{"gname":"University of Connecticut Health Center ","grp_id":"16","rels":[{"rel_title":"Single-Molecule Dwell Times in Biomolecular Condensates","rel_doi":"10.64898\/2026.06.29.735418","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735418","rel_abs":"Biomolecular condensates are dynamic, membrane-free compartments that continuously exchange molecules with their surroundings. The dwell time, defined as the time a molecule remains inside a condensate between entry and exit, determines how extensively the molecule can explore the dense phase and encounter potential binding partners or reaction sites, thereby modulating condensate function. Motivated by our single-molecule measurements of RNA dwell times, we developed an analytical theory to understand dwell-time distributions in biomolecular condensates. Our theory predicts that the dwell-time distributions generally exhibit an early-time power-law regime followed by a late-time exponential tail. The form of the distribution encodes the rate-limiting mechanism of molecular escape: dense-phase diffusion-limited transport feature a -1.5 power law with an exponential tail set by a diffusion timescale, whereas interfacial barrier-crossing-limited transport feature a -0.5 power law with a decay governed by a barrier-crossing timescale. These distinct signatures provide a direct readout of the physical processes that control molecular retention in condensates, with implications for both natural and synthetic condensates.","rel_num_authors":6,"rel_authors":[{"author_name":"Fengshuo Yang","author_inst":"Johns Hopkins University"},{"author_name":"Roumita Moulick","author_inst":"Johns Hopkins University"},{"author_name":"Cailing Wang","author_inst":"Johns Hopkins University"},{"author_name":"Margaret L. Rodgers","author_inst":"National Institutes of Health"},{"author_name":"Sarah A. Woodson","author_inst":"Johns Hopkins University"},{"author_name":"Yaojun Zhang","author_inst":"Johns Hopkins University"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"msaGUI: Multispectral Analysis Graphical User Interface for Ratiometric Analysis and Background Correction","rel_doi":"10.64898\/2026.06.30.735666","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.735666","rel_abs":"Chemical imaging is a powerful branch of modern microscopy encumbered by a lack of flexible, high-throughput analysis tools. Bespoke analytical pipelines typically perform ratiometric analysis on two layers in a multispectral image to describe the relative composition of molecules in a sample. This strategy has been implemented across fields, spanning histopathology, cell biology, environmental science, and materials science. The commercialization of chemical imaging microscopes has facilitated the collection of large multispectral datasets, necessitating accessible ways to process them. This paper describes Multispectral Analysis Graphical User Interface (msaGUI), a desktop graphical user interface to analyze individual and batch datasets of multispectral images. Data is loaded as CSV, TSV, or TIFFs and processed through a user-defined sequence of modular image operations that can be flexibly combined, e.g. to reduce spectral crosstalk or background noise. After analysis, data is visualized as exportable images, histograms, and statistics. To yield publication-quality figures, outputted images are fully customizable. Written in Python with open-source libraries, the msaGUI program is packaged into an executable for Windows and Mac for a fully no-code application. Other operating systems are supported via the Python source code. In summary, msaGUI provides a rapid and user-friendly solution for analyzing and visualizing multispectral data.","rel_num_authors":2,"rel_authors":[{"author_name":"Grayson R Hoy","author_inst":"Yale University"},{"author_name":"Caitlin M Davis","author_inst":"Yale University"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"MycoCirc: A Pan-Fungal Multi-Modal Pretrained Model for Fungal circRNA Prediction from Genome Sequence","rel_doi":"10.64898\/2026.06.29.735431","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735431","rel_abs":"Motivation: Exploring the fungal circular RNA (circRNA) landscape is bottlenecked by both experimental and computational limits. While standard mRNA-seq systematically discards circRNAs due to their lack of poly(A) tails, high-cost total RNA-seq remains prohibitive for large-scale screening. Consequently, discovery relies heavily on computational prediction. However, existing models trained exclusively on human or plant sequences fail in fungi because of the extreme genomic divergence across fungal lineages, which span from intron-poor Candida to intron-rich filamentous fungi. As a result, no computational framework currently exists for de novo fungal circRNA prediction, leaving the vast majority of non-model fungi entirely inaccessible. Results: We present mycoCirc, the first end-to-end pan-fungal multi-modal pretrained model for fungal circRNA prediction, integrating three mandatory modalities with bidirectional cross-attention for donor-acceptor site interaction. Pre-trained on 22 strains with 16,483 positive gene-circRNA associations spanning Ascomycete yeast, Basidiomycete yeast, and Filamentous fungi groups and fine-tuned per group using 5-fold cross-validation, mycoCirc achieved AUROC 0.69-0.70 on held-out test species under Mode A (Genome+GTF, no RNA-seq), substantially outperforming JEDI (0.51-0.57) and CircPCBL (0.49-0.53). Cross-species evaluation on four independent fungi datasets demonstrated robust generalization across all fine-tuned variants (AUROC 0.63-0.72). Beyond gene-level classification, the JunctionEncoder module enabled backsplicing junction identification for detailed circRNA validation. We further build mycoCircAtlas, a companion database providing 319,860 high-confidence gene-circRNA predictions across 768 fungal species from Ensembl Fungi Release 113, enabling researchers to query precomputed predictions and design validation primers without local model deployment.","rel_num_authors":4,"rel_authors":[{"author_name":"Xueyan Hu","author_inst":"Peking University Health Science Center"},{"author_name":"Yueqi Jin","author_inst":"School of Basic Medical Sciences, Peking University"},{"author_name":"Juan Wang","author_inst":"Peking University Health Science Center"},{"author_name":"Ence Yang","author_inst":"Peking University Health Science Center"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Pathogen context reshapes antimicrobial peptide generation","rel_doi":"10.64898\/2026.07.01.735178","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735178","rel_abs":"Antimicrobial peptide discovery is constrained less by the number of molecules that can be generated than by the choice of which few should be tested against a defined pathogen. Most peptide generators produce broadly antimicrobial-like sequences and leave target specificity to downstream filters. Here we show that pathogen context can be introduced during generation. AMPHORA conditions a peptide-native generator on target class, pathogen genome features and strain-description text. Matched, ablated and shuffled controls showed that aligned pathogen inputs redirected generated libraries beyond coarse activity labels, whereas global shuffling weakened this effect. Same-noise counterfactuals showed that strain descriptions drove larger sequence changes, whereas genome features more strongly affected predicted structural properties. Species-level analyses revealed target-dependent enrichment. Matched bacterial inputs also shifted APEX-predicted activity rankings relative to class-only generation. The resulting libraries remained diverse, largely non-memorizing and compatible with predicted peptide-like structural features. Together, these results establish pathogen-context conditioning as a new paradigm for computational library reshaping in antimicrobial peptide generation.","rel_num_authors":10,"rel_authors":[{"author_name":"Shiyang You","author_inst":"The Hong Kong University of Science and Technology (Guangzhou), Guangzhou, Guangdong 511400, China"},{"author_name":"Chen Zhang","author_inst":"Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325000, China"},{"author_name":"Yingchun Han","author_inst":"Key Laboratory of Marine Genetic Resources, Third Institute of Oceanography, Ministry of Natural Resources, Xiamen 361005, China"},{"author_name":"Qiuyun Jiang","author_inst":"Key Laboratory of Marine Genetic Resources, Third Institute of Oceanography, Ministry of Natural Resources, Xiamen 361005, China"},{"author_name":"Xuan Guo","author_inst":"The Hong Kong University of Science and Technology (Guangzhou), Guangzhou, Guangdong 511400, China"},{"author_name":"Mingjia Li","author_inst":"The Hong Kong University of Science and Technology (Guangzhou), Guangzhou, Guangdong 511400, China"},{"author_name":"Yongxin Su","author_inst":"The Hong Kong University of Science and Technology (Guangzhou), Guangzhou, Guangdong 511400, China"},{"author_name":"Xiyang Dong","author_inst":"Key Laboratory of Marine Genetic Resources, Third Institute of Oceanography, Ministry of Natural Resources, Xiamen 361005, China"},{"author_name":"Menglin Yang","author_inst":"The Hong Kong University of Science and Technology (Guangzhou), Guangzhou, Guangdong 511400, China"},{"author_name":"Hongyuan Lu","author_inst":"The Hong Kong University of Science and Technology (Guangzhou), Guangzhou, Guangdong 511400, China"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Annual life-history strategy hitchhikes low-light adaptation in a clonal seagrass","rel_doi":"10.64898\/2026.06.29.735426","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735426","rel_abs":"While life-history strategies are typically fixed within species, evolutionary transitions between perenniality and annuality can occur. In clonal seagrasses, annual and perennial plants often coexist in the same population, providing a unique model for studying the genetic basis of this transition. Two seagrass Zostera marina populations in South Korea display a striking dichotomy: shallow-water sub-populations follow a typical perennial strategy, whereas their deep-water counterparts are annual. Here we show that this shift from perenniality to annuality, potentially caused by the SAPK7 gene, is genetically coupled with the CAO gene, which is under strong positive selection for low-light adaptation. The up-regulation of the SAPK7 gene triggers early flowering in seedlings, before the formation of any lateral shoots via asexual reproduction. In this special case where the genet contains only one ramet, the post-reproductive death of the ramet is equivalent to the death of the whole genet, which explains the annual phenotype. Our findings reveal a mechanistic example where annuality overcomes perenniality by hitchhiking on a positively selected gene. Given that the ancestral state of plants is perennial, this coupling of annuality with beneficial alleles may represent one of the pathways for the repeated evolution of annual life histories across flowering plants.","rel_num_authors":10,"rel_authors":[{"author_name":"Xiaomei Zhang","author_inst":"Laboratory of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China"},{"author_name":"Fei Zhang","author_inst":"Department of Biological Sciences, Pusan National University, Pusan 46241, Republic of Korea"},{"author_name":"Zhaxi Suonan","author_inst":"Department of Biological Sciences, Pusan National University, Pusan 46241, Republic of Korea"},{"author_name":"Yu Zhang","author_inst":"Laboratory of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China"},{"author_name":"Yu-Long Li","author_inst":"Laboratory of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China"},{"author_name":"Xiaoyu Li","author_inst":"Laboratory of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China"},{"author_name":"Seung Hyeon Kim","author_inst":"Department of Marine Biology and Aquaculture, Gyeongsang National University, Tongyeong 53064, Republic of Korea"},{"author_name":"Yi Zhou","author_inst":"Laboratory of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China"},{"author_name":"Kun-Seop Lee","author_inst":"Department of Biological Sciences, Pusan National University, Pusan 46241, Republic of Korea"},{"author_name":"Lei Yu","author_inst":"Laboratory of Marine Ecology and Environmental Sciences, Institute of Oceanology, Chinese Academy of Sciences, Qingdao 266071, China"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Synteny-aware microbial pangenome graphs reveal blueprints of genomic variation","rel_doi":"10.64898\/2026.07.03.736256","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736256","rel_abs":"Pangenomics quantifies the conserved and variable gene repertoire among genomes, but popular implementations ignore gene synteny. Graph-based approaches incorporate both gene homology and synteny, but become difficult to interpret due to pervasive rearrangements. Here we present network-pruning and graph-layout algorithms that enable interactive, synteny-aware quantification and visualization of gene conservation and variability. Applied to 29 genomes of the marine genus Undatipelagibacter (formerly SAR11 subclade Ia.3.VI), we find that genomic variability forms not a few hypervariable islands against a static backbone but a structured continuum, whose variable regions differ in scale, topology, function, and evolutionary character. Genome variation spans from ancient, specialized regions of hundreds of genes whose propensity to vary is conserved across genera, to single hypervariable genes shaped by epistatic co-selection with partners dispersed genome-wide, and shows that chromosomal context carries evolutionary information synteny-unaware pangenomics cannot capture, and some evolutionary processes act on entire functional subsystems throughout a pangenome.","rel_num_authors":11,"rel_authors":[{"author_name":"Alexander Henoch","author_inst":"Helmholtz Institute for Functional Marine Biodiversity, 26129 Oldenburg, Germany"},{"author_name":"Metehan Sever","author_inst":"Helmholtz Institute for Functional Marine Biodiversity, 26129 Oldenburg, Germany"},{"author_name":"Sarah J Tucker","author_inst":"Marine Biological Laboratory, Woods Hole, MA, United States"},{"author_name":"Florian Trigodet","author_inst":"Helmholtz Institute for Functional Marine Biodiversity, 26129 Oldenburg, Germany"},{"author_name":"Iva Veseli","author_inst":"Helmholtz Institute for Functional Marine Biodiversity, 26129 Oldenburg, Germany"},{"author_name":"Tianyi Chang","author_inst":"Helmholtz Institute for Functional Marine Biodiversity, 26129 Oldenburg, Germany"},{"author_name":"James O McInerney","author_inst":"Department of Evolution, Ecology and Behaviour, University of Liverpool, Liverpool, United Kingdom"},{"author_name":"Arda Soylev","author_inst":"Department of Computer Engineering, Necmettin Erbakan University, Konya, Turkiye"},{"author_name":"Kelle C Freel","author_inst":"Hawai'i Institute of Marine Biology, University of Hawai'i at Manoa, Kane'ohe, HI, United States"},{"author_name":"Michael S Rappe","author_inst":"Hawai'i Institute of Marine Biology, University of Hawai'i at Manoa, Kane'ohe, HI, United States"},{"author_name":"A. Murat Eren","author_inst":"University of Chicago"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"A uniform tissue-clearing framework and mesoSPIM-ultra enable cm-scale single-neuron tracing","rel_doi":"10.64898\/2026.06.29.734841","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.734841","rel_abs":"Tissue-clearing and light-sheet microscopy have transformed volumetric imaging of intact organs, yet limited mechanistic understanding of dehydration-based clearing continues to constrain rational protocol design and broader applicability. Here, we define the cardinal chemical and physical principles underlying dehydration-based tissue-clearing and establish a new pipeline for large-volume imaging. To maximize imaging performance, we developed the mesoSPIM-ultra, an upgraded mesoSPIM platform with a temperature-controlled sample chamber, a large field-of-view (FoV) camera and specialized optics to achieve long-working-distance, high-resolution imaging of cleared samples. We applied this approach to investigate the projectome of Chx10+ neurons, a cell population with complex axonal morphologies along the entire mouse spinal-cord and brain, and implicated in ipsilateral orienting behaviors. By combining behavioral analysis with post-hoc single-neuron reconstructions, we revealed previously inaccessible branching architectures and long-range projections extending from the brainstem to the spinal cord. Together, our work establishes a mechanistic foundation for tissue-clearing and scalable imaging.","rel_num_authors":35,"rel_authors":[{"author_name":"Marko Pende","author_inst":"MDI Biological Laboratory, Bar Harbor, Maine, USA"},{"author_name":"Jared M Cregg","author_inst":"Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA"},{"author_name":"Saiedeh Saghafi","author_inst":"Meso Aspheric Optics & Light Sheet Fluorescence Microscopy, FKE, TU Wien, Vienna, Austria"},{"author_name":"Samuel Broadbent","author_inst":"MDI Biological Laboratory, Bar Harbor, Maine, USA"},{"author_name":"Alma Avdibasic","author_inst":"Section of Bioelectronics, Center for Brain Research, Medical University of Vienna, Vienna, Austria"},{"author_name":"Johannes Roeles","author_inst":"MDI Biological Laboratory, Bar Harbor, Maine, USA"},{"author_name":"Sofia-Christina Papadopoulos","author_inst":"MDI Biological Laboratory, Bar Harbor, Maine, USA"},{"author_name":"Ryan P. Seaman","author_inst":"MDI Biological Laboratory, Bar Harbor, Maine, USA"},{"author_name":"Nika Pende","author_inst":"Archaea Physiology & Biotechnology Group, Department of Functional and Evolutionary Ecology, University of Vienna, Vienna, Austria"},{"author_name":"Marta Solano Mateos","author_inst":"Division of Cognitive Neurobiology, Center for Brain Research, Medical University of Vienna, Vienna, Austria"},{"author_name":"Katelyn Jamwal","author_inst":"MDI Biological Laboratory, Bar Harbor, Maine, USA"},{"author_name":"Melody Wunch","author_inst":"The Jackson Laboratory, Bar Harbor, Maine, USA"},{"author_name":"Pawel Pasierbek","author_inst":"Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna BioCenter, Vienna, Austria"},{"author_name":"Alberto Moreno-Cencerrado","author_inst":"Research Institute of Molecular Pathology, Vienna BioCenter, Vienna, Austria"},{"author_name":"Solomiia Korchynska","author_inst":"Section of Bioelectronics, Center for Brain Research, Medical University of Vienna, Vienna, Austria"},{"author_name":"Romana Hauer","author_inst":"Division of Cognitive Neurobiology, Center for Brain Research, Medical University of Vienna, Vienna, Austria"},{"author_name":"Paul Anderson","author_inst":"Division of Cognitive Neurobiology, Center for Brain Research, Medical University of Vienna, Vienna, Austria"},{"author_name":"Paul Supper","author_inst":"Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria"},{"author_name":"Maria Eleni Kastriti","author_inst":"Division of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Vienna, Austria"},{"author_name":"Daniel Reumann","author_inst":"Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna BioCenter, Vienna, Austria"},{"author_name":"Michael Moorhead","author_inst":"SyGlass Inc., Morgantown, WV, USA"},{"author_name":"Joel  H H. Graber","author_inst":"Mount Desert Island Biological Laboratory"},{"author_name":"Petra Scholze","author_inst":"Division of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna, Austria"},{"author_name":"Julia U. Henschke","author_inst":"Leibniz Institute for Neurobiology, Magdeburg, Germany"},{"author_name":"Eike Budinger","author_inst":"Leibniz Institute for Neurobiology, Magdeburg, Germany"},{"author_name":"Juergen A. Knoblich","author_inst":"Institute of Molecular Biotechnology"},{"author_name":"Thomas Klausberger","author_inst":"Division of Cognitive Neurobiology, Center for Brain Research, Medical University of Vienna, Vienna, Austria"},{"author_name":"Igor Adameyko","author_inst":"Karolinska Institutet"},{"author_name":"Tibor Harkany","author_inst":"Medical University of Vienna"},{"author_name":"Vivek Kumar","author_inst":"The Jackson Laboratory"},{"author_name":"Mary Teena Joy","author_inst":"The Jackson Laboratory, Bar Harbor, Maine, USA"},{"author_name":"Ole Kiehn","author_inst":"Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark"},{"author_name":"Hans-Ulrich Dodt","author_inst":"Section of Bioelectronics, Center for Brain Research, Medical University of Vienna, Vienna, Austria"},{"author_name":"Fabian Voigt","author_inst":"Harvard University"},{"author_name":"Prayag Murawala","author_inst":"MDI Biological Laboratory"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Dissociable structural and molecular pathways of age-related change in sustained attention","rel_doi":"10.64898\/2026.06.29.735429","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735429","rel_abs":"Sustained attention, the capacity to maintain goal-directed attention over extended periods, declines with age but with substantial individual variability across cognitively unimpaired (CU) older adults. The neurobiological mechanisms driving both the decline and its variability across CU remain poorly understood. Two candidate processes may contribute: microstructural deterioration of the superior longitudinal fasciculus (SLF), the principal white-matter tract coupling prefrontal and parietal nodes of the dorsal attention network, and subclinical accumulation of Alzheimer's disease (AD)-related pathology, which may erode attentional function through disruption of neuromodulatory systems and progressive involvement of frontoparietal cortical substrates. We combined (a) diffusion MRI tractography, quantifying SLF fractional anisotropy (FA) and mean diffusivity (MD) alongside two control tracts, the corticospinal tract (CST) and cingulum (CGC), with (b) a plasma panel indexing AD-related pathology (pTau-181, pTau-217), neuroaxonal injury (NfL), and astrocytic reactivity (GFAP) in 162 CU older adults drawn from two Stanford cohorts (plasma subsample N = 146). Sustained attention was assessed using the gradual-onset Continuous Performance Task (gradCPT) and indexed by a composite score (Att-Z) derived from discriminability (d') and response-time variability (RTV). Parallel mediation and commonality analyses were used to test whether structural and molecular pathways contribute independently to age-related attentional decline. Older age was associated with lower Att-Z ({beta} = -0.315, p < 0.001). In simultaneous three-tract regression models, only SLF microstructure uniquely predicted Att-Z (FA: {beta} = +0.275, p < 0.001; MD: {beta} = -0.320, p < 0.001). SLF microstructure mediated the age-attention relationship. At the molecular level, plasma pTau-181 ({beta} = -0.212, pFDR < 0.03) and pTau-217 ({beta} = -0.163, pFDR < 0.05) predicted Att-Z and each mediated age-related attentional decline. Yet, neither pTau isoform predicted SLF microstructure, indicating that the molecular pathway operates independently of white-matter integrity. NfL also reached FDR-corrected significance for Att-Z ({beta} = -0.156, pFDR < 0.05) but attenuated to non-significance when modelled jointly with pTau-181 or pTau-217, suggesting that the attentionally relevant component of molecular ageing is specific to AD-related pathology rather than NfL-related neuroaxonal damage. GFAP showed no association with sustained attention in any model. In parallel mediation models, SLF microstructure and plasma pTau carried significant independent indirect effects with negligible shared variance, and both pathways retained significance when modelled jointly. These findings reveal a multi-pathway architecture of attentional ageing in which structural disconnection of the dorsal attention network and accumulation of AD-related pathology operate as dissociable and additive mediators of individual differences in attention and of age-related attentional decline, detectable before clinical impairment. Their mechanistic independence identifies two separable biological targets for preserving attentional capacity in CU older adults, including those in the preclinical phase of AD.","rel_num_authors":14,"rel_authors":[{"author_name":"S Subbulakshmi","author_inst":"Stanford University"},{"author_name":"Jennifer Park","author_inst":"Stanford University"},{"author_name":"Julia Julia Rathmann-Bloch","author_inst":"Stanford University"},{"author_name":"Tyler Ward","author_inst":"Stanford University"},{"author_name":"Gloria L Cheng","author_inst":"Stanford University"},{"author_name":"Douglas S Miller","author_inst":"Stanford University"},{"author_name":"Shawn T Schwartz","author_inst":"Stanford University"},{"author_name":"Jintao Sheng","author_inst":"Stanford University"},{"author_name":"Tammy T Tran","author_inst":"Georgia Tech"},{"author_name":"Sharon J Sha","author_inst":"Stanford University"},{"author_name":"Gayle Deutsch","author_inst":"Stanford University"},{"author_name":"Alexandra N Trelle","author_inst":"STANFORD UNIVERSITY SCHOOL OF MEDICINE"},{"author_name":"Elizabeth C Mormino","author_inst":"Stanford University"},{"author_name":"Anthony D Wagner","author_inst":"Stanford University"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Dissociable structural and molecular pathways of age-related change in sustained attention","rel_doi":"10.64898\/2026.06.29.735429","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735429","rel_abs":"Sustained attention, the capacity to maintain goal-directed attention over extended periods, declines with age but with substantial individual variability across cognitively unimpaired (CU) older adults. The neurobiological mechanisms driving both the decline and its variability across CU remain poorly understood. Two candidate processes may contribute: microstructural deterioration of the superior longitudinal fasciculus (SLF), the principal white-matter tract coupling prefrontal and parietal nodes of the dorsal attention network, and subclinical accumulation of Alzheimer's disease (AD)-related pathology, which may erode attentional function through disruption of neuromodulatory systems and progressive involvement of frontoparietal cortical substrates. We combined (a) diffusion MRI tractography, quantifying SLF fractional anisotropy (FA) and mean diffusivity (MD) alongside two control tracts, the corticospinal tract (CST) and cingulum (CGC), with (b) a plasma panel indexing AD-related pathology (pTau-181, pTau-217), neuroaxonal injury (NfL), and astrocytic reactivity (GFAP) in 162 CU older adults drawn from two Stanford cohorts (plasma subsample N = 146). Sustained attention was assessed using the gradual-onset Continuous Performance Task (gradCPT) and indexed by a composite score (Att-Z) derived from discriminability (d') and response-time variability (RTV). Parallel mediation and commonality analyses were used to test whether structural and molecular pathways contribute independently to age-related attentional decline. Older age was associated with lower Att-Z ({beta} = -0.315, p < 0.001). In simultaneous three-tract regression models, only SLF microstructure uniquely predicted Att-Z (FA: {beta} = +0.275, p < 0.001; MD: {beta} = -0.320, p < 0.001). SLF microstructure mediated the age-attention relationship. At the molecular level, plasma pTau-181 ({beta} = -0.212, pFDR < 0.03) and pTau-217 ({beta} = -0.163, pFDR < 0.05) predicted Att-Z and each mediated age-related attentional decline. Yet, neither pTau isoform predicted SLF microstructure, indicating that the molecular pathway operates independently of white-matter integrity. NfL also reached FDR-corrected significance for Att-Z ({beta} = -0.156, pFDR < 0.05) but attenuated to non-significance when modelled jointly with pTau-181 or pTau-217, suggesting that the attentionally relevant component of molecular ageing is specific to AD-related pathology rather than NfL-related neuroaxonal damage. GFAP showed no association with sustained attention in any model. In parallel mediation models, SLF microstructure and plasma pTau carried significant independent indirect effects with negligible shared variance, and both pathways retained significance when modelled jointly. These findings reveal a multi-pathway architecture of attentional ageing in which structural disconnection of the dorsal attention network and accumulation of AD-related pathology operate as dissociable and additive mediators of individual differences in attention and of age-related attentional decline, detectable before clinical impairment. Their mechanistic independence identifies two separable biological targets for preserving attentional capacity in CU older adults, including those in the preclinical phase of AD.","rel_num_authors":14,"rel_authors":[{"author_name":"S Subbulakshmi","author_inst":"Stanford University"},{"author_name":"Jennifer Park","author_inst":"Stanford University"},{"author_name":"Julia Julia Rathmann-Bloch","author_inst":"Stanford University"},{"author_name":"Tyler Ward","author_inst":"Stanford University"},{"author_name":"Gloria L Cheng","author_inst":"Stanford University"},{"author_name":"Douglas S Miller","author_inst":"Stanford University"},{"author_name":"Shawn T Schwartz","author_inst":"Stanford University"},{"author_name":"Jintao Sheng","author_inst":"Stanford University"},{"author_name":"Tammy T Tran","author_inst":"Georgia Tech"},{"author_name":"Sharon J Sha","author_inst":"Stanford University"},{"author_name":"Gayle Deutsch","author_inst":"Stanford University"},{"author_name":"Alexandra N Trelle","author_inst":"STANFORD UNIVERSITY SCHOOL OF MEDICINE"},{"author_name":"Elizabeth C Mormino","author_inst":"Stanford University"},{"author_name":"Anthony D Wagner","author_inst":"Stanford University"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Distillation enables scalable high-fidelity virtual screening across ultra-large chemical libraries","rel_doi":"10.64898\/2026.06.29.735361","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735361","rel_abs":"Accurate virtual screening of ultra-large chemical libraries remains challenging. Existing approaches rely on lower-fidelity scoring functions or sampling-based strategies that can limit predictive accuracy and bias the exploration of chemical space. Here, we present FastBindRank, a distillation-based framework that transfers the predictive power of the structure-based model Boltz-2 into an efficient sequence-based surrogate. Trained on ~1% of the 122-million-compound PubChem library, FastBindRank enables high-fidelity screening at scale. Applied to histone deacetylase 11 (HDAC11), FastBindRank substantially enriched high-confidence binders relative to the background chemical space. The lightweight model captured structural patterns associated with predicted binding, revealing structural determinants of binding. Under a comparable computational budget, FastBindRank achieved a 74-fold increase in hit rate and over a 30-fold increase in discovery yield over direct subset-based screening. Experimental validation confirmed the activity of two novel compounds. These results establish distillation as a practical strategy for scalable, high-fidelity virtual screening of ultra-large chemical libraries.","rel_num_authors":10,"rel_authors":[{"author_name":"Jiawei Dai","author_inst":"Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA."},{"author_name":"Yueyue Wang","author_inst":"Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA."},{"author_name":"Naing Lin Shan","author_inst":"Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA."},{"author_name":"Marco Mariani","author_inst":"Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA."},{"author_name":"Zimeng Yu","author_inst":"Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA."},{"author_name":"Qin Yan","author_inst":"Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA."},{"author_name":"Lalit K. Golani","author_inst":"Yale Center for Molecular Discovery, West Haven, Connecticut, USA."},{"author_name":"Yulia V. Surovtseva","author_inst":"Yale Center for Molecular Discovery, West Haven, Connecticut, USA."},{"author_name":"William H. Lee","author_inst":"Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA."},{"author_name":"Lajos Pusztai","author_inst":"Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA."}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Opportunistic pathogenicity in fungi can transcend species boundaries","rel_doi":"10.64898\/2026.07.02.736111","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736111","rel_abs":"The ability to opportunistically infect humans has evolved multiple times across fungi and is a major burden to public health. Opportunistic pathogenicity requires the confluence of pre-existing traits in the fungus that facilitate host colonization (e.g., the ability to grow at 37C) and the existence of host immune filters that permit the survival of some colonizers (e.g., inborn errors of immunity). Numerous studies have previously shown that fungal pathogens can exhibit extensive strain-to-strain variation in the ability to cause disease. Moreover, it is also well established that non-pathogenic fungi can occasionally cause severe infections. Together, these observations provoke the question: what differentiates opportunistic fungal pathogens from non-pathogens? To empirically address this, we directly compared phenotypic, metabolomic, and genomic variation between Aspergillus fumigatus, an organism responsible for more than 300,000 infections per year, and Aspergillus fischeri, a close relative of A. fumigatus that is not considered clinically relevant. By examining 26 phenotypic traits across 16 representative strains of A. fumigatus and 16 of A. fischeri, we find that infection-relevant traits measured under in vitro monoculture conditions show species-specific distributions, whereas traits measured under in vitro coculture with murine macrophages overlap in their distributions. Strikingly, strains of the two species also overlap in their virulence profiles in an immunocompromised murine model of pulmonary aspergillosis; three strains of A. fischeri exhibit lethality rates of >50% while two A. fumigatus strains were among the least virulent of all 32 strains tested. Consistent with the observed overlap, we could not statistically associate variation in virulence to variation in the presence of specific genomic elements, phenotypic traits, or secondary metabolites. Our results raise the hypothesis that opportunistic pathogenicity can extend beyond the boundaries of individual species. We propose a conceptual model where the opportunistic pathogenic potential of any fungal strain is the product of complex interactions among numerous genomic, ecological, and host immunity factors.","rel_num_authors":14,"rel_authors":[{"author_name":"David Rinker","author_inst":"Vanderbilt University"},{"author_name":"Thomas J. C. Sauters","author_inst":"Vanderbilt University"},{"author_name":"Adiyantara Gumilang","author_inst":"Vanderbilt University"},{"author_name":"Olivia L. Riedling","author_inst":"Vanderbilt University"},{"author_name":"Karin Steffen","author_inst":"Vanderbilt University"},{"author_name":"Camila F Pinzan","author_inst":"Universidade de Sao Paulo Campus de Ribeirao Preto"},{"author_name":"Thaila Reis","author_inst":"Universidade de Sao Paulo"},{"author_name":"Patricia Alves de Castro","author_inst":"Universidade de Sao Paulo"},{"author_name":"Manuel Rangel-Grimaldo","author_inst":"University of North Carolina at Greensboro"},{"author_name":"Huzefa  A. Raja","author_inst":"University of North Carolina at Greensboro"},{"author_name":"John G Gibbons","author_inst":"University of Massachusetts Amherst"},{"author_name":"Gustavo Goldman","author_inst":"Universidade de Sao Paulo"},{"author_name":"Nicholas H. Oberlies","author_inst":"University of North Carolina at Greensboro"},{"author_name":"Antonis Rokas","author_inst":"Vanderbilt University"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Protein Surface Site Determines the Evolutionary Accessibility of Allosteric Regulation","rel_doi":"10.64898\/2026.07.02.735819","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.735819","rel_abs":"Domain recombination is a major source of new allosteric regulation in both evolved and engineered proteins. However, the sequence and structural features that govern where new allostery may emerge remain poorly understood. Here, we test the hypothesis that the evolutionary accessibility of allosteric regulation following domain insertion is constrained by local surface context, specifically association with pre-existing cooperative networks known as protein sectors. We began with two synthetic domain fusions wherein the Avena sativa light-oxygen-voltage (LOV2) domain was inserted into Escherichia coli dihydrofolate reductase (DHFR) at either a sector connected or non-sector connected surface. The insertion sites are only separated by five residues and both DHFR enzymes retain similar catalytic activity, yet the sector connected version exhibits a light-dependent allosteric phenotype, while the non-sector connected version does not. Using deep mutational scanning, we measured the effect of nearly all single point mutations on allostery in each chimera. The sector-connected DL121 was significantly more evolvable, possessing numerous allostery-tuning single mutants. In contrast, DL116 lacked statistically significant mutants that introduce allosteric regulation, suggesting the protein surface used by DL116 may be an evolutionary \"dead end\" for a regulatory phenotype. Surprisingly, DL116 did not show cooperative unfolding at temperatures up to 80 {degrees}C, suggesting that enhanced protein stability does not promote the evolvability of allosteric regulation as it does with other phenotypes. Together, our findings show that protein surface context influences the mutational pathways available for allosteric regulation, consistent with the view that sector-connected surface sites harbor a latent capacity for allostery while other locations are more evolutionarily inert.","rel_num_authors":5,"rel_authors":[{"author_name":"Jerry C Dinan","author_inst":"Johns Hopkins University"},{"author_name":"James W McCormick","author_inst":"University of Michigan"},{"author_name":"Rishi Soni","author_inst":"Johns Hopkins University"},{"author_name":"Samuel Thompson","author_inst":"Stanford University"},{"author_name":"Kimberly A Reynolds","author_inst":"Johns Hopkins University"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Drug Functional Site-Unknown Molecular Targets Exemplified by SARS-CoV-2 pseudoknot and ribosomal frameshifting-modulators","rel_doi":"10.64898\/2026.07.02.735960","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.735960","rel_abs":"The -1 Programmed Ribosomal Frameshifting (-1 PRF) signal of SARS-CoV-2, driven by a conserved three-stemmed RNA pseudoknot (PK), is indispensable for viral replication and represents a structurally stable yet underexplored therapeutic target. Unlike rapidly mutating viral proteins, this RNA element offers an opportunity for durable intervention but has historically been considered 'undruggable'. We developed an integrative drug discovery and characterization pipeline that combines molecular docking, molecular dynamics simulations, and dual-luciferase assays to systematically identify and validate frameshifting-efficiency (Feff) modulators from FDA-approved compounds. To move beyond traditional similarity-based screening, we introduced a contact-distribution-matching method, which ranks candidate compounds by comparing their predicted RNA interaction fingerprints with those of reference modulators. This computational approach, paired with experimental validation, enabled us to expand the repertoire of Feff modulators and establish correlations between binding patterns and functional outcomes. To uncover the underlying mechanisms, we applied steered molecular dynamics simulations and single-molecule optical tweezers measurements, revealing that Feff-enhancing modulators preferentially stabilize the remote stem (stem 3) of the PK, promoting variety of intermediate force species with the beginning base pairs of stem 1 being refolded, even after those base pairs have been unwound by ribosome. The refold of the tips of the stem 1 in turn 'push back' the ribosome on the slippery sequence to result in enhanced frameshifting. On the other hand, Feff-suppressing modulators rigidify early stem regions, increasing resistance to ribosomal progression and increase the drop-off rate, eventually leading to a reduced -1 frame to 0 frame ratio in translation. Together, these findings provide the first integrated demonstration of how small molecules can modulate -1 PRF by altering RNA PK folding dynamics. More broadly, our framework establishes a generalizable strategy for rationally targeting structured RNAs with repurposed drugs and offers new opportunities to expand the druggable genome to include noncoding RNA elements and other biomolecular targets lacking known functional sites.","rel_num_authors":6,"rel_authors":[{"author_name":"Ahmed Mohamed Ragab","author_inst":"Institute of Bioinformatics and Structural Biology, National Tsing Hua University"},{"author_name":"Christopher Llynard D Ortiz","author_inst":"Institute of Bioinformatics and Structural Biology, National Tsing Hua University"},{"author_name":"Yu-Tong Huang","author_inst":"Institute of Molecular and Cellular Biology, National Taiwan University"},{"author_name":"Jian-Zhou Wang","author_inst":"Institute of Molecular and Cellular Biology, National Taiwan University"},{"author_name":"Jin-Der Wen","author_inst":"Institute of Molecular and Cellular Biology, National Taiwan University"},{"author_name":"Lee-Wei Yang","author_inst":"National Tsing Hua University"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Rare sex punctuates strict asexual reproduction in the clonal raider ant, Ooceraea biroi","rel_doi":"10.64898\/2026.07.01.735869","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735869","rel_abs":"While asexual species can often outcompete their sexual counterparts over ecological timescales, their long-term evolutionary success is hindered by a diminished ability to purge deleterious mutations and to adapt to changing environments. However, some asexual species persist for millions of years, and a major question in evolutionary biology is how they do so. One solution is to occasionally reproduce sexually, as has been shown in a handful of primarily asexual species. Here, we investigate the possibility of rare sex in the clonal raider ant, Ooceraea biroi. We report the whole-genome sequence of a previously uncharacterized clonal line and, using population genetic and phylogenetic analyses, show that it originated through sexual reproduction between two extensively studied clonal lines. The mitochondrial genome of this clonal line differs from that of the maternal clonal line at only a single nucleotide, suggesting that the sexual reproduction event occurred within the past few hundred years. These