{"gname":"University of Massachusetts Chan Medical School ","grp_id":"44","rels":[{"rel_title":"Autism associated Cntnap2 deletion disrupts vestibular sensory signaling and spatial cognition in mice","rel_doi":"10.64898\/2026.05.28.728446","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.28.728446","rel_abs":"Autism spectrum disorder (ASD) is frequently accompanied by sensory and motor abnormalities, including impaired balance, postural control, and spatial orientation, that are often attributed largely to altered central circuitry. Emerging evidence, however, suggests that peripheral sensory dysfunction can also shape ASD related behavioral phenotypes. Here, we tested whether loss of the ASD associated gene Cntnap2 alters vestibular signaling in Cntnap2-\/- mice. Developmental transcriptomic analysis showed that Cntnap2 is expressed in vestibular sensory organs and increases during the first postnatal month, coincident with vestibular pathway maturation. Vestibular sensory evoked potentials revealed reduced response amplitudes and prolonged latencies in Cntnap2-\/- mice, indicating impaired peripheral afferent responses to transient linear acceleration. Cntnap2-\/- mice also showed delayed contact righting, reduced ocular counter roll, and increased hindlimb slips and compensatory tail excursions during balance beam walking, whereas rotational vestibulo-ocular reflex gain and phase were preserved. These vestibular and balance abnormalities were accompanied by reduced novel arm preference in the Y maze and severe impairment of Barnes maze acquisition, consistent with impaired spatial learning. Together, these findings identify Cntnap2 as a regulator of vestibular sensory signaling and support a model in which disrupted peripheral vestibular input, likely acting together with central effects of Cntnap2 loss, contributes to sensorimotor and spatial cognitive phenotypes relevant to ASD.","rel_num_authors":7,"rel_authors":[{"author_name":"Yvette Shu","author_inst":"Johns Hopkins University"},{"author_name":"Yushan Chen","author_inst":"Johns Hopkins University"},{"author_name":"Dyllan Zhou","author_inst":"Johns Hopkins University"},{"author_name":"Xiaoya Deng","author_inst":"Johns Hopkins University"},{"author_name":"Liliana D Florea","author_inst":"Johns Hopkins University"},{"author_name":"Tara Deemyad","author_inst":"Johns Hopkins University"},{"author_name":"Soroush G Sadeghi","author_inst":"Johns Hopkins University"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Conditional and marginal SNP-heritability to leverage ancestral and environmental diversity","rel_doi":"10.64898\/2026.05.28.728536","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.28.728536","rel_abs":"SNP-heritability is defined as the fraction of variance of a trait that is explained by the SNPs in a genome-wide association study. Several methodologies have been proposed to estimate this quantity. More recent methods aim to do so with ancestrally diverse datasets and yet obtain a single heritability for an entire dataset, which we refer to as marginal heritability. However, the different underlying subpopulations that compose a genetically diverse dataset might have different environmental and genetic exposures, and thus may have different heritabilities. In order to address this, we propose a conditional SNP-heritability approach that allows to estimate multiple SNP-heritabilities on a dataset corresponding to different ancestral compositions and environmental exposures. We take a careful statistical approach, including estimation of conditional genetic and environmental variances, and calculation of standard errors via a combination of the delta method with bootstrapping. We validate our method via extensive simulations. We then apply it to an ancestrally and socio-economically diverse dataset of 6603 subjects aged around 9 to 11 from the Adolescent Brain Cognitive Development study, and illustrate how the SNP-heritability of intelligence scores can change due to differing extrinsic variances in different socio-economic groups, which coincides with previous work in the literature. This conditional estimation approach can be a valuable tool for understanding differences in risks across subpopulations. Our work here improves on existing methodology and allows us to leverage the heterogeneity of the data to obtain new insights.","rel_num_authors":3,"rel_authors":[{"author_name":"Anubhav Nikunj Singh Sachan","author_inst":"University of California San Diego"},{"author_name":"Armin Schwartzman","author_inst":"University of California, San Diego"},{"author_name":"David Azriel","author_inst":"Techion - Israel Institute of Technology"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Gradients in excitability generate hippocampal waves and shape their interactions with cortex","rel_doi":"10.64898\/2026.05.27.728116","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.27.728116","rel_abs":"Travelling waves are a prominent feature of hippocampal activity, but the mechanisms determining their propagation and influence on the cerebral cortex remain unclear. Using a biophysically-grounded model of neural activity evolving across hippocampal and cortical surfaces, we show that spatial gradients in external input or neural excitability are a sufficient mechanism for the emergence of travelling waves along the long axis of the hippocampus. These waves emerge only above a critical gradient threshold, propagate with biologically-plausible velocities and exhibit frequency-dependent reversals in direction across slow and fast theta regimes. When coupled to the cerebral cortex, anterior-to-posterior hippocampal waves selectively reorganise globally synchronous cortical activity into metastable travelling waves, whereas posterior-to-anterior hippocampal waves do not, revealing a directional asymmetry in hippocampal-cortical communication. Conversely, cortical waves aligned with large-scale functional gradients induce structured hippocampal waves, revealing complementary direction specific effects across the two systems. These analyses identify structured excitability gradients as a principle governing wave propagation in the hippocampus and suggest how wave-to-wave interactions may coordinate complex cortical and hippocampal interactions during mnemonic and perceptual processes.","rel_num_authors":5,"rel_authors":[{"author_name":"Anna Behler","author_inst":"The University of Newcastle"},{"author_name":"Richa Phogat","author_inst":"The University of Newcastle"},{"author_name":"David T. Jones","author_inst":"Department of Neurology, Mayo Clinic, Rochester, MN, USA"},{"author_name":"James Shine","author_inst":"The University of Sydney"},{"author_name":"Michael Breakspear","author_inst":"University of Newcastle"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Comparative connectomics reveals stage-specific gap junction rewiring that reshapes avoidance behavior","rel_doi":"10.64898\/2026.05.28.728331","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.28.728331","rel_abs":"Environmental stress can remodel neural circuits, yet how such rewiring generates behavioral adaptation remains poorly understood. The dauer stage of Caenorhabditis elegans provides a unique model to address this question. Here, we investigated how dauer-specific circuit remodeling alters nociceptive behavior. We found that dauers exhibit markedly shorter avoidance durations than adults. Comparative connectomics revealed substantial expansion of gap junctions within the dauer nociceptive circuit. Calcium imaging further showed that dauer neurons exhibit faster and more transient activity dynamics throughout the circuit. Introducing synthetic dauer-specific gap junctions into adults was sufficient to recapitulate dauer-like neuronal activity patterns and significantly shorten avoidance duration. Despite extensive circuit rewiring, however, avoidance initiation remained preserved across developmental stages. Together, our findings demonstrate that the dauer connectome is selectively rewired through gap junction remodeling to tune behavioral persistence while robustly preserving behavioral initiation, revealing how developmental circuit reorganization balances flexibility and stability for survival under stress.","rel_num_authors":6,"rel_authors":[{"author_name":"Daniel T. Choe","author_inst":"SEOUL NATIONAL UNIVERSITY"},{"author_name":"David  H Hall","author_inst":"Yeshiva University Albert Einstein College of Medicine"},{"author_name":"Ken  C.Q. Nguyen","author_inst":"Yeshiva University Albert Einstein College of Medicine"},{"author_name":"Myunghwan Choi","author_inst":"Seoul National University"},{"author_name":"J. Alexander Bae","author_inst":"KAIST"},{"author_name":"Junho Lee","author_inst":"Seoul National University"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Clonal dynamics of germinal center refueling by secondary immunization","rel_doi":"10.64898\/2026.05.26.728008","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.26.728008","rel_abs":"Many vaccine regimens involve delivery of multiple doses to the same anatomical site, such that booster doses frequently encounter germinal centers (GCs) still active from prior immunization. The consequences of this \"GC refueling\" to B cell clonality have not been systematically investigated. Using mouse models of mRNA-LNP vaccination combined with multicolor fate-mapping, longitudinal GC imaging, and immunoglobulin sequencing, we show that refueling triggers clonal burst-type expansion of GC-resident B cells, rather than recruiting local memory, resulting in marked focusing of GCs on the descendants of individual B cells. Refueling with a drifted antigen led to limited but detectable retraining of primary-cohort clones, although most variant-specific responses in this setting arose from newly recruited naive B cells. These findings identify GC refueling as a distinct mode of vaccine response with implications for sequential immunization strategies against rapidly evolving pathogens.","rel_num_authors":10,"rel_authors":[{"author_name":"Luka Mesin","author_inst":"The Rockefeller University"},{"author_name":"Alvaro Hobbs","author_inst":"The Rockefeller University"},{"author_name":"Jin-Jie Shen","author_inst":"The Rockefeller University"},{"author_name":"Juhee Pae","author_inst":"The Rockefeller University"},{"author_name":"Arien Schiepers","author_inst":"The Rockefeller University"},{"author_name":"Nadine Abrahamse","author_inst":"The Rockefeller University"},{"author_name":"Hiromi Muramatsu","author_inst":"University of Pennsylvania"},{"author_name":"Ying K Tam","author_inst":"Acuitas Therapeutics"},{"author_name":"Norbert Pardi","author_inst":"University of Pennsylvania"},{"author_name":"Gabriel D Victora","author_inst":"The Rockefeller University"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Circadian misalignment underlies immune escape in breast cancer","rel_doi":"10.64898\/2026.05.26.726543","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.26.726543","rel_abs":"Circadian regulation shapes tissue physiology, yet how it organizes cellular and molecular dynamics within the tumor microenvironment (TME) and influences tumor immunity remains unclear. Using temporal single-nucleus multiomic profiling of mouse breast tumors, we uncovered extensive circadian programs that are both cell-type-specific and shared across the TME, governing proliferation and immune responses. Notably, cancer epithelial cells exhibited global acrophase misalignment relative to immune populations. This intercellular desynchrony manifests as temporal decoupling between tumor proliferation and immune activation, discordant antigen presentation and T cell recognition with intrinsic activation exhaustion overlap in T cells, and asynchronous PD-1\/PD-L1 oscillations that sustain checkpoint-mediated suppression. Similar patterns were observed in human triple-negative breast cancer (TNBC). Together, these findings establish intercellular circadian misalignment as a mechanism of tumor immune evasion and position the circadian architecture of the tumor-immune ecosystem as a previously underappreciated determinant of tumor development and therapeutic response.","rel_num_authors":27,"rel_authors":[{"author_name":"Chuqian Liang","author_inst":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"},{"author_name":"Zunpeng Liu","author_inst":"Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, Massachusetts 02139, USA"},{"author_name":"Xiaoke Xu","author_inst":"Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, Massachusetts 02139, USA"},{"author_name":"Zhen Xu","author_inst":"Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"},{"author_name":"Qi Zhang","author_inst":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"},{"author_name":"Tao Zhang","author_inst":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"},{"author_name":"Riley J. Mangan","author_inst":"Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, Massachusetts 02139, USA"},{"author_name":"Bingqiu Xiu","author_inst":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"},{"author_name":"Gongwei Wu","author_inst":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"},{"author_name":"Tara Akhshi","author_inst":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"},{"author_name":"Zachary M. Sandusky","author_inst":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"},{"author_name":"G. Kenneth Gray","author_inst":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"},{"author_name":"Na Zhang","author_inst":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"},{"author_name":"Genevra Kuziel","author_inst":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"},{"author_name":"Nicole A. Traphagen","author_inst":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"},{"author_name":"Stuart Benjamin Fass","author_inst":"Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, Massachusetts 02139, USA"},{"author_name":"Amy Grayson","author_inst":"Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, Massachusetts 02139, USA"},{"author_name":"Li-Lun Ho","author_inst":"Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, Massachusetts 02139, USA"},{"author_name":"Shengqing Stan Gu","author_inst":"Department of Hematopoietic Biology and Malignancy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"},{"author_name":"Song Wang","author_inst":"Department of Computer Science, University of Central Florida, Orlando, FL 32816, USA"},{"author_name":"Zion Zihan Sheng","author_inst":"Department of Neurosurgery, Duke University, Durham, NC 27710, USA"},{"author_name":"Yi Zhang","author_inst":"Department of Neurosurgery, Duke University, Durham, NC 27710, USA"},{"author_name":"Elio Adib","author_inst":"Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA"},{"author_name":"Tianlong Chen","author_inst":"Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"},{"author_name":"Rinath Jeselsohn","author_inst":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"},{"author_name":"Manolis Kellis","author_inst":"Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, Massachusetts 02139, USA"},{"author_name":"Myles Brown","author_inst":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Rapid reduction in global chromatin loop size after acute STAG2 reconstitution in human cancer cells","rel_doi":"10.64898\/2026.05.26.727913","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.26.727913","rel_abs":"Truncating mutations in the tumor suppressor STAG2, which encodes a component of the cohesin complex, are prevalent across diverse human cancers. Here, we report that acute reconstitution of physiological STAG2 levels in STAG2-mutant human glioblastoma multiforme cancer cells triggers a rapid reduction in the size of chromatin loops genome-wide. Despite this global change in chromatin loop size, early transcriptional responses to STAG2 restoration are limited to a small number of genes, most of which are induced by STAG2 reconstitution. Notably, the growth-suppressor EFEMP1 (Fibulin-3), a secreted glycoprotein that functions as an extracellular matrix-associated inhibitor of glioblastoma growth and invasion, was the only gene consistently induced across all experimental models. The most robust and conserved STAG2-induced genes all reside within intense chromatin loops whose anchors and overall intensity did not appear to change in response to STAG2 reconstitution. These findings suggest that inactivating mutations of STAG2 promote neoplastic transformation by alleviating a restriction on chromatin loop size, allowing for an expanded range of chromatin interactions that disrupts the maintenance of a tumor-suppressive transcriptome.","rel_num_authors":10,"rel_authors":[{"author_name":"Tianyi Yang","author_inst":"Case Western Reserve University"},{"author_name":"Jung-Sik Kim","author_inst":"Georgetown University School of Medicine"},{"author_name":"Clara Mellows","author_inst":"Georgetown University School of Medicine"},{"author_name":"Wanying Xu","author_inst":"Case Western Reserve University"},{"author_name":"Alvin Ya","author_inst":"Georgetown University School of Medicine"},{"author_name":"Lisa Sadzewicz","author_inst":"University of Maryland"},{"author_name":"Luke Tallon","author_inst":"University of Maryland"},{"author_name":"Jann Sarkaria","author_inst":"Mayo Clinic"},{"author_name":"Fulai Jin","author_inst":"Case Western Reserve University"},{"author_name":"Todd Waldman","author_inst":"Georgetown University School of Medicine"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Diffusion models learn underlying trends in actomyosin networks and predict behavior at unseen filament turnover","rel_doi":"10.64898\/2026.05.26.727950","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.26.727950","rel_abs":"Generative diffusion models have demonstrated an ability to produce novel images sampled from the learned underlying data distribution. These models are able to infer system characteristics for parameter combinations that were not seen during training. We investigate the ability of these models to infer trends in biological data from limited samples. Specifically, we consider the response of system scale behaviors such as cortical flow in a simulated actomyosin system as we tune filament turnover rates. We train a diffusion model on coarse grained actin curvature and density heatmap images, and are able to generate images from conditioning variables not seen during training. These images are predictive of nonlinear trends in the system. We also consider characteristics of the system that allows this level of inference, such as the strong linear relationship between average density and filament turnover in the system, and by exploring minimal underlying dynamics with a motor binding model.","rel_num_authors":4,"rel_authors":[{"author_name":"Elisabeth Rennert","author_inst":"University of Chicago"},{"author_name":"Agnish Kumar Behera","author_inst":"Flatiron Institute"},{"author_name":"Yuqing Qiu","author_inst":"The University of Tennessee Knoxville"},{"author_name":"Suriyanarayanan Vaikuntanathan","author_inst":"University of Chicago"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Implicit vs. explicit choice promotes the combination vs. selection of sensorimotor memories under contextual uncertainty","rel_doi":"10.64898\/2026.05.26.727900","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.26.727900","rel_abs":"Skilled action requires expressing motor memories as appropriate for the current context, but context is often uncertain. Theoretical models make conflicting proposals about memory expression under contextual uncertainty, predicting belief-weighted combination of memories versus the selection of the most probable memory. We tested these predictions by training human participants to reach in two opposing force fields cued by the direction of a random dot motion stimulus whose coherence varied. When participants moved before reporting dot direction, adaptation scaled with coherence: low-reliability cues produced partial expression of both memories. Fitting Bayesian observer models to behavior favored belief-weighted memory combination. In contrast, when participants reported their choice before moving, adaptation was independent of coherence and model fits favored categorical memory selection. Thus, sensorimotor memories are expressed as either a probabilistic combination or categorical selection, depending on whether participants' contextual inference remains implicit or is made explicit at the time of memory expression.","rel_num_authors":6,"rel_authors":[{"author_name":"Anvesh S. Naik","author_inst":"Columbia University"},{"author_name":"Sabyasachi Shivkumar","author_inst":"Columbia University"},{"author_name":"Carlos Velazquez-Vargas","author_inst":"Columbia University"},{"author_name":"James N. Ingram","author_inst":"University of Cambridge"},{"author_name":"Mate Lengyel","author_inst":"University of Cambridge; Central European University"},{"author_name":"Daniel M. Wolpert","author_inst":"Columbia University; University of Cambridge"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Neuropeptide Receptors Harbor More Genomic Regulatory Elements in Their Loci Than the Loci of Their Ligands","rel_doi":"10.64898\/2026.05.26.727860","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.26.727860","rel_abs":"The neuropeptide signaling pathway is vital for the physiology and behavior of multicellular organisms. This pathway is mediated by ligand-receptor binding, wherein neuropeptides (NPs) are often released from neurons, while their receptors (NPRs) are ubiquitously expressed in both neuronal and non-neuronal cell types. To elucidate the underlying mechanisms of this expression pattern divergence, here we dissect the genomic and epigenomic architectures of these two distinct gene classes. We first characterized the genomic architecture of NP and NPR genes to compare their total gene length, exon and intron lengths, exon counts, and number of alternatively spliced transcripts per gene. We also profiled their regulatory genomic elements including CpG islands, TATA boxes, and their overlapping antisense transcripts. These analyses were then expanded to non-human model organisms to evaluate the evolutionary conservation of the underlying mechanisms. We found that NPRs encompass larger genomic loci and encode longer transcripts than NPs. Furthermore, the increased length of NPR transcripts was driven by longer exons rather than higher exon counts. Consistently, the number of spliced variants per gene was similar between NPs and NPRs, suggesting that alternative splicing events are a minor contributor to their distinct expression patterns. At the RNA level, NPR mRNAs possess significantly longer 3'UTRs compared to NPs, indicating a greater potential for post-transcriptional gene regulation. This complexity is also mirrored at the chromatin level, where NPR loci exhibit a higher density of epigenetic marks than NPs. Together, these findings highlight the multi-layered nature of gene regulation prioritizing control at the receptor level.","rel_num_authors":4,"rel_authors":[{"author_name":"Hadi Najafihajivar","author_inst":"University of Massachusetts Chan Medical School Department of Molecular Cell and Cancer Biology"},{"author_name":"Seung Hun Jeong","author_inst":"Kangwon National University"},{"author_name":"Woo Jae Kim","author_inst":"Harbin Institute of Technology"},{"author_name":"Sun Shim Choi","author_inst":"Kangwon National University"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Dominant resistance alleles accelerate population suppression by CRISPR-based gene drive","rel_doi":"10.64898\/2026.05.28.728369","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.28.728369","rel_abs":"CRISPR-based gene drive is a promising strategy for pest control. However, when targeting a recessive fertility gene, nonfunctional resistance alleles generated by end-joining slow the spread of drive and can even impair suppressive power. It was recently discovered that a doublesex target site can result in dominant female-sterile alleles when disrupted. It could serve as an ideal target for suppression drives, as disrupted alleles are efficiently removed when inherited by a female, increasing the suppressive power of the drive. Here, to better understand how dominant sterile target sites can improve suppression, we used an individual-based, continuous space model to investigate chasing dynamics of homing drives that produce dominant female-sterile resistance. Our results indicate that dominant-sterile resistance allows homing drives to achieve higher population elimination rates and a lower probability of chasing over a broader range of performance parameters. In addition, we propose a confined gene drive system, termed TADFI (Toxin-Antidote Dominant Female Intersex), that is also based on formation of dominant female sterile alleles. TADFI has two variants, designed for population suppression and modification, respectively. We estimate the introduction frequency threshold of TADFI in a panmictic model, and evaluate its suppression dynamics in a spatial model. Though spreading less rapidly than Toxin-Antidote Dominant Embryo (TADE) suppression drive, it has similar favorable dynamics related to confinement and suppressive power, while potentially being easier to construct. Together these results show that drives generating dominant-female sterile alleles may be promising candidates for a variety of population suppression applications.","rel_num_authors":3,"rel_authors":[{"author_name":"Weizhe Chen","author_inst":"Peking University"},{"author_name":"Jingyun Liang","author_inst":"Peking University"},{"author_name":"Jackson Champer","author_inst":"Peking University"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"A pistillate-biased epidermal regulatory program underlies glandular trichome development in Cannabis sativa","rel_doi":"10.64898\/2026.05.26.727882","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.26.727882","rel_abs":"Glandular trichomes are specialized epidermal structures on Cannabis sativa L. inflorescences that synthesize and store cannabinoids and terpenoids, making them central to the species' economic and medicinal value. Although trichome development is a multistage genetic process, its regulatory basis in C. sativa remains poorly understood, particularly with respect to sexual dimorphism and sex plasticity. Here, we combined orthology-based gene discovery with transcriptomic profiling to investigate trichome development across four floral phenotypes: female flowers (FF), male flowers (MF), induced male flowers on XX plants (IMF), and induced female flowers on XY plants (IFF). Using trichome development-related genes from Arabidopsis thaliana, a model for unicellular non-glandular trichome development, and Solanum lycopersicum, a model for multicellular glandular trichomes, we identified and mapped 53 candidate C. sativa trichome development regulator genes (CsTDRGs). The CsTDRG set did not support a simple Arabidopsis- or tomato-like model, but instead included Arabidopsis-like epidermal fate components, including MBW-related regulators and GL2, alongside tomato-like multicel-lular trichome regulators, including MIXTA-like, HD-ZIP IV, WOX, MTR, GRAS, and hormone-associated candidates. RNA-seq analysis showed that CsTDRG expression was more strongly associated with floral phenotype than chromosomal sex. Genes with preferential expression in pistillate tissues were CsTT8, CsMYC1\/GL3, CsGL2, CsYABBY4 and CsMIXTA-like1\/MYB106, whereas CsMTR1, CsGRAS9, and CsCKX3 were upregulated in male (MF and IMF) flower. These findings suggest that sexually dimorphic trichome development in C. sativa reflects differential regulation of a shared developmental toolkit that combines conserved epidermal fate components with multicellular and glandular trichome regulatory modules.","rel_num_authors":5,"rel_authors":[{"author_name":"Adrian S Monthony","author_inst":"Universite Laval"},{"author_name":"Julien Roy","author_inst":"Universite Laval"},{"author_name":"Mohsen Niazian","author_inst":"University of Tehran"},{"author_name":"Thomas Jarrin","author_inst":"Universite Catholique de Lyon"},{"author_name":"Davoud Torkamaneh","author_inst":"University of Guelph and Universite Laval"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"The free-living wellspring of symbiotic nitrogen fixation in Bradyrhizobium","rel_doi":"10.64898\/2026.05.28.728359","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.28.728359","rel_abs":"The evolutionary origin of nitrogen-fixing symbiosis has been a long-standing question. To address this, we focused on Bradyrhizobium, a globally abundant bacterial genus that includes classic symbiotic lineages, which rely on the common Nod factor signaling pathway to form nodules, and close relatives capable of fixing nitrogen in a free-living state. We isolated 88 strains carrying the key genes for nitrogen fixation (nif) from non-legume environments and analyzed them alongside 586 public Bradyrhizobium genomes harboring these genes to reconstruct a robust phylogeny of nif genes. Analysis reveals that the earliest-diverging nif lineages are members capable of free-living nitrogen fixation, establishing this as the ancestral state. The Nod factor-dependent symbiotic lineages are polyphyletic, demonstrating at least three independent origins via horizontal acquisition of symbiosis islands. This evolutionary history is reflected in a genomic dichotomy: lineages capable of free-living nitrogen fixation possess a conserved nif island architecture that consistently includes the oxygen-protective gene glbO, whereas the symbiotic nif-associated regions are highly variable and universally lack glbO. Using both loss-of-function and gain-of-function genetic approaches, we show that glbO contributes significantly to nitrogenase activity under free-living conditions, whereas it is dispensable within the protected nodule environment. This work establishes a new framework for the evolution of symbiosis, identifying free-living ancestors as the source from which nitrogen-fixing symbiosis repeatedly and independently evolved in Bradyrhizobium.","rel_num_authors":10,"rel_authors":[{"author_name":"Lu LING","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Sishuo Wang","author_inst":"Chinese University of Hong Kong"},{"author_name":"Jinjin Tao","author_inst":"CUHK"},{"author_name":"Marjorie Pervent","author_inst":"PHIM Plant Health Institute of Montpellier"},{"author_name":"Kaitlyn E. Ho","author_inst":"The Chinese University of Hong Kong"},{"author_name":"Coline Sciallano","author_inst":"IRD: Institut de recherche pour le developpement"},{"author_name":"Alicia Camuel","author_inst":"PHIM Plant Health Institute of Montpellier"},{"author_name":"Nico Nouwen","author_inst":"PHIM Plant Health Institute of Montpellier"},{"author_name":"Eric Giraud","author_inst":"PHIM Plant Health Institute of Montpellier"},{"author_name":"Haiwei Luo","author_inst":"The Chinese University of Hong Kong"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Molecular grammar of RNA m6A modification in ribonucleoprotein granules","rel_doi":"10.64898\/2026.05.26.727807","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.26.727807","rel_abs":"Diverse RNA chemical modifications collectively regulate nearly all aspects of RNA metabolism. Among these, N6-methyladenosine (m6A) is the most prevalent internal modification in eukaryotic messenger RNAs. Recent studies have implicated m6A in the formation and regulation of ribonucleoprotein (RNP) granules-biomolecular condensates that organize RNA metabolism in space and time. However, the underlying biophysical mechanisms remain to be elucidated. Here, building on SMART, a single-molecule platform for quantitatively measuring RNP granule assembly across nanometer-to-mesoscale regimes, we develop SMART-epi to enable precise control of the m6A modification ratio. Using this approach, we show that physiological m6A levels inhibit YTHDF2 RNP granule assembly while directing specific RNA-RNA interaction architectures. Moreover, YTHDF1\/2\/3 exhibit distinct assembly kinetics, suggesting functional divergence. Together, these findings reveal a molecular grammar by which m6A modulates condensate dynamics and suggest that RNA modifications can encode regulatory information to tune RNP granule behavior, with potential implications for therapeutic intervention.","rel_num_authors":5,"rel_authors":[{"author_name":"Mengmeng Xu","author_inst":"Tsinghua University"},{"author_name":"Yuchen Li","author_inst":"Peking University"},{"author_name":"Tianyu Wang","author_inst":"Peking University"},{"author_name":"Jun Liu","author_inst":"Peking University"},{"author_name":"Zhi Qi","author_inst":"Peking University"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"The GNMT N-terminus Couples Folate Feedback to Methyl-donor Homeostasis","rel_doi":"10.64898\/2026.05.26.727678","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.26.727678","rel_abs":"Maintenance of S-adenosylmethionine (SAM) homeostasis is essential for methylation of biomolecules, nucleotide and polyamine synthesis, and redox homeostasis. While all methyltransferases consume SAM, only a subset of highly tissue specific methyltransferases regulates SAM homeostasis. Among them, glycine N-methyltransferase (GNMT) is enriched in the liver and its dysregulated activity has been linked to compromised liver function. GNMT is inhibited by the methyl carrier 5-methyltetrahydrofolate (5mTHF), suggesting a negative-feedback mechanism regulating its activity. Here, we identify the GNMT N-terminal tail, and specifically phosphorylation at serine 9 (S9ph), as a regulatory modification linking folate-dependent feedback inhibition to SAM homeostasis. Structural and biochemical analyses and molecular dynamics simulations revealed that the N-terminal tail is required for catalytic turnover of SAM and for 5mTHF binding. Phosphoproteomic analysis showed that GNMT S9ph is abundant in mouse liver and further enriched in aged mice. Consistent with loss of folate-dependent negative feedback, both distal N-terminal truncation (residues 1-8) and a phosphomimetic substitution abolished 5mTHF binding while maintaining catalytic activity. In hepatocyte cell lines lacking endogenous GNMT, lentiviral overexpression of constitutively active GNMT mutants depleted SAM, increased SAH, disrupted protein methylation, impaired growth, and induced transcriptional responses consistent with methyl-donor stress. Together, these findings identify the GNMT N-terminus as a tunable phosphoregulatory domain that dynamically regulates GNMT activity and cellular methylation potential.","rel_num_authors":17,"rel_authors":[{"author_name":"Isaac Kraz","author_inst":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461"},{"author_name":"Oi Wei Mak","author_inst":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461"},{"author_name":"Subray Hegde","author_inst":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461"},{"author_name":"Benjamin M. Lorton","author_inst":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461"},{"author_name":"Harrison Hector","author_inst":"Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461; Institute for Geroscience, Albert Einstein College of Medicine, Bron"},{"author_name":"Michael K. Broussalian","author_inst":"Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461; Institute for Geroscience, Albert Einstein College of Medicine, Bron"},{"author_name":"Sarah Graff","author_inst":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461"},{"author_name":"Jennifer Aguilan","author_inst":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461"},{"author_name":"Jeffrey Bonanno","author_inst":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461"},{"author_name":"Roozbeh Eskandari","author_inst":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461"},{"author_name":"Daniel Groom","author_inst":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461"},{"author_name":"Simone Sidoli","author_inst":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461"},{"author_name":"Steve Almo","author_inst":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461"},{"author_name":"Michael Brenowitz","author_inst":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461"},{"author_name":"Evripidis Gavathiotis","author_inst":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461; Institute for Geroscience, Albert Einstein College of Medicine, Bronx, NY 1046"},{"author_name":"Derek M. Huffman","author_inst":"Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461; Institute for Geroscience, Albert Einstein College of Medicine, Bron"},{"author_name":"David Shechter","author_inst":"Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Integrated Transcriptomic and Functional Analysis Reveals Tissue-Specific Molecular Pathology in Adolescent Idiopathic Scoliosis","rel_doi":"10.64898\/2026.05.27.727643","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.27.727643","rel_abs":"Adolescent idiopathic scoliosis (AIS), the spontaneous development of a lateral spine curvature during puberty, is the most common pediatric spine disorder, affecting ~3% of children worldwide. As the underlying etiology remains unclear, AIS is treated purely symptomatically, initially by bracing and ultimately by highly invasive, costly surgeries. Genome-wide association studies (GWAS) have identified numerous risk loci in non-coding genomic regions, making it difficult to link them to a biological function. To address this, we performed a multi-tissue investigation to connect genetic risk to tissue-specific molecular pathology. We conducted RNA sequencing on the primary tissues implicated in AIS, paravertebral muscle and spinal cartilage, from patients and unaffected controls. In paravertebral muscle, we identified differentially expressed genes (DEGs) enriched for pathways related to muscle structure, myogenesis, and metabolism. Key upregulated genes include the transcription factor EGR1 and structural components such as MYH1. In spinal cartilage, we found enrichment of genes related to TGF-beta; and FoxO signaling, as well as metabolic pathways. Notably, genes crucial for chondrocyte differentiation (e.g., SOX5 and SOX6) were significantly downregulated. We then examined genes at known GWAS loci and found that several risk-associated genes were differentially expressed in one or both tissues. To investigate the function of non-coding variants at these loci, we identified and validated several enhancer elements harboring AIS risk SNPs at the BCL2, ADGRG6, BNC2, and FTO loci. We reveal distinct pathological signatures in muscle and cartilage and lay the foundation for connecting non-coding genetic risk to the dysregulation of key developmental and structural