eLife最新文献

{"title":"Soluble immune mediators orchestrate protective <i>in vitro</i> granulomatous responses across <i>Mycobacterium tuberculosis</i> complex lineages.","authors":"Ainhoa Arbués, Sarah Schmidiger, Miriam Reinhard, Sonia Borrell, Sebastien Gagneux, Damien Portevin","doi":"10.7554/eLife.99062","DOIUrl":"https://doi.org/10.7554/eLife.99062","url":null,"abstract":"<p><p>The members of the <i>Mycobacterium tuberculosis</i> complex (MTBC) causing human tuberculosis comprise 10 phylogenetic lineages that differ in their geographical distribution. The human consequences of this phylogenetic diversity remain poorly understood. Here, we assessed the phenotypic properties at the host-pathogen interface of 14 clinical strains representing five major MTBC lineages. Using a human <i>in vitro</i> granuloma model combined with bacterial load assessment, microscopy, flow cytometry, and multiplexed-bead arrays, we observed considerable intra-lineage diversity. Yet, modern lineages were overall associated with increased growth rate and more pronounced granulomatous responses. MTBC lineages exhibited distinct propensities to accumulate triglyceride lipid droplets-a phenotype associated with dormancy-that was particularly pronounced in lineage 2 and reduced in lineage 3 strains. The most favorable granuloma responses were associated with strong CD4 and CD8 T cell activation as well as inflammatory responses mediated by CXCL9, granzyme B, and TNF. Both of which showed consistent negative correlation with bacterial proliferation across genetically distant MTBC strains of different lineages. Taken together, our data indicate that different virulence strategies and protective immune traits associate with MTBC genetic diversity at lineage and strain level.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751442","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":"Respiratory and cardiac interoceptive sensitivity in the first two years of life.","authors":"Markus R Tünte, Stefanie Hoehl, Moritz Wunderwald, Johannes Bullinger, Asena Boyadziheva, Lara Maister, Birgit Elsner, Manos Tsakiris, Ezgi Kayhan","doi":"10.7554/eLife.91579","DOIUrl":"https://doi.org/10.7554/eLife.91579","url":null,"abstract":"<p><p>Several recent theoretical accounts have posited that interoception, the perception of internal bodily signals, plays a vital role in early human development. Yet, empirical evidence of cardiac interoceptive sensitivity in infants to date has been mixed. Furthermore, existing evidence does not go beyond the perception of cardiac signals and focuses only on the age of 5-7 mo, limiting the generalizability of the results. Here, we used a modified version of the cardiac interoceptive sensitivity paradigm introduced by Maister et al., 2017 in 3-, 9-, and 18-mo-old infants using cross-sectional and longitudinal approaches. Going beyond, we introduce a novel experimental paradigm, namely the iBREATH, to investigate respiratory interoceptive sensitivity in infants. Overall, for cardiac interoceptive sensitivity (<i>total n</i>=135) we find rather stable evidence across ages with infants on average preferring stimuli presented synchronously to their heartbeat. For respiratory interoceptive sensitivity (<i>total n</i>=120) our results show a similar pattern in the first year of life, but not at 18 mo. We did not observe a strong relationship between cardiac and respiratory interoceptive sensitivity at 3 and 9 mo but found some evidence for a relationship at 18 mo. We validated our results using specification curve- and mega-analytic approaches. By examining early cardiac and respiratory interoceptive processing, we provide evidence that infants are sensitive to their interoceptive signals.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"12 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751475","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 tale of two caspases.","authors":"Denise M Monack","doi":"10.7554/eLife.106581","DOIUrl":"https://doi.org/10.7554/eLife.106581","url":null,"abstract":"<p><p>Macrophages control intracellular pathogens like <i>Salmonella</i> by using two caspase enzymes at different times during infection.