eLife最新文献

{"title":"In mice, discrete odors can selectively promote the neurogenesis of sensory neuron subtypes that they stimulate.","authors":"Kawsar Hossain, Madeline Smith, Karlin E Rufenacht, Rebecca O'Rourke, Stephen W Santoro","doi":"10.7554/eLife.96152","DOIUrl":"10.7554/eLife.96152","url":null,"abstract":"<p><p>In mammals, olfactory sensory neurons (OSNs) are born throughout life, ostensibly solely to replace neurons lost <i>via</i> turnover or injury. This assumption follows from the hypothesis that olfactory neurogenesis is stochastic with respect to neuron subtype, as defined by the single odorant receptor that each neural precursor stochastically chooses out of hundreds of possibilities. This assumption is challenged, however, by recent findings that the birthrates of a fraction of OSN subtypes are selectively reduced by olfactory deprivation. These findings raise questions about how, and why, olfactory stimuli are required to accelerate the neurogenesis rates of some subtypes, including whether the stimuli are specific (e.g. discrete odorants) or generic (e.g. broadly activating odors or mechanical stimuli). Based on previous findings that the exposure of mice to sex-specific odors can increase the representations of subtypes responsive to those odors, we hypothesized that the neurogenic stimuli comprise discrete odorants that selectively stimulate OSNs of the same subtypes whose birthrates are accelerated. In support of this, we have found, using scRNA-seq and subtype-specific OSN birthdating, that exposure to male and exogenous musk odors can accelerate the birthrates of subtypes responsive to those odors. These findings reveal that certain odor experiences can selectively 'amplify' specific OSN subtypes and suggest that persistent OSN neurogenesis serves, in part, an adaptive function.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12176391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324809","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":"Trained immunity: A new player in cancer immunotherapy.","authors":"Shu Li, Yi Zou, Austin McMasters, Fuxiang Chen, Jun Yan","doi":"10.7554/eLife.104920","DOIUrl":"10.7554/eLife.104920","url":null,"abstract":"<p><p>In the past, immune memory was considered an exclusive feature of the adaptive immune system. However, accumulating evidence suggests that the innate immune system, the most primitive and fundamental component of immunity, can mount more robust responses to non-specific stimuli following prior exposure to different types of initial stimuli, a phenomenon known as trained immunity. Trained immunity has been extensively studied in diverse disease contexts, including infectious diseases, autoimmune disorders, and chronic inflammatory conditions. Notably, significant advancements have been made in recent years in understanding the roles and therapeutic potential of trained immunity in oncology. This review aims to explore the multifaceted roles of trained immunity across different cancer types, providing a comprehensive summary of the pertinent stimuli and associated molecular mechanisms. Additionally, we evaluate the clinical applications of various trained immunity stimuli in cancer therapy and offer perspectives on future directions for integrating trained immunity into cancer treatment strategies.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12176388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324813","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":"Reading the DNA of telomeres.","authors":"Shamayita Roy, Claus M Azzalin","doi":"10.7554/eLife.107648","DOIUrl":"10.7554/eLife.107648","url":null,"abstract":"<p><p>Experiments with tools designed to detect DNA damage reveal unique and conserved features of telomeres in cancer cells.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12176385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324811","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":"Stimulatory and inhibitory G-protein signaling relays drive cAMP accumulation for timely metamorphosis in the chordate <i>Ciona</i>.","authors":"Akiko Hozumi, Nozomu M Totsuka, Arata Onodera, Yanbin Wang, Mayuko Hamada, Akira Shiraishi, Honoo Satake, Takeo Horie, Kohji Hotta, Yasunori Sasakura","doi":"10.7554/eLife.99825","DOIUrl":"10.7554/eLife.99825","url":null,"abstract":"<p><p>Larvae of the ascidian <i>Ciona</i> initiate metamorphosis tens of minutes after adhesion to a substratum via their adhesive organ. The gap between adhesion and metamorphosis initiation is suggested to ensure the rigidity of adhesion, allowing <i>Ciona</i> to maintain settlement after losing locomotive activity through metamorphosis. The mechanism producing the gap is unknown. Here, by combining gene functional analyses, pharmacological analyses, and live imaging, we propose that the gap represents the time required for sufficient cyclic adenosine monophosphate (cAMP) accumulation to trigger metamorphosis. Not only the Gs pathway but also the Gi and Gq pathways are involved in the initiation of metamorphosis in the downstream signaling cascade of the neurotransmitter GABA, the known initiator of <i>Ciona</i> metamorphosis. The mutual crosstalk of stimulatory and inhibitory G-proteins functions as the accelerator and brake for cAMP production, ensuring the faithful initiation of metamorphosis at an appropriate time and in the right situation.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12176390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324810","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":"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}