PLoS Biology最新文献

{"title":"Regulation to function: A computational approach to specialized metabolism.","authors":"Justin R Nodwell","doi":"10.1371/journal.pbio.3003205","DOIUrl":"10.1371/journal.pbio.3003205","url":null,"abstract":"<p><p>Despite a century of use in drug discovery, specialized metabolism continues to churn out astonishing discoveries. A new study in PLOS Biology uses a novel computational approach to uncover previously unknown functions of a compound produced by Streptomyces coelicolor.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 6","pages":"e3003205"},"PeriodicalIF":9.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12165377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289707","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 unified framework to model synaptic dynamics during the sleep-wake cycle.","authors":"Fukuaki L Kinoshita, Rikuhiro G Yamada, Koji L Ode, Hiroki R Ueda","doi":"10.1371/journal.pbio.3003198","DOIUrl":"10.1371/journal.pbio.3003198","url":null,"abstract":"<p><p>Understanding synaptic dynamics during the sleep-wake cycle in the cortex is crucial yet remains controversial. The synaptic homeostasis hypothesis (SHY) suggests synaptic depression during non-rapid eye movement (NREM) sleep, while other studies report synaptic potentiation or synaptic changes during NREM sleep depending on activities in wakefulness. To find boundary conditions between these contradictory observations, we focused on learning rules and firing patterns that contribute to the synaptic dynamics. Using computational models considering mammalian cortical neurons, we found that under Hebbian and spike-timing dependent plasticity (STDP), wake-like firing patterns decrease synaptic weights, while sleep-like patterns strengthen synaptic weights. We refer to this tendency as Wake Inhibition and Sleep Excitation (WISE). Conversely, under Anti-Hebbian and Anti-STDP, synaptic depression during NREM sleep was observed, aligning with the conventional synaptic homeostasis hypothesis. Moreover, synaptic changes depended on firing rate differences between NREM sleep and wakefulness. We provide a unified framework that could explain synaptic homeodynamics under the sleep-wake cycle.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 6","pages":"e3003198"},"PeriodicalIF":9.8,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12161594/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144286845","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":"Genome mining based on transcriptional regulatory networks uncovers a novel locus involved in desferrioxamine biosynthesis.","authors":"Hannah E Augustijn, Zachary L Reitz, Le Zhang, Jeanine A Boot, Somayah S Elsayed, Gregory L Challis, Marnix H Medema, Gilles P van Wezel","doi":"10.1371/journal.pbio.3003183","DOIUrl":"10.1371/journal.pbio.3003183","url":null,"abstract":"<p><p>Bacteria produce a plethora of natural products that are in clinical, agricultural and biotechnological use. Genome mining has uncovered millions of biosynthetic gene clusters (BGCs) that encode their biosynthesis, the vast majority of them lacking a clear product or function. Thus, a major challenge is to predict the bioactivities of the molecules these BGCs specify, and how to elicit their expression. Here, we present an innovative strategy whereby we harness the power of regulatory networks combined with global gene expression patterns to predict BGC functions. Bioinformatic analysis of all genes predicted to be controlled by the iron master regulator DmdR1 combined with co-expression data, led to identification of the novel operon desJGH that plays a key role in the biosynthesis of the iron overload drug desferrioxamine (DFO) B in Streptomyces coelicolor. Deletion of either desG or desH strongly reduces the biosynthesis of DFO B, while that of DFO E is enhanced. DesJGH most likely act by changing the balance between the DFO precursors. Our work shows the power of harnessing regulation-based genome mining to functionally prioritize BGCs, accelerating the discovery of novel bioactive molecules.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 6","pages":"e3003183"},"PeriodicalIF":9.8,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12161575/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144286846","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":"Mutant EZH2 alters the epigenetic network and increases epigenetic heterogeneity in B cell lymphoma.","authors":"Ofir Griess, Noa Furth, Nofar Harpaz, Nicoletta Di Bernardo, Tomer-Meir Salame, Bareket Dassa, Ioannis Karagiannidis, Yusuke Isshiki, Menachem Gross, Ari M Melnick, Wendy Béguelin, Guy Ron, Efrat Shema","doi":"10.1371/journal.pbio.3003191","DOIUrl":"10.1371/journal.pbio.3003191","url":null,"abstract":"<p><p>Diffuse large B cell lymphomas and follicular lymphomas show recurrent mutations in epigenetic regulators; among these are loss-of-function mutations in KMT2D and gain-of-function mutations in EZH2. To systematically explore the effects of these mutations on the wiring of the epigenetic network, we applied a single-cell approach to probe a wide array of histone modifications. We show that mutant-EZH2 elicits extensive effects on the epigenome of lymphomas, beyond alterations to H3K27 methylations, and is epistatic over KMT2D mutations. Utilizing the single-cell data, we present computational methods to measure epigenetic heterogeneity. We identify an unexpected characteristic of mutant-EZH2, but not KMT2D, in increasing heterogeneity, shedding light on a novel oncogenic mechanism mediated by this mutation. Finally, we present tools to reconstruct known interactions within the epigenetic network, as well as reveal potential novel cross talk between various modifications, supported by functional perturbations. Our work highlights novel roles for mutant-EZH2 in lymphomagenesis and establishes new concepts for measuring epigenetic heterogeneity and intra-chromatin connectivity in cancer cells.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 6","pages":"e3003191"},"PeriodicalIF":9.8,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12161531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144286848","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":"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}