PLoS Biology最新文献

{"title":"The evolution of antimicrobial peptide resistance in Pseudomonas aeruginosa is severely constrained by random peptide mixtures.","authors":"Bernardo Antunes, Caroline Zanchi, Paul R Johnston, Bar Maron, Christopher Witzany, Roland R Regoes, Zvi Hayouka, Jens Rolff","doi":"10.1371/journal.pbio.3002692","DOIUrl":"10.1371/journal.pbio.3002692","url":null,"abstract":"<p><p>The prevalence of antibiotic-resistant pathogens has become a major threat to public health, requiring swift initiatives for discovering new strategies to control bacterial infections. Hence, antibiotic stewardship and rapid diagnostics, but also the development, and prudent use, of novel effective antimicrobial agents are paramount. Ideally, these agents should be less likely to select for resistance in pathogens than currently available conventional antimicrobials. The usage of antimicrobial peptides (AMPs), key components of the innate immune response, and combination therapies, have been proposed as strategies to diminish the emergence of resistance. Herein, we investigated whether newly developed random antimicrobial peptide mixtures (RPMs) can significantly reduce the risk of resistance evolution in vitro to that of single sequence AMPs, using the ESKAPE pathogen Pseudomonas aeruginosa (P. aeruginosa) as a model gram-negative bacterium. Infections of this pathogen are difficult to treat due the inherent resistance to many drug classes, enhanced by the capacity to form biofilms. P. aeruginosa was experimentally evolved in the presence of AMPs or RPMs, subsequentially assessing the extent of resistance evolution and cross-resistance/collateral sensitivity between treatments. Furthermore, the fitness costs of resistance on bacterial growth were studied and whole-genome sequencing used to investigate which mutations could be candidates for causing resistant phenotypes. Lastly, changes in the pharmacodynamics of the evolved bacterial strains were examined. Our findings suggest that using RPMs bears a much lower risk of resistance evolution compared to AMPs and mostly prevents cross-resistance development to other treatments, while maintaining (or even improving) drug sensitivity. This strengthens the case for using random cocktails of AMPs in favour of single AMPs, against which resistance evolved in vitro, providing an alternative to classic antibiotics worth pursuing.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11218975/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141493953","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":"Canonical and noncanonical roles of Hop1 are crucial for meiotic prophase in the fungus Sordaria macrospora.","authors":"Emeline Dubois, Stéphanie Boisnard, Henri-Marc Bourbon, Kenza Yefsah, Karine Budin, Robert Debuchy, Liangran Zhang, Nancy Kleckner, Denise Zickler, Eric Espagne","doi":"10.1371/journal.pbio.3002705","DOIUrl":"10.1371/journal.pbio.3002705","url":null,"abstract":"<p><p>We show here that in the fungus Sordaria macrospora, the meiosis-specific HORMA-domain protein Hop1 is not essential for the basic early events of chromosome axis development, recombination initiation, or recombination-mediated homolog coalignment/pairing. In striking contrast, Hop1 plays a critical role at the leptotene/zygotene transition which is defined by transition from pairing to synaptonemal complex (SC) formation. During this transition, Hop1 is required for maintenance of normal axis structure, formation of SC from telomere to telomere, and development of recombination foci. These hop1Δ mutant defects are DSB dependent and require Sme4/Zip1-mediated progression of the interhomolog interaction program, potentially via a pre-SC role. The same phenotype occurs not only in hop1Δ but also in absence of the cohesin Rec8 and in spo76-1, a non-null mutant of cohesin-associated Spo76/Pds5. Thus, Hop1 and cohesins collaborate at this crucial step of meiotic prophase. In addition, analysis of 4 non-null mutants that lack this transition defect reveals that Hop1 also plays important roles in modulation of axis length, homolog-axis juxtaposition, interlock resolution, and spreading of the crossover interference signal. Finally, unexpected variations in crossover density point to the existence of effects that both enhance and limit crossover formation. Links to previously described roles of the protein in other organisms are discussed.