eLife最新文献

{"title":"Neuronal detection triggers systemic digestive shutdown in response to adverse food sources in <i>Caenorhabditis elegans</i>.","authors":"Yating Liu, Guojing Tian, Ziyi Wang, Junkang Zheng, Huimin Liu, Sucheng Zhu, Zhao Shan, Bin Qi","doi":"10.7554/eLife.104028","DOIUrl":"10.7554/eLife.104028","url":null,"abstract":"<p><p>The ability to sense and adapt to adverse food conditions is essential for survival across species, but the detailed mechanisms of neuron-digestive crosstalk in food sensing and adaptation remain poorly understood. Here, we identify a novel mechanism by which <i>Caenorhabditis elegans</i> detect unfavorable food sources through neurons and initiate a systemic response to shut down digestion, thus safeguarding against potential harm. Specifically, we demonstrate that NSY-1, expressed in AWC neurons, detects <i>Staphylococcus saprophyticus</i> (SS) as an unfavorable food source, prompting the animal to avoid and halt digestion of SS. Upon detection, the animals activate the AWC^OFF neural circuit, leading to a systemic digestive shutdown, which is mediated by NSY-1-dependent STR-130. Additionally, NSY-1 mutation triggers the production of insulin peptides, including INS-23, which interact with the DAF-2 receptor to modulate SS digestion and affect the expression of intestinal BCF-1. These findings uncover a crucial survival strategy through neuron-digestive crosstalk, where the NSY-1 pathway in AWC neurons orchestrates food evaluation and initiates digestive shutdown to adapt effectively to harmful food sources.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12494379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212027","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":"Age-related changes in 'cortical' 1/f dynamics are linked to cardiac activity.","authors":"Fabian Schmidt, Sarah K Danböck, Eugen Trinka, Dominic P Klein, Gianpaolo Demarchi, Nathan Weisz","doi":"10.7554/eLife.100605","DOIUrl":"10.7554/eLife.100605","url":null,"abstract":"<p><p>The power of electrophysiologically measured cortical activity decays with an approximately <i>1 /f^X</i> function. The slope of this decay (i.e. the spectral exponent, <i>X</i>) is modulated by various factors such as age, cognitive states or psychiatric/neurological disorders. Interestingly, a mostly parallel line of research has also uncovered similar effects for the spectral slope in the electrocardiogram (ECG). This raises the question of whether these bodywide changes in spectral slopes are (in-)dependent. Focusing on well-established age-related changes in spectral slopes, we analyzed a total of 1282 recordings of magnetoencephalography (MEG) resting state measurements with concurrent ECG in an age-diverse sample (18-88 years). Using a diverse array of analytical approaches, we demonstrate that the aperiodic signal recorded via surface electrodes/sensors originates from multiple physiological sources. Furthermore, our results suggest that common 'artifact' rejection approaches (i.e. ICA) may not be sufficient to separate cardiac from neural activity. In particular, significant parts of age-related changes in aperiodic activity normally interpreted to be of neural origin can be explained by cardiac activity. Moreover, our results suggest that changes (flattening/steepening) of the spectral slope with age are dependent on the recording site and investigated frequency range. Our results highlight the complexity of aperiodic activity while raising concerns when interpreting aperiodic activity as 'cortical' without considering physiological influences.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205823","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":"Endophilin A1 facilitates organization of the GABAergic postsynaptic machinery to maintain excitation-inhibition balance.","authors":"Xue Chen, Deng Pan, Jia-Jia Liu, Yanrui Yang","doi":"10.7554/eLife.102792","DOIUrl":"10.7554/eLife.102792","url":null,"abstract":"<p><p>The assembly and operation of neural circuits in the brain rely on the coordination and balance of excitatory and inhibitory activities. Inhibitory synapses are key regulators of the functional balance of neural circuits. However, due to the diversity of inhibitory presynaptic neurons, the complex composition of postsynaptic receptor subunits, and the lack of typical postsynaptic dense structure, there are relatively few studies on the regulatory mechanisms for inhibitory synaptic structure and function, and insufficient understanding of the cellular and molecular abnormalities of inhibitory synapses in neurological and neuropsychiatric disorders. Here, we report a crucial