{"gname":"University of California, San Diego","grp_id":"41","rels":[{"rel_title":"Microbial community response and recovery through an aeration-cessation time series in a eutrophic estuary","rel_doi":"10.64898\/2026.09.24.754275","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.24.754275","rel_abs":"Eutrophication-driven hypoxia and harmful algal blooms are an expanding threat to water quality in estuaries. Engineered aeration is a technology used in freshwater and, to a lesser extent, estuarine systems to mitigate both hypoxia and algal blooms. However, the efficacy of engineered aeration has not been well studied within estuarine ecosystems and very little is known about the impact of aeration on microbial communities in either estuarine or freshwater environments. Here we present a time series investigation of microbial community response to aeration and cessation of aeration in a eutrophic estuary. Samples for 16S rRNA gene analysis were collected over about a month-long period during which time the aerators transitioned from being \"on\" to \"off\" to \"on\" again. Cessation of aeration selected for the dominance of a eukaryotic algae similar to Heterosigma akashiwo. After the resumption of aeration, H. akashiwo dominance decreased rapidly. Cessation of aeration also shifted the structure of the entire microbial community, where diversity decreased and the structure of microbial communities at the surface diverged from those from the bottom of the water column. These changes did not occur at non-aerated control sites. Distinct groups of taxa responded to the disruption in a successional pattern through time, with most taxa never returning to their pre-aeration-cessation abundance during the observational period. These findings demonstrate the complex community response to anthropogenic interventions and provide support for bloom suppression through aeration.","rel_num_authors":9,"rel_authors":[{"author_name":"William Schroer","author_inst":"Johns Hopkins University"},{"author_name":"Yue Zhang","author_inst":"Johns Hopkins University"},{"author_name":"Keith Arora-Williams","author_inst":"Johns Hopkins University"},{"author_name":"Alice Turnham","author_inst":"Johns Hopkins University"},{"author_name":"Lora Harris","author_inst":"University of Maryland Center for Environmental Science Chesapeake Biological Laboratory"},{"author_name":"Andrew Heyes","author_inst":"University of Maryland Center for Environmental Science"},{"author_name":"Jeremy Testa","author_inst":"University of Maryland Center for Environmental Science"},{"author_name":"Laura Lapham","author_inst":"University of Maryland Center for Environmental Science Chesapeake Biological Laboratory"},{"author_name":"Sarah Pacocha Preheim","author_inst":"Johns Hopkins University"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Microbial community response and recovery through an aeration-cessation time series in a eutrophic estuary","rel_doi":"10.64898\/2026.09.24.754275","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.24.754275","rel_abs":"Eutrophication-driven hypoxia and harmful algal blooms are an expanding threat to water quality in estuaries. Engineered aeration is a technology used in freshwater and, to a lesser extent, estuarine systems to mitigate both hypoxia and algal blooms. However, the efficacy of engineered aeration has not been well studied within estuarine ecosystems and very little is known about the impact of aeration on microbial communities in either estuarine or freshwater environments. Here we present a time series investigation of microbial community response to aeration and cessation of aeration in a eutrophic estuary. Samples for 16S rRNA gene analysis were collected over about a month-long period during which time the aerators transitioned from being \"on\" to \"off\" to \"on\" again. Cessation of aeration selected for the dominance of a eukaryotic algae similar to Heterosigma akashiwo. After the resumption of aeration, H. akashiwo dominance decreased rapidly. Cessation of aeration also shifted the structure of the entire microbial community, where diversity decreased and the structure of microbial communities at the surface diverged from those from the bottom of the water column. These changes did not occur at non-aerated control sites. Distinct groups of taxa responded to the disruption in a successional pattern through time, with most taxa never returning to their pre-aeration-cessation abundance during the observational period. These findings demonstrate the complex community response to anthropogenic interventions and provide support for bloom suppression through aeration.","rel_num_authors":9,"rel_authors":[{"author_name":"William Schroer","author_inst":"Johns Hopkins University"},{"author_name":"Yue Zhang","author_inst":"Johns Hopkins University"},{"author_name":"Keith Arora-Williams","author_inst":"Johns Hopkins University"},{"author_name":"Alice Turnham","author_inst":"Johns Hopkins University"},{"author_name":"Lora Harris","author_inst":"University of Maryland Center for Environmental Science Chesapeake Biological Laboratory"},{"author_name":"Andrew Heyes","author_inst":"University of Maryland Center for Environmental Science"},{"author_name":"Jeremy Testa","author_inst":"University of Maryland Center for Environmental Science"},{"author_name":"Laura Lapham","author_inst":"University of Maryland Center for Environmental Science Chesapeake Biological Laboratory"},{"author_name":"Sarah Pacocha Preheim","author_inst":"Johns Hopkins University"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Diverse genome organization strategies for polysaccharide utilization in the oceans","rel_doi":"10.64898\/2026.09.21.753266","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.753266","rel_abs":"Carbohydrate-active enzymes (CAZymes) drive the turnover of polysaccharides in the oceans. However, the scale of diversity in polysaccharide utilization and genome organization strategies has yet to be characterized, particularly in marine ecosystems. In this paper, we introduce mpcgcdb.com as an interactive web catalog for marine CAZyme gene clusters, their associated metagenome-assembled genomes, and relevant enzyme families found in marine metagenomic samples. This database contains nearly 290,000 marine CAZyme gene clusters from more than 22,000 genomes, enabling user-initiated exploratory visualizations for genome organization networks and enzyme phylogeny. This tool will assist researchers in developing hypotheses about gene function, connecting species to metabolic niches, and identifying gaps where future work is needed to understand different pathways in marine glycan cycling.","rel_num_authors":3,"rel_authors":[{"author_name":"Aaron Oliver","author_inst":"Scripps Institution of Oceanography"},{"author_name":"Sheila Podell","author_inst":"University of California San Diego Scripps Institution of Oceanography"},{"author_name":"Eric E Allen","author_inst":"University of California, San Diego"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Genome assembly of Eucalyptus recurva provides insights into inbreeding and conservation priorities in Australia's rarest Eucalyptus","rel_doi":"10.64898\/2026.09.21.753279","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.753279","rel_abs":"Eucalyptus recurva (Mongarlowe Mallee) is Critically Endangered, with only six known adult individuals persisting across two sites in the Southern Tablelands of New South Wales, Australia. Its extreme rarity, uniquely long lifespan, and limited reproductive output make it a priority for conservation genomics. Here we report the first genome assembly of E. recurva: a haplotype-resolved, gapless, telomere-to-telomere (T2T) assembly produced from Oxford Nanopore Technologies (ONT) long-read sequencing. Both haplotypes span 11 chromosomes (consistent with the conserved Eucalyptus karyotype of 2n = 22), with assembly sizes of 521.1 Mb (Hap 1) and 501.5 Mb (Hap 2), BUSCO completeness >99.6%, and quality values of >QV 62. Comparative analyses place E. recurva within section Maidenaria as sister to Eucalyptus viminalis and reveal high synteny between the two species. Inter-haplotype comparison identified 3.6 million SNPs and modest structural variation, suggesting that, despite extreme demographic bottlenecking, E. recurva retains meaningful genomic heterozygosity. We also characterise the chloroplast genome, which exhibits heteroplasmy, and report an apparently bipartite mitochondrial genome. This reference genome provides an essential resource for conservation management, population genetics, and the study of eucalypt genome evolution.","rel_num_authors":2,"rel_authors":[{"author_name":"Eilish Summer McMaster","author_inst":"The University of Sydney"},{"author_name":"Ashley Jones","author_inst":"Australian National University"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Polyketide synthase 12 is an in vivo essential source of novel mycolyl lipids in Mycobacterium tuberculosis","rel_doi":"10.64898\/2026.09.25.754250","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.25.754250","rel_abs":"Mycobacterium tuberculosis (Mtb) is a major pathogen worldwide that infects and transmits only among humans, yet nearly all in vivo virulence research occurs in non-human hosts. To overcome this central challenge in tuberculosis research, we leveraged a dataset of more than 50,000 sequenced isolates to identify Mtb genes that that are functionally preserved during natural infection, disease causation, and transmission between humans. This whole-genome ranking identified polyketide synthase 12 (pks12 ) as an exceptionally in vivo essential gene in human tuberculosis, which we validated in zebrafish and mouse models. Though Pks12 produces a mycoketide lipid in only trace amounts, pks12 deletion severely altered the host-facing surface and arabinoglycan architecture of Mtb. This amplified effect was explained through the discovery of mannosyl-{beta}-1-phosphomycoketide monomycolate (MPMMM), which is synthesized from the known Pks12 product at higher abundance by antigen 85 mycolyltransferases. Thus, we used a new host-facing genomic-metabolomic-phenotypic approach to discover the functions of an in vivo essential Mtb gene, which controls the physical structure of the Mtb-host interface.","rel_num_authors":24,"rel_authors":[{"author_name":"Gregory H Babunovic","author_inst":"Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA"},{"author_name":"Sanne van der Niet","author_inst":"Electron Microscopy Center, Amsterdam University Medical Center, Amsterdam, NL"},{"author_name":"Marco TP Gontijo","author_inst":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC"},{"author_name":"Katherine Abrahams","author_inst":"School of Biosciences and Institute of Microbiology and Infection, University of Birmingham, Edgbaston, UK"},{"author_name":"Rongfeng Sun","author_inst":"Department of Genetics, University of North Carolina, Chapel Hill, NC"},{"author_name":"Kiranmai Bhatt","author_inst":"Walsall Manor Hospital NHS Trust, UK"},{"author_name":"Ella Meirav","author_inst":"Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA"},{"author_name":"Catherine Vilch\u00e8ze","author_inst":"Departments of Microbiology & Immunology and Genetics, Albert Einstein College of Medicine, New York, NY"},{"author_name":"David C Young","author_inst":"Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA"},{"author_name":"Lara Rosbach","author_inst":"Electron Microscopy Center, Amsterdam University Medical Center, Amsterdam, NL"},{"author_name":"Ign\u0117 Kanopait\u0117","author_inst":"Electron Microscopy Center, Amsterdam University Medical Center, Amsterdam, NL"},{"author_name":"Oyinda O Adefisayo","author_inst":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC"},{"author_name":"Kirsten M Smith","author_inst":"Department of Molecular Genetics and Microbiology and University Program in Genetics and Genomics, Duke University School of Medicine, Durham, NC"},{"author_name":"Ana Mar\u00eda Xet-Mull","author_inst":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC"},{"author_name":"V Grace Dellinger","author_inst":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC"},{"author_name":"Emilie Layre","author_inst":"Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA"},{"author_name":"Clare M Smith","author_inst":"Department of Molecular Genetics and Microbiology and University Program in Genetics and Genomics, Duke University School of Medicine, Durham, NC"},{"author_name":"William R Jacobs Jr.","author_inst":"Departments of Microbiology & Immunology and Genetics, Albert Einstein College of Medicine, New York, NY"},{"author_name":"Apoorva Bhatt","author_inst":"School of Biosciences and Institute of Microbiology and Infection, University of Birmingham, Edgbaston, UK"},{"author_name":"Gurdyal S Besra","author_inst":"School of Biosciences and Institute of Microbiology and Infection, University of Birmingham, Edgbaston, UK"},{"author_name":"David M Tobin","author_inst":"Departments of Molecular Genetics and Microbiology and Integrative Immunology, Duke University School of Medicine, Durham, NC"},{"author_name":"Qingyun Liu","author_inst":"Departments of Genetics and Microbiology & Immunology, University of North Carolina, Chapel Hill, NC"},{"author_name":"Nicole van der Wel","author_inst":"Electron Microscopy Center, Amsterdam University Medical Center, Amsterdam, NL"},{"author_name":"D Branch Moody","author_inst":"Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Boston, MA"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Genomic and phenotype-based framework for rational design of phage cocktails against Escherichia coli isolates from urinary tract infections","rel_doi":"10.64898\/2026.09.24.754182","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.24.754182","rel_abs":"Urinary tract infections (UTIs) are frequently caused by Escherichia coli and are increasingly associated with antimicrobial resistance, highlighting the need for alternative therapies. Although phage therapy is a promising approach, the rational selection of phages and phage cocktails remains challenging, particularly when detailed genomic information on the infecting strain is unavailable. In this study, we isolated 18 phages from environmental samples collected in Sherbrooke, Quebec, Canada. Genome sequencing identified 15 pure lytic phages representing diverse taxonomic groups and revealed prophage-derived contaminants in three isolates, underscoring the importance of genomic validation during phage discovery. Host range was determined using efficiency-of-plating (EOP) assays against UTI-associated E. coli isolates. Based on host-range overlap and cumulative EOP values, we developed a phenotype-based framework for phage cocktail design and classified combinations as redundant or complementary. Complementary cocktails composed of phages with distinct host ranges and high infection effectiveness consistently outperformed redundant combinations in time-kill assays, demonstrating that host-range diversity and lytic effectiveness are independent properties that should be considered separately during cocktail design. To evaluate cocktail performance under physiologically relevant conditions, the most effective combinations were tested in artificial urine. Both cocktails exhibited reduced activity compared with standard laboratory media, indicating that environmental conditions strongly influence phage-host interactions. Together, our results demonstrate that host-range overlap and cumulative infection effectiveness provide a practical framework for identifying effective phage combinations in the absence of detailed bacterial genomic information and may facilitate the rational development of phage therapies for UTIs.","rel_num_authors":7,"rel_authors":[{"author_name":"Paul Ugalde Silva","author_inst":"Universite de Sherbrooke"},{"author_name":"Ally Champoux","author_inst":"Universite de Sherbrooke"},{"author_name":"Annie Chenard","author_inst":"Universite de Sherbrooke"},{"author_name":"Serena Tuytschaevers","author_inst":"Yale University"},{"author_name":"Elodie Jolicoeur","author_inst":"Universite de Sherbrooke"},{"author_name":"Nathalie Rivard","author_inst":"Universite de Sherbrooke"},{"author_name":"Louis-Charles Fortier","author_inst":"Universite de Sherbrooke"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Restoring Aquaporin-4 alleviates molecular and motor phenotypes in zQ175 mouse model of Huntington disease","rel_doi":"10.64898\/2026.09.20.753038","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.20.753038","rel_abs":"Huntington&'s disease (HD) is characterized by progressive accumulation of mutant huntingtin (mHTT), neurodegeneration and motor dysfunction. Increasing evidence implicates impaired glymphatic function and loss of perivascular aquaporin 4 (AQP4) polarization in HD, suggesting that defective brain waste clearance may contribute to disease pathogenesis. Whether restoration of AQP4&-mediated glymphatic transport can ameliorate HD pathology remains unknown. We tested whether genetic restoration of AQP4 improves glymphatic function and HD&-associated phenotypes in heterozygous zQ175 knock-in mice. At 2 months of age, premanifest zQ175 mice received a single retro-orbital injection of BBB-penetrant AAV9&-PHP.eB encoding the AQP4 (M1 isoform). Glymphatic transport was assessed by intracisternal injection of fluorescent BSA 647 and quantification of parenchymal influx and drainage to the deep cervical lymph nodes. Perivascular AQP4 localization, mHTT aggregation, gliosis, DARPP32 immunoreactivity, CSF neurofilament light chain (NfL) and total Tau, structural brain volumes by 11.7T MRI, and motor behavior were assessed longitudinally through 12 months of age. AAV9&-PHP.eB&-AQP4 produced widespread brain expression and restored perivascular AQP4 localization in the striatum and cortex of zQ175 mice. AQP4 overexpression significantly increased glymphatic tracer influx into brain parenchyma and BSA-647 drainage to the deep cervical lymph nodes. At 12 months, AQP4 restoration reduced CSF NfL and total Tau concentrations, mHTT aggregate number and mean aggregate size, and striatal Iba1 positive microglia and GFAP-positive astrocytes (P < 0.05). AQP4 overexpression also preserved striatal DARPP32 immunoreactivity and significantly attenuated striatal atrophy measured by MRI. Female zQ175 mice showed improved balance-beam performance and locomotor activity, while effects on motor performance in males did not reach statistical significance. AQP4 overexpression attenuated body-weight loss in both sexes. No detectable structural, behavioral or body-weight abnormalities were observed following sustained AQP4 overexpression in wild-type mice. In summary, restoration of AQP4 enhances glymphatic transport and is associated with reduced proteopathic, neuroinflammatory and neurodegenerative phenotypes in zQ175 HD mice. These findings provide proof-of-concept that impaired glymphatic function is a modifiable component of HD pathology and support AQP4&-mediated restoration of brain waste clearance pathways as a potential disease-modifying therapeutic strategy.","rel_num_authors":11,"rel_authors":[{"author_name":"Hongshuai Liu","author_inst":"Johns Hopkins University"},{"author_name":"Zichen Ding","author_inst":"Johns Hopkins University"},{"author_name":"Yadi Wang","author_inst":"Johns Hopkins University"},{"author_name":"Helen Moniz","author_inst":"Johns Hopkins University"},{"author_name":"Yuguo Li","author_inst":"Johns Hopkins University"},{"author_name":"Yuxiao Ouyang","author_inst":"Johns Hopkins University"},{"author_name":"Chang Liu","author_inst":"Johns Hopkins University"},{"author_name":"John Andersen","author_inst":"Johns Hopkins University"},{"author_name":"Jun Hua","author_inst":"Kennedy Krieger Institute"},{"author_name":"Jiadi Xu","author_inst":"Kennedy Krieger Institute"},{"author_name":"Wenzhen Duan","author_inst":"Johns Hopkins University"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Restoring Aquaporin-4 alleviates molecular and motor phenotypes in zQ175 mouse model of Huntington disease","rel_doi":"10.64898\/2026.09.20.753038","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.20.753038","rel_abs":"Huntington&'s disease (HD) is characterized by progressive accumulation of mutant huntingtin (mHTT), neurodegeneration and motor dysfunction. Increasing evidence implicates impaired glymphatic function and loss of perivascular aquaporin 4 (AQP4) polarization in HD, suggesting that defective brain waste clearance may contribute to disease pathogenesis. Whether restoration of AQP4&-mediated glymphatic transport can ameliorate HD pathology remains unknown. We tested whether genetic restoration of AQP4 improves glymphatic function and HD&-associated phenotypes in heterozygous zQ175 knock-in mice. At 2 months of age, premanifest zQ175 mice received a single retro-orbital injection of BBB-penetrant AAV9&-PHP.eB encoding the AQP4 (M1 isoform). Glymphatic transport was assessed by intracisternal injection of fluorescent BSA 647 and quantification of parenchymal influx and drainage to the deep cervical lymph nodes. Perivascular AQP4 localization, mHTT aggregation, gliosis, DARPP32 immunoreactivity, CSF neurofilament light chain (NfL) and total Tau, structural brain volumes by 11.7T MRI, and motor behavior were assessed longitudinally through 12 months of age. AAV9&-PHP.eB&-AQP4 produced widespread brain expression and restored perivascular AQP4 localization in the striatum and cortex of zQ175 mice. AQP4 overexpression significantly increased glymphatic tracer influx into brain parenchyma and BSA-647 drainage to the deep cervical lymph nodes. At 12 months, AQP4 restoration reduced CSF NfL and total Tau concentrations, mHTT aggregate number and mean aggregate size, and striatal Iba1 positive microglia and GFAP-positive astrocytes (P < 0.05). AQP4 overexpression also preserved striatal DARPP32 immunoreactivity and significantly attenuated striatal atrophy measured by MRI. Female zQ175 mice showed improved balance-beam performance and locomotor activity, while effects on motor performance in males did not reach statistical significance. AQP4 overexpression attenuated body-weight loss in both sexes. No detectable structural, behavioral or body-weight abnormalities were observed following