PLoS Biology最新文献

{"title":"Variant mutation G215C in SARS-CoV-2 nucleocapsid enhances viral infection via altered genomic encapsidation.","authors":"Hannah C Kubinski, Hannah W Despres, Bryan A Johnson, Madaline M Schmidt, Sara A Jaffrani, Allyson H Turner, Conor D Fanuele, Margaret G Mills, Kumari G Lokugamage, Caroline M Dumas, David J Shirley, Leah K Estes, Andrew Pekosz, Jessica W Crothers, Pavitra Roychoudhury, Alexander L Greninger, Keith R Jerome, Bruno Martorelli Di Genova, David H Walker, Bryan A Ballif, Mark S Ladinsky, Pamela J Bjorkman, Vineet D Menachery, Emily A Bruce","doi":"10.1371/journal.pbio.3003115","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003115","url":null,"abstract":"<p><p>The evolution of SARS-CoV-2 variants and their respective phenotypes represents an important set of tools to understand basic coronavirus biology as well as the public health implications of individual mutations in variants of concern. While mutations outside of spike are not well studied, the entire viral genome is undergoing evolutionary selection, with several variants containing mutations in the central disordered linker region of the nucleocapsid (N) protein. Here, we identify a mutation (G215C), characteristic of the Delta variant, that introduces a novel cysteine into this linker domain, which results in the formation of a more stable N-N dimer. Using reverse genetics, we determined that this cysteine residue is necessary and sufficient for stable dimer formation in a WA1 SARS-CoV-2 background, where it results in significantly increased viral growth both in vitro and in vivo. Mechanistically, we show that the N:G215C mutant has more encapsidation as measured by increased RNA binding to N, N incorporation into virions, and electron microscopy showing that individual virions are larger, with elongated morphologies.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003115"},"PeriodicalIF":9.8,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12040272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143994042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The innate immune system: A double-edged sword.","authors":"Ditte S Andersen, Julien Colombani","doi":"10.1371/journal.pbio.3003088","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003088","url":null,"abstract":"<p><p>Innate immunity serves as a crucial surveillance framework, but can be exploited to facilitate tumor progression. Two new PLOS Biology studies independently show how premalignant cells can exploit Toll-NF-κB signaling, in concert with oncogenic Ras, to enable unchecked growth.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003088"},"PeriodicalIF":9.8,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12040342/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative single-cell transcriptomic atlases of drosophilid brains suggest glial evolution during ecological adaptation.","authors":"Daehan Lee, Michael P Shahandeh, Liliane Abuin, Richard Benton","doi":"10.1371/journal.pbio.3003120","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003120","url":null,"abstract":"<p><p>To explore how brains change upon species evolution, we generated single-cell transcriptomic atlases of the central brains of three closely related but ecologically distinct drosophilids: the generalists Drosophila melanogaster and Drosophila simulans, and the noni fruit specialist Drosophila sechellia. The global cellular composition of these species' brains is well-conserved, but we predicted a few cell types with different frequencies, notably perineurial glia of the blood-brain barrier, which we validate in vivo. Gene expression analysis revealed that distinct cell types evolve at different rates and patterns, with glial populations exhibiting the greatest divergence between species. Compared to the D. melanogaster brain, cellular composition and gene expression patterns are more divergent in D. sechellia than in D. simulans-despite their similar phylogenetic distance from D. melanogaster-indicating that the specialization of D. sechellia is reflected in the structure and function of its brain. Expression changes in D. sechellia include several metabolic signaling genes, suggestive of adaptations to its novel source of nutrition. Additional single-cell transcriptomic analysis on D. sechellia revealed genes and cell types responsive to dietary supplement with noni, pointing to glia as sites for both physiological and genetic adaptation to this fruit. Our atlases represent the first comparative datasets for \"whole\" central brains and provide a comprehensive foundation for studying the evolvability of nervous systems in a well-defined phylogenetic and ecological framework.