role for endophilin A1 in inhibitory synapses. We show that endophilin A1 directly interacts with the inhibitory postsynaptic scaffold protein gephyrin in excitatory neurons and promotes organization of the inhibitory postsynaptic density and synaptic recruitment/stabilization of the γ-aminobutyric acid type A receptors via its plasma membrane association and actin polymerization-promoting activities. Loss of endophilin A1 by gene knockout in mouse hippocampal CA1 pyramidal cells weakens inhibitory synaptic transmission and causes imbalance in the excitatory/inhibitory function of neural circuits, leading to increased susceptibility to epilepsy. Our findings identify endophilin A1 as an iPSD component and provide new insights into the organization and stabilization of inhibitory postsynapses to maintain E/I balance as well as the pathogenesis of epilepsy.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490859/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205824","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":"Balancing safety and efficiency in human decision-making.","authors":"Pranav Mahajan, Shuangyi Tong, Sang Wan Lee, Ben Seymour","doi":"10.7554/eLife.101371","DOIUrl":"10.7554/eLife.101371","url":null,"abstract":"<p><p>The safety-efficiency dilemma describes the problem of maintaining safety during efficient exploration and is a special case of the exploration-exploitation dilemma in the face of potential dangers. Conventional exploration-exploitation solutions collapse punishment and reward into a single feedback signal, whereby early losses can be overcome by later gains. However, the brain has a separate system for Pavlovian fear learning, suggesting a possible computational advantage to maintaining a specific fear memory during exploratory decision-making. In a series of simulations, we show this promotes safe but efficient learning and is optimised by arbitrating Pavlovian avoidance of instrumental decision-making according to uncertainty. We provide a basic test of this model in a simple human approach-withdrawal experiment in virtual reality and show that this flexible avoidance model captures choice and reaction times. These results show that the Pavlovian fear system has a more sophisticated role in decision-making than previously thought, by shaping flexible exploratory behaviour in a computationally precise manner.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205900","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":"Genome organization by SATB1 binding to base-unpairing regions (BURs) provides a scaffold for SATB1-regulated gene expression.","authors":"Yoshinori Kohwi, Xianrong Wong, Mari Grange, Thomas Sexton, Hunter W Richards, Yohko Kitagawa, Shimon Sakaguchi, Ya-Chen Liang, Cheng-Ming Chuong, Vladimir A Botchkarev, Ichiro Taniuchi, Karen L Reddy, Terumi Kohwi-Shigematsu","doi":"10.7554/eLife.105915","DOIUrl":"10.7554/eLife.105915","url":null,"abstract":"<p><p>Mammalian genomes are organized by multi-level folding; yet how this organization contributes to cell-type-specific transcription remains unclear. SATB1 forms a nuclear substructure that resists high-salt extraction. SATB1 binds base-unpairing regions (BURs), genomic elements with high unwinding propensities. In mouse thymocytes, we found that SATB1 establishes a two-tiered chromatin organization: one through indirect binding to transcriptionally active DNase 1-accessible chromatin and another by direct binding to BURs in the DNase 1-inaccessible nuclear substructure. Recently published ChIP-seq datasets show SATB1 binding to accessible chromatin at enhancers and CTCF sites, but not to BURs. By employing urea ChIP-seq, which retains only directly bound protein:DNA complexes, we found that BURs, but not CTCF sites, are direct SATB1 binding targets genome-wide. BURs bound to the SATB1 nuclear substructure interact with accessible chromatin, crossing multiple topologically associated domains (TADs). SATB1 is required for these megabase-scale interactions linked to cell-type-specific gene expression. BURs are highly enriched within transcriptionally repressive lamina-associated domains (LADs). Besides these BURs, SATB1 anchors some BURs (18%) outside LADs near genes in otherwise accessible chromatin to the SATB1 nuclear substructure. Only a subset of total BURs is bound to SATB1, depending on cell type. Notably, despite the mutually exclusive SATB1-binding profiles uncovered by the two ChIP-seq methods, we found most peaks in both profiles are valid and require SATB1. Based on these and previous data, we propose that the SATB1 protein network forms a chromatin scaffold, providing an interface that connects accessible chromatin to a subnuclear architectural structure, thereby facilitating the three-dimensional organization linked to cell-type-specific gene expression.