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11244814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141477815","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":"Beyond fission and fusion-Diving into the mysteries of mitochondrial shape.","authors":"Noga Preminger, Maya Schuldiner","doi":"10.1371/journal.pbio.3002671","DOIUrl":"10.1371/journal.pbio.3002671","url":null,"abstract":"<p><p>Mitochondrial shape and network formation have been primarily associated with the well-established processes of fission and fusion. However, recent research has unveiled an intricate and multifaceted landscape of mitochondrial morphology that extends far beyond the conventional fission-fusion paradigm. These less-explored dimensions harbor numerous unresolved mysteries. This review navigates through diverse processes influencing mitochondrial shape and network formation, highlighting the intriguing complexities and gaps in our understanding of mitochondrial architecture. The exploration encompasses various scales, from biophysical principles governing membrane dynamics to molecular machineries shaping mitochondria, presenting a roadmap for future research in this evolving field.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11216622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141477814","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":"Retrieval of contextual memory can be predicted by CA3 remapping and is differentially influenced by NMDAR activity in rat hippocampus subregions.","authors":"Magdalena Miranda, Azul Silva, Juan Facundo Morici, Marcos Antonio Coletti, Mariano Belluscio, Pedro Bekinschtein","doi":"10.1371/journal.pbio.3002706","DOIUrl":"10.1371/journal.pbio.3002706","url":null,"abstract":"<p><p>Episodic memory is essential to navigate in a changing environment by recalling past events, creating new memories, and updating stored information from experience. Although the mechanisms for acquisition and consolidation have been profoundly studied, much less is known about memory retrieval. Hippocampal spatial representations are key for retrieval of contextually guided episodic memories. Indeed, hippocampal place cells exhibit stable location-specific activity which is thought to support contextual memory, but can also undergo remapping in response to environmental changes. It is unclear if remapping is directly related to the expression of different episodic memories. Here, using an incidental memory recognition task in rats, we showed that retrieval of a contextually guided memory is reflected by the levels of CA3 remapping, demonstrating a clear link between external cues, hippocampal remapping, and episodic memory retrieval that guides behavior. Furthermore, we describe NMDARs as key players in regulating the balance between retrieval and memory differentiation processes by controlling the reactivation of specific memory traces. While an increase in CA3 NMDAR activity boosts memory retrieval, dentate gyrus NMDAR activity enhances memory differentiation. Our results contribute to understanding how the hippocampal circuit sustains a flexible balance between memory formation and retrieval depending on the environmental cues and the internal representations of the individual. They also provide new insights into the molecular mechanisms underlying the contributions of hippocampal subregions to generate this balance.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11244845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141477816","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":"Spontaneous single-nucleotide substitutions and microsatellite mutations have distinct distributions of fitness effects.","authors":"Yevgeniy Plavskin, Maria Stella de Biase, Naomi Ziv, Libuše Janská, Yuan O Zhu, David W Hall, Roland F Schwarz, Daniel Tranchina, Mark L Siegal","doi":"10.1371/journal.pbio.3002698","DOIUrl":"10.1371/journal.pbio.3002698","url":null,"abstract":"<p><p>The fitness effects of new mutations determine key properties of evolutionary processes. Beneficial mutations drive evolution, yet selection is also shaped by the frequency of small-effect deleterious mutations, whose combined effect can burden otherwise adaptive lineages and alter evolutionary trajectories and outcomes in clonally evolving organisms such as viruses, microbes, and tumors. The small effect sizes of these important mutations have made accurate measurements of their rates difficult. In microbes, assessing the effect of mutations on growth can be especially instructive, as this complex phenotype is closely linked to fitness in clonally evolving organisms. Here, we perform high-throughput time-lapse microscopy on cells from mutation-accumulation strains to precisely infer the distribution of mutational effects on growth rate in the budding yeast, Saccharomyces cerevisiae. We show that mutational effects on growth rate are overwhelmingly negative, highly skewed towards very small effect sizes, and frequent enough to suggest that deleterious hitchhikers may impose a significant burden on evolving lineages. By using lines that accumulated mutations in either wild-type or slippage repair-defective backgrounds, we further disentangle the effects of 2 common types of mutations, single-nucleotide substitutions and simple sequence repeat indels, and show that they have distinct effects on yeast growth rate. Although the average effect of a simple sequence repeat mutation is very small (approximately 0.3%), many do alter growth rate, implying that this class of frequent mutations has an important evolutionary impact.