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003120"},"PeriodicalIF":9.8,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12040179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144058109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A multi-strategy antimicrobial discovery approach reveals new ways to treat Chlamydia.","authors":"Magnus Ölander, Daniel Rea Vázquez, Karsten Meier, Aakriti Singh, Amanda Silva de Sousa, Fabiola Puértolas-Balint, Milica Milivojevic, Lieke Mooij, Johanna Fredlund, Eduard Calpe Bosch, María Rayón Díaz, Moa Lundgren, Karin van der Wal, Shaochun Zhu, André Mateus, Bjoern O Schroeder, Jeremy R Lohman, Barbara S Sixt","doi":"10.1371/journal.pbio.3003123","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003123","url":null,"abstract":"<p><p>While the excessive use of broad-spectrum antibiotics is a major driver of the global antibiotic resistance crisis, more selective therapies remain unavailable for the majority of bacterial pathogens. This includes the obligate intracellular bacterial pathogens of the genus Chlamydia, which cause millions of urogenital, ocular, and respiratory infections each year. Conducting a comprehensive search of the chemical space for novel antichlamydial activities, we identified over 60 compounds that are chemically diverse, structurally distinct from known antibiotics, non-toxic to human cells, and highly potent in preventing the growth of Chlamydia trachomatis in cell cultures. Some blocked C. trachomatis development reversibly, while others eradicated both established and persistent infections in a bactericidal manner. The top molecules displayed compelling selectivity, yet broad activity against diverse Chlamydia strains and species, including both urogenital and ocular serovars of C. trachomatis, as well as Chlamydia muridarum and Chlamydia caviae. Some compounds also displayed synergies with clinically used antibiotics. Critically, we found the most potent antichlamydial compound to inhibit fatty acid biosynthesis via covalent binding to the active site of Chlamydia FabH, identifying a new mechanism of FabH inhibition and highlighting a possible way to selectively treat Chlamydia infections.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003123"},"PeriodicalIF":9.8,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12040169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A sensitive soma-localized red fluorescent calcium indicator for in vivo imaging of neuronal populations at single-cell resolution.","authors":"Shihao Zhou, Qiyu Zhu, Minho Eom, Shilin Fang, Oksana M Subach, Chen Ran, Jonnathan Singh Alvarado, Praneel S Sunkavalli, Yuanping Dong, Yangdong Wang, Jiewen Hu, Hanbin Zhang, Zhiyuan Wang, Xiaoting Sun, Tao Yang, Yu Mu, Young-Gyu Yoon, Zengcai V Guo, Fedor V Subach, Kiryl D Piatkevich","doi":"10.1371/journal.pbio.3003048","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003048","url":null,"abstract":"<p><p>Recent advancements in genetically encoded calcium indicators, particularly those based on green fluorescent proteins, have optimized their performance for monitoring neuronal activities in a variety of model organisms. However, progress in developing red-shifted GECIs, despite their advantages over green indicators, has been slower, resulting in fewer options for end users. In this study, we explored topological inversion and soma-targeting strategies, which are complementary to conventional mutagenesis, to re-engineer a red genetically encoded calcium indicator, FRCaMP, for enhanced in vivo performance. The resulting sensors, FRCaMPi and soma-targeted FRCaMPi (SomaFRCaMPi), exhibit up to 2-fold higher dynamic range and peak ΔF/F0 per single AP compared to widely used jRGECO1a in neurons both in culture and in vivo. Compared to jRGECO1a and FRCaMPi, SomaFRCaMPi reduces erroneous correlation of neuronal activity in the brains of mice and zebrafish by two- to 4-fold due to diminished neuropil contamination without compromising the signal-to-noise ratio. Under wide-field imaging in primary somatosensory and visual cortices in mice with high labeling density (80-90%), SomaFRCaMPi exhibits up to 40% higher SNR and decreased artifactual correlation across neurons. Altogether, SomaFRCaMPi improves the accuracy and scale of neuronal activity imaging at single-neuron resolution in densely labeled brain tissues due to a 2-3-fold enhanced automated neuronal segmentation, 50% higher fraction of responsive cells, up to 2-fold higher SNR compared to jRGECO1a. Our findings highlight the potential of SomaFRCaMPi, comparable to the most sensitive soma-targeted GCaMP, for precise spatial recording of neuronal populations using popular imaging modalities in model organisms such as zebrafish and mice.