sustained AQP4 overexpression in wild-type mice. In summary, restoration of AQP4 enhances glymphatic transport and is associated with reduced proteopathic, neuroinflammatory and neurodegenerative phenotypes in zQ175 HD mice. These findings provide proof-of-concept that impaired glymphatic function is a modifiable component of HD pathology and support AQP4&-mediated restoration of brain waste clearance pathways as a potential disease-modifying therapeutic strategy.","rel_num_authors":11,"rel_authors":[{"author_name":"Hongshuai Liu","author_inst":"Johns Hopkins University"},{"author_name":"Zichen Ding","author_inst":"Johns Hopkins University"},{"author_name":"Yadi Wang","author_inst":"Johns Hopkins University"},{"author_name":"Helen Moniz","author_inst":"Johns Hopkins University"},{"author_name":"Yuguo Li","author_inst":"Johns Hopkins University"},{"author_name":"Yuxiao Ouyang","author_inst":"Johns Hopkins University"},{"author_name":"Chang Liu","author_inst":"Johns Hopkins University"},{"author_name":"John Andersen","author_inst":"Johns Hopkins University"},{"author_name":"Jun Hua","author_inst":"Kennedy Krieger Institute"},{"author_name":"Jiadi Xu","author_inst":"Kennedy Krieger Institute"},{"author_name":"Wenzhen Duan","author_inst":"Johns Hopkins University"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"MetExPred: A Comprehensive Prediction Framework with Protein-Context-Aware Multi-view Learning for Drug Metabolism and Excretion","rel_doi":"10.64898\/2026.09.21.753060","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.753060","rel_abs":"Within the ADMET continuum, metabolism and excretion (ME) form a critical bridge between drug exposure established by absorption and distribution and downstream efficacy and toxicity. However, no existing framework for drug ME prediction has simultaneously achieved broad coverage of endpoints and robust data recency and completeness. Here, we developed MetExPred, a multi-view prediction framework that comprises 17 classification endpoints and two regression endpoints, covering the overall drug ME process. The framework combines sequence-based and graph-based molecular representations, while optionally incorporating ESM-2 protein representations when experimentally annotated targets are available. A protein-aware masking strategy enables the same architecture to operate in both molecular-only and target-enhanced settings, and multi-view attention adaptively integrates the available representations. Across the classification tasks, MetExPred achieved mean AUROC, AUPRC and F1 scores of 0.844, 0.734 and 0.697, respectively. For clearance and half-life prediction, the model achieved RMSE values of 0.686 and 0.668. MetExPred showed the strongest average performance among the evaluated baselines, while ablation studies confirmed the complementary contributions of molecular sequence, graph and protein information. These results provide a unified and flexible modeling framework for systematic ME prediction of drug compounds, enabling early-stage virtual screening and pharmacokinetic assessment during lead optimization.","rel_num_authors":7,"rel_authors":[{"author_name":"Yuxin Huang","author_inst":"Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen"},{"author_name":"Jingting Wan","author_inst":"Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen"},{"author_name":"Gexuyang Wu","author_inst":"School of Medicine, The Chinese University of Hong Kong, Shenzhen"},{"author_name":"Danhong Dong","author_inst":"Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen"},{"author_name":"Yang-Chi-Dung Lin","author_inst":"Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen"},{"author_name":"Hsi-Yuan Huang","author_inst":"Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen"},{"author_name":"Hsien-Da Huang","author_inst":"Warshel Institute for Computational Biology, School of Medicine, The Chinese University of Hong Kong, Shenzhen"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"The Female Side of Autism: Sexual Dichotomies impacting the Helsmoortel-Van der Aa syndrome pathology.","rel_doi":"10.64898\/2026.09.20.752986","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.20.752986","rel_abs":"Background: Helsmoortel-Van der Aa syndrome, caused by pathogenic variants in ADNP, is characterised by substantial clinical heterogeneity, but how biological sex influences disease biology and treatment response remains an emerging area of investigation. Here, we investigated whether sex modifies the behavioural and molecular consequences of Adnp deficiency, the response to the investigational drug candidate davunetide (NAP), and the clinical phenotype of Helsmoortel-Van der Aa syndrome. Methods: We studied male and female Adnp heterozygous mice harbouring the p.Leu822Hisfs*6 variant and sex-matched wild-type littermates using continuous 24-h behavioural phenotyping, hippocampal genome-wide DNA methylation and bulk RNA sequencing. NAP effects on behaviour, hippocampal ADNP protein abundance, and epi-transcriptomic responses were assessed using genotype-by-treatment models. Four Core Genotypes mice were assessed to distinguish sex-chromosome and gonadal contributions to hippocampal Adnp transcript expression, and reproductive-tissue transcriptomes were analysed in Adnp mice to unravel a possible endocrine component of the disease. Findings were compared with clinical and developmental data from 129 individuals with Helsmoortel-Van der Aa syndrome. Findings: Adnp deficiency produced a shared overall behavioural phenotype in male and female mice, but through distinct patterns of behavioural disruption, indicating that sex modifies the implementation rather than the magnitude of the phenotype. This distinction was also evident at the molecular level: hippocampal DNA methylation was predominantly determined by genotype and showed convergence between sexes, whereas transcriptional responses diverged, with mitochondrial pathways predominating in males and chromatin, RNA processing, and cell-cycle pathways in females. NAP partially shifted behavioural abnormalities towards the wild-type state in both sexes and increased hippocampal ADNP protein abundance in heterozygous mice, without reversing the underlying methylation phenotype. Its transcriptional effects were markedly broader in males, indicating a sex-dependent molecular response to treatment. In reproductive tissues, Adnp deficiency was associated with convergent alterations in steroid hormone biosynthesis, despite no evidence for direct regulation of hippocampal Adnp expression by sex-chromosome complement or gonadal hormonal state. By contrast, sex was not associated with robust differences across the clinical and developmental features assessed in 129 individuals with Helsmoortel-Van der Aa syndrome after correction for multiple testing. Interpretation: Biological sex modifies how Adnp deficiency is expressed at behavioural and molecular levels, but these differences do not necessarily define distinct clinical phenotypes. The convergence of the methylation response alongside greater divergence in transcriptional and behavioural responses identifies sex as a modifier of disease biology rather than a determinant of the core phenotype. The sex-dependent response to NAP further indicates that biological sex may influence pharmacological responses even when treatment-associated behavioural improvement is observed in both sexes. These findings support consideration of biological sex as a prespecified variable in preclinical and clinical studies of Helsmoortel-Van der Aa syndrome and suggest that systematic investigation of sex-dependent biology may also be relevant to therapeutic development across rare diseases. Keywords: Helsmoortel-Van der Aa syndrome (HVDAS), Activity-Dependent Neuroprotective Protein (ADNP), autism spectrum disorder, intellectual disability, sex, mouse model, behaviour.","rel_num_authors":23,"rel_authors":[{"author_name":"Claudio Peter D'Incal","author_inst":"University of Antwerp"},{"author_name":"Joe Ibrahim","author_inst":"University of Antwerp"},{"author_name":"Mathijs B. Van der Lei","author_inst":"University of Antwerp"},{"author_name":"Lusine Harutyunyan","author_inst":"University of Antwerp"},{"author_name":"Kim Van Meel","author_inst":"University of Antwerp"},{"author_name":"Ellen Elinck","author_inst":"University of Antwerp"},{"author_name":"Ayu Scott","author_inst":"University of Antwerp"},{"author_name":"Anne Schepers","author_inst":"University of Antwerp"},{"author_name":"Lauren Moons","author_inst":"University of Antwerp"},{"author_name":"Marie Hannaert","author_inst":"University of Antwerp"},{"author_name":"Zlatko Marusic","author_inst":"University Hospital Centre Zagreb, Croatia"},{"author_name":"Mirna Anicic","author_inst":"University Hospital Centre Zagreb, Croatia"},{"author_name":"Jurica Vukovic","author_inst":"University Hospital Centre Zagreb, Croatia"},{"author_name":"Paschalis Theotokis","author_inst":"Aristotle University of Thessaloniki, Greece"},{"author_name":"Nikolaos Grigoriadis","author_inst":"Aristotle University of Thessaloniki, Greece"},{"author_name":"Monique de Booij Oomen","author_inst":"Erasmus MC, The Netherlands"},{"author_name":"Ligia Mateiu","author_inst":"University of Antwerp"},{"author_name":"Erik Fransen","author_inst":"University of Antwerp"},{"author_name":"Anna C Jansen","author_inst":"University Hospital Antwerp"},{"author_name":"Marije Meuwissen","author_inst":"University Hospital Antwerp"},{"author_name":"Dale John Annear","author_inst":"University of Antwerp"},{"author_name":"Illana Gozes","author_inst":"Tel Aviv University, Israel"},{"author_name":"R. Frank Kooy","author_inst":"University of Antwerp"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Efficacy of postmenopausal estrogen replacement in SIV-infected female macaques on antiretroviral therapy.","rel_doi":"10.64898\/2026.09.21.746440","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.746440","rel_abs":"The success of modern antiretroviral therapy (ART) has increased the life expectancy of people living with HIV to levels approaching that of uninfected individuals. For women living with HIV (WLWH), this means that more will survive to undergo menopause and experience the consequences of decreased ovarian hormone levels, particularly estrogen (E2). The recent change in federal guidance for use of postmenopausal hormone therapy is increasing demand for both E2-alone and E2+progestogen formulations to control adverse symptoms of menopause. The consequences and efficacy of hormone therapy in WLWH are thus an important issue for WLWH and their healthcare providers. The role of E2 replacement in postmenopausal WLWH is a significant issue because of its potential effects on control the viral reservoir and its demonstrated beneficial metabolic effects in uninfected postmenopausal women. To address these questions, we employed a novel nonhuman primate model of postmenopausal WLWH undergoing E2 replacement. Reproductively competent female rhesus macaques were infected with simian immunodeficiency virus (SIV) and then subjected to a daily ART regimen. After complete suppression of plasma viremia, all animals were ovariectomized (OVX) and then implanted with Silastic capsules containing either cholesterol vehicle or sufficient E2 to restore pre-OVX plasma levels. Plasma and cell-associated viral dynamics, immune responses, body composition, systemic and tissue-specific metabolic parameters, cytokine profiles, and parameters of bone health were followed longitudinally from baseline through 34 weeks of E2 deficiency or replacement. We found that E2 status did not significantly affect plasma or tissue viral dynamics or overall metabolic homeostasis. However, E2 replacement exerted beneficial effects on several aspects of bone health in spite of a chronic inflammatory state that persisted following effective ART suppression of the SIV reservoir. Our findings suggest that hormone therapy, specifically E2 replacement, offers benefit to WLWH, particularly with respect to bone loss.","rel_num_authors":23,"rel_authors":[{"author_name":"Gabriela M Webb","author_inst":"Oregon Health & Science University"},{"author_name":"Diana  L Takahashi","author_inst":"Oregon Health & Science University"},{"author_name":"Melissa  A Kirigiti","author_inst":"Oregon Health & Science University"},{"author_name":"Sarah R Lindsley","author_inst":"Oregon Health & Science University"},{"author_name":"Hannah Blomenkamp","author_inst":"Oregon Health & Science University"},{"author_name":"Cicely Zaro","author_inst":"Oregon Health & Science University"},{"author_name":"Molly Shallman","author_inst":"Oregon Health & Science University"},{"author_name":"Casey  M McGuire","author_inst":"Oregon Health & Science University"},{"author_name":"Heather Hofmeister","author_inst":"Oregon Health & Science University"},{"author_name":"Cleiton Pessoa","author_inst":"Oregon Health & Science University"},{"author_name":"Allyson McCullen","author_inst":"Oregon Health & Science University"},{"author_name":"Matthew Humkey","author_inst":"Oregon Health & Science University"},{"author_name":"Vahid Monfared","author_inst":"Oregon State University"},{"author_name":"Urszula T Iwaniec","author_inst":"Oregon State University"},{"author_name":"Russel T Turner","author_inst":"Oregon State University"},{"author_name":"Lina Gao","author_inst":"Oregon Health & Science University"},{"author_name":"Oleg Varlamov","author_inst":"Oregon Health & Science University"},{"author_name":"Phyllis C Tien","author_inst":"University of California, San Francisco"},{"author_name":"Jeffrey T Jensen","author_inst":"Oregon Health & Science University"},{"author_name":"Jonah  B Sacha","author_inst":"Oregon Health & Science University"},{"author_name":"Paul Kievit","author_inst":"Oregon Health & Science University"},{"author_name":"Charles T Roberts","author_inst":"Oregon National Primate Research Center"},{"author_name":"Kristen A Sauter","author_inst":"Oregon Health & Science University"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Efficacy of postmenopausal estrogen replacement in SIV-infected female macaques on antiretroviral therapy.","rel_doi":"10.64898\/2026.09.21.746440","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.746440","rel_abs":"The success of modern antiretroviral therapy (ART) has increased the life expectancy of people living with HIV to levels approaching that of uninfected individuals. For women living with HIV (WLWH), this means that more will survive to undergo menopause and experience the consequences of decreased ovarian hormone levels, particularly estrogen (E2). The recent change in federal guidance for use of postmenopausal hormone therapy is increasing demand for both E2-alone and E2+progestogen formulations to control adverse symptoms of menopause. The consequences and efficacy of hormone therapy in WLWH are thus an important issue for WLWH and their healthcare providers. The role of E2 replacement in postmenopausal WLWH is a significant issue because of its potential effects on control the viral reservoir and its demonstrated beneficial metabolic effects in uninfected postmenopausal women. To address these questions, we employed a novel nonhuman primate model of postmenopausal WLWH undergoing E2 replacement. Reproductively competent female rhesus macaques were infected with simian immunodeficiency virus (SIV) and then subjected to a daily ART regimen. After complete suppression of plasma viremia, all animals were ovariectomized (OVX) and then implanted with Silastic capsules containing either cholesterol vehicle or sufficient E2 to restore pre-OVX plasma levels. Plasma and cell-associated viral dynamics, immune responses, body composition, systemic and tissue-specific metabolic parameters, cytokine profiles, and parameters of bone health were followed longitudinally from baseline through 34 weeks of E2 deficiency or replacement. We found that E2 status did not significantly affect plasma or tissue viral dynamics or overall metabolic homeostasis. However, E2 replacement exerted beneficial effects on several aspects of bone health in spite of a chronic inflammatory state that persisted following effective ART suppression of the SIV reservoir. Our findings suggest that hormone therapy, specifically E2 replacement, offers benefit to WLWH, particularly with respect to bone loss.","rel_num_authors":23,"rel_authors":[{"author_name":"Gabriela M Webb","author_inst":"Oregon Health & Science University"},{"author_name":"Diana  L Takahashi","author_inst":"Oregon Health & Science University"},{"author_name":"Melissa  A Kirigiti","author_inst":"Oregon Health & Science University"},{"author_name":"Sarah R Lindsley","author_inst":"Oregon Health & Science University"},{"author_name":"Hannah Blomenkamp","author_inst":"Oregon Health & Science University"},{"author_name":"Cicely Zaro","author_inst":"Oregon Health & Science University"},{"author_name":"Molly Shallman","author_inst":"Oregon Health & Science University"},{"author_name":"Casey  M McGuire","author_inst":"Oregon Health & Science University"},{"author_name":"Heather Hofmeister","author_inst":"Oregon Health & Science University"},{"author_name":"Cleiton Pessoa","author_inst":"Oregon Health & Science University"},{"author_name":"Allyson McCullen","author_inst":"Oregon Health & Science University"},{"author_name":"Matthew Humkey","author_inst":"Oregon Health & Science University"},{"author_name":"Vahid Monfared","author_inst":"Oregon State University"},{"author_name":"Urszula T Iwaniec","author_inst":"Oregon State University"},{"author_name":"Russel T Turner","author_inst":"Oregon State University"},{"author_name":"Lina Gao","author_inst":"Oregon Health & Science University"},{"author_name":"Oleg Varlamov","author_inst":"Oregon Health & Science University"},{"author_name":"Phyllis C Tien","author_inst":"University of California, San Francisco"},{"author_name":"Jeffrey T Jensen","author_inst":"Oregon Health & Science University"},{"author_name":"Jonah  B Sacha","author_inst":"Oregon Health & Science University"},{"author_name":"Paul Kievit","author_inst":"Oregon Health & Science University"},{"author_name":"Charles T Roberts","author_inst":"Oregon National Primate Research Center"},{"author_name":"Kristen A Sauter","author_inst":"Oregon Health & Science University"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"TE-aware state analysis and evolution in dynamic network connectivity","rel_doi":"10.64898\/2026.09.20.753026","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.20.753026","rel_abs":"Multi-echo functional magnetic resonance imaging (fMRI) acquires signals with distinct contrast profiles across echo times (TEs). Empirical evidence suggests that different TEs capture distinct signal contributions with varying sensitivity to BOLD and non-BOLD processes from long to short TEs (Stroman, 2002; Krishnamurthy, 2023; Dong, 2024). Previous literature has not yet examined how brain states extracted from temporal dynamic functional connectivity (dFNC) evolve across TEs. Here we present a methodological and empirical study of TE-dependent evolution of dynamic connectivity states, with a phenomenological two-component model for interpretation. Multiple echoes were acquired with an echo planar time-resolved imaging (EPTI) sequence. TE-specific components were extracted via atlas-based group ICA (Neuromark 1.0), and brain connectivity states were generated via windowed dFNC and spatial ICA clustering of windows. Within-subject and group-level states evolved across TEs in network organization and variance. States exhibited TE-dependent variance profiles, with distinct peak echo times; and group-level points of state transition were independently mapped to TE-dependent transitions in variance. We modified a bi-exponential model to simulate and model changes in the dFNC time-course across TEs. The bi-exponential model revealed high consistency with subject states (R2 fit=0.86, res. error=0.55, 86% model convergence rate), suggesting a two-component signal system contributing to dynamic TE-dependent connectivity changes in state. A significant correlation between relative model terms was estimated on a cell-wise basis across states (r(24) = -0.43, p=0.03, 95% CI [-0.70, -0.04]). This suggests that specific bi-exponential signal parameters (i.e., short FNC1,TE=0, long FNC2,TE=0, and long FNC2,decay) were associated with the observed TE-dependent variations in connectivity states across TEs. In sum, our analyses provide downstream implications for TE-aware state analysis dependent on connectivity magnitude (FNCTE=0) and rate of connectivity decay (FNCdecay), in a two-component signal model, with future implications for TE-dependent state biomarkers.","rel_num_authors":8,"rel_authors":[{"author_name":"Micah Holness","author_inst":"Georgia State University"},{"author_name":"Anastasia Bohsali","author_inst":"Georgia State University"},{"author_name":"Bradley Baker","author_inst":"Georgia Tech: Georgia Institute of Technology"},{"author_name":"Sir-Lord Wiafe","author_inst":"Georgia State University"},{"author_name":"Zijing Dong","author_inst":"Athinoula A. Martinos Center for Biomedical Imaging"},{"author_name":"Fuyixue Wang","author_inst":"Athinoula A. Martinos Center for Biomedical Imaging"},{"author_name":"Lisa Krishnamurthy","author_inst":"Emory University"},{"author_name":"Vince Calhoun","author_inst":"Georgia State, Georgia Tech, and Emory"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Quantitative Systems Pharmacology Model for Trop-2 Targeting Antibody-Drug Conjugate in Triple-Negative Breast Cancer","rel_doi":"10.64898\/2026.09.20.752985","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.20.752985","rel_abs":"TROP2-targeted antibody-drug conjugates (ADCs) have demonstrated promising clinical activity in triple-negative breast cancer (TNBC) as monotherapies; however, therapeutic benefit varies among patients. Combination strategies pairing TROP2-targeted ADCs with immune checkpoint inhibitors are also being investigated. Elucidating the mechanistic drivers of ADC monotherapy variability and enabling the rational development of combination regimens require computational frameworks that integrate ADC pharmacology with tumor-immune interactions. A quantitative systems pharmacology (QSP) model is presented that incorporates