eLife最新文献

{"title":"Evidence from pupillometry, fMRI, and RNN modelling shows that gain neuromodulation mediates task-relevant perceptual switches.","authors":"Gabriel Wainstein, Christopher J Whyte, Kaylena A Ehgoetz Martens, Eli J Müller, Vicente Medel, Britt Anderson, Elisabeth Stöttinger, James Danckert, Brandon R Munn, James M Shine","doi":"10.7554/eLife.93191","DOIUrl":"10.7554/eLife.93191","url":null,"abstract":"<p><p>Perceptual updating has been hypothesised to rely on a network reset modulated by bursts of ascending neuromodulatory neurotransmitters, such as noradrenaline, abruptly altering the brain's susceptibility to changing sensory activity. To test this hypothesis at a large-scale, we analysed an ambiguous figures task using pupillometry and functional magnetic resonance imaging (fMRI). Behaviourally, qualitative shifts in the perceptual interpretation of an ambiguous image were associated with peaks in pupil diameter, an indirect readout of phasic bursts in neuromodulatory tone. We further hypothesised that stimulus ambiguity drives neuromodulatory tone, leading to heightened neural gain, hastening perceptual switches. To explore this hypothesis computationally, we trained a recurrent neural network (RNN) on an analogous perceptual categorisation task, allowing gain to change dynamically with classification uncertainty. As predicted, higher gain accelerated perceptual switching by transiently destabilising the network's dynamical regime in periods of maximal uncertainty. We leveraged a low-dimensional readout of the RNN dynamics to develop two novel macroscale predictions: perceptual switches should occur with peaks in low-dimensional brain state velocity and with a flattened egocentric energy landscape. Using fMRI, we confirmed these predictions, highlighting the role of the neuromodulatory system in the large-scale network reconfigurations mediating adaptive perceptual updates.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12180899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336325","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":"Mapping HIV-1 RNA structure, homodimers, long-range interactions and persistent domains by HiCapR.","authors":"Yan Zhang, Jingwan Han, Xie Dejian, Wenlong Shen, Ping Li, Jian You Lau, Jingyun Li, Lin Li, Grzegorz Kudla, Zhihu Zhao","doi":"10.7554/eLife.102550","DOIUrl":"10.7554/eLife.102550","url":null,"abstract":"<p><p>Human Immunodeficiency Virus type 1 (HIV-1) RNA genome organization remains a critical knowledge gap in understanding its replication cycle. To address this, we developed HiCapR, a psoralen crosslinking-based RNA proximity ligation method coupled with post-library hybridization, enabling high-resolution mapping of RNA-RNA interactions across the HIV-1 genome. This approach confirmed canonical structural motifs, including stem-loop architectures in the 5'-untranslated region (5'-UTR) and Rev Response Element (RRE), as well as dimerization sites within the 5'-UTR critical for viral packaging. Notably, HiCapR identified novel homodimerization events distributed along the genome, suggesting an expanded regulatory role of RNA multimerization in splicing regulation and selective encapsidation. Intriguingly, while infected cells exhibited extensive long-range RNA interactions-particularly within the 5'-UTR-virion-packaged genomes displayed a marked reduction in such interactions, indicative of a structural transition from a loosely organized state to a condensed conformation. This spatial reorganization coincided with the preservation of stable genomic domains essential for dimerization, which persisted throughout virion assembly. These domains, enriched at homodimer interfaces, likely serve as structural scaffolds ensuring fidelity during genome packaging. This work establishes HiCapR as a robust tool for probing RNA interactomes and provides mechanistic insights into how HIV-1 exploits RNA topological heterogeneity to regulate its life cycle. The identification of conserved structural domains and transient interaction networks opens avenues for targeting RNA conformation in antiviral strategies.