{"source":"biorxiv","name":"bioRxiv preprints","kind":"widget","via":"aiden","records":[{"id":"10.1101/2025.04.03.646846","title":"Single-nucleus transcriptomics reveals convergent effects of THC exposure and Reelin signaling on nucleus accumbens maturation in adolescence","subtitle":"Francesca Telese · Department of Psychiatry, University of California San Diego · 2026-01-01","value":"neuroscience","href":"https://doi.org/10.1101/2025.04.03.646846","props":{"doi":"10.1101/2025.04.03.646846","authors":"Zuo, Y.; Libster, A.; Gupta, A.; Liaw, L.; Formoli, N.; Sun, D.; Turner, A.; Iemolo, A.; Telese, F.","institution":"Department of Psychiatry, University of California San Diego","category":"neuroscience","date":"2026-01-01","abstract":"The nucleus accumbens undergoes extensive maturation during adolescence, but how drug exposure and genetic vulnerability interact to shape this process remains poorly understood. Here, we used single-nucleus RNA sequencing to examine the effects of chronic adolescent tetrahydrocannabinol (THC) exposure and reduced Reelin signaling in mice. THC produced broader transcriptional changes than Reelin haploinsufficiency, particularly in medium spiny neurons (MSNs). Analysis of cell-cell communication identified a THC-sensitive signaling program in which inhibitory interneurons were the principal receivers of MSN-derived signals related to axon-guidance and synaptic maturation. Despite the dominant effect of THC, both perturbations converged on shared gene networks linked to human genetic risk for substance use and psychiatric disorders. These effects were strongest in a population of immature neurons that we confirmed are generated in the adolescent nucleus accumbens and decline in adulthood. These findings show that adolescent THC exposure and Reelin signaling converge on transcriptional programs that regulate late neuronal maturation in striatal circuits."}},{"id":"10.1101/2025.02.19.638920","title":"Cytokines mediate increased endothelial-leukocyte interaction and brain capillary plugging during CAR T cell neurotoxicity","subtitle":"Juliane Gust · Seattle Children's · 2026-01-01","value":"immunology","href":"https://doi.org/10.1101/2025.02.19.638920","props":{"doi":"10.1101/2025.02.19.638920","authors":"Park, L.; Tsai, Y.-T.; Hu, R.; Lim, H.-K.; Faulhaber, L. D.; Burleigh, K.; Faulhaber, E. M.; Bose, M.; Draper, I. H.; Smith, S. E. P.; Shih, A. Y.; Hirayama, A. V.; Turtle, C. J.; Annesley, C. E.; Gardner, R. A.; Gustafson, H. H.; ZHENG, Y.; Gust, J.","institution":"Seattle Children's","category":"immunology","date":"2026-01-01","abstract":"CAR-T cells treat cancer, but also cause systemic cytokine release and immune effector cell associated neurotoxicity syndrome (ICANS). In an immunocompetent mouse model, we show by in vivo two-photon imaging that CD19-CAR T treatment causes brain capillary plugging by circulating CAR-T cells and other CD45+ leukocytes, as well as cortical hypoxia. This is accompanied by increased endothelial ICAM-1 and VCAM-1 expression in the brain capillary-venule transition zone, where most of the capillary stalls occur. In the mouse model, circulating CAR-T cells strongly upregulate integrin 4{beta}1 affinity to VCAM-1, but not affinity of integrin L{beta}2 to ICAM-1. Blockade of integrin 4 but not integrin L improves locomotion behavior. In vitro, human brain microendothelial cells upregulate ICAM-1 more than VCAM-1 in response to TNF, IFN-{gamma}, and IL-1{beta}. In a 3D brain human microvessel model, treatment with TNF and IFN-{gamma} is sufficient to induce adhesion of CAR T cells under flow conditions, which is blocked synergistically by antibodies against integrins 4 and L. Finally, patients with the highest levels of TNF and IFN-{gamma} also have the highest blood levels of soluble ICAM-1 and VCAM-1, which in turn correlate with ICANS. Integrin 4 but not L increases in CAR-T cells after they are infused into patients. Combined data from patients, mouse models and in vitro microvessels indicate differential regulation of interactions of ICAM-1 and VCAM-1 with their respective leukocyte integrins. Overall, our study supports the hypothesis that cytokine-driven upregulation of endothelial-leukocyte adhesion is sufficient to induce acute, reversible neurotoxicity.\n\nOne Sentence SummaryDuring CAR T cell therapy, cytokine release induces white blood cell stalling in brain capillaries by upregulating ICAM-1/VCAM-1-integrin interactions."}},{"id":"10.1101/2025.09.22.677801","title":"Engineering Spatial Control of Bacterial Organelles","subtitle":"Shyamal Mosalaganti · University of Michigan-Ann Arbor · 2026-01-01","value":"microbiology","href":"https://doi.org/10.1101/2025.09.22.677801","props":{"doi":"10.1101/2025.09.22.677801","authors":"Hoang, Y.; Jadhav, P. V.; Trettel, D.; Dow, R. E.; Kwon, S.; Matej, K.; Byrne, J. A.; Azaldegui, C. A.; Giessen, T. W.; Pi, H.; Mosalaganti, S.; Vecchiarelli, A. G.","institution":"University of Michigan-Ann Arbor","category":"microbiology","date":"2026-01-01","abstract":"Bacteria were once thought to lack organelles, but it is now clear they confine cellular reactions using an array of membrane- and protein-based compartments. A central question, however, is how bacterial organelles are organized in the cell, and whether their spatial control can be engineered. Here, we show that a two-protein system (McdAB) that positions carboxysomes-CO2-fixing organelles found in autotrophic bacteria-can be repurposed to provide programmable spatial control to diverse organelles in Escherichia coli. McdAB not only restores proper assembly and positioning of heterologously expressed carboxysomes in E. coli, but can also be reprogrammed to spatially organize all other known types of bacterial organelles, including encapsulins, biomolecular condensates, and even membrane-bound organelles. Programmable spatial organization of bacterial organelles establishes a new design principle for synthetic biology, where the location of reactions is as tunable as their content. Our work paves the way for more efficient biocatalysis in engineered microbes."}},{"id":"10.1101/2024.04.24.590951","title":"Oncogenic MAPK pathway activation induces a congenital and progressively lethal rare neuropathy in mice","subtitle":"Heather C. Etchevers · MMG, INSERM, Aix-Marseille Univ · 2026-01-01","value":"developmental biology","href":"https://doi.org/10.1101/2024.04.24.590951","props":{"doi":"10.1101/2024.04.24.590951","authors":"Marechal, E.; Aldea, D. A.; Quintana, P.; Mondielli, G.; Bernard-Marissal, N.; Moreno, M.; El Yazidi, C.; Broucqsault, N.; Delague, V.; Weiss, L.; Barlier, A.; Etchevers, H. C.","institution":"MMG, INSERM, Aix-Marseille Univ","category":"developmental biology","date":"2026-01-01","abstract":"RASopathies, rare congenital syndromes affecting multiple organ systems, often include peripheral neuropathy of unknown origin. While RASopathy-associated gene variants are proto-oncogenic, the impact of timing and mosaicism on pathogenicity remains poorly understood. Here, we investigate the links between Braf, a key mitogen-activated protein kinase (MAPK) effector, and peripheral neuropathy. By targeting Braf p.V600E, an oncogenic variant found in mosaic RASopathies, to embryonic Mpz-expressing cells in mice, we induced a congenital Charcot-Marie-Tooth-like degenerative neuropathy. This phenotype was characterized by hyperplastic nerves, hindlimb weakness, and unexpectedly reduced body size. Constitutively active Braf expanded a Jun+ Schwann cell repair state, impairing myelination and nerve homeostasis. To examine relevance to RASopathies, we differentiated patient-derived stem cells bearing the cardio-facio-cutaneous syndrome-associated BRAF p.Q257R variant into Schwann cells. Compared to wild-type controls, CFC-derived cells failed to acquire mature phenotypes, instead exhibiting progenitor or repair-type transcriptional profiles. Our findings implicate somatic mosaicism in the unresolved genetic heterogeneity of neuropathies and expand the candidate gene list for peripheral nerve disorders. Moreover, they reveal a MAPK-dependent mechanism linking neural crest-derived Schwann cell dysfunction to both body growth and nerve homeostasis, providing new insights into the mechanisms in RASopathy-associated neuropathy and potential therapeutic targets."