (also known as GPER). We found that estrogen dose-dependently induced calcium release in leiomyoma cells. The GPR30-specific agonist G-1 also induced calcium release, indicating that GPR30 mediates estrogen-mediated calcium release. The GPR30 antagonist G-15 blocked estrogen-induced calcium release and significantly reduced leiomyoma proliferation. Our results demonstrate that GPR30 is a major driver of estrogen-dependent growth in leiomyoma cells by modulating intracellular calcium. These findings may have high therapeutic relevance to leiomyomas and other estrogen-dependent tumors.","rel_num_authors":6,"rel_authors":[{"author_name":"Ariana Machado","author_inst":"Rowan University"},{"author_name":"Jasmine Kaur","author_inst":"Rowan University"},{"author_name":"Veronica Kan","author_inst":"Rowan-Virtua School of Osteopathic Medicine"},{"author_name":"Ying Fan","author_inst":"Cooper Medical School of Rowan University"},{"author_name":"Mostafa Borahay","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Darren Boehning","author_inst":"Cooper Medical School of Rowan University"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"Integrated stress response activation in combination PG3 and cisplatin-treated TP53-mutated head and neck squamous carcinoma cells induces potent apoptotic response","rel_doi":"10.64898\/2026.09.22.752907","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.752907","rel_abs":"Cisplatin remains as standard chemotherapy for patients with HNSCC, but rapid development of drug resistance has limited patient benefit. The p53 tumor suppressor plays a central role in the cellular response to DNA damage in cancer, triggering apoptosis to prevent propagation of damaged cells in tumor development. TP53 gene mutations occur in 65-86% of HNSCC. Small molecule PG3 induces the integrated stress response (ISR), leading to apoptosis via the HRI-eIF2-ATF4-PUMA axis. We hypothesized that a combination of PG3 plus cisplatin could increase apoptosis in TP53-mutated HNSCC cells through enhanced induction of the ISR and ATF4. PG3 synergized with cisplatin to inhibit cell viability, leading to potent apoptosis in TP53-deficient cells. The effect was regulated through the HRI-ATF4-NOXA pathway. Furthermore, we identified that cisplatin activates HRI and leads to the degradation of CReP (constitutive repressor of eIF2 phosphorylation) via E3 ligase {beta}-TrCP, contributing to the induction of the ISR. We noted decreased ATF4 levels after treatment with cisplatin, CPT, or PG3 and cisplatin. Thus, combined therapy of PG3 plus cisplatin likely results in adaptation and acquired resistance via degradation of ATF4. We targeted the degradation mechanism of ATF4 by inhibiting {beta}-TrCP1, CK1{delta}, or CK2, respectively. Each approach successfully blocked ATF4 degradation induced by cisplatin or PG3 plus cisplatin and enhanced apoptosis. Our results provide a rational strategy for triple treatments, involving an ISR inducer, a DNA damaging drug, and a {beta}-TrCP inhibitor\/CK1{delta} inhibitor\/CK2 inhibitor, to achieve potent and prolonged anti-tumor effects and overcome chemoresistance in HNSCC.","rel_num_authors":3,"rel_authors":[{"author_name":"Xiaobing Tian","author_inst":"Brown University"},{"author_name":"Praveen Srinivasan","author_inst":"Brown University"},{"author_name":"Wafik S. El-Deiry","author_inst":"Brown University"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"An NR2F1-dependent retinoic acid network controls retinal specialization in mice and reveals foveal hypoplasia in patients with BBSOAS","rel_doi":"10.64898\/2026.09.22.753406","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.753406","rel_abs":"The molecular programs that establish specialized retinal regions during development are essential for high-acuity vision, yet how their disruption contributes to human visual disorders remains poorly understood. Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS), caused by pathogenic variants in NR2F1 and characterized by visual impairment, provides an opportunity to investigate these mechanisms. Using single-cell RNA sequencing of three complementary Nr2f1 mouse models, including two carrying patient-specific mutations, we identified a shared Nr2f1-dependent transcriptional program enriched in retinoic acid (RA) pathway genes. Loss or mutation of Nr2f1 disrupted the spatial organization of RA signaling, most prominently by expanding the dorso-equatorial Cyp26a1 expression domain into ventral retina and reducing ventral determinants such as Vax2. These molecular changes were associated with altered dorso-ventral distribution of S- and M-opsin-expressing cone photoreceptors. We further demonstrate that human NR2F1 binds a conserved regulatory region upstream of CYP26A1, supporting its direct role in regulating local RA availability. Finally, high-resolution optical coherence tomography in individuals with BBSOAS revealed reproducible foveal abnormalities, including a smaller and shallower foveal pit and increased central retinal thickness, consistent with foveal hypoplasia. These findings uncover a previously unrecognized retina-intrinsic component of BBSOAS visual pathology and establish an NR2F1-RA\/CYP26A1 regulatory axis linking developmental retinal regionalization to human foveal specialization.","rel_num_authors":12,"rel_authors":[{"author_name":"Paolo Piovani","author_inst":"Institute of Biology Valrose - University Cote d'Azur- Nice, France"},{"author_name":"Carole Belliardo","author_inst":"University Cote d'Azur - Nice, France"},{"author_name":"Rahul Makam","author_inst":"Moorfields Eye Hospital NHS Foundation Trust, London, UK"},{"author_name":"Boglarka Zambo","author_inst":"Institute of Biology Valrose - University Cote d'Azur - Nice, France"},{"author_name":"Annabelle Mantilleri","author_inst":"Institute of Biology Valrose - University Cote d'Azur - Nice, France"},{"author_name":"Amandine Chassot","author_inst":"Institute of Biology Valrose - University Cote d'Azur - Nice, France"},{"author_name":"Gergo Gogl","author_inst":"Institute of Biology Valrose - University Cote d'Azur - Nice, France"},{"author_name":"Christian P. Schaaf","author_inst":"Institute of Human Genetics, Heidelberg University, Heidelberg, Germany"},{"author_name":"Seth Blackshaw","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Patrick Yu-Wai-Man","author_inst":"Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK"},{"author_name":"Michele Bertacchi","author_inst":"Institute of Biology Valrose - University Cote d'Azur - Nice, France"},{"author_name":"Michele Studer","author_inst":"Institute of Biology Valrose (iBV) - University Cote d'Azur - Nice, France"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"Spatiotemporal atlas resolves the mesenchymal-epithelial stem cell axis governing human hair follicle aging and pathology","rel_doi":"10.64898\/2026.09.22.753364","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.753364","rel_abs":"How adult stem cell populations coordinate tissue regeneration across physiological and pathological states remains unclear. Hair follicles contain epithelial and mesenchymal stem cells that codetermine hair regeneration. Here, we integrate a multimodal spatiotemporal atlas with functional validation to define the mesenchymal-epithelial stem cell dynamics governing human hair follicle homeostasis, aging, and androgenetic alopecia. Aging is characterized by passive depletion of hDSC-derived regenerative cues, whereas AGA involves a shift of hDSC toward an inhibitory signaling hub that promotes HFSC dysfunction. We further pinpoint hDSC-secreted PTN as a key regenerative factor that promotes hair growth and counteracts androgen-induced growth suppression. This study provides a holistic framework of adult stem cell crosstalk across physiological and pathological states, offering a mechanistic roadmap to reinstate tissue regeneration.","rel_num_authors":29,"rel_authors":[{"author_name":"Xiaoyu Wei","author_inst":"State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Hangzhou 310030, China; Key Laboratory of Brain Cell Mapping of Zhejiang Province, BG"},{"author_name":"Yanwen Xu","author_inst":"Department of Medical Cosmetic Center, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310006, China"},{"author_name":"Jiaxin Du","author_inst":"BGI Research, Hangzhou 310030, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China"},{"author_name":"Ruikang Li","author_inst":"BGI Research, Hangzhou 310030, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of Resources Bi"},{"author_name":"Zhentao Zhou","author_inst":"Department of Medical Cosmetic Center, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310006, China"},{"author_name":"Yeya Yu","author_inst":"Key Laboratory of Brain Cell Mapping of Zhejiang Province, BGI Research, Hangzhou 310030, China"},{"author_name":"Zishuo Yuan","author_inst":"State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Hangzhou 310030, China; Key Laboratory of Spatial Omics of Zhejiang Province, BGI Res"},{"author_name":"Hanxiao Cheng","author_inst":"Department of Medical Cosmetic Center, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310006, China"},{"author_name":"Yujia Jiang","author_inst":"Key Laboratory of Spatial Omics of Zhejiang Province, BGI Research, Hangzhou 310030, China; Department of Biology, University of Copenhagen, DK-2100 Copenhagen,"},{"author_name":"Fei Zhu","author_inst":"Department of Medical Cosmetic Center, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310006, China"},{"author_name":"Pengfei Cai","author_inst":"State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Hangzhou 310030, China; Key Laboratory of Spatial Omics of Zhejiang Province, BGI Res"},{"author_name":"Haiyan Shen","author_inst":"Department of Medical Cosmetic Center, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310006, China"},{"author_name":"Shuai Wang","author_inst":"BGI Research, HangzhouCollege of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; BGI Research, Shenzhen 518083, China"},{"author_name":"Yue Yuan","author_inst":"State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Hangzhou 310030, China; Key Laboratory of Spatial Omics of Zhejiang Province, BGI Res"},{"author_name":"Xiawei Liu","author_inst":"BGI Research, Qingdao 266555, China"},{"author_name":"Tao Yang","author_inst":"China National GeneBank, BGI Research, Shenzhen 518120, China; Guangdong Provincial Genomics Data Center, BGI Research, Shenzhen 518120, China"},{"author_name":"Yinghua Huang","author_inst":"BGI Cell, Hangzhou 310030, China"},{"author_name":"Yiwei Lai","author_inst":"State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Hangzhou 310030, China; BGI Research, Shenzhen 518083, China"},{"author_name":"Shiwei Wang","author_inst":"Key Laboratory of Resources Biology and Biotechnology in Western China, Ministry of Education, Provincial Key Laboratory of Biotechnology of Shaanxi Province, t"},{"author_name":"Hanbo Li","author_inst":"State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Hangzhou 310030, China; BGI Research, Shenzhen 518083, China; BGI Research, Qingdao 2"},{"author_name":"Jun Xie","author_inst":"MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China; Shanxi Medical University-BGI Collabora"},{"author_name":"Ying Gu","author_inst":"State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Hangzhou 310030, China; BGI Research, Shenzhen 518083, China; BGI Cell, Shenzhen 5180"},{"author_name":"Dong Niu","author_inst":"College of Animal Science and Technology, College of Veterinary Medicine, Zhejiang AF University, Hangzhou 311300, China"},{"author_name":"Zhenxing Wang","author_inst":"Department of Plastic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China"},{"author_name":"Xun Xu","author_inst":"State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Hangzhou 310030, China; BGI Research, Shenzhen 518083, China"},{"author_name":"Longqi Liu","author_inst":"State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Hangzhou 310030, China; Key Laboratory of Brain Cell Mapping of Zhejiang Province, BG"},{"author_name":"Mingxing Lei","author_inst":"Key Laboratory of Biorheological Science and Technology of Ministry of Education and 111 Project Laboratory of Biomechanics and Tissue Repair, College of Bioeng"},{"author_name":"Pengcheng Guo","author_inst":"State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Hangzhou 310030, China; Key Laboratory of Brain Cell Mapping of Zhejiang Province, BG"},{"author_name":"Jufang Zhang","author_inst":"Department of Medical Cosmetic Center, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310006, China; Center for "}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"The HBV basal core promoter mutation confers a replicative advantage and transcriptionally reprograms hepatocytes toward HCC subtypes","rel_doi":"10.64898\/2026.09.22.752323","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.752323","rel_abs":"Background: Hepatitis B virus (HBV) basal core promoter (BCP) and precore (PC) mutations occur during chronic HBV infection with the BCP-mutant being associated with increased hepatocellular carcinoma (HCC) risk. Objectives: The effects of these mutants on viral replication, hepatocyte biology, and carcinogenesis remain poorly defined. To address this, we characterized BCP- and PC-mutants using human hepatocyte chimeric mice and asked whether the resulting infection-induced transcriptomes correspond to subsets of human HBV-related hepatocellular carcinomas (HBV-HCCs). Design: Isogenic wild-type (WT), BCP- and PC-mutants of HBV genotypes A, C, and D (HBV-A, -C, -D) were generated from recombinant covalently-closed circular DNA to infect chimeric mice. HBV-HCC transcriptomic datasets from The Cancer Genome Atlas (TCGA) were used to stratify association of HBV variants with HCC subtypes. Results: WT, BCP-mutant, and PC-mutant HBV sequences remained genetically stable. The BCP mutation, but not the PC mutation, accelerated the rise in serum viremia in HBV-D- and HBV-A-infected chimeras; in HBV-C, acceleration required both (PC+BCP) mutations. Further comparisons of HBV-D variants revealed that the BCP-mutant increased intrahepatic viral DNA, viral protein expression, and upregulated cancer-related pathways, including transcripts associated with a subset of HBV-HCCs. Analysis of HBV-HCC samples from the TCGA revealed that tumors often harbor a mixture of WT and mutant transcripts, and that WT- and BCP-mutant-associated HCCs exhibit distinct transcriptional profiles. Conclusions: The HBV BCP-mutant directly perturbs hepatocyte homeostasis via virus-intrinsic mechanisms, selectively activating cancer-related pathways and defining a molecularly distinct subset of HBV-HCC. These findings suggest that HBV variants form distinct subcategories of HBV-HCCs.","rel_num_authors":25,"rel_authors":[{"author_name":"Leon L Seifert","author_inst":"Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA"},{"author_name":"Georgios Dangas","author_inst":"Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University, Atlanta, GA, USA."},{"author_name":"Hoyin Chu","author_inst":"Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"Yingpu Yu","author_inst":"Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA"},{"author_name":"Kosuke Ogata","author_inst":"Department of Molecular Systems BioAnalysis, Kyoto University, Kyoto, Japan"},{"author_name":"Xupeng Hong","author_inst":"Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA"},{"author_name":"Mengyin Zhang","author_inst":"Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA"},{"author_name":"Yichen Zhou","author_inst":"Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY, USA"},{"author_name":"Chenhui Zou","author_inst":"Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY, USA"},{"author_name":"Alireza Ramandi","author_inst":"Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY, USA"},{"author_name":"Corrine Quirk","author_inst":"Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA"},{"author_name":"Evgenia Moschogianni","author_inst":"Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University, Atlanta, GA, USA"},{"author_name":"Catherine A Freije","author_inst":"Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA"},{"author_name":"Antonis Athanasiadis","author_inst":"Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University, Atlanta, GA, USA"},{"author_name":"Leonardo Gonzales","author_inst":"Department of Pathology, NYU School of Medicine, New York, NY, USA"},{"author_name":"Luis Chiriboga","author_inst":"Department of Pathology, NYU School of Medicine, New York, NY, USA"},{"author_name":"Clifton Fulmer","author_inst":"Department of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, Ohio, USA"},{"author_name":"Hong Hur","author_inst":"Department of Research Bioinformatics, Center for Clinical and Translational Science, The Rockefeller University Hospital, New York, NY, USA"},{"author_name":"Manoj Kandpal","author_inst":"Department of Research Bioinformatics, Center for Clinical and Translational Science, The Rockefeller University Hospital, New York, NY, USA"},{"author_name":"Anna S Lok","author_inst":"Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, Michigan"},{"author_name":"Caleb Lareau","author_inst":"Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"author_name":"William M Schneider","author_inst":"Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA"},{"author_name":"Charles M Rice","author_inst":"Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA"},{"author_name":"Eleftherios Michailidis","author_inst":"Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University, Atlanta, GA, USA"},{"author_name":"Ype P de Jong","author_inst":"Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY, USA"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"Lineage-informed factor analysis reveals heritable programs of single-cell gene expression","rel_doi":"10.64898\/2026.09.21.753290","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.753290","rel_abs":"Single-cell transcriptomics has transformed our ability to characterize cellular identity, but present-day gene expression profiles capture only a snapshot of a process that unfolds across cell division history. Recent single-cell lineage-tracing technologies make it possible to reconstruct cell division histories for thousands of cells, opening a window into how gene expression evolves. Yet observed gene expression is often redundant, with correlations among genes reflecting underlying latent biological programs and regulatory networks. To capture this structure, we introduce scPFA, a single-cell phylogenetic factor analysis framework that represents gene expression through a small set of latent factors that evolve along lineages under a phylogenetic prior, capturing correlated structure hidden in present-day observations alone. Simulations demonstrate accurate recovery of latent factors and covariance structure across conditions. Applied to developmental and cancer lineage-tracing datasets, the model uncovers biologically interpretable, lineage-associated expression programs. Together, these results demonstrate how lineage-informed factor analysis can reveal temporal biological structure hidden within high-dimensional single-cell data.","rel_num_authors":2,"rel_authors":[{"author_name":"Stephen J Staklinski","author_inst":"Cold Spring Harbor Laboratory"},{"author_name":"Adam Siepel","author_inst":"Cold Spring Harbor Laboratory"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"Striatal interneuron microcircuits gate reinforcement to stabilize adaptive choice","rel_doi":"10.64898\/2026.09.21.753300","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.753300","rel_abs":"The dorsomedial striatum guides learning and adaptive decision-making through excitatory synaptic control of its spiny projection neuron outputs. However, the contributions of local inhibitory microcircuitry remain poorly understood. Here, we identify an interneuron circuit in the dorsomedial striatum that links outcome processing to adaptive action selection. During probabilistic push-pull reversal learning, interneurons represented immediate outcomes: somatostatin interneurons were recruited on unrewarded trials and unexpected rewarded trials, whereas tyrosine hydroxylase interneurons were suppressed on unrewarded trials and recruited on rewarded trials. In vivo recruitment of tyrosine hydroxylase interneurons suppressed somatostatin interneuron activity and increased activity in both direct- and indirect-pathway striatal projection neurons, revealing a polysynaptic disinhibitory microcircuit. Transient inhibition of somatostatin interneurons in this pull-tuned region produced a sustained increase in aberrant pull choices and occupancy of a suboptimal pull-preferring behavioral state, whereas inhibition of tyrosine hydroxylase interneurons produced a sustained impairment of pull reinforcement. Longer-term policy changes following somatostatin interneuron inhibition coincided with postsynaptic potentiation of excitatory synapses onto striatal projection neurons, suggesting a potential substrate for the persistence of altered behavioral policies. Together, these findings identify a disinhibitory striatal circuit motif gating reinforcement which transforms individual trial outcomes into temporally broader policy.","rel_num_authors":18,"rel_authors":[{"author_name":"Evan A Iliakis","author_inst":"University of Pennsylvania"},{"author_name":"Jonibek M Muhsinov","author_inst":"University of Pennsylvania"},{"author_name":"Alexandra N Ramirez","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Francesco G Rinaldi","author_inst":"International School of Advanced Studies (SISSA)"},{"author_name":"Jamie Galanaugh","author_inst":"University of Pennsylvania"},{"author_name":"Saurabh Pandey","author_inst":"University of Pennsylvania"},{"author_name":"Carlos Ivan Linares-Garcia","author_inst":"Rutgers University"},{"author_name":"Aaron R Tachau","author_inst":"University of Pennsylvania"},{"author_name":"Eric Z Song","author_inst":"University of Pennsylvania"},{"author_name":"Luigim Vargas","author_inst":"University of Pennsylvania"},{"author_name":"Kyuhyun Choi","author_inst":"Hallym University"},{"author_name":"Joel T Woolley","author_inst":"University of Pennsylvania"},{"author_name":"Sarah M Ferrigno","author_inst":"University of Pennsylvania"},{"author_name":"Edgar Arturo Diaz-Hernandez","author_inst":"University of Pennsylvania"},{"author_name":"Elizabeth N Holly","author_inst":"Rutgers University"},{"author_name":"David J Margolis","author_inst":"Rutgers, The State University of New Jersey"},{"author_name":"Eugenio Piasini","author_inst":"International School for Advanced Studies (SISSA)"},{"author_name":"Marc V Fuccillo","author_inst":"University of Pennsylvania"}],"rel_date":"2026-09-23","rel_site":"biorxiv"},{"rel_title":"Cysteine supplementation reverses immune dysfunction in cancer patients with severe COVID-19","rel_doi":"10.64898\/2026.09.21.26363550","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363550","rel_abs":"Severe COVID-19 infection in patients with cancer is characterized by a unique pattern of immunologic dysfunction including muted adaptive immune responses. The molecular drivers of immune dysfunction in cancer patients with severe COVID-19 remain unclear, and therapeutic strategies to overcome immune dysfunction in this setting have not been identified. We performed integrated proteomic and metabolomic profiling of matched cohorts of cancer and non-cancer patients with or without COVID-19 and identified dysfunctional cysteine metabolism as uniquely associated with severe COVID-19 in cancer patients. Treatment of patients with cancer and steroid-refractory COVID-19 with N-acetylcysteine in a prospective clinical trial (NCT04374461) improved clinical outcomes compared with disease severity-matched hospitalized patients during the period immediately preceding clinical trial initiation. N-AC treatment reduced circulating markers of innate inflammation, decreased severe disease-associated MHC-II low monocytes, and increased circulating CD8+ T cell abundance, activation, and effector differentiation. Mechanistically, N-AC reduced prostaglandin E2-driven interactions between suppressive monocytes and T cells, which we confirmed was sufficient to limit T cell expansion and effector differentiation in a dose- and avidity-dependent fashion. Moreover, N-AC reduced the activity of inhibitory, redox sensitive transcription factors such as KLF6, enabling clonal expansion and effector T cell differentiation. We confirmed these observations in two murine models of severe respiratory viral infection, in which N-AC treatment significantly enhanced lung-infiltrating CD8+ T cell abundance. These findings establish cysteine supplementation as a viable therapeutic strategy to reverse redox-driven immune dysregulation in severe respiratory viral infection, particularly in the high-risk cancer population.","rel_num_authors":24,"rel_authors":[{"author_name":"Tiffany Merlinsky","author_inst":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"Jahan Rahman","author_inst":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"William T Johnson","author_inst":"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"Lisa McGary","author_inst":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"Simon Grassmann","author_inst":"Immunology Program, Sloan Kettering Institute for Cancer Research; New York, NY, USA."},{"author_name":"Jennifer Zhang","author_inst":"Immunology Program, Sloan Kettering Institute for Cancer Research; New York, NY, USA."},{"author_name":"Abdulraouf Abdulraouf","author_inst":"Laboratory of Single Cell Genomics and Population Dynamics, The Rockefeller University; New York, NY, USA"},{"author_name":"Hannah L Kalvin","author_inst":"Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"Katherine Panageas","author_inst":"Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"Jasmine Nicodemus","author_inst":"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"Elizabeth Cathcart","author_inst":"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"Ya-Hui Lin","author_inst":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"Kinga K Hosszu","author_inst":"Stem Cell Transplantation and Cellular Therapies, MSK Kids, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"Mirela Berisa","author_inst":"Metabolomics Core, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"author_name":"Olga Lyudovyk","author_inst":"Memorial Sloan Kettering Cancer Center"},{"author_name":"Gilles Salles","author_inst":"Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"Jaap J Boelens","author_inst":"Stem Cell Transplantation and Cellular Therapies, MSK Kids, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"N Esther Babady","author_inst":"Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"Junyue Cao","author_inst":"Laboratory of Single Cell Genomics and Population Dynamics, The Rockefeller University; New York, NY, USA"},{"author_name":"Jedd D Wolchok","author_inst":"Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine; New York, NY, USA"},{"author_name":"Joseph C Sun","author_inst":"Immunology Program, Sloan Kettering Institute for Cancer Research; New York, NY, USA."