eLife最新文献

{"title":"Executioner caspase is proximal to Fasciclin 3 which facilitates non-lethal activation in <i>Drosophila</i> olfactory receptor neurons.","authors":"Masaya Muramoto, Nozomi Hanawa, Misako Okumura, Takahiro Chihara, Masayuki Miura, Natsuki Shinoda","doi":"10.7554/eLife.99650","DOIUrl":"10.7554/eLife.99650","url":null,"abstract":"<p><p>The nervous system undergoes functional modification independent of cell turnover. Caspase participates in reversible neuronal modulation via non-lethal activation. However, the mechanism that enables non-lethal activation remains unclear. Here, we analyzed proximal proteins of <i>Drosophila</i> executioner caspase in the adult brain using TurboID. We discovered that executioner caspase Drice is, as an inactive proform, proximal to cell membrane proteins, including a specific splicing isoform of cell adhesion molecule Fasciclin 3 (Fas3), Fas3G. To investigate whether sequestration of executioner caspase to plasma membrane of axons is the mechanism for non-lethal activation, we developed a Gal4-Manipulated Area-Specific CaspaseTracker/CasExpress system for sensitive monitoring of caspase activity near the plasma membrane. We demonstrated that <i>Fas3G</i> overexpression promotes caspase activation in olfactory receptor neurons without killing them, by inducing expression of initiator caspase Dronc, which also comes close to Fas3G. Physiologically, <i>Fas3G</i> overexpression-facilitated non-lethal caspase activation suppresses innate olfactory attraction behavior. Our findings suggest that subcellularly restricted caspase activation, defined by caspase-proximal proteins, is the mechanism for non-lethal activation, opening the methodological development of reversible modification of neuronal function via regulating caspase-proximal proteins.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12173457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309722","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":"Single-cell dissection of prognostic architecture and immunotherap response in <i>Helicobacter pylori</i> infection-associated gastric cancer.","authors":"Xin Zhang, Guangyu Zhang, Shuli Sang, Yang Fei, Xiaopeng Cao, Wenge Song, Feide Liu, Jinze Che, Haoxia Tao, Hongwei Wang, Lihua Zhang, Yiyan Guan, Shipeng Rong, Lijuan Pei, Sheng Yao, Yanchun Wang, Min Zhang, Chunjie Liu","doi":"10.7554/eLife.99337","DOIUrl":"10.7554/eLife.99337","url":null,"abstract":"<p><p>Most of the human gastric cancer (GC) worldwide are ascribed to <i>Helicobacter pylori</i> infections, which have a detrimental effect on the immunotherapy's efficacy. Comprehensively dissecting the key cell players and molecular pathways associated with cancer immunotherapies is critical for developing novel therapeutic strategies against <i>H. pylori</i> infection-associated human GC. We performed a comprehensive single-cell transcriptome analysis of nine GC patients with current <i>H. pylori</i> infection (HpGC), three GC patients with previous <i>H. pylori</i> infection (ex-HpGC), six GC patients without <i>H. pylori</i> infection (non-HpGC), and six healthy controls (HC). We also investigated key cell players and molecular pathways associated with GC immunotherapy outcomes. We revealed the molecular heterogeneity of different cell components in GC, including epithelium, immune cells, and cancer-associated fibroblasts (CAFs) at the single-cell level. The malignant epithelium of HpGC exhibited high expression level of inflammatory and epithelial-mesenchymal transition signature, HpGC and ex-HpGC were enriched with VEGFA+ angiogenic tumor-associated macrophages (Angio-TAM) and IL11+ inflammatory CAF (iCAF), characterized by high expression levels of NECTIN2 and VEGFA/B. Additionally, we found significant correlations between the abundance of iCAF with Angio-TAM and TIGIT+ suppressive T cells, and iCAF interacted with Angio-TAM through the VEGF and ANGPTL angiogenic pathways. We also developed an immune signature and angiogenic signature and demonstrated that the iCAF abundance and angiogenic signature could predict poor immunotherapy outcomes in GC. We revealed the transcriptome characteristics and heterogeneity of various cellular constituents of HpGC patients and demonstrated that a synergistic combination of immunotherapy and anti-angiogenic targeted therapy may be an effective therapeutic modality for HpGC patients.