results demonstrate that sex occurs sporadically in the clonal raider ant, allowing it to generate new genetic combinations and potentially to overcome some of the costs of asexuality.","rel_num_authors":3,"rel_authors":[{"author_name":"Kip D Lacy","author_inst":"Laboratory of Social Evolution and Behavior, The Rockefeller University, New York, NY, USA"},{"author_name":"Nicolas Ch\u00e2line","author_inst":"Institute of Psychology, University of S\u00e3o Paulo, S\u00e3o Paulo, Brazil"},{"author_name":"Daniel J.C. Kronauer","author_inst":"Laboratory of Social Evolution and Behavior, The Rockefeller University, New York, NY, USA; Howard Hughes Medical Institute, New York, NY, USA"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Quantifying Asymmetric Coevolutionary Dynamics using Normalized Phylogenetic Costs","rel_doi":"10.64898\/2026.06.29.734822","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.734822","rel_abs":"Coevolutionary studies aim to characterize associations, such as virus-host relationships, by using phylogenetic distances to quantify the topological concordance between the phylogenies of interacting taxa. However, phylogenetic distances cannot capture asymmetrical relationships that arise from differences in sampling, evolutionary rates, or characterizations between datasets. Furthermore, a lack of accurate normalization complicates the interpretation and validation of coevolutionary analyses. To address these limitations, we employed the Asymmetric Cluster Affinity and Cluster Support costs as a general framework to quantify coevolutionary patterns across multiple biological scales. We benchmarked the precision of these costs by reanalyzing a curated dataset documenting interspecies transmission frequencies across nineteen virus-host phylogenies. Our results corroborate prior findings showing that all virus families under study can cross species boundaries; however, the asymmetric costs provide a more granular representation, demonstrating that the frequency of such events varies significantly across families. We then applied the Asymmetric Cluster Support cost to quantify preferential gene segment pairings within the Bluetongue virus genome. This analysis revealed a close phylogenetic association between the outer capsid proteins VP2 and VP5, likely reflecting shared selective pressures due to their critical roles in cell entry and exit. In contrast, gene segments encoding nonstructural proteins exhibited discordant evolutionary histories relative to other segments. Finally, we demonstrated that the Asymmetric Cluster Support cost can detect coevolutionary dynamics in swine influenza A virus, identifying novel gene pairings indicative of major viral reassortment events. Overall, our approach demonstrates that normalized asymmetric phylogenetic costs accurately capture complex biological relationships and provide a robust framework for quantifying fine-scale coevolutionary dynamics in rapidly evolving pathogens.","rel_num_authors":10,"rel_authors":[{"author_name":"Sanket Wagle","author_inst":"Department of Computer Science, Iowa State University, Ames, IA 50010, USA"},{"author_name":"Alexey Markin","author_inst":"Virus and Prion Research Unit, National Animal Disease Center, Agricultural Research Service, United States Department of Agriculture, Ames, IA 50010, USA"},{"author_name":"Tyler J Sherman","author_inst":"Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80526, USA"},{"author_name":"Christie Mayo","author_inst":"Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80526, USA"},{"author_name":"Tillie J Dunham","author_inst":"Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80526, USA"},{"author_name":"Corey Brelsfoard","author_inst":"Department of Biological Sciences, Texas Tech University, Lubbock, TX 79409, USA"},{"author_name":"Lee W. Cohnstaedt","author_inst":"Foreign Arthropod-Borne Animal Diseases Research Unit, The National Bio and Agro-Defense Facility, Agricultural Research Service, United States Department of Ag"},{"author_name":"William C Wilson","author_inst":"Foreign Arthropod-Borne Animal Diseases Research Unit, The National Bio and Agro-Defense Facility, Agricultural Research Service, United States Department of Ag"},{"author_name":"Tavis K Anderson","author_inst":"Virus and Prion Research Unit, National Animal Disease Center, Agricultural Research Service, United States Department of Agriculture, Ames, IA 50010, USA"},{"author_name":"Oliver Eulenstein","author_inst":"Department of Computer Science, Iowa State University, Ames, IA 50010, USA"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"The Effect of Depriving the Aedes aegypti Mosquito of Natural Levels of Radiation","rel_doi":"10.64898\/2026.06.29.735377","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735377","rel_abs":"Organisms have spent their life histories exposed to background levels of natural ionizing radiation. To document the role that radiation plays, the deprivation of these natural levels has been studied by incubating organisms in the shielded space of underground laboratories. We report here on two studies (Study I and Study II) using Aedes aegypti for the first time as a model organism incubated 655 meters underground at the Waste Isolation Pilot Plant (WIPP) outside of Carlsbad, New Mexico, U.S.A. Male mosquitos were incubated at the surface exposed to natural background radiation, and were compared to two underground treatments in which incubators were supplemented with radiation sources used to mimic background and these groups were compared to the underground, radiation-deprived treatment. In Study I, the mosquitos incubated underground in the absence of natural radiation had higher levels of mortality compared to those incubated at the surface and PCA plots of the two transcriptomes were clearly differentiated. Study II was conducted the following year and the experiment was narrowed to include only the surface control and underground, radiation-deprived treatment which allowed for four biological replicates. Again, there was a higher level of mortality in the mosquitos grown underground compared mosquitos grown at the surface. Transcriptomes were not as clearly differentiated by PCA analysis and fecundity data were similar between the two groups. Functional analysis of transcriptomic DEGs from two independent studies suggested there are stress responses in radiation deprived mosquitoes. The absence of a secondary stressor in Study II is discussed as an explanation for the transcriptome differences in the two experiments.","rel_num_authors":4,"rel_authors":[{"author_name":"Liam Goodale","author_inst":"University of New Mexico School of Medicine"},{"author_name":"Cung Thawng","author_inst":"DNA Polymerase Technology Inc"},{"author_name":"Immo Hansen","author_inst":"New Mexico State University"},{"author_name":"Geoffrey Smith","author_inst":"New Mexico State University Department of Biology"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Linguistic Analysis of Chinese Oral Performance in Different Tasks of Chinese Second Language Learners and Native Speakers","rel_doi":"10.64898\/2026.06.29.735371","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735371","rel_abs":"This study investigated how different forms of task influence the oral performance of Chinese second-language learners and native speakers. By analyzing data from 40 Chinese second-language learners and 40 native speakers through picture description tasks, formal and informal questions, and questions with different emotions (happy and unhappy), it was found that different task characteristics significantly affected language performance. Short picture tasks led to higher communication efficiency and noun rates but more errors, while long story tasks showed higher verb rates, function word rates, etc. Formal questions had more characters and nouns but lower communication efficiency compared to informal ones. Also, happy emotion questions resulted in fewer characters, sentences, and errors than unhappy emotion questions. These findings contribute to the theoretical understanding of task-based language performance in Chinese as a second language and offer practical implications for teaching, textbook compilation, and student evaluation.","rel_num_authors":2,"rel_authors":[{"author_name":"Yuru Gao","author_inst":"Ningxia Medical University"},{"author_name":"Ling Zhang","author_inst":"The Education University of Hong Kong"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Pangenome-based human genome analysis improves trait association and genomic prediction","rel_doi":"10.64898\/2026.07.01.735728","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735728","rel_abs":"The Human Pangenome Reference Consortium has generated 462 open-access reference genomes and a variation graph that represents differences among them, providing a substrate for pangenome-based analysis methods that overcome the longstanding limitation of comparing all genomic data to a single linear reference. A key unresolved question is the extent to which these approaches can improve trait mapping. We investigate this using the genetics of gene expression variation as a model. We developed a graph-based method (EdgeDepth) for associating sequence variation with traits using short-read genome sequencing data, and show that it captures complex forms of genetic variation missed by other methods. We evaluated trait mapping performance using 430 samples with deep RNA-seq data, and found that pangenomic methods enable the detection of expression quantitative trait loci involving multiallelic indels and structural variants, leading to increased power at a subset of genes. These include 812 genes (7.9% of total) with [&ge;]20% improvement in statistical significance relative to the 1000 Genomes Project callset, and 185 (1.8%) with a 50% improvement, 10 of which are candidates to explain prior GWAS results. Notably, these analyses implicate GBAP1 pseudogene copy number as a causal factor in Crohn's disease, likely via miRNA-mediated regulation of GBA1, which explains prior GWAS results based on flanking SNPs. The inclusion of pangenome-specific variation also improved the performance of gene expression prediction models, with median variance explained increasing from 10.1% to 12.5%, and 14.6% of genes showing significant improvement ({Delta}r2>0.05). Taken together, these results suggest that integration of pangenomic methods into human genetic studies will improve trait association and genomic prediction at a meaningful subset of genes.","rel_num_authors":11,"rel_authors":[{"author_name":"Shuangjia Lu","author_inst":"Yale University School of Medicine"},{"author_name":"Wen-Wei Liao","author_inst":"Yale University School of Medicine"},{"author_name":"Marianne K. DeGorter","author_inst":"Stanford University School of Medicine"},{"author_name":"Page C. Goddard","author_inst":"Stanford University School of Medicine"},{"author_name":"Jana Ebler","author_inst":"Heinrich Heine University"},{"author_name":"Tsung-Yu Lu","author_inst":"University of Southern California"},{"author_name":"Mark J. P. Chaisson","author_inst":"University of Southern California"},{"author_name":"Tobias Marschall","author_inst":"Heinrich Heine University"},{"author_name":"Stephen B. Montgomery","author_inst":"Stanford University School of Medicine"},{"author_name":"Nathan O. Stitziel","author_inst":"Washington University School of Medicine"},{"author_name":"Ira M. Hall","author_inst":"Yale School of Medicine"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Pangenome-based human genome analysis improves trait association and genomic prediction","rel_doi":"10.64898\/2026.07.01.735728","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.735728","rel_abs":"The Human Pangenome Reference Consortium has generated 462 open-access reference genomes and a variation graph that represents differences among them, providing a substrate for pangenome-based analysis methods that overcome the longstanding limitation of comparing all genomic data to a single linear reference. A key unresolved question is the extent to which these approaches can improve trait mapping. We investigate this using the genetics of gene expression variation as a model. We developed a graph-based method (EdgeDepth) for associating sequence variation with traits using short-read genome sequencing data, and show that it captures complex forms of genetic variation missed by other methods. We evaluated trait mapping performance using 430 samples with deep RNA-seq data, and found that pangenomic methods enable the detection of expression quantitative trait loci involving multiallelic indels and structural variants, leading to increased power at a subset of genes. These include 812 genes (7.9% of total) with [&ge;]20% improvement in statistical significance relative to the 1000 Genomes Project callset, and 185 (1.8%) with a 50% improvement, 10 of which are candidates to explain prior GWAS results. Notably, these analyses implicate GBAP1 pseudogene copy number as a causal factor in Crohn's disease, likely via miRNA-mediated regulation of GBA1, which explains prior GWAS results based on flanking SNPs. The inclusion of pangenome-specific variation also improved the performance of gene expression prediction models, with median variance explained increasing from 10.1% to 12.5%, and 14.6% of genes showing significant improvement ({Delta}r2>0.05). Taken together, these results suggest that integration of pangenomic methods into human genetic studies will improve trait association and genomic prediction at a meaningful subset of genes.","rel_num_authors":11,"rel_authors":[{"author_name":"Shuangjia Lu","author_inst":"Yale University School of Medicine"},{"author_name":"Wen-Wei Liao","author_inst":"Yale University School of Medicine"},{"author_name":"Marianne K. DeGorter","author_inst":"Stanford University School of Medicine"},{"author_name":"Page C. Goddard","author_inst":"Stanford University School of Medicine"},{"author_name":"Jana Ebler","author_inst":"Heinrich Heine University"},{"author_name":"Tsung-Yu Lu","author_inst":"University of Southern California"},{"author_name":"Mark J. P. Chaisson","author_inst":"University of Southern California"},{"author_name":"Tobias Marschall","author_inst":"Heinrich Heine University"},{"author_name":"Stephen B. Montgomery","author_inst":"Stanford University School of Medicine"},{"author_name":"Nathan O. Stitziel","author_inst":"Washington University School of Medicine"},{"author_name":"Ira M. Hall","author_inst":"Yale School of Medicine"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Adenosine A2B Receptor Activation: A Novel Therapeutic Strategy for Accelerating Liver Recovery After Acetaminophen Overdose","rel_doi":"10.64898\/2026.06.29.735109","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735109","rel_abs":"An acetaminophen (APAP) overdose is the leading cause of drug-induced hepatotoxicity and acute liver failure (ALF) in the United States. While N-acetylcysteine (NAC), is highly effective when administered early after an overdose, its efficacy decreases with delayed administration. Since most patients present late to the clinic, there is an urgent need for novel late-acting therapeutic options to prevent progression to ALF. We previously demonstrated the benefit of delayed activation of the Adenosine A2B Receptor (A2BAR) in attenuating APAP-induced hepatotoxicity and this study focuses on its effects on liver recovery after injury. Fasted male C57BL\/6J mice were treated with 300 mg\/kg APAP, followed by activation of A2BAR 6 or 9 h later and sacrifice 24, 48 or 72 h post-APAP with evaluation of liver injury, the innate immune response and liver regeneration. Delayed activation of A2BAR significantly enhanced liver recovery, with accelerated repopulation of the liver by Kupffer cells, increased macrophage migration to the necrotic areas and their faster resolution. A2BAR activation also upregulated lipid metabolism related genes in non-parenchymal cells and cell proliferation and metabolism genes in hepatocytes. Remarkably, genes such as Cidec and Plin2, crucial for lipid droplet formation, were upregulated, indicating that A2ABR activation enhances lipid metabolism which plays a key role in providing energy for liver regeneration. Overall, these findings highlight the potential of A2BAR activation not only in protecting against liver injury, but also in promoting and accelerating liver regeneration by modulating the innate immune responses and metabolic pathways.","rel_num_authors":5,"rel_authors":[{"author_name":"Giselle Sanchez-Guerrero","author_inst":"University of Kansas Medical Center"},{"author_name":"David Umbaugh","author_inst":"University of Kansas Medical Center"},{"author_name":"Nga Nguyen","author_inst":"University of Kansas Medical Center"},{"author_name":"Hartmut Jaeschke","author_inst":"University of Kansas Medical Center"},{"author_name":"Anup Ramachandran","author_inst":"University of Kansas Medical Center"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Contextualised real-time mass spectrometry improves glycosylation detection and characterisation","rel_doi":"10.64898\/2026.07.03.736344","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736344","rel_abs":"Glycosylation is a structurally diverse, non-template-driven modification whose analysis by liquid chromatography-mass spectrometry is constrained by discovery-mode acquisition rules developed for proteomics. Data-dependent acquisition filters, such as intensity-based precursor selection and charge-state exclusion, map poorly onto glycan analysis, which span wide ranges of charge state and abundance independent of their biological importance. Here we present glycosylation real-time mass spectrometry (GlycoRTMS), an instrument-API method that annotates observed precursor masses with glycan compositions in real time and uses this context to guide fragmentation. Composition-aware precursor prioritisation sampled deeper into the precursor space, expanding MS2 coverage of a hyaluronic acid hydrolysate from four to eight oligosaccharide subunits. Charge-state-specific collision energy equations tailored to oligosaccharides produced complete fragment ladders where fixed normalised collision energy did not. MS3 triggering gated by both diagnostic ions and glycan composition matching enabled efficient, chromatography-compatible characterisation of O-acetylated sialic acids and identified product ions specific to O-acetylation. Together, these strategies improve both the depth and quality of glycan detection and characterisation within a single injection.","rel_num_authors":2,"rel_authors":[{"author_name":"Maia I Kelly","author_inst":"Protea Glycosciences Pty Ltd"},{"author_name":"Christopher Ashwood","author_inst":"Protea Glycosciences Pty Ltd"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Internalized Components of Membrane Attack Complexes Disrupt Proteostasis and Acquire Alarmin-Like Properties","rel_doi":"10.64898\/2026.07.03.736247","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.03.736247","rel_abs":"Immune effects of membrane attack complexes (MAC) have been widely attributed to their abilities to cause cell death. Here, we show that the MAC component, C9, forms non-cytolytic aggregates with pro-inflammatory effects. Intracellular aggregates of C9 are detected within inflamed tissues of patients in association with endothelial cell (EC) activation but not increased cell death. We identify NUMBL as a Rab35 effector that directly binds surface-bound C9 to promote C9 internalization and entry into the endolysosomal pathway. Within acidified endolysosomes, C9 forms insoluble aggregates that are targeted for degradative aggrephagy in a process that activates NF-{kappa}B. For C9 aggrephagy to occur, ZFYVE21, a Rab5 effector, complexes with RNF34 to bridge C9 aggregates to LC3B+ aggresome membranes. We detect C9 aggregates in vivo, and we show that a ZFYVE21-RNF34 signaling axis is required for C9 aggrephagy and NF-{kappa}B -dependent EC activation in three separate mouse models. Mice with conditional loss of ZFYVE21 in ECs show reduced aggregraphy, resulting in attenuated systemic inflammation and reduced tissue injury following skin transplantation. Our data show that the C9 component of MACs forms intracellular aggregates with alarmin-like properties.","rel_num_authors":26,"rel_authors":[{"author_name":"Guiyu Song","author_inst":"Section of Cardiovascular Medicine, Yale University School of Medicine"},{"author_name":"Zihan Ma","author_inst":"Section of Cardiovascular Medicine, Yale University School of Medicine"},{"author_name":"Matthew Fan","author_inst":"Section of Cardiovascular Medicine, Yale University School of Medicine"},{"author_name":"Liying He","author_inst":"Section of Cardiovascular Medicine, Yale University School of Medicine"},{"author_name":"Yulong Lan","author_inst":"Department of Neurosurgery, School of Medicine Zhejiang University"},{"author_name":"Weihao Li","author_inst":"Department of Vascular Surgery, Peking University Peoples Hospital"},{"author_name":"Zhengtao Jiang","author_inst":"Section of Cardiovascular Medicine, Yale University School of Medicine"},{"author_name":"Quan Jiang","author_inst":"Yale University School of Medicine"},{"author_name":"Dylan P. Noone","author_inst":"Department of Life Sciences, Imperial College London"},{"author_name":"Andrea Nans","author_inst":"Structural Biology Science Technology Platform The Francis Crick Institute"},{"author_name":"Kamal L. Nahas","author_inst":"Beamline B24, Diamond Light Source"},{"author_name":"Mahsa Nouri Barkestani","author_inst":"Section of Cardiovascular Medicine, Yale University School of Medicine"},{"author_name":"Shaoxun Wang","author_inst":"Dept of Surgery, Yale University School of Medicine"},{"author_name":"Qianxun Wang","author_inst":"Section of Cardiovascular Medicine, Yale University School of Medicine"},{"author_name":"Pengwei Ren","author_inst":"Dept of Surgery, Yale University School of Medicine"},{"author_name":"Jolin Cheng","author_inst":"Section of Cardiovascular Medicine, Yale University School of Medicine"},{"author_name":"Yinuo Zang","author_inst":"Section of Cardiovascular Medicine, Yale University School of Medicine"},{"author_name":"Haitian Zhou","author_inst":"Section of Cardiovascular Medicine, Yale University School of Medicine"},{"author_name":"Justin Johnson","author_inst":"Department of Immunobiology, Yale University School of Medicine"},{"author_name":"Clancy Mullan","author_inst":"Department of Immunobiology, Yale University School of Medicine"},{"author_name":"Xiangyu Gong","author_inst":"Dept of Pharmacological Sciences, Yale University School of Medicine"},{"author_name":"Doryen Bubeck","author_inst":"Imperial College London, The Francis Crick Institute"},{"author_name":"Gilbert Moeckel","author_inst":"Dept of Pathology, Yale University School of Medicine"},{"author_name":"Michael Mak","author_inst":"Dept of Pharmacological Sciences, Yale University School of Medicine"},{"author_name":"George Tellides","author_inst":"Dept of Surgery, Yale University School of Medicine"},{"author_name":"Dan Jane-wit","author_inst":"Section of Cardiovascular Medicine, Yale University School of Medicine"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Carboxypeptidase activity drives L,D-transpeptidase essentiality during vegetative growth and sporulation in Clostridioides difficile","rel_doi":"10.64898\/2026.06.30.735746","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.735746","rel_abs":"In most bacteria, peptidoglycan contains mainly 4-3 crosslinks formed by penicillin-binding proteins (PBPs). But in the opportunistic pathogen Clostridioides difficile, 70% of the crosslinks are 3-3 crosslinks formed by L,D-transpeptidases (LDTs), and LDTs are essential for viability. PBPs and LDTs use different acyl donors for crosslinking; PBPs require a pentapeptide, while LDTs require a tetrapeptide. Here, we determined the source of the tetrapeptides in C. difficile and investigated the consequences of reengineering PG crosslinking from predominantly 3-3 to exclusively 4-3. We found that two D-alanyl-D-alanine carboxypeptidases (DD-CPase), DacA and DacC, supply LDTs with tetrapeptides during vegetative growth. Deleting these enzymes was sufficient to bypass the normal requirement for LDTs. The resulting mutant ({Delta}dacAC {Delta}ldt) was remarkably healthy despite the absence of 3-3 crosslinks. Its only major phenotypic defect was a 3- to 4-log decrease in sporulation, which could, however, be overcome by deleting a third DD-CPase, dacB. These findings fill gaps in our understanding of the pathway for LD-transpeptidation in C. difficile and imply that LDTs are not essential components of the elongasome or divisome, both of which function well in the complete absence of LDTs, provided there is sufficient pentapeptide to sustain crosslinking by PBPs. Thus, LDTs are essential for viability because C. difficile has intrinsically high levels of DD-CPase activity. Finally, we propose a model for how PBPs and LDTs work together during PG synthesis. In this model, PBPs construct a sparsely crosslinked PG sacculus that is subsequently strengthened with crosslinks introduced by LDTs.","rel_num_authors":6,"rel_authors":[{"author_name":"Kevin Bollinger","author_inst":"The University of Iowa"},{"author_name":"Ute M\u00fch","author_inst":"The University of Iowa Department of Microbiology and Immunology"},{"author_name":"Paige B Brannen","author_inst":"The University of Iowa Department of Microbiology and Immunology"},{"author_name":"David L Popham","author_inst":"Virginia Polytechnic Institute and State University"},{"author_name":"David S. Weiss","author_inst":"The University of Iowa Department of Microbiology and Immunology"},{"author_name":"Craig D. Ellermeier","author_inst":"The University of Iowa"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"The NORAD-pumilio regulatory axis links lncRNA dysregulation to tau propagation-associated phenotypes","rel_doi":"10.64898\/2026.06.30.735697","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.735697","rel_abs":"Long non-coding RNAs (lncRNAs) are increasingly implicated in neurodegenerative disease, yet their roles in tauopathy remain poorly understood. Here, we defined the lncRNA landscape across iPSC-derived neurons, astrocytes, and microglia harboring the frontotemporal dementia-associated MAPT IVS10+16 mutation and investigated how lncRNA dysregulation interfaces with tau pathology. Transcriptomic analyses revealed extensive cell-type specific lncRNA expression changes, with neurons exhibiting the greatest degree of mutation-associated remodeling. Comparative analyses with MAPT IVS10+16 patient brain tissue identified NORAD and MIR22HG as lncRNAs significantly dysregulated across all three cell types and human brains. NORAD was also altered in Alzheimer disease and Parkinson disease brains, suggesting a broader role in neurodegenerative disease. Mechanistically, NORAD-associated protein networks converged on pathways related to RNA regulation, cytoskeletal organization, proteostasis, and tau interaction networks. Given the established role of NORAD in regulating PUM1 and PUM2 RNA-binding (pumilio) proteins, we examined the NORAD-pumilio axis and identified enrichment of pumilio-associated pathways linked to autophagy, endocytosis, proteostasis, and cytoskeletal regulation. NORAD depletion reduced tau seeding and uptake, whereas functional depletion of PUM1 or PUM2 increased both processes, supporting an antagonistic relationship between NORAD and pumilio signaling in modulation of tau aggregation. Together, these findings identify widespread lncRNA dysregulation across neural cell types in the setting of a MAPT mutation and nominate the NORAD-pumilio axis as a regulatory pathway linking RNA homeostasis and tau propagation biology.","rel_num_authors":13,"rel_authors":[{"author_name":"Joseph E Zemke","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Guangming Huang","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Emma Starr","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Matthew Broder","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Jacob Marsh","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Arun Renganathan","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Bridget Phillips","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Thomas Marsh","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Miguel Minaya","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Carlos Cruchaga","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Abhirami K Iyer","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"- Dominantly Inherited Alzheimer Network","author_inst":"Washington University in St. Louis School of Medicine"},{"author_name":"Celeste M Karch","author_inst":"Washington University in St. Louis School of Medicine"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Humanized tauopathy chimeras uncover microglial and lncRNA strategies for neuroprotection","rel_doi":"10.64898\/2026.07.02.736124","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736124","rel_abs":"Human genetics implicates innate immunity as a key modifier of tau toxicity, yet human-specific neuroimmune mechanisms remain difficult to test in vivo. Here, we developed HuMiNAX, the first humanized iPSC-based neuroimmune xenograft model of tau-associated neurodegeneration, enabling human microglia to interact with human neurons and astrocytes in the adult mouse brain. In HuMiNAX, tau seeding induced aggregation only in mutation-carrying human neural grafts, causing neuron loss and inflammatory activation of human microglia. Progranulin-overexpressing human microglia dampened tau-associated inflammation, preserved neurons, and restored neuronal gene-expression and RNA-splicing programs, supporting microglial control of neuronal resilience. CRISPRi knockdown of the human-specific lncRNA HNRNPK-AS1 also protected neurons in HuMiNAX. These findings establish HuMiNAX as a human neuroimmune model of tauopathy and identify microglial and RNA-mediated strategies of neuronal resilience.","rel_num_authors":15,"rel_authors":[{"author_name":"Wenhui Qu","author_inst":"Weill Cornell Medicine"},{"author_name":"Li Fan","author_inst":"Weill Cornell Medicine"},{"author_name":"Minwoo Wendy Jang","author_inst":"Weill Cornell Medicine"},{"author_name":"Pearly Ye","author_inst":"Weill Cornell Medicine"},{"author_name":"Ethan Cordes","author_inst":"Weill Cornell Medicine"},{"author_name":"Abulimiti Aikedan","author_inst":"Weill Cornell Medicine"},{"author_name":"Wen Hu","author_inst":"Weill Cornell Medicine"},{"author_name":"Ravi Kumar Nagiri","author_inst":"Weill Cornell Medicine"},{"author_name":"Man Ying Wong","author_inst":"Weill Cornell Medicine"},{"author_name":"Wenjie Luo","author_inst":"Weill Cornell Medicine"},{"author_name":"Mathew Blurton-Jones","author_inst":"University of California Irvine"},{"author_name":"Hagen U Tilgner","author_inst":"Weill Cornell Medicine"},{"author_name":"Anna G. Orr","author_inst":"Weill Cornell Medicine"},{"author_name":"Shiaoching Gong","author_inst":"Weill Cornell Medicine"},{"author_name":"Li Gan","author_inst":"Weill Cornell Medicine"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Lung hypoperfusion stimulates liquid absorption in alveoli","rel_doi":"10.64898\/2026.06.29.735362","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735362","rel_abs":"Tissue hypoperfusion is common in clinical settings, but how tissues respond to hypoperfusion on a microphysiological scale is not clear. We used real-time confocal microscopy of live, perfused lungs to gain insights into the effects of hypoperfusion on the microcirculation and microphysiology of lung alveoli, where gas exchange occurs. We focused on effects of hypoperfusion on alveolar liquid secretion, since alveolar liquid secretion is important for alveolar homeostatic functions. Our findings show lung hypoperfusion stimulated a reversal of alveolar liquid transport, from homeostatic liquid secretion to absorption. Specifically, lung perfusion at or near physiological perfusion pressure led to alveolar liquid secretion that depended on the alveolar epithelial cystic fibrosis transmembrane conductance regulator (CFTR), Na+-K+-Cl- cotransporters, and the Na+\/K+-ATPase. Within minutes of halting lung perfusion or majorly reducing it, alveoli stopped secreting liquid and instead absorbed it via the epithelial Na+ channel, CFTR, and K+-Cl- cotransporters. We provide evidence that hypoperfusion caused alveolar microvessel lumens to shrink and airspaces to expand, leading to epithelial stretch that stimulated liquid absorption. These findings show lung hypoperfusion initiates mechanical signals that stimulate the alveolar epithelium to absorb liquid, and they may inform the pathogenesis of lung diseases characterized by acute microvascular hypoperfusion.","rel_num_authors":10,"rel_authors":[{"author_name":"Jimmy Zhang","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Deebly Chavez","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Sayahi Suthakaran","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Chaya Sussman","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Stephanie Tang","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Sarah K.L. Moore","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Clemente J. Britto","author_inst":"Yale University School of Medicine"},{"author_name":"Jaymin Kathiriya","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Hooman D. Poor","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Jaime L. Hook","author_inst":"Icahn School of Medicine at Mount Sinai"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Resolving symmetry-masked allosteric cooperativity in the M. tuberculosis proteasome core particle","rel_doi":"10.64898\/2026.07.02.736129","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736129","rel_abs":"The 20S proteasome core particle (CP) is a stacked 7-{beta}7-{beta}7-7 assembly in which the central {beta}-rings host fourteen catalytic active sites responsible for regulated protein degradation. Allosteric coupling between catalytic {beta}-subunits has been characterized in eukaryotic proteasomes, whose heteromeric {beta}-rings permit subunit-specific perturbation. In bacterial proteasomes, however, the {beta}-rings are homomeric, and any allosteric relationships between subunits with identical sequences have remained refractory to conventional ensemble-averaging structural methods, including to hydrogen\/deuterium exchange mass spectrometry (HDX-MS). Here we show that orthosteric inhibitors paradoxically activate the Mycobacterium tuberculosis 20S CP at substoichiometric concentrations, revealing positive cooperativity between its {beta}-subunits. To dissect this cooperativity within the {beta}-ring, we co-assemble wild-type and catalytically inactive (T1A) {beta}-subunits into hybrid 20S CPs. We develop a probabilistic model relating bulk mixing ratios to the ensemble of hybrid 20S CP stoichiometries. Differential 15N-labelling of the wild-type subunits then resolves WT and T1A peptide signals by mass during HDX-MS, enabling subunit-resolved measurements within a single complex. Using this approach, we demonstrate that ligand binding at one {beta}-subunit remodels the conformational dynamics of binding-incompetent neighbours. Measuring deuterium uptake against ring composition identifies two allosteric routes: a lateral pathway from switch helix II to the active site of the adjacent intra-ring subunit, and an axial pathway connecting a loop at the {beta}-ring interface to the S pockets of the opposing ring. More broadly, this work establishes a framework for resolving symmetry-masked allostery in multi-subunit assemblies.","rel_num_authors":11,"rel_authors":[{"author_name":"Madison Turner","author_inst":"University of Guelph"},{"author_name":"Verena Wittlinger","author_inst":"University of Vienna"},{"author_name":"Cristina Lento","author_inst":"York University"},{"author_name":"Anisha Haris","author_inst":"Waters Corporation"},{"author_name":"Jakub Ujma","author_inst":"Waters Corporation"},{"author_name":"David Bruton","author_inst":"Waters Corporation"},{"author_name":"Keith Richardson","author_inst":"Waters Corporation"},{"author_name":"Kevin Giles","author_inst":"Waters Corporation"},{"author_name":"Thomas Bottcher","author_inst":"University of Vienna"},{"author_name":"Derek Wilson","author_inst":"York University"},{"author_name":"Siavash Vahidi","author_inst":"University of Guelph"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"AART enables fast and accurate cross-platform proteomic translation","rel_doi":"10.64898\/2026.06.29.735313","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735313","rel_abs":"Plasma proteomic profiling has been widely used for biomarker discovery, disease prediction and diagnosis, and patient stratification. However, technical differences across assay platforms often result in low-to-moderate agreement, limiting study reproducibility, data integration, and model transferability. Here we present AART, a cross-platform proteomic translation framework that integrates matched-protein ridge regression with proteome-wide residual learning. We benchmarked AART spanning three independent cohorts profiled using three major platforms, including Olink, SomaScan, and mass spectrometry. Across all six translation directions, AART achieved the best performance compared with baseline methods for both overlapping and non-overlapping protein translations, with a relative improvement of 92.0% on average over direct mapping and by up to 31.6% over cpiVAE, the strongest baseline. Proteins that were accurately translated and improved by AART were enriched for extracellular, vesicle-associated, and tissue-restricted plasma biology. In downstream applications, AART improved the reproducibility of proteomic association analyses relative to direct cross-platform comparison by 75.5% for type 2 diabetes and 370.6% for Alzheimer's disease. AART-enabled cohort integration enhanced diagnostic accuracy for amyotrophic lateral sclerosis by 92.6% compared with non-integration analysis. AART was overall one to three orders of magnitude faster than cpiVAE, facilitating biobank-scale applications. Together, these results establish AART as a fast, accurate, and scalable framework for cross-platform proteomic translation, enabling more reproducible, transferable, and integrated proteomic research.","rel_num_authors":2,"rel_authors":[{"author_name":"yurui chen","author_inst":"Yale University"},{"author_name":"Sai Zhang","author_inst":"Yale University"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Genome-Wide Markers Predict Metribuzin Tolerance in Southern Soft Red Winter Wheat","rel_doi":"10.64898\/2026.06.28.733875","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.28.733875","rel_abs":"Metribuzin is a versatile herbicide effective against various annual grasses and broadleaf weeds found in wheat fields. However, it can cause foliar damage to wheat, impacting plant health and yield. A clearer understanding of the genetic architecture associated with metribuzin tolerance is necessary to guide marker-based breeding strategies. This study evaluated 351 historic Gulf Atlantic Wheat Nursery (GAWN) wheat breeding lines representative of southern US soft red winter wheat (SRWW) germplasm. Field trials were conducted at Winnsboro (WN) and Baton Rouge (BR), Louisiana, in 2016 and 2017. Metribuzin was applied at specific growth stages[DN1.1], and tolerance was assessed based on visual foliar damage. Genomic data from 6,252 filtered single nucleotide polymorphism (SNP) markers were used to estimate narrow-sense heritability, conduct genome-wide association (GWAS), and assess genomic prediction accuracy using genomic best linear unbiased prediction (GBLUP). Broad-sense heritability ranged from 0.54 to 0.69 within environments and reached 0.77 across environments, while narrow-sense heritability ranged from 0.35 to 0.47, indicating moderate additive genetic control. No SNP surpassed the significance threshold, but genomic prediction (GP) showed moderate to strong predictive ability (PA) across environments, with the highest accuracy (r = 0.62) observed between BR17 and WN17. These results indicate that metribuzin tolerance in SRWW is primarily controlled by multiple small-effect loci and that GS provides a more effective breeding strategy than marker-assisted selection for improving tolerance in southern wheat germplasm.","rel_num_authors":7,"rel_authors":[{"author_name":"Julio Sellani","author_inst":"Louisiana State University"},{"author_name":"Hugo Anzueto","author_inst":"Louisiana State University"},{"author_name":"Kelly Arcenaux","author_inst":"Louisiana State University"},{"author_name":"Paul Trey Price III","author_inst":"Louisiana State University"},{"author_name":"Gina Brown-Guedira","author_inst":"NC State University"},{"author_name":"Stephen Harrison","author_inst":"Louisiana State University"},{"author_name":"Noah DeWitt","author_inst":"Louisiana State University"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Ultra-accurate sequencing reveals an extreme transmission bottleneck in a deep-sea clam symbiosis","rel_doi":"10.64898\/2026.06.29.735038","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735038","rel_abs":"Vertically transmitted symbionts experience progressive genome degradation driven by transmission bottlenecks each host generation that reduce genetic diversity and promote fixation of deleterious mutations. Direct estimates remain rare because inference requires scarce parent-offspring samples and sequencing sensitive enough to detect rare variants. Here, we investigate symbiont transmission bottlenecks in a vesicomyid clam by deeply sampling within-host endosymbiont genetic diversity using two ultra-accurate sequencing methods. Demographic modeling revealed an effective bottleneck size of approximately eight symbionts (95% CI: 1-17 genomes) per host generation. This estimate is sharply reduced relative to prior cytological estimates of bottleneck census size, with important implications for understanding the rate and dynamics of endosymbiont genome degradation.","rel_num_authors":5,"rel_authors":[{"author_name":"Cade Mirchandani","author_inst":"Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA, United States"},{"author_name":"Evan Pepper-Tunick","author_inst":"Molecular Engineering and Sciences Institute, University of Washington, Seattle, Washington, USA"},{"author_name":"Landen Gozashti","author_inst":"Department of Integrative Biology, University of California, Berkeley"},{"author_name":"Shelbi Russell","author_inst":"Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA, United States"},{"author_name":"Russell Corbett-Detig","author_inst":"Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA, United States"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Inferring viral proteins that act as public goods during coinfection","rel_doi":"10.64898\/2026.07.02.736036","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736036","rel_abs":"Interactions