},{"author_name":"James Heath","author_inst":"Institute for Systems Biology; Seattle, WA, USA"},{"author_name":"Benjamin Greenbaum","author_inst":"Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center; New York, NY, USA"},{"author_name":"Santosha Vardhana","author_inst":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center; New York, NY, USA"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"CREBRF rs373863828 minimally regulates gene expression in subcutaneous adipose tissue of Samoan adults","rel_doi":"10.64898\/2026.09.21.26363571","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363571","rel_abs":"A population-specific missense variant, rs373863828 (G > A, p.Arg457Gln), has been identified in Pacific Islanders and is associated with increased body mass index and lower odds of type 2 diabetes. However, the mechanism underlying these associations is unknown. The variant is located in exon 5 of CREBRF, a gene which is rapidly upregulated in response to nutrient deprivation. This study aimed to assess the effect of rs373863828 on gene expression in adipose tissue from Samoan adults from the Soifua Manuia (''Good Health'') study. Needle subcutaneous adipose (upper buttock) biopsies were obtained in Apia, Samoa, from fasting Samoans without diabetes. RNA isolated from adipose tissue (n=91, 65.9% female) was subjected to bulk paired-end mRNA-sequencing (2x150 base pair). Differential gene expression among the three rs373863828 genotypes (GG, AG, AA) was assessed using a likelihood-ratio test implemented in DESeq2, and overrepresentation analysis for significant differentially expressed genes (DEGs) (padj < 0.1) was performed with clusterProfiler and oRG.DB. Bulk expression was deconvoluted to determine the cell type composition of the adipose tissue. Twenty-two DEGs were associated with rs373863828 genotype including CBX7 (padj=0.026 ) and SELENOM (padj= 0.004), both of which have roles in adipogenesis and metabolism. A single expression profile comprising 13 of the 22 DEGs corresponding to CREBRF genotype was identified, and overrepresentation analysis supported this finding, with terms such as ''keratinocyte differentiation'' and ''skin development'' enriched among significant DEGs. However, PERMANOVA of adipose cell type proportions showed no difference (p > 0.05) among the three genotypes. rs373863828 genotype was associated with expression of 22 genes in whole subcutaneous adipose tissue of this sample of fasting Samoan adults without diabetes. Future work should assess cell- and tissue-specific rs373863828 genotype effects using a combination of single-cell approaches and human cell models with perturbations associated with nutritional stress.","rel_num_authors":25,"rel_authors":[{"author_name":"Samantha L Manna","author_inst":"Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, "},{"author_name":"Anna C Rivara","author_inst":"Department of Social and Behavioral Sciences, O'Donnell School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"author_name":"Angela T Prescott","author_inst":"Department of Plastic and Reconstructive Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA"},{"author_name":"Corina S Penaia","author_inst":"Department of Health Policy and Management, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA"},{"author_name":"Muagututia Sefuiva Reupena","author_inst":"Lutia I Puava Ae Mapu I Fagalele, Apia, Samoa"},{"author_name":"Take Naseri","author_inst":"Ministry of Health, Apia, Samoa"},{"author_name":"Satupaitea Viali","author_inst":"Oceania University of Medicine, Samoa; Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Melania Selu","author_inst":"Obesity, Lifestyle and Genetic Adaptations Study Group, Apia, Samoa"},{"author_name":"Gloria Siufaga","author_inst":"Obesity, Lifestyle and Genetic Adaptations Study Group, Apia, Samoa"},{"author_name":"Kima Faasalele-Savusa","author_inst":"Obesity, Lifestyle and Genetic Adaptations Study Group, Apia, Samoa"},{"author_name":"Folla Unasa","author_inst":"Obesity, Lifestyle and Genetic Adaptations Study Group, Apia, Samoa"},{"author_name":"Vaimoana Lupematisila","author_inst":"Obesity, Lifestyle and Genetic Adaptations Study Group, Apia, Samoa"},{"author_name":"Alysa Pomer","author_inst":"Center for Surgery and Public Health, Brigham and Women's Hospital, Boston, MA, USA"},{"author_name":"Elizabeth C Lawrence","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Jenna C Carlson","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biostatistics and Health Data Science, Schoo"},{"author_name":"Emily M Russell","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Mohanraj Krishnan","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biostatistics and Health Data Science, Schoo"},{"author_name":"Katie L Whytock","author_inst":"Translational Research Institute, AdventHealth, Orlando, Florida, USA"},{"author_name":"Lacey W Heinsberg","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Health Promotion and Development, School of "},{"author_name":"Erin E Kershaw","author_inst":"Division of Endocrinology and Metabolism, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Ryan L Minster","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Daniel E Weeks","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biostatistics and Health Data Science, Schoo"},{"author_name":"Stephen T McGarvey","author_inst":"Center for Global Public Health, Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA; Department of Anthropology, Brown Un"},{"author_name":"Nicola L Hawley","author_inst":"Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Zsolt Urban","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"CREBRF rs373863828 minimally regulates gene expression in subcutaneous adipose tissue of Samoan adults","rel_doi":"10.64898\/2026.09.21.26363571","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363571","rel_abs":"A population-specific missense variant, rs373863828 (G > A, p.Arg457Gln), has been identified in Pacific Islanders and is associated with increased body mass index and lower odds of type 2 diabetes. However, the mechanism underlying these associations is unknown. The variant is located in exon 5 of CREBRF, a gene which is rapidly upregulated in response to nutrient deprivation. This study aimed to assess the effect of rs373863828 on gene expression in adipose tissue from Samoan adults from the Soifua Manuia (''Good Health'') study. Needle subcutaneous adipose (upper buttock) biopsies were obtained in Apia, Samoa, from fasting Samoans without diabetes. RNA isolated from adipose tissue (n=91, 65.9% female) was subjected to bulk paired-end mRNA-sequencing (2x150 base pair). Differential gene expression among the three rs373863828 genotypes (GG, AG, AA) was assessed using a likelihood-ratio test implemented in DESeq2, and overrepresentation analysis for significant differentially expressed genes (DEGs) (padj < 0.1) was performed with clusterProfiler and oRG.DB. Bulk expression was deconvoluted to determine the cell type composition of the adipose tissue. Twenty-two DEGs were associated with rs373863828 genotype including CBX7 (padj=0.026 ) and SELENOM (padj= 0.004), both of which have roles in adipogenesis and metabolism. A single expression profile comprising 13 of the 22 DEGs corresponding to CREBRF genotype was identified, and overrepresentation analysis supported this finding, with terms such as ''keratinocyte differentiation'' and ''skin development'' enriched among significant DEGs. However, PERMANOVA of adipose cell type proportions showed no difference (p > 0.05) among the three genotypes. rs373863828 genotype was associated with expression of 22 genes in whole subcutaneous adipose tissue of this sample of fasting Samoan adults without diabetes. Future work should assess cell- and tissue-specific rs373863828 genotype effects using a combination of single-cell approaches and human cell models with perturbations associated with nutritional stress.","rel_num_authors":25,"rel_authors":[{"author_name":"Samantha L Manna","author_inst":"Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, "},{"author_name":"Anna C Rivara","author_inst":"Department of Social and Behavioral Sciences, O'Donnell School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"author_name":"Angela T Prescott","author_inst":"Department of Plastic and Reconstructive Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA"},{"author_name":"Corina S Penaia","author_inst":"Department of Health Policy and Management, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA"},{"author_name":"Muagututia Sefuiva Reupena","author_inst":"Lutia I Puava Ae Mapu I Fagalele, Apia, Samoa"},{"author_name":"Take Naseri","author_inst":"Ministry of Health, Apia, Samoa"},{"author_name":"Satupaitea Viali","author_inst":"Oceania University of Medicine, Samoa; Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Melania Selu","author_inst":"Obesity, Lifestyle and Genetic Adaptations Study Group, Apia, Samoa"},{"author_name":"Gloria Siufaga","author_inst":"Obesity, Lifestyle and Genetic Adaptations Study Group, Apia, Samoa"},{"author_name":"Kima Faasalele-Savusa","author_inst":"Obesity, Lifestyle and Genetic Adaptations Study Group, Apia, Samoa"},{"author_name":"Folla Unasa","author_inst":"Obesity, Lifestyle and Genetic Adaptations Study Group, Apia, Samoa"},{"author_name":"Vaimoana Lupematisila","author_inst":"Obesity, Lifestyle and Genetic Adaptations Study Group, Apia, Samoa"},{"author_name":"Alysa Pomer","author_inst":"Center for Surgery and Public Health, Brigham and Women's Hospital, Boston, MA, USA"},{"author_name":"Elizabeth C Lawrence","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Jenna C Carlson","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biostatistics and Health Data Science, Schoo"},{"author_name":"Emily M Russell","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Mohanraj Krishnan","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biostatistics and Health Data Science, Schoo"},{"author_name":"Katie L Whytock","author_inst":"Translational Research Institute, AdventHealth, Orlando, Florida, USA"},{"author_name":"Lacey W Heinsberg","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Health Promotion and Development, School of "},{"author_name":"Erin E Kershaw","author_inst":"Division of Endocrinology and Metabolism, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Ryan L Minster","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Daniel E Weeks","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biostatistics and Health Data Science, Schoo"},{"author_name":"Stephen T McGarvey","author_inst":"Center for Global Public Health, Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA; Department of Anthropology, Brown Un"},{"author_name":"Nicola L Hawley","author_inst":"Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Zsolt Urban","author_inst":"Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Interrater reliability of Tremor Characterization","rel_doi":"10.64898\/2026.09.21.26363551","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363551","rel_abs":"Background: Tremor is a repetitive, oscillatory movement with multiple subtypes requiring accurate characterization for diagnosis and treatment. While frequency, amplitude, and context are routinely used to describe tremor, recent recommendations have emphasized oscillation shape and regularity. However, these descriptors lack strict operational definitions, and differences in how clinicians interpret them introduce inconsistency into tremor classification. Objective: We quantified inter-rater reliability for commonly used tremor descriptors and determined which objectively measured signal parameters: peak amplitude, peak frequency, and frequency variability best explained inconsistency in rater assessments. Methods: We developed the Tremor Waveform Morphology Questionnaire (TWMQ) and obtained standardized video recordings of 34 individuals with upper-extremity tremor performing rest, postural, and kinetic tasks, with simultaneous kinematic recordings using an inertial sensor. Movement disorder experts rated tremor presence, shape, symmetry, regularity, rhythmicity, and diagnosis. We assessed inter-rater reliability, cross-feature dependencies, and modeled the influence of objective signal parameters on each subjective rating. Results: Tremor presence and symmetry showed high agreement, whereas jerkiness, rhythmicity, amplitude stability, and clinical diagnosis showed lower reliability. Modeling revealed that peak amplitude primarily influenced judgments of tremor presence, jerkiness, and diagnosis, while frequency variability drove ratings of rhythmicity and amplitude stability. Conclusions: Morphology-based descriptors remain subjective, but disagreement systematically reflects measurable signal properties. Objective definitions based on peak amplitude and frequency variability may improve the reliability and reproducibility of tremor characterization.","rel_num_authors":9,"rel_authors":[{"author_name":"Prajakta Joshi","author_inst":"Case Western Reserve University"},{"author_name":"Yuri Ferreira Felloni Borges","author_inst":"University of Toronto"},{"author_name":"Sanjay Pandey","author_inst":"Amrita Hospital, Faridabad"},{"author_name":"Marie Vidailhet","author_inst":"Paris Brain Institute"},{"author_name":"Victor Fung","author_inst":"University of Sydney"},{"author_name":"Mark Hallett","author_inst":"NIH"},{"author_name":"Hyder A Jinnah","author_inst":"Emory University"},{"author_name":"Aasef G Shaikh","author_inst":"Case Western Reserve University"},{"author_name":"Alfonso Fasano","author_inst":"University of Toronto"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Interrater reliability of Tremor Characterization","rel_doi":"10.64898\/2026.09.21.26363551","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363551","rel_abs":"Background: Tremor is a repetitive, oscillatory movement with multiple subtypes requiring accurate characterization for diagnosis and treatment. While frequency, amplitude, and context are routinely used to describe tremor, recent recommendations have emphasized oscillation shape and regularity. However, these descriptors lack strict operational definitions, and differences in how clinicians interpret them introduce inconsistency into tremor classification. Objective: We quantified inter-rater reliability for commonly used tremor descriptors and determined which objectively measured signal parameters: peak amplitude, peak frequency, and frequency variability best explained inconsistency in rater assessments. Methods: We developed the Tremor Waveform Morphology Questionnaire (TWMQ) and obtained standardized video recordings of 34 individuals with upper-extremity tremor performing rest, postural, and kinetic tasks, with simultaneous kinematic recordings using an inertial sensor. Movement disorder experts rated tremor presence, shape, symmetry, regularity, rhythmicity, and diagnosis. We assessed inter-rater reliability, cross-feature dependencies, and modeled the influence of objective signal parameters on each subjective rating. Results: Tremor presence and symmetry showed high agreement, whereas jerkiness, rhythmicity, amplitude stability, and clinical diagnosis showed lower reliability. Modeling revealed that peak amplitude primarily influenced judgments of tremor presence, jerkiness, and diagnosis, while frequency variability drove ratings of rhythmicity and amplitude stability. Conclusions: Morphology-based descriptors remain subjective, but disagreement systematically reflects measurable signal properties. Objective definitions based on peak amplitude and frequency variability may improve the reliability and reproducibility of tremor characterization.","rel_num_authors":9,"rel_authors":[{"author_name":"Prajakta Joshi","author_inst":"Case Western Reserve University"},{"author_name":"Yuri Ferreira Felloni Borges","author_inst":"University of Toronto"},{"author_name":"Sanjay Pandey","author_inst":"Amrita Hospital, Faridabad"},{"author_name":"Marie Vidailhet","author_inst":"Paris Brain Institute"},{"author_name":"Victor Fung","author_inst":"University of Sydney"},{"author_name":"Mark Hallett","author_inst":"NIH"},{"author_name":"Hyder A Jinnah","author_inst":"Emory University"},{"author_name":"Aasef G Shaikh","author_inst":"Case Western Reserve University"},{"author_name":"Alfonso Fasano","author_inst":"University of Toronto"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Personalized Pediatrician-Scientist Training Program Optimizes Institutional Research Investment","rel_doi":"10.64898\/2026.09.21.26363577","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363577","rel_abs":"Abstract Objective: Physician-scientists are a diminishing subset of the pediatrician work force, uniquely trained to advance child health through scientific discovery. The current financial landscape of academic medical centers makes traditional resource-intensive training programs untenable. Continued renewal of this critical pediatric workforce requires new resource-efficient methodologies. Thus, we evaluated the impact of the NICHD supported Vanderbilt K12 program, a personalized, intensive training program. Study Design: We tracked academic outcomes for scholars with K12 appointments between January 2015 and December 2022. Our primary outcome was receipt of a mentored career development award (K08 or K23). Successful transition from mentored to independent NIH funding (K to R transition) was used as a secondary outcome. Academic outcomes for faculty participating in a large, institutional training program, the Vanderbilt Faculty Research Scholars program (VFRS), served as a comparison cohort. A complementary qualitative evaluation of the K12 program was performed. Results: K12 scholars earned career development awards (73%) at an equivalent rate to VFRS faculty (71%) and transitioned K to R funding at equivalent rates, 45% of K12 scholars compared to 50% for VFRS. Qualitative analysis demonstrated K12 scholars valued a personalized training program that incorporated self-efficacy and adaptability, key tenets of Social Cognitive Career Theory. Conclusion: Personalized physician-scientist training programs may enhance efficient utilization of research resources in Pediatric academic departments and serve as a viable alternative to traditional programs. Our qualitative evaluation suggests scholar self-efficacy and adaptability can be achieved through a personalized training program.","rel_num_authors":8,"rel_authors":[{"author_name":"Erin Plosa","author_inst":"University of North Carolina at Chapel Hill"},{"author_name":"Mark R. Denison","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Kemberlee Bonnet","author_inst":"Vanderbilt University"},{"author_name":"Anika Yarlagadda","author_inst":"University of North Carolina"},{"author_name":"Nikita Muthakana","author_inst":"University of North Carolina"},{"author_name":"David Schlundt","author_inst":"Vanderbilt University"},{"author_name":"Julie Bastarache","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Michael DeBaun","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"SickMix: Temporal Changes in Social Contact Patterns among People with Acute Infection and Their Close Contacts","rel_doi":"10.64898\/2026.09.21.26362162","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26362162","rel_abs":"Infected individuals drive infectious disease transmission, yet empirical data on social interactions during acute infection remain limited. We conducted a prospective longitudinal study of 1,000 medically attended acute gastroenteritis and acute respiratory infection cases and 709 household members in the northwestern United States from 2024 to 2025 to quantify illness-associated changes in social contacts and their implications for transmission modeling. Cases substantially reduced social contacts during peak illness; weighted mean number of contacts increased 2.0-fold (95% confidence interval, 1.8-2.2) over the two-week follow-up. In transmission modeling, the simulated outbreak trajectory and estimated effectiveness of interventions differed substantially between models that did and did not account for temporal reductions in social contacts during acute infection. These findings show that behavioral responses during acute infection could substantially influence transmission dynamics and intervention evaluation, and provide an empirical framework for incorporating illness-associated behavioral change into infectious disease models.","rel_num_authors":12,"rel_authors":[{"author_name":"Jessica C Ibiebele","author_inst":"Boston University Center on Emerging Infectious Diseases"},{"author_name":"Aarushi Tuli","author_inst":"Boston University School of Public Health"},{"author_name":"Grissel Lopes","author_inst":"Boston University School of Public Health"},{"author_name":"Gina Lombard","author_inst":"Boston University School of Public Health"},{"author_name":"Anne Shapiro","author_inst":"Boston University School of Public Health"},{"author_name":"Judy Donald","author_inst":"Kaiser Permanente Northwest"},{"author_name":"Mark A Schmidt","author_inst":"Kaiser Permanente Northwest"},{"author_name":"Maria Litvinova","author_inst":"Indiana University School of Public Health"},{"author_name":"Dehao Chen","author_inst":"Emory University Rollins School of Public Health"},{"author_name":"Samuel Jenness","author_inst":"Emory University Rollins School of Public Health"},{"author_name":"Ben Lopman","author_inst":"Emory University Rollins School of Public Health"},{"author_name":"Kayoko Shioda","author_inst":"Boston University School of Public Health"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Beyond Words: Natural Language Sampling of Lexical and Non-Word Vocalizations in Preschool Children with Autism, Down Syndrome, and Fragile X Syndrome","rel_doi":"10.64898\/2026.09.21.26363560","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363560","rel_abs":"Purpose: This study examined whether word-based and non-word natural language sampling (NLS) measures complement standardized language scores in characterizing expressive communication among preschool children with autism with language impairment (AUT-LI), Down syndrome (DS), and fragile X syndrome (FXS). Method: Participants included 82 preschool children with AUT-LI (n = 32), DS (n = 34), or FXS (n = 16). Expressive communication was characterized using the Preschool Language Scales and 10-minute natural language samples collected during a standardized play-based protocol. NLS measures included traditional word-based metrics, such as lexical diversity, intelligibility, and word approximations, as well as tiered non-word vocalization measures, including non-speech, single-phoneme, and multi-phoneme vocalizations. Analyses examined age associations, diagnostic group differences, between group differences in variability, and exploratory communication profiles derived using principal component analysis and partitioning around medoids clustering. Results: Diagnostic groups did not significantly differ on standardized expressive language scores. Children with FXS showed higher performance than the AUT-LI and DS groups on several word-based NLS measures, whereas non-word vocalization measures primarily revealed differences in within-group variability. Word-based NLS measures were consistently associated with standardized expressive language skills, while associations for non-word vocalizations varied by vocalizations type. Cluster-validity indices factored a two-cluster solution. A hypothesis-informed three cluster solution that included non-word vocalizations suggested Higher Language, Lower Output, and High Output-Low Structure profiles. Conclusions: Standardized and NLS measures provide complementary descriptions of expressive communication in children with neurodevelopmental disorders. Non-word vocalization coding may be especially useful for describing clinical meaningful variation among children with limited expressive language. Keywords: Natural language sampling; expressive language; neurodevelopmental disorders; autism spectrum disorder; Down syndrome; Fragile X syndrome","rel_num_authors":22,"rel_authors":[{"author_name":"Anna S Adekogbe","author_inst":"Harvard University"},{"author_name":"Anna S Adekogbe","author_inst":"Harvard University"},{"author_name":"Antuan Tran","author_inst":"Boston Children's Hospital"},{"author_name":"Antuan Tran","author_inst":"Boston Children's Hospital"},{"author_name":"Gabriela Miller","author_inst":"Boston Children's Hospital"},{"author_name":"Gabriela Miller","author_inst":"Boston Children's Hospital"},{"author_name":"Margaret Norberg","author_inst":"Boston Children's Hospital"},{"author_name":"Margaret Norberg","author_inst":"Boston Children's Hospital"},{"author_name":"Alexis Monk","author_inst":"Harvard University"},{"author_name":"Alexis Monk","author_inst":"Harvard University"},{"author_name":"Tanisha Chanda","author_inst":"Georgia Institute of Technology"},{"author_name":"Tanisha Chanda","author_inst":"Georgia Institute of Technology"},{"author_name":"Xinran Hou","author_inst":"Boston Children's Hospital"},{"author_name":"Xinran Hou","author_inst":"Boston Children's Hospital"},{"author_name":"Katherine Palowski","author_inst":"Boston Children's Hospital"},{"author_name":"Katherine Palowski","author_inst":"Boston Children's Hospital"},{"author_name":"Nicole Baumer","author_inst":"University of Colorado Anschutz Medical Center"},{"author_name":"Nicole Baumer","author_inst":"University of Colorado Anschutz Medical Center"},{"author_name":"Kristina T Johnson","author_inst":"Northeastern University"},{"author_name":"Kristina T Johnson","author_inst":"Northeastern University"},{"author_name":"Carol Wilkinson","author_inst":"Boston Children's Hospital"},{"author_name":"Carol Wilkinson","author_inst":"Boston Children's Hospital"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Beyond Words: Natural Language Sampling of Lexical and Non-Word Vocalizations in Preschool Children with Autism, Down Syndrome, and Fragile X Syndrome","rel_doi":"10.64898\/2026.09.21.26363560","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363560","rel_abs":"Purpose: This study examined whether word-based and non-word natural language sampling (NLS) measures complement standardized language scores in characterizing expressive communication among preschool children with autism with language impairment (AUT-LI), Down syndrome (DS), and fragile X syndrome (FXS). Method: Participants included 82 preschool children with AUT-LI (n = 32), DS (n = 34), or FXS (n = 16). Expressive communication was characterized using the Preschool Language Scales and 10-minute natural language samples collected during a standardized play-based protocol. NLS measures included traditional word-based metrics, such as lexical diversity, intelligibility, and word approximations, as well as tiered non-word vocalization measures, including non-speech, single-phoneme, and multi-phoneme vocalizations. Analyses examined age associations, diagnostic group differences, between group differences in variability, and exploratory communication profiles derived using principal component analysis and partitioning around medoids clustering. Results: Diagnostic groups did not significantly differ on standardized expressive language scores. Children with FXS showed higher performance than the AUT-LI and DS groups on several word-based NLS measures, whereas non-word vocalization measures primarily revealed differences in within-group variability. Word-based NLS measures were consistently associated with standardized expressive language skills, while associations for non-word vocalizations varied by vocalizations type. Cluster-validity indices factored a two-cluster solution. A hypothesis-informed three cluster solution that included non-word vocalizations suggested Higher Language, Lower Output, and High Output-Low Structure profiles. Conclusions: Standardized and NLS measures provide complementary descriptions of expressive communication in children with neurodevelopmental disorders. Non-word vocalization coding may be especially useful for describing clinical meaningful variation among children with limited expressive language. Keywords: Natural language sampling; expressive language; neurodevelopmental disorders; autism spectrum disorder; Down syndrome; Fragile X syndrome","rel_num_authors":22,"rel_authors":[{"author_name":"Anna S Adekogbe","author_inst":"Harvard University"},{"author_name":"Anna S Adekogbe","author_inst":"Harvard University"},{"author_name":"Antuan Tran","author_inst":"Boston Children's Hospital"},{"author_name":"Antuan Tran","author_inst":"Boston Children's Hospital"},{"author_name":"Gabriela Miller","author_inst":"Boston Children's Hospital"},{"author_name":"Gabriela Miller","author_inst":"Boston Children's Hospital"},{"author_name":"Margaret Norberg","author_inst":"Boston Children's Hospital"},{"author_name":"Margaret Norberg","author_inst":"Boston Children's Hospital"},{"author_name":"Alexis Monk","author_inst":"Harvard University"},{"author_name":"Alexis Monk","author_inst":"Harvard University"},{"author_name":"Tanisha Chanda","author_inst":"Georgia Institute of Technology"},{"author_name":"Tanisha Chanda","author_inst":"Georgia Institute of Technology"},{"author_name":"Xinran Hou","author_inst":"Boston Children's Hospital"},{"author_name":"Xinran Hou","author_inst":"Boston Children's Hospital"},{"author_name":"Katherine Palowski","author_inst":"Boston Children's Hospital"},{"author_name":"Katherine Palowski","author_inst":"Boston Children's Hospital"},{"author_name":"Nicole Baumer","author_inst":"University of Colorado Anschutz Medical Center"},{"author_name":"Nicole Baumer","author_inst":"University of Colorado Anschutz Medical Center"},{"author_name":"Kristina T Johnson","author_inst":"Northeastern University"},{"author_name":"Kristina T Johnson","author_inst":"Northeastern University"},{"author_name":"Carol Wilkinson","author_inst":"Boston Children's Hospital"},{"author_name":"Carol Wilkinson","author_inst":"Boston Children's Hospital"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Diagnostic Accuracy of WHO IMCI Visual Inspection for Neonatal Jaundice: A Prospective Multi-Country Cohort","rel_doi":"10.64898\/2026.09.16.26362263","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.16.26362263","rel_abs":"BACKGROUND: Adverse consequences of neonatal hyperbilirubinemia disproportionately affect babies in low- and middle-income countries. Laboratory measurement of total serum bilirubin is limited in low-resource settings, necessitating simpler alternatives. Our study aimed to evaluate the diagnostic accuracy of visual inspection of jaundice via the World Health Organization Integrated Management of Childhood Illnesses algorithm compared to transcutaneous bilirubinometry for the identification of hyperbilirubinemia in community settings. METHODS: Hyperbilirubinemia was assessed by visual inspection for jaundice and transcutaneous bilirubinometry at 0-72 hours, 3-5 days, and 5-14 days postnatal in the PRISMA prospective cohort study in six sites in Asia and Africa. We assessed sensitivity, specificity, and positive and negative percent agreement. RESULTS: We analyzed data from 14,331 infants, including 1,852 preterm infants. 