PLoS Biology最新文献_第2页

Discovery of non-retinoid compounds that suppress the pathogenic effects of misfolded rhodopsin in a mouse model of retinitis pigmentosa.

IF 9.8 1区生物学

PLoS Biology Pub Date : 2025-01-14 eCollection Date: 2025-01-01 DOI: 10.1371/journal.pbio.3002932

Joseph T Ortega, Jacklyn M Gallagher, Andrew G McKee, Yidan Tang, Miguel Carmena-Bargueňo, Maria Azam, Zaiddodine Pashandi, Marcin Golczak, Jens Meiler, Horacio Pérez-Sánchez, Jonathan P Schlebach, Beata Jastrzebska

{"title":"Discovery of non-retinoid compounds that suppress the pathogenic effects of misfolded rhodopsin in a mouse model of retinitis pigmentosa.","authors":"Joseph T Ortega, Jacklyn M Gallagher, Andrew G McKee, Yidan Tang, Miguel Carmena-Bargueňo, Maria Azam, Zaiddodine Pashandi, Marcin Golczak, Jens Meiler, Horacio Pérez-Sánchez, Jonathan P Schlebach, Beata Jastrzebska","doi":"10.1371/journal.pbio.3002932","DOIUrl":"10.1371/journal.pbio.3002932","url":null,"abstract":"Pathogenic mutations that cause rhodopsin misfolding lead to a spectrum of currently untreatable blinding diseases collectively termed retinitis pigmentosa. Small molecules to correct rhodopsin misfolding are therefore urgently needed. In this study, we utilized virtual screening to search for drug-like molecules that bind to the orthosteric site of rod opsin and improve its folding and trafficking. We identified and validated the biological effects of 2 non-retinoid compounds with favorable pharmacological properties that cross the blood-retina barrier. These compounds reversibly bind to unliganded rod opsin, each with a Kd comparable to 9-cis-retinal and improve opsin stability. By improving the internal protein structure network (PSN), these rod opsin ligands also enhanced the plasma membrane expression of total 36 of 123 tested clinical RP variants, including the most prevalent P23H variant. Importantly, these compounds protected retinas against light-induced degeneration in mice vulnerable to bright light injury and prolonged survival of photoreceptors in a retinitis pigmentosa mouse model for rod opsin misfolding.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 1","pages":"e3002932"},"PeriodicalIF":9.8,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11731721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142985136","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}

引用次数: 0

Subregions in the ventromedial prefrontal cortex integrate threat and protective information to meta-represent safety.

IF 9.8 1区生物学

PLoS Biology Pub Date : 2025-01-13 eCollection Date: 2025-01-01 DOI: 10.1371/journal.pbio.3002986

Sarah M Tashjian, Joseph Cussen, Wenning Deng, Bo Zhang, Dean Mobbs

{"title":"Subregions in the ventromedial prefrontal cortex integrate threat and protective information to meta-represent safety.","authors":"Sarah M Tashjian, Joseph Cussen, Wenning Deng, Bo Zhang, Dean Mobbs","doi":"10.1371/journal.pbio.3002986","DOIUrl":"10.1371/journal.pbio.3002986","url":null,"abstract":"Pivotal to self-preservation is the ability to identify when we are safe and when we are in danger. Previous studies have focused on safety estimations based on the features of external threats and do not consider how the brain integrates other key factors, including estimates about our ability to protect ourselves. Here, we examine the neural systems underlying the online dynamic encoding of safety. The current preregistered study used 2 novel tasks to test 4 facets of safety estimation: Safety Prediction, Meta-representation, Recognition, and Value Updating. We experimentally manipulated safety estimation changing both levels of external threats and self-protection. Data were collected in 2 independent samples (behavioral N = 100; MRI N = 30). We found consistent evidence of subjective changes in the sensitivity to safety conferred through protection. Neural responses in the ventromedial prefrontal cortex (vmPFC) tracked increases in safety during all safety estimation facets, with specific tuning to protection. Further, informational connectivity analyses revealed distinct hubs of safety coding in the posterior and anterior vmPFC for external threats and protection, respectively. These findings reveal a central role of the vmPFC for coding safety.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 1","pages":"e3002986"},"PeriodicalIF":9.8,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730396/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980354","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}

引用次数: 0

The ability of pentose pathways to form all essential metabolites provides clues to the origins of metabolism.