an ADC module into our established immuno-oncology model for TNBC. The module captures ADC and payload pharmacokinetics and pharmacodynamics. TNBC heterogeneity is represented by two tumor cell clones with high and low TROP2 expression, informed by prior characterizations, and differential sensitivity to the ADC payload is incorporated as an intrinsic property of each clone. Although generalizable, the model was applied to the TROP2-targeted ADC sacituzumab govitecan (SG, TRODELVY). A virtual patient cohort was generated using Latin hypercube sampling and calibrated against objective response rate (ORR) data from SG Phase I\/II TNBC basket trial. The model predicted an ORR of 33.2% consistent with ASCENT study (NCT02574455). Simulations suggest TROP2-mediated delivery contributes modestly to SG efficacy with tumor exposure driven largely by systemically released SN-38 payload being sufficient to induce cytotoxicity. Tumor heterogeneity emerged as a key determinant of response with ORR increasing as the fraction of payload-sensitive clones increased. Overall, this QSP framework for TROP2-targeted ADCs accounts for TNBC heterogeneity and is extendable to other ADCs and targets enabling interrogation of ADC mechanisms of action in conjunction with tumor-immune interactions.","rel_num_authors":6,"rel_authors":[{"author_name":"Sedat Dogru","author_inst":"Johns Hopkins University"},{"author_name":"Ashwatha Suresh","author_inst":"Johns Hopkins University"},{"author_name":"Edward P. Bowman","author_inst":"Merck & Co., Inc., Rahway, NJ, USA"},{"author_name":"Anshu Marathe","author_inst":"Merck & Co., Inc., Rahway, NJ, USA"},{"author_name":"Azher M. Hussain","author_inst":"Merck & Co., Inc., Rahway, NJ, USA"},{"author_name":"Aleksander S. Popel","author_inst":"Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Physiological Aging and Cardiovascular Disease Distinctly Remodel the Human Cardiac Lymphatic Endothelium","rel_doi":"10.64898\/2026.09.22.750171","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.750171","rel_abs":"Aims: Cardiac lymphatic endothelial cells (LECs) regulate tissue homeostasis, immune trafficking, and remodeling, but how human cardiac LEC heterogeneity changes with physiological aging and cardiovascular disease remains poorly defined. We sought to define age- and disease-associated LEC states, their regulatory and microenvironmental programs, and the functional relevance of selected pathways. Methods and results: We integrated human cardiac single-nucleus transcriptomic datasets spanning physiological aging, dilated and hypertrophic cardiomyopathy, doxorubicin-associated cardiomyopathy, and heart failure with preserved ejection fraction. Aging redistributed LECs among pre-existing states, with expansion of a homeostatic immune-surveillance state and loss of cytokine-responsive and polarity-associated states. Cardiovascular diseases showed a distinct trajectory, with depletion of a non-failing homeostatic state and expansion of shared and disease-associated remodeling states. SCENIC and NicheNet\/MultiNicheNet identified state-specific regulatory programs and disease-dependent signaling networks, with recurrent BMP\/TGF-{beta}\/activin-family signaling. ACVR2A was prioritized in human doxorubicin-associated cardiomyopathy; endothelial Acvr2a deletion in aged doxorubicin-treated mice was associated with improved cardiac function and increased open cardiac lymphatic vessels. Independent human spatial transcriptomic analyses supported selected aging- and disease-associated programs. Conclusion: Physiological aging and cardiovascular disease remodel cardiac LECs through distinct changes in cellular state, transcriptional regulation, and microenvironmental signaling. Aging is associated with redistribution and reduced representation of specialized LEC programs, whereas cardiovascular diseases redirect LECs through disease-associated signaling environments, highlighting context-dependent remodeling of the cardiac lymphatic endothelium across aging and disease.","rel_num_authors":7,"rel_authors":[{"author_name":"Haotian Chen","author_inst":"UCSD"},{"author_name":"Sydney Chao","author_inst":"Wellesley University"},{"author_name":"Yanxi Shi","author_inst":"MGB"},{"author_name":"Zihui Yang","author_inst":"MGB"},{"author_name":"Jason Roh","author_inst":"Massachusetts General Hospital"},{"author_name":"Paul B. Yu","author_inst":"Massachusetts General Hospital"},{"author_name":"Peng Xia","author_inst":"Mass General Brigham"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"MCseg: AI agent-guided workflow search for no-code cell segmentation and transcript attribution in spatial transcriptomics","rel_doi":"10.64898\/2026.09.20.752837","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.20.752837","rel_abs":"Cell-level analysis of high-resolution spatial transcriptomics depends on accurate segmentation and transcript assignment, yet current workflows often trade transcript capture for boundary purity and can require substantial image-analysis expertise. We developed MCseg, a downloadable no-code platform whose fixed segmentation engine was derived by an AI-agent-guided search in which an AI agent iteratively proposed and evaluated combinations of image-processing and segmentation operations against Xenium-derived cell boundaries. In a lung adenocarcinoma development set, fixed-parameter MCseg increased mean panoptic quality from 0.432 to 0.472 relative to an Optuna-tuned two-diameter Cellpose baseline, while a reference-guided calibration analysis reached 0.554. In an independent expert-annotated colorectal cancer region, MCseg showed higher lineage recall and micro-F1 than the StarDist-based ENACT workflow among cells covered by both methods. Across 15 colorectal cancer regions, MCseg increased neighborhood expression discordance and reduced lineage-exclusive co-expression relative to Space Ranger at similar UMI density. The fixed workflow also transferred to fresh-frozen breast cancer without tissue-specific architecture search, illustrating an agent-guided route to reproducible, locally deployable cell-level spatial transcriptomic analysis.","rel_num_authors":5,"rel_authors":[{"author_name":"Chi-Ru Chan","author_inst":"Department of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei 106, Taiwan"},{"author_name":"Nai-Wen Chang","author_inst":"Department of Medical Research, National Taiwan University Hospital, Taipei 100, Taiwan"},{"author_name":"Chia-Yi Wang","author_inst":"Department of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei 106, Taiwan"},{"author_name":"Hsin-Yuan Tan","author_inst":"Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou, Taiwan"},{"author_name":"Sung-Jan Lin","author_inst":"Department of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei 106, Taiwan"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"AetherXeno: an allele-resolved receptor-occupancy atlas for regulatory pharmacogenomics","rel_doi":"10.64898\/2026.09.20.752952","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.20.752952","rel_abs":"Motivation: Interpreting noncoding pharmacogenomic variants requires identifying the regulatory program that may be perturbed and the direction of the effect, information not supplied by population frequency or general regulatory annotations. Results: We developed AetherXeno, an allele-resolved atlas that scores all substitutions across 8,691 experimentally supported elements for PXR, FXR and AhR and connects 17.27 million variants to evidence matched by exact allele. Across the six paired comparisons, the gain in Spearman correlation ranged from 0.039 to 0.334. Every regional bootstrap interval excluded zero. Homology exclusion preserved these findings, while motif core and liver expression enrichment supported biological organization of the score landscape. The browser, programmatic interface and bulk files expose the same versioned records from individual variants to cohort analyses. Availability and implementation: The web resource is available at https:\/\/aetherxeno.org and the versioned data at doi:10.5281\/zenodo.20753827.","rel_num_authors":4,"rel_authors":[{"author_name":"Yen-Hung Chen","author_inst":"China Medical University"},{"author_name":"Teng-Che Chuang","author_inst":"China Medical University Hospital"},{"author_name":"Hsiang-Wen Lin","author_inst":"China Medical University"},{"author_name":"Yi-Chuan Li","author_inst":"China Medical University"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"MERFISHEYES: Web-based Visualization and Sharing Platform for Single-cell and Single-molecule Spatial Transcriptomics","rel_doi":"10.64898\/2026.09.20.753029","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.20.753029","rel_abs":"Interactive exploration and sharing of hybridization-based spatial transcriptomics datasets remain limited by large file sizes, specialized software, and computationally intensive preprocessing, restricting rapid access to publicly available resources such as the Brain Image Library. Here we present MERFISHEYES (https:\/\/merfisheyes.com), a browser-based platform for interactive visualization of single-cell and single-molecule spatial transcriptomics data across commercial and emerging high-throughput platforms. MERFISHEYES enables marker gene exploration, cross-dataset and cross-species comparison, visualization of subcellular RNA localization, and collaborative sharing through browser-accessible links generated directly from drag-and-drop datasets. We use MERFISHEYES to enable browser-based visualization of all 158 spatial transcriptomics datasets in the Brain Image Library and demonstrate its capabilities in handling high-throughput 3D data with genome-scale imputation of gene expression and DNA accessibility. MERFISHEYES provides a scalable framework for rapid exploration, sharing, and collaborative analysis of spatial transcriptomics data.","rel_num_authors":9,"rel_authors":[{"author_name":"Ignatius Jenie","author_inst":"Department of Bioengineering, University of California San Diego"},{"author_name":"Evan Mishkin","author_inst":"Department of Cellular and Molecular Medicine, University of California San Diego"},{"author_name":"Elvis Smith","author_inst":"Department of Cellular and Molecular Medicine, University of California San Diego"},{"author_name":"Mariah Kenney","author_inst":"Pittsburgh Supercomputing Center, Carnegie Mellon University"},{"author_name":"Ivan Cao-Berg","author_inst":"Pittsburgh Supercomputing Center, Carnegie Mellon University"},{"author_name":"Roy Maimon","author_inst":"Department of Biomedical Engineering, New York University Tandon School of Engineering"},{"author_name":"Alexander J. Ropelewski","author_inst":"Pittsburgh Supercomputing Center, Carnegie Mellon University"},{"author_name":"Don W. Cleveland","author_inst":"Department of Bioengineering, University of California San Diego"},{"author_name":"Bogdan Bintu","author_inst":"Department of Bioengineering, University of California San Diego; Department of Cellular and Molecular Medicine, University of California San Diego"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Brain age prediction from structural and functional connectivity across the lifespan using connectome-based predictive modeling","rel_doi":"10.64898\/2026.09.21.753233","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.753233","rel_abs":"Brain maturation and aging are characterized by widespread changes in structural and functional brain organization. The extent to which these modalities capture shared versus distinct signatures of lifespan development and aging remains unclear. In this study, we applied connectome-based predictive modeling (CPM) to connectomes derived from diffusion MRI and resting-state functional MRI in Human Connectome Project Development, Young Adult, Aging, and combined Lifespan cohorts to predict chronological age. Both structural and functional connectomes significantly predicted age across cohorts, demonstrating that age-related information is distributed throughout whole-brain connectivity patterns. Prediction performance varied across lifespan stages, with generally stronger performance in the Development, Aging, and Lifespan cohorts than in Young Adulthood. Structural and functional models produced significantly correlated predicted ages in several cohorts, indicating shared age-related information across modalities. Structural-functional convergence analyses revealed limited and variable correspondence between modality-specific predictive features, suggesting that structural and functional connectomes capture both shared and complementary aspects of brain maturation and aging. Network-level analyses demonstrated that age-predictive information was distributed across canonical brain networks, including cerebellar, frontoparietal, salience, somatomotor, and subcortical networks, with patterns varying across cohorts and modalities. Multimodal CPM improved prediction relative to unimodal models in several cohorts, supporting the complementary contribution of structural and functional connectivity to age prediction. Cross-cohort, cross-sex, and cross-modality analyses further characterized the generalizability and shared information of predictive models across lifespan stages, sexes, and imaging modalities. This work demonstrates the utility of CPM for characterizing distributed structural and functional connectivity patterns associated with chronological age across the lifespan and provides a foundation for future studies of individual variability in brain maturation and aging.","rel_num_authors":5,"rel_authors":[{"author_name":"Marie C McCusker","author_inst":"Yale University"},{"author_name":"Javid Dadashkarimi","author_inst":"University of Pennsylvania"},{"author_name":"Huili Sun","author_inst":"Yale University"},{"author_name":"Matthew Rosenblatt","author_inst":"Massachusetts General Hospital"},{"author_name":"Dustin Scheinost","author_inst":"Yale University"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Differential roles of frontoparietal regions in working memory and decision-making","rel_doi":"10.64898\/2026.09.23.753872","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.23.753872","rel_abs":"Working memory (WM) and decision-making (DM) are closely linked cognitive processes that rely on frontoparietal regions, yet their distinct and shared neural dynamics remain unclear. Using intracranial EEG recordings from 24 human subjects performing a delayed match-to-sample task, we examined high-frequency broadband (HFB) activity to dissociate WM- and DM-related processes with high spatiotemporal resolution. Principal component analysis of frontoparietal HFB activity revealed multiple temporally distinct patterns spanning stimulus presentation and delay phases. The most dominant component reflected sustained WM-related activity across task phases, consistent with persistent maintenance of internal representations. Additional components captured transient WM encoding across trial phases, as well as both stimulus-linked and ramping DM-related activity suggesting dual early and late stages of evaluative processing. These processes were distributed across frontoparietal regions but showed systematic differences in anatomical focus, with WM-related activity concentrated in dorsolateral prefrontal cortex (PFC) and DM-related activity concentrated in ventrolateral PFC, while inferior parietal cortex preferentially tracked the behavioral significance of incoming stimuli and superior parietal cortex tracked the appearance of new information that may require updating ongoing processing. Together, these findings demonstrate that WM and DM processes are separable yet interleaved over time within distributed cortical networks, revealing coordinated but functionally distinct contributions to goal-directed behavior.","rel_num_authors":13,"rel_authors":[{"author_name":"Sophie Elinore Ack","author_inst":"Northwestern University"},{"author_name":"Samantha M. Gray","author_inst":"Stanford University"},{"author_name":"Adam J. O. Dede","author_inst":"Northwestern University"},{"author_name":"David King-Stephens","author_inst":"University of California, Irvine"},{"author_name":"Kenneth D. Laxer","author_inst":"California Pacific Medical Center"},{"author_name":"Ignacio Saez","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Fady Girgis","author_inst":"University of California, Davis; University of Calgary"},{"author_name":"Stephan U. Schuele","author_inst":"Northwestern University"},{"author_name":"Joshua M. Rosenow","author_inst":"Northwestern University"},{"author_name":"Eishi Asano","author_inst":"Children's Hospital of Michigan"},{"author_name":"Robert T. Knight","author_inst":"UC Berkeley"},{"author_name":"Rodrigo M. Braga","author_inst":"Northwestern University"},{"author_name":"Elizabeth L. Johnson","author_inst":"Northwestern University"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Frontoparietal effective connectivity supports working memory in early childhood","rel_doi":"10.64898\/2026.09.23.753700","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.23.753700","rel_abs":"Working memory (WM), a core executive function that supports learning and reasoning, undergoes rapid development during early childhood years. Neural activation patterns underlying WM have been extensively studied in both adults and children, revealing increasing involvement of the frontoparietal network (FPN) with age and coordinated interactions with the default mode network (DMN). However, relatively little is known about how these network interactions develop in children, particularly within the visuospatial domain. The present study investigated the influence of age and task performance on effective connectivity within the FPN and its interactions with DMN hubs during a visuospatial WM task in early childhood. Functional MRI data were collected during a visual n-back task with two WM load levels (0-back and 2-back) in 120 typically developing children aged 5-8 years. Dynamic Causal Modeling (DCM) with parametric empirical Bayes was used to estimate effective connectivity among eight regions of interest spanning the FPN and DMN. Behaviorally, age-related gains were steepest under high-load for accuracy, and under low-load for reaction time, suggesting WM capacity is a demand-sensitive marker of development at this age. At the network level, high-load robustly engaged the FPN, whereas low-load was associated with relatively greater engagement of DMN and episodic memory-related regions. Baseline effective connectivity was dominated by parietal-to-frontal drive and strong self-inhibition in the anterior cingulate cortex. Age-related effects on this architecture were sparse, involving asymmetric interhemispheric frontal coupling and reduced parieto-cingulate coupling, whereas accuracy-related effects were larger in magnitude, particularly at self-connections. More accurate children showed greater excitability in frontal and parietal FPN nodes alongside increased self-inhibition in the precuneus, a DMN hub, consistent with a neural efficiency account in which better performance reflects more selective, rather than more global, network engagement. Task load further shaped connectivity in distinct ways: low-load elicited widespread inter-regional modulation, whereas high-load predominantly modulated self-connections, with age and accuracy effects on this modulation dissociating by load. These findings suggest that, in primary school children, current task performance was associated with more pronounced differences in frontoparietal effective connectivity than was age, and that WM-related network engagement becomes increasingly selective and load-dependent across this developmental window.","rel_num_authors":9,"rel_authors":[{"author_name":"Carole Guedj","author_inst":"University of Geneva"},{"author_name":"Lia Bollinger","author_inst":"University of Applied Sciences and Arts Western Switzerland HES-SO, Geneva School of Health Sciences, Geneva Musical Minds lab (GEMMI lab), Geneva, Switzerland"},{"author_name":"Damien Marie","author_inst":"University of Applied Sciences and Arts Western Switzerland HES-SO, Geneva School of Health Sciences, Geneva Musical Minds lab (GEMMI lab), Geneva, Switzerland"},{"author_name":"Gianvito Laera","author_inst":"University of Applied Sciences and Arts Western Switzerland HES-SO, Geneva School of Health Sciences, Geneva Musical Minds lab (GEMMI lab), Geneva, Switzerland"},{"author_name":"Romain Ceresetti","author_inst":"University of Applied Sciences and Arts Western Switzerland HES-SO, Geneva School of Health Sciences, Geneva Musical Minds lab (GEMMI lab), Geneva, Switzerland"},{"author_name":"Alessio Comparini","author_inst":"CIBM Center for Biomedical Imaging, University of Geneva, 1211 Geneva, Switzerland."