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205997","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":"Lipid peroxidation and type I interferon coupling fuels pathogenic macrophage activation causing tuberculosis susceptibility.","authors":"Shivraj M Yabaji, Vadim Zhernovkov, Prasanna Babu Araveti, Suruchi Lata, Oleksii S Rukhlenko, Salam Al Abdullatif, Arthur Vanvalkenburg, Yuriy O Alekseyev, Qicheng Ma, Gargi Dayama, Nelson C Lau, W Evan Johnson, William R Bishai, Nicholas A Crossland, Joshua D Campbell, Boris N Kholodenko, Alexander A Gimelbrant, Lester Kobzik, Igor Kramnik","doi":"10.7554/eLife.106814","DOIUrl":"10.7554/eLife.106814","url":null,"abstract":"<p><p>A quarter of the human population is infected with <i>Mycobacterium tuberculosis</i>, but less than 10% of those infected develop pulmonary TB. We developed a genetically defined sst1-susceptible mouse model that uniquely reproduces a defining feature of human TB: the development of necrotic lung granulomas and determined that the sst1-susceptible phenotype was driven by the aberrant macrophage activation. This study demonstrates that the aberrant response of the sst1-susceptible macrophages to prolonged stimulation with TNF is primarily driven by conflicting Myc and antioxidant response pathways leading to a coordinated failure (1) to properly sequester intracellular iron and (2) to activate ferroptosis inhibitor enzymes. Consequently, iron-mediated lipid peroxidation fueled superinduction of Ifnβ and sustained the type I interferon (IFN-I) pathway hyperactivity that locked the sst1-susceptible macrophages in a state of unresolving stress and compromised their resistance to Mtb. The accumulation of the aberrantly activated, stressed, macrophages within the granuloma microenvironment led to the local failure of anti-tuberculosis immunity and tissue necrosis. The upregulation of the Myc pathway in peripheral blood cells of human TB patients was significantly associated with poor outcomes of TB treatment. Thus, Myc dysregulation in activated macrophages results in an aberrant macrophage activation and represents a novel target for host-directed TB therapies.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205955","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 in skin infections: Macrophages and beyond.","authors":"Vitka Gres, Merve Göcer, Julia Kolter, Philipp Henneke","doi":"10.7554/eLife.106688","DOIUrl":"10.7554/eLife.106688","url":null,"abstract":"<p><p>The skin is frequently subjected to minor mechanical insults that may compromise its barrier integrity and permit the entry of pathogens. Therefore, the immune system of the skin needs to rapidly balance antimicrobial defense with tissue repair. To maintain homeostasis, the skin relies both on acute immune defenses and on mechanisms of innate memory or trained immunity. This enhanced inflammatory response to a second challenge has been well characterized in bone marrow cells, such as monocytes, monocyte-derived macrophages, and stem cells. Yet, the specific memory responses in skin-resident immune cells remain less understood. Importantly, the common skin colonizer <i>Staphylococcus aureus</i> has been identified as a potent inducer of trained immunity, triggering both metabolic and epigenetic changes at local sites such as the skin, and centrally in the bone marrow. This review explores the emerging understanding of trained immunity in the skin, that is how infection-driven cellular processes induce long-lasting immune adaptation and modulate skin barrier integrity.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490854/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205927","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":"Understanding the global rise of artemisinin resistance: Insights from over 100,000 <i>Plasmodium falciparum</i> samples.","authors":"Andrew J Balmer, Nina F D White, Eyyüb S Ünlü, Chiyun Lee, Richard D Pearson, Jacob Almagro-Garcia, Cristina Ariani","doi":"10.7554/eLife.105544","DOIUrl":"10.7554/eLife.105544","url":null,"abstract":"<p><p>Artemisinin partial resistance (ART-R) in <i>Plasmodium falciparum</i> is a major challenge to malaria control globally. Over the last two decades, ART-R has spread widely across Southeast Asia, undermining public health strategies and hindering elimination. As of 2024, ART-R has now emerged in East Africa, with the potential to dramatically impact current efforts to control malaria in the region. Mitigating its