eLife最新文献

{"title":"Neural representation of time across complementary reference frames.","authors":"Yangwen Xu, Nicola Sartorato, Léo Dutriaux, Roberto Bottini","doi":"10.7554/eLife.107273","DOIUrl":"https://doi.org/10.7554/eLife.107273","url":null,"abstract":"<p><p>Humans conceptualize time in terms of space, allowing flexible time construals from various perspectives. We can travel internally through a timeline to remember the past and imagine the future (i.e., mental time travel) or watch from an external standpoint to have a panoramic view of history (i.e., mental time watching). However, the neural mechanisms that support these flexible temporal construals remain unclear. To investigate this, we asked participants to learn a fictional religious ritual of 15 events. During fMRI scanning, they were guided to consider the event series from either an internal or external perspective in different tasks. Behavioral results confirmed the success of our manipulation, showing the expected symbolic distance effect in the internal-perspective task and the reverse effect in the external-perspective task. We found that the activation level in the posterior parietal cortex correlated positively with sequential distance in the external-perspective task but negatively in the internal-perspective task. In contrast, the activation level in the anterior hippocampus positively correlated with sequential distance regardless of the observer's perspectives. These results suggest that the hippocampus stores the memory of the event sequences allocentrically in a perspective-agnostic manner. Conversely, the posterior parietal cortex retrieves event sequences egocentrically from the optimal perspective for the current task context. Such complementary allocentric and egocentric representations support both the stability of memory storage and the flexibility of time construals.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835210","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":"<i>Mettl5</i> coordinates protein production and degradation of PERIOD to regulate sleep in <i>Drosophila</i>.","authors":"Xiaoyu Wu, Xingzhuo Yang, Tiantian Fu, Yikang Rong, Juan Du","doi":"10.7554/eLife.103427","DOIUrl":"https://doi.org/10.7554/eLife.103427","url":null,"abstract":"<p><p>Sleep plays a critical role in animal physiology, primarily governed by the brain, and its disruption is prevalent in various brain disorders. Mettl5 is associated with intellectual disability (ID), which often includes sleep disturbances. However, the mechanism underlying these sleep disruptions in ID remains poorly understood. In this study, we investigated the sleep phenotypes resulting from <i>Drosophila Mettl5</i> mutations. Rescue experiments revealed that <i>Mettl5</i> functions predominantly within neurons and glia marked by <i>Mettl5</i>-Gal4 to regulate sleep. Previous work established that Mettl5 forms a complex with Trmt112 to influence rRNA methylation. Notably, a mutation in <i>Trmt112</i> recapitulated these sleep disturbances, implicating translational regulation by the Mettl5/Trmt112 complex. Subsequent RNA-seq and Ribo-seq analyses of <i>Mettl5^1bp</i> mutants uncovered downstream effects, including altered expression of proteasome components and clock genes. Rescue experiments confirmed that the net increase in PERIOD protein underlies the sleep phenotype. This study illuminates the interplay between ribosome function, clock genes, and the proteasome in sleep regulation, highlighting the integrated roles of protein synthesis and degradation. These findings could potentially provide an example for in vivo study of rRNA methylation function, expand our understanding of protein homeostasis in sleep, and offer insights into the sleep phenotypes associated with ID.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835125","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":"A novel 3D visualization method in mice identifies the periportal lamellar complex (PLC) as a key regulator of hepatic ductal and neuronal branching morphogenesis.","authors":"Tongtong Xu, Fujun Cao, Ruihan Zhou, Qin Chen, Jian Zhong, Yulin Wang, Chaoxin Xiao, Banglei Yin, Chong Chen, Chengjian Zhao","doi":"10.7554/eLife.108669","DOIUrl":"10.7554/eLife.108669","url":null,"abstract":"<p><p>The liver is a complex organ responsible for multiple functions, including metabolism, energy storage, detoxification, bile secretion, and immune regulation. Its highly organized vascular system plays a crucial role in maintaining functional zonation and tissue homeostasis. Within the liver, the hepatic artery, portal vein, hepatic vein, bile duct, and nerve networks intertwine to form an intricate three-dimensional architecture; however, traditional two-dimensional imaging fails to reveal their true spatial relationships, and current