pathways.","rel_num_authors":9,"rel_authors":[{"author_name":"Darius Ramkhalawan","author_inst":"University of Florida"},{"author_name":"Paola Parrales","author_inst":"University of Florida"},{"author_name":"Justin Koesterich","author_inst":"Rutgers University"},{"author_name":"Gloria Montoya-Vazquez","author_inst":"University of Florida"},{"author_name":"Carlos Cuna","author_inst":"University of Florida"},{"author_name":"Anat Kreimer","author_inst":"Rutgers University"},{"author_name":"Jessica McQuerry","author_inst":"University of Florida"},{"author_name":"Stephanie Ihnow","author_inst":"University of Florida"},{"author_name":"Nadja Makki","author_inst":"University of Florida"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Expansive Diversity and Temporal Dynamics of Emerging Polinton-like Viruses in a Marine Ecosystem","rel_doi":"10.64898\/2026.05.28.728513","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.28.728513","rel_abs":"Polinton-like viruses (PLVs) are an emerging group of double-stranded DNA viruses of microbial eukaryotes whose ecological roles in marine ecosystems remain poorly understood. Using a five-year monthly viromic time series from the San Pedro Ocean Time-series (SPOT), we investigated the diversity, temporal dynamics, and functional potential of PLVs in a coastal marine ecosystem. We identified 2,355 distinct PLV populations, revealing PLVs to be a highly abundant and diverse component of the marine virosphere. Phylogenetic analyses resolved multiple major PLV clades, including abundant Group X\/Trimcap PLVs characterized by triplicate major capsid proteins, supporting the widespread occurrence of this unusual viral architecture in marine PLVs. Approximately half of the PLV populations exhibited significant repeatable seasonal dynamics, partitioning into numerous chronotypes that reflect highly modular temporal niches. PLV abundance correlated positively with multiple productivity-linked environmental variables, including nitrate, particulate organic carbon, and primary productivity, suggesting close coupling between PLVs and seasonal ecosystem productivity. Functional analyses further identified diverse auxiliary metabolic genes in many PLV genomes involved in carbohydrate, lipid, redox, and nucleotide metabolism, with strong phylogenetic structuring across PLV clades. Together, these findings demonstrate that PLVs are abundant, functionally diverse, and ecologically dynamic members of marine viral communities, and suggest they are important yet underappreciated regulators of protist ecology and evolution in marine ecosystems.","rel_num_authors":5,"rel_authors":[{"author_name":"Ethan Mimick","author_inst":"Rosenstiel School of Marine, Atmospheric, and Earth Science, University of Miami, Miami, FL, USA"},{"author_name":"Christopher Bellas","author_inst":"Department of Ecology, Universitat Innsbruck, Innsbruck, Austria; The Roslin Institute and Royal (Dick) School of Veterinary Medicine, University of Edinburgh, "},{"author_name":"Nathan Ahlgren","author_inst":"Department of Biology, Clark University, Worcester, MA"},{"author_name":"Jed Fuhrman","author_inst":"Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA"},{"author_name":"Mohammad Moniruzzaman","author_inst":"Rosenstiel School of Marine, Atmospheric, and Earth Science, University of Miami, Miami, FL, USA"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"A new Persister Enrichment Model in Mycobacterium tuberculosis links multidrug persistence to drug sequencing and maltokinase-dependent carbon distribution.","rel_doi":"10.64898\/2026.05.28.728405","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.28.728405","rel_abs":"Prolonged combination chemotherapy is required to cure Tuberculosis, in part because Mycobacterium tuberculosis(Mtb) forms antibiotic-tolerant persister cells that survive exposure to bactericidal drugs. Experimental systems to study multidrug persistence in Mtb remain limited. Here, we describe a rapid and tractable Persister Enrichment Model (PEM) in which removal of glycerol markedly increases the frequency of multidrug-tolerant Mtb cells that survive exposure to high concentrations of bactericidal antibiotics with distinct mechanisms of action. Persister enrichment in PEM depends on carbon source identity rather than carbon abundance and enables direct interrogation at the transition from active growth into multidrug tolerance. Using PEM, we show that the temporal order of isoniazid (INH) and rifampicin (RIF)exposure shapes the magnitude of multidrug persistence. A transposon sequencing screen under combination drug pressure identified maltokinase (mak) as a major determinant of multidrug persistence. Deletion of mak enhanced susceptibility to INH+RIF in PEM and impaired bacterial survival during the persistent phase of infection in mice. Metabolic analyses reveal that loss of mak destabilizes carbon distribution during co-catabolism of glycolytic carbon sources, leading to defective growth and antibiotic persistence. This defect is ameliorated by inactivating mutations in glucose-1-phosphate adenylyltransferase (glgC), which alleviate the buildup of ADP-glucose. Together, these findings establish PEM as a practical platform to study multidrug persistence, reveal that drug sequencing can influence entry into multidrug tolerance, and identify maltokinase-dependent carbon distribution as a metabolic vulnerability that constrains Mtb survival.","rel_num_authors":7,"rel_authors":[{"author_name":"Michael W Shultis","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Claire V Mulholland","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Jinhua Cui","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Mei Chen","author_inst":"Albert Einstein College of Medicine Department of Medicine"},{"author_name":"Samantha Johnson","author_inst":"Albert Einstein College of Medicine Department of Medicine"},{"author_name":"Christopher Hiner","author_inst":"Albert Einstein College of Medicine"},{"author_name":"Michael Berney","author_inst":"Albert Einstein College of Medicine"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Phage RyR-domain proteins degrade ADPR-based immune signals and fuel NAD synthesis","rel_doi":"10.64898\/2026.05.28.727677","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.28.727677","rel_abs":"Bacterial, plant, and animal cells synthesize nucleotide immune signals as a conserved strategy to defend against viral infection. In bacteria, Thoeris anti-phage defense systems convert nicotinamide adenine dinucleotide (NAD) into the cyclic ADP-ribose signals 2'cADPR and 3'cADPR to activate downstream effectors and restrict viral replication. Phage proteins can bind and sequester Thoeris signals, but no mechanisms are known to degrade the exceptionally stable 2'cADPR and 3'cADPR molecules and terminate immune activation. Here we use a forward biochemical screen to discover the mycobacteriophage protein RyDEP as the founding member of an enzyme family that cleaves 2'cADPR and 3'cADPR to inactivate Thoeris defense. We show that RyDEP is a glycosidase that cleaves the ribose-ribose linkage in 2' and 3' cADPR immune signals to both inactivate host defense and enable direct restoration of NAD. A crystal structure of the RyDEP-3'cADPR complex in the post-cleavage state explains the molecular basis of immune signal degradation and reveals surprising homology with the Repeat12 domain of animal ryanodine receptors (RyRs) that control calcium flux and muscle contraction. We demonstrate that diverse phage RyDEP proteins tune RyR-domain activity to either degrade or sequester immune signals. Our results define RyR-domain proteins as regulators of nucleotide immune signaling and explain how viruses subvert host antiviral defense.","rel_num_authors":10,"rel_authors":[{"author_name":"Miguel L\u00f3pez Rivera","author_inst":"Harvard Medical School \/ Dana-Farber Cancer Institute"},{"author_name":"Renee B Chang","author_inst":"Harvard Medical School \/ Dana-Farber Cancer Institute"},{"author_name":"Colin M Lewis","author_inst":"University of Pittsburgh"},{"author_name":"Romi Hadary","author_inst":"Weizmann Institute of Science"},{"author_name":"Julia M Kovalski","author_inst":"University of Pittsburgh"},{"author_name":"Krista G Freeman","author_inst":"University of Pittsburgh"},{"author_name":"Zhen-Yu J Sun","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Rotem Sorek","author_inst":"Weizmann Institute of Science"},{"author_name":"Graham Hatfull","author_inst":"University of Pittsburgh"},{"author_name":"Philip Kranzusch","author_inst":"Harvard Medical School \/ Dana-Farber Cancer Institute"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Phage RyR-domain proteins degrade ADPR-based immune signals and fuel NAD synthesis","rel_doi":"10.64898\/2026.05.28.727677","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.28.727677","rel_abs":"Bacterial, plant, and animal cells synthesize nucleotide immune signals as a conserved strategy to defend against viral infection. In bacteria, Thoeris anti-phage defense systems convert nicotinamide adenine dinucleotide (NAD) into the cyclic ADP-ribose signals 2'cADPR and 3'cADPR to activate downstream effectors and restrict viral replication. Phage proteins can bind and sequester Thoeris signals, but no mechanisms are known to degrade the exceptionally stable 2'cADPR and 3'cADPR molecules and terminate immune activation. Here we use a forward biochemical screen to discover the mycobacteriophage protein RyDEP as the founding member of an enzyme family that cleaves 2'cADPR and 3'cADPR to inactivate Thoeris defense. We show that RyDEP is a glycosidase that cleaves the ribose-ribose linkage in 2' and 3' cADPR immune signals to both inactivate host defense and enable direct restoration of NAD. A crystal structure of the RyDEP-3'cADPR complex in the post-cleavage state explains the molecular basis of immune signal degradation and reveals surprising homology with the Repeat12 domain of animal ryanodine receptors (RyRs) that control calcium flux and muscle contraction. We demonstrate that diverse phage RyDEP proteins tune RyR-domain activity to either degrade or sequester immune signals. Our results define RyR-domain proteins as regulators of nucleotide immune signaling and explain how viruses subvert host antiviral defense.","rel_num_authors":10,"rel_authors":[{"author_name":"Miguel L\u00f3pez Rivera","author_inst":"Harvard Medical School \/ Dana-Farber Cancer Institute"},{"author_name":"Renee B Chang","author_inst":"Harvard Medical School \/ Dana-Farber Cancer Institute"},{"author_name":"Colin M Lewis","author_inst":"University of Pittsburgh"},{"author_name":"Romi Hadary","author_inst":"Weizmann Institute of Science"},{"author_name":"Julia M Kovalski","author_inst":"University of Pittsburgh"},{"author_name":"Krista G Freeman","author_inst":"University of Pittsburgh"},{"author_name":"Zhen-Yu J Sun","author_inst":"Dana-Farber Cancer Institute"},{"author_name":"Rotem Sorek","author_inst":"Weizmann Institute of Science"},{"author_name":"Graham Hatfull","author_inst":"University of Pittsburgh"},{"author_name":"Philip Kranzusch","author_inst":"Harvard Medical School \/ Dana-Farber Cancer Institute"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Single-cell analysis of Plasmodium falciparum transcripts after drug perturbation identifies feedback regulation as well as increased transmission potential","rel_doi":"10.64898\/2026.05.27.728291","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.27.728291","rel_abs":"Gene expression analysis in malaria parasites has been used to define transcriptional regulatory networks but has been used less frequently to characterize parasite response to drug treatment or to show how parasites may evade killing. Here, we applied single-cell RNA sequencing (scRNA-seq) to hundreds of thousands of individually infected asynchronous red blood cells to evaluate the parasite's response to treatment with three chemotypes that can be used for treatment (artemisinin) or prophylaxis and treatment (atovaquone, ganaplacide). We found that each treatment gave rise to different cell populations with different transcriptional profiles. Comparing single cell transcription patterns in compound-treated cells, to transcript patterns observed previously with synchronized cells showed an enrichment of cells expressing gametocyte-associated genes after artemisinin treatment but fewer lifecycle perturbations after treatment with the two other compounds. In contrast, bulk analysis showed an enrichment of pyrimidine biosynthesis transcripts for atovaquone treatment. Our results show that scRNA-seq may be used to profile diverse drug responses across many lifecycle stages and to potentially classify drug classes.","rel_num_authors":4,"rel_authors":[{"author_name":"Karla P Godinez-Macias","author_inst":"University of California, San Diego"},{"author_name":"Jaeson Calla","author_inst":"University of California, San Diego"},{"author_name":"Kristen Jepsen","author_inst":"University of California, San Diego"},{"author_name":"Elizabeth A Winzeler","author_inst":"University of California, San Diego"}],"rel_date":"2026-05-29","rel_site":"biorxiv"},{"rel_title":"Utility of the ADAS-Cog as a Cognitive Screening Tool in Older Adults with Epilepsy: A Multicenter Cohort Study","rel_doi":"10.64898\/2026.05.27.26354210","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.27.26354210","rel_abs":"Objective: Cognitive impairment is common among older adults with epilepsy, although efficient screening tools suitable for routine use are lacking. Here we examine, for the first time, the utility of the Alzheimers Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) as a screening tool to identify cognitive impairment in older adults with epilepsy. Methods: Participants included 83 adults (ages over 55) with epilepsy from the Brain, Aging, and Cognition in Epilepsy (BrACE) study and 83 age-, sex-, and education-matched cognitively healthy controls from the Alzheimers Disease Neuroimaging Initiative (ADNI-3). All completed the ADAS-Cog and a comprehensive neuropsychological battery to identify cognitive phenotypes (intact vs impaired). Performance on individual ADAS-Cog items and the total score was assessed, and diagnostic efficiency statistics were determined. Results: Epilepsy participants (mean age=66.4 years) performed significantly worse across the ADAS-Cog total score and 8 of the 13 individual test items compared to controls. The largest effect sizes were observed on verbal learning and memory tasks, particularly word recall (d=0.87) and delayed word recall (d=1.06). An ADAS-Cog total score of at or exceeding 15 yielded optimal diagnostic efficiency (67.5% accuracy, 68.8% sensitivity, 66.7% specificity) for identifying cognitive impairment. Significance: The ADAS-Cog is sensitive to detecting cognitive impairment in older adults with epilepsy and may represent a scalable screening option in this population. Additional comparative studies in older epilepsy populations are needed to determine the sensitivity of this measure to longitudinal change, cross-cultural applicability, and availability across languages. Plain language summary: Cognitive decline is common among older adults with epilepsy, although sufficient evidence supporting the use of screening tools to identify cognitive impairment in this population is lacking. The ADAS-Cog may be a useful screening option in epilepsy research and clinical care, although additional studies are needed to compare it with other cognitive screening tests and to confirm its applicability for clinical care and across cultures and healthcare settings.","rel_num_authors":13,"rel_authors":[{"author_name":"Bruce  P. Hermann","author_inst":"University of Wisconsin Madison School of Medicine and Public Health"},{"author_name":"Jessica Kania","author_inst":"University of Wisconsin School of Medicine and Public Health"},{"author_name":"Ifrah Zawar","author_inst":"University of Virginia School of Medicine"},{"author_name":"Anny Reyes","author_inst":"Cleveland Clinic"},{"author_name":"Victoria J Williams","author_inst":"University of Wosconsin School of Medicine and Public Health"},{"author_name":"Rani Sarkis","author_inst":"Brigham and Women's Hospiral"},{"author_name":"Vineet Punia Punia","author_inst":"Cleveland Clinic"},{"author_name":"McKenna Williams","author_inst":"University of California-San Diego"},{"author_name":"Lisa Ferguson","author_inst":"Cleveland Clinic"},{"author_name":"kayela Arrotta","author_inst":"Cleveland Clinic"},{"author_name":"Robyn Busch","author_inst":"Cleveland Clinic"},{"author_name":"Jana E Jones","author_inst":"University of Wisconsin School of Medicine and Public Health"},{"author_name":"Carrie McDonald","author_inst":"University of California-San Diego"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Segmental Lung Sound Analysis in Obstructive Lung Diseases Using Electronic Stethoscope; a protocol to establish an acoustic repository","rel_doi":"10.64898\/2026.05.27.26354263","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.27.26354263","rel_abs":"Introduction Obstructive lung diseases (OLDs) are responsible for high rates of illness and death worldwide. Inflammation, chronic airflow limitation, and bronchial remodeling occur in OLD and eventually result in the unique respiratory sounds. Despite its subjective and having low reproducibility, still traditional auscultation using a manual stethoscope is the main method used to identify the lung sounds. Nevertheless, the combination of recent advancements in digital stethoscopes and AI (Artificial Intelligence) has permitted the objective measurement of lung sounds. Nevertheless, there is a lack of standardized, region-specific databases for AI training and validation. Even though lung sound classification is an emerging aspect in research and telerehabilitation the lobar wise acoustic pattern is still novel due to lack of prevailing database to train AI models. Identifying this gap this study aims to develop an acoustic repository and analyze the data using segmental lung sounds from patients with OLDs and healthy controls through an electronic stethoscope. Methods and analysis This is a cross sectional observational study involving 120 participants (60 OLD patients and 60 healthy controls). Lobar wise acoustic signals will be captured using an electronic stethoscope in healthy and diseases population. The data will be analyzed using Audacity software for annotations and then it will be used for feature extraction and statistical analysis. The acoustic features extracted through Audacity, will include frequency, intensity, pitch, and root mean square (RMS) energy. Repeated measures ANOVA will be applied to compare mean sound intensities across lung segments while Pearson correlation will be used to assess associations with body composition parameters. The data will then be standardized for AI-based diagnostic applications. Ethics and dissemination The study is being reviewed from the Ethics Review Committee, Faculty of Medicine, University of Peradeniya (2025\/EC\/87) will be sought. Informed consent will be obtained in writing. The dissemination of results will take place through peer-reviewed publications and the creation of a public database containing lung sounds from the region.","rel_num_authors":5,"rel_authors":[{"author_name":"Helani Anuradha","author_inst":"University of Peradeniya Faculty of Allied Health Sciences"},{"author_name":"Duminda Yasaratne","author_inst":"University of Peradeniya"},{"author_name":"Godaliyadda GMRI","author_inst":"University of Peradeniya"},{"author_name":"Ekanayake Parakrama","author_inst":"University of Peradeniya"},{"author_name":"R Severin","author_inst":"University of Illinois Chicago College of Applied Health Sciences"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Nicotine pouch adverts reach ten times more young men than women: targeting and reach on Meta social media platforms in the UK","rel_doi":"10.64898\/2026.05.27.26354221","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.27.26354221","rel_abs":"Abstract Aims To examine which demographic groups nicotine pouch advertisers chose to target on social media, and which groups Meta's algorithms actually delivered the adverts to. Design Cross-sectional analysis of advert-level data from the Meta Ad Library. Setting Meta social media platforms (including Facebook and Instagram) in the UK. Cases A random sample of 741 nicotine pouch adverts shown in the 12 months up to December 2025, and a comparison sample of 1,125 general adverts. Analyses of reach were restricted to adverts eligible for all genders and adult ages (444 pouch adverts; 674 general). Measurements Outcomes were advertiser-set gender and age-group targeting criteria (i.e., groups eligible to be shown each advert) and estimated advert reach to each group (i.e., number of people who saw each advert). Male-to-female reach ratios within age groups, and reach ratios comparing age groups, were calculated per advert and summarised using geometric means. To assess whether patterns were pouch-specific, comparisons with general adverts were made using ratios of reach ratios (RRR). Findings Advertisers of nicotine pouches targeted a broad sample; most adverts (79.1%; 586\/741) were eligible to be shown to all genders, the remainder were restricted to men only. All were restricted to adults (minimum age 18 years) and most (95.6%; 708\/741) had no upper age limit. Despite this, of pouch adverts eligible to be shown to all adults, adverts were more likely to reach men, particularly among younger men. Among 18-24-year-olds, pouch adverts reached around ten times as many men as women (RR 10.0, 95% CI 8.7-11.5), compared with a slight skew towards women for general adverts (RR 0.81, 95% CI 0.71-0.94), corresponding to an RRR of 12.3 (95% CI 10.0-15.1). Pouch adverts also showed a skew in reach towards younger age groups. Relative to those aged 35-44 years, reach was higher among 18-24-year-olds for nicotine pouch adverts (RR 1.33, 95% CI 1.17-1.51) but much lower for general adverts (RR 0.19, 95% CI 0.17-0.21), corresponding to an RRR of 7.0 (95% CI 6.0-8.2). Conclusions Nicotine pouch adverts on social media are often eligible to be shown broadly to all demographic groups but are disproportionately delivered to young men.","rel_num_authors":6,"rel_authors":[{"author_name":"Haoxiong Sun","author_inst":"University College London"},{"author_name":"Sarah E Jackson","author_inst":"University College London"},{"author_name":"Leon Xiao","author_inst":"School of Creative Media, City University of Hong Kong, Hong Kong"},{"author_name":"Sharon Cox","author_inst":"University College London"},{"author_name":"Melissa Oldham","author_inst":"University College London"},{"author_name":"Harry Oisin Tattan-Birch","author_inst":"University College London"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Establishing a framework for human dose prediction in anti-tuberculosis drug development","rel_doi":"10.64898\/2026.05.26.26354063","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354063","rel_abs":"Rationale: Efficacious dose selection for anti-tuberculosis drugs has traditionally relied on achieving plasma exposures above the minimum inhibitory concentration, but this approach has not consistently aligned with clinical outcomes. Objectives: We sought to identify early pharmacokinetic-pharmacodynamic targets most predictive of clinical efficacious dose. Methods: We conducted a back-translational, pharmacokinetic-pharmacodynamic simulation-based analysis of 15 anti-tuberculosis drugs. Using pharmacokinetic data from multiple biological matrices and a range of pharmacodynamic metrics, we established candidate exposure-response targets for attainment. We systematically evaluated the predictive accuracy of each target pair against established clinical doses to formulate a decision-making framework linking key drug properties to the most predictive targets. Measurements and Main Results: Depending on the target used, projected clinical doses varied widely - both within and across compounds - highlighting the importance of target selection for dose projection and go\/no-go decisions. In general, targeting cellular lesion-level drug exposures relative to in vivo preclinical potency provided an effective approach for early dose selection. However, for highly penetrating drugs, targeting site-of-action therapeutic exposures in the caseum was more predictive of clinical dose. Based on these findings, we developed a preliminary dose prediction tool that enables drug developers to estimate clinically relevant dose ranges of compounds using in vitro and early in vivo data. Conclusions: This work establishes and validates a simple, evidence-based framework to standardize early translational decision-making on dose selection of anti-tuberculosis candidates in development.","rel_num_authors":4,"rel_authors":[{"author_name":"Anu Patel","author_inst":"University of California, San Francisco"},{"author_name":"Angela T Li","author_inst":"University of California, San Francisco"},{"author_name":"Bel\u00e9n Solans","author_inst":"University of California, San Francisco"},{"author_name":"Radojka Savic","author_inst":"University of California, San Francisco"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Diabetes, impaired fasting glucose, and cognitive trajectories: a multi-cohort study","rel_doi":"10.64898\/2026.05.26.26354185","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354185","rel_abs":"INTRODUCTION: Cognitive trajectories may clarify how type 2 diabetes (T2D) and impaired fasting glucose (IFG) relate to dementia risk, but longitudinal associations remain unclear, particularly in the context of stroke. METHODS: Data from 5,631 dementia- and stroke-free older adults (mean age 75 years) from 7 international population-based cohorts were analyzed. Linear mixed-effects models estimated cognitive trajectories during stroke-free and post-stroke follow-up. Glucose status was defined by fasting glucose and prior T2D diagnosis. RESULTS: Over 6.6 years of follow-up (4.5% with incident stroke), T2D was associated with lower baseline cognitive performance compared with normal fasting glucose (-0.14 SD, 95% CI -0.21 to -0.07), but not with faster cognitive decline during stroke-free or post-stroke follow-up. IFG was not associated with lower cognitive performance or faster decline. DISCUSSION: In older adults, T2D was associated with persistently lower cognitive performance but not faster decline, suggesting adverse cognitive effects may be established before late life.","rel_num_authors":27,"rel_authors":[{"author_name":"Jessica W Lo","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"John D Crawford","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"Katherine Samaras","author_inst":"Department of Endocrinology, St Vincent's Hospital, Darlinghurst, New South Wales, Australia"},{"author_name":"Richard B Lipton","author_inst":"Saul B. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA"},{"author_name":"Mindy J Katz","author_inst":"Saul B. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA"},{"author_name":"Carol A Derby","author_inst":"Saul B. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA"},{"author_name":"Pierre-Marie Preux","author_inst":"Inserm U1094, IRD UMR270, Univ. Limoges, CHU Limoges, EpiMaCT - Epidemiology of chronic diseases in tropical zone, Institute of Epidemiology and Global Health -"},{"author_name":"Maelenn Guerchet","author_inst":"Inserm U1094, IRD UMR270, Univ. Limoges, CHU Limoges, EpiMaCT - Epidemiology of chronic diseases in tropical zone, Institute of Epidemiology and Global Health -"},{"author_name":"Eleonora d'Orsi","author_inst":"Federal University of Santa Catarina, Public Health Department, Florianopolis, Santa Catarina, Brazil"},{"author_name":"Anna Quialheiro","author_inst":"Federal University of Santa Catarina, Public Health Department, Florianopolis, Santa Catarina, Brazil"},{"author_name":"Cassiano Ricardo Rech","author_inst":"Federal University of Santa Catarina, Department of Physical Education, Florianopolis, Santa Catarina, Brazil"},{"author_name":"Karen Ritchie","author_inst":"Inserm, Institut de Neurosciences de Montpellier, France"},{"author_name":"Elena Rolandi","author_inst":"Golgi Cenci Foundation, Abbiategrasso (MI), Italy"},{"author_name":"Annalisa Davin","author_inst":"Golgi Cenci Foundation, Abbiategrasso (MI), Italy"},{"author_name":"Michele Rossi","author_inst":"Golgi Cenci Foundation, Abbiategrasso (MI), Italy"},{"author_name":"Suzana Shahar","author_inst":"Center for Healthy Ageing & Wellness, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, Malaysia"},{"author_name":"Norfadilah Rajab","author_inst":"Centre for Healthy Aging and Wellness, Faculty of Health Science, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, Malaysia"},{"author_name":"Nurul Fatin Malek Rivan","author_inst":"Centre for Healthy Aging and Wellness, Faculty of Health Science, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, Malaysia"},{"author_name":"Mary Ganguli","author_inst":"Departments of Psychiatry, Neurology, and Epidemiology, School of Medicine and School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Erin Jacobsen","author_inst":"University of Pittsburgh School of Medicine, Department of Psychiatry. Pittsburgh, PA, USA"},{"author_name":"Beth E. Snitz","author_inst":"University of Pittsburgh School of Medicine, Department of Neurology. Pittsburgh, PA, USA"},{"author_name":"Henry Brodaty","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"Yen-Ching Chen","author_inst":"Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan"},{"author_name":"Jen-Hau Chen","author_inst":"Department of Geriatrics and Gerontology, National Taiwan University Hospital Yunlin Branch, Yunlin County, Taiwan"},{"author_name":"Matthew Lennon","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"Darren M Lipnicki","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"Perminder S Sachdev","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Diabetes, impaired fasting glucose, and cognitive trajectories: a multi-cohort study","rel_doi":"10.64898\/2026.05.26.26354185","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354185","rel_abs":"INTRODUCTION: Cognitive trajectories may clarify how type 2 diabetes (T2D) and impaired fasting glucose (IFG) relate to dementia risk, but longitudinal associations remain unclear, particularly in the context of stroke. METHODS: Data from 5,631 dementia- and stroke-free older adults (mean age 75 years) from 7 international population-based cohorts were analyzed. Linear mixed-effects models estimated cognitive trajectories during stroke-free and post-stroke follow-up. Glucose status was defined by fasting glucose and prior T2D diagnosis. RESULTS: Over 6.6 years of follow-up (4.5% with incident stroke), T2D was associated with lower baseline cognitive performance compared with normal fasting glucose (-0.14 SD, 95% CI -0.21 to -0.07), but not with faster cognitive decline during stroke-free or post-stroke follow-up. IFG was not associated with lower cognitive performance or faster decline. DISCUSSION: In older adults, T2D was associated with persistently lower cognitive performance but not faster decline, suggesting adverse cognitive effects may be established before late life.","rel_num_authors":27,"rel_authors":[{"author_name":"Jessica W Lo","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"John D Crawford","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"Katherine Samaras","author_inst":"Department of Endocrinology, St Vincent's Hospital, Darlinghurst, New South Wales, Australia"},{"author_name":"Richard B Lipton","author_inst":"Saul B. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA"},{"author_name":"Mindy J Katz","author_inst":"Saul B. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA"},{"author_name":"Carol A Derby","author_inst":"Saul B. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA"},{"author_name":"Pierre-Marie Preux","author_inst":"Inserm U1094, IRD UMR270, Univ. Limoges, CHU Limoges, EpiMaCT - Epidemiology of chronic diseases in tropical zone, Institute of Epidemiology and Global Health -"},{"author_name":"Maelenn Guerchet","author_inst":"Inserm U1094, IRD UMR270, Univ. Limoges, CHU Limoges, EpiMaCT - Epidemiology of chronic diseases in tropical zone, Institute of Epidemiology and Global Health -"},{"author_name":"Eleonora d'Orsi","author_inst":"Federal University of Santa Catarina, Public Health Department, Florianopolis, Santa Catarina, Brazil"},{"author_name":"Anna Quialheiro","author_inst":"Federal University of Santa Catarina, Public Health Department, Florianopolis, Santa Catarina, Brazil"},{"author_name":"Cassiano Ricardo Rech","author_inst":"Federal University of Santa Catarina, Department of Physical Education, Florianopolis, Santa Catarina, Brazil"},{"author_name":"Karen Ritchie","author_inst":"Inserm, Institut de Neurosciences de Montpellier, France"},{"author_name":"Elena Rolandi","author_inst":"Golgi Cenci Foundation, Abbiategrasso (MI), Italy"},{"author_name":"Annalisa Davin","author_inst":"Golgi Cenci Foundation, Abbiategrasso (MI), Italy"},{"author_name":"Michele Rossi","author_inst":"Golgi Cenci Foundation, Abbiategrasso (MI), Italy"},{"author_name":"Suzana Shahar","author_inst":"Center for Healthy Ageing & Wellness, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, Malaysia"},{"author_name":"Norfadilah Rajab","author_inst":"Centre for Healthy Aging and Wellness, Faculty of Health Science, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, Malaysia"},{"author_name":"Nurul Fatin Malek Rivan","author_inst":"Centre for Healthy Aging and Wellness, Faculty of Health Science, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, Malaysia"},{"author_name":"Mary Ganguli","author_inst":"Departments of Psychiatry, Neurology, and Epidemiology, School of Medicine and School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Erin Jacobsen","author_inst":"University of Pittsburgh School of Medicine, Department of Psychiatry. Pittsburgh, PA, USA"},{"author_name":"Beth E. Snitz","author_inst":"University of Pittsburgh School of Medicine, Department of Neurology. Pittsburgh, PA, USA"},{"author_name":"Henry Brodaty","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"Yen-Ching Chen","author_inst":"Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan"},{"author_name":"Jen-Hau Chen","author_inst":"Department of Geriatrics and Gerontology, National Taiwan University Hospital Yunlin Branch, Yunlin County, Taiwan"},{"author_name":"Matthew Lennon","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"Darren M Lipnicki","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"Perminder S Sachdev","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Diabetes, impaired fasting glucose, and cognitive trajectories: a multi-cohort study","rel_doi":"10.64898\/2026.05.26.26354185","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354185","rel_abs":"INTRODUCTION: Cognitive trajectories may clarify how type 2 diabetes (T2D) and impaired fasting glucose (IFG) relate to dementia risk, but longitudinal associations remain unclear, particularly in the context of stroke. METHODS: Data from 5,631 dementia- and stroke-free older adults (mean age 75 years) from 7 international population-based cohorts were analyzed. Linear mixed-effects models estimated cognitive trajectories during stroke-free and post-stroke follow-up. Glucose status was defined by fasting glucose and prior T2D diagnosis. RESULTS: Over 6.6 years of follow-up (4.5% with incident stroke), T2D was associated with lower baseline cognitive performance compared with normal fasting glucose (-0.14 SD, 95% CI -0.21 to -0.07), but not with faster cognitive decline during stroke-free or post-stroke follow-up. IFG was not associated with lower cognitive performance or faster decline. DISCUSSION: In older adults, T2D was associated with persistently lower cognitive performance but not faster decline, suggesting adverse cognitive effects may be established before late life.","rel_num_authors":27,"rel_authors":[{"author_name":"Jessica W Lo","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"John D Crawford","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"Katherine Samaras","author_inst":"Department of Endocrinology, St Vincent's Hospital, Darlinghurst, New South Wales, Australia"},{"author_name":"Richard B Lipton","author_inst":"Saul B. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA"},{"author_name":"Mindy J Katz","author_inst":"Saul B. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA"},{"author_name":"Carol A Derby","author_inst":"Saul B. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA"},{"author_name":"Pierre-Marie Preux","author_inst":"Inserm U1094, IRD UMR270, Univ. Limoges, CHU Limoges, EpiMaCT - Epidemiology of chronic diseases in tropical zone, Institute of Epidemiology and Global Health -"},{"author_name":"Maelenn Guerchet","author_inst":"Inserm U1094, IRD UMR270, Univ. Limoges, CHU Limoges, EpiMaCT - Epidemiology of chronic diseases in tropical zone, Institute of Epidemiology and Global Health -"},{"author_name":"Eleonora d'Orsi","author_inst":"Federal University of Santa Catarina, Public Health Department, Florianopolis, Santa Catarina, Brazil"},{"author_name":"Anna Quialheiro","author_inst":"Federal University of Santa Catarina, Public Health Department, Florianopolis, Santa Catarina, Brazil"},{"author_name":"Cassiano Ricardo Rech","author_inst":"Federal University of Santa Catarina, Department of Physical Education, Florianopolis, Santa Catarina, Brazil"},{"author_name":"Karen Ritchie","author_inst":"Inserm, Institut de Neurosciences de Montpellier, France"},{"author_name":"Elena Rolandi","author_inst":"Golgi Cenci Foundation, Abbiategrasso (MI), Italy"},{"author_name":"Annalisa Davin","author_inst":"Golgi Cenci Foundation, Abbiategrasso (MI), Italy"},{"author_name":"Michele Rossi","author_inst":"Golgi Cenci Foundation, Abbiategrasso (MI), Italy"},{"author_name":"Suzana Shahar","author_inst":"Center for Healthy Ageing & Wellness, Faculty of Health Sciences, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, Malaysia"},{"author_name":"Norfadilah Rajab","author_inst":"Centre for Healthy Aging and Wellness, Faculty of Health Science, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, Malaysia"},{"author_name":"Nurul Fatin Malek Rivan","author_inst":"Centre for Healthy Aging and Wellness, Faculty of Health Science, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, Malaysia"},{"author_name":"Mary Ganguli","author_inst":"Departments of Psychiatry, Neurology, and Epidemiology, School of Medicine and School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Erin Jacobsen","author_inst":"University of Pittsburgh School of Medicine, Department of Psychiatry. Pittsburgh, PA, USA"},{"author_name":"Beth E. Snitz","author_inst":"University of Pittsburgh School of Medicine, Department of Neurology. Pittsburgh, PA, USA"},{"author_name":"Henry Brodaty","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"Yen-Ching Chen","author_inst":"Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan"},{"author_name":"Jen-Hau Chen","author_inst":"Department of Geriatrics and Gerontology, National Taiwan University Hospital Yunlin Branch, Yunlin County, Taiwan"},{"author_name":"Matthew Lennon","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"Darren M Lipnicki","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"},{"author_name":"Perminder S Sachdev","author_inst":"Centre for Healthy Brain Ageing (CHeBA), Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Austral"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Same household, different choices: variation in health behaviors related to respiratory viruses in Illinois","rel_doi":"10.64898\/2026.05.26.26354179","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354179","rel_abs":"While SARS-CoV-2 and influenza continue to place a significant burden on population health, within-household differences in decisions towards vaccination and seeking care across these two pathogens, and across sociodemographic groups, remain largely unexplored. By conducting a household-level survey in Illinois, we found that many individuals made inconsistent decisions about vaccination: among all adults, 29% were vaccinated for only one of COVID-19 or influenza, and among those with children in the home, 39% lived with a child whose influenza or COVID-19 vaccination status differed from their own. A higher proportion of adults were vaccinated against COVID-19 compared to influenza, while the opposite was true for those younger than 18 years old. These differences hold even when accounting for disparities in coverage by age, race\/ethnicity, political affiliation, and socioeconomic status. While vaccinated individuals consistently reported wanting to protect themselves or others, those who declined vaccination reported highly heterogeneous reasons ranging from resource constraints to distrust or misconceptions about vaccination. These differences are even more pronounced for COVID-19, with larger partisan gaps and higher refusal driven by safety concerns, lack of trust, or religious reasons than those who decide not to get the influenza vaccine. In contrast to vaccination, the decision to seek medical care when sick showed opposite sociodemographic trends, that are likely attributable to illness severity. Our findings highlight that closing gaps in COVID-19 and influenza vaccination coverage will require an integrative strategy that accounts for diverse motivations, fears, and barriers to access, while addressing social inequalities common to both diseases.","rel_num_authors":8,"rel_authors":[{"author_name":"Soren L Larsen","author_inst":"University of California, Berkeley"},{"author_name":"Junke Yang","author_inst":"The Ohio State University"},{"author_name":"Erin M Haslett","author_inst":"Emory University"},{"author_name":"Alyssa Anastasi","author_inst":"University of Wisconsin Madison"},{"author_name":"Annika Venegas","author_inst":"University of Illinois at Urbana Champaign"},{"author_name":"Lydia Schieleit","author_inst":"University of Illinois at Urbana Champaign"},{"author_name":"Ayesha Mahmud","author_inst":"University of California, Berkeley"},{"author_name":"Pamela P. Martinez","author_inst":"University of Illinois at Urbana Champaign"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Tobacco Use is Related to Parietal-Hippocampal Connectivity in People at Clinical High Risk for Psychosis","rel_doi":"10.64898\/2026.05.26.26354136","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354136","rel_abs":"Background: Tobacco use is prevalent in clinical high risk for psychosis (CHR-P) population and has widespread negative health consequences, but understanding of its neural substrates is limited. Abnormal default mode network (DMN) may underlie tobacco dependence in CHR-P. We investigated how tobacco use relates to DMN connectivity and how CHR-P status impacts this relationship. Methods: We used baseline substance use and resting-state functional magnetic resonance imaging data from the North American Prodrome Longitudinal Study (NAPLS2; CHR-P: n=211, mean age 19.2, 37.9% female; healthy control: n=132, mean age 19.9, 47.7% female). Voxel-wise connectivity was calculated from the left lateral parietal (LLP) node of the DMN to the rest of the brain. We regressed LLP-brainwide connectivity against tobacco use frequency in the past month to generate a spatial map of how connectivity relates to current tobacco use. Results: Brainwide connectivity analysis identified two clusters in R hippocampus (peak voxel at MNI [+30,-12,-27]) and in L parahippocampus (peak voxel at MNI [-27,-27,-27]), where higher LLP-cluster connectivity was associated with more frequent tobacco use. LLP - R hippocampus connectivity was higher in current tobacco users compared to non-tobacco users (t=-3.5466, df=101.88, p=0.0006), and higher in CHR-P than controls (t=-2.8651, df=279.47, p=0.0049). Among current tobacco users, there was a significant tobacco-by-diagnosis interaction on LLP - R hippocampus connectivity (estimate=0.306, SE=0.149, t=2.051, p=0.045) such that heavier tobacco use predicted hyperconnectivity only in CHR. Conclusions: More frequent tobacco use was associated with higher DMN-hippocampal connectivity in both CHR-P and controls. CHR-P diagnosis enhanced this relationship.","rel_num_authors":19,"rel_authors":[{"author_name":"Yunong Bai","author_inst":"Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center"},{"author_name":"Maxwell J Roeske","author_inst":"Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center"},{"author_name":"Adam Beermann","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Jean Addington","author_inst":"Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary"},{"author_name":"Carrie E Bearden","author_inst":"UCLA"},{"author_name":"Kristin Cadenhead","author_inst":"Department of Psychiatry, University of California, San Diego"},{"author_name":"Tyrone D Cannon","author_inst":"Department of Psychology and Psychiatry, Yale University"},{"author_name":"Ricardo E Carrion","author_inst":"Department of Psychiatry, Zucker Hillside Hospital and Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell"},{"author_name":"Barbara Cornblatt","author_inst":"Department of Psychiatry, Zucker Hillside Hospital and Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell"},{"author_name":"Matcheri Keshavan","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Daniel H Mathalon","author_inst":"Department of Psychiatry and Behavioral Sciences, University of California, San Francisco"},{"author_name":"Diana O Perkins","author_inst":"Department of Psychiatry, University of North Carolina at Chapel Hill"},{"author_name":"Larry Seidman","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"William S Stone","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Ming T Tsuang","author_inst":"Departments of Psychiatry and Behavioral Sciences and Psychology, University of California, Los Angeles"},{"author_name":"Elaine F Walker","author_inst":"Department of Psychology, Emory University"},{"author_name":"Scott W Woods","author_inst":"Yale University"},{"author_name":"Roscoe O Brady","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Heather Burrell Ward","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Tobacco Use is Related to Parietal-Hippocampal Connectivity in People at Clinical High Risk for Psychosis","rel_doi":"10.64898\/2026.05.26.26354136","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354136","rel_abs":"Background: Tobacco use is prevalent in clinical high risk for psychosis (CHR-P) population and has widespread negative health consequences, but understanding of its neural substrates is limited. Abnormal default mode network (DMN) may underlie tobacco dependence in CHR-P. We investigated how tobacco use relates to DMN connectivity and how CHR-P status impacts this relationship. Methods: We used baseline substance use and resting-state functional magnetic resonance imaging data from the North American Prodrome Longitudinal Study (NAPLS2; CHR-P: n=211, mean age 19.2, 37.9% female; healthy control: n=132, mean age 19.9, 47.7% female). Voxel-wise connectivity was calculated from the left lateral parietal (LLP) node of the DMN to the rest of the brain. We regressed LLP-brainwide connectivity against tobacco use frequency in the past month to generate a spatial map of how connectivity relates to current tobacco use. Results: Brainwide connectivity analysis identified two clusters in R hippocampus (peak voxel at MNI [+30,-12,-27]) and in L parahippocampus (peak voxel at MNI [-27,-27,-27]), where higher LLP-cluster connectivity was associated with more frequent tobacco use. LLP - R hippocampus connectivity was higher in current tobacco users compared to non-tobacco users (t=-3.5466, df=101.88, p=0.0006), and higher in CHR-P than controls (t=-2.8651, df=279.47, p=0.0049). Among current tobacco users, there was a significant tobacco-by-diagnosis interaction on LLP - R hippocampus connectivity (estimate=0.306, SE=0.149, t=2.051, p=0.045) such that heavier tobacco use predicted hyperconnectivity only in CHR. Conclusions: More frequent tobacco use was associated with higher DMN-hippocampal connectivity in both CHR-P and controls. CHR-P diagnosis enhanced this relationship.","rel_num_authors":19,"rel_authors":[{"author_name":"Yunong Bai","author_inst":"Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center"},{"author_name":"Maxwell J Roeske","author_inst":"Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center"},{"author_name":"Adam Beermann","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Jean Addington","author_inst":"Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary"},{"author_name":"Carrie E Bearden","author_inst":"UCLA"},{"author_name":"Kristin Cadenhead","author_inst":"Department of Psychiatry, University of California, San Diego"},{"author_name":"Tyrone D Cannon","author_inst":"Department of Psychology and Psychiatry, Yale University"},{"author_name":"Ricardo E Carrion","author_inst":"Department of Psychiatry, Zucker Hillside Hospital and Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell"},{"author_name":"Barbara Cornblatt","author_inst":"Department of Psychiatry, Zucker Hillside Hospital and Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell"},{"author_name":"Matcheri Keshavan","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Daniel H Mathalon","author_inst":"Department of Psychiatry and Behavioral Sciences, University of California, San Francisco"},{"author_name":"Diana O Perkins","author_inst":"Department of Psychiatry, University of North Carolina at Chapel Hill"},{"author_name":"Larry Seidman","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"William S Stone","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Ming T Tsuang","author_inst":"Departments of Psychiatry and Behavioral Sciences and Psychology, University of California, Los Angeles"},{"author_name":"Elaine F Walker","author_inst":"Department of Psychology, Emory University"},{"author_name":"Scott W Woods","author_inst":"Yale University"},{"author_name":"Roscoe O Brady","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Heather Burrell Ward","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Tobacco Use is Related to Parietal-Hippocampal Connectivity in People at Clinical High Risk for Psychosis","rel_doi":"10.64898\/2026.05.26.26354136","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354136","rel_abs":"Background: Tobacco use is prevalent in clinical high risk for psychosis (CHR-P) population and has widespread negative health consequences, but understanding of its neural substrates is limited. Abnormal default mode network (DMN) may underlie tobacco dependence in CHR-P. We investigated how tobacco use relates to DMN connectivity and how CHR-P status impacts this relationship. Methods: We used baseline substance use and resting-state functional magnetic resonance imaging data from the North American Prodrome Longitudinal Study (NAPLS2; CHR-P: n=211, mean age 19.2, 37.9% female; healthy control: n=132, mean age 19.9, 47.7% female). Voxel-wise connectivity was calculated from the left lateral parietal (LLP) node of the DMN to the rest of the brain. We regressed LLP-brainwide connectivity against tobacco use frequency in the past month to generate a spatial map of how connectivity relates to current tobacco use. Results: Brainwide connectivity analysis identified two clusters in R hippocampus (peak voxel at MNI [+30,-12,-27]) and in L parahippocampus (peak voxel at MNI [-27,-27,-27]), where higher LLP-cluster connectivity was associated with more frequent tobacco use. LLP - R hippocampus connectivity was higher in current tobacco users compared to non-tobacco users (t=-3.5466, df=101.88, p=0.0006), and higher in CHR-P than controls (t=-2.8651, df=279.47, p=0.0049). Among current tobacco users, there was a significant tobacco-by-diagnosis interaction on LLP - R hippocampus connectivity (estimate=0.306, SE=0.149, t=2.051, p=0.045) such that heavier tobacco use predicted hyperconnectivity only in CHR. Conclusions: More frequent tobacco use was associated with higher DMN-hippocampal connectivity in both CHR-P and controls. CHR-P diagnosis enhanced this relationship.","rel_num_authors":19,"rel_authors":[{"author_name":"Yunong Bai","author_inst":"Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center"},{"author_name":"Maxwell J Roeske","author_inst":"Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center"},{"author_name":"Adam Beermann","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Jean Addington","author_inst":"Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary"},{"author_name":"Carrie E Bearden","author_inst":"UCLA"},{"author_name":"Kristin Cadenhead","author_inst":"Department of Psychiatry, University of California, San Diego"},{"author_name":"Tyrone D Cannon","author_inst":"Department of Psychology and Psychiatry, Yale University"},{"author_name":"Ricardo E Carrion","author_inst":"Department of Psychiatry, Zucker Hillside Hospital and Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell"},{"author_name":"Barbara Cornblatt","author_inst":"Department of Psychiatry, Zucker Hillside Hospital and Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell"},{"author_name":"Matcheri Keshavan","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Daniel H Mathalon","author_inst":"Department of Psychiatry and Behavioral Sciences, University of California, San Francisco"},{"author_name":"Diana O Perkins","author_inst":"Department of Psychiatry, University of North Carolina at Chapel Hill"},{"author_name":"Larry Seidman","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"William S Stone","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Ming T Tsuang","author_inst":"Departments of Psychiatry and Behavioral Sciences and Psychology, University of California, Los Angeles"},{"author_name":"Elaine F Walker","author_inst":"Department of Psychology, Emory University"},{"author_name":"Scott W Woods","author_inst":"Yale University"},{"author_name":"Roscoe O Brady","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Heather Burrell Ward","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Tobacco Use is Related to Parietal-Hippocampal Connectivity in People at Clinical High Risk for Psychosis","rel_doi":"10.64898\/2026.05.26.26354136","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354136","rel_abs":"Background: Tobacco use is prevalent in clinical high risk for psychosis (CHR-P) population and has widespread negative health consequences, but understanding of its neural substrates is limited. Abnormal default mode network (DMN) may underlie tobacco dependence in CHR-P. We investigated how tobacco use relates to DMN connectivity and how CHR-P status impacts this relationship. Methods: We used baseline substance use and resting-state functional magnetic resonance imaging data from the North American Prodrome Longitudinal Study (NAPLS2; CHR-P: n=211, mean age 19.2, 37.9% female; healthy control: n=132, mean age 19.9, 47.7% female). Voxel-wise connectivity was calculated from the left lateral parietal (LLP) node of the DMN to the rest of the brain. We regressed LLP-brainwide connectivity against tobacco use frequency in the past month to generate a spatial map of how connectivity relates to current tobacco use. Results: Brainwide connectivity analysis identified two clusters in R hippocampus (peak voxel at MNI [+30,-12,-27]) and in L parahippocampus (peak voxel at MNI [-27,-27,-27]), where higher LLP-cluster connectivity was associated with more frequent tobacco use. LLP - R hippocampus connectivity was higher in current tobacco users compared to non-tobacco users (t=-3.5466, df=101.88, p=0.0006), and higher in CHR-P than controls (t=-2.8651, df=279.47, p=0.0049). Among current tobacco users, there was a significant tobacco-by-diagnosis interaction on LLP - R hippocampus connectivity (estimate=0.306, SE=0.149, t=2.051, p=0.045) such that heavier tobacco use predicted hyperconnectivity only in CHR. Conclusions: More frequent tobacco use was associated with higher DMN-hippocampal connectivity in both CHR-P and controls. CHR-P diagnosis enhanced this relationship.","rel_num_authors":19,"rel_authors":[{"author_name":"Yunong Bai","author_inst":"Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center"},{"author_name":"Maxwell J Roeske","author_inst":"Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center"},{"author_name":"Adam Beermann","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Jean Addington","author_inst":"Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary"},{"author_name":"Carrie E Bearden","author_inst":"UCLA"},{"author_name":"Kristin Cadenhead","author_inst":"Department of Psychiatry, University of California, San Diego"},{"author_name":"Tyrone D Cannon","author_inst":"Department of Psychology and Psychiatry, Yale University"},{"author_name":"Ricardo E Carrion","author_inst":"Department of Psychiatry, Zucker Hillside Hospital and Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell"},{"author_name":"Barbara Cornblatt","author_inst":"Department of Psychiatry, Zucker Hillside Hospital and Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell"},{"author_name":"Matcheri Keshavan","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Daniel H Mathalon","author_inst":"Department of Psychiatry and Behavioral Sciences, University of California, San Francisco"},{"author_name":"Diana O Perkins","author_inst":"Department of Psychiatry, University of North Carolina at Chapel Hill"},{"author_name":"Larry Seidman","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"William S Stone","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Ming T Tsuang","author_inst":"Departments of Psychiatry and Behavioral Sciences and Psychology, University of California, Los Angeles"},{"author_name":"Elaine F Walker","author_inst":"Department of Psychology, Emory University"},{"author_name":"Scott W Woods","author_inst":"Yale University"},{"author_name":"Roscoe O Brady","author_inst":"Department of Psychiatry, Beth Israel Deaconess Medical Center and Harvard Medical School"},{"author_name":"Heather Burrell Ward","author_inst":"Vanderbilt University Medical Center"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Development and Validation of a Machine Learning Model to Predict Prognosis in Patients with Advanced Head and Neck Cancer","rel_doi":"10.64898\/2026.05.27.26354194","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.27.26354194","rel_abs":"Importance Prognostic tools beyond staging are needed to guide treatment and counseling in head and neck squamous cell carcinoma (HNSCC). Objective To develop and externally validate a machine learning model predicting survival in advanced HNSCC using routinely collected clinical and biomarker data. Design, Setting, and Participants Retrospective, multi-institutional cohort study including 2,385 patients with stage III-IV HNSCC diagnosed from 2012-2022 in the University of California Health Data Warehouse (UCHDW). Patients were randomly split into training (n = 1,908) and test (n = 477) sets. Partial external validation used 7,749 patients from the Surveillance, Epidemiology, and End Results (SEER) registry (2010-2020). Exposures Demographic, tumor, treatment, comorbidity, and biomarker variables recorded at or before diagnosis. Main Outcomes and Measures The primary outcome was all-cause mortality within 70 months. Cox proportional hazards models included all predictors. Discrimination was assessed with Harrell's concordance index (C-index), calibration with predicted vs observed survival, and stratification with Kaplan-Meier curves. A Random Survival Forest (RSF) was trained for benchmarking and interpretability using Shapley Additive exPlanations (SHAP). Results Among 2,385 patients in UCHDW (median age, 63 years; 29.0% mortality), the Cox model achieved a C-index of 0.735 in the internal test set. Risk quartiles showed clear separation on Kaplan-Meier curves (log-rank p < 0.0001). In the SEER cohort (n = 7,749), where only demographic, staging, subsite, and treatment variables were available, the reduced Cox model achieved a C-index of 0.688, with calibration showing modest underestimation of survival in high-risk groups. Age, T stage, Charlson Comorbidity Index, neutrophil-to-lymphocyte ratio, and platelet count were among the strongest predictors, while surgery was associated with improved survival. The RSF achieved a C-index of 0.758 internally, with SHAP highlighting nonlinear effects of albumin, BMI, and inflammatory markers. Conclusions and Relevance A machine learning model using routine clinical and biomarker data demonstrated good prognostic performance in advanced HNSCC, with partial external validation. Such approaches may support individualized survival estimates, risk stratification, and treatment discussions, but broader validation is required before clinical adoption.","rel_num_authors":7,"rel_authors":[{"author_name":"Kevin Zhang","author_inst":"University of California San Diego"},{"author_name":"Lan Gao","author_inst":"University of California San Diego"},{"author_name":"Daniel John","author_inst":"University of California San Diego"},{"author_name":"Wei Tse Li","author_inst":"University of California, San Francisco"},{"author_name":"Michael Hogarth","author_inst":"University of California San Diego"},{"author_name":"Charles S. Coffey","author_inst":"University of California San Diego"},{"author_name":"Weg M. Ongkeko","author_inst":"University of California San Diego"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Development and Validation of a Machine Learning Model to Predict Prognosis in Patients with Advanced Head and Neck Cancer","rel_doi":"10.64898\/2026.05.27.26354194","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.27.26354194","rel_abs":"Importance Prognostic tools beyond staging are needed to guide treatment and counseling in head and neck squamous cell carcinoma (HNSCC). Objective To develop and externally validate a machine learning model predicting survival in advanced HNSCC using routinely collected clinical and biomarker data. Design, Setting, and Participants Retrospective, multi-institutional cohort study including 2,385 patients with stage III-IV HNSCC diagnosed from 2012-2022 in the University of California Health Data Warehouse (UCHDW). Patients were randomly split into training (n = 1,908) and test (n = 477) sets. Partial external validation used 7,749 patients from the Surveillance, Epidemiology, and End Results (SEER) registry (2010-2020). Exposures Demographic, tumor, treatment, comorbidity, and biomarker variables recorded at or before diagnosis. Main Outcomes and Measures The primary outcome was all-cause mortality within 70 months. Cox proportional hazards models included all predictors. Discrimination was assessed with Harrell's concordance index (C-index), calibration with predicted vs observed survival, and stratification with Kaplan-Meier curves. A Random Survival Forest (RSF) was trained for benchmarking and interpretability using Shapley Additive exPlanations (SHAP). Results Among 2,385 patients in UCHDW (median age, 63 years; 29.0% mortality), the Cox model achieved a C-index of 0.735 in the internal test set. Risk quartiles showed clear separation on Kaplan-Meier curves (log-rank p < 0.0001). In the SEER cohort (n = 7,749), where only demographic, staging, subsite, and treatment variables were available, the reduced Cox model achieved a C-index of 0.688, with calibration showing modest underestimation of survival in high-risk groups. Age, T stage, Charlson Comorbidity Index, neutrophil-to-lymphocyte ratio, and platelet count were among the strongest predictors, while surgery was associated with improved survival. The RSF achieved a C-index of 0.758 internally, with SHAP highlighting nonlinear effects of albumin, BMI, and inflammatory markers. Conclusions and Relevance A machine learning model using routine clinical and biomarker data demonstrated good prognostic performance in advanced HNSCC, with partial external validation. Such approaches may support individualized survival estimates, risk stratification, and treatment discussions, but broader validation is required before clinical adoption.","rel_num_authors":7,"rel_authors":[{"author_name":"Kevin Zhang","author_inst":"University of California San Diego"},{"author_name":"Lan Gao","author_inst":"University of California San Diego"},{"author_name":"Daniel John","author_inst":"University of California San Diego"},{"author_name":"Wei Tse Li","author_inst":"University of California, San Francisco"},{"author_name":"Michael Hogarth","author_inst":"University of California San Diego"},{"author_name":"Charles S. Coffey","author_inst":"University of California San Diego"},{"author_name":"Weg M. Ongkeko","author_inst":"University of California San Diego"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Antibiotic Timing and Survival After Immune Checkpoint Inhibitor Initiation in Patients With Cancer","rel_doi":"10.64898\/2026.05.27.26354193","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.27.26354193","rel_abs":"Importance: While gut dysbiosis is known to impair response to immune checkpoint inhibitors (ICIs), the relative clinical impact of antibiotic timing (pre- vs. post-ICI initiation) remains unclear. Objective: To evaluate whether antibiotic timing differentially influences overall survival (OS) in a large, multi-institutional pan-cancer cohort. Design, Setting, and Participants: This retrospective cohort study utilized deidentified electronic health record data from six academic medical centers within the University of California Health system. We included 21,108 adults with any malignancy who received PD-1, PD-L1, or CTLA-4 inhibitors between January 2014 and December 2024. Exposures: Antibiotic exposure windows were categorized as pre-only (-60 to -1 days), post-only (+1 to +60 days), both windows, or none. Main Outcomes and Measures: The primary outcome was overall survival (OS) calculated from the first ICI dose. Multivariable Cox proportional hazards models adjusted for demographics, tumor type, line of therapy, and baseline health indicators (albumin, NLR, and recent hospitalization). Results: Among 21,108 patients, 17.3% had pre-only exposure, 13.3% had post-only exposure, and 60.6% had no exposure. In the multivariable model, post-only exposure (HR, 1.27; 95% CI, 1.20-1.35) and combined pre- and post- exposure (HR, 1.31; 95% CI, 1.23-1.40) were significantly associated with higher mortality. Pre-only exposure was not significantly associated with OS (HR, 1.04; 95% CI, 0.99-1.10). Subgroup analyses by tumor type showed consistent trends across major malignancies, including head and neck (Post HR, 1.46) and renal cell carcinoma (Post HR, 1.26). Conclusions and Relevance: In contrast to some smaller studies, this large-scale analysis indicates that antibiotic exposure after ICI initiation carries a greater risk than exposure prior to treatment. These findings highlight the need for rigorous antibiotic stewardship strategies specifically during the early phases of immunotherapy treatment.","rel_num_authors":6,"rel_authors":[{"author_name":"Kevin Zhang","author_inst":"University of California San Diego"},{"author_name":"Daniel John","author_inst":"University of California San Diego"},{"author_name":"Wei Tse Li","author_inst":"University of California, San Francisco"},{"author_name":"Michael Hogarth","author_inst":"University of California San Diego"},{"author_name":"Rana R. McKay","author_inst":"University of California San Diego"},{"author_name":"Weg M. Ongkeko","author_inst":"University of California San Diego"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Antibiotic Timing and Survival After Immune Checkpoint Inhibitor Initiation in Patients With Cancer","rel_doi":"10.64898\/2026.05.27.26354193","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.27.26354193","rel_abs":"Importance: While gut dysbiosis is known to impair response to immune checkpoint inhibitors (ICIs), the relative clinical impact of antibiotic timing (pre- vs. post-ICI initiation) remains unclear. Objective: To evaluate whether antibiotic timing differentially influences overall survival (OS) in a large, multi-institutional pan-cancer cohort. Design, Setting, and Participants: This retrospective cohort study utilized deidentified electronic health record data from six academic medical centers within the University of California Health system. We included 21,108 adults with any malignancy who received PD-1, PD-L1, or CTLA-4 inhibitors between January 2014 and December 2024. Exposures: Antibiotic exposure windows were categorized as pre-only (-60 to -1 days), post-only (+1 to +60 days), both windows, or none. Main Outcomes and Measures: The primary outcome was overall survival (OS) calculated from the first ICI dose. Multivariable Cox proportional hazards models adjusted for demographics, tumor type, line of therapy, and baseline health indicators (albumin, NLR, and recent hospitalization). Results: Among 21,108 patients, 17.3% had pre-only exposure, 13.3% had post-only exposure, and 60.6% had no exposure. In the multivariable model, post-only exposure (HR, 1.27; 95% CI, 1.20-1.35) and combined pre- and post- exposure (HR, 1.31; 95% CI, 1.23-1.40) were significantly associated with higher mortality. Pre-only exposure was not significantly associated with OS (HR, 1.04; 95% CI, 0.99-1.10). Subgroup analyses by tumor type showed consistent trends across major malignancies, including head and neck (Post HR, 1.46) and renal cell carcinoma (Post HR, 1.26). Conclusions and Relevance: In contrast to some smaller studies, this large-scale analysis indicates that antibiotic exposure after ICI initiation carries a greater risk than exposure prior to treatment. These findings highlight the need for rigorous antibiotic stewardship strategies specifically during the early phases of immunotherapy treatment.","rel_num_authors":6,"rel_authors":[{"author_name":"Kevin Zhang","author_inst":"University of California San Diego"},{"author_name":"Daniel John","author_inst":"University of California San Diego"},{"author_name":"Wei Tse Li","author_inst":"University of California, San Francisco"},{"author_name":"Michael Hogarth","author_inst":"University of California San Diego"},{"author_name":"Rana R. McKay","author_inst":"University of California San Diego"},{"author_name":"Weg M. Ongkeko","author_inst":"University of California San Diego"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Targeted Connectomic Neuromodulation of the Orbitofrontal Cortex To Treat Obsessive-Compulsive Disorder","rel_doi":"10.64898\/2026.05.26.26354163","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354163","rel_abs":"Pathological activity within frontal cortical circuits is common in many neuropsychiatric disorders, such as obsessive-compulsive disorder (OCD). We developed an invasive brain mapping protocol in which temporary electrodes are implanted in candidate sites to identify personalized stimulation targets that can acutely relieve OCD symptoms. We found that stimulation within segments of the anterior limb of the internal capsule (ALIC) focally suppressed the structurally and functionally connected region of prefrontal and cingulate cortex. By leveraging the topographic organization of the ALIC, we reversibly inactivated frontal cortical sites with ALIC stimulation to determine which cortical regions are necessary for sustaining OCD symptoms. Stimulation of ventral capsule (VC) near the globus pallidus within the ALIC was associated with suppression of lateral orbitofrontal cortex activity and acute and long-term improvements in OCD symptoms. These results provide a paradigm for leveraging ALIC topography to deliver targeted connectomic neuromodulation to frontal cortex to treat neuropsychiatric disorders.","rel_num_authors":28,"rel_authors":[{"author_name":"Emma Anderson","author_inst":"UCSF"},{"author_name":"Audrey Kist","author_inst":"Grenoble Institut Neuroscience"},{"author_name":"Zachary D Simon","author_inst":"UCSF"},{"author_name":"Jason Raj","author_inst":"UCSF"},{"author_name":"Sneha Ray","author_inst":"UCSF"},{"author_name":"Dani Astudillo","author_inst":"UCSF"},{"author_name":"Natalie Becker","author_inst":"UCSF"},{"author_name":"Tenzin Norbu","author_inst":"UCSF"},{"author_name":"Starlette Khim","author_inst":"UCSF"},{"author_name":"Dennis Lambert","author_inst":"UCSF"},{"author_name":"John Alvarez","author_inst":"UCSF"},{"author_name":"Kelly Kadlec","author_inst":"UCSF"},{"author_name":"Anusha B Allawala","author_inst":"UCSF"},{"author_name":"Alexandra Tremblay-McGaw","author_inst":"UCSF"},{"author_name":"Jessica Verhein","author_inst":"UCSF"},{"author_name":"Caroline Racine","author_inst":"UCSF"},{"author_name":"Pierre Naldec","author_inst":"UCSF"},{"author_name":"Ahmad Alhourani","author_inst":"UCSF"},{"author_name":"Keaton Piper","author_inst":"UCSF"},{"author_name":"Joline Fan","author_inst":"UCSF"},{"author_name":"Doris D Wang","author_inst":"UCSF"},{"author_name":"Ankit N Khambhatti","author_inst":"UCSF"},{"author_name":"Kristin K Sellers","author_inst":"UCSF"},{"author_name":"Philip A Starr","author_inst":"UCSF"},{"author_name":"Leo P Sugrue","author_inst":"UCSF"},{"author_name":"Edward F Chang","author_inst":"UCSF"},{"author_name":"Andrew D Krystal","author_inst":"UCSF"},{"author_name":"A Moses Lee","author_inst":"UCSF"}],"rel_date":"2026-05-28","rel_site":"medrxiv"},{"rel_title":"Evaluating Long-Range Temporal Structure in Foundation Model-Based Forecasts of Heartbeat Dynamics","rel_doi":"10.64898\/2026.05.25.727760","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.25.727760","rel_abs":"We examine the long-range temporal structure of forecasts produced by Time-Series Foundation Models (TSFMs) on heartbeat dynamics using the MIT-BIH Normal Sinus Rhythm Database (NSRDB). Our findings indicate that these models do not adequately capture long-range dependencies, as reflected in growing errors in RR-interval predictions over longer forecast horizons.","rel_num_authors":3,"rel_authors":[{"author_name":"Adrian Serapio","author_inst":"UC Berkeley; UCSF"},{"author_name":"Bharath Ramsundar","author_inst":"Deep Forest Sciences"},{"author_name":"Sandya Subramanian","author_inst":"UC Berkeley; UCSF"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"Evaluating Long-Range Temporal Structure in Foundation Model-Based Forecasts of Heartbeat Dynamics","rel_doi":"10.64898\/2026.05.25.727760","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.25.727760","rel_abs":"We examine the long-range temporal structure of forecasts produced by Time-Series Foundation Models (TSFMs) on heartbeat dynamics using the MIT-BIH Normal Sinus Rhythm Database (NSRDB). Our findings indicate that these models do not adequately capture long-range dependencies, as reflected in growing errors in RR-interval predictions over longer forecast horizons.","rel_num_authors":3,"rel_authors":[{"author_name":"Adrian Serapio","author_inst":"UC Berkeley; UCSF"},{"author_name":"Bharath Ramsundar","author_inst":"Deep Forest Sciences"},{"author_name":"Sandya Subramanian","author_inst":"UC Berkeley; UCSF"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"Cyclin D1 regulates the hepatic response to feeding: Evidence for non-cell cycle roles in the liver","rel_doi":"10.64898\/2026.05.25.727739","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.25.727739","rel_abs":"Objectives: Prior studies have shown that cyclin D1 regulates diverse aspects of liver metabolism during cell cycle progression. Interestingly, this protein is induced in hepatocytes by feeding, but its function in modulating hepatic postprandial physiology is poorly characterized. The aim of this study was to evaluate the contribution of cyclin D1 to the hepatic response to feeding and to gain insight into its potential non-proliferative roles in other conditions. Methods: Mice with or without hepatocyte cyclin D1 (D1fl\/fl or D{Delta}Hep) were fasted and refed a high-carbohydrate diet. Mouse and human liver in the setting of aging and MASLD were analyzed. The C. elegans model was used to evaluate the role of cyclin D1 (CYD-1) in response to overnutrition. Results: Cyclin D1 regulated hepatic gene networks involved in glucose and lipid metabolism, protein synthesis, immune response, and other pathways after feeding. Induction of acute phase response proteins was markedly inhibited in D1{Delta}Hep mice, which was associated with corresponding changes in histone acetylation on key genes. In aged liver, hepatocyte cyclin D1 was induced without associated proliferation; this was markedly pronounced in progeroid Ercc1-deficient mice. Cyclin D1 was upregulated in MASLD and diminished with successful treatment. CYD-1 was induced by overnutrition in the intestine of Caenorhabditis elegans (which performs metabolic functions similar to liver) and regulates key nutrient-responsive proteins. CYD-1 inhibition prolonged lifespan in this setting. Conclusions: Cyclin D1 regulates nutrient-mediated physiology in the liver and C. elegans, indicating that it has unexpected and highly conserved metabolic functions. Further study is warranted to define its role in hepatic disease and aging.","rel_num_authors":17,"rel_authors":[{"author_name":"Heng Wu","author_inst":"University of Minnesota"},{"author_name":"Jonathan I Hauser","author_inst":"University of Minnesota"},{"author_name":"Na Yang","author_inst":"National Institute on Aging"},{"author_name":"Nikolai