}},{"id":"10.1101/2025.09.12.675835","title":"Maternal antibodies and density dependence affect suppression of host populations by novel pathogens","subtitle":"Rustom Antia · Emory University · 2026-01-01","value":"ecology","href":"https://doi.org/10.1101/2025.09.12.675835","props":{"doi":"10.1101/2025.09.12.675835","authors":"Bull, J. J.; Antia, R.","institution":"Emory University","category":"ecology","date":"2026-01-01","abstract":"Current theory for the regulation of host populations by pathogens suggests that a high level of suppression during the initial epidemic phase will be followed by a population rebound with decreased virulence due to pathogen and host evolution, and the extent of host suppression increases with increasing pathogen transmissibility (R0) and virulence. Using simple epidemiological models, we explore the effect of two factors on short- and long-term suppression: the strength of density-dependent population regulation (homeostasis) and maternal antibodies. We showed previously that, in the absence of maternal antibodies, the strength of homeostasis can greatly effect long term population suppression. Here we find that maternal antibodies can significantly reduce suppression of the host population if they attenuate rather than block infections, but then only for rapid homeostasis. A higher R0 can result in lower suppression, and the average virulence can decline over time without any (genetic) evolution. Our results suggest the need for a nuanced view of long-term suppression by a new pathogen, with the outcome sensitive to many details even in the absence of evolution."}},{"id":"10.1101/2025.04.14.648850","title":"Scaling Large Language Models for Next-Generation Single-Cell Analysis","subtitle":"David van Dijk · Yale University · 2026-01-01","value":"bioinformatics","href":"https://doi.org/10.1101/2025.04.14.648850","props":{"doi":"10.1101/2025.04.14.648850","authors":"Rizvi, S. A.; Levine, D.; Patel, A.; Zhang, S.; Wang, E.; Perry, C. J.; Vrkic, I.; Constante, N. M.; Fu, Z.; He, S.; Zhang, D.; Tang, C.; Lyu, Z.; Darji, R.; Li, M.; Sun, E.; Jeong, D.; Zhao, L.; Kwan, J.; Braun, D.; Hafler, B.; Chung, H.; Dhodapkar, R.; Jaeger, P.; Perozzi, B.; Ishizuka, J.; Azizi, S.; van Dijk, D.","institution":"Yale University","category":"bioinformatics","date":"2026-01-01","abstract":"AO_SCPLOWBSTRACTC_SCPLOWSingle-cell RNA sequencing has transformed our understanding of cellular diversity, yet current single-cell foundation models (scFMs) remain limited in their scalability, flexibility across diverse tasks, and ability to natively integrate textual information. In this work, we build upon the Cell2Sentence (C2S) framework, which represents scRNA-seq profiles as textual \"cell sentences,\" to train Large Language Models (LLMs) on a corpus comprising over one billion tokens of transcriptomic data, biological text, and metadata. Scaling the model to 27 billion parameters yields consistent improvements in predictive and generative capabilities and supports advanced downstream tasks that require synthesis of information across multi-cellular contexts. Targeted fine-tuning with modern reinforcement learning techniques produces strong performance in perturbation response prediction, natural language interpretation, and complex biological reasoning. This predictive strength enabled a dual-context virtual screen that nominated the kinase inhibitor silmitasertib (CX-4945) as a candidate for context-selective upregulation of antigen presentation. Experimental assessment in human cell models unseen during training supported this prediction, demonstrating that C2S-Scale can effectively guide the discovery of context-conditioned biology. C2S-Scale unifies transcriptomic and textual data at unprecedented scales, surpassing both specialized single-cell models and general-purpose LLMs to provide a platform for next-generation single-cell analysis and the development of \"virtual cells.\""}},{"id":"10.64898/2025.12.28.696719","title":"yallHap: Modern Y-chromosome haplogroup inference with probabilistic scoring and ancient DNA support","subtitle":"Alaina Hardie · Lakehead University · 2026-01-01","value":"bioinformatics","href":"https://doi.org/10.64898/2025.12.28.696719","props":{"doi":"10.64898/2025.12.28.696719","authors":"Hardie, A.","institution":"Lakehead University","category":"bioinformatics","date":"2026-01-01","abstract":"1The human Y chromosome enables detailed reconstruction of paternal lineages through haplogroup classification. Existing tools for this purpose typically rely on outdated phylogenies, lack ancient DNA handling, or provide limited confidence metrics. Here I present yallHap, a Y-chromosome haplogroup classifier that integrates the YFull phylogenetic tree (185,780 SNPs) with probabilistic scoring, built-in ancient DNA damage filtering, and parallel processing for population-scale studies. Validation on 1,231 high-coverage gnomAD samples achieved 99.9% accuracy (95% CI: 99.5-100%) on GRCh38, and 1,233 samples from 1000 Genomes Phase 3 achieved 99.8% accuracy (95% CI: 99.3-100%). For ancient DNA with moderate variant density (4-10%), Bayesian ancient mode achieves +19.3 pp improvement over heuristic mode (+12 to +24 pp at 1% increments; see Supplementary Table S3), reaching 60-86% accuracy. On full AADR ancient DNA validation (7,333 samples spanning [~]45,000 years), this translates to 90.7% overall accuracy (95% CI: 90.0-91.3%) versus 88.3% for heuristic transversions-only mode. At variant densities [&ge;]10%, both modes reach 97-99% accuracy. yallHap supports multiple reference genomes (GRCh37, GRCh38, T2T-CHM13v2.0), provides detailed quality metrics including optional ISOGG nomenclature output, and offers multi-threaded batch processing for large-scale studies. The tool is designed for integration into modern bioinformatics pipelines, with example wrappers for nf-core/eager [16,17] and Snakemake [18] workflows. The software is open source, available at https://github.com/trianglegrrl/yallHap, and distributed via pip, Bioconda, and Docker.\n\nO_TBL View this table:\norg.highwire.dtl.DTLVardef@b0b57dorg.highwire.dtl.DTLVardef@15b4bf4org.highwire.dtl.DTLVardef@d7a8dforg.highwire.dtl.DTLVardef@900360org.highwire.dtl.DTLVardef@cdaa7b_HPS_FORMAT_FIGEXP  M_TBL O_FLOATNOSupplementary Table S3:C_FLOATNO O_TABLECAPTION1-10% Variant Density Breakdown (n=1,214 samples) Fine-grained analysis of the 1-10% variant density range reveals that Bayesian ancient modes advantage emerges above approximately 4% density. Statistical significance assessed via two-proportion z-test. Note: Sample total (1,214) equals Table 3s 1-4% + 4-10% bins (478 + 736 = 1,214).\n\nC_TABLECAPTION C_TBL"}},{"id":"10.1101/2025.06.10.658941","title":"Multi-axial DNA origami force spectroscopy unlocks conformational dynamics hidden under single-axial tension","subtitle":"Rizal F. Hariadi · Arizona State University · 2026-01-01","value":"biophysics","href":"https://doi.org/10.1101/2025.06.10.658941","props":{"doi":"10.1101/2025.06.10.658941","authors":"Wisna, G. B. M.; Saurabh, A.; Karna, D.; Sasmal, R.; Chopade, P.; Presse, S.; Hariadi, R. F.","institution":"Arizona State University","category":"biophysics","date":"2026-01-01","abstract":"Biomolecules in living cells experience complex multi-directional mechanical forces that regulate their structure, dynamics, and function. However, most single-molecule techniques primarily exert force along a single axis, thereby failing to emulate the mechanical environment of cells. Here, we demonstrate that single-axis force application fundamentally restricts conformational dynamics by kinetically trapping molecules within distinct dynamic classes, preventing interconversion and exploration of the full conformational landscape. We developed MAESTRO (Multi-Axial Entropic Spring Tweezer along a Rigid Origami), a molecular platform that applies up to 9 pN forces from up to 4 directions simultaneously using programmable ssDNA entropic springs anchored to a DNA origami scaffold. We applied MAESTRO to Holliday junctions (HJs), 4-way DNA intermediates that experience multi-directional tension during homologous recombination. Counterintuitively, we discovered >5x slower kinetics of the HJ conformations under multi-axial tension than under tension-free conditions, enabling direct observations of previously hidden HJ conformational intermediates. Most remarkably, we discovered that multi-axial forces unlock conformational dynamics, enabling interconversion between 5 distinct kinetic classes that remain kinetically inaccessible under zero force or single-axial tension. Furthermore, we demonstrated that tension regulates T7 endonuclease I cleavage site selection, directly linking mechanical environments and molecular mechanics to enzymatic function. By overcoming single-axis limitations, MAESTRO opens new frontiers in molecular mechanobiology, revealing how multi-directional cellular force environments are essential for unlocking the full conformational landscape of biomolecules, and that these complex force patterns serve as master regulators of biological function through mechanisms hidden from conventional approaches."