PLoS Biology最新文献

{"title":"Phosphatase-independent activity of smooth-muscle calcineurin orchestrates a gene expression program leading to hypertension.","authors":"Paula Sofía Yunes-Leites, Yilin Sun, Sara Martínez-Martínez, Álvaro Alfayate, Marta Toral, María José Méndez-Olivares, Ángel Colmenar, Ana Isabel Torralbo, Dolores López-Maderuelo, Sergio Mateos-García, David N Cornfield, Jesús Vázquez, Juan Miguel Redondo, Miguel R Campanero","doi":"10.1371/journal.pbio.3003163","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003163","url":null,"abstract":"<p><p>Angiotensin-II (Ang-II) drives pathological vascular wall remodeling in hypertension and abdominal aortic aneurysm (AAA) through mechanisms that are not completely understood. Previous studies showed that the phosphatase activity of calcineurin (Cn) mediates Ang-II-induced AAA, but the cell type involved in the action of Cn in AAA formation remained unknown. Here, by employing newly created smooth muscle cell (SMC)-specific and endothelial cell (EC)-specific Cn-deficient mice (SM-Cn-/- and EC-Cn-/- mice), we show that Cn expressed in SMCs, but not ECs, was required for Ang-II-induced AAA. Unexpectedly, SMC Cn also played a structural role in the early onset and maintenance of Ang-II-induced hypertension, independently of its known phosphatase activity. Among the signaling pathways activated by Ang-II, Cn signaling is essential in SMCs, as nearly 90% of the genes regulated by Ang-II in the aorta required Cn expression in SMCs. Cn orchestrated, independently of its enzymatic activity, the induction by Ang-II of a transcriptional program closely related to SMC contractility and hypertension. Cn deletion in SMCs, but not its pharmacological inhibition, impaired the regulation of arterial contractility. Among the genes whose regulation by Ang-II required Cn expression but not its phosphatase activity, we discovered that Serpine1 was critical for Ang-II-induced hypertension. Indeed, pharmacological inhibition of PAI-1, the protein encoded by Serpine1, impaired SMCs contractility and readily regressed hypertension. Mechanistically, Serpine1 induction was mediated by Smad2 activation via the structural role of Cn. These findings uncover an unexpected role for Cn in vascular pathophysiology and highlight PAI-1 as a potential therapeutic target for hypertension.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 5","pages":"e3003163"},"PeriodicalIF":9.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081585","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":"Gene promoters are genomically encoded to facilitate histone exchange/incorporation.","authors":"Blaine Bartholomew","doi":"10.1371/journal.pbio.3003160","DOIUrl":"10.1371/journal.pbio.3003160","url":null,"abstract":"<p><p>Gene promoters are intrinsically hardwired not only to facilitate transcription preinitiation complex formation but also the release of paused RNA polymerase by H2A.Z. A new PLOS Biology study reveals poly (dA) tracts at promoters positively stimulate H2A.Z incorporation by the SWR complex in yeast.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 5","pages":"e3003160"},"PeriodicalIF":9.8,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12074589/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144064586","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":"H2A.Z deposition by the SWR complex is stimulated by polyadenine DNA sequences in nucleosomes.","authors":"Cynthia Converso, Leonidas Pierrakeas, Lirong Chan, Shalvi Chowdhury, Emily de Onis, Vyacheslav I Kuznetsov, John M Denu, Ed Luk","doi":"10.1371/journal.pbio.3003059","DOIUrl":"10.1371/journal.pbio.3003059","url":null,"abstract":"<p><p>The variant histone H2A.Z is deposited into nucleosomes immediately downstream of promoters, where it plays a critical role in transcription. The site-specific deposition of H2A.Z is catalyzed by the SWR complex, a conserved chromatin remodeler with affinity for promoter-proximal nucleosome-depleted regions (NDRs) and histone acetylation. By comparing the genomic distribution of H2A.Z in wild-type and SWR-deficient cells, we found that SWR is also responsible for depositing H2A.Z at thousands of non-canonical sites not directly linked to NDRs or histone acetylation. To understand the targeting mechanism of H2A.Z, we presented SWR to a library of canonical nucleosomes isolated from yeast and analyzed the preferred substrates. Our results revealed that SWR preferentially deposited H2A.Z into a subset of endogenous H2A.Z sites, which are overrepresented by polyadenine tracts on the top strands of the DNA duplex at the nucleosomal entry-exit sites. Insertion of polyadenine sequences into recombinant nucleosomes near the outgoing H2A-H2B dimer enhanced SWR's affinity for the nucleosomal substrate and increased its H2A.Z insertion activity. These findings suggest that the genome encodes sequence-based information that facilitates remodeler-mediated targeting of H2A.Z.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 5","pages":"e3003059"},"PeriodicalIF":9.8,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12068740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035789","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":"Upstream open reading frames dynamically modulate CLOCK protein translation to regulate circadian rhythms and sleep.","authors":"Yuanqiang Sun, Ke Shui, Qinyu Li, Chenlu Liu, Wanting Jin, Jian-Quan Ni, Jian Lu, Luoying Zhang","doi":"10.1371/journal.pbio.3003173","DOIUrl":"10.1371/journal.pbio.3003173","url":null,"abstract":"<p><p>The circadian rhythm is an evolutionarily conserved mechanism with translational regulation increasingly recognized as pivotal in its modulation. In this study, we found that upstream open reading frames (uORFs) are enriched in Drosophila circadian rhythm genes, with particularly conserved uORFs present in core circadian clock genes. We demonstrate