},{"author_name":"Jonas Richiardi","author_inst":"Lausanne University Hospital and University of Lausanne"},{"author_name":"Matthias Kliegel","author_inst":"Faculty of Psychology and Educational Sciences, University of Geneva, Switzerland"},{"author_name":"Clara E. James","author_inst":"HES-SO University of Applied Sciences and Arts Western Switzerland"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Modelling pairwise and coalitional contests with reinforcement learning","rel_doi":"10.64898\/2026.09.23.753778","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.23.753778","rel_abs":"Game theory in biology started as an attempt to model animal contests by making assumptions about the fitness costs individuals pay in aggressive interactions. Among the different approaches, a notable one is to construct mechanistic models, using assumptions about behaviours and cognitive processes. Reinforcement learning is an important cognitive process, and we use it here to model pairwise and coalitional contests. We study situations where territorial neighbours become so-called dear enemies. A defending individual can get help from a neighbour through a defender-neighbour coalition against a challenger attempting territory takeover. In our model, coalition members have an advantage in contests in terms of costs of aggression, with the challenger being exposed to aggression from both members and each member only receiving part of the aggression from the challenger. We find that notable costs of border conflicts between neighbours, together with substantial advantages for coalitions, favour intervention. Neighbours intervene when they can help weaker defenders, in this way avoiding costs of border renegotiation with a new and potentially stronger territory owner. We also introduce different forms of perceived costs into the model, which we show correspond to the range from pure mutual assessment to partial self-assessment.","rel_num_authors":2,"rel_authors":[{"author_name":"Olof Leimar","author_inst":"Stockholm University"},{"author_name":"Redouan Bshary","author_inst":"University of Neuchatel"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Translation fidelity mechanisms and their changes in aging","rel_doi":"10.64898\/2026.09.24.754133","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.24.754133","rel_abs":"Protein errors (amino acid misincorporations) are associated to protein misfolding and misfunction, and lower levels correlate with longer lifespan. Despite their prevalence, proteome-wide tracking of misincorporations in eukaryotes is challenging, with most insights being recent and coming from the mining of extensive proteomics data sets. These experimental challenges have precluded the direct in vivo probing and full understanding of the bases of fidelity in higher eukaryotes, and their influence in complex processes such as aging. Here we measured proteome-wide misincorporation frequencies in two experimentally tractable eukaryotic systems, yeast and mouse, using mass spectrometry. We find translation fidelity is organism and organ specific. The measured error frequencies correlate with codon:anticodon pairing thermodynamics and tRNA pool composition, which can have synergistic or opposing effects on fidelity depending on organism or tissue type. Most identified protein errors carry a negative fitness burden. Aging experiments in our two systems reveal that, with age, error frequencies increase in post-mitotic cells, but not so in mitotic ones. These changes correlate with remodeling of the tRNA pool, which we identify as a crucial regulator of translation fidelity during lifespan.","rel_num_authors":8,"rel_authors":[{"author_name":"Mauricio Aguilar Rangel","author_inst":"Department of Structural Biology, Stanford University; Stanford, USA"},{"author_name":"Casey Powers","author_inst":"SUMS, Stanford University; Stanford, USA"},{"author_name":"Jaeyoon Lee","author_inst":"Department of Bioengineering, Stanford University; Stanford, USA"},{"author_name":"Haley E. Tarbox","author_inst":"Department of Chemistry, Johns Hopkins University; Baltimore, USA"},{"author_name":"Neil B. Wood","author_inst":"T.C. Jenkins Department of Biophysics, Johns Hopkins University; Baltimore, USA"},{"author_name":"Stephen D. Fried","author_inst":"Department of Chemistry, Johns Hopkins University; Baltimore, USA"},{"author_name":"Stephen Quake","author_inst":"Department of Bioengineering, Stanford University; Stanford, USA"},{"author_name":"Joseph Puglisi","author_inst":"Department of Structural Biology, Stanford University; Stanford, USA"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"ALDH1B1 promotes mitochondrial \u03b3-butyrobetaine biosynthesisand fatty acid oxidation in colorectal cancer","rel_doi":"10.64898\/2026.09.24.753323","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.24.753323","rel_abs":"Metabolic reprogramming is a hallmark of cancer cells, and stem-like populations often upregulate aldehyde dehydrogenases (ALDHs). Functional studies have established essential roles for individual ALDH isoforms in tumor initiation, progression, and metastasis; however, the mechanisms by which these enzymes promote malignancy remain poorly understood. Here we show that aldehyde dehydrogenase 1B1 (ALDH1B1), a mitochondrial enzyme highly expressed in colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC), generates {gamma}-butyrobetaine (GBB) and {gamma}-aminobutyric acid (GABA) in CRC cells. The biosynthesis of both aminocarboxylic acids has been attributed to the cytosolic enzyme ALDH9A1, and we demonstrate that mitochondrial GBB and GABA are functionally distinct from the cytosolic pools of these metabolites. We further demonstrate that mitochondrial GBB can function as an antiport substrate of carnitine-acylcarnitine translocase (CACT), the transporter that mediates fatty acid uptake into the mitochondrial inner matrix. This activity complements the role of cytosolic GBB as the biosynthetic precursor to carnitine. Accordingly, ALDH1B1 can markedly enhance mitochondrial fatty acid oxidation (FAO), a catabolic process that has been linked to CRC and PDAC stemness, progression, and metastasis. Our findings reveal an unexpected role for ALDH1B1 in carnitine metabolism, GABA biosynthesis, and FAO and illustrate how the compartmental reprogramming of metabolic pathways can promote tumor growth.","rel_num_authors":13,"rel_authors":[{"author_name":"Zhiping Feng","author_inst":"Stanford University"},{"author_name":"Thomas E Bearrood","author_inst":"Stanford University"},{"author_name":"Sydney L Campbell","author_inst":"UCLA"},{"author_name":"Adrianne M Kinsey","author_inst":"Stanford University"},{"author_name":"Nedas Matulionis","author_inst":"UCLA"},{"author_name":"Che-Hong Chen","author_inst":"Stanford University"},{"author_name":"Takuya Seike","author_inst":"Stanford University"},{"author_name":"Logan Leak","author_inst":"Stanford University"},{"author_name":"Ahit Kaan Tarhan","author_inst":"Stanford University"},{"author_name":"Scott J Dixon","author_inst":"Stanford University"},{"author_name":"Daria Mochly-Rosen","author_inst":"Stanford University"},{"author_name":"Heather R Christofk","author_inst":"UCLA"},{"author_name":"James K Chen","author_inst":"Stanford University"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Loss of polr1c disrupts myelination in a zebrafish model of POLR1C-associated disease","rel_doi":"10.64898\/2026.09.24.752997","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.24.752997","rel_abs":"Pathogenic variants in POLR1C, which encodes a shared subunit of RNA Polymerases (Pols) I and III, cause Treacher Collins syndrome (TCS) and POLR3-related leukodystrophy. While Pol I and Tp53-dependent mechanisms have been implicated in the pathogenesis of TCS, the basis of hypomyelination in POLR1C-associated POLR3-related leukodystrophy remains incompletely understood. Here, we show that polr1c mutant zebrafish exhibit reduced myelination in addition to previously described craniofacial anomalies. Oligodendrocyte precursor cells exhibit increased activation of the Tp53 pathway; however, these cells do not undergo apoptosis. Consistent with this finding, tp53 inhibition reduces cell death in polr1c mutants but fails to restore myelination, indicating that myelination deficits are not driven by Tp53-dependent progenitor loss in this model. polr1c mutants also exhibit reduced rRNA transcription by Pol I and reduced expression of some Pol III-transcribed tRNAs. Altogether, these data indicate distinct tissue-specific responses to polr1c deficiency and suggest persistent impairment of rRNA transcription contributes to deficient myelin development. These findings expand the developmental consequences of polr1c loss and advance our understanding of the molecular basis of POLR1C-associated diseases.","rel_num_authors":10,"rel_authors":[{"author_name":"Lauren B. Sands","author_inst":"Department of Craniofacial, Oral and Materials Sciences, University of Colorado Anschutz, Aurora, CO, USA"},{"author_name":"Camille E.A. Goo","author_inst":"Department of Craniofacial, Oral and Materials Sciences, University of Colorado Anschutz, Aurora, CO, USA"},{"author_name":"Laura K. White","author_inst":"Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz, Aurora, CO, USA"},{"author_name":"Bailey T. Lubash","author_inst":"Department of Craniofacial, Oral and Materials Sciences, University of Colorado Anschutz, Aurora, CO, USA"},{"author_name":"M. Cathleen McKinney","author_inst":"Stowers Institute for Medical Research, Kansas City, MO, USA"},{"author_name":"Fengli Guo","author_inst":"Stowers Institute for Medical Research, Kansas City, MO, USA"},{"author_name":"Chris W. Seidel","author_inst":"Stowers Institute for Medical Research, Kansas City, MO, USA"},{"author_name":"Xia Zhao","author_inst":"Stowers Institute for Medical Research, Kansas City, MO, USA"},{"author_name":"Paul A. Trainor","author_inst":"Department of Pediatrics, McGovern School of Medicine, UTHealth, Houston, TX, USA"},{"author_name":"Kristin Watt","author_inst":"Department of Craniofacial, Oral and Materials Sciences, University of Colorado Anschutz, Aurora, CO, USA"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"APOA1 links a late fetal epithelial program to colonic maturation and injury responses","rel_doi":"10.64898\/2026.09.24.754040","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.24.754040","rel_abs":"Developmental programs establish tissue identity and organization, but how their reactivation contributes to adult tissue responses remains poorly understood. Here, we identify a functional contribution of apolipoprotein A-I (APOA1), which marks a late fetal colonic epithelial state that reappears after injury. Spatial and temporal profiling localized Apoa1 transcription predominantly to epithelial cells at the tips of developing proximal colonic folds. Apoa1 loss delayed fold maturation and altered the abundance and composition of developing enteroendocrine populations, linking this apolipoprotein to mucosal architecture and epithelial differentiation. APOA1 protein closely interacted with WNT5A during development and injury, while Apoa1 deficiency increased Wnt5a expression and altered its epithelial protein distribution. Following colonic injury, single-cell and spatial profiling identified genotype-associated transcriptional changes involving stress responses, barrier and immune functions, and metabolism, with a shared component across males and females. These changes accompanied reduced enteroendocrine representation and increased representation of inflammation-associated macrophages. Finally, regional and compartmental expression analyses, together with hindgut explant perturbation, identified HOXB7 transcription factor as a regulator of developmental Apoa1 expression. Together, these findings establish functional relevance for a component of a reactivated late fetal epithelial program, connecting APOA1 to colonic maturation and the epithelial and inflammatory organization of injured tissue.","rel_num_authors":10,"rel_authors":[{"author_name":"Aline B\u00f6niger","author_inst":"Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland"},{"author_name":"Valerie Georgette Katimi Varela","author_inst":"Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland"},{"author_name":"Dillon King","author_inst":"Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland"},{"author_name":"Tomas Valenta","author_inst":"Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland; Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czec"},{"author_name":"Giulia Moro","author_inst":"Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland"},{"author_name":"Costanza Borrelli","author_inst":"Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland; Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY, U"},{"author_name":"Michael David Br\u00fcgger","author_inst":"Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland"},{"author_name":"Patrick Diener","author_inst":"Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland"},{"author_name":"Andreas E. Moor","author_inst":"Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland"},{"author_name":"Hassan Fazilaty","author_inst":"Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland; Department of Gastroenterology and Hepatology, University Hospital Zurich, Uni"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Disrupting aberrant EGFR catalytic trimers reverses T790M gefitinib resistance","rel_doi":"10.64898\/2026.09.24.754095","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.24.754095","rel_abs":"Epidermal growth factor receptor (EGFR) mutations drive up to 50% of non-small-cell lung cancers (NSCLC). Although tyrosine kinase inhibitors provide substantial clinical benefit, remissions are prematurely terminated by the inevitable acquisition of on-target resistance. Beyond structural changes that alter ATP-pocket affinity, EGFR oligomerization drives this resistance, though the underlying mechanisms remain unclear. Here we show that progressive secondary and tertiary resistant NSCLC EGFR-mutants form ligand-free cell surface oligomers that contain catalytic trimers instead of the canonical dimers found within these oligomers in wild-type and gefitinib-sensitive EGFR-mutants. Genetically disrupting these pathological trimers into dimers via a single-point mutation rewires downstream signaling, decelerates tumor progression, and reverses gefitinib resistance in vivo. Conversely, genetic engineering of dimers into trimers reinstates normal tumor growth. These findings reveal a structural vulnerability specific to these refractory variants, demonstrating that targeting intra-oligomer interactions can overcome resistance, and providing a blueprint for protein-protein interface modulation strategies in NSCLC.","rel_num_authors":13,"rel_authors":[{"author_name":"Selene K Roberts","author_inst":"UKRI-STFC Rutherford Appleton Laboratory, Didcot, United Kingdom"},{"author_name":"Ioannis Galdadas","author_inst":"Atomistic Simulations, Italian Institute of Technology, Genova, Italy"},{"author_name":"Nicola Piasentin","author_inst":"School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland"},{"author_name":"Sarah R Needham","author_inst":"Central Laser Facility, UKRI-STFC Rutherford Appleton Laboratory, Didcot, Oxfordshire, UK"},{"author_name":"Laura C Zanetti-Domingues","author_inst":"Central Laser Facility, UKRI-STFC Rutherford Appleton Laboratory, Didcot, Oxfordshire, UK"},{"author_name":"Benjamin M Davis","author_inst":"Central Laser Facility, UKRI-STFC Rutherford Appleton Laboratory, Didcot, Oxfordshire, UK"},{"author_name":"Rico C H Man","author_inst":"Imaging Therapies and Cancer Group, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, Kings College London, London, UK"},{"author_name":"David T Clarke","author_inst":"Central Laser Facility, UKRI-STFC Rutherford Appleton Laboratory, Didcot, Oxfordshire, UK"},{"author_name":"Andrew H A Clayton","author_inst":"Optical Sciences Centre, School of Science, Computing and Emerging Technologies, Swinburne University of Technology, Melbourne, Australia"},{"author_name":"Daniel J Rolfe","author_inst":"Central Laser Facility, UKRI-STFC Rutherford Appleton Laboratory, Didcot, Oxfordshire, UK"},{"author_name":"Gilbert O Fruhwirth","author_inst":"Imaging Therapies and Cancer Group, Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Sciences, Kings College London, London, UK"},{"author_name":"Francesco L Gervasio","author_inst":"School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland"},{"author_name":"Marisa L Martin-Fernandez","author_inst":"Central Laser Facility, UKRI-STFC Rutherford Appleton Laboratory, Didcot, Oxfordshire, UK"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Stimulatrix: An open-source automated platform for high-throughput functional characterization of engineered contractile tissues","rel_doi":"10.64898\/2026.09.24.750079","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.24.750079","rel_abs":"Engineered cardiac and skeletal muscle tissues suspended between flexible posts support disease modeling and pharmacology, yet their stimulation, longitudinal imaging and quantitative analysis often remain fragmented and labor-intensive. Here we present Stimulatrix, an open-source platform integrating automated video acquisition within a cell culture incubator, synchronized electrical stimulation and deep learning for longitudinal assessment of contractile tissues in multiwell plates. The platform quantifies tissue compaction, force generation and contraction kinetics with optional cloud processing reducing dependence on local GPU hardware. We demonstrate the workflow in cardiac tissues comprising human induced pluripotent stem cell-derived cardiomyocytes and cardiac fibroblasts, and in primary human skeletal muscle constructs. Force and kinetic measurements were benchmarked against manual annotations. Longitudinal profiling resolved responses to matrix composition and pacing regimens and tracked doxorubicin-associated loss of cardiac contractile force. Stimulatrix provides an accessible workflow for automated functional phenotyping of engineered muscle tissues.","rel_num_authors":13,"rel_authors":[{"author_name":"Michael Winkelbauer","author_inst":"ETH Zurich"},{"author_name":"Julien Bast","author_inst":"ETH Zurich"},{"author_name":"Elena Sophie Casalino","author_inst":"ETH Zurich"},{"author_name":"Maria Bulatova","author_inst":"ETH Zurich"},{"author_name":"Melanie Generali","author_inst":"Universitat Zurich"},{"author_name":"Shafeeq Mohammed","author_inst":"University of Zurich"},{"author_name":"Gommaar D'Hulst","author_inst":"ETH Zurich"},{"author_name":"Thomas Laumonier","author_inst":"University of Geneva"},{"author_name":"Francesco Paneni","author_inst":"University Hospital Zurich"},{"author_name":"Katrien De Bock","author_inst":"ETH Zurich"},{"author_name":"Prateek Katiyar","author_inst":"Novartis"},{"author_name":"Ori Bar-Nur","author_inst":"ETH Zurich"},{"author_name":"Parth Chansoria","author_inst":"ETH Zurich"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"4-Dimensional Chess: Acoustic Localisation Reveals Nested Spatio-temporal Strategies in an Arboreal Communication Network","rel_doi":"10.64898\/2026.09.21.752596","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.752596","rel_abs":"1. Adaptive behavioural strategies require animals to simultaneously navigate social and ecological domains across multiple spatial and temporal scales. Although drones and computer vision have recently transformed the study of wild animal societies, many nocturnal species and those occupying structurally complex habitats remain inaccessible to these approaches, limiting our understanding of behaviour in natural settings. 2. We aimed to determine how behavioural strategies are organised across nested spatial and temporal scales within a wild communication network. 3. We used three-dimensional acoustic localisation and source separation to track individual male Hyperolius sp. A, a nocturnal African reed frog, within a natural rainforest chorus and quantify patterns of site fidelity, movement, spatial organisation, and call-timing interactions. 4. Males exhibited significant site fidelity across nights, while chorus spatial structure varied with local caller density. Within nights, individuals followed a stereotyped behavioural sequence, descending from elevated arboreal refugia before settling into lower calling positions near breeding sites. At finer temporal scales, call-timing interactions varied according to both local competitor density and the proximity of neighbouring rivals. 