}},{"id":"10.1101/2025.11.05.686786","title":"Predator-prey scaling laws support a suspension-feeding lifestyle in Cambrian luolishaniid lobopodians","subtitle":"Jared Richards · Department of Organsimic and Evolutionary Biology, Harvard University · 2026-01-01","value":"paleontology","href":"https://doi.org/10.1101/2025.11.05.686786","props":{"doi":"10.1101/2025.11.05.686786","authors":"Richards, J.; Ortega-Hernandez, J.","institution":"Department of Organsimic and Evolutionary Biology, Harvard University","category":"paleontology","date":"2026-01-01","abstract":"The early Paleozoic saw a dramatic diversification of shelly epibenthic metazoans adapted to suspension and filter-feeding, but the extent to which these radiations affected the evolution of non-biomineralized suspension-feeding taxa is uncertain because these organisms are not typically well represented in the fossil record. Luolishaniids are a highly derived and disparate clade of (typically) armoured lobopodians widely interpreted as having a suspension-feeding ecology based on the presence of five or six anterior pairs of setulose appendages. Luolishaniids are globally widespread and represent the only Cambrian non-biomineralized free living epibenthic bilaterians regarded as having a suspension feeding mode of life, but their proposed ecology only relies on a qualitative interpretation of their functional morphology. Here we test the hypothesis that the setulose appendages of luolishaniids were adapted for a suspension feeding function. Quantitative morphological comparisons reveal a positive and statistically significant relationship between body length and the mesh spacing of the setulose anterior limbs of luolishaniids. This pattern correlates with suspension-feeding scaling in extant aquatic organisms, and suggests that luolishaniids primarily fed on mesoplanktonic seston. We provide quantitative evidence for suspension-feeding in luolishaniids, which represents the first statistically supported example of modern-like predator-prey scaling patterns observed in Cambrian soft-bodied metazoans."}},{"id":"10.64898/2025.12.31.697154","title":"Two phytohormones synergistically induce parasitic weeds seed germination via KAI2d receptors","subtitle":"Yoshiya Seto · School of Agriculture, Meiji University · 2026-01-01","value":"plant biology","href":"https://doi.org/10.64898/2025.12.31.697154","props":{"doi":"10.64898/2025.12.31.697154","authors":"Suzuki, T.; Ishikawa, T.; Burger, M.; Otani, M.; Miyamoto, K.; Jiang, W.; Kaku, H.; Kitaoka, N.; Matsuura, H.; Kuruma, M.; Nishiyama, K.; Seto, Y.","institution":"School of Agriculture, Meiji University","category":"plant biology","date":"2026-01-01","abstract":"Root parasitic plants can severely decrease global crop production. The germination of their seeds is induced by host root-derived strigolactones (SLs). Considering this unique germination system, a \"suicidal germination\" method has been proposed to control root parasitic plants. However, this method requires the cost-effective production of germination inducers. In this study, we determined that jasmonates and SLs can synergistically induce the seed germination of root parasitic plants (Orobanche minor and Striga hermonthica). Biochemical analyses indicated that jasmonates and SLs cooperatively activate multiple divergent KARRIKIN INSENSITIVE 2 receptors. Our findings have elucidated the host recognition systems associated with these highly duplicated promiscuous receptors, with potential implications for developing a new strategy to protect crops against root parasitic plants."}},{"id":"10.1101/2025.01.26.634937","title":"Transcranial Direct Current Stimulation in Alzheimer's Disease: Long-term impact","subtitle":"ANU AGGARWAL · UNIVERSITY OF ILLINOIS URBANA CHAMPAIGN · 2026-01-01","value":"neuroscience","href":"https://doi.org/10.1101/2025.01.26.634937","props":{"doi":"10.1101/2025.01.26.634937","authors":"AGGARWAL, A.","institution":"UNIVERSITY OF ILLINOIS URBANA CHAMPAIGN","category":"neuroscience","date":"2026-01-01","abstract":"The goal of this work was to integrate results from clinical trials related to transcranial direct current stimulation (tDCS) treatment of Alzheimers disease (AD) into a machine learning model of the disease to understand its impact on disease progression over a decade. tDCS is a new emerging treatment modality for AD. The impact of tDCS has so far been only sparsely studied in AD patients over a short duration in small sample sizes. Since AD is a progressive disease, it is useful to know about the impact of tDCS over a longer duration and predict the duration and site of treatment. This paper integrates limited data from tDCS treatment of AD patients and extrapolates it to a decade using the AD prediction model (ADPM). Based on this, it provides guidelines for best site and duration of treatment for a patient with AD."}},{"id":"10.64898/2025.12.30.697051","title":"Multi-modal choroid plexus pathology in aging and Alzheimer's disease","subtitle":"Maria K Lehtinen · Boston Children's Hospital · 2026-01-01","value":"neuroscience","href":"https://doi.org/10.64898/2025.12.30.697051","props":{"doi":"10.64898/2025.12.30.697051","authors":"Xu, H.; Lotfy, P.; Englert, B.; Oberhauser, J.; Byer, L. I. J.; Wihlman, J.; Colangelo, K.; Okar, S. V.; Thommana, A.; Puttonen, H.; Mäyränpää, M. I.; Tuimala, J.; Pedrosa, R.; Kumar, D.; Haberberger, J. F.; Atkins, M. E.; Alimukhamedov, S.; Pragana, A.; Benson, J.; Gabrielle, M. E.; Dong, A.; DurantLaforet, V.; Lin, P. B.-C.; Keene, C. D.; Latimer, C. S.; Prater, K. E.; Holtzman, D. M.; Isakova, A. E.; Wyss-Coray, T.; Schafer, D. P.; Reich, D. S.; Lehtimäki, T.; Karhunen, P. J.; Kok, E.; Jansson, D.; Yang, A. C.; Myllykangas, L.; Ordovas-Montanes, J.; Lehtinen, M. K.","institution":"Boston Children's Hospital","category":"neuroscience","date":"2026-01-01","abstract":"Brain barriers, cerebrospinal fluid (CSF) dynamics, and peripheral factors are implicated as significant contributors to Alzheimers disease (AD). The choroid plexus (ChP) is a blood-brain interface that produces CSF and forms the blood-CSF barrier. However, how ChP pathology develops across the lifespan and contributes to AD has not been systematically characterized. Here, we report a multi-modal ChP atlas integrating single-nucleus transcriptomics from 49 individuals, AI-assisted quantitative histopathology across >500 postmortem samples age 16 to 105, spatial transcriptomics, and functional studies in 5xFAD mice. We identify fibrosis, calcification, and macrophage abnormalities as hallmarks of ChP aging, with AD pathology conferring additional effects, including expansion of a pro-inflammatory fibroblast-macrophage signaling niche. In 5xFAD mice, macrophage dysfunction is associated with impaired epithelial barrier maintenance and repair. Together, these data provide a foundational resource for understanding ChP dysfunction in aging and AD and propose the macrophage-fibroblast-epithelial barrier axis as a driver of ChP pathology."