IF 9.8 1区生物学

PLoS Biology Pub Date : 2025-01-10 eCollection Date: 2025-01-01 DOI: 10.1371/journal.pbio.3002996

Steffen N Lindner, Markus Ralser

引用次数: 0

Are oligodendrocytes bystanders or drivers of Parkinson's disease pathology?

IF 9.8 1区生物学

PLoS Biology Pub Date : 2025-01-08 eCollection Date: 2025-01-01 DOI: 10.1371/journal.pbio.3002977

José María Salazar Campos, Lena F Burbulla, Sarah Jäkel

{"title":"Are oligodendrocytes bystanders or drivers of Parkinson's disease pathology?","authors":"José María Salazar Campos, Lena F Burbulla, Sarah Jäkel","doi":"10.1371/journal.pbio.3002977","DOIUrl":"10.1371/journal.pbio.3002977","url":null,"abstract":"The major pathological feature of Parkinson 's disease (PD), the second most common neurodegenerative disease and most common movement disorder, is the predominant degeneration of dopaminergic neurons in the substantia nigra, a part of the midbrain. Despite decades of research, the molecular mechanisms of the origin of the disease remain unknown. While the disease was initially viewed as a purely neuronal disorder, results from single-cell transcriptomics have suggested that oligodendrocytes may play an important role in the early stages of Parkinson's. Although these findings are of high relevance, particularly to the search for effective disease-modifying therapies, the actual functional role of oligodendrocytes in Parkinson's disease remains highly speculative and requires a concerted scientific effort to be better understood. This Unsolved Mystery discusses the limited understanding of oligodendrocytes in PD, highlighting unresolved questions regarding functional changes in oligodendroglia, the role of myelin in nigral dopaminergic neurons, the impact of the toxic environment, and the aggregation of alpha-synuclein within oligodendrocytes.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 1","pages":"e3002977"},"PeriodicalIF":9.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11709285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142957292","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}

引用次数: 0

Cortical direction selectivity increases from the input to the output layers of visual cortex.

IF 9.8 1区生物学

PLoS Biology Pub Date : 2025-01-08 eCollection Date: 2025-01-01 DOI: 10.1371/journal.pbio.3002947

Weifeng Dai, Tian Wang, Yang Li, Yi Yang, Yange Zhang, Yujie Wu, Tingting Zhou, Hongbo Yu, Liang Li, Yizheng Wang, Gang Wang, Dajun Xing

{"title":"Cortical direction selectivity increases from the input to the output layers of visual cortex.","authors":"Weifeng Dai, Tian Wang, Yang Li, Yi Yang, Yange Zhang, Yujie Wu, Tingting Zhou, Hongbo Yu, Liang Li, Yizheng Wang, Gang Wang, Dajun Xing","doi":"10.1371/journal.pbio.3002947","DOIUrl":"10.1371/journal.pbio.3002947","url":null,"abstract":"Sensitivity to motion direction is a feature of visual neurons that is essential for motion perception. Recent studies have suggested that direction selectivity is re-established at multiple stages throughout the visual hierarchy, which contradicts the traditional assumption that direction selectivity in later stages largely derives from that in earlier stages. By recording laminar responses in areas 17 and 18 of anesthetized cats of both sexes, we aimed to understand how direction selectivity is processed and relayed across 2 successive stages: the input layers and the output layers within the early visual cortices. We found a strong relationship between the strength of direction selectivity in the output layers and the input layers, as well as the preservation of preferred directions across the input and output layers. Moreover, direction selectivity was enhanced in the output layers compared to the input layers, with the response strength maintained in the preferred direction but reduced in other directions and under blank stimuli. We identified a direction-tuned gain mechanism for interlaminar signal transmission, which likely originated from both feedforward connections across the input and output layers and recurrent connections within the output layers. This direction-tuned gain, coupled with nonlinearity, contributed to the enhanced direction selectivity in the output layers. Our findings suggest that direction selectivity in later cortical stages partially inherits characteristics from earlier cortical stages and is further refined by intracortical connections.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 1","pages":"e3002947"},"PeriodicalIF":9.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11709279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142957295","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}