5. These findings demonstrate that behavioural strategies emerge across nested spatial and temporal scales and that long-term spatial positioning, short-term movement decisions, and moment-to-moment signalling interactions are tightly linked within natural communication networks. More broadly, acoustic localisation provides a powerful framework for studying behaviour in species and habitats that remain difficult to observe using conventional approaches.","rel_num_authors":5,"rel_authors":[{"author_name":"Edmund W Basham","author_inst":"University of Texas at Austin"},{"author_name":"Luke Cullen Larter","author_inst":"Brown University, Smithsonian Tropical Research Institute, University of Texas at Austin"},{"author_name":"Patrick S Champagne","author_inst":"University of Queensland, New Brunswick Museum"},{"author_name":"Douglas L Jones","author_inst":"University of Illinois at Urbana-Champaign"},{"author_name":"Timothy H Keitt","author_inst":"University of Texas at Austin"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Postnatal maternal separation alters caregiving patterns but fails to promote anxiety- and depressive-like behaviour in C57BL\/6N mouse dams","rel_doi":"10.64898\/2026.09.22.753354","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.753354","rel_abs":"Stressors experienced during the postnatal period may increase vulnerability to mental health disorders, including postpartum depression and anxiety. In rodents, maternal separation (MS) has been shown to alter behaviours in dams, but these observations have been made almost exclusively in rats and thus robust mouse models of postpartum mental health disorders using this stressor remain limited. Here we first examined, in mice, the effects of MS on maternal caregiving and on anxiety- and depressive-like behaviours. As stress-induced inflammatory activation in the gut-brain axis has been associated with behavioural alterations in non-postpartum contexts, changes in pro-inflammatory cytokines and tight junction proteins in the brain and intestinal tract were also examined. Female C57BL\/6N mice were assigned to a No Separation (NS) or a MS condition that consisted of 3-hour daily separation sessions from postnatal days (P) 2 to 14. Maternal care behaviours were assessed on P3 and P7, followed by anxiety- and depressive-like behaviours on P22 and P23, and the collection of the medial prefrontal cortex (mPFC) and colon on P24 to determine the expression of selected genes. Caregiving patterns in MS dams fluctuated throughout the early postnatal period. Although behaviours and gene expression outcomes remained unchanged by MS, grooming time in the splash test was correlated with the expression of different genes in the mPFC. These findings suggest that C57BL\/6 mouse dams may be less sensitive to the actions of MS on behaviour and on brain and intestinal markers of inflammation and barrier permeability, at least when examined shortly after weaning.","rel_num_authors":3,"rel_authors":[{"author_name":"Victoria Mordvinova","author_inst":"University of Ottawa"},{"author_name":"Tamara Trowsse","author_inst":"Carleton University"},{"author_name":"Marie-Claude Audet","author_inst":"University of Ottawa"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Postnatal maternal separation alters caregiving patterns but fails to promote anxiety- and depressive-like behaviour in C57BL\/6N mouse dams","rel_doi":"10.64898\/2026.09.22.753354","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.753354","rel_abs":"Stressors experienced during the postnatal period may increase vulnerability to mental health disorders, including postpartum depression and anxiety. In rodents, maternal separation (MS) has been shown to alter behaviours in dams, but these observations have been made almost exclusively in rats and thus robust mouse models of postpartum mental health disorders using this stressor remain limited. Here we first examined, in mice, the effects of MS on maternal caregiving and on anxiety- and depressive-like behaviours. As stress-induced inflammatory activation in the gut-brain axis has been associated with behavioural alterations in non-postpartum contexts, changes in pro-inflammatory cytokines and tight junction proteins in the brain and intestinal tract were also examined. Female C57BL\/6N mice were assigned to a No Separation (NS) or a MS condition that consisted of 3-hour daily separation sessions from postnatal days (P) 2 to 14. Maternal care behaviours were assessed on P3 and P7, followed by anxiety- and depressive-like behaviours on P22 and P23, and the collection of the medial prefrontal cortex (mPFC) and colon on P24 to determine the expression of selected genes. Caregiving patterns in MS dams fluctuated throughout the early postnatal period. Although behaviours and gene expression outcomes remained unchanged by MS, grooming time in the splash test was correlated with the expression of different genes in the mPFC. These findings suggest that C57BL\/6 mouse dams may be less sensitive to the actions of MS on behaviour and on brain and intestinal markers of inflammation and barrier permeability, at least when examined shortly after weaning.","rel_num_authors":3,"rel_authors":[{"author_name":"Victoria Mordvinova","author_inst":"University of Ottawa"},{"author_name":"Tamara Trowsse","author_inst":"Carleton University"},{"author_name":"Marie-Claude Audet","author_inst":"University of Ottawa"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Comparing morphological and molecular methods for stream macroinvertebrate biodiversity assessment across seven watersheds in the southern United States","rel_doi":"10.64898\/2026.09.24.754159","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.24.754159","rel_abs":"Freshwater biodiversity is declining at alarming rates globally, yet our capacity to monitor it depends heavily on the methods used for biodiversity assessment. Stream benthic macroinvertebrates are widely used as bioindicators, but traditional morphological identification is labor-intensive and limited by taxonomic expertise, while DNA metabarcoding offers a promising but incompletely evaluated alternative. Here, we compared biodiversity patterns detected by four macroinvertebrate sampling and identification methods (morphological identification of benthic samples, morphological identification of combined benthic and stream-edge samples, eDNA metabarcoding of bulk benthic samples, and eDNA metabarcoding of streamwater) across 62 sites in seven watersheds spanning the southern continental United States. We compared methods across three facets of biodiversity (gamma diversity, alpha diversity, and taxonomic composition) and three taxonomic levels (family, genus, and species). We found that which method detected more taxa shifted with taxonomic resolution: morphological methods detected more families and genera, while metabarcoding methods detected more species. Bulk benthic metabarcoding detected more families and genera than water eDNA metabarcoding, consistent with the \"watered-down biodiversity\" effect of DNA dilution in water samples, but the two metabarcoding methods did not differ significantly in species richness. All four methods detected largely distinct suites of taxa, with metabarcoding methods yielding more unique taxa than morphological methods. Notably, taxa uniquely detected by water eDNA were dominated by soft-bodied organisms (oligochaetes, leeches, earthworms) and water-column-associated taxa, while benthic eDNA uniquely detected hard-bodied EPT insects. We attribute this pattern to fundamental differences in eDNA shedding, transport, and deposition dynamics across organism types. These results demonstrate that no single method captures a complete picture of stream macroinvertebrate biodiversity, and that method choice should be guided by the taxonomic resolution and community components most relevant to the goals of the bioassessment program.","rel_num_authors":25,"rel_authors":[{"author_name":"Daniel C. Allen","author_inst":"The Pennsylvania State University"},{"author_name":"Zacchaeus G. Compson","author_inst":"University of North Texas"},{"author_name":"Chelsea Smith","author_inst":"University of Alabama"},{"author_name":"Michael T. Bogan","author_inst":"University of Arizona"},{"author_name":"Lindsey E. Vande Streek","author_inst":"University of North Texas"},{"author_name":"Kaley Cave","author_inst":"University of North Texas"},{"author_name":"Arial Shogren","author_inst":"University of Alabama"},{"author_name":"Carla L. Atkinson","author_inst":"University of Alabama"},{"author_name":"Brian A. Gill","author_inst":"University of Arizona"},{"author_name":"Luiza Goncalves Lazzaro","author_inst":"The Pennsylvania State University"},{"author_name":"Fagbohun Ibrahim","author_inst":"The Pennsylvania State University"},{"author_name":"Meryl C. Mims","author_inst":"Virginia Tech"},{"author_name":"Travis Apgar","author_inst":"California Department of Fish and Wildlife"},{"author_name":"Albert Ruhi","author_inst":"University of California, Berkeley"},{"author_name":"Sean Emmons","author_inst":"Climate Central, Inc."},{"author_name":"Kierstyn T. Higgins","author_inst":"The Pennsylvania State University"},{"author_name":"Stephen C. Cook","author_inst":"University of Oklahoma"},{"author_name":"Samuel Silknetter","author_inst":"Susquehanna University"},{"author_name":"Kyle Leathers","author_inst":"University of California, Berkeley"},{"author_name":"Megan Malish","author_inst":"Michigan State University"},{"author_name":"Michelle H. Busch","author_inst":"Michigan State University Extension"},{"author_name":"Thomas Neeson","author_inst":"University of Oklahoma"},{"author_name":"Veronica Saenz","author_inst":"University of Michigan"},{"author_name":"Rose Mohammadi","author_inst":"University of California, Berkeley"},{"author_name":"Yang Hong","author_inst":"University of Oklahoma"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Comparing morphological and molecular methods for stream macroinvertebrate biodiversity assessment across seven watersheds in the southern United States","rel_doi":"10.64898\/2026.09.24.754159","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.24.754159","rel_abs":"Freshwater biodiversity is declining at alarming rates globally, yet our capacity to monitor it depends heavily on the methods used for biodiversity assessment. Stream benthic macroinvertebrates are widely used as bioindicators, but traditional morphological identification is labor-intensive and limited by taxonomic expertise, while DNA metabarcoding offers a promising but incompletely evaluated alternative. Here, we compared biodiversity patterns detected by four macroinvertebrate sampling and identification methods (morphological identification of benthic samples, morphological identification of combined benthic and stream-edge samples, eDNA metabarcoding of bulk benthic samples, and eDNA metabarcoding of streamwater) across 62 sites in seven watersheds spanning the southern continental United States. We compared methods across three facets of biodiversity (gamma diversity, alpha diversity, and taxonomic composition) and three taxonomic levels (family, genus, and species). We found that which method detected more taxa shifted with taxonomic resolution: morphological methods detected more families and genera, while metabarcoding methods detected more species. Bulk benthic metabarcoding detected more families and genera than water eDNA metabarcoding, consistent with the \"watered-down biodiversity\" effect of DNA dilution in water samples, but the two metabarcoding methods did not differ significantly in species richness. All four methods detected largely distinct suites of taxa, with metabarcoding methods yielding more unique taxa than morphological methods. Notably, taxa uniquely detected by water eDNA were dominated by soft-bodied organisms (oligochaetes, leeches, earthworms) and water-column-associated taxa, while benthic eDNA uniquely detected hard-bodied EPT insects. We attribute this pattern to fundamental differences in eDNA shedding, transport, and deposition dynamics across organism types. These results demonstrate that no single method captures a complete picture of stream macroinvertebrate biodiversity, and that method choice should be guided by the taxonomic resolution and community components most relevant to the goals of the bioassessment program.","rel_num_authors":25,"rel_authors":[{"author_name":"Daniel C. Allen","author_inst":"The Pennsylvania State University"},{"author_name":"Zacchaeus G. Compson","author_inst":"University of North Texas"},{"author_name":"Chelsea Smith","author_inst":"University of Alabama"},{"author_name":"Michael T. Bogan","author_inst":"University of Arizona"},{"author_name":"Lindsey E. Vande Streek","author_inst":"University of North Texas"},{"author_name":"Kaley Cave","author_inst":"University of North Texas"},{"author_name":"Arial Shogren","author_inst":"University of Alabama"},{"author_name":"Carla L. Atkinson","author_inst":"University of Alabama"},{"author_name":"Brian A. Gill","author_inst":"University of Arizona"},{"author_name":"Luiza Goncalves Lazzaro","author_inst":"The Pennsylvania State University"},{"author_name":"Fagbohun Ibrahim","author_inst":"The Pennsylvania State University"},{"author_name":"Meryl C. Mims","author_inst":"Virginia Tech"},{"author_name":"Travis Apgar","author_inst":"California Department of Fish and Wildlife"},{"author_name":"Albert Ruhi","author_inst":"University of California, Berkeley"},{"author_name":"Sean Emmons","author_inst":"Climate Central, Inc."},{"author_name":"Kierstyn T. Higgins","author_inst":"The Pennsylvania State University"},{"author_name":"Stephen C. Cook","author_inst":"University of Oklahoma"},{"author_name":"Samuel Silknetter","author_inst":"Susquehanna University"},{"author_name":"Kyle Leathers","author_inst":"University of California, Berkeley"},{"author_name":"Megan Malish","author_inst":"Michigan State University"},{"author_name":"Michelle H. Busch","author_inst":"Michigan State University Extension"},{"author_name":"Thomas Neeson","author_inst":"University of Oklahoma"},{"author_name":"Veronica Saenz","author_inst":"University of Michigan"},{"author_name":"Rose Mohammadi","author_inst":"University of California, Berkeley"},{"author_name":"Yang Hong","author_inst":"University of Oklahoma"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Fine-tuning neuron number: Lzts as a key regulator of neurogenesis and cell proliferation in Ciona","rel_doi":"10.64898\/2026.09.24.754029","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.24.754029","rel_abs":"How progenitor mitotic timing is coupled to the number of neurons in a nervous system remains poorly understood, in part because most model systems have large, variable progenitor pools that obscure this relationship. The non-vertebrate chordate Ciona robusta offers a tractable alternative: its larval nervous system arises from an invariant lineage, including four Bipolar Tail Neurons (BTNs) that are reproducibly generated from the caudal neural plate border. Here we investigate the developmental function of the single Ciona ortholog belonging to the leucine zipper tumor suppressor (Lzts) gene family, whose vertebrate members are implicated in cell-cycle regulation and tumor suppression. In Ciona, Lzts is expressed in several embryonic tissues, including differentiating BTNs. Tissue-specific CRISPR\/Cas9 knockout of Lzts in the BTN lineage produced supernumerary BTNs, without expanding the embryonic Neurog+ domain, indicating that Lzts acts downstream of BTN specification to limit neuron number. Lzts1 promotes Cdk1 activity via stabilization of Cdc25C, co-expression of Ciona Cdc25C or a non-phosphorylatable Cdk1\/2\/3 mutant rescued normal BTN number in Lzts crispants, proving the existence of an ancestral Lzts-Cdc25-Cdk1 circuit controlling neural cell cycle. These findings establish Ciona Lzts as a regulator of mitotic tempo determining the BTN number and suggest that this cell-cycle regulatory axis links proliferation to neurogenesis across chordates in vivo.","rel_num_authors":7,"rel_authors":[{"author_name":"Paola Olivo","author_inst":"Stazione Zoologica Anton Dohrn, Georgia Institute of Technology"},{"author_name":"Ugo C Coppola","author_inst":"Florida Gulf Coast University"},{"author_name":"Mark Passero","author_inst":"Florida Gulf Coast University"},{"author_name":"Christopher Johnson","author_inst":"Georgia Institute of Technology"},{"author_name":"Sabrina A. Hernandez","author_inst":"Georgia Institute of Technology"},{"author_name":"Alberto Stolfi","author_inst":"Georgia Institute of Technology"},{"author_name":"Filomena Ristoratore","author_inst":"Stazione Zoologica Anton Dohrn"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Regulation of polyphosphate homeostasis in S. cerevisiae by the Sky1 protein kinase","rel_doi":"10.64898\/2026.09.24.753767","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.24.753767","rel_abs":"Eukaryotic cells store inorganic phosphate in the form of long chains called polyphosphates (polyP) that can reach many hundreds of residues in length. In the budding yeast Saccharomyces cerevisiae, polyP is synthesized by the VTC complex using ATP as a substrate and sequestered at high concentrations in the vacuole. Here, polyP chain length and turnover are regulated by the polyphosphatase enzymes Ppn1 and Ppn2. In the vacuole lumen, polyP plays a critical role in phosphate and ion homeostasis. Beyond the vacuole, minor populations of polyP are thought to impact various cellular functions, including in the nucleus, in part by binding to target proteins. We speculated that polyP metabolism must be tightly coupled to mechanisms of homeostatic control operating elsewhere in the cell. In this work, we report that cells lacking Sky1, a serine-arginine repeat protein kinase, have very low levels of polyP, an effect that is exacerbated by alkaline stress. Under these conditions sky1{triangleup} mutants also display increased expression of a subset of genes from the PHO regulon. Genetic analysis suggests that both phenotypes are linked to an increase in potassium influx via the Trk1 potassium transporter. Loss of Npl3, a known target of Sky1, partially rescues the phosphate homeostasis defects in sky1{triangleup} mutants, although this occurs independently of a well characterized Sky1 phosphorylation site on Npl3. Finally, the loss of polyP in sky1{triangleup} mutants depends on the Ppn1 and Ppn2 polyphosphatases and the Pep4 protease located in the vacuole. Altogether, our work provides novel insights into how polyP homeostasis in the vacuole is coordinated with events occurring throughout the cell.","rel_num_authors":4,"rel_authors":[{"author_name":"Alix Denoncourt","author_inst":"University of Ottawa"},{"author_name":"Sarah McKeague","author_inst":"University of Ottawa"},{"author_name":"Selin Gabbarizadeh","author_inst":"University of Ottawa"},{"author_name":"Mike Downey","author_inst":"University of Ottawa"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Regulation of polyphosphate homeostasis in S. cerevisiae by the Sky1 protein kinase","rel_doi":"10.64898\/2026.09.24.753767","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.24.753767","rel_abs":"Eukaryotic cells store inorganic phosphate in the form of long chains called polyphosphates (polyP) that can reach many hundreds of residues in length. In the budding yeast Saccharomyces cerevisiae, polyP is synthesized by the VTC complex using ATP as a substrate and sequestered at high concentrations in the vacuole. Here, polyP chain length and turnover are regulated by the polyphosphatase enzymes Ppn1 and Ppn2. In the vacuole lumen, polyP plays a critical role in phosphate and ion homeostasis. Beyond the vacuole, minor populations of polyP are thought to impact various cellular functions, including in the nucleus, in part by binding to target proteins. We speculated that polyP metabolism must be tightly coupled to mechanisms of homeostatic control operating elsewhere in the cell. In this work, we report that cells lacking Sky1, a serine-arginine repeat protein kinase, have very low levels of polyP, an effect that is exacerbated by alkaline stress. Under these conditions sky1{triangleup} mutants also display increased expression of a subset of genes from the PHO regulon. Genetic analysis suggests that both phenotypes are linked to an increase in potassium influx via the Trk1 potassium transporter. Loss of Npl3, a known target of Sky1, partially rescues the phosphate homeostasis defects in sky1{triangleup} mutants, although this occurs independently of a well characterized Sky1 phosphorylation site on Npl3. Finally, the loss of polyP in sky1{triangleup} mutants depends on the Ppn1 and Ppn2 polyphosphatases and the Pep4 protease located in the vacuole. Altogether, our work provides novel insights into how polyP homeostasis in the vacuole is coordinated with events occurring throughout the cell.","rel_num_authors":4,"rel_authors":[{"author_name":"Alix Denoncourt","author_inst":"University of Ottawa"},{"author_name":"Sarah McKeague","author_inst":"University of Ottawa"},{"author_name":"Selin Gabbarizadeh","author_inst":"University of Ottawa"},{"author_name":"Mike Downey","author_inst":"University of Ottawa"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"Chemical Synthesis of Thrombostasin: An Anticoagulant Protein Produced by the Horn Fly Haematobia irritans","rel_doi":"10.64898\/2026.09.24.754047","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.24.754047","rel_abs":"Thrombostasin is a cysteine-free anticoagulant protein produced by the horn fly Haematobia irritans, featuring an unusual stretch of seven consecutive aspartate residues within the polypeptide sequence. Here, we report the first chemical synthesis of native thrombostasin and a hepta-glutamate analogue, together with assessment of their thrombin inhibitory and anticoagulant activity.","rel_num_authors":10,"rel_authors":[{"author_name":"Sameer S. Kulkarni","author_inst":"The University of Sydney"},{"author_name":"Daniel J. Ford","author_inst":"The University of Sydney"},{"author_name":"Lucas Kambanis","author_inst":"The University of Sydney"},{"author_name":"Chenming Tang","author_inst":"The University of Sydney"},{"author_name":"Nisharnthi M. Duggan","author_inst":"The University of Sydney"},{"author_name":"Mel Shishido","author_inst":"The University of Sydney"},{"author_name":"Joshua W. C. Maxwell","author_inst":"The University of Sydney"},{"author_name":"Jorge Ripoll-Rozada","author_inst":"The University of Sydney"},{"author_name":"Pedro Jose Barbosa Pereira","author_inst":"The University of Sydney"},{"author_name":"Richard J Payne","author_inst":"The University of Sydney"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"A Community-Driven Single-Cell PBMC Reference Integrating Landmark Datasets Spanning Health and Disease","rel_doi":"10.64898\/2026.09.21.749940","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.21.749940","rel_abs":"Blood provides an accessible window into human health, yet the absence of a peripheral blood mononuclear cells (PBMCs) reference with standardized immune cell annotations has constrained comparisons between single-cell RNA sequencing (scRNAseq) studies. Here, we present HARP (Human Cell Atlas Reference for PBMCs), an integrated atlas of ~9 million PBMCs from >2,600 donors across 15 studies spanning four continents, encompassing diverse populations, neonates to 97 years, across health and diverse immune-related diseases. We developed optimized integration workflows, including novel label-free metrics to assess integration quality, and generated community-driven consensus annotations for 192 immune cell subsets, identifying rare populations representing as few as 0.004% of PBMCs. HARP reveals coordinated cellular modules associated with age, sex, and disease, identifies female-biased interferon and inflammatory gene programs and their perturbation by COVID-19, and uncovers a novel sexual dimorphism in prostaglandin signaling. Finally, we introduce scTiger, a hierarchical label-transfer framework that accurately projects these 192 cell annotations onto ~18 million additional PBMCs, providing a robust and transferable reference for harmonizing future PBMC studies. HARP provides a high-resolution community-driven reference atlas for PBMC annotation and analysis, as a basis for emerging clinical applications of single-cell genomics.","rel_num_authors":50,"rel_authors":[{"author_name":"Ana-Maria Cujba","author_inst":"Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK"},{"author_name":"Sergio Aguilar-Fernandez","author_inst":"Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Adrien Antoinette","author_inst":"Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Wamia Said","author_inst":"Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Michaela F. Mueller","author_inst":"Institute of Computational Biology, Helmholtz Munich, Neuherberg\/Munich, Germany"},{"author_name":"Kian Hong Kock","author_inst":"Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Republic of Singapore"},{"author_name":"Jacquelyn Nestor","author_inst":"Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Radhika Sonthalia","author_inst":"Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Republic of Singapore"},{"author_name":"Eliora V. Buyamin","author_inst":"Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Republic of Singapore"},{"author_name":"Pragya Rawat","author_inst":"Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Alexander