}},{"id":"10.1101/2025.07.07.663524","title":"Lipid-mediated GPR32 signaling reprograms macrophage metabolism to impair anti-tuberculous immunity","subtitle":"Luciana Balboa · Instituto de Investigaciones Biomedicas en Retrovirus y SIDA (INBIRS). Facultad de Medicina. Universidad de Buenos Aires- Consejo Nacional de Investigaciones Ci · 2026-01-01","value":"immunology","href":"https://doi.org/10.1101/2025.07.07.663524","props":{"doi":"10.1101/2025.07.07.663524","authors":"Barros, J.; Maio, M.; Ledesma, M. M.; Ferrini, L.; Boix, M. E.; Faivre, N.; Monard, S.; Franco, J. L. M.; Metais, A.; Sabbione, F.; Fuentes, F.; Grosso, T. M.; Errea, A. J.; Aragone, X.; Cunto, M. S.; Palmero, D.; Matteo, M.; Ostrowski, M.; ARGUELLO, R. J.; Nanda, R.; Layre, E.; Neyrolles, O.; Verollet, C.; Lugo-Villarino, G.; Balboa, L.","institution":"Instituto de Investigaciones Biomedicas en Retrovirus y SIDA (INBIRS). Facultad de Medicina. Universidad de Buenos Aires- Consejo Nacional de Investigaciones Ci","category":"immunology","date":"2026-01-01","abstract":"Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), has evolved strategies to evade innate immunity and establish persistent infection. However, the mechanisms by which M. tuberculosis reprograms human macrophage metabolism remain incompletely defined. Tuberculous pleural effusion (TB-PE), a common extrapulmonary manifestation that frequently coexists with pulmonary TB, offers a unique, clinically relevant immunometabolic window into the TB microenvironment. Here, using patient-derived TB-PE samples, we demonstrate that this microenvironment induces a metabolic state in human macrophages that compromises their antimicrobial function. Lipidomic analysis identified an enrichment of the specialized pro-resolving mediator Resolvin D5 (RvD5), which signals through GPR32 to suppress macrophage microbicidal activity. The acellular fraction of TB-PE was sufficient to induce RvD5 secretion by monocytes, correlating with increased expression of RvD5 biosynthetic enzymes in pleural monocytes from TB patients. Mechanistically, RvD5-GPR32 signaling inhibited glycolysis without promoting oxidative phosphorylation, reducing HIF-1 activity and impairing intracellular M. tuberculosis control. HIF-1 stabilization restored antimicrobial function. These findings uncover the RvD5-GPR32-HIF-1 axis as a mechanism of metabolic immune suppression and a potential target for host-directed TB therapy.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC=\"FIGDIR/small/663524v3_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (68K):\norg.highwire.dtl.DTLVardef@64feceorg.highwire.dtl.DTLVardef@948ab0org.highwire.dtl.DTLVardef@1d387forg.highwire.dtl.DTLVardef@682f72_HPS_FORMAT_FIGEXP  M_FIG C_FIG"}},{"id":"10.1101/2025.05.15.654386","title":"Telomerase reverse transcriptase is required for resistance to mycobacterial infection","subtitle":"Stefan H Oehlers · Agency for Science, Technology and Research (A*STAR) · 2026-01-01","value":"immunology","href":"https://doi.org/10.1101/2025.05.15.654386","props":{"doi":"10.1101/2025.05.15.654386","authors":"Han, D. J.; Costa, D. M.; Luo, G.; Wright, K.; Pandey, M.; Wee, D.; Chen, Y.; Akincilar, S. C.; Tergaonkar, V.; Dorajoo, R.; Carissimo, G.; Singhal, A.; Elks, P. M.; Ellis, P. S.; Henriques, C. M.; Yan, B.; Mostowy, S.; Oehlers, S. H.","institution":"Agency for Science, Technology and Research (A*STAR)","category":"immunology","date":"2026-01-01","abstract":"Age is an important risk factor for infections such as tuberculosis (TB). Telomerase is expressed in immune cells yet leukocyte telomere length declines during ageing suggesting an age-dependent loss of telomerase activity in the immune system. Leukocyte telomere length has been correlated with worse outcomes in TB patients, however the mechanisms linking telomere biology to TB susceptibility and response to therapy are unexplored. Here we use the zebrafish-Mycobacterium marinum model to investigate the role of telomerase in TB resistance. We find depletion and inhibition of Tert, the catalytic subunit of telomerase, increases bacterial burden in zebrafish embryos. The Tert depletion infection susceptibility phenotype could not be rescued by p53 or STING depletion suggesting a non-canonical role for Tert in controlling mycobacterial infection. Consistent with a previously described role for Tert in developmental hematopoiesis, we find Tert is necessary for demand-driven emergency myelopoiesis to support containment of extended mycobacterial infection. Our findings establish a previously undescribed role for host telomerase in supporting infection demand-driven hematopoiesis to control infection."}},{"id":"10.1101/2025.06.29.662231","title":"AI-Based Detection of Coliform Colonies Using CNN Transfer Learning for Application to Cultured Plate Analysis in Water Quality Research","subtitle":"Olcay Kursun · Auburn University at Montgomery · 2026-01-01","value":"microbiology","href":"https://doi.org/10.1101/2025.06.29.662231","props":{"doi":"10.1101/2025.06.29.662231","authors":"Mallela, S.; Gates, A.; Medepalli, S.; Okeke, B.; Kursun, O.","institution":"Auburn University at Montgomery","category":"microbiology","date":"2026-01-01","abstract":"Pathogenic bacterial contamination of water poses a severe public health risk, particularly in settings with limited laboratory resources. We propose a two-stage artificial intelligence (AI) pipeline for automated detection and classification of coliform colonies on agar plates. In the first stage, a YOLOv8-based detector localizes colonies on full-plate images, eliminating the need for manual annotation. In the second stage, detected colony patches are classified using a convolutional neural network (CNN) trained via transfer learning, where models are first pretrained on a diverse public bacterial colony dataset and subsequently fine-tuned on coliform-specific classification tasks. Across both in-house and public datasets, transfer learning consistently improves classification performance relative to training from scratch. The complete pipeline processes each plate in under five seconds and outperforms classical feature-based baselines, including Histogram of Oriented Gradients, Local Binary Patterns, and Haralick descriptors with conventional classifiers. These results demonstrate the potential of a modular, low-cost AI framework for scalable and accessible microbiological analysis, with future work targeting color-aware models and on-device inference for field deployment."}},{"id":"10.64898/2025.12.27.696689","title":"Fifteen-year microbiome survey of endangered killer whales (Orcinus orca) reveals declining diversity and population differences","subtitle":"David A. Relman · Stanford University · 2026-01-01","value":"microbiology","href":"https://doi.org/10.64898/2025.12.27.696689","props":{"doi":"10.64898/2025.12.27.696689","authors":"Switzer, A. D.; Parsons, K. M.; Hanson, M. B.; Emmons, C.; Park, L.; Hempelmann, J.; Robeck, T.; Herrick, K.; Osborn, S.; Jaffe, A. L.; Olsen, D.; Matkin, C.; Bik, E. M.; Robaczewska, A.; Wells, A.; May, D.; Wasser, S.; Thornton, S. J.; Relman, D. A.","institution":"Stanford University","category":"microbiology","date":"2026-01-01","abstract":"The endangered Southern Resident killer whale (Orcinus orca) (SRKW) population is burdened by multiple anthropogenic stressors with limited non-invasive approaches for health surveillance. The gut microbiome is interconnected with host physiology and can be characterized using remotely collected fecal samples, creating unique opportunities to integrate environmental and individualized host-associated features of health. In this study, we used fecal samples collected over a 15-year period (2005-2019) from 77% of the living, wild SRKW population (56 individuals, 1-17 time points per individual), as well as fecal samples from the conspecific Northern and Alaska Resident killer whale populations, to characterize distal gut microbiota structure and genomic composition. SRKW microbiotas were individualized and distinct from those of the nearby Northern and Alaska Resident populations, both of which exhibit consistently higher fecundity and survivorship. During the study period, SRKW fecal microbiota species richness declined, despite stability over periods of time less than or equal to 1 year. Several potential bacterial pathogens, such as Fusobacterium spp., achieved dominance in the fecal microbiotas of SRKW individuals sampled within 6 months of death. These findings demonstrate the feasibility and value of harnessing non-invasively collected fecal samples and microbiome profiles for longitudinal killer whale health surveillance."