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751448","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":"Architecture of genome-wide transcriptional regulatory network reveals dynamic functions and evolutionary trajectories in <i>Pseudomonas syringae</i>.","authors":"Yue Sun, Jingwei Li, Jiadai Huang, Shumin Li, Youyue Li, Beifang Lu, Xin Deng","doi":"10.7554/eLife.96172","DOIUrl":"https://doi.org/10.7554/eLife.96172","url":null,"abstract":"<p><p>The model Gram-negative plant pathogen <i>Pseudomonas syringae</i> utilises hundreds of transcription factors (TFs) to regulate its functional processes, including virulence and metabolic pathways that control its ability to infect host plants. Although the molecular mechanisms of regulators have been studied for decades, a comprehensive understanding of genome-wide TFs in <i>Psph</i> 1448A remains limited. Here, we investigated the binding characteristics of 170 of 301 annotated TFs through chromatin immunoprecipitation sequencing (ChIP-seq). Fifty-four TFs, 62 TFs, and 147 TFs were identified in top-level, middle-level, and bottom-level, reflecting multiple higher-order network structures and direction of information flow. More than 40,000 TF pairs were classified into 13 three-node submodules which revealed the regulatory diversity of TFs in <i>Psph</i> 1448A regulatory network. We found that bottom-level TFs performed high co-associated scores to their target genes. Functional categories of TFs at three levels encompassed various regulatory pathways. Three and 25 master TFs were identified to involve in virulence and metabolic regulation, respectively. Evolutionary analysis and topological modularity network revealed functional variability and various conservation of TFs in <i>P. syringae</i> (<i>Psph</i> 1448A, <i>Pst</i> DC3000, <i>Pss</i> B728a, and <i>Psa</i> C48). Overall, our findings demonstrated a global transcriptional regulatory network of genome-wide TFs in <i>Psph</i> 1448A. This knowledge can advance the development of effective treatment and prevention strategies for related infectious diseases.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751662","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":"Evolutionary rescue of spherical <i>mreB</i> deletion mutants of the rod-shape bacterium <i>Pseudomonas fluorescens</i> SBW25.","authors":"Paul Richard J Yulo, Nicolas Desprat, Monica L Gerth, Barbara Ritzl-Rinkenberger, Andrew D Farr, Yunhao Liu, Xue-Xian Zhang, Michael Miller, Felipe Cava, Paul B Rainey, Heather L Hendrickson","doi":"10.7554/eLife.98218","DOIUrl":"https://doi.org/10.7554/eLife.98218","url":null,"abstract":"<p><p>Maintenance of rod-shape in bacterial cells depends on the actin-like protein MreB. Deletion of <i>mreB</i> from <i>Pseudomonas fluorescens</i> SBW25 results in viable spherical cells of variable volume and reduced fitness. Using a combination of time-resolved microscopy and biochemical assay of peptidoglycan synthesis, we show that reduced fitness is a consequence of perturbed cell size homeostasis that arises primarily from differential growth of daughter cells. A 1000-generation selection experiment resulted in rapid restoration of fitness with derived cells retaining spherical shape. Mutations in the peptidoglycan synthesis protein Pbp1A were identified as the main route for evolutionary rescue with genetic reconstructions demonstrating causality. Compensatory <i>pbp1A</i> mutations that targeted transpeptidase activity enhanced homogeneity of cell wall synthesis on lateral surfaces and restored cell size homeostasis. Mechanistic explanations require enhanced understanding of why deletion of <i>mreB</i> causes heterogeneity in cell wall synthesis. We conclude by presenting two testable hypotheses, one of which posits that heterogeneity stems from non-functional cell wall synthesis machinery, while the second posits that the machinery is functional, albeit stalled. Overall, our data provide support for the second hypothesis and draw attention to the importance of balance between transpeptidase and glycosyltransferase functions of peptidoglycan building enzymes for cell shape determination.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751157","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":"Dimeric ^R25CPTH(1-34) activates the parathyroid hormone-1 receptor in vitro and stimulates bone formation in osteoporotic female mice.","authors":"Minsoo Noh, Xiangguo Che, Xian Jin, Dong-Kyo Lee, Hyun-Ju Kim, Doo Ri Park, Soo Young Lee, Hunsang Lee, Thomas J Gardella, Je-Yong Choi, Sihoon Lee","doi":"10.7554/eLife.97579","DOIUrl":"10.7554/eLife.97579","url":null,"abstract":"<p><p>Osteoporosis, characterized by reduced bone density and strength, increases fracture risk, pain, and limits mobility. Established therapies of parathyroid hormone (PTH) analogs effectively promote bone formation and reduce fractures in severe osteoporosis, but their use is limited by potential adverse effects. In the pursuit of safer osteoporosis treatments, we investigated ^R25CPTH, a PTH variant wherein the native arginine at position 25 is substituted by cysteine. These studies were prompted by our finding of high bone mineral