15% had hyperbilirubinemia, as defined by transcutaneous bilirubin values and the NICE nomograms, at 3-5 days postnatal. Visual inspection had a sensitivity of 16%, specificity of 96%, positive percent agreement of 56%, and negative percent agreement of 86% at 3-5 days postnatal age, pooled across all sites and gestational ages, versus transcutaneous bilirubin defined by NICE nomograms. CONCLUSION: The poor sensitivity of visual inspection underscores an urgent need for accurate, affordable screening tools to improve screening for hyperbilirubinemia.","rel_num_authors":31,"rel_authors":[{"author_name":"Amna Khan","author_inst":"Department of Paediatrics and Child Health, Aga Khan University (AKU), Karachi, Pakistan"},{"author_name":"Alyssa Shapiro","author_inst":"Department of Global Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States"},{"author_name":"Nida Salman Yazdani","author_inst":"Department of Paediatrics and Child Health, Aga Khan University (AKU), Karachi, Pakistan"},{"author_name":"Sebin George Abraham","author_inst":"Department of Community Health, Christian Medical College (CMC) Vellore, Vellore, India"},{"author_name":"Victor Akelo","author_inst":"1:Kenya Medical Research Institute, Kisumu, Kenya; 2: Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, England"},{"author_name":"Kwaku Poku Asante","author_inst":"Kintampo Health Research Center, Research and Development Division, Ghana Health"},{"author_name":"Florence Aweyo","author_inst":"Department of Family Health Unit, Kenya Medical Research Institute, Kisumu, Kenya"},{"author_name":"Anne George Cherian","author_inst":"Department of Community Medicine (OG), Christian Medical College (CMC) Vellore, Vellore, India"},{"author_name":"Munita Jat","author_inst":"Implementation Science Domain, Society for Applied Studies, New Delhi, India"},{"author_name":"Fyezah Jehan","author_inst":"Department of Paediatrics and Child Health, Aga Khan University (AKU), Karachi, Pakistan"},{"author_name":"Indhumathi K","author_inst":"Department of Community Health, Christian Medical College (CMC) Vellore, Vellore, India"},{"author_name":"Kevin Kasadhe","author_inst":"Department of Family Health Unit, Kenya Medical Research Institute, Kisumu, Kenya"},{"author_name":"Margaret Kasaro","author_inst":"1: University of North Carolina--Global Projects Zambia, Lusaka, Zambia; 2: Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill"},{"author_name":"Anne CC Lee","author_inst":"Department of Pediatrics, Global Alliance for Infant and Maternal Health Research, Warren Alpert Medical School of Brown University, Providence, RI, US"},{"author_name":"Azqa Mazhar","author_inst":"Department of Paediatrics and Child Health, Aga Khan University (AKU), Karachi, Pakistan"},{"author_name":"Sarmila Mazumder","author_inst":"Implementation Science Domain, Society for Applied Studies, New Delhi, India"},{"author_name":"Christopher Mores","author_inst":"Department of Global Health, Milken Institute School for Public Health, George Washington University (GWU), Washington, DC, United States"},{"author_name":"Wilbroad Mutale","author_inst":"University of North Carolina--Global Projects Zambia, Lusaka, Zambia"},{"author_name":"Humphrey Mwape","author_inst":"University of North Carolina--Global Projects Zambia, Lusaka, Zambia"},{"author_name":"Sam Newton","author_inst":"Kintampo Health Research Center, Research and Development Division, Ghana Health"},{"author_name":"Muhammad Imran Nisar","author_inst":"Department of Paediatrics and Child Health, Aga Khan University (AKU), Karachi, Pakistan"},{"author_name":"Linda Ogala","author_inst":"Department of Family Health Unit, Kenya Medical Research Institute, Kisumu, Kenya"},{"author_name":"Nancy Ogola","author_inst":"Department of Family Health Unit, Kenya Medical Research Institute, Kisumu, Kenya"},{"author_name":"Neeraj Sharma","author_inst":"Implementation Science Domain, Society for Applied Studies, New Delhi, India"},{"author_name":"M. Bridget Spelke","author_inst":"Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States"},{"author_name":"Jasmine Sugirtha","author_inst":"Department of Community Health, Christian Medical College (CMC) Vellore, Vellore, India"},{"author_name":"Yipeng Wei","author_inst":"Department of Statistics, George Washington University (GWU), Washington, DC, United States"},{"author_name":"Wen-Chien Yang","author_inst":"Department of Global Health, Milken Institute School of Public Health, George Washington University (GWU), Washington, DC, United States"},{"author_name":"Zahra Hoodbhoy","author_inst":"Department of Paediatrics and Child Health, Aga Khan University (AKU), Karachi, Pakistan"},{"author_name":"Qing Pan","author_inst":"Department of Biostatistics and Bioinformatics, George Washington University (GWU), Washington, DC, United States"},{"author_name":"Emily R. Smith","author_inst":"Department of Global Health, Milken Institute School of Public Health, George Washington University (GWU), Washington, DC, United States"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Diagnostic Accuracy of WHO IMCI Visual Inspection for Neonatal Jaundice: A Prospective Multi-Country Cohort","rel_doi":"10.64898\/2026.09.16.26362263","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.16.26362263","rel_abs":"BACKGROUND: Adverse consequences of neonatal hyperbilirubinemia disproportionately affect babies in low- and middle-income countries. Laboratory measurement of total serum bilirubin is limited in low-resource settings, necessitating simpler alternatives. Our study aimed to evaluate the diagnostic accuracy of visual inspection of jaundice via the World Health Organization Integrated Management of Childhood Illnesses algorithm compared to transcutaneous bilirubinometry for the identification of hyperbilirubinemia in community settings. METHODS: Hyperbilirubinemia was assessed by visual inspection for jaundice and transcutaneous bilirubinometry at 0-72 hours, 3-5 days, and 5-14 days postnatal in the PRISMA prospective cohort study in six sites in Asia and Africa. We assessed sensitivity, specificity, and positive and negative percent agreement. RESULTS: We analyzed data from 14,331 infants, including 1,852 preterm infants. 15% had hyperbilirubinemia, as defined by transcutaneous bilirubin values and the NICE nomograms, at 3-5 days postnatal. Visual inspection had a sensitivity of 16%, specificity of 96%, positive percent agreement of 56%, and negative percent agreement of 86% at 3-5 days postnatal age, pooled across all sites and gestational ages, versus transcutaneous bilirubin defined by NICE nomograms. CONCLUSION: The poor sensitivity of visual inspection underscores an urgent need for accurate, affordable screening tools to improve screening for hyperbilirubinemia.","rel_num_authors":31,"rel_authors":[{"author_name":"Amna Khan","author_inst":"Department of Paediatrics and Child Health, Aga Khan University (AKU), Karachi, Pakistan"},{"author_name":"Alyssa Shapiro","author_inst":"Department of Global Health, Milken Institute School of Public Health, George Washington University, Washington, DC, United States"},{"author_name":"Nida Salman Yazdani","author_inst":"Department of Paediatrics and Child Health, Aga Khan University (AKU), Karachi, Pakistan"},{"author_name":"Sebin George Abraham","author_inst":"Department of Community Health, Christian Medical College (CMC) Vellore, Vellore, India"},{"author_name":"Victor Akelo","author_inst":"1:Kenya Medical Research Institute, Kisumu, Kenya; 2: Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, England"},{"author_name":"Kwaku Poku Asante","author_inst":"Kintampo Health Research Center, Research and Development Division, Ghana Health"},{"author_name":"Florence Aweyo","author_inst":"Department of Family Health Unit, Kenya Medical Research Institute, Kisumu, Kenya"},{"author_name":"Anne George Cherian","author_inst":"Department of Community Medicine (OG), Christian Medical College (CMC) Vellore, Vellore, India"},{"author_name":"Munita Jat","author_inst":"Implementation Science Domain, Society for Applied Studies, New Delhi, India"},{"author_name":"Fyezah Jehan","author_inst":"Department of Paediatrics and Child Health, Aga Khan University (AKU), Karachi, Pakistan"},{"author_name":"Indhumathi K","author_inst":"Department of Community Health, Christian Medical College (CMC) Vellore, Vellore, India"},{"author_name":"Kevin Kasadhe","author_inst":"Department of Family Health Unit, Kenya Medical Research Institute, Kisumu, Kenya"},{"author_name":"Margaret Kasaro","author_inst":"1: University of North Carolina--Global Projects Zambia, Lusaka, Zambia; 2: Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill"},{"author_name":"Anne CC Lee","author_inst":"Department of Pediatrics, Global Alliance for Infant and Maternal Health Research, Warren Alpert Medical School of Brown University, Providence, RI, US"},{"author_name":"Azqa Mazhar","author_inst":"Department of Paediatrics and Child Health, Aga Khan University (AKU), Karachi, Pakistan"},{"author_name":"Sarmila Mazumder","author_inst":"Implementation Science Domain, Society for Applied Studies, New Delhi, India"},{"author_name":"Christopher Mores","author_inst":"Department of Global Health, Milken Institute School for Public Health, George Washington University (GWU), Washington, DC, United States"},{"author_name":"Wilbroad Mutale","author_inst":"University of North Carolina--Global Projects Zambia, Lusaka, Zambia"},{"author_name":"Humphrey Mwape","author_inst":"University of North Carolina--Global Projects Zambia, Lusaka, Zambia"},{"author_name":"Sam Newton","author_inst":"Kintampo Health Research Center, Research and Development Division, Ghana Health"},{"author_name":"Muhammad Imran Nisar","author_inst":"Department of Paediatrics and Child Health, Aga Khan University (AKU), Karachi, Pakistan"},{"author_name":"Linda Ogala","author_inst":"Department of Family Health Unit, Kenya Medical Research Institute, Kisumu, Kenya"},{"author_name":"Nancy Ogola","author_inst":"Department of Family Health Unit, Kenya Medical Research Institute, Kisumu, Kenya"},{"author_name":"Neeraj Sharma","author_inst":"Implementation Science Domain, Society for Applied Studies, New Delhi, India"},{"author_name":"M. Bridget Spelke","author_inst":"Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States"},{"author_name":"Jasmine Sugirtha","author_inst":"Department of Community Health, Christian Medical College (CMC) Vellore, Vellore, India"},{"author_name":"Yipeng Wei","author_inst":"Department of Statistics, George Washington University (GWU), Washington, DC, United States"},{"author_name":"Wen-Chien Yang","author_inst":"Department of Global Health, Milken Institute School of Public Health, George Washington University (GWU), Washington, DC, United States"},{"author_name":"Zahra Hoodbhoy","author_inst":"Department of Paediatrics and Child Health, Aga Khan University (AKU), Karachi, Pakistan"},{"author_name":"Qing Pan","author_inst":"Department of Biostatistics and Bioinformatics, George Washington University (GWU), Washington, DC, United States"},{"author_name":"Emily R. Smith","author_inst":"Department of Global Health, Milken Institute School of Public Health, George Washington University (GWU), Washington, DC, United States"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Multi-Ancestry Genome-wide Association Analyses Identify Shared and Specific Genetic Architecture in Mild and Moderate-to-Severe Asthma","rel_doi":"10.64898\/2026.09.20.26363488","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.20.26363488","rel_abs":"Background: Moderate-to-severe asthma affects 15-30% of asthma patients, but accounts for over 50% of healthcare costs and disproportionate morbidity. However, the genetic mechanisms underlying moderate-to-severe versus mild asthma remain poorly understood. Methods: We performed separate pooled multi-ancestry GWAS of mild (N = 14,372) and moderate-to-severe asthma (N = 7,096) versus non-asthma controls (N = 28,816) among adult participants in the NIH All of Us Research Program (version 8). European, African, and Latino\/admixed ancestry-specific GWAS were combined using fixed-effect meta-analysis. Lung expression quantitative trait loci (eQTL) and pathway analyses were performed to identify candidate genes and biological pathways across asthma phenotypes. Results: Mild and moderate-to-severe asthma shared susceptibility loci at IL1RL1, IKZF3, and the GTF3AP1-IL33, GTF3AP1-RANBP6, LINC02757-EMSY and HLA-DRB1-HLA-DQA1 regions. Shared lung eQTLs implicated IL18R1, IL18RAP, HLA genes, IL33, LRRC32, GRB7, MIEN1 and GSDMB. In contrast, the phenotypes exhibited distinct genetic architectures. Mild asthma was characterized by broader HLA class II signals and associations at SMAD3 and GSDMB, with enrichment of antigen presentation, T-helper cell differentiation, and TGF-{beta} regulation, consistent with adaptive immune mechanisms. Moderate-to-severe asthma was characterized by WDR36 and PTCH1, with lung eQTLs implicating TSLP, CAMK4, and FANCC. Pathway analysis identified enrichment of IL-13, IL-6, and IL-10 production, myeloid leukocyte differentiation, and oxidative stress responses, consistent with innate inflammation and pathways implicated in steroid resistance. The IL33 signals showed a severity-gradient effect, with stronger associations in moderate-to-severe asthma. Conclusion: Mild and moderate-to-severe asthma exhibit shared and distinct genetic architectures that support existing biologic targets and suggest novel therapeutic candidates.","rel_num_authors":8,"rel_authors":[{"author_name":"Angelico Mendy","author_inst":"Louisiana State University Health Sciences Center"},{"author_name":"Yadu Gautam","author_inst":"Indiana University School of Medicine"},{"author_name":"Bradley H. Rosen","author_inst":"Indiana University School of Medicine"},{"author_name":"Joseph Castlen","author_inst":"Indiana University School of Medicine"},{"author_name":"Michael B. Fessler","author_inst":"National Institute for Environmental Health Sciences"},{"author_name":"Darryl C. Zeldin","author_inst":"National Institute for Environmental Health Sciences"},{"author_name":"Peter S. Thorne","author_inst":"University of Iowa"},{"author_name":"Tesfaye B. Mersha","author_inst":"Indiana University School of Medicine"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Polygenic effects on cortical size and ADHD converge on a mid-gestational progenitor-to-neuron transition programme","rel_doi":"10.64898\/2026.09.21.26363544","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363544","rel_abs":"Neurodevelopmental and psychiatric conditions have long been hypothesised to emerge from changes in the structure and function of the brain. However, the molecular and cellular mechanisms linking brain structure to these conditions remain unknown. Here, using genetic and structural\/diffusion neuroimaging data from 59,283 individuals spanning adults, children and neonates, we identify widespread genetic associations between ADHD, anxiety and depression and multiple phenotypes indexing cortical size and subcortical volume. Multivariate genetic analyses demonstrate that these associations are largely driven by a common cortical size genetic factor and ADHD. Mendelian randomisation indicates that genetically predicted reduced cortical size is causal for ADHD and not vice versa. Using single-nucleus RNA sequencing of the developing cortex, we further demonstrate that although cortical size and ADHD are enriched in different cell types - proliferating progenitors and postmitotic neurons, respectively, they converge on neurogenic genetic programmes active during the transition between the two cell types. This programme peaks at mid-gestation and is localised to the outer subventricular and intermediate zones, the regions where progenitor amplification and early neuronal migration drive human cortical expansion, and is enriched for genes that are differentially expressed in human and macaque developing cortex. Separately, the negative genetic correlation between ADHD and cortical size measures are strongest in cortical regions that have expanded most in humans relative to macaques. Together, these findings identify a novel, spatiotemporally restricted molecular mechanism underlying neurogenesis that is enriched for polygenic effects of both cortical size and ADHD.","rel_num_authors":31,"rel_authors":[{"author_name":"Yuankai He","author_inst":"University of Cambridge"},{"author_name":"Amir Ebneabbasi","author_inst":"University of Cambridge"},{"author_name":"Koen Rademaker","author_inst":"Wellcome Sanger Institute"},{"author_name":"Elina Z Jin","author_inst":"Wellcome Sanger Institute"},{"author_name":"Yuanjun Gu","author_inst":"University of Cambridge"},{"author_name":"Fani Femi","author_inst":"Wellcome Sanger Institute"},{"author_name":"Clara M.L. Riegis","author_inst":"University of Cambridge"},{"author_name":"Bess Pearson","author_inst":"Imperial College, London"},{"author_name":"Renato Polimanti","author_inst":"Yale University"},{"author_name":"Jakob Grove","author_inst":"Aarhus University"},{"author_name":"Anders B\u00f8rglum","author_inst":"Aarhus University"},{"author_name":"Nadine Parker","author_inst":"University of Oslo"},{"author_name":"Ole Andreassen","author_inst":"Oslo University Hospital and University of Oslo"},{"author_name":"Oleksandr Frei","author_inst":"University of Oslo"},{"author_name":"Darren Cameron","author_inst":"Cardiff University"},{"author_name":"Nicholas J Bray","author_inst":"Cardiff University"},{"author_name":"Ang Li","author_inst":"University of Oxford"},{"author_name":"Jian Zeng","author_inst":"University of Queensland"},{"author_name":"Naomi R. Wray","author_inst":"University of Oxford"},{"author_name":"Rafael Romero-Garcia","author_inst":"University of Seville"},{"author_name":"Timothy Rittman","author_inst":"University of Cambridge"},{"author_name":"Simon Baron-Cohen","author_inst":"University of Cambridge"},{"author_name":"Melissa J. Gladstone","author_inst":"University of Liverpool"},{"author_name":"Shivaram Avula","author_inst":"Alder Hey Children's Hospital"},{"author_name":"Mary-Ellen Lynall","author_inst":"University of Cambridge"},{"author_name":"Sarah Rae","author_inst":"University of Cambridge"},{"author_name":"Duncan Astle","author_inst":"University of Cambridge"},{"author_name":"Richard A.I. Bethlehem","author_inst":"University of Cambridge"},{"author_name":"Edward T. Bullmore","author_inst":"King's College London"},{"author_name":"Omer A. Bayraktar","author_inst":"Wellcome Sanger Institute"},{"author_name":"Varun Warrier","author_inst":"University of Cambridge"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Concordance Between Capillary Dried Plasma Spot and Venous Plasma Biomarkers in Traumatic Brain Injury: An Analytical Feasibility Pilot Study","rel_doi":"10.64898\/2026.09.16.26361861","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.16.26361861","rel_abs":"Background: Traumatic brain injury (TBI) increases long-term risk for cognitive decline and neurodegeneration, motivating objective blood biomarkers that can be measured repeatedly over time. However, reliance on venipuncture limits longitudinal monitoring, particularly outside clinic settings. Objective: We conducted a pilot feasibility study comparing fingerstick capillary blood collected as dried plasma spots (DPS) with matched venous EDTA plasma for quantification of glial fibrillary acidic protein (GFAP) and neurofilament light (NfL). Methods: Paired samples were collected prospectively across matched time points spanning hours to decades post-injury and assayed using high-sensitivity immunoassays. Results: Absolute protein recovery from DPS was lower and more variable than venous plasma, but paired GFAP and NfL measurements remained well-correlated. We further evaluated the GFAP\/NfL ratio as an internal, sample-based normalization strategy and observed improved concordance between capillary DPS and venous plasma compared with either analyte alone. Conclusions: These pilot findings support the analytical feasibility of capillary DPS sampling for GFAP and NfL measurement in TBI and identify the GFAP\/NfL ratio as an exploratory internal-normalization approach. Formal analytical and clinical validation, including outcome linkage and prospective evaluation, will be required before capillary DPS can be considered for clinical monitoring applications.","rel_num_authors":14,"rel_authors":[{"author_name":"Devin Jackson","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Katie Tehas","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Kristy Radeker","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Anthony DeLizza","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Caroline Popper","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Elaine Peskind","author_inst":"VA Northwest Mental Illness Research, Education and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, WA 98108, USA; and Department of Psych"},{"author_name":"Ava Puccio","author_inst":"Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA"},{"author_name":"Raquel C. Gardner","author_inst":"Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel HaShomer, Ramat Gan 52621, Israel; and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Is"},{"author_name":"John B. Williamson","author_inst":"Brain Rehabilitation Research Center, North Florida\/South Georgia Veterans Affairs Medical Center, Gainesville, FL 32608, USA; and Department of Psychiatry, McK"},{"author_name":"Abigail B. Waters","author_inst":"Brain Rehabilitation Research Center, North Florida\/South Georgia Veterans Affairs Medical Center, Gainesville, FL 32608, USA; and Department of Clinical and He"},{"author_name":"Lisa H. Merck","author_inst":"Department of Emergency Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA; Warren Alpert Medical School of Brown University"},{"author_name":"Geoff Manley","author_inst":"Department of Neurological Surgery, University of California San Francisco, and Brain and Spinal Injury Center, Zuckerberg San Francisco General Hospital, San F"},{"author_name":"Kevin K. Wang","author_inst":"Center for Neurotrauma, Multiomics & Biomarkers (CNMB), Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive SW,"},{"author_name":"William E. Haskins","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA; Owl Therapeutics, 255 Main St Ste 200, Cambridge, MA 02142, USA"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Concordance Between Capillary Dried Plasma Spot and Venous Plasma Biomarkers in Traumatic Brain Injury: An Analytical Feasibility Pilot Study","rel_doi":"10.64898\/2026.09.16.26361861","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.16.26361861","rel_abs":"Background: Traumatic brain injury (TBI) increases long-term risk for cognitive decline and neurodegeneration, motivating objective blood biomarkers that can be measured repeatedly over time. However, reliance on venipuncture limits longitudinal monitoring, particularly outside clinic settings. Objective: We conducted a pilot feasibility study comparing fingerstick capillary blood collected as dried plasma spots (DPS) with matched venous EDTA plasma for quantification of glial fibrillary acidic protein (GFAP) and neurofilament light (NfL). Methods: Paired samples were collected prospectively across matched time points spanning hours to decades post-injury and assayed using high-sensitivity immunoassays. Results: Absolute protein recovery from DPS was lower and more variable than venous plasma, but paired GFAP and NfL measurements remained well-correlated. We further evaluated the GFAP\/NfL ratio as an internal, sample-based normalization strategy and observed improved concordance between capillary DPS and venous plasma compared with either analyte alone. Conclusions: These pilot findings support the analytical feasibility of capillary DPS sampling for GFAP and NfL measurement in TBI and identify the GFAP\/NfL ratio as an exploratory internal-normalization approach. Formal analytical and clinical validation, including outcome linkage and prospective evaluation, will be required before capillary DPS can be considered for clinical monitoring applications.","rel_num_authors":14,"rel_authors":[{"author_name":"Devin Jackson","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Katie Tehas","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Kristy Radeker","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Anthony DeLizza","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Caroline Popper","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Elaine Peskind","author_inst":"VA Northwest Mental Illness Research, Education and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, WA 98108, USA; and Department of Psych"},{"author_name":"Ava Puccio","author_inst":"Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA"},{"author_name":"Raquel C. Gardner","author_inst":"Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel HaShomer, Ramat Gan 52621, Israel; and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Is"},{"author_name":"John B. Williamson","author_inst":"Brain Rehabilitation Research Center, North Florida\/South Georgia Veterans Affairs Medical Center, Gainesville, FL 32608, USA; and Department of Psychiatry, McK"},{"author_name":"Abigail B. Waters","author_inst":"Brain Rehabilitation Research Center, North Florida\/South Georgia Veterans Affairs Medical Center, Gainesville, FL 32608, USA; and Department of Clinical and He"},{"author_name":"Lisa H. Merck","author_inst":"Department of Emergency Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA; Warren Alpert Medical School of Brown University"},{"author_name":"Geoff Manley","author_inst":"Department of Neurological Surgery, University of California San Francisco, and Brain and Spinal Injury Center, Zuckerberg San Francisco General Hospital, San F"},{"author_name":"Kevin K. Wang","author_inst":"Center for Neurotrauma, Multiomics & Biomarkers (CNMB), Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive SW,"},{"author_name":"William E. Haskins","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA; Owl Therapeutics, 255 Main St Ste 200, Cambridge, MA 02142, USA"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Concordance Between Capillary Dried Plasma Spot and Venous Plasma Biomarkers in Traumatic Brain Injury: An Analytical Feasibility Pilot Study","rel_doi":"10.64898\/2026.09.16.26361861","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.16.26361861","rel_abs":"Background: Traumatic brain injury (TBI) increases long-term risk for cognitive decline and neurodegeneration, motivating objective blood biomarkers that can be measured repeatedly over time. However, reliance on venipuncture limits longitudinal monitoring, particularly outside clinic settings. Objective: We conducted a pilot feasibility study comparing fingerstick capillary blood collected as dried plasma spots (DPS) with matched venous EDTA plasma for quantification of glial fibrillary acidic protein (GFAP) and neurofilament light (NfL). Methods: Paired samples were collected prospectively across matched time points spanning hours to decades post-injury and assayed using high-sensitivity immunoassays. Results: Absolute protein recovery from DPS was lower and more variable than venous plasma, but paired GFAP and NfL measurements remained well-correlated. We further evaluated the GFAP\/NfL ratio as an internal, sample-based normalization strategy and observed improved concordance between capillary DPS and venous plasma compared with either analyte alone. Conclusions: These pilot findings support the analytical feasibility of capillary DPS sampling for GFAP and NfL measurement in TBI and identify the GFAP\/NfL ratio as an exploratory internal-normalization approach. Formal analytical and clinical validation, including outcome linkage and prospective evaluation, will be required before capillary DPS can be considered for clinical monitoring applications.","rel_num_authors":14,"rel_authors":[{"author_name":"Devin Jackson","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Katie Tehas","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Kristy Radeker","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Anthony DeLizza","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Caroline Popper","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA"},{"author_name":"Elaine Peskind","author_inst":"VA Northwest Mental Illness Research, Education and Clinical Center (MIRECC), VA Puget Sound Health Care System, Seattle, WA 98108, USA; and Department of Psych"},{"author_name":"Ava Puccio","author_inst":"Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA"},{"author_name":"Raquel C. Gardner","author_inst":"Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel HaShomer, Ramat Gan 52621, Israel; and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Is"},{"author_name":"John B. Williamson","author_inst":"Brain Rehabilitation Research Center, North Florida\/South Georgia Veterans Affairs Medical Center, Gainesville, FL 32608, USA; and Department of Psychiatry, McK"},{"author_name":"Abigail B. Waters","author_inst":"Brain Rehabilitation Research Center, North Florida\/South Georgia Veterans Affairs Medical Center, Gainesville, FL 32608, USA; and Department of Clinical and He"},{"author_name":"Lisa H. Merck","author_inst":"Department of Emergency Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA; Warren Alpert Medical School of Brown University"},{"author_name":"Geoff Manley","author_inst":"Department of Neurological Surgery, University of California San Francisco, and Brain and Spinal Injury Center, Zuckerberg San Francisco General Hospital, San F"},{"author_name":"Kevin K. Wang","author_inst":"Center for Neurotrauma, Multiomics & Biomarkers (CNMB), Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive SW,"},{"author_name":"William E. Haskins","author_inst":"Gryphon Bio, 611 Gateway Blvd, Suite 120 Unit 253, South San Francisco, CA 94080, USA; Owl Therapeutics, 255 Main St Ste 200, Cambridge, MA 02142, USA"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Menstrual Health in South India: Knowledge, Stigma, and Barriers to Participation","rel_doi":"10.64898\/2026.09.16.26363278","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.16.26363278","rel_abs":"Menstrual health remains a neglected public health challenge in India, where persistent stigma, incomplete education, inadequate sanitation, and limited access to menstrual health resources can adversely affect health and social participation. Institution-based educational programs represent an underexplored opportunity to improve menstrual health literacy while promoting more inclusive discussions surrounding menstruation. Bridging this gap, an exploratory, prospective educational evaluation was conducted at a hospital in Coimbatore, Tamil Nadu and an engineering college in Wayanad, Kerala. Anonymous pre- and post-course surveys assessed menstrual health knowledge, attitudes, practices, perceived barriers, and perspectives on emerging digital health technologies. Quantitative responses were summarized descriptively, and open-ended responses were reviewed to identify recurring perspectives that contextualized the quantitative findings. The standardized educational program integrated evidence-based menstrual health education with discussions of bioengineering and wearable technologies. Eighty-three participants completed the pre-course survey, 68 attended the educational program, and 20 completed the post-course survey. Because responses could not be linked at the individual level, the survey cohorts were compared descriptively. At baseline, 80 of 82 respondents (97.6%) recognized menstruation as a biological process, yet only 38 of 82 (46.3%) indicated that it was not solely a woman's issue. The mean agreement that menstruation remained taboo was 7.44 of 10 (SD 1.99; n=78), and 51 of 77 respondents (66.2%) reported that they or others avoided activities during menstruation. Painful periods were identified as a barrier by 56 of 67 respondents (83.6%), and 18 of 67 (26.9%) considered institutional or community toilets insufficiently clean and private for menstrual management. Open-ended responses illustrated how pain, fear of leakage, stigma, and inadequate facilities constrained participation in school, physical activity, and social life. These findings document a marked gap between basic biological recognition and the social normalization and practical support of menstruation in two South Indian institutions, and support further evaluation of gender-inclusive, context-responsive menstrual health education using paired assessments, stronger follow-up, comparison groups, and long-term outcomes.","rel_num_authors":3,"rel_authors":[{"author_name":"Rupa Ravi","author_inst":"Lehigh University"},{"author_name":"Joseph  A. Amitrano","author_inst":"Lehigh University"},{"author_name":"Dhruv Seshadri","author_inst":"Lehigh University"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"How Autism impacts mothers in a selected autism center in Karachi, Pakistan- A qualitative study","rel_doi":"10.64898\/2026.09.16.26361740","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.16.26361740","rel_abs":"Background: The mothers of children with autism spectrum disorder (ASD) are more stressed than those of neurotypical or any other children with special needs. There remains a notable lack of contextually grounded evidence on the experiences of mothers raising children with autism in resource-constrained settings of a lower middle-income country (LMIC). Methodology: A qualitative phenomenological study was carried out at a government-run autism rehabilitation center over a period of six months. The main purpose of the study was to explore the lived experiences of the mothers of autistic children