eLife最新文献

{"title":"Malnutrition drives infection susceptibility and dysregulated myelopoiesis that persists after refeeding intervention.","authors":"Alisa Sukhina, Clemence Queriault, Saptarshi Roy, Elise Hall, Kelly Rome, Muskaan Aggarwal, Elizabeth Nunn, Ashley Weiss, Janet Nguyen, F Chris Bennett, Will Bailis","doi":"10.7554/eLife.101670","DOIUrl":"10.7554/eLife.101670","url":null,"abstract":"<p><p>Undernutrition remains a major global health crisis, with nearly 1 billion people experiencing severe food insecurity. Malnourished individuals are especially vulnerable to infectious diseases, which is the leading cause of morbidity and mortality for this population. Despite the known link between undernutrition and infection susceptibility, the mechanisms remain poorly understood, and it is unclear whether refeeding can reverse nutritionally acquired immunodeficiency. Here, we investigate how malnutrition leads to immune dysfunction and the ability of refeeding to repair it. Malnourished mice show an inability to control sublethal <i>Listeria monocytogenes</i> infection, reduced immune cell function and expansion, and early contraction before pathogen clearance. Myelopoiesis is particularly affected, with fewer neutrophils and monocytes present both before and after infection in malnourished mice. While refeeding restores body mass, lymphoid organ cellularity, and T cell responses, refed mice remain susceptible to <i>Listeria</i> infection, revealing that recovery from lymphoid atrophy alone is not sufficient to restore protective immunity. Accordingly, peripheral neutrophils and monocytes fail to fully recover, and emergency myelopoiesis remains impaired in refed animals. Altogether, this work identifies dysregulated myelopoiesis as a link between prior nutritional state and immunocompetency, indicating that food scarcity is an immunologic risk factor, even after nutritional recovery.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263150/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636555","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":"Old age variably impacts chimpanzee engagement and efficiency in stone tool use.","authors":"Elliot Howard-Spink, Tetsuro Matsuzawa, Susana Carvalho, Catherine Hobaiter, Katarina Almeida-Warren, Thibaud Gruber, Dora Biro","doi":"10.7554/eLife.105411","DOIUrl":"10.7554/eLife.105411","url":null,"abstract":"<p><p>We know vanishingly little about how long-lived apes experience senescence in the wild, particularly with respect to their foraging behaviors. Chimpanzees use tools during foraging, and given the cognitive and physical challenges presented by tool use, tool-use behaviors are potentially at a heightened risk of senescence, though this has never been investigated in wild individuals. Accordingly, we sampled data from a longitudinal video archive that contained footage of wild chimpanzees using stone hammers and anvils to crack hard-shelled nuts (<i>nut cracking</i>) at an 'outdoor laboratory' over a 17-year period (with focal chimpanzees aging from approximately 39-44 to 56-61 years across this period). Over time, elderly chimpanzees began attending experimental nut-cracking sites less frequently than younger individuals. Several elderly chimpanzees exhibited reductions in efficiency across multiple stages of nut cracking, including taking longer to both select stone tools prior to use and use tools to crack open nuts and consume the associated pieces of kernel. Two chimpanzees began using less streamlined behavioral sequences to crack nuts, including a greater number of actions (such as more numerous hammer strikes). Notably, we report interindividual variability in the extent to which elderly chimpanzees' tool-use behaviors changed during our sample period - ranging from small to profound reductions in engagement and efficiency - as well as differences in the specific aspects of nut cracking that changed for each individual. We discuss the possible causes of these changes - and recommendations for future research - with reference to literature surrounding the senescence of captive and wild primates.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263151/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636558","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":"Opposing regulation of TNF responses by IFN-γ and a PGE2-cAMP axis that is apparent in rheumatoid and immune checkpoint inhibitor-induced arthritis human IL-1β+ macrophages.","authors":"Upneet K Sokhi, Ruoxi Yuan, Bikash Mishra, Yurii Chinenov, Anvita Singaraju, Karmela K Chan, Anne Bass, Richard D Bell, Laura Donlin, Lionel B Ivashkiv","doi":"10.7554/eLife.104367","DOIUrl":"10.7554/eLife.104367","url":null,"abstract":"<p><p>IL-1β-expressing macrophages have been described in rheumatoid arthritis (RA), immune checkpoint inhibitor-induced inflammatory arthritis (ICI-arthritis), and pancreatic cancer and proposed to be pathogenic. IL-1β+ macrophages express genes cooperatively induced by PGE2 and TNF signaling, but mechanisms that induce these cells are not