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12173458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144316209","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 contextual fear conditioning paradigm in head-fixed mice exploring virtual reality.","authors":"Seetha Krishnan, Can Dong, Heather Ratigan, Denisse Morales-Rodriguez, Chery Cherian, Mark Sheffield","doi":"10.7554/eLife.105422","DOIUrl":"10.7554/eLife.105422","url":null,"abstract":"<p><p>Contextual fear conditioning (CFC) is a classical laboratory task that tests associative memory formation and recall. Techniques such as multi-photon microscopy and holographic stimulation offer tremendous opportunities to understand the neural underpinnings of these memories. However, these techniques generally require animals to be head-fixed. Few paradigms examine contextual fear in head-fixed mice, and none use freezing-the most common measure of fear in freely moving animals-as the behavioral readout. To address this gap, we developed a CFC paradigm for head-fixed mice using virtual reality (VR). We designed an apparatus to deliver tail shocks while mice navigated a VR environment. We tested three versions of this paradigm and, in all of them, observed increased freezing, particularly on the first trial, in the shock-paired VR compared to a neutral one. These results demonstrate that head-fixed mice can be fear-conditioned in VR and exhibit context-specific freezing behavior. Additionally, using two-photon calcium imaging, we tracked large populations of hippocampal CA1 neurons before, during, and following CFC. As in freely moving mice, CA1 place cells remapped and developed narrower fields following fear conditioning. Thus, our approach enables new opportunities to study the neural mechanisms underlying the formation, recall, and extinction of contextual fear memories.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12173461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309723","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":"Glycolytic flux controls retinal progenitor cell differentiation via regulating Wnt signaling.","authors":"Joseph Hanna, Yacine Touahri, Alissa Pak, Lauren Belfiore, Edwin van Oosten, Luke Ajay David, Sisu Han, Yaroslav Ilnytskyy, Igor Kovalchuk, Deborah Kurrasch, Satoshi Okawa, Antonio Del Sol, Robert A Screaton, Isabelle Aubert, Carol Schuurmans","doi":"10.7554/eLife.100604","DOIUrl":"10.7554/eLife.100604","url":null,"abstract":"<p><p>Metabolic pathways are remodeled in response to energy and other homeostatic demands and are dynamically regulated during embryonic development, suggesting a role in guiding cellular differentiation. Here, we show that glycolytic flux is required and sufficient to bias multipotent retinal progenitor cells (RPCs) to acquire a rod photoreceptor fate in the murine retina. In RPC-specific <i>Phosphatase and tensin homolog</i> conditional knockout (<i>Pten-</i>cKO) and RPC-specific conditional gain-of-function of dominant active PFKFB3 (cytoPFKFB3) mice, glycolytic gene expression and activity are elevated, correlating with precocious rod photoreceptor differentiation and outer segment (OS) maturation. Conversely, glycolytic inhibition in retinal explants suppresses RPC proliferation and photoreceptor differentiation, achieved either with 2-deoxy-D-glucose, a competitive inhibitor of glucose metabolism, by lowering media pH, which disables PKM2, a rate-limiting enzyme, or by inhibiting lactate/H⁺ symporters, which lowers intracellular pH. Mechanistically, we show that Wnt signaling, the top-upregulated pathway in <i>Pten-</i>cKO retinas, is a glycolysis-dependent pathway. Pharmacological and genetic perturbation of Wnt signaling by knocking-out <i>Ctnnb1</i>, encoding β-catenin, phenocopies glycolytic inhibition, suppressing RPC proliferation, photoreceptor differentiation, and OS maturation. Thus, developmental rewiring of glycolytic flux modulates Wnt signaling to drive rod photoreceptor differentiation and maturation, an instructive role that may be exploited therapeutically for cell replacement strategies.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12173459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144316208","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":"Targeted protein degradation by KLHDC2 ligands identified by high-throughput screening.","authors":"Han Zhou, Tonglian Zhou, Wenli Yu, Liping Liu, Yeonjin Ko, Kristen A Johnson, Ian A Wilson, Peter G Schultz, Michael J Bollong","doi":"10.7554/eLife.106844","DOIUrl":"10.7554/eLife.106844","url":null,"abstract":"<p><p>Proteolysis-targeting chimeras (PROTACs) enable the selective and sub-stoichiometric elimination of pathological proteins, yet only two E3 ligases are routinely used for this purpose. Here, we expand the repertoire of PROTAC-compatible E3 ligases by identifying a novel small molecule scaffold targeting the ubiquitin E3 ligase KLHDC2 using a fluorescence polarization-based high-throughput screen. We highlight the utility of this ligand with the synthesis of PROTACs capable of potently degrading BRD4 in cells. This work affords additional chemical matter for targeting KLHDC2 and suggests a practical approach for identifying novel E3 binders by high-throughput screening.