evidence that the uORFs of the core clock gene, Clock (Clk), rhythmically and substantially attenuate CLK protein translation in Drosophila, with pronounced suppression occurring during daylight hours. Eliminating Clk uORFs leads to increased CLK protein levels during the day and results in a shortened circadian cycle, along with a broad shift in clock gene expression rhythms. Notably, Clk uORF deletion also augments morning sleep by reducing dopaminergic activity. Beyond daily circadian adjustments, Clk uORFs play a role in modulating sleep patterns in response to seasonal daylight variations. Furthermore, the Clk uORFs act as an important regulator to shape the rhythmic expression of a vast array of genes and influence multifaceted physiological outcomes. Collectively, our research sheds light on the intricate ways uORFs dynamically adjust downstream coding sequences to acclimate to environmental shifts.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 5","pages":"e3003173"},"PeriodicalIF":9.8,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144038843","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":"Variation in adult sex ratios in tetrapods is linked to sex chromosomes through mortality differences between males and females.","authors":"Ivett Pipoly, Veronika Bókony, Jean-Michel Gaillard, Jean-François Lemaître, Tamás Székely, András Liker","doi":"10.1371/journal.pbio.3003156","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003156","url":null,"abstract":"<p><p>Sex chromosomes can determine male and female phenotypes, and the resulting sex differences may have significant impacts on ecology and life history. One manifestation of this link is that ZW/ZZ sex-determination systems are associated with more male-skewed adult sex ratio (ASR, proportion of males in the adult population) than XX/XY systems across tetrapods (amphibians, reptiles, birds, and mammals). Here, we investigate four demographic processes: male and female offspring production, sex differences in juvenile and adult mortalities and in timing of maturation that can contribute to ASR variation between XX/XY and ZW/ZZ systems, using phylogenetic analyses of a large dataset collected from tetrapod species in the wild. We show that sex differences in adult mortality reliably predict ASR that is also more male-biased in XX/XY species than in ZW/ZZ species. Sex differences in juvenile mortality and in maturation time also contribute to ASR skews, but do not differ consistently between XX/XY and ZW/ZZ systems. Phylogenetic path analyses confirm an influence of sex-determination system on ASR through sex-biased adult mortalities. Together these results infer that sex chromosomes can impact, via demographic pathways, frequency-dependent selection emerging from the relative number of males and females. We call for follow-up studies to uncover the potentially complex web of associations between sex determination, population dynamics, and social behavior.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 5","pages":"e3003156"},"PeriodicalIF":9.8,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144041418","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":"More science friction for less science fiction.","authors":"Jennifer A Byrne, Stefan Stender","doi":"10.1371/journal.pbio.3003167","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003167","url":null,"abstract":"<p><p>AI-ready health datasets can be exploited to generate many research articles with potentially limited scientific value. A study in PLOS Biology highlights this problem, by describing a recent, sudden explosion in papers analyzing the NHANES health dataset.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 5","pages":"e3003167"},"PeriodicalIF":9.8,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991606","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":"Loss of neuropeptidergic regulation of cholinergic transmission induces homeostatic compensation in muscle cells to preserve synaptic strength.","authors":"Jiajie Shao, Jana F Liewald, Wagner Steuer Costa, Christiane Ruse, Jens Gruber, Mohammad S Djamshedzad, Wulf Gebhardt, Alexander Gottschalk","doi":"10.1371/journal.pbio.3003171","DOIUrl":"10.1371/journal.pbio.3003171","url":null,"abstract":"<p><p>Chemical synaptic transmission at the neuromuscular junction (NMJ) is regulated by electrical activity of the motor circuit, but may also be affected by neuromodulation. Here, we assessed the role of neuropeptide signaling in the plasticity of NMJ function in Caenorhabditis elegans. We show that the CAPS (Ca2+-dependent activator protein for secretion) ortholog UNC-31, which regulates exocytosis of dense core vesicles, affects both pre- and post-synaptic functional properties, as well as NMJ-mediated locomotion. Despite reduced evoked acetylcholine (ACh) transmission, the loss of unc-31 results in a more vigorous response to presynaptic stimulation, i.e., enhanced muscle contraction and Ca2+ transients. Based on expression profiles, we identified neuropeptides involved in both cholinergic (FLP-6, FLP-15, NLP-9, NLP-15, NLP-21, and NLP-38) and GABAergic motor neurons (FLP-15, NLP-15), that mediate normal transmission at the NMJ. In the absence of these peptides, neurons fail to upregulate their ACh output in response to increased cAMP signaling; for flp-15; nlp-15 double mutants, we observed overall increased postsynaptic currents, indicating that these neuropeptides may be inhibitory. We also identified proprotein convertases encoded by aex-5/kpc-3 and egl-3/kpc-2 that act synergistically to generate these neuropeptides. We propose that postsynaptic homeostatic scaling, mediated by increased muscle activation, likely through excitability, might compensate for the reduced cholinergic transmission in mutants affected for neuropeptide signaling, thus maintaining net synaptic strength. We show that in the absence of UNC-31 muscle excitability is modulated by upregulating the expression of the muscular L-type voltage-gated Ca2+ channel EGL-19. Our results unveil a role for neuropeptidergic regulation in synaptic plasticity, linking changes in presynaptic transmission to compensatory changes in muscle excitability.