PLoS Biology最新文献

{"title":"Global siRNA screen identifies human host factors critical for SARS-CoV-2 replication and late stages of infection.","authors":"Xin Yin, Yuan Pu, Shuofeng Yuan, Lars Pache, Christopher Churas, Stuart Weston, Laura Riva, Lacy M Simons, William J Cisneros, Thomas Clausen, Grace Biddle, Simon Doss-Gollin, Meagan Deming, Paul D De Jesus, Ha Na Kim, Daniel Fuentes, John M Whitelock, Jeffrey D Esko, Megan S Lord, Ignacio Mena, Adolfo García-Sastre, Judd F Hultquist, Matthew B Frieman, Trey Ideker, Dexter Pratt, Laura Martin-Sancho, Sumit K Chanda","doi":"10.1371/journal.pbio.3002738","DOIUrl":"10.1371/journal.pbio.3002738","url":null,"abstract":"<p><p>Defining the subset of cellular factors governing SARS-CoV-2 replication can provide critical insights into viral pathogenesis and identify targets for host-directed antiviral therapies. While a number of genetic screens have previously reported SARS-CoV-2 host dependency factors, most of these approaches relied on utilizing pooled genome-scale CRISPR libraries, which are biased toward the discovery of host proteins impacting early stages of viral replication. To identify host factors involved throughout the SARS-CoV-2 infectious cycle, we conducted an arrayed genome-scale siRNA screen. Resulting data were integrated with published functional screens and proteomics data to reveal (i) common pathways that were identified in all OMICs datasets-including regulation of Wnt signaling and gap junctions, (ii) pathways uniquely identified in this screen-including NADH oxidation, or (iii) pathways supported by this screen and proteomics data but not published functional screens-including arachionate production and MAPK signaling. The identified proviral host factors were mapped into the SARS-CoV-2 infectious cycle, including 32 proteins that were determined to impact viral replication and 27 impacting late stages of infection, respectively. Additionally, a subset of proteins was tested across other coronaviruses revealing a subset of proviral factors that were conserved across pandemic SARS-CoV-2, epidemic SARS-CoV-1 and MERS-CoV, and the seasonal coronavirus OC43-CoV. Further studies illuminated a role for the heparan sulfate proteoglycan perlecan in SARS-CoV-2 viral entry and found that inhibition of the non-canonical NF-kB pathway through targeting of BIRC2 restricts SARS-CoV-2 replication both in vitro and in vivo. These studies provide critical insight into the landscape of virus-host interactions driving SARS-CoV-2 replication as well as valuable targets for host-directed antivirals.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 6","pages":"e3002738"},"PeriodicalIF":9.8,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144286847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The mysterious link between migraine aura and migraine headache.","authors":"Anders Hougaard, Cenk Ayata, K C Brennan, Arn M J M van den Maagdenberg, Messoud Ashina","doi":"10.1371/journal.pbio.3003168","DOIUrl":"10.1371/journal.pbio.3003168","url":null,"abstract":"<p><p>Migraine aura - manifesting as transient, neurological disturbances - presents a complex and unresolved relationship with migraine headache. Cortical spreading depolarization (SD), recognized as the mechanism underlying aura symptoms, has been shown to trigger head pain through activation of trigeminal nociceptors in animal models. However, recent clinical data challenge the notion that aura causes migraine headache in patients. In this Essay, we critically examine the pathophysiology of migraine aura and migraine headache, exploring evidence from clinical observations, (genetic) mouse models, and pharmacological studies. We also discuss the role of SD, the trigeminovascular system, and the impact of pharmacological agents that both trigger and treat migraine attacks. Our essay highlights the complexities and conflicting data surrounding the interplay between aura and headache, emphasizing the need for further research to unravel this mystery and improve therapeutic strategies for individuals with migraine.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 6","pages":"e3003168"},"PeriodicalIF":9.8,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12157119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144276351","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":"Condensate dynamics at the synapse: Phase separation tunes presynaptic function.","authors":"Janine Lützkendorf, Stephan J Sigrist","doi":"10.1371/journal.pbio.3003201","DOIUrl":"10.1371/journal.pbio.3003201","url":null,"abstract":"<p><p>A new study in PLOS Biology shows that Liprin-α and RIM form condensates which not only scaffold presynaptic protein architectures but also fine-tune vesicle priming and release dynamics.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 6","pages":"e3003201"},"PeriodicalIF":9.8,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12157082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144276350","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 fifth era of science: Artificial scientific intelligence.","authors":"Nina Miolane","doi":"10.1371/journal.pbio.3003230","DOIUrl":"10.1371/journal.pbio.3003230","url":null,"abstract":"<p><p>The era of artificial scientific intelligence is here. As algorithms generate discoveries at scale, what role remains for human scientists?