Timchenko","author_inst":"University of Cincinnati College of Medicine"},{"author_name":"Maggie Klaers","author_inst":"University of Minnesota"},{"author_name":"Rahagir Salekeen","author_inst":"University of Minnesota"},{"author_name":"Juan C Manivel","author_inst":"Minneapolis VA Health Care System"},{"author_name":"Juan E. Abrahante","author_inst":"University of Minnesota"},{"author_name":"Linshan Laux","author_inst":"University of Minnesota"},{"author_name":"Matthew  J Yousefzadeh","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Michael P Schonfeld","author_inst":"University of Kansas Medical Center"},{"author_name":"Sayeed Ikramuddin","author_inst":"University of Minnesota"},{"author_name":"Satdarshan S Monga","author_inst":"University of Pittsburgh"},{"author_name":"Oyedele A Adeyi","author_inst":"University of Alabama at Birmingham"},{"author_name":"Laura J Niedernhofer","author_inst":"University of Minnesota"},{"author_name":"Matthew S Gill","author_inst":"University of Minnesota"},{"author_name":"Jeffrey H Albrecht","author_inst":"University of Minnesota"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"Cyclin D1 regulates the hepatic response to feeding: Evidence for non-cell cycle roles in the liver","rel_doi":"10.64898\/2026.05.25.727739","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.25.727739","rel_abs":"Objectives: Prior studies have shown that cyclin D1 regulates diverse aspects of liver metabolism during cell cycle progression. Interestingly, this protein is induced in hepatocytes by feeding, but its function in modulating hepatic postprandial physiology is poorly characterized. The aim of this study was to evaluate the contribution of cyclin D1 to the hepatic response to feeding and to gain insight into its potential non-proliferative roles in other conditions. Methods: Mice with or without hepatocyte cyclin D1 (D1fl\/fl or D{Delta}Hep) were fasted and refed a high-carbohydrate diet. Mouse and human liver in the setting of aging and MASLD were analyzed. The C. elegans model was used to evaluate the role of cyclin D1 (CYD-1) in response to overnutrition. Results: Cyclin D1 regulated hepatic gene networks involved in glucose and lipid metabolism, protein synthesis, immune response, and other pathways after feeding. Induction of acute phase response proteins was markedly inhibited in D1{Delta}Hep mice, which was associated with corresponding changes in histone acetylation on key genes. In aged liver, hepatocyte cyclin D1 was induced without associated proliferation; this was markedly pronounced in progeroid Ercc1-deficient mice. Cyclin D1 was upregulated in MASLD and diminished with successful treatment. CYD-1 was induced by overnutrition in the intestine of Caenorhabditis elegans (which performs metabolic functions similar to liver) and regulates key nutrient-responsive proteins. CYD-1 inhibition prolonged lifespan in this setting. Conclusions: Cyclin D1 regulates nutrient-mediated physiology in the liver and C. elegans, indicating that it has unexpected and highly conserved metabolic functions. Further study is warranted to define its role in hepatic disease and aging.","rel_num_authors":17,"rel_authors":[{"author_name":"Heng Wu","author_inst":"University of Minnesota"},{"author_name":"Jonathan I Hauser","author_inst":"University of Minnesota"},{"author_name":"Na Yang","author_inst":"National Institute on Aging"},{"author_name":"Nikolai Timchenko","author_inst":"University of Cincinnati College of Medicine"},{"author_name":"Maggie Klaers","author_inst":"University of Minnesota"},{"author_name":"Rahagir Salekeen","author_inst":"University of Minnesota"},{"author_name":"Juan C Manivel","author_inst":"Minneapolis VA Health Care System"},{"author_name":"Juan E. Abrahante","author_inst":"University of Minnesota"},{"author_name":"Linshan Laux","author_inst":"University of Minnesota"},{"author_name":"Matthew  J Yousefzadeh","author_inst":"Columbia University Irving Medical Center"},{"author_name":"Michael P Schonfeld","author_inst":"University of Kansas Medical Center"},{"author_name":"Sayeed Ikramuddin","author_inst":"University of Minnesota"},{"author_name":"Satdarshan S Monga","author_inst":"University of Pittsburgh"},{"author_name":"Oyedele A Adeyi","author_inst":"University of Alabama at Birmingham"},{"author_name":"Laura J Niedernhofer","author_inst":"University of Minnesota"},{"author_name":"Matthew S Gill","author_inst":"University of Minnesota"},{"author_name":"Jeffrey H Albrecht","author_inst":"University of Minnesota"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"Nucleic acid turnover and lipid remodeling distinguish T cell activation and exhaustion states via label-free Raman spectroscopy","rel_doi":"10.64898\/2026.05.25.727733","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.25.727733","rel_abs":"T cell exhaustion impairs immune control of chronic diseases including tuberculosis, HIV, malaria, and cancer. Its clinical implications are vast, predicting HIV-associated malignancy and treatment response and limiting the efficacy of cell therapies. Despite the advantages of monitoring and removing exhausted T cells, current detection methods require expensive antibody labeling, destructive workflows, or days-long functional assays. Here, we introduce Raman spectroscopy as a label-free assay for distinguishing T cell states directly from culture while preserving viability for downstream use. We achieve >97% accuracy in discriminating unstimulated, activated, and exhausted T cells across three donors and multiple hardware setups. We identify vibrational modes associated with nucleic acid turnover and lipid remodeling as key features that distinguish T cell activation and exhaustion. In heterogeneous populations, we quantify exhaustion percentage with R2= 1 and strong correlation to adenine (r= -0.91) and amide II protein (r= 0.94) vibrational modes. This work establishes vibrational fingerprinting as a direct measure of T cell exhaustion beyond surface marker expression towards scalable immune diagnostics, in-line monitoring, and selective immunopheresis.","rel_num_authors":4,"rel_authors":[{"author_name":"Marissa Morales","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Srilakshmi Premachandran","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Shruthi Ravichandran","author_inst":"Massachusetts Institute of Technology"},{"author_name":"Loza F. Tadesse","author_inst":"Massachusetts Institute of Technology"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"Chromatin architecture sets origin licensing capacity","rel_doi":"10.64898\/2026.05.25.727720","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.25.727720","rel_abs":"Replication origin licensing enables complete and faithful genome duplication, yet how chromatin regulates this process in vivo remains unclear. Using MCM-ChEC-seq to track helicase loading from metaphase through G1 in budding yeast, we find that licensing occurs in a rapid, synchronous burst at mitotic exit and then reaches an early plateau despite continued permissive cell-cycle conditions and persistent ORC binding at origins. Here we show that this plateau is imposed by chromatin architecture at replication origins, which limits the extent of origin licensing. Histone H3K56 acetylation marks newly replicated chromatin and is removed at S-phase exit by the deacetylases Hst3 and Hst4. Persistent H3K56ac severely impairs MCM loading without affecting ORC occupancy, indicating that chromatin limits licensing at the helicase-loading step. Strikingly, deletion or catalytic inactivation of the chromatin remodeler Isw2 increases licensing by approximately 40% in wild-type cells and fully suppresses the licensing defect in hst3{Delta} hst4{Delta} mutants, identifying Isw2 as a physiological inhibitor of origin licensing. Isw2-dependent nucleosome repositioning narrows the origin nucleosome-depleted region and restricts helicase loading. Together, these findings show that chromatin architecture at replication origins sets licensing capacity. Newly replicated chromatin transiently adopts an Isw2-dependent inhibitory configuration that is relieved, but not completely eliminated, by post-replicative chromatin maturation. Genome-wide licensing thus reflects integration of chromatin-imposed licensing capacity with cell cycle-dependent control of licensing timing.","rel_num_authors":11,"rel_authors":[{"author_name":"Eric J Foss","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Ilana M Nodelman","author_inst":"Johns Hopkins University"},{"author_name":"Alexa Usenko","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Holden Furutani","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Ayush Goel","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Brandon Lofts","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Shawna Miles","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Zhiguo Zhang","author_inst":"Columbia University"},{"author_name":"Gregory Bowman","author_inst":"Johns Hopkins University"},{"author_name":"Toshio Tsukiyama","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Antonio Bedalov","author_inst":"Fred Hutchinson Cancer Research Center"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"Chromatin architecture sets origin licensing capacity","rel_doi":"10.64898\/2026.05.25.727720","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.25.727720","rel_abs":"Replication origin licensing enables complete and faithful genome duplication, yet how chromatin regulates this process in vivo remains unclear. Using MCM-ChEC-seq to track helicase loading from metaphase through G1 in budding yeast, we find that licensing occurs in a rapid, synchronous burst at mitotic exit and then reaches an early plateau despite continued permissive cell-cycle conditions and persistent ORC binding at origins. Here we show that this plateau is imposed by chromatin architecture at replication origins, which limits the extent of origin licensing. Histone H3K56 acetylation marks newly replicated chromatin and is removed at S-phase exit by the deacetylases Hst3 and Hst4. Persistent H3K56ac severely impairs MCM loading without affecting ORC occupancy, indicating that chromatin limits licensing at the helicase-loading step. Strikingly, deletion or catalytic inactivation of the chromatin remodeler Isw2 increases licensing by approximately 40% in wild-type cells and fully suppresses the licensing defect in hst3{Delta} hst4{Delta} mutants, identifying Isw2 as a physiological inhibitor of origin licensing. Isw2-dependent nucleosome repositioning narrows the origin nucleosome-depleted region and restricts helicase loading. Together, these findings show that chromatin architecture at replication origins sets licensing capacity. Newly replicated chromatin transiently adopts an Isw2-dependent inhibitory configuration that is relieved, but not completely eliminated, by post-replicative chromatin maturation. Genome-wide licensing thus reflects integration of chromatin-imposed licensing capacity with cell cycle-dependent control of licensing timing.","rel_num_authors":11,"rel_authors":[{"author_name":"Eric J Foss","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Ilana M Nodelman","author_inst":"Johns Hopkins University"},{"author_name":"Alexa Usenko","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Holden Furutani","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Ayush Goel","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Brandon Lofts","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Shawna Miles","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Zhiguo Zhang","author_inst":"Columbia University"},{"author_name":"Gregory Bowman","author_inst":"Johns Hopkins University"},{"author_name":"Toshio Tsukiyama","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Antonio Bedalov","author_inst":"Fred Hutchinson Cancer Research Center"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"Chromatin architecture sets origin licensing capacity","rel_doi":"10.64898\/2026.05.25.727720","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.25.727720","rel_abs":"Replication origin licensing enables complete and faithful genome duplication, yet how chromatin regulates this process in vivo remains unclear. Using MCM-ChEC-seq to track helicase loading from metaphase through G1 in budding yeast, we find that licensing occurs in a rapid, synchronous burst at mitotic exit and then reaches an early plateau despite continued permissive cell-cycle conditions and persistent ORC binding at origins. Here we show that this plateau is imposed by chromatin architecture at replication origins, which limits the extent of origin licensing. Histone H3K56 acetylation marks newly replicated chromatin and is removed at S-phase exit by the deacetylases Hst3 and Hst4. Persistent H3K56ac severely impairs MCM loading without affecting ORC occupancy, indicating that chromatin limits licensing at the helicase-loading step. Strikingly, deletion or catalytic inactivation of the chromatin remodeler Isw2 increases licensing by approximately 40% in wild-type cells and fully suppresses the licensing defect in hst3{Delta} hst4{Delta} mutants, identifying Isw2 as a physiological inhibitor of origin licensing. Isw2-dependent nucleosome repositioning narrows the origin nucleosome-depleted region and restricts helicase loading. Together, these findings show that chromatin architecture at replication origins sets licensing capacity. Newly replicated chromatin transiently adopts an Isw2-dependent inhibitory configuration that is relieved, but not completely eliminated, by post-replicative chromatin maturation. Genome-wide licensing thus reflects integration of chromatin-imposed licensing capacity with cell cycle-dependent control of licensing timing.","rel_num_authors":11,"rel_authors":[{"author_name":"Eric J Foss","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Ilana M Nodelman","author_inst":"Johns Hopkins University"},{"author_name":"Alexa Usenko","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Holden Furutani","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Ayush Goel","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Brandon Lofts","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Shawna Miles","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Zhiguo Zhang","author_inst":"Columbia University"},{"author_name":"Gregory Bowman","author_inst":"Johns Hopkins University"},{"author_name":"Toshio Tsukiyama","author_inst":"Fred Hutchinson Cancer Research Center"},{"author_name":"Antonio Bedalov","author_inst":"Fred Hutchinson Cancer Research Center"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"Distinct senescent \u03b2-cell senotypes differentially drive islet aging and dysfunction","rel_doi":"10.64898\/2026.05.25.727705","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.25.727705","rel_abs":"Biological aging greatly impacts the body's ability to handle glucose, and represents a major risk factor the development and progression of type 2 diabetes (T2D). Nonetheless, despite advances in cellular senescence research and the development of new senolytic therapies, the heterogeneity of cellular senescence in the human endocrine pancreas, as well as its roles in normal aging, remains to be elucidated at the single-cell level. Here, we performed single-cell-resolved spatial proteomics and transcriptomics on intact pancreas from 26 donors (ages 20-80) and multiplexed single-cell RNA sequencing and functional assays on dispersed islets from 14 donors (ages 34-69). We identify two discrete SnC subpopulations distinguished by relative expression of CDKN1A and CDKN2A. CDKN1A+ senescent cells (SnCs) exhibit loss of {beta}-cell identity, impaired insulin secretion, and a proinflammatory SASP associated with increased islet immune infiltration. In contrast, CDKN2A+ SnCs retain transcriptional identity and functional competence, with lower inflammatory signaling. Together, these findings identify heterogeneous and functionally divergent senotypes in the human pancreas, distinguishing an adaptive (CDKN2A+) from a maladaptive (CDKN1A+) senescence program, thus providing a mechanism-guided framework for senescence-targeted therapies in T2D.","rel_num_authors":32,"rel_authors":[{"author_name":"Kanako Iwasaki","author_inst":"Joslin Diabetes Center, Harvard Medical School"},{"author_name":"Hui Pan","author_inst":"Joslin Diabetes Center, Harvard Medical School"},{"author_name":"Jonathan M. Dreyfuss","author_inst":"Joslin Diabetes Center, Harvard Medical School"},{"author_name":"Maya Jackson","author_inst":"Joslin Diabetes Center, Harvard Medical School"},{"author_name":"Sergii Domanskyi","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Dylan Baker","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Priscila Carapeto","author_inst":"Joslin Diabetes Center, Harvard Medical School"},{"author_name":"Christopher Cahill","author_inst":"Joslin Diabetes Center, Harvard Medical School"},{"author_name":"Sandra Le","author_inst":"Joslin Diabetes Center, Harvard Medical School"},{"author_name":"Francesko Hela","author_inst":"Joslin Diabetes Center, Harvard Medical School"},{"author_name":"Juliana Alcoforado Diniz","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Giray Naim Eryilmaz","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Fan Wu","author_inst":"Institute for NanoBioTechnology, The Johns Hopkins University"},{"author_name":"Pei-Hsun Wu","author_inst":"Institute for NanoBioTechnology, The Johns Hopkins University"},{"author_name":"Bofei Yu","author_inst":"Institute for NanoBioTechnology, The Johns Hopkins University"},{"author_name":"Denis Wirtz","author_inst":"Institute for NanoBioTechnology, The Johns Hopkins University"},{"author_name":"Sara Espinoza","author_inst":"Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center"},{"author_name":"Alejandro Pena","author_inst":"UT Health San Antonio Transplant Center"},{"author_name":"Francisco G. Cigarroa","author_inst":"UT Health San Antonio Transplant Center"},{"author_name":"Gregory Abrahamian","author_inst":"UT Health San Antonio Transplant Center"},{"author_name":"Jillian L Woodworth","author_inst":"UT Health San Antonio Transplant Center"},{"author_name":"Peter D. Adams","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Duygu Ucar","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Jeffrey H Chuang","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Qian Wu","author_inst":"Pathology and Laboratory Medicine, UConn Health"},{"author_name":"Vesna D Garovic","author_inst":"Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic"},{"author_name":"James L Kirkland","author_inst":"Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center"},{"author_name":"Tamar Tchkonia","author_inst":"Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center"},{"author_name":"Nicolas Musi","author_inst":"Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center"},{"author_name":"George A Kuchel","author_inst":"UConn Center on Aging, UConn Health"},{"author_name":"Paul Robson","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Cristina Aguayo-Mazzucato","author_inst":"Joslin Diabetes Center, Harvard Medical School"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"Distinct senescent \u03b2-cell senotypes differentially drive islet aging and dysfunction","rel_doi":"10.64898\/2026.05.25.727705","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.25.727705","rel_abs":"Biological aging greatly impacts the body's ability to handle glucose, and represents a major risk factor the development and progression of type 2 diabetes (T2D). Nonetheless, despite advances in cellular senescence research and the development of new senolytic therapies, the heterogeneity of cellular senescence in the human endocrine pancreas, as well as its roles in normal aging, remains to be elucidated at the single-cell level. Here, we performed single-cell-resolved spatial proteomics and transcriptomics on intact pancreas from 26 donors (ages 20-80) and multiplexed single-cell RNA sequencing and functional assays on dispersed islets from 14 donors (ages 34-69). We identify two discrete SnC subpopulations distinguished by relative expression of CDKN1A and CDKN2A. CDKN1A+ senescent cells (SnCs) exhibit loss of {beta}-cell identity, impaired insulin secretion, and a proinflammatory SASP associated with increased islet immune infiltration. In contrast, CDKN2A+ SnCs retain transcriptional identity and functional competence, with lower inflammatory signaling. Together, these findings identify heterogeneous and functionally divergent senotypes in the human pancreas, distinguishing an adaptive (CDKN2A+) from a maladaptive (CDKN1A+) senescence program, thus providing a mechanism-guided framework for senescence-targeted therapies in T2D.","rel_num_authors":32,"rel_authors":[{"author_name":"Kanako Iwasaki","author_inst":"Joslin Diabetes Center, Harvard Medical School"},{"author_name":"Hui Pan","author_inst":"Joslin Diabetes Center, Harvard Medical School"},{"author_name":"Jonathan M. Dreyfuss","author_inst":"Joslin Diabetes Center, Harvard Medical School"},{"author_name":"Maya Jackson","author_inst":"Joslin Diabetes Center, Harvard Medical School"},{"author_name":"Sergii Domanskyi","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Dylan Baker","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Priscila Carapeto","author_inst":"Joslin Diabetes Center, Harvard Medical School"},{"author_name":"Christopher Cahill","author_inst":"Joslin Diabetes Center, Harvard Medical School"},{"author_name":"Sandra Le","author_inst":"Joslin Diabetes Center, Harvard Medical School"},{"author_name":"Francesko Hela","author_inst":"Joslin Diabetes Center, Harvard Medical School"},{"author_name":"Juliana Alcoforado Diniz","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Giray Naim Eryilmaz","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Fan Wu","author_inst":"Institute for NanoBioTechnology, The Johns Hopkins University"},{"author_name":"Pei-Hsun Wu","author_inst":"Institute for NanoBioTechnology, The Johns Hopkins University"},{"author_name":"Bofei Yu","author_inst":"Institute for NanoBioTechnology, The Johns Hopkins University"},{"author_name":"Denis Wirtz","author_inst":"Institute for NanoBioTechnology, The Johns Hopkins University"},{"author_name":"Sara Espinoza","author_inst":"Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center"},{"author_name":"Alejandro Pena","author_inst":"UT Health San Antonio Transplant Center"},{"author_name":"Francisco G. Cigarroa","author_inst":"UT Health San Antonio Transplant Center"},{"author_name":"Gregory Abrahamian","author_inst":"UT Health San Antonio Transplant Center"},{"author_name":"Jillian L Woodworth","author_inst":"UT Health San Antonio Transplant Center"},{"author_name":"Peter D. Adams","author_inst":"Sanford Burnham Prebys Medical Discovery Institute"},{"author_name":"Duygu Ucar","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Jeffrey H Chuang","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Qian Wu","author_inst":"Pathology and Laboratory Medicine, UConn Health"},{"author_name":"Vesna D Garovic","author_inst":"Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic"},{"author_name":"James L Kirkland","author_inst":"Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center"},{"author_name":"Tamar Tchkonia","author_inst":"Center for Advanced Gerotherapeutics, Department of Medicine, Cedars-Sinai Medical Center"},{"author_name":"Nicolas Musi","author_inst":"Center for Translational Geroscience, Department of Medicine, Cedars-Sinai Medical Center"},{"author_name":"George A Kuchel","author_inst":"UConn Center on Aging, UConn Health"},{"author_name":"Paul Robson","author_inst":"The Jackson Laboratory for Genomic Medicine"},{"author_name":"Cristina Aguayo-Mazzucato","author_inst":"Joslin Diabetes Center, Harvard Medical School"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"The Limbic Overload Hypothesis of Hypomanic Vulnerability: A Dynamic Biosocial Perspective","rel_doi":"10.64898\/2026.05.25.727695","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.25.727695","rel_abs":"Hypomanic tendencies are associated with elevated goal-directed behavior, creativity, charisma, sociability, and entrepreneurial drive, but also with mood instability, irritability, impulsive persistence, and elevated risk for bipolar disorder and other psychopathology. Existing models often emphasize unidimensional constructs such as reward sensitivity or behavioral activation, yet these approaches incompletely capture the dynamic and often contradictory nature of the hypomanic temperament. We propose the Limbic Overload Hypothesis of Hypomanic Vulnerability, a dynamic biosocial framework suggesting that hypomanic tendencies reflect a persistent pattern of elevated engagement despite potential loss, coupled with reduced integration of negative emotional experience into subsequent behavioral regulation. Over time, this pattern may contribute to progressive limbic overload, characterized by increasing emotional dysregulation, hypersensitivity to salient experiences, and vulnerability to psychopathology. Integrating evidence from personality research, affective neuroscience, and preliminary neuroimaging findings, we propose a dynamic cortico-limbic model linking prefrontal-limbic coordination, loss tolerance, emotional updating, and social reinforcement cycles. Preliminary pilot data suggest that individual differences in hypomanic tendencies are reflected not simply in baseline cortico-limbic organization, but in dynamic neural reconfiguration across pre-task resting-state - task - post-task resting-state transitions during loss-related decision making. Specifically, elevated hypomanic tendencies were associated with persistently elevated tolerance of potential losses and reduced integration of negative emotional information into subsequent behavioral regulation. We further propose that social connectedness and cognitive-emotional integration may mitigate progressive limbic overload and contribute to resilience. Together, this framework generates experimentally testable predictions regarding the neural, behavioral, and social processes underlying hypomanic vulnerability and resilience.","rel_num_authors":3,"rel_authors":[{"author_name":"Helen Pushkarskaya","author_inst":"Yale School of Medicine"},{"author_name":"Godfrey Pearlson","author_inst":"Yale School of Medicine"},{"author_name":"Christopher Pittenger","author_inst":"Yale School of Medicine"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"Transient ATR inhibition following ionizing radiation enhances immune-mediated antitumor response and survival","rel_doi":"10.64898\/2026.05.25.727700","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.25.727700","rel_abs":"Background. ATR activation following DNA damage from cancer treatments such as radiation can mitigate anticancer efficacy, making ATR inhibitors (ATRi) an attractive therapeutic. In vivo and in vitro studies have shown enhanced tumor cell radiosensitivity with the ATRi ceralasertib, elimusertib, and berzosertib, however, the potentiating effect of ATRi on ionizing radiation (IR) through immune-based mechanisms has only been studied with ceralasertib. Methods. We aimed to determine if antitumor immune responses observed with ceralasertib in combination with IR extend to the other ATRi class members in the preclinical CT26 mouse model. We also examined the relationship between exposure and immune stimulation, efficacy and survival outcomes of each ATRi when combined with IR. Results. Ceralasertib and elimusertib, not berzosertib, synergized with IR in a dose and schedule-dependent manner to modify tumor antigen-specific CD8+ T cell populations in the draining lymph node. Transient ATRi therapy, combined with IR, enhances antitumor efficacy, promoted tumor shrinkage, and increased survival. ATRi elicited differential inflammatory gene induction and dose-dependent unique cytotoxicity profiles in vitro. Conclusion. The immune mediated antitumor effect of ATRi combined with radiation is dose and schedule dependent, and while likely a class effect, may differ between ATRi compounds.","rel_num_authors":13,"rel_authors":[{"author_name":"Joshua Deppas","author_inst":"University of Pittsburgh"},{"author_name":"Brian F Kiesel","author_inst":"University of Pittsburgh"},{"author_name":"Frank P Vendetti","author_inst":"University of Pittsburgh"},{"author_name":"Pinakin Pandya","author_inst":"University of Pittsburgh"},{"author_name":"Jianxia Guo","author_inst":"University of Pittsburgh"},{"author_name":"Kristine L Cooper","author_inst":"University of Pittsburgh"},{"author_name":"Matthew J Bakkenist","author_inst":"University of Pittsburgh"},{"author_name":"Meysam Tavakoli","author_inst":"UPMC Hillman Cancer Center"},{"author_name":"Maria diMayorca","author_inst":"University of Pittsburgh"},{"author_name":"Naveed M Islam","author_inst":"University of Pittsburgh"},{"author_name":"David A Clump","author_inst":"West Virginia University"},{"author_name":"Christopher J Bakkenist","author_inst":"University of Pittsburgh"},{"author_name":"Jan H Beumer","author_inst":"Johns Hopkins University"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"MINA: linear probes reveal coding-sequence family signal in frozen DNA encoders","rel_doi":"10.64898\/2026.05.25.727711","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.25.727711","rel_abs":"Frozen DNA encoders are often used as genomic feature extractors, but downstream fine-tuning does not show what information is already linearly accessible in their unchanged embeddings. We introduce MINA (Model Interrogation of Nucleotide Architectures), a lightweight probing benchmark for testing whether frozen DNA embeddings can recover (i) a 5-way protein-family label for each gene and (ii) the 1,536-dimensional GenePT embedding of each gene's natural-language summary. We compare recoverability between canonical coding sequence and TSS-centred genomic contexts. In 3,244 human protein-coding genes from five families, frozen encoders recovered the family-annotation target most clearly from coding sequence. NT-v2 with meanD pooling reached macro-F1 0.828 \/ kappa 0.821, compared with 0.672 \/ kappa 0.702 for a CDS 4-mer baseline. Alignment to GenePT natural-language descriptions was weaker. Replacing CDS with 196,608 bp TSS-centred windows substantially reduced performance across all four encoders, indicating that the recoverable signal is primarily coding-sequence family signal rather than generic gene-function signal from arbitrary genomic context.","rel_num_authors":3,"rel_authors":[{"author_name":"Austin Senna Wijaya","author_inst":"Columbia University"},{"author_name":"Hayden Leung","author_inst":"Columbia University"},{"author_name":"Hyoungjoon Yoo","author_inst":"Columbia University"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"A general framework explaining variation in plant economics traits with environment and through ontogeny","rel_doi":"10.64898\/2026.05.25.727577","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.25.727577","rel_abs":"Plant economics traits, such as leaf mass per unit leaf area and stem specific density, capture diversity among plant species in how common tissues (leaf, wood, root) are constructed. These traits are key descriptors of plant strategy, yet it has proven difficult to explain this variation with theory and process-based models. Here we reveal a general explanation on why these economics traits vary with environment, through ontogeny, and with other plant traits. This explanation relies on three core assumptions: 1) plants seek to maximise growth rate, 2) growth rate can be decomposed into a product, and 3) there is a tradeoff between the efficiency of tissue construction and tissue turnover rate. Formulation of growth as a product is essential, as it causes the optimal value of an economics trait to vary with the plant's biomass production rate, which means economics traits will naturally covary with the abiotic environment, the competitive context, and other strategical features of the plant. Finally, we show how a modification of the trait into plastic and non-plastic components alters the magnitude of intra-specific responses, aligning model responses with empirical trends. Broadly, our results help explain how plant form and function for a wide diversity of species is shaped to suit their environment and, moreover, they reveal insight into a general fast-slow spectrum with coordinated shifts among organs (leaf stem) through tradeoffs between efficient tissue construction and turnover.","rel_num_authors":4,"rel_authors":[{"author_name":"Daniel S Falster","author_inst":"University of New South Wales"},{"author_name":"Isaac Towers","author_inst":"The University of New South Wales"},{"author_name":"Peter Vesk","author_inst":"University of Melbourne"},{"author_name":"Mark Westoby","author_inst":"Macquarie University"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"Isolation and Characterization of Extracellular Vesicles from Mouse Retina Tissue","rel_doi":"10.64898\/2026.05.24.724732","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.24.724732","rel_abs":"This protocol provides a standardized workflow for the isolation of extracellular vesicles (EVs) from mouse retinal tissue, and includes an assessment of EV size and concentration, marker expression, and EV visualization in accordance with the International Society for Extracellular Vesicles Minimal Information for Studies of Extracellular Vesicles (MISEV) guidelines. Most retinal EV studies rely on cell culture, which may not fully capture in vivo biology. Our approach more accurately reflects physiological and pathological EV states in vivo by enabling the extraction of EVs from intact retinal tissue. This method addresses a key gap in the field by providing a reproducible and rigorous protocol for studying retinal EVs in a biologically relevant context.","rel_num_authors":9,"rel_authors":[{"author_name":"Ishrat Ahmed","author_inst":"Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA."},{"author_name":"Olesia Gololobova","author_inst":"Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA"},{"author_name":"Mohammed Amanullah","author_inst":"Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA."},{"author_name":"Zach Troyer","author_inst":"Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA"},{"author_name":"Joshua H Yu","author_inst":"Georgetown University School of Medicine"},{"author_name":"James T Handa","author_inst":"Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA."},{"author_name":"Jiang Qian","author_inst":"Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA."},{"author_name":"Seth Blackshaw","author_inst":"Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, MD, USA. Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD"},{"author_name":"Kenneth Witwer","author_inst":"Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, MD, USA.  