density in a hypoparathyroidism patient with the R25C homozygous mutation, and we explored its effects on PTH type-1 receptor (PTH1R) signaling in cells and bone metabolism in mice. Our findings indicate that ^R25CPTH(1-84) forms dimers both intracellularly and extracellularly, and the synthetic dimeric peptide, ^R25CPTH(1-34), exhibits altered activity in PTH1R-mediated cyclic AMP (cAMP) response. Upon a single injection in mice, dimeric ^R25CPTH(1-34) induced acute calcemic and phosphaturic responses comparable to PTH(1-34). Furthermore, repeated daily injections increased calvarial bone thickness in intact mice and improved trabecular and cortical bone parameters in ovariectomized (OVX) mice, akin to PTH(1-34). The overall results reveal a capacity of a dimeric PTH peptide ligand to activate the PTH1R in vitro and in vivo as PTH, suggesting a potential path of therapeutic PTH analog development.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143735827","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":"Layer 6 corticocortical neurons are a major route for intra- and interhemispheric feedback.","authors":"Simon Weiler, Manuel Teichert, Troy W Margrie","doi":"10.7554/eLife.100478","DOIUrl":"10.7554/eLife.100478","url":null,"abstract":"<p><p>The neocortex comprises anatomically discrete yet interconnected areas that are symmetrically located across the two hemispheres. Determining the logic of these macrocircuits is necessary for understanding high level brain function. Here in mice, we have mapped the areal and laminar organization of the ipsi- and contralateral cortical projection onto the primary visual, somatosensory, and motor cortices. We find that although the ipsilateral hemisphere is the primary source of cortical input, there is substantial contralateral symmetry regarding the relative contribution and areal identity of input. Laminar analysis of these input areas show that excitatory Layer 6 corticocortical cells (L6 CCs) are a major projection pathway within and between the two hemispheres. Analysis of the relative contribution of inputs from supra- (feedforward) and infragranular (feedback) layers reveals that contra-hemispheric projections reflect a dominant feedback organization compared to their ipsi-cortical counterpart. The magnitude of the interhemispheric difference in hierarchy was largest for sensory and motor projection areas compared to frontal, medial, or lateral brain areas due to a proportional increase in input from L6 neurons. L6 CCs therefore not only mediate long-range cortical communication but also reflect its inherent feedback organization.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143735830","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":"3D reconstruction of neuronal allometry and neuromuscular projections in asexual planarians using expansion tiling light sheet microscopy.","authors":"Jing Lu, Hao Xu, Dongyue Wang, Yanlu Chen, Takeshi Inoue, Liang Gao, Kai Lei","doi":"10.7554/eLife.101103","DOIUrl":"10.7554/eLife.101103","url":null,"abstract":"<p><p>The intricate coordination of the neural network in planarian growth and regeneration has remained largely unrevealed, partly due to the challenges of imaging the CNS in three dimensions (3D) with high resolution and within a reasonable timeframe. To address this gap in systematic imaging of the CNS in planarians, we adopted high-resolution, nanoscale imaging by combining tissue expansion and tiling light-sheet microscopy, achieving up to fourfold linear expansion. Using an automatic 3D cell segmentation pipeline, we quantitatively profiled neurons and muscle fibers at the single-cell level in over 400 wild-type planarians during homeostasis and regeneration. We validated previous observations of neuronal cell number changes and muscle fiber distribution. We found that the increase in neuron cell number tends to lag behind the rapid expansion of somatic cells during the later phase of homeostasis. By imaging the planarian with up to 120 nm resolution, we also observed distinct muscle distribution patterns at the anterior and posterior poles. Furthermore, we investigated the effects of <i>β-catenin-1</i> RNAi on muscle fiber distribution at the posterior pole, consistent with changes in anterior-posterior polarity. The glial cells were observed to be close in contact with dorsal-ventral muscle fibers. Finally, we observed disruptions in neural-muscular networks in <i>inr-1</i> RNAi planarians. These findings provide insights into the detailed structure and potential functions of the neural-muscular system in planarians and highlight the accessibility of our imaging tool in unraveling the biological functions underlying their diverse phenotypes and behaviors.