eLife最新文献

{"title":"Harnessing AlphaFold to reveal hERG channel conformational state secrets.","authors":"Khoa Ngo, Pei-Chi Yang, Vladimir Yarov-Yarovoy, Colleen E Clancy, Igor Vorobyov","doi":"10.7554/eLife.104901","DOIUrl":"10.7554/eLife.104901","url":null,"abstract":"<p><p>To design safe, selective, and effective new therapies, there must be a deep understanding of the structure and function of the drug target. One of the most difficult problems to solve has been the resolution of discrete conformational states of transmembrane ion channel proteins. An example is K_V11.1 (hERG), comprising the primary cardiac repolarizing current, <i>I</i>_kr. hERG is a notorious drug anti-target against which all promising drugs are screened to determine potential for arrhythmia. Drug interactions with the hERG inactivated state are linked to elevated arrhythmia risk, and drugs may become trapped during channel closure. While prior studies have applied AlphaFold to predict alternative protein conformations, we show that the inclusion of carefully chosen structural templates can guide these predictions toward distinct functional states. This targeted modeling approach is validated through comparisons with experimental data, including proposed state-dependent structural features, drug interactions from molecular docking, and ion conduction properties from molecular dynamics simulations. Remarkably, AlphaFold not only predicts inactivation mechanisms of the hERG channel that prevent ion conduction but also uncovers novel molecular features explaining enhanced drug binding observed during inactivation, offering a deeper understanding of hERG channel function and pharmacology. Furthermore, leveraging AlphaFold-derived states enhances computational screening by significantly improving agreement with experimental drug affinities, an important advance for hERG as a key drug safety target where traditional single-state models miss critical state-dependent effects. By mapping protein residue interaction networks across closed, open, and inactivated states, we identified critical residues driving state transitions validated by prior mutagenesis studies. This innovative methodology sets a new benchmark for integrating deep learning-based protein structure prediction with experimental validation. It also offers a broadly applicable approach using AlphaFold to predict discrete protein conformations, reconcile disparate data, and uncover novel structure-function relationships, ultimately advancing drug safety screening and enabling the design of safer therapeutics.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625530","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":"Normative evidence weighing and accumulation in correlated environments.","authors":"Nathan Tardiff, Jiwon Kang, Joshua I Gold","doi":"10.7554/eLife.100258","DOIUrl":"10.7554/eLife.100258","url":null,"abstract":"<p><p>The brain forms certain deliberative decisions following normative principles related to how sensory observations are weighed and accumulated over time. Previously we showed that these principles can account for how people adapt their decisions to the temporal dynamics of the observations (Glaze et al., 2015). Here, we show that this adaptability extends to accounting for correlations in the observations, which can have a dramatic impact on the weight of evidence provided by those observations. We tested online human participants on a novel visual-discrimination task with pairwise-correlated observations. With minimal training, the participants adapted to uncued, trial-by-trial changes in the correlations and produced decisions based on an approximately normative weighing and accumulation of evidence. The results highlight the robustness of our brain's ability to process sensory observations with respect to not just their physical features but also the weight of evidence they provide for a given decision.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625542","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 microbiome interacts with the circadian clock and dietary composition to regulate metabolite cycling in the <i>Drosophila</i> gut.","authors":"Yueliang Zhang, Sara B Noya, Yongjun Li, Jichao Fang, Amita Sehgal","doi":"10.7554/eLife.97130","DOIUrl":"10.7554/eLife.97130","url":null,"abstract":"<p><p>The gut microbiome plays a key role in the maintenance of host metabolic homeostasis and health. Most metabolic processes cycle with a 24-hour rhythm, but the extent to which the microbiome influences metabolite cycling under different conditions, such as variations in dietary composition, remains largely unknown. In this study, we utilized high temporal resolution metabolite profiling of the <i>Drosophila</i> gut to investigate the role of the microbiome in metabolite cycling. We find that the microbiome increases the number of oscillating metabolites despite the previous finding that it dampens transcript cycling in the gut. Time-restricted feeding also promotes metabolite cycling and does so to a larger extent