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12169847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301384","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":"CARD8 inflammasome activation during HIV-1 cell-to-cell transmission.","authors":"Jessie Kulsuptrakul, Michael Emerman, Patrick S Mitchell","doi":"10.7554/eLife.102676","DOIUrl":"10.7554/eLife.102676","url":null,"abstract":"<p><p>Our previous work demonstrated that CARD8 detects HIV-1 infection by sensing the enzymatic activity of the HIV protease, resulting in CARD8-dependent inflammasome activation (Kulsuptrakul et al., 2023). CARD8 harbors a motif in its N-terminus that functions as a HIV protease substrate mimic, permitting innate immune recognition of HIV-1 protease activity, which when cleaved by HIV protease triggers CARD8 inflammasome activation. Here, we sought to understand CARD8 responses in the context of HIV-1 cell-to-cell transmission via a viral synapse. We observed that cell-to-cell transmission of HIV-1 between infected T cells and primary human monocyte-derived macrophages induces CARD8 inflammasome activation in a manner that is dependent on viral protease activity and largely independent of the NLRP3 inflammasome. Additionally, to further evaluate the viral determinants of CARD8 sensing, we tested a panel of HIV protease inhibitor-resistant clones to establish how variation in HIV protease affects CARD8 activation. We identified mutant HIV-1 proteases that differentially cleave and activate CARD8 compared to wildtype HIV-1, thus indicating that natural variation in HIV protease affects not only the cleavage of the viral Gag-Pol polyprotein but also likely impacts innate sensing and inflammation.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12169848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309721","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":"Rate of brain aging associates with future executive function in Asian children and older adults.","authors":"Susan F Cheng, Wan Lin Yue, Kwun Kei Ng, Xing Qian, Siwei Liu, Trevor W K Tan, Kim-Ngan Nguyen, Ruth L F Leong, Saima Hilal, Ching-Yu Cheng, Ai Peng Tan, Evelyn C Law, Peter D Gluckman, Christopher Li-Hsian Chen, Yap Seng Chong, Michael J Meaney, Michael W L Chee, B T Thomas Yeo, Juan Helen Zhou","doi":"10.7554/eLife.97036","DOIUrl":"10.7554/eLife.97036","url":null,"abstract":"<p><p>Brain age has emerged as a powerful tool to understand neuroanatomical aging and its link to health outcomes like cognition. However, there remains a lack of studies investigating the rate of brain aging and its relationship to cognition. Furthermore, most brain age models are trained and tested on cross-sectional data from primarily Caucasian, adult participants. It is thus unclear how well these models generalize to non-Caucasian participants, especially children. Here, we tested a previously published deep learning model on Singaporean elderly participants (55-88 years old) and children (4-11 years old). We found that the model directly generalized to the elderly participants, but model finetuning was necessary for children. After finetuning, we found that the rate of change in brain age gap was associated with future executive function performance in both elderly participants and children. We further found that lateral ventricles and frontal areas contributed to brain age prediction in elderly participants, while white matter and posterior brain regions were more important in predicting brain age of children. Taken together, our results suggest that there is potential for generalizing brain age models to diverse populations. Moreover, the longitudinal change in brain age gap reflects developing and aging processes in the brain, relating to future cognitive function.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12169851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301381","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":"Spectral decomposition unlocks ascidian morphogenesis.","authors":"Joel Dokmegang, Emmanuel Faure, Patrick Lemaire, Edwin Munro, Madhav Mani","doi":"10.7554/eLife.94391","DOIUrl":"10.7554/eLife.94391","url":null,"abstract":"<p><p>Describing morphogenesis generally consists in aggregating the multiple high-resolution spatiotemporal processes involved into reproducible low-dimensional morphological processes consistent across individuals of the same species or group. In order to achieve this goal, biologists often have to submit movies issued from live imaging of developing embryos either to a qualitative analysis or to basic statistical analysis. These approaches, however, present noticeable drawbacks as they can be time consuming, hence unfit for scale, and