bioRxiv : the preprint server for biology最新文献

{"title":"Interpreting SNP heritability in admixed populations.","authors":"Jinguo Huang, Nicole Kleman, Saonli Basu, Mark D Shriver, Arslan A Zaidi","doi":"10.1101/2023.08.04.551959","DOIUrl":"10.1101/2023.08.04.551959","url":null,"abstract":"<p><p>SNP heritability is defined as the proportion of phenotypic variance explained by genotyped SNPs and is believed to be a lower bound of heritability ( <i>h</i> ² ), being equal to it if all causal variants are genotyped. Despite the simple intuition behind , its interpretation and equivalence to <i>h</i> ² is unclear, particularly in the presence of admixture and assortative mating. Here we use analytical theory and simulations to describe the behavior of <i>h</i> ² and three widely used random-effect estimators of Genome-wide restricted maximum likelihood (GREML), Haseman-Elston (HE) regression, and LD score regression (LDSC) - in admixed populations. We show that estimates can be biased in admixed populations, even if all causal variants are genotyped and in the absence of confounding due to shared environment. This is largely because admixture generates directional LD, which contributes to the genetic variance, and therefore to heritability. Random-effect estimators of , because they assume that SNP effects are independent, do not capture the contribution, which can be positive or negative depending on the genetic architecture, leading to under- or over-estimates of relative to <i>h</i> ² . For the same reason, estimates of local ancestry heritability are also biased in the presence of directional LD. We describe this bias in and as a function of admixture history and the genetic architecture of the trait, clarifying their interpretation and implication for genome-wide association studies and polygenic prediction in admixed populations.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10418213/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10413392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transitions in dynamical regime and neural mode underlie perceptual decision-making.","authors":"Thomas Zhihao Luo, Timothy Doyeon Kim, Diksha Gupta, Adrian G Bondy, Charles D Kopec, Verity A Elliot, Brian DePasquale, Carlos D Brody","doi":"10.1101/2023.10.15.562427","DOIUrl":"10.1101/2023.10.15.562427","url":null,"abstract":"<p><p>Perceptual decision-making is the process by which an animal uses sensory stimuli to choose an action or mental proposition. This process is thought to be mediated by neurons organized as attractor networks ^1,2 . However, whether attractor dynamics underlie decision behavior and the complex neuronal responses remains unclear. Here we use simultaneous recordings from hundreds of neurons, together with an unsupervised, deep learning-based method, to discover decision-related neural dynamics in frontal cortex and striatum of rats while the subjects accumulate pulsatile auditory evidence. We found that trajectories evolved along two sequential regimes, the first dominated by sensory inputs, and the second dominated by the autonomous dynamics, with flow in a direction (i.e., \"neural mode\") largely orthogonal to that in the first regime. We propose that the transition to the second regime corresponds to the moment of decision commitment. We developed a simplified model that approximates the coupled transition in dynamics and neural mode and allows precise inference, from each trial's large-scale neural population activity, of a putative neurally-inferred time of commitment (\"nTc\") on that trial. The simplified model captures diverse and complex single-neuron temporal profiles, such as ramping and stepping ^3-5 , as well as trial-averaged curved trajectories ^6-8 , and reveals distinctions between brain regions. The estimated nTc times were not time-locked to stimulus onset or offset, or to response onset, but were instead broadly distributed across trials. If nTc marks the moment of decision commitment, sensory evidence before nTc should affect the decision, while evidence afterward should not. Behavioral analysis of trials aligned to their estimated nTc times confirmed this prediction. Our results show that the formation of a perceptual choice involves a rapid, coordinated transition in both the dynamical regime and the neural mode of the decision process that corresponds to commitment to a decision, and suggest this moment as a useful entry point for dissecting mechanisms underlying rapid changes in internal state.