three-dimensional imaging methods remain insufficient to capture fine structural details. To achieve comprehensive visualization of these multi-ductal systems, we established a high-resolution three-dimensional imaging platform that combines multicolor perfusion of metallic compound nanoparticles (MCNPs) with an optimized tissue-clearing protocol (Liver-CUBIC), enabling simultaneous 3D reconstruction of the portal vein, hepatic artery, bile duct, and hepatic vein in mouse livers. Based on these data, we identified and defined a previously unrecognized structure located in the outer layer of the portal vein, termed the periportal lamellar complex (PLC). The PLC encircles the portal vein between the vascular endothelium and the perisinusoidal region, exhibits low-permeability barrier characteristics, and contains a distinctive population of CD34⁺Sca-1⁺ endothelial cells. During liver fibrosis, the PLC extends from the portal vein toward the hepatic lobule, forming a structural scaffold that guides bile duct and nerve migration.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13152276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835055","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":"Prolonged oscillating preoptic area kisspeptin neuron activity underlies the preovulatory luteinizing hormone surge in mice.","authors":"Ziyue Zhou, Cheng-Yu Huang, Allan Edward Herbison","doi":"10.7554/eLife.109215","DOIUrl":"10.7554/eLife.109215","url":null,"abstract":"<p><p>The population of kisspeptin neurons located in the rostral periventricular area of the third ventricle (RP3V) is thought to have a key role in generating the GnRH surge that triggers ovulation. Using a modified GCaMP fibre photometry procedure, we have been able to record the in vivo population activity of RP3V^KISS neurons across the estrous cycle of female mice. A marked increase in GCaMP activity was detected beginning on the afternoon of proestrus that lasted in total for 13±1 hr. This was comprised of slow baseline oscillations with a period of 91±4 min associated with high-frequency rapid transients. Very little oscillating baseline or transient activity was detected at other stages of the estrous cycle. Concurrent blood sampling showed that the peak of the LH surge occurred 3.5±1.1 hr after the first baseline RP3V^KISS neuron baseline oscillation on the afternoon of proestrus. The time of onset of RP3V^KISS neuron oscillations varied between mice and across subsequent proestrous stages in the same mice. To assess the impact of estradiol on RP3V^KISS neuron activity, mice were ovariectomized and given an incremental estradiol replacement regimen. Minimal patterned GCaMP activity was found in OVX mice, and this was not changed acutely by any of the estradiol treatments. However, on the afternoon of the expected LH surge, the same oscillating baseline activity with associated transients occurred for 7.1±0.5 hr. These observations reveal an unexpected prolonged oscillatory pattern of RP3V^KISS neuron activity that is dependent on estrogen and underlies the preovulatory LH surge as well as potentially other facets of reproductive behavior.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13152274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835224","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":"How membranes shape up for lipid transfer.","authors":"Takashi Hirashima, Toshiya Endo","doi":"10.7554/eLife.111373","DOIUrl":"10.7554/eLife.111373","url":null,"abstract":"<p><p>The extraction of a phospholipid called phosphatidic acid from the mitochondrial outer membrane is regulated by the curvature of this membrane.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"15 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13152273/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835158","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":"HER2-driven mammary tumorigenesis enhances bioenergetics despite reductions in mitochondrial content.","authors":"Sara M Frangos, Henver S Brunetta, Dongdong Wang, Maria Joy Therese Jabile, Leslie M Jeffries, Grace Mencfeld, David W L Ma, William J Muller, Cezar M Khursigara, Kelsey H Fisher-Wellman, Jim Petrik, Gregory R Steinberg, Graham P Holloway","doi":"10.7554/eLife.104079","DOIUrl":"https://doi.org/10.7554/eLife.104079","url":null,"abstract":"<p><p>It is now recognized that mitochondria play a crucial role in tumorigenesis; however, it has become clear that tumor metabolism varies significantly between cancer types. The failure of recent clinical trials aimed at directly targeting tumor respiration through oxidative phosphorylation inhibitors underscores the critical need for further studies providing an in-depth evaluation of mitochondrial bioenergetics. Accordingly, we comprehensively assessed the bulk tumor and mitochondrial metabolic