Predeus","author_inst":"Wellcome Sanger Institute, Cambridge, UK"},{"author_name":"Lorenz Kretschmer","author_inst":"Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK"},{"author_name":"Lijiang Fei","author_inst":"Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK"},{"author_name":"Kamil Slowikowski","author_inst":"Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Pritha Sen","author_inst":"Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Christopher V. Cosgriff","author_inst":"Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"- MGH COVID-19 Collection & Processing Team","author_inst":""},{"author_name":"Olli Dufva","author_inst":"Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK"},{"author_name":"Mohamad Askari","author_inst":"Sapienza University of Rome, Rome, Italy"},{"author_name":"Kyle Kimler","author_inst":"Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Mary Futey","author_inst":"Broad Institute of MIT and Harvard, Cambridge, MA, USA"},{"author_name":"Ida Zucchi","author_inst":"European Bioinformatics Institute (EMBL-EBI), Cambridge, UK"},{"author_name":"Arsenios Chatzigeorgiou","author_inst":"European Bioinformatics Institute (EMBL-EBI), Cambridge, UK"},{"author_name":"Parisa Nejad","author_inst":"UC Santa Cruz Genomics Institute, Santa Cruz, CA, USA"},{"author_name":"Liying Jin","author_inst":"Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK"},{"author_name":"Blake Bowen","author_inst":"Garvan Institute for Medical Research, Darlinghurst, Australia"},{"author_name":"Andrian Yang","author_inst":"Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK"},{"author_name":"Rik G.H. Lindeboom","author_inst":"The Netherlands Cancer Institute, Amsterdam, The Netherlands"},{"author_name":"Rachelly Normand","author_inst":"Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Stathis Megas","author_inst":"Medical University of Vienna, Vienna, Austria"},{"author_name":"Yoshinari Ando","author_inst":"RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan"},{"author_name":"Ankita Chatterjee","author_inst":"John C. Martin Centre for Liver Research and Innovations, Sonarpur, Kolkata, India"},{"author_name":"Jong-Eun Park","author_inst":"Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Republic of Korea"},{"author_name":"Partha P. Majumder","author_inst":"John C. Martin Centre for Liver Research and Innovations, Sonarpur, Kolkata, India"},{"author_name":"Ponpan Matangkasombut","author_inst":"Single-cell Omics and Systems Biology of Diseases Research Unit, Faculty of Science, Mahidol University, Bangkok, Thailand"},{"author_name":"Varodom Charoensawan","author_inst":"Single-cell Omics and Systems Biology of Diseases Research Unit, Faculty of Science, Mahidol University, Bangkok, Thailand"},{"author_name":"Jay W. Shin","author_inst":"Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Republic of Singapore"},{"author_name":"Woong-Yang Park","author_inst":"Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea"},{"author_name":"- Asian Immune Diversity Atlas (AIDA) Network","author_inst":""},{"author_name":"Stephen Sansom","author_inst":"Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK"},{"author_name":"Berthold Gottgens","author_inst":"Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK"},{"author_name":"Joseph E. Powell","author_inst":"Garvan Institute for Medical Research, Darlinghurst, Australia"},{"author_name":"Lloyd Bod","author_inst":"Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Holger Heyn","author_inst":"Centro Nacional de Analisis Genomico (CNAG), Barcelona, Spain"},{"author_name":"Fabian J. Theis","author_inst":"Institute of Computational Biology, Helmholtz Munich, Neuherberg\/Munich, Germany"},{"author_name":"Sarah A. Teichmann","author_inst":"Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK"},{"author_name":"Malte D. Luecken","author_inst":"Institute of Computational Biology, Helmholtz Munich, Neuherberg\/Munich, Germany"},{"author_name":"Shyam Prabhakar","author_inst":"Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Republic of Singapore"},{"author_name":"Alexandra-Chloe Villani","author_inst":"Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA"},{"author_name":"Gary Reynolds","author_inst":"Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA"}],"rel_date":"2026-09-25","rel_site":"biorxiv"},{"rel_title":"A closed-loop language-model agent for target-specific multi-objective hit-to-lead optimization","rel_doi":"10.64898\/2026.09.19.752921","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.19.752921","rel_abs":"Hit-to-lead optimization is a multi-objective molecular-design problem in which binding-related scores must be considered together with drug-likeness and synthetic accessibility. We developed a closed-loop language-model medicinal-chemistry agent that combines target and starting-hit context, PubMed retrieval, molecular-property tools, docking, and feedback from previously scored analogues. In a matched computational benchmark comprising six kinase targets, six methods, a 40-candidate budget, and six independent campaigns per method, the agent achieved the highest mean aggregate score under a pre-specified composite objective on four targets. Re-analysis of the same candidate sets with drug-likeness-gated docking and docking-drug-likeness hypervolume produced different target-level winners, showing that evaluation rules can change the comparative interpretation of an optimization campaign. Candidate distributions and component ablations indicated that the agent's advantage was associated primarily with retention of scored-candidate feedback and higher-QED regions rather than with docking alone. An EGFR case study illustrates a scaffold-preserving in-silico optimization trajectory from erlotinib. The study is a computational benchmark and evaluation framework; the prioritized molecules are hypotheses for subsequent experimental testing, not experimentally validated leads.","rel_num_authors":8,"rel_authors":[{"author_name":"Wentao Cui","author_inst":"Beijing Life Science Academy, Beijing, China; Key Laboratory of Biosynthesis and Biomanufacturing in Model Plants (Beijing Life Science Academy), Ministry of In"},{"author_name":"Limeng Tian","author_inst":"School of Aerospace Engineering, Tsinghua University, Beijing, China"},{"author_name":"Xiaoning Qi","author_inst":"State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China"},{"author_name":"Haoran Wang","author_inst":"State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China"},{"author_name":"Huanhuan Wu","author_inst":"State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China"},{"author_name":"Houxin He","author_inst":"Institute of Automation, Chinese Academy of Sciences, Beijing, China"},{"author_name":"Chen Fang","author_inst":"College of Electronic Engineering, National University of Defense Technology, Hefei, 230031, China"},{"author_name":"Jiaxin Hu","author_inst":"State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"A prefrontal cortex-hypothalamus circuit for heart rate control in non-human primates","rel_doi":"10.64898\/2026.09.18.752614","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.752614","rel_abs":"Humans exhibit changes in heart rate during cognitive and emotional events, and dysregulation of this brain-heart coupling is a hallmark of many psychiatric disorders. Yet, how circuits that regulate cognition exert direct control over heart physiology remains poorly understood, particularly in primates. Here, we identify a prefrontal-hypothalamic circuit that exerts powerful, bidirectional control over heart rate in monkeys. We show that electrical stimulation of a small ventral subregion within the ventrolateral prefrontal cortex (area 47\/12; a12) evokes rapid and robust decreases in heart rate and increases heart rate variability, whereas neighboring prefrontal regions produce weaker or no effects. And a12 neurons are coupled to heart rate on a moment-by-moment basis. Anatomical tracing data reveal projections from a12 to a circumscribed region of lateral hypothalamus (LHA), and stimulation of this LHA target recapitulates the cardiac effects of prefrontal activation. Consistent with a prefrontal-to-hypothalamus system for heart rate control, stimulation of LHA produces faster, stronger, state-independent heart effects, whereas stimulation of a12 produces effects that are sensitive to internal states. Oppositely to its activation, chemogenetic inactivation of a12 or its projections to LHA increases heart rate, demonstrating that this pathway can provide tonic inhibitory control over cardiac function. To make steps towards a more cell-type-specific and minimally invasive causal control of this circuit, we developed a primate sonogenetic approach based on ultrasound activation of CaMKII+ neurons virally transduced with TRPV1. Sonogenetic stimulation of a12 produced increases in heart rate variability, and these effects were attenuated by inactivation of LHA. Finally, we found that sonogenetic and chemogenetic perturbation of the same prefrontal region during a value-based decision-making task bidirectionally alters risky decision making. Together, our work identifies how a12 regulates heart rate and cognition, revealing a mechanistic substrate for brain-body interactions and a potential therapeutic target for disorders of cognitive-autonomic dysregulation.","rel_num_authors":11,"rel_authors":[{"author_name":"Kevin Xu","author_inst":"Washington University in St. Louis"},{"author_name":"Takaya Ogasawara","author_inst":"Washington University in St. Louis; Johns Hopkins University"},{"author_name":"Jinyun Yuan","author_inst":"Washington University in St. Louis"},{"author_name":"Ethan S. Bromberg-Martin","author_inst":"Washington University in St. Louis; Johns Hopkins University"},{"author_name":"Mengxi Yun","author_inst":"Washington University in St. Louis"},{"author_name":"Steven P. Errington","author_inst":"Washington University in St. Louis"},{"author_name":"Andrew H. Stark","author_inst":"Washington University in St. Louis"},{"author_name":"Takafumi Minamimoto","author_inst":"National Institutes for Quantum Science and Technology"},{"author_name":"Ken-ichi Inoue","author_inst":"Kyoto University"},{"author_name":"Hong Chen","author_inst":"Washington University in St. Louis"},{"author_name":"Ilya E. Monosov","author_inst":"Washington University in St. Louis; Johns Hopkins University"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"A prefrontal cortex-hypothalamus circuit for heart rate control in non-human primates","rel_doi":"10.64898\/2026.09.18.752614","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.752614","rel_abs":"Humans exhibit changes in heart rate during cognitive and emotional events, and dysregulation of this brain-heart coupling is a hallmark of many psychiatric disorders. Yet, how circuits that regulate cognition exert direct control over heart physiology remains poorly understood, particularly in primates. Here, we identify a prefrontal-hypothalamic circuit that exerts powerful, bidirectional control over heart rate in monkeys. We show that electrical stimulation of a small ventral subregion within the ventrolateral prefrontal cortex (area 47\/12; a12) evokes rapid and robust decreases in heart rate and increases heart rate variability, whereas neighboring prefrontal regions produce weaker or no effects. And a12 neurons are coupled to heart rate on a moment-by-moment basis. Anatomical tracing data reveal projections from a12 to a circumscribed region of lateral hypothalamus (LHA), and stimulation of this LHA target recapitulates the cardiac effects of prefrontal activation. Consistent with a prefrontal-to-hypothalamus system for heart rate control, stimulation of LHA produces faster, stronger, state-independent heart effects, whereas stimulation of a12 produces effects that are sensitive to internal states. Oppositely to its activation, chemogenetic inactivation of a12 or its projections to LHA increases heart rate, demonstrating that this pathway can provide tonic inhibitory control over cardiac function. To make steps towards a more cell-type-specific and minimally invasive causal control of this circuit, we developed a primate sonogenetic approach based on ultrasound activation of CaMKII+ neurons virally transduced with TRPV1. Sonogenetic stimulation of a12 produced increases in heart rate variability, and these effects were attenuated by inactivation of LHA. Finally, we found that sonogenetic and chemogenetic perturbation of the same prefrontal region during a value-based decision-making task bidirectionally alters risky decision making. Together, our work identifies how a12 regulates heart rate and cognition, revealing a mechanistic substrate for brain-body interactions and a potential therapeutic target for disorders of cognitive-autonomic dysregulation.","rel_num_authors":11,"rel_authors":[{"author_name":"Kevin Xu","author_inst":"Washington University in St. Louis"},{"author_name":"Takaya Ogasawara","author_inst":"Washington University in St. Louis; Johns Hopkins University"},{"author_name":"Jinyun Yuan","author_inst":"Washington University in St. Louis"},{"author_name":"Ethan S. Bromberg-Martin","author_inst":"Washington University in St. Louis; Johns Hopkins University"},{"author_name":"Mengxi Yun","author_inst":"Washington University in St. Louis"},{"author_name":"Steven P. Errington","author_inst":"Washington University in St. Louis"},{"author_name":"Andrew H. Stark","author_inst":"Washington University in St. Louis"},{"author_name":"Takafumi Minamimoto","author_inst":"National Institutes for Quantum Science and Technology"},{"author_name":"Ken-ichi Inoue","author_inst":"Kyoto University"},{"author_name":"Hong Chen","author_inst":"Washington University in St. Louis"},{"author_name":"Ilya E. Monosov","author_inst":"Washington University in St. Louis; Johns Hopkins University"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Convergent evolutionary loss of chemosensory and blood-feeding pathways in non-blood-feeding mosquitoes","rel_doi":"10.64898\/2026.09.23.753750","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.23.753750","rel_abs":"Complex traits that span multiple tissues and systems often integrate large numbers of genes across development, physiology, and behavior, making it challenging to identify their essential components. Blood feeding in mosquitoes is one such trait. It is ancestral to the mosquito family, maintained in most species for ~200 million years, and was independently lost in three lineages. These convergent losses offer a natural experiment to discover the genetic, physiological, and neural features required for blood feeding. We assembled high-quality, chromosome-level genomes for seven mosquito species, along with whole-brain tomographic reconstructions. Our study spanned the three known non-blood-feeding lineages (Toxorhynchites rutilus, Topomyia yanbarensis, and Malaya genurostris), blood-feeding relatives, and the variable blood feeder Wyeomyia smithii. Comparing orthologous gene clades, we detected convergent gene loss specific to the three lineages that had lost blood feeding. The losses include the salivary platelet-aggregation inhibitor Aegyptin, blood-activated serine proteases such as Chymotrypsin-1 and 2, and a carboxylesterase expressed in the female fat body and brain glia. The loss of blood feeding also extended to chemosensation. Non-blood feeders lack two odorant-binding protein clades, two ionotropic receptor clades associated with blood-component taste detection, and odorant receptor clades expressed in a discrete, strongly female-biased population of antennal neurons. Female-biased head gene expression was reduced in non-blood feeders. Finally, examination of whole-brain tomographic reconstructions across the species revealed smaller antennal lobes in non-blood-feeding females, consistent with reduced olfactory input. Together, these findings identify a compact set of genes, expression patterns, and brain regions associated with blood feeding, offering an evolutionary entry point for functional dissection of how this complex and dangerous trait is built and dismantled.","rel_num_authors":18,"rel_authors":[{"author_name":"Leah Houri-Zeevi","author_inst":"The Rockefeller University"},{"author_name":"Philipp Brand","author_inst":"The Rockefeller University"},{"author_name":"Irene Arnoldi","author_inst":"University of Milan"},{"author_name":"Alexandra E DeFoe","author_inst":"The Rockefeller University"},{"author_name":"Jennifer R Balacco","author_inst":"The Rockefeller University"},{"author_name":"Nadav Shai","author_inst":"The Rockefeller University"},{"author_name":"Alex Makunin","author_inst":"Wellcome Sanger Institute"},{"author_name":"Umberto Palatini","author_inst":"The Rockefeller University"},{"author_name":"Takako Toma","author_inst":"University of the Ryukyus Museum (Fujukan)"},{"author_name":"Takao Okazawa","author_inst":"Kanazawa University"},{"author_name":"Christopher M Stone","author_inst":"University of Illinois Urbana-Champaign"},{"author_name":"Anita Schiller","author_inst":"Harris County PCT4 Mosquito Biological Control Initiative"},{"author_name":"Olivier Fedrigo","author_inst":"The Rockefeller University"},{"author_name":"Erich D Jarvis","author_inst":"The Rockefeller University"},{"author_name":"Mara KN Lawniczak","author_inst":"Wellcome Sanger Institute"},{"author_name":"Ichiro Miyagi","author_inst":"University of the Ryukyus Museum (Fujukan)"},{"author_name":"Paolo Gabrieli","author_inst":"University of Milan"},{"author_name":"Leslie B Vosshall","author_inst":"The Rockefeller University"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Sociality in weevils is shaped by sheltering and convergent gene losses","rel_doi":"10.64898\/2026.09.19.752859","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.19.752859","rel_abs":"Eusociality, characterized by overlapping generations, cooperative brood care, and reproductive division of labour, has arisen independently across diverse, phylogenetically distant insect orders, including Hymenoptera (ants, bees, and wasps), Blattodea (termites), and Coleoptera (weevils). While multiple studies have investigated the molecular evolution of sociality from solitary ancestors in Hymenoptera and Blattodea, so far little is known about the evolutionary signatures of social evolution in Coleoptera. Weevils (Curculionidae) provide an ideal system for addressing this question, as they cover the full spectrum of social complexity from parental care, through several origins of facultative eusociality to the only obligately eusocial beetle, Austroplatypus incompertus. We generated genome assemblies for A. incompertus and two facultatively eusocial weevil species, Xylosandrus germanus and Xyleborinus saxesenii, which together with 18 publicly available weevil genomes span two independent evolutionary origins of sociality. Our analyses reveal a genome-wide relaxation of purifying selection with increasing social complexity, which is most pronounced in A. incompertus. We find a significant excess of convergent gene family contractions in lineages where sociality evolved, and no evidence of elevated positive selection. These findings indicate that the molecular mechanisms of social evolution in weevils are primarily characterised by relaxed selection and gene loss, rather than adaptive innovation and gene family expansions. These observations are consistent with sheltering and reduced effective population size playing an important role, a pattern not previously observed in other clades.","rel_num_authors":7,"rel_authors":[{"author_name":"Sarah Rinke","author_inst":"University of Muenster"},{"author_name":"James Bickerstaff","author_inst":"CSIRO"},{"author_name":"Peter H.W. Biedermann","author_inst":"University of Freiburg"},{"author_name":"Carsten Kemena-Rinke","author_inst":"University of Muenster"},{"author_name":"Markus Riegler","author_inst":"Western Sydney University"},{"author_name":"Martin Schebeck","author_inst":"University of Goettingen"},{"author_name":"Mark C Harrison","author_inst":"Coventry University"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Two Ume6 target gene classes in the biofilm regulatory network of Candida albicans","rel_doi":"10.64898\/2026.09.24.753443","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.24.753443","rel_abs":"Biofilm formation by the fungal pathogen Candida albicans is a major source of infection. The biofilm regulator Ume6 forms complexes with partner transcription factors Efg1, Ndt80, and Upc2 to drive expression of biofilm-related genes. Here we present chromatin immunoprecipitation with sequencing (ChIP-seq) data for Ume6-chromatin association in both wild-type and efg1{Delta}\/{Delta} ndt80{Delta}\/{Delta} upc2{Delta}\/{Delta} backgrounds. Ume6 associates with two promoter region classes. For one class, Ume6 association is significantly decreased in the efg1{Delta}\/{Delta} ndt80{Delta}\/{Delta} upc2{Delta}\/{Delta} background. This class includes 577 genes, many with well-established roles in biofilm formation or the related process of filamentation. For the second class, Ume6 association is unperturbed in the triple mutant background. This class includes 534 genes, some with roles in iron homeostasis (e.g., SFU1) and ergosterol synthesis (e.g., ERG11), which may contribute to the impact of Ume6 on ndt80{Delta}\/{Delta} mutant azole drug sensitivity. It also includes FLO9, a putative adhesin gene that is required for the emergent biofilm state produced by efg1{Delta}\/{Delta} ndt80{Delta}\/{Delta} double mutants. The data show that Ume6 binding to ~half of its targets requires known partners, and Ume6 binding to ~half of its targets does not. Ume6 may bind to the latter set of promoter regions independently of any partner, or perhaps with additional partners that have yet to be discovered.","rel_num_authors":3,"rel_authors":[{"author_name":"Eunsoo Do","author_inst":"The University of Georgia"},{"author_name":"Joel McManus","author_inst":"Carnegie Mellon University"},{"author_name":"Aaron P. Mitchell","author_inst":"University of Georgia"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"NLRP3 inflammasome signaling orchestrates hepatic granuloma organization and protective immunity","rel_doi":"10.64898\/2026.09.18.752760","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.752760","rel_abs":"Granulomas are organized immune structures that contribute to host defense against persistent pathogens, yet the mechanisms that coordinate their assembly and protective function remain incompletely understood. Here, using experimental visceral leishmaniasis caused by Leishmania infantum and samples from patients with active disease, we identify the NLRP3 inflammasome as a regulator of protective hepatic granulomatous immunity. Inflammasome-associated mediators were elevated in patients and correlated with systemic inflammation. In mice, L. infantum induced NLRP3 inflammasome activation within hepatic granulomas, while single-cell and spatial transcriptomic analyses revealed enrichment of inflammasome-associated transcription in hepatic macrophages and granuloma-associated regions. NLRP3 deficiency did not prevent granuloma initiation but impaired granuloma expansion, cellular organization, and leukocyte accumulation. This response required Caspase-1\/11 and IL-18, but was independent of IL-1{beta}. Loss of NLRP3 also impaired parasite control despite reducing hepatic inflammation and histopathological alterations. Together, our findings identify NLRP3-Caspase-1\/11-IL-18 signaling as a mechanism that coordinates the cellular and spatial organization of protective hepatic granulomas, revealing granuloma architecture as a previously unrecognized function of inflammasome-mediated immunity and providing mechanistic insight into host resistance in visceral leishmaniasis, a potentially fatal neglected tropical disease.","rel_num_authors":22,"rel_authors":[{"author_name":"Isadora M. de Oliveira","author_inst":"Department of Cellular and Molecular Biology, School of Medicine of Ribeirao Preto, University of Sao Paulo. Ribeirao Preto, SP 14049-900, Brazil"},{"author_name":"Mariana M. Chaves","author_inst":"Department of Cellular and Molecular Biology, School of Medicine of Ribeirao Preto, University of Sao Paulo. Ribeirao Preto, SP 14049-900, Brazil"},{"author_name":"Juliana Costa-Madeira","author_inst":"Department of Cellular and Molecular Biology, School of Medicine of Ribeirao Preto, University of Sao Paulo. Ribeirao Preto, SP 14049-900, Brazil"},{"author_name":"Ana Luisa Barbosa","author_inst":"Department of Cellular and Molecular Biology, School of Medicine of Ribeirao Preto, University of Sao Paulo. Ribeirao Preto, SP 14049-900, Brazil"},{"author_name":"Pedro S. Corradi","author_inst":"Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas G"},{"author_name":"Bianca de Oliveira","author_inst":"Vaccine Technology Center (CT Vacinas), Federal University of Minas Gerais, Parque Tecnologico de Belo Horizonte, Belo Horizonte 31310-260, MG, Brazil."