among individuals in structured populations can alter fitness effects of mutations and reshape evolutionary processes. In many systems, including bacteria, yeast, and viruses, such interactions often result in public goods: gene products that are costly to produce yet exploitable by others. During viral coinfection of the same cell, gene products from one genome may complement deleterious mutations in another, allowing defective genomes to persist. Yet it remains difficult to infer which proteins are shareable from population sequencing data, because mutation, selection, drift, and complementation are intertwined. Here, we developed a quantitative framework to infer protein-specific public goods in the RNA bacteriophage MS2, which encodes only four proteins. We analyzed experimental evolution data generated under two multiplicity-of-infection (MOI) regimes: low MOI, where coinfection is rare, and high MOI, where coinfection is common. We first compared empirical mutation patterns between regimes and then applied a Wright-Fisher model combined with simulation-based Bayesian inference using neural posterior estimation. In a two-stage strategy, gene-specific fitness effects were inferred from low-MOI data and subsequently used to estimate protein sharing under high-MOI conditions. Across two statistical inference frameworks, lysis emerged as the strongest public-good candidate, replicase and coat showed an intermediate signal, and maturation showed the weakest evidence for sharing. Together, our results show that viral proteins differ markedly in their propensity to act as public goods. More broadly, they illustrate how coinfection can generate density-dependent selection, a general feature of social evolution that may shape evolutionary dynamics.","rel_num_authors":5,"rel_authors":[{"author_name":"Yael Maoz","author_inst":"Tel Aviv University"},{"author_name":"Moran Meir","author_inst":"Tel-Aviv University"},{"author_name":"Nadav Ben Nun","author_inst":"Tel Aviv University"},{"author_name":"Yoav Ram","author_inst":"Tel Aviv University"},{"author_name":"Adi Stern","author_inst":"Tel-Aviv University"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Integrated multi-omics profiling of gut bacterial extracellular vesicles links cargo composition to host transcriptional responses","rel_doi":"10.64898\/2026.07.01.732738","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.01.732738","rel_abs":"Bacterial extracellular vesicles (bEVs) enable gut microbiota to deliver bioactive cargo to host cells, yet the specific bacterial producers have not been systematically identified. Here, we profiled stool-derived bEVs from healthy individuals using metaproteomic profiling, revealing that vesiculation is widespread across gut bacterial phyla. We selected a subset of vesiculating species, showing that bEVs localize to distinct tissues in vivo, including extraintestinal sites such as lung, liver, kidney, and bone, suggesting roles beyond the gastrointestinal tract. We profiled intestinal epithelial cells and macrophages after endocytosing bEVs from various species, uncovering pronounced, cell-type-specific responses. For example, Bacteroides fragilis bEVs promote anti-inflammatory mitochondrial-telomeric regulation, while a set of commensal-derived bEVs contribute to epithelial survival and structural renewal. By combining proteomic, lipidomic, and metabolomic cargo profiling with transcriptional output, we find that specific Bacteroidota-derived protein cargo activates cytoprotective stress defenses while attenuating inflammatory signaling. Together, these findings establish a multi-layered comparative atlas of bEV composition, uptake, and host response, providing a framework for understanding bEV-mediated microbiome-host communication.","rel_num_authors":13,"rel_authors":[{"author_name":"Adarsh Singh","author_inst":"Cornell University"},{"author_name":"Yanjia Zhang","author_inst":"University of Pennsylvania"},{"author_name":"Jiucheng Ding","author_inst":"University of California, Berkeley"},{"author_name":"Qiaojuan Shi","author_inst":"Cornell University"},{"author_name":"Anas Saleh","author_inst":"NewYork-Presbyterian Weill Cornell Medical Center"},{"author_name":"Joshua Jones","author_inst":"Cornell University"},{"author_name":"Xieyue Xiao","author_inst":"Cornell Unviersity"},{"author_name":"Ian Lee","author_inst":"Cornell University"},{"author_name":"Kevin B Weyant","author_inst":"Cornell University"},{"author_name":"Matthew P DeLisa","author_inst":"Cornell University"},{"author_name":"Aaron Timperman","author_inst":"University of Pennsylvania"},{"author_name":"Kyu Young Rhee","author_inst":"Weill Cornell Medical College"},{"author_name":"Ilana L Brito","author_inst":"Cornell University"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"DPP9-mediated inflammasome repression protects against checkpoint inhibitor lung toxicity","rel_doi":"10.64898\/2026.06.30.735609","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.735609","rel_abs":"Over one million patients receive cancer immunotherapy annually, yet the mechanisms underlying life-threatening immune-mediated toxicities remain poorly understood. Checkpoint inhibitor pneumonitis (CIP) is the leading cause of immunotherapy-related mortality, with a case fatality rate approaching 10%, and no genetic risk factors have been described to date. We identified Dipeptidyl-peptidase 9 (DPP9) as the first genetic susceptibility gene for CIP in a clinico-genomics cohort of 4,397 patients treated with immune checkpoint inhibitors. Mechanistically, DPP9 suppresses CARD8 inflammasome activation and IL-18 secretion in human monocytes, a pathway which is engaged prior to CIP onset, with IL-18 selectively elevated in the plasma of patients who subsequently develop CIP. Myeloid-restricted ablation of Dpp8 and Dpp9 in mice recapitulated the pulmonary histopathological and immunological hallmarks of CIP, including granuloma formation, accumulation of IFN{gamma}-producing T cells and monocyte-derived macrophages. Each of these phenotypes were driven by excessive IL-18 secretion. Together, these findings establish DPP9 as a genetic determinant of CIP and nominate IL-18 blockade as a mechanistically rational therapeutic strategy.","rel_num_authors":35,"rel_authors":[{"author_name":"J. Richard Brewer","author_inst":"Yale University"},{"author_name":"Ailin Han","author_inst":"Yale University"},{"author_name":"Amin H. Nassar","author_inst":"Yale Uniersity"},{"author_name":"Elias Bou Farhat","author_inst":"Harvard Medical School"},{"author_name":"Holly N. Blackburn","author_inst":"Yale University"},{"author_name":"Tianli Xiao","author_inst":"Yale University"},{"author_name":"Haris Mirza","author_inst":"Yale University"},{"author_name":"Walter K. Mowel","author_inst":"Yale University"},{"author_name":"Esen Sefik","author_inst":"Yale University"},{"author_name":"Saskia Hartner","author_inst":"McGill University"},{"author_name":"Michael Chiorazzi","author_inst":"Yale University"},{"author_name":"Takeshi Itoh","author_inst":"Yale University"},{"author_name":"Min-Hee Oh","author_inst":"Yale University"},{"author_name":"Matthew Z. Madden","author_inst":"Yale University"},{"author_name":"Athreya Rangavajhula","author_inst":"Yale University"},{"author_name":"Elio Adib","author_inst":"Harvard Medical School"},{"author_name":"Mustafa J. Saleh","author_inst":"Harvard Medical School"},{"author_name":"Marc Machaalani","author_inst":"Harvard Medical School"},{"author_name":"Mehrdad Rakaee","author_inst":"Harvard Medical School"},{"author_name":"Masoud Tafavvoghi","author_inst":"Oslo University Hospital"},{"author_name":"Claire Quattropani","author_inst":"Yale New Haven Hospital"},{"author_name":"Nicole Gazetos","author_inst":"Yale New Haven Hospital"},{"author_name":"David Gerber","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Farjana Fattah","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Jeffrey A. SoRelle","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Dominic Choo","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Mitchell S. von Itzstein","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Shannon Bevans-Fonti","author_inst":"Johns Hopkins University"},{"author_name":"Mohammad Ghanbar","author_inst":"Johns Hopkins University"},{"author_name":"Karthik Suresh","author_inst":"Johns Hopkins University"},{"author_name":"Thomas Mazumder","author_inst":"University of California San Francisco"},{"author_name":"Chun J. Ye","author_inst":"Genentech"},{"author_name":"Toni K. Choueiri","author_inst":"Harvard Medical School"},{"author_name":"Alexander Gusev","author_inst":"Harvard Medical School"},{"author_name":"Richard A. Flavell","author_inst":"Yale University"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"DPP9-mediated inflammasome repression protects against checkpoint inhibitor lung toxicity","rel_doi":"10.64898\/2026.06.30.735609","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.735609","rel_abs":"Over one million patients receive cancer immunotherapy annually, yet the mechanisms underlying life-threatening immune-mediated toxicities remain poorly understood. Checkpoint inhibitor pneumonitis (CIP) is the leading cause of immunotherapy-related mortality, with a case fatality rate approaching 10%, and no genetic risk factors have been described to date. We identified Dipeptidyl-peptidase 9 (DPP9) as the first genetic susceptibility gene for CIP in a clinico-genomics cohort of 4,397 patients treated with immune checkpoint inhibitors. Mechanistically, DPP9 suppresses CARD8 inflammasome activation and IL-18 secretion in human monocytes, a pathway which is engaged prior to CIP onset, with IL-18 selectively elevated in the plasma of patients who subsequently develop CIP. Myeloid-restricted ablation of Dpp8 and Dpp9 in mice recapitulated the pulmonary histopathological and immunological hallmarks of CIP, including granuloma formation, accumulation of IFN{gamma}-producing T cells and monocyte-derived macrophages. Each of these phenotypes were driven by excessive IL-18 secretion. Together, these findings establish DPP9 as a genetic determinant of CIP and nominate IL-18 blockade as a mechanistically rational therapeutic strategy.","rel_num_authors":35,"rel_authors":[{"author_name":"J. Richard Brewer","author_inst":"Yale University"},{"author_name":"Ailin Han","author_inst":"Yale University"},{"author_name":"Amin H. Nassar","author_inst":"Yale Uniersity"},{"author_name":"Elias Bou Farhat","author_inst":"Harvard Medical School"},{"author_name":"Holly N. Blackburn","author_inst":"Yale University"},{"author_name":"Tianli Xiao","author_inst":"Yale University"},{"author_name":"Haris Mirza","author_inst":"Yale University"},{"author_name":"Walter K. Mowel","author_inst":"Yale University"},{"author_name":"Esen Sefik","author_inst":"Yale University"},{"author_name":"Saskia Hartner","author_inst":"McGill University"},{"author_name":"Michael Chiorazzi","author_inst":"Yale University"},{"author_name":"Takeshi Itoh","author_inst":"Yale University"},{"author_name":"Min-Hee Oh","author_inst":"Yale University"},{"author_name":"Matthew Z. Madden","author_inst":"Yale University"},{"author_name":"Athreya Rangavajhula","author_inst":"Yale University"},{"author_name":"Elio Adib","author_inst":"Harvard Medical School"},{"author_name":"Mustafa J. Saleh","author_inst":"Harvard Medical School"},{"author_name":"Marc Machaalani","author_inst":"Harvard Medical School"},{"author_name":"Mehrdad Rakaee","author_inst":"Harvard Medical School"},{"author_name":"Masoud Tafavvoghi","author_inst":"Oslo University Hospital"},{"author_name":"Claire Quattropani","author_inst":"Yale New Haven Hospital"},{"author_name":"Nicole Gazetos","author_inst":"Yale New Haven Hospital"},{"author_name":"David Gerber","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Farjana Fattah","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Jeffrey A. SoRelle","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Dominic Choo","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Mitchell S. von Itzstein","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Shannon Bevans-Fonti","author_inst":"Johns Hopkins University"},{"author_name":"Mohammad Ghanbar","author_inst":"Johns Hopkins University"},{"author_name":"Karthik Suresh","author_inst":"Johns Hopkins University"},{"author_name":"Thomas Mazumder","author_inst":"University of California San Francisco"},{"author_name":"Chun J. Ye","author_inst":"Genentech"},{"author_name":"Toni K. Choueiri","author_inst":"Harvard Medical School"},{"author_name":"Alexander Gusev","author_inst":"Harvard Medical School"},{"author_name":"Richard A. Flavell","author_inst":"Yale University"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"DPP9-mediated inflammasome repression protects against checkpoint inhibitor lung toxicity","rel_doi":"10.64898\/2026.06.30.735609","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.30.735609","rel_abs":"Over one million patients receive cancer immunotherapy annually, yet the mechanisms underlying life-threatening immune-mediated toxicities remain poorly understood. Checkpoint inhibitor pneumonitis (CIP) is the leading cause of immunotherapy-related mortality, with a case fatality rate approaching 10%, and no genetic risk factors have been described to date. We identified Dipeptidyl-peptidase 9 (DPP9) as the first genetic susceptibility gene for CIP in a clinico-genomics cohort of 4,397 patients treated with immune checkpoint inhibitors. Mechanistically, DPP9 suppresses CARD8 inflammasome activation and IL-18 secretion in human monocytes, a pathway which is engaged prior to CIP onset, with IL-18 selectively elevated in the plasma of patients who subsequently develop CIP. Myeloid-restricted ablation of Dpp8 and Dpp9 in mice recapitulated the pulmonary histopathological and immunological hallmarks of CIP, including granuloma formation, accumulation of IFN{gamma}-producing T cells and monocyte-derived macrophages. Each of these phenotypes were driven by excessive IL-18 secretion. Together, these findings establish DPP9 as a genetic determinant of CIP and nominate IL-18 blockade as a mechanistically rational therapeutic strategy.","rel_num_authors":35,"rel_authors":[{"author_name":"J. Richard Brewer","author_inst":"Yale University"},{"author_name":"Ailin Han","author_inst":"Yale University"},{"author_name":"Amin H. Nassar","author_inst":"Yale Uniersity"},{"author_name":"Elias Bou Farhat","author_inst":"Harvard Medical School"},{"author_name":"Holly N. Blackburn","author_inst":"Yale University"},{"author_name":"Tianli Xiao","author_inst":"Yale University"},{"author_name":"Haris Mirza","author_inst":"Yale University"},{"author_name":"Walter K. Mowel","author_inst":"Yale University"},{"author_name":"Esen Sefik","author_inst":"Yale University"},{"author_name":"Saskia Hartner","author_inst":"McGill University"},{"author_name":"Michael Chiorazzi","author_inst":"Yale University"},{"author_name":"Takeshi Itoh","author_inst":"Yale University"},{"author_name":"Min-Hee Oh","author_inst":"Yale University"},{"author_name":"Matthew Z. Madden","author_inst":"Yale University"},{"author_name":"Athreya Rangavajhula","author_inst":"Yale University"},{"author_name":"Elio Adib","author_inst":"Harvard Medical School"},{"author_name":"Mustafa J. Saleh","author_inst":"Harvard Medical School"},{"author_name":"Marc Machaalani","author_inst":"Harvard Medical School"},{"author_name":"Mehrdad Rakaee","author_inst":"Harvard Medical School"},{"author_name":"Masoud Tafavvoghi","author_inst":"Oslo University Hospital"},{"author_name":"Claire Quattropani","author_inst":"Yale New Haven Hospital"},{"author_name":"Nicole Gazetos","author_inst":"Yale New Haven Hospital"},{"author_name":"David Gerber","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Farjana Fattah","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Jeffrey A. SoRelle","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Dominic Choo","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Mitchell S. von Itzstein","author_inst":"University of Texas Southwestern Medical Center"},{"author_name":"Shannon Bevans-Fonti","author_inst":"Johns Hopkins University"},{"author_name":"Mohammad Ghanbar","author_inst":"Johns Hopkins University"},{"author_name":"Karthik Suresh","author_inst":"Johns Hopkins University"},{"author_name":"Thomas Mazumder","author_inst":"University of California San Francisco"},{"author_name":"Chun J. Ye","author_inst":"Genentech"},{"author_name":"Toni K. Choueiri","author_inst":"Harvard Medical School"},{"author_name":"Alexander Gusev","author_inst":"Harvard Medical School"},{"author_name":"Richard A. Flavell","author_inst":"Yale University"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"N-Acetylaspartate Synthesis as a Thermodynamic Relief Mechanism for Mitochondrial Aspartate Aminotransferase","rel_doi":"10.64898\/2026.06.29.735215","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735215","rel_abs":"N-acetylaspartate (NAA) is the most abundant neuron-enriched acetylated metabolite in the mammalian brain, but its metabolic purpose remains unresolved. We developed a simplified kinetic model of mitochondrial aspartate metabolism to test whether NAA synthesis by aspartate N-acetyltransferase (ASPNAT) acts as a thermodynamic relief valve for mitochondrial aspartate aminotransferase (AAT) under the low-oxaloacetate (OAA) conditions expected in neuronal mitochondria. In the mitochondrial-compartment model, ASPNAT lowered steady-state mitochondrial aspartate from 141 to 105 M and increased net forward AAT flux by 30.9%. The relative AAT-relief effect was largest when OAA and aspartate-glutamate carrier 1 (AGC1\/Aralar1)-mediated export were both low, whereas acetyl-CoA availability controlled the substrate-supported capacity for NAA synthesis. That places the relief effect in a narrow regime where product removal matters most. ASPNAT titration produced a graded, concentration-dependent response rather than a binary on\/off response. Energetic comparisons showed that the gain in AAT-linked support comes at a modest acetyl-CoA cost, which makes NAA synthesis easier to sustain in carbon-replete states than in carbon-poor ones. Some studies have suggested a secondary cytoplasmic site of NAA synthesis, and we therefore examined how the network response changed with a change in ASPNAT topology. Mitochondrial matrix ASPNAT increased forward AAT flux by 53.32%, whereas cytoplasmic ASPNAT decreased ASPNAT flux by 17.8%. Allowing OAA to vary preserved the positive ASPNAT-dependent relief of AAT flux, but because this simplified extension produced unrealistically low absolute fluxes, it is interpreted as a robustness check on the direction of the mechanism rather than as a prediction of physiological metabolic rates. These results identify mitochondrial NAA synthesis as a plausible thermodynamic relief valve for mitochondrial AAT and define a directional prediction that could test whether severe metabolic stress reroutes effective ASPNAT-linked aspartate metabolism.","rel_num_authors":4,"rel_authors":[{"author_name":"Narayanan Puthillathu","author_inst":"Biophysics Graduate Program, The Ohio State University"},{"author_name":"John R Moffett","author_inst":"Uniformed Services University of the Health Sciences"},{"author_name":"Barbara S Slusher","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Aryan M.A. Namboodiri","author_inst":"Uniformed Services University of the Health Sciences"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Shared Neuroanatomy, Separate Mechanism: in vivo ERK and mTOR Manipulations Reveal Female-Specific Molecular Signaling for Auditory Forebrain-Dependent Learning in Juveniles","rel_doi":"10.64898\/2026.07.02.736152","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736152","rel_abs":"Developmental experience can produce lasting changes in neural function and behavior. Zebra finch offers a powerful model for identifying the molecular mechanisms underlying this process. Both juvenile male and female zebra finches perform developmental sensory song learning that influences their adult behaviors: in males, the structure of the song they sing and in female, the song preferences they exhibit (females cannot sing). The auditory forebrain, a region distinct from but connected to nodes of the male singing circuitry, is required for male sensory song learning. Song experience induces epigenetic, genomic, molecular, cellular and systems-level alterations in the auditory forebrain of males. Much less evidence is available for females. Although epigenetic and molecular data implicate the auditory forebrain in female sensory song learning, there has been no causal test of its role. Further, molecular evidence indicates the potential for distinct mechanisms for male and female sensory song learning, even though they learn during a largely overlapping developmental period. We used pharmacological manipulations of the ERK and mTOR cascades in the auditory forebrain of juvenile females during controlled tutoring, and an operant assay for adult song preference, to test the causal role of the auditory forebrain and the two cascades known to be required for male sensory song learning. We demonstrate that the auditory forebrain is required for female sensory song learning, and that while ERK signaling is necessary for both sexes, that of mTOR is sex specific. Results raise implications for alternative molecular cascade cross-talks and protein synthesis processes that successfully support the developmental learning at the same age and brain region.","rel_num_authors":3,"rel_authors":[{"author_name":"Kruthika V Maheshwar","author_inst":"University of Chicago"},{"author_name":"Siddhanth Chari","author_inst":"University of Chicago"},{"author_name":"Sarah E London","author_inst":"University of Chicago"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Learning-related population dynamics in right and left dorsal premotor cortex during typing skill acquisition","rel_doi":"10.64898\/2026.07.02.736059","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736059","rel_abs":"Advances in intracortical brain-computer interface (BCI) technology have enabled increasingly sophisticated communication paradigms, including for decoding intended speech and touch typing. However, the methods by which intracortical neural population dynamics are engaged during practice-related skill acquisition in humans remain poorly understood. Here, we examined learning-related changes in neural activity during motor skill acquisition in a right-handed BCI clinical trial participant with tetraplegia, with intracortical microelectrode arrays placed in the bilateral dorsal precentral gyri (Brodmann area 6d), who learned how to type using a BCI-enabled typing interface. While decoder performance remained stable across sessions, typing speed improved with practice, indicating practice-related skill acquisition. Over weeks, low-dimensional neural population activity became progressively more compact, and this compaction was strongly associated with faster typing, independent of decoder accuracy. Although this compaction was observed bilaterally in 6d, firing-rate modulation and cross-session generalization were selectively enhanced in left 6d. Moreover, neural population changes across sessions were largely accounted for by canonical correlation analysis in right 6d, but only partially accounted for in left 6d. Together, these findings demonstrate that human intracortical neuro-motor skill acquisition related to intended typing engages shared bilateral population-level dynamics, with additional learning-related changes selectively expressed in dominant dorsal premotor cortex.","rel_num_authors":7,"rel_authors":[{"author_name":"Hiroaki Hashimoto","author_inst":"Massachusetts General Hospital"},{"author_name":"Justin J Jude","author_inst":"Massachusetts General Hospital"},{"author_name":"Hadar Levi Aharoni","author_inst":"Massachusetts General Hospital"},{"author_name":"Ziv M Williams","author_inst":"Massachusetts General Hospital"},{"author_name":"John D Simeral","author_inst":"Brown University"},{"author_name":"Leigh R Hochberg","author_inst":"Massachusetts General Hospital"},{"author_name":"Daniel B Rubin","author_inst":"Massachusetts General Hospital"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"POGZ safeguards neuronal gene chromatin architecture and transcription","rel_doi":"10.64898\/2026.07.02.736104","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736104","rel_abs":"Disruption of chromatin organization is a common pathogenic mechanism in neurodevelopmental disorders, yet how changes in 3D genome architecture relate to transcriptional dysfunction in the developing brain remains unclear. POGZ, a transposase-derived chromatin regulator mutated in White-Sutton syndrome and autism spectrum disorder (ASD), has been linked to both heterochromatin and accessible regulatory DNA, but its in vivo function in the brain is unresolved. Using immunoprecipitation-mass spectrometry in embryonic day 13.5 (E13.5) mouse cortex, we identify the H3K9 methyltransferases G9a\/GLP as principal POGZ interactors, placing POGZ within the core H3K9 methylation machinery in vivo. We find that POGZ loss in embryonic mouse cortex drives bidirectional, megabase-scale redistribution of H3K9me3, with ectopic losses and gains over discrete neuronal gene loci. In developing Pogz-\/- cortex, regions with H3K9me3 gains are repositioned to the nuclear lamina and exhibit strengthened B-compartment scores by Micro-C, locus-restricted erosion of TAD architecture, weakened boundary insulation, and reduced CTCF occupancy. Within these domains, nascent RNA synthesis at neuronal genes is markedly diminished. These results identify POGZ as a G9a\/GLP-associated chromatin regulator that protects neurodevelopmental gene domains from heterochromatinization and perinuclear sequestering, preserving 3D architecture and transcription during cortical development.","rel_num_authors":11,"rel_authors":[{"author_name":"Natasha Ann Mariano","author_inst":"Cornell University"},{"author_name":"Katerina J. Williams","author_inst":"Cornell University"},{"author_name":"Katie Munechika","author_inst":"Cornell University"},{"author_name":"Katherine M. Bonefas","author_inst":"Cornell University"},{"author_name":"Yu Sun","author_inst":"Cornell University"},{"author_name":"Weiyu Zhang","author_inst":"Cornell University"},{"author_name":"Jared L. Klein","author_inst":"Cornell University"},{"author_name":"Kevin Monahan","author_inst":"Rutgers University"},{"author_name":"Haiyuan Yu","author_inst":"Cornell University"},{"author_name":"Cedric Feschotte","author_inst":"Cornell University"},{"author_name":"Eirene Markenscoff","author_inst":"Cornell University"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Functional Organization of the Neonatal Basal Ganglia and Thalamus","rel_doi":"10.64898\/2026.07.02.736181","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736181","rel_abs":"The basal ganglia and thalamus are key nodes in subcortico-cortical loops involved in sensory, motor, and cognitive function. In adults, posterior regions of the subcortex link to cortical sensorimotor networks and anterior regions link to association networks. Alterations in the size, strength, and selectivity of these subcortical regional network representations are implicated in several neuropsychiatric disorders, many of which originate early in development. However, the organization of these network representations at birth remains incompletely understood, limiting our ability to devise normative and atypical developmental models of subcortico-cortical interactions. Using resting-state fMRI, we characterized the size, strength, and selectivity of cortical network representations in the basal ganglia and thalamus in a set of neonates (n=261) and compared results to children (age range 9-11 years, n=69) and adults (n=120). We found that the broad anterior-posterior organization of the subcortex is present at birth, yet representations of somatomotor networks were larger at birth compared to children and adults (p<0.001). The strength and selectivity of subcortico-cortical functional connectivity (FC) exhibited interactions between age group and network (all p<0.001), such that subcortical representations of sensorimotor networks exhibited stronger FC and higher selectivity in neonates, while subcortical representations of association networks exhibited stronger FC and higher selectivity in older cohorts. In parallel, data-driven clustering revealed areas with integration of multiple networks in the neonatal subcortex. These results suggest that subcortico-cortical FC evolves over development largely in a sensorimotor-association manner and provide a baseline for normative and disordered subcortical development.","rel_num_authors":14,"rel_authors":[{"author_name":"Samantha Lynn Blake","author_inst":"Washington University in St. Louis"},{"author_name":"Jeanette K. Kenley","author_inst":"Washington University in St. Louis"},{"author_name":"Tara A. Smyser","author_inst":"Washington University in St. Louis"},{"author_name":"Aidan Latham","author_inst":"Washington University in St. Louis"},{"author_name":"Dimitrios Alexopoulos","author_inst":"Washington University in St. Louis"},{"author_name":"Deanna J. Greene","author_inst":"University of California San Diego"},{"author_name":"Rachel E. Lean","author_inst":"Washington University in St. Louis"},{"author_name":"Deanna M. Barch","author_inst":"Washington University in St. Louis"},{"author_name":"Barbara B. Warner","author_inst":"Washington University in St. Louis"},{"author_name":"Joan L. Luby","author_inst":"Washington University in St. Louis"},{"author_name":"Cynthia E. Rogers","author_inst":"Washington University in St. Louis"},{"author_name":"Christopher D. Smyser","author_inst":"Washington University in St. Louis"},{"author_name":"Chad M. Sylvester","author_inst":"Washington University in St. Louis"},{"author_name":"Ashley N. Nielsen","author_inst":"Washington University in St. Louis"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"PIP2 stabilizes Nav1.5 gating and links receptor signaling to cardiac late sodium current","rel_doi":"10.64898\/2026.06.29.735321","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735321","rel_abs":"The cardiac sodium channel NaV1.5 initiates each heartbeat by generating the rapid depolarizing upstroke of the action potential. Dysregulation of NaV1.5 gating can produce cardiac arrhythmias by slowing inactivation, increasing late sodium current (INa,L), and impairing electrical stability. Here, we show that phosphatidylinositol-4,5-bisphosphate (PIP2) is a critical membrane cofactor that stabilizes NaV1.5 gating. Acute PIP2 depletion in human iPSC-derived cardiomyocytes, produced by activation of endogenous AT1 receptors, activation of an engineered M3q-DREADD, or optogenetic recruitment of CRY2-pseudojanin, shifted voltage dependence, slowed fast inactivation, and increased INa,L. These effects were prevented by augmenting intracellular PIP2, required PLC activity when driven by Gq-coupled receptors, and were independent of downstream Ca2+ or PKC signaling. Unlike the skeletal-muscle isoform NaV1.4, NaV1.5 displayed PIP2-dependent shifts in both activation and steady-state inactivation, indicating isoform-specific lipid coupling. Induced-fit docking and molecular dynamics simulations identified a PIP2-interaction interface between the domain IV voltage sensor and pore that contains disease-linked residues. The disease-reported variant R1644C weakened and redistributed the predicted PIP2-contact network, produced elevated basal INa,L, showed enhanced sensitivity to PIP2 depletion, and caused an approximately 30-fold reduction in apparent functional PIP2 sensitivity in excised patches. These findings define a lipid-dependent mechanism that stabilizes NaV1.5 gating and reveal how physiological Gq signaling and inherited channel variants can converge on the channel-PIP2 axis to promote proarrhythmic late sodium current.","rel_num_authors":11,"rel_authors":[{"author_name":"Kirin D Gada","author_inst":"Massachusetts College of Pharmacy & Health Sciences"},{"author_name":"Jordie m Kamuene","author_inst":"Northeastern University"},{"author_name":"Ana Santa Cruz","author_inst":"Northeastern University"},{"author_name":"Ziyue Meng","author_inst":"Northeastern University"},{"author_name":"Jenna G Connolly","author_inst":"Northeastern University"},{"author_name":"Florence Ng","author_inst":"Northeastern University"},{"author_name":"Xinyi Ma","author_inst":"Northeastern University"},{"author_name":"Aishwarya Chandrashekar","author_inst":"Northeastern University"},{"author_name":"Yu Xu","author_inst":"Northeastern University"},{"author_name":"Meng Cui","author_inst":"Northeastern University"},{"author_name":"Leigh D. Plant","author_inst":"Northeastern University"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"GLproxScape reconstructs spatial chromatin occupancy landscapes from tiled genomic locus proteomics","rel_doi":"10.64898\/2026.06.29.735243","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735243","rel_abs":"Genomic locus proteomics combines proximity labeling with mass spectrometry to identify the proteins associated with user-defined genomic loci. However, per-region enrichment values from tiledguide designs are typically pooled before hit calling, collapsing the latent spatial structure encodedby overlapping measurements. Here, we describe GLproxScape, an R package that treats per-region enrichments as indirect spatial measurements and reconstructs latent chromatin occupancylandscapes through a Gaussian labeling-kernel forward model. Sequence-specific transcriptionfactors are resolved by motif-anchored non-negative least-squares deconvolution against JASPARor HOCOMOCO position weight matrices, while chromatin regulators which lack defined DNA-binding motifs are inferred as broad occupancy zones, enabling recovery of overlapping membersof multi-subunit complexes. Applied to published genomic locus proteomics datasets at the humanTERT, MYC, FOXP2, and FOXQ1 loci and the mouse Ripk3 locus, GLproxScape recovered knownregulators with predicted positions independently supported by ChIP-Atlas peaks, reconstructedcandidate co-binding relationships, and identified chromatin complexes inaccessible to pooledanalyses. Systematic sgRNA-ablation experiments further showed that densely tiled designsimprove event recovery and positional stability, providing concrete experimental guidance for futuregenomic locus proteomics studies.","rel_num_authors":6,"rel_authors":[{"author_name":"Selahattin Can Ozcan","author_inst":"Koc University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey"},{"author_name":"Baris Sergi","author_inst":"Koc University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey"},{"author_name":"Busra Yildirim","author_inst":"Koc University, Graduate School of Health Sciences, Istanbul, Turkey"},{"author_name":"Umut Cagiral","author_inst":"Koc University, Graduate School of Health Sciences, Istanbul, Turkey"},{"author_name":"Mehmet Gonen","author_inst":"Koc University, School of Medicine, Istanbul, Turkey"},{"author_name":"Ceyda ACILAN AYHAN","author_inst":"Koc University, School of Medicine, Istanbul, Turkey"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"GLproxScape reconstructs spatial chromatin occupancy landscapes from tiled genomic locus proteomics","rel_doi":"10.64898\/2026.06.29.735243","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735243","rel_abs":"Genomic locus proteomics combines proximity labeling with mass spectrometry to identify the proteins associated with user-defined genomic loci. However, per-region enrichment values from tiledguide designs are typically pooled before hit calling, collapsing the latent spatial structure encodedby overlapping measurements. Here, we describe GLproxScape, an R package that treats per-region enrichments as indirect spatial measurements and reconstructs latent chromatin occupancylandscapes through a Gaussian labeling-kernel forward model. Sequence-specific transcriptionfactors are resolved by motif-anchored non-negative least-squares deconvolution against JASPARor HOCOMOCO position weight matrices, while chromatin regulators which lack defined DNA-binding motifs are inferred as broad occupancy zones, enabling recovery of overlapping membersof multi-subunit complexes. Applied to published genomic locus proteomics datasets at the humanTERT, MYC, FOXP2, and FOXQ1 loci and the mouse Ripk3 locus, GLproxScape recovered knownregulators with predicted positions independently supported by ChIP-Atlas peaks, reconstructedcandidate co-binding relationships, and identified chromatin complexes inaccessible to pooledanalyses. Systematic sgRNA-ablation experiments further showed that densely tiled designsimprove event recovery and positional stability, providing concrete experimental guidance for futuregenomic locus proteomics studies.","rel_num_authors":6,"rel_authors":[{"author_name":"Selahattin Can Ozcan","author_inst":"Koc University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey"},{"author_name":"Baris Sergi","author_inst":"Koc University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey"},{"author_name":"Busra Yildirim","author_inst":"Koc University, Graduate School of Health Sciences, Istanbul, Turkey"},{"author_name":"Umut Cagiral","author_inst":"Koc University, Graduate School of Health Sciences, Istanbul, Turkey"},{"author_name":"Mehmet Gonen","author_inst":"Koc University, School of Medicine, Istanbul, Turkey"},{"author_name":"Ceyda ACILAN AYHAN","author_inst":"Koc University, School of Medicine, Istanbul, Turkey"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Multi-modality Graph Representation Learning for Malignant Cell Identification from scRNA-seq using DeepMalignant","rel_doi":"10.64898\/2026.06.29.734828","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.734828","rel_abs":"Distinguishing malignant from normal cells in single-cell RNA sequencing data remains a critical yet challenging task in cancer genomics. Existing methods often suffer from poor precision, limited generalizability across cancer types, and reduced robustness across different sequencing platforms. We developed DeepMalignant, an unsupervised multimodal graph attention autoencoder for malignant cell identification that jointly integrates gene expression and copy number alteration (CNA) information. We applied DeepMalignant to five datasets covering 26 samples and four cancer types (breast, colorectal, pancreatic, and ovarian cancers), generated by three platforms (10x Genomics, inDrop, and Drop-seq) for benchmarking and compared it with existing state-of-the-art methods including scMalignantFinder, PreCanCell, CopyKAT, ikarus, and Cancer-Finder. DeepMalignant achieved the best overall balance of precision and recall and consistently outperformed the existing methods that used either gene expression or CNA in F1 scores. Ablation studies showed that both CNA-based edge weighting and graph attention aggregation contribute independently to performance, and attribution analysis further indicated that the learned embeddings capture biologically meaningful malignant programs. We further applied DeepMalignant to two ductal carcinoma in situ (DCIS) samples, DCIS2 and DCIS1, that have matched spatial transcriptomics and scRNA-seq data. DeepMalignant identified tumor-enriched regions that were highly consistent with the matched histological image. The downstream cell-cell communications analysis revealed that fibroblast-derived C3 and MIF both directed signaling more toward normal epithelial cells than tumor epithelial cells, demonstrating that accurate tumor-normal cell classification by DeepMalignant enables biologically meaningful interrogation of the tumor microenvironment and revealing how stromal cells differentially communicate with malignant versus normal epithelial populations.","rel_num_authors":5,"rel_authors":[{"author_name":"Pankaj Bhattarrai","author_inst":"Florida State University"},{"author_name":"Weiman Yuan","author_inst":"Vanderbilt University"},{"author_name":"Hongmei Chi","author_inst":"Florida Agricultural and Mechanical University"},{"author_name":"Xin Maizie Zhou","author_inst":"Vanderbilt university"},{"author_name":"Xian Mallory","author_inst":"Florida State University"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Competing effects modulate the rate of poly(A) RNA deadenylation in a biomolecular condensate","rel_doi":"10.64898\/2026.07.02.736149","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736149","rel_abs":"The unique solvent milieu found in biomolecular condensates can control cellular enzymatic reactions and shift reaction kinetics by modulating reactant concentrations, structural dynamics, and enzyme activities. Here we explore the interplay of multiple regulatory factors within a condensate to control poly(A) RNA deadenylation, the first and rate-limiting step in mRNA turnover. The deadenylase CNOT7, a subunit of the CCR4-NOT deadenylation complex, localizes to cytoplasmic RNA granules and shows increased degradation activity in vitro in condensates formed by the C-terminal low complexity disordered region of CAPRIN1, a component of RNA granules. We use a combination of enzymatic assays, kinetic modeling, microscopy, Nuclear Magnetic Resonance (NMR) spectroscopy, and molecular dynamics simulations to deconvolute and define the components that underlie this enhancement. We found that enzyme and RNA are concentrated in condensates relative to buffer, which increases CNOT7 activity, while the equilibrium between CNOT7's active and inactive states remains unchanged. The concentration-dependent increase in enzymatic rates is counterbalanced by a substantial decrease in the enzyme's catalytic efficiency, likely due to slower diffusion of CNOT7 and RNA within the condensates, which lessens the probability of enzyme-substrate complex formation. Molecular dynamics simulations reveal CNOT7-CAPRIN1 interactions that rely on conserved CAPRIN1 sequence features, hinting at an evolutionarily conserved role for CAPRIN1 condensation. With this quantitative kinetic analysis, we describe the multifaceted mechanism behind regulation of CNOT7 deadenylation by a condensate environment.","rel_num_authors":8,"rel_authors":[{"author_name":"Rose M Irwin","author_inst":"Hospital for Sick Children"},{"author_name":"Robert W Harkness","author_inst":"University of Guelph"},{"author_name":"Zi Hao Liu","author_inst":"University of Toronto"},{"author_name":"Kunyang Sun","author_inst":"University of California, Berkeley"},{"author_name":"Tian Hao Huang","author_inst":"University of Toronto"},{"author_name":"Teresa Head-Gordon","author_inst":"UC Berkeley"},{"author_name":"Lewis Kay","author_inst":"University of Toronto"},{"author_name":"Julie Deborah Forman-Kay","author_inst":"Hospital for Sick Children"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Competing effects modulate the rate of poly(A) RNA deadenylation in a biomolecular condensate","rel_doi":"10.64898\/2026.07.02.736149","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736149","rel_abs":"The