PLoS Biology最新文献

{"title":"Mapping mutational fitness effects across the coxsackievirus B3 proteome reveals distinct profiles of mutation tolerability.","authors":"Beatriz Álvarez-Rodríguez, Sebastian Velandia-Álvarez, Christina Toft, Ron Geller","doi":"10.1371/journal.pbio.3002709","DOIUrl":"10.1371/journal.pbio.3002709","url":null,"abstract":"<p><p>RNA viruses have notoriously high mutation rates due to error-prone replication by their RNA polymerase. However, natural selection concentrates variability in a few key viral proteins. To test whether this stems from different mutation tolerance profiles among viral proteins, we measured the effect of >40,000 non-synonymous mutations across the full proteome of coxsackievirus B3 as well as >97% of all possible codon deletions in the nonstructural proteins. We find significant variation in mutational tolerance within and between individual viral proteins, which correlated with both general and protein-specific structural and functional attributes. Furthermore, mutational fitness effects remained stable across cell lines, suggesting selection pressures are mostly conserved across environments. In addition to providing a rich dataset for understanding virus biology and evolution, our results illustrate that incorporation of mutational tolerance data into druggable pocket discovery can aid in selecting targets with high barriers to drug resistance.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11251597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141628130","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":"Collective peroxide detoxification determines microbial mutation rate plasticity in E. coli.","authors":"Rowan Green, Hejie Wang, Carol Botchey, Siu Nam Nancy Zhang, Charles Wadsworth, Francesca Tyrrell, James Letton, Andrew J McBain, Pawel Paszek, Rok Krašovec, Christopher G Knight","doi":"10.1371/journal.pbio.3002711","DOIUrl":"10.1371/journal.pbio.3002711","url":null,"abstract":"<p><p>Mutagenesis is responsive to many environmental factors. Evolution therefore depends on the environment not only for selection but also in determining the variation available in a population. One such environmental dependency is the inverse relationship between mutation rates and population density in many microbial species. Here, we determine the mechanism responsible for this mutation rate plasticity. Using dynamical computational modelling and in culture mutation rate estimation, we show that the negative relationship between mutation rate and population density arises from the collective ability of microbial populations to control concentrations of hydrogen peroxide. We demonstrate a loss of this density-associated mutation rate plasticity (DAMP) when Escherichia coli populations are deficient in the degradation of hydrogen peroxide. We further show that the reduction in mutation rate in denser populations is restored in peroxide degradation-deficient cells by the presence of wild-type cells in a mixed population. Together, these model-guided experiments provide a mechanistic explanation for DAMP, applicable across all domains of life, and frames mutation rate as a dynamic trait shaped by microbial community composition.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11272383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141621282","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 immune modules conserved across the tree of life: Towards a definition of ancestral immunity.","authors":"Aude Bernheim, Jean Cury, Enzo Z Poirier","doi":"10.1371/journal.pbio.3002717","DOIUrl":"10.1371/journal.pbio.3002717","url":null,"abstract":"<p><p>Immune defence mechanisms exist across the tree of life in such diversity that prokaryotic antiviral responses have historically been considered unrelated to eukaryotic immunity. Mechanisms of defence in divergent eukaryotes were similarly believed to be largely clade specific. However, recent data indicate that a subset of modules (domains and proteins) from prokaryote defence systems are conserved in eukaryotes and populate many stages of innate immune pathways. In this Essay, we propose the notion of ancestral immunity, which corresponds to the set of immune modules conserved between prokaryotes and eukaryotes. After offering a typology of ancestral immunity, we speculate on the selective pressures that could have led to the differential conservation of specific immune modules across domains of life. The exploration of ancestral immunity is in its infancy and appears full of promises to illuminate immune evolution, and also to identify and decipher immune mechanisms of economic, ecological, and therapeutic importance.