known. We used an integrated transcriptomic and epigenomic analysis in primary human monocytes to study PGE2-TNF crosstalk, and how it is regulated by IFN-γ, as occurs in RA synovial macrophages. We identified a TNF + PGE2 (TP) induced gene expression signature that is enriched in IL1β+ RA and ICI-arthritis monocytic subsets, and includes genes in pathogenic IL-1, Notch and neutrophil chemokine pathways. ICI-arthritis myeloid cells mapped primarily onto four previously defined RA synovial monocytic clusters, and TP genes were expressed in a manner suggestive of a new functional monocyte subset. TP signature genes are distinct from canonical inflammatory NF-κB target genes such as <i>TNF</i>, <i>IL6</i> and <i>IL12B</i> and are activated by cooperation of PGE2-induced AP-1, CEBP and NR4A family transcription factors with TNF-induced NF-κB activity. Unexpectedly, IFN-γ suppressed induction of AP-1, CEBP and NR4A activity to ablate induction of IL-1, Notch and neutrophil chemokine genes, while promoting expression of distinct inflammatory genes such as <i>TNF</i> and T cell chemokines like CXCL10. The opposing cross-regulation of PGE2 and IFN signaling in vitro was reflected in vivo in mutually exclusive expression of TP and IFN signatures in different cell clusters in RA and ICI-arthritis monocytes. These results reveal the basis for synergistic induction of inflammatory genes by PGE2 and TNF, and a novel regulatory axis whereby IFN-γ and PGE2 oppose each other to determine the balance between two distinct TNF-induced inflammatory gene expression programs relevant for RA and ICI-arthritis.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12263154/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636559","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>S100a4</i>⁺ alveolar macrophages accelerate the progression of precancerous atypical adenomatous hyperplasia by promoting the angiogenic function regulated by fatty acid metabolism.","authors":"Hong Huang, Ying Yang, Qiuju Zhang, Yongfeng Yang, Zhenqi Xiong, Shengqiang Mao, Tingting Song, Yilong Wang, Zhiqiang Liu, Hong Bu, Li Zhang, Le Zhang","doi":"10.7554/eLife.101731","DOIUrl":"10.7554/eLife.101731","url":null,"abstract":"<p><p>Lung cancer is preceded by premalignant lesions, and what factors drive this transformation and the potential regulatory mode in the context of tumor initiation remain to be elucidated. In the course of precancerous lesions in mice, we found a phasic shift in metabolic patterns. Macrophages are a heterogeneous cell population with high plasticity in the tumor microenvironment. Single-cell interaction and metabolic analyses highlighted a cellular state, <i>S100a4</i>⁺ alveolar macrophages, which exhibited distinct fatty acid metabolic activity, such as palmitic acid metabolism, at the atypical adenomatous hyperplasia stage, accompanied by an angiogenic-promoting function in a pre-neoplastic setting of mice. These findings were reproducible in human single-cell transcriptomes and had been confirmed by histopathological staining and in vitro cell coculture assays. Taken together, the results from this study demonstrated that the <i>S100a4</i>⁺ alveolar macrophage subset contributes to tumorigenesis by altering its metabolic state, suggesting that metabolic interventions targeting this cell state in the early stage of disease may delay neoplastic transformation of the lung epithelium.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636550","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":"Polyphosphate discriminates protein conformational ensembles more efficiently than DNA promoting diverse assembly and maturation behaviors.","authors":"Saloni Goyal, Divya Rajendran, Anup Kumar Mani, Athi N Naganathan","doi":"10.7554/eLife.105461","DOIUrl":"10.7554/eLife.105461","url":null,"abstract":"<p><p>Disordered proteins and domains often assemble into condensates with polyanionic nucleic acids, primarily via charge complementarity, regulating numerous cellular functions. However, the assembly mechanisms associated with the other abundant and ubiquitous, anionic, stress-response regulating polymer, polyphosphate (polyP), are less understood. Here, we employ the intrinsically disordered DNA-binding domain (DBD) of cytidine repressor (CytR) from <i>E. coli</i> to study the nature of assembly processes with polyP and DNA. CytR forms metastable liquid-like condensates with polyP and DNA, while undergoing liquid-to-solid transition in the former and dissolving in the latter. On mutationally engineering the ensemble to exhibit more or less structure and dimensions than the WT, the assembly process with polyP is directed to either condensates with partial time-dependent dissolution or spontaneous aggregation, respectively. On the other hand, the CytR variants form <i>only</i> liquid-like but metastable droplets with DNA which dissolve within a few hours. Polyphosphate induces large secondary-structure changes, with two of the mutants adopting polyproline II-like structures within droplets, while DNA has only minimal structural effects. Our findings reveal how polyphosphate can more efficiently discern conformational heterogeneity in the starting protein ensemble, its structure, and compactness, with broad implications in assembly mechanisms involving polyP and stress response in bacterial systems.