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71415675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tyrosinase-induced neuromelanin accumulation triggers rapid dysregulation and degeneration of the mouse locus coeruleus.","authors":"Alexa F Iannitelli, Leslie Hassanein, Margaret M Tish, Bernard Mulvey, Harris E Blankenship, Anu Korukonda, L Cameron Liles, Amanda L Sharpe, Jean-Francoise Pare, Rosa Villalba, Arielle Segal, Steven A Sloan, Keri Martinowich, Joseph D Dougherty, Katharine E McCann, Yoland Smith, Michael J Beckstead, David Weinshenker","doi":"10.1101/2023.03.07.530845","DOIUrl":"10.1101/2023.03.07.530845","url":null,"abstract":"<p><p>The locus coeruleus (LC), the major source of norepinephrine (NE) in the brain, is among the earliest site of pathology in both Alzheimer's disease (AD) and Parkinson's disease (PD), and it undergoes catastrophic degeneration later in both disorders. Dysregulation of the LC is thought to contribute to prodromal symptoms of AD and PD such as anxiety and sleep disturbances, while frank LC loss promotes cognitive decline. However, the mechanisms responsible for its selective vulnerability are unknown. It has been suggested that neuromelanin (NM) pigment contributes to LC susceptibility, but causal relationships have been difficult to test because rodents do not naturally produce NM. Here, we report that viral-mediated expression of human tyrosinase induced pigmentation in mouse LC neurons that recapitulated key features of natural primate NM. One week of NM accumulation resulted in LC neuron hyperactivity, reduced tissue NE levels, transcriptional changes, and anxiety-like behavior. By 6-10 weeks, NM accumulation was associated with severe LC neuron neurodegeneration and microglial engulfment of the pigment granules, while the anxiety-like behavior abated. These phenotypes are reminiscent of LC dysfunction and cell death in AD and PD, validating this model for studying the consequences of NM accumulation in the LC as it relates to neurodegenerative disease.</p><p><strong>Significance statement: </strong>Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most common neurodegenerative diseases worldwide. Because therapies that cure or even prevent their progression are lacking, research is focused on the identifying earliest signs of disease as targets for diagnosis and treatment. The locus coeruleus (LC), the main source of the neurotransmitter n norepinephrine (NE) in the brain, is one of the first brain regions affected in both AD and PD. LC dysregulation promotes prodromal AD and PD symptoms, while its degeneration accelerates disease progression. Here we identify neuromelanin (NM) pigment as a LC vulnerability factor that induces neuronal hyperactivity followed by cell death. Approaches that mitigate NM accumulation and toxicity may target the earliest phases of neurodegenerative disease.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/36/c8/nihpp-2023.03.07.530845v1.PMC10028911.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9752933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zinc stimulation of phytoplankton in a low carbon dioxide, coastal Antarctic environment: evidence for the Zn hypothesis.","authors":"Riss M Kell, Adam V Subhas, Nicole L Schanke, Lauren E Lees, Rebecca J Chmiel, Deepa Rao, Margaret M Brisbin, Dawn M Moran, Matthew R McIlvin, Francesco Bolinesi, Olga Mangoni, Raffaella Casotti, Cecilia Balestra, Tristan J Horner, Robert B Dunbar, Andrew E Allen, Giacomo R DiTullio, Mak A Saito","doi":"10.1101/2023.11.05.565706","DOIUrl":"10.1101/2023.11.05.565706","url":null,"abstract":"<p><p>The ocean acts as a carbon sink, absorbing carbon from the atmosphere and resulting in substantial uptake of anthropogenic CO ₂ emissions. As biological processes in the oceans such as net primary production (NPP) contribute significantly to this sink, understanding how they will shift in response to increasing atmospheric CO ₂ is necessary to project future ocean carbon storage capacity. Macronutrient and micronutrient resource limitation within the oceans regulates NPP, and while some micronutrients such as zinc (Zn) are present at very low concentrations, their ability to limit NPP has remained unclear. Zn is a key micronutrient used by phytoplankton for a multitude of metabolic functions, yet there have been few observations of its influence on natural oceanic phytoplankton populations. In this study, we observed Zn