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 5","pages":"e3003171"},"PeriodicalIF":9.8,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12088594/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144042789","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":"Explosion of formulaic research articles, including inappropriate study designs and false discoveries, based on the NHANES US national health database.","authors":"Tulsi Suchak, Anietie E Aliu, Charlie Harrison, Reyer Zwiggelaar, Nophar Geifman, Matt Spick","doi":"10.1371/journal.pbio.3003152","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003152","url":null,"abstract":"<p><p>With the growth of artificial intelligence (AI)-ready datasets such as the National Health and Nutrition Examination Survey (NHANES), new opportunities for data-driven research are being created, but also generating risks of data exploitation by paper mills. In this work, we focus on two areas of potential concern for AI-supported research efforts. First, we describe the production of large numbers of formulaic single-factor analyses, relating single predictors to specific health conditions, where multifactorial approaches would be more appropriate. Employing AI-supported single-factor approaches removes context from research, fails to capture interactions, avoids false discovery correction, and is an approach that can easily be adopted by paper mills. Second, we identify risks of selective data usage, such as analyzing limited date ranges or cohort subsets without clear justification, suggestive of data dredging, and post-hoc hypothesis formation. Using a systematic literature search for single-factor analyses, we identified 341 NHANES-derived research papers published over the past decade, each proposing an association between a predictor and a health condition from the wide range contained within NHANES. We found evidence that research failed to take account of multifactorial relationships, that manuscripts did not account for the risks of false discoveries, and that researchers selectively extracted data from NHANES rather than utilizing the full range of data available. Given the explosion of AI-assisted productivity in published manuscripts (the systematic search strategy used here identified an average of 4 papers per annum from 2014 to 2021, but 190 in 2024-9 October alone), we highlight a set of best practices to address these concerns, aimed at researchers, data controllers, publishers, and peer reviewers, to encourage improved statistical practices and mitigate the risks of paper mills using AI-assisted workflows to introduce low-quality manuscripts to the scientific literature.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 5","pages":"e3003152"},"PeriodicalIF":9.8,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12061153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027158","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 standardized nomenclature for the rods and cones of the vertebrate retina.","authors":"Tom Baden, Juan M Angueyra, Jenny M Bosten, Shaun P Collin, Bevil R Conway, Fabio Cortesi, Karin Dedek, Thomas Euler, Iñigo Novales Flamarique, Anna Franklin, Silke Haverkamp, Almut Kelber, Stephan C F Neuhauss, Wei Li, Robert J Lucas, Daniel C Osorio, Karthik Shekhar, Dario Tommasini, Takeshi Yoshimatsu, Joseph C Corbo","doi":"10.1371/journal.pbio.3003157","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003157","url":null,"abstract":"<p><p>Vertebrate photoreceptors have been studied for well over a century, but a fixed nomenclature for referring to orthologous cell types across diverse species has been lacking. Instead, photoreceptors have been variably-and often confusingly-named according to morphology, presence/absence of 'rhodopsin', spectral sensitivity, chromophore usage, and/or the gene family of the opsin(s) they express. Here, we propose a unified nomenclature for vertebrate rods and cones that aligns with the naming systems of other retinal cell classes and that is based on the photoreceptor type's putative evolutionary history. This classification is informed by the functional, anatomical, developmental, and molecular identities of the neuron as a whole, including the expression of deeply conserved transcription factors required for development. The proposed names will be applicable across all vertebrates and indicative of the widest possible range of properties, including their postsynaptic wiring, and hence will allude to their common and species-specific roles in vision. Furthermore, the naming system is open-ended to accommodate the future discovery of as-yet unknown photoreceptor types.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 5","pages":"e3003157"},"PeriodicalIF":9.8,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027069","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":"Old cytokine, new tricks: A refined model of interferon's antiviral activity.","authors":"John W Schoggins","doi":"10.1371/journal.pbio.3003154","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003154","url":null,"abstract":"<p><p>Interferon is a central component of the vertebrate antiviral immune response, thought to act through induction of hundreds of interferon-stimulated genes, with some redundancy. Recent findings suggest a more refined 'limited set' model, in which distinct viruses are targeted by small subsets of the induced gene repertoire.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 5","pages":"e3003154"},"PeriodicalIF":9.8,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144055083","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}