unique solvent milieu found in biomolecular condensates can control cellular enzymatic reactions and shift reaction kinetics by modulating reactant concentrations, structural dynamics, and enzyme activities. Here we explore the interplay of multiple regulatory factors within a condensate to control poly(A) RNA deadenylation, the first and rate-limiting step in mRNA turnover. The deadenylase CNOT7, a subunit of the CCR4-NOT deadenylation complex, localizes to cytoplasmic RNA granules and shows increased degradation activity in vitro in condensates formed by the C-terminal low complexity disordered region of CAPRIN1, a component of RNA granules. We use a combination of enzymatic assays, kinetic modeling, microscopy, Nuclear Magnetic Resonance (NMR) spectroscopy, and molecular dynamics simulations to deconvolute and define the components that underlie this enhancement. We found that enzyme and RNA are concentrated in condensates relative to buffer, which increases CNOT7 activity, while the equilibrium between CNOT7's active and inactive states remains unchanged. The concentration-dependent increase in enzymatic rates is counterbalanced by a substantial decrease in the enzyme's catalytic efficiency, likely due to slower diffusion of CNOT7 and RNA within the condensates, which lessens the probability of enzyme-substrate complex formation. Molecular dynamics simulations reveal CNOT7-CAPRIN1 interactions that rely on conserved CAPRIN1 sequence features, hinting at an evolutionarily conserved role for CAPRIN1 condensation. With this quantitative kinetic analysis, we describe the multifaceted mechanism behind regulation of CNOT7 deadenylation by a condensate environment.","rel_num_authors":8,"rel_authors":[{"author_name":"Rose M Irwin","author_inst":"Hospital for Sick Children"},{"author_name":"Robert W Harkness","author_inst":"University of Guelph"},{"author_name":"Zi Hao Liu","author_inst":"University of Toronto"},{"author_name":"Kunyang Sun","author_inst":"University of California, Berkeley"},{"author_name":"Tian Hao Huang","author_inst":"University of Toronto"},{"author_name":"Teresa Head-Gordon","author_inst":"UC Berkeley"},{"author_name":"Lewis Kay","author_inst":"University of Toronto"},{"author_name":"Julie Deborah Forman-Kay","author_inst":"Hospital for Sick Children"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Large parks and city-wide tree cover boost butterfly diversity across 22 major U.S. cities","rel_doi":"10.64898\/2026.07.02.736135","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736135","rel_abs":"Accelerating global urbanization necessitates a better understanding of how to manage cities that promote biodiversity. However, we currently lack multi-year, multi-city studies, which limits a generalizable understanding of how both within and between city differences impact the spatial and temporal dynamics of urban biodiversity. Here, we tested hypotheses about the drivers of butterfly diversity within and across urban parks by applying Bayesian occupancy models to five years of iNaturalist community science data from 2,550 parks in 22 major U.S. cities. We found that cities with bigger parks supported more species per park, including more disturbance- and edge-avoidant species. This was driven by a positive effect of park size on butterfly species colonization rates. We also found that attributes of habitat quality (plant diversity within parks and tree cover surrounding parks) contributed to butterfly species occupancy. Park connectivity increased species persistence, but the overall effects on butterfly species occupancy varied across cities. Finally, we found that the total area of tree cover throughout a city, rather than the size or connectivity of individual parks, was the primary determinant of city-wide diversity: Increasing total tree canopy cover from below-average (~6%) to above-average (~22%) increased city-wide species richness by ~10%. These findings highlight the need for cities to maintain large parks while also increasing city-wide tree cover to support biodiversity across local to regional scales. By integrating high-resolution community science data across the continental U.S., this study provides mechanistic insight into how cross-scale processes shape urban biodiversity dynamics and identifies generalizable recommendations for improving urban conservation management.","rel_num_authors":5,"rel_authors":[{"author_name":"Jens Ulrich","author_inst":"University of Ottawa"},{"author_name":"Yan Yin Jenny Cheung","author_inst":"Cornell University"},{"author_name":"Christopher T Cosma","author_inst":"Conservation Biology Institute"},{"author_name":"Heather Kharouba","author_inst":"University of Ottawa"},{"author_name":"Laura Melissa Guzman","author_inst":"Cornell University"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Large parks and city-wide tree cover boost butterfly diversity across 22 major U.S. cities","rel_doi":"10.64898\/2026.07.02.736135","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.07.02.736135","rel_abs":"Accelerating global urbanization necessitates a better understanding of how to manage cities that promote biodiversity. However, we currently lack multi-year, multi-city studies, which limits a generalizable understanding of how both within and between city differences impact the spatial and temporal dynamics of urban biodiversity. Here, we tested hypotheses about the drivers of butterfly diversity within and across urban parks by applying Bayesian occupancy models to five years of iNaturalist community science data from 2,550 parks in 22 major U.S. cities. We found that cities with bigger parks supported more species per park, including more disturbance- and edge-avoidant species. This was driven by a positive effect of park size on butterfly species colonization rates. We also found that attributes of habitat quality (plant diversity within parks and tree cover surrounding parks) contributed to butterfly species occupancy. Park connectivity increased species persistence, but the overall effects on butterfly species occupancy varied across cities. Finally, we found that the total area of tree cover throughout a city, rather than the size or connectivity of individual parks, was the primary determinant of city-wide diversity: Increasing total tree canopy cover from below-average (~6%) to above-average (~22%) increased city-wide species richness by ~10%. These findings highlight the need for cities to maintain large parks while also increasing city-wide tree cover to support biodiversity across local to regional scales. By integrating high-resolution community science data across the continental U.S., this study provides mechanistic insight into how cross-scale processes shape urban biodiversity dynamics and identifies generalizable recommendations for improving urban conservation management.","rel_num_authors":5,"rel_authors":[{"author_name":"Jens Ulrich","author_inst":"University of Ottawa"},{"author_name":"Yan Yin Jenny Cheung","author_inst":"Cornell University"},{"author_name":"Christopher T Cosma","author_inst":"Conservation Biology Institute"},{"author_name":"Heather Kharouba","author_inst":"University of Ottawa"},{"author_name":"Laura Melissa Guzman","author_inst":"Cornell University"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"A Male Expressed Copulatory Plug Increases Female Fertility in Caenorhabditis Nematodes","rel_doi":"10.64898\/2026.06.29.735219","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.29.735219","rel_abs":"The genomes of self-fertilizing hermaphrodites offer a unique opportunity to probe why some genes with sex-specific functions are lost while others are maintained. In the androdiecious species, Caenorhabditis elegans, the presence of mate plugging is polymorphic across genetic backgrounds. The production of a mating plug is controlled by a single gene, plg-1, which has male-specific expression. Given that males are present less than 1% of the time, this gene is likely lost through relaxed selection or purifying selection, especially if mate plugging is maintained through intrasexual selection in males as is often hypothesized. We capitalized on a diverse panel of almost 2,000 C. elegans natural strains to show that plg-1 is maintained in at least 61% of genetic backgrounds, despite the androdiecious mating system. Genetic diversity estimates suggest that the loss of plg-1 is correlated with species globalization. We show that hermaphrodite total fecundity is not correlated with plg-1 genotype, indicating that this gene is not being maintained through linkage to a hermaphrodite beneficial gene. We then demonstrate in both C. elegans and the obligate outcrossing species, C. remanei, that the presence of a mating plug does not assure paternity by preventing subsequent males from mating. Instead, females with a mating plug have an extended peak reproductive window and higher fecundity than females without a mating plug. Together, these results indicate that mate plugging is female beneficial. We suggest that this benefit is derived from mating plugs acting as a vulval cover that can inhibit sperm loss during egg laying, thus reducing sperm limitation. Our work indicates that mate plugging may not always invoke male competition and can instead represent reproductive cooperation. More broadly, it demonstrates that male-specific gene expression does not equate to male-specific function, especially in the context of reproductive interactions.","rel_num_authors":5,"rel_authors":[{"author_name":"Lynsey J Blevins","author_inst":"University of Virginia"},{"author_name":"Andrew Grieve","author_inst":"University of Virginia"},{"author_name":"Michael Sauria","author_inst":"Johns Hopkins University"},{"author_name":"Erik C Andersen","author_inst":"Johns Hopkins University"},{"author_name":"Katja R Kasimatis","author_inst":"University of Virginia"}],"rel_date":"2026-07-03","rel_site":"biorxiv"},{"rel_title":"Smarter, Shorter, Safer: Study protocol for a stepped-wedge cluster randomised controlled trial and process evaluation of a behavioural intervention bundle to reduce antibiotic use in residential aged care","rel_doi":"10.64898\/2026.07.01.26357003","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.01.26357003","rel_abs":"Introduction The overuse and prolonged use of antibiotics in residential aged care (RAC) increases the risk of adverse effects and contributes to the global threat of antimicrobial resistance. Behavioural science-informed interventions have effectively reduced antibiotic prescribing in primary care but have rarely been implemented in RAC settings. We co-developed a behavioural science intervention bundle named Smarter, Shorter, Safer with RAC providers. We aim to assess the effectiveness of the intervention on rates of antibiotic use, measure effect persistence 6-months after the final intervention round, and investigate stakeholder experiences of the intervention. Methods and analysis We will conduct a stepped-wedge cluster randomised controlled trial with an embedded qualitative process evaluation. RAC homes (n=46) will be stratified into tertiles of baseline antibiotic use and randomly allocated to three intervention roll-out steps. Each RAC home will receive a bundled intervention consisting of social norm feedback, public commitment messaging and consumer information, staggered by step. Three rounds of the intervention will be delivered to each home at quarterly intervals. The primary outcome is antibiotic days of therapy per 1000 resident days (DOT\/1000 days). Secondary outcomes are the percentage of antibiotic courses with a duration longer than guidelines and the percentage of residents on an antibiotic. Qualitative interviews will investigate staff and consumer experiences of the intervention bundle over time and by high, median and low baseline antibiotic use rates. Ethics and dissemination We obtained ethical approval from the Macquarie University Human Research Ethics Committee. Our findings will be disseminated through a range of forums including the publication of results in peer-reviewed journals and presentations at national and international conferences. Trial registration number Australian New Zealand Clinical Trials Registry ACTRN12625001132437 (https:\/\/anzctr.org.au\/ACTRN12625001132437.aspx)","rel_num_authors":16,"rel_authors":[{"author_name":"Magdalena Z Raban","author_inst":"Macquarie University"},{"author_name":"Rachel Urwin","author_inst":"Australian Institute of Health Innovation, Macquarie University, NSW, Australia"},{"author_name":"Bayzidur Rahman","author_inst":"Australian Institute of Health Innovation, Macquarie University, NSW, Australia"},{"author_name":"Sandun M. Silva","author_inst":"Australian Institute of Health Innovation, Macquarie University, NSW, Australia"},{"author_name":"Sangita Neupane","author_inst":"Australian Institute of Health Innovation, Macquarie University, NSW, Australia"},{"author_name":"Ben R Newell","author_inst":"UNSW Institute for Climate Risk & Response Sydney, University of New South Wales, Australia; School of Psychology, University of South Wales, Australia"},{"author_name":"Lyn-li Lim","author_inst":"4Victorian Healthcare Associated Infection Surveillance System (VICNISS), At the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia; Depar"},{"author_name":"Nasir Wabe","author_inst":"Australian Institute of Health Innovation, Macquarie University, Sydney, Australia"},{"author_name":"Ling Li","author_inst":"Australian Institute of Health Innovation, Macquarie University, Sydney, Australia"},{"author_name":"Gaston Arnolda","author_inst":"Australian Institute of Health Innovation, Macquarie University, Sydney, Australia"},{"author_name":"Sangita Neupane","author_inst":"Australian Institute of Health Innovation, Macquarie University, Sydney, Australia"},{"author_name":"Sarah Balmer","author_inst":"BaptistCare, Baulkham Hills, NSW, Australia"},{"author_name":"Travis Dunstan","author_inst":"Scalabrini Communities, Chatswood, Sydney, Australia"},{"author_name":"Sonali Pinto","author_inst":"Anglicare NSW, Macquarie Park, Sydney, Australia"},{"author_name":"Verily Thomas","author_inst":"Anglicare NSW, Macquarie Park, Sydney, Australia"},{"author_name":"Johanna Westbrook","author_inst":"Australian Institute of Health Innovation, Macquarie University, Sydney, Australia"}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"Consensus Recommendations for the Clinical Management of Wolfram syndrome Using a Delphi Method","rel_doi":"10.64898\/2026.07.02.26357130","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.02.26357130","rel_abs":"BackgroundWolfram syndrome is a rare neurodegenerative disorder, most commonly caused by pathogenic variants in WFS1, while cases due to CISD2 are exceedingly rare. The estimated prevalence is 1 in 160,000 to 770,000 individuals worldwide. In these clinical guidelines, disorders caused by WFS1 are referred to as WFS1-Wolfram syndrome, and those caused by CISD2 as CISD2-Wolfram syndrome. Historically, it has been characterized by early-onset, antibody-negative, insulin-dependent diabetes mellitus, progressive optic atrophy, sensorineural hearing loss, arginine vasopressin deficiency, and brainstem and cerebellar atrophy. More recently, partial and late onset forms have been identified. There are currently no licensed disease-modifying treatments, and international clinical guidelines have not previously been established.\n\nMethodsAn international steering committee systematically reviewed 273 peer-reviewed publications and generated draft consensus statements across six clinical domains. These statements were evaluated by international specialists in endocrinology, clinical genetics, neurology, ophthalmology and neuro-ophthalmology, psychiatry, and urology, drawn from North America, Europe, Latin America, Oceania, and Asia, using a modified three-round Delphi process. Additional feedback was incorporated from nurses specializing in multidisciplinary Wolfram syndrome care, from leaders of international patient organizations, and from specialists in the genetic diagnosis of monogenic diabetes. Structured feedback from patients and families was gathered through multiple international patient advocacy organizations. Consensus was defined as [&ge;]80% agreement.\n\nResultsAll 35 final consensus statements reached the pre-specified consensus threshold of [&ge;]80% agreement, spanning diagnosis and genetic testing, multidisciplinary care organization, neuro-ophthalmology, neurology, endocrinology, urology, gastroenterology, and psychiatry.\n\nConclusionsThese guidelines are the first international clinical consensus for Wolfram syndrome and provide actionable recommendations for clinicians worldwide. Implementation should be accompanied by a prospective audit to expand the evidence base and support future iterations.","rel_num_authors":9,"rel_authors":[{"author_name":"Fumihiko Urano","author_inst":"Washington University School of Medicine"},{"author_name":"Josephine Elliott","author_inst":"University of Birmingham"},{"author_name":"Saumel Ahmadi","author_inst":"Washington University School of Medicine"},{"author_name":"Patrick Yu Wai Man","author_inst":"University of Cambridge"},{"author_name":"Sarah Gladstone","author_inst":"The Snow Foundation"},{"author_name":"Stephanie Gebel","author_inst":"The Snow Foundation"},{"author_name":"Tracy Lynch","author_inst":"Wolfram Syndrome UK"},{"author_name":"Timothy Barrett","author_inst":"University of Birmingham"},{"author_name":"- International Wolfram Syndrome Clinical Guidelines Consortium","author_inst":""}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"Reciprocal Feedback Blockade with Trametinib and Imatinib Overcomes the Limitations of Current KRAS-targeted Therapy","rel_doi":"10.64898\/2026.07.01.26356985","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.01.26356985","rel_abs":"Although KRAS G12C-specific inhibitors such as sotorasib have been approved by US FDA and currently used in clinic, treating non-G12C mutants and overcoming acquired resistance for these inhibitors remain critical challenges. Here, we introduce a reciprocal feedback blockade therapy combining the MEK inhibitor trametinib and the multi-tyrosine kinase inhibitor imatinib to overcome these limitations. Our study reveals their compensatory roles: trametinib suppresses MEK activity yet promotes tyrosine kinase signaling and angiogenesis, while imatinib, a pan-tyrosine kinase inhibitor unleashes the MEK\/ERK pathway via phosphatase suppression. Combining these agents blocks the reciprocal survival signals, inducing robust cell death across diverse KRAS-mutant models. Mechanistically, this combination reprograms cellular metabolism, leading to autophagy-dependent lipid peroxidation accumulation and ferroptosis. This strategy was effective in sotorasib-resistant lung cancer cells and various mouse models, including pancreatic cancer patient-derived xenograft. Furthermore, a pilot clinical trial for KRAS-mutant pancreatic cancer yielded encouraging responses. Consequently, the trametinib-imatinib combination represents a promising, broad-spectrum therapeutic strategy to overcome the constraints of current KRAS-targeted therapies.","rel_num_authors":15,"rel_authors":[{"author_name":"Yu-Chun Hsiao","author_inst":"China Medical University"},{"author_name":"Li-Yuan Bai","author_inst":"China Medicial University Hospital"},{"author_name":"Yu-Jung Chen","author_inst":"China Medical University"},{"author_name":"Yi-Syuan Wu","author_inst":"China Medical University"},{"author_name":"Wei-Jan Wang","author_inst":"China Medical University"},{"author_name":"Ya-Ling Chuang","author_inst":"China Medical University Hospital"},{"author_name":"Han Chang","author_inst":"China Medical University Hospital"},{"author_name":"Muhammad Zeshan","author_inst":"China Medical University"},{"author_name":"Heng-Hsiung Wu","author_inst":"China Medical University"},{"author_name":"Hsiu-Ju Yang","author_inst":"China Medical University"},{"author_name":"Pei-Chih Lee","author_inst":"China Medical University"},{"author_name":"Chang-Fan Chiu","author_inst":"China Medical University Hospital"},{"author_name":"Li-Tzong Chen","author_inst":"National Cheng Kung University"},{"author_name":"Hirohito Yamaguchi","author_inst":"China Medical University"},{"author_name":"Mien-Chie Hung","author_inst":"China Medical University"}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"Temporal and Geographic Variation in Outcomes After Poor-Grade Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Meta-analysis","rel_doi":"10.64898\/2026.06.29.26356892","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26356892","rel_abs":"BackgroundPoor-grade aneurysmal subarachnoid hemorrhage (aSAH) remains associated with high mortality and severe disability, yet contemporary outcomes may differ substantially from historical estimates. We performed a systematic review and meta-analysis to evaluate long-term outcomes after poor-grade aSAH and assess temporal, geographic, and treatment-related factors associated with prognosis.\n\nMethodsPubMed\/MEDLINE, Embase, Cochrane Central, Scopus, and Google Scholar were searched from inception through March 2026. Studies enrolling consecutive adults with poor-grade aSAH (World Federation of Neurosurgical Societies grades IV-V, Hunt-Hess grades IV-V, or equivalent) reporting mortality and\/or functional outcomes at [&ge;]3 months were included. To minimize survivorship bias, studies excluding untreated patients or patients dying before aneurysm treatment were excluded. Random-effects meta-analyses of proportions were performed using generalized linear mixed models. Prespecified subgroup analyses and exploratory meta-regression analyses evaluated temporal, geographic, and treatment-related factors associated with outcomes.\n\nResultsForty-two studies including 7,726 patients from 16 countries across 4 continents were included. The pooled favorable functional outcome rate was 27.2% (95% CI, 23.9%-30.8%), whereas pooled overall mortality was 53.3% (95% CI, 49.0%-57.5%). Pre- and post-treatment mortality were 25.9% and 33.9%, respectively. Aneurysm treatment rate was 72.0% (95% CI, 65.6%-77.7%). Favorable outcomes improved over time from 13.5% (95% CI, 7.0%-24.3%) in the 1980s to 33.7% in the 1990s but plateaued thereafter. In exploratory meta-regression analyses, higher aneurysm treatment rates were independently associated with improved favorable functional outcome (0.134 log-odds increase per 10% increase in treatment rate; p = 0.01) and lower mortality (-0.224 log-odds per 10% increase in treatment rate; p < .001). Publication year was associated with lower mortality (p = 0.03) but not favorable outcome. Geographic region, country income group, and the proportion of grade V patients were not independently associated with outcomes.\n\nConclusionsMortality after poor-grade aSAH remains high, but approximately one-third of patients achieved favorable outcome. Higher aneurysm treatment rates were independently associated with improved functional outcomes and lower mortality.","rel_num_authors":7,"rel_authors":[{"author_name":"Airton Leonardo de Oliveira Manoel","author_inst":"Hamad Medical Corporation"},{"author_name":"Ali Msheik","author_inst":"Hamad Medical Corporation"},{"author_name":"Fernando Godinho Zampieri","author_inst":"University of Alberta Libraries"},{"author_name":"Ruben Peralta","author_inst":"Hamad Medical Corporation"},{"author_name":"Ghaya Al Rumaihi","author_inst":"Hamad Medical Corporation"},{"author_name":"Hassan Al-Thani","author_inst":"Hamad Medical Corporation"},{"author_name":"Jose I Suarez","author_inst":"Johns Hopkins University"}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"The Effects of Cognitive Behavioral Therapy for Insomnia on Cardiovascular and Immunological Outcomes: A Randomized-Controlled Study","rel_doi":"10.64898\/2026.06.30.26356933","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.30.26356933","rel_abs":"Evidence suggests that insomnia disorder is associated with pathophysiological alterations that may contribute to long-term physical, mental and inflammatory-related health risks. Cognitive behavioral therapy for insomnia (CBTi) is the first-line treatment for insomnia disorder, yet its effects on physiological outcomes remain unclear. This randomized-controlled trial examined the effects of CBTi on cardiovascular and immunological biomarkers.\n\nSixty-two participants with insomnia disorder were randomized to group-CBTi (N = 33, 75.8% female, Mage = 48.8 {+\/-} 17.1 years) or Waitlist (WL) control (N = 29, 75.9% female, Mage = 52.2 {+\/-} 15.6 years). Cardiovascular parameters included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and nocturnal heart rate variability (HRV). Inflammatory markers from blood samples included C-reactive protein (CRP), tumor necrosis factor-alpha (TNF- ), interleukin-6 (IL-6) and brain-derived neurotrophic factor (BDNF). All outcomes were assessed at baseline (T1), post-treatment assessment (T2, following completion of CBTi or WL period), and 6-months for the WL group (T3, after CBTi for the WL participants).\n\nNo significant Group-by-time effects were observed for SBP, DBP, HR, HRV and any inflammatory markers (ps > .05) from T1 to T2. When pooling treatment effects following CBTi exposure across both groups (T1 to T2 in CBTi group and T1 to T3 in WL group), no significant biomarker changes were observed. Overall, results indicate that CBTi did not produce detectable changes in cardiovascular or inflammatory markers among healthy individuals with insomnia disorder. These findings suggest physiological responses to CBTi are complex and may reflect dynamic and context-dependent processes (https:\/\/www.isrctn.com\/ISRCTN13983243).\n\nHIGHLIGHTSO_LIInsomnia disorder is associated with physiological alterations\nC_LIO_LIWe found no significant cardiovascular changes following CBTi\nC_LIO_LINo significant effects of CBTi on inflammatory biomarkers were observed\nC_LIO_LIThe findings suggest dissociation between subjective and physiological outcomes of CBTi\nC_LI","rel_num_authors":10,"rel_authors":[{"author_name":"Mathilde Reyt","author_inst":"Concordia University"},{"author_name":"Denise C Jarrin","author_inst":"Dawson College"},{"author_name":"Aurore A Perrault","author_inst":"Concordia University"},{"author_name":"Florence Borgetto","author_inst":"Centre de Recherche de l Institut Universitaire de Geriatrie de Montreal"},{"author_name":"Dylan Smith","author_inst":"University of Ottawa"},{"author_name":"Kirsten Gong","author_inst":"Concordia University"},{"author_name":"Lukia Tarelli","author_inst":"Centre de Recherche de l Institut Universitaire de Geriatrie de Montreal"},{"author_name":"Josee Savard","author_inst":"Universite Laval"},{"author_name":"Thien Thanh Dang-Vu","author_inst":"Concordia University"},{"author_name":"Jean Philippe Gouin","author_inst":"Concordia University"}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"The Effects of Cognitive Behavioral Therapy for Insomnia on Cardiovascular and Immunological Outcomes: A Randomized-Controlled Study","rel_doi":"10.64898\/2026.06.30.26356933","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.30.26356933","rel_abs":"Evidence suggests that insomnia disorder is associated with pathophysiological alterations that may contribute to long-term physical, mental and inflammatory-related health risks. Cognitive behavioral therapy for insomnia (CBTi) is the first-line treatment for insomnia disorder, yet its effects on physiological outcomes remain unclear. This randomized-controlled trial examined the effects of CBTi on cardiovascular and immunological biomarkers.\n\nSixty-two participants with insomnia disorder were randomized to group-CBTi (N = 33, 75.8% female, Mage = 48.8 {+\/-} 17.1 years) or Waitlist (WL) control (N = 29, 75.9% female, Mage = 52.2 {+\/-} 15.6 years). Cardiovascular parameters included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and nocturnal heart rate variability (HRV). Inflammatory markers from blood samples included C-reactive protein (CRP), tumor necrosis factor-alpha (TNF- ), interleukin-6 (IL-6) and brain-derived neurotrophic factor (BDNF). All outcomes were assessed at baseline (T1), post-treatment assessment (T2, following completion of CBTi or WL period), and 6-months for the WL group (T3, after CBTi for the WL participants).\n\nNo significant Group-by-time effects were observed for SBP, DBP, HR, HRV and any inflammatory markers (ps > .05) from T1 to T2. When pooling treatment effects following CBTi exposure across both groups (T1 to T2 in CBTi group and T1 to T3 in WL group), no significant biomarker changes were observed. Overall, results indicate that CBTi did not produce detectable changes in cardiovascular or inflammatory markers among healthy individuals with insomnia disorder. These findings suggest physiological responses to CBTi are complex and may reflect dynamic and context-dependent processes (https:\/\/www.isrctn.com\/ISRCTN13983243).\n\nHIGHLIGHTSO_LIInsomnia disorder is associated with physiological alterations\nC_LIO_LIWe found no significant cardiovascular changes following CBTi\nC_LIO_LINo significant effects of CBTi on inflammatory biomarkers were observed\nC_LIO_LIThe findings suggest dissociation between subjective and physiological outcomes of CBTi\nC_LI","rel_num_authors":10,"rel_authors":[{"author_name":"Mathilde Reyt","author_inst":"Concordia University"},{"author_name":"Denise C Jarrin","author_inst":"Dawson College"},{"author_name":"Aurore A Perrault","author_inst":"Concordia University"},{"author_name":"Florence Borgetto","author_inst":"Centre de Recherche de l Institut Universitaire de Geriatrie de Montreal"},{"author_name":"Dylan Smith","author_inst":"University of Ottawa"},{"author_name":"Kirsten Gong","author_inst":"Concordia University"},{"author_name":"Lukia Tarelli","author_inst":"Centre de Recherche de l Institut Universitaire de Geriatrie de Montreal"},{"author_name":"Josee Savard","author_inst":"Universite Laval"},{"author_name":"Thien Thanh Dang-Vu","author_inst":"Concordia University"},{"author_name":"Jean Philippe Gouin","author_inst":"Concordia University"}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"A foundation model of wearable pulse oximetry reveals physiological signatures of health and cardiometabolic risk","rel_doi":"10.64898\/2026.07.01.26356992","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.01.26356992","rel_abs":"While Photoplethysmography (PPG) is established as a noninvasive optical tool for monitoring heart rate and oxygen saturation, its high-resolution blood flow waveforms contain rich physiological data that extend far beyond conventional vital signs.\n\nWe introduce PulseOx-FM, a foundation model, trained using self-supervised learning on 6,995,558 segments of pulse oximetry signals collected during 42,282 overnight sleep monitoring recordings of 10,704 participants in the Human Phenotype Project (HPP).\n\nUsing chronological age as a global health benchmark, PulseOx-FM significantly outperformed existing open-source and proprietary feature extraction methods while demonstrating robust generalization in an external out-of-distribution cohort. PulseOx-FM representations predicted 64 phenotypic targets spanning cardiometabolic, and neuropsychiatric domains beyond demographic baselines, and prospectively identified two-year hypertension incidence in normotensive individuals. Nightly embeddings further tracked next-day glycemic, dietary and activity-based state within individuals, dissociating this signal from sleep architecture alone. This next-day glycemic signal was predominantly a direct physiological effect, not explained by next-day dietary intake.\n\nThese findings suggest that PulseOx-FM provides a generalizable framework for encoding physiological patterns from sleep, offering a non-invasive tool for global health risk stratification and precision medicine.","rel_num_authors":12,"rel_authors":[{"author_name":"Sarah Kohn","author_inst":"Weizman Institute of Science"},{"author_name":"Guy Lutsker","author_inst":"Weizmann Institute of Science"},{"author_name":"Alon Diament","author_inst":"Pheno.ai"},{"author_name":"Smadar Shilo","author_inst":"Weizmann Institute of Science"},{"author_name":"Adam Gabet","author_inst":"Weizmann Institute of Science"},{"author_name":"Gil Sasson","author_inst":"Weizmann Institute of Science"},{"author_name":"Gili Wolf","author_inst":"Weizmann Institute of Science"},{"author_name":"Adva Wolf","author_inst":"Pheno.ai"},{"author_name":"Anastasia Godneva","author_inst":"Weizmann Institute of Science"},{"author_name":"Adina Weinberger","author_inst":"Weizmann Institute of Science"},{"author_name":"Hagai Rossman","author_inst":"Pheno.ai"},{"author_name":"Eran Segal","author_inst":"Weizmann Institute of Science"}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"Ambient AI Documentation in Clinical Genetics: Perspectives on Implementation and Impact on Burnout","rel_doi":"10.64898\/2026.06.30.26356723","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.30.26356723","rel_abs":"ObjectivesTo assess genetic counselors perspectives on ambient AI adoption and its impact on counselor burnout.\n\nMaterials and MethodsWe utilized a mixed methods approach, surveying burnout using the validated Stanford Professional Fulfilment Index (PFI) before and after ambient AI adoption and exploring adoption perspectives through semi-structured interviews.\n\nResults64% of participants (16\/25) completed the pre-survey, with eleven completing post-surveys (69% response rate for completion of all three surveys). 14\/25 participants completed interviews. Ambient AI use was associated with reduction in burnout after 90 days; respondents who reported using ambient AI (vs. non-use) had burnout scores 1.05 points lower, on average (p=0.008). Benefits of adoption included effective use with interpreters, memory aid, summarization of non-templated note sections (e.g. family\/social history), and improved patient engagement. Challenges included template customization, variable accuracy, oversimplified medical language, and rapport disruption during consent. Ethical and regulatory considerations included data privacy, bias, awareness of training resources, and concerns about job displacement.\n\nDiscussionAmbient AI documentation can reduce documentation burden and burnout among genetic counselors. By evaluating both outcomes and real-world implementation considerations, our study provides evidence to guide scalable integration of AI-enabled documentation tools in clinical genomic medicine.\n\nConclusionAmbient AI can help support the sustainability of the clinical genetics workforce as genomic medicine initiatives are scaled across health systems. Addressing genetics-specific documentation needs while prioritizing patient trust, transparency, and provider oversight is essential for responsible ambient AI implementation.","rel_num_authors":5,"rel_authors":[{"author_name":"Anjali Narain","author_inst":"University of Iowa Health Care"},{"author_name":"Jason Misurac","author_inst":"2Division of Pediatric Nephrology, University of Iowa Stead Family Children's Hospital"},{"author_name":"Jennifer Van Tiem","author_inst":"Department of Family and Community Medicine, Carver College of Medicine, University of Iowa"},{"author_name":"Chase LaSpisa","author_inst":"Department of Political Science, College of Liberal Arts and Science, University of Iowa"},{"author_name":"Colleen A Campbell","author_inst":"Department of Internal Medicine, Carver College of Medicine, University of Iowa,"}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"Disease Outcomes in Boys with ABCD1 Variants Identified by Newborn Screening for X-ALD","rel_doi":"10.64898\/2026.06.30.26356979","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.30.26356979","rel_abs":"Objectives To determine whether boys with VUS detected through newborn screening (NBS) for adrenoleukodystrophy (ALD) develop adrenal insufficiency (aiALD) and cerebral ALD (cALD) at rates comparable to those with pathogenic variants, and to evaluate the relationship between C26:0-lysophosphatidylcholine (C26:0-LPC) levels and clinical outcomes. Methods We conducted a retrospective multicenter cohort study (2013 - 2025) across six US centers, including 201 males identified through NBS in 19 states. Variants were classified as pathogenic (n=65), likely pathogenic (n=45), or VUS (n=88). Primary outcomes were development of aiALD and cALD; secondary outcomes included C26:0-LPC levels. Statistical analyses included Kaplan-Meier, mixed-effects regression, and Cox models. Results 201 males with ABCD1 variants identified through NBS for ALD. Median age at last follow-up was 4.2 years (IQR 2.5 - 7.9). Overall, 26% developed aiALD (54% pathogenic, 16% likely pathogenic, 11% VUS), and 8% developed cALD (11%, 9%, and 4.5%, respectively). Pathogenic\/likely pathogenic variants were associated with higher odds of aiALD than VUS (OR 5.8; 95% CI 2.16 - 15.58; p=0.001). At 150 months, 39% of individuals with pathogenic\/likely pathogenic variants remained free of aiALD versus 85% with VUS. C26:0-LPC levels were higher in pathogenic variants and correlated with genotype (p=0.0006). Higher levels were associated with increased aiALD risk and earlier onset (HR 1.38 per 0.1 umol\/L; 95% CI 1.20 - 1.59; p<0.0001). Conclusions Boys with VUS had lower rates of aiALD and lower C26:0-LPC levels than those with pathogenic variants, although some developed disease. C26:0-LPC correlates with genotype and risk, supporting its role in variant classification and risk-stratified surveillance.","rel_num_authors":24,"rel_authors":[{"author_name":"Cecilie S. Videbaek","author_inst":"Copenhagen University Hospital"},{"author_name":"Danielle HJ Kim","author_inst":"Stanford University School of Medicine"},{"author_name":"Hannah S. Hart","author_inst":"University of Utah"},{"author_name":"Robert Thompson","author_inst":"Massachusetts General Hospital"},{"author_name":"Razina Aziz-Bose","author_inst":"Massachusetts General Hospital"},{"author_name":"Lachelle Purnell-Savoy","author_inst":"Kennedy Krieger Institute"},{"author_name":"Sonum Bharill","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Ezzat Hashemi","author_inst":"Stanford University School of Medicine"},{"author_name":"Joseph Orsini","author_inst":"New York State Department of Health"},{"author_name":"Elisa Seeger","author_inst":"ALD Alliance"},{"author_name":"Miranda McAuliffe","author_inst":"ALD Alliance"},{"author_name":"Isha Srivastava","author_inst":"Stanford University School of Medicine"},{"author_name":"Jennifer MacLean","author_inst":"Stanford Children's Healthcare"},{"author_name":"Sejal Shah","author_inst":"Stanford University School of Medicine"},{"author_name":"Ali Fatemi","author_inst":"Kennedy Krieger Institute"},{"author_name":"Julie S Cohen","author_inst":"Kennedy Krieger Institute"},{"author_name":"Eric Mallack","author_inst":"Kennedy Krieger Institute"},{"author_name":"Troy Lund","author_inst":"University of Minnesota Medical School"},{"author_name":"Florian Eichler","author_inst":"Massachusetts General Hospital"},{"author_name":"Joshua L. Bonkowsky","author_inst":"University of Utah"},{"author_name":"Laura Adang","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Zihuai L. He","author_inst":"Stanford University"},{"author_name":"Allan M Lund","author_inst":"University of Copenhagen"},{"author_name":"Keith Mai Van Haren","author_inst":"Stanford University School of Medicine"}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"Development of a Biology-Informed Chemical Mixture Index for Oxidative Stress and Mortality in NHANES 2005-2010: A Survey-Weighted Quantile G-Computation Approach","rel_doi":"10.64898\/2026.06.30.26356938","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.30.26356938","rel_abs":"BackgroundCurrent chemical mixture approaches are largely data-driven without considering shared biological mechanisms among mixture components, highlighting the need for biology-informed approaches.\n\nObjectivesWe constructed an integrated measure of a chemical mixtures oxidative stress potential and assessed its association with mortality in the US population.\n\nMethodsThe sample comprised 4,574 adults ([&ge;]20 years) from National Health and Nutrition Examination Survey (NHANES) 2005-2010. To obtain robust estimates, we performed 1,000 repeated random 50:50 splits into training and testing sets. In each training set, we used survey-weighted quantile g-computation to model serum gamma-glutamyl transferase (GGT), an oxidative stress biomarker, as a function of a 30-chemical mixture (blood metals, urinary polycyclic aromatic hydrocarbons (PAHs), pesticides, phenols\/parabens, and phthalates), adjusting for sociodemographic, behavioral, and dietary factors. We then applied the fitted model from each training set to the corresponding testing set to derive the environmental risk score for oxidative stress (ERSOS), defined by predicted GGT values. Associations of ERSOS with all-cause, cardiovascular, and cancer mortality over 11 years of follow-up were estimated in the testing sets using survey-weighted Cox proportional hazards models and summarized across the 1,000 repeated splits.\n\nResultsChemicals with the largest positive weights in quantile g-computation included mono-(2-ethyl-5-hydroxyhexyl) phthalate, mono-2-ethyl-5-carboxypentyl phthalate, 2-hydroxyfluorene, methyl paraben, and benzophenone-3; chemicals with the largest negative weights included mono-(2-ethyl-5-oxohexyl) phthalate and PAH metabolites (1-hydroxynaphthalene, 3-hydroxyphenanthrene, and 3-hydroxyfluorene). The median correlation between observed and predicted GGT in the testing sets was 0.43 (2.5th, 97.5th percentiles: 0.40-0.48). A one standard deviation increase in ERSOS was associated with a median hazard ratio of 1.60 (2.5th, 97.5th percentiles: 1.01-2.57) for cardiovascular mortality. No associations were found for all-cause mortality or cancer mortality.\n\nDiscussionThe proposed survey-weighted quantile g-computation approach may help estimate biology-informed chemical mixture effects in complex survey data, supporting the potential utility for population-generalizable environmental mixture research.","rel_num_authors":7,"rel_authors":[{"author_name":"Yanelli Rodr\u00edguez-Carmona","author_inst":"University of Michigan, School of Public Health"},{"author_name":"Kelly M Bakulski","author_inst":"University of Michigan, School of Public Health"},{"author_name":"Erika Walker","author_inst":"University of Michigan, School of Public Health"},{"author_name":"Xin Wang","author_inst":"University of Michigan, School of Public Health"},{"author_name":"Wei Hao","author_inst":"University of Michigan, School of Public Health"},{"author_name":"Bhramar Mukherjee","author_inst":"Yale University, Yale School of Public Health"},{"author_name":"Sung Kyun Park","author_inst":"University of Michigan, School of Public Health"}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"Barriers to surgical care delivery are harming our planet: a case for decentralized provider services","rel_doi":"10.64898\/2026.06.30.26354345","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.30.26354345","rel_abs":"BackgroundSurgical care centralization in the U.S. delays access and increases carbon emissions. Global targets suggest patients live within 2-hours of a surgical facility. This study quantifies the environmental impact of travel for cataract surgery in rural Michigan and models the potential emissions reductions from decentralizing surgical and follow-up services.