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11244821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141477817","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 human hypothalamus coordinates switching between different survival actions.","authors":"Jaejoong Kim, Sarah M Tashjian, Dean Mobbs","doi":"10.1371/journal.pbio.3002624","DOIUrl":"https://doi.org/10.1371/journal.pbio.3002624","url":null,"abstract":"<p><p>Comparative research suggests that the hypothalamus is critical in switching between survival behaviors, yet it is unclear if this is the case in humans. Here, we investigate the role of the human hypothalamus in survival switching by introducing a paradigm where volunteers switch between hunting and escape in response to encounters with a virtual predator or prey. Given the small size and low tissue contrast of the hypothalamus, we used deep learning-based segmentation to identify the individual-specific hypothalamus and its subnuclei as well as an imaging sequence optimized for hypothalamic signal acquisition. Across 2 experiments, we employed computational models with identical structures to explain internal movement generation processes associated with hunting and escaping. Despite the shared structure, the models exhibited significantly different parameter values where escaping or hunting were accurately decodable just by computing the parameters of internal movement generation processes. In experiment 2, multi-voxel pattern analyses (MVPA) showed that the hypothalamus, hippocampus, and periaqueductal gray encode switching of survival behaviors while not encoding simple motor switching outside of the survival context. Furthermore, multi-voxel connectivity analyses revealed a network including the hypothalamus as encoding survival switching and how the hypothalamus is connected to other regions in this network. Finally, model-based fMRI analyses showed that a strong hypothalamic multi-voxel pattern of switching is predictive of optimal behavioral coordination after switching, especially when this signal was synchronized with the multi-voxel pattern of switching in the amygdala. Our study is the first to identify the role of the human hypothalamus in switching between survival behaviors and action organization after switching.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11213486/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141471889","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":"From hidden hearing loss to supranormal auditory processing by neurotrophin 3-mediated modulation of inner hair cell synapse density.","authors":"Lingchao Ji, Beatriz C Borges, David T Martel, Calvin Wu, M Charles Liberman, Susan E Shore, Gabriel Corfas","doi":"10.1371/journal.pbio.3002665","DOIUrl":"https://doi.org/10.1371/journal.pbio.3002665","url":null,"abstract":"<p><p>Loss of synapses between spiral ganglion neurons and inner hair cells (IHC synaptopathy) leads to an auditory neuropathy called hidden hearing loss (HHL) characterized by normal auditory thresholds but reduced amplitude of sound-evoked auditory potentials. It has been proposed that synaptopathy and HHL result in poor performance in challenging hearing tasks despite a normal audiogram. However, this has only been tested in animals after exposure to noise or ototoxic drugs, which can cause deficits beyond synaptopathy. Furthermore, the impact of supernumerary synapses on auditory processing has not been evaluated. Here, we studied mice in which IHC synapse counts were increased or decreased by altering neurotrophin 3 (Ntf3) expression in IHC supporting cells. As we previously showed, postnatal Ntf3 knockdown or overexpression reduces or increases, respectively, IHC synapse density and suprathreshold amplitude of sound-evoked auditory potentials without changing cochlear thresholds. We now show that IHC synapse density does not influence the magnitude of the acoustic startle reflex or its prepulse inhibition. In contrast, gap-prepulse inhibition, a behavioral test for auditory temporal processing, is reduced or enhanced according to Ntf3 expression levels. These results indicate that IHC synaptopathy causes temporal processing deficits predicted in HHL. Furthermore, the improvement in temporal acuity achieved by increasing Ntf3 expression and synapse density suggests a therapeutic strategy for improving hearing in noise for individuals with synaptopathy of various etiologies.