eLife最新文献

{"title":"Focal adhesion-derived liquid-liquid phase separations regulate mRNA translation.","authors":"Abhishek Kumar, Keiichiro Tanaka, Martin A Schwartz","doi":"10.7554/eLife.96157","DOIUrl":"10.7554/eLife.96157","url":null,"abstract":"<p><p>Liquid-liquid phase separation (LLPS) has emerged as a major organizing principle in cells. Recent work showed that multiple components of integrin-mediated focal adhesions, including p130Cas can form LLPS, which govern adhesion dynamics and related cell behaviors. In this study, we found that the focal adhesion protein p130Cas drives the formation of structures with the characteristics of LLPS that bud from focal adhesions into the cytoplasm. Condensing concentrated cytoplasm around p130Cas-coated beads allowed their isolation, which were enriched in a subset of focal adhesion proteins, mRNAs, and RNA binding proteins, including those implicated in inhibiting mRNA translation. Plating cells on very high concentrations of fibronectin to induce large focal adhesions inhibited message translation which required p130Cas and correlated with droplet formation. Photo-induction of p130Cas condensates using the Cry2 system also reduced translation. These results identify a novel regulatory mechanism in which high adhesion limits message translation via induction of p130Cas-dependent cytoplasmic LLPS. This mechanism may contribute to the quiescent state of very strongly adhesive myofibroblasts and senescent cells.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12201949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144495227","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":"Gamma Knife stereotactic radiotherapy combined with tislelizumab as later-line therapy in pMMR/MSS/MSI-L metastatic colorectal cancer: a phase II trial analysis.","authors":"Yiran Zhang, Hanyang Guan, Shijin Liu, Haoquan Li, Zili Bian, Jiashuai He, Zhan Zhao, Shenghui Qiu, Tianmu Mo, Xiangwei Zhang, Zuyang Chen, Hui Ding, Xiaoxu Zhao, Liang Wang, Yunlong Pan, Jinghua Pan","doi":"10.7554/eLife.103559","DOIUrl":"10.7554/eLife.103559","url":null,"abstract":"<p><strong>Background: </strong>An immunosuppressive tumor microenvironment limits the efficacy of immunotherapy, thus patients with MSS and pMMR mCRC often face great challenges.</p><p><strong>Methods: </strong>In this phase II trial, patients received Gamma Knife SBRT combined with Tislelizumab. Biomarker analysis was performed pre- and post-treatment.</p><p><strong>Results: </strong>From November 2022 to July 2024, 1of 20 patients achieved CR, 13 of 20 patients achieved PR, 6 achieved SD. mPFS was 10.7 months (95% CI, 6.4-15.0). With no grade 4 events noted, common adverse events included nausea (65%), anemia (55%), and fatigue (45%). RNA sequencing indicated enhanced immune infiltration in PR patients. For patients with pMMR/MSS/MSI-L mCRC who had not responded to first and second-line therapies, the combo of Gamma Knife SBRT and tislelizumab showed high efficacy and reasonable safety. Significant post-radiotherapy improvements in the tumor's immunosuppressive microenvironment, including lower fibrosis, normalizing of tumor vasculature, and activation of the PD-1/PD-L1 checkpoint pathway were revealed by biomarker analysis.</p><p><strong>Conclusions: </strong>These results imply that patients with pMMR/MSS/MSI-L mCRC who were unresponsive to the first and second-line chemotherapy, Gamma Knife SBRT with tislelizumab provides a safe and powerful later-line treatment alternative.</p><p><strong>Funding: </strong>This research was supported by the Clinical Frontier Technology Program of the First Affiliated Hospital of Jinan University (No. JNU1AF-CFTP-2022-a01223), the National Natural Science Foundation of China (82204436), Natural Science Foundation of Guangdong Province (2024A1515030010, 2022A1515011695), Science and Technology Projects in Guangzhou (2024A03J0825).</p><p><strong>Clinical trial number: </strong>ChiCTR2200066117.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12201948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144495229","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":"Investigating working memory updating processes of the human subcortex using 7T MRI.","authors":"Anne C Trutti, Zsuzsika Sjoerds, Russell J Boag, Solenn L Y Walstra, Steven Miletić, Scott J S Isherwood, Pierre-Louis Bazin, Bernhard Hommel, Sarah Habli, Desmond H Y Tse, Asta K Håberg, Birte U Forstmann","doi":"10.7554/eLife.97874","DOIUrl":"10.7554/eLife.97874","url":null,"abstract":"<p><p>A growing body of research suggests that dopamine is involved in working memory updating and that the striatum takes up a critical role in the subprocess of working memory gating . In this study, we investigated subcortical - in particular, possible dopaminergic - involvement in working memory updating subprocesses using the reference-back task and ultrahigh field 7 Tesla functional magnetic