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003048"},"PeriodicalIF":9.8,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12040222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144053018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dorsomedial and ventromedial prefrontal cortex lesions differentially impact social influence and temporal discounting.","authors":"Zhilin Su, Mona M Garvert, Lei Zhang, Todd A Vogel, Jo Cutler, Masud Husain, Sanjay G Manohar, Patricia L Lockwood","doi":"10.1371/journal.pbio.3003079","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003079","url":null,"abstract":"<p><p>The medial prefrontal cortex (mPFC) has long been associated with economic and social decision-making in neuroimaging studies. Several debates question whether different ventral mPFC (vmPFC) and dorsal mPFC (dmPFC) regions have specific functions or whether there is a gradient supporting social and nonsocial cognition. Here, we tested an unusually large sample of rare participants with focal damage to the mPFC (N = 33), individuals with lesions elsewhere (N = 17), and healthy controls (N = 71) (total N = 121). Participants completed a temporal discounting task to estimate their baseline discounting preferences before learning the preferences of two other people, one who was more temporally impulsive and one more patient. We used Bayesian computational models to estimate baseline discounting and susceptibility to social influence after learning others' economic preferences. mPFC damage increased susceptibility to impulsive social influence compared to healthy controls and increased overall susceptibility to social influence compared to those with lesions elsewhere. Importantly, voxel-based lesion-symptom mapping (VLSM) of computational parameters showed that this heightened susceptibility to social influence was attributed specifically to damage to the dmPFC (area 9; permutation-based threshold-free cluster enhancement (TFCE) p < 0.025). In contrast, lesions in the vmPFC (areas 13 and 25) and ventral striatum were associated with a preference for seeking more immediate rewards (permutation-based TFCE p < 0.05). We show that the dmPFC is causally implicated in susceptibility to social influence, with distinct ventral portions of mPFC involved in temporal discounting. These findings provide causal evidence for sub-regions of the mPFC underpinning fundamental social and cognitive processes.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003079"},"PeriodicalIF":9.8,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12036846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of the Drosophila innate immune system accelerates growth in cooperation with oncogenic Ras.","authors":"Fabienne Brutscher, Federico Germani, George Hausmann, Lena Jutz, Konrad Basler","doi":"10.1371/journal.pbio.3003068","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003068","url":null,"abstract":"<p><p>Innate immunity in Drosophila acts as an organismal surveillance system for external stimuli or cellular fitness and triggers context-specific responses to fight infections and maintain tissue homeostasis. However, uncontrolled activation of innate immune pathways can be detrimental. In mammals, innate immune signaling is often overactivated in malignant cells and contributes to tumor progression. Drosophila tumor models have been instrumental in the discovery of interactions between pathways that promote tumorigenesis, but little is known about whether and how the Toll innate immune pathway interacts with oncogenes. Here we use a Drosophila epithelial in vivo model to investigate the interplay between Toll signaling and oncogenic Ras. In the absence of oncogenic Ras (RasV12), Toll signaling suppresses differentiation and induces apoptosis. In contrast, in the context of RasV12, cells are protected from cell death and Dorsal promotes cell survival and proliferation to drive hyperplasia. Taken together, we show that the tissue-protective functions of innate immune activity can be hijacked by pre-malignant cells to induce tumorous overgrowth.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003068"},"PeriodicalIF":9.8,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12036928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NF-κB signaling driven by oncogenic Ras contributes to tumorigenesis in a Drosophila carcinoma model.","authors":"Caroline Dillard, José Teles-Reis, Ashish Jain, Marina Gonçalves Antunes, Paula Ruiz-Duran, Yanyan Qi, Roland Le Borgne, Heinrich Jasper, Tor Erik Rusten","doi":"10.1371/journal.pbio.3002663","DOIUrl":"https://doi.org/10.1371/journal.pbio.3002663","url":null,"abstract":"<p><p>Cancer-driving mutations synergize with inflammatory stress signaling pathways during carcinogenesis. Drosophila melanogaster tumor models are increasingly recognized as models to inform conserved molecular mechanisms of tumorigenesis with both local and systemic effects of cancer. Although initial discoveries of the Toll-NFκB signaling pathway