in germ-free flies, thereby increasing cycling in these flies to levels comparable to those in microbiome-containing flies. Enhancement of cycling by the microbiome depends upon a circadian clock, which also maintains phase in the face of changes in the microbiome. Interestingly, a high protein diet increases microbiome-dependent metabolite cycling, while a high sugar diet suppresses it. Gene Ontology identifies amino acid metabolism as the metabolic pathway most affected by changes in the gut microbiome, the circadian clock, and timed feeding, suggesting that it is subject to regulation by multiple inputs. Collectively, our observations highlight a key role of the gut microbiome in host metabolite cycling and reveal a complex interaction with internal and external factors.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12252545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607770","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":"Ultraslow serotonin oscillations in the hippocampus delineate substates across NREM and waking.","authors":"Claire Cooper, Daniel Parthier, Jeremie Sibille, John J Tukker, Nicolas Tritsch, Dietmar Schmitz","doi":"10.7554/eLife.101105","DOIUrl":"10.7554/eLife.101105","url":null,"abstract":"<p><p>Beyond the vast array of functional roles attributed to serotonin (5-HT) in the brain, changes in 5-HT levels have been shown to accompany changes in behavioral states, including WAKE, NREM, and REM sleep. Whether 5-HT dynamics at shorter time scales can be seen to delineate substates within these larger brain states remains an open question. Here, we performed simultaneous recordings of extracellular 5-HT using a recently developed G-Protein-Coupled Receptor-Activation-Based 5-HT sensor (GRAB5-HT3.0) and local field potential in the hippocampal CA1 of mice, which revealed the presence of prominent ultraslow (<0.05 Hz) 5-HT oscillations both during NREM and WAKE states. Interestingly, the phase of these ultraslow 5-HT oscillations was found to distinguish substates both within and across larger behavioral states. Hippocampal ripples occurred preferentially on the falling phase of ultraslow 5-HT oscillations during both NREM and WAKE, with higher power ripples concentrating near the peak specifically during NREM. By contrast, hippocampal-cortical coherence was strongest, and microarousals and intracranial EMG peaks were most prevalent during the rising phase in both wake and NREM. Overall, ultraslow 5-HT oscillations delineate substates within the larger behavioral states of NREM and WAKE, thus potentially temporally segregating internal memory consolidation processes from arousal-related functions.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12252544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607771","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":"Acquisition of auditory discrimination mediated by different processes through two distinct circuits linked to the lateral striatum.","authors":"Susumu Setogawa, Takashi Okauchi, Di Hu, Yasuhiro Wada, Keigo Hikishima, Hirotaka Onoe, Kayo Nishizawa, Nobuyuki Sakayori, Hiroyuki Miyawaki, Takuma Kitanishi, Kenji Mizuseki, Yilong Cui, Kazuto Kobayashi","doi":"10.7554/eLife.97326","DOIUrl":"10.7554/eLife.97326","url":null,"abstract":"<p><p>The striatum, the central hub of cortico-basal ganglia loops, contains functionally heterogeneous subregions distinguished by the topographic patterns of structural connectivity. These subregions mediate various processes of procedural learning. However, it remains unclear when and how striatal subregions engage in the acquisition of sensory stimulus-based decision-making. A neuroimaging of regional brain activity shows that the anterior dorsolateral striatum (aDLS) and posterior ventrolateral striatum (pVLS) in rats are activated in a different temporal pattern during the acquisition phase of auditory discrimination. Chronic and transient pharmacologic manipulations show that the aDLS promotes the behavioral strategy driven by the stimulus-response association while suppressing that by the response-outcome association, and that the pVLS contributes to forming and maintaining the stimulus-response strategy. Electrophysiological recording indicates that subpopulations of aDLS neurons predominantly represent the outcome of specific behaviors at the initial period of discrimination learning, and that pVLS subpopulations encode the beginning and ending of each behavior according to the progress of learning. In addition, other subpopulations of striatal neurons indicate sustained activation after obtaining reward with distinct patterns reflecting the stimulus-response associations. Our findings demonstrate that aDLS and pVLS neurons integrate the new learning of auditory discrimination in spatiotemporally and functionally different manners.