引用次数: 0

Dynamic collateral sensitivity profiles highlight opportunities and challenges for optimizing antibiotic treatments.

IF 9.8 1区生物学

PLoS Biology Pub Date : 2025-01-08 eCollection Date: 2025-01-01 DOI: 10.1371/journal.pbio.3002970

Jeff Maltas, Anh Huynh, Kevin B Wood

{"title":"Dynamic collateral sensitivity profiles highlight opportunities and challenges for optimizing antibiotic treatments.","authors":"Jeff Maltas, Anh Huynh, Kevin B Wood","doi":"10.1371/journal.pbio.3002970","DOIUrl":"10.1371/journal.pbio.3002970","url":null,"abstract":"As failure rates for traditional antimicrobial therapies escalate, recent focus has shifted to evolution-based therapies to slow resistance. Collateral sensitivity-the increased susceptibility to one drug associated with evolved resistance to a different drug-offers a potentially exploitable evolutionary constraint, but the manner in which collateral effects emerge over time is not well understood. Here, we use laboratory evolution in the opportunistic pathogen Enterococcus faecalis to phenotypically characterize collateral profiles through evolutionary time. Specifically, we measure collateral profiles for 400 strain-antibiotic combinations over the course of 4 evolutionary time points as strains are selected in increasing concentrations of antibiotic. We find that at a global level-when results from all drugs are combined-collateral resistance dominates during early phases of adaptation, when resistance to the selecting drug is lower, while collateral sensitivity becomes increasingly likely with further selection. At the level of individual populations; however, the trends are idiosyncratic; for example, the frequency of collateral sensitivity to ceftriaxone increases over time in isolates selected by linezolid but decreases in isolates selected by ciprofloxacin. We then show experimentally how dynamic collateral sensitivity relationships can lead to time-dependent dosing windows that depend on finely timed switching between drugs. Finally, we develop a stochastic mathematical model based on a Markov decision process consistent with observed dynamic collateral profiles to show measurements across time are required to optimally constrain antibiotic resistance.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 1","pages":"e3002970"},"PeriodicalIF":9.8,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11709278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142957297","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}

引用次数: 0

Conserved features of recombination control in vertebrates.

IF 9.8 1区生物学

PLoS Biology Pub Date : 2025-01-07 eCollection Date: 2025-01-01 DOI: 10.1371/journal.pbio.3002959

Linda Odenthal-Hesse

引用次数: 0

FLCCR is a fluorescent reporter system that quantifies the duration of different cell cycle phases at the single-cell level in fission yeast.

IF 9.8 1区生物学

PLoS Biology Pub Date : 2025-01-07 eCollection Date: 2025-01-01 DOI: 10.1371/journal.pbio.3002969

Guillem Murciano-Julià, Marina Francos-Cárdenas, Clàudia Salat-Canela, Elena Hidalgo, José Ayté