},{"author_name":"Amanda M Becerra","author_inst":"Department of Cellular and Molecular Biology, School of Medicine of Ribeirao Preto, University of Sao Paulo. Ribeirao Preto, SP 14049-900, Brazil"},{"author_name":"Pedro Henrique Marques","author_inst":"Department of Cellular and Molecular Biology, School of Medicine of Ribeirao Preto, University of Sao Paulo. Ribeirao Preto, SP 14049-900, Brazil"},{"author_name":"Tamara S Rodrigues","author_inst":"Department of Cellular and Molecular Biology, School of Medicine of Ribeirao Preto, University of Sao Paulo. Ribeirao Preto, SP 14049-900, Brazil"},{"author_name":"Adriana Simizo","author_inst":"Hospital Israelita Albert Einstein, Sao Paulo, SP, Brazil"},{"author_name":"Lucas Lorenzon","author_inst":"Department of Cellular and Molecular Biology, School of Medicine of Ribeirao Preto, University of Sao Paulo. Ribeirao Preto, SP 14049-900, Brazil"},{"author_name":"Sabrina S Batah","author_inst":"Department of Pathology and Legal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto (SP), Brazil"},{"author_name":"Andrea JR Herrera","author_inst":"Department of Pathology and Legal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto (SP), Brazil"},{"author_name":"Helder I Nakaya","author_inst":"Hospital Israelita Albert Einstein, Sao Paulo, SP, Brazil. Department of Clinical and Toxicological Analyses, University of Sao Paulo, SP, Brazil. Institut Past"},{"author_name":"Amanda M da Silva","author_inst":"Instituto de Doencas Tropicais Natan Portella. Centro de Ciencias da Saude da Universidade Federal do Piaui. Teresina-PI, Brazil."},{"author_name":"Ricardo T Gazzinelli","author_inst":"Vaccine Technology Center (CT Vacinas), Federal University of Minas Gerais, Parque Tecnologico de Belo Horizonte, Belo Horizonte 31310-260, MG, Brazil."},{"author_name":"Angela K Cruz","author_inst":"Department of Cellular and Molecular Biology, School of Medicine of Ribeirao Preto, University of Sao Paulo. Ribeirao Preto, SP 14049-900, Brazil"},{"author_name":"Cristina M Takiya","author_inst":"Instituto de Biofisica Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil."},{"author_name":"Alexandre T Fabro","author_inst":"Department of Pathology, Botucatu Medical School, Sao Paulo State University"},{"author_name":"Gustavo B Menezes","author_inst":"Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas G"},{"author_name":"Carlos HN Costa","author_inst":"Instituto de Doencas Tropicais Natan Portella. Centro de Ciencias da Saude da Universidade Federal do Piaui. Teresina-PI, Brazil."},{"author_name":"Dario S Zamboni","author_inst":"Department of Cellular and Molecular Biology, School of Medicine of Ribeirao Preto, University of Sao Paulo. Ribeirao Preto, SP 14049-900, Brazil"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Standardized human tests show that most vision models are face-blind","rel_doi":"10.64898\/2026.09.18.750666","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.750666","rel_abs":"Face recognition ability varies enormously across humans. Individuals with face-blindness (prosopagnosia) struggle to recognize even close family members while super-recognizers can identify strangers with exceptional accuracy. Where do ANNs fall within the human face recognition spectrum? Here, we administered the standardized tests used to characterize human face recognition ability to a diverse set of models, allowing us to contextualize a model's performance within the distribution of human behavior. We found that the majority 55% of models to be classified as face-blind and that even the best face-trained models do not cross the human threshold to be considered a super-recognizer. Interrogating the internal representations of these models showed that models that performed well on standardized face recognition tasks were more identity-selective and viewpoint-invariant. We also found that low-performing models did contain some identity information in independent representational subspaces. Removing viewpoint-dependent subspace improved face recognition abilities in 49 of the 53 models tested. Targeted unit ablations further identified opposing contributions, with viewpoint-dependent units disrupting identity coding and viewpoint-tolerant units supporting it. Together, our results show that most AI models are face-blind with worse face recognition ability than humans, and demonstrate how differences across AI models can be used generate testable hypotheses about the computational basis of human face recognition in humans which can then be probed in future studies.","rel_num_authors":5,"rel_authors":[{"author_name":"Kushal R Dudipala","author_inst":"Georgia Institute of Technology"},{"author_name":"Florencia Martinez-Addiego","author_inst":"Georgia Institute of Technology"},{"author_name":"Dobromir Rahnev","author_inst":"Georgia Institute of Technology"},{"author_name":"Bradley C Duchaine","author_inst":"Dartmouth College"},{"author_name":"N. Apurva Ratan Murty","author_inst":"Georgia Institute of Technology"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"State-specific binding thermodynamics predicts ligand efficacy across ion-channel families.","rel_doi":"10.64898\/2026.09.22.753602","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.22.753602","rel_abs":"Predicting ligand efficacy is a critical challenge in drug discovery, as a target's functional response is often determined by the way a ligand shifts conformational equilibria between different functional states, a process that is particularly intricate in ion channels. We classify ligands based on the difference of their binding free energies on putative active and inactive conformations, calculated via free energy perturbation (FEP) for 78 protein-ligand pairs across six ion channels from four structural superfamilies: GluA2, GABAAR {rho}1, 3{beta}4 nAChR, 5-HT3AR, TRPML1, and KCNQ2. This approach accurately distinguishes agonists from antagonists across all these ion-channel families with large or subtle structural differences, including at membrane-facing sites, and enables quantitative prediction of maximum response and partial agonism. Importantly, we find that local binding-pocket conformations encode the bound ligand's efficacy even when global channel states are ambiguous. Our results demonstrate that state-specific binding thermodynamics provides a robust framework for leveraging ion channel structures of diverse conformational states to elucidate mechanisms of action and to advance ion-channel drug discovery beyond simple affinity measurements, enabling the identification of new chemical matter with desired functional attributes.","rel_num_authors":7,"rel_authors":[{"author_name":"Martin V\u00f6gele","author_inst":"Schr\u00f6dinger, Inc."},{"author_name":"Abba E. Leffler","author_inst":"Schr\u00f6dinger, Inc."},{"author_name":"Kevin C. Felt","author_inst":"Department of Pharmacology, Case Western Reserve University"},{"author_name":"Lindsay Denluck","author_inst":"Schr\u00f6dinger, Inc."},{"author_name":"Edward B. Miller","author_inst":"Schr\u00f6dinger, Inc."},{"author_name":"Sudha Chakrapani","author_inst":"Department of Pharmacology, Case Western Reserve University"},{"author_name":"Lingle Wang","author_inst":"Schr\u00f6dinger, Inc."}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Designed IDPs phase separate and mix or demix according to sequence designed parameters","rel_doi":"10.64898\/2026.09.23.753891","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.23.753891","rel_abs":"Biomolecular condensates are condensed assemblies of biomolecules that form through the process of liquid phase separation. Condensates in biology typically function as membraneless organelles, providing compartmentalization in the absence of a dividing lipid membrane. The molecular make-up of different condensates includes diverse multivalent proteins and nucleic acids as the primary drivers, many of them including significant fractions of intrinsically disordered regions (IDRs). To date, the sequence to phase separation relationship of IDRs has focused largely on one protein at a time, studying single-component condensate formation, or single-component partitioning into condensates. The co-phase separation and mixing of two or more IDRs is considerably more complex as both sequences can vary widely in their self- and cross-interactions, as well as their relative abundance in solution. It is unclear that a rule which predicts how a single sequence behaves will also predict what happens when two sequences are mixed. In this study, we disentangle the influence of sequence from that of composition using a set of 18 LAF-1 RGG variants that keep the same length and amino-acid composition and change only the order of the residues. This lets us vary charge patterning and, to a lesser extent, hydropathy patterning while keeping protein composition fixed. By themselves, the sequences phase separation and single-chain compaction are controlled by their degree of charge and hydropathy patterning. Within single-component condensed phases, each sequence adopts a more extended conformational ensemble, due to a more favorable, selfsolvated environment. We find that mixing two IDRs together into a condensate causes this universal scaling behavior to break, impacted by the relative interactions of the two components and overall composition of the slab. We find two different qualitative behaviors, one characterized by cooperative co-condensation when both sequences are subcritical, and the other by scaffold-client behavior when one sequence is supercritical. The scaffold-client systems generally show a high degree of demixing, while the co-condensing systems are generally quite well-mixed in the dense phase. This is surprising because even in cases where both partners have significantly different patterning parameters, they still mix. Thus, the descriptor that predicts a sequence's behavior alone can help indicate whether it will mix with or separate from a second component, but it does not fully determine the outcome on its own.","rel_num_authors":2,"rel_authors":[{"author_name":"Arjun Singh","author_inst":"Department of Chemical and Biochemical Engineering, Rutgers University, Piscataway, NJ, United States"},{"author_name":"Gregory L Dignon","author_inst":"Department of Chemical and Biochemical Engineering, Rutgers University, Piscataway, NJ, United States"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Environmentally-mediated yield effects of vernalization and photoperiod alleles in historic winter wheat trials","rel_doi":"10.64898\/2026.09.18.752491","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.752491","rel_abs":"In common wheat (Triticum aestivum L.), variation at the Vrn1 and Ppd1 loci changes plant phenology, resulting in differential adaptation useful to breeders. Because the effects of phenology on grain yield are conditional on environmental factors, the incorporation of markers for Vrn1 and Ppd1 alleles into breeding approaches has proven difficult. Historic phenotypic, genotypic, and environmental data can provide insight into the relationship between major phenology alleles and grain yield as mediated by environmental variables. Analyses of eight years of breeding trials (1,038 lines at 219 site-years) determined that weak vrn1 alleles and Ppd1 insensitivity alleles have variable effects. These effects change depending on an environment's winter temperature and latitude, respectively, but the environmentally-driven changes in effect of vrn1 alleles are much more variable than effects of Ppd1 alleles. Mediation analyses showed phenologically-dependent environmental variables are one mechanism through which phenological changes created by vrn1 and Ppd1 variants alter yield across multiple developmental stages. Environmentally-driven relationships between flowering time and yield were modeled to estimate yield allele effects as a function of effects on phenology and environmental variables. Weak winter alleles at vrn1 may play a stabilizing role on yield, due to the correlation of winter conditions that drive larger effects with later-season warm temperatures that penalize later maturity. A better mechanistic understanding of how these loci drive environment-specific yield effects may facilitate utilization of markers for these alleles and improve predictive modeling of yield.","rel_num_authors":27,"rel_authors":[{"author_name":"Noah DeWitt","author_inst":"Department of Soil, Plant, and Environmental Sciences, Louisiana State University"},{"author_name":"Zachary Winn","author_inst":"Department of Soil and Crop Sciences, Colorado State University"},{"author_name":"Mohammed Guedira","author_inst":"Department of Crop and Soil Sciences, North Carolina State University"},{"author_name":"Jeanette Lyerly","author_inst":"Department of Crop and Soil Sciences, North Carolina State University"},{"author_name":"Christian Maltecca","author_inst":"Department of Animal Science, North Carolina State University"},{"author_name":"Brian Ward","author_inst":"Forage Genetics International"},{"author_name":"William Stafstrom","author_inst":"Pee Dee Research and Education Center, Clemson University"},{"author_name":"Md. Ali Babar","author_inst":"Agronomy Department, University of Florida"},{"author_name":"Nonoy Bandillo","author_inst":"Department of Crop and Soil Sciences, North Carolina State University"},{"author_name":"Richard Boyles","author_inst":"Pee Dee Research and Education Center, Clemson University"},{"author_name":"Stephen Harrison","author_inst":"Department of Soil, Plant, and Environmental Sciences, Louisiana State University"},{"author_name":"Kimberly Howell","author_inst":"SEA, Plant Science Research, USDA-ARS"},{"author_name":"R. Esten Mason","author_inst":"Department of Soil and Crop Sciences, Colorado State University"},{"author_name":"Ellen Melson","author_inst":"Texas A and M University"},{"author_name":"Mohamed Mergoum","author_inst":"Department of Crop Science, University of Georgia"},{"author_name":"Mohsen Mohammadi","author_inst":"Department of Agronomy, Purdue University"},{"author_name":"J. Paul Murphy","author_inst":"Department of Crop and Soil Sciences, North Carolina State University"},{"author_name":"Eric Olson","author_inst":"Department of Plant, Soil and Microbial Sciences, Michigan State University"},{"author_name":"Jessica Rutkoski","author_inst":"Department of Crop Science, University of Illinois Urbana-Champaign"},{"author_name":"Nicholas Santantonio","author_inst":"Department of Crop and Soil Environmental Sciences, Virginia Polytechnic Institute and State University"},{"author_name":"Jared H. Smith","author_inst":"SEA, Plant Science Research, USDA-ARS"},{"author_name":"Clay Sneller","author_inst":"Department of Horticulture and Crop Science, The Ohio State University"},{"author_name":"Mark Sorrells","author_inst":"School of Integrative Plant Science, Cornell University"},{"author_name":"Russell Sutton","author_inst":"Texas A&M AgriLife Research, Texas A&M University"},{"author_name":"Vijay Tiwari","author_inst":"Department of Plant Science and Landscape Architecture, University of Maryland"},{"author_name":"David A. Van Sanford","author_inst":"Department of Plant and Soil Sciences, University of Kentucky"},{"author_name":"Gina Brown-Guedira","author_inst":"SEA, Plant Science Research, Department of Crop and Soil Sciences, USDA ARS, North Carolina State University"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"rel_title":"Environmentally-mediated yield effects of vernalization and photoperiod alleles in historic winter wheat trials","rel_doi":"10.64898\/2026.09.18.752491","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.09.18.752491","rel_abs":"In common wheat (Triticum aestivum L.), variation at the Vrn1 and Ppd1 loci changes plant phenology, resulting in differential adaptation useful to breeders. Because the effects of phenology on grain yield are conditional on environmental factors, the incorporation of markers for Vrn1 and Ppd1 alleles into breeding approaches has proven difficult. Historic phenotypic, genotypic, and environmental data can provide insight into the relationship between major phenology alleles and grain yield as mediated by environmental variables. Analyses of eight years of breeding trials (1,038 lines at 219 site-years) determined that weak vrn1 alleles and Ppd1 insensitivity alleles have variable effects. These effects change depending on an environment's winter temperature and latitude, respectively, but the environmentally-driven changes in effect of vrn1 alleles are much more variable than effects of Ppd1 alleles. Mediation analyses showed phenologically-dependent environmental variables are one mechanism through which phenological changes created by vrn1 and Ppd1 variants alter yield across multiple developmental stages. Environmentally-driven relationships between flowering time and yield were modeled to estimate yield allele effects as a function of effects on phenology and environmental variables. Weak winter alleles at vrn1 may play a stabilizing role on yield, due to the correlation of winter conditions that drive larger effects with later-season warm temperatures that penalize later maturity. A better mechanistic understanding of how these loci drive environment-specific yield effects may facilitate utilization of markers for these alleles and improve predictive modeling of yield.","rel_num_authors":27,"rel_authors":[{"author_name":"Noah DeWitt","author_inst":"Department of Soil, Plant, and Environmental Sciences, Louisiana State University"},{"author_name":"Zachary Winn","author_inst":"Department of Soil and Crop Sciences, Colorado State University"},{"author_name":"Mohammed Guedira","author_inst":"Department of Crop and Soil Sciences, North Carolina State University"},{"author_name":"Jeanette Lyerly","author_inst":"Department of Crop and Soil Sciences, North Carolina State University"},{"author_name":"Christian Maltecca","author_inst":"Department of Animal Science, North Carolina State University"},{"author_name":"Brian Ward","author_inst":"Forage Genetics International"},{"author_name":"William Stafstrom","author_inst":"Pee Dee Research and Education Center, Clemson University"},{"author_name":"Md. Ali Babar","author_inst":"Agronomy Department, University of Florida"},{"author_name":"Nonoy Bandillo","author_inst":"Department of Crop and Soil Sciences, North Carolina State University"},{"author_name":"Richard Boyles","author_inst":"Pee Dee Research and Education Center, Clemson University"},{"author_name":"Stephen Harrison","author_inst":"Department of Soil, Plant, and Environmental Sciences, Louisiana State University"},{"author_name":"Kimberly Howell","author_inst":"SEA, Plant Science Research, USDA-ARS"},{"author_name":"R. Esten Mason","author_inst":"Department of Soil and Crop Sciences, Colorado State University"},{"author_name":"Ellen Melson","author_inst":"Texas A and M University"},{"author_name":"Mohamed Mergoum","author_inst":"Department of Crop Science, University of Georgia"},{"author_name":"Mohsen Mohammadi","author_inst":"Department of Agronomy, Purdue University"},{"author_name":"J. Paul Murphy","author_inst":"Department of Crop and Soil Sciences, North Carolina State University"},{"author_name":"Eric Olson","author_inst":"Department of Plant, Soil and Microbial Sciences, Michigan State University"},{"author_name":"Jessica Rutkoski","author_inst":"Department of Crop Science, University of Illinois Urbana-Champaign"},{"author_name":"Nicholas Santantonio","author_inst":"Department of Crop and Soil Environmental Sciences, Virginia Polytechnic Institute and State University"},{"author_name":"Jared H. Smith","author_inst":"SEA, Plant Science Research, USDA-ARS"},{"author_name":"Clay Sneller","author_inst":"Department of Horticulture and Crop Science, The Ohio State University"},{"author_name":"Mark Sorrells","author_inst":"School of Integrative Plant Science, Cornell University"},{"author_name":"Russell Sutton","author_inst":"Texas A&M AgriLife Research, Texas A&M University"},{"author_name":"Vijay Tiwari","author_inst":"Department of Plant Science and Landscape Architecture, University of Maryland"},{"author_name":"David A. Van Sanford","author_inst":"Department of Plant and Soil Sciences, University of Kentucky"},{"author_name":"Gina Brown-Guedira","author_inst":"SEA, Plant Science Research, Department of Crop and Soil Sciences, USDA ARS, North Carolina State University"}],"rel_date":"2026-09-24","rel_site":"biorxiv"},{"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":"BackgroundCancer-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.