}},{"id":"10.1101/2025.04.16.649164","title":"Evolutionarily Optimal Phage Life-History Traits: Burst Size vs. Lysis Time","subtitle":"Joan Roughgarden · University of Hawaii · 2026-01-01","value":"evolutionary biology","href":"https://doi.org/10.1101/2025.04.16.649164","props":{"doi":"10.1101/2025.04.16.649164","authors":"Roughgarden, J.","institution":"University of Hawaii","category":"evolutionary biology","date":"2026-01-01","abstract":"A new model based on a dynamical equation for the virus to microbe ratio (VMR) during log phase population growth shows that an optimal balance occurs between a short lysis time with low burst size vs. a long lysis time with large burst size. The model predicts that interventions lowering phage adsorption by killing free virus and/or limiting their access to bacteria favors the evolution of an increased lysis time and higher burst per infecting microbe until the intervention either drives a virulent phage extinct or, for temperate phage, drives the phage from its lytic phase into its lysogenic phase. The model also predicts that along an environmental gradient of increasing primary productivity the optimal lysis time shortens along the gradient, implying that the lytic life cycle goes around faster along the gradient.\n\nImportanceA new approach to modeling phage life history predicts that virus respond to interventions that limit their adsorption onto bacteria by evolving a longer lysis time. The new model also predicts that lysis time of virus in nature shortens and the virus life cycle goes around faster as environmental conditions favoring virus production increase. These predictions show that virus life-history traits are not arbitrary and can be predicted in advance based on environmental conditions."}},{"id":"10.1101/2025.09.24.678295","title":"Super-resolved spatial transcriptomics reveals early hippocampal RNA localization changes in a mouse model of Alzheimer's disease","subtitle":"Shahar Alon · Bar-Ilan University · 2026-01-01","value":"genomics","href":"https://doi.org/10.1101/2025.09.24.678295","props":{"doi":"10.1101/2025.09.24.678295","authors":"Diamant Karasik, Y.; Eger, H.; Goldberg, T.; Seri, Y.; Schottlender, N.; Ben Mor, T.; Safra, M.; Shenhav, M.; Zak, H.; Danino, M.; Rosenberg, Y.; Glick, A.; Feldman, N.; Slater, N.; Gottfried, I.; Ashery, U.; Alon, S.","institution":"Bar-Ilan University","category":"genomics","date":"2026-01-01","abstract":"Cell-type-specific changes in gene expression and RNA localization are hallmarks of Alzheimers disease (AD) and other neurodegenerative disorders, yet spatial dysregulation in early disease stages remains poorly defined. Here, we applied Expansion Sequencing (ExSeq) to map the spatial distribution of 101 genes at super-resolution in the hippocampus of 4-week-old 5xFAD and wild-type (WT) mice, prior to overt pathology. We uncovered early alterations in RNA spatial organization and gene expression, including 23 genes showing altered localization without changes in abundance in the 5xFAD hippocampus. Using spatial expression analysis and single-cell neighborhood analysis, we identified cell-type- and region-specific molecular programs associated with synaptic function, neuroinflammation, and metabolic stress that differed between 5xFAD and WT mice. Spatial RNA velocity further revealed state differences influenced by local cell to cell interactions. Together, these results suggest that RNA positioning and transcriptional programs are perturbed at early disease stages. Finally, we provide the full super-resolution ExSeq dataset as an open resource for spatial and cell-type-specific analyses in early Alzheimers disease research.\n\nHighlightsO_LISuper-resolved transcriptomic profiling of the hippocampus at early disease stages\nC_LIO_LIIdentification of 23 genes with altered spatial localization without changes in abundance\nC_LIO_LIEarly alterations in single-cell neighborhood organization in the 5xFAD hippocampus\nC_LIO_LISpatial RNA velocity reveals cell-type-specific cell state differences shaped by cell-cell proximity\nC_LI\n\nGraphical abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=187 SRC=\"FIGDIR/small/678295v2_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (41K):\norg.highwire.dtl.DTLVardef@1b46cf2org.highwire.dtl.DTLVardef@5cc55eorg.highwire.dtl.DTLVardef@a1ade4org.highwire.dtl.DTLVardef@9f833e_HPS_FORMAT_FIGEXP  M_FIG C_FIG"}},{"id":"10.1101/2025.08.16.670673","title":"Ancestral intronic splicing regulatory elements in the SCNα gene family","subtitle":"Dmitri Pervouchine · Center for Molecular and Cellular Biology · 2026-01-01","value":"bioinformatics","href":"https://doi.org/10.1101/2025.08.16.670673","props":{"doi":"10.1101/2025.08.16.670673","authors":"Chernyavskaya, E.; Vorobeva, M.; Spirin, S. A.; Skvortsov, D. A.; Pervouchine, D.","institution":"Center for Molecular and Cellular Biology","category":"bioinformatics","date":"2026-01-01","abstract":"SCN genes encode components of voltage-gated sodium channels that are crucial for generating electrical signals. Humans have ten paralogous SCN genes, some of which contain duplicated mutually exclusive exons 5a and 5b. In reconstructing their evolutionary history, we found multiple unannotated copies of exon 5 in distant species and showed that exon 5 duplication goes back to a common ancestor of the SCN gene family. We char-acterized splicing patterns of exons 5a and 5b across tissues, tumors, and developmental stages, and demonstrated that the nonsense mediated decay (NMD) system is not the ma-jor factor contributing to their mutually exclusive choice. Comparison of SCN2A, SCN3A, SCN5A, and SCN9A intronic nucleotide sequences revealed multiple Rbfox2 binding sites and two highly conserved intronic splicing regulatory elements (ISRE) that are shared be-tween paralogs. Minigene mutagenesis and blockage by antisense oligonucleotides showed that the formation of RNA structure between ISRE promotes exon 5b skipping in SCN9A. The inclusion of exon 5b is also suppressed in siRNA-mediated knockdown of Rbfox2, which makes the collective action of RNA structure and Rbfox2 compatible with the model of a structural RNA bridge. ISRE sequences are conserved from human to elephant shark and may represent an ancient, evolutionarily conserved regulatory mechanism. Our results demonstrate the power of comparative sequences analysis in application to paralogs for elucidating splicing regulatory programs."}},{"id":"10.64898/2025.12.03.691928","title":"A Type III secretion system effector evolved to be mechanically labile and initiate unfolding from the N-terminus.","subtitle":"Marcelo C Sousa · University of Colorado Boulder · 2026-01-01","value":"biophysics","href":"https://doi.org/10.64898/2025.12.03.691928","props":{"doi":"10.64898/2025.12.03.691928","authors":"Dapron, K. E.; Plastow, A. M.; Fink, M. R.; Dzuba, B.; Leblanc, M.-A.; Perkins, T. T.; Tajkhorshid, E.; Sousa, M. C.","institution":"University of Colorado Boulder","category":"biophysics","date":"2026-01-01","abstract":"Many Gram-negative pathogens critically depend on the Type III secretion system (T3SS) to inject effector proteins into host cells for colonization. Because the channel of the T3SS is narrow ([~]2 nm), effectors must be unfolded for secretion. However, the T3SS cannot unfold mechanically robust substrates (GFP, ubiquitin, and dihydrofolate reductase), severely impairing their secretion. Consistent with this, effectors are exceptionally mechanically labile, unfolding at low forces. Thus, secretion competency is correlated with mechanical properties. Effector sequences have significantly diverged from non-effectors, suggesting that secretion exerts evolutionary pressure selecting mechanical lability. Here, using atomic-force-microscopy-based force spectroscopy, we show that effector NleC is mechanically labile (Funfold = 13.5 pN at 100 nm/s) and mechanically compliant, as characterized by a large distance to the transition state ({Delta}x{ddagger} = 2.7 nm). In contrast, the non-effector homolog protealysin is mechanically stable (Funfold = 50.7 pN at 100 nm/s) and brittle ({Delta}x{ddagger} = 0.7 nm), comparable to proteins known to impair secretion (Funfold > 80 pN; {Delta}x{ddagger} < 0.4 nm). Denaturant-induced unfolding assays demonstrate that effectors exhibit rates typical of their fold, further reinforcing mechanical properties rather than fast unfolding kinetics (k0) predicts secretion. Steered molecular dynamic simulations revealed NleC unfolding initiates at the N-terminus, consistent with current secretion models, whereas protealysin unfolding initiates at the C-terminus. Notably, the NleC N-terminus is primarily -helical while non-effector homologs contain {beta}-sheets, which may account for the distinct unfolding pathway. Together, these results support the notion that mechanical lability is an evolved, structurally encoded feature underlying effector secretion.