limitation of growth in the natural phytoplankton community of Terra Nova Bay, Antarctica, in addition to primary iron (Fe) limitation. Shipboard incubation experiments amended with Zn and Fe resulted in significantly higher chlorophyll <i>a</i> content and dissolved inorganic carbon drawdown compared to Fe addition alone. Zn and Fe stress response proteins detected in incubation and environmental biomass provided independent verification of algal co-stress for these micronutrients. We consider total biomass and low surface ocean pCO ₂ as potential drivers of environmental Zn stress. This study definitively establishes that Zn limitation can occur in the modern oceans, opening up new possibility space in our understanding of nutrient regulation of NPP through geologic time, and we consider the future of oceanic Zn limitation in the face of climate change.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10635156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92158379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNAi-based screen for pigmentation in <i>Drosophila melanogaster</i> reveals regulators of brain dopamine and sleep.","authors":"Samantha L Deal, Danqing Bei, Shelley B Gibson, Harim Delgado-Seo, Yoko Fujita, Kyla Wilwayco, Elaine S Seto, Shinya Yamamoto","doi":"10.1101/2023.07.20.549932","DOIUrl":"10.1101/2023.07.20.549932","url":null,"abstract":"<p><p>The dopaminergic system has been extensively studied for its role in behavior in animals as well as human neuropsychiatric and neurological diseases. However, we still know little about how dopamine levels are tightly regulated <i>in vivo</i> . To identify novel regulators of dopamine, we utilized <i>Drosophila melanogaster</i> cuticle pigmentation as a readout, where dopamine is a precursor to melanin. We measured dopamine from genes known to be critical for cuticle pigmentation and performed an RNAi-based screen to identify new regulators of pigmentation. We found 153 potential pigmentation genes, which were enriched for conserved homologs and disease- associated genes as well as developmental signaling pathways and mitochondria-associated proteins. From 35 prioritized candidates, we found 10 caused significant reduction in head dopamine levels and one caused an increase. Two genes, <i>clueless</i> and <i>mask (multiple ankyrin repeats single KH domain),</i> upon knockdown, reduced dopamine levels in the brain. Further examination suggests that Mask regulates the transcription of the rate-limiting dopamine synthesis enzyme, <i>tyrosine hydroxylase</i> , and its knockdown causes dopamine-dependent sleep phenotypes. In summary, by studying genes that affect cuticle pigmentation, a phenotype seemingly unrelated to the nervous system, we were able to identify several genes that affect dopamine metabolism as well as a novel regulator of behavior.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":"51 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11996387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89188842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Growth directions and stiffness across cell layers determine whether tissues stay smooth or buckle.","authors":"Avilash Singh Yadav, Lilan Hong, Patrick M Klees, Annamaria Kiss, Manuel Petit, Xi He, Iselle M Barrios, Michelle Heeney, Anabella Maria D Galang, Richard S Smith, Arezki Boudaoud, Adrienne H K Roeder","doi":"10.1101/2023.07.22.549953","DOIUrl":"10.1101/2023.07.22.549953","url":null,"abstract":"<p><p>From smooth shapes to buckles, nature exhibits organs of various shapes and forms. How cells grow to produce smooth shaped leaves and sepals remain unclear. Here, we show that growth along the longitudinal axis during early developmental stages and comparable stiffness across both epidermal layers of Arabidopsis sepals are essential for smoothness, as seen in the wild type. We identified a mutant (<i>as2-7D</i>) with ectopic expression of <i>ASYMMETRIC LEAVES 2</i> (<i>AS2</i>) on the outer epidermis. Our analysis reveals that ectopic <i>AS2</i> expression causes the outer epidermis of <i>as2-7D</i> sepals to buckle during early stages of sepal development. We show that buckling of the outer epidermis occurs due to conflicting cell growth directions and unequal tissue stiffness across the epidermal layers. Overexpression of cyclin-dependent kinase (CDK) inhibitor Kip-related protein 1 (KRP1) in <i>as2-7D</i> restores sepal smoothness by aligning the growth directions of the outer epidermal cells along the longitudinal axis, while also increasing the overall stiffness of the outer epidermis. Furthermore, buckling is associated with the convergence of auxin efflux transporter protein PIN-FORMED 1 (PIN1) to generate outgrowth in the sepals at later stages, suggesting that buckling can initiate outgrowths. Our findings suggest that in addition to molecular cues influencing tissue mechanics, tissue mechanics can also modulate molecular signals, giving rise to well-defined shapes.