resonance imaging (fMRI). Using a scanning protocol optimized for BOLD sensitivity in the subcortex, we found no evidence of subcortical activation during working memory gate opening, predominantly activations in frontoparietal network regions, which challenges the idea of a striatal gating mechanism. However, during gate closing, subcortical activation was observed. Furthermore, a ready-to-update mode demonstrated large-spread subcortical activation, including basal ganglia nuclei, suggesting that the basal ganglia are engaged in general updating processes rather than specifically controlling the working memory gate. Moreover, substituting new information into working memory elicited activation in dopamine-producing midbrain regions along with the striatum, thalamus, and prefrontal cortex, indicating engagement of the basal ganglia-thalamo-cortical loop possibly driven by (potential) dopaminergic activity. These findings expand our understanding of subcortical regions involved in working memory updating, shifting the focus from gate opening to substitution as a midbrain-driven updating process.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12194129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144483661","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":"<i>mirror</i> determines the far posterior domain in butterfly wings.","authors":"Martik Chatterjee, Xin Yi Yu, Noah K Brady, Connor Amendola, Gabriel C Hatto, Robert D Reed","doi":"10.7554/eLife.96904","DOIUrl":"10.7554/eLife.96904","url":null,"abstract":"<p><p>Insect wings, a key innovation that contributed to the explosive diversification of insects, are recognized for their remarkable variation and many splendid adaptations. Classical morphological work subdivides insect wings into several distinct domains along the anteroposterior (AP) axis, each of which can evolve relatively independently to produce the myriad forms we see in nature. Important insights into AP subdivision of insect wings come from work in <i>Drosophila melanogaster</i>; however, they do not fully explain the diversity of AP domains observed across broad-winged insects. Here, we show that the transcription factor <i>mirror</i> acts as a selector gene to differentiate a far posterior domain in the butterfly wing, classically defined as the vannus, and has effects on wing shape, scale morphology, and color pattern. Our results support models of how selector genes may facilitate evolutionarily individuation of distinct AP domains in insect wings outside of <i>Drosophila</i> and suggest that the <i>D. melanogaster</i> wing blade has been reduced to represent only a portion of the archetypal insect wing.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12194122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144483660","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":"Atoh1 is required for the formation of lateral line electroreceptors and hair cells, whereas Foxg1 represses an electrosensory fate.","authors":"Martin Minařík, Alexander S Campbell, Roman Franěk, Michaela Vazačová, Miloš Havelka, David Gela, Martin Pšenička, Clare V H Baker","doi":"10.7554/eLife.96285","DOIUrl":"https://doi.org/10.7554/eLife.96285","url":null,"abstract":"<p><p>In electroreceptive jawed fishes and amphibians, individual lateral line placodes form lines of neuromasts on the head containing mechanosensory hair cells, flanked by fields of ampullary organs containing electroreceptors - modified hair cells that respond to weak electric fields. Extensively shared gene expression between neuromasts and ampullary organs suggests that conserved molecular mechanisms are involved in their development, but a few transcription factor genes are restricted either to the developing electrosensory or mechanosensory lateral line. Here, we used CRISPR/Cas9-mediated mutagenesis in G0-injected sterlet embryos (<i>Acipenser ruthenus</i>, a sturgeon) to test the function of three such genes. We found that the 'hair cell' transcription factor gene <i>Atoh1</i> is required for both hair cell and electroreceptor differentiation in sterlet, and for <i>Pou4f3</i> and <i>Gfi1</i> expression in both neuromasts and ampullary organs. These data support the conservation of developmental mechanisms between hair cells and electroreceptors. Targeting ampullary organ-restricted <i>Neurod4</i> did not yield any phenotype, potentially owing to redundancy with other <i>Neurod</i> genes that we found to be expressed in sterlet ampullary organs. After targeting mechanosensory-restricted <i>Foxg1</i>, ampullary organs formed within neuromast lines, suggesting that Foxg1 normally represses their development, whether directly or indirectly. We speculate that electrosensory organs may be the 'default' developmental fate of lateral line primordia in electroreceptive vertebrates.