Department of Neurology, The Johns Hopkins University School of Medicine, Balt"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"Mapping Genetic Risk Associations to Cellular Contexts via Deep Learning and Biological Ontologies","rel_doi":"10.64898\/2026.05.25.726449","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.25.726449","rel_abs":"Translating genome-wide association studies (GWAS) signals into trait-relevant cellular contexts remains challenging due to the complexity of the genomic regulatory code and linkage disequilibrium among associated variants. We present a novel computational framework that aggregates deep learning-based predictions of the functional effects of noncoding variants on transcriptional regulatory elements across GWAS loci and empirically evaluates their statistical significance. By organizing these aggregated signals within biological ontologies, our approach enables statistically calibrated interpretation of GWAS associations, highlighting relevant cell-type and tissue contexts across human traits.","rel_num_authors":4,"rel_authors":[{"author_name":"Thomy Margalit","author_inst":"Tel-Aviv University"},{"author_name":"Hagai Levi","author_inst":"Tel Aviv University"},{"author_name":"Ron Shamir","author_inst":"tel aviv university"},{"author_name":"Ran Elkon","author_inst":"Tel Aviv University"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"Dual lineages of Langerhans cells cooperate to restore the immune barrier after skin injury","rel_doi":"10.64898\/2026.05.25.727646","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.25.727646","rel_abs":"Langerhans cells (LCs) are key immune sentinels of the epidermis. How this network reorganizes to safeguard epidermal immunity after injury has remained unclear. Here, we uncover a previously unrecognized two-lineage program of LC repopulation during wound repair. Classically, tissue-resident embryonically derived LCs (eLCs) migrate to lymph nodes in response to antigens. In contrast, we find that injury triggers nearby eLCs to migrate into wounds, providing immediate coverage. In parallel, circulating monocytes infiltrate the skin and differentiate into long-lived monocyte-derived LCs (mLCs) that integrate stably into the network. We identify the chemokine receptor CXCR2 as a novel regulator of eLC migration into wounds, distinct from the CXCR4\/CCR7 pathways mediating LC egress to lymph nodes. Pharmacological inhibition of CXCR2 impairs directional eLC migration and is accompanied by increased mLC infiltration, preserving immune barrier density. These findings reveal a coordinated and flexible two-lineage repair program that ensures robust restoration of epidermal immunity.","rel_num_authors":10,"rel_authors":[{"author_name":"Axel D Schmitter-Sanchez","author_inst":"Michigan State University"},{"author_name":"Nicholas Basista","author_inst":"Michigan State University"},{"author_name":"Artem Kiselev","author_inst":"Michigan State University"},{"author_name":"Sudhanshu Mishra","author_inst":"Michigan State University"},{"author_name":"Hyeri Kim","author_inst":"Michigan State University"},{"author_name":"Audrey Bench","author_inst":"Michigan State University"},{"author_name":"Catherine Matte-Martone","author_inst":"Yale University"},{"author_name":"Min-Soo Seo","author_inst":"Kyungpook National University"},{"author_name":"Gun Woo Lee","author_inst":"Yeungnam University"},{"author_name":"Sangbum Park","author_inst":"Michigan State University"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"Dual lineages of Langerhans cells cooperate to restore the immune barrier after skin injury","rel_doi":"10.64898\/2026.05.25.727646","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.25.727646","rel_abs":"Langerhans cells (LCs) are key immune sentinels of the epidermis. How this network reorganizes to safeguard epidermal immunity after injury has remained unclear. Here, we uncover a previously unrecognized two-lineage program of LC repopulation during wound repair. Classically, tissue-resident embryonically derived LCs (eLCs) migrate to lymph nodes in response to antigens. In contrast, we find that injury triggers nearby eLCs to migrate into wounds, providing immediate coverage. In parallel, circulating monocytes infiltrate the skin and differentiate into long-lived monocyte-derived LCs (mLCs) that integrate stably into the network. We identify the chemokine receptor CXCR2 as a novel regulator of eLC migration into wounds, distinct from the CXCR4\/CCR7 pathways mediating LC egress to lymph nodes. Pharmacological inhibition of CXCR2 impairs directional eLC migration and is accompanied by increased mLC infiltration, preserving immune barrier density. These findings reveal a coordinated and flexible two-lineage repair program that ensures robust restoration of epidermal immunity.","rel_num_authors":10,"rel_authors":[{"author_name":"Axel D Schmitter-Sanchez","author_inst":"Michigan State University"},{"author_name":"Nicholas Basista","author_inst":"Michigan State University"},{"author_name":"Artem Kiselev","author_inst":"Michigan State University"},{"author_name":"Sudhanshu Mishra","author_inst":"Michigan State University"},{"author_name":"Hyeri Kim","author_inst":"Michigan State University"},{"author_name":"Audrey Bench","author_inst":"Michigan State University"},{"author_name":"Catherine Matte-Martone","author_inst":"Yale University"},{"author_name":"Min-Soo Seo","author_inst":"Kyungpook National University"},{"author_name":"Gun Woo Lee","author_inst":"Yeungnam University"},{"author_name":"Sangbum Park","author_inst":"Michigan State University"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"IDRs lead the way: Cooperativity between intrinsically disordered regions and structured interaction domains drives enrichment in transcription condensates","rel_doi":"10.64898\/2026.05.25.727758","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.25.727758","rel_abs":"Many biomolecular condensates are thought to form through phase separation driven by weak and multivalent, non-stoichiometric interactions between intrinsically disordered protein regions (IDRs). IDRs are abundant in the transcription-related proteome. In vitro, different transcription-related IDRs coalesce into the same droplets, providing support for this IDR-centric paradigm of protein enrichment in transcription condensates in the cell nucleus. But our experiments show that IDRs are not sufficient to account for the degree of enrichment observed for full-length proteins in endogenous transcription condensates. Instead, we find a pattern in which IDRs facilitate engagement of structured interaction domains with a binding substrate. Instead, we find a pattern in which IDRs facilitate engagement of structured interaction domains with a binding substrate. Our results indicate that the role of IDRs in transcription condensates requires further investigation with tools that assess their mode of action in situ. Understanding the role of different protein domains and their interplay will also be important for interpreting biotechnological assays that utilize parts of condensate forming proteins.","rel_num_authors":6,"rel_authors":[{"author_name":"Arad Abazari","author_inst":"University of Illinois Chicago"},{"author_name":"Dinitha Yasas Caldera","author_inst":"University of Illinois Chicago"},{"author_name":"Alisha Budhathoki","author_inst":"University of Illinois Chicago"},{"author_name":"Ganesh Pandey","author_inst":"University of Illinois Chicago"},{"author_name":"Mehdi Shafiei Aporvari","author_inst":"University of Illinois Chicago"},{"author_name":"Jan-Hendrik Spille","author_inst":"University of Illinois Chicago"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"The molecular architecture of tunneling nanotubes","rel_doi":"10.64898\/2026.05.27.728322","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.27.728322","rel_abs":"Tunneling nanotubes (TNTs) are thin intercellular bridges that mediate the exchange of proteins, organelles, and nucleic acids between neighboring cells. They are enriched in tumor cells, implicated in chemotherapy resistance, induced in models of aggregation-based diseases, and their formation is stimulated by viruses that use TNTs to enhance infection. Despite their broad relevance and therapeutic potential, TNT morphology and function remain poorly understood, owing to the absence of clear morphological criteria and the limitations of light microscopy. Here, we establish two complementary systems to study TNT formation and function: stimulation with the pseudorabies viral kinase US3 to model viral transmission, and treatment of acute monocytic leukemia THP-1 cells with daunorubicin to model chemotherapy resistance. Using live-cell imaging, we characterize cytoskeletal organization and bidirectional lysosome transport in both contexts, and apply cryo-correlative light and electron microscopy (cryo-CLEM) with cryogenic electron tomography (cryo-ET) to visualize TNTs in their native state at molecular resolution. We show that TNTs display a rich molecular architecture, comprising actin filaments, microtubules, intermediate filaments, active ribosomes, and diverse organelles including multivesicular bodies, autophagosomes, and lysosomes. Sub-nanometer microtubule reconstructions reveal mixed polarity within individual TNTs, suggesting that both connected cells actively contribute to TNT formation and cargo trafficking. This organization is conserved across both systems, implying that TNT biogenesis reflects a shared cellular program rather than a context-specific response. Our findings provide the first structural framework for TNTs, revealing an unexpectedly rich molecular architecture and laying the groundwork for understanding how TNTs orchestrate intercellular communication in disease.","rel_num_authors":14,"rel_authors":[{"author_name":"Eva P Karasmanis","author_inst":"Vanderbilt University"},{"author_name":"Siyu Chen","author_inst":"University of California San Diego"},{"author_name":"Farhaz Shaikh","author_inst":"University of California San Francisco"},{"author_name":"Robert G. Abrisch","author_inst":"University of Colorado Boulder"},{"author_name":"Alex Flaherty","author_inst":"University of California San Diego"},{"author_name":"Rafael A. Badell-Grau","author_inst":"University of California San Diego"},{"author_name":"Margot Riggi","author_inst":"Max Planck Institute of Biochemistry"},{"author_name":"Landon Vu Nguyen","author_inst":"University of California San Francisco"},{"author_name":"Joshua Hutchings","author_inst":"Biohub"},{"author_name":"Tamar Basiashvili","author_inst":"University of California San Diego"},{"author_name":"Nicholas Lattal","author_inst":"Weill Cornell Medicine"},{"author_name":"Stephanie Cherqui","author_inst":"University of California San Diego"},{"author_name":"Elizabeth P Villa","author_inst":"University of California San Diego"},{"author_name":"Samara L Reck-Peterson","author_inst":"Weill Cornell Medicine"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"The molecular architecture of tunneling nanotubes","rel_doi":"10.64898\/2026.05.27.728322","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.27.728322","rel_abs":"Tunneling nanotubes (TNTs) are thin intercellular bridges that mediate the exchange of proteins, organelles, and nucleic acids between neighboring cells. They are enriched in tumor cells, implicated in chemotherapy resistance, induced in models of aggregation-based diseases, and their formation is stimulated by viruses that use TNTs to enhance infection. Despite their broad relevance and therapeutic potential, TNT morphology and function remain poorly understood, owing to the absence of clear morphological criteria and the limitations of light microscopy. Here, we establish two complementary systems to study TNT formation and function: stimulation with the pseudorabies viral kinase US3 to model viral transmission, and treatment of acute monocytic leukemia THP-1 cells with daunorubicin to model chemotherapy resistance. Using live-cell imaging, we characterize cytoskeletal organization and bidirectional lysosome transport in both contexts, and apply cryo-correlative light and electron microscopy (cryo-CLEM) with cryogenic electron tomography (cryo-ET) to visualize TNTs in their native state at molecular resolution. We show that TNTs display a rich molecular architecture, comprising actin filaments, microtubules, intermediate filaments, active ribosomes, and diverse organelles including multivesicular bodies, autophagosomes, and lysosomes. Sub-nanometer microtubule reconstructions reveal mixed polarity within individual TNTs, suggesting that both connected cells actively contribute to TNT formation and cargo trafficking. This organization is conserved across both systems, implying that TNT biogenesis reflects a shared cellular program rather than a context-specific response. Our findings provide the first structural framework for TNTs, revealing an unexpectedly rich molecular architecture and laying the groundwork for understanding how TNTs orchestrate intercellular communication in disease.","rel_num_authors":14,"rel_authors":[{"author_name":"Eva P Karasmanis","author_inst":"Vanderbilt University"},{"author_name":"Siyu Chen","author_inst":"University of California San Diego"},{"author_name":"Farhaz Shaikh","author_inst":"University of California San Francisco"},{"author_name":"Robert G. Abrisch","author_inst":"University of Colorado Boulder"},{"author_name":"Alex Flaherty","author_inst":"University of California San Diego"},{"author_name":"Rafael A. Badell-Grau","author_inst":"University of California San Diego"},{"author_name":"Margot Riggi","author_inst":"Max Planck Institute of Biochemistry"},{"author_name":"Landon Vu Nguyen","author_inst":"University of California San Francisco"},{"author_name":"Joshua Hutchings","author_inst":"Biohub"},{"author_name":"Tamar Basiashvili","author_inst":"University of California San Diego"},{"author_name":"Nicholas Lattal","author_inst":"Weill Cornell Medicine"},{"author_name":"Stephanie Cherqui","author_inst":"University of California San Diego"},{"author_name":"Elizabeth P Villa","author_inst":"University of California San Diego"},{"author_name":"Samara L Reck-Peterson","author_inst":"Weill Cornell Medicine"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"A Computational Pipeline for Quantifying Kinetochore Morphological Changes in Live Cells","rel_doi":"10.64898\/2026.05.26.727517","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.26.727517","rel_abs":"To segregate chromosomes kinetochores must resist yet deform under spindle forces. Measuring changes in kinetochore morphology can provide insight into kinetochore structure and function. This remains challenging in live cells because kinetochores are diffraction-limited with irregular, changing shapes. Here, we present a computational pipeline for quantifying kinetochore morphology in live cells, using mammalian cells with fluorescently tagged kinetochore proteins. First, the pipeline tracks, pairs and rotates kinetochores to align with their load-bearing axis. Second, it segments kinetochore signal from background, removing frames with overlapping neighboring kinetochore signals. Third, it provides metrics to define complex, non-Gaussian shape changes: (i) a non-parametric size metric that is more robust than the commonly used full-width-at-half-maximum (FWHM); (ii) analysis to classify common morphological patterns such as asymmetry, low intensity tails and multimodality; (iii) a 2D protein1-to-protein2 kinetochore vector as a reporter of structural rearrangements, if two kinetochore proteins were imaged. Finally, we validate the method using simulations, convolving ground-truth objects with the measured point spread function. Although kinetochore shape diversity makes assigning kinetochore size challenging, we show that our metrics better capture kinetochore size and shape changes than FWHM. Together, this pipeline provides a framework for analyzing complex kinetochore shape changes, with potential applications to other small and dynamic cellular structures.","rel_num_authors":4,"rel_authors":[{"author_name":"Jinghui Tao","author_inst":"University of California, San Francisco"},{"author_name":"Vanna M Tran","author_inst":"University of California, San Francisco"},{"author_name":"Caleb J Rux","author_inst":"University of California, San Francisco"},{"author_name":"Sophie Dumont","author_inst":"UCSF"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"Proteostatic significance of helix O alanine residues in CLC channels","rel_doi":"10.64898\/2026.05.25.725697","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.25.725697","rel_abs":"The voltage-gated chloride channels ClC-1 and ClC-2 are homodimeric structures essential for maintaining muscle excitability and tissue fluid homeostasis, respectively. Mutations in these channels disrupt protein homeostasis (proteostasis), leading to hereditary disorders such as myotonia congenita and leukodystrophy. Specifically, the substitution of highly conserved alanine residues within the transmembrane helix O, exemplified by ClC-1 (A531V) and ClC-2 (A500V), results in severe proteostatic defects characterized by reduced protein stability and impaired surface trafficking. However, the precise role of helix O in these pathological processes remains poorly understood. In this study, we investigated these conserved residues using biochemical and functional approaches. Our findings demonstrate that even subtle structural alterations at these critical sites significantly interfere with channel stability and membrane expression. This study highlights the critical contribution of helix O to proper CLC channel folding and endoplasmic reticulum (ER) quality control, providing deeper insights into the molecular mechanisms of CLC-related channelopathies.","rel_num_authors":7,"rel_authors":[{"author_name":"Chia-Ying You","author_inst":"Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan"},{"author_name":"Ciao-Yu Zhong","author_inst":"Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan"},{"author_name":"Pei-Chen Tsai","author_inst":"Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan"},{"author_name":"An-Ting Cheng","author_inst":"Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan"},{"author_name":"Yu-Xuan Chen","author_inst":"Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan"},{"author_name":"Chung-Jiuan Jeng","author_inst":"Institute of Anatomy and Cell Biology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan"},{"author_name":"Chih-Yung Tang","author_inst":"Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"Microbiota-derived TMAO links PM2.5 exposure to cognitive impairment: A gut liver brain axis","rel_doi":"10.64898\/2026.05.24.727565","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.24.727565","rel_abs":"Although fine particulate matter (PM2.5) is linked to cognitive impairment, the mechanistic links between pulmonary exposure and neurodegeneration remain poorly understood. This study investigates the role of the gut liver brain axis in mediating PM2.5-induced neurotoxicity. We demonstrate that three weeks of intratracheal PM2.5 instillation in mice causes significant memory deficits, impaired hippocampal adult neurogenesis, and reduced synaptic plasticity in both sexes. Metagenomic analysis revealed that PM2.5 alters gut microbiota composition, specifically by upregulating pathways involved in trimethylamine (TMA) synthesis. This microbial shift led to a systemic increase in the metabolite trimethylamine N-oxide (TMAO) and its accumulation in the hippocampus. Mechanistic experiments revealed that TMAO drives neurotoxicity by activating the hippocampal PERK-mediated endoplasmic reticulum (ER) stress pathway. Critically, these deficits were reversed by suppressing hepatic TMAO production via either pharmacological inhibitors or genetic knockdown. Additionally, hippocampal-specific PERK silencing or dietary resveratrol intervention attenuated hippocampal ER stress, thereby protecting against PM2.5 induced cognitive and hippocampal impairments. These results identify the microbial metabolite TMAO as a key mediator of air pollution-related neurotoxicity and highlight the gut liver brain axis as a promising therapeutic strategy to counteract the neurological impacts of air pollution.","rel_num_authors":17,"rel_authors":[{"author_name":"Akhlaq Hussain","author_inst":"The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R., China"},{"author_name":"Yunxiao Zhong","author_inst":"The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R., China"},{"author_name":"Shicong Du","author_inst":"City University of Hong Kong, Hong Kong., SAR China"},{"author_name":"Zonghao Ma","author_inst":"The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R., China"},{"author_name":"Tong Cheng","author_inst":"The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R., China"},{"author_name":"Jiasui Yu","author_inst":"The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R., China"},{"author_name":"Cheuk Hin Lee","author_inst":"The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R., China"},{"author_name":"Formolo Douglas Affonso","author_inst":"The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R., China"},{"author_name":"Patrick K. H. Lee","author_inst":"City University of Hong Kong, Hong Kong., SAR Chinaa"},{"author_name":"Baomin Wang","author_inst":"The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R., China"},{"author_name":"Kenneth King-yip Cheng","author_inst":"The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R., China"},{"author_name":"Siu-Wai Wan","author_inst":"The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R., China"},{"author_name":"Daniel Kam-wah Mok","author_inst":"The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R., China"},{"author_name":"Jiachi Chiou","author_inst":"The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R., China"},{"author_name":"Xiangdong Li","author_inst":"The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R., China"},{"author_name":"Hai Guo","author_inst":"The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R., China"},{"author_name":"Suk-yu Yau","author_inst":"The Hong Kong Polytechnic University, Hung Hom, Hong Kong S.A.R., China"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"Neuronal UBE3A loss engages a TNF-driven neuron-to-microglia axis that promotes synapse remodeling","rel_doi":"10.64898\/2026.05.27.728269","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.27.728269","rel_abs":"Neuron-microglia communication shapes neuroimmune homeostasis and circuit maturation, yet the neuron-derived cues that tune microglial inflammatory state and phagocytic programs remain incompletely defined. The E3 ubiquitin ligase UBE3A is critical for brain development and synaptic function, and altered UBE3A dosage or activity is linked to neurodevelopmental phenotypes with emerging connections to inflammation. Using Angelman syndrome (AS), where UBE3A loss is largely neuron-selective due to imprinting, as a tractable framework, we investigated how neuronal UBE3A deficiency engages microglial programs. In human iPSC-derived neuron-microglia co-cultures, neuronal UBE3A depletion induced a TNF-associated secretory signature and was accompanied by increased microglial inflammatory markers, including complement components. Neuron-conditioned media was sufficient to elicit microglial cytokine\/complement transcripts, supporting a role for soluble neuron-derived cues. In these co-cultures, neuronal UBE3A loss increased synapse engulfment by microglia, which was reduced by TNF receptor pathway inhibition with the TNFR1 antagonist R7050 alongside decreased microglial inflammatory readouts. In vivo, juvenile AS mouse hippocampus showed early microglial dysregulation, and reanalysis of a maternal-deletion AS pig single-nucleus RNA-seq dataset revealed enrichment of microglial activation and phagosome\/lysosome pathways. Together, these findings implicate a TNF-linked neuron-to-microglia signaling axis downstream of neuronal UBE3A loss that can be pharmacologically modulated during development.","rel_num_authors":3,"rel_authors":[{"author_name":"Xin Yang","author_inst":"Brown University"},{"author_name":"Xu Zhang","author_inst":"Barshop Institute for Longevity and Aging Studies"},{"author_name":"Yu-Wen Alvin Huang","author_inst":"Brown University"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"Brain Organoids, Lessons from Fetal Neocortex Formation, and Rational Design for Quality Control","rel_doi":"10.64898\/2026.05.27.728332","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.27.728332","rel_abs":"Recent widespread adoption of cerebral organoid protocols has led to many new studies assessing the human-specific features of neural diseases. However, not all organoid studies employ proper quality control, which limits the physiological relevance of their findings. Here, we discuss the stages of in vivo neocortex formation and how those stages are recapitulated in organoid protocols. We then present the first guide for real-time operator removal of maldeveloped organoids in shaking culture. Finally, we show preliminary work on an organoid imaging and mesofluidic control platform for automated quality control of organoid development. Taken together, this approach for assessing the morphological features of organoids will improve the rigor and reproducibility of organoid studies, increase effect sizes of physiologically relevant disease etiology, and pave the way for cortical organoid GMP in high-throughput.","rel_num_authors":15,"rel_authors":[{"author_name":"Michael Q Fitzgerald","author_inst":"UC San Diego"},{"author_name":"Dennis Zhou","author_inst":"UC San Diego"},{"author_name":"Honieh Hemati","author_inst":"UC San Diego"},{"author_name":"Daniel Labelle","author_inst":"UC San Diego"},{"author_name":"Aiden Momtaz","author_inst":"UC San Diego"},{"author_name":"Erica Harris","author_inst":"UC San Diego"},{"author_name":"Shubham Patil","author_inst":"UC San Diego"},{"author_name":"Gautham Prabhakar","author_inst":"UC San Diego"},{"author_name":"Haonan Hu","author_inst":"UC San Diego"},{"author_name":"Nidhi Pareddy","author_inst":"UC San Diego"},{"author_name":"Visvesh Jegadheesh","author_inst":"UC San Diego"},{"author_name":"Jie Cui","author_inst":"UC San Diego"},{"author_name":"Alysson Muotri","author_inst":"UC San Diego"},{"author_name":"Reem Khojah","author_inst":"UC San Diego"},{"author_name":"Shankar Subramaniam","author_inst":"UC San Diego"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"Leveraging cis- and trans-variants to improve protein expression level prediction for proteome-wide association studies","rel_doi":"10.64898\/2026.05.28.728201","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.28.728201","rel_abs":"Since genetic effects are often mediated through proteins, the analysis of proteomic data can provide insights into disease etiology. However, most studies lack proteomic data. To address this problem, we developed TransCisPredict to perform proteome-wide association studies (PWAS) at a biobank scale. TransCisPredict reduces computational burden through linkage-disequilibrium block selection which facilitates incorporating cis- and trans-variants to predict protein expression and performs protein-phenotype association analyses. To account for differences in protein regulatory architecture, four prediction methods are used for weight estimation, i.e., BayesR, Elastic Net, LASSO, and SuSiE. Five-fold cross-validation (CV) is used to select the optimal method for each protein. Weight estimation was performed using White British UK Biobank study subjects (N=42,644) with proteomic and genotype array data. Of the 2,920 available protein expression levels, 2,339 could be predicted with a CV-R2>0.05 when cis- and trans-variants were used. Since most methods are limited to cis-variation, for comparison only cis-variants were used for prediction yielding 466 proteins with a CV-R2>0.05. A PWAS was performed for 2,339 predicted protein expression levels and type 2 diabetes (T2D) using White British UK Biobank study subjects without proteomic data (N=364,132) followed by two-sample Mendelian randomization using a method that controls for horizontal pleiotropy for validation. Forty proteins were associated with T2D and validated. For the 466 cis-only predicted protein expression levels, three proteins were associated with T2D and validated. Incorporating both cis- and trans-variation using TransCisPredict facilitates the prediction of many more proteins compared to using cis-only variants, thereby increasing the power of PWAS.","rel_num_authors":5,"rel_authors":[{"author_name":"Rui Dong","author_inst":"Columbia University"},{"author_name":"Derek Lamb","author_inst":"Columbia University"},{"author_name":"Gao Wang","author_inst":"Columbia University"},{"author_name":"Andrew DeWan","author_inst":"Yale University"},{"author_name":"Suzanne M Leal","author_inst":"Columbia University"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"Leveraging cis- and trans-variants to improve protein expression level prediction for proteome-wide association studies","rel_doi":"10.64898\/2026.05.28.728201","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.28.728201","rel_abs":"Since genetic effects are often mediated through proteins, the analysis of proteomic data can provide insights into disease etiology. However, most studies lack proteomic data. To address this problem, we developed TransCisPredict to perform proteome-wide association studies (PWAS) at a biobank scale. TransCisPredict reduces computational burden through linkage-disequilibrium block selection which facilitates incorporating cis- and trans-variants to predict protein expression and performs protein-phenotype association analyses. To account for differences in protein regulatory architecture, four prediction methods are used for weight estimation, i.e., BayesR, Elastic Net, LASSO, and SuSiE. Five-fold cross-validation (CV) is used to select the optimal method for each protein. Weight estimation was performed using White British UK Biobank study subjects (N=42,644) with proteomic and genotype array data. Of the 2,920 available protein expression levels, 2,339 could be predicted with a CV-R2>0.05 when cis- and trans-variants were used. Since most methods are limited to cis-variation, for comparison only cis-variants were used for prediction yielding 466 proteins with a CV-R2>0.05. A PWAS was performed for 2,339 predicted protein expression levels and type 2 diabetes (T2D) using White British UK Biobank study subjects without proteomic data (N=364,132) followed by two-sample Mendelian randomization using a method that controls for horizontal pleiotropy for validation. Forty proteins were associated with T2D and validated. For the 466 cis-only predicted protein expression levels, three proteins were associated with T2D and validated. Incorporating both cis- and trans-variation using TransCisPredict facilitates the prediction of many more proteins compared to using cis-only variants, thereby increasing the power of PWAS.","rel_num_authors":5,"rel_authors":[{"author_name":"Rui Dong","author_inst":"Columbia University"},{"author_name":"Derek Lamb","author_inst":"Columbia University"},{"author_name":"Gao Wang","author_inst":"Columbia University"},{"author_name":"Andrew DeWan","author_inst":"Yale University"},{"author_name":"Suzanne M Leal","author_inst":"Columbia University"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"Supporting-like cells constitute an alternative steroidogenic lineage conserved in amniotes","rel_doi":"10.64898\/2026.05.25.726204","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.05.25.726204","rel_abs":"In mammals, the production of sex hormones is widely considered to depend on the interstitial lineage of the gonad, which differentiates into Leydig cells in males or theca cells in females. However, certain mammalian species evidence gonadal steroidogenic activity prior to the specialization of these interstitial lineages, suggesting that alternative cell types may assume this function. Here we reveal a previously unrecognized role for supporting-like cells (SLCs), which can act as a major steroidogenic lineage during mammalian embryonic development. Through comparative single-cell transcriptomics, steroidomics and in toto organ imaging we find that in rabbits, SLCs not only contribute to the formation of gonadal rete structures, as described for other mammals, but also differentiate into a steroid-producing population. The steroidogenic program of SLCs is initially activated in both sexes but selectively maintained in ovaries, whereas in testes it is progressively replaced by that of interstitially derived Leydig cells. Evolutionary comparisons indicate that SLCs may represent an ancestral lineage that is homologous to the steroidogenic cells of non-mammalian species, which also derive from supporting precursors and share expression of cell fate regulators such as PAX2\/8 and TBX1. Altogether, our findings redefine current models of gonadal lineages, revealing an unexpected plasticity in sex differentiation and exemplifying how distinct cell types can converge on analogous functions during evolution.","rel_num_authors":16,"rel_authors":[{"author_name":"Iv\u00e1n Barber\u00e1-Aura","author_inst":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD), Consejo Superior de Investigaciones Cient\u00edficas\/Universidad Pablo de Olavide\/Junta de Andaluc\u00eda, Sevilla, Spai"},{"author_name":"Wai-Yee Chung","author_inst":"Institute of Molecular and Clinical Ophthalmology, Basel, Switzerland"},{"author_name":"Emilie Dujardin","author_inst":"Institute for Reproductive and Developmental Sciences, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, US"},{"author_name":"Alicia Hurtado","author_inst":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD), Consejo Superior de Investigaciones Cient\u00edficas\/Universidad Pablo de Olavide\/Junta de Andaluc\u00eda, Sevilla, Spai"},{"author_name":"Mathieu Galmiche","author_inst":"School of Pharmaceutical Sciences, University of Geneva, CMU, Geneva, Switzerland"},{"author_name":"Chlo\u00e9 May\u00e8re","author_inst":"Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland"},{"author_name":"Ma\u00ebva Guy","author_inst":"Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland"},{"author_name":"B\u00e9atrice Mandon-P\u00e9pin","author_inst":"Universit\u00e9 Paris-Saclay, UVSQ, INRAE, BREED, 78350, Jouy-en-Josas, France"},{"author_name":"Vedran Franke","author_inst":"Bioinformatics and Omics Data Science Platform, Max Delbruck Center for Molecular Medicine, The Berlin Institute for Molecular Systems Biology, Hannoversche Str"},{"author_name":"Yan Jaszczyszyn","author_inst":"Universit\u00e9 Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), Gif-sur-Yvette 91198, France."},{"author_name":"Rafael D. Acemel","author_inst":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD), Consejo Superior de Investigaciones Cient\u00edficas\/Universidad Pablo de Olavide\/Junta de Andaluc\u00eda, Sevilla, Spai"},{"author_name":"Serge Rudaz","author_inst":"School of Pharmaceutical Sciences, University of Geneva, CMU, Geneva, Switzerland"},{"author_name":"Jennifer Mckey","author_inst":"Section of Developmental Biology, Department of Pediatrics, University of Colorado Anschutz, Aurora, CO, USA"},{"author_name":"Serge Nef","author_inst":"Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland"},{"author_name":"Eric Pailhoux","author_inst":"Universit\u00e9 Paris-Saclay, UVSQ, INRAE, BREED, 78350, Jouy-en-Josas, France"},{"author_name":"Dar\u00edo G. Lupi\u00e1\u00f1ez","author_inst":"Centro Andaluz de Biolog\u00eda del Desarrollo (CABD), Consejo Superior de Investigaciones Cient\u00edficas\/Universidad Pablo de Olavide\/Junta de Andaluc\u00eda, Sevilla, Spai"}],"rel_date":"2026-05-28","rel_site":"biorxiv"},{"rel_title":"Data Assimilation Substitutes for Biological Complexity in Hybrid Influenza Forecasting Models","rel_doi":"10.64898\/2026.05.19.26353597","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.19.26353597","rel_abs":"Hybrid mechanistic-statistical models offer interpretability and adaptability for short-term seasonal epidemic forecasting, but it remains unclear whether their accuracy depends more on increased biological complexity or on the assimilation of richer data. Using eight retrospective influenza seasons in North Carolina, we evaluate whether training on historical data and assimilating auxiliary emergency department (ED) visit data improves four-week-ahead hospital admission forecasts more than adding biological complexity (multi-subtype structure and cross-season immunity). Hierarchical Bayesian training on historical data improves accuracy by 22.4 % (95 % CI: 16.4-28.1 %), and inclusion of ED visit data yields a further 5.3 % (95 % CI: 3.0-7.6 %) improvement, whereas added biological complexity produces diminishing or null gains. We further observe a substitution effect in which ED visit data partially compensates for omitted biological structure. We deployed a simplified model variant in the 2025-2026 CDC FluSight Challenge and ranked among the top ensemble performers, supporting the robustness of Bayesian hierarchical training in real time. Together, these findings indicate that short-term forecast accuracy is driven more by historical learning and assimilating auxiliary signals than by biological fidelity, with implications for how forecasting systems should balance mechanistic complexity.","rel_num_authors":11,"rel_authors":[{"author_name":"Tijs W Alleman","author_inst":"Cornell College of Veterinary Medicine, Johns Hopkins Bloomberg School of Public Health, Ghent University"},{"author_name":"Tim Van Wesemael","author_inst":"Ghent University"},{"author_name":"Neha Shanker","author_inst":"North Carolina Department of Health and Human Services"},{"author_name":"Matthew S Mietchen","author_inst":"University of North Carolina at Chapel Hill Gillings School of Public Health"},{"author_name":"Sara Loo","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Sore O Ajagbe","author_inst":"Cornell University"},{"author_name":"Jan M Baetens","author_inst":"Ghent University"},{"author_name":"Joseph Lemaitre","author_inst":"University of North Carolina at Chapel Hill Gillings School of Public Health"},{"author_name":"Alison L Hill","author_inst":"University of Toronto"},{"author_name":"Shaun A Truelove","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Ana I Bento","author_inst":"Cornell University College of Veterinary Medicine"}],"rel_date":"2026-05-27","rel_site":"medrxiv"},{"rel_title":"Vaginal Antisepsis for Major Gynecologic Surgeries Using Chlorhexidine Gluconate versus Povidone Iodine: A Systematic Review and Meta-Analysis","rel_doi":"10.64898\/2026.05.26.26353429","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26353429","rel_abs":"OBJECTIVEWe performed a systematic review and meta-analysis (SRMA) of post-surgical outcomes, comparing chlorhexidine gluconate (CHG) versus povidone iodine (PI) for vaginal antisepsis of major gynecologic procedures.\n\nDATA SOURCESOvid Medline, Embase, Scopus, Embase, Cochrane, and Clinicaltrials.gov were searched between 1986 and December 2023, for studies comparing CHG with PI for vaginal antisepsis of major gynecologic operations.\n\nSTUDY ELIGIBILITY CRITERIAWe included Randomized Controlled Trials (RCTs) and non-RCTs comparing CHG to PI for vaginal antisepsis of major gynecologic operations. The primary outcome was surgical site infections (SSIs) and the secondary outcome was urinary tract infections (UTIs) and vaginal irritation.\n\nMETHODSSummary estimates were calculated by fixed effects models when I2 [&le;] 25% and by random effects models when I2 > 25%. Statistical analysis was performed using RevMan 5.4.1. The protocol for this systematic review was registered on PROSPERO (ID CRD42022378101).\n\nRESULTSNine studies met the inclusion criteria, four of which were randomized controlled trials (RCTs). 9538 patients were included, 4300 (45%) of whom were allocated to CHG and 5238 (55%) to PI. No statistically significant difference in SSI incidence was found for vaginal antisepsis with CHG versus PI in pooled analyses (n= 9538 patients; RR 1.20; 95% CI 0.92-1.57; I2 =0%). In contrast, a significantly higher risk of UTIs was observed for vaginal antisepsis with CHG than with PI (n=6061 patients; RR 1.48 95% CI 1.03-2.14; I2 = 0%).\n\nCONCLUSIONIn our SRMA, there were no significant differences in SSI risk when either CHG or PI was utilized for antiseptic vaginal preparation. Interestingly, vaginal antisepsis with PI was associated with a lower incidence of post-operative UTIs following major gynecologic surgery. Our findings support current guidelines that form of vaginal antisepsis can be used for SSI prevention. They also suggest that PI may result in fewer postoperative UTIs but further randomized studies are needed to support these findings.\n\nCONDENSATION PAGEO_ST_ABSTweetable statementC_ST_ABSOur meta-analysis found that chlorhexidine gluconate and povidone iodine are both acceptable for vaginal preparation in major GYN surgery.\n\nAJOG at a Glancea) Why was this study conducted?\n\nAlthough vaginal antisepsis is recommended before major gynecologic surgeries, there is no consensus over the preferred vaginal preparation solution.\n\nb) What are the key findings?\n\nOur systematic review and meta-analysis showed that the risk of surgical site infections (SSIs) after major gynecologic surgery was similar following vaginal antisepsis with chlorhexidine gluconate (CHG) and povidone iodine (PI). However, the risk of urinary tract infections (UTIs) was significantly lower following antisepsis with PI.\n\nc) What does this study add to what is already known?