\n\nSignificanceThe Type III secretion system (T3SS) delivers effector proteins directly into host cells to promote bacterial colonization. Effectors must be unfolded for secretion, and this particular selective pressure is hypothesized to have driven significant sequence divergence from non-effector proteins. Here, we show that effectors are not characterized by unusually fast unfolding rates. Rather as hypothesized, effector NleC is more mechanically labile than its non-effector homolog, indicating that mechanical lability underlies both effector sequence divergence and T3SS unfolding. Simulations revealed that NleC unfolding initiates via the N-terminus consistent with the current secretion mechanism, while protealysin unfolds from the C-terminus. Together, these results strongly suggest mechanical lability is an evolved property of effectors and provide structural insight into how it is encoded."}},{"id":"10.1101/2025.04.03.646846","title":"Single-nucleus transcriptomics reveals convergent effects of THC exposure and Reelin signaling on nucleus accumbens maturation in adolescence","subtitle":"Francesca Telese · Department of Psychiatry, University of California San Diego · 2026-01-01","value":"neuroscience","href":"https://doi.org/10.1101/2025.04.03.646846","props":{"doi":"10.1101/2025.04.03.646846","authors":"Zuo, Y.; Libster, A.; Gurha, A.; Liaw, L.; Formoli, N.; Sun, D.; Turner, A.; Iemolo, A.; Telese, F.","institution":"Department of Psychiatry, University of California San Diego","category":"neuroscience","date":"2026-01-01","abstract":"The nucleus accumbens undergoes extensive maturation during adolescence, but how drug exposure and genetic vulnerability interact to shape this process remains poorly understood. Here, we used single-nucleus RNA sequencing to examine the effects of chronic adolescent tetrahydrocannabinol (THC) exposure and reduced Reelin signaling in mice. THC produced broader transcriptional changes than Reelin haploinsufficiency, particularly in medium spiny neurons (MSNs). Analysis of cell-cell communication identified a THC-sensitive signaling program in which inhibitory interneurons were the principal receivers of MSN-derived signals related to axon-guidance and synaptic maturation. Despite the dominant effect of THC, both perturbations converged on shared gene networks linked to human genetic risk for substance use and psychiatric disorders. These effects were strongest in a population of immature neurons that we confirmed are generated in the adolescent nucleus accumbens and decline in adulthood. These findings show that adolescent THC exposure and Reelin signaling converge on transcriptional programs that regulate late neuronal maturation in striatal circuits."}},{"id":"10.1101/2025.10.15.682664","title":"Functional and antigenic constraints on the Nipah virus fusion protein","subtitle":"Jesse D Bloom · Fred Hutch Cancer Center · 2026-01-01","value":"microbiology","href":"https://doi.org/10.1101/2025.10.15.682664","props":{"doi":"10.1101/2025.10.15.682664","authors":"Larsen, B. B.; Harari, S.; Gen, R.; Stewart, C.; Veesler, D.; Bloom, J. D.","institution":"Fred Hutch Cancer Center","category":"microbiology","date":"2026-01-01","abstract":"Nipah virus is a highly pathogenic virus in the family Paramyxoviridae that utilizes two distinct surface glycoproteins to infect cells. The receptor-binding protein (RBP) binds host receptors whereas the fusion protein (F) merges viral and host membranes. Here, we use non-replicative pseudoviruses to safely measure the effects of all F single amino-acid residue mutations on its cell entry function and neutralization by monoclonal antibodies. We compare mutational tolerance in F with previous experimental measurements for RBP and show that F is much more functionally constrained than the RBP. We also identify mutationally intolerant sites on the F trimer surface and core that are critical for proper function, and describe mutations that are candidates for stabilizing F in the prefusion conformation for vaccine design. We quantify how F mutations affect neutralization by six monoclonal antibodies, and show that the magnitude of mutational effects on neutralization varies among antibodies. Our measurements of mutational effects on Nipah virus F predict the ability of the antibodies to neutralize the related Hendra virus. Overall, our work defines the functional and antigenic constraints on the F protein from an important zoonotic virus.\n\nImportanceNipah virus sporadically spills over into humans, where it is often fatal. The Nipah fusion (F) protein is necessary for infection, and is a target for vaccines and antibody therapies. To better understand the constraints on this protein, we experimentally measured how [~]8,500 single amino-acid mutations to F affected its function using pseudoviruses that enable the safe study of protein mutants without the generation of actual replicative virus. We examined the effects of these mutations in the context of structural data and publicly available Nipah virus sequences to characterize the constraints that shape F protein evolution. This work has implications for understanding paramyxovirus fusion proteins, and informs the development of vaccines and monoclonal antibody therapies."}},{"id":"10.64898/2025.12.28.696729","title":"A tunable immune-evasion function of Zika virus NS5 governs viral fitness and pathogenesis","subtitle":"Qiang Ding · Center for Infection Biology, School of Basic Medical Sciences, Tsinghua University, Beijing, China · 2026-01-01","value":"microbiology","href":"https://doi.org/10.64898/2025.12.28.696729","props":{"doi":"10.64898/2025.12.28.696729","authors":"Zhang, Y.; Zhang, Y.; Liu, C.; Ren, W.; Li, C.; Guo, Y.; Bai, L.; Wang, P.; An, J.; Liu, W. J.; Ding, Q.","institution":"Center for Infection Biology, School of Basic Medical Sciences, Tsinghua University, Beijing, China","category":"microbiology","date":"2026-01-01","abstract":"Type I interferon (IFN) signaling is a central antiviral defense, with STAT2 driving the expression of IFN-stimulated genes (ISGs) to restrict viral infection. Many flaviviruses, including Zika virus (ZIKV), evade this pathway through non-structural protein 5 (NS5)-mediated ubiquitination and proteasomal degradation of STAT2, yet the contribution of this immune evasion strategy to viral fitness and pathogenesis remains incompletely defined. Here, using a multi-step mutational scanning strategy that jointly assessed STAT2 degradation and viral RNA replication, we identified a single NS5 residue, L162, as uniquely permissive to substitution that abolishes STAT2 degradation without compromising intrinsic replication functions. Substitution of L162 with alanine or glycine (L162A or L162G) selectively disrupted NS5 recruitment of the ZSWIM8-CUL3 E3 ubiquitin ligase, thereby preserving STAT2 stability and restoring IFN signaling. Recombinant ZIKV carrying these mutations exhibited reduced replication and enhanced ISG induction in human cells, defects fully rescued by STAT2 knockout. In A129 mice (type I IFN receptor deficient), mutant and WT viruses replicated comparably, but in human STAT2 knock-in mice, ZIKV-NS5L162G exhibited markedly reduced viral loads and disease. Notably, infection with ZIKV-NS5L162G elicited robust neutralizing antibody and T cell responses that conferred protection against WT challenge. Together, these findings establish NS5-mediated STAT2 degradation as a central determinant of ZIKV immune evasion, viral fitness and pathogenesis, and highlight disruption of NS5-STAT2 antagonism as a promising strategy for antiviral intervention and rational attenuation."}},{"id":"10.1101/2025.07.02.662873","title":"mRNA 3'UTRs chaperone intrinsically disordered regions to control protein activity","subtitle":"Christine Mayr · Sloan Kettering Institute · 2026-01-01","value":"molecular biology","href":"https://doi.org/10.1101/2025.07.02.662873","props":{"doi":"10.1101/2025.07.02.662873","authors":"Luo, Y.; Zhong, Y.; Basu, S.; Wu, M.