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144483663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct adaptation and epidemiological success of different genotypes within <i>Salmonella enterica</i> serovar Dublin.","authors":"Cheryll M Sia, Rebecca L Ambrose, Mary Valcanis, Patiyan Andersson, Susan A Ballard, Benjamin P Howden, Deborah A Williamson, Jaclyn S Pearson, Danielle J Ingle","doi":"10.7554/eLife.102253","DOIUrl":"10.7554/eLife.102253","url":null,"abstract":"<p><p><i>Salmonella</i> Dublin is a host-adapted, invasive nontyphoidal <i>Salmonella</i> (iNTS) serovar that causes bloodstream infections in humans and demonstrates increasing prevalence of antimicrobial resistance (AMR). Using a global dataset of 1303 genomes, coupled with in vitro assays, we examined the evolutionary, resistance, and virulence characteristics of <i>S</i>. Dublin. Our analysis revealed strong geographical associations between AMR profiles and plasmid types, with highly resistant isolates confined predominantly to North America, linked to IncC plasmids co-encoding AMR and heavy metal resistance. By contrast, Australian isolates were largely antimicrobial-susceptible, reflecting differing AMR pressures. We identified two phylogenetically distinct Australian lineages, ST10 and ST74, with a small number of ST10 isolates harbouring a novel hybrid plasmid encoding both AMR and mercuric resistance. Whereas the ST10 lineage remains globally dominant, the ST74 lineage was less prevalent. ST74 exhibited unique genomic features including a larger pan genome compared to ST10 and the absence of key virulence loci, including <i>Salmonella</i> pathogenicity island (SPI)-19 which encodes a type VI secretion system (T6SS). Despite these genomic differences, the ST74 lineage displayed enhanced intracellular replication in human macrophages and induced less pro-inflammatory responses compared with ST10, suggesting alternative virulence strategies that may support systemic dissemination of ST74. The Vi antigen was absent in all ST10 and ST74 genomes, highlighting challenges for serotyping and vaccine development, and has implications for current diagnostic and control strategies for <i>S.</i> Dublin infections. Collectively, this study represents the most comprehensive investigation of <i>S</i>. Dublin to date and, importantly, has revealed distinct adaptations of two genotypes within the same serovar, leading to different epidemiological success. The regional emergence and evolution of distinct <i>S.</i> Dublin lineages highlight the need to understand the divergence of intra-serovar virulence mechanisms which may impact the development of effective control measures against this important global pathogen.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12194135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144495226","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":"Myosin light chain 3 serves as a receptor for nervous necrosis virus entry into host cells via the macropinocytosis pathway.","authors":"Lan Yao, Wanwan Zhang, Xiaogang Yang, Meisheng Yi, Kuntong Jia","doi":"10.7554/eLife.104772","DOIUrl":"10.7554/eLife.104772","url":null,"abstract":"<p><p>Nodaviridae infections cause severe mortality in insects and fish, with nervous necrosis virus (NNV) posing significant threats to global fish populations. However, the host factors involved in NNV entry remain poorly understood. We identify myosin light chain 3 from marine medaka (<i>Oryzias melastigma</i>) (MmMYL3) as a novel receptor for red-spotted grouper NNV (RGNNV), facilitating internalization via macropinocytosis. MmMYL3 directly binds the RGNNV capsid protein (CP), which depends on the arm and S domains of CP and the EF-hand2 domain of MmMYL3. In vitro experiments showed that MmMYL3 siRNA, protein, anti-MYL3 antibodies, or the arm domain synthetic peptides blocked RGNNV entry. Moreover, in vivo administration of MmMYL3 protein also inhibited RGNNV infection. Ectopic MmMYL3 expression enabled RGNNV internalization into resistant cells. Notably, MmMYL3 facilitated RGNNV internalization through the macropinocytosis pathway via the IGF1R-Rac1/Cdc42 axis. Collectively, our findings underscore MYL3's crucial role in NNV entry and its potential as an antiviral target.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12194134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144495228","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":"Learning and cognition in highspeed decision making.","authors":"Martin Krause, Wolfram Schulze, Stefan Schuster","doi":"10.7554/eLife.99634","DOIUrl":"10.7554/eLife.99634","url":null,"abstract":"<p><p>It is widely accepted that more time and information yield better decisions. However, some decisions manage to be extremely fast and yet accurate. The trick of such highspeed decisions appears to be the use of simplifying heuristics that works well for the most common condition but lacks flexibility otherwise. Here, we describe an unexpected level of flexibility in a complex