spread requires detailed genomic surveillance of point mutations in the <i>kelch13</i> gene, the primary known determinant of artemisinin resistance. Although extensive surveillance data on these markers is available, it is distributed across many literature studies and open databases. In this review, we aggregate spatiotemporal data for 112,933 <i>P. falciparum</i> samples collected between 1980 and 2023 into a single resource, providing the most comprehensive overview of <i>kelch13</i> markers to date. We outline the history and current status of these mutations globally, with particular focus on their emergence in Southeast Asia and East/Northeast Africa. Concerningly, we find the recent increases in ART-R in Africa mirror patterns observed in Southeast Asia 10-15 years ago. We examine factors that may influence its spread, including fitness costs, treatment strategies, and local epidemiological dynamics, before discussing potential scenarios for how resistance may spread in Africa in coming years. This review provides a comprehensive account of how the situation of ART-R has unfolded globally so far, highlighting insights for researchers and public health bodies which aim to reduce its negative effects.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12490857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206012","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 influence of temporal context on vision over multiple time scales.","authors":"Kacie Lee, Reuben Rideaux","doi":"10.7554/eLife.106614","DOIUrl":"10.7554/eLife.106614","url":null,"abstract":"<p><p>Past sensory experiences influence perception of the present. Multiple research subfields have emerged to study this phenomenon at different temporal scales. These phenomena fall into three categories: the influence of immediately preceding sensory events (micro), expectations established by short sequences of events (meso), and regularities over long sequences of events (macro). In a single paradigm, we examined the influence of temporal context on human perception at each scale. By integrating behavioral and pupillometry recordings with electroencephalographical recordings from a previous study, we identify two distinct mechanisms that operate across all scales. The first is moderated by attention and supports rapid motor responses to expected events. The second operates independently of task demands and dampens the feedforward neural responses produced by expected events, leading to unexpected events eliciting earlier and more precise neural representations.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12488186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198732","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":"Patchy striatonigral neurons modulate locomotor vigor in response to environmental valence.","authors":"Sarah Hawes, Bo Liang, Braden Oldham, Breanna T Sullivan, Lupeng Wang, Bin Song, Lisa Chang, Da-Ting Lin, Huaibin Cai","doi":"10.7554/eLife.106403","DOIUrl":"10.7554/eLife.106403","url":null,"abstract":"<p><p>Spiny projection neurons (SPNs) in the dorsal striatum play crucial roles in locomotion control and value-based decision-making. SPNs, which include both direct-pathway striatonigral and indirect-pathway striatopallidal neurons, can be further classified into subtypes based on distinct transcriptomic profiles and cell body distribution patterns. However, how these SPN subtypes regulate spontaneous locomotion in the context of environmental valence remains unclear. Using Sepw1-Cre transgenic mice, which label a specific SPN subtype characterized by a patchy distribution of cell bodies in the dorsal striatum, we found that these patchy striatonigral neurons constrain motor vigor in response to valence differentials. In a modified light/dark box test, mice exhibited differential walking speeds between the light and dark zones. Genetic ablation of these patchy SPNs disrupted restful slowing in the dark zone and increased zone discrimination by speed. In vivo recordings linked the activity of these neurons to zone occupancy, speed, and deceleration, with a specific role in mediating deceleration. Furthermore, chemogenetic activation of patchy SPNs-and optical activation of striatonigral neurons in particular-reduced locomotion and attenuated speed-based zone discrimination. These findings reveal that a subtype of patchy striatonigral neurons regulates implicit walking speed selection based on innate valence differentials.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12488187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198737","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}