\n\nMethodsA retrospective, cross-sectional study analyzed electronic medical records from a rural Michigan ophthalmology practice (March-November 2023). We calculated travel distances using population-weighted centroids and estimated emissions using U.S. Department of Energy vehicle data. A k-means clustering model optimized additional facility placement, and a gradient analysis identified optimal numbers for decentralization points, for emissions reductions.\n\nResultsThe 920 patients traveled a median of 55.45 km (IQR: 43.33-88.20 km) for surgery and 55.07 km (IQR: 43.54-87.82 km) for follow-up visits, generating Total Surgical Access Emissions (TSAE) of 57,168 kgCO (median of 59.20 kgCO ; IQR: 32.31-81.87) under the centralized model. The k-means decentralization model and gradient analysis identified 7 hospitals and 9 clinics, respectively, as the optimal expansion points, reducing emissions by 34.07% (19,475 kgCO saved) and 39.52% (22,590 kgCO saved). The Surgical Access Carbon Impact (SACI) model demonstrated that achieving two-hour access to clinic services reduced excess emissions by 54.7%. Sensitivity analyses using fuel-efficient vehicles (Toyota Prius and Tesla Model 3) or reducing follow-up visit frequency reduced emissions by 54.03% (30,888 kgCO) and 25.83% (14,768 kgCO), respectively.\n\nConclusionDecentralizing surgical services in rural U.S. settings could cut travel-related emissions by up to 40%, significantly reducing healthcare-related carbon footprints while improving timely access to care. The SACI metric provides a novel framework for integrating environmental sustainability into U.S. health policy and service planning.","rel_num_authors":5,"rel_authors":[{"author_name":"Gabriella Y Hyman","author_inst":"Boston Children's Hospital; Program in Global Surgery and Social Change, Harvard Medical School; University of the Witwatersrand"},{"author_name":"Ramya Reddy","author_inst":"Program in Global Surgery and Social Change, Harvard Medical School; University of Florida College of Medicine"},{"author_name":"Taylor Wurdeman","author_inst":"Program in Global Surgery and Social Change, Harvard Medical School; Loma Linda University, General Surgery"},{"author_name":"Ralph P Crew","author_inst":"Michigan State University, College of Osteopathic Medicine. Dept. of Neurology and Ophthalmology"},{"author_name":"Mark G Shrime","author_inst":"Royal College of Surgeons in Ireland; Program in Global Surgery and Social Change, Harvard Medical School"}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"Multi-modal recruitment efficiency in ScreenPlus, a large-scale consented pilot NBS program","rel_doi":"10.64898\/2026.06.30.26356857","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.30.26356857","rel_abs":"ScreenPlus is a consented pilot program that aims to screen 100,000 babies for a panel of rare disorders. Given its size, ScreenPlus provides a unique opportunity to learn about optimal recruitment practices. ScreenPlus recruitment strategy includes recruiter-initiated Active and Hybrid modes and parent-initiated Independent mode. Active recruitment occurs in-person at the postpartum bedside, whereas Hybrid recruitment includes other attempt types. In Independent recruitment, parents access online educational and e-consent forms. Analysis of 47,642 completed recruitment profiles from May 2021 through April 2025 showed that Active recruitment was used in 72.2% and had the highest percentage of parents consenting (65.5%) in an average of 1.2 days. Hybrid recruitment was used in 27.1% of profiles and resulted in a 44.5% consent rate in an average of 8.6 days, with electronic medical record messaging being the attempt type most likely to lead to a consent. Independent recruitment was used in less than 1% of profiles. In Active and Hybrid Recruitment, non-English speakers were more likely to consent compared with English speakers. Collectively, these findings emphasize that although optimal pilot NBS recruitment is multi-modal, direct communication between parents and study team has the highest consent yield.","rel_num_authors":12,"rel_authors":[{"author_name":"Megan J Clarke","author_inst":"The Children's Hosp. at Montefiore\/Genetics Div."},{"author_name":"Katrina Paleologos","author_inst":"The Children's Hosp. at Montefiore\/Genetics Div."},{"author_name":"Nicole R Kelly","author_inst":"The Children's Hosp. at Montefiore\/Genetics Div."},{"author_name":"Sean M Bailey","author_inst":"Division of Neonatology, NYU Grossman School of Medicine"},{"author_name":"Marjorie Joseph","author_inst":"Mount Sinai West Hospital"},{"author_name":"Gabriel S Kupchik","author_inst":"Maimonides Children Hospital of Brooklyn, Maimonides Medical Center"},{"author_name":"Rishi Lumba","author_inst":"Division of Neonatology, NYU Grossman School of Medicine"},{"author_name":"Jaya J Ganesh","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Annemarie Stroustrup","author_inst":"Northwell Health Cohen Children Medical Center and the Departments of Pediatrics and Occupational Medicine"},{"author_name":"Joseph Orsini","author_inst":"Laboratory of Human Genetics, Wadsworth Center, New York State Department of Health"},{"author_name":"Aaron J Goldenberg","author_inst":"Case Western Reserve University School of Medicine"},{"author_name":"Melissa P Wasserstein","author_inst":"The Children's Hosp. at Montefiore\/Genetics Div."}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"Multi-modal recruitment efficiency in ScreenPlus, a large-scale consented pilot NBS program","rel_doi":"10.64898\/2026.06.30.26356857","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.30.26356857","rel_abs":"ScreenPlus is a consented pilot program that aims to screen 100,000 babies for a panel of rare disorders. Given its size, ScreenPlus provides a unique opportunity to learn about optimal recruitment practices. ScreenPlus recruitment strategy includes recruiter-initiated Active and Hybrid modes and parent-initiated Independent mode. Active recruitment occurs in-person at the postpartum bedside, whereas Hybrid recruitment includes other attempt types. In Independent recruitment, parents access online educational and e-consent forms. Analysis of 47,642 completed recruitment profiles from May 2021 through April 2025 showed that Active recruitment was used in 72.2% and had the highest percentage of parents consenting (65.5%) in an average of 1.2 days. Hybrid recruitment was used in 27.1% of profiles and resulted in a 44.5% consent rate in an average of 8.6 days, with electronic medical record messaging being the attempt type most likely to lead to a consent. Independent recruitment was used in less than 1% of profiles. In Active and Hybrid Recruitment, non-English speakers were more likely to consent compared with English speakers. Collectively, these findings emphasize that although optimal pilot NBS recruitment is multi-modal, direct communication between parents and study team has the highest consent yield.","rel_num_authors":12,"rel_authors":[{"author_name":"Megan J Clarke","author_inst":"The Children's Hosp. at Montefiore\/Genetics Div."},{"author_name":"Katrina Paleologos","author_inst":"The Children's Hosp. at Montefiore\/Genetics Div."},{"author_name":"Nicole R Kelly","author_inst":"The Children's Hosp. at Montefiore\/Genetics Div."},{"author_name":"Sean M Bailey","author_inst":"Division of Neonatology, NYU Grossman School of Medicine"},{"author_name":"Marjorie Joseph","author_inst":"Mount Sinai West Hospital"},{"author_name":"Gabriel S Kupchik","author_inst":"Maimonides Children Hospital of Brooklyn, Maimonides Medical Center"},{"author_name":"Rishi Lumba","author_inst":"Division of Neonatology, NYU Grossman School of Medicine"},{"author_name":"Jaya J Ganesh","author_inst":"Icahn School of Medicine at Mount Sinai"},{"author_name":"Annemarie Stroustrup","author_inst":"Northwell Health Cohen Children Medical Center and the Departments of Pediatrics and Occupational Medicine"},{"author_name":"Joseph Orsini","author_inst":"Laboratory of Human Genetics, Wadsworth Center, New York State Department of Health"},{"author_name":"Aaron J Goldenberg","author_inst":"Case Western Reserve University School of Medicine"},{"author_name":"Melissa P Wasserstein","author_inst":"The Children's Hosp. at Montefiore\/Genetics Div."}],"rel_date":"2026-07-02","rel_site":"medrxiv"},{"rel_title":"Hepatic Cholesteryl Ester Transfer Protein Regulates Sex-specific Liver Metabolic Adaptation and Metabolic-Associated Steatotic Liver Disease Risk in Diet-induced Obesity","rel_doi":"10.64898\/2026.06.28.735072","rel_link":"http:\/\/biorxiv.org\/content\/10.64898\/2026.06.28.735072","rel_abs":"Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) and associated dyslipidemia is a growing health issue that gives rise to cardiovascular risk. Men are more prone to development of MASLD than women. Understanding mechanisms underlying sex differences in MASLD may lead to improved prevention and treatment approaches. Cholesteryl ester transfer protein (CETP) is a lipid transfer protein that shuttles triglycerides and cholesteryl esters between blood lipoproteins and tissues. In this study investigate the impact of hepatic CETP expression on MASLD. Hepatic CETP expression (L-HuCETP) was achieved by injecting liver-targeted CETP-expressing adeno-associated virus into C57BL\/6J mice. In females, L-HuCETP improved glucose tolerance, consistent with our prior clamp results in global human CETP transgenic mice. Whereas in males, L-HuCETP worsened glucose metabolism and impaired insulin signaling. Correspondingly, L-HuCETP expression reduced the expression of gluconeogenic pathway genes in females but upregulated these genes in males. In males, L-HuCETP mice exhibited increased hepatic lipid droplet accumulation, lipogenesis proteins and these changes were not observed in females. L-HuCETP expression resulted in sex-specific hepatic responses, with increased expression of inflammation and fibrosis related genes in male, but decreased expression of these genes in females. Mechanistic studies indicate that L-HuCETP had sex specific effects on transcription factors ChREBP and HNF4, which are important for glucose and lipid metabolism. Our studies suggest that sex-specific roles of L-HuCETP with regard to liver metabolic adaptation and MASLD risk in obesity, highlighting CETP-mediated pathways as potential targets for sex-specific precision medicine approaches to improve MASLD.","rel_num_authors":4,"rel_authors":[{"author_name":"Sivaprakasam Chinnarasu","author_inst":"The Ohio State University Wexner Medical Center"},{"author_name":"Uche Anozie","author_inst":"Vanderbilt University Medical Center"},{"author_name":"Lin Zhu","author_inst":"The Ohio State University Wexner Medical Center"},{"author_name":"John M Stafford","author_inst":"The Ohio State University Wexner Medical Center"}],"rel_date":"2026-07-02","rel_site":"biorxiv"},{"rel_title":"Categorical and Dimensional Alterations Along Two Principal Cortical Gradient Axes Across the Schizophrenia-Bipolar Spectrum","rel_doi":"10.64898\/2026.06.30.26356921","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.30.26356921","rel_abs":"Background and HypothesisSchizophrenia (SZ) and bipolar disorder (BD) share overlapping yet distinct clinical profiles and system-wide brain alterations. Macroscale functional connectivity gradients capture principal axes of cortical organization, including the separation of unimodal and transmodal systems, offering a low-dimensional lens on individual differences in brain architecture. Whether these axes reflect shared or diagnosis-specific variation across the SZ-BD spectrum is unknown.\n\nStudy DesignUsing resting-state fMRI from 187 adults (110 HC, 37 SZ, 40 BD) from the UCLA Consortium for Neuropsychiatric Phenomics, we derived individual low-dimensional gradients and applied three analyses: case-control comparisons at both the cortical network and subcortical region-of-interest level, Partial Least Squares (PLS) regression linking gradients to clinical phenotypes, and individual-level similarity indices (SI-PLS) positioning participants within a gradient-behaviour space.\n\nStudy ResultsWhile the gradient structure (G1: visual-somatomotor and G2: unimodal-transmodal) was preserved across groups, patient groups showed greater deviations along both axes. Network analyses revealed transdiagnostic frontoparietal compression in G2, alongside disorder-specific effects: visual pole contraction and subcortical amygdala displacement in SZ, and somatomotor displacement in BD. PLS identified a BD-associated profile of preserved gradient architecture and lower symptom burden, contrasting with an SZ-associated profile of greater cognitive impairment and symptom severity. SI-PLS scores placed SZ and BD in distinct regions of a shared two-dimensional neural space, with HC between them.\n\nConclusionsDifferences across the SZ-BD spectrum organize along two principal axes, revealing transdiagnostic alterations in higher-order association systems alongside disorder-specific sensory signatures. These findings support a multi-axis dimensional framework for understanding clinical heterogeneity in psychosis.","rel_num_authors":14,"rel_authors":[{"author_name":"Asia Ferrari","author_inst":"University of Geneva"},{"author_name":"Bin Wan","author_inst":"Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland"},{"author_name":"Judith Kabbeck","author_inst":"Department of Adult Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, Zurich, Switzerland"},{"author_name":"Amin Saberi","author_inst":"Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany"},{"author_name":"Stefan Kaiser","author_inst":"Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland"},{"author_name":"Valeria Kebets","author_inst":"Department of Electrical and Computer Engineering, Clinical Imaging Research Centre, N.1 Institute for Health and Memory Networks Program, National University o"},{"author_name":"Clara Moreau","author_inst":"Centre de recherche Azrieli CHU Sainte Justine, Department of Psychiatry and Addictology, University of Montreal, Montreal, Quebec, Canada"},{"author_name":"Paul M. Thompson","author_inst":"Imaging Genetics Center, Mark and Mary Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of the University of Southern California, Marina de"},{"author_name":"Theo G.M. Van Erp","author_inst":"Clinical Translational Neuroscience Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, USA"},{"author_name":"Jessica A. Turner","author_inst":"Department of Psychiatry and Behavioral Health, the Ohio State University, Columbus, OH, USA"},{"author_name":"Thomas B.T. Yeo","author_inst":"Department of Electrical and Computer Engineering, Clinical Imaging Research Centre, N.1 Institute for Health and Memory Networks Program, National University o"},{"author_name":"Boris C. Bernhardt","author_inst":"Centre of Excellence in Epilepsy at the Neuro (CEEN) and McConnell Brain Imaging Centre (BIC), Montreal Neurological Institute and Hospital, McGill University, "},{"author_name":"Sofie L. Valk","author_inst":"Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany"},{"author_name":"Matthias Kirschner","author_inst":"Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Inherited human TFIIIA deficiency disrupts T cell development","rel_doi":"10.64898\/2026.07.01.26356670","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.07.01.26356670","rel_abs":"Molecular characterization of human monogenic inborn errors of T cell immunity provides both biological insights and medical progress. We report rare biallelic deleterious variants in GTF3A, encoding transcription factor IIIA (TFIIIA), a zinc-finger protein required for transcription and chaperoning of 5S ribosomal RNA (rRNA). These variants were identified in ten patients from eight unrelated families and eight countries presenting with either T-B+NK+ severe combined immunodeficiency (SCID) or combined immune deficiency (CID), characterized by T cell lymphopenia and variable antibody deficiency. The GTF3A variants disrupt TFIIIA function through distinct mechanisms, including defective DNA binding, aberrant nuclear localization, and reduced protein stability compromising TFIIIA-mediated transcription and chaperoning of 5S rRNA. Using artificial thymic organoids derived from TFIIIA-deficient CD34 progenitors, an early developmental arrest at the T cell commitment stage was documented in vitro. Zebrafish deficient for gtf3aa recapitulated the impaired thymocyte development in vivo. Together, these findings establish TFIIIA deficiency as a novel cause of (S)CID, expanding the genetic and mechanistic landscape of inborn errors of T cell immunity and uncovering an essential role for TFIIIA in human adaptive immunity.\n\nOne-sentence summaryBiallelic GTF3A variants causing TFIIIA deficiency, which disrupts 5S rRNA transcription, represent a novel monogenic cause of (S)CID, unveiling a crucial role of TFIIIA in T cell development.","rel_num_authors":46,"rel_authors":[{"author_name":"Evi Duthoo","author_inst":"Department of Internal Medicine, Ghent University"},{"author_name":"Sueun Park","author_inst":"Department of Internal Medicine, Ghent University"},{"author_name":"Tamara Jarayseh","author_inst":"Department of Internal Medicine, Ghent University"},{"author_name":"Marita Bosticardo","author_inst":"National Institutes of Health (NIH)"},{"author_name":"Rafah Mackeh","author_inst":"Research Branch, Sidra Medicine"},{"author_name":"Yana Van Droogenbroeck","author_inst":"Department of Diagnostic Sciences, Ghent University"},{"author_name":"Imke Velghe","author_inst":"Department of Diagnostic Sciences, Ghent University"},{"author_name":"Veronique Debacker","author_inst":"Department of Internal Medicine, Ghent University"},{"author_name":"Hailun Li","author_inst":"Imagine Institute, University of Paris Cite"},{"author_name":"Nourhen Agrebi","author_inst":"Research Branch, Sidra Medicine"},{"author_name":"Francesca Pala","author_inst":"National Institutes of Health (NIH)"},{"author_name":"Sarah Ghistelinck","author_inst":"Department of Internal Medicine, Ghent University"},{"author_name":"Julie Braet","author_inst":"Department of Internal Medicine and Pediatrics, Ghent University"},{"author_name":"Sandra Van Lint","author_inst":"Department of Internal Medicine and Pediatrics, Ghent University"},{"author_name":"Lukas Pieters","author_inst":"Department of Internal Medicine and Pediatrics, Ghent University"},{"author_name":"Martin Watelet","author_inst":"Department of Internal Medicine and Pediatrics, Ghent University"},{"author_name":"Hajar Besbassi","author_inst":"University of Antwerp"},{"author_name":"Leslie Naesens","author_inst":"Ghent University Hospital"},{"author_name":"Tessa Kerre","author_inst":"Ghent University Hospital"},{"author_name":"Delfien Bogaert","author_inst":"Children's Health Ireland at Crumlin"},{"author_name":"Hye Sun Kuehn","author_inst":"National Institutes of Health (NIH)"},{"author_name":"Sergio D. Rosenzweig","author_inst":"National Institutes of Health (NIH)"},{"author_name":"Emmanuelle Jouanguy","author_inst":"Imagine Institute, University of Paris Cite"},{"author_name":"Ottavia M. Delmonte","author_inst":"National Institutes of Health (NIH)"},{"author_name":"Ivan Chinn","author_inst":"Baylor College of Medicine"},{"author_name":"Stephen Hughes","author_inst":"Royal Manchester Children's Hospital"},{"author_name":"Amel Hassan","author_inst":"Sidra Medicine"},{"author_name":"Karim Y. Mohammed","author_inst":"Sidra Medicine"},{"author_name":"Asha Elmi","author_inst":"Research Branch, Sidra Medicine"},{"author_name":"Giuliana Giardino","author_inst":"Federico II University"},{"author_name":"Claudio Pignata","author_inst":"Federico II University"},{"author_name":"Benedicte Neven","author_inst":"Necker-Enfants Malades Hospital"},{"author_name":"Benson Ogunjimi","author_inst":"University of Antwerp"},{"author_name":"Karim Vermaelen","author_inst":"Department of Internal Medicine and Pediatrics, Ghent University"},{"author_name":"Denis L.J. Lafontaine","author_inst":"Universite libre de Bruxelles (ULB)"},{"author_name":"Mirjam van der Burg","author_inst":"Leiden University Medical Center"},{"author_name":"Anne Puel","author_inst":"Imagine Institute, University of Paris Cite"},{"author_name":"J\u00e9r\u00e9mie Rosain","author_inst":"Imagine Institute, University of Paris Cite"},{"author_name":"Jean-Laurent Casanova","author_inst":"The Rockefeller University"},{"author_name":"Bernice Lo","author_inst":"Research Branch, Sidra Medicine"},{"author_name":"Patrick Sips","author_inst":"Department of Biomolecular Medicine, Ghent University"},{"author_name":"Tom Taghon","author_inst":"Department of Diagnostic Sciences, Ghent University"},{"author_name":"Jacinta Bustamante","author_inst":"Imagine Institute, University of Paris Cite"},{"author_name":"Luigi D. Notarangelo","author_inst":"National Institutes of Health (NIH)"},{"author_name":"Simon J. Tavernier","author_inst":"Department of Internal Medicine and Pediatrics, Ghent University"},{"author_name":"Filomeen Haerynck","author_inst":"Department of Internal Medicine and Pediatrics, Ghent University"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Perceptions of Open Science in the Editorial and Peer Review Process: A Cross-Sectional Survey of Traditional, Complementary, and Integrative Medicine Journal Editors","rel_doi":"10.64898\/2026.06.30.26356457","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.30.26356457","rel_abs":"BackgroundOpen science (OS) offers opportunities to address challenges in the editorial and peer review processes of traditional, complementary, and integrative medicine (TCIM) journals. This study assessed TCIM journal editors perceptions of OS and the perceived benefits and challenges of integrating OS into editorial and peer review processes.\n\nMethodsA cross-sectional survey was distributed to editors-in-chief, associate editors, and editorial board members of 115 TCIM journals. The survey examined demographics, current use and familiarity with OS, perceived advantages and obstacles, and future perspectives on OS in academic publishing. Quantitative data were analyzed descriptively, and qualitative data were examined using thematic analysis.\n\nResultsA total of 267 respondents completed the survey, with most identifying as faculty members or academic research staff (n = 201\/335, 60.0%). Most respondents were familiar (n = 128\/212, 60.3%) or very familiar (n = 64\/212, 30.2%) with OS practices, although many had received no formal OS training (n = 94\/210, 44.8%).\n\nRespondents were most familiar with open access (n = 131\/213, 61.5%) and preprints (n = 92\/211, 43.6%). Among the seven OS practices examined, open access was viewed most favorably, with many considering it \"very important\" (n = 97\/206, 47.1%) and strongly agreeing that it enhances the accessibility of research findings (n = 118\/195, 60.5%).\n\nConclusionMost respondents were familiar with OS but held varying perceptions regarding the importance, advantages, and disadvantages of different OS practices. These findings may inform the development and implementation of evidence-based practices and policies that meet the needs of the TCIM research community.","rel_num_authors":23,"rel_authors":[{"author_name":"Jeremy Y. Ng","author_inst":"University Hospital Tubingen"},{"author_name":"Daivat Bhavsar","author_inst":"University Hospital Tubingen"},{"author_name":"Julian T. Lau","author_inst":"University Hospital Tubingen"},{"author_name":"Neha Dhanvanthry","author_inst":"University Hospital Tubingen"},{"author_name":"Daniel Fry","author_inst":"University Hospital Tubingen"},{"author_name":"Ji Woo Kim","author_inst":"University Hospital Tubingen"},{"author_name":"Amelia King","author_inst":"University Hospital Tubingen"},{"author_name":"Jaimie Lai","author_inst":"University Hospital Tubingen"},{"author_name":"Anthony Makwanda","author_inst":"University Hospital Tubingen"},{"author_name":"Priscilla Olugbemiro","author_inst":"University Hospital Tubingen"},{"author_name":"Jeel Patel","author_inst":"University Hospital Tubingen"},{"author_name":"Insha Virani","author_inst":"University Hospital Tubingen"},{"author_name":"Ella Ying","author_inst":"University Hospital Tubingen"},{"author_name":"Kingsley Yong","author_inst":"University Hospital Tubingen"},{"author_name":"Abdullah Zaidi","author_inst":"University Hospital Tubingen"},{"author_name":"Jasmine Zouhair","author_inst":"University Hospital Tubingen"},{"author_name":"Susan Arentz","author_inst":"Western Sydney University"},{"author_name":"Erik J. Groessl","author_inst":"University of California, San Diego"},{"author_name":"Myeong Soo Lee","author_inst":"Korea Institute of Oriental Medicine"},{"author_name":"Ye-Seul Lee","author_inst":"Jaseng Medical Foundation"},{"author_name":"Ava Lorenc","author_inst":"University of Bristol"},{"author_name":"L. Susan Wieland","author_inst":"University Hospital Tubingen"},{"author_name":"Holger Cramer","author_inst":"University Hospital Tubingen"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Perceptions of Open Science in the Editorial and Peer Review Process: A Cross-Sectional Survey of Traditional, Complementary, and Integrative Medicine Journal Editors","rel_doi":"10.64898\/2026.06.30.26356457","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.30.26356457","rel_abs":"BackgroundOpen science (OS) offers opportunities to address challenges in the editorial and peer review processes of traditional, complementary, and integrative medicine (TCIM) journals. This study assessed TCIM journal editors perceptions of OS and the perceived benefits and challenges of integrating OS into editorial and peer review processes.\n\nMethodsA cross-sectional survey was distributed to editors-in-chief, associate editors, and editorial board members of 115 TCIM journals. The survey examined demographics, current use and familiarity with OS, perceived advantages and obstacles, and future perspectives on OS in academic publishing. Quantitative data were analyzed descriptively, and qualitative data were examined using thematic analysis.\n\nResultsA total of 267 respondents completed the survey, with most identifying as faculty members or academic research staff (n = 201\/335, 60.0%). Most respondents were familiar (n = 128\/212, 60.3%) or very familiar (n = 64\/212, 30.2%) with OS practices, although many had received no formal OS training (n = 94\/210, 44.8%).\n\nRespondents were most familiar with open access (n = 131\/213, 61.5%) and preprints (n = 92\/211, 43.6%). Among the seven OS practices examined, open access was viewed most favorably, with many considering it \"very important\" (n = 97\/206, 47.1%) and strongly agreeing that it enhances the accessibility of research findings (n = 118\/195, 60.5%).\n\nConclusionMost respondents were familiar with OS but held varying perceptions regarding the importance, advantages, and disadvantages of different OS practices. These findings may inform the development and implementation of evidence-based practices and policies that meet the needs of the TCIM research community.","rel_num_authors":23,"rel_authors":[{"author_name":"Jeremy Y. Ng","author_inst":"University Hospital Tubingen"},{"author_name":"Daivat Bhavsar","author_inst":"University Hospital Tubingen"},{"author_name":"Julian T. Lau","author_inst":"University Hospital Tubingen"},{"author_name":"Neha Dhanvanthry","author_inst":"University Hospital Tubingen"},{"author_name":"Daniel Fry","author_inst":"University Hospital Tubingen"},{"author_name":"Ji Woo Kim","author_inst":"University Hospital Tubingen"},{"author_name":"Amelia King","author_inst":"University Hospital Tubingen"},{"author_name":"Jaimie Lai","author_inst":"University Hospital Tubingen"},{"author_name":"Anthony Makwanda","author_inst":"University Hospital Tubingen"},{"author_name":"Priscilla Olugbemiro","author_inst":"University Hospital Tubingen"},{"author_name":"Jeel Patel","author_inst":"University Hospital Tubingen"},{"author_name":"Insha Virani","author_inst":"University Hospital Tubingen"},{"author_name":"Ella Ying","author_inst":"University Hospital Tubingen"},{"author_name":"Kingsley Yong","author_inst":"University Hospital Tubingen"},{"author_name":"Abdullah Zaidi","author_inst":"University Hospital Tubingen"},{"author_name":"Jasmine Zouhair","author_inst":"University Hospital Tubingen"},{"author_name":"Susan Arentz","author_inst":"Western Sydney University"},{"author_name":"Erik J. Groessl","author_inst":"University of California, San Diego"},{"author_name":"Myeong Soo Lee","author_inst":"Korea Institute of Oriental Medicine"},{"author_name":"Ye-Seul Lee","author_inst":"Jaseng Medical Foundation"},{"author_name":"Ava Lorenc","author_inst":"University of Bristol"},{"author_name":"L. Susan Wieland","author_inst":"University Hospital Tubingen"},{"author_name":"Holger Cramer","author_inst":"University Hospital Tubingen"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Multi-ancestry modeling improves fine-mapping resolution, protein prediction, and discovery for proteome-wide association studies","rel_doi":"10.64898\/2026.06.29.26356716","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26356716","rel_abs":"Proteomic predictive models are predominantly trained on cis-acting variants in European-ancestry cohorts, limiting power and predictive accuracy in ancestrally diverse populations. We performed cis- and trans-protein quantitative trait locus (pQTL) mapping and developed protein-prediction models using whole-genome sequencing (WGS) and plasma protein levels (Olink) across four ancestry groups from the Trans-omics for Precision Medicine (TOPMed) Multi-Ethnic Study of Atherosclerosis (MESA): European (EUR, n=1270), African (AFR, n=675), Hispanic (HIS, n=642), and Chinese (CHN, n=366), and a combined population (ALL, n=2953). African-ancestry samples demonstrated improved fine-mapping resolution relative to cohort size, yielding significantly smaller cis-credible sets than European-ancestry samples, consistent with shorter linkage disequilibrium (LD) blocks and greater allele frequency diversity in African-ancestry populations. For the first time, we benchmarked fine-mapping models SuSiE, SuShiE, MultiSuSiE, and SuSiEx with multi-ancestral cohorts, revealing a precision-recall tradeoff driven by model assumptions. Comparing protein-prediction models, multivariate adaptive shrinkage (MASHR) and ultimate deconvolution in R (UDR) outperformed elastic net (EN) regression, with trans-pQTL inclusion and fine-mapping improving prediction performance and proteome-wide association study (PWAS) discovery. Applying our models in PWAS of 10 phenotypes, we discovered 68 protein-phenotype associations in All of Us (AoU) that also replicated in Pan-UK Biobank. MASHR and UDR models identified 60% more protein-phenotype associations than EN. Notably, 32 of these associations were not previously reported in the GWAS Catalog. Overall, our study demonstrates the importance of including multiple ancestries in genomic studies to capture the full spectrum of regulatory variation and improve cross-ancestry generalizability.","rel_num_authors":15,"rel_authors":[{"author_name":"Claudia J. Krueger","author_inst":"Loyola University Chicago"},{"author_name":"Matthew Fischer","author_inst":"Loyola University Chicago"},{"author_name":"Tooba Rizwan","author_inst":"Loyola University Chicago"},{"author_name":"Mira M. Kumar","author_inst":"Loyola University Chicago"},{"author_name":"Siyaa Bhargava","author_inst":"Loyola University Chicago"},{"author_name":"Robert  E. Gerszten","author_inst":"Harvard Medical School"},{"author_name":"Kent D. Taylor","author_inst":"The Lundquist Institute"},{"author_name":"Michael H. Cho","author_inst":"Brigham and Women's Hospital"},{"author_name":"Jerome I. Rotter","author_inst":"The Lundquist Institute"},{"author_name":"- NHLBI TOPMed Consortium","author_inst":"-"},{"author_name":"Minoli Perera","author_inst":"Northwestern University"},{"author_name":"Xiaowei Hu","author_inst":"University of Virginia"},{"author_name":"Ani W. Manichaikul","author_inst":"University of Virginia"},{"author_name":"Hae Kyung Im","author_inst":"The University of Chicago"},{"author_name":"Heather E. Wheeler","author_inst":"Loyola University Chicago"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Automating neoantigen selection for personalized cancer vaccine design","rel_doi":"10.64898\/2026.06.24.26356293","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.24.26356293","rel_abs":"Advancements in immunogenomics and immuno-oncology have enabled the development of personalized cancer vaccines (PCVs) that target cancer cell-specific somatic variants. A subset of these variants produce neoantigens that, when presented on tumor cells by MHC molecules, have the potential to elicit a robust and specific immune response. To date, there are over one hundred interventional studies listed on clinicaltrials.gov that explore the use of PCVs. We have supported a number of these trials through the creation of bioinformatic pipelines, tools, and procedures for the identification of patient-specific neoantigen candidates. While many of these steps have been automated, the final selection of neoantigen candidates often relies on expert manual review, creating a bottleneck that limits scalability and full automation of PCV workflows. Addressing this challenge, we introduce NEAT (Neoantigen Evaluation & Automated Triage), a machine learning-based approach that enables automated neoantigen candidate prioritization and supports the transition toward more scalable and reproducible PCV design. We implemented a prediction model trained and tested on existing vaccine design results from 33 patients and 1,943 peptides, across 3 clinical trials, including 439 peptides prioritized for PCV inclusion. This model uses features such as tumor variant allele frequency, RNA expression, driver gene status, binding\/presentation scores, and transcript support level to automatically predict whether a peptide will be accepted, rejected, or require further human review before inclusion in a vaccine. The model achieved a sensitivity of 0.847 and specificity of 0.924, with an area under the curve of 0.955. The model predictions have been incorporated in pVACtools v7.0.0. By integrating this model into the vaccine development pipeline, we foresee a significant reduction in the time required to transition from patient sample collection to vaccine manufacturing, thereby enhancing the efficiency and scalability of PCV production.","rel_num_authors":29,"rel_authors":[{"author_name":"Jennie X Yao","author_inst":"Washington University School of Medicine"},{"author_name":"Kartik Singhal","author_inst":"Washington University School of Medicine"},{"author_name":"Susanna Kiwala","author_inst":"Washington University School of Medicine"},{"author_name":"Evelyn Schmidt","author_inst":"Washington University School of Medicine"},{"author_name":"S. Peter Goedegebuure","author_inst":"Washington University School of Medicine"},{"author_name":"Christopher A Miller","author_inst":"Washington University School of Medicine"},{"author_name":"Huiming Xia","author_inst":"Washington University School of Medicine"},{"author_name":"Kelsy C Cotto","author_inst":"Washington University School of Medicine"},{"author_name":"Adam Coffman","author_inst":"Washington University School of Medicine"},{"author_name":"My H Hoang","author_inst":"Washington University School of Medicine"},{"author_name":"Mariam Khanfar","author_inst":"Washington University School of Medicine"},{"author_name":"Jinglun Li","author_inst":"Washington University School of Medicine"},{"author_name":"Luke Hendrickson","author_inst":"Washington University School of Medicine"},{"author_name":"Isabel Risch","author_inst":"Washington University School of Medicine"},{"author_name":"Sherri R Davies","author_inst":"Washington University School of Medicine"},{"author_name":"Feiyu Du","author_inst":"Washington University School of Medicine"},{"author_name":"Gue Su Chang","author_inst":"Washington University School of Medicine"},{"author_name":"Jasreet Hundal","author_inst":"Washington University School of Medicine"},{"author_name":"Jeffrey P Ward","author_inst":"Washington University School of Medicine"},{"author_name":"William B Inabinett","author_inst":"Jaime Leandro Foundation for Therapeutic Cancer Vaccines"},{"author_name":"William A Hoos","author_inst":"Jaime Leandro Foundation for Therapeutic Cancer Vaccines"},{"author_name":"Tanner M Johanns","author_inst":"Washington University School of Medicine"},{"author_name":"Gavin P Dunn","author_inst":"Massachusetts General Hospital\/Mass General Brigham"},{"author_name":"Russell K Pachynski","author_inst":"Washington University School of Medicine"},{"author_name":"Todd A Fehniger","author_inst":"Washington University School of Medicine"},{"author_name":"Jennifer A Foltz","author_inst":"Washington University School of Medicine"},{"author_name":"William E Gillanders","author_inst":"Washington University School of Medicine"},{"author_name":"Malachi Griffith","author_inst":"Washington University School of Medicine"},{"author_name":"Obi L Griffith","author_inst":"Washington University School of Medicine"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Longitudinal plasma neurofilament light chain and patient-reported outcomes as complementary markers of vincristine-associated peripheral neuropathy in adults with lymphoma: a cohort study","rel_doi":"10.64898\/2026.06.28.26356741","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.28.26356741","rel_abs":"Chemotherapy-induced peripheral neuropathy (CIPN) is a common neurotoxicity of cancer treatment with limited diagnostic, monitoring, and treatment options. Neurofilament light chain (NfL) is an axonal cytoskeletal protein released during neuroaxonal injury and a promising biomarker of CIPN, but prospective evidence for NfL as a marker of CIPN from vincristine-containing lymphoma chemotherapy treatment remains limited. To fill this gap, we conducted a pragmatic single-center prospective observational cohort study of adults with non-Hodgkin lymphoma (NHL) receiving first-line vincristine-containing chemotherapy to evaluate NfL dynamics across multiple pre-cycle visits and assess relationships with patient-reported and clinician-graded neuropathy measures. We followed 25 participants during 4-6 months of chemotherapy, and a small subset of those participants (n=6) for 24-42 months post-chemotherapy. Serial plasma NfL was measured and CIPN symptoms were assessed using patient- and clinician-reported measures. Longitudinal changes were analyzed using mixed-effects models. Plasma NfL increased relative to pre-cycle1 at all timepoints (all p<0.001), increasing more than threefold by pre-cycle4. Patient-reported CIPN scores and clinician-graded neuropathy also increased during treatment. Exploratory pooled visit-level analyses showed a modest NfL-CIPN association (Spearman {rho}=0.393, p=0.004), while timepoint-specific, lagged, and post hoc sensitivity analyses suggested potential to predict persistent CIPN symptoms from early NfL concentrations. To our knowledge, these findings provide the first prospective evidence that NfL is sensitive to vincristine exposure in adults with NHL and may complement patient-reported symptom assessment, clinician grading, and dose-modification context in future CIPN monitoring studies.","rel_num_authors":13,"rel_authors":[{"author_name":"Gretchen A. McNally","author_inst":"Department of Nursing, The Ohio State University, Arthur G. James Cancer Hospital and Comprehensive Cancer Center, Columbus, OH, USA"},{"author_name":"Grace Ji-eun Shin","author_inst":"The Ohio State University"},{"author_name":"Lise Worthen-Chaudhari","author_inst":"The Ohio State University College of Medicine"},{"author_name":"Patrick M. Schnell","author_inst":"The Ohio State University Division of Biostatistics, College of Public Health, The Ohio State University, Department of Medical Epidemiology and Biostatistics, "},{"author_name":"Laura Flora","author_inst":"Department of Nursing, The Ohio State University, Arthur G. James Cancer Hospital and Comprehensive Cancer Center, Columbus, OH, USA"},{"author_name":"Surith Sanjay Krishna","author_inst":"Department of Neurology, The Ohio State University College of Medicine, Columbus, OH, USA"},{"author_name":"Timothy Voorhees","author_inst":"The Ohio State University Comprehensive Cancer Center, Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, C"},{"author_name":"Robert A. Baiocchi","author_inst":"The Ohio State University Comprehensive Cancer Center, Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, C"},{"author_name":"David Bond","author_inst":"The Ohio State University Comprehensive Cancer Center Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Co"},{"author_name":"Beth Christian","author_inst":"The Ohio State University Comprehensive Cancer Center Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Co"},{"author_name":"Kami Maddocks","author_inst":"The Ohio State University Comprehensive Cancer Center Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Co"},{"author_name":"Yazeed Sawalha","author_inst":"The Ohio State University Comprehensive Cancer Center Division of Hematology, Department of Internal Medicine, The Ohio State University College of Medicine, Co"},{"author_name":"Maryam B. Lustberg","author_inst":"Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Long-Term Brain White Matter Outcomes Following Neonatal Acute Kidney Injury","rel_doi":"10.64898\/2026.06.24.26356471","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.24.26356471","rel_abs":"Acute kidney injury (AKI) is common among neonates in the intensive care unit and has been linked to abnormal neurodevelopment, yet long-term effects on brain structure remain uncharacterized. In this secondary analysis, we compared brain white matter integrity, measured by fractional anisotropy (FA) on 3T MRI, in children ages 5-12 years born preterm with (n=5) versus without (n=10) a history of neonatal AKI. Contrary to our hypothesis, children with prior neonatal AKI showed higher FA across seven white matter regions in unadjusted analyses. After adjustment for sex, birth weight, and age at MRI, the AKI group retained significantly greater FA in the corticospinal tract ({beta}=0.7, 95% CI 0.09-1.31) and superior frontooccipital fasciculus ({beta}=0.68, 95% CI 0.02-1.34). Because elevated FA may reflect compensatory glial responses rather than improved neurological function, these findings suggest neonatal AKI may have lasting, complex effects on white matter microstructure. Larger studies pairing neuroimaging with neurocognitive assessment are needed.","rel_num_authors":8,"rel_authors":[{"author_name":"Ryan C Ward","author_inst":"University of Iowa"},{"author_name":"Emily J Steinbach","author_inst":"University of Iowa"},{"author_name":"Peggy  C Nopoulos","author_inst":"University of Iowa Hospitals and Clinics"},{"author_name":"Ellen van der Plas","author_inst":"University of Arkansas Medical Sciences"},{"author_name":"Lauren Hopkins","author_inst":"University of Iowa"},{"author_name":"Danielle E Soranno","author_inst":"Indiana University"},{"author_name":"Amy L Conrad","author_inst":"University of Iowa"},{"author_name":"Lyndsay A Harshman","author_inst":"University of Iowa"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Autonomous generation of decision-grade clinical evidence","rel_doi":"10.64898\/2026.06.26.26356653","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356653","rel_abs":"Medical practice is bottlenecked by the slow production of high-quality clinical evidence. Despite progress in automating selected stages, autonomous conduct of the entire research life cycle remains beyond reach. Here we present OpenEBM, the first autonomous system to generate decision-grade clinical evidence by conducting evidence-synthesis research end to end. To enable and evaluate this, we develop OpenEBM-Corpus, a foundation resource of expert-annotated research trajectories that enables training of a specialist model, and OpenEBM-Bench, a multidisciplinary benchmark that evaluates the entire research life cycle. Our compact specialist model generates valid clinical evidence in 90.7% of end-to-end evaluations and matches expert performance across the research trajectory, whereas GPT-5 falls to 3.8% as failures propagate through dependent stages. In blinded evaluations across clinical domains, independent evaluators prefer OpenEBM at multiple stages and cannot distinguish its reasoning traces from expert-conducted work above chance. Applied to a question left unresolved by current guidelines, OpenEBM produces de novo evidence addressing the efficacy and safety of neoadjuvant chemotherapy for locally advanced rectal cancer. OpenEBM brings within reach the founding aspiration of evidence-based medicine and establishes a paradigm for scalable evidence generation.","rel_num_authors":5,"rel_authors":[{"author_name":"Shaopeng Yang","author_inst":"Sun Yat-sen University"},{"author_name":"Jiayu Wu","author_inst":"The University of Sydney"},{"author_name":"Hao Xie","author_inst":"Sun Yat-sen University"},{"author_name":"Zhuoyao Xin","author_inst":"Johns Hopkins University"},{"author_name":"Wei Wang","author_inst":"Sun Yat-sen University"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Autonomous generation of decision-grade clinical evidence","rel_doi":"10.64898\/2026.06.26.26356653","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356653","rel_abs":"Medical practice is bottlenecked by the slow production of high-quality clinical evidence. Despite progress in automating selected stages, autonomous conduct of the entire research life cycle remains beyond reach. Here we present OpenEBM, the first autonomous system to generate decision-grade clinical evidence by conducting evidence-synthesis research end to end. To enable and evaluate this, we develop OpenEBM-Corpus, a foundation resource of expert-annotated research trajectories that enables training of a specialist model, and OpenEBM-Bench, a multidisciplinary benchmark that evaluates the entire research life cycle. Our compact specialist model generates valid clinical evidence in 90.7% of end-to-end evaluations and matches expert performance across the research trajectory, whereas GPT-5 falls to 3.8% as failures propagate through dependent stages. In blinded evaluations across clinical domains, independent evaluators prefer OpenEBM at multiple stages and cannot distinguish its reasoning traces from expert-conducted work above chance. Applied to a question left unresolved by current guidelines, OpenEBM produces de novo evidence addressing the efficacy and safety of neoadjuvant chemotherapy for locally advanced rectal cancer. OpenEBM brings within reach the founding aspiration of evidence-based medicine and establishes a paradigm for scalable evidence generation.","rel_num_authors":5,"rel_authors":[{"author_name":"Shaopeng Yang","author_inst":"Sun Yat-sen University"},{"author_name":"Jiayu Wu","author_inst":"The University of Sydney"},{"author_name":"Hao Xie","author_inst":"Sun Yat-sen University"},{"author_name":"Zhuoyao Xin","author_inst":"Johns Hopkins University"},{"author_name":"Wei Wang","author_inst":"Sun Yat-sen University"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Sugar sweetened and artificially sweetened beverages, fruit and vegetable juices and cancer risk: a World Cancer Research Fund International Global Cancer Update Programme (CUP Global) systematic literature review and meta-analysis","rel_doi":"10.64898\/2026.06.22.26355879","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.22.26355879","rel_abs":"BackgroundSugar sweetened beverages (SSBs), artificially sweetened beverages (ASBs), and fruit and vegetable juices are consumed worldwide, yet their associations with cancer remain unclear.