-C.; Mayr, C.","institution":"Sloan Kettering Institute","category":"molecular biology","date":"2026-01-01","abstract":"Nearly 3,000 human mRNA 3'UTRs have hundreds of highly conserved nucleotides, but their biological roles are unclear. These mRNAs mostly encode proteins with long intrinsically disordered regions (IDRs), including MYC, UTX, and JMJD3. We show that these proteins are only fully active when translated from mRNA templates that include their 3'UTRs, raising the possibility of functional interactions between 3'UTRs and IDRs. Rather than affecting protein abundance or localization, we find that the KDM6B 3'UTR in the mRNA template changes the folding of the encoded IDR-containing JMJD3 protein. It promotes IDR-IDR interactions and suppresses folding between domains, suggesting that RNA acts as IDR chaperone that prevents interference of hydrophobic clusters in the IDR with folding of the structured domain. mRNA-based IDR chaperones are enriched in meshlike cytoplasmic condensates, suggesting localized chaperone activity. As hydrophobic clusters in IDRs are widespread, our data suggest that 3'UTR-dependent protein folding could be a widely used mechanism for activity regulation of transcriptional regulators."}},{"id":"10.64898/2025.12.05.692625","title":"Clean Air Travel: Evaluation of Mask-Free Alternatives to N95 During the Delhi \"Air Emergency\"","subtitle":"Devabhaktuni Srikrishna · Patient Knowhow, Inc. · 2026-01-01","value":"bioengineering","href":"https://doi.org/10.64898/2025.12.05.692625","props":{"doi":"10.64898/2025.12.05.692625","authors":"Srikrishna, D.","institution":"Patient Knowhow, Inc.","category":"bioengineering","date":"2026-01-01","abstract":"BackgroundAir travelers, healthcare workers aiming to prevent infection and pollution-sufferers (e.g. Delhi \"Air Emergency\") may experience difficulty during prolonged use of respirators (e.g. N95) incompatible with eating/drinking/sleeping. Protection factor of 5x-1000x (80%-99.9%) is targeted for infection prevention. Daily PM 2.5 time-series data suggest at least 4x-5x (75%-80%) protection factor 24x7 during the worst stagnant pollution days may reduce daily inhaled exposure to annual averages in Delhi.\n\nMethodsHandheld Do-It-Yourself test methods were developed using a 7-channel optical particle counter. Three baseball cap visor-mounted air purifiers were prototyped enabling eating/drinking, \"Air\" (1 lb), \"Pro\" (2 lb), \"Max\" (2 lb 10 oz), and one bed-mounted prototype, \"Sleep\". Clean air delivery rate per watt was measured for vertically stackable portable air purifiers to optimize power/floorspace/cost-efficiency.\n\nResultsAt 0.3 {micro}m at nose-level, \"Air\" measured 87%, \"Pro\" measured 94%, \"Max\" measured 98%, a 2x-10x improvement in particle penetration over prior wearable purifiers (unobstructed in horizontal and lower visual fields) reporting approximately 60% (< 70%) of 0.3 {micro}m particles at nose level. At 1.0 {micro}m and 5.0 {micro}m at nose-level, they measured 94-99% and 95-99% respectively. \"Sleep\" measured 91% at 0.3 {micro}m at nose level. Stackable air purifiers measured 6-19 ACH in [~]3000 cubic foot room (300-900 cubic feet per minute) at 20-220 watts, with highest power-efficiency 19 CFM/Watt at 962 CFM.\n\nConclusionsIn principle, maskless alternatives to N95 combine with floorspace- and power-efficient stackable/sleeping air purifiers for protection factor of 99%-99.98% (100x-5000x) in airplanes, submarines, ships, trains, hospitals, shelters with limited floorspace (e.g. berths)."}},{"id":"10.64898/2025.12.31.697202","title":"Multi-omic analysis reveals nitric oxide dependent remodeling in classically activated macrophages and identifies negative regulation mediated by AKR1A1","subtitle":"Jing Fan · Morgridge Institute for Research · 2026-01-01","value":"immunology","href":"https://doi.org/10.64898/2025.12.31.697202","props":{"doi":"10.64898/2025.12.31.697202","authors":"Arp, N. L.; Urquiza, U. S.; Morgenstern, M.; Schrope, J. H.; Votava, J. A.; John, S. V.; Stevens, J. J.; Huttenlocher, A.; Coon, J. J.; Fan, J.","institution":"Morgridge Institute for Research","category":"immunology","date":"2026-01-01","abstract":"Nitric oxide (NO*) is an important signaling molecule in many biological processes, including immune response. During response to classical activation stimuli lipopolysaccharide (LPS) and interferon-{gamma} (IFN{gamma}), macrophages generate NO* via inducible nitric oxide synthase (iNOS). To comprehensively define the effects of NO*, we applied a multi-omic strategy integrating proteomics and transcriptomics to profile murine macrophages across conditions with or without LPS/IFN{gamma}-activation, with or without iNOS expression or exogenous NO* donor treatment. The results revealed NO* has broad, yet selected and controlled, regulatory effects, playing a key role in coordinating the systematic remodeling during macrophage classical activation. Among the proteins that are most suppressed in a NO*-dependent manner, electron transport chain (ETC) is the most enriched. NO* drives complex-specific remodeling of ETC, causing selected downregulation of complex I, II, and IV, through a different combination of transcriptional and post-transcriptional mechanisms for each complex. Functionally, we found NO* is required, but not sufficient, for the strong suppression of cellular respiration upon macrophage activation. Among the most consistently upregulated proteins are many enzymes involved in redox defense. AKR1A1 was identified as a top hit. We found Akr1a1 induction requires both NO* and LPS/IFN{gamma} stimulation. The S-nitroso-CoA reductase activity of AKR1A1 mitigates NO*-driven inhibition of pyruvate dehydrogenase complex by limiting the inhibitory modifications targeting its lipoyl cofactor. Knocking out Akr1a1 causes accelerated remodeling of TCA cycle, dysregulated immunoregulatory metabolite level, and altered functional gene expression and cytokine production at later stage of immune response. Thus, the NO*-dependent upregulation of AKR1A1 forms a negative regulatory loop to fine-tune NO*-mediated metabolic and functional remodeling during immune response. Together, this work provided a systems-level map of NO*-dependent regulation, revealed the crosstalk between NO* and immune signaling, and demonstrated mechanisms providing redox adaptation and precise control of NO*s effects."}},{"id":"10.64898/2025.12.31.697141","title":"Mucosally sourced complement factor B modulates the host response to colitis","subtitle":"Devesha H Kulkarni · Department of Medicine, David Geffen School of Medicine at the University of California-Los Angeles, Los Angeles, CA, USA · 2026-01-01","value":"immunology","href":"https://doi.org/10.64898/2025.12.31.697141","props":{"doi":"10.64898/2025.12.31.697141","authors":"Thapa, A.; Nallapu, A.; Muogboh, N.; Nedunchezian, S.; Talati, K.; Yang, B.; Hyun, J.; Sanchez, J. M. S.; Seet, C. S.; Koon, H. W.; Li, Z.; Ciorba, M. A.; Michelsen, K. S.; Kulkarni, H. S.; Kulkarni, D. H.","institution":"Department of Medicine, David Geffen School of Medicine at the University of California-Los Angeles, Los Angeles, CA, USA","category":"immunology","date":"2026-01-01","abstract":"Distinct host factors maintain intestinal homeostasis but are incompletely understood. The complement system is primarily liver-derived and serum-operative. However, there is growing recognition for complement-mediated host defense at mucosal surfaces. The alternative pathway, which is constitutively active at low levels and amplifies complement activation independent of antibodies, requires Complement Factor B (CFB). Despite its evolutionary conservation, the spatial, cellular, and functional roles of CFB in the intestine are poorly understood. Here, we show that CFB is produced in the human colon and is increased in patients with active inflammatory bowel disease. To isolate the role of local CFB in mucosal responses, we interrogated a mouse strain that has no circulating, liver-derived CFB but retains intact CFB expression in the gut. Global CFB-deficient mice succumb to colitis compared to these liver-specific knockout mice, suggesting that locally synthesized CFB mitigates colitis. Single-cell analyses identify enterocytes and fibroblasts as key CFB producers in the gut. Compartment-specific deletion of CFB from epithelial or stromal cells abrogates mucosal protection independent of circulating levels, which corroborates with pharmacological CFB inhibition. These findings redefine complement in the intestine as a locally regulated mucosal defense system and establish gut-derived CFB as a critical determinant of intestinal homeostasis.\n\nBRIEF SUMMARYThe role of local immune mediators in gut mucosal immune responses is still not entirely understood. In this study, we demonstrate a novel role for complement protein Factor B, a key component of the alternative pathway, which is locally sourced through epithelial and stromal cells. In vivo modeling of impaired local Factor B synthesis results in worse colitis, revealing a key role for mucosal sourced components of the alternative pathway."