in a setting like Karachi, Pakistan. Twenty-five mothers of 3-18 years old children enrolled in the selected facility participated in two focus group discussions (FGD) and seven In-depth interviews (IDIs) until data saturation was achieved. Consolidated Criteria for Reporting Qualitative Research (COREQ) guidelines and Guba s constructs of trustworthiness were followed. Results: Several themes were derived, corresponding to the different layers of the Ecological Systems Theory. Themes included maternal emotional journey, interpersonal relationships, societal perceptions, access to support services and adaptation over time. Conclusion: Mothers of children with Autism in Pakistan face significant challenges at the personal, family, societal, and support systems levels. Removing misconceptions and improving access and quality of services to children with Autism and their families is essential for easing their burden.","rel_num_authors":3,"rel_authors":[{"author_name":"Aroosa Nighat","author_inst":"APPNA Institute of Public Health, Jinnah Sindh Medical University"},{"author_name":"Hira Tariq","author_inst":"Department of Community Health Sciences, The Aga Khan University, Karachi"},{"author_name":"Fatima Bismah Athar","author_inst":"Dow Medical College, Dow University of Health Sciences"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Gene-Based Rare Variant Burden Analyses Across Biobanks Identify Novel High-Risk Genes for Thoracic Aortic Disease","rel_doi":"10.64898\/2026.09.16.26363254","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.16.26363254","rel_abs":"Background: Thoracic aortic aneurysms enlarge silently and can cause fatal aortic dissection without timely surgical repair, underscoring the need for improved approaches to identify individuals at high risk. Rare pathogenic variants in established heritable thoracic aortic disease (HTAD) genes explain only a subset of familial and fewer nonfamilial thoracic aortic disease (TAD) cases. Methods: We performed phenotype-stratified, genome-wide, gene-based rare-variant burden analyses of ultrarare damaging missense and predicted loss-of-function variants. Primary analyses focused on aortic dissection, thoracic aortic aneurysm requiring surgical repair, and their combined phenotype. Broader thoracic aortic aneurysm (TAA) was evaluated as a secondary phenotype. Discovery analyses were conducted in the UK Biobank and All of Us, followed by independent replication in the Penn Medicine BioBank, Mass General Brigham Biobank, and Million Veteran Program. Discovery and replication results were subsequently combined in an overall fixed-effect, inverse-variance-weighted meta-analysis across up to five biobanks. Implicated genes were further evaluated in additional clinically ascertained TAD cohorts and using single-cell transcriptomic data from human thoracic aortic tissue. Results: Discovery analyses identified 80 genes reaching study-wide significance across the prespecified TAD phenotypes. These included six established and two putative HTAD genes. Fourteen genes demonstrated independent replication support and reached study-wide significance in the overall meta-analysis across up to five biobanks, which included more than 10,000 cases and 880,000 controls. The eight novel candidate genes among these were FNDC3B, ROCK1, URM1, SLFN11, ENPP1, CLEC16A, CREM, and VCAN. Associations were strongest for dissection and TAA requiring surgical repair. Four novel associations were driven exclusively by missense variants. FNDC3B was observed in a family with HTAD, while additional variants were identified primarily in sporadic dissection or aortic surgery cohorts, suggesting that other genetic or physiologic factors may influence penetrance. The implicated genes showed cell-type-specific expression patterns in human thoracic aortic tissue. Conclusions: These findings expand the genetic architecture of TAD by identifying eight novel candidate genes and demonstrate the utility of phenotype-stratified rare variant burden analyses across large biobanks for gene discovery.","rel_num_authors":23,"rel_authors":[{"author_name":"David R Murdock","author_inst":"The University of Texas Health Science Center at Houston"},{"author_name":"Pujun Guan","author_inst":"UTHealth Houston"},{"author_name":"Dongchuan Guo","author_inst":"UTHealth Houston"},{"author_name":"Francisca Bermudez","author_inst":"University of Pennsylvania"},{"author_name":"John DePaolo","author_inst":"University of Pennsylvania"},{"author_name":"John Cabot","author_inst":"Stanford University School of Medicine"},{"author_name":"Sumaiya Nazeen","author_inst":"Harvard Medical School; Brigham and Women's Hospital; Broad Institute of MIT and Harvard"},{"author_name":"Habib Nasir","author_inst":"Harvard Medical School"},{"author_name":"Rajat Gupta","author_inst":"Brigham and Women's Hospital; Harvard Medical School"},{"author_name":"Alok Jha","author_inst":"Weill Cornell Medicine"},{"author_name":"John Elefteriades","author_inst":"Yale-New Haven Hospital; Yale University School of Medicine"},{"author_name":"Bobbi McGivern","author_inst":"GeneDx, LLC"},{"author_name":"Kirsty McWalter","author_inst":"GeneDx, LLC"},{"author_name":"Samantha Anderson","author_inst":"Rush University Medical Center"},{"author_name":"Carolyn Jones","author_inst":"Rush University Medical Center"},{"author_name":"Julie Lynch","author_inst":"VA Informatics and Computing Infrastructure (VINCI); University of Utah School of Medicine"},{"author_name":"Kyong-Mi Chang","author_inst":"Corporal Michael J. Crescenz VA Medical Center; University of Pennsylvania"},{"author_name":"Philip Tsao","author_inst":"Stanford University School of Medicine; VA Palo Alto Health Care System"},{"author_name":"- VA Million Veteran Program","author_inst":""},{"author_name":"- Penn Medicine BioBank","author_inst":""},{"author_name":"Scott Damrauer","author_inst":"University of Pennsylvania; Corporal Michael J. Crescenz VA Medical Center"},{"author_name":"Han Chen","author_inst":"UTHealth Houston"},{"author_name":"Dianna Milewicz","author_inst":"UTHealth Houston"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"A Genome-wide Genetic Data Resource for the 45 and Up Study","rel_doi":"10.64898\/2026.09.20.26363524","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.20.26363524","rel_abs":"Large population-based cohorts enable investigation of disease risk and precision prevention, but often lack genome-wide genetic data. We generated and validated new genomic data within the Australian 45 and Up Study, one of the largest Southern Hemisphere cohorts (recruited 2005-2009) with extensive longitudinal and linked health data. In 2022-2023, 30,541 participants were invited (random sub-cohort and all individuals with history of four most common invasive cancers: breast, prostate, melanoma, colorectal), with in-depth mapping of participants' characteristics for people who consented to provide a DNA sample and those who did not. Low-coverage whole-genome sequencing data (0.4-6.3x) followed by imputation yielded ~79 million variants for n=7,408 individuals; data for n=6,827 passed stringent quality control. Genotype concordance was high between duplicates (n=85) and with dense genotyping arrays (n=188). Most unrelated participants with high-quality data had inferred European genetic ancestry (n=6,631, 98%), with n=141 (2%) of inferred non-European or admixed ancestry. As proof-of-principle integration of new genomic data with extensive existing linked health records, polygenic risk scores (PGS) for four most common cancers showed predictive performance broadly consistent with previous studies, including association between PGS and earlier age at prostate cancer diagnosis, and no meaningful differences in cancer stage at diagnosis by PGS. This new resource has substantially enhanced the 45 and Up Study, supporting investigations of disease aetiology, risk stratification, and precision health in Australia and globally.","rel_num_authors":12,"rel_authors":[{"author_name":"Hamzeh Mesrian Tanha","author_inst":"The Daffodil Centre, The University of Sydney and Cancer Council NSW, Sydney, Australia"},{"author_name":"David Goldsbury","author_inst":"The Daffodil Centre, The University of Sydney and Cancer Council NSW, Sydney, Australia"},{"author_name":"Richard Parker","author_inst":"QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia"},{"author_name":"Natalie Garden","author_inst":"QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia"},{"author_name":"Erika de Guzman","author_inst":"Central Analytical Research Facility (CARF), Queensland University of Technology (QUT), Brisbane, QLD, Australia"},{"author_name":"Greer Dawson","author_inst":"Sax Institute, Sydney, NSW, Australia"},{"author_name":"Kerrin Bleicher","author_inst":"Sax Institute, Sydney, NSW, Australia"},{"author_name":"Alison Cowle","author_inst":"Sax Institute, Sydney, NSW, Australia"},{"author_name":"Martin McNamara","author_inst":"Sax Institute, Sydney, NSW, Australia"},{"author_name":"Anne E Cust","author_inst":"The Daffodil Centre, The University of Sydney and Cancer Council NSW, Sydney, Australia"},{"author_name":"Nicholas G Martin","author_inst":"QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia"},{"author_name":"Julia Steinberg","author_inst":"The Daffodil Centre, The University of Sydney and Cancer Council NSW, Sydney, Australia"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"A Genome-wide Genetic Data Resource for the 45 and Up Study","rel_doi":"10.64898\/2026.09.20.26363524","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.20.26363524","rel_abs":"Large population-based cohorts enable investigation of disease risk and precision prevention, but often lack genome-wide genetic data. We generated and validated new genomic data within the Australian 45 and Up Study, one of the largest Southern Hemisphere cohorts (recruited 2005-2009) with extensive longitudinal and linked health data. In 2022-2023, 30,541 participants were invited (random sub-cohort and all individuals with history of four most common invasive cancers: breast, prostate, melanoma, colorectal), with in-depth mapping of participants' characteristics for people who consented to provide a DNA sample and those who did not. Low-coverage whole-genome sequencing data (0.4-6.3x) followed by imputation yielded ~79 million variants for n=7,408 individuals; data for n=6,827 passed stringent quality control. Genotype concordance was high between duplicates (n=85) and with dense genotyping arrays (n=188). Most unrelated participants with high-quality data had inferred European genetic ancestry (n=6,631, 98%), with n=141 (2%) of inferred non-European or admixed ancestry. As proof-of-principle integration of new genomic data with extensive existing linked health records, polygenic risk scores (PGS) for four most common cancers showed predictive performance broadly consistent with previous studies, including association between PGS and earlier age at prostate cancer diagnosis, and no meaningful differences in cancer stage at diagnosis by PGS. This new resource has substantially enhanced the 45 and Up Study, supporting investigations of disease aetiology, risk stratification, and precision health in Australia and globally.","rel_num_authors":12,"rel_authors":[{"author_name":"Hamzeh Mesrian Tanha","author_inst":"The Daffodil Centre, The University of Sydney and Cancer Council NSW, Sydney, Australia"},{"author_name":"David Goldsbury","author_inst":"The Daffodil Centre, The University of Sydney and Cancer Council NSW, Sydney, Australia"},{"author_name":"Richard Parker","author_inst":"QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia"},{"author_name":"Natalie Garden","author_inst":"QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia"},{"author_name":"Erika de Guzman","author_inst":"Central Analytical Research Facility (CARF), Queensland University of Technology (QUT), Brisbane, QLD, Australia"},{"author_name":"Greer Dawson","author_inst":"Sax Institute, Sydney, NSW, Australia"},{"author_name":"Kerrin Bleicher","author_inst":"Sax Institute, Sydney, NSW, Australia"},{"author_name":"Alison Cowle","author_inst":"Sax Institute, Sydney, NSW, Australia"},{"author_name":"Martin McNamara","author_inst":"Sax Institute, Sydney, NSW, Australia"},{"author_name":"Anne E Cust","author_inst":"The Daffodil Centre, The University of Sydney and Cancer Council NSW, Sydney, Australia"},{"author_name":"Nicholas G Martin","author_inst":"QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia"},{"author_name":"Julia Steinberg","author_inst":"The Daffodil Centre, The University of Sydney and Cancer Council NSW, Sydney, Australia"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Pathogenic variants in myoferlin (MYOF) cause arrhythmogenic cardiomyopathy","rel_doi":"10.64898\/2026.09.21.26363590","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363590","rel_abs":"Arrhythmogenic cardiomyopathy (ACM) is an inherited disease characterized by fibrofatty remodeling and sudden cardiac death linked to desmosomal dysfunction. Yet, 40% of cases remain genetically unexplained, and non-desmosomal mutations offer insight into ACM pathophysiology. Myoferlin (MYOF), a calcium (Ca2+)-binding protein in cardiomyocytes, is linked to cardiomyopathy, but its mechanism remains unknown. Whole-exome sequencing identified a heterozygous MYOF missense variant (p.G1654S) in an ACM family; we subsequently found three unrelated p.G1654S cases. We hypothesized that MYOF deficiency promotes Ca2+ handling deficits and arrhythmogenesis in ACM. In patient iPSC-derived cardiomyocytes, MYOF p.G1654S protein dimerized with wild-type protein and underwent accelerated lysosomal degradation, showed disrupted Ca2+ handling, and displayed increased arrhythmia burden, all rescued by genomic correction. MYOF interacted with CaV1.2, and verapamil pharmacologically rescued arrhythmias. Heterozygous Myof knockout mice showed systolic dysfunction and fibrosis. These findings establish MYOF as a causative ACM gene and therapeutic target that mediates arrhythmogenesis by disrupting MYOF-CaV1.2.","rel_num_authors":32,"rel_authors":[{"author_name":"Anna Kirillova","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Metin Aytekin","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Irene Chan","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Amir I Mina","author_inst":"Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Yucheng Shao","author_inst":"Carnegie Mellon University, Department of Computational Biology, Pittsburgh, PA, USA"},{"author_name":"Almina Kirdar","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"David Y Zhang","author_inst":"Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Nishita Kalepalli","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"William S Girard","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Yassmin Y Al Aaraj","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Chloe Reuter","author_inst":"Stanford Health Care, Stanford, CA, USA"},{"author_name":"Jeffery S Annis","author_inst":"Vanderbilt University Medical Center, Nashville, TN"},{"author_name":"Yunshan Yue","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Siyi Jiang","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Rashmi J Rao","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"S Mehdi Nouraie","author_inst":"Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"},{"author_name":"Joseph Park","author_inst":"Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Ying Tang","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Christopher Flores","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Michael D Creager","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Paul J Kim","author_inst":"UC San Diego Health, San Diego, California, USA"},{"author_name":"Evan L Brittain","author_inst":"Vanderbilt University Medical Center, Nashville, TN"},{"author_name":"Stuart A Scott","author_inst":"Clinical Genomics Laboratory, Stanford Health Care, Palo Alto, CA, USA"},{"author_name":"Janet R Manning","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Satoshi Okawa","author_inst":"Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"},{"author_name":"Guy Salama","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Haodi Wu","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Manling Zhang","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Carlos J Camacho","author_inst":"Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"},{"author_name":"Michael S Gold","author_inst":"Department of Anesthesiology, Center for Pain Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"},{"author_name":"Victoria N Parikh","author_inst":"Stanford Center for Inherited Cardiovascular Disease, Stanford, CA, USA"},{"author_name":"Stephen Y Chan","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Pathogenic variants in myoferlin (MYOF) cause arrhythmogenic cardiomyopathy","rel_doi":"10.64898\/2026.09.21.26363590","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.21.26363590","rel_abs":"Arrhythmogenic cardiomyopathy (ACM) is an inherited disease characterized by fibrofatty remodeling and sudden cardiac death linked to desmosomal dysfunction. Yet, 40% of cases remain genetically unexplained, and non-desmosomal mutations offer insight into ACM pathophysiology. Myoferlin (MYOF), a calcium (Ca2+)-binding protein in cardiomyocytes, is linked to cardiomyopathy, but its mechanism remains unknown. Whole-exome sequencing identified a heterozygous MYOF missense variant (p.G1654S) in an ACM family; we subsequently found three unrelated p.G1654S cases. We hypothesized that MYOF deficiency promotes Ca2+ handling deficits and arrhythmogenesis in ACM. In patient iPSC-derived cardiomyocytes, MYOF p.G1654S protein dimerized with wild-type protein and underwent accelerated lysosomal degradation, showed disrupted Ca2+ handling, and displayed increased arrhythmia burden, all rescued by genomic correction. MYOF interacted with CaV1.2, and verapamil pharmacologically rescued arrhythmias. Heterozygous Myof knockout mice showed systolic dysfunction and fibrosis. These findings establish MYOF as a causative ACM gene and therapeutic target that mediates arrhythmogenesis by disrupting MYOF-CaV1.2.","rel_num_authors":32,"rel_authors":[{"author_name":"Anna Kirillova","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Metin Aytekin","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Irene Chan","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Amir I Mina","author_inst":"Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Yucheng Shao","author_inst":"Carnegie Mellon University, Department of Computational Biology, Pittsburgh, PA, USA"},{"author_name":"Almina Kirdar","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"David Y Zhang","author_inst":"Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Nishita Kalepalli","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"William S Girard","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Yassmin Y Al Aaraj","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Chloe Reuter","author_inst":"Stanford Health Care, Stanford, CA, USA"},{"author_name":"Jeffery S Annis","author_inst":"Vanderbilt University Medical Center, Nashville, TN"},{"author_name":"Yunshan Yue","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Siyi Jiang","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Rashmi J Rao","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"S Mehdi Nouraie","author_inst":"Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"},{"author_name":"Joseph Park","author_inst":"Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Ying Tang","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Christopher Flores","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Michael D Creager","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Paul J Kim","author_inst":"UC San Diego Health, San Diego, California, USA"},{"author_name":"Evan L Brittain","author_inst":"Vanderbilt University Medical Center, Nashville, TN"},{"author_name":"Stuart A Scott","author_inst":"Clinical Genomics Laboratory, Stanford Health Care, Palo Alto, CA, USA"},{"author_name":"Janet R Manning","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Satoshi Okawa","author_inst":"Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"},{"author_name":"Guy Salama","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Haodi Wu","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Manling Zhang","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"},{"author_name":"Carlos J Camacho","author_inst":"Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"},{"author_name":"Michael S Gold","author_inst":"Department of Anesthesiology, Center for Pain Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"},{"author_name":"Victoria N Parikh","author_inst":"Stanford Center for Inherited Cardiovascular Disease, Stanford, CA, USA"},{"author_name":"Stephen Y Chan","author_inst":"Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, Division of Cardiology, Department of Medicine"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Immunogenicity and vaccine effectiveness of COVID-19 vaccines in people on immunosuppressive therapies","rel_doi":"10.64898\/2026.09.16.26363194","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.16.26363194","rel_abs":"Neutralizing antibodies are a correlate of protection (CoP) of SARS-CoV-2 vaccine efficacy. However, data informing CoPs often explicitly exclude people on immunosuppressive therapies who are at an increased risk of symptomatic and severe COVID-19, delayed viral clearance, and death. Investigating the relationship between antibodies and protection for people on immunosuppressive therapies could provide insights into mechanisms of protection. We performed a systematic search to identify studies reporting SARS-CoV-2 binding antibody levels after mRNA vaccination in people with hematological malignancies, neurological disorders, rheumatic diseases, and mixed immune-mediated inflammatory disorders (IMIDs) on immunosuppressive therapies including B-cell depletion, JAK inhibitors, and S1P inhibitors, as well as healthy controls. Binding antibody levels varied between cohorts receiving different immunosuppressive treatments. Compared to healthy controls the lowest antibody levels were observed in subjects treated with B-cell depletion (54.5-fold reduction, 95% CI: 34.5-86.2) and S1P inhibitors (24.8-fold reduction, 95% CI: 13.2-46.7). To assess the association between antibody level and protection, we used data from a previous study of COVID-19 vaccine effectiveness in people with the same underlying conditions. We linked vaccine effectiveness estimates with the predicted antibody level in people on immunosuppressive therapies (using antibody data including this meta-analysis of binding antibody levels). Predicted neutralizing antibody levels were correlated with vaccine effectiveness both for infection and hospitalization (p<0.0001 and p<0.0001, respectively). However, we found that for any given antibody level, people who are immunosuppressed had lower protection against infection and hospitalization than a healthy population.","rel_num_authors":13,"rel_authors":[{"author_name":"Eva Stadler","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Shanchita R Khan","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Karen M Elias","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Ece Egilmezer","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Chansavath Phetsouphanh","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Priyanka Hastak","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Rehana V Hewavisenti","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Ruchika V Joshi","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Tari Turner","author_inst":"School of Public Health and Preventive Medicine, Monash University"},{"author_name":"Deborah Cromer","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Sarah C Sasson","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"Miles P Davenport","author_inst":"Kirby Institute, UNSW Sydney"},{"author_name":"David S Khoury","author_inst":"Kirby Institute, UNSW Sydney"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Genomic Landscape of Early-Onset and Familial Latin American Parkinson's Patients","rel_doi":"10.64898\/2026.09.16.26359514","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.16.26359514","rel_abs":"Background Parkinson's disease (PD), the most common neurodegenerative movement disorder, is commonly thought of as an aging and sporadic disease; however, 5-14% of individuals experience disease onset before the age of 50 years (early-onset PD; EOPD) and about 20% have a positive family history. In the case of both EOPD and people with a family history of PD, evidence suggests higher rates of a disease-causing genetic contribution. Objectives Our goal was to perform a variant screening of seven PD-related genes and 21 genes associated with related parkinsonian disorders to identify pathogenic\/likely pathogenic variants and variants of uncertain significance within EOPD and family-history-positive individuals within the Latin American Research Consortium on the Genetics of PD (LARGE-PD). Methods We performed short-read whole-genome sequencing on a subset of 263 individuals with EOPD and\/or a familial history of PD who had no known pathogenic PD variant in genotyping data. Results Of the analyzed individuals, a monogenic burden in primary and secondary PD genes due to pathogenic or likely pathogenic variants for PD was observed in 4.7%, an additional 5.5% had pathogenic or likely pathogenic variants for Gaucher's disease, and 2.7% had known risk variants in GBA1. Conclusions By expanding the reported spectrum of disease-associated variants in a Latin American population, we identified previously unreported or underrepresented variants that would likely be missed by array-based or targeted screening approaches and contribute to the characterization of EOPD and familial PD in Latin America.","rel_num_authors":40,"rel_authors":[{"author_name":"Emily Waldo","author_inst":"Cleveland Clinic Foundation"},{"author_name":"Henry Mauricio Chaparro-Solano","author_inst":"Cleveland Clinic Foundation; Cleveland Clinic Lerner College of Medicine, Case Western Reserve University"},{"author_name":"Mariam Isayan","author_inst":"Cleveland Clinic Foundation"},{"author_name":"Thiago P Leal","author_inst":"Morehouse School of Medicine; Cleveland Clinic Foundation"},{"author_name":"Felipe Duarte-Zambrano","author_inst":"Cleveland Clinic Foundation"},{"author_name":"Miguel Inca-Martinez","author_inst":"Cleveland Clinic Foundation"},{"author_name":"Janvi Ramchandra","author_inst":"University of California San Diego"},{"author_name":"Maria Rivera Paz","author_inst":"Cleveland Clinic Foundation; Case Western Reserve University"},{"author_name":"Mary Makarious","author_inst":"DataTecnica LLC"},{"author_name":"Carlos F. Hernandez","author_inst":"Universidad del Desarrollo"},{"author_name":"Emilia M Gatto","author_inst":"Sanatorio de la Trinidad Mitre"},{"author_name":"Natalia Gonzalez Rojas","author_inst":"Sanatorio de la Trinidad Mitre"},{"author_name":"Martin Cesarini","author_inst":"Sanatorio de la Trinidad Mitre"},{"author_name":"Bruno Lopes Santos-Lobato","author_inst":"Universidade Federal do Para; Hospital Ophir Loyola"},{"author_name":"Grace Helena Letro","author_inst":"Hospital da Pontificia Catolica de Campinas"},{"author_name":"Jorge Luis Orozco","author_inst":"Fundacion Valle del Lili"},{"author_name":"Beatriz Munoz Ospina","author_inst":"Universidad Icesi; Fundacion Valle del Lili"},{"author_name":"Pedro Chana-Cuevas","author_inst":"Universida de Santiago de Chile"},{"author_name":"Natalia Andrea Rojas","author_inst":"Centro de Trastornos del Movimiento"},{"author_name":"David Aguillon","author_inst":"Universidad de Antioquia"},{"author_name":"Valentina Muller","author_inst":"Hospital General Jose de San Martin"},{"author_name":"Pedro Braga-Neto","author_inst":"Federal University of Ceara; State University of Ceara"},{"author_name":"Mayela Rodriguez-Violante","author_inst":"Instituto Nacional de Neurologia y Neurocirugia"},{"author_name":"Amin Cervantes-Arriaga","author_inst":"Instituto Nacional de Neurologia y Neurocirugia"},{"author_name":"Artur Schuh","author_inst":"Universidade Federal do Rio Grande do Sul; Hospital de Clinicas de Porto Alegre"},{"author_name":"Mario Cornejo-Olivas","author_inst":"Universidad Cientifica del Sur; Instituto Nacional de Ciencias Neurologicas"},{"author_name":"Koni Mejia Rojas","author_inst":"Instituto Nacional de Ciencias Neurologicas"},{"author_name":"Cintia Armas","author_inst":"EDMECON Medical Center; Daniel Alcides Carrion National Hospital"},{"author_name":"Angel Vinuela","author_inst":"Fundacion Parkinson Puerto Rico"},{"author_name":"Alan Osvaldo Espinal Martinez","author_inst":"Fundacion Parkinson Puerto Rico; Neurosciences Institute Manati Medical Center"},{"author_name":"Vitor Tumas","author_inst":"Ribeirao Preto Medical School - University of Sao Paulo"},{"author_name":"Vanderci Borges","author_inst":"Universidade Federal de Sao Paulo"},{"author_name":"Cesar Luis Avila","author_inst":"UNT-CONICET"},{"author_name":"Patricio Olguin","author_inst":"Universidad de Chile"},{"author_name":"Sarael Alcauter","author_inst":"Universidad Nacional Autonoma de Mexico"},{"author_name":"Marcelo Kauffman","author_inst":"Hospital JM Ramos Mejia"},{"author_name":"Dolores Gonzalez-Moron","author_inst":"Hospital JM Ramos Mejia"},{"author_name":"Susana Lissette Pena Martinez","author_inst":"Universidad Dr. Andres Bello (UNAB)"},{"author_name":"Ignacio F Mata","author_inst":"Cleveland Clinic Foundation"},{"author_name":"- Latin American Research consortium on the Genetics of Parkinson's Disease (LARGE-PD)","author_inst":"-"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Genomic Landscape of Early-Onset and Familial Latin American Parkinson's Patients","rel_doi":"10.64898\/2026.09.16.26359514","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.16.26359514","rel_abs":"Background Parkinson's disease (PD), the most common neurodegenerative movement disorder, is commonly thought of as an aging and sporadic disease; however, 5-14% of individuals experience disease onset before the age of 50 years (early-onset PD; EOPD) and about 20% have a positive family history. In the case of both EOPD and people with a family history of PD, evidence suggests higher rates of a disease-causing genetic contribution. Objectives Our goal was to perform a variant screening of seven PD-related genes and 21 genes associated with related parkinsonian disorders to identify pathogenic\/likely pathogenic variants and variants of uncertain significance within EOPD and