\n\nMethodsWithin World Cancer Research Fund Internationals Global Cancer Update Programme (CUP Global), we conducted a systematic review by searching PubMed and Embase until September 2024 for cohort studies of SSBs, ASBs, and juices and cancer risk. Meta-analyses were conducted to calculate the relative risks (RRs) and 95% CIs per 1 serving\/day (355 mL for SSBs\/ASBs; 177 mL for juices). Evidence was graded by the CUP Global Expert Panel. The CUP Global standard protocol was registered at: https:\/\/osf.io\/7utbm\/.\n\nFindingsWe identified 158 publications from 51 cohorts. There was evidence of a probable causal positive association for SSBs, including carbonated SSBs, with pancreatic cancer incidence (RR 1.09 [95% CI 1.01-1.16]; I2=8%, n=18 studies), and for SSBs with colorectal cancer incidence (RR 1.07 [95% CI 1.00-1.14]; I2=41%, n=13). Limited suggestive evidence supported positive associations of SSBs with ovarian (RR 1.61 [95%CI 1.03-2.53]; I2=0%, n=2), endometrial (RR 1.21 [95%CI 1.03-1.42]; I2=0%, n=3), and postmenopausal breast cancer incidence (RR 1.05 [95%CI 1.00-1.10] ; I2=0%, n=6), and of carbonated ASBs with leukaemia incidence (RR 1.29 [95%CI 1.01-1.64]; I2=0%, n=2). There was evidence of a probable causal positive association for orange juice with different types of skin cancer including melanoma (RR 1.21 [95%CI 1.08-1.34]; I2=0%, n=4), and basal (RR 1.12 [95%CI 1.06-1.17]; I2=46%, n=2) and squamous cell carcinoma (RR 1.13 [95%CI 1.04-1.24]; I2=0%, n=2). An interactive evidence platform is available at: https:\/\/teacup.cc.ic.ac.uk\/soft-drinks-cancer.html.\n\nInterpretationThis review provides evidence supporting probable causal associations of SSBs with pancreatic and colorectal cancers, and of orange juice with skin cancers, with additional suggestive evidence for SSBs with other obesity-related cancers, extending concerns about sugary drink consumption beyond cardiometabolic health to cancer risk.\n\nFundingWorld Cancer Research Fund network of charities (American Institute for Cancer Research; World Cancer Research Fund; Wereld Kanker Onderzoek Fonds).","rel_num_authors":41,"rel_authors":[{"author_name":"Ahmad Jayedi","author_inst":"Imperial College"},{"author_name":"Georgios Markozannes","author_inst":"Imperial College"},{"author_name":"Sayada Zartasha Kazmi","author_inst":"Imperial College"},{"author_name":"Margarita Cariolou","author_inst":"Imperial College London"},{"author_name":"Rita Vieira","author_inst":"Imperial College London"},{"author_name":"Sonia Kiss","author_inst":"Imperial College London"},{"author_name":"Katia Balducci","author_inst":"Imperial College London"},{"author_name":"Eirini Pagkalidou","author_inst":"University of Ioannina Medical School"},{"author_name":"Sofia Cividini","author_inst":"Imperial College London"},{"author_name":"Dagfinn Aune","author_inst":"Imperial College London"},{"author_name":"Darren C Greenwood","author_inst":"University of Leeds"},{"author_name":"Laure Dossus","author_inst":"International Agency for Research on Cancer, Lyon"},{"author_name":"Emma Fontvieille","author_inst":"International Agency for Research on Cancer"},{"author_name":"Nahid Ahmadi","author_inst":"International Agency for Research on Cancer"},{"author_name":"Yahya Mahamat-Saleh","author_inst":"International Agency for Research on Cancer"},{"author_name":"Amanda J. Cross","author_inst":"Imperial College London"},{"author_name":"Marc J. Gunter","author_inst":"Imperial College London"},{"author_name":"Shalini Jayasekar Zurn","author_inst":"Union for International Cancer Control"},{"author_name":"Christian C. Abnet","author_inst":"National Cancer Institute, National Institutes of Health"},{"author_name":"Pietro Ferrari","author_inst":"IARC"},{"author_name":"Vanessa L.Z. Gordon-Dseagu","author_inst":"World Cancer Research Fund International"},{"author_name":"Kristy Maskell","author_inst":"World Cancer Research Fund International"},{"author_name":"Christelle Clary","author_inst":"World Cancer Research Fund International, London, UK"},{"author_name":"Helen Croker","author_inst":"World Cancer Research Fund International"},{"author_name":"Panagiota Mitrou","author_inst":"World Cancer Research Fund International"},{"author_name":"Elio Riboli","author_inst":"World Cancer Research Fund International"},{"author_name":"Monica Baskin","author_inst":"Massey Comprehensive Cancer Center"},{"author_name":"Rajiv Chowdhury","author_inst":"Florida International University"},{"author_name":"Mia Gaudet","author_inst":"National Cancer Institute"},{"author_name":"Edward L. Giovannucci","author_inst":"Harvard T. H. Chan School of Public Health"},{"author_name":"Ellen Kampman","author_inst":"Wageningen University & Research"},{"author_name":"Sarah J. Lewis","author_inst":"University of Bristol"},{"author_name":"Anne M. May","author_inst":"University Medical Centre Utrecht"},{"author_name":"Yikyung Park","author_inst":"Washington University School of Medicine"},{"author_name":"Tobias Pischon","author_inst":"Max Delbruck Center for Molecular Medicine in the Helmholtz Association"},{"author_name":"Gianluca Severi","author_inst":"CESP: Centre de recherche en Epidemiologie et Sante des Populations"},{"author_name":"Lynette Hill","author_inst":"Public Representative"},{"author_name":"Matty P. Weijenberg","author_inst":"Maastricht University, Maastricht"},{"author_name":"John Krebs","author_inst":"University of Oxford"},{"author_name":"Konstantinos K Tsilidis","author_inst":"Imperial College London"},{"author_name":"Doris Chan","author_inst":"Imperial College London"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Prediction of post-operative delirium with machine learning in abdominal surgery with comorbidity indices and laboratory values","rel_doi":"10.64898\/2026.06.28.26356787","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.28.26356787","rel_abs":"BackgroundPostoperative delirium (POD) is a complication associated with most types of surgery, and is associated with a number of detrimental effects. Therefore, it is of interest to determine which patients may be at higher risk of POD so that mitigating steps may be taken. We sought to determine whether POD can be accurately predicted with common machine learning (ML) models.\n\nMethodsUsing the Medical Information Mart for Intensive Care (MIMIC)-IV database, we identified 8026 abdominal surgery procedures across 7215 adult patients. Using demographic information, such as age, type of surgery, sex; as well as commonly measured laboratory values (such as electrolytes and blood counts) and comorbidity indices, we determined to what extend common ML models, such as random forests, support vector machines, extreme gradient boosted machines, and neural networks, could predict POD.\n\nResultsRandom forests outperformed logistic regression, support vector machines, extreme gradient boosted machines, and neural networks, with respect to individual t-tests. The random forest model had a sensitivity of 73.11, a specificity of 71.14, and an area under the receiver operator characteristic curve of 0.800. Age, comorbidity indices, gender, and alcohol use carried significant predictive weight in this cohort.\n\nConclusionsMachine learning models are effective predictors of postoperative delirium, although further work is required to increase clinical utility of such tools. Markers of inflammation, comorbidity indices, and alcohol use are important predictive features alongside better-known features such as age.","rel_num_authors":4,"rel_authors":[{"author_name":"Wesley Chorney","author_inst":"University College Cork"},{"author_name":"Shinhee Kang","author_inst":"Georgia Institute of Technology College of Computing"},{"author_name":"Sing Hui Ling","author_inst":"University of Limerick School of Medicine"},{"author_name":"Michael Lisi","author_inst":"Collingwood General and Marine Hospital"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Evaluating the impact of antiviral post-exposure prophylaxis for health-care workers during ebolavirus outbreaks: a modelling study","rel_doi":"10.64898\/2026.06.26.26356717","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356717","rel_abs":"BackgroundEbolavirus outbreaks place health-care workers (HCWs) at substantial risk, and HCW illness or death can weaken response capacity. The 2026 Bundibugyo virus disease outbreak in the DRC highlights the need for deployable countermeasures where species-specific vaccines are unavailable. With candidate antivirals under evaluation, but limited evidence on how best to use them if they become available, we assessed HCW-targeted antiviral post-exposure prophylaxis (PEP) across deployment and disruption scenarios.\n\nMethodsWe developed a stochastic branching-process model of ebolavirus transmission, representing health-care, community, and funeral transmission, time-varying non-pharmaceutical interventions and HCW-targeted PEP. Calibrated to previous outbreaks (a high-burden \"West Africa-like\" scenario and a \"DRC-like\" scenario with conflict-disrupted response) we estimated HCW deaths and capacity loss averted by PEP, varying antiviral efficacy, coverage, deployment readiness, dosing delay, disruption, and allocation policy.\n\nFindingsAt 80% efficacy and 80% coverage, PEP averted approximately 64% of HCW deaths across both archetypes. Under low readiness, where clinical evaluation and access expansion occurred during the outbreak and coverage reached only 50% over one year, reductions fell to 19% and 22% in the West Africa-like and DRC-like archetypes. In disruption scenarios, delayed dose receipt reduced HCW deaths averted from 83% to 50%; combined dosing delay and coverage loss retained only 35% of achievable impact. Dose efficiency varied by allocation: targeting recognised highest-risk exposures required 44 doses per HCW death averted, compared with 109 under broad allocation.\n\nInterpretationHCW-targeted antiviral PEP could reduce occupational mortality and preserve clinical capacity during ebolavirus epidemics where vaccines are unavailable, but realising this benefit depends on implementation readiness, rapid delivery, operational coverage and efficient allocation.\n\nFundingGilead Sciences; UK NIHR; Oxford Martin School; Miller Institute; EDCTP; CEPI","rel_num_authors":12,"rel_authors":[{"author_name":"Jacob N Stapley","author_inst":"University of California, Berkeley"},{"author_name":"Youngsuk Ko","author_inst":"University of California, Berkeley"},{"author_name":"Geetha Jeyapragasan","author_inst":"University of California, Berkeley"},{"author_name":"Elana MG Chan","author_inst":"University of California, Berkeley"},{"author_name":"Abel W Walekhwa","author_inst":"Makerere University School of Public Health"},{"author_name":"Cathal Mills","author_inst":"University of Oxford"},{"author_name":"Christophe Fraser","author_inst":"University of Oxford"},{"author_name":"Arthur L Reingold","author_inst":"University of California, Berkeley"},{"author_name":"Dav Ebengo","author_inst":"INRB: Institut National de Recherche Biomedicale"},{"author_name":"Christl A. Donnelly","author_inst":"University of Oxford"},{"author_name":"Placide K Mbala","author_inst":"INRB: Institut National de Recherche Biomedicale"},{"author_name":"Charles Whittaker","author_inst":"University of California, Berkeley"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"The Health and Economic Impacts of a Heat Wave: a Scenario-Based Risk Assessment","rel_doi":"10.64898\/2026.06.29.26356451","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26356451","rel_abs":"The impact of weather on the health of Americans and the American health system is substantial. Using available health and economic data, we developed a data-driven scenario that describes a compounded heat emergency in an archetypal community in the United States. We then characterize the potential human and economic costs of such a heat emergency to demonstrate the widespread impact on health outcomes, health systems, and society.","rel_num_authors":5,"rel_authors":[{"author_name":"Alison Kelly","author_inst":"Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Richard Bruns","author_inst":"Max Welfare"},{"author_name":"Hannah Goodtree","author_inst":"Johns Hopkins University Bloomberg School of Public Health"},{"author_name":"Amanda Mui","author_inst":"Biosecurity and Pandemic Policy Center within the Scowcroft Institute of International Affairs"},{"author_name":"Crystal Watson","author_inst":"Johns Hopkins University Bloomberg School of Public Health"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"OCPD Symptoms in Veterans Receiving PTSD Specialty Care","rel_doi":"10.64898\/2026.06.24.26356458","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.24.26356458","rel_abs":"Post-traumatic stress disorder (PTSD) is associated with high rates of comorbid personality disorders, which may contribute to PTSD severity. Among veterans with PTSD, obsessive compulsive personality disorder (OCPD) is common, with reported prevalence estimates ranging from 7-44%. Despite this, the relationship between OCPD traits and PTSD severity remains poorly understood. This retrospective, cross-sectional study examined associations between PTSD severity and OCPD traits in a naturalistic sample of 99 Veterans evaluated by a single clinician in a PTSD\/Trauma Recovery Services clinic. PTSD symptoms were measured with the PTSD Checklist for DSM-V (PCL-5), and OCPD traits were measured with the Pathological Obsessive-Compulsive Personality Scale (POPS). Relationships between these two constructs were examined using Pearsons correlations. Overall PTSD severity was significantly and positively correlated with total OCPD traits (r = 0.46, p < 0.001). Among OCPD domains, maladaptive perfectionism showed the strongest association with PTSD severity (r = 0.44, p <.001), followed by emotional overcontrol and reluctance to delegate (both r = .38, p < .01), rigidity (r = .35, p < .01), and difficulty with change (r = .28, p < .05). These findings suggest OCPD traits impact PTSD symptom burden in veterans, warranting further research and clinical attention.\n\nPublic SignificanceVeterans living with post-traumatic stress disorder (PTSD) have high rates of obsessive-compulsive personality disorder (OCPD) traits such as rigidity, perfectionism, and emotional overcontrol. This study found that in one VA clinic, veterans with higher levels of OCPD traits tended to experience more severe PTSD symptoms. Understanding how personality traits impact trauma recovery may help clinicians tailor treatments more effectively.","rel_num_authors":7,"rel_authors":[{"author_name":"Jennifer Barredo","author_inst":"Brown University"},{"author_name":"Meghan J. Kulak","author_inst":"Department of Psychiatry, Warren Alpert Medical School of Brown University, Providence, RI"},{"author_name":"Hannah R. Swearingen","author_inst":"Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, Providence, RI"},{"author_name":"M. Tracie Shea","author_inst":"Department of Psychiatry, Warren Alpert Medical School of Brown University, Providence, RI"},{"author_name":"Timothy Y. Mariano","author_inst":"Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, Providence, RI"},{"author_name":"Anthony Pinto","author_inst":"Northwell Health OCD Center, Glen Oaks, NY, USA"},{"author_name":"Benjamin D. Greenberg","author_inst":"Center for Neurorestoration and Neurotechnology, VA Providence Healthcare System, Providence, RI"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Association between saturated fat intake and low-density lipoprotein cholesterol across the genetic spectrum: Results from the Women's Health Initiative","rel_doi":"10.64898\/2026.06.29.26356854","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26356854","rel_abs":"BackgroundElevated low-density lipoprotein cholesterol (LDL-C) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Guidelines recommend reducing saturated fat intake to lower LDL-C. However, LDL-C responses to saturated fat vary substantially from person to person. Genetic factors may contribute to individual differences in response to saturated fat.\n\nObjectivesWe aimed to examine whether genetic propensity for higher LDL-C modifies the association of saturated fat intake with LDL-C and incident ASCVD.\n\nMethodsWe studied 20,940 genotyped postmenopausal women from the Womens Health Initiative. Exposures included saturated fat intake (percentage of total calories) derived from food frequency questionnaires and a genome-wide polygenic score for LDL-C (PGSLDL). The primary outcome was LDL-C. The secondary outcome was incident ASCVD. Associations were assessed using multivariable linear and Cox regressions. Effect modification was evaluated using interaction terms and restricted cubic spline analyses.\n\nResultsThe median LDL-C at baseline for participants with PGSLDL below and above the median was 135 mg\/dL [Q1: 114, Q3: 160] and 162 mg\/dL [137, 188], respectively. Saturated fat intake was positively associated with LDL-C in the high PGSLDL group, but the association attenuated in the low PGSLDL group (P-interaction=0.01). Spline analysis revealed a non-linear interaction between PGSLDL and saturated fat, with modifying effects emerging at higher PGSLDL. Compared to individuals with low PGSLDL and low saturated fat intake, only those with both high PGSLDL and high saturated fat intake had increased risk for ASCVD in an adjusted analysis (HR 1.30, 95% CI 1.13-1.51). This association remained significant after further adjustment for baseline LDL-C (HR 1.17, 95% CI 1.01-1.37). Spline analyses of ASCVD risk revealed a similar interaction pattern to that observed for LDL-C.\n\nConclusionsThese findings suggest that the association between saturated fat intake and LDL-C and subsequent ASCVD risk may be stronger for individuals with a genetic propensity towards high LDL-C.","rel_num_authors":12,"rel_authors":[{"author_name":"Alexa Barad","author_inst":"Department of Medicine, Stanford Prevention Research Center, Stanford University School of Medicine, Stanford University, Stanford, CA, USA"},{"author_name":"Victor Ritter","author_inst":"Quantitative Sciences Unit, Biomedical Informatics Research Division, Stanford University School of Medicine, Stanford University, Stanford, CA, USA."},{"author_name":"Matthew Nudy","author_inst":"Department of Medicine and Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA"},{"author_name":"Linda Van Horn","author_inst":"Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA"},{"author_name":"Matthew A. Allison","author_inst":"Department of Family Medicine, University of California San Diego, La Jolla, CA, USA"},{"author_name":"Cassandra N. Spracklen","author_inst":"Department of Biostatistics and Epidemiology, University of Massachusetts Amherst, Amherst, MA, USA"},{"author_name":"Longjian Liu","author_inst":"Department of Epidemiology and Biostatistics, Dornsife School of Public Health, Drexel University, Philadelphia, PA, USA"},{"author_name":"Su Yon Jung","author_inst":"Translational Sciences Section, School of Nursing, Department of Epidemiology, Fielding School of Public Health, Jonsson Comprehensive Cancer Center, University"},{"author_name":"JoAnn E. Manson","author_inst":"Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA"},{"author_name":"Themistocles L. Assimes","author_inst":"Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford University, Stanford, CA, USA"},{"author_name":"Marcia L. Stefanick","author_inst":"Department of Medicine, Stanford Prevention Research Center, Stanford University School of Medicine, Stanford University, Stanford, CA, USA"},{"author_name":"Shoa L. Clarke","author_inst":"Department of Medicine, Stanford Prevention Research Center, Stanford University School of Medicine, Stanford University, Stanford, CA, USA"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Early Mucosal Type II Interferon Limits SARS-CoV-2 Replication in Humans","rel_doi":"10.64898\/2026.06.29.26356894","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26356894","rel_abs":"COVID-19 vaccines markedly reduce disease severity, but their ability to block infection and transmission remains limited and variable.1 A better understanding of early mucosal immune programs that constrain viral replication at susceptible upper respiratory sites is needed to develop more effective antiviral strategies. However, temporal and anatomical antiviral dynamics are difficult to resolve without longitudinal, paired-site sampling beginning before infection onset. We quantified longitudinal viral load by RT-qPCR and human gene expression by mRNA sequencing in 1,237 samples prospectively collected daily from the nasal cavity, oral cavity, and oropharynx of 16 individuals starting from the onset of naturally acquired SARS-CoV-2 infection, and 16 age-, sex-, and vaccination-matched uninfected individuals. Here we show that Type I interferon (IFN) responses are initiated concurrently across these upper respiratory sites, even before local viral detection. In contrast, Type II IFN initiation is more spatially variable, and earlier nasal Type II IFN initiation is associated with reduced viral replication, prior COVID-19 vaccination, and higher tissue-resident memory T cell (TRM) signature expression. These findings demonstrate that in addition to humoral immunity, prior vaccination primes rapid, inducible mucosal Type II IFN responses, likely mediated by rare TRM upon viral encounter, to limit viral replication and spread.\n\nONE SENTENCE SUMMARYUsing a unique study design with temporally-dense, paired sampling of the oral cavity, nasal cavity and oropharynx from the onset of naturally acquired human SARS-CoV-2 infection, we demonstrate that Type I IFN responses are initiated synchronously in the upper respiratory mucosa during early infection, whereas the timing of Type II IFN response initiation is asynchronous but earlier initiation is associated with prior COVID-19 vaccination, enhanced tissue-resident memory T cells signatures, and reduced local viral replication.\n\nGraphical Abstract.Among participants who prospectively collected daily, paired specimens from multiple upper respiratory anatomical sites while enrolled in a case-ascertained COVID-19 household transmission study conducted in Los Angeles, California between September 2020 and April 2022, a subset of participants were found to initially be negative upon enrollment but later became positive for SARS-CoV-2. These were defined as Cases of naturally acquired, incident SARS-CoV-2 infection, and for whom age, sex, and prior COVID-19 vaccination status matched Control participants without SARS-CoV-2 infection were identified, and demographic data is shown. Samples underwent viral load quantification by RT-qPCR, validated by RT-ddPCR, and human transcriptome sequencing to calculate immune pathway activation and determine the timing of Type I and II IFN response initiation, and expression of a tissue resident memory T cell (TRM) signature. Differences in the magnitude and timing of these pathways were compared by vaccination status, and by subsequent viral RNA shedding to identify mucosal immune correlates of reduced viral replication. Created in https:\/\/BioRender.com.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=183 HEIGHT=200 SRC=\"FIGDIR\/small\/26356894v1_ufig1.gif\" ALT=\"Figure 1000\">\nView larger version (61K):\norg.highwire.dtl.DTLVardef@811a37org.highwire.dtl.DTLVardef@1e01b65org.highwire.dtl.DTLVardef@269856org.highwire.dtl.DTLVardef@1db6c8c_HPS_FORMAT_FIGEXP  M_FIG C_FIG","rel_num_authors":19,"rel_authors":[{"author_name":"Alexander V Winnett","author_inst":"California Institute of Technology"},{"author_name":"Alexandra Tabachnikova","author_inst":"Yale University School of Medicine"},{"author_name":"Jonathan Chen","author_inst":"Zymo Research Corporation"},{"author_name":"Kerrie Greene","author_inst":"Yale University School of Medicine"},{"author_name":"Anna E Romano","author_inst":"California Institute of Technology"},{"author_name":"Xinyue Penny Pei","author_inst":"California Institute of Technology"},{"author_name":"Matthew M Cooper","author_inst":"California Institute of Technology"},{"author_name":"Julio Silva","author_inst":"Yale University School of Medicine"},{"author_name":"Alyssa M Carter","author_inst":"California Institute of Technology"},{"author_name":"Jialong Jiang","author_inst":"California Institute of Technology"},{"author_name":"Yong Kong","author_inst":"Yale University School of Public Health"},{"author_name":"Morgan Roos","author_inst":"Illumina Inc."},{"author_name":"Christina Middle","author_inst":"Illumina Inc."},{"author_name":"Hianqiao Zhang","author_inst":"California Institute of Technology"},{"author_name":"Matt Thomson","author_inst":"California Institute of Technology"},{"author_name":"Keith Booher","author_inst":"Zymo Research Corporation"},{"author_name":"Scott Kuersten","author_inst":"Illumina Inc."},{"author_name":"Akiko Iwasaki","author_inst":"Yale University School of Medicine, Howard Hughes Medical Institute"},{"author_name":"Rustem F Ismagilov","author_inst":"California Institute of Technology"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Early Mucosal Type II Interferon Limits SARS-CoV-2 Replication in Humans","rel_doi":"10.64898\/2026.06.29.26356894","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26356894","rel_abs":"COVID-19 vaccines markedly reduce disease severity, but their ability to block infection and transmission remains limited and variable.1 A better understanding of early mucosal immune programs that constrain viral replication at susceptible upper respiratory sites is needed to develop more effective antiviral strategies. However, temporal and anatomical antiviral dynamics are difficult to resolve without longitudinal, paired-site sampling beginning before infection onset. We quantified longitudinal viral load by RT-qPCR and human gene expression by mRNA sequencing in 1,237 samples prospectively collected daily from the nasal cavity, oral cavity, and oropharynx of 16 individuals starting from the onset of naturally acquired SARS-CoV-2 infection, and 16 age-, sex-, and vaccination-matched uninfected individuals. Here we show that Type I interferon (IFN) responses are initiated concurrently across these upper respiratory sites, even before local viral detection. In contrast, Type II IFN initiation is more spatially variable, and earlier nasal Type II IFN initiation is associated with reduced viral replication, prior COVID-19 vaccination, and higher tissue-resident memory T cell (TRM) signature expression. These findings demonstrate that in addition to humoral immunity, prior vaccination primes rapid, inducible mucosal Type II IFN responses, likely mediated by rare TRM upon viral encounter, to limit viral replication and spread.\n\nONE SENTENCE SUMMARYUsing a unique study design with temporally-dense, paired sampling of the oral cavity, nasal cavity and oropharynx from the onset of naturally acquired human SARS-CoV-2 infection, we demonstrate that Type I IFN responses are initiated synchronously in the upper respiratory mucosa during early infection, whereas the timing of Type II IFN response initiation is asynchronous but earlier initiation is associated with prior COVID-19 vaccination, enhanced tissue-resident memory T cells signatures, and reduced local viral replication.\n\nGraphical Abstract.Among participants who prospectively collected daily, paired specimens from multiple upper respiratory anatomical sites while enrolled in a case-ascertained COVID-19 household transmission study conducted in Los Angeles, California between September 2020 and April 2022, a subset of participants were found to initially be negative upon enrollment but later became positive for SARS-CoV-2. These were defined as Cases of naturally acquired, incident SARS-CoV-2 infection, and for whom age, sex, and prior COVID-19 vaccination status matched Control participants without SARS-CoV-2 infection were identified, and demographic data is shown. Samples underwent viral load quantification by RT-qPCR, validated by RT-ddPCR, and human transcriptome sequencing to calculate immune pathway activation and determine the timing of Type I and II IFN response initiation, and expression of a tissue resident memory T cell (TRM) signature. Differences in the magnitude and timing of these pathways were compared by vaccination status, and by subsequent viral RNA shedding to identify mucosal immune correlates of reduced viral replication. Created in https:\/\/BioRender.com.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=183 HEIGHT=200 SRC=\"FIGDIR\/small\/26356894v1_ufig1.gif\" ALT=\"Figure 1000\">\nView larger version (61K):\norg.highwire.dtl.DTLVardef@811a37org.highwire.dtl.DTLVardef@1e01b65org.highwire.dtl.DTLVardef@269856org.highwire.dtl.DTLVardef@1db6c8c_HPS_FORMAT_FIGEXP  M_FIG C_FIG","rel_num_authors":19,"rel_authors":[{"author_name":"Alexander V Winnett","author_inst":"California Institute of Technology"},{"author_name":"Alexandra Tabachnikova","author_inst":"Yale University School of Medicine"},{"author_name":"Jonathan Chen","author_inst":"Zymo Research Corporation"},{"author_name":"Kerrie Greene","author_inst":"Yale University School of Medicine"},{"author_name":"Anna E Romano","author_inst":"California Institute of Technology"},{"author_name":"Xinyue Penny Pei","author_inst":"California Institute of Technology"},{"author_name":"Matthew M Cooper","author_inst":"California Institute of Technology"},{"author_name":"Julio Silva","author_inst":"Yale University School of Medicine"},{"author_name":"Alyssa M Carter","author_inst":"California Institute of Technology"},{"author_name":"Jialong Jiang","author_inst":"California Institute of Technology"},{"author_name":"Yong Kong","author_inst":"Yale University School of Public Health"},{"author_name":"Morgan Roos","author_inst":"Illumina Inc."},{"author_name":"Christina Middle","author_inst":"Illumina Inc."},{"author_name":"Hianqiao Zhang","author_inst":"California Institute of Technology"},{"author_name":"Matt Thomson","author_inst":"California Institute of Technology"},{"author_name":"Keith Booher","author_inst":"Zymo Research Corporation"},{"author_name":"Scott Kuersten","author_inst":"Illumina Inc."},{"author_name":"Akiko Iwasaki","author_inst":"Yale University School of Medicine, Howard Hughes Medical Institute"},{"author_name":"Rustem F Ismagilov","author_inst":"California Institute of Technology"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Machine-Learning Model Identifies New Diagnostic Criteria for Beckwith-Wiedemann Spectrum","rel_doi":"10.64898\/2026.06.22.26355886","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.22.26355886","rel_abs":"ObjectiveBeckwith-Wiedemann spectrum (BWSp) is an overgrowth and cancer predisposition disorder caused by genetic and epigenetic alterations of chromosome 11p15. The 2018 international consensus produced a clinical scoring system to capture the phenotypic variability of BWSp and guide genetic testing and clinical management, including tumor screening, in patients without molecular confirmation. In this study, we evaluated BWSp predictors to identify the most informative features.\n\nMethodsSupervised machine learning analyzed 25 phenotypic features in 555 patients with BWSp and 150 controls. Logistic regression, combined with a purposeful stepwise selection algorithm, identified a subset of features that can accurately classify subjects. Model performance was evaluated in a testing set and validated externally.\n\nResultsThe final model included six predictors: macroglossia, lateralized overgrowth, midface flattening, hepatomegaly, omphalocele, and developmental delay. Developmental delay was the only negative predictor; macroglossia (OR 46.10) and lateralized overgrowth (OR 27.87) were the strongest predictors. The proposed model and 2018 system did not differ in classification performance for testing (P = .39) or external (P = .15) sets.\n\nConclusionA simplified diagnostic model, driven by macroglossia and lateralized overgrowth, differentiates between patients with BWSp and controls with performance comparable to the 2018 system.\n\nAnd may help physicians prioritize BWSp evaluation.","rel_num_authors":8,"rel_authors":[{"author_name":"Sylvie A Adams","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Aravind Viswanathan","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Bamelak T Duki","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Andrew M George","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Jill A Fahrner","author_inst":"Johns Hopkins University School of Medicine"},{"author_name":"Darko Stefanovski","author_inst":"University of Pennsylvania School of Veterinary Medicine"},{"author_name":"Christopher M Cielo","author_inst":"Children's Hospital of Philadelphia"},{"author_name":"Jennifer M Kalish","author_inst":"Children's Hospital of Philadelphia"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Association between motor cortex grey matter loss and inability to control an ECoG-based implanted Brain-Computer Interface in ALS","rel_doi":"10.64898\/2026.06.23.26355654","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.23.26355654","rel_abs":"BackgroundThe field of implantable Brain-Computer Interfaces (iBCIs) is rapidly advancing, with individuals with amyotrophic lateral sclerosis (ALS) as key beneficiaries. However, ALS-related cortical degeneration may impair iBCI effectiveness. This study investigated whether structural magnetic resonance imaging (MRI) and functional MRI (fMRI) metrics are associated with the quality of electrocorticography (ECoG) signals critical for iBCI use.\n\nMethodsSix late-stage ALS participants and 76 controls underwent T1-weighted structural MRI and task-based fMRI during right-hand movement or attempts thereof. ECoG data of ALS participants was benchmarked using ECoG data acquired in epilepsy patients. Grey matter thickness in the sensorimotor cortex and fMRI activation in the motor-hand area were measured.\n\nResultsFour ALS participants showed >0.4 mm thinning in the precentral gyrus, while the postcentral gyrus was spared. ECoG signal quality was significantly associated with precentral grey matter thickness, but not with fMRI activity.\n\nConclusionsThese findings suggest that presurgical assessment of precentral grey matter thickness could potentially prove useful for iBCI candidate selection in advanced ALS.\n\nPlain Language SummaryPeople with amyotrophic lateral sclerosis (ALS) can lose the ability to move and speak, but their thinking often remains intact. Implantable brain-computer interfaces (iBCIs) can help by translating brain signals into commands for communication devices. However, ALS damages the motor cortex, which may reduce the quality of these signals. In this study, we examined brain scans and electrical recordings from six people with advanced ALS. We found that thinning of the motor cortex was linked to weaker brain signals needed for iBCI control, while functional MRI activity was less predictive. This suggests that measuring motor cortex thickness before surgery could help identify who will benefit most from an iBCI, improving treatment decisions and future clinical trials.\n\nTwo sentence summaryWe examine presurgical MRI\/fMRI and ECoG recordings from people with advanced ALS receiving implanted brain-computer interfaces. Motor cortex thinning is associated with poorer ECoG signal quality, suggesting cortical thickness may help identify candidates likely to benefit.","rel_num_authors":11,"rel_authors":[{"author_name":"Mathijs Raemaekers","author_inst":"University Medical Center Utrecht"},{"author_name":"Simon H Geukes","author_inst":"University Medical Center Utrecht"},{"author_name":"Erik J Aarnoutse","author_inst":"University Medical Center Utrecht"},{"author_name":"Mariana Pedroso Branco","author_inst":"University Medical Center Utrecht"},{"author_name":"Zachary V Freudenburg","author_inst":"University Medical Center Utrecht"},{"author_name":"Anouck P Schippers","author_inst":"University Medical Center Utrecht Brain Center"},{"author_name":"Nathan Crone","author_inst":"The Johns Hopkins Hospital"},{"author_name":"Sacha Leinders","author_inst":"University Medical Center Utrecht"},{"author_name":"Julia Berezutskaya","author_inst":"University Medical Center Utrecht"},{"author_name":"Nick F Ramsey","author_inst":"Radboud University Nijmegen"},{"author_name":"Mariska J Vansteensel","author_inst":"UMC Utrecht"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Heterogeneity across race and ethnicity for menopause onset","rel_doi":"10.64898\/2026.06.28.26356782","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.28.26356782","rel_abs":"The heterogeneity onset of menopause varies across racial and ethnic groups, yet this heterogeneity may partially reflect methodological differences rather than true biological differences. Using the All of Us Research Program Controlled Tier dataset (v8), we analyzed age at first menopause diagnosis across three progressively refined cohorts: a full ICD-based cohort (Cohort 1, n = 11,306), a survey-linked subcohort adjusted for neighborhood deprivation, smoking, and alcohol use (Cohort 2, n = 10,639), and a confirmatory sensitivity cohort applying SNOMED-based surgical exclusions to the same adjusted framework (Cohort 3, n = 10,222). Asian & Pacific Islander and Indigenous\/Other individuals experienced significantly earlier menopause onset than White individuals across both adjusted cohorts. The Black-White heterogeneity was attenuated after covariate adjustment and did not re-emerge after surgical exclusion. Current smoking was the sole significant behavioral predictor across adjusted models. These findings demonstrate that menopause definition and cohort selection critically shape estimates across race and ethnicity, and that EHR-based ascertainment combined with structured surgical exclusion yields broadly consistent adjusted results.","rel_num_authors":6,"rel_authors":[{"author_name":"Sarika Pasumarthy","author_inst":"University of California Berkeley"},{"author_name":"Maggie Hurley","author_inst":"University of California San Francisco"},{"author_name":"Irene Y. Chen","author_inst":"University of California Berkeley"},{"author_name":"Nitya Thakkar","author_inst":"Stanford University"},{"author_name":"Monica Agrawal","author_inst":"Duke University"},{"author_name":"Yulin Hswen","author_inst":"University of Maryland"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Extracellular vesicles as biomarkers and disease mediators in lichen planus: a systematic review & meta-analysis","rel_doi":"10.64898\/2026.06.29.26356896","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26356896","rel_abs":"BackgroundLichen Planus (LP) is a chronic inflammatory disorder that can affect the skin, hair, nails, and mucous membranes. Oral lichen planus (OLP), the most common LP subtype, is a disease of the oral mucosa, often diagnosed through clinical examination and histopathological confirmation. Extracellular vesicles (EVs) transfer proteins, lipids, and nucleic acids among cells and have become increasingly studied for their potential as minimally invasive diagnostic biomarkers and therapeutic agents in inflammatory and autoimmune diseases.