phenotype in murine HER2-driven mammary cancer tumors and benign mammary tissue. Transcriptomic and proteomic profiling revealed a broad downregulation of mitochondrial genes/proteins in tumors, including OXPHOS subunits comprising Complexes I-IV. Despite reductions in tumor mitochondrial proteins, mitochondrial respiration was several-fold higher compared to benign mammary tissue, which persisted regardless of normalization method (wet weight, total protein content, and when corrected for mitochondrial content). This upregulated respiratory capacity could not be explained by OXPHOS uncoupling, suggesting HER2 signaling regulates intrinsic mitochondrial bioenergetics. In further support, lapatinib, an EGFR/HER2 tyrosine kinase inhibitor, attenuated mitochondrial respiration in NF639 murine mammary tumor epithelial cells. Together, this data highlights that the typical correlation between mitochondrial content and respiratory capacity may not apply to all tumor types and implicates HER2-linked activation of mitochondrial respiration supporting tumorigenesis in this model.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835111","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":"Natural xanthones as α-Mangostin induce vasorelaxation involving key gating residues in the S6 domain of BK channels.","authors":"Soenke Cordeiro, Robert Patejdl, Thomas Baukrowitz, Marianne A Musinszki","doi":"10.7554/eLife.109479","DOIUrl":"https://doi.org/10.7554/eLife.109479","url":null,"abstract":"<p><p>Polyphenolic compounds are widely explored for health benefits, including hypertension, but their active ingredients, molecular targets, and mechanisms remain poorly defined. We identify the xanthone Mangostin from <i>Garcinia mangostana</i> as a potent modulator of several potassium channels, with large-conductance K⁺ (BK) channels as its primary target for vasorelaxation. Mangostin-activated BK channels as α subunits alone, in complexes with vascular β1 subunits, and in reconstituted BKα/β1-Ca_v nanodomains. It shifted BK voltage activation to more negative potentials by antagonizing channel closure and promoting channel opening without markedly altering Ca²⁺ sensitivity. Docking, competition, single-channel analysis, and mutagenesis localized the binding site in the pore cavity below the SF, involving gating-critical S6 residues I308, L312, and A316, and suggest that Mangostin stays bound in closed and open states. These findings establish BK channel activation as the core molecular mechanism driving Mangostin's vascular effects and define its structural mode of action, informing nutraceutical safety assessment and BK-targeted drug design.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148824/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835167","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":"Continuous flash suppression of neural responses and population orientation coding in macaque V1.","authors":"Cai-Xia Chen, Xin Wang, Dan-Qing Jiang, Shi-Ming Tang, Cong Yu","doi":"10.7554/eLife.107518","DOIUrl":"https://doi.org/10.7554/eLife.107518","url":null,"abstract":"<p><p>Continuous flash suppression (CFS), in which a dynamic masker presented to one eye suppresses awareness of a stimulus in the other eye, is widely used to study visual subconsciousness. Although some studies report preserved high-level processing under CFS, these effects have been increasingly questioned and may partly reflect residual low-level feature processing. A key unresolved issue is how strongly neuronal responses in V1, where inputs from the two eyes first converge, are affected by CFS, and how much the remaining signals can support downstream processing. Here, we used two-photon calcium imaging to record large populations of V1 neurons in awake, fixating macaques while presenting grating stimuli under CFS. CFS strongly suppressed V1 orientation responses in an ocular-dominance-dependent manner, nearly abolishing responses in neurons preferring the masker eye or both eyes, and significantly reducing responses in neurons preferring the grating eye. Modeling analyses further indicated that V1 population activity under CFS may still support coarse orientation classification but not accurate stimulus reconstruction. These results suggest that CFS substantially degrades orientation information in V1. The residual signals may support limited low-level processing but are likely insufficient for downstream higher-level visual and cognitive tasks.