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12180898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332655","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":"Efficacy and mechanism of action of cipargamin as an antibabesial drug candidate.","authors":"Hang Li, Shengwei Ji, Nanang R Ariefta, Eloiza May S Galon, Shimaa A E S El-Sayed, Thom Do, Lijun Jia, Miako Sakaguchi, Masahito Asada, Yoshifumi Nishikawa, Xin Qin, Mingming Liu, Xuenan Xuan","doi":"10.7554/eLife.101128","DOIUrl":"10.7554/eLife.101128","url":null,"abstract":"<p><p>Babesiosis is a disease brought on by intraerythrocytic parasites of the genus <i>Babesia</i>. Current chemotherapies are accompanied by side effects and parasite relapse. Therefore, it is crucial to develop highly effective drugs against <i>Babesia</i>. Cipargamin (CIP) has shown inhibition against apicomplexan parasites, mainly <i>Plasmodium</i> and <i>Toxoplasma</i>. This study evaluated the growth-inhibiting properties of CIP against <i>Babesia</i> spp. and investigated the mechanism of CIP on <i>B. gibsoni</i>. The half inhibitory concentration (IC₅₀) values of CIP against the in vitro growth of <i>B. bovis</i> and <i>B. gibsoni</i> were 20.2 ± 1.4 and 69.4 ± 2.2 nM, respectively. CIP significantly inhibited the growth of <i>B. microti</i> and <i>B. rodhaini</i> in vivo. Resistance was conferred by L921V and L921I mutations in BgATP4, which reduced the sensitivity to CIP by 6.1- and 12.8-fold. The inhibitory potency of CIP against BgATP4-associated ATPase activity was moderately reduced in mutant strains, with a 1.3- and 2.4-fold decrease in BgATP4^L921V and BgATP4^L921I, respectively, compared to that of BgATP4^WT. An in silico investigation revealed reductions in affinity for CIP binding to BgATP4^L921V and BgATP4^L921I compared to BgATP4^WT. Resistant strains showed no significant cross-resistance to atovaquone or tafenoquine succinate (TQ), with less than a onefold change in IC₅₀ values. Combining CIP with TQ effectively eliminated <i>B. microti</i> infection in SCID mice with no relapse, and parasite DNA was not detected by qPCR within 90 days post-infection. Our findings reveal the efficacy of CIP as an antibabesial agent, its limitations as a monotherapy due to resistance development, and the potential of combination therapy with TQ to overcome said resistance and achieve complete parasite clearance.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12178600/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324808","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>Salmonella</i> exploits host- and bacterial-derived β-alanine for replication inside host macrophages.","authors":"Shuai Ma, Bin Yang, Yuyang Sun, Xinyue Wang, Houliang Guo, Ruiying Liu, Ting Ye, Chenbo Kang, Jingnan Chen, Lingyan Jiang","doi":"10.7554/eLife.103714","DOIUrl":"10.7554/eLife.103714","url":null,"abstract":"<p><p><i>Salmonella</i> is a major foodborne pathogen that can effectively replicate inside host macrophages to establish life-threatening systemic infections. <i>Salmonella</i> must utilize diverse nutrients for growth in nutrient-poor macrophages, but which nutrients are required for intracellular <i>Salmonella</i> growth is largely unknown. Here, we found that either acquisition from the host or de novo synthesis of a nonprotein amino acid, β-alanine, is critical for <i>Salmonella</i> replication inside macrophages. The concentration of β-alanine is decreased in <i>Salmonella</i>-infected macrophages, while the addition of exogenous β-alanine enhances <i>Salmonella</i> replication in macrophages, suggesting that <i>Salmonella</i> can uptake host-derived β-alanine for intracellular growth. Moreover, the expression of <i>panD,</i> the rate-limiting gene required for β-alanine synthesis in <i>Salmonella,</i> is upregulated when <i>Salmonella</i> enters macrophages. Mutation of <i>panD</i> impaired <i>Salmonella</i> replication in macrophages and colonization in the mouse liver and spleen, indicating that de novo synthesis of β-alanine is essential for intracellular <i>Salmonella</i> growth and systemic infection. Additionally, we revealed that β-alanine influences <i>Salmonella</i> intracellular replication and in vivo virulence partially by increasing expression of the zinc transporter genes <i>znuABC</i>, which in turn facilitates the uptake of the essential micronutrient zinc by <i>Salmonella</i>. Taken together, these findings highlight the important role of β-alanine in the intracellular replication and virulence of <i>Salmonella</i>, and <i>panD</i> is a promising target for controlling systemic <i>Salmonella</i> infection.