\n\nOur findings support current guidelines recommending use of either form of vaginal antisepsis for major gynecologic procedures that require vaginal preparation.","rel_num_authors":5,"rel_authors":[{"author_name":"Yasmin Dias","author_inst":"University of Missouri Kansas City"},{"author_name":"Feven Gebrekidan","author_inst":"Washington University in St. Louis"},{"author_name":"Jerry Lowder","author_inst":"Washington University in St. Louis"},{"author_name":"Siobhan Sutcliffe","author_inst":"Washington University in St. Louis"},{"author_name":"Lauren Yaeger","author_inst":"Washington University in St\/ Louis"}],"rel_date":"2026-05-27","rel_site":"medrxiv"},{"rel_title":"Optical coherence tomography as a biomarker for frontotemporal dementia: a systematic review & meta-analysis","rel_doi":"10.64898\/2026.05.19.26353366","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.19.26353366","rel_abs":"Background: Frontotemporal dementia (FTD) lacks widely accessible disease-specific biomarkers. Optical coherence tomography (OCT) and OCT angiography (OCTA) may provide non-invasive measures of retinal changes associated with neurodegeneration. We conducted a systematic review and meta-analysis evaluating retinal biomarkers in FTD compared with Alzheimer disease (AD) and controls. Methods: A systematic search of PubMed and Embase was conducted through April 25, 2026 according to PRISMA guidelines. Studies evaluating OCT\/OCTA biomarkers in FTD with comparator groups were included. Inverse weighted random-effects models, publication bias assessments, and meta-regressions were performed. Results: Ten studies involving 139 individuals with FTD, 87 with AD, 29 with mild cognitive impairment, 14 with TDP-43 proteinopathy, 5 with tauopathy, and 255 controls were included in the systematic review; five studies were eligible for meta-analysis. Compared with AD, individuals with FTD demonstrated significantly thinner retinal nerve fiber layer (RNFL) thickness (SMD = -0.61, 95% CI -0.98, -0.24). Compared with controls, individuals with FTD exhibited significantly thinner ganglion cell layer-inner plexiform layer (GCL-IPL) thickness (SMD = -0.55, 95% CI -1.02, -0.08), whereas pooled analyses across multiple retinal biomarkers were non-significant (SMD = -0.19, 95% CI -0.52, 0.14). RNFL thickness correlated negatively with female % in FTD and positively with age in both AD and controls. Conclusions: Individuals with FTD exhibit lower RNFL thickness than AD and lower GCL-IPL thickness than controls, suggesting retinal alterations may reflect neurodegeneration. However, larger longitudinal studies with standardized OCT\/OCTA protocols are needed to determine the diagnostic and prognostic utility of retinal biomarkers in FTD","rel_num_authors":3,"rel_authors":[{"author_name":"Eric Wang","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Anish Kohli","author_inst":"Washington University in St. Louis"},{"author_name":"Hash Brown Taha","author_inst":"Washington University School of Medicine in St. Louis"}],"rel_date":"2026-05-27","rel_site":"medrxiv"},{"rel_title":"A Multisite, Randomized Trial Testing a Community-Digital Health Intervention among Black and Latino Adults with Cardiometabolic Conditions: The Roots of Wellness (Raices del Bienestar) Protocol","rel_doi":"10.64898\/2026.05.26.26354175","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354175","rel_abs":"BackgroundBlack and Latino adults in the United States experience a disproportionate burden of cardiometabolic conditions due to interacting behavioral, social, and structural drivers of health. Less is known about the impact of integrating digital health tools into CHW-led interventions to improve cardiometabolic health. This trial evaluates a multilevel community-digital health promotion model delivered by CHWs to improve service utilization, health behaviors and cardiometabolic health among Black and Latino adults.\n\nMethodsThis community-partnered trial uses a randomized delayed-control group with a phased recruitment design. Four cohorts (N = 664) are enrolled through three community-based organizations (CBOs). Eligible participants are [&ge;]18 years who self-identify as Black or Latino, and have prediabetes\/diabetes, hypertension, or overweight\/obesity. Participants are allocated to either (1) a multilevel intervention consisting of CBO and CHW capacity building combined with individualized CHW-led lifestyle coaching and group activities supported by digital tools, or (2) a delayed control group receiving SMS-only cardiometabolic health education. Data collected at baseline, 6, 9, and 18 months include surveys and health metrics. Qualitative data are collected from participants and community partners to assess intervention acceptability, implementation facilitators and barriers, and sustainability.\n\nResultsThe primary outcome is health service utilization at 6 and 9 months. Secondary outcomes include health behaviors, health metrics, and social determinants of health. Sustainability of health behaviors and health metrics is assessed at 18 months.\n\nConclusionsFindings will provide evidence to inform scalable, sustainable community-digital health models for CHW-supported cardiometabolic health interventions in underserved communities.\n\nTrial registrationProspectively registered at ClinicalTrials.gov (NCT06607341) on May 23, 2025.\n\nSponsor name and contactNational Institute of Health\/National Heart, Lung and Blood Institute 9000 Rockville Pike, Bethesda, Maryland 20892 Phone: (301) 402-9612; Email: kimberly.durkin@nih.gov","rel_num_authors":17,"rel_authors":[{"author_name":"Cheryl R. Himmelfarb","author_inst":"Johns Hopkins University School of Nursing"},{"author_name":"Joyline Chepkorir","author_inst":"Johns Hopkins University"},{"author_name":"Hailey Miller","author_inst":"Johns Hopkins University"},{"author_name":"Oluwabunmi Ogungbe","author_inst":"John Hopkins School of Nursing"},{"author_name":"Nancy Ann Perrin","author_inst":"Johns Hopkins University"},{"author_name":"Wuraola Olawole","author_inst":"Johns Hopkins School of Nursing"},{"author_name":"Gloria Cain","author_inst":"Howard University"},{"author_name":"Ballington L Kinlock","author_inst":"Morgan State University School of Community Health and Policy"},{"author_name":"C. Daniel Mullins","author_inst":"University of Maryland"},{"author_name":"India Kutcherman","author_inst":"Johns Hopkins School of Nursing"},{"author_name":"Patricia Barger","author_inst":"Baltimore CONNECT"},{"author_name":"Manuel Diaz-Ramirez","author_inst":"La Cl\u00ednica del Pueblo"},{"author_name":"Jhoselyn Rodriguez","author_inst":"Coaching Salud Hol\u00edstica"},{"author_name":"Rosalynn Trujillo","author_inst":"La Cl\u00ednica del Pueblo"},{"author_name":"Anna Gonz\u00e1lez-Salinas","author_inst":"The George Washington University Milken Institute School of Public Health"},{"author_name":"Roger Clark","author_inst":"Johns Hopkins Institute for Clinical and Translational Research"},{"author_name":"Elizabeth L Andrade","author_inst":"The George Washington University Milken Institute School of Public Health"}],"rel_date":"2026-05-27","rel_site":"medrxiv"},{"rel_title":"Widespread Hyperalgesia Predicts Mortality in Pancreatic Adenocarcinoma","rel_doi":"10.64898\/2026.05.19.26353594","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.19.26353594","rel_abs":"Pain in pancreatic ductal adenocarcinoma (PDAC) is associated with poor survival, but whether altered pain processing carries prognostic significance is unknown. We analyzed a prospective cohort of 143 patients with PDAC who underwent pancreatic quantitative sensory testing (PQST) after diagnosis. Patients were classified as having normal pain processing (n=84), segmental hyperalgesia (n=30), or widespread hyperalgesia (n=29). Survival was measured from the date of P-QST assessment. During follow-up, 70 deaths occurred. Widespread hyperalgesia was associated with increased mortality in unadjusted Cox analysis (HR 1.96, 95% CI 1.14,3.35) and after adjustment for age, sex, tumor stage, comorbidity, opioid treatment, and body mass index (adjusted HR 2.33, 95% CI 1.30,4.15). Segmental hyperalgesia was not associated with mortality. Kaplan Meier analysis demonstrated lower survival probability in the widespread hyperalgesia group (log rank p=0.025). These findings suggest that widespread hyperalgesia, reflecting altered central pain processing, identifies a subgroup of PDAC patients at increased risk of mortality independent of conventional clinical factors.","rel_num_authors":14,"rel_authors":[{"author_name":"Mahya Faghih","author_inst":"Johns Hopkins Medical Institutions"},{"author_name":"Marko Damm","author_inst":"University Hospital Halle"},{"author_name":"Marie-Theres Kassik","author_inst":"University Hospital Halle"},{"author_name":"Lara Cheesman","author_inst":"Johns Hopkins Medical Institutions"},{"author_name":"Sophie Rauschenberg","author_inst":"University Hospital Halle"},{"author_name":"Soren S Olesen","author_inst":"Aalborg University Hospital"},{"author_name":"Daniel A Laheru","author_inst":"Johns Hopkins Medical Institutions"},{"author_name":"Lei Zheng","author_inst":"Johns Hopkins Medical Institutions"},{"author_name":"Anna E Phillips","author_inst":"University of Pittsburgh School of Medicine"},{"author_name":"Dhiraj Yadav","author_inst":"University of Pittsburgh School of Medicine"},{"author_name":"Asbjorn M Drewes","author_inst":"Aalborg University Hospital"},{"author_name":"Jonas Rosendahl","author_inst":"University Hospital Halle"},{"author_name":"Vikesh K Singh","author_inst":"Johns Hopkins Medical Institutions"},{"author_name":"- International Pancreatic Pain Consortium","author_inst":""}],"rel_date":"2026-05-27","rel_site":"medrxiv"},{"rel_title":"A phase 1 randomized controlled trial to evaluate the safety and immunogenicity of a HIV monomeric gp120 protein B-cell lineage targeting HIV vaccine in healthy adults","rel_doi":"10.64898\/2026.05.26.26353896","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26353896","rel_abs":"Background: The isolation of many HIV broadly neutralizing antibodies (bnAbs) from people living with HIV (PLWH) and rigorous characterization of their ontogeny has promoted the goal of reverse engineering their natural development as a strategy for achieving an effective preventive HIV vaccine. We previously described the developmental process of CH103, a CD4-binding site (CD4bs)-specific monoclonal antibody, and the associated evolution of HIV Envelopes (Envs) within the person (CH505) from whom it was isolated. A series of monomeric gp120 protein subunit immunogens representing the transmitted founder (TF) and Envs that evolved during infection and optimally reacted with lineage members at each step of the CH103 clone maturation path were evaluated in this placebo controlled randomized vaccine trial to test for the first time in humans the concept of whether sequential immunization with gp120 monomeric proteins can recapitulate the development of CD4bs B-cell clonal lineages, including CH103. Methods: HIV Vaccine Trials Network 115 (HVTN 115) was a randomized placebo-controlled vaccine trial at US clinical research sites. We tested the safety and immunogenicity of CH505TF gp120 + GLA-SE (Part A), and then the ability of sequential CH505 gp120 proteins (corresponding to CH505s weeks 53 and 78 Envs) + GLA-SE immunizations to induce CD4bs-specific neutralizing antibodies (Part B). We assessed binding and neutralizing antibody responses, antibody dependent cellular cytotoxicity, antibody dependent cellular phagocytosis, T-cell responses and B-cell phenotyping. Results: We enrolled 42 participants between October 2017 and May 2018 for Part A, and 65 participants from December 2020 to October 2022 for Part B. Immunization with the CH505 gp120 proteins adjuvanted with GLA-SE was well tolerated and induced CD4bs-specific B cells and Env-specific plasma antibodies. The plasma neutralizing antibody response was limited to primarily tier 1 autologous and heterologous HIV-1 strains. Blood-derived B-cell repertoire analyses identified CD4bs antibodies that preferentially bound to open-occluded trimeric Envs that exist in an intermediate state between prefusion-closed to CD4-bound open confirmations, consistent with tier 1 HIV neutralizing activity. Conclusions: Together, these results suggest that the low-affinity CH505TF gp120 monomer elicited CD4bs antibodies in the sera and B-cell repertoires of humans. However, our findings also indicate that gp120 monomers are insufficient to induce detectable bnAb precursors to epitopes on native Env trimers. Nonetheless, our data provide a benchmark for comparison with ongoing clinical trials testing high-affinity CH505 Env trimers for induction of CD4bs bnAb precursors.","rel_num_authors":31,"rel_authors":[{"author_name":"James J Kobie","author_inst":"University of Alabama at Birmingham"},{"author_name":"Wilton B Williams","author_inst":"Duke University"},{"author_name":"William O Hahn","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Paul T Edlefsen","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Margaret Brewinski Isaacs","author_inst":"National Institute of Allergy and Infectious Diseases"},{"author_name":"Maurine D Miner","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"K Rachael Parks","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Stephen C De Rosa","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Huijun An","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Claudio Yurdadon","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Jordan Spreng","author_inst":"Duke University"},{"author_name":"Jongln Hwang","author_inst":"Duke University"},{"author_name":"Matthew Clark","author_inst":"Duke University"},{"author_name":"Vaibhav Jain","author_inst":"Duke University"},{"author_name":"Simon G Gregory","author_inst":"Duke University"},{"author_name":"Madison Berry","author_inst":"Duke University"},{"author_name":"Kevin Wiehe","author_inst":"Duke University"},{"author_name":"Paul A Geopfert","author_inst":"University of Alabama at Birmingham"},{"author_name":"Hong-Van Tieu","author_inst":"Columbia University"},{"author_name":"Michael C Keefer","author_inst":"University of Rochester"},{"author_name":"Lindsey R Baden","author_inst":"Brigham & Women's Hospital"},{"author_name":"Spyros Kalams","author_inst":"Vanderbilt University"},{"author_name":"Cecilia Morgan","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"David C Montefiori","author_inst":"Duke University"},{"author_name":"Guido Ferrari","author_inst":"Duke University"},{"author_name":"Stephanie Regenold","author_inst":"National Institute of Allergy and Infectious Diseases"},{"author_name":"Georgia D Tomaras","author_inst":"Duke University"},{"author_name":"M Juliana McElrath","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Lawrence Corey","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Magdalena E Sobieszczyk","author_inst":"Columbia University"},{"author_name":"Barton F Haynes","author_inst":"Duke University"}],"rel_date":"2026-05-27","rel_site":"medrxiv"},{"rel_title":"A phase 1 randomized controlled trial to evaluate the safety and immunogenicity of a HIV monomeric gp120 protein B-cell lineage targeting HIV vaccine in healthy adults","rel_doi":"10.64898\/2026.05.26.26353896","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26353896","rel_abs":"Background: The isolation of many HIV broadly neutralizing antibodies (bnAbs) from people living with HIV (PLWH) and rigorous characterization of their ontogeny has promoted the goal of reverse engineering their natural development as a strategy for achieving an effective preventive HIV vaccine. We previously described the developmental process of CH103, a CD4-binding site (CD4bs)-specific monoclonal antibody, and the associated evolution of HIV Envelopes (Envs) within the person (CH505) from whom it was isolated. A series of monomeric gp120 protein subunit immunogens representing the transmitted founder (TF) and Envs that evolved during infection and optimally reacted with lineage members at each step of the CH103 clone maturation path were evaluated in this placebo controlled randomized vaccine trial to test for the first time in humans the concept of whether sequential immunization with gp120 monomeric proteins can recapitulate the development of CD4bs B-cell clonal lineages, including CH103. Methods: HIV Vaccine Trials Network 115 (HVTN 115) was a randomized placebo-controlled vaccine trial at US clinical research sites. We tested the safety and immunogenicity of CH505TF gp120 + GLA-SE (Part A), and then the ability of sequential CH505 gp120 proteins (corresponding to CH505s weeks 53 and 78 Envs) + GLA-SE immunizations to induce CD4bs-specific neutralizing antibodies (Part B). We assessed binding and neutralizing antibody responses, antibody dependent cellular cytotoxicity, antibody dependent cellular phagocytosis, T-cell responses and B-cell phenotyping. Results: We enrolled 42 participants between October 2017 and May 2018 for Part A, and 65 participants from December 2020 to October 2022 for Part B. Immunization with the CH505 gp120 proteins adjuvanted with GLA-SE was well tolerated and induced CD4bs-specific B cells and Env-specific plasma antibodies. The plasma neutralizing antibody response was limited to primarily tier 1 autologous and heterologous HIV-1 strains. Blood-derived B-cell repertoire analyses identified CD4bs antibodies that preferentially bound to open-occluded trimeric Envs that exist in an intermediate state between prefusion-closed to CD4-bound open confirmations, consistent with tier 1 HIV neutralizing activity. Conclusions: Together, these results suggest that the low-affinity CH505TF gp120 monomer elicited CD4bs antibodies in the sera and B-cell repertoires of humans. However, our findings also indicate that gp120 monomers are insufficient to induce detectable bnAb precursors to epitopes on native Env trimers. Nonetheless, our data provide a benchmark for comparison with ongoing clinical trials testing high-affinity CH505 Env trimers for induction of CD4bs bnAb precursors.","rel_num_authors":31,"rel_authors":[{"author_name":"James J Kobie","author_inst":"University of Alabama at Birmingham"},{"author_name":"Wilton B Williams","author_inst":"Duke University"},{"author_name":"William O Hahn","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Paul T Edlefsen","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Margaret Brewinski Isaacs","author_inst":"National Institute of Allergy and Infectious Diseases"},{"author_name":"Maurine D Miner","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"K Rachael Parks","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Stephen C De Rosa","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Huijun An","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Claudio Yurdadon","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Jordan Spreng","author_inst":"Duke University"},{"author_name":"Jongln Hwang","author_inst":"Duke University"},{"author_name":"Matthew Clark","author_inst":"Duke University"},{"author_name":"Vaibhav Jain","author_inst":"Duke University"},{"author_name":"Simon G Gregory","author_inst":"Duke University"},{"author_name":"Madison Berry","author_inst":"Duke University"},{"author_name":"Kevin Wiehe","author_inst":"Duke University"},{"author_name":"Paul A Geopfert","author_inst":"University of Alabama at Birmingham"},{"author_name":"Hong-Van Tieu","author_inst":"Columbia University"},{"author_name":"Michael C Keefer","author_inst":"University of Rochester"},{"author_name":"Lindsey R Baden","author_inst":"Brigham & Women's Hospital"},{"author_name":"Spyros Kalams","author_inst":"Vanderbilt University"},{"author_name":"Cecilia Morgan","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"David C Montefiori","author_inst":"Duke University"},{"author_name":"Guido Ferrari","author_inst":"Duke University"},{"author_name":"Stephanie Regenold","author_inst":"National Institute of Allergy and Infectious Diseases"},{"author_name":"Georgia D Tomaras","author_inst":"Duke University"},{"author_name":"M Juliana McElrath","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Lawrence Corey","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Magdalena E Sobieszczyk","author_inst":"Columbia University"},{"author_name":"Barton F Haynes","author_inst":"Duke University"}],"rel_date":"2026-05-27","rel_site":"medrxiv"},{"rel_title":"A phase 1 randomized controlled trial to evaluate the safety and immunogenicity of a HIV monomeric gp120 protein B-cell lineage targeting HIV vaccine in healthy adults","rel_doi":"10.64898\/2026.05.26.26353896","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26353896","rel_abs":"Background: The isolation of many HIV broadly neutralizing antibodies (bnAbs) from people living with HIV (PLWH) and rigorous characterization of their ontogeny has promoted the goal of reverse engineering their natural development as a strategy for achieving an effective preventive HIV vaccine. We previously described the developmental process of CH103, a CD4-binding site (CD4bs)-specific monoclonal antibody, and the associated evolution of HIV Envelopes (Envs) within the person (CH505) from whom it was isolated. A series of monomeric gp120 protein subunit immunogens representing the transmitted founder (TF) and Envs that evolved during infection and optimally reacted with lineage members at each step of the CH103 clone maturation path were evaluated in this placebo controlled randomized vaccine trial to test for the first time in humans the concept of whether sequential immunization with gp120 monomeric proteins can recapitulate the development of CD4bs B-cell clonal lineages, including CH103. Methods: HIV Vaccine Trials Network 115 (HVTN 115) was a randomized placebo-controlled vaccine trial at US clinical research sites. We tested the safety and immunogenicity of CH505TF gp120 + GLA-SE (Part A), and then the ability of sequential CH505 gp120 proteins (corresponding to CH505s weeks 53 and 78 Envs) + GLA-SE immunizations to induce CD4bs-specific neutralizing antibodies (Part B). We assessed binding and neutralizing antibody responses, antibody dependent cellular cytotoxicity, antibody dependent cellular phagocytosis, T-cell responses and B-cell phenotyping. Results: We enrolled 42 participants between October 2017 and May 2018 for Part A, and 65 participants from December 2020 to October 2022 for Part B. Immunization with the CH505 gp120 proteins adjuvanted with GLA-SE was well tolerated and induced CD4bs-specific B cells and Env-specific plasma antibodies. The plasma neutralizing antibody response was limited to primarily tier 1 autologous and heterologous HIV-1 strains. Blood-derived B-cell repertoire analyses identified CD4bs antibodies that preferentially bound to open-occluded trimeric Envs that exist in an intermediate state between prefusion-closed to CD4-bound open confirmations, consistent with tier 1 HIV neutralizing activity. Conclusions: Together, these results suggest that the low-affinity CH505TF gp120 monomer elicited CD4bs antibodies in the sera and B-cell repertoires of humans. However, our findings also indicate that gp120 monomers are insufficient to induce detectable bnAb precursors to epitopes on native Env trimers. Nonetheless, our data provide a benchmark for comparison with ongoing clinical trials testing high-affinity CH505 Env trimers for induction of CD4bs bnAb precursors.","rel_num_authors":31,"rel_authors":[{"author_name":"James J Kobie","author_inst":"University of Alabama at Birmingham"},{"author_name":"Wilton B Williams","author_inst":"Duke University"},{"author_name":"William O Hahn","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Paul T Edlefsen","author_inst":"Fred Hutch Cancer Center"},{"author_name":"Margaret Brewinski Isaacs","author_inst":"National Institute of Allergy and Infectious Diseases"},{"author_name":"Maurine D Miner","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"K Rachael Parks","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Stephen C De Rosa","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Huijun An","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Claudio Yurdadon","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Jordan Spreng","author_inst":"Duke University"},{"author_name":"Jongln Hwang","author_inst":"Duke University"},{"author_name":"Matthew Clark","author_inst":"Duke University"},{"author_name":"Vaibhav Jain","author_inst":"Duke University"},{"author_name":"Simon G Gregory","author_inst":"Duke University"},{"author_name":"Madison Berry","author_inst":"Duke University"},{"author_name":"Kevin Wiehe","author_inst":"Duke University"},{"author_name":"Paul A Geopfert","author_inst":"University of Alabama at Birmingham"},{"author_name":"Hong-Van Tieu","author_inst":"Columbia University"},{"author_name":"Michael C Keefer","author_inst":"University of Rochester"},{"author_name":"Lindsey R Baden","author_inst":"Brigham & Women's Hospital"},{"author_name":"Spyros Kalams","author_inst":"Vanderbilt University"},{"author_name":"Cecilia Morgan","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"David C Montefiori","author_inst":"Duke University"},{"author_name":"Guido Ferrari","author_inst":"Duke University"},{"author_name":"Stephanie Regenold","author_inst":"National Institute of Allergy and Infectious Diseases"},{"author_name":"Georgia D Tomaras","author_inst":"Duke University"},{"author_name":"M Juliana McElrath","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Lawrence Corey","author_inst":"Fred Hutchinson Cancer Center"},{"author_name":"Magdalena E Sobieszczyk","author_inst":"Columbia University"},{"author_name":"Barton F Haynes","author_inst":"Duke University"}],"rel_date":"2026-05-27","rel_site":"medrxiv"},{"rel_title":"Translational bioinformatics and machine learning framework for biomarker discovery, disease prediction, and patient profiling for precision medicine","rel_doi":"10.64898\/2026.05.23.26353961","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.23.26353961","rel_abs":"Precision medicine aims to advance our ability from a \"one-size-fits-all\" approach to personalized and predictive healthcare across diverse populations. It promotes integration of multi-omics and phenotypic data to understand disease mechanisms and discover novel biomarkers and risk factors, which could be used to predict and prevent critical diseases in individual patients across diverse populations. The potential implications of precision medicine approach can accelerate our ability to classify patients at higher risk of developing critical diseases, improve diagnostic capabilities, develop deeper understanding of individual risk, investigate racial differences and demographic characteristics, and find relationships between genetic variants, expressions, and diseases. This study focuses on implementing an innovative and data driven framework of translational bioinformatics and Machine Learning (ML) techniques to analyze multi-omics, including RNA-seq and Whole-Genome Sequencing (WGS) data, generated using blood samples of randomly consented patients. First, we utilized bioinformatics pipelines to identify differentially expressed genes and their pathogenic and likely pathogenic variants for the downstream data analysis, annotation, and visualization. Then, applied a nexus of ML models for multi-omics biomarker discovery, disease prediction, density-based clustering, single-patient profiling, and pathogenicity classification. WGS data analysis supported the exploration of genetic variation and diversity among patients to identify known and novel biomarkers, whereas RNA-seq data analysis improved our understanding of functional and biological pathways that underlying disease states. We classified and clustered pathogenic variants and expressions across various genes and discovered numerous diseases leading risk factors. Our results include gene-disease associations and captured common pathways across the broader population, demonstrating a level of sensitivity and accuracy that has broad clinical implications. We validated our results through clinical records, and state of the science literature. This study delves into the strengths of multi-omics data integration and capabilities of ML application in genetically diverse and complex patient cohorts. Our approach has the potential to elucidate complex gene-disease interactions for genetically diverse populations, which can support earlier diagnoses for patients in many disease realms.","rel_num_authors":6,"rel_authors":[{"author_name":"Zeeshan Ahmed","author_inst":"Department of Medicine, Robert Wood Johnson Medical School. Rutgers Institute for Health, Health Care Policy and Aging Research."},{"author_name":"Prithvi Govindareddy","author_inst":"Rutgers Institute for Health, Health Care Policy and Aging Research"},{"author_name":"William DeGroat","author_inst":"Rutgers Institute for Health, Health Care Policy and Aging Research."},{"author_name":"Rishabh Narayanan","author_inst":"Rutgers Institute for Health, Health Care Policy and Aging Research"},{"author_name":"Elizabeth Peker","author_inst":"Rutgers Institute for Health, Health Care Policy and Aging Research"},{"author_name":"Saman Zeeshan","author_inst":"Department of Biomedical and Health Informatics, UMKC School of Medicine"}],"rel_date":"2026-05-27","rel_site":"medrxiv"},{"rel_title":"The Global Pediatric Diarrhea Surveillance network: Rationale and methods","rel_doi":"10.64898\/2026.05.21.26352576","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.21.26352576","rel_abs":"BackgroundDiarrhea remains a leading cause of child morbidity and mortality worldwide. Improved and ongoing estimates of the etiologies of severe diarrhea, particularly in low- and middle-income countries (LMICs), are crucial to inform the use of current vaccines and other interventions and to help prioritize the development of new vaccines. Producing rigorous longitudinal data on the global burden and etiology of pediatric diarrhea requires a geographically broad surveillance network with standardized epidemiologic, laboratory, and analytic protocols.\n\nMethodsWe describe the rationale and methods of the Global Pediatric Diarrhea Surveillance (GPDS) network, a World Health Organization (WHO)-coordinated public health surveillance network investigating the etiology of hospitalized diarrhea among children aged <5 years in LMICs. The GPDS network enrolls children hospitalized with diarrhea at 38 sentinel surveillance sites in 31 LMICs across all 6 WHO Regions. Randomly selected stool specimens were tested by TaqMan Array Card quantitative polymerase chain reaction for 16 enteric pathogens previously associated with pediatric diarrhea. GPDS produces estimates of pathogen-specific attributable fractions and incidence of diarrheal hospitalizations at the global, regional, and country levels.\n\nConclusionsAs a WHO-coordinated global surveillance network, GPDS evaluates pathogens associated with hospitalized pediatric diarrhea. The network monitors the changing burden of pathogens over time, monitors circulating strains, and generates data to inform decision-making around public health interventions. GPDS also improves global, regional, and country diarrheal disease burden estimates, informs new enteric vaccine development, and potentially provides a platform for future enteric vaccine evaluation.","rel_num_authors":42,"rel_authors":[{"author_name":"Heidi  M. Soeters","author_inst":"Independent Researcher"},{"author_name":"S\u00e9bastien Antoni","author_inst":"World Health Organization"},{"author_name":"Shilpa  S Iyer","author_inst":"World Health Organization"},{"author_name":"Goitom Weldegebriel","author_inst":"World Health Organization Regional Office for Africa: Organisation mondiale de la Sante pour Afrique"},{"author_name":"Joseph Biey","author_inst":"World Health Organization Regional Office for Africa: Organisation mondiale de la Sante pour Afrique"},{"author_name":"Jason  M Mwenda","author_inst":"World Health Organization Regional Office for Africa: Organisation mondiale de la Sante pour Afrique"},{"author_name":"Gloria Rey-Benito","author_inst":"Pan American Health Organization"},{"author_name":"Claudia Ortiz","author_inst":"Pan American Health Organization"},{"author_name":"Roberta Pastore","author_inst":"World Health Organization Regional Office for Europe"},{"author_name":"Dovile Videbaek","author_inst":"World Health Organization Regional Office for Europe"},{"author_name":"Simarjit Singh","author_inst":"World Health Organization Regional Office for Europe"},{"author_name":"Emmanuel Njambe","author_inst":"World Health Organization Regional Office for South-East Asia"},{"author_name":"Lucky Sangal","author_inst":"World Health Organization Regional Office for South-East Asia"},{"author_name":"Deepak Dhongde","author_inst":"World Health Organization Regional Office for South-East Asia"},{"author_name":"Varja Grabovac","author_inst":"World Health Organization Regional Office for the Western Pacific"},{"author_name":"Josephine Logronio","author_inst":"World Health Organization Regional Office for the Western Pacific"},{"author_name":"Kamal Fahmy","author_inst":"World Health Organisation Regional Office for the Eastern Mediterranean"},{"author_name":"Amany Ghoniem","author_inst":"World Health Organisation Regional Office for the Eastern Mediterranean"},{"author_name":"George Armah","author_inst":"University of Ghana College of Health Sciences"},{"author_name":"Francis  E Dennis","author_inst":"University of Ghana College of Health Sciences"},{"author_name":"Mapaseka  L Seheri","author_inst":"Sefako Makgatho Health Sciences University"},{"author_name":"Nonkululeko Magagula","author_inst":"Sefako Makgatho Health Sciences University"},{"author_name":"Kebareng Rakau-Nondela","author_inst":"Sefako Makgatho Health Sciences University"},{"author_name":"Tulio  M Fumian","author_inst":"Instituto Oswaldo Cruz"},{"author_name":"Irene  T.A. Maciel","author_inst":"Instituto Oswaldo Cruz"},{"author_name":"Elena Samoilovich","author_inst":"Ministry of Health"},{"author_name":"Galina Semeiko","author_inst":"Ministry of Health"},{"author_name":"Tintu Varghese","author_inst":"Christian Medical College Vellore"},{"author_name":"Sarah Thomas","author_inst":"Murdoch Children's Research Institute"},{"author_name":"Julie Bines","author_inst":"Murdoch Children's Research Institute"},{"author_name":"Dandi Li","author_inst":"Chinese Center for Disease Control and Prevention"},{"author_name":"Furqan Kabir","author_inst":"Aga Khan University"},{"author_name":"Jie Liu","author_inst":"University of Virginia"},{"author_name":"Eric  R Houpt","author_inst":"University of Virginia"},{"author_name":"Rashi Gautam","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Sara  A Mirza","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Jan Vinj\u00e9","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Mick  N Mulders","author_inst":"World Health Organization"},{"author_name":"Jacqueline  E Tate","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"Umesh  D Parashar","author_inst":"Centers for Disease Control and Prevention"},{"author_name":"James  A Platts-Mills","author_inst":"University of Virginia"},{"author_name":"- Global Pediatric Diarrhea Surveillance network","author_inst":"-"}],"rel_date":"2026-05-27","rel_site":"medrxiv"},{"rel_title":"Genome-wide discovery reveals 30 loci for choroidal thickness and uncovers potential causal links with angle-closure glaucoma","rel_doi":"10.64898\/2026.05.26.26354075","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354075","rel_abs":"The choroid is critical for maintaining vision and implicated in several ocular diseases, being the sole source of nutrients and waste removal for the outer retina. Genetic discovery can help elucidate the pathways through which choroidal features influence disease risk. Our meta-analysis of genome-wide association studies (n= 78,682 participants) identified 30 genomic regions, including 20 novel loci, associated with choroidal thickness. Findings suggest inflammatory and vascular processes drive choroidal thickness, with overlapping mechanisms shared with refractive error. Genome-wide independently significant SNPs accounted for 18.7% of the genetic variance in choroidal thickness. Mendelian randomisation analyses showed a causal effect of age-related macular degeneration on choroidal thickness, and suggest a bidirectional causal effect between choroidal thickness and primary angle-closure glaucoma. These findings provide insight into the shared genetic architecture and biological pathways linking choroidal thickness and related diseases.","rel_num_authors":34,"rel_authors":[{"author_name":"Samantha Sze-Yee Lee","author_inst":"Lions Eye Institute"},{"author_name":"Carol A Wang","author_inst":"University of Newcastle"},{"author_name":"Victor A de Vries","author_inst":"Erasmus MC"},{"author_name":"Dirk J van Hemert","author_inst":"Erasmus MC"},{"author_name":"Alicia Schulze","author_inst":"University Medical Center of the Johannes Gutenberg-University of Mainz"},{"author_name":"Caroline Brandl","author_inst":"University of Regensburg"},{"author_name":"Asma M Aman","author_inst":"QIMR Berghofer"},{"author_name":"David Alonso-Caneiro","author_inst":"Queensland University of Technology"},{"author_name":"Helene Choquet","author_inst":"Kaiser Permanente"},{"author_name":"Mathias Gorski","author_inst":"University of Regensburg"},{"author_name":"Christopher J Hammond","author_inst":"Kings College London"},{"author_name":"Iris M Heid","author_inst":"University of Regensburg"},{"author_name":"Michael L Hunter","author_inst":"University of Western Australia"},{"author_name":"Pirro Hysi","author_inst":"Kings College London"},{"author_name":"Chen Jiang","author_inst":"Kaiser Permanente"},{"author_name":"Jost B Jonas","author_inst":"Rothschild Foundation Hospital"},{"author_name":"Caroline CW Klaver","author_inst":"Erasmus MC"},{"author_name":"Sander Kneepkens","author_inst":"Erasmus MC"},{"author_name":"Simon C Koenig","author_inst":"University Medical Center of the Johannes Gutenberg-University Mainz"},{"author_name":"Gareth Lingham","author_inst":"Lions Eye Institute"},{"author_name":"Christian Luber","author_inst":"University of Regensburg"},{"author_name":"Philip E Melton","author_inst":"University of Western Australia"},{"author_name":"Craig E Pennell","author_inst":"University of Newcastle"},{"author_name":"Wishal D Ramdas","author_inst":"Erasmus MC"},{"author_name":"Scott A Read","author_inst":"Queensland University of Technology"},{"author_name":"Alexander K Schuster","author_inst":"University Medical Center of the Johannes Gutenberg-University of Mainz"},{"author_name":"Ya Xing Wang","author_inst":"Tsinghua University"},{"author_name":"Martina E Zimmermann","author_inst":"University of Regensburg"},{"author_name":"- International Glaucoma Genetics Consortium","author_inst":""},{"author_name":"Anthony P Khawaja","author_inst":"Moorfields Eye Hospital"},{"author_name":"Puya Gharahkhani","author_inst":"QIMR Berghofer"},{"author_name":"Stuart MacGregor","author_inst":"QIMR Berghofer"},{"author_name":"Jeremy A Guggenheim","author_inst":"Cardiff University"},{"author_name":"David A Mackey","author_inst":"Lions Eye Institute"}],"rel_date":"2026-05-27","rel_site":"medrxiv"},{"rel_title":"Gray Matter Morphological Networks are Associated with Neurobiological Features, Cognitive Status and Clinical Recovery in Traumatic Brain Injury","rel_doi":"10.64898\/2026.05.25.26354074","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.25.26354074","rel_abs":"Generalizable neuroimaging biomarkers that detect cerebral cortical changes after traumatic brain injury (TBI) and