</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 6","pages":"e3003230"},"PeriodicalIF":9.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12176288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144267713","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":"Correction: The forkhead transcription factor Foxj1 controls vertebrate olfactory cilia biogenesis and sensory neuron differentiation.","authors":"Dheeraj Rayamajhi, Mert Ege, Kirill Ukhanov, Christa Ringers, Yiliu Zhang, Inyoung Jeong, Percival P D'Gama, Summer Shijia Li, Mehmet Ilyas Cosacak, Caghan Kizil, Hae-Chul Park, Emre Yaksi, Jeffrey R Martens, Steven L Brody, Nathalie Jurisch-Yaksi, Sudipto Roy","doi":"10.1371/journal.pbio.3003229","DOIUrl":"10.1371/journal.pbio.3003229","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1371/journal.pbio.3002468.].</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 6","pages":"e3003229"},"PeriodicalIF":9.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12151390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144267712","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 liprin-α/RIM complex regulates the dynamic assembly of presynaptic active zones via liquid-liquid phase separation.","authors":"Gaowei Jin, Joaquín Campos, Yang Liu, Berta Marcó de la Cruz, Shujing Zhang, Mingfu Liang, Kaiyue Li, Xingqiao Xie, Fredrik H Sterky, Claudio Acuna, Zhiyi Wei","doi":"10.1371/journal.pbio.3002817","DOIUrl":"10.1371/journal.pbio.3002817","url":null,"abstract":"<p><p>Presynaptic scaffold proteins, including liprin-α, RIM, and ELKS, are pivotal to the assembly of the active zone and regulating the coupling of calcium signals and neurotransmitter release, yet the underlying mechanism remains poorly understood. Here, we determined the crystal structure of the liprin-α2/RIM1 complex, revealing a multifaceted intermolecular interaction that drives the liprin-α/RIM assembly. Neurodevelopmental disease-associated mutations block the formation of the complex. Disrupting this interaction in cultured human neurons impairs synaptic transmission and reduces the readily releasable pool of synaptic vesicles. Super-resolution imaging analysis supports a role for liprin-α in recruiting RIM1 to the active zone, presumably by promoting the liquid-liquid phase separation (LLPS) of RIM1. Strikingly, the liprin-α/RIM interaction modulates the competitive distribution of ELKS1 and voltage-gated Ca2+ channels (VGCCs) in RIM1 condensates. Disrupting the liprin-α/RIM interaction significantly decreased VGCC accumulation in the condensed phase and rendered release more sensitive to the slow calcium buffer EGTA, suggesting an increased physical distance between VGCC and vesicular calcium sensors. Together, our findings provide a plausible mechanism of the liprin-α/RIM complex in regulating the coupling of calcium channels and primed synaptic vesicles via LLPS for efficient synaptic transmission and uncover the pathological implication of liprin-α mutations in neurodevelopmental disorders.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 6","pages":"e3002817"},"PeriodicalIF":9.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12151379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144267714","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":"Species-wide gene editing of a flowering regulator reveals hidden phenotypic variation.","authors":"Ulrich Lutz, Ilja Bezrukov, Rebecca Schwab, Wei Yuan, Marius Kollmar, Detlef Weigel","doi":"10.1371/journal.pbio.3003226","DOIUrl":"10.1371/journal.pbio.3003226","url":null,"abstract":"<p><p>Genes do not act in isolation, and the effects of a specific variant at one locus can often be greatly modified by polymorphic variants at other loci. A good example is FLOWERING LOCUS C (FLC), which has been inferred to explain much of the flowering time variation in Arabidopsis thaliana. We use a set of 62 flc species-wide mutants to document pleiotropic, genotype-dependent effects for FLC on flowering as well as several other traits. Time to flowering was greatly reduced in all mutants, with the remaining variation explained mainly by allelic variation at the FLC target FT. Analysis of FT sequence variation suggested that extremely early combinations of FLC and FT alleles should exist in the wild, which we confirmed by targeted collections. Our study provides a proof of concept on how pan-genetic analysis of hub genes can reveal the true extent of genetic networks in a species.