\n\nMethodsPUBMED and Embase were searched from inception through June 27th, 2026. Human studies investigating EV-associated miRNA or protein biomarkers in LP and its subtypes were included, with risk of bias assessed using a modified Newcastle-Ottawa Scale. Diagnostic accuracy was evaluated using receiver operating characteristic (ROC) and BRMA models when sufficient data were available.\n\nResultsTen articles met the inclusion criteria, encompassing biomarker discovery, functional, and mechanistic studies of EVs in OLP. These included studies (n = 10) comprised 298 individuals with LP (weighted mean age 50.7 years; 61.5% female) and 194 controls (weighted mean age 47.8 years; 58.5% female). OLP-specific cohorts (n = 9 studies) included 261 individuals with OLP (weighted mean age 50.7 years; 61.4% female). Although no individual EV-associated miRNAs or proteins overlapped across studies, EV-associated miRNAs demonstrated substantial heterogeneity, while EV-associated protein findings centered on pathways related to antigen presentation, inflammatory signaling, and immune activation. Several candidate biomarkers, including miR-4484, miR-34a-5p, GJA1, PDIA3, and Cx43, showed potential diagnostic or prognostic relevance. ROC analyses demonstrated good diagnostic utility for miR-4484 (AUC = 0.81), and the combination of GJA1 and Cx43 showed the strongest discriminatory ability (AUC = 0.892). The diagnostic accuracy meta-analysis showed good discrimination (pooled AUC = 0.89). Functional and mechanistic studies suggested that EVs may actively contribute to OLP pathogenesis through promoting epithelial injury and activating inflammatory signalling pathways.\n\nConclusionsEV-associated miRNAs and proteins are potential biomarker candidates for LP and may provide insight into the inflammatory and immune mechanisms underlying disease pathophysiology. Functional and mechanistic evidence further suggests that EVs may play an active role in disease progression. However, current evidence has limitations such as small sample sizes and methodological heterogeneity. Larger, standardized, and longitudinal studies are needed to validate candidate EV biomarkers and determine whether EVs can serve as therapeutic tools in LP.","rel_num_authors":3,"rel_authors":[{"author_name":"Sarah Ning","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Erin Suh","author_inst":"Washington University School of Medicine in St. Louis"},{"author_name":"Hash Brown Taha","author_inst":"Washington University School of Medicine in St. Louis"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Intraoral Ultrasound for Detection of Alveolar Bone Changes Following Periodontal Surgery: A Prospective Validity and Precision Study","rel_doi":"10.64898\/2026.06.29.26356850","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26356850","rel_abs":"BackgroundAlveolar bone assessment in periodontal practice relies on radiography and clinical probing, both of which have well-documented limitations in precision. Intraoral high-frequency ultrasonography (US) offers a radiation-free alternative with potential for sub-millimeter resolution, the validity and precision for detecting minute osseous changes have not been established. The purpose of this study was to evaluate the concurrent validity and measurement precision of intraoral US for detecting alveolar bone-level changes in patients undergoing crown lengthening and osseous surgery, thereby enabling its translation to monitor osseous changes in patients with periodontitis.\n\nMethodsTen patients (28 tooth sites) undergoing crown lengthening or osseous surgery at a USC Advanced Grad Perio clinic were enrolled in this prospective observational study. Distance from the cementoenamel junction (CEJ) to the Alveolar bone crest (ABC) was measured at pre- and post-operative time points using a 40 MHz handheld intraoral US transducer and, intraoperatively, by standardized clinical photography. Agreement was assessed by Pearson correlation and Bland-Altman analysis. Measurement precision was quantified using the standard error of measurement (SEM) and minimum detectable change (MDC).\n\nResultsPreoperative agreement between methods was excellent (r = 0.977; Bland-Altman bias = -0.009 mm; 95% limits of agreement [LoA]: {+\/-}0.40 mm). Post-operative correlation remained strong (r = 0.912; bias = 0.123 mm; LoA: -0.85 to +1.10 mm). Both methods detected statistically significant post-surgical increases in the ABC-to-CEJ distance (p < 0.001), as anticipated. US demonstrated substantially superior precision: preoperative SEM 0.058 mm with US versus 0.128 mm clinically, yielding MDC values of 0.160 mm (US) versus 0.354 mm (clinical), providing a 2.2-fold precision advantage.\n\nConclusionsIntraoral US demonstrated strong concurrent validity with clinical photography and a reproducible precision advantage in detecting alveolar bone-level changes in patients with periodontitis. These findings support its clinical utility as a radiation-free, high-sensitivity bone monitoring tool. Larger longitudinal studies with CBCT validation are warranted.","rel_num_authors":9,"rel_authors":[{"author_name":"Mirali Pandya","author_inst":"Herman Ostrow School of Dentistry, University of Southern California, 925 West 34th Street, Los Angeles, CA, USA."},{"author_name":"Bryant Tran","author_inst":"Herman Ostrow School of Dentistry, University of Southern California, 925 West 34th Street, Los Angeles, CA, USA."},{"author_name":"Mohammadreza Amjadian","author_inst":"Aiiso Yufeng Li Family Department of Chemical and NanoEngineering, University of California, San Diego, La Jolla, CA 92093, USA."},{"author_name":"Sabrina Alterman","author_inst":"Herman Ostrow School of Dentistry, University of Southern California, 925 West 34th Street, Los Angeles, CA, USA."},{"author_name":"Harrison Chang","author_inst":"Herman Ostrow School of Dentistry, University of Southern California, 925 West 34th Street, Los Angeles, CA, USA."},{"author_name":"Youyoung Min","author_inst":"Herman Ostrow School of Dentistry, University of Southern California, 925 West 34th Street, Los Angeles, CA, USA."},{"author_name":"Suhel Khan","author_inst":"Aiiso Yufeng Li Family Department of Chemical and NanoEngineering, University of California, San Diego, La Jolla, CA 92093, USA."},{"author_name":"Jesse Jokerst","author_inst":"Aiiso Yufeng Li Family Department of Chemical and NanoEngineering, University of California, San Diego, La Jolla, CA 92093, USA."},{"author_name":"Casey Chen","author_inst":"Herman Ostrow School of Dentistry, University of Southern California, 925 West 34th Street, Los Angeles, CA, USA."}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Identifying and Prioritizing Barriers to TB Prevention and Care in High-Burden Countries: A Community-Engaged Approach Using Best-Worst Scaling","rel_doi":"10.64898\/2026.06.29.26356773","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26356773","rel_abs":"ObjectiveTo comprehensively identify the multi-level barriers to tuberculosis prevention and care in high-burden settings, and prioritize them according to their perceived harm and modifiability.\n\nMethodsWe conducted a multi-phase stakeholder-engaged study, synthesized barriers from two scoping reviews, and then convened regional workshops in Hyderabad, India, and Nairobi, Kenya, prioritizing TB survivors, community advocates, and frontline healthcare workers (HCWs). Participants refined existing barriers and added new ones. They then completed a Best-Worst Scaling (BWS) exercise to assess the perceived impact (harm) of each barrier, and Likert-based questions to assess perceived modifiability. Hierarchical Bayes (HB) modeling was used to generate mean impact scores (MIS) for each barrier, and mean scores for barrier modifiability (range, 1-4) were calculated.\n\nFindings81 stakeholders from 28 countries participated, and 65 completed the survey (24% community representatives\/advocates, 36% frontline HCWs; 17% were TB survivors). Stakeholder input expanded the barrier set from 31 to 39, with most newly added barriers at the health systems level. The BWS identified systems-level drug and supply challenges (MIS=5.8), patient\/community-level financial factors (MIS=5.2), and inadequate provision of holistic care (MIS=4.9) as the highest-impact barriers; 7 of the top 10 barriers overlapped across regions. Asia participants placed 5 barriers, and Africa participants 10 in the high-impact\/high-modifiability priority quadrant; four were shared across both: patient\/community knowledge, HCW knowledge, HCW attitudes, and lack of community engagement mechanisms.\n\nConclusionIncorporating the lived experience of TB-affected groups revealed substantial gaps in literature-derived TB care barriers. The high-impact, modifiable barriers identified provide actionable targets for programs in high-burden settings.","rel_num_authors":11,"rel_authors":[{"author_name":"Andrew D. Kerkhoff","author_inst":"University of California San Francisco"},{"author_name":"Kalee Singh","author_inst":"University of California San Francisco"},{"author_name":"Nyiko Kubai","author_inst":"Afrocab Treatment Access Partnership"},{"author_name":"Mangala Namasivayam","author_inst":"APCASO"},{"author_name":"Ketholelie Angami","author_inst":"Access to Rights and Knowledge Foundation"},{"author_name":"Samyra R. Cox","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Colleen F. Hanrahan","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Thea Sigerman","author_inst":"University of California San Francisco"},{"author_name":"Matthew Brandner","author_inst":"University of California San Francisco"},{"author_name":"Erica Lessem","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Priya Shete","author_inst":"University of California San Francisco"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Identifying and Prioritizing Barriers to TB Prevention and Care in High-Burden Countries: A Community-Engaged Approach Using Best-Worst Scaling","rel_doi":"10.64898\/2026.06.29.26356773","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26356773","rel_abs":"ObjectiveTo comprehensively identify the multi-level barriers to tuberculosis prevention and care in high-burden settings, and prioritize them according to their perceived harm and modifiability.\n\nMethodsWe conducted a multi-phase stakeholder-engaged study, synthesized barriers from two scoping reviews, and then convened regional workshops in Hyderabad, India, and Nairobi, Kenya, prioritizing TB survivors, community advocates, and frontline healthcare workers (HCWs). Participants refined existing barriers and added new ones. They then completed a Best-Worst Scaling (BWS) exercise to assess the perceived impact (harm) of each barrier, and Likert-based questions to assess perceived modifiability. Hierarchical Bayes (HB) modeling was used to generate mean impact scores (MIS) for each barrier, and mean scores for barrier modifiability (range, 1-4) were calculated.\n\nFindings81 stakeholders from 28 countries participated, and 65 completed the survey (24% community representatives\/advocates, 36% frontline HCWs; 17% were TB survivors). Stakeholder input expanded the barrier set from 31 to 39, with most newly added barriers at the health systems level. The BWS identified systems-level drug and supply challenges (MIS=5.8), patient\/community-level financial factors (MIS=5.2), and inadequate provision of holistic care (MIS=4.9) as the highest-impact barriers; 7 of the top 10 barriers overlapped across regions. Asia participants placed 5 barriers, and Africa participants 10 in the high-impact\/high-modifiability priority quadrant; four were shared across both: patient\/community knowledge, HCW knowledge, HCW attitudes, and lack of community engagement mechanisms.\n\nConclusionIncorporating the lived experience of TB-affected groups revealed substantial gaps in literature-derived TB care barriers. The high-impact, modifiable barriers identified provide actionable targets for programs in high-burden settings.","rel_num_authors":11,"rel_authors":[{"author_name":"Andrew D. Kerkhoff","author_inst":"University of California San Francisco"},{"author_name":"Kalee Singh","author_inst":"University of California San Francisco"},{"author_name":"Nyiko Kubai","author_inst":"Afrocab Treatment Access Partnership"},{"author_name":"Mangala Namasivayam","author_inst":"APCASO"},{"author_name":"Ketholelie Angami","author_inst":"Access to Rights and Knowledge Foundation"},{"author_name":"Samyra R. Cox","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Colleen F. Hanrahan","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Thea Sigerman","author_inst":"University of California San Francisco"},{"author_name":"Matthew Brandner","author_inst":"University of California San Francisco"},{"author_name":"Erica Lessem","author_inst":"Johns Hopkins Bloomberg School of Public Health"},{"author_name":"Priya Shete","author_inst":"University of California San Francisco"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Integrating Genetic, Environmental, Cognitive, and Temperament Data for ADHD Prediction in Explainable Deep Learning Models","rel_doi":"10.64898\/2026.06.29.26356796","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.29.26356796","rel_abs":"AbstractO_ST_ABSObjectiveC_ST_ABSAttention-deficit\/hyperactivity disorder (ADHD) is clinically and etiologically heterogeneous, and diagnostic decisions may benefit from integrating multiple sources of information. We developed an explainable deep learning approach to test whether genetic, environmental, cognitive, demographic, and temperament data could classify ADHD diagnosis and identify features contributing to model decisions.\n\nMethodWe analyzed participants from the Oregon ADHD-1000 cohort split into training, validation, and test subsets. We trained modular neural network models classifying ADHD case-control status using SNP-level genotype data with biological annotations, polygenic scores, demographics, parenting and family conflict, stress and trauma, geocoded measures, cognitive task measures, temperament factor scores, and missingness indicators. Hyperparameter optimization selected model architecture and feature block inclusion. We evaluated model performance using AUC, precision-recall curves, calibration analyses, prediction certainty analyses, and decision curve analysis. We used integrated gradients to quantify block-level, feature-level, and individualized feature importance.\n\nResultsThe best model using temperament features had an AUC of 0.97 in the held-out test subset, with high accuracy, sensitivity, and specificity and a Brier score of 0.06. The best model excluding temperament had an AUC of 0.75. Feature importance analyses highlighted temperament, demographic, and cognitive domains in the temperament-inclusive model.\n\nIndividualized explanations showed that prediction drivers varied across participants and could help reveal conflicting or supporting evidence across domains.\n\nConclusionExplainable, multi-modal classification models can integrate heterogeneous ADHD-relevant information and identify features that contribute to individual predictions. These types of models may advance ADHD risk modeling research and clinician-led decision support, especially in complex or diagnostically uncertain cases.","rel_num_authors":5,"rel_authors":[{"author_name":"Eric J Barnett","author_inst":"Norton College of Medicine at SUNY Upstate Medical University"},{"author_name":"Michael A. Mooney","author_inst":"Oregon Health & Science University"},{"author_name":"Yanli Zhang-James","author_inst":"Norton College of Medicine at Upstate Medical University"},{"author_name":"Peter Ryabinin","author_inst":"Oregon Health & Science University"},{"author_name":"Stephen V Faraone","author_inst":"Norton College of Medicine at SUNY Upstate Medical University"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Genomic Variation Predicts Real-Time \u0394\u2079-tetrahydrocannabinol Response in Humans","rel_doi":"10.64898\/2026.06.26.26356685","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356685","rel_abs":"BackgroundCannabis is one of the most widely used psychoactive substances worldwide. {Delta}9-tetrahydrocannabinol ({Delta}9-THC) is the main contributor to cannabis-induced effects such as euphoria, anxiety, and psychotomimetic effects, and is metabolized by several hepatic enzymes, including CYP3A4. There are interindividual differences in how cannabis affects users, which have substantial genetic contributors.\n\nMethodsWe examined how real-time effects of {Delta}9-THC on psychotomimetic measures and on subjective effects of \"high\", sadness and anxiety in 188 healthy volunteers in a laboratory infusion paradigm, relate to polygenic risk scores (PRS) for cannabis lifetime use (CanLU), cannabis use disorder (CanUD), and CYP3A4 expression.\n\nResultsCYP3A4 expression PRS was significantly associated with {Delta}9-THC-induced psychotomimetic effects. Genetic liability to use and misuse cannabis is potentially associated with lower {Delta}9-THC-induced psychotomimetic symptoms. CanLU PRS nominally predicted enhanced {Delta}9-THC-induced \"high\", while CanUD PRS predicted it to be lower.\n\nConclusionsOur findings suggest that genetic liability to produce more CYP3A4 enzyme may be associated with faster {Delta}9-THC degradation and the consequential diminution of the latters effects. Nominal effects suggest that aversive outcomes may reduce cannabis use and use disorder genetic liability, and that CanUD subjects may need higher {Delta}9-THC doses to experience euphoria (\"high\"). In total, this study provides novel insights regarding some of the specific genetic factors that influence interindividual variability in {Delta}9-THC effects, mainly via {Delta}9-THC metabolism.","rel_num_authors":12,"rel_authors":[{"author_name":"Uri Bright","author_inst":"Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Suhas Ganesh","author_inst":"Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Daniel F Levey","author_inst":"Yale University; VA Connecticut Healthcare System"},{"author_name":"Priya Gupta","author_inst":"Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"- the Yale THC Studies Consortium","author_inst":"-"},{"author_name":"Mohini Ranganathan","author_inst":"Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"- the IOP THC Studies Consortium","author_inst":"-"},{"author_name":"Robin M Murray","author_inst":"Department of Psychosis Studies, Institute of Psychiatry Psychology and Neuroscience, London, U.K"},{"author_name":"Marta DiForti","author_inst":"Department of Social Genetics and Developmental Psychiatry, Institute of Psychiatry Psychology and Neuroscience, London, U.K"},{"author_name":"Paul Morrison","author_inst":"Highland Health and Social Care Partnership, Lochgilphead, UK"},{"author_name":"Deepak C D'Souza","author_inst":"Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA"},{"author_name":"Joel Gelernter","author_inst":"Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA"}],"rel_date":"2026-07-01","rel_site":"medrxiv"},{"rel_title":"Health conditions and RSV-related Pediatric Intensive Care Unit admissions in children during their second RSV season","rel_doi":"10.64898\/2026.06.26.26356705","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356705","rel_abs":"ImportanceRespiratory syncytial virus (RSV) hospitalization rates are highest among children <2 years of age. RSV immunization with infant monoclonal antibody or maternal vaccine is recommended to protect all U.S. infants in their first RSV season. For certain high-risk children aged 8-19 months entering their second RSV season, the monoclonal antibody nirsevimab is recommended. Little is known regarding preexisting health conditions as risk factors for RSV-associated respiratory failure in children during their second season.\n\nObjectivesTo describe children admitted to the pediatric intensive care unit (PICU) for RSV during their second RSV season by preexisting health conditions, and to compare demographic and clinical characteristics across groups.\n\nDesign, Setting, and ParticipantsSurveillance registry of children 8-<24 months old admitted to the PICU in 30 pediatric hospitals in the 2023-2024\/2024-2025 RSV seasons. All children had an RSV-positive respiratory sample and received respiratory support with high flow nasal cannula, noninvasive ventilation, or invasive mechanical ventilation (IMV).\n\nExposurePreexisting health conditions potentially increasing risk of severe RSV disease.\n\nMain Outcomes and MeasuresPatients were classified into four mutually exclusive groups by preexisting health conditions: 1) U.S. nirsevimab eligible criteria, 2) other identified RSV risk conditions (with some evidence of increased risk for severe RSV), 3) other preexisting conditions, and 4) no preexisting conditions. Patient demographic characteristics and level of respiratory support received were compared.\n\nResultsAmong 574 children: 47 (8.2%) had U.S. nirsevimab eligibility criteria, 76 (13.2%) had other RSV risk conditions, 96 (16.7%) had other preexisting conditions, and 355 (61.8%) had none. A higher proportion of children with nirsevimab eligibility factors (40.4%) than those with other identified RSV risk conditions (17.1%) required IMV, which was higher than other (10.4%) or no (5.9%) preexisting health conditions (ptrend<0.001).\n\nConclusions and RelevanceApproximately 20% of children admitted to the PICU with severe RSV were in the defined groups that met U.S. nirsevimab-eligibility criteria or that had an identified RSV risk condition associated with known risk for severe RSV. A considerable proportion of both groups of children required IMV for respiratory support. These findings may help inform future deliberations regarding U.S. second season nirsevimab-eligibility recommendations.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSWhat preexisting health conditions are present in children aged 8-<24 months admitted to the pediatric intensive care unit for severe RSV disease in their second RSV season and how do clinical outcomes differ?\n\nFindingsAmong 574 children, 8% were eligible for nirsevimab in the U.S. and 13% had other preexisting conditions with known risk for severe RSV. Children with preexisting conditions, particularly those eligible for nirsevimab, were more likely to require invasive mechanical ventilation than those without.\n\nMeaningThese findings may inform future deliberations regarding which children in their second RSV season might benefit from RSV preventive products.","rel_num_authors":39,"rel_authors":[{"author_name":"Regina M. Simeone","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Laura Zambrano","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Margaret M. Newhams","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts"},{"author_name":"Amanda B. Payne","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Amber O. Orzel-Lockwood","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts"},{"author_name":"Natasha B. Halasa","author_inst":"Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee"},{"author_name":"Jemima Calixte","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts"},{"author_name":"Aline B. Maddux","author_inst":"Department of Pediatrics, Section of Critical Care Medicine, University of Colorado School of Medicine and Childrens Hospital Colorado, Aurora, Colorado"},{"author_name":"Kathleen Chiotos","author_inst":"Division of Critical Care Medicine, Department of Anesthesiology and Critical Care, Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania"},{"author_name":"Satoshi Kamidani","author_inst":"The Center for Childhood Infections and Vaccines of Childrens Healthcare of Atlanta and the Department of Pediatrics, Emory University School of Medicine, Atlan"},{"author_name":"Hillary Crandall","author_inst":"Division of Pediatric Critical Care, Department of Pediatrics, University of Utah and Primary Childrens Hospital, Salt Lake City, Utah"},{"author_name":"Danielle M. Zerr","author_inst":"Division of Infectious Diseases, Department of Pediatrics, University of Washington, Seattle, Washington; Seattle Children's Research Institute, Seattle, Washin"},{"author_name":"Melissa A. Cameron","author_inst":"Division of Pediatric Hospital Medicine, UC San Diego Rady Childrens Hospital, San Diego, California"},{"author_name":"Shira J. Gertz","author_inst":"Division of Pediatric Critical Care, Department of Pediatrics, Cooperman Barnabas Medical Center, Livingston, New Jersey"},{"author_name":"Bria M. Coates","author_inst":"Division of Pediatric Critical Care Medicine, Ann and Robert H. Lurie Childrens Hospital of Chicago, Chicago, Illinois"},{"author_name":"Kelly N. Michelson","author_inst":"Division of Pediatric Critical Care Medicine, Ann and Robert H. Lurie Childrens Hospital of Chicago, Chicago, Illinois"},{"author_name":"Jennifer E. Schuster","author_inst":"Division of Pediatric Infectious Diseases, Department of Pediatrics, Childrens Mercy Kansas City, Kansas City, Missouri"},{"author_name":"Ryan A. Nofziger","author_inst":"Division of Critical Care Medicine, Department of Pediatrics, Akron Childrens Hospital, Akron, Ohio"},{"author_name":"Jigar C. Chauhan","author_inst":"Division of Pediatric Critical Care, Nemours Childrens Hospital, Wilmington, Delaware"},{"author_name":"Mia Maamari","author_inst":"University of Texas Southwestern, Childrens Medical Center Dallas, Dallas, Texas"},{"author_name":"Steven L. Shein","author_inst":"Department of Pediatrics, Rainbow Babies and Childrens Hospital, Cleveland, OH"},{"author_name":"Michele Kong","author_inst":"Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama"},{"author_name":"Janet R. Hume","author_inst":"Division of Pediatric Critical Care, University of Minnesota Masonic Childrens Hospital, Minneapolis, Minnesota"},{"author_name":"Lora M. Martine","author_inst":"Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi"},{"author_name":"Judith A. Guzman-Cottrill","author_inst":"Department of Pediatrics, Oregon Health and Sciences University, Portland, Oregon"},{"author_name":"Samina S. Bhumbra","author_inst":"Ryan White Center for Pediatric Infectious Disease and Global Health, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana USA"},{"author_name":"Katherine Irby","author_inst":"Section of Pediatric Critical Care, Department of Pediatrics, Arkansas Childrens Hospital, Little Rock, Arkansas"},{"author_name":"Mary Allen Staat","author_inst":"Department of Pediatrics, Cincinnati Childrens Hospital, Cincinnati, OH"},{"author_name":"Tamara T. Bradford","author_inst":"Division of Cardiology, Department of Pediatrics, Louisiana State University Health Sciences Center; Childrens Hospital of New Orleans, New Orleans, Louisiana"},{"author_name":"Kari Wellnitz","author_inst":"Division of Pediatric Critical Care, Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa USA"},{"author_name":"Melissa S. Stockwell","author_inst":"Division of Child and Adolescent Health, Columbia University Vagelos College of Physicians and Surgeons, New York, New York"},{"author_name":"Matt Zinter","author_inst":"UCSF Benioff Childrens Hospital, San Francisco"},{"author_name":"Stephanie P. Schwartz","author_inst":"Department of Pediatrics, University of North Carolina at Chapel Hill Childrens Hospital, Chapel Hill, North Carolina"},{"author_name":"Saul Hymes","author_inst":"Bernard & Millie Duker Childrens Hospital, Albany, New York"},{"author_name":"Emily R. Levy","author_inst":"Divisions of Pediatric Infectious Diseases and Pediatric Critical Care Medicine, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnes"},{"author_name":"Austin Biggs","author_inst":"Department of Pediatric Critical Care, Medical University of South Carolina and Shawn Jenkins Childrens Hospital, Charleston, South Carolina"},{"author_name":"Katherine Lindsey","author_inst":"CDC; 4ES Corporation, Atlanta, Georgia"},{"author_name":"Angela P. Campbell","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Adrienne G. Randolph","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts; Departments of Anesthesia and Pediatrics, Harv"}],"rel_date":"2026-06-30","rel_site":"medrxiv"},{"rel_title":"Health conditions and RSV-related Pediatric Intensive Care Unit admissions in children during their second RSV season","rel_doi":"10.64898\/2026.06.26.26356705","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356705","rel_abs":"ImportanceRespiratory syncytial virus (RSV) hospitalization rates are highest among children <2 years of age. RSV immunization with infant monoclonal antibody or maternal vaccine is recommended to protect all U.S. infants in their first RSV season. For certain high-risk children aged 8-19 months entering their second RSV season, the monoclonal antibody nirsevimab is recommended. Little is known regarding preexisting health conditions as risk factors for RSV-associated respiratory failure in children during their second season.\n\nObjectivesTo describe children admitted to the pediatric intensive care unit (PICU) for RSV during their second RSV season by preexisting health conditions, and to compare demographic and clinical characteristics across groups.\n\nDesign, Setting, and ParticipantsSurveillance registry of children 8-<24 months old admitted to the PICU in 30 pediatric hospitals in the 2023-2024\/2024-2025 RSV seasons. All children had an RSV-positive respiratory sample and received respiratory support with high flow nasal cannula, noninvasive ventilation, or invasive mechanical ventilation (IMV).\n\nExposurePreexisting health conditions potentially increasing risk of severe RSV disease.\n\nMain Outcomes and MeasuresPatients were classified into four mutually exclusive groups by preexisting health conditions: 1) U.S. nirsevimab eligible criteria, 2) other identified RSV risk conditions (with some evidence of increased risk for severe RSV), 3) other preexisting conditions, and 4) no preexisting conditions. Patient demographic characteristics and level of respiratory support received were compared.\n\nResultsAmong 574 children: 47 (8.2%) had U.S. nirsevimab eligibility criteria, 76 (13.2%) had other RSV risk conditions, 96 (16.7%) had other preexisting conditions, and 355 (61.8%) had none. A higher proportion of children with nirsevimab eligibility factors (40.4%) than those with other identified RSV risk conditions (17.1%) required IMV, which was higher than other (10.4%) or no (5.9%) preexisting health conditions (ptrend<0.001).\n\nConclusions and RelevanceApproximately 20% of children admitted to the PICU with severe RSV were in the defined groups that met U.S. nirsevimab-eligibility criteria or that had an identified RSV risk condition associated with known risk for severe RSV. A considerable proportion of both groups of children required IMV for respiratory support. These findings may help inform future deliberations regarding U.S. second season nirsevimab-eligibility recommendations.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSWhat preexisting health conditions are present in children aged 8-<24 months admitted to the pediatric intensive care unit for severe RSV disease in their second RSV season and how do clinical outcomes differ?\n\nFindingsAmong 574 children, 8% were eligible for nirsevimab in the U.S. and 13% had other preexisting conditions with known risk for severe RSV. Children with preexisting conditions, particularly those eligible for nirsevimab, were more likely to require invasive mechanical ventilation than those without.\n\nMeaningThese findings may inform future deliberations regarding which children in their second RSV season might benefit from RSV preventive products.","rel_num_authors":39,"rel_authors":[{"author_name":"Regina M. Simeone","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Laura Zambrano","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Margaret M. Newhams","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts"},{"author_name":"Amanda B. Payne","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Amber O. Orzel-Lockwood","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts"},{"author_name":"Natasha B. Halasa","author_inst":"Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee"},{"author_name":"Jemima Calixte","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts"},{"author_name":"Aline B. Maddux","author_inst":"Department of Pediatrics, Section of Critical Care Medicine, University of Colorado School of Medicine and Childrens Hospital Colorado, Aurora, Colorado"},{"author_name":"Kathleen Chiotos","author_inst":"Division of Critical Care Medicine, Department of Anesthesiology and Critical Care, Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania"},{"author_name":"Satoshi Kamidani","author_inst":"The Center for Childhood Infections and Vaccines of Childrens Healthcare of Atlanta and the Department of Pediatrics, Emory University School of Medicine, Atlan"},{"author_name":"Hillary Crandall","author_inst":"Division of Pediatric Critical Care, Department of Pediatrics, University of Utah and Primary Childrens Hospital, Salt Lake City, Utah"},{"author_name":"Danielle M. Zerr","author_inst":"Division of Infectious Diseases, Department of Pediatrics, University of Washington, Seattle, Washington; Seattle Children's Research Institute, Seattle, Washin"},{"author_name":"Melissa A. Cameron","author_inst":"Division of Pediatric Hospital Medicine, UC San Diego Rady Childrens Hospital, San Diego, California"},{"author_name":"Shira J. Gertz","author_inst":"Division of Pediatric Critical Care, Department of Pediatrics, Cooperman Barnabas Medical Center, Livingston, New Jersey"},{"author_name":"Bria M. Coates","author_inst":"Division of Pediatric Critical Care Medicine, Ann and Robert H. Lurie Childrens Hospital of Chicago, Chicago, Illinois"},{"author_name":"Kelly N. Michelson","author_inst":"Division of Pediatric Critical Care Medicine, Ann and Robert H. Lurie Childrens Hospital of Chicago, Chicago, Illinois"},{"author_name":"Jennifer E. Schuster","author_inst":"Division of Pediatric Infectious Diseases, Department of Pediatrics, Childrens Mercy Kansas City, Kansas City, Missouri"},{"author_name":"Ryan A. Nofziger","author_inst":"Division of Critical Care Medicine, Department of Pediatrics, Akron Childrens Hospital, Akron, Ohio"},{"author_name":"Jigar C. Chauhan","author_inst":"Division of Pediatric Critical Care, Nemours Childrens Hospital, Wilmington, Delaware"},{"author_name":"Mia Maamari","author_inst":"University of Texas Southwestern, Childrens Medical Center Dallas, Dallas, Texas"},{"author_name":"Steven L. Shein","author_inst":"Department of Pediatrics, Rainbow Babies and Childrens Hospital, Cleveland, OH"},{"author_name":"Michele Kong","author_inst":"Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama"},{"author_name":"Janet R. Hume","author_inst":"Division of Pediatric Critical Care, University of Minnesota Masonic Childrens Hospital, Minneapolis, Minnesota"},{"author_name":"Lora M. Martine","author_inst":"Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi"},{"author_name":"Judith A. Guzman-Cottrill","author_inst":"Department of Pediatrics, Oregon Health and Sciences University, Portland, Oregon"},{"author_name":"Samina S. Bhumbra","author_inst":"Ryan White Center for Pediatric Infectious Disease and Global Health, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana USA"},{"author_name":"Katherine Irby","author_inst":"Section of Pediatric Critical Care, Department of Pediatrics, Arkansas Childrens Hospital, Little Rock, Arkansas"},{"author_name":"Mary Allen Staat","author_inst":"Department of Pediatrics, Cincinnati Childrens Hospital, Cincinnati, OH"},{"author_name":"Tamara T. Bradford","author_inst":"Division of Cardiology, Department of Pediatrics, Louisiana State University Health Sciences Center; Childrens Hospital of New Orleans, New Orleans, Louisiana"},{"author_name":"Kari Wellnitz","author_inst":"Division of Pediatric Critical Care, Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa USA"},{"author_name":"Melissa S. Stockwell","author_inst":"Division of Child and Adolescent Health, Columbia University Vagelos College of Physicians and Surgeons, New York, New York"},{"author_name":"Matt Zinter","author_inst":"UCSF Benioff Childrens Hospital, San Francisco"},{"author_name":"Stephanie P. Schwartz","author_inst":"Department of Pediatrics, University of North Carolina at Chapel Hill Childrens Hospital, Chapel Hill, North Carolina"},{"author_name":"Saul Hymes","author_inst":"Bernard & Millie Duker Childrens Hospital, Albany, New York"},{"author_name":"Emily R. Levy","author_inst":"Divisions of Pediatric Infectious Diseases and Pediatric Critical Care Medicine, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnes"},{"author_name":"Austin Biggs","author_inst":"Department of Pediatric Critical Care, Medical University of South Carolina and Shawn Jenkins Childrens Hospital, Charleston, South Carolina"},{"author_name":"Katherine Lindsey","author_inst":"CDC; 4ES Corporation, Atlanta, Georgia"},{"author_name":"Angela P. Campbell","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Adrienne G. Randolph","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts; Departments of Anesthesia and Pediatrics, Harv"}],"rel_date":"2026-06-30","rel_site":"medrxiv"},{"rel_title":"Health conditions and RSV-related Pediatric Intensive Care Unit admissions in children during their second RSV season","rel_doi":"10.64898\/2026.06.26.26356705","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356705","rel_abs":"ImportanceRespiratory syncytial virus (RSV) hospitalization rates are highest among children <2 years of age. RSV immunization with infant monoclonal antibody or maternal vaccine is recommended to protect all U.S. infants in their first RSV season. For certain high-risk children aged 8-19 months entering their second RSV season, the monoclonal antibody nirsevimab is recommended. Little is known regarding preexisting health conditions as risk factors for RSV-associated respiratory failure in children during their second season.\n\nObjectivesTo describe children admitted to the pediatric intensive care unit (PICU) for RSV during their second RSV season by preexisting health conditions, and to compare demographic and clinical characteristics across groups.\n\nDesign, Setting, and ParticipantsSurveillance registry of children 8-<24 months old admitted to the PICU in 30 pediatric hospitals in the 2023-2024\/2024-2025 RSV seasons. All children had an RSV-positive respiratory sample and received respiratory support with high flow nasal cannula, noninvasive ventilation, or invasive mechanical ventilation (IMV).\n\nExposurePreexisting health conditions potentially increasing risk of severe RSV disease.\n\nMain Outcomes and MeasuresPatients were classified into four mutually exclusive groups by preexisting health conditions: 1) U.S. nirsevimab eligible criteria, 2) other identified RSV risk conditions (with some evidence of increased risk for severe RSV), 3) other preexisting conditions, and 4) no preexisting conditions. Patient demographic characteristics and level of respiratory support received were compared.\n\nResultsAmong 574 children: 47 (8.2%) had U.S. nirsevimab eligibility criteria, 76 (13.2%) had other RSV risk conditions, 96 (16.7%) had other preexisting conditions, and 355 (61.8%) had none. A higher proportion of children with nirsevimab eligibility factors (40.4%) than those with other identified RSV risk conditions (17.1%) required IMV, which was higher than other (10.4%) or no (5.9%) preexisting health conditions (ptrend<0.001).\n\nConclusions and RelevanceApproximately 20% of children admitted to the PICU with severe RSV were in the defined groups that met U.S. nirsevimab-eligibility criteria or that had an identified RSV risk condition associated with known risk for severe RSV. A considerable proportion of both groups of children required IMV for respiratory support. These findings may help inform future deliberations regarding U.S. second season nirsevimab-eligibility recommendations.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSWhat preexisting health conditions are present in children aged 8-<24 months admitted to the pediatric intensive care unit for severe RSV disease in their second RSV season and how do clinical outcomes differ?\n\nFindingsAmong 574 children, 8% were eligible for nirsevimab in the U.S. and 13% had other preexisting conditions with known risk for severe RSV. Children with preexisting conditions, particularly those eligible for nirsevimab, were more likely to require invasive mechanical ventilation than those without.