predict patient outcomes are needed to improve care and to develop targeted therapies. We used morphometric inverse divergence (MIND) analysis of structural MRI to investigate cortical gray matter morphological networks cross-sectionally and longitudinally after TBI and correlate these with symptoms, disability and cognition six months after injury. Our findings support the Triple Network Model from functional MRI of post-traumatic alterations in the relationship between task-positive, default mode and salience networks. However, the strongest associations between early cortical similarity metrics and long-term patient outcomes involved the dorsal attention network and the limbic network as well as similarity metrics across Mesulams hierarchy of laminar differentiation. Since MIND mapping of cortical gray matter networks only requires data that is a routine part of standard clinical MRI protocols and does not need image harmonization across different scanners, this work reports a promising new tool that is immediately available for advancing research and clinical care in TBI.","rel_num_authors":19,"rel_authors":[{"author_name":"Amir Sadikov","author_inst":"University of California, San Francisco"},{"author_name":"Lanya T. Cai","author_inst":"Department of Radiology & Biomedical Imaging, UCSF, San Francisco, CA, USA"},{"author_name":"Jaclyn Xiao","author_inst":"Department of Radiology & Biomedical Imaging, UCSF, San Francisco, CA, USA"},{"author_name":"Esther L. Yuh","author_inst":"Department of Radiology & Biomedical Imaging, UCSF, San Francisco, CA, USA; Brain and Spinal Cord Injury Center, Zuckerberg San Francisco General Hospital and T"},{"author_name":"Hannah L. Choi","author_inst":"Department of Radiology & Biomedical Imaging, UCSF, San Francisco, CA, USA"},{"author_name":"Xiaoying Sun","author_inst":"Biostatistics Research Center, Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Christine L. Mac Donald","author_inst":"Department of Neurological Surgery, University of Washington, Seattle, WA, USA"},{"author_name":"Mary J. Vassar","author_inst":"Brain and Spinal Cord Injury Center, Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, CA, USA; Department of Neurological Surgery, UC"},{"author_name":"Ramon Diaz-Arrastia","author_inst":"Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Joseph T. Giacino","author_inst":"Department of Physical Medicine & Rehabilitation, Spaulding Rehabilitation Hospital, Charlestown, MA, USA; Department of Physical Medicine & Rehabilitation, Har"},{"author_name":"David O. Okonkwo","author_inst":"Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA"},{"author_name":"Claudia S. Robertson","author_inst":"Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Murray B. Stein","author_inst":"Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Nancy Temkin","author_inst":"Department of Neurological Surgery, University of Washington, Seattle, WA, USA; Department of Biostatistics, University of Washington, Seattle, WA, USA"},{"author_name":"Michael A. McCrea","author_inst":"Departments of Neurosurgery and Neurology, Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Sonia Jain","author_inst":"Biostatistics Research Center, Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Geoffrey T. Manley","author_inst":"Brain and Spinal Cord Injury Center, Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, CA, USA; Department of Neurological Surgery, UC"},{"author_name":"Pratik Mukherjee","author_inst":"Department of Radiology & Biomedical Imaging, UCSF, San Francisco, CA, USA; Brain and Spinal Cord Injury Center, Zuckerberg San Francisco General Hospital and T"},{"author_name":"- TRACK-TBI Investigators","author_inst":"TRACK-TBI Investigators"}],"rel_date":"2026-05-27","rel_site":"medrxiv"},{"rel_title":"Gray Matter Morphological Networks are Associated with Neurobiological Features, Cognitive Status and Clinical Recovery in Traumatic Brain Injury","rel_doi":"10.64898\/2026.05.25.26354074","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.25.26354074","rel_abs":"Generalizable neuroimaging biomarkers that detect cerebral cortical changes after traumatic brain injury (TBI) and predict patient outcomes are needed to improve care and to develop targeted therapies. We used morphometric inverse divergence (MIND) analysis of structural MRI to investigate cortical gray matter morphological networks cross-sectionally and longitudinally after TBI and correlate these with symptoms, disability and cognition six months after injury. Our findings support the Triple Network Model from functional MRI of post-traumatic alterations in the relationship between task-positive, default mode and salience networks. However, the strongest associations between early cortical similarity metrics and long-term patient outcomes involved the dorsal attention network and the limbic network as well as similarity metrics across Mesulams hierarchy of laminar differentiation. Since MIND mapping of cortical gray matter networks only requires data that is a routine part of standard clinical MRI protocols and does not need image harmonization across different scanners, this work reports a promising new tool that is immediately available for advancing research and clinical care in TBI.","rel_num_authors":19,"rel_authors":[{"author_name":"Amir Sadikov","author_inst":"University of California, San Francisco"},{"author_name":"Lanya T. Cai","author_inst":"Department of Radiology & Biomedical Imaging, UCSF, San Francisco, CA, USA"},{"author_name":"Jaclyn Xiao","author_inst":"Department of Radiology & Biomedical Imaging, UCSF, San Francisco, CA, USA"},{"author_name":"Esther L. Yuh","author_inst":"Department of Radiology & Biomedical Imaging, UCSF, San Francisco, CA, USA; Brain and Spinal Cord Injury Center, Zuckerberg San Francisco General Hospital and T"},{"author_name":"Hannah L. Choi","author_inst":"Department of Radiology & Biomedical Imaging, UCSF, San Francisco, CA, USA"},{"author_name":"Xiaoying Sun","author_inst":"Biostatistics Research Center, Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Christine L. Mac Donald","author_inst":"Department of Neurological Surgery, University of Washington, Seattle, WA, USA"},{"author_name":"Mary J. Vassar","author_inst":"Brain and Spinal Cord Injury Center, Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, CA, USA; Department of Neurological Surgery, UC"},{"author_name":"Ramon Diaz-Arrastia","author_inst":"Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA"},{"author_name":"Joseph T. Giacino","author_inst":"Department of Physical Medicine & Rehabilitation, Spaulding Rehabilitation Hospital, Charlestown, MA, USA; Department of Physical Medicine & Rehabilitation, Har"},{"author_name":"David O. Okonkwo","author_inst":"Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA"},{"author_name":"Claudia S. Robertson","author_inst":"Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA"},{"author_name":"Murray B. Stein","author_inst":"Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Nancy Temkin","author_inst":"Department of Neurological Surgery, University of Washington, Seattle, WA, USA; Department of Biostatistics, University of Washington, Seattle, WA, USA"},{"author_name":"Michael A. McCrea","author_inst":"Departments of Neurosurgery and Neurology, Medical College of Wisconsin, Milwaukee, WI, USA"},{"author_name":"Sonia Jain","author_inst":"Biostatistics Research Center, Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, La Jolla, CA, USA"},{"author_name":"Geoffrey T. Manley","author_inst":"Brain and Spinal Cord Injury Center, Zuckerberg San Francisco General Hospital and Trauma Center, San Francisco, CA, USA; Department of Neurological Surgery, UC"},{"author_name":"Pratik Mukherjee","author_inst":"Department of Radiology & Biomedical Imaging, UCSF, San Francisco, CA, USA; Brain and Spinal Cord Injury Center, Zuckerberg San Francisco General Hospital and T"},{"author_name":"- TRACK-TBI Investigators","author_inst":"TRACK-TBI Investigators"}],"rel_date":"2026-05-27","rel_site":"medrxiv"},{"rel_title":"High-resolution Orbitofrontal Cortex Morphometry and Cannabis Use Disorder Severity in High-risk Emerging Adults: A Preliminary Study","rel_doi":"10.64898\/2026.05.26.26354113","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354113","rel_abs":"BackgroundCannabis use is highly prevalent among emerging adults (18-25 years), a developmental period marked by ongoing neurodevelopment and heightened risk for cannabis use disorder (CUD). Structural alterations in the orbitofrontal cortex (OFC) and medial prefrontal\/anterior cingulate cortex (mPFC\/ACC) have been linked to cannabis use, though findings remain inconsistent in directionality. To address this, we examined cortical thickness and surface area of the OFC and mPFC\/ACC subregions using the high-resolution Glasser atlas, allowing for more granular characterization of associations with CUD severity.\n\nMethodOne hundred eleven emerging adults (41% male, aged=20.6{+\/-}1.1 years) reporting significant alcohol and\/or cannabis use completed clinical assessments and structural MRI. The OFC and mPFC\/ACC were segmented into seven and six subregions per hemisphere, respectively. Multiple linear regressions tested associations between cortical thickness or surface area and DSM-5 CUD symptom count, controlling for alcohol use and intracranial volume. Subregions surviving false discovery rate correction were examined in relation to depression, trauma-related symptoms, impulsivity, and cannabis use motives.\n\nResultsGreater CUD severity was associated with lower cortical surface area and greater cortical thickness in OFC and mPFC\/ACC subregions. Lower OFC surface area was correlated with coping- and enhancement-related cannabis use motives. Lower mPFC\/ACC surface area and greater thickness were associated with more severe depression, trauma-related symptoms, and impulsivity.\n\nConclusionIn high-risk emerging adults, greater CUD symptom burden is associated with lower surface area and greater thickness in OFC and mPFC\/ACC subregions. Using the high-resolution Glasser atlas, these findings provide a more precise characterization of structural correlates of CUD and highlight potential neurobiological markers linked to affective and motivational processes underlying cannabis use.","rel_num_authors":11,"rel_authors":[{"author_name":"Tegan L. Hargreaves","author_inst":"McMaster University"},{"author_name":"Carly McIntyre-Wood","author_inst":"McMaster University"},{"author_name":"Mahmoud Elsayed","author_inst":"McMaster University"},{"author_name":"Emily Vandehei","author_inst":"St. Joseph's Healthcare Hamilton"},{"author_name":"Kyla L. Belisario","author_inst":"McMaster University"},{"author_name":"Laura Lee","author_inst":"St.Joseph's Healthcare Hamilton"},{"author_name":"Ashley Blakely","author_inst":"St. Joseph's Healthcare Hamilton"},{"author_name":"Jillian L. Halladay","author_inst":"McMaster University"},{"author_name":"Michael Amlung","author_inst":"University of Kansas"},{"author_name":"Lawrence H. Sweet","author_inst":"University of Georgia"},{"author_name":"James MacKillop","author_inst":"McMaster University"}],"rel_date":"2026-05-27","rel_site":"medrxiv"},{"rel_title":"HIV Transmission Dynamics in Greater Mexico City are Shaped by Dense Spatial Mixing","rel_doi":"10.64898\/2026.05.26.26354122","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354122","rel_abs":"Understanding HIV transmission in densely populated urban settings is essential to mitigate ongoing epidemic spread. We present a comprehensive analysis of recent HIV transmission dynamics in Greater Mexico City, one of the worlds largest metropolitan areas comprising Mexico City and neighbouring municipalities of the State of Mexico. Drawing from over 7,000 complete pol gene sequences representing around 50% of new cases reported between 2019 and 2022 within the study region, we reconstructed the transmission network based on pairwise genetic distance. We identified ten large transmission clusters exhibiting sustained growth up to the most recent sampling period. We further analysed paired genetic and high-resolution human mobility data using an integrated phylogeographic approach. We observed a heterogeneous pattern of viral spread across the region, supported by an extensive mixing at a wider geographic scale. Across Greater Mexico City, displaying a high population density, HIV transmission is minimally spatially constrained, a pattern likely fuelled by intense human mobility. Thus, population movement weakens isolation by distance in large urban areas even for a chronic infection that is sexually and vertically transmitted. We demonstrate the value of integrating large-scale genetic, epidemiological, and mobility data to resolve contemporary HIV transmission dynamics in densely populated urban settings.","rel_num_authors":32,"rel_authors":[{"author_name":"Marina Escalera","author_inst":"UCL"},{"author_name":"Eduardo Lopez Ortiz","author_inst":"CIENI-INER \/ UNAM"},{"author_name":"Claudia Garcia Morales","author_inst":"CIENI-INER"},{"author_name":"Erika Cruz-Bonilla","author_inst":"CINVESTAV"},{"author_name":"Shaday Guerrero Flores","author_inst":"CCM-UNAM"},{"author_name":"Steven Weaver","author_inst":"Temple University \/ UCSD"},{"author_name":"Margarita Matias Florentino","author_inst":"CIENI-INER"},{"author_name":"Daniela Tapia Trejo","author_inst":"CIENI-INER"},{"author_name":"Vanessa Davila Conn","author_inst":"CIENI-INER \/ SDSU"},{"author_name":"- Roberto Cardenas Porras","author_inst":"CIENI-INER"},{"author_name":"- Eduardo Zarza Sanchez","author_inst":"CIENI-INER"},{"author_name":"- Silvia del Arenal Sanchez","author_inst":"CIENI-INER"},{"author_name":"- A Jorge A Gutierrez Soto","author_inst":"CEC"},{"author_name":"- Karina Nava Memije","author_inst":"CECI"},{"author_name":"- Jessica Monreal Flores","author_inst":"CIENI-INER"},{"author_name":"- Alejandro Guzman","author_inst":"CECI"},{"author_name":"- E Rebecca E Garcia Mendiola","author_inst":"CECI"},{"author_name":"- Patricia Iracheta","author_inst":"CEC"},{"author_name":"- Veronica Ruiz Gonzalez","author_inst":"CEC"},{"author_name":"- Veronica Quiroz Morales","author_inst":"CIENI-INER"},{"author_name":"- Israel Macias Gonzalez","author_inst":"CEC"},{"author_name":"- A Manuel A Becerril Rodriguez","author_inst":"CIENI-INER"},{"author_name":"- A Raul A Cruz Flores","author_inst":"CECI"},{"author_name":"- Andrea Gonzalez Rodriguez","author_inst":"CEC"},{"author_name":"- M Dulce M Lopez Sanchez","author_inst":"CIENI-INER"},{"author_name":"- Miroslava Cardenas Sandoval","author_inst":"CIENI-INER"},{"author_name":"- dlA Maria dlA Beristain Barreda","author_inst":"CIENI-INER"},{"author_name":"Maribel Hernandez","author_inst":"CINVESTAV"},{"author_name":"Simon Dellicour","author_inst":"ULB \/ KU Leuven"},{"author_name":"Tetyana I Vasylyeva","author_inst":"UCI"},{"author_name":"Joel O Wertheim","author_inst":"UCSD"},{"author_name":"Santiago Avila Rios","author_inst":"CIENI-INER"}],"rel_date":"2026-05-27","rel_site":"medrxiv"},{"rel_title":"SAA positivity rate amongst dual LRRK2-GBA1, GBA1 and LRRK2 carriers with Parkinson's disease","rel_doi":"10.64898\/2026.05.26.26354106","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26354106","rel_abs":"We investigated whether people with Parkinsons disease who are dual GBA1+LRRK2 carriers have a milder, LRRK2-like phenotype as previously reported. This was accomplished by comparing clinical features and alpha-synuclein seed amplification assay (SAA) positivity rates between dual GBA1+LRRK2-PD(n=13), GBA1-PD(n=169) and LRRK2-PD(n=175) carriers in a cross-sectional retrospective study of Parkinsons Progression Markers Initiative (PPMI) data. Our results show that GBA1+LRRK2-PD SAA positivity rate(83%) is closer to GBA1-PD rate(87%) rather than LRRK2-PD rate(62%,p-value>0.05). GBA1+LRRK2-PD have both non-motor and motor phenotypic similarity to GBA1-PD,(p-value>0.05). This small PPMI cohort indicates that dual GBA1+LRRK2-PD carriers SAA positivity and phenotype are aligned with GBA1-PD.","rel_num_authors":6,"rel_authors":[{"author_name":"Penina Ponger","author_inst":"TASMC"},{"author_name":"Anuprita R Nair","author_inst":"University of Iowa"},{"author_name":"Noah Noah","author_inst":"university of Iowa"},{"author_name":"Chelsea Caspell-Garcia","author_inst":"university of Iowa"},{"author_name":"David-Erick Lafontant","author_inst":"university of Iowa"},{"author_name":"Roy N Alcalay","author_inst":"TASMC"}],"rel_date":"2026-05-27","rel_site":"medrxiv"},{"rel_title":"The Associations of Cerebral Blood Flow and White Matter Hyperintensities with Tau and Amyloid-beta Across the Alzheimer's Disease Spectrum","rel_doi":"10.64898\/2026.05.25.26354067","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.25.26354067","rel_abs":"Although the associations between cerebrovascular dysfunctions and Alzheimers disease are increasingly appreciated, the relationship of cerebral blood flow and white matter hyperintensities with tau and amyloid-{beta} pathology remains unclear, particularly in the longitudinal context. This study investigated cross-sectional and longitudinal associations of cerebral blood flow and white matter hyperintensities with tau and amyloid-{beta} pathology using multimodal imaging and blood biomarkers in 179 participants from the ADNI3 cohort. Participants underwent structural (T1-weighted, T2-weighted FLAIR) and arterial spin labelling perfusion MRI, tau and amyloid-{beta} PET, and plasma assay tests for amyloid-{beta} 42, amyloid-{beta} 40, and phosphorylated tau-217. Tau from PET was negatively associated with cerebral blood flow both cross-sectionally and longitudinally in the posterior brain, independent of amyloid-{beta} quantified from PET. Higher white matter hyperintensities volumes were associated with higher levels of tau and amyloid-{beta} at baseline, but the associations were significantly attenuated after further adjusting for amyloid-{beta} and tau, respectively. Plasma amyloid-{beta} 42\/40 ratio was negatively associated with white matter hyperintensity volumes both cross-sectionally and longitudinally. In conclusion, tau pathology showed spatially specific associations with cerebral hypoperfusion, independent of amyloid-{beta}, particularly in posterior regions. The attenuation of associations of white matter hyperintensities with amyloid-{beta} and tau after adjustment may reflect shared disease-related variance rather than distinct independent effects.","rel_num_authors":4,"rel_authors":[{"author_name":"Keshuo Lin","author_inst":"UNSW"},{"author_name":"Perminder Sachdev","author_inst":"Centre for Healthy Brain Ageing Neuropsychiatric Institute"},{"author_name":"Jiyang Jiang","author_inst":"Research Imaging NSW"},{"author_name":"- Alzheimer's Disease Neuroimaging Initiative","author_inst":"-"}],"rel_date":"2026-05-27","rel_site":"medrxiv"},{"rel_title":"Associations between lack of social support and food insecurity: A cross-sectional analysis of the 2024 BRFSS","rel_doi":"10.64898\/2026.05.24.26353990","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.24.26353990","rel_abs":"Objective: To verify the association between perceived social & emotional support and self-reported food insecurity in the United States Design: Cross-sectional secondary data analysis Setting: Behavioral Risk Factor Surveillance System (BRFSS) data from 2024, collected via a nationwide telephone survey. Food insecurity was defined as responding always, usually, or sometimes to \"During the past 12 months how often did the food that you bought not last, and you didn't have money to buy more?\" Social support was measured using a BRFSS item assessing the frequency with which respondents received the social and emotional support they needed. Adjusted logistic regression models were used to assess the relationship between these variables while controlling for a wide variety of demographic, socioeconomic, and health status factors. Participants: Adults (n = 190,577) aged 18-80 years old (72.3% non-Hispanic White) Results: Individuals who reported only \"sometimes\" receiving the social and emotional support they need were more likely to report food insecurity as compared to those who \"always\" receive such support (aOR = 1.75; 95% CI 1.56, 1.96). Conclusions: These findings indicate that decreased social support may put individuals at higher risk of food insecurity. Future work should seek to understand the mechanisms of this association to inform targeted policy and other interventional programs.","rel_num_authors":8,"rel_authors":[{"author_name":"Eashwar Sree Cherukuri Krishna","author_inst":"University of Minnesota Medical School, Duluth"},{"author_name":"Neha Shanavas","author_inst":"University of Connecticut"},{"author_name":"Fatima Mir","author_inst":"Columbia University"},{"author_name":"Ahan Kothapeta","author_inst":"University of Connecticut"},{"author_name":"Carlos Duluc","author_inst":"University of Connecticut"},{"author_name":"Roma Kale","author_inst":"University of Connecticut"},{"author_name":"Priya Bheemanakunta","author_inst":"University of Connecticut"},{"author_name":"Eshita Mathur","author_inst":"University of Connecticut"}],"rel_date":"2026-05-27","rel_site":"medrxiv"},{"rel_title":"Breath volatile profiling reveals a diagnostic signature of MASLD in children","rel_doi":"10.64898\/2026.05.26.26353794","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.26.26353794","rel_abs":"Background & AimsMetabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is the leading cause of chronic liver disease in children. However, accurate, noninvasive diagnostic tools remain limited. Current screening methods are invasive or lack sensitivity. Breath-based volatile organic compound (VOC) analysis offers a simple approach with potential for point-of-care screening. This study aimed to identify and validate breath VOC signatures of pediatric MASLD.\n\nApproach & ResultsWe conducted a prospective IRB-approved cohort study at the Childrens Hospital of Philadelphia (CHOP). Children aged 7-20 years with MASLD (n=22), as defined by hepatic steatosis either by liver biopsy or imaging and 1 cardiometabolic risk factor, and a control group without MASLD (n=20) were enrolled. Breath samples were collected using a standardized protocol and analyzed by untargeted comprehensive two-dimensional gas chromatography-mass spectrometry (GCxGC-MS). Machine learning and unsupervised clustering were applied to identify discriminatory VOCs and assess heterogeneity. Untargeted GCxGC-MS analysis identified a distinct breath VOC signature in children with MASLD compared with non-MASLD controls. A Random Forest model achieved a sensitivity of 73% and specificity of 65%, with AUC of 0.84. The VOC 2,4-dimethyl-1-heptene demonstrated strong diagnostic performance in the discovery cohort with a sensitivity of 85%, specificity of 77% and an AUC of 0.81. Unsupervised clustering revealed four MASLD subgroups with distinct volatile phenotypes associated with differences in liver enzymes and metabolic parameters. External validation in a second pediatric cohort confirmed reproducible reductions in o\/p-xylene in subjects with MASLD.\n\nConclusionsPediatric MASLD is associated with a reproducible breath VOC signature identified by untargeted GCxGC-MS. These findings support breath analysis as a scalable, noninvasive screening and stratification tool for pediatric MASLD and warrant validation in larger, longitudinal studies.\n\nIMPACT AND IMPLICATIONSPediatric MASLD lacks scalable, noninvasive diagnostic tools capable of early identification of at-risk children, providing strong scientific justification for the development of breath-based biomarkers. This study demonstrates that untargeted breath VOC profiling can distinguish children with MASLD from controls and reveals biologically meaningful heterogeneity in breath signatures, highlighting the potential of breath analysis for both detection and risk stratification. These findings are most relevant to physicians managing children with cardiometabolic risk and to researchers developing noninvasive liver biomarkers. Broader validation is required before clinical implementation.","rel_num_authors":11,"rel_authors":[{"author_name":"Amalia Z. Berna","author_inst":"Division of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"},{"author_name":"Jennifer Panganiban","author_inst":"Division of Gastroenterology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"},{"author_name":"Yang Liu","author_inst":"Division of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"},{"author_name":"Joey Logan","author_inst":"Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"},{"author_name":"Pierre Russo","author_inst":"Division of Pathology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"},{"author_name":"Aakanshya Aryal","author_inst":"Division of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"},{"author_name":"Kathryn Hafertepe","author_inst":"Division of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"},{"author_name":"Sarah Abu-Alreesh","author_inst":"Division of Gastroenterology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"},{"author_name":"Brian DeBosch","author_inst":"Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Indiana University, Indianapolis, Indiana USA"},{"author_name":"Janis Stoll","author_inst":"Division of Gastroenterology, Washington University School of Medicine, St Louis, Missouri, USA"},{"author_name":"Audrey Ragan Odom John","author_inst":"Division of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"}],"rel_date":"2026-05-27","rel_site":"medrxiv"},{"rel_title":"Determinants of cancer care delays in Kinshasa, Democratic Republic of the Congo (DRC)","rel_doi":"10.64898\/2026.05.19.26353550","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.19.26353550","rel_abs":"PURPOSECancer outcomes in sub-Saharan Africa are driven by delayed diagnosis and treatment initiation. We evaluated the magnitude and determinants of diagnostic and treatment delays among cancer patients in Kinshasa, Democratic Republic of the Congo (DRC).\n\nMETHODSWe conducted a hospital-based cross-sectional study of 460 adults with confirmed cancer at Nganda Hospital Center in Kinshasa, DRC. Two outcomes were assessed: delay from symptom onset to diagnosis and delay from diagnosis to treatment initiation. Log-normal regression models were fitted for each outcome to estimate adjusted geometric mean ratios (aGMRs) and 95% confidence intervals (CIs). Covariates included demographic, socioeconomic, clinical, behavioral, and stigma-related factors.\n\nRESULTSThe median age was 55 years, and 76.2% of participants were women. Overall, 55.0% of participants experienced symptom-to-diagnosis delays >6 months, and 49.4% experienced diagnosis-to-treatment delays >3 months. Older age was associated with longer diagnostic delay (aGMR 1.55, 95% CI 1.03-2.31) and treatment delay (1.51, 1.07-2.14). Unemployment was strongly associated with both diagnostic delay (1.68, 1.15-2.47) and treatment delay (2.27, 1.54-3.33), as was hepatitis B co-infection (1.88, 1.06-3.34 and 2.42, 1.15-5.11, respectively). Longer diagnostic delay was additionally associated with informal trading (1.99, 1.21-3.28), taxi or motorbike transport (1.92, 1.25-2.94), and smoking history (2.25, 1.03-4.91), while high cancer-stereotype stigma was associated with longer treatment delay (1.56, 1.04-2.34).\n\nCONCLUSIONSubstantial delays exist across the DRC cancer care continuum, driven by socioeconomic vulnerability, transport barriers, hepatitis B co-infection, and cancer-related stigma. These findings highlight the need for integrated interventions to improve timely diagnosis and treatment initiation, including strengthening financial protection, decentralizing cancer services, and reducing stigma in cancer care.","rel_num_authors":9,"rel_authors":[{"author_name":"Jean Claude Dusingize","author_inst":"Department of Medicine, Albert Einstein College of Medicine, New York, USA"},{"author_name":"Natalia Zotova","author_inst":"Department of Medicine, Albert Einstein College of Medicine, New York, USA"},{"author_name":"Rafi Kabarriti","author_inst":"Department of Radiation Oncology, Montefiore Einstein; New York, USA"},{"author_name":"Kavita Sehrawat","author_inst":"Department of Radiation Oncology, Montefiore Einstein; New York, USA"},{"author_name":"Pelagie Babakazo","author_inst":"Kinshasa School of Public Health, University of Kinshasa, Democratic Republic of Congo"},{"author_name":"Ali Shongo Alisho","author_inst":"Kinshasa School of Public Health, University of Kinshasa, Democratic Republic of Congo"},{"author_name":"Fidele Lumande Kasindi","author_inst":"Kinshasa School of Public Health, University of Kinshasa, Democratic Republic of Congo"},{"author_name":"Ilyass Yessoufou","author_inst":"Nganda Hospital Center, Democratic Republic of Congo"},{"author_name":"Marcel Yotebieng","author_inst":"Department of Medicine, Albert Einstein College of Medicine, New York, USA"}],"rel_date":"2026-05-26","rel_site":"medrxiv"},{"rel_title":"A mixed-methods assessment of malaria case investigations and response in the elimination setting of Southern Province, Zambia","rel_doi":"10.64898\/2026.05.23.26353921","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.23.26353921","rel_abs":"BackgroundIn 2017, Zambia adopted surveillance as a core intervention towards achieving malaria elimination. Among the surveillance strategies is the malaria case investigation and response 1-3-7 (MCIR 1-3-7), which has been piloted in two low-incidence districts in the Southern Province since 2021. The study aimed to assess the implementation of MCIR 1-3-7 under programmatic conditions. It examined the timeliness, and completeness of the MCIR 1-3-7 activities, including the completeness of data entry in surveillance forms, and explored the experiences and perspectives of healthcare workers involved in the pilot.\n\nMethodsA mixed-methods design was employed to assess the MCIR 1-3-7. Using a descriptive cross-sectional design, quantitative data were collected from 19 healthcare facilities in the two districts to assess the timeliness and completeness of MCIR 1-3-7. Additionally, 12 qualitative interviews were conducted with 29 healthcare workers from 11 of the 19 healthcare facilities. The interviews were voice-recorded and then transcribed manually. A codebook was developed using an iterative process to explore the facilitators and barriers encountered by healthcare workers in implementing the MCIR 1-3-7 intervention. All the visited facilities were purposively selected based on logistical convenience.\n\nResultsThis study retrospectively assessed 510 malaria cases that were diagnosed between January 2022 and June 2023, presenting at 19 health facilities: 283 cases in Chikankata and 227 in Mazabuka districts. A total of 278 cases (54.5%) were deemed to have been imported from outside the district, province, or country, while 45.5% (232\/510) of the cases were classified as transmitted locally. Overall, 29.6% of case notification forms were found to be complete. Twelve interviews with 29 healthcare workers revealed a lack of transportation modalities as the main obstacle in executing the MCIR 1-3-7 intervention. The healthcare workers also indicated that monetary incentives, and supportive supervision would help them succeed in implementing this intervention.\n\nConclusionsThe MCIR 1-3-7 has the potential to accelerate elimination in areas with low-transmission of malaria in Zambia. This study highlights opportunities to improve future implementation of the MCIR 1-3-7 intervention via strengthening supportive supervision, availing job aids, and ensuring access to malaria commodities as the intervention expands.","rel_num_authors":13,"rel_authors":[{"author_name":"Refilwe Karabo","author_inst":"Tulane University School of Public Health and Tropical Medicine"},{"author_name":"Salima  M. Kalyalya","author_inst":"Tulane University School of Public Health and Tropical Medicine"},{"author_name":"John Miller","author_inst":"PATH"},{"author_name":"Kafula Silumbe","author_inst":"PATH"},{"author_name":"Busiku Hamainza","author_inst":"Zambia National Malaria Elimination Center"},{"author_name":"Chris Lungu","author_inst":"PATH"},{"author_name":"Javan Chanda","author_inst":"PATH"},{"author_name":"Adam Bennett","author_inst":"UCSF School of Medicine: University of California San Francisco School of Medicine"},{"author_name":"Caterina Guinovart","author_inst":"PATH"},{"author_name":"Zhiyuan Mao","author_inst":"Tulane University School of Public Health and Tropical Medicine"},{"author_name":"Ruth  A. Ashton","author_inst":"Tulane University School of Public Health and Tropical Medicine"},{"author_name":"Jeni  A. Stolow","author_inst":"Tulane University School of Public Health and Tropical Medicine"},{"author_name":"Thomas  P. Eisele","author_inst":"Tulane University School of Public Health and Tropical Medicine"}],"rel_date":"2026-05-26","rel_site":"medrxiv"},{"rel_title":"Variation in Telehealth Use in a National Home Test-to-Treat Program for Acute Respiratory Infections","rel_doi":"10.64898\/2026.05.24.26353984","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.24.26353984","rel_abs":"BackgroundHome Test-to-Treat (HTTT) programs deliver timely antiviral treatment for acute respiratory infections, including COVID-19 and influenza, through at-home testing and telehealth. Because access is often measured by visit occurrence, variation in how and when care is delivered may be overlooked. We hypothesized that telehealth access follows distinct process-based patterns.\n\nMethodsWe analyzed de-identified encounters from the national HTTT program (September 2023-July 2024); 6,213 of 8,160 eligible individuals remained after exclusions for missing data. Phenotypes were derived by k-means clustering of standardized variables capturing encounter timing, modality preference, process duration, and sociodemographic and digital access attributes. Ten-day surveys assessed symptom duration and healthcare utilization.\n\nResultsThree phenotypes emerged: Delayed\/Disrupted Access (n = 1,537; 24.7%), Digitally Engaged but Socioeconomically Vulnerable (n = 1,460; 23.5%), and Mainstream Access and Efficient Utilization (n = 3,216; 51.8%). Mean process duration differed (15.93 [SD 3.84] vs 3.69 [3.31] vs 2.87 [2.41] hours; p < 0.001). Synchronous preference was lowest in the Digitally Engaged group (22.9%); antiviral prescribing was high (88.6%-91.9%). Among 10-day respondents (n = 1,023), symptom duration did not differ. Emergency department visits were most frequent in the Digitally Engaged group (2.3% vs 0.0% and 0.5%; p = 0.02) and urgent care in the Delayed\/Disrupted group (5.8% vs 4.1% vs 2.0%; p = 0.02).\n\nConclusionsTelehealth use in a national HTTT program formed distinct phenotypes defined by timing, modality, and care-process efficiency. Evaluating equity requires attention to how and when care is delivered, not simply whether it occurred.","rel_num_authors":6,"rel_authors":[{"author_name":"Wojciech Losos","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Biqi Wang","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Kimberly Fisher","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Laurel O'Connor","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Apurv Soni","author_inst":"University of Massachusetts Chan Medical School"},{"author_name":"Ben Gerber","author_inst":"University of Massachusetts Chan Medical School"}],"rel_date":"2026-05-26","rel_site":"medrxiv"},{"rel_title":"Dual-Metric Energy Analysis of Intracranial EEG: Seizure Onset Zones and Energy-Dominant Regions in Drug-Resistant Epilepsy","rel_doi":"10.64898\/2026.05.25.26354017","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.25.26354017","rel_abs":"ObjectiveTo determine whether absolute ictal energy on intracranial EEG identifies brain regions whose epileptogenic involvement is attenuated under existing baseline-normalized, dynamic-systems, and event-based frameworks.\n\nApproachIntracranial EEG from 56 patients (five centers; 21 SEEG, 35 ECoG) was analyzed using the Teager-Kaiser Energy Operator computed as z-scored and raw envelopes; energy-dominant network regions (EDNRs) were defined as electrodes whose raw-energy rank exceeded their z-score rank by at least 2 positions. Hilbert decomposition characterized instantaneous amplitude and frequency.\n\nMain resultsEDNRs were identified in 51 of 56 patients (91%; mean 3.4). Hilbert decomposition revealed elevated baseline amplitude in EDNRs relative to both non-involved regions (p < 0.001) and potential seizure onset zones (PSOZs, the top-ranked electrodes under both metrics; p = 0.029), with EDNRs participating in seizure-frequency dynamics comparable to PSOZs (mean ictal frequency shift +3.7 versus +4.1 Hz). EDNR detectability correlated directly with electrode count (Spearman r = 0.899, p < 0.001) without plateau.\n\nSignificanceAbsolute ictal energy identifies an epileptogenic network component with elevated baseline amplitude attenuated under baseline-normalized metrics. The dual-metric framework defines a complementary energy-based axis and establishes the second layer of a two-layer approach with seizure onset and propagation mapping as the first layer. EDNR detectability scales with electrode count, directly relevant to SEEG implantation strategy and to network-level inferences from heterogeneously covered cohorts.\n\nHighlightsO_LIDual-metric Teager-Kaiser energy operator (TKEO) identifies seizure onset zones and energy-dominant network regions\nC_LIO_LIEnergy-dominant network regions (EDNRs) were identified in 91% of 56 patients across five epilepsy centers\nC_LIO_LIEDNRs combine highest baseline amplitude with seizure-frequency dynamics; detection scales with electrode count\nC_LI","rel_num_authors":1,"rel_authors":[{"author_name":"Ahmet Fatih Atik","author_inst":"University of Chicago"}],"rel_date":"2026-05-26","rel_site":"medrxiv"},{"rel_title":"Labour Induction in low-risk women at 39 weeks of gestation: a Randomised trial in China (LIRIC) - Protocol of an open label, randomised controlled trial","rel_doi":"10.64898\/2026.05.24.26354001","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.24.26354001","rel_abs":"IntroductionThe ARRIVE trial first demonstrated that elective induction of labour (IOL) at 39 weeks in low-risk pregnancies reduced the likelihood of caesarean section (CS) without compromising perinatal safety; however, the generalizability of these findings remains debated, leading to uncertainty in clinical practice. The LIRIC trial aims to evaluate whether 39-week elective IOL reduces CS rates compared with expectant management, while exploring its impact on infant neurodevelopment and multi-omics profiles.