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12252547/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607769","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":"NR2F2 is required in the embryonic testis for fetal Leydig cell development.","authors":"Aitana Perea-Gomez, Natividad Bellido Carreras, Magali Dhellemmes, Furong Tang, Coralie Le Gallo, Marie-Christine Chaboissier","doi":"10.7554/eLife.103783","DOIUrl":"10.7554/eLife.103783","url":null,"abstract":"<p><p>Male genital development in XY mammalian fetuses is triggered by the action of hormones, including testosterone, secreted by the developing testes. Defects in this process are a cause for differences in sex development (DSD), one of the most common congenital abnormalities in humans. Fetal Leydig cells (FLCs) play a central role in the synthesis of masculinizing hormones in the developing testes. Yet, the genetic cascade controlling their differentiation is poorly understood. Here, we investigate the role of the orphan nuclear receptor NR2F2 (COUP-TFII) in FLC development. We report that NR2F2 is expressed in interstitial progenitor cells of the mouse embryonic testes and is downregulated upon their differentiation into FLC. By using two mouse models for conditional mutation of <i>Nr2f2</i> in the developing testes, we demonstrate that NR2F2 is required for testis morphogenesis and FLC development. NR2F2 acts in interstitial progenitors to regulate the initiation and progression of FLC differentiation. These results establish NR2F2 as an essential regulator of FLC development and steroid hormone synthesis in the mouse fetal testis and provide an entry point in understanding the etiology of 46,XY DSD associated with pathogenic NR2F2 variants.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12245173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599743","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":"Aiming for spatial and temporal control of gene expression.","authors":"Stanislao Igor Travisano, Ching-Ling Lien","doi":"10.7554/eLife.107945","DOIUrl":"10.7554/eLife.107945","url":null,"abstract":"<p><p>Bioluminescent imaging is helping researchers better understand the effectiveness of tissue regeneration enhancers delivered to injured heart tissue by different adeno-associated virus vectors.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12245171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599742","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":"Bacteriophage infection drives loss of β-lactam resistance in methicillin-resistant <i>Staphylococcus aureus</i>.","authors":"My Tran, Angel J Hernandez Viera, Patricia Q Tran, Erick D Nilsen, Lily Tran, Charlie Y Mo","doi":"10.7554/eLife.102743","DOIUrl":"10.7554/eLife.102743","url":null,"abstract":"<p><p>Bacteriophage (phage) therapy is a promising means to combat drug-resistant bacterial pathogens. Infection by phage can select for mutations in bacterial populations that confer resistance against phage infection. However, resistance against phage can yield evolutionary trade-offs of biomedical relevance. Here, we report the discovery that infection by certain staphylococcal phages sensitizes different strains of methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) to β-lactams, a class of antibiotics against which MRSA is typically resistant. MRSA cells that survive infection by these phages display significant reductions in minimal inhibitory concentration against different β-lactams compared to uninfected bacteria. Transcriptomic profiling reveals that these evolved MRSA strains possess highly modulated transcriptional profiles, where numerous genes involved in <i>S. aureus</i> virulence are downregulated. Phage-treated MRSA exhibited attenuated virulence phenotypes in the form of reduced hemolysis and clumping. Despite sharing similar phenotypes, whole-sequencing analysis revealed that the different MRSA strains evolved unique genetic profiles during infection. These results suggest complex evolutionary trajectories in MRSA during phage predation and open up new possibilities to reduce drug resistance and virulence in MRSA infections.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12245174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599741","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: Stress-induced Cdk5 activity enhances cytoprotective basal autophagy in <i>Drosophila melanogaster</i> by phosphorylating acinus at serine⁴³⁷.","authors":"Nilay Nandi, Lauren K Tyra, Drew Stenesen, Helmut Krämer","doi":"10.7554/eLife.108230","DOIUrl":"10.7554/eLife.108230","url":null,"abstract":"<p><p></p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12240582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590719","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: A phosphoswitch at acinus-serine⁴³⁷ controls autophagic responses to cadmium exposure and neurodegenerative stress.","authors":"Nilay Nandi, Zuhair Zaidi, Charles Tracy, Helmut Krämer","doi":"10.7554/eLife.108297","DOIUrl":"10.7554/eLife.108297","url":null,"abstract":"<p><p></p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12240580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590718","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}