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11249213/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141621285","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":"KCTD proteins regulate morphine dependence via heterologous sensitization of adenylyl cyclase 1 in mice.","authors":"Zhong Ding, Chunsheng Zhang, Huicui Yang, Jiaojiao Chen, Zhiruo Sun, Xuechu Zhen","doi":"10.1371/journal.pbio.3002716","DOIUrl":"10.1371/journal.pbio.3002716","url":null,"abstract":"<p><p>Heterologous sensitization of adenylyl cyclase (AC) results in elevated cAMP signaling transduction that contributes to drug dependence. Inhibiting cullin3-RING ligases by blocking the neddylation of cullin3 abolishes heterologous sensitization, however, the modulating mechanism remains uncharted. Here, we report an essential role of the potassium channel tetramerization domain (KCTD) protein 2, 5, and 17, especially the dominant isoform KCTD5 in regulating heterologous sensitization of AC1 and morphine dependence via working with cullin3 and the cullin-associated and neddylation-dissociated 1 (CAND1) protein. In cellular models, we observed enhanced association of KCTD5 with Gβ and cullin3, along with elevated dissociation of Gβ from AC1 as well as of CAND1 from cullin3 in heterologous sensitization of AC1. Given binding of CAND1 inhibits the neddylation of cullin3, we further elucidated that the enhanced interaction of KCTD5 with both Gβ and cullin3 promoted the dissociation of CAND1 from cullin3, attenuated the inhibitory effect of CAND1 on cullin3 neddylation, ultimately resulted in heterologous sensitization of AC1. The paraventricular thalamic nucleus (PVT) plays an important role in mediating morphine dependence. Through pharmacological and biochemical approaches, we then demonstrated that KCTD5/cullin3 regulates morphine dependence via modulating heterologous sensitization of AC, likely AC1 in PVT in mice. In summary, the present study revealed the underlying mechanism of heterologous sensitization of AC1 mediated by cullin3 and discovered the role of KCTD proteins in regulating morphine dependence in mice.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11271871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141621284","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":"Goal-directed attention transforms both working and long-term memory representations in the human parietal cortex.","authors":"Huinan Hu, Anqi Li, Liang Zhang, Chuqi Liu, Liang Shi, Xiaojing Peng, Tong Li, Yu Zhou, Gui Xue","doi":"10.1371/journal.pbio.3002721","DOIUrl":"10.1371/journal.pbio.3002721","url":null,"abstract":"<p><p>The abundance of distractors in the world poses a major challenge to our brain's limited processing capacity, but little is known about how selective attention modulates stimulus representations in the brain to reduce interference and support durable target memory. Here, we collected functional magnetic resonance imaging (fMRI) data in a selective attention task in which target and distractor pictures of different visual categories were simultaneously presented. Participants were asked to selectively process the target according to the effective cue, either before the encoding period (i.e., perceptual attention) or the maintenance period (i.e., reflective attention). On the next day, participants were asked to perform a memory recognition task in the scanner in which the targets, distractors, and novel items were presented in a pseudorandom order. Behavioral results showed that perceptual attention was better at enhancing target memory and reducing distractor memory than reflective attention, although the overall memory capacity (memory for both target and distractor) was comparable. Using multiple-voxel pattern analysis of the neural data, we found more robust target representation and weaker distractor representation in working memory for perceptual attention than for reflective attention. Interestingly, perceptual attention partially shifted the regions involved in maintaining the target representation from the visual cortex to the parietal cortex. Furthermore, the targets and distractors simultaneously presented in the perceptual attention condition showed reduced pattern similarity in the parietal cortex during retrieval compared to items not presented together. This neural pattern repulsion positively correlated with individuals' recognition of both targets and distractors. These results emphasize the critical role of selective attention in transforming memory representations to reduce interference and improve long-term memory performance.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11271952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141621283","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":"Dominant activities of fear engram cells in the dorsal dentate gyrus underlie fear generalization in mice.","authors":"Kun Cui, Xuetao Qi, Zilong Liu, Weiqi Sun, Peijie Jiao, Chang Liu, Jifu Tong, Xiaoyan Sun, Haojie Sun, Su Fu, Jiaxin Wang, Yawen Zheng, Tianyu Liu, Shuang Cui, Fengyu Liu, Jian Mao, Jie Zheng, You Wan, Ming Yi","doi":"10.1371/journal.pbio.3002679","DOIUrl":"10.1371/journal.pbio.3002679","url":null,"abstract":"<p><p>Over-generalized fear is a maladaptive response to harmless stimuli or situations characteristic of posttraumatic stress disorder (PTSD) and other anxiety disorders. The dorsal dentate gyrus (dDG) contains engram cells that play a crucial role in accurate memory retrieval. However, the coordination mechanism of neuronal subpopulations within the dDG network during fear generalization is not well understood. Here, with the Tet-off system combined with immunostaining and two-photon calcium imaging, we report that dDG fear engram cells labeled in the conditioned context constitutes a significantly higher proportion of dDG neurons activated in a similar context where mice show generalized fear. The activation of these dDG fear engram cells encoding the conditioned context is both sufficient and necessary for inducing fear generalization in the similar context. Activities of mossy cells in the ventral dentate gyrus (vMCs) are significantly suppressed in mice showing fear generalization in a similar context, and activating the vMCs-dDG pathway suppresses generalized but not conditioned fear. Finally, modifying fear memory engrams in the dDG with \"safety\" signals effectively rescues fear generalization. These findings reveal that the competitive advantage of dDG engram cells underlies fear generalization, which can be rescued by activating the vMCs-dDG pathway or modifying fear memory engrams, and provide novel insights into the dDG network as the neuronal basis of fear generalization.