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636560","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":"Self-other generalisation shapes social interaction and is disrupted in borderline personality disorder.","authors":"Joseph M Barnby, Jen Nguyen, Julia Griem, Magdalena Wloszek, Henry Burgess, Linda J Richards, Jessica Kingston, Gavin Cooper, P Read Montague, Peter Dayan, Tobias Nolte, Peter Fonagy","doi":"10.7554/eLife.104008","DOIUrl":"10.7554/eLife.104008","url":null,"abstract":"<p><p>Generalising information from ourselves to others, and others to ourselves allows for both a dependable source of navigation and adaptability in interpersonal exchange. Disturbances to social development in sensitive periods can cause enduring and distressing damage to lasting healthy relationships. However, identifying the mechanisms of healthy exchange has been difficult. We introduce a theory of self-other generalisation tested with data from a three-phase social value orientation task - the Intentions Game. We involved humans with (<i>n</i>=50) and without (<i>n</i>=53) a diagnosis of borderline personality disorder and assessed whether infractions to self-other generalisation may explain prior findings of disrupted social learning and instability. Healthy controls initially used their preferences to predict others and were influenced by their partners, leading to self-other convergence. In contrast, individuals with borderline personality disorder maintained distinct self-other representations when learning about others. This allowed for equal predictive performance compared to controls despite reduced updating sensitivity. Furthermore, we explored theory-driven individual differences underpinning contagion. Overall, the findings provide a clear explanation of how self-other generalisation constrains and assists learning, and how childhood adversity is associated with separation of internalised beliefs. Our model makes clear predictions about the mechanisms of social information generalisation concerning both joint and individual reward.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625544","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":"Harnessing AlphaFold to reveal hERG channel conformational state secrets.","authors":"Khoa Ngo, Pei-Chi Yang, Vladimir Yarov-Yarovoy, Colleen E Clancy, Igor Vorobyov","doi":"10.7554/eLife.104901","DOIUrl":"10.7554/eLife.104901","url":null,"abstract":"<p><p>To design safe, selective, and effective new therapies, there must be a deep understanding of the structure and function of the drug target. One of the most difficult problems to solve has been the resolution of discrete conformational states of transmembrane ion channel proteins. An example is K_V11.1 (hERG), comprising the primary cardiac repolarizing current, <i>I</i>_kr. hERG is a notorious drug anti-target against which all promising drugs are screened to determine potential for arrhythmia. Drug interactions with the hERG inactivated state are linked to elevated arrhythmia risk, and drugs may become trapped during channel closure. While prior studies have applied AlphaFold to predict alternative protein conformations, we show that the inclusion of carefully chosen structural templates can guide these predictions toward distinct functional states. This targeted modeling approach is validated through comparisons with experimental data, including proposed state-dependent structural features, drug interactions from molecular docking, and ion conduction properties from molecular dynamics simulations. Remarkably, AlphaFold not only predicts inactivation mechanisms of the hERG channel that prevent ion conduction but also uncovers novel molecular features explaining enhanced drug binding observed during inactivation, offering a deeper understanding of hERG channel function and pharmacology. Furthermore, leveraging AlphaFold-derived states enhances computational screening by significantly improving agreement with experimental drug affinities, an important advance for hERG as a key drug safety target where traditional single-state models miss critical state-dependent effects. By mapping protein residue interaction networks across closed, open, and inactivated states, we identified critical residues driving state transitions validated by prior mutagenesis studies. This innovative methodology sets a new benchmark for integrating deep learning-based protein structure prediction with experimental validation. It also offers a broadly applicable approach using AlphaFold to predict discrete protein conformations, reconcile disparate data, and uncover novel structure-function relationships, ultimately advancing drug safety screening and enabling the design of safer therapeutics.