family-history-positive individuals within the Latin American Research Consortium on the Genetics of PD (LARGE-PD). Methods We performed short-read whole-genome sequencing on a subset of 263 individuals with EOPD and\/or a familial history of PD who had no known pathogenic PD variant in genotyping data. Results Of the analyzed individuals, a monogenic burden in primary and secondary PD genes due to pathogenic or likely pathogenic variants for PD was observed in 4.7%, an additional 5.5% had pathogenic or likely pathogenic variants for Gaucher's disease, and 2.7% had known risk variants in GBA1. Conclusions By expanding the reported spectrum of disease-associated variants in a Latin American population, we identified previously unreported or underrepresented variants that would likely be missed by array-based or targeted screening approaches and contribute to the characterization of EOPD and familial PD in Latin America.","rel_num_authors":40,"rel_authors":[{"author_name":"Emily Waldo","author_inst":"Cleveland Clinic Foundation"},{"author_name":"Henry Mauricio Chaparro-Solano","author_inst":"Cleveland Clinic Foundation; Cleveland Clinic Lerner College of Medicine, Case Western Reserve University"},{"author_name":"Mariam Isayan","author_inst":"Cleveland Clinic Foundation"},{"author_name":"Thiago P Leal","author_inst":"Morehouse School of Medicine; Cleveland Clinic Foundation"},{"author_name":"Felipe Duarte-Zambrano","author_inst":"Cleveland Clinic Foundation"},{"author_name":"Miguel Inca-Martinez","author_inst":"Cleveland Clinic Foundation"},{"author_name":"Janvi Ramchandra","author_inst":"University of California San Diego"},{"author_name":"Maria Rivera Paz","author_inst":"Cleveland Clinic Foundation; Case Western Reserve University"},{"author_name":"Mary Makarious","author_inst":"DataTecnica LLC"},{"author_name":"Carlos F. Hernandez","author_inst":"Universidad del Desarrollo"},{"author_name":"Emilia M Gatto","author_inst":"Sanatorio de la Trinidad Mitre"},{"author_name":"Natalia Gonzalez Rojas","author_inst":"Sanatorio de la Trinidad Mitre"},{"author_name":"Martin Cesarini","author_inst":"Sanatorio de la Trinidad Mitre"},{"author_name":"Bruno Lopes Santos-Lobato","author_inst":"Universidade Federal do Para; Hospital Ophir Loyola"},{"author_name":"Grace Helena Letro","author_inst":"Hospital da Pontificia Catolica de Campinas"},{"author_name":"Jorge Luis Orozco","author_inst":"Fundacion Valle del Lili"},{"author_name":"Beatriz Munoz Ospina","author_inst":"Universidad Icesi; Fundacion Valle del Lili"},{"author_name":"Pedro Chana-Cuevas","author_inst":"Universida de Santiago de Chile"},{"author_name":"Natalia Andrea Rojas","author_inst":"Centro de Trastornos del Movimiento"},{"author_name":"David Aguillon","author_inst":"Universidad de Antioquia"},{"author_name":"Valentina Muller","author_inst":"Hospital General Jose de San Martin"},{"author_name":"Pedro Braga-Neto","author_inst":"Federal University of Ceara; State University of Ceara"},{"author_name":"Mayela Rodriguez-Violante","author_inst":"Instituto Nacional de Neurologia y Neurocirugia"},{"author_name":"Amin Cervantes-Arriaga","author_inst":"Instituto Nacional de Neurologia y Neurocirugia"},{"author_name":"Artur Schuh","author_inst":"Universidade Federal do Rio Grande do Sul; Hospital de Clinicas de Porto Alegre"},{"author_name":"Mario Cornejo-Olivas","author_inst":"Universidad Cientifica del Sur; Instituto Nacional de Ciencias Neurologicas"},{"author_name":"Koni Mejia Rojas","author_inst":"Instituto Nacional de Ciencias Neurologicas"},{"author_name":"Cintia Armas","author_inst":"EDMECON Medical Center; Daniel Alcides Carrion National Hospital"},{"author_name":"Angel Vinuela","author_inst":"Fundacion Parkinson Puerto Rico"},{"author_name":"Alan Osvaldo Espinal Martinez","author_inst":"Fundacion Parkinson Puerto Rico; Neurosciences Institute Manati Medical Center"},{"author_name":"Vitor Tumas","author_inst":"Ribeirao Preto Medical School - University of Sao Paulo"},{"author_name":"Vanderci Borges","author_inst":"Universidade Federal de Sao Paulo"},{"author_name":"Cesar Luis Avila","author_inst":"UNT-CONICET"},{"author_name":"Patricio Olguin","author_inst":"Universidad de Chile"},{"author_name":"Sarael Alcauter","author_inst":"Universidad Nacional Autonoma de Mexico"},{"author_name":"Marcelo Kauffman","author_inst":"Hospital JM Ramos Mejia"},{"author_name":"Dolores Gonzalez-Moron","author_inst":"Hospital JM Ramos Mejia"},{"author_name":"Susana Lissette Pena Martinez","author_inst":"Universidad Dr. Andres Bello (UNAB)"},{"author_name":"Ignacio F Mata","author_inst":"Cleveland Clinic Foundation"},{"author_name":"- Latin American Research consortium on the Genetics of Parkinson's Disease (LARGE-PD)","author_inst":"-"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"The United States CADASIL Consortium: Baseline Findings from a Natural History Study","rel_doi":"10.64898\/2026.09.20.26363512","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.20.26363512","rel_abs":"Background and Objectives: Vascular contributions to cognitive impairment and dementia (VCID) represent the second leading cause of dementia and a common comorbidity for reduced functional capacity in many individuals, but clinical management and clinical trial readiness are severely hindered by extreme phenotypic and mechanistic heterogeneity. This study establishes the baseline clinical, functional, and multimodal biomarker characteristics of the first United States (US) cohort of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), serving as a single-cause, monogenic small vessel disease model for sporadic VCID. Methods: Cross-sectional analysis of baseline data collected from October 2022 through January 2025 from a longitudinal cohort at 12 US enrollment sites. Adults from families with a documented NOTCH3 variant were recruited through clinical referrals, medical record review, advocacy organizations, and community outreach. Exclusion criteria included other conditions that prevented interpretation of findings and modified Rankin Scale (mRS) scores greater than 3. Central genetic characterization assigned persons with a pathogenic or likely pathogenic NOTCH3 variant to low-, medium-, or high-risk tiers based on epidermal growth factor-like repeat domains. Standardized assessments included clinical histories, exams, objective cognitive and physical assessments, self-reported, companion-reported, and clinician-rated measures, MRI, genetics, and proteomics acquired under harmonized protocols. Group comparisons used Fishers exact and Kruskal-Wallis tests. Multivariable regression used adjustment for age, sex, race, and education. Results: Of 560 participants completing baseline visits, 46 had variants of unknown significance, and 55 had pending genetic analyses. The analytic cohort included 343 persons with a CADASIL-causing NOTCH3 variant and 116 non-carrier family controls. Median age was 47.9 years (IQR 38.7-59.1), median education was 16 years (IQR 14-17), 62.5% were female, and 91.4% were White. Carriers were classified in CADASIL risk tiers: low (7.0%), medium (18.4%), or high (74.6%). Compared with controls, adjusted odds of classification into a more impaired CDR category were higher in all tiers (OR 2.55-5.08, 95% CI 1.22-11.34). Discussion: The US CADASIL Consortium has established a large, genetics-confirmed cohort spanning presymptomatic to moderate disease stages, providing a robust, harmonized platform to define early biomarker signatures and endpoints for targeted VCID therapies.","rel_num_authors":26,"rel_authors":[{"author_name":"Jane S. Paulsen","author_inst":"University of Wisconsin-Madison"},{"author_name":"H. Jeremy Bockholt","author_inst":"Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology, Emory Universit"},{"author_name":"William H. Adams","author_inst":"Loyola University Chicago"},{"author_name":"Deven K. Burks","author_inst":"University of Wisconsin-Madison"},{"author_name":"Jennifer J. Majersik","author_inst":"The University of Utah"},{"author_name":"Stephen P. Salloway","author_inst":"Butler Hospital"},{"author_name":"Songmi Lee","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Myriam Fornage","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Cara Joyce","author_inst":"Loyola University Chicago"},{"author_name":"Jamie L. Elliott","author_inst":"University of Wisconsin-Madison"},{"author_name":"Edward D. Huey","author_inst":"Butler Hospital"},{"author_name":"Megan R. Caruso","author_inst":"Butler Hospital"},{"author_name":"Suman Jayadev","author_inst":"University of Washington"},{"author_name":"Jose Biller","author_inst":"Loyola University Chicago"},{"author_name":"Helmi L. Lutsep","author_inst":"Oregon Health & Science University"},{"author_name":"Sara J. Doyle","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"David S. Liebeskind","author_inst":"University of Southern California"},{"author_name":"Kelsey Eklund","author_inst":"University of Colorado, Anschutz"},{"author_name":"Imama A. Naqvi","author_inst":"Columbia University"},{"author_name":"Arash Salardini","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Sudha Seshadri","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Jason D. Hinman","author_inst":"David Geffen School of Medicine, University of California, Los Angeles"},{"author_name":"Lisa C. Krishnamurthy","author_inst":"Emory University"},{"author_name":"Barbara L. Fischer","author_inst":"University of Wisconsin-Madison"},{"author_name":"Michael D. Geschwind","author_inst":"University of California, San Francisco"},{"author_name":"- The United States CADASIL Consortium","author_inst":""}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"The United States CADASIL Consortium: Baseline Findings from a Natural History Study","rel_doi":"10.64898\/2026.09.20.26363512","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.20.26363512","rel_abs":"Background and Objectives: Vascular contributions to cognitive impairment and dementia (VCID) represent the second leading cause of dementia and a common comorbidity for reduced functional capacity in many individuals, but clinical management and clinical trial readiness are severely hindered by extreme phenotypic and mechanistic heterogeneity. This study establishes the baseline clinical, functional, and multimodal biomarker characteristics of the first United States (US) cohort of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), serving as a single-cause, monogenic small vessel disease model for sporadic VCID. Methods: Cross-sectional analysis of baseline data collected from October 2022 through January 2025 from a longitudinal cohort at 12 US enrollment sites. Adults from families with a documented NOTCH3 variant were recruited through clinical referrals, medical record review, advocacy organizations, and community outreach. Exclusion criteria included other conditions that prevented interpretation of findings and modified Rankin Scale (mRS) scores greater than 3. Central genetic characterization assigned persons with a pathogenic or likely pathogenic NOTCH3 variant to low-, medium-, or high-risk tiers based on epidermal growth factor-like repeat domains. Standardized assessments included clinical histories, exams, objective cognitive and physical assessments, self-reported, companion-reported, and clinician-rated measures, MRI, genetics, and proteomics acquired under harmonized protocols. Group comparisons used Fishers exact and Kruskal-Wallis tests. Multivariable regression used adjustment for age, sex, race, and education. Results: Of 560 participants completing baseline visits, 46 had variants of unknown significance, and 55 had pending genetic analyses. The analytic cohort included 343 persons with a CADASIL-causing NOTCH3 variant and 116 non-carrier family controls. Median age was 47.9 years (IQR 38.7-59.1), median education was 16 years (IQR 14-17), 62.5% were female, and 91.4% were White. Carriers were classified in CADASIL risk tiers: low (7.0%), medium (18.4%), or high (74.6%). Compared with controls, adjusted odds of classification into a more impaired CDR category were higher in all tiers (OR 2.55-5.08, 95% CI 1.22-11.34). Discussion: The US CADASIL Consortium has established a large, genetics-confirmed cohort spanning presymptomatic to moderate disease stages, providing a robust, harmonized platform to define early biomarker signatures and endpoints for targeted VCID therapies.","rel_num_authors":26,"rel_authors":[{"author_name":"Jane S. Paulsen","author_inst":"University of Wisconsin-Madison"},{"author_name":"H. Jeremy Bockholt","author_inst":"Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology, Emory Universit"},{"author_name":"William H. Adams","author_inst":"Loyola University Chicago"},{"author_name":"Deven K. Burks","author_inst":"University of Wisconsin-Madison"},{"author_name":"Jennifer J. Majersik","author_inst":"The University of Utah"},{"author_name":"Stephen P. Salloway","author_inst":"Butler Hospital"},{"author_name":"Songmi Lee","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Myriam Fornage","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Cara Joyce","author_inst":"Loyola University Chicago"},{"author_name":"Jamie L. Elliott","author_inst":"University of Wisconsin-Madison"},{"author_name":"Edward D. Huey","author_inst":"Butler Hospital"},{"author_name":"Megan R. Caruso","author_inst":"Butler Hospital"},{"author_name":"Suman Jayadev","author_inst":"University of Washington"},{"author_name":"Jose Biller","author_inst":"Loyola University Chicago"},{"author_name":"Helmi L. Lutsep","author_inst":"Oregon Health & Science University"},{"author_name":"Sara J. Doyle","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"David S. Liebeskind","author_inst":"University of Southern California"},{"author_name":"Kelsey Eklund","author_inst":"University of Colorado, Anschutz"},{"author_name":"Imama A. Naqvi","author_inst":"Columbia University"},{"author_name":"Arash Salardini","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Sudha Seshadri","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Jason D. Hinman","author_inst":"David Geffen School of Medicine, University of California, Los Angeles"},{"author_name":"Lisa C. Krishnamurthy","author_inst":"Emory University"},{"author_name":"Barbara L. Fischer","author_inst":"University of Wisconsin-Madison"},{"author_name":"Michael D. Geschwind","author_inst":"University of California, San Francisco"},{"author_name":"- The United States CADASIL Consortium","author_inst":""}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"The United States CADASIL Consortium: Baseline Findings from a Natural History Study","rel_doi":"10.64898\/2026.09.20.26363512","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.20.26363512","rel_abs":"Background and Objectives: Vascular contributions to cognitive impairment and dementia (VCID) represent the second leading cause of dementia and a common comorbidity for reduced functional capacity in many individuals, but clinical management and clinical trial readiness are severely hindered by extreme phenotypic and mechanistic heterogeneity. This study establishes the baseline clinical, functional, and multimodal biomarker characteristics of the first United States (US) cohort of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), serving as a single-cause, monogenic small vessel disease model for sporadic VCID. Methods: Cross-sectional analysis of baseline data collected from October 2022 through January 2025 from a longitudinal cohort at 12 US enrollment sites. Adults from families with a documented NOTCH3 variant were recruited through clinical referrals, medical record review, advocacy organizations, and community outreach. Exclusion criteria included other conditions that prevented interpretation of findings and modified Rankin Scale (mRS) scores greater than 3. Central genetic characterization assigned persons with a pathogenic or likely pathogenic NOTCH3 variant to low-, medium-, or high-risk tiers based on epidermal growth factor-like repeat domains. Standardized assessments included clinical histories, exams, objective cognitive and physical assessments, self-reported, companion-reported, and clinician-rated measures, MRI, genetics, and proteomics acquired under harmonized protocols. Group comparisons used Fishers exact and Kruskal-Wallis tests. Multivariable regression used adjustment for age, sex, race, and education. Results: Of 560 participants completing baseline visits, 46 had variants of unknown significance, and 55 had pending genetic analyses. The analytic cohort included 343 persons with a CADASIL-causing NOTCH3 variant and 116 non-carrier family controls. Median age was 47.9 years (IQR 38.7-59.1), median education was 16 years (IQR 14-17), 62.5% were female, and 91.4% were White. Carriers were classified in CADASIL risk tiers: low (7.0%), medium (18.4%), or high (74.6%). Compared with controls, adjusted odds of classification into a more impaired CDR category were higher in all tiers (OR 2.55-5.08, 95% CI 1.22-11.34). Discussion: The US CADASIL Consortium has established a large, genetics-confirmed cohort spanning presymptomatic to moderate disease stages, providing a robust, harmonized platform to define early biomarker signatures and endpoints for targeted VCID therapies.","rel_num_authors":26,"rel_authors":[{"author_name":"Jane S. Paulsen","author_inst":"University of Wisconsin-Madison"},{"author_name":"H. Jeremy Bockholt","author_inst":"Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology, Emory Universit"},{"author_name":"William H. Adams","author_inst":"Loyola University Chicago"},{"author_name":"Deven K. Burks","author_inst":"University of Wisconsin-Madison"},{"author_name":"Jennifer J. Majersik","author_inst":"The University of Utah"},{"author_name":"Stephen P. Salloway","author_inst":"Butler Hospital"},{"author_name":"Songmi Lee","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Myriam Fornage","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Cara Joyce","author_inst":"Loyola University Chicago"},{"author_name":"Jamie L. Elliott","author_inst":"University of Wisconsin-Madison"},{"author_name":"Edward D. Huey","author_inst":"Butler Hospital"},{"author_name":"Megan R. Caruso","author_inst":"Butler Hospital"},{"author_name":"Suman Jayadev","author_inst":"University of Washington"},{"author_name":"Jose Biller","author_inst":"Loyola University Chicago"},{"author_name":"Helmi L. Lutsep","author_inst":"Oregon Health & Science University"},{"author_name":"Sara J. Doyle","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"David S. Liebeskind","author_inst":"University of Southern California"},{"author_name":"Kelsey Eklund","author_inst":"University of Colorado, Anschutz"},{"author_name":"Imama A. Naqvi","author_inst":"Columbia University"},{"author_name":"Arash Salardini","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Sudha Seshadri","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Jason D. Hinman","author_inst":"David Geffen School of Medicine, University of California, Los Angeles"},{"author_name":"Lisa C. Krishnamurthy","author_inst":"Emory University"},{"author_name":"Barbara L. Fischer","author_inst":"University of Wisconsin-Madison"},{"author_name":"Michael D. Geschwind","author_inst":"University of California, San Francisco"},{"author_name":"- The United States CADASIL Consortium","author_inst":""}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"The United States CADASIL Consortium: Baseline Findings from a Natural History Study","rel_doi":"10.64898\/2026.09.20.26363512","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.20.26363512","rel_abs":"Background and Objectives: Vascular contributions to cognitive impairment and dementia (VCID) represent the second leading cause of dementia and a common comorbidity for reduced functional capacity in many individuals, but clinical management and clinical trial readiness are severely hindered by extreme phenotypic and mechanistic heterogeneity. This study establishes the baseline clinical, functional, and multimodal biomarker characteristics of the first United States (US) cohort of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), serving as a single-cause, monogenic small vessel disease model for sporadic VCID. Methods: Cross-sectional analysis of baseline data collected from October 2022 through January 2025 from a longitudinal cohort at 12 US enrollment sites. Adults from families with a documented NOTCH3 variant were recruited through clinical referrals, medical record review, advocacy organizations, and community outreach. Exclusion criteria included other conditions that prevented interpretation of findings and modified Rankin Scale (mRS) scores greater than 3. Central genetic characterization assigned persons with a pathogenic or likely pathogenic NOTCH3 variant to low-, medium-, or high-risk tiers based on epidermal growth factor-like repeat domains. Standardized assessments included clinical histories, exams, objective cognitive and physical assessments, self-reported, companion-reported, and clinician-rated measures, MRI, genetics, and proteomics acquired under harmonized protocols. Group comparisons used Fishers exact and Kruskal-Wallis tests. Multivariable regression used adjustment for age, sex, race, and education. Results: Of 560 participants completing baseline visits, 46 had variants of unknown significance, and 55 had pending genetic analyses. The analytic cohort included 343 persons with a CADASIL-causing NOTCH3 variant and 116 non-carrier family controls. Median age was 47.9 years (IQR 38.7-59.1), median education was 16 years (IQR 14-17), 62.5% were female, and 91.4% were White. Carriers were classified in CADASIL risk tiers: low (7.0%), medium (18.4%), or high (74.6%). Compared with controls, adjusted odds of classification into a more impaired CDR category were higher in all tiers (OR 2.55-5.08, 95% CI 1.22-11.34). Discussion: The US CADASIL Consortium has established a large, genetics-confirmed cohort spanning presymptomatic to moderate disease stages, providing a robust, harmonized platform to define early biomarker signatures and endpoints for targeted VCID therapies.","rel_num_authors":26,"rel_authors":[{"author_name":"Jane S. Paulsen","author_inst":"University of Wisconsin-Madison"},{"author_name":"H. Jeremy Bockholt","author_inst":"Tri-Institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology, Emory Universit"},{"author_name":"William H. Adams","author_inst":"Loyola University Chicago"},{"author_name":"Deven K. Burks","author_inst":"University of Wisconsin-Madison"},{"author_name":"Jennifer J. Majersik","author_inst":"The University of Utah"},{"author_name":"Stephen P. Salloway","author_inst":"Butler Hospital"},{"author_name":"Songmi Lee","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Myriam Fornage","author_inst":"University of Texas Health Science Center at Houston"},{"author_name":"Cara Joyce","author_inst":"Loyola University Chicago"},{"author_name":"Jamie L. Elliott","author_inst":"University of Wisconsin-Madison"},{"author_name":"Edward D. Huey","author_inst":"Butler Hospital"},{"author_name":"Megan R. Caruso","author_inst":"Butler Hospital"},{"author_name":"Suman Jayadev","author_inst":"University of Washington"},{"author_name":"Jose Biller","author_inst":"Loyola University Chicago"},{"author_name":"Helmi L. Lutsep","author_inst":"Oregon Health & Science University"},{"author_name":"Sara J. Doyle","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"David S. Liebeskind","author_inst":"University of Southern California"},{"author_name":"Kelsey Eklund","author_inst":"University of Colorado, Anschutz"},{"author_name":"Imama A. Naqvi","author_inst":"Columbia University"},{"author_name":"Arash Salardini","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Sudha Seshadri","author_inst":"University of Texas Health Science Center at San Antonio"},{"author_name":"Jason D. Hinman","author_inst":"David Geffen School of Medicine, University of California, Los Angeles"},{"author_name":"Lisa C. Krishnamurthy","author_inst":"Emory University"},{"author_name":"Barbara L. Fischer","author_inst":"University of Wisconsin-Madison"},{"author_name":"Michael D. Geschwind","author_inst":"University of California, San Francisco"},{"author_name":"- The United States CADASIL Consortium","author_inst":""}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Human-centred co-design of a dual-purpose heart failure dashboard","rel_doi":"10.64898\/2026.09.20.26363523","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.20.26363523","rel_abs":"Introduction: Heart failure care requires coordination across hospital and community settings, yet information is often fragmented across electronic medical records and clinical systems. Clinical dashboards can bring together and display information to support care delivery and service management; however, existing dashboards have generally focused on specific measures, interventions and monitoring pathways. This study aimed to co-design, iteratively develop and user-test an integrated heart failure dashboard that links patient-level clinical decision-making with service-level management. Methods: A human-centred design approach comprising needs identification, collaborative ideation, iterative prototype development and end-user testing was applied across two complementary operational and clinical dashboard streams. Thirty-six clinicians, health service managers, data and implementation scientists, and consumers from metropolitan and regional services participated. Results: For operational decision-making, participants prioritised real-time visibility of patients across heart failure services, patient trajectories, service-performance information, and identification of variation in guideline-directed care and outcomes. Clinical priorities included rapid synthesis of longitudinal information, optimisation of guideline-directed medical therapy, continuity across care settings, and clinical workload prioritisation. These requirements informed the dashboard prototypes. Many prioritised information elements were incompletely represented in structured data and distributed across disconnected systems and structured and unstructured clinical data sources. Conclusion: Human-centred co-design identified complementary patient- and service-level information needs and translated them into linked dashboard prototypes. The proposed dashboard brings together current clinical status and longitudinal heart failure care history at the patient-level alongside service-level patterns. Implementation is required to evaluate whether these linked views improve care processes and patient outcomes.","rel_num_authors":8,"rel_authors":[{"author_name":"Victoria K Blake","author_inst":"Centre for Big Data Research in Health, UNSW"},{"author_name":"Sarah Emily Craig","author_inst":"eHealth NSW"},{"author_name":"Liesl Carvalho","author_inst":"eHealth NSW"},{"author_name":"Michelle Thomson","author_inst":"eHealth NSW"},{"author_name":"Jennifer Yu","author_inst":"Prince of Wales Hospital"},{"author_name":"Louisa Jorm","author_inst":"Centre for Big Data Research in Health, UNSW"},{"author_name":"Nigel Lovell","author_inst":"University of New South Wales"},{"author_name":"Sze-Yuan Ooi","author_inst":"Prince of Wales Hospital"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Evaluation of an eHealth Assistive Device Provision Training Tool: A Quasi-Experimental Study","rel_doi":"10.64898\/2026.09.20.26363517","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.20.26363517","rel_abs":"Background: Approximately 2.5 billion people require assistive products (APs), yet access remains limited partly because of shortages of trained personnel. eHealth tools may help strengthen workforce capacity and translate evidence into practice. The World Health Organization's Training in Assistive Products (TAP) program is an open-access eHealth tool designed to strengthen AP provision. However, its impact on learner outcomes remains insufficiently evaluated. This study assessed the usability and acceptability of the TAP module and changes in self-efficacy in mobility aid provision. Methods: We conducted a quasi-experimental pre-post study with health science students who completed the WHO TAP \"Introduction to Assistive Products\" module. We assessed usability using the System Usability Scale, acceptability using the Technology Acceptance Model and Theoretical Framework of Acceptability, and self-efficacy using an adapted version of Bandura's Multidimensional Scales of Perceived Self-Efficacy. We analyzed data using descriptive statistics and paired-samples t-tests. Results: Of 53 participants, 33 completed both assessments. Usability exceeded established benchmarks (76.97 +\/- 9.66), indicating a positive user experience. Acceptability findings demonstrated favourable responses across domains, with high ratings for ease of use and intervention coherence, and comparatively lower burden scores. Mean self-efficacy increased across all competencies from 2.32 +\/- 0.58 before the module to 4.23 +\/- 0.36 afterward (p < 0.001), reflecting substantial gains in confidence in AP provision. Conclusion: The eHealth TAP module demonstrated above-average usability and favourable acceptability, while significantly improving self-efficacy in AP provision. These findings highlight the potential for eHealth training implementation to strengthen workforce capacity and bridge training gaps in global health.","rel_num_authors":3,"rel_authors":[{"author_name":"Rachel Sudhakar","author_inst":"University of Ottawa"},{"author_name":"Katrine Sauv\u00e9-Schenk","author_inst":"University of Ottawa"},{"author_name":"Jennifer O'Neil","author_inst":"University of Ottawa"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Evaluation of an eHealth Assistive Device Provision Training Tool: A Quasi-Experimental Study","rel_doi":"10.64898\/2026.09.20.26363517","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.20.26363517","rel_abs":"Background: Approximately 2.5 billion people require assistive products (APs), yet access remains limited partly because of shortages of trained personnel. eHealth tools may help strengthen workforce capacity and translate evidence into practice. The World Health Organization's Training in Assistive Products (TAP) program is an open-access eHealth tool designed to strengthen AP provision. However, its impact on learner outcomes remains insufficiently evaluated. This study assessed the usability and acceptability of the TAP module and changes in self-efficacy in mobility aid provision. Methods: We conducted a quasi-experimental pre-post study with health science students who completed the WHO TAP \"Introduction to Assistive Products\" module. We assessed usability using the System Usability Scale, acceptability using the Technology