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e7/dd/nihpp-2023.07.22.549953v2.PMC10401922.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9998901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recurrent Composite Markers of Cell Types and States.","authors":"Xubin Li, Justin Nguyen, Anil Korkut","doi":"10.1101/2023.07.17.549344","DOIUrl":"10.1101/2023.07.17.549344","url":null,"abstract":"<p><p>Biological function is mediated by the hierarchical organization of cell types and states within tissue ecosystems. Identifying interpretable composite marker sets that both define and distinguish hierarchical cell identities is essential for decoding biological complexity, yet remains a major challenge. Here, we present RECOMBINE, an algorithm that identifies recurrent composite marker sets to define hierarchical cell identities. Validation using both simulated and biological datasets demonstrates that RECOMBINE achieves higher accuracy in identifying discriminative markers compared to existing approaches, including differential gene expression analysis. When applied to single-cell data and validated with spatial transcriptomics data from the mouse visual cortex, RECOMBINE identified key cell type markers and generated a robust gene panel for targeted spatial profiling. It also uncovered markers of CD8+; T cell states, including GZMK+;HAVCR2-; effector memory cells associated with anti-PD-1 therapy response, and revealed a rare intestinal subpopulation with composite markers in mice. Finally, using data from the Tabula Sapiens project, RECOMBINE identified composite marker sets across a broad range of human tissues. Together, these results highlight RECOMBINE as a robust, data-driven framework for optimized marker selection, enabling the discovery and validation of hierarchical cell identities across diverse tissue contexts.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10370072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9886161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An adult clock regulator links circadian rhythms to pancreatic β-cell maturation.","authors":"Ana P Montalvo Landivar, Zihan Gao, Mai Liu, Zoe L Gruskin, Andrew Leduc, Sam Preza, Yu Xie, Andrea V Rozo, June H Ahn, Juerg R Straubhaar, Nicolai Doliba, Doris A Stoffers, Nikolai Slavov, Juan R Alvarez-Dominguez","doi":"10.1101/2023.08.11.552890","DOIUrl":"10.1101/2023.08.11.552890","url":null,"abstract":"<p><p>The circadian clock attunes metabolism to daily energy cycles, but how it regulates maturation of metabolic tissues is poorly understood. Here we show that DEC1, a clock transcription factor induced in adult islet β cells, coordinates their glucose responsiveness by synchronizing energetic and secretory rhythms. DEC1 binds and regulates maturity-linked genes to integrate insulin exocytosis with energy metabolism, and β-cell <i>Dec1</i> ablation disrupts their transcription synchrony. <i>Dec1</i>-disrupted mice develop lifelong glucose intolerance and insulin deficiency, despite normal islet formation and intact <i>Clock/Bmal1</i> genes. Metabolic dysfunction upon β-cell <i>Dec1</i> loss stems from poor coupling of insulin secretion to glucose metabolism, reminiscent of fetal/neonatal immaturity. We link stunted maturation to a deficit in circadian bioenergetics, prompted by compromised glucose utilization, mitochondrial dynamics, and respiratory metabolism, which is rescued by increased metabolic flux. Thus, DEC1 links circadian clockwork to β-cell metabolic maturation, revealing a hierarchy for how the clock programs metabolic tissue specialization.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/26/be/nihpp-2023.08.11.552890v1.PMC10441398.