eLife最新文献

{"title":"Brain-derived exosomal hemoglobin transfer contributes to neuronal mitochondrial homeostasis under hypoxia.","authors":"Zhengming Tian, Yuning Li, Feiyang Jin, Zirui Xu, Yakun Gu, Mengyuan Guo, Qianqian Shao, Yingxia Liu, Hanjiang Luo, Yue Wang, Suyu Zhang, Chenlu Yang, Xin Liu, Xunming Ji, Jia Liu","doi":"10.7554/eLife.99986","DOIUrl":"https://doi.org/10.7554/eLife.99986","url":null,"abstract":"<p><p>Hypoxia is an important physiological stress causing nerve injuries and several brain diseases. However, the mechanism of brain response to hypoxia remains unclear, thus limiting the development of interventional strategies. This study conducted combined analyses of single-nucleus transcriptome sequencing and extracellular vesicle transcriptome sequencing on hypoxic mouse brains, described cell-cell communication in the brain under hypoxia from intercellular and extracellular dimensions, confirmed that hemoglobin mRNA was transferred from non-neuronal cells to neurons, and eventually expressed. Then we further explored the role of exosomal hemoglobin transfer in vitro, using human-derived cell lines, and clarified that hypoxia promoted the transfer and expression of exosomal hemoglobin between endothelial cells and neurons. We found the vital function of exosomal hemoglobin to protect against neurological injury by maintaining mitochondrial homeostasis in neurons. In conclusion, this study identified a novel mechanism of 'mutual aid' in hypoxia responses in the brain, involving exosomal hemoglobin transfer, clarified the important role of exosomal communication in the process of brain stress response, and provided a novel interventional perspective for hypoxia-related brain diseases.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144474259","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":"The geometry and dimensionality of brain-wide activity.","authors":"Zezhen Wang, Weihao Mai, Yuming Chai, Kexin Qi, Hongtai Ren, Chen Shen, Shiwu Zhang, Guodong Tan, Yu Hu, Quan Wen","doi":"10.7554/eLife.100666","DOIUrl":"https://doi.org/10.7554/eLife.100666","url":null,"abstract":"<p><p>Understanding neural activity organization is vital for deciphering brain function. By recording whole-brain calcium activity in larval zebrafish during hunting and spontaneous behaviors, we find that the shape of the neural activity space, described by the neural covariance spectrum, is scale-invariant: a smaller, <i>randomly sampled</i> cell assembly resembles the entire brain. This phenomenon can be explained by Euclidean Random Matrix theory, where neurons are reorganized from anatomical to functional positions based on their correlations. Three factors contribute to the observed scale invariance: slow neural correlation decay, higher functional space dimension, and neural activity heterogeneity. In addition to matching data from zebrafish and mice, our theory and analysis demonstrate how the geometry of neural activity space evolves with population sizes and sampling methods, thus revealing an organizing principle of brain-wide activity.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144474283","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 direct neural signature of serial dependence in working memory.","authors":"Cora Fischer, Jochen Kaiser, Christoph Bledowski","doi":"10.7554/eLife.99478","DOIUrl":"https://doi.org/10.7554/eLife.99478","url":null,"abstract":"<p><p>Serial dependence describes the phenomenon that current object representations are attracted to previously encoded and reported representations. While attractive biases have been observed reliably in behavior, a direct neural correlate has not been established. Previous studies have either shown a reactivation of past information without observing a neural signal related to the bias of the current information, or a repulsive distortion of current neural representations contrasting the behavioral bias. The present study recorded neural signals with magnetoencephalography (MEG) during a working memory task to identify neural correlates of serial dependence. Participants encoded and memorized two sequentially presented motion directions per trial, one of which was later retro-cued for report. Multivariate analyses provided reliable reconstructions of both motion directions. Importantly, the reconstructed directions in the current trial were attractively shifted toward the target direction of the previous trial. This neural bias mirrored the behavioral attractive bias, thus reflecting a direct neural signature of serial dependence. The use of a retro-cue task in combination with MEG allowed us to determine that this neural bias emerged at later, post-encoding time points. This timing suggests that serial dependence in working memory affects memorized information during read-out and reactivation processes that happen after the initial encoding.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144474258","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":"PDZ-directed substrate recruitment is the primary determinant of specific 4E-BP1 dephosphorylation by PP1-Neurabin.","authors":"Roman O Fedoryshchak, Karim El-Bouri, Dhira Joshi, Stephane Mouilleron, Richard Treisman","doi":"10.7554/eLife.103403","DOIUrl":"https://doi.org/10.7554/eLife.103403","url":null,"abstract":"<p><p>Phosphoprotein phosphatase 1 (PP1) relies on association with PP1-interacting proteins (PIPs) to generate substrate-specific PIP/PP1 holoenzymes, but the lack of well-defined substrates has hindered elucidation of the mechanisms involved. We previously demonstrated that the Phactr1 PIP confers sequence specificity on the Phactr1/PP1 holoenzyme by remodelling the PP1 hydrophobic substrate groove. Phactr1 defines a group of 'RVxF-ΦΦ-R-W' PIPs that all interact with PP1 in a similar fashion. Here, we use a PP1-PIP fusion approach to address sequence specificity and identify substrates of the RVxF-ΦΦ-R-W family PIPs. We show that the four Phactr proteins confer identical sequence specificities on their holoenzymes. We identify the 4E-BP and p70 S6K translational regulators as substrates for the Neurabin/Spinophilin PIPs, implicated in neuronal plasticity, pointing to a role for their holoenzymes in mTORC1-dependent translational control. Biochemical and structural experiments show that in contrast to the Phactrs, substrate recruitment and catalytic efficiency of the PP1-Neurabin and PP1-Spinophilin fusions is primarily determined by substrate interaction with the PDZ domain adjoining their RVxF-ΦΦ-R-W motifs, rather than by recognition of the remodelled PP1 hydrophobic groove. Thus, even PIPs that interact with PP1 in a similar manner use different mechanisms to ensure substrate selectivity.