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729437","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 peptide-neurotensin conjugate that crosses the blood-brain barrier induces pharmacological hypothermia associated with anticonvulsant, neuroprotective, and anti-inflammatory properties following status epilepticus in mice.","authors":"Lotfi Ferhat, Rabia Soussi, Maxime Masse, Grigorios Kyriatzis, Stéphane Girard, Fanny Gassiot, Nicolas Gaudin, Mathieu Laurencin, Anne Bernard, Angélique Bôle, Géraldine Ferracci, Maria Smirnova, François Roman, Vincent Dive, Salvatore Cisternino, Jamal Temsamani, Marion David, Pascaline Lécorché, Guillaume Jacquot, Michel Khrestchatisky","doi":"10.7554/eLife.100527","DOIUrl":"10.7554/eLife.100527","url":null,"abstract":"<p><p>Preclinical and clinical studies show that mild to moderate hypothermia is neuroprotective in sudden cardiac arrest, ischemic stroke, perinatal hypoxia/ischemia, traumatic brain injury, and seizures. Induction of hypothermia largely involves physical cooling therapies, which induce several clinical complications, while some molecules have shown to be efficient in pharmacologically induced hypothermia (PIH). Neurotensin (NT), a 13 amino acid neuropeptide that regulates body temperature, interacts with various receptors to mediate its peripheral and central effects. NT induces PIH when administered intracerebrally. However, these effects are not observed if NT is administered peripherally, due to its rapid degradation and poor passage of the blood-brain barrier (BBB). We conjugated NT to peptides that bind the low-density lipoprotein receptor (LDLR) to generate 'vectorized' forms of NT with enhanced BBB permeability. We evaluated their effects in epileptic conditions following peripheral administration. One of these conjugates, VH-N412, displayed improved stability, binding potential to both the LDLR and NTSR-1, rodent/human cross-reactivity and improved brain distribution. In a mouse model of kainate (KA)-induced status epilepticus (SE), VH-N412 elicited rapid hypothermia associated with anticonvulsant effects, potent neuroprotection, and reduced hippocampal inflammation. VH-N412 also reduced sprouting of the dentate gyrus mossy fibers and preserved learning and memory skills in the treated mice. In cultured hippocampal neurons, VH-N412 displayed temperature-independent neuroprotective properties. To the best of our knowledge, this is the first report describing the successful treatment of SE with PIH. In all, our results show that vectorized NT may elicit different neuroprotection mechanisms mediated by hypothermia and/or by intrinsic neuroprotective properties.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729448","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 value of initiating a pursuit in temporal decision-making.","authors":"Elissa Sutlief, Charlie Walters, Tanya Marton, Marshall G Hussain Shuler","doi":"10.7554/eLife.99957","DOIUrl":"10.7554/eLife.99957","url":null,"abstract":"<p><p>Reward-rate maximization is a prominent normative principle in behavioral ecology, neuroscience, economics, and AI. Here, we identify, compare, and analyze equations to maximize reward rate when assessing whether to initiate a pursuit. In deriving expressions for the value of a pursuit, we show that time's cost consists of both apportionment and opportunity cost. Reformulating value as a discounting function, we show precisely how a reward-rate-optimal agent's discounting function (1) combines hyperbolic and linear components reflecting apportionment and opportunity costs, and (2) is dependent not only on the considered pursuit's properties but also on time spent and rewards obtained outside the pursuit. This analysis reveals how purported signs of suboptimal behavior (hyperbolic discounting, and the Delay, Magnitude, and Sign effects) are in fact consistent with reward-rate maximization. To better account for observed decision-making errors in humans and animals, we then analyze the impact of misestimating reward-rate-maximizing parameters and find that suboptimal decisions likely stem from errors in assessing time's apportionment-specifically, underweighting time spent outside versus inside a pursuit-which we term the 'Malapportionment Hypothesis'. This understanding of the true pattern of temporal decision-making errors is essential to deducing the learning algorithms and representational architectures actually used by humans and animals.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952749/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143735849","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}