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12178601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324805","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 causal role of the NMDA receptor in recurrent processing during perceptual integration.","authors":"Samuel Noorman, Timo Stein, Jasper Zantvoord, Johannes Fahrenfort, Simon van Gaal","doi":"10.7554/eLife.100530","DOIUrl":"10.7554/eLife.100530","url":null,"abstract":"<p><p>Perceptual inference requires the integration of visual features through recurrent processing, the dynamic exchange of information between higher- and lower-level cortical regions. While animal research has demonstrated a crucial role of NMDA receptors in recurrent processing, establishing a causal link between NMDA receptors and recurrent processing in humans has remained challenging. Here, we report two pharmacological studies with randomized, double-blind, crossover designs in which we administered the NMDA antagonist memantine, while collecting human electroencephalography (EEG). We trained and tested EEG classifiers to reflect the processing of specific stimulus features with increasing levels of complexity, namely differences in stimulus contrast, collinearity between local line elements, and illusory surfaces of a Kanizsa triangle. In two experiments involving different participants and visual tasks, we found that memantine selectively improved decoding of the Kanizsa illusion, known to depend on recurrent processing, while leaving decoding of contrast and collinearity largely unaffected. Interestingly, the results from an attentional blink (experiment 1) and task-relevance manipulation (experiment 2) showed that memantine was only effective when the stimulus was attended and consciously accessed. These findings suggest that NMDA inhibition through memantine enhances recurrent processing, especially for attended objects, and thereby provide a crucial step toward bridging animal and human research, shedding light on the neural mechanisms underpinning perceptual inference and conscious perception.</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/PMC12176389/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324806","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":"Retraction: Targeting posttranslational modifications of RIOK1 inhibits the progression of colorectal and gastric cancers.","authors":"Xuehui Hong, He Huang, Xingfeng Qiu, Zhijie Ding, Xing Feng, Yuekun Zhu, Huiqin Zhuo, Jingjing Hou, Jiabao Zhao, Wangyu Cai, Ruihua Sha, Xinya Hong, Yongxiang Li, Hongjiang Song, Zhiyong Zhang","doi":"10.7554/eLife.108007","DOIUrl":"10.7554/eLife.108007","url":null,"abstract":"<p><p></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/PMC12176384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324812","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 multi-gene predictive model for the radiation sensitivity of nasopharyngeal carcinoma based on machine learning.","authors":"Kailai Li, Junyi Liang, Nan Li, Jianbo Fang, Xinyi Zhou, Jian Zhang, Anqi Lin, Peng Luo, Hui Meng","doi":"10.7554/eLife.99849","DOIUrl":"10.7554/eLife.99849","url":null,"abstract":"<p><p>Radiotherapy resistance in nasopharyngeal carcinoma (NPC) is a major cause of recurrence and metastasis. Identifying radiotherapy-related biomarkers is crucial for improving patient survival outcomes. This study developed the nasopharyngeal carcinoma radiotherapy sensitivity score (NPC-RSS) to predict radiotherapy response. By evaluating 113 machine learning algorithm combinations, the glmBoost+NaiveBayes model was selected to construct the NPC-RSS based on 18 key genes, which demonstrated good predictive performance in both public and in-house datasets. The study found that NPC-RSS is closely associated with immune features, including chemokine factors and their receptor families and the major histocompatibility complex (MHC). Gene functional analysis revealed that NPC-RSS influences key signaling pathways such as Wnt/β-catenin, JAK-STAT, NF-κB, and T cell receptors. Cell line validation confirmed that SMARCA2 and CD9 gene expression is consistent with NPC-RSS. Single-cell analysis revealed that the radiotherapy-sensitive group exhibited richer immune infiltration and activation states. NPC-RSS can serve as a predictive tool for radiotherapy sensitivity in NPC, offering new insights for precise screening of patients who may benefit from radiotherapy.</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/PMC12176387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324807","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":"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}