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11210788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141471887","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":"Retraction: Noncanonical TGF-β signaling leads to FBXO3-mediated degradation of ΔNp63α promoting breast cancer metastasis and poor clinical prognosis.","authors":"Mengmeng Niu, Yajun He, Jing Xu, Liangping Ding, Tao He, Yong Yi, Mengyuan Fu, Rongtian Guo, Fengtian Li, Hu Chen, Ye-Guang Chen, Zhi-Xiong Jim Xiao","doi":"10.1371/journal.pbio.3002708","DOIUrl":"https://doi.org/10.1371/journal.pbio.3002708","url":null,"abstract":"","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11210768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141471888","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 high-throughput behavioral screening platform for measuring chemotaxis by C. elegans.","authors":"Emily Fryer, Sujay Guha, Lucero E Rogel-Hernandez, Theresa Logan-Garbisch, Hodan Farah, Ehsan Rezaei, Iris N Mollhoff, Adam L Nekimken, Angela Xu, Lara Selin Seyahi, Sylvia Fechner, Shaul Druckmann, Thomas R Clandinin, Seung Y Rhee, Miriam B Goodman","doi":"10.1371/journal.pbio.3002672","DOIUrl":"https://doi.org/10.1371/journal.pbio.3002672","url":null,"abstract":"<p><p>Throughout history, humans have relied on plants as a source of medication, flavoring, and food. Plants synthesize large chemical libraries and release many of these compounds into the rhizosphere and atmosphere where they affect animal and microbe behavior. To survive, nematodes must have evolved the sensory capacity to distinguish plant-made small molecules (SMs) that are harmful and must be avoided from those that are beneficial and should be sought. This ability to classify chemical cues as a function of their value is fundamental to olfaction and represents a capacity shared by many animals, including humans. Here, we present an efficient platform based on multiwell plates, liquid handling instrumentation, inexpensive optical scanners, and bespoke software that can efficiently determine the valence (attraction or repulsion) of single SMs in the model nematode, Caenorhabditis elegans. Using this integrated hardware-wetware-software platform, we screened 90 plant SMs and identified 37 that attracted or repelled wild-type animals but had no effect on mutants defective in chemosensory transduction. Genetic dissection indicates that for at least 10 of these SMs, response valence emerges from the integration of opposing signals, arguing that olfactory valence is often determined by integrating chemosensory signals over multiple lines of information. This study establishes that C. elegans is an effective discovery engine for determining chemotaxis valence and for identifying natural products detected by the chemosensory nervous system.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11210793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141471886","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":"Subpopulations of neurons in the perirhinal cortex enable both modality-specific and modality-invariant recognition of objects.","authors":"Heung-Yeol Lim, Inah Lee","doi":"10.1371/journal.pbio.3002713","DOIUrl":"10.1371/journal.pbio.3002713","url":null,"abstract":"<p><p>The perirhinal cortex (PER) supports multimodal object recognition, but how multimodal information of objects is integrated within the PER remains unknown. Here, we recorded single units within the PER while rats performed a PER-dependent multimodal object-recognition task. In this task, audiovisual cues were presented simultaneously (multimodally) or separately (unimodally). We identified 2 types of object-selective neurons in the PER: crossmodal cells, showing constant firing patterns for an object irrespective of its modality, and unimodal cells, showing a preference for a specific modality. Unimodal cells further dissociated unimodal and multimodal versions of the object by modulating their firing rates according to the modality condition. A population-decoding analysis confirmed that the PER could perform both modality-invariant and modality-specific object decoding-the former for recognizing an object as the same in various conditions and the latter for remembering modality-specific experiences of the same object.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":9.8,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11233021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141460190","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}