\n\nMethodsWe 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.\n\nResultsDIO2 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.\n\nConclusions\n\nDIO2 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":"BackgroundCancer-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.\n\nMethodsWe 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.\n\nResultsDIO2 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.\n\nConclusions\n\nDIO2 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":"BackgroundCancer-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.\n\nMethodsWe 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.\n\nResultsDIO2 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.\n\nConclusions\n\nDIO2 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":"BackgroundCancer-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.\n\nMethodsWe 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.\n\nResultsDIO2 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.\n\nConclusions\n\nDIO2 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":"ObjectiveTo assess the knowledge, willingness and barriers to human papillomavirus (HPV) vaccination among caregivers of adolescent girls living with HIV in Sierra Leone.\n\nMethodsThis 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.\n\nResultsOnly 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 as disrupted vaccination services, vaccine supplies and cold chain limited uptake, healthcare workers emerged as the most effective information source (rank sum = 889.5, p = 0.039).\n\nConclusionThe study highlights the need for culturally tailored education to dispel myths and 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":"BackgroundSub-Saharan Africa (sSA) faces accelerated growth in Alzheimers 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.\n\nMethodsFour 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.\n\nResultsTabCAT 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.\n\nDiscussionTabCAT 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":"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.\n\nWe 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.\n\nOne Sentence SummaryMerlinsky et al show that cysteine supplementation can therapeutically reverse immune dysregulation in cancer patients with severe COVID-19 infection.","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.\n\nAUTHOR SUMMARYA genetic variant (change in DNA, G >A) is associated with higher body mass index and lower risk for type 2 diabetes. This variant, called rs373863828, is only present in people of Pacific Islander ancestry, who are underrepresented in genetic and genomic studies, and is in the CREBRF gene, which is not well-understood. Studies in mice, flies, and cells from humans and mice suggest CREBRF is important for cellular growth and stress response, and that rs373863828 increases these functions. In this study, we tested the hypothesis that CREBRF affects these cellular processes by controlling gene expression--how genes are \"turned on or off\" -in fat tissue from Samoan adults as part of the Soifua Manuia (\"Good Health\") study. We found 22 genes that were affected by how many G to A changes (0, 1, or 2) an individual has at this position in CREBRF. We also found that the variant did not affect the proportion of the cell types that make up adipose tissue. This work helps us to better understand the function of the CREBRF gene in human fat and gives some clues about how the variant affects BMI and type 2 diabetes risk in healthy Samoan adults.","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.\n\nAUTHOR SUMMARYA genetic variant (change in DNA, G >A) is associated with higher body mass index and lower risk for type 2 diabetes. This variant, called rs373863828, is only present in people of Pacific Islander ancestry, who are underrepresented in genetic and genomic studies, and is in the CREBRF gene, which is not well-understood. Studies in mice, flies, and cells from humans and mice suggest CREBRF is important for cellular growth and stress response, and that rs373863828 increases these functions. In this study, we tested the hypothesis that CREBRF affects these cellular processes by controlling gene expression--how genes are \"turned on or off\" -in fat tissue from Samoan adults as part of the Soifua Manuia (\"Good Health\") study. We found 22 genes that were affected by how many G to A changes (0, 1, or 2) an individual has at this position in CREBRF. We also found that the variant did not affect the proportion of the cell types that make up adipose tissue. This work helps us to better understand the function of the CREBRF gene in human fat and gives some clues about how the variant affects BMI and type 2 diabetes risk in healthy Samoan adults.","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":"BackgroundTremor 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.\n\nObjectiveWe 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.\n\nMethodsWe 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.\n\nResultsTremor 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.\n\nConclusionsMorphology-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":"BackgroundTremor 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.\n\nObjectiveWe 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.\n\nMethodsWe 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.\n\nResultsTremor 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.\n\nConclusionsMorphology-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":"ObjectivePhysician-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.\n\nStudy DesignWe 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.\n\nResultsK12 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.\n\nConclusionPersonalized 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":"PurposeThis 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).\n\nMethodParticipants 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.\n\nResultsDiagnostic 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.\n\nConclusionsStandardized 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.","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":"PurposeThis 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).\n\nMethodParticipants 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.\n\nResultsDiagnostic 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.\n\nConclusionsStandardized 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.","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":"BACKGROUNDAdverse 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.\n\nMETHODSHyperbilirubinemia 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.\n\nRESULTSWe 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.\n\nCONCLUSIONThe poor sensitivity of visual inspection underscores an urgent need for accurate, affordable screening tools to improve screening for hyperbilirubinemia.\n\nImpact StatementO_LIWe found poor sensitivity of visual inspection, identifying fewer than one in five neonatal jaundice cases, suggesting much worse diagnostic accuracy in this community-based context across five low- and middle-income countries (LMICs) as compared to the previous studies conducted in health facilities.\nC_LIO_LIAmong preterm infants, sensitivity was modestly higher than in term infants but remained clinically inadequate, reinforcing that visual inspection alone is insufficient for this high-risk group.\nC_LIO_LIDespite standardized training and biannual refresher sessions, our study suggests that training for health care workers alone is unlikely to make visual inspection a reliable case-detection tool.\nC_LIO_LIOur findings suggest that the WHO should re-evaluate the IMCI recommendations to include tools with higher diagnostic accuracy to identify neonatal jaundice.\nC_LIO_LICommunity-level jaundice screening should move beyond visual inspection alone towards validated, low-cost, objective tools; icterometers and smartphone apps with high diagnostic accuracy are promising alternatives.\nC_LI","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":"BACKGROUNDAdverse 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.\n\nMETHODSHyperbilirubinemia 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.\n\nRESULTSWe 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.\n\nCONCLUSIONThe poor sensitivity of visual inspection underscores an urgent need for accurate, affordable screening tools to improve screening for hyperbilirubinemia.\n\nImpact StatementO_LIWe found poor sensitivity of visual inspection, identifying fewer than one in five neonatal jaundice cases, suggesting much worse diagnostic accuracy in this community-based context across five low- and middle-income countries (LMICs) as compared to the previous studies conducted in health facilities.\nC_LIO_LIAmong preterm infants, sensitivity was modestly higher than in term infants but remained clinically inadequate, reinforcing that visual inspection alone is insufficient for this high-risk group.\nC_LIO_LIDespite standardized training and biannual refresher sessions, our study suggests that training for health care workers alone is unlikely to make visual inspection a reliable case-detection tool.\nC_LIO_LIOur findings suggest that the WHO should re-evaluate the IMCI recommendations to include tools with higher diagnostic accuracy to identify neonatal jaundice.\nC_LIO_LICommunity-level jaundice screening should move beyond visual inspection alone towards validated, low-cost, objective tools; icterometers and smartphone apps with high diagnostic accuracy are promising alternatives.\nC_LI","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":"BackgroundModerate-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.\n\nMethodsWe 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.\n\nResultsMild 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.\n\nConclusionMild 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":"BackgroundTraumatic 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.\n\nObjectiveWe 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).\n\nMethodsPaired samples were collected prospectively across matched time points spanning hours to decades post-injury and assayed using high-sensitivity immunoassays.\n\nResultsAbsolute 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.\n\nConclusionsThese 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.\n\nHighlightsO_LIFirst high-frequency (twice-daily for 14 days) paired capillary-DPS \/ venous-plasma GFAP and NfL trajectories in acute TBI (Cohort #1, n = 4).\nC_LIO_LIStrong within-subject capillary-venous correlations for GFAP ({rho} up to 0.647) and NfL ({rho} up to 0.902); the GFAP \/ NfL ratio reaches {rho} = 0.797-0.977.\nC_LIO_LICross-sectional capillary-DPS biomarkers separate acute, subacute, and chronic TBI populations across a multi-site cohort (Cohort #2).\nC_LIO_LIConcurrent work by Bouthors et al. (CCLM 2026) supports prioritizing GFAP and NfL over UCH-L1 for capillary panels because UCH-L1 is intra-erythrocytic and hemolysis-sensitive.\nC_LIO_LICapillary DPS sampling establishes analytical feasibility for paired capillary-venous GFAP and NfL measurement; formal validation of context-of-use, unsupervised collection, and outcome linkage is required before clinical deployment.\nC_LI","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":"BackgroundTraumatic 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.\n\nObjectiveWe 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).\n\nMethodsPaired samples were collected prospectively across matched time points spanning hours to decades post-injury and assayed using high-sensitivity immunoassays.\n\nResultsAbsolute 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.\n\nConclusionsThese 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.\n\nHighlightsO_LIFirst high-frequency (twice-daily for 14 days) paired capillary-DPS \/ venous-plasma GFAP and NfL trajectories in acute TBI (Cohort #1, n = 4).\nC_LIO_LIStrong within-subject capillary-venous correlations for GFAP ({rho} up to 0.647) and NfL ({rho} up to 0.902); the GFAP \/ NfL ratio reaches {rho} = 0.797-0.977.\nC_LIO_LICross-sectional capillary-DPS biomarkers separate acute, subacute, and chronic TBI populations across a multi-site cohort (Cohort #2).\nC_LIO_LIConcurrent work by Bouthors et al. (CCLM 2026) supports prioritizing GFAP and NfL over UCH-L1 for capillary panels because UCH-L1 is intra-erythrocytic and hemolysis-sensitive.\nC_LIO_LICapillary DPS sampling establishes analytical feasibility for paired capillary-venous GFAP and NfL measurement; formal validation of context-of-use, unsupervised collection, and outcome linkage is required before clinical deployment.\nC_LI","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":"BackgroundTraumatic 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.\n\nObjectiveWe 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).\n\nMethodsPaired samples were collected prospectively across matched time points spanning hours to decades post-injury and assayed using high-sensitivity immunoassays.\n\nResultsAbsolute 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.\n\nConclusionsThese 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.\n\nHighlightsO_LIFirst high-frequency (twice-daily for 14 days) paired capillary-DPS \/ venous-plasma GFAP and NfL trajectories in acute TBI (Cohort #1, n = 4).\nC_LIO_LIStrong within-subject capillary-venous correlations for GFAP ({rho} up to 0.647) and NfL ({rho} up to 0.902); the GFAP \/ NfL ratio reaches {rho} = 0.797-0.977.\nC_LIO_LICross-sectional capillary-DPS biomarkers separate acute, subacute, and chronic TBI populations across a multi-site cohort (Cohort #2).\nC_LIO_LIConcurrent work by Bouthors et al. (CCLM 2026) supports prioritizing GFAP and NfL over UCH-L1 for capillary panels because UCH-L1 is intra-erythrocytic and hemolysis-sensitive.\nC_LIO_LICapillary DPS sampling establishes analytical feasibility for paired capillary-venous GFAP and NfL measurement; formal validation of context-of-use, unsupervised collection, and outcome linkage is required before clinical deployment.\nC_LI","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 womans 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":"BackgroundThe 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).\n\nMethodologyA 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 Gubas constructs of trustworthiness were followed.\n\nResultsSeveral 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.\n\nConclusionMothers 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.\n\nARTICLE SUMMARYO_LIThis study provides in-depth insight into mothers lived experiences in an under-researched LMIC setting.\nC_LIO_LIMethodological rigor was enhanced through COREQ, triangulation, member checking, and an audit trail.\nC_LIO_LIConducting the study at a single public-sector center limits transferability. 4-Exclusion of fathers limits broader family perspectives\nC_LI\n\nWhat is already known on the topicThe mothers of children with autism spectrum disorder (ASD) are more stressed than those of neurotypical or any other type of special needs children.\n\nSocioeconomic problems, societal stigma and lack of service availability are reported as the major contributors to the caregiver strain experienced by them.\n\nWhat this study addsThe study highlights key needs, barriers, and contextual realities faced by mothers of children with autism within the setting of an LMIC.\n\nEffect on research, practice or policyIt can help greatly in managing stigma related to mental health through the perspective of the mothers. Another possible benefit can be the evidence-based formulation of policies and infrastructure required for inclusion of children with ASD into the society.","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":"BackgroundThoracic 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.\n\nMethodsWe 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.\n\nResultsDiscovery 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.\n\nConclusionsThese 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.\n\nIn 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.\n\nThis 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.\n\nIn 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.\n\nThis 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 (Ca{superscript 2})-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 Ca{superscript 2} 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 Ca{superscript 2} 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.\n\nOne Sentence SummaryMYOF deficiency disrupts MYOF-CaV1.2 interaction and calcium handling, causing arrhythmogenic cardiomyopathy.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=144 HEIGHT=200 SRC=\"FIGDIR\/small\/26363590v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (41K):\norg.highwire.dtl.DTLVardef@1057f08org.highwire.dtl.DTLVardef@1d71b0forg.highwire.dtl.DTLVardef@1318309org.highwire.dtl.DTLVardef@1920208_HPS_FORMAT_FIGEXP  M_FIG C_FIG","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 (Ca{superscript 2})-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 Ca{superscript 2} 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 Ca{superscript 2} 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.\n\nOne Sentence SummaryMYOF deficiency disrupts MYOF-CaV1.2 interaction and calcium handling, causing arrhythmogenic cardiomyopathy.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=144 HEIGHT=200 SRC=\"FIGDIR\/small\/26363590v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (41K):\norg.highwire.dtl.DTLVardef@1057f08org.highwire.dtl.DTLVardef@1d71b0forg.highwire.dtl.DTLVardef@1318309org.highwire.dtl.DTLVardef@1920208_HPS_FORMAT_FIGEXP  M_FIG C_FIG","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.\n\nWe 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).\n\nTo 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":"BackgroundParkinsons 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.\n\nObjectivesOur 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).\n\nMethodsWe 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.\n\nResultsOf 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 Gauchers disease, and 2.7% had known risk variants in GBA1.\n\nConclusionsBy 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":"BackgroundParkinsons 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.\n\nObjectivesOur 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).\n\nMethodsWe 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.\n\nResultsOf 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 Gauchers disease, and 2.7% had known risk variants in GBA1.\n\nConclusionsBy 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 ObjectivesVascular 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.\n\nMethodsCross-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.\n\nResultsOf 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).\n\nDiscussionThe 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 ObjectivesVascular 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.\n\nMethodsCross-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.\n\nResultsOf 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).\n\nDiscussionThe 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 ObjectivesVascular 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.\n\nMethodsCross-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.\n\nResultsOf 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).\n\nDiscussionThe 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 ObjectivesVascular 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.\n\nMethodsCross-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.\n\nResultsOf 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).\n\nDiscussionThe 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":"IntroductionHeart 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.\n\nMethodsA 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.\n\nResultsFor 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.\n\nConclusionHuman-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":"BackgroundApproximately 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 Organizations 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.\n\nMethodsWe 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 Banduras Multidimensional Scales of Perceived Self-Efficacy. We analyzed data using descriptive statistics and paired-samples t-tests.\n\nResultsOf 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.\n\nConclusionThe 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":"BackgroundApproximately 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 Organizations 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.\n\nMethodsWe 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 Banduras Multidimensional Scales of Perceived Self-Efficacy. We analyzed data using descriptive statistics and paired-samples t-tests.\n\nResultsOf 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.\n\nConclusionThe 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":"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"}]}