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 6","pages":"e3003226"},"PeriodicalIF":9.8,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Embodiment of an artificial limb in mice.","authors":"Zineb Hayatou, Hongkai Wang, Antoine Chaillet, Daniel E Shulz, Valérie Ego-Stengel, Luc Estebanez","doi":"10.1371/journal.pbio.3003186","DOIUrl":"10.1371/journal.pbio.3003186","url":null,"abstract":"<p><p>Body ownership disorders can be triggered by disease or body damage. Methods to probe limb embodiment are required to address those disorders. This includes the development of neuroprostheses that better integrate into the body scheme of the user. To this end, the \"rubber hand illusion\" protocol is a key behavioral method to probe the powerful embodiment that can be triggered by congruent somatosensory and visual inputs from the limb. So far, the neurophysiology of limb embodiment remains poorly known, in part because translating the rubber hand illusion to animal models such as the mouse remains challenging. Yet, mapping out the brain circuits of embodiment thanks to the use of genetic and optogenetic research tools would allow to propose novel embodiment restoration strategies. Here, we show that the rubber hand illusion described in humans can be translated to the mouse forelimb model using an automated, videography-based procedure. We exposed head-fixed mice to a visible, static 3D-printed replica of the right forelimb, while their own forelimb was hidden from their sight. We synchronously brushed their hidden forelimb and the replica. Following these visuo-tactile associations, the replica was visually threatened, and we probed the reaction of the mice using automated tracking of pupils and facial expression. The mice focused significantly more of their gaze toward the threatened forelimb replica after receiving synchronous tactile and visual information compared to asynchronous. More generally, across test and control conditions, the mouse pupillary response was consistent with the human overt response to the rubber hand illusion. Thus, our results show that mice exhibit quantifiable behavioral markers of the embodiment of an artificial forelimb.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 6","pages":"e3003186"},"PeriodicalIF":9.8,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12140191/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144235620","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 hormone-dependent tRNA half promotes cell cycle progression via destabilization of p21 mRNA.","authors":"Takuya Kawamura, Megumi Shigematsu, Yohei Kirino","doi":"10.1371/journal.pbio.3003194","DOIUrl":"10.1371/journal.pbio.3003194","url":null,"abstract":"<p><p>tRNA halves are among the most abundant short non-coding RNAs in the cellular transcriptome. Here we report that in androgen receptor-positive LNCaP prostate cancer cells, the hormone-dependent 5'-tRNALysCUU half promoted cell proliferation by facilitating cell cycle progression. Global mRNA profiling upon the 5'-tRNALysCUU half depletion revealed that the mRNA of p21, a negative regulator of the cell cycle, is post-transcriptionally destabilized via a 5'-tRNALysCUU half-driven mechanism. YBX1, identified as a protein interacting with 5'-tRNALysCUU half in the cytosol, was shown to stabilize p21 mRNA. Specific sequences resembling the 5'-tRNALysCUU half, located in the 3'-UTR of p21 mRNA and termed LL588, were identified as the binding site for YBX1 and are required for p21 mRNA stability. In vitro binding assays demonstrated that the 5'-tRNALysCUU half is capable of displacing YBX1 from LL588. Collectively, our findings suggest that the 5'-tRNALysCUU half directly binds to and displaces YBX1 from p21 mRNA, leading to the destabilization of p21 mRNA and the promotion of cell cycle progression in hormone-dependent cancers. Our study illuminates the role of tRNA halves in regulating mRNA stability and suggests that this may be part of broader regulatory networks affecting mRNA levels, orchestrated by various tRNA halves and their interacting proteins.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 6","pages":"e3003194"},"PeriodicalIF":9.8,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12140204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144235619","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":"Neural evidence that humans reuse strategies to solve new tasks.","authors":"Sam Hall-McMaster, Momchil S Tomov, Samuel J Gershman, Nicolas W Schuck","doi":"10.1371/journal.pbio.3003174","DOIUrl":"10.1371/journal.pbio.3003174","url":null,"abstract":"<p><p>Generalization from past experience is an important feature of intelligent systems. When faced with a new task, one efficient computational approach is to evaluate solutions to earlier tasks as candidates for reuse. Consistent with this idea, we found that human participants (n = 38) learned optimal solutions to a set of training tasks and generalized them to novel test tasks in a reward-selective manner. This behavior was consistent with a computational process based on the successor representation known as successor features and generalized policy improvement (SF&GPI). Neither model-free perseveration or model-based control using a complete model of the environment could explain choice behavior. Decoding from functional magnetic resonance imaging data revealed that solutions from the SF&GPI algorithm were activated on test tasks in visual and prefrontal cortex. This activation had a functional connection to behavior in that stronger activation of SF&GPI solutions in visual areas was associated with increased behavioral reuse. These findings point to a possible neural implementation of an adaptive algorithm for generalization across tasks.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 6","pages":"e3003174"},"PeriodicalIF":9.8,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12140246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144235621","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}