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11244812/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141602023","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":"Activity-induced reactivity of astrocytes impairs cognition.","authors":"Kirsten Bohmbach, Christian Henneberger","doi":"10.1371/journal.pbio.3002712","DOIUrl":"10.1371/journal.pbio.3002712","url":null,"abstract":"<p><p>Glial cells such as astrocytes can modulate neuronal signaling. Astrocytes can also acquire a reactive phenotype that correlates with cognitive impairments in brain diseases. A study in PLOS Biology shows that prolonged activation of astrocytes can trigger both cognitive impairments and a reactive astrocyte phenotype.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11245315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141602022","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":"Uncovering the hidden complexity of multicellular magnetotactic bacteria.","authors":"Kayla S Stoy, William C Ratcliff","doi":"10.1371/journal.pbio.3002695","DOIUrl":"10.1371/journal.pbio.3002695","url":null,"abstract":"<p><p>Multicellular magnetotactic bacteria (MMB) have a surprisingly complex multicellular lifestyle. A new study in PLOS Biology combines genomics, microscopy, and isotopic labeling to show that MMB form obligately multicellular consortia of genetically diverse cells with rudimentary division of labor.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11244792/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141602025","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":"Dopamine and acetylcholine have distinct roles in delay- and effort-based decision-making in humans.","authors":"Mani Erfanian Abdoust, Monja Isabel Froböse, Alfons Schnitzler, Elisabeth Schreivogel, Gerhard Jocham","doi":"10.1371/journal.pbio.3002714","DOIUrl":"10.1371/journal.pbio.3002714","url":null,"abstract":"<p><p>In everyday life, we encounter situations that require tradeoffs between potential rewards and associated costs, such as time and (physical) effort. The literature indicates a prominent role for dopamine in discounting of both delay and effort, with mixed findings for delay discounting in humans. Moreover, the reciprocal antagonistic interaction between dopaminergic and cholinergic transmission in the striatum suggests a potential opponent role of acetylcholine in these processes. We found opposing effects of dopamine D2 (haloperidol) and acetylcholine M1 receptor (biperiden) antagonism on specific components of effort-based decision-making in healthy humans: haloperidol decreased, whereas biperiden increased the willingness to exert physical effort. In contrast, delay discounting was reduced under haloperidol, but not affected by biperiden. Together, our data suggest that dopamine, acting at D2 receptors, modulates both effort and delay discounting, while acetylcholine, acting at M1 receptors, appears to exert a more specific influence on effort discounting only.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11268711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141602024","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":"Aberrant activation of hippocampal astrocytes causes neuroinflammation and cognitive decline in mice.","authors":"Jae-Hong Kim, Nakamura Michiko, In-Sun Choi, Yujung Kim, Ji-Young Jeong, Maan-Gee Lee, Il-Sung Jang, Kyoungho Suk","doi":"10.1371/journal.pbio.3002687","DOIUrl":"10.1371/journal.pbio.3002687","url":null,"abstract":"<p><p>Reactive astrocytes are associated with neuroinflammation and cognitive decline in diverse neuropathologies; however, the underlying mechanisms are unclear. We used optogenetic and chemogenetic tools to identify the crucial roles of the hippocampal CA1 astrocytes in cognitive decline. Our results showed that repeated optogenetic stimulation of the hippocampal CA1 astrocytes induced cognitive impairment in mice and decreased synaptic long-term potentiation (LTP), which was accompanied by the appearance of inflammatory astrocytes. Mechanistic studies conducted using knockout animal models and hippocampal neuronal cultures showed that lipocalin-2 (LCN2), derived from reactive astrocytes, mediated neuroinflammation and induced cognitive impairment by decreasing the LTP through the reduction of neuronal NMDA receptors. Sustained chemogenetic stimulation of hippocampal astrocytes provided similar results. Conversely, these phenomena were attenuated by a metabolic inhibitor of astrocytes. Fiber photometry using GCaMP revealed a high level of hippocampal astrocyte activation in the neuroinflammation model. Our findings suggest that reactive astrocytes in the hippocampus are sufficient and required to induce cognitive decline through LCN2 release and synaptic modulation. This abnormal glial-neuron interaction may contribute to the pathogenesis of cognitive disturbances in neuroinflammation-associated brain conditions.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11239238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141591822","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}