{"title":"FLCCR is a fluorescent reporter system that quantifies the duration of different cell cycle phases at the single-cell level in fission yeast.","authors":"Guillem Murciano-Julià, Marina Francos-Cárdenas, Clàudia Salat-Canela, Elena Hidalgo, José Ayté","doi":"10.1371/journal.pbio.3002969","DOIUrl":"https://doi.org/10.1371/journal.pbio.3002969","url":null,"abstract":"Fission yeast is an excellent model system that has been widely used to study the mechanism that control cell cycle progression. However, there is a lack of tools that allow to measure with high precision the duration of the different phases of the cell cycle in individual cells. To circumvent this problem, we have developed a fluorescent reporter that allows the quantification of the different phases of the cell cycle at the single-cell level in most genetic backgrounds. To prove the accuracy of this fluorescent reporter, we have tested the reporter in strains known to have a delay in the G1/S or G2/M transitions, confirming the strength and versatility of the system. An advantage of this reporter is that it eliminates the need for culture synchronization, avoiding stressing the cells. Using this reporter, we show that unperturbed cells lacking Sty1 have a standard cell cycle length and distribution and that the extended length of these cells is due to their increased cell growth rate but not to alterations in their cell cycle progression.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 1","pages":"e3002969"},"PeriodicalIF":9.8,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11706491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142957299","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}

引用次数: 0

Functional analysis of conserved C. elegans bHLH family members uncovers lifespan control by a peptidergic hub neuron.

IF 9.8 1区生物学

PLoS Biology Pub Date : 2025-01-06 eCollection Date: 2025-01-01 DOI: 10.1371/journal.pbio.3002979

G Robert Aguilar, Berta Vidal, Hongzhu Ji, Joke Evenblij, Chien-Po Liao, Hongfei Ji, Giulio Valperga, Christopher Fang-Yen, Oliver Hobert

{"title":"Functional analysis of conserved C. elegans bHLH family members uncovers lifespan control by a peptidergic hub neuron.","authors":"G Robert Aguilar, Berta Vidal, Hongzhu Ji, Joke Evenblij, Chien-Po Liao, Hongfei Ji, Giulio Valperga, Christopher Fang-Yen, Oliver Hobert","doi":"10.1371/journal.pbio.3002979","DOIUrl":"https://doi.org/10.1371/journal.pbio.3002979","url":null,"abstract":"Throughout the animal kingdom, several members of the basic helix-loop-helix (bHLH) family act as proneural genes during early steps of nervous system development. Roles of bHLH genes in specifying terminal differentiation of postmitotic neurons have been less extensively studied. We analyze here the function of 5 Caenorhabditis elegans bHLH genes, falling into 3 phylogenetically conserved subfamilies, which are continuously expressed in a very small number of postmitotic neurons in the central nervous system. We show (a) that 2 orthologs of the vertebrate bHLHe22/e23 genes, called hlh-17 and hlh-32, function redundantly to specify the identity of a single head interneuron class (AUA), as well as an individual motor neuron (VB2); (b) that the PTF1a ortholog hlh-13 acts as a terminal selector to control terminal differentiation and function of the sole octopaminergic neuron class in C. elegans, RIC; and (c) that the NHLH1/2 ortholog hlh-15 controls terminal differentiation and function of the peptidergic AVK head interneuron class, a known neuropeptidergic signaling hub in the animal. Strikingly, through null mutant analysis and cell-specific rescue experiments, we find that loss of hlh-15/NHLH in the peptidergic AVK neurons and the resulting abrogation of neuropeptide secretion from these neurons causes a substantially extended lifespan of the animal, which we propose to be akin to hypothalamic control of lifespan in vertebrates. Our functional analysis reveals themes of bHLH gene function during terminal differentiation that are complementary to the earlier lineage specification roles of other bHLH family members. However, such late functions are much more sparsely employed by members of the bHLH transcription factor family, compared to the function of the much more broadly employed homeodomain transcription factor family.","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 1","pages":"e3002979"},"PeriodicalIF":9.8,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11703107/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980352","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}

引用次数: 0

Correction: Thalamic spindles and Up states coordinate cortical and hippocampal co-ripples in humans.

IF 9.8 1区生物学

PLoS Biology Pub Date : 2024-12-23 eCollection Date: 2024-12-01 DOI: 10.1371/journal.pbio.3002971

引用次数: 0