}},{"id":"10.64898/2025.12.31.697210","title":"State-dependent geometric constraints reveal a regulatory gate in hematopoietic progenitors","subtitle":"Elkin Navarro Quiroz · Universidad Simon Bolivar · 2026-01-01","value":"immunology","href":"https://doi.org/10.64898/2025.12.31.697210","props":{"doi":"10.64898/2025.12.31.697210","authors":"Quiroz, r. c. n.; Quiroz, E. N.","institution":"Universidad Simon Bolivar","category":"immunology","date":"2026-01-01","abstract":"Single-cell multiome technologies have revealed geometric constraints in the joint distribution of chromatin accessibility and gene expression--regions termed \"forbidden zones\" that are systematically underpopulated. These patterns are particularly prominent in progenitor cells, leading to interpretations that developmental plasticity involves reduced informational coupling between epigenetic and transcriptional layers. Here, we characterize these geometric constraints in human bone marrow hematopoiesis (GSE194122; N=13 donors, 69,249 cells) and directly test whether they imply informational independence. We demonstrate that forbidden zones are robust, reproducible, and strongly enriched in progenitor populations (5- to 8-fold enrichment; Fishers exact test, FDR < 10-10). However, mutual information (MI) analysis using donor-level inference, within-donor residualization, and blocked permutation null models reveals a negative but informative result: progenitors exhibit higher, not lower, chromatin-transcription coupling than differentiated cells (median {Delta}MI = +0.0085; all 5 valid donors show positive {Delta}MI; Wilcoxon p = 1.0 for H0: {Delta}MI < 0). This falsifies the hypothesis that geometric constraints reflect informational dissociation. We propose that forbidden zones constitute a \"regulatory gate\"--a topological organization where geometric restriction coexists with efficient informational coupling. Progenitors operate in a high-precision regime where chromatin state tightly constrains transcriptional potential. These findings establish geometric gating as a principle of developmental regulation and caution against inferring information-theoretic properties from visualization alone.\n\neLife DigestCells read their genetic instructions through two coordinated processes: first, DNA becomes accessible by unwrapping from its protein packaging, then the cell copies the relevant genes into RNA messages. New technologies can now measure both processes simultaneously in thousands of individual cells. When scientists plot these measurements together, they observe a curious pattern: certain combinations almost never occur. In particular, cells rarely maintain highly accessible DNA while producing very little RNA--creating geometric \"forbidden zones\" in the data.\n\nA popular interpretation suggested that stem cells and early progenitors operate in a \"disconnected\" regulatory mode, where DNA accessibility provides no information about gene activity. We tested this idea using rigorous mathematical tools from information theory. Contrary to expectation, we found that progenitor cells exhibit tighter, not looser, connections between DNA accessibility and RNA production. The geometric forbidden zones are real, but they do not reflect regulatory disorder. Instead, progenitors operate a precisely tuned \"regulatory gate\" that constrains which accessibility-expression combinations are permitted while maintaining efficient information transfer within those boundaries. This distinction matters for understanding how stem cells balance flexibility with control during blood cell development."}},{"id":"10.64898/2025.12.31.697204","title":"Quenching corrinoid-based interactions in a model bacterial coculture.","subtitle":"Michiko E Taga · University of California, Berkeley · 2026-01-01","value":"microbiology","href":"https://doi.org/10.64898/2025.12.31.697204","props":{"doi":"10.64898/2025.12.31.697204","authors":"Hallberg, Z. F.; Alvarez-Aponte, Z. I.; Gaudinier, A.; Taga, M. E.","institution":"University of California, Berkeley","category":"microbiology","date":"2026-01-01","abstract":"Microbial community structure is driven, in part, by the metabolic interdependencies of resident microbes. Thus, manipulating specific metabolic interactions represents one attractive way to both understand how microbial communities perform complex functions and alter them for therapeutic or environmental effects. However, it is not yet possible to control the availability of those metabolites produced by some members of the community that are required by others. Here, we report the development of a metabolite  quenching strategy that disrupts a specific metabolic interaction involving corrinoids, the vitamin B12 family of cofactors, by applying a high-affinity corrinoid-binding protein, BtuG, to bacteria engaged corrinoid cross-feeding. Using a model coculture composed of Sinorhizobium meliloti, a bacterium that produces a corrinoid (cobalamin), and an Escherichia coli strain engineered to be corrinoid-dependent, we demonstrate corrinoid quenching by sequestration of extracellular corrinoid and show that BtuG specifically blocks corrinoid-dependent growth. We use this tool to calculate the amount of cobalamin released by S. meliloti cells and find that the cobalamin release rate is dependent on the growth phase of the producer, increasing to a maximum of approximately 40 cobalamin molecules per minute per cell in late exponential phase. This work establishes a strategy to selectively block microbial interactions that may be more broadly applied to dissecting community structure and function. We expect that applying high-affinity  molecular sponges to quench nutrient sharing will allow for the identification of key nutrients that structure microbial communities and empower precision microbiome manipulation strategies."}},{"id":"10.64898/2025.12.31.695943","title":"Puf3 contributes to changes in mRNA solubility, translation elongation dynamics at rare arginine codons and loss of protein homeostasis in cells lacking Not4","subtitle":"Martine Collart · University of Geneva, Faculty of Medicine · 2026-01-01","value":"molecular biology","href":"https://doi.org/10.64898/2025.12.31.695943","props":{"doi":"10.64898/2025.12.31.695943","authors":"Collart, M.; Audebert, L.; Allen, G. E.; Chen, S.; Panasenko, O. O.; Huch, S.; Polte, C.; Ignatova, Z. O.; Pelechano, V.","institution":"University of Geneva, Faculty of Medicine","category":"molecular biology","date":"2026-01-01","abstract":"The Not proteins of the Ccr4-Not complex regulate translation elongation dynamics, essential for proper folding and assembly of new proteins. In yeast, ribosomes with non-optimal codons in the A-site are enriched within the pool of ribosomes bound by Not4 and Not5. Such ribosomes accumulate in cells lacking Not4 or Not5 that show defects in co-translational assembly and aggregation of new proteins. Recently we observed that depletion of Not1 and Not4 inversely regulate changes in mRNA solubility, correlating with inverse codon-specific changes in A-site ribosome dwelling occupancies (RDOs). Here we describe that mRNAs less soluble upon Not4 depletion are enriched for targets of the RNA-binding protein Puf3. We determine that Puf3 contributes to inverse changes of A-site RDOs upon Not1 and Not4 depletion, in particular at rare arginine codons, and it contributes to changes in mRNA solubility in not4{Delta}. Moreover, deletion of Puf3 suppresses temperature sensitivity and protein aggregation in the not4{Delta} strain, while overexpression of Puf3 is toxic. Puf3 post-translational modifications and the Puf3 interactome are altered in not4{Delta}. Taken together, our results associate alterations in Puf3 post-translational status and function, including contribution to translation elongation dynamics, with not4{Delta} mutant phenotypes.\n\nGRAPHICAL ABSTRACT\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC=\"FIGDIR/small/695943v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (18K):\norg.highwire.dtl.DTLVardef@855afdorg.highwire.dtl.DTLVardef@118addaorg.highwire.dtl.DTLVardef@13dd015org.highwire.dtl.DTLVardef@12824c6_HPS_FORMAT_FIGEXP  M_FIG C_FIG"}}],"count":30,"generated_at":"2026-07-20T15:52:38.698Z","cached":true}