in development and immunity were pioneered in Drosophila, limited information is available for its role in cancer progression. Using a well-studied cooperative RasV12-driven epithelial-derived tumor model, we here describe functions of Toll-NF-κB signaling in malignant RasV12, scrib- tumors. The extracellular Toll pathway components ModSP and PGRP-SA and intracellular signaling Kinase, Pelle/IRAK, are rate-limiting for tumor growth. The Toll pathway NFκB protein Dorsal as well as cactus/IκΒ show elevated expression in tumors with highest expression in invasive cell populations. Oncogenic RasV12, and not loss of scribble, confers increased expression and heterogenous distribution of two Dorsal isoforms, DorsalA and DorsalB, in different tumor cell populations. Mechanistic analyses demonstrates that Dorsal, in concert with the BTB-transcription factor Chinmo, drives growth and malignancy by suppressing differentiation, counteracting apoptosis, and promoting invasion of RasV12, scrib- tumors.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3002663"},"PeriodicalIF":9.8,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144020684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Scalable eQTL mapping using single-nucleus RNA-sequencing of recombined gametes from a small number of individuals.","authors":"Matthew T Parker, Samija Amar, José A Campoy, Kristin Krause, Sergio Tusso, Magdalena Marek, Bruno Huettel, Korbinian Schneeberger","doi":"10.1371/journal.pbio.3003085","DOIUrl":"10.1371/journal.pbio.3003085","url":null,"abstract":"<p><p>Phenotypic differences between individuals of a species are often caused by differences in gene expression, which are in turn caused by genetic variation. Expression quantitative trait locus (eQTL) analysis is a methodology by which we can identify such causal variants. Scaling eQTL analysis is costly due to the expense of generating mapping populations, and the collection of matched transcriptomic and genomic information. We developed a rapid eQTL analysis approach using single-cell/nucleus RNA sequencing of gametes from a small number of heterozygous individuals. Patterns of inherited polymorphisms are used to infer the recombinant genomes of thousands of individual gametes and identify how different haplotypes correlate with variation in gene expression. Applied to Arabidopsis pollen nuclei, our approach uncovers both cis- and trans-eQTLs, ultimately mapping variation in a master regulator of sperm cell development that affects the expression of hundreds of genes. This establishes snRNA-sequencing as a powerful, cost-effective method for the mapping of meiotic recombination, addressing the scalability challenges of eQTL analysis and enabling eQTL mapping in specific cell-types.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003085"},"PeriodicalIF":9.8,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144041415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Total cerebral blood volume changes drive macroscopic cerebrospinal fluid flux in humans.","authors":"Juliana Zimmermann, Clara Boudriot, Christiane Eipert, Gabriel Hoffmann, Rachel Nuttall, Viktor Neumaier, Moritz Bonhoeffer, Sebastian Schneider, Lena Schmitzer, Jan Kufer, Stephan Kaczmarz, Dennis M Hedderich, Andreas Ranft, Daniel Golkowski, Josef Priller, Claus Zimmer, Rüdiger Ilg, Gerhard Schneider, Christine Preibisch, Christian Sorg, Benedikt Zott","doi":"10.1371/journal.pbio.3003138","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003138","url":null,"abstract":"<p><p>In the mammalian brain, the directed motion of cerebrospinal fluid (CSF-flux) is instrumental in the distribution and removal of solutes. Changes in total cerebral blood volume (CBV) have been hypothesized to drive CSF-flux. We tested this hypothesis in two multimodal brain imaging experiments in healthy humans, in which we drove large changes in total CBV by neuronal burst-suppression under anesthesia or by transient global vasodilation in a hypercapnic challenge. We indirectly monitored CBV changes with a high temporal resolution based on associated changes in total brain volume by functional MRI (fMRI) and measured cerebral blood flow by arterial spin-labeling. Relating CBV-sensitive signals to fMRI-derived measures of macroscopic CSF flow across the basal cisternae, we demonstrate that increasing total CBV extrudes CSF from the skull and decreasing CBV allows its influx. Moreover, CSF largely stagnates when CBV is stable. Together, our results establish the direct coupling between total CBV changes and CSF-flux.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 4","pages":"e3003138"},"PeriodicalIF":9.8,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12061420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144023601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}