highspeed decision that is made faster than an Olympic sprinter can respond to the start gun. In this decision, archerfish observe the initial speed, direction, and height of falling prey and then use these initial values to turn right towards where ballistically falling prey would later land. To analyze the limits in flexibility of this highspeed decision, we developed and critically tested a system that allowed us to replace the usual ballistic relation between initial prey motion and the expected landing point with another deterministic rule. We discovered that, surprisingly, adult fish could reprogram their highspeed decision to the new rule. Moreover, after reprogramming their decision fish were immediately able to generalize their decision to novel untrained settings, showing a remarkable degree of abstraction in how the decision circuit represented the novel rule. The decision circuit is even capable of simultaneously using two distinct sets of rules, one for each of two visually distinct objects. The flexibility and level of cognition are unexpected for a decision that lacks a speed-accuracy tradeoff and is made in less than 100 ms. Our findings demonstrate the enormous potential highspeed decision making can have and strongly suggest that we presently underappreciate this form of decision making.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12194133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144483662","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":"Disentangling acute motor deficits and adaptive responses evoked by the loss of cerebellar output.","authors":"Nirvik Sinha, Sharon Israely, Ora Ben Harosh, Ran Harel, Julius P A Dewald, Yifat Prut","doi":"10.7554/eLife.105152","DOIUrl":"10.7554/eLife.105152","url":null,"abstract":"<p><p>Patients with cerebellar damage experience various motor impairments, but the specific sequence of primary and compensatory processes that contribute to these deficits remains unclear. To clarify this, we reversibly blocked cerebellar outflow in monkeys engaged in planar reaching tasks. This intervention led to a spatially selective reduction in hand velocity, primarily due to decreased muscle torque, especially in movements requiring high inter-joint torque coupling. When examining repeated reaches to the same target, we found that the reduced velocity resulted from both an immediate deficit and a gradually developing compensatory slowing to reduce passive inter-joint interactions. However, the slowed hand velocity did not account for the fragmented and variable movement trajectories observed during the cerebellar block. Our findings indicate that cerebellar impairment results in motor deficits due to both inadequate muscle torque and an altered motor control strategy for managing impaired limb dynamics. Additionally, impaired motor control elevates noise, which cannot be entirely mitigated through compensatory strategies.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12194117/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144483664","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":"Tissue-resident memory CD4⁺ T cells are sustained by site-specific levels of self-renewal and continuous replacement.","authors":"Jodie Chandler, M Elise Bullock, Arpit C Swain, Cayman Williams, Christiaan H van Dorp, Benedict Seddon, Andrew J Yates","doi":"10.7554/eLife.104278","DOIUrl":"10.7554/eLife.104278","url":null,"abstract":"<p><p>Tissue-resident memory T cells (T_RM) protect from repeat infections within organs and barrier sites. The breadth and duration of such protection are defined at minimum by three quantities: the rate at which new T_RM are generated from precursors, their rate of self-renewal, and their rate of loss through death, egress, or differentiation. Quantifying these processes individually is challenging. Here we combine genetic fate mapping tools and mathematical models to untangle these basic homeostatic properties of CD4⁺ T_RM in the skin and gut lamina propria (LP) of healthy adult mice. We show that CD69⁺CD4⁺ T_RM in skin reside for ∼24 days and self-renew more slowly, such that clones halve in size approximately every 5 weeks, and approximately 2% of cells are replaced daily from precursors. CD69⁺CD4⁺ T_RM in LP have shorter residencies (∼14 days) and are maintained largely by immigration (4-6% per day). We also find evidence that the continuous replacement of CD69⁺CD4⁺ T_RM at both sites derives from circulating effector-memory CD4⁺ T cells, in skin possibly via a local CD9^- intermediate. Our approach maps the ontogeny of CD4⁺ T_RM in skin and LP and exposes their dynamic and distinct behaviours, with continuous seeding and erosion potentially impacting the duration of immunity at these sites.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12194125/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144483665","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}