\n\nMeaningThese findings may inform future deliberations regarding which children in their second RSV season might benefit from RSV preventive products.","rel_num_authors":39,"rel_authors":[{"author_name":"Regina M. Simeone","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Laura Zambrano","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Margaret M. Newhams","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts"},{"author_name":"Amanda B. Payne","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Amber O. Orzel-Lockwood","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts"},{"author_name":"Natasha B. Halasa","author_inst":"Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee"},{"author_name":"Jemima Calixte","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts"},{"author_name":"Aline B. Maddux","author_inst":"Department of Pediatrics, Section of Critical Care Medicine, University of Colorado School of Medicine and Childrens Hospital Colorado, Aurora, Colorado"},{"author_name":"Kathleen Chiotos","author_inst":"Division of Critical Care Medicine, Department of Anesthesiology and Critical Care, Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania"},{"author_name":"Satoshi Kamidani","author_inst":"The Center for Childhood Infections and Vaccines of Childrens Healthcare of Atlanta and the Department of Pediatrics, Emory University School of Medicine, Atlan"},{"author_name":"Hillary Crandall","author_inst":"Division of Pediatric Critical Care, Department of Pediatrics, University of Utah and Primary Childrens Hospital, Salt Lake City, Utah"},{"author_name":"Danielle M. Zerr","author_inst":"Division of Infectious Diseases, Department of Pediatrics, University of Washington, Seattle, Washington; Seattle Children's Research Institute, Seattle, Washin"},{"author_name":"Melissa A. Cameron","author_inst":"Division of Pediatric Hospital Medicine, UC San Diego Rady Childrens Hospital, San Diego, California"},{"author_name":"Shira J. Gertz","author_inst":"Division of Pediatric Critical Care, Department of Pediatrics, Cooperman Barnabas Medical Center, Livingston, New Jersey"},{"author_name":"Bria M. Coates","author_inst":"Division of Pediatric Critical Care Medicine, Ann and Robert H. Lurie Childrens Hospital of Chicago, Chicago, Illinois"},{"author_name":"Kelly N. Michelson","author_inst":"Division of Pediatric Critical Care Medicine, Ann and Robert H. Lurie Childrens Hospital of Chicago, Chicago, Illinois"},{"author_name":"Jennifer E. Schuster","author_inst":"Division of Pediatric Infectious Diseases, Department of Pediatrics, Childrens Mercy Kansas City, Kansas City, Missouri"},{"author_name":"Ryan A. Nofziger","author_inst":"Division of Critical Care Medicine, Department of Pediatrics, Akron Childrens Hospital, Akron, Ohio"},{"author_name":"Jigar C. Chauhan","author_inst":"Division of Pediatric Critical Care, Nemours Childrens Hospital, Wilmington, Delaware"},{"author_name":"Mia Maamari","author_inst":"University of Texas Southwestern, Childrens Medical Center Dallas, Dallas, Texas"},{"author_name":"Steven L. Shein","author_inst":"Department of Pediatrics, Rainbow Babies and Childrens Hospital, Cleveland, OH"},{"author_name":"Michele Kong","author_inst":"Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama"},{"author_name":"Janet R. Hume","author_inst":"Division of Pediatric Critical Care, University of Minnesota Masonic Childrens Hospital, Minneapolis, Minnesota"},{"author_name":"Lora M. Martine","author_inst":"Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi"},{"author_name":"Judith A. Guzman-Cottrill","author_inst":"Department of Pediatrics, Oregon Health and Sciences University, Portland, Oregon"},{"author_name":"Samina S. Bhumbra","author_inst":"Ryan White Center for Pediatric Infectious Disease and Global Health, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana USA"},{"author_name":"Katherine Irby","author_inst":"Section of Pediatric Critical Care, Department of Pediatrics, Arkansas Childrens Hospital, Little Rock, Arkansas"},{"author_name":"Mary Allen Staat","author_inst":"Department of Pediatrics, Cincinnati Childrens Hospital, Cincinnati, OH"},{"author_name":"Tamara T. Bradford","author_inst":"Division of Cardiology, Department of Pediatrics, Louisiana State University Health Sciences Center; Childrens Hospital of New Orleans, New Orleans, Louisiana"},{"author_name":"Kari Wellnitz","author_inst":"Division of Pediatric Critical Care, Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa USA"},{"author_name":"Melissa S. Stockwell","author_inst":"Division of Child and Adolescent Health, Columbia University Vagelos College of Physicians and Surgeons, New York, New York"},{"author_name":"Matt Zinter","author_inst":"UCSF Benioff Childrens Hospital, San Francisco"},{"author_name":"Stephanie P. Schwartz","author_inst":"Department of Pediatrics, University of North Carolina at Chapel Hill Childrens Hospital, Chapel Hill, North Carolina"},{"author_name":"Saul Hymes","author_inst":"Bernard & Millie Duker Childrens Hospital, Albany, New York"},{"author_name":"Emily R. Levy","author_inst":"Divisions of Pediatric Infectious Diseases and Pediatric Critical Care Medicine, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnes"},{"author_name":"Austin Biggs","author_inst":"Department of Pediatric Critical Care, Medical University of South Carolina and Shawn Jenkins Childrens Hospital, Charleston, South Carolina"},{"author_name":"Katherine Lindsey","author_inst":"CDC; 4ES Corporation, Atlanta, Georgia"},{"author_name":"Angela P. Campbell","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Adrienne G. Randolph","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts; Departments of Anesthesia and Pediatrics, Harv"}],"rel_date":"2026-06-30","rel_site":"medrxiv"},{"rel_title":"Health conditions and RSV-related Pediatric Intensive Care Unit admissions in children during their second RSV season","rel_doi":"10.64898\/2026.06.26.26356705","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356705","rel_abs":"ImportanceRespiratory syncytial virus (RSV) hospitalization rates are highest among children <2 years of age. RSV immunization with infant monoclonal antibody or maternal vaccine is recommended to protect all U.S. infants in their first RSV season. For certain high-risk children aged 8-19 months entering their second RSV season, the monoclonal antibody nirsevimab is recommended. Little is known regarding preexisting health conditions as risk factors for RSV-associated respiratory failure in children during their second season.\n\nObjectivesTo describe children admitted to the pediatric intensive care unit (PICU) for RSV during their second RSV season by preexisting health conditions, and to compare demographic and clinical characteristics across groups.\n\nDesign, Setting, and ParticipantsSurveillance registry of children 8-<24 months old admitted to the PICU in 30 pediatric hospitals in the 2023-2024\/2024-2025 RSV seasons. All children had an RSV-positive respiratory sample and received respiratory support with high flow nasal cannula, noninvasive ventilation, or invasive mechanical ventilation (IMV).\n\nExposurePreexisting health conditions potentially increasing risk of severe RSV disease.\n\nMain Outcomes and MeasuresPatients were classified into four mutually exclusive groups by preexisting health conditions: 1) U.S. nirsevimab eligible criteria, 2) other identified RSV risk conditions (with some evidence of increased risk for severe RSV), 3) other preexisting conditions, and 4) no preexisting conditions. Patient demographic characteristics and level of respiratory support received were compared.\n\nResultsAmong 574 children: 47 (8.2%) had U.S. nirsevimab eligibility criteria, 76 (13.2%) had other RSV risk conditions, 96 (16.7%) had other preexisting conditions, and 355 (61.8%) had none. A higher proportion of children with nirsevimab eligibility factors (40.4%) than those with other identified RSV risk conditions (17.1%) required IMV, which was higher than other (10.4%) or no (5.9%) preexisting health conditions (ptrend<0.001).\n\nConclusions and RelevanceApproximately 20% of children admitted to the PICU with severe RSV were in the defined groups that met U.S. nirsevimab-eligibility criteria or that had an identified RSV risk condition associated with known risk for severe RSV. A considerable proportion of both groups of children required IMV for respiratory support. These findings may help inform future deliberations regarding U.S. second season nirsevimab-eligibility recommendations.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSWhat preexisting health conditions are present in children aged 8-<24 months admitted to the pediatric intensive care unit for severe RSV disease in their second RSV season and how do clinical outcomes differ?\n\nFindingsAmong 574 children, 8% were eligible for nirsevimab in the U.S. and 13% had other preexisting conditions with known risk for severe RSV. Children with preexisting conditions, particularly those eligible for nirsevimab, were more likely to require invasive mechanical ventilation than those without.\n\nMeaningThese findings may inform future deliberations regarding which children in their second RSV season might benefit from RSV preventive products.","rel_num_authors":39,"rel_authors":[{"author_name":"Regina M. Simeone","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Laura Zambrano","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Margaret M. Newhams","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts"},{"author_name":"Amanda B. Payne","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Amber O. Orzel-Lockwood","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts"},{"author_name":"Natasha B. Halasa","author_inst":"Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee"},{"author_name":"Jemima Calixte","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts"},{"author_name":"Aline B. Maddux","author_inst":"Department of Pediatrics, Section of Critical Care Medicine, University of Colorado School of Medicine and Childrens Hospital Colorado, Aurora, Colorado"},{"author_name":"Kathleen Chiotos","author_inst":"Division of Critical Care Medicine, Department of Anesthesiology and Critical Care, Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania"},{"author_name":"Satoshi Kamidani","author_inst":"The Center for Childhood Infections and Vaccines of Childrens Healthcare of Atlanta and the Department of Pediatrics, Emory University School of Medicine, Atlan"},{"author_name":"Hillary Crandall","author_inst":"Division of Pediatric Critical Care, Department of Pediatrics, University of Utah and Primary Childrens Hospital, Salt Lake City, Utah"},{"author_name":"Danielle M. Zerr","author_inst":"Division of Infectious Diseases, Department of Pediatrics, University of Washington, Seattle, Washington; Seattle Children's Research Institute, Seattle, Washin"},{"author_name":"Melissa A. Cameron","author_inst":"Division of Pediatric Hospital Medicine, UC San Diego Rady Childrens Hospital, San Diego, California"},{"author_name":"Shira J. Gertz","author_inst":"Division of Pediatric Critical Care, Department of Pediatrics, Cooperman Barnabas Medical Center, Livingston, New Jersey"},{"author_name":"Bria M. Coates","author_inst":"Division of Pediatric Critical Care Medicine, Ann and Robert H. Lurie Childrens Hospital of Chicago, Chicago, Illinois"},{"author_name":"Kelly N. Michelson","author_inst":"Division of Pediatric Critical Care Medicine, Ann and Robert H. Lurie Childrens Hospital of Chicago, Chicago, Illinois"},{"author_name":"Jennifer E. Schuster","author_inst":"Division of Pediatric Infectious Diseases, Department of Pediatrics, Childrens Mercy Kansas City, Kansas City, Missouri"},{"author_name":"Ryan A. Nofziger","author_inst":"Division of Critical Care Medicine, Department of Pediatrics, Akron Childrens Hospital, Akron, Ohio"},{"author_name":"Jigar C. Chauhan","author_inst":"Division of Pediatric Critical Care, Nemours Childrens Hospital, Wilmington, Delaware"},{"author_name":"Mia Maamari","author_inst":"University of Texas Southwestern, Childrens Medical Center Dallas, Dallas, Texas"},{"author_name":"Steven L. Shein","author_inst":"Department of Pediatrics, Rainbow Babies and Childrens Hospital, Cleveland, OH"},{"author_name":"Michele Kong","author_inst":"Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama"},{"author_name":"Janet R. Hume","author_inst":"Division of Pediatric Critical Care, University of Minnesota Masonic Childrens Hospital, Minneapolis, Minnesota"},{"author_name":"Lora M. Martine","author_inst":"Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi"},{"author_name":"Judith A. Guzman-Cottrill","author_inst":"Department of Pediatrics, Oregon Health and Sciences University, Portland, Oregon"},{"author_name":"Samina S. Bhumbra","author_inst":"Ryan White Center for Pediatric Infectious Disease and Global Health, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana USA"},{"author_name":"Katherine Irby","author_inst":"Section of Pediatric Critical Care, Department of Pediatrics, Arkansas Childrens Hospital, Little Rock, Arkansas"},{"author_name":"Mary Allen Staat","author_inst":"Department of Pediatrics, Cincinnati Childrens Hospital, Cincinnati, OH"},{"author_name":"Tamara T. Bradford","author_inst":"Division of Cardiology, Department of Pediatrics, Louisiana State University Health Sciences Center; Childrens Hospital of New Orleans, New Orleans, Louisiana"},{"author_name":"Kari Wellnitz","author_inst":"Division of Pediatric Critical Care, Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa USA"},{"author_name":"Melissa S. Stockwell","author_inst":"Division of Child and Adolescent Health, Columbia University Vagelos College of Physicians and Surgeons, New York, New York"},{"author_name":"Matt Zinter","author_inst":"UCSF Benioff Childrens Hospital, San Francisco"},{"author_name":"Stephanie P. Schwartz","author_inst":"Department of Pediatrics, University of North Carolina at Chapel Hill Childrens Hospital, Chapel Hill, North Carolina"},{"author_name":"Saul Hymes","author_inst":"Bernard & Millie Duker Childrens Hospital, Albany, New York"},{"author_name":"Emily R. Levy","author_inst":"Divisions of Pediatric Infectious Diseases and Pediatric Critical Care Medicine, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnes"},{"author_name":"Austin Biggs","author_inst":"Department of Pediatric Critical Care, Medical University of South Carolina and Shawn Jenkins Childrens Hospital, Charleston, South Carolina"},{"author_name":"Katherine Lindsey","author_inst":"CDC; 4ES Corporation, Atlanta, Georgia"},{"author_name":"Angela P. Campbell","author_inst":"CDC, Atlanta, Georgia"},{"author_name":"Adrienne G. Randolph","author_inst":"Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Childrens Hospital, Boston, Massachusetts; Departments of Anesthesia and Pediatrics, Harv"}],"rel_date":"2026-06-30","rel_site":"medrxiv"},{"rel_title":"Evaluating Polygenic Score Transferability for Lipid Traits in Underrepresented Populations: Evidence from Samoan Cohorts","rel_doi":"10.64898\/2026.06.26.26356725","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356725","rel_abs":"Dyslipidemia is a significant risk factor for cardiovascular disease (CVD), the leading cause of death in Samoa.1 Polygenic scores (PGS) for lipid traits offer promise for improved CVD risk prediction,4,5 yet their performance in Pacific Islander populations -- comprising only 0.002% of GWAS participants as of 20243 -- remains unknown. We evaluated the transferability of multi-ancestry PGS for LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), triglycerides (TG), and total cholesterol (TC) in 4,342 Samoan adults across five cohorts spanning 1990-2010. PGS from Graham et al.8 and Kanoni et al.9 multi-ancestry meta-analyses were harmonized with genome-wide imputed genotypes using a Samoan-specific reference panel21 and performance was assessed via incremental R{superscript 2} from linear mixed models with bootstrapped confidence intervals.25 HDL-C showed the highest performance (incremental R{superscript 2} 5.0-15.0%), followed by TC (5.0-10.7%), LDL-C (5.7-8.6%), and TG (3.5-7.0%). Critically, meaningful LDL-C performance was achieved only with the genome-wide PRS-CS score (99.6-99.7% variant matching), while a curated pruning-and-thresholding score achieved [~]9% matching and near-zero performance. These findings establish the first systematic lipid PGS benchmarks in Samoans, demonstrating meaningful transferability when genome-wide variant coverage is ensured, and highlight variant harmonization as a critical precondition for PGS deployment in underrepresented populations.","rel_num_authors":15,"rel_authors":[{"author_name":"Toni-Ann J. Yapp","author_inst":"Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Mohanraj Krishnan","author_inst":"Department of Biobehavioral Health, Pennsylvania State University, State College, PA, USA"},{"author_name":"Shuwei Liu","author_inst":"Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Samantha L. Manna","author_inst":"Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sc"},{"author_name":"Hong Cheng","author_inst":"Department of Environmental & Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, OH, USA"},{"author_name":"Take Naseri","author_inst":"Naseri & Associates Public Health Consultancy Firm and Family Health Clinic, Apia, Samoa; Center for Global Public Health, School of Public Health, Brown Univer"},{"author_name":"Muagututi'a Sefuiva Reupena","author_inst":"Lutia i Puava 'ae Mapu i Fagalele, Apia, Samoa"},{"author_name":"Satupa'itea Viali","author_inst":"Oceania University of Medicine, Samoa"},{"author_name":"John Tuitele","author_inst":"Department of Public Health, Government of American Samoa, Pago Pago, AS, USA"},{"author_name":"Ranjan Deka","author_inst":"Department of Environmental & Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, OH, USA"},{"author_name":"Nicola L. Hawley","author_inst":"Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA"},{"author_name":"Stephen T. McGarvey","author_inst":"Center for Global Public Health, School of Public Health, Brown University, Providence, RI, USA; Department of Epidemiology, School of Public Health, Brown Univ"},{"author_name":"Daniel E. Weeks","author_inst":"Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biostatistics and Health Data Science, University of Pittsburgh, Pitt"},{"author_name":"Ryan L. Minster","author_inst":"Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA"},{"author_name":"Jenna C. Carlson","author_inst":"Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA; Department of Biostatistics and Health Data Science, University of Pittsburgh, Pitt"}],"rel_date":"2026-06-30","rel_site":"medrxiv"},{"rel_title":"Early immune activation in the prediagnostic phases of immune-mediated neurological diseases","rel_doi":"10.64898\/2026.06.26.26356707","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356707","rel_abs":"Multiple sclerosis (MS), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and neuromyelitis optica spectrum disorder (NMOSD) are immune-mediated inflammatory disorders of the central nervous system (CNS). The temporal relationship between disease-specific autoantibodies and biomarkers of CNS injury before diagnosis remains unclear and is relevant for understanding early pathobiology. Here, we conducted a multicentre retrospective longitudinal case-control study using prediagnostic plasma from 362 individuals who later developed MS, 145 who developed MOGAD, and 60 who developed NMOSD.\n\nPlasma IgG levels against CNS antigens, MOG, and AQP4, as well as neurofilament light chain (pNfL), were quantified, and temporal relationships between immune activation, neuroaxonal injury, and clinical disease onset were modelled using linear mixed-effects models and survival analyses.\n\nIn MS, EBNA-1-specific and CNS-cross-reactive IgG were elevated up to 77.8 months before diagnosis, preceding pNfL increases by 44.9 months. In NMOSD, AQP4-IgG seroconversion occurred 32.5 months before diagnosis and preceded pNfL elevations by 40.4 months. In MOGAD, pNfL elevations preceded MOG-IgG seroconversion by 11.2 months.\n\nThus, in MS and NMOSD, humoral autoimmunity precedes detectable CNS injury, whereas in MOGAD, neuroaxonal injury occurs before circulating MOG-IgG. These distinct temporal patterns suggest differing early immunopathological trajectories and may provide a framework for future studies of early disease biology and biomarker-guided risk stratification.","rel_num_authors":35,"rel_authors":[{"author_name":"Hannes Vietzen","author_inst":"Medical University of Vienna"},{"author_name":"Raphael Reinecke","author_inst":"Raphael Reinecke Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna,"},{"author_name":"Jan Nolte","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Laura M. Kuehner","author_inst":"Center for Virology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Sarah M. Berger","author_inst":"Center for Virology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Jeremy V. Camp","author_inst":"Medical University of Vienna"},{"author_name":"Markus Ponleitner","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Kevin Rostasy","author_inst":"Department of Pediatric Neurology, Childrens Hospital Datteln, Witten\/Herdecke University, Datteln, Germany"},{"author_name":"Henrieke Saucke","author_inst":"Department of Pediatric Neurology, Childrens Hospital Datteln, Witten\/Herdecke University, Datteln, Germany"},{"author_name":"Franziska Kauth","author_inst":"Department of Pediatric Neurology, Childrens Hospital Datteln, Witten\/Herdecke University, Datteln, Germany"},{"author_name":"Georgia Koukou","author_inst":"Department of Pediatric Neurology, Childrens Hospital Datteln, Witten\/Herdecke University, Datteln, Germany"},{"author_name":"Simon Sommer","author_inst":"Department of Pediatric Neurology, Childrens Hospital Datteln, Witten\/Herdecke University, Datteln, Germany"},{"author_name":"Eva-Maria Wendel","author_inst":"Division of Pediatric Neurology, Department of Pediatrics, Olgahospital, Stuttgart, Germany"},{"author_name":"Marianne Graninger","author_inst":"Center for Virology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Verena Endmayr","author_inst":"Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna"},{"author_name":"Katrin Koebl-Shkreli","author_inst":"Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna,"},{"author_name":"Sophie Nitsch","author_inst":"Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna,"},{"author_name":"Johanna Wachutka","author_inst":"Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna,"},{"author_name":"Emmanuelle L. Waubant","author_inst":"Emmanuelle.Waubant@ucsf.edu"},{"author_name":"Soe Mar","author_inst":"Washington University in St. Louis, St. Louis, Missouri"},{"author_name":"Lauren B. Krupp","author_inst":"NYU Langone Multiple Sclerosis Comprehensive Care Center, New York, USA"},{"author_name":"Amy T. Waldman","author_inst":"Children's Hospital of Philadelphia, Philadelphia, Pennsylvania"},{"author_name":"T. Charles Casper","author_inst":"teri.schreiner@cuanschutz.edu"},{"author_name":"Tanuja Chitnis","author_inst":"Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA."},{"author_name":"Lisa Weidner","author_inst":"Austrian Red Cross, Blood Service for Vienna, Lower Austria and Burgenland, Vienna, Austria"},{"author_name":"Charlotte Pistorius","author_inst":"Austrian Red Cross, Blood Service for Vienna, Lower Austria and Burgenland, Vienna, Austria"},{"author_name":"Christof Jungbauer","author_inst":"Austrian Red Cross, Blood Service for Vienna, Lower Austria and Burgenland, Vienna, Austria"},{"author_name":"Markus Reindl","author_inst":"Medical University of Innsbruck"},{"author_name":"Barbara Kornek","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Markus Breu","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Gabriel Bsteh","author_inst":"Medical University of Vienna"},{"author_name":"Hans Lassmann","author_inst":"Center for Brain Research, Medical University of Vienna"},{"author_name":"Thomas Berger","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Romana Hoeftberger","author_inst":"Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna,"},{"author_name":"Paulus Rommer","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria"}],"rel_date":"2026-06-30","rel_site":"medrxiv"},{"rel_title":"Early immune activation in the prediagnostic phases of immune-mediated neurological diseases","rel_doi":"10.64898\/2026.06.26.26356707","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356707","rel_abs":"Multiple sclerosis (MS), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and neuromyelitis optica spectrum disorder (NMOSD) are immune-mediated inflammatory disorders of the central nervous system (CNS). The temporal relationship between disease-specific autoantibodies and biomarkers of CNS injury before diagnosis remains unclear and is relevant for understanding early pathobiology. Here, we conducted a multicentre retrospective longitudinal case-control study using prediagnostic plasma from 362 individuals who later developed MS, 145 who developed MOGAD, and 60 who developed NMOSD.\n\nPlasma IgG levels against CNS antigens, MOG, and AQP4, as well as neurofilament light chain (pNfL), were quantified, and temporal relationships between immune activation, neuroaxonal injury, and clinical disease onset were modelled using linear mixed-effects models and survival analyses.\n\nIn MS, EBNA-1-specific and CNS-cross-reactive IgG were elevated up to 77.8 months before diagnosis, preceding pNfL increases by 44.9 months. In NMOSD, AQP4-IgG seroconversion occurred 32.5 months before diagnosis and preceded pNfL elevations by 40.4 months. In MOGAD, pNfL elevations preceded MOG-IgG seroconversion by 11.2 months.\n\nThus, in MS and NMOSD, humoral autoimmunity precedes detectable CNS injury, whereas in MOGAD, neuroaxonal injury occurs before circulating MOG-IgG. These distinct temporal patterns suggest differing early immunopathological trajectories and may provide a framework for future studies of early disease biology and biomarker-guided risk stratification.","rel_num_authors":35,"rel_authors":[{"author_name":"Hannes Vietzen","author_inst":"Medical University of Vienna"},{"author_name":"Raphael Reinecke","author_inst":"Raphael Reinecke Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna,"},{"author_name":"Jan Nolte","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Laura M. Kuehner","author_inst":"Center for Virology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Sarah M. Berger","author_inst":"Center for Virology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Jeremy V. Camp","author_inst":"Medical University of Vienna"},{"author_name":"Markus Ponleitner","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Kevin Rostasy","author_inst":"Department of Pediatric Neurology, Childrens Hospital Datteln, Witten\/Herdecke University, Datteln, Germany"},{"author_name":"Henrieke Saucke","author_inst":"Department of Pediatric Neurology, Childrens Hospital Datteln, Witten\/Herdecke University, Datteln, Germany"},{"author_name":"Franziska Kauth","author_inst":"Department of Pediatric Neurology, Childrens Hospital Datteln, Witten\/Herdecke University, Datteln, Germany"},{"author_name":"Georgia Koukou","author_inst":"Department of Pediatric Neurology, Childrens Hospital Datteln, Witten\/Herdecke University, Datteln, Germany"},{"author_name":"Simon Sommer","author_inst":"Department of Pediatric Neurology, Childrens Hospital Datteln, Witten\/Herdecke University, Datteln, Germany"},{"author_name":"Eva-Maria Wendel","author_inst":"Division of Pediatric Neurology, Department of Pediatrics, Olgahospital, Stuttgart, Germany"},{"author_name":"Marianne Graninger","author_inst":"Center for Virology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Verena Endmayr","author_inst":"Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna"},{"author_name":"Katrin Koebl-Shkreli","author_inst":"Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna,"},{"author_name":"Sophie Nitsch","author_inst":"Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna,"},{"author_name":"Johanna Wachutka","author_inst":"Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna,"},{"author_name":"Emmanuelle L. Waubant","author_inst":"Emmanuelle.Waubant@ucsf.edu"},{"author_name":"Soe Mar","author_inst":"Washington University in St. Louis, St. Louis, Missouri"},{"author_name":"Lauren B. Krupp","author_inst":"NYU Langone Multiple Sclerosis Comprehensive Care Center, New York, USA"},{"author_name":"Amy T. Waldman","author_inst":"Children's Hospital of Philadelphia, Philadelphia, Pennsylvania"},{"author_name":"T. Charles Casper","author_inst":"teri.schreiner@cuanschutz.edu"},{"author_name":"Tanuja Chitnis","author_inst":"Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA."},{"author_name":"Lisa Weidner","author_inst":"Austrian Red Cross, Blood Service for Vienna, Lower Austria and Burgenland, Vienna, Austria"},{"author_name":"Charlotte Pistorius","author_inst":"Austrian Red Cross, Blood Service for Vienna, Lower Austria and Burgenland, Vienna, Austria"},{"author_name":"Christof Jungbauer","author_inst":"Austrian Red Cross, Blood Service for Vienna, Lower Austria and Burgenland, Vienna, Austria"},{"author_name":"Markus Reindl","author_inst":"Medical University of Innsbruck"},{"author_name":"Barbara Kornek","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Markus Breu","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Gabriel Bsteh","author_inst":"Medical University of Vienna"},{"author_name":"Hans Lassmann","author_inst":"Center for Brain Research, Medical University of Vienna"},{"author_name":"Thomas Berger","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria"},{"author_name":"Romana Hoeftberger","author_inst":"Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna,"},{"author_name":"Paulus Rommer","author_inst":"Department of Neurology, Medical University of Vienna, Vienna, Austria"}],"rel_date":"2026-06-30","rel_site":"medrxiv"},{"rel_title":"Prognostic value of plasma brain-derived pTau","rel_doi":"10.64898\/2026.06.26.26356597","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356597","rel_abs":"BackgroundPlasma brain-derived pTau217 (BD-pTau217) may provide a Alzheimers disease-specific plasma tau measure than total pTau217, but its prognostic value is unclear. We compared BD-pTau217 and total plasma pTau217 for predicting clinical and amyloid PET progression in cognitively unimpaired (CU) ADNI participants.\n\nMethodsPlasma NULISAseq biomarkers were measured in 1,427 ADNI participants, including 529 CU individuals. Amyloid PET progression was assessed in baseline CU amyloid-negative participants (Centiloid [&ge;]24.1) with longitudinal PET imaging; clinical progression was assessed in all baseline CU participants. Associations were evaluated using Cox models and time-dependent AUC.\n\nResultsBD-pTau217 did not clearly outperform total pTau217 for predicting progression to mild cognitive impairment or dementia. However, among baseline amyloid-negative participants (N=175), BD-pTau217 better predicted amyloid PET positivity at 2.5 years (tdAUC 0.82 vs 0.69; HR=10.54, p=0.00015) and 4 years (tdAUC 0.77 vs 0.64; HR=7.03, p=0.00055).\n\nConclusionBD-pTau217 improved prediction of near-term amyloid PET progression, with less clear advantage for clinical progression.\n\nHIGHLIGHTSO_LIBD-pTau217 predicted amyloid PET progression in CU ADNI participants.\nC_LIO_LIBD-pTau217 outperformed total pTau217 at the CL [&ge;]24.1 threshold.\nC_LIO_LIBD-pTau217 and total pTau217 performed similarly for clinical progression.\nC_LIO_LIPrognostic performance varied across amyloid PET thresholds.\nC_LIO_LIBD-pTau217 may support risk stratification in prevention trials.\nC_LI\n\nRESEARCH IN CONTEXTO_ST_ABSSystematic reviewC_ST_ABSPlasma pTau217 biomarkers show strong cross-sectional associations with amyloid and tau pathology and are increasingly used to support Alzheimers disease diagnosis and trial screening. Recent assay designs selectively measuring brain-derived pTau217 may reduce peripheral contributions to total pTau217 measurements, but their longitudinal prognostic value relative to total pTau217 remains less well established.\n\nInterpretationIn cognitively unimpaired ADNI participants, plasma BD-pTau217 showed stronger prognostic performance than total pTau217 for progression from amyloid PET negative to amyloid PET positive status, particularly at the primary CL [&ge;]24.1 threshold. In contrast, BD-pTau217 and total pTau217 showed more similar performance for predicting clinical progression to MCI or dementia.\n\nFuture directionsThese findings support further evaluation of BD-pTau217 for biological risk stratification and prevention trial enrichment. Validation is needed in more diverse cohorts, longer follow-up intervals, and across clinical-grade assay platforms.","rel_num_authors":18,"rel_authors":[{"author_name":"Valentina Ghisays","author_inst":"Banner Alzheimer's Institute, Phoenix, AZ, USA"},{"author_name":"Marisa N. Denkinger","author_inst":"Banner Sun Health Research Institute, Sun City, AZ, USA"},{"author_name":"Alpana Singh","author_inst":"Banner Sun Health Research Institute, Sun City, AZ, USA"},{"author_name":"Taina M. Marques","author_inst":"Banner Sun Health Research Institute, Sun City, AZ, USA"},{"author_name":"Michael Malek-Ahmadi","author_inst":"Banner Alzheimer's Institute, Phoenix, AZ, USA"},{"author_name":"Kendall Van-Keuren Jensen","author_inst":"Translational Genomics Research Institute, Phoenix, Arizona, USA"},{"author_name":"Hillary D. Protas","author_inst":"Banner Alzheimer's Institute, Phoenix, AZ, USA"},{"author_name":"Javad Sohankar","author_inst":"Banner Alzheimer's Institute, Phoenix, AZ, USA"},{"author_name":"Dhruman D. Goradia","author_inst":"Banner Alzheimer's Institute, Phoenix, AZ, USA"},{"author_name":"Vivek Devadas","author_inst":"Banner Alzheimer's Institute, Phoenix, AZ, USA"},{"author_name":"Yinghua Chen","author_inst":"Banner Alzheimer's Institute, Phoenix, AZ, USA"},{"author_name":"Shan Li","author_inst":"Banner Alzheimer's Institute, Phoenix, AZ, USA"},{"author_name":"Jessica B. Langbaum","author_inst":"Banner Alzheimer's Institute, Phoenix, AZ, USA"},{"author_name":"Michael W. Weiner","author_inst":"University of California San Francisco, San Francisco, CA, USA"},{"author_name":"Eric M. Reiman","author_inst":"Banner Alzheimer's Institute, Phoenix, AZ, USA"},{"author_name":"Yi Su","author_inst":"Banner Alzheimer's Institute, Phoenix, AZ, USA"},{"author_name":"Nicholas J. Ashton","author_inst":"Banner Alzheimer's Institute, Phoenix, AZ, USA; Banner Sun Health Research Institute, Sun City, AZ, USA"},{"author_name":"- Alzheimer's Disease Neuroimaging Initiative","author_inst":""}],"rel_date":"2026-06-30","rel_site":"medrxiv"},{"rel_title":"Robustness of Wolbachia-mediated incompatible-insect technique to future climate change scenarios","rel_doi":"10.64898\/2026.06.26.26356650","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356650","rel_abs":"Wolbachia-mediated incompatible-insect technique (IIT) via wAlbB, wMel or wPip\/wAlbA\/wAlbB strains are promising approaches for suppressing wildtype Aedes mosquitoes and therefore Aedes-borne diseases. Yet, the effectiveness of this technique under climate change remains uncertain. Here, we evaluate the long-term robustness of male Wolbachia-infected mosquito releases to suppress wildtype Aedes aegypti and Ae. albopictus populations across future climate scenarios across diverse geographical regions. We compiled large publicly available datasets on Aedes abundance across Singapore, China, the European Union and the United States, historical and projected climatic conditions in these regions and conducted experiments to test the thermal stability of cytoplasmic incompatibility in Wolbachia-infected male Aedes aegypti and albopictus. A climatically-driven entomological model was developed and calibrated using a Bayesian approach to model observed Aedes population dynamics and infer area-specific climate-driven variation in mosquito life-history traits. We back-inferred historical mosquito abundance and projected mosquito abundance in future climate change scenarios incorporating experimental and locally inferred entomological parameters and then simulated the counterfactual implementation of IIT in these regions. We find that Aedes populations are projected to increase in most regions across all climate change scenarios from 2050-2100 even under high heat conditions in the absence of interventions. While we found that IIT can suppress wild-type populations effectively across all future scenarios and in high heat conditions, effectiveness was found to depend heavily on mosquito emigration rates, overflooding ratios, release intervals and release strategies Extensive robustness checks confirmed that the model reproduced historical temporal trends, captured the influence of individual parameters on outcome and was sensitive to changes in values of inferred parameters and implement policy. These findings demonstrate that IIT may be a robust vector control tool under future climate conditions.\n\nResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSIncompatible Insect Technique (IIT) is a promising strategy for vector control. IIT involves the release of male mosquitoes infected with the Wolbachia bacterium; when these males mate with wild females without Wolbachia or infected with a different strain, cytoplasmic incompatibility yields non-viable offspring, thereby suppressing mosquito populations and reducing dengue transmission. We searched Embase, MEDLINE, Global Health, and PubMed for publications between database inception and Dec 1, 2025, with the search terms capturing the type of intervention (((\"Wolbachia\") OR (\"incompatible insect technique\")) and (\"intervention\")) and (\"climate change\")) as well as the type of outcome (\"Aegypti\") of interest for our study. We also contacted key field experts for relevant articles. The search returned 26 articles. 1 study evaluated the robustness of Wolbachia replacement in future heat scenarios. No study has ascertained the long-term robustness of Wolbachia-mediated IIT deployments in the context of climate change.\n\nAdded value of this studyThis study ascertains the long-term viability of Wolbachia-IIT via wAlbB, wMel or wPip\/wAlbA\/wAlbB strains to suppress mosquito populations under future climate change scenarios. Our approach advances the field by providing first-of-its-kind evidence that IIT can be a highly effective climate-resilient, and sustainable Aedes-control tool with global applicability.\n\nImplications of all the available evidenceOur findings demonstrate strong evidence that IIT can be a robust vector control tool under future climate conditions in the European Union, United States, China and Singapore. Policy makers can consider Wolbachia-mediated IIT as a strong tool to combat Aedes-borne diseases with long-term efficacy.","rel_num_authors":12,"rel_authors":[{"author_name":"Lin Geng","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"},{"author_name":"Perran Scott Ross","author_inst":"Pest and Environmental Research Group, Bio21 Institute, University of Melbourne, Parkville, VIC, 3010, Australia"},{"author_name":"Yu Cai","author_inst":"Temasek Life Science Laboratories, Singapore"},{"author_name":"Tao Huang","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Centre for Climate Change and Environmental Health, Nanyang Technological Univer"},{"author_name":"Joyi Chow","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"},{"author_name":"Zihao Wang","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"},{"author_name":"Esther Li Wen Choo","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"},{"author_name":"Chia-Chen Chang","author_inst":"Environmental Health Institute, National Environment Agency, Singapore; Department of Biological Sciences, National University of Singapore, Singapore"},{"author_name":"Lisa Couper","author_inst":"University of California, Berkeley, United States of America"},{"author_name":"Xinyue Gu","author_inst":"Pest and Environmental Research Group, Bio21 Institute, University of Melbourne, Parkville, VIC, 3010, Australia"},{"author_name":"Ary Hoffmann","author_inst":"Pest and Environmental Research Group, Bio21 Institute, University of Melbourne, Parkville, VIC, 3010, Australia"},{"author_name":"Jue Tao Lim","author_inst":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore"}],"rel_date":"2026-06-30","rel_site":"medrxiv"},{"rel_title":"Statins May Not be Associated with a Reduction in Primary Cardiovascular Events in Patients with Systemic Lupus Erythematosus","rel_doi":"10.64898\/2026.06.26.26356369","rel_link":"http:\/\/medrxiv.org\/content\/10.64898\/2026.06.26.26356369","rel_abs":"ImportanceCardiovascular disease (CVD) is a leading cause of morbidity and mortality in patients with Systemic Lupus Erythematosus (SLE), due to both traditional CVD risk factors and SLE specific factors. Although statins are first-line therapy for primary prevention of CVD in the general population, it is unclear whether statins protect against first time cardiovascular events (CVEs) in patients with SLE.\n\nObjectiveDetermine whether statins are protective in primary prevention of CVEs among patients with SLE.\n\nDesign, setting, and participantsThis cohort study is a retrospective analysis of a well-characterized, prospective cohort of patients with SLE with patient follow-up beginning in 2013.\n\nMain outcome and measuresCVEs were defined as the occurrence of myocardial infarction, thrombotic stroke, onset of angina, or coronary bypass procedure. Statin use in the prior year was quantified based on standardized defined daily doses (DDD). Rates of occurrence were compared using pooled logistic regression. A multivariable model was performed to adjust for possible confounders.\n\nResultsThe analysis was based on 8708 person-years of follow-up from 1396 cohort participants: 1283 (92%) were women, 567 (41%) Black, and 665 (48%) White. Patients were stratified by use of statin within the last year: none, < standard DDD, or [&ge;] standard DDD. The rate of events per 1000 person-years was respectively 5.3, 8.5, and 8.0 (p=0.31) within these 3 groups, suggesting potential lack of protective effect of statin treatment. The rates of CVEs among statin versus non-statin users remained the same after adjusting for and stratifying by total cholesterol level (p=0.18). Significantly higher rates of CVEs occurred among those with BMI 25-30 kg\/m2 (p=0.0066) and those prescribed [&ge;] 10 mg\/day of prednisone (p=0.0003). Multivariable analysis also suggested a potential lack of protective effect of statins against CVEs (OR 1.48; 95% CI, 0.79-2.75; p=0.21883) and diabetes mellitus was found to be independently associated with an increased risk for development of CVEs (OR 4.48; 95% CI 1.99-10.08; p=0.00029).\n\nConclusion and RelevanceAmong patients with SLE, statin use may not be protective in primary prevention of CVEs, regardless of statin exposure. Prednisone use, history of diabetes mellitus, and elevated BMI were drivers of increased cardiovascular risk in univariate analysis. Diabetes mellitus persisted as an independent risk factor for CVEs in a multivariable model. Our work reinforces findings from clinical trials which have shown no reduction in subclinical measures of atherosclerosis with statin use among patients with SLE, as well as a mechanistic substudy which demonstrated that statins are ineffective in normalizing the pro-atherogenic changes induced by SLE.","rel_num_authors":6,"rel_authors":[{"author_name":"Lea R. Goren","author_inst":"Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD"},{"author_name":"Michelle Petri","author_inst":"Division of Rheumatology, Department of Medicine, Johns Hopkins University, Baltimore, MD"},{"author_name":"Andrea Fava","author_inst":"Division of Rheumatology, Department of Medicine, Johns Hopkins University, Baltimore, MD"},{"author_name":"Daniel Goldman","author_inst":"Division of Rheumatology, Department of Medicine, Johns Hopkins University, Baltimore, MD"},{"author_name":"Laurence Magder","author_inst":"Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD"},{"author_name":"Luigi Adamo","author_inst":"Center for Cardiac Immunology, Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD"}],"rel_date":"2026-06-30","rel_site":"medrxiv"}]}