\n\nMethods and analysisThis is a single-centre, open-label, randomized controlled trial in China. A total of 1,074 low-risk pregnant women (nulliparous or multiparous) will be randomly assigned (1:1 ratio) to either 39-week IOL or expectant management. The primary outcome is the caesarean section (CS) rate. Secondary outcomes include a composite of severe neonatal morbidity and perinatal mortality and infant neurodevelopmental scores (Bayley-4 and ASQ-3), among others. Data analysis will follow the Intention-to-Treat (ITT) principle. Biospecimen will be collected for metagenomic and metabolomic analyses, with results to be reported separately.\n\nEthics and disseminationThe protocol has been approved by the Ethics Committee of Womens Hospital, School of Medicine, Zhejiang University. Informed consent will be obtained from all participants. Results will be disseminated via peer-reviewed journals, and standardized infant developmental reports will be provided to participants to enhance study benefit.\n\nTrial registration number NCT07082530.","rel_num_authors":16,"rel_authors":[{"author_name":"Huajing Gao","author_inst":"Institute of Medical Genetics and Development, Zhejiang University, and Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reprod"},{"author_name":"Junhua Shen","author_inst":"Department of Obstetrics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China."},{"author_name":"Danqing Chen","author_inst":"Department of Obstetrics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China."},{"author_name":"Ben W. Mol","author_inst":"Monash University"},{"author_name":"Wensheng Hun","author_inst":"Department of Obstetrics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China."},{"author_name":"Zhaoxia Liang","author_inst":"Department of Obstetrics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China."},{"author_name":"Xiaoxia Bai","author_inst":"Department of Obstetrics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China."},{"author_name":"Xiujun Han","author_inst":"Department of Obstetrics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China."},{"author_name":"Jiajun Zhu","author_inst":"Department of Neonatology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China."},{"author_name":"Hong Wang","author_inst":"Department of Obstetrics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China."},{"author_name":"Xiaozhen Liu","author_inst":"Department of Obstetrics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China."},{"author_name":"Chang Su","author_inst":"Department of Obstetrics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China."},{"author_name":"Ruopeng Weng","author_inst":"Department of Obstetrics, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China."},{"author_name":"Yifeng Liu","author_inst":"Institute of Medical Genetics and Development, Zhejiang University, and Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reprod"},{"author_name":"Wentao Li","author_inst":"National Perinatal Epidemiology and Statistics Unit, Centre for Big Data Research in Health, Faculty of Medicine and Health, University of New South Wales, Sydn"},{"author_name":"Dan Zhang","author_inst":"Women's Hospital, Zhejiang University School of Medicine"}],"rel_date":"2026-05-26","rel_site":"medrxiv"},{"rel_title":"Genital Inflammatory Responses in Women Living with HIV Randomized to Copper or Levonorgestrel Intrauterine Contraceptives: A secondary analysis of a randomized trial","rel_doi":"10.64898\/2026.05.24.26353969","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.24.26353969","rel_abs":"BackgroundIntrauterine contraceptives (IUCs) are effective, but effects on genital inflammation among women living with HIV (WLHIV) by antiretroviral therapy (ART) use are unclear. We evaluated the longitudinal effects of copper IUC (CLIUC) and the levonorgestrel intrauterine system (LNGLIUS) on cervicovaginal cytokine profiles in a secondary analysis of a randomized trial (NCT01721798, 2013-2016).\n\nMethodsCervicovaginal secretions were collected from 100 WLHIV (nonLART usersL=L48; ART usersL=L52) randomized 1:1 to ClZIUC or LNGlZIUS. TwentyLeight cytokines were measured prior to insertion and 3- and 6-months postLinsertion. Cytokine concentrations at each followLup visit were compared with baseline, using participant fixedLeffects models stratified by ART status.\n\nResultsAt enrollment, nonLART users had higher average concentrations of most cytokines (21\/28) than women using ART. Among non-ART users, IUC use was not associated with cytokine increases; only MCPL1 increased significantly at 3 months among CLIUC users (log10 geometric mean ratio 0.77, 95%CI 0.38-1.17), while none increased with LNG-IUS use. Among ART users, C-IUC insertion resulted in broad and sustained cytokine increases at both 3 (16\/28) and 6 months (15\/28). At month 3, the largest increases in log10 geometric mean were observed for IL-6 (1.04, 0.72-1.36), RANTES (0.97, 0.54-1.40), MCP-1 (0.71, 0.46-0.96), MIP-1 (0.66, 0.37-0.94), and G-CSF (0.63, 0.36-0.89), which was maintained until month 6. Cytokine changes following LNGLIUS insertion were minimal (IL-5, month 3).\n\nConclusionsAmong ART users, CLIUC is associated with increases in cervicovaginal cytokines, across functional classes. This supports LNGLIUS as a less inflammatory option for WLHIV to minimize genital immune activation.","rel_num_authors":11,"rel_authors":[{"author_name":"Anna-Ursula Happel","author_inst":"University of Cape Town"},{"author_name":"Jo-Ann Shelley Passmore","author_inst":"Stellenbosch University"},{"author_name":"Musalula Sinkala","author_inst":"University of Cape Town"},{"author_name":"Shameem Jaumdally","author_inst":"University of Cape Town"},{"author_name":"Hoyam Gamieldien","author_inst":"University of Cape Town"},{"author_name":"Nai-Chung Hu","author_inst":"University of Cape Town"},{"author_name":"Nontokozo Langwenya","author_inst":"University of Cape Town"},{"author_name":"Heidi E Jones","author_inst":"CUNY School of Public Health"},{"author_name":"Donald Hoover","author_inst":"Rutgers University"},{"author_name":"Landon Myer","author_inst":"University of Cape Town"},{"author_name":"Catherine Todd","author_inst":"FHI360"}],"rel_date":"2026-05-26","rel_site":"medrxiv"},{"rel_title":"Random Forest Model for Predicting Post-Lockdown Antenatal Depression Risk: A Cross-Sectional Study of Pregnant Women in China","rel_doi":"10.64898\/2026.05.23.26353929","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.23.26353929","rel_abs":"BackgroundAs lockdown measures was eased, pregnant women faced an elevated risk of COVID-19 infection, potentially impacting their mental health. This study aimed to investigate the prevalence of antenatal depression (AD) post-lockdown and develop predictive models for AD risk using machine learning.\n\nMethodsA cross-sectional study utilizing the Edinburgh Postnatal Depression Scale was conducted in Beijing and Guizhou, China, from January to August 2023. Data was randomly split into training and test datasets (6:4 ratio), with logistic regression (LR), Support Vector Machine (SVM), K-Nearest Neighbors (KNN), Random Forest (RF), eXtreme Gradient Boosting (XGBoost), and Gradient Boosting Decision Tree (GBDT) models trained and compared. The best model underwent further examination, including SHapley Additive exPlanations (SHAP) for feature importance, calibration curve (CC) for discrimination, and decision curve analysis (DCA) for clinical benefit.\n\nResultsThe effective response rate was 91.07% (459\/504), with 25.7% (118\/459) testing positive for AD. Multivariate analysis identified \"sleep disorders,\" \"family support level,\" and \"COVID-19 symptom severity\" as independent predictors. RF model showed the highest area under the curve in both training (0.842) and testing (0.724) datasets, with SHAP emphasizing the greatest impact of \"sleep disorders\" on AD. The RF models calibration (P > 0.05) and clinical utility across thresholds (8%-95% and 10%-58%) were confirmed by CC and DCA, respectively.\n\nConclusionsAD strongly correlated with \"sleep disorders,\" \"family support level,\" and \"COVID-19 symptom severity\" post-lockdown, and the EPDS-based RF model effectively predicted AD risk.","rel_num_authors":6,"rel_authors":[{"author_name":"Yijin Pan","author_inst":"Peking Union Medical College Hospital"},{"author_name":"Hai Lin","author_inst":"Peking University Health Science Center"},{"author_name":"TAKAE HIRONO","author_inst":"Peking University Health Science Center"},{"author_name":"Yifan Yang","author_inst":"Peking University Health Science Center"},{"author_name":"Yang Liu","author_inst":"Qiandongnanzhou People's Hospital"},{"author_name":"Yinqiang Zhang","author_inst":"Peking Union Medical College Hospital"}],"rel_date":"2026-05-26","rel_site":"medrxiv"},{"rel_title":"Why is team-based hypertension care failing to take hold in Australia? Real-world evidence from primary care","rel_doi":"10.64898\/2026.05.25.26354005","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.25.26354005","rel_abs":"ObjectiveAustralias shortage of general practitioners (GPs) has intensified interest in team-based care for hypertension, involving pharmacists and nurses. This study explored primary care providers experiences, barriers, and facilitators related to implementing team-based care in Australia.\n\nDesignQualitative study using semi-structured interviews with primary care providers.\n\nMethodsWe conducted 51 interviews with GPs (n=24), nurses (n=12), and pharmacists (n=15), purposively selected from diverse primary care settings. Analysis combined deductive coding, informed by the Theoretical Domains Framework and Consolidated Framework for Implementation Research, with inductive thematic analysis to identify emergent themes.\n\nResultsInterviews demonstrated a predominantly GP-centred care model, with nurse and pharmacist involvement largely confined to supporting roles, including blood pressure measurement, prescription refills, patient follow-up and counselling. Their contributions were constrained by barriers at both practice (e.g., limited GP support, fragmented communication across providers) and health system levels (e.g., limited financial incentives and restricted reimbursement pathways). Despite their critical role in care planning, nurses described being \"hamstrung\" by workload and limited direct funding for hypertension-related services. Pharmacists reported unreimbursed blood pressure checks and restricted funding for medication reviews that constrained the sustainability of their hypertension services. Role ambiguity and the absence of standardised protocols on task sharing further limited collaboration, with nurses and pharmacists describing concerns about overstepping professional boundaries. Attitudes towards team-based care ranged from active disregard (outright rejection) to conditional acceptance and occasional active uptake (strong endorsement).\n\nConclusionDespite clear willingness among nurses and pharmacists to alleviate GP burden, team-based care is rarely implemented in routine practice. Addressing system-level barriers (funding models that incentivise team-based care and standardised treatment protocols that clarify shared workflows), alongside provider-level barriers (stronger awareness and training that normalises task sharing), is critical to support genuine team-based hypertension care in Australia.\n\nWhat is already known on this topicO_LIOnly 32% of Australians with hypertension achieve blood pressure control, and care remains heavily GP-centred amid a projected shortage of over 8000 GPs by 2030 and worsening rural access.\nC_LIO_LIGlobal evidence strongly supports team-based care involving nurses and pharmacists as clinically effective and cost-effective, yet its uptake in Australian primary care remains limited.\nC_LI\n\nWhat this study addsO_LIDrawing on 51 interviews with GPs, nurses, and pharmacists, we identify barriers to team-based care at the practice-level (workload, role ambiguity, professional hierarchies) and system-level (misaligned financial incentives, fragmented communication).\nC_LIO_LIDespite their willingness to contribute more, nurses and pharmacists remain systematically undervalued, with their contributions constrained by attitudes, incentives, and authority that continue to reinforce GP-centred care.\nC_LI\n\nHow this study might affect research, practice or policyO_LIAustralias 70% blood pressure control target by 2030 will remain out of reach without urgent structural reforms to primary care--blended funding models, standardised task-sharing protocols, clearer scopes of practice, and interoperable digital systems are prerequisites for genuine, person-centred, team-based hypertension care.\nC_LI","rel_num_authors":12,"rel_authors":[{"author_name":"Gautam Satheesh","author_inst":"University of Sydney"},{"author_name":"Kaylee Slater","author_inst":"The University of Sydney"},{"author_name":"Ritu Trivedi","author_inst":"The University of Sydney Faculty of Medicine and Health"},{"author_name":"Eleanor Clapham","author_inst":"University of Sydney"},{"author_name":"Florence Margeret Lopez","author_inst":"University of Sydney"},{"author_name":"Brednan McCormack","author_inst":"University of Sydney"},{"author_name":"J. Jaime Miranda","author_inst":"University of Sydney - Faculty of Medicine and Health"},{"author_name":"Shiva Raj Mishra","author_inst":"Western Sydney University"},{"author_name":"Gregory M Peterson","author_inst":"University of Tasmania"},{"author_name":"Mitchell Sarkies","author_inst":"University of Sydney"},{"author_name":"Aletta E. Schutte","author_inst":"University of New South Wales"},{"author_name":"Niamh Chapman","author_inst":"University of Sydney"}],"rel_date":"2026-05-26","rel_site":"medrxiv"},{"rel_title":"Why is team-based hypertension care failing to take hold in Australia? Real-world evidence from primary care","rel_doi":"10.64898\/2026.05.25.26354005","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.25.26354005","rel_abs":"ObjectiveAustralias shortage of general practitioners (GPs) has intensified interest in team-based care for hypertension, involving pharmacists and nurses. This study explored primary care providers experiences, barriers, and facilitators related to implementing team-based care in Australia.\n\nDesignQualitative study using semi-structured interviews with primary care providers.\n\nMethodsWe conducted 51 interviews with GPs (n=24), nurses (n=12), and pharmacists (n=15), purposively selected from diverse primary care settings. Analysis combined deductive coding, informed by the Theoretical Domains Framework and Consolidated Framework for Implementation Research, with inductive thematic analysis to identify emergent themes.\n\nResultsInterviews demonstrated a predominantly GP-centred care model, with nurse and pharmacist involvement largely confined to supporting roles, including blood pressure measurement, prescription refills, patient follow-up and counselling. Their contributions were constrained by barriers at both practice (e.g., limited GP support, fragmented communication across providers) and health system levels (e.g., limited financial incentives and restricted reimbursement pathways). Despite their critical role in care planning, nurses described being \"hamstrung\" by workload and limited direct funding for hypertension-related services. Pharmacists reported unreimbursed blood pressure checks and restricted funding for medication reviews that constrained the sustainability of their hypertension services. Role ambiguity and the absence of standardised protocols on task sharing further limited collaboration, with nurses and pharmacists describing concerns about overstepping professional boundaries. Attitudes towards team-based care ranged from active disregard (outright rejection) to conditional acceptance and occasional active uptake (strong endorsement).\n\nConclusionDespite clear willingness among nurses and pharmacists to alleviate GP burden, team-based care is rarely implemented in routine practice. Addressing system-level barriers (funding models that incentivise team-based care and standardised treatment protocols that clarify shared workflows), alongside provider-level barriers (stronger awareness and training that normalises task sharing), is critical to support genuine team-based hypertension care in Australia.\n\nWhat is already known on this topicO_LIOnly 32% of Australians with hypertension achieve blood pressure control, and care remains heavily GP-centred amid a projected shortage of over 8000 GPs by 2030 and worsening rural access.\nC_LIO_LIGlobal evidence strongly supports team-based care involving nurses and pharmacists as clinically effective and cost-effective, yet its uptake in Australian primary care remains limited.\nC_LI\n\nWhat this study addsO_LIDrawing on 51 interviews with GPs, nurses, and pharmacists, we identify barriers to team-based care at the practice-level (workload, role ambiguity, professional hierarchies) and system-level (misaligned financial incentives, fragmented communication).\nC_LIO_LIDespite their willingness to contribute more, nurses and pharmacists remain systematically undervalued, with their contributions constrained by attitudes, incentives, and authority that continue to reinforce GP-centred care.\nC_LI\n\nHow this study might affect research, practice or policyO_LIAustralias 70% blood pressure control target by 2030 will remain out of reach without urgent structural reforms to primary care--blended funding models, standardised task-sharing protocols, clearer scopes of practice, and interoperable digital systems are prerequisites for genuine, person-centred, team-based hypertension care.\nC_LI","rel_num_authors":12,"rel_authors":[{"author_name":"Gautam Satheesh","author_inst":"University of Sydney"},{"author_name":"Kaylee Slater","author_inst":"The University of Sydney"},{"author_name":"Ritu Trivedi","author_inst":"The University of Sydney Faculty of Medicine and Health"},{"author_name":"Eleanor Clapham","author_inst":"University of Sydney"},{"author_name":"Florence Margeret Lopez","author_inst":"University of Sydney"},{"author_name":"Brednan McCormack","author_inst":"University of Sydney"},{"author_name":"J. Jaime Miranda","author_inst":"University of Sydney - Faculty of Medicine and Health"},{"author_name":"Shiva Raj Mishra","author_inst":"Western Sydney University"},{"author_name":"Gregory M Peterson","author_inst":"University of Tasmania"},{"author_name":"Mitchell Sarkies","author_inst":"University of Sydney"},{"author_name":"Aletta E. Schutte","author_inst":"University of New South Wales"},{"author_name":"Niamh Chapman","author_inst":"University of Sydney"}],"rel_date":"2026-05-26","rel_site":"medrxiv"},{"rel_title":"Non-inferiority of a red-blood-cell--only transfusion strategy compared with balanced resuscitation in adults with massive gastrointestinal haemorrhage: a propensity-score-weighted cohort study","rel_doi":"10.64898\/2026.05.25.26354037","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.25.26354037","rel_abs":"BackgroundBalanced (1:1:1) transfusion of red blood cells (RBCs), plasma, and platelets is the standard of care in trauma-induced massive haemorrhage, where early coagulopathy is a defining feature. In gastrointestinal (GI) haemorrhage this physiology is non-prominent, and whether plasma and platelets provide benefit when [&ge;] 10 RBC units are required within 24 hours is unknown.\n\nObjectiveTo test whether a red-blood-cell-only (RBC-only) transfusion strategy is non-inferior to a balanced (Balanced) strategy for in-hospital mortality in adults meeting massive-transfusion criteria for GI haemorrhage.\n\nDesignSingle-centre retrospective cohort of 559 adult massive-transfusion encounters (536 patients; 2021-2025) with a primary admitting diagnosis of upper, lower, or unspecified GI haemorrhage. Exposures were RBC-only versus Balanced (RBCs with any plasma and\/or platelets). The primary outcome was in-hospital mortality, with a pre-specified 5-percentage-point (pp) non-inferiority margin on the absolute risk difference and a 3-pp sensitivity margin. Analysis used augmented inverse-probability-of-treatment weighting (AIPTW) with bootstrap inference (2,000 resamples by patient). Five pre-specified sensitivity analyses were performed.\n\nResults505 encounters (90.3%) received RBC-only and 54 (9.7%) received Balanced transfusion. The AIPTW risk difference for in-hospital mortality (RBC-only - Balanced) was -19.8 pp (95% CI -68.1 - -2.2 pp). Non-inferiority was demonstrated at both the primary 5-pp and the more stringent 3-pp margins. Five pre-specified sensitivity analyses, (1) a propensity-score matched cohort, (2) a complete-case model incorporating INR, (3) a broader GI diagnosis set (n = 749), (4) a first encounter per patient restriction, and (5) E-value bound analysis were concordant with the primary estimate.\n\nConclusionIn this propensity-score-weighted cohort of adults with massive GI haemorrhage, an RBC-only transfusion strategy was non-inferior to a balanced strategy for in-hospital mortality at both 5-pp and 3-pp margins. The findings support individualized use of plasma and platelets in GI haemorrhage rather than reflexive application of the 1:1:1 trauma protocol; prospective confirmation is warranted.\n\nSignificance of this studyO_ST_ABSWhat is already known on this topicC_ST_ABSBalanced 1:1:1 transfusion is the standard of care for trauma-induced massive haemorrhage, where early coagulopathy, hypothermia, and acidosis frequently coexist. Whether this model should be extrapolated to non-traumatic gastrointestinal haemorrhage, a population in which the trauma triad is generally absent, is uncertain. To date, randomized trials in acute GI bleeding tested restrictive RBC thresholds and antifibrinolytic therapy but have not directly compared red-cell-only with balanced component strategies in patients meeting massive-transfusion criteria.1-3\n\nWhat this study addsIn a propensity-score-weighted cohort of 559 adults meeting massive-transfusion criteria for GI haemorrhage, an RBC-only strategy was non-inferior to a balanced strategy for in-hospital mortality at both the pre-specified 5-pp margin and a more stringent 3-pp sensitivity margin. The finding was consistent across all pre-specified sensitivity analyses, including 1:1 propensity-score matching, complete-case adjustment for admission INR, a broader GI-diagnosis cohort, a first encounter per patient restriction, and an E-value bound for unmeasured confounding.\n\nHow this study might affect research, practice or policyThese results support individualized use of plasma and platelets rather than universal and reflexive 1:1:1 transfusion in GI haemorrhage. The results support a randomized trial comparing goal-directed component therapy with a fixed-ratio resuscitation in non-traumatic massive GI bleeding.","rel_num_authors":3,"rel_authors":[{"author_name":"Burak Bahar","author_inst":"Brown University"},{"author_name":"Joseph D Sweeney","author_inst":"Brown University"},{"author_name":"Christian Nixon","author_inst":"Brown University"}],"rel_date":"2026-05-26","rel_site":"medrxiv"},{"rel_title":"Glycemic response trajectories on metformin monotherapy in real-world diabetes care","rel_doi":"10.64898\/2026.05.24.26353996","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.24.26353996","rel_abs":"ObjectivesDiabetes affects over 500 million people globally and glycemia is inadequately managed. Metformin is the most frequently prescribed initial treatment for type 2 diabetes globally, yet glycemic response trajectories to metformin in routine real-world care and predictors of treatment response have not been well described. We aimed to identify glycemic response trajectories in adults prescribed metformin monotherapy as initial type 2 diabetes treatment and predictors of poor glycemic response to metformin.\n\nDesignObservational cohort study using latent class mixed models to identify hemoglobin A1c (HbA1c) trajectory classes, followed by random forests machine learning to predict trajectory class membership.\n\nSettingUS Veterans Affairs Healthcare System\n\nParticipantsAdults treated with metformin alone for >30 days after diabetes diagnosis with a minimum of two HbA1c measurements from 90 days prior to two years after the first metformin prescription (N=140,413).\n\nExposuresDemographic, laboratory, vital sign, and comorbidity data were included as predictors of metformin response trajectory\n\nMain Outcomes and MeasuresWe included all HbA1c measurements (487,604 total) for two years after metformin initiation to define metformin glycemic response trajectories.\n\nResultsWe identified three HbA1c trajectories: stably low (89.7% of sample, mean HbA1c decrease from 7.2% to 6.6%), brisk response (7.1% of sample, mean HbA1c decrease from 11.4% to 7.0%), and non-response (3.1% of sample, mean HbA1c increase from 8.9% to 10.8%). Of those in the stably low and brisk response classes at 2 years, 91% maintained HbA1c at approximately 7% on metformin alone for 5 years after drug initiation. Prediction models could accurately predict brisk response (91% accuracy) but not metformin non-response (59% accuracy).\n\nConclusionsMost individuals treated initially with metformin monotherapy have a beneficial and durable glycemic response. Predicting individuals who will not respond to metformin may be challenging but is evident within six months with recommended glycemic surveillance. The findings support current guidelines for HbA1c surveillance when initiating diabetes treatment.\n\nSummary Box\n\nO_TBL View this table:\norg.highwire.dtl.DTLVardef@a39955org.highwire.dtl.DTLVardef@a7cbfdorg.highwire.dtl.DTLVardef@417348org.highwire.dtl.DTLVardef@f795beorg.highwire.dtl.DTLVardef@8821c2_HPS_FORMAT_FIGEXP  M_TBL C_TBL","rel_num_authors":7,"rel_authors":[{"author_name":"Sridharan Raghavan","author_inst":"Rocky Mountain Regional VA Medical Center"},{"author_name":"Wenhui G Liu","author_inst":"Rocky Mountain Regional VA Medical Center"},{"author_name":"Max R Ho","author_inst":"University of Colorado Anschutz Medical Campus"},{"author_name":"Theodore Warsavage","author_inst":"Rocky Mountain Regional VA Medical Center"},{"author_name":"Debashis Ghosh","author_inst":"CU Anschutz: University of Colorado - Anschutz Medical Campus"},{"author_name":"Liron Caplan","author_inst":"Rocky Mountain Regional VA Medical Center"},{"author_name":"Jane EB Reusch","author_inst":"Rocky Mountain Regional VA Medical Center"}],"rel_date":"2026-05-26","rel_site":"medrxiv"},{"rel_title":"Multimodal atlas of human atherosclerosis links granular vascular cell states to coronary artery disease risk","rel_doi":"10.64898\/2026.05.24.26353986","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.24.26353986","rel_abs":"Advances in single-cell and spatial assays have revolutionized the scale and resolution of molecular tissue profiling. Here we present MetaPlaq, a multimodal atlas of human atherosclerotic arterial beds comprising over a million cells across single-cell transcriptomics, epigenomics and high-resolution spatial expression assays. We map granular cell states and disease-relevant transcriptional programs within the native tissue context of coronary arteries. Furthermore, we map cardiovascular GWAS signals to smooth muscle cells (SMCs) and endothelial cells (ECs) and uncover the cis-regulatory architecture governing their phenotypic transitions. Our comprehensive epigenomic reference allowed us to build cell-specific enhancer-gene link maps and multimodal gene regulatory networks (GRNs) underlying disease-relevant states such as osteogenic SMCs and ECs undergoing mesenchymal transition. We also integrate SMC and EC disease-associated gene sets with GRNs to nominate key transcription factors such as PRRX1, BNC2 and ELK3 regulating atherosclerosis-relevant transcriptional programs. Finally, we layer single-cell and spatial modalities to fine-map GWAS variants with improved cell and anatomical context. We highlight candidate cell-specific regulatory mechanisms at less characterized CAD loci, including FGD5 and MCF2L in ECs. Together, this atlas represents an important step towards fully interpreting genetic risk loci and informing new therapeutic strategies for cardiovascular disease.","rel_num_authors":28,"rel_authors":[{"author_name":"Jose Verdezoto Mosquera","author_inst":"University of Virginia"},{"author_name":"Ivory Tang","author_inst":"University of Virginia"},{"author_name":"Maria Murach","author_inst":"University of Virginia"},{"author_name":"Gaelle Auguste","author_inst":"University of Virginia"},{"author_name":"Aditi Kodali","author_inst":"University of Virginia"},{"author_name":"Patrick Hart","author_inst":"University of Virginia"},{"author_name":"Douglas M. Shaw","author_inst":"AstraZeneca"},{"author_name":"Minghong Li","author_inst":"University of Virginia"},{"author_name":"Adam W. Turner","author_inst":"University of Virginia and Broad Institute of MIT and Harvard"},{"author_name":"Chani J. Hodonsky","author_inst":"University of Virginia and Ionis Pharmaceuticals"},{"author_name":"Natalia M. Dworak","author_inst":"University of Virginia"},{"author_name":"Ana Karina de Oliveira","author_inst":"University of Virginia"},{"author_name":"Katia Sol-Church","author_inst":"University of Virginia"},{"author_name":"Teresa Jhee","author_inst":"University Medical Center Utrecht"},{"author_name":"Kirsten I.M. van der Sijs","author_inst":"University Medical Center Utrecht"},{"author_name":"Shaunak S. Adkar","author_inst":"Stanford University School of Medicine"},{"author_name":"Ryan B. Choi","author_inst":"Stanford University School of Medicine"},{"author_name":"Francesca Vacante","author_inst":"Stanford University School of Medicine"},{"author_name":"Joseph C. Wu","author_inst":"Stanford University School of Medicine"},{"author_name":"Paul Cheng","author_inst":"Stanford University School of Medicine"},{"author_name":"Chiara Giannarelli","author_inst":"New York University Grossman School of Medicine"},{"author_name":"Nicholas J. Leeper","author_inst":"Stanford University School of Medicine"},{"author_name":"Aloke V. Finn","author_inst":"CVPath Institute"},{"author_name":"Johan L.M. Bjorkegren","author_inst":"Karolinska Institute"},{"author_name":"Jason C. Kovacic","author_inst":"Victor Chang Cardiac Research Institute and Icahn School of Medicine at Mount Sinai"},{"author_name":"Arif Yurdagul Jr.","author_inst":"Louisiana State University Health Sciences Center at Shreveport"},{"author_name":"Sander W. van der Laan","author_inst":"University Medical Center Utrecht"},{"author_name":"Clint L. Miller","author_inst":"University of Virginia"}],"rel_date":"2026-05-26","rel_site":"medrxiv"},{"rel_title":"VACS 2.0 Frailty Index Correlates with Soluble TNF Receptor Levels in Aging Veterans","rel_doi":"10.64898\/2026.05.24.26353987","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.24.26353987","rel_abs":"The VACS 2.0 Frailty Index was developed using the VA health records system to identify frailty and predict mortality in older Veterans that were living with HIV. Systemic inflammatory indices have been associated with frailty, but little is known about the association between frailty and immunosenescence. We aim to investigate the potential link between soluble inflammatory indices, T cell expression of exhaustion and senescence markers, and frailty as measured by the VACS 2.0 index. We analyzed a one-time blood draw for plasma levels of inflammatory indices, T cell subsets and expression of exhaustion and senescence markers, and calculated VACS 2.0 index scores in a cohort of 30 older (>65 years) Veteran participants. We found that VACS 2.0 scores correlated with the number of prescribed medications in the older Veterans. Soluble TNF receptor levels strongly correlated with VACS 2.0 frailty scores. How these soluble TNF receptors are generated and whether they mechanistically contribute to frailty warrants further investigation.","rel_num_authors":7,"rel_authors":[{"author_name":"Sarah Carbone","author_inst":"VA Northeast Ohio Medical Center"},{"author_name":"Brigid Wilson","author_inst":"VA NEO Medical Center"},{"author_name":"Corinne Kowal","author_inst":"VA NEO Medical Center"},{"author_name":"Teresa Dolinar","author_inst":"VA NEO Medical Center"},{"author_name":"Lenche Kostadinova","author_inst":"VA NEO Medical Center"},{"author_name":"Donald D Anthony","author_inst":"Case Western Reserve University"},{"author_name":"Carey L Shive","author_inst":"VA NEO Medical Center"}],"rel_date":"2026-05-26","rel_site":"medrxiv"},{"rel_title":"Metabolomic Signatures of Brain Atrophy and Ibudilast Response in Progressive Multiple Sclerosis","rel_doi":"10.64898\/2026.05.21.26353780","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.05.21.26353780","rel_abs":"BackgroundProgressive multiple sclerosis (MS) is characterized by ongoing neurodegeneration and limited therapeutic options. Circulating metabolites provide insight into disease biology, yet biomarkers that predict disability progression and reflect treatment response are lacking. We aimed to identify metabolomic signatures associated with longitudinal MRI measures of brain atrophy and to evaluate whether ibudilast treatment was associated with metabolite trajectories over time.\n\nMethodsWe repeatedly profiled 1,726 plasma metabolites using untargeted UPLC-MS\/MS in 244 participants (mean age 55.6 years; 53.3% female; 3.3% non-White) from the 96-week SPRINT-MS randomized trial of oral ibudilast ([&le;]100 mg daily; n=123) versus placebo (n=121). Weighted gene co-expression network analysis was used to derive groups of related metabolites. Associations between baseline metabolites groups and longitudinal MRI outcomes were evaluated using linear mixed-effects models adjusted for demographic, clinical, and treatment covariates. The primary outcome was the rate of whole-brain atrophy measured by brain parenchymal fraction (BPF), defined as the proportion of intracranial volume occupied by brain tissue. Secondary outcomes included white matter fraction (WMF), gray matter fraction (GMF), and cortical thickness (CTH). Metabolite groups nominally associated with MRI outcomes (p<0.05) were followed by individual metabolite analyses to identify potential drivers. Significant metabolites were tested for replication in a comparable real-world observational HEAL-MS cohort with longitudinal MRI data (n=249; mean age 56.3 years; 71.1% female; 19.4% non-White). Lastly, we tested whether ibudilast treatment was associated with metabolite trajectories and performed metabolite set enrichment analysis.\n\nFindingsHigher baseline levels of glycerophospholipids were associated with slower decline in both BPF and WMF, and sphingomyelins were similarly associated with slower BPF decline. For example, higher 1-palmityl-2-stearoyl-GPC (O-16:0\/18:0) levels were associated with slower BPF decline in SPRINT-MS ({beta}=0.016 [0.008, 0.024]; p=4.35x10-5) and replicated in HEAL-MS ({beta}=0.108 [0.006, 0.211], p=3.90x10-2). Metabolites associated with GMF preservation were enriched in androgenic steroids and steroid sulfates, with consistent positive associations observed in the replication cohort, whereas metabolites inversely associated with CTH were predominantly xenobiotic-related. Ibudilast treatment was associated with increased sphingomyelin species (e.g., palmitoyl sphingomyelin (d18:1\/16:0); {beta} = 0.185 [0.085, 0.286], FDR = 1.79x10-2) and decreased levels of amino acid-related metabolites (e.g., anthranilate; {beta} = -0.270 [-0.403, -0.137]; FDR = 3.87x10-2). Pathway-based analyses corroborated these findings, highlighting glycerophospholipid and sphingolipid metabolism as key pathways implicated in brain atrophy in MS.\n\nInterpretationDistinct lipid subsets were associated with slower brain atrophy in people with MS, and ibudilast treatment was associated with metabolite alterations in potentially neuroprotective directions. Metabolomics may provide prognostic and pharmacodynamic biomarkers for progressive MS.\n\nFundingThe study was supported by the National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS133005 and the National Institute of Nursing Research (NINR) grants R01NR018851.\n\nResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSCirculating metabolites are altered in people with multiple sclerosis (MS). Before conducting this work, we systematically searched PubMed from database inception to March 23, 2026, for articles published in English using the search terms (\"metabolomics\" OR \"plasma metabolites\") AND (\"multiple sclerosis\" OR \"MS\") AND (\"MRI\" OR \"brain atrophy\" OR \"brain parenchymal fraction\" OR \"gray matter\" OR \"white matter\") AND (\"longitudinal\" OR \"progression\" OR \"brain atrophy\"). We also reviewed reference lists of relevant publications. Prior studies have linked selected metabolites to clinical disability and brain atrophy in MS. However, most studies have been cross-sectional, limited by small sample sizes, or focused on case-control comparisons. Importantly, few studies have evaluated longitudinal associations between circulating metabolites and MRI-derived measures of brain atrophy, and studies integrating clinical trial data, external replication, and treatment-related metabolic changes remain scarce.\n\nAdded value of this studyIn a multicenter randomized clinical trial with longitudinal metabolomic profiling and MRI outcomes, we identified lipid-related metabolic signatures associated with brain atrophy, with consistent directionality observed in an independent cohort. We further demonstrated that ibudilast treatment was associated with longitudinal changes in specific metabolites, linking metabolic pathways to both disease progression and therapeutic response.\n\nImplications of all the available evidenceThese findings support circulating metabolomic signatures as potential markers of brain atrophy in MS. Metabolomics may provide a scalable approach to identify individuals at risk of progressive brain tissue loss and to inform future mechanistic and therapeutic investigations targeting metabolic pathways involved in disability progression.","rel_num_authors":9,"rel_authors":[{"author_name":"Mingjing Chen","author_inst":"Johns Hopkins University"},{"author_name":"Rose Noroozi","author_inst":"Johns Hopkins University"},{"author_name":"Matthew D. Smith","author_inst":"Johns Hopkins University"},{"author_name":"Muraleetharan Sanjayan","author_inst":"Johns Hopkins University"},{"author_name":"Cesar Higgins Tejera","author_inst":"Johns Hopkins University"},{"author_name":"Pavan Bhargava","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Blake E. Dewey","author_inst":"Johns Hopkins University"},{"author_name":"Ellen M Mowry","author_inst":"Johns Hopkins University"},{"author_name":"Kathryn C Fitzgerald","author_inst":"Johns Hopkins University"}],"rel_date":"2026-05-26","rel_site":"medrxiv"}]}