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835103","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":"Fully computational design of PAM-relaxed <i>Staphylococcus aureus</i> Cas9 with expanded targeting capability using UniDesign.","authors":"Youcai Xiong, Li-Kuang Tsai, Jun Zhou, Shuang Chen, Xiaofeng Xia, Jifeng Zhang, Y Eugene Chen, Jie Xu, Xiaoqiang Huang","doi":"10.7554/eLife.110906","DOIUrl":"https://doi.org/10.7554/eLife.110906","url":null,"abstract":"<p><p>CRISPR-Cas9 nucleases have transformed genome engineering, yet their application is often constrained by protospacer-adjacent motif (PAM) requirements. <i>Staphylococcus aureus</i> Cas9 (SaCas9) is particularly attractive for in vivo applications due to its compact size; however, its NNGRRT PAM limits targetable genomic sites. Here, we report KRH, a SaCas9 variant designed entirely from the wild-type enzyme through a fully computational point-mutation design workflow, UniDesign, without additional experimental optimization. As expected, KRH efficiently recognizes an expanded NNNRRT PAM and exhibits substantially enhanced editing efficiency at non-canonical PAM sites, with improvements of up to 116-fold over the wild type. KRH achieves genome- and base-editing efficiencies comparable to, or exceeding, those of the well-known evolution-derived KKH variant. Computational modeling by UniDesign provides a mechanistic explanation for the PAM relaxation observed in both KRH and KKH, with structural and energetic analyses revealing that KRH relaxes PAM specificity by fine-tuning the balance between sequence-specific interactions with PAM bases and nonspecific contacts with the DNA backbone. Beyond its practical utility, KRH demonstrates that computational design can identify a minimal set of mutations sufficient to remodel the PAM interface while preserving high nuclease activity. This approach recapitulates-and in some cases surpasses-the performance of evolution-derived variants, offering a scalable strategy for high-throughput Cas9 engineering. Overall, these results establish KRH as a blueprint for rationally engineered, PAM-relaxed nucleases and underscore the power of computational design to accelerate next-generation genome editing.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"15 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835185","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":"Canonical neurodevelopmental trajectories of structural and functional manifolds.","authors":"Alicja Monaghan, Richard A I Bethlehem, Danyal Akarca, Daniel S Margulies, Duncan E Astle","doi":"10.7554/eLife.103097","DOIUrl":"https://doi.org/10.7554/eLife.103097","url":null,"abstract":"<p><p>Organisational gradients refer to a continuous low-dimensional embedding of brain regions and can quantify core organisational principles of complex systems like the human brain. Mapping how these organisational principles are altered or refined across development and phenotypes is essential to understanding the relationship between brain and behaviour. Taking a developmental approach and leveraging longitudinal and cross-sectional data from two multi-modal neuroimaging datasets, spanning the full neurotypical-neurodivergent continuum, we charted the organisational variability of structural (610 participants, N=390 with one observation, N=163 with two observations and N=57 with three) and functional (512 participants, N=340 with one observation, N=128 with two observations and N=44 with three). Across datasets, despite differing phenotypes, we observe highly similar structural and functional gradients. These gradients, or organisational principles, are highly stable across development, with the exact same ordering across early childhood into mid-adolescence. However, there is substantial developmental change in the strength of embedding within those gradients: by modelling developmental trajectories as non-linear splines, we show that structural and functional gradients are refined across development. Specifically, structural gradients gradually contract in low-dimensional space as networks become more integrated, whilst the functional manifold expands, indexing functional specialisation. The coupling of these structural and functional gradients follows a unimodal-association axis and varies across individuals, with developmental effects concentrated in the more plastic higher-order networks. Importantly, these developmental effects on coupling, in these higher-order networks, are attenuated in the neurodivergent sample. Finally, we mapped structure-function coupling onto dimensions of psychopathology and cognition and demonstrate that dimensions of cognition, such as working memory, are robust predictors of coupling. In summary, across clinical and community samples, we demonstrate consistent principles of structural and functional brain organisation, with progressive structural integration and functional segregation. These gradients are established early in life, refined through development, and their coupling is predicted by working memory.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835052","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}