often lack standardization and a firm foundation. In this work, we leverage the power of a continuum mechanics approach and flexibility of spectral decompositions to propose a standardized framework for automatic detection and timing of morphological processes. First, we quantify whole-embryo scale shape changes in developing ascidian embryos by statistically estimating the strain rate tensor field of its time-evolving surface without the requirement of cellular segmentation and tracking. We then apply to this data spectral decomposition in space using spherical harmonics and in time using wavelets transforms. These transformations result in the identification of the principal dynamical modes of ascidian embryogenesis and the automatic unveiling of its blueprint in the form of scalograms that tell the story of development in ascidian embryos.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12169852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301382","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 common alteration in effort-based decision-making in apathy, anhedonia, and late circadian rhythm.","authors":"Sara Z Mehrhof, Camilla L Nord","doi":"10.7554/eLife.96803","DOIUrl":"10.7554/eLife.96803","url":null,"abstract":"<p><p>Motivational deficits are common in several brain disorders, and motivational syndromes like apathy and anhedonia predict worse outcomes. Disrupted effort-based decision-making may represent a neurobiological underpinning of motivational deficits, shared across neuropsychiatric disorders. We measured effort-based decision-making in 994 participants using a gamified online task, combined with computational modelling, and validated offline for test-retest reliability. In two pre-registered studies, we first replicated studies linking impaired effort-based decision-making to neuropsychiatric syndromes, taking both a transdiagnostic and a diagnostic-criteria approach. Next, testing participants with <i>early</i> and <i>late</i> circadian rhythms in the morning and evening, we find circadian rhythm interacts with time-of-testing to produce parallel effects on effort-based decision-making. Circadian rhythm may be an important variable in computational psychiatry, decreasing reliability or distorting results when left unaccounted for. Disentangling effects of neuropsychiatric syndromes and circadian rhythm on effort-based decision-making will be essential to understand motivational pathologies and to develop tailored clinical interventions.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12169849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301378","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":"Predictive learning rules generate a cortical-like replay of probabilistic sensory experiences.","authors":"Toshitake Asabuki, Tomoki Fukai","doi":"10.7554/eLife.92712","DOIUrl":"10.7554/eLife.92712","url":null,"abstract":"<p><p>The brain is thought to construct an optimal internal model representing the probabilistic structure of the environment accurately. Evidence suggests that spontaneous brain activity gives such a model by cycling through activity patterns evoked by previous sensory experiences with the experienced probabilities. The brain's spontaneous activity emerges from internally driven neural population dynamics. However, how cortical neural networks encode internal models into spontaneous activity is poorly understood. Recent computational and experimental studies suggest that a cortical neuron can implement complex computations, including predictive responses, through soma-dendrite interactions. Here, we show that a recurrent network of spiking neurons subject to the same predictive learning principle provides a novel mechanism to learn the spontaneous replay of probabilistic sensory experiences. In this network, the learning rules minimize probability mismatches between stimulus-evoked and internally driven activities in all excitatory and inhibitory neurons. This learning paradigm generates stimulus-specific cell assemblies that internally remember their activation probabilities using within-assembly recurrent connections. Our model contrasts previous models that encode the statistical structure of sensory experiences into Markovian transition patterns among cell assemblies. We demonstrate that the spontaneous activity of our model well replicates the behavioral biases of monkeys performing perceptual decision making. Our results suggest that interactions between intracellular processes and recurrent network dynamics are more crucial for learning cognitive behaviors than previously thought.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12169850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301380","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}