Acceptance Model and Theoretical Framework of Acceptability, and self-efficacy using an adapted version of Bandura's Multidimensional Scales of Perceived Self-Efficacy. We analyzed data using descriptive statistics and paired-samples t-tests. Results: Of 53 participants, 33 completed both assessments. Usability exceeded established benchmarks (76.97 +\/- 9.66), indicating a positive user experience. Acceptability findings demonstrated favourable responses across domains, with high ratings for ease of use and intervention coherence, and comparatively lower burden scores. Mean self-efficacy increased across all competencies from 2.32 +\/- 0.58 before the module to 4.23 +\/- 0.36 afterward (p < 0.001), reflecting substantial gains in confidence in AP provision. Conclusion: The eHealth TAP module demonstrated above-average usability and favourable acceptability, while significantly improving self-efficacy in AP provision. These findings highlight the potential for eHealth training implementation to strengthen workforce capacity and bridge training gaps in global health.","rel_num_authors":3,"rel_authors":[{"author_name":"Rachel Sudhakar","author_inst":"University of Ottawa"},{"author_name":"Katrine Sauv\u00e9-Schenk","author_inst":"University of Ottawa"},{"author_name":"Jennifer O'Neil","author_inst":"University of Ottawa"}],"rel_date":"2026-09-22","rel_site":"medrxiv"},{"rel_title":"Uncertainty-Guided Decision-Making in Bumble Bees","rel_doi":"10.64898\/2026.09.15.751944","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.15.751944","rel_abs":"The evolutionary origins of cognitive monitoring remain contested. Metacognition, the capacity to monitor one's own cognitive states, has long been linked to complex vertebrate brains, yet whether a miniature brain can evaluate the reliability of its internal representations is unknown. Here we demonstrate that bumble bees engage in uncertainty-guided decision-making. Bees dynamically adjusted opt-out choices according to perceptual difficulty, settling for a smaller guaranteed reward to avoid errors, and actively paid a reward cost to seek information under uncertainty. Without any retraining, bees transferred this 'opt-out-under-uncertainty' rule to novel tactile and working-memory tasks under an all-probe design. This strategy was stable across individuals and accurately captured by a confidence-based decision model. Our findings suggest that a brain of approximately one million neurons can support an abstract domain-general uncertainty-monitoring policy, indicating that the neural substrates for uncertainty-guided decision-making may be far more ancient and widely distributed than previously assumed.","rel_num_authors":7,"rel_authors":[{"author_name":"LIN YUAN","author_inst":"Peking University Shenzhen Hospital"},{"author_name":"Yingying He","author_inst":"Peking University Shenzhen Hospital"},{"author_name":"Qiao Ye","author_inst":"Clinical Medicine Laboratory, Air Force Medical Center"},{"author_name":"Lin Lin","author_inst":"Institute of Health Service and Transfusion Medicine"},{"author_name":"Runzhu Yuan","author_inst":"Southern University of Science and Technology"},{"author_name":"Qian Wang","author_inst":"The Third Affiliated Hospital & South China Hospital of Shenzhen University"},{"author_name":"Song Chen","author_inst":"Academy of Medical Sciences, Zhengzhou University"}],"rel_date":"2026-09-22","rel_site":"biorxiv"},{"rel_title":"Cryptic whole-genome duplication in bryozoans","rel_doi":"10.64898\/2026.09.16.752000","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.16.752000","rel_abs":"Whole-genome duplications (WGDs) have long been proposed as evolutionary facilitators of biological complexity and diversification. Ancient WGDs occurred deep in the evolutionary history of both plants and vertebrates, but appear to be rare in invertebrates. However, it is unclear whether this reflects genuine scarcity or inadequate detection methodologies, and current methods may be insufficient to detect very old WGDs where extensive gene loss has followed. Here, we used a combination of paralogous and orthologous synteny-based methods incorporating bilaterian ancestral linkage groups (ALGs) to search for genomic signatures of WGD in members of the invertebrate phylum Bryozoa. This revealed strong evidence for an ancient WGD in the freshwater bryozoan Cristatella mucedo, Class Phylactolaemata, with duplicated paralogous regions across every chromosome. Only ~10% of duplicated genes are retained, including a Hox cluster duplication. All eight genomes from the bryozoan class Gymnolaemata also show signatures of ancient WGD in the form of 2:1 ratios in orthologous synteny comparisons, which remain detectable despite only ~5% duplicate retention. Gene trees support a scenario in which all extant bryozoans share an ancient WGD and much of the genome rediploidised independently in the two clades. Duplicates retained after bryozoan WGD are enriched in cilia genes and are preferentially expressed in the lophophore, the tentacular feeding organ covered in highly specialised cilia. We argue that cryptic WGD in bryozoan evolution facilitated adaptation to a sessile, filter-feeding lifestyle, and propose that incorporation of ALGs adds to the power of synteny-based WGD-detection methods.","rel_num_authors":5,"rel_authors":[{"author_name":"Thomas D. Lewin","author_inst":"School of Biological and Behavioural Sciences, Queen Mary University of London, London, UK"},{"author_name":"Dearbhaile Casey","author_inst":"Department of Biology, University of Oxford, Oxford, UK"},{"author_name":"Yi-Jyun Luo","author_inst":"Biodiversity Research Center, Academia Sinica, Taipei, Taiwan"},{"author_name":"Anthony K. Redmond","author_inst":"School of Medicine, University College Dublin, Dublin, Ireland"},{"author_name":"Peter W. H. Holland","author_inst":"Department of Biology, University of Oxford, Oxford, UK"}],"rel_date":"2026-09-22","rel_site":"biorxiv"},{"rel_title":"Clade B serpins promote direct basal-to-goblet cell differentiation in airways of patients with chronic obstructive pulmonary disease","rel_doi":"10.64898\/2026.09.21.753278","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.753278","rel_abs":"Goblet cell hyperplasia (GCH) is a hallmark of chronic obstructive pulmonary disease (COPD) and contributes to morbidity and mortality. We investigated the cellular and molecular origins of GCH in COPD using single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and in vitro models. We identified \"basal-to-goblet transitional cells\" (BGTC) which are transcriptionally and physically located between basal and goblet cells and are characterized by expression of clade B serpins. In vitro studies indicate that inflammatory cytokines, including IL-1{beta}, stimulate basal-to-goblet differentiation through a SERPINB3\/4+ intermediate and SERPINB3 overexpression induces differentiation of airway basal cells into IL1B-producing inflammatory goblet cells. In addition, we identified a subset of SERPINB4+ \"goblet-variant basal cells\" from lungs of COPD patients that express goblet cell and inflammatory genes ex vivo. Together, these results indicate clade B serpins contribute to altered epithelial differentiation and inflammatory signaling in COPD and support therapeutic targeting of clade B serpins to reduce GCH.","rel_num_authors":8,"rel_authors":[{"author_name":"Tiffany S Tufenkjian","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Jessica B Blackburn","author_inst":"Vanderbilt University Medical Center"},{"author_name":"David Nichols","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Alfredo Vasquez","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Ciara Shaver","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Lorraine Ware","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Timothy S Blackwell","author_inst":"University of Michigan Medical School"},{"author_name":"Bradley W Richmond","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-09-22","rel_site":"biorxiv"},{"rel_title":"The Rap1 GTPase performs two separable functions during cellularization to enable ventral furrow formation","rel_doi":"10.64898\/2026.09.21.753314","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.753314","rel_abs":"Morphogenetic processes involve dynamic cell-level events, such as contractility, shape changes, and adhesion between cells and extracellular structures. These cell-level changes require intercellular coordination in order to generate the appropriate tissue-level output. Although the repertoire of these cell-level changes is limited, these processes are reused serially during development to generate diverse tissue-level transformations. Dissecting any one of them benefits from perturbations controlled with high spatiotemporal resolution. Despite extensive analysis of ventral furrow formation, a model gastrulation event in the early Drosophila embryo, it remains unclear how tissue-level events are orchestrated at the molecular level. We therefore developed a biosensor and optogenetic tools for spatiotemporal modulation of Rap1, a small GTPase known to be required for ventral furrow formation. Using the biosensor, we show that Rap1 activity declines in ventral cells as the furrow forms. Optogenetic dissection of Rap1 activity reveals that acute inhibition during furrowing has little effect. Instead, Rap1 contributes to furrowing through two separable functions during the preceding process, cellularization: it is continuously required for efficient membrane ingression, and transiently required to nucleate the adherens junctions that later coordinate contractility across the ventral epithelium.","rel_num_authors":2,"rel_authors":[{"author_name":"Amruta P Nayak","author_inst":"The University of Chicago"},{"author_name":"Michael Glotzer","author_inst":"The University of Chicago"}],"rel_date":"2026-09-22","rel_site":"biorxiv"},{"rel_title":"Evaluations of retrospective frequency and phase correction methods for single-voxel MR spectroscopy at 7T","rel_doi":"10.64898\/2026.09.21.753210","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.753210","rel_abs":"Subject motion and gradient heating-induced frequency and phase offsets result in spectral misalignment during single-voxel MR spectroscopy (SVS) acquisitions. Several methods have been presented to align the spectra, but their performance on a 7T system is unclear. This study aimed to evaluate the practical importance of four retrospective correction methods, namely creatine fitting, residual water, spectral registration, and cross-correlation. SVS data were collected from 127 participants (88\/39 female\/male, 39{+\/-}15 years) using a semi-localization by adiabatic selective refocusing sequence at 7T. Changes in the spectral linewidth, signal-to-noise ratio (SNR), similarity (mean similarity matrix (SImean)), and metabolite quantification (concentration, relative Cramer-Rao lower bounds (rCRLB)) after correction were evaluated. A Wilcoxon signed rank test was used to evaluate these changes. The p-values were adjusted using the false discovery rate (q<0.05) for multiple comparisons. For significant changes, the effect size was further calculated using the Rosenthal formula. The results demonstrated that all correction methods resulted in a significant decrease in the spectral linewidth and significant increases in the spectral SNR and SImean. The mean changes by using the four methods were 0.76-0.99 Hz for the spectral linewidth change (effect sizes:0.73-0.86), 5.79-6.95 for the SNR change (effect size:0.60-0.72), and 0.03-0.03 for the SImean change (effect size:0.87-0.87). The correction also significantly increased the estimates of the metabolite concentrations of PCr, Gln, Glu, GPC, Ins, NAA, Scyllo, and Tau (effect size:0.25-0.57), and significantly decreased the rCRLBs (effect size:0.26-0.42) of Scyllo, Tau, and Gly. These results indicate that each method provides practical benefits in improving the spectral linewidth, SNR, and similarity by showing a strong to very strong effect of the improvements (effect size>0.60). The correction only showed a weak to moderate effect of the changes in the metabolite quantification (effect size<0.60), suggesting that whether the correction results in more reliable metabolite quantification requires further validation.","rel_num_authors":5,"rel_authors":[{"author_name":"Chu-Yu Lee","author_inst":"University of Iowa"},{"author_name":"Jia Xu","author_inst":"University of Iowa"},{"author_name":"Baolian Yang","author_inst":"GE Healthcare"},{"author_name":"Ralph Noeske","author_inst":"GE Healthcare"},{"author_name":"Vincent Magnotta","author_inst":"University of Iowa"}],"rel_date":"2026-09-22","rel_site":"biorxiv"},{"rel_title":"A phytocannabinoid-sensitive phosphorylation switch converts endocannabinoids into alternative lipid GPCR activators","rel_doi":"10.64898\/2026.09.21.753239","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.753239","rel_abs":"Abstract: Endocannabinoids (eCBs) like anandamide and 2-arachidonoylglycerol are endogenous lipid ligands for CB1 and CB2 G protein-coupled receptors (GPCRs). Here, we show that phosphorylation of biologically important anandamide generates naturally occurring anandamide phosphate (AEAp), which switches GPCR ligand specificity to lysophosphatidic acid (LPA) receptors (LPARs) and the primate-specific bile acid sensory receptor MRGPRX4. The kinase responsible for anandamide phosphorylation was identified asdiacylglycerol kinase (DGK) theta (DGKq or DGKQ) using activity-guided brain fractionation, inhibitor profiling, recombinant reconstitution, and DGK isozyme screening. DGKQ showed noncanonical biphasic lipid kinetics and was inhibited by phytocannabinoids, most notably tetrahydrocannabinolic acid. Thus, eCBs are not only cannabinoid receptor ligands but also enzymatically adaptable lipid signals activating LPARs and MRGPRX4, thus linking metabolism of the distinct lipid LPA with Cannabis pharmacology.","rel_num_authors":9,"rel_authors":[{"author_name":"Anna C Love","author_inst":"UC San Diego"},{"author_name":"Yasuyuki Kihara","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Hirotaka Mizuno","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Kazufumi Nagai","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"David Coronel","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Douglas J Sheffler","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Valerie Tan","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Bradley Moore","author_inst":"UC San Diego"},{"author_name":"Jerold Chun","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"}],"rel_date":"2026-09-22","rel_site":"biorxiv"},{"rel_title":"Adult corals enhance juvenile recruitment through cumulative ecological niche construction","rel_doi":"10.64898\/2026.09.21.753173","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.753173","rel_abs":"Ecosystem engineers are ecological niche constructors: by modifying local environments, they alter the conditions under which organisms establish, persist and interact. Although niche construction is often framed as a population-level evolutionary feedback, it could also operate at the assemblage level when communities collectively shape their environments and filter future recruitment. Reef-building corals provide a perfect system to test this idea because adult colonies form three-dimensional carbonate structures that can persist after colony death, creating an inherited habitat for subsequent coral generations. Here, we tested whether coral recruitment to the juvenile stage was associated with local adult coral abundance, reef structure, and larval settlement supply. Combining spatially explicit coral censuses, photogrammetric reef digital elevation models and data from settlement tiles across 15 reef sites at two time points at Jiigurru, Great Barrier Reef, we found that juvenile abundance increased additively on the log scale with adult abundance and with fractal dimension, a metric of fine-scale structural complexity. Surface rugosity had weaker effects, and interactions between adult abundance and habitat structure were limited, indicating largely additive, rather than synergistic or antagonistic, effects. Our results show that both adult assemblages and the concurrent structural complexity, consistent with assemblage-level niche construction and ecological inheritance theory, shape coral recruitment.","rel_num_authors":18,"rel_authors":[{"author_name":"Viviana Brambilla","author_inst":"MARE, Faculdade de Ciencias da Universidade de Lisboa, Lisboa, Portugal"},{"author_name":"Mollie Asbury","author_inst":"National Geographic Society"},{"author_name":"Andrew Baird","author_inst":"James Cook University, Townsville, Australia"},{"author_name":"Matthew-James Bennett","author_inst":"MARE, Faculdade de Ciencias da Universidade de Lisboa, Lisboa, Portugal"},{"author_name":"Nader Boutros","author_inst":"Australian Institute of Marine Science, Perth, Australia"},{"author_name":"James Cant","author_inst":"MARE, Faculdade de Ciencias da Universidade de Lisboa, Lisboa, Portugal"},{"author_name":"Cher Chow","author_inst":"Lancaster Environment Centre, Lancaster University, Lancaster, UK"},{"author_name":"Garrett Fundakowski","author_inst":"Centre for Biological Diversity, University of St Andrews, St Andrews, UK"},{"author_name":"Wilhelm Marais","author_inst":"Nortek Group, Oslo, Norway"},{"author_name":"Oscar Pizarro","author_inst":"Norwegian University of Science and Technology, Trondheim, Norway"},{"author_name":"Damaris Torres-Pulliza","author_inst":"Cooperative Institute for Marine and Atmospheric Research, University of Hawaii at Manoa, Honolulu, HI, USA"},{"author_name":"Nina Schiettekatte","author_inst":"MARE, Faculdade de Ciencias da Universidade de Lisboa, Lisboa, Portugal"},{"author_name":"Rachael Woods","author_inst":"NSW Department of Climate Change, Energy, the Environment and Water, Sydney, Australia"},{"author_name":"Stefan Williams","author_inst":"Australian Centre for Field Robotics, University of Sydney, Sydney, Australia"},{"author_name":"Devynn Wulstein","author_inst":"Hawaiian Institute of Marine Biology, Kaneohe, HI, USA"},{"author_name":"Kyle Zawada","author_inst":"Macquarie University, Sydney, Australia"},{"author_name":"Joshua S Madin","author_inst":"Hawaiian Institute of Marine Biology, Kaneohe, HI, USA"},{"author_name":"Maria Dornelas","author_inst":"MARE, Faculdade de Ciencias da Universidade de Lisboa, Lisboa, Portugal"}],"rel_date":"2026-09-22","rel_site":"biorxiv"},{"rel_title":"FFPE-CUTAC: A Single Assay, Multiple Layers","rel_doi":"10.64898\/2026.09.21.753320","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.753320","rel_abs":"Background: Archival biobanks of formalin-fixed paraffin-embedded (FFPE) specimens represent a vast and underused resource for retrospective molecular studies linked to clinical follow-up. However, fixation-induced chemical modification and nucleic acid fragmentation limit scalable genomic and transcriptomic profiling. FFPE-CUTAC (Cleavage Under Targeted Accessible Chromatin) is an RNA polymerase II-targeted DNA assay specifically designed to profile regulatory activity in FFPE tissue. Here, we assess its archival robustness, information content, compatibility with RNA-seq, and ability to recover copy-number alterations. Results: In meningioma and breast cancer cohorts, we benchmarked FFPE-CUTAC against matched fresh-frozen RNA-seq, FFPE RNA-seq and FFPE whole-genome sequencing. For FFPE specimens spanning up to 25 years, FFPE-CUTAC showed no systematic collection-year-associated decline in library yield or signal-quality metrics. In contrast, FFPE RNA-seq is more affected by the FFPE tissue degradation and specimen age on read composition, gene-body coverage, and gene detection. By measuring RNA polymerase II occupancy on chromatin rather than mature RNA abundance, FFPE-CUTAC is less constrained by transcript half-life, polyadenylation or transcript-capture design. FFPE-CUTAC extends beyond gene regions to non-coding regulatory elements, while the shared gene-level signals supported its integration with existing RNA-seq cohorts for large-scale, long-term clinical association study. FFPE-CUTAC libraries also retain DNA dosage information and can be used to recover chromosome-arm gain, loss and intact states with 96% concordance to matched whole-genome sequencing. Conclusions: By converting routinely preserved pathology sections into integrated regulatory and copy-number profiles, FFPE-CUTAC provides a practical foundation for constructing clinically annotated disease maps to support molecular stratification, prognostic modeling and treatment-association studies.","rel_num_authors":12,"rel_authors":[{"author_name":"Yiyang Niu","author_inst":"The University of Texas MD Anderson Cancer Center"},{"author_name":"Qunzhi Xu","author_inst":"The University of Texas MD Anderson Cancer Center"},{"author_name":"Chun Yin Mak","author_inst":"The University of Texas MD Anderson Cancer Center"},{"author_name":"Yiling Xu","author_inst":"University of Washington"},{"author_name":"Aditya Parmar","author_inst":"The University of Texas MD Anderson Cancer Center"},{"author_name":"Alex Zevin","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Nadiya Khyzha","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Ronald Paranal","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Eric Holland","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Kami Ahmad","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Steven Henikoff","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Ye Zheng","author_inst":"The University of Texas MD Anderson Cancer Center"}],"rel_date":"2026-09-22","rel_site":"biorxiv"},{"rel_title":"Catalytically inactive PARP1 protein drives PARP inhibitor induced hematological toxicity","rel_doi":"10.64898\/2026.09.21.753312","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.753312","rel_abs":"Dual PARP1\/2 inhibitors (PARPi) selectively eliminate BRCA1\/2-deficient cancers and represent the first targeted therapy for homologous recombination (HR)-deficient cancers. However, their use in maintenance therapy is limited by severe anemia and an increased risk for therapy-related leukemia. These toxicities are unexpected because PARP1 loss, which eliminates most DNA-damage-induced PARylation, does not cause anemia in mice. In contrast, PARP2 loss or catalytic inactivation causes anemia, motivating the development of PARP1-selective inhibitors. Using wild-type (WT), Parp1-\/- and Parp2-\/- mice, we show that hematopoietic toxicity of FDA-approved PARPi is driven primarily by inactive PARP1 rather than PARP2 inhibition. Accordingly, PARP1-selective inhibitors also cause PARP1-dependent anemia. Somatic expression of catalytically inactive Parp1 (Parp1E988A) causes lethal bone marrow failure, not found with somatic deletion of both Parp1&2. Mechanistically, inactive PARP1 obstructs the repair of diverse DNA lesions, including gaps, nicks, and Top1-cc, in contrast to the nick-selectivity of Parp2. In cells, inactive PARP1 compromises PARP2 recruitment to DNA lesions and causes severe genomic instability and mitotic bridges absent in Parp1&2-null cells. Thus, PARPi-induced hematopoietic toxicity is driven primarily by PARP1 inactivation, informing the design and use of next-generation PARP inhibitors.","rel_num_authors":12,"rel_authors":[{"author_name":"Xiaohui Lin","author_inst":"Columbia University"},{"author_name":"Zhengping Shao","author_inst":"Columbia University"},{"author_name":"Denitsa Yaneva","author_inst":"Ludwig-Maximilians-Universitat Munchen"},{"author_name":"Wenxia Jiang","author_inst":"Columbia University"},{"author_name":"Demis Menolfi","author_inst":"Columbia University"},{"author_name":"Seema Khattri Bhandari","author_inst":"University of New Mexico"},{"author_name":"Brian J Lee","author_inst":"Columbia University"},{"author_name":"Mirjam Schmucker","author_inst":"Ludwig-Maximilians-Universitat Munchen"},{"author_name":"Faye Yaneva","author_inst":"Columbia University"},{"author_name":"Alan E Tomkinson","author_inst":"University of New Mexico"},{"author_name":"Julian Stingele","author_inst":"Ludwig-Maximilians-Universitat Munchen"},{"author_name":"Shan Zha","author_inst":"Columbia University"}],"rel_date":"2026-09-22","rel_site":"biorxiv"},{"rel_title":"Parental B-MYB\/FOXM1 controls mitotic E2F to determine daughter cell fate","rel_doi":"10.64898\/2026.09.21.753170","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.753170","rel_abs":"Mitogens trigger cell-cycle entry by activating E2F at the restriction point, which is followed by B-MYB\/FOXM1 activation and progression to mitosis. How mitogens control continued cycling and cell-cycle exit after the restriction point is not well-understood. By developing an E2F and B-MYB\/FOXM1 dual transcriptional biosensor system, we show that S\/G2 phase duration is set by timed mitogen-regulated B-MYB\/FOXM1 activation, while E2F activity gradually declines before mitosis. As a striking consequence, rapid B-MYB\/FOXM1 activation shortens S\/G2, delivering high mitotic E2F activity to daughter cells which keeps them cycling. Delayed B-MYB\/FOXM1 activation prolongs S\/G2, depleting mitotic E2F which drives daughters to quiescence. When S\/G2 is further prolonged, partially activated B-MYB\/FOXM1 frequently reverts, triggering mitotic bypass and polyploid quiescence. Thus, B-MYB\/FOXM1 governs a tri-directional (G2 restriction point) where cells commit to continued cycling through early B-MYB\/FOXM1 activation; cell-cycle exit through delayed B-MYB\/FOXM1 activation; or mitotic bypass by B-MYB\/FOXM1 inactivation.","rel_num_authors":11,"rel_authors":[{"author_name":"Tobias MEYER","author_inst":"Weill Cornell Medicine"},{"author_name":"David Rosenthal","author_inst":"Weill Cornell Medicine"},{"author_name":"Tatsuki Tsuruoka","author_inst":"Weill Cornell Medicine"},{"author_name":"Vinodhini Govindaraj","author_inst":"Weill Cornell Medicine"},{"author_name":"Yumi Konagaya","author_inst":"Weill Cornell Medicine"},{"author_name":"Bo Gong","author_inst":"Weill Cornell Medicine"},{"author_name":"Samsara Upadhya","author_inst":"Weill Cornell Medicine"},{"author_name":"Nalin Ratnayeke","author_inst":"Weill Cornell Medicine"},{"author_name":"Debarya Saha","author_inst":"Weill Cornell Medicine"},{"author_name":"Wenxin Xia","author_inst":"Weill Cornell Medicine"},{"author_name":"Mary Teruel","author_inst":"Weill Cornell Medicine"}],"rel_date":"2026-09-22","rel_site":"biorxiv"},{"rel_title":"Phased Chromosome-level Genome and Organellar Assemblies of Castilleja foliolosa Provide Vital Resource for Orobanchaceae Genomics","rel_doi":"10.64898\/2026.09.21.753328","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.753328","rel_abs":"Castilleja (Orobanchaceae) is a diverse, facultatively hemiparasitic plant genus characterized by a complex evolutionary history of reticulate evolution and significant taxonomic ambiguity. High-quality genomic resources have historically been limited, hindering robust macro-evolutionary and macro-ecological inquiries. Here, we present the first high-quality, phased, chromosome-level reference genome for the diploid species Castilleja foliolosa. Utilizing a hybrid assembly strategy, we integrated long-read PacBio HiFi sequencing with Omni-C proximity ligation data to generate a highly contiguous nuclear assembly, complemented by reconstructed mitochondrial and chloroplastic genomes. The primary nuclear haplotype spans approximately 510 Mbp, containing 39,417 predicted genes and a substantial repetitive landscape covering ~66% of the genome. Our organellar assemblies reveal notable structural complexity: the chloroplast maintains heteroplasmy via two primary structural haplotypes, while the 611 kbp mitogenome adopts a circular master topology existing in two isomeric forms. Comparative genomic analyses demonstrate a largely conserved chromosomal architecture relative to the closely related Pedicularis cranolopha, punctuated by the presence of lineage-specific genes. Functional enrichment of Castilleja-specific orthogroups identifies a consistent association with telomere maintenance, DNA integration, and zinc ion binding, likely stemming from the substantial repeat content. This reference genome provides a robust framework for dissecting the genomic drivers of taxonomic diversification and adaptation within the Orobanchaceae family. This resource significantly enhances our capacity to untangle reticulate evolutionary patterns, offering a definitive foundation for future comparative studies of genome evolution in the Orobanchaceae lineage of parasitic plants.","rel_num_authors":5,"rel_authors":[{"author_name":"Ren N Hamm","author_inst":"California Academy of Sciences"},{"author_name":"Jason Leung","author_inst":"Columbia University, New York, USA"},{"author_name":"Magdalene S Lo","author_inst":"Department of Botany, California Academy of Sciences, San Francisco, USA"},{"author_name":"Adriana I Hernandez","author_inst":"Jasper Ridge Biological Preserve, Stanford University, Stanford, California, USA"},{"author_name":"Sarah J Jacobs","author_inst":"Department of Botany, California Academy of Sciences, San Francisco, USA"}],"rel_date":"2026-09-22","rel_site":"biorxiv"},{"rel_title":"Distribution of target-site resistance mechanisms to nicosulfuron and glyphosate in Amaranthus palmeri accessions from two different regions of Turkiye","rel_doi":"10.64898\/2026.09.21.753262","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.753262","rel_abs":"Palmer amaranth (Amaranthus palmeri S. Watson) is a highly competitive weed that has evolved resistance to several modes of action and has recently become a significant problem in Turkiye. This study was designed to determine the distribution of common target-site resistance (TSR) mechanisms to the acetolactate synthase (ALS)-inhibiting herbicide, nicosulfuron, and the 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS)-inhibiting herbicide, glyphosate, in A. palmeri accessions collected from two agricultural regions of Turkiye; the Cukurova Region and the Gediz Basin. A total of 96 accessions were analyzed for ALS gene mutations and relative EPSPS gene copy number variation. Whole-plant responses were also evaluated based on relative dry weight following treatment with nicosulfuron and glyphosate applied at twice the field rate. The ALS mutations Pro197Ser, Trp574Leu, and Ser653Asn were far more prevalent in plants from the Cukurova Region than those from the Gediz Basin. Elevated relative EPSPS gene copy numbers were more common and higher in the Gediz Basin. Single rate herbicide screening experiments confirmed that accessions from the Cukurova Region exhibited higher dry weight response to nicosulfuron, whereas those from the Gediz