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10103162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cortical structure in relation to empathy and psychopathy in 800 incarcerated men.","authors":"Marcin A Radecki, J Michael Maurer, Keith A Harenski, David D Stephenson, Erika Sampaolo, Giada Lettieri, Giacomo Handjaras, Emiliano Ricciardi, Samantha N Rodriguez, Craig S Neumann, Carla L Harenski, Sara Palumbo, Silvia Pellegrini, Jean Decety, Pietro Pietrini, Kent A Kiehl, Luca Cecchetti","doi":"10.1101/2023.06.14.543399","DOIUrl":"10.1101/2023.06.14.543399","url":null,"abstract":"<p><strong>Background: </strong>Reduced affective empathy is a hallmark of psychopathy, which incurs major interpersonal and societal costs. Advancing our neuroscientific understanding of this reduction and other psychopathic traits is crucial for improving their treatment.</p><p><strong>Methods: </strong>In 804 incarcerated adult men, we administered the Perspective Taking (IRI-PT) and Empathic Concern (IRI-EC) subscales of the Interpersonal Reactivity Index, Hare Psychopathy Checklist-Revised (PCL-R; two factors), and T1-weighted MRI to quantify cortical thickness (CT) and surface area (SA). We also included the male sample of the Human Connectome Project (HCP; N = 501) to replicate patterns of macroscale structural organization.</p><p><strong>Results: </strong>Factor 1 (Interpersonal/Affective) uniquely negatively related to IRI-EC, while Factor 2 (Lifestyle/Antisocial) uniquely negatively related to IRI-PT. Cortical structure did not relate to either IRI subscale, although there was effect-size differentiation by microstructural class and/or functional network. CT related to Factor 1 (mostly positively), SA related to both factors (only positively), and both cortical indices demonstrated out-of-sample predictive utility for Factor 1. The high-psychopathy group (N = 178) scored uniquely lower on IRI-EC while having increased SA (but not CT). Regionally, these SA increases localized primarily in the paralimbic class and somatomotor network, with meta-analytic task-based activations corroborating affective-sensory importance. High psychopathy also showed \"compressed\" global and/or network-level organization of both cortical indices, and this organization in the total sample replicated in HCP. All findings accounted for age, IQ, and/or total intracranial volume.</p><p><strong>Conclusions: </strong>Psychopathy had negative relationships with affective empathy and positive relationships with paralimbic/somatomotor SA, highlighting the role of affect and sensation.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":"11 suppl_1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11996374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88667717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interleukin-1 receptor antagonist is a conserved early factor for exacerbating tuberculosis susceptibility.","authors":"Ophelia V Lee, Daisy X Ji, Bruce A Rosa, David L Jaye, Sara Suliman, Makedonka Mitreva, Cem Gabay, Russell E Vance, Dmitri I Kotov","doi":"10.1101/2023.10.27.564420","DOIUrl":"10.1101/2023.10.27.564420","url":null,"abstract":"<p><p><i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) causes 1.25 million deaths a year. However, tuberculosis (TB) pathogenesis remains poorly understood and is not fully recapitulated in standard mouse models. Here we find that gene signatures from three different <i>Mtb</i>-susceptible mouse models predict active TB disease in humans significantly better than a signature from resistant C57BL/6 (B6) mice. Conserved among susceptible mice, non-human primates, and humans, but largely absent from B6 mice, was <i>Mtb</i>-induced differentiation of macrophages into an <i>Spp1</i> ⁺ differentiation state. <i>Spp1</i> ⁺ macrophages expressed high levels of immunosuppressive molecules including IL-1 receptor antagonist (IL-1Ra). IL-1Ra was previously reported to cause <i>Mtb</i> susceptibility in one mouse model, but whether IL-1Ra is broadly important remains uncertain. Here we report that enhancement of IL-1 signaling via deletion of IL-Ra promoted bacterial control across three susceptible mouse models. We found IL-1 signaling amplified production of multiple cytokines by lymphoid and stromal cells, providing a multifactorial mechanism for how IL-1 promotes <i>Mtb</i> control. Our results indicate that myeloid cell expression of immunosuppressive molecules, in particular IL-1 receptor antagonist, is a conserved early mechanism limiting <i>Mtb</i> control in mice, non-human primates, and humans.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10634924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92157699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}