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625530","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":"Normative evidence weighing and accumulation in correlated environments.","authors":"Nathan Tardiff, Jiwon Kang, Joshua I Gold","doi":"10.7554/eLife.100258","DOIUrl":"10.7554/eLife.100258","url":null,"abstract":"<p><p>The brain forms certain deliberative decisions following normative principles related to how sensory observations are weighed and accumulated over time. Previously we showed that these principles can account for how people adapt their decisions to the temporal dynamics of the observations (Glaze et al., 2015). Here, we show that this adaptability extends to accounting for correlations in the observations, which can have a dramatic impact on the weight of evidence provided by those observations. We tested online human participants on a novel visual-discrimination task with pairwise-correlated observations. With minimal training, the participants adapted to uncued, trial-by-trial changes in the correlations and produced decisions based on an approximately normative weighing and accumulation of evidence. The results highlight the robustness of our brain's ability to process sensory observations with respect to not just their physical features but also the weight of evidence they provide for a given decision.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625542","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":"PRDM16 functions as a co-repressor in the BMP pathway to suppress neural stem cell proliferation.","authors":"Li He, Jiayu Wen, Qi Dai","doi":"10.7554/eLife.104076","DOIUrl":"10.7554/eLife.104076","url":null,"abstract":"<p><p>BMP signaling acts as an instructive cue in various developmental processes such as tissue patterning, stem cell proliferation, and differentiation. However, it is not fully understood how this signaling pathway generates different cell-specific outputs. Here, we have identified PRDM16 as a key co-factor for BMP signaling in the mouse brain. PRDM16 contributes to a repressive role of BMP signaling on neural stem cell (NSC) proliferation. We demonstrate that PRDM16 regulates the genomic distribution of BMP pathway transcription factors, the SMAD4/pSMAD complex, preventing the activation of cell proliferation genes. When <i>Prdm16</i> is lost, the SMAD complex relocates to nearby genomic regions, leading to abnormal upregulation of BMP target genes. This function of PRDM16 is also required for the specification of choroid plexus (ChP) epithelial cells. Through a single-cell resolution fluorescent in situ approach, we have observed that genes co-repressed by SMAD and PRDM16, such as <i>Wnt7b</i> and several cell cycle regulators, become overexpressed in <i>Prdm16</i> mutant ChP. Our findings elucidate a mechanism through which SMAD4 and pSMAD1/5/8 repress gene expression. Moreover, our study suggests a regulatory circuit composed of BMP and Wnt signaling, along with PRDM16, in controlling stem cell behaviors.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625543","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 microbiome interacts with the circadian clock and dietary composition to regulate metabolite cycling in the <i>Drosophila</i> gut.","authors":"Yueliang Zhang, Sara B Noya, Yongjun Li, Jichao Fang, Amita Sehgal","doi":"10.7554/eLife.97130","DOIUrl":"10.7554/eLife.97130","url":null,"abstract":"<p><p>The gut microbiome plays a key role in the maintenance of host metabolic homeostasis and health. Most metabolic processes cycle with a 24-hour rhythm, but the extent to which the microbiome influences metabolite cycling under different conditions, such as variations in dietary composition, remains largely unknown. In this study, we utilized high temporal resolution metabolite profiling of the <i>Drosophila</i> gut to investigate the role of the microbiome in metabolite cycling. We find that the microbiome increases the number of oscillating metabolites despite the previous finding that it dampens transcript cycling in the gut. Time-restricted feeding also promotes metabolite cycling and does so to a larger extent in germ-free flies, thereby increasing cycling in these flies to levels comparable to those in microbiome-containing flies. Enhancement of cycling by the microbiome depends upon a circadian clock, which also maintains phase in the face of changes in the microbiome. Interestingly, a high protein diet increases microbiome-dependent metabolite cycling, while a high sugar diet suppresses it. Gene Ontology identifies amino acid metabolism as the metabolic pathway most affected by changes in the gut microbiome, the circadian clock, and timed feeding, suggesting that it is subject to regulation by multiple inputs. Collectively, our observations highlight a key role of the gut microbiome in host metabolite cycling and reveal a complex interaction with internal and external factors.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12252545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607770","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}