Basin had higher to glyphosate Multivariable regression analyses revealed that nicosulfuron response was primarily associated with the Pro197Ser and Trp574Leu mutations, while glyphosate response was correlated with EPSPS gene copy number. These findings reveal distinct regional patterns of TSR mechanisms in A. palmeri in Turkiye that are consistent with differences in herbicide use and\/or introduction history, but the roles of local selection, demographic processes, and gene flow remain unclear.","rel_num_authors":4,"rel_authors":[{"author_name":"filiz erbas","author_inst":"Aydin Adnan Menderes University"},{"author_name":"Sara Alvarez Rodriguez","author_inst":"Michigan State University"},{"author_name":"Michael Ozolins","author_inst":"Michigan State University"},{"author_name":"Eric Patterson","author_inst":"Michigan State University"}],"rel_date":"2026-09-22","rel_site":"biorxiv"},{"rel_title":"baltic: the Backronymed Adaptable Lightweight Tree vIsualisation Code","rel_doi":"10.64898\/2026.09.20.752947","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.20.752947","rel_abs":"For ten years, baltic (Backronymed Adaptable Lightweight Tree vIsualization Code) has been used to make annotated phylogeny figures in molecular epidemiology, including during the West African Ebola epidemic, the Zika epidemic in the Americas, and the SARS-CoV-2 pandemic, as well as other fields. At its core, baltic is a Python library used for the efficient parsing, traversal, manipulation, and visualisation of phylogenetic trees. It is a small library with few dependencies that reads tree formats common in phylodynamic analyses and gives the user leverage to interact with a lightweight tree data structure to produce publication-ready figures with matplotlib. We present baltic v1.0, its first formally released and documented version. baltic reads and writes BEAST Nexus, Newick, and Nextstrain\/Auspice JSON, and can process large BEAST posterior tree files in parallel to extract user-defined posterior statistics. The same objects are used for tree manipulation and for plotting in a single script. New to this release: a set of rooting methods (midpoint rooting, rerooting on any branch, and root-to-tip regression); support for reticulate evolution, with reassortment and recombination edges; and composite figures that combine a tree with other data, such as Muller plots, skygrid plots, tanglegrams, and plots connecting trees to maps. The release includes a documentation site with an API reference, tutorials, and a matplotlib-style gallery of worked examples.","rel_num_authors":5,"rel_authors":[{"author_name":"Barney I Potter","author_inst":"Yale School of Public Health, Yale University, New Haven, Connecticut, USA"},{"author_name":"Karthik Gangavarapu","author_inst":"Department of Translational Medicine, Scripps Research Institute, San Diego, California, USA"},{"author_name":"Maria Fernanda Torres Jimenez","author_inst":"Department of Zoology, Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania"},{"author_name":"Sidney M Bell","author_inst":"Chan Zuckerberg Initiative, Redwood City, California, USA"},{"author_name":"Gytis Dudas","author_inst":"Department of Eukaryote Gene Engineering, Institute of Biotechnology, Life Sciences Center, Vilnius University"}],"rel_date":"2026-09-22","rel_site":"biorxiv"},{"rel_title":"Dual recognition of negative charge by pleckstrin homology (PH) domains","rel_doi":"10.64898\/2026.09.21.753330","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.753330","rel_abs":"Pleckstrin homology (PH) domains are typically assumed to be phosphoinositide-binding modules, although most lack strong lipid specificity and their broader ligand repertoire remains poorly defined. We find that many yeast PH domains bind Nsr1p, the ortholog of nucleolin, also identified as a PH domain ligand, suggesting widespread recognition of negatively charged protein regions. The phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2)-binding PLC{delta}1 PH domain also binds a highly phosphorylated region of IRBIT through the same site that recognizes PtdIns(4,5)P2. Using high-throughput integrated phosphopeptide (Hi-P) screening, we surveyed 38,624 mammalian sequences containing three documented phosphoserines. PLC{delta}1-PH bound numerous phosphorylated and unphosphorylated acidic peptides, and phosphorylation generally strengthened pre-existing interactions rather than conferring strict specificity, without requiring a fixed phosphoserine spacing. Instead, favored phosphopeptides combined a key phosphoserine with upstream acidic residues. Structural modeling suggests that this phosphoserine occupies the canonical inositol phosphate binding pocket, while adjacent acidic residues make delocalized electrostatic contacts. Thus, PH domains can recognize various patterns of protein negative charge, expanding their potential regulatory roles beyond membrane targeting.","rel_num_authors":7,"rel_authors":[{"author_name":"Christopher K Ng","author_inst":"Yale University School of Medicine"},{"author_name":"James W Murphy","author_inst":"Yale University School of Medicine"},{"author_name":"Jeannine M Mendrola","author_inst":"University of Pennsylvania Perelman School of Medicine"},{"author_name":"Michael Sarullo","author_inst":"Yale University"},{"author_name":"Steven E Stayrook","author_inst":"Yale University School of Medicine"},{"author_name":"Kathryn M Ferguson","author_inst":"Yale University School of Medicine"},{"author_name":"Mark A Lemmon","author_inst":"Yale University School of Medicine"}],"rel_date":"2026-09-22","rel_site":"biorxiv"},{"rel_title":"Deconvolution of the mechanisms of T cell drug response in multiple myeloma induction therapy","rel_doi":"10.64898\/2026.09.15.751861","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.15.751861","rel_abs":"Lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone, are used alone or in combination (RVd therapy) as first-line therapies for hematologic malignancies including the plasma cell dyscrasia, Multiple Myeloma (MM). The effects of RVd treatment on tumor cells have been documented, but little is known about their impacts on \"healthy\" immune cells. New therapeutics, including chimeric antigen receptor T cell (CAR-T) and bispecific T-cell engagers (BiTEs) depend on robust T cell function but these are often harvested for cellular therapies after or in tandem with RVd therapy. Understanding the molecular effects of these drugs on healthy T cells is therefore of particular importance. Since the molecular effects of each drug includes regulation of key transcription factors, we used a tri-modal, single-cell assay (TEA-seq), simultaneously profiling mRNA transcripts, cell surface proteins, and chromatin accessibility in primary human peripheral blood T cells treated for 4, 24, or 72 hours in vitro. Synergies and conflicts potentially arising from combinatorial therapy were identified and validated by flow cytometry. Doublet and triplet drug combinations were used to assess effects on cell-surface marker expression and on T cell activation. Our results suggest that T cell function can be optimized by the administration of these drugs individually and that sequential administration may offer an opportunity to enhance T cell function by affecting localization and altering T cell states. This work provides those interested in immunology, oncology, and cell therapies an opportunity to explore molecular pathways that could be manipulated by these commonly used drugs to modify T cell function.","rel_num_authors":22,"rel_authors":[{"author_name":"Lucas T. Graybuck","author_inst":"Allen Institute"},{"author_name":"Lauren Y. Okada","author_inst":"Allen Institute"},{"author_name":"Wei-Ling Chang","author_inst":"Allen Institute"},{"author_name":"Jessica Garber","author_inst":"Allen Institute"},{"author_name":"Catalina Sakai","author_inst":"Allen Institute"},{"author_name":"Morgan D.A. Weiss","author_inst":"Allen Institute"},{"author_name":"Samir Rachid Zaim","author_inst":"Allen Institute"},{"author_name":"Veronica Hernandez","author_inst":"Allen Institute"},{"author_name":"Ziyuan He","author_inst":"Allen Institute"},{"author_name":"Upaasana Krishnan","author_inst":"Allen Institute"},{"author_name":"Padmapriyadarshini Ravisankar","author_inst":"Allen Institute"},{"author_name":"Julian Reading","author_inst":"Allen Institute"},{"author_name":"Ernest M. Coffey","author_inst":"Allen Institute"},{"author_name":"Thomas F. Bumol","author_inst":"Allen Institute"},{"author_name":"Jimena Meladze","author_inst":"Allen Institute"},{"author_name":"Mackenzie S. Kopp","author_inst":"Allen Institute"},{"author_name":"Sandra B. Munro","author_inst":"Allen Institute"},{"author_name":"Gregory L. Szeto","author_inst":"Pfizer Oncology"},{"author_name":"Evan W. Newell","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Xiao-jun Li","author_inst":"Allen Institute"},{"author_name":"Peter J. Skene","author_inst":"Allen Institute"},{"author_name":"Troy R. Torgerson","author_inst":"Allen Institute"}],"rel_date":"2026-09-22","rel_site":"biorxiv"},{"rel_title":"Benchmarking Uncertainty and Improving Risk Ranking in Multi-task Bioactivity Prediction","rel_doi":"10.64898\/2026.09.15.751772","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.15.751772","rel_abs":"Multi-task bioactivity prediction transfers information across assays, but experimental prioritization also requires uncertainty estimates that identify unreliable predictions. We benchmarked prediction accuracy and uncertainty calibration for five multi-task predictors on 100 ChEMBL27 test assays and 100 CHEMBL37 assays under the random split and the clustering split. Calibration used native, Deep Ensemble and MC Dropout uncertainty; risk ranking was compared for two Gaussian process (GP) backbones. Adaptive deep kernel fitting (ADKF) achieved the best mean calibration results, while deep kernel transfer (DKT) ranked errors more effectively than ADKF with native uncertainty. We also introduce Influence Calibrated Support Reconstruction (ICSR), a risk score for kernel-based predictors. ICSR combines measured support reconstruction errors with query-specific influence and stabilizes their weighted average toward the full-support mean to adjust Gaussian process uncertainty while preserving predicted activities. With DKT and ADKF, ICSR improved all three mean risk-ranking metrics over native uncertainty and an adapted neighborhood comparator in every panel and split. ICSR achieved a mean half-query MAE reduction (R50) of 14.2-19.6%, where R50 measures the percentage decrease in mean absolute error (MAE) after retaining the lowest-risk half of the queries. A retrospectively selected SARS-CoV-2 main protease case further illustrated its use for selecting more reliable predictions. The benchmark supports joint assessment of calibration and error ranking, while ICSR improves selective use of kernel-based bioactivity predictions.","rel_num_authors":3,"rel_authors":[{"author_name":"Zijian Wang","author_inst":"Laboratory for Synthetic Chemistry and Chemical Biology Limited; State Key Laboratory of Synthetic Chemistry and Department of Chemistry, The University of Hong"},{"author_name":"Li Tian","author_inst":"Laboratory for Synthetic Chemistry and Chemical Biology Limited; State Key Laboratory of Synthetic Chemistry and Department of Chemistry, The University of Hong"},{"author_name":"Chi-Ming Che","author_inst":"Laboratory for Synthetic Chemistry and Chemical Biology Limited; State Key Laboratory of Synthetic Chemistry and Department of Chemistry, The University of Hong"}],"rel_date":"2026-09-22","rel_site":"biorxiv"},{"rel_title":"KMT2E recruitment by H3 serotonylation regulates neurodevelopmental chromatin dynamics","rel_doi":"10.64898\/2026.09.20.752984","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.20.752984","rel_abs":"Histone H3 Gln 5 serotonylation (H3Q5ser) is a recently identified epigenetic modification in brain that modulates reader interactions with adjacent H3 Lys 4 trimethylation (H3K4me3) to promote transcriptional permissiveness. However, whether H3K4me3Q5ser and its associated binding proteins regulate neurodevelopmental gene expression programs remains unknown. Here, we identified the catalytically inactive Lysine methyltransferase 2E (KMT2E) as a reader of combinatorial H3K4me3Q5ser. KMT2E preferentially binds H3K4me3Q5ser over H3K4me3 alone, and enriches at broad chromatin domains marking actively transcribed neurodevelopmental loci. Notably, heterozygous variants in KMT2E have been implicated in ODLURO syndrome, a recently characterized neurodevelopmental disorder (NDD). To identify the molecular mechanisms underlying ODLURO syndrome, we generated a Kmt2e transgenic mouse model that reproduces behavioral, physiological, and cellular endophenotypes associated with this and other NDDs. Furthermore, we observed that KMT2E mediates these effects by recruiting the NCoR\/HDAC3 repressor complex to H3K4me3Q5ser-marked loci to restrict spreading of co-localized H3 Lys 9 acetylation (H3K9ac). Inhibition of aberrant H3K9ac spreading was sufficient to rescue transcriptional dysregulation in Kmt2e haploinsufficient neurons. These findings thus establish KMT2E as a critical reader of H3 serotonylation during neurodevelopment and provide mechanistic insights into the pathogenesis of ODLURO syndrome.","rel_num_authors":27,"rel_authors":[{"author_name":"Jennifer C O'Chan","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Benjamin H. Weekley","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Celi Yang","author_inst":"Tsinghua University"},{"author_name":"Min Chen","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Ashley M. Cunningham","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Sohini Dutta","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Winnie Chen","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Rasika R. Iyer","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Newaz I. Ahmed","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Bulent Cetin","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Cari A. Sagum","author_inst":"University of Texas MD Anderson Cancer Center"},{"author_name":"Bradley J. Lukasak","author_inst":"Princeton University"},{"author_name":"Erdene Baljinnyam","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Zoe Christenson Wick","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Vishwendra Patel","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Emma Andraka","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Aarthi Ramakrishnan","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Christopher Peralta","author_inst":"The Rockefeller University"},{"author_name":"Li Shen","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Henrik Molina","author_inst":"The Rockefeller University"},{"author_name":"Tristan Shuman","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Robert D. Blitzer","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Tom W. Muir","author_inst":"Princeton University"},{"author_name":"Mark T T. Bedford","author_inst":"University of Texas MD Anderson Cancer Center"},{"author_name":"Samuele G. Marro","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Haitao Li","author_inst":"Tsinghua University"},{"author_name":"Ian Maze","author_inst":"Icahn School of Medicine at Mount Sinai"}],"rel_date":"2026-09-22","rel_site":"biorxiv"},{"rel_title":"A brain locus for viable gestation","rel_doi":"10.64898\/2026.09.15.751878","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.15.751878","rel_abs":"The expectant mother's body is systemically remodeled by her hormones to weather the physiological vicissitudes of pregnancy. In contrast to other reproductive organs, how the expectant mother's brain promotes these system-wide changes is largely unexplored. Here we show that pregnancy induces profound changes in gene expression and identity of hormone-sensitive neurons and report a previously unknown class of such cells that is required for viable pregnancy. We performed RNA sequencing from late mid-gestation mice of four estrogen receptor alpha-expressing populations from hypothalamus and amygdala that regulate reproductive behaviors altered during gestation. Each of these populations undergoes such large, specific transcriptional shifts during pregnancy that these changes even exceed their transcriptional differences between the sexes. The gene expression changes during pregnancy also imbue particular transcriptomically-defined neuronal types within these four populations with new molecular identities. Targeted ablation of one such neuronal type, POANpy2r cells, precludes implantation and abrogates viable pregnancy. Taken together, we have uncovered an essential role of hormone-sensitive neurons in the brain in sustaining pregnancy. The etiology of spontaneous gestational loss, which afflicts ~15% of human pregnancies, remains idiopathic in many cases, and our findings suggest a brain-based mechanism that contributes to such events. More broadly, we provide a molecular and cellular foundation to study gestational processes in health and disease from the perspective of the pregnant brain-body axis.","rel_num_authors":16,"rel_authors":[{"author_name":"Sakura Tanaka","author_inst":"Departments of Psychiatry and Behavioral Sciences, Stanford University"},{"author_name":"Joseph R Knoedler","author_inst":"Departments of Psychiatry and Behavioral Sciences, Stanford University"},{"author_name":"Vinicius Miessler de Andrade Carvalho","author_inst":"Departments of Psychiatry and Behavioral Sciences, Stanford University"},{"author_name":"Maricruz Alvarado Mandujano","author_inst":"Departments of Psychiatry and Behavioral Sciences, Stanford University"},{"author_name":"Yichao Wei","author_inst":"Departments of Psychiatry and Behavioral Sciences, Stanford University"},{"author_name":"Renzhi Yang","author_inst":"Departments of Psychiatry and Behavioral Sciences, Stanford University"},{"author_name":"Adarsh Tantry","author_inst":"Departments of Psychiatry and Behavioral Sciences; Stanford Neurosciences Graduate Program, Stanford University"},{"author_name":"Sheruni A.E. Pilapitiya","author_inst":"Program in Human Biology, Stanford University"},{"author_name":"Bibudha Parasar","author_inst":"Departments of Neurobiology, Stanford University"},{"author_name":"Miao Wang","author_inst":"Department of Biochemistry and Biophysics, Columbia University"},{"author_name":"Chung-ha O. Davis","author_inst":"Departments of Neurobiology; Stanford Neurosciences Graduate Program, Stanford University"},{"author_name":"Lele Cui","author_inst":"Departments of Psychiatry and Behavioral Sciences, Stanford University"},{"author_name":"Mariko H Foecke","author_inst":"Department of Obstetrics, Gynecology, and Reproductive Sciences, UC San Francisco"},{"author_name":"Diana J Laird","author_inst":"Department of Obstetrics, Gynecology, and Reproductive Sciences, UC San Francisco"},{"author_name":"Longzhi Tan","author_inst":"Departments of Neurobiology, Stanford University"},{"author_name":"Nirao M Shah","author_inst":"Departments of Psychiatry and Behavioral Sciences; Neurobiology; Obstetrics and Gynecology, Stanford University"}],"rel_date":"2026-09-22","rel_site":"biorxiv"},{"rel_title":"A brain locus for viable gestation","rel_doi":"10.64898\/2026.09.15.751878","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.15.751878","rel_abs":"The expectant mother's body is systemically remodeled by her hormones to weather the physiological vicissitudes of pregnancy. In contrast to other reproductive organs, how the expectant mother's brain promotes these system-wide changes is largely unexplored. Here we show that pregnancy induces profound changes in gene expression and identity of hormone-sensitive neurons and report a previously unknown class of such cells that is required for viable pregnancy. We performed RNA sequencing from late mid-gestation mice of four estrogen receptor alpha-expressing populations from hypothalamus and amygdala that regulate reproductive behaviors altered during gestation. Each of these populations undergoes such large, specific transcriptional shifts during pregnancy that these changes even exceed their transcriptional differences between the sexes. The gene expression changes during pregnancy also imbue particular transcriptomically-defined neuronal types within these four populations with new molecular identities. Targeted ablation of one such neuronal type, POANpy2r cells, precludes implantation and abrogates viable pregnancy. Taken together, we have uncovered an essential role of hormone-sensitive neurons in the brain in sustaining pregnancy. The etiology of spontaneous gestational loss, which afflicts ~15% of human pregnancies, remains idiopathic in many cases, and our findings suggest a brain-based mechanism that contributes to such events. More broadly, we provide a molecular and cellular foundation to study gestational processes in health and disease from the perspective of the pregnant brain-body axis.","rel_num_authors":16,"rel_authors":[{"author_name":"Sakura Tanaka","author_inst":"Departments of Psychiatry and Behavioral Sciences, Stanford University"},{"author_name":"Joseph R Knoedler","author_inst":"Departments of Psychiatry and Behavioral Sciences, Stanford University"},{"author_name":"Vinicius Miessler de Andrade Carvalho","author_inst":"Departments of Psychiatry and Behavioral Sciences, Stanford University"},{"author_name":"Maricruz Alvarado Mandujano","author_inst":"Departments of Psychiatry and Behavioral Sciences, Stanford University"},{"author_name":"Yichao Wei","author_inst":"Departments of Psychiatry and Behavioral Sciences, Stanford University"},{"author_name":"Renzhi Yang","author_inst":"Departments of Psychiatry and Behavioral Sciences, Stanford University"},{"author_name":"Adarsh Tantry","author_inst":"Departments of Psychiatry and Behavioral Sciences; Stanford Neurosciences Graduate Program, Stanford University"},{"author_name":"Sheruni A.E. Pilapitiya","author_inst":"Program in Human Biology, Stanford University"},{"author_name":"Bibudha Parasar","author_inst":"Departments of Neurobiology, Stanford University"},{"author_name":"Miao Wang","author_inst":"Department of Biochemistry and Biophysics, Columbia University"},{"author_name":"Chung-ha O. Davis","author_inst":"Departments of Neurobiology; Stanford Neurosciences Graduate Program, Stanford University"},{"author_name":"Lele Cui","author_inst":"Departments of Psychiatry and Behavioral Sciences, Stanford University"},{"author_name":"Mariko H Foecke","author_inst":"Department of Obstetrics, Gynecology, and Reproductive Sciences, UC San Francisco"},{"author_name":"Diana J Laird","author_inst":"Department of Obstetrics, Gynecology, and Reproductive Sciences, UC San Francisco"},{"author_name":"Longzhi Tan","author_inst":"Departments of Neurobiology, Stanford University"},{"author_name":"Nirao M Shah","author_inst":"Departments of Psychiatry and Behavioral Sciences; Neurobiology; Obstetrics and Gynecology, Stanford University"}],"rel_date":"2026-09-22","rel_site":"biorxiv"},{"rel_title":"Differentiating nonfluent\/agrammatic and logopenic primary progressive aphasia in Catalan-Spanish bilinguals by applying multilingual multimodal machine learning to connected speech","rel_doi":"10.64898\/2026.09.18.26363435","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.18.26363435","rel_abs":"BackgroundThe nonfluent\/agrammatic (nfv) and logopenic (lv) variants of primary progressive aphasia (PPA) disrupt fluency through distinct underlying neurocognitive mechanisms. Differential diagnosis currently requires hours of cognitive-linguistic testing, with additional barriers for bilingual patients due to a shortage of bilingual service providers and a lack of well-established assessment methods. In English speakers, a promising automated approach for differentiating nfvPPA and lvPPA is to derive speech-timing measures and linguistic features from connected speech as input to machine learning (ML) classification algorithms. To our knowledge, this approach has not been evaluated in the context of bilingualism.\n\nMethodsThirty-four Catalan-Spanish simultaneous bilingual patients (lv = 24, nfv = 10) were asked to describe a picture (Western Aphasia Battery Picnic Scene) in both their dominant and non-dominant language. From the participants recorded response, we derived four feature sets: speech-timing measures, derived with PRAAT; word-level parameters, derived from corpora; linguistic features, derived with the natural language processing tools SpaCy and CLAN; image-text congruence scores, derived with the vision-language encoder Multilingual-CLIP. Each feature set was fed into classification algorithms for differentiating nfv from lv in participants non-dominant and dominant samples. Then, we combined each feature sets classifier into an ensemble model. We used the McNemar test to determine the statistical significance of differences in classification performance between responses in the non-dominant and dominant language.\n\nResultsThe best-performing classifier achieved F1 macro scores of 93% (word-level parameters) and 92% (ensemble) in the non-dominant and dominant language, respectively. For all feature sets and ensemble models, classification performance did not significantly differ between the non-dominant and dominant language. Ensemble modeling did not significantly improve classification performance in either language.\n\nConclusionsTaking advantage of recent advances in multilingual multimodal machine learning, we accurately differentiate Spanish-Catalan bilingual individuals with nfvPPA and lvPPA using a largely automated, time-efficient (1-2 minutes), and ecologically valid connected-speech-based approach. Future directions include evaluating this approach on larger datasets balanced by PPA subtype, using automated transcriptions of connected speech. Our study represents a step towards addressing current inequities in PPA differential diagnosis for non-English-speaking bilingual speakers.\n\nTrial registrationData from the clinical trial NCT05741853 was retrospectively analyzed","rel_num_authors":21,"rel_authors":[{"author_name":"Lokesha Srinivas Pugalenthi","author_inst":"Rice University"},{"author_name":"Andrew Parker Collins","author_inst":"University of Connecticut"},{"author_name":"N\u00faria Montagut Colomer","author_inst":"Hospital Cl\u00ednic de Barcelona"},{"author_name":"Sonia-Karin Marqu\u00e9s-Kiderle","author_inst":"Hospital Cl\u00ednic de Barcelona"},{"author_name":"Camille Wagner Rodriguez","author_inst":"The University of Texas at Austin"},{"author_name":"Jan Christian Holst Chaires","author_inst":"The University of Texas at Austin"},{"author_name":"Whendy Avila Motta","author_inst":"The University of Texas at Austin"},{"author_name":"Julia Filella-Merc\u00e8","author_inst":"Hospital de la Santa Creu i Sant Pau"},{"author_name":"Junyi Jessy Li","author_inst":"The University of Texas at Austin"},{"author_name":"Fernando Llanos","author_inst":"The University of Texas at Austin"},{"author_name":"Nuole Zhu","author_inst":"Hospital de la Santa Creu i Sant Pau"},{"author_name":"Sara Rubio-Guerra","author_inst":"Hospital de la Santa Creu i Sant Pau"},{"author_name":"Ignacio Illan-Gala","author_inst":"Hospital de la Santa Creu i Sant Pau"},{"author_name":"Sergi Borrego-\u00c9cija","author_inst":"Hospital de la Santa Creu i Sant Pau"},{"author_name":"Albert Llad\u00f3","author_inst":"Hospital Cl\u00ednic de Barcelona"},{"author_name":"Juan Fortea","author_inst":"Hospital de la Santa Creu i Sant Pau"},{"author_name":"Alberto Lle\u00f3","author_inst":"Hospital de la Santa Creu i Sant Pau"},{"author_name":"Raquel S\u00e1nchez-Valle","author_inst":"Hospital Cl\u00ednic de Barcelona"},{"author_name":"Maya L. Henry","author_inst":"The University of Texas at Austin"},{"author_name":"Miguel \u00c1ngel Santos Santos","author_inst":"Hospital de la Santa Creu i Sant Pau"},{"author_name":"Stephanie M. Grasso","author_inst":"The University of Texas at Austin"}],"rel_date":"2026-09-21","rel_site":"medrxiv"},{"rel_title":"Privacy-Aware Distillation of Large Language Models for Enhanced Multimorbidity Scoring","rel_doi":"10.64898\/2026.09.19.26363476","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.19.26363476","rel_abs":"The truthful use of large language models (LLMs) is a growing challenge in safeguarding sensitive patient data from leakage. We introduce and evaluate a privacy-preserving knowledge distillation framework for LLM-based clinical modeling, using multimorbidity scoring as a healthcare task. Although LLMs can encode rich clinical knowledge and improve upon traditional rule-based comorbidity scoring, their direct evaluation on large-scale biobank data remains constrained by patient privacy. In our framework, multimorbidity reasoning is distilled from state-of-the-art LLM teacher models into compact student models (CoLLMs) using synthetic cohorts that preserve UK Biobank distributions, without exposing real patient data. This approach achieves high-fidelity knowledge transfer (Spearman {rho} = 0.75-0.89). Independent LLM-as-Judge evaluation confirms the clinical significance of the distilled knowledge and reveals substantial variability among teacher models. When applied to real UK Biobank data, CoLLM-derived multimorbidity scores improve survival prediction (C-index up to 0.91) and exhibit higher SNP heritability (h2 {approx} 0.05). Our work establishes a trustworthy, privacy-compliant pathway for large-scale healthcare applications of LLMs.","rel_num_authors":4,"rel_authors":[{"author_name":"Raghav Awasthi","author_inst":"Case Western Reserve University"},{"author_name":"Yihe Yang","author_inst":"Case Western Reserve University"},{"author_name":"Mengxuan Li","author_inst":"Case Western Reserve University"},{"author_name":"Xiaofeng Zhu","author_inst":"Case Western Reserve university"}],"rel_date":"2026-09-21","rel_site":"medrxiv"},{"rel_title":"Weighing the Odds: Body Mass Index and Recurrence-Free Survival in Early-Onset Colorectal Cancer","rel_doi":"10.64898\/2026.09.19.26363465","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.19.26363465","rel_abs":"BackgroundEarly-Onset Colorectal Cancer (EOCRC, < 50 years) is rising sharply in many parts of the world. The \"obesity paradox\", where overweight correlates with better outcome despite obesity being a risk factor, is established in colorectal cancer (CRC) overall but remains ambiguous in EOCRC.\n\nAimTo investigate the association of Body Mass Index (BMI) at diagnosis and recurrence-free survival (RFS) in EOCRC and compare it to average-onset colorectal cancer (AOCRC, [&ge;] 50 years).