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144474275","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":"Regulative synthesis of capsular polysaccharides in the pathogenesis of <i>Streptococcus suis</i>.","authors":"Xingye Wang, Jie Wang, Ning Li, Xin Fan, Beinan Wang","doi":"10.7554/eLife.101760","DOIUrl":"https://doi.org/10.7554/eLife.101760","url":null,"abstract":"<p><p><i>Streptococcus suis</i> (<i>S. suis</i>) is an important zoonotic pathogen causing substantial economic losses in the swine industry. <i>S. suis</i> serotype 2 (SS2) is often isolated from the diseased. <i>S. suis</i> expresses capsular polysaccharide (CPS), a virulence factor crucial for their survival in the blood. However, the role of CPS in the pathogenesis of <i>S. suis</i> is incomplete. Here, we showed that thin CPS or no CPS was associated with efficient binding of an SS2 strain, 05ZYH33, to respiratory epithelial cells, while thick CPS increased resistance of 05ZYH33 to blood clearance. In a mouse infection model, 05ZYH33 was detected in the nasal-associated lymphoid tissue (NALT) and cerebrospinal fluid (CSF) as early as 30 min after intranasal inoculation without bacteremia. Histological analysis revealed that 05ZYH33 in the nasal cavity invaded the olfactory epithelium, resulting in early brain inflammation. Transmission electron microscopy showed that 05ZYH33 isolated from NALT and CSF at early infection time had a thin layer of CPS, and those detected in the blood 5 hr post-inoculation showed a much thicker CPS. In addition, adoptive transfer of anti-CPS restricted 05ZYH33 in the blood but not in NALT or CSF. However, an antiserum directed to multiple non-CPS virulence factors (anti-V5) efficiently inhibited 05ZYH33 in NALT, CSF, and blood. Thus, 05ZYH33 colonizes NALT more efficiently without CPS and subsequently invades the meninges through the olfactory nerve system. These findings provide valuable information for the treatment of <i>S. suis</i> infection and the development of vaccines across serotypes of <i>S. suis</i> by targeting CPS-independent immunity.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144474276","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":"Cognitive control of behavior and hippocampal information processing without medial prefrontal cortex.","authors":"Eun Hye Park, Kally C O'Reilly Sparks, Griffin Grubbs, David Taborga, Kyndall Nicholas, Armaan S Ahmed, Natalie Ruiz-Péreza, Natalie Kim, Simon Segura-Carrillo, André A Fenton","doi":"10.7554/eLife.104475","DOIUrl":"https://doi.org/10.7554/eLife.104475","url":null,"abstract":"<p><p>Cognitive control tasks require using one class of information while ignoring competing classes of information. The central role of the medial prefrontal cortex (mPFC) in cognitive control is well established in the primate literature and largely accepted in the rodent literature because mPFC damage causes deficits in tasks that may require cognitive control, as inferred, typically from the task design. In prior work, we used an active place avoidance task where a rat or mouse on a rotating arena is required to avoid the stationary task-relevant locations of a mild shock and ignore the rotating task-irrelevant locations of those shocks. The task is impaired by hippocampal manipulations, and the discharge of hippocampal place cell populations judiciously alternates between representing stationary locations near the shock zone and rotating locations far from the shock zone, demonstrating cognitive control concurrently in behavior and the hippocampal representation of spatial information. Here, we test whether rat mPFC lesion impairs the active place avoidance task to evaluate two competing hypotheses, a 'central-computation' hypothesis that the mPFC is essential for the computations required for cognitive control and an alternative 'local-computation' hypothesis that other brain areas can perform the computations required for cognitive control, independent of mPFC. Ibotenic acid lesion of the mPFC was effective, damaging the cingulate, prelimbic, and infralimbic cortices. The lesion also altered the normal coordination of metabolic activity across remaining structures. The lesion did not impair learning to avoid the initial location of shock or long-term place avoidance memory, but impaired avoidance after the shock was relocated. The lesion also did not impair the alternation between task-relevant and task-irrelevant hippocampal representations of place information. These findings support the local-computation hypothesis that computations required for cognitive control can occur locally in brain networks independently of the mPFC.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144474261","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":"Synaptic connectivity of sensorimotor circuits for vocal imitation in the songbird.","authors":"Massimo Trusel, Ziran Zhao, Danyal H Alam, Ethan S Marks, Maaya Z Ikeda, Todd F Roberts","doi":"10.7554/eLife.104609","DOIUrl":"https://doi.org/10.7554/eLife.104609","url":null,"abstract":"<p><p>Sensorimotor computations for learning and behavior rely on precise patterns of synaptic connectivity. Yet, we typically lack the synaptic wiring diagrams for long-range connections between sensory and motor circuits in the brain. Here, we provide the synaptic wiring diagram for sensorimotor circuits involved in learning and production of male zebra finch song, a natural and ethologically relevant behavior. We examined the functional synaptic connectivity from the 4 main sensory afferent pathways onto the three known classes of projection neurons of the song premotor cortical region HVC. Recordings from hundreds of identified projection neurons reveal rules for monosynaptic connectivity and the existence of polysynaptic ensembles of excitatory and inhibitory neuronal populations in HVC. Circuit tracing further identifies novel connections between HVC's presynaptic partners. Our results indicate a modular organization of ensemble-like networks for integrating long-range input with local circuits, providing important context for information flow and computations for learned vocal behavior.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144474282","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":"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}