\n\nMethodsA retrospective cohort study at Sahlgrenska University Hospital included 1,459 patients with curative-intent colorectal adenocarcinoma surgery comprising EOCRC (n=159) and AOCRC (n=1,300) cohorts. Cox proportional hazards models assessed the relation of BMI to RFS, adjusted for tumour stage, location, and differentiation. Restricted cubic splines were used to model BMI as a continuous variable, and model fit was assessed with likelihood-ratio tests (LRT).\n\nResultsIn EOCRC, continuous BMI was significantly associated with RFS (LRT p=0.02), displaying a U-shaped association with the lowest hazard at BMI 27 and highest at BMI <20 and >30. In AOCRC continuous BMI was not associated with RFS (LRT p=0.15) and the spline curve was flat. An interaction analysis showed a significant difference between the cohorts (LRT p=0.046).\n\nConclusionContinuous BMI was significantly associated with RFS in EOCRC but not in AOCRC suggesting the \"obesity paradox\" may be specific to EOCRC. This may reflect differences in body composition, tumour biology and systemic metabolism between EOCRC and AOCRC or may be due to methodological biases. Future research should incorporate biomarkers, as well as refined measures of body composition.","rel_num_authors":4,"rel_authors":[{"author_name":"Erik Delryd","author_inst":"Institute of Clinical Science, Sahlgrenska Academy"},{"author_name":"Andy Tran","author_inst":"University of Iowa"},{"author_name":"Elinor Bexe Lindskog","author_inst":"Institute of Clinical Sciences, Sahlgrenska Academy"},{"author_name":"David Ljungman","author_inst":"Institute of Clinical Sciences, Sahlgrenska Academy"}],"rel_date":"2026-09-21","rel_site":"medrxiv"},{"rel_title":"Decision Support in Publicly Available Patient Information Policies at U.S. Osteopathic Medical Schools: A Vignette-Based Document Analysis","rel_doi":"10.64898\/2026.09.18.26363437","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.18.26363437","rel_abs":"Research ObjectivesTo evaluate whether publicly available institutional guidance supports patient-information decisions across scenarios and schools, and characterize document synthesis and evaluation consistency.\n\nMethodsWe conducted an exploratory, vignette-based document analysis of a geographically diverse nonprobability sample of 20 U.S. osteopathic medical schools. Eight educational vignettes yielded 160 school-vignette pairs. Each pair underwent three separate AI-assisted retrieval-and-evaluation runs, classifying decision support as Explicitly Supported, Inferable, Ambiguous, or Not Addressed. Response selection prioritized greater support for discordant pairs, followed by fewer contributing documents and run order. One investigator verified or revised selected discordant classifications against cited evidence. Explicitly Supported and Inferable were grouped post hoc as sufficient decision support. Analyses were descriptive and included an exploratory two-school model-investigator comparison.\n\nResultsAt least one eligible source was retrieved for 159 of 160 pairs (99.4%). Final classifications were Explicitly Supported for 18 pairs (11.3%), Inferable for 3 (1.9%), Ambiguous for 132 (82.5%), and Not Addressed for 7 (4.4%). Sufficient support occurred in 21 pairs (13.1%), most frequently for generative AI-assisted reflective writing (7\/20 schools, 35%), and in none for personal cloud notes or official clinical logs. Ten schools had no sufficiently supported vignette; the maximum was four of eight. Multiple documents contributed to 111 evaluations (69.4%). Three-run ratings were unanimous for 113 pairs (70.6%), with 80.2% pairwise exact agreement. Investigator review retained 44 of 47 selected discordant ratings and revised three upward. In the two-school comparison, the investigator more frequently judged evidence sufficient when models judged it insufficient than the reverse.\n\nConclusionsRelevant public guidance was frequently retrieved, but few school-vignette pairs were classified as providing sufficient scenario-specific decision support. These findings highlight a gap between identifying relevant guidance and determining an appropriate course of action within this evaluation framework. They support institutional review of how student-facing materials explain information use, storage, sharing, and approval requirements. Vignette-based review identifies questions requiring clarification. Evaluation with learners and assessment of internal and clinical-site guidance would help determine how these findings translate to students decisions.","rel_num_authors":2,"rel_authors":[{"author_name":"Na Dai","author_inst":"Independent Researcher"},{"author_name":"Kirsten L Waarala","author_inst":"College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA"}],"rel_date":"2026-09-21","rel_site":"medrxiv"},{"rel_title":"Compound climate extremes, socioeconomic conditions and human mobility influence dengue dynamics heterogeneously across Vietnam","rel_doi":"10.64898\/2026.09.19.26363468","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.19.26363468","rel_abs":"Dengue presents a major public health challenge in Vietnam, driven by biological, behavioural, and environmental factors. Compound climate extremes, such as sequential hydrometeorological events, can influence dengue risk yet remain understudied. We evaluated the effects of compound climate extremes, socioeconomic conditions, and human mobility on dengue relative risk across 670 districts in Vietnam over 20 years, stratifying by eight subregions spanning emerging to endemic transmission. Dengue risk was greatest following dry-then-wet conditions in seven subregions. Higher temperatures increased risk across North and Central Vietnam, but had limited effect in the South. Mobility associations followed an urban-rural gradient, with increased risk in highly rural districts where residents travelled more frequently to fewer destinations, and in urban districts with more visitors and dispersed outgoing mobility. Stratifying climatic and socioeconomic effects by subregion improved predictive skill at lead times of 1 to 6 months over unstratified and baseline models, with substantial spatial variation. Accounting for compound extremes across distinct spatial contexts could strengthen disease early warning systems in Vietnam and beyond.","rel_num_authors":15,"rel_authors":[{"author_name":"Chloe Fletcher","author_inst":"Barcelona Supercomputing Center"},{"author_name":"Sophie Belman","author_inst":"Yale School of Public Health"},{"author_name":"Kien Quoc Do","author_inst":"Pasteur Institute in Ho Chi Minh City"},{"author_name":"Quang Duy Pham","author_inst":"Pasteur Institute in Ho Chi Minh City"},{"author_name":"Thi Thanh Thao Nguyen","author_inst":"Pasteur Institute in Ho Chi Minh City"},{"author_name":"Rory Gibb","author_inst":"University College London"},{"author_name":"Phan Trong Lan","author_inst":"National Institute of Hygiene and Epidemiology"},{"author_name":"Tran Cong Tu","author_inst":"National Institute of Hygiene and Epidemiology"},{"author_name":"Nguyen Hai Tuan","author_inst":"National Institute of Hygiene and Epidemiology"},{"author_name":"Daniela L\u00fchrsen","author_inst":"Barcelona Supercomputing Center"},{"author_name":"Gina Tsarouchi","author_inst":"HR Wallingford"},{"author_name":"Quillon Harpham","author_inst":"HR Wallingford"},{"author_name":"Felipe J Col\u00f3n-Gonz\u00e1lez","author_inst":"Wellcome Trust"},{"author_name":"John Rossman Bertholf Palmer","author_inst":"Universitat Pompeu Fabra"},{"author_name":"Rachel Lowe","author_inst":"Barcelona Supercomputing Center"}],"rel_date":"2026-09-21","rel_site":"medrxiv"},{"rel_title":"Multi-component chlorination intervention to reduce neonatal infections in healthcare facilities in western Kenya (CLEAN Trial): study protocol for a cluster randomized controlled trial","rel_doi":"10.64898\/2026.09.18.26363445","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.18.26363445","rel_abs":"BackgroundThe proportion of births occurring at healthcare facilities is rising globally, yet the birthing environment in healthcare facilities in low-income settings is often contaminated with bacterial pathogens, including antibiotic-resistant pathogens, that can lead to serious infections for newborns and their mothers. There is a need for effective strategies to reduce environmental contamination in healthcare facilities to reduce infection risks among facility-born neonates and their mothers.\n\nMethodsWe designed the CLEAN (ChLorine to reduce Enteric and Antibiotic resistant infections in Neonates) cluster randomized controlled trial in western Kenya to evaluate the impact of a multi-component chlorination intervention on environmental contamination and maternal and neonatal infection risks. Thirty-six medium-sized public health facilities will be randomized in a 1:1 allocation ratio to receive a passive chlorination technology for water supply treatment paired with a reliable supply of chlorine-based disinfectant or status quo. Up to 22,500 mothers-neonate dyads will be enrolled and followed from birth through 28 days to collect symptoms of infection and mortality, with a subset of mother-neonate dyads selected for rectal swab collection to measure rectal colonization with sepsis-associated bacterial species. Environmental samples will be collected to measure bacterial pathogens on staff hands, high-touch surfaces, and in water supply. The primary objectives of the study are to evaluate the impact of the intervention on the following outcomes: (1) rectal carriage of bacterial pathogens one week post-birth among facility-born neonates and their mothers, (2) cumulative incidence in the first 7 days post-birth of possible serious bacterial infection among facility-born neonates, and (3) cumulative incidence in the first 7 days post-birth of symptoms of possible maternal sepsis.\n\nDiscussionThis study will generate evidence on the effectiveness of a novel chlorination intervention to reduce healthcare associated infections, including antibiotic resistant infections, and improve maternal and neonatal survival.\n\nTrial registrationClinical Trials NCT06824350. Registered 7 February 2025, https:\/\/clinicaltrials.gov\/study\/NCT06824350","rel_num_authors":25,"rel_authors":[{"author_name":"Mwale Chiyenge","author_inst":"University of California, Berkeley"},{"author_name":"Yoshika Crider","author_inst":"University of Minnesota"},{"author_name":"Erick Odoyo","author_inst":"Walter Reed Army Institute of Research-Africa, Kenya"},{"author_name":"Mwale Chiyenge","author_inst":"University of California, Berkeley"},{"author_name":"Joyce Kisiangani","author_inst":"University of California, Berkeley"},{"author_name":"Erick Odoyo","author_inst":"Walter Reed Army Institute of Research-Africa, Kenya"},{"author_name":"Jeremy Lowe","author_inst":"University of California, Berkeley"},{"author_name":"Joyce Kisiangani","author_inst":"University of California, Berkeley"},{"author_name":"Josline Wangia","author_inst":"Kenya Medical Research Institute"},{"author_name":"Jeremy Lowe","author_inst":"University of California, Berkeley"},{"author_name":"Blastus Bwire","author_inst":"Remit Kenya"},{"author_name":"Josline Wangia","author_inst":"Kenya Medical Research Institute"},{"author_name":"Mwanzia Kioko","author_inst":"CARE"},{"author_name":"Blastus Bwire","author_inst":"Remit Kenya"},{"author_name":"Kelly Alexander","author_inst":"CARE"},{"author_name":"Mwanzia Kioko","author_inst":"CARE"},{"author_name":"Carol Nekesa","author_inst":"Remit Kenya"},{"author_name":"Kelly Alexander","author_inst":"CARE"},{"author_name":"Lillian Musila","author_inst":"Kenya Medical Research Institute"},{"author_name":"Carol Nekesa","author_inst":"Remit Kenya"},{"author_name":"Phelgona Otieno","author_inst":"Kenya Medical Research Institute"},{"author_name":"Lillian Musila","author_inst":"Kenya Medical Research Institute"},{"author_name":"Amy Pickering","author_inst":"University of California, Berkeley"},{"author_name":"Phelgona Otieno","author_inst":"Kenya Medical Research Institute"},{"author_name":"Amy Pickering","author_inst":"University of California, Berkeley"}],"rel_date":"2026-09-21","rel_site":"medrxiv"},{"rel_title":"Smartphone Passive Digital Phenotyping in Frontotemporal Lobar Degeneration","rel_doi":"10.64898\/2026.09.18.26363439","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.18.26363439","rel_abs":"IntroductionFrontotemporal lobar degeneration (FTLD) is a devastating disease that commonly results in early onset dementia, yet its rarity and heterogeneity limit large-scale research and clinical trials. Remote monitoring via low-burden digital health tools may overcome these barriers. We evaluated clinical utility of passive smartphone monitoring in FTLD using a multi-domain mobile assessment platform.\n\nMethodsParticipants were 567 adults (53% clinically normal, 21% prodromal FTLD, 26% symptomatic FTLD) who completed an in-person study visit and downloaded the ALLFTD Mobile App on their personal smartphones. The app delivered unsupervised cognitive tests and passively collected continuous data on battery percentage (proxy for smartphone use) and step count. Longitudinal follow-up included smartphone monitoring and annual in-person study visits. Primary analyses examined associations between passive smartphone features and markers of disease severity at baseline and longitudinally, and tested whether passive features added incremental value beyond app-based cognitive testing.\n\nResultsPassive smartphone features were feasible to collect and showed excellent reliability with <2 weeks of monitoring (ICCs>0.9). Features capturing smartphone use and movement demonstrated sensitivity to gold-standard clinical measures of disease severity both at baseline and longitudinally. A classification model combining passive features, the app-based cognitive composite score, and demographics detected longitudinal functional decline (AUC=0.89); passive features alone (AUC=0.84) performed comparably to a cognitive screener (AUC=0.85).\n\nDiscussionPassive smartphone monitoring is a valid, zero-burden measure of disease severity and progression in FTLD that adds modest incremental value beyond app-based cognitive testing. Findings support its use as a scalable digital endpoint in longitudinal FTLD research.","rel_num_authors":51,"rel_authors":[{"author_name":"Emily W Paolillo","author_inst":"University of California, San Francisco"},{"author_name":"Sreya Dhanam","author_inst":"University of California, San Francisco"},{"author_name":"Jack Carson Taylor","author_inst":"University of California, San Francisco"},{"author_name":"Mark Sanderson-Cimino","author_inst":"University of California, San Francisco"},{"author_name":"Ray Fregly","author_inst":"University of California, San Francisco"},{"author_name":"Rowan Saloner","author_inst":"University of California, San Francisco"},{"author_name":"Kaitlin B Casaletto","author_inst":"University of California, San Francisco"},{"author_name":"Joel H Kramer","author_inst":"University of California, San Francisco"},{"author_name":"Bruce L Miller","author_inst":"University of California, San Francisco"},{"author_name":"William W Seeley","author_inst":"University of California, San Francisco"},{"author_name":"Maria Luisa Gorno-Tempini","author_inst":"University of California, San Francisco"},{"author_name":"Peter A Ljubenkov","author_inst":"University of California, San Francisco"},{"author_name":"Julio C Rojas","author_inst":"University of California, San Francisco"},{"author_name":"Suzee Lee","author_inst":"University of California, San Francisco"},{"author_name":"Virginia Sturm","author_inst":"University of California, San Francisco"},{"author_name":"Brian Appleby","author_inst":"Case Western Reserve University"},{"author_name":"Ece Bayram","author_inst":"University of Colorado Anschutz"},{"author_name":"David Clark","author_inst":"Indiana University"},{"author_name":"Ciaran M Considine","author_inst":"Vanderbilt University"},{"author_name":"Richard R Darby","author_inst":"Vanderbilt University"},{"author_name":"Gregory S Day","author_inst":"Mayo Clinic, Jacksonville"},{"author_name":"Alyssa De Vito","author_inst":"Brown University"},{"author_name":"Mark Eldaief","author_inst":"Massachusetts General Hospital & Harvard Medical School"},{"author_name":"Julie A Fields","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Nupur Ghoshal","author_inst":"Washington University"},{"author_name":"Edward D Huey","author_inst":"Brown University"},{"author_name":"David J Irwin","author_inst":"University of Pennsylvania"},{"author_name":"Kejal Kantarci","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Justin Y Kwan","author_inst":"National Institutes of Health"},{"author_name":"Ian R Mackenzie","author_inst":"University of British Columbia"},{"author_name":"Joseph C Masdeu","author_inst":"Houston Methodist"},{"author_name":"Chiadi U Onyike","author_inst":"Johns Hopkins University"},{"author_name":"Alexander Pantelyat","author_inst":"Johns Hopkins University"},{"author_name":"Belen Pascual","author_inst":"Houston Methodist"},{"author_name":"Tanav Popli","author_inst":"University of Michigan"},{"author_name":"Katya Rascovsky","author_inst":"University of Pennsylvania"},{"author_name":"Neguine Rezaii","author_inst":"Massachusetts General Hospital"},{"author_name":"Sonja W Scholz","author_inst":"National Institutes of Health"},{"author_name":"Allison Snyder","author_inst":"National Institutes of Health"},{"author_name":"M. Carmela Tartaglia","author_inst":"University of Toronto"},{"author_name":"Bryan J Traynor","author_inst":"National Institutes of Health"},{"author_name":"Bonnie Wong","author_inst":"MGH"},{"author_name":"John Kornak","author_inst":"University of California, San Francisco"},{"author_name":"Walter K Kremers","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Leah K Forsberg","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Hilary W Heuer","author_inst":"University of California, San Francisco"},{"author_name":"Bradley F Boeve","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Howard J Rosen","author_inst":"University of California, San Francisco"},{"author_name":"Adam L Boxer","author_inst":"University of California, San Francisco"},{"author_name":"Adam M Staffaroni","author_inst":"University of California, San Francisco"},{"author_name":"- ALLFTD Consortium","author_inst":""}],"rel_date":"2026-09-21","rel_site":"medrxiv"},{"rel_title":"Smartphone Passive Digital Phenotyping in Frontotemporal Lobar Degeneration","rel_doi":"10.64898\/2026.09.18.26363439","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.18.26363439","rel_abs":"IntroductionFrontotemporal lobar degeneration (FTLD) is a devastating disease that commonly results in early onset dementia, yet its rarity and heterogeneity limit large-scale research and clinical trials. Remote monitoring via low-burden digital health tools may overcome these barriers. We evaluated clinical utility of passive smartphone monitoring in FTLD using a multi-domain mobile assessment platform.\n\nMethodsParticipants were 567 adults (53% clinically normal, 21% prodromal FTLD, 26% symptomatic FTLD) who completed an in-person study visit and downloaded the ALLFTD Mobile App on their personal smartphones. The app delivered unsupervised cognitive tests and passively collected continuous data on battery percentage (proxy for smartphone use) and step count. Longitudinal follow-up included smartphone monitoring and annual in-person study visits. Primary analyses examined associations between passive smartphone features and markers of disease severity at baseline and longitudinally, and tested whether passive features added incremental value beyond app-based cognitive testing.\n\nResultsPassive smartphone features were feasible to collect and showed excellent reliability with <2 weeks of monitoring (ICCs>0.9). Features capturing smartphone use and movement demonstrated sensitivity to gold-standard clinical measures of disease severity both at baseline and longitudinally. A classification model combining passive features, the app-based cognitive composite score, and demographics detected longitudinal functional decline (AUC=0.89); passive features alone (AUC=0.84) performed comparably to a cognitive screener (AUC=0.85).\n\nDiscussionPassive smartphone monitoring is a valid, zero-burden measure of disease severity and progression in FTLD that adds modest incremental value beyond app-based cognitive testing. Findings support its use as a scalable digital endpoint in longitudinal FTLD research.","rel_num_authors":51,"rel_authors":[{"author_name":"Emily W Paolillo","author_inst":"University of California, San Francisco"},{"author_name":"Sreya Dhanam","author_inst":"University of California, San Francisco"},{"author_name":"Jack Carson Taylor","author_inst":"University of California, San Francisco"},{"author_name":"Mark Sanderson-Cimino","author_inst":"University of California, San Francisco"},{"author_name":"Ray Fregly","author_inst":"University of California, San Francisco"},{"author_name":"Rowan Saloner","author_inst":"University of California, San Francisco"},{"author_name":"Kaitlin B Casaletto","author_inst":"University of California, San Francisco"},{"author_name":"Joel H Kramer","author_inst":"University of California, San Francisco"},{"author_name":"Bruce L Miller","author_inst":"University of California, San Francisco"},{"author_name":"William W Seeley","author_inst":"University of California, San Francisco"},{"author_name":"Maria Luisa Gorno-Tempini","author_inst":"University of California, San Francisco"},{"author_name":"Peter A Ljubenkov","author_inst":"University of California, San Francisco"},{"author_name":"Julio C Rojas","author_inst":"University of California, San Francisco"},{"author_name":"Suzee Lee","author_inst":"University of California, San Francisco"},{"author_name":"Virginia Sturm","author_inst":"University of California, San Francisco"},{"author_name":"Brian Appleby","author_inst":"Case Western Reserve University"},{"author_name":"Ece Bayram","author_inst":"University of Colorado Anschutz"},{"author_name":"David Clark","author_inst":"Indiana University"},{"author_name":"Ciaran M Considine","author_inst":"Vanderbilt University"},{"author_name":"Richard R Darby","author_inst":"Vanderbilt University"},{"author_name":"Gregory S Day","author_inst":"Mayo Clinic, Jacksonville"},{"author_name":"Alyssa De Vito","author_inst":"Brown University"},{"author_name":"Mark Eldaief","author_inst":"Massachusetts General Hospital & Harvard Medical School"},{"author_name":"Julie A Fields","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Nupur Ghoshal","author_inst":"Washington University"},{"author_name":"Edward D Huey","author_inst":"Brown University"},{"author_name":"David J Irwin","author_inst":"University of Pennsylvania"},{"author_name":"Kejal Kantarci","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Justin Y Kwan","author_inst":"National Institutes of Health"},{"author_name":"Ian R Mackenzie","author_inst":"University of British Columbia"},{"author_name":"Joseph C Masdeu","author_inst":"Houston Methodist"},{"author_name":"Chiadi U Onyike","author_inst":"Johns Hopkins University"},{"author_name":"Alexander Pantelyat","author_inst":"Johns Hopkins University"},{"author_name":"Belen Pascual","author_inst":"Houston Methodist"},{"author_name":"Tanav Popli","author_inst":"University of Michigan"},{"author_name":"Katya Rascovsky","author_inst":"University of Pennsylvania"},{"author_name":"Neguine Rezaii","author_inst":"Massachusetts General Hospital"},{"author_name":"Sonja W Scholz","author_inst":"National Institutes of Health"},{"author_name":"Allison Snyder","author_inst":"National Institutes of Health"},{"author_name":"M. Carmela Tartaglia","author_inst":"University of Toronto"},{"author_name":"Bryan J Traynor","author_inst":"National Institutes of Health"},{"author_name":"Bonnie Wong","author_inst":"MGH"},{"author_name":"John Kornak","author_inst":"University of California, San Francisco"},{"author_name":"Walter K Kremers","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Leah K Forsberg","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Hilary W Heuer","author_inst":"University of California, San Francisco"},{"author_name":"Bradley F Boeve","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Howard J Rosen","author_inst":"University of California, San Francisco"},{"author_name":"Adam L Boxer","author_inst":"University of California, San Francisco"},{"author_name":"Adam M Staffaroni","author_inst":"University of California, San Francisco"},{"author_name":"- ALLFTD Consortium","author_inst":""}],"rel_date":"2026-09-21","rel_site":"medrxiv"},{"rel_title":"Smartphone Passive Digital Phenotyping in Frontotemporal Lobar Degeneration","rel_doi":"10.64898\/2026.09.18.26363439","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.09.18.26363439","rel_abs":"IntroductionFrontotemporal lobar degeneration (FTLD) is a devastating disease that commonly results in early onset dementia, yet its rarity and heterogeneity limit large-scale research and clinical trials. Remote monitoring via low-burden digital health tools may overcome these barriers. We evaluated clinical utility of passive smartphone monitoring in FTLD using a multi-domain mobile assessment platform.\n\nMethodsParticipants were 567 adults (53% clinically normal, 21% prodromal FTLD, 26% symptomatic FTLD) who completed an in-person study visit and downloaded the ALLFTD Mobile App on their personal smartphones. The app delivered unsupervised cognitive tests and passively collected continuous data on battery percentage (proxy for smartphone use) and step count. Longitudinal follow-up included smartphone monitoring and annual in-person study visits. Primary analyses examined associations between passive smartphone features and markers of disease severity at baseline and longitudinally, and tested whether passive features added incremental value beyond app-based cognitive testing.\n\nResultsPassive smartphone features were feasible to collect and showed excellent reliability with <2 weeks of monitoring (ICCs>0.9). Features capturing smartphone use and movement demonstrated sensitivity to gold-standard clinical measures of disease severity both at baseline and longitudinally. A classification model combining passive features, the app-based cognitive composite score, and demographics detected longitudinal functional decline (AUC=0.89); passive features alone (AUC=0.84) performed comparably to a cognitive screener (AUC=0.85).\n\nDiscussionPassive smartphone monitoring is a valid, zero-burden measure of disease severity and progression in FTLD that adds modest incremental value beyond app-based cognitive testing. Findings support its use as a scalable digital endpoint in longitudinal FTLD research.","rel_num_authors":51,"rel_authors":[{"author_name":"Emily W Paolillo","author_inst":"University of California, San Francisco"},{"author_name":"Sreya Dhanam","author_inst":"University of California, San Francisco"},{"author_name":"Jack Carson Taylor","author_inst":"University of California, San Francisco"},{"author_name":"Mark Sanderson-Cimino","author_inst":"University of California, San Francisco"},{"author_name":"Ray Fregly","author_inst":"University of California, San Francisco"},{"author_name":"Rowan Saloner","author_inst":"University of California, San Francisco"},{"author_name":"Kaitlin B Casaletto","author_inst":"University of California, San Francisco"},{"author_name":"Joel H Kramer","author_inst":"University of California, San Francisco"},{"author_name":"Bruce L Miller","author_inst":"University of California, San Francisco"},{"author_name":"William W Seeley","author_inst":"University of California, San Francisco"},{"author_name":"Maria Luisa Gorno-Tempini","author_inst":"University of California, San Francisco"},{"author_name":"Peter A Ljubenkov","author_inst":"University of California, San Francisco"},{"author_name":"Julio C Rojas","author_inst":"University of California, San Francisco"},{"author_name":"Suzee Lee","author_inst":"University of California, San Francisco"},{"author_name":"Virginia Sturm","author_inst":"University of California, San Francisco"},{"author_name":"Brian Appleby","author_inst":"Case Western Reserve University"},{"author_name":"Ece Bayram","author_inst":"University of Colorado Anschutz"},{"author_name":"David Clark","author_inst":"Indiana University"},{"author_name":"Ciaran M Considine","author_inst":"Vanderbilt University"},{"author_name":"Richard R Darby","author_inst":"Vanderbilt University"},{"author_name":"Gregory S Day","author_inst":"Mayo Clinic, Jacksonville"},{"author_name":"Alyssa De Vito","author_inst":"Brown University"},{"author_name":"Mark Eldaief","author_inst":"Massachusetts General Hospital & Harvard Medical School"},{"author_name":"Julie A Fields","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Nupur Ghoshal","author_inst":"Washington University"},{"author_name":"Edward D Huey","author_inst":"Brown University"},{"author_name":"David J Irwin","author_inst":"University of Pennsylvania"},{"author_name":"Kejal Kantarci","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Justin Y Kwan","author_inst":"National Institutes of Health"},{"author_name":"Ian R Mackenzie","author_inst":"University of British Columbia"},{"author_name":"Joseph C Masdeu","author_inst":"Houston Methodist"},{"author_name":"Chiadi U Onyike","author_inst":"Johns Hopkins University"},{"author_name":"Alexander Pantelyat","author_inst":"Johns Hopkins University"},{"author_name":"Belen Pascual","author_inst":"Houston Methodist"},{"author_name":"Tanav Popli","author_inst":"University of Michigan"},{"author_name":"Katya Rascovsky","author_inst":"University of Pennsylvania"},{"author_name":"Neguine Rezaii","author_inst":"Massachusetts General Hospital"},{"author_name":"Sonja W Scholz","author_inst":"National Institutes of Health"},{"author_name":"Allison Snyder","author_inst":"National Institutes of Health"},{"author_name":"M. Carmela Tartaglia","author_inst":"University of Toronto"},{"author_name":"Bryan J Traynor","author_inst":"National Institutes of Health"},{"author_name":"Bonnie Wong","author_inst":"MGH"},{"author_name":"John Kornak","author_inst":"University of California, San Francisco"},{"author_name":"Walter K Kremers","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Leah K Forsberg","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Hilary W Heuer","author_inst":"University of California, San Francisco"},{"author_name":"Bradley F Boeve","author_inst":"Mayo Clinic, Rochester"},{"author_name":"Howard J Rosen","author_inst":"University of California, San Francisco"},{"author_name":"Adam L Boxer","author_inst":"University of California, San Francisco"},{"author_name":"Adam M Staffaroni","author_inst":"University of California, San Francisco"},{"author_name":"- ALLFTD Consortium","author_inst":""}],"rel_date":"2026-09-21","rel_site":"medrxiv"}]}