eLife最新文献

{"title":"Combined forces of hydrostatic pressure and actin polymerization drive endothelial tip cell migration and sprouting angiogenesis.","authors":"Igor Kondrychyn, Liqun He, Haymar Wint, Christer Betsholtz, Li-Kun Phng","doi":"10.7554/eLife.98612","DOIUrl":"10.7554/eLife.98612","url":null,"abstract":"<p><p>Cell migration is a key process in the shaping and formation of tissues. During sprouting angiogenesis, endothelial tip cells invade avascular tissues by generating actomyosin-dependent forces that drive cell migration and vascular expansion. Surprisingly, endothelial cells (ECs) can still invade if actin polymerization is inhibited. In this study, we show that endothelial tip cells employ an alternative mechanism of cell migration that is dependent on Aquaporin (Aqp)-mediated water inflow and increase in hydrostatic pressure. In the zebrafish, ECs express <i>aqp1a.1</i> and <i>aqp8a.1</i> in newly formed vascular sprouts in a VEGFR2-dependent manner. Aqp1a.1 and Aqp8a.1 loss-of-function studies show an impairment in intersegmental vessels formation because of a decreased capacity of tip cells to increase their cytoplasmic volume and generate membrane protrusions, leading to delayed tip cell emergence from the dorsal aorta and slower migration. Further inhibition of actin polymerization resulted in a greater decrease in sprouting angiogenesis, indicating that ECs employ two mechanisms for robust cell migration in vivo. Our study thus highlights an important role of hydrostatic pressure in tissue morphogenesis.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457247","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":"Differences in HIV-1 reservoir size, landscape characteristics, and decay dynamics in acute and chronic treated HIV-1 Clade C infection.","authors":"Kavidha Reddy, Guinevere Q Lee, Nicole Reddy, Tatenda J B Chikowore, Kathy Baisley, Krista L Dong, Bruce D Walker, Xu G Yu, Mathias Lichterfeld, Thumbi Ndung'u","doi":"10.7554/eLife.96617","DOIUrl":"10.7554/eLife.96617","url":null,"abstract":"<p><p>Persisting HIV reservoir viruses in resting CD4 T cells and other cellular subsets are a barrier to cure efforts. Early antiretroviral therapy (ART) enables post-treatment viral control in some cases, but mechanisms remain unclear. We hypothesised that ART initiated before peak viremia impacts HIV-1 subtype C reservoirs. We studied 35 women at high risk of infection from Durban, South Africa, identified with hyperacute HIV by twice-weekly HIV-RNA testing. Participants included 11 starting ART at a median of 456 (297-1203) days post-onset of viremia (DPOV) and 24 at 1 (1-3) DPOV. Peripheral blood mononuclear cells (PBMCs) were used to measured total HIV-1 DNA by droplet digital PCR (ddPCR) and sequence viral reservoir genomes by full-length proviral sequencing (FLIP-seq). ART during hyperacute infection blunted peak viremia (p<0.0001), but contemporaneous total HIV-1 DNA did not differ (p=0.104). Over 1 year, a decline of total HIV-1 DNA was observed in early treated persons (p=0.0004), but not late treated. Among 697 viral genome sequences, the proviral genetic landscape differed between untreated, late treated, and early treated groups. Intact genomes after 1 year were higher in untreated (31%) versus late treated (14%) and early treated (0%). Treatment in both late and early infection caused more rapid decay of intact (13% and 51% per month) versus defective (2% and 35%) viral genomes. However, intact genomes persisted 1 year post chronic treatment but were undetectable with early ART. Early ART also reduced phylogenetic diversity of intact genomes and limited cytotoxic T lymphocyte immune escape variants in the reservoir. Overall, ART initiated in hyperacute HIV-1 subtype C infection did not impact reservoir seeding but was associated with rapid intact viral genome decay, reduced genetic complexity, and limited immune escape, which may accelerate reservoir clearance in combination with other interventional strategies.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457250","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":"Robust variability of grid cell properties within individual grid modules enhances encoding of local space.","authors":"William T Redman, Santiago Acosta-Mendoza, Xue-Xin Wei, Michael J Goard","doi":"10.7554/eLife.100652","DOIUrl":"10.7554/eLife.100652","url":null,"abstract":"<p><p>Although grid cells are one of the most well-studied functional classes of neurons in the mammalian brain, whether there is a single orientation and spacing value per grid module has not been carefully tested. We analyze a recent large-scale recording of medial entorhinal cortex to characterize the presence and degree of heterogeneity of grid properties within individual modules. We find evidence for small, but robust, variability and hypothesize that this property of the grid code could enhance the encoding of local spatial information. Performing analysis on synthetic populations of grid cells, where we have complete control over the amount heterogeneity in grid properties, we demonstrate that grid property variability of a similar magnitude to the analyzed data leads to significantly decreased decoding error. This holds even when restricted to activity from a single module. Our results highlight how the heterogeneity of the neural response properties may benefit coding and opens new directions for theoretical and experimental analysis of grid cells.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457268","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":"Impact of liver-specific survival motor neuron (SMN) depletion on central nervous system and peripheral tissue pathology.","authors":"Monique Marylin Alves de Almeida, Yves De Repentigny, Sabrina Gagnon, Emma R Sutton, Rashmi Kothary","doi":"10.7554/eLife.99141","DOIUrl":"10.7554/eLife.99141","url":null,"abstract":"<p><p>Spinal muscular atrophy (SMA) is caused by mutations in the Survival Motor Neuron 1 (<i>SMN1</i>) gene. While traditionally viewed as a motor neuron disorder, there is involvement of various peripheral organs in SMA. Notably, fatty liver has been observed in SMA mouse models and SMA patients. Nevertheless, it remains unclear whether intrinsic depletion of SMN protein in the liver contributes to pathology in the peripheral or central nervous systems. To address this, we developed a mouse model with a liver-specific depletion of SMN by utilizing an <i>Alb-Cre</i> transgene together with one <i>Smn^2B</i> allele and one <i>Smn1</i> exon 7 allele flanked by loxP sites. Initially, we evaluated phenotypic changes in these mice at postnatal day 19 (P19), when the severe model of SMA, the <i>Smn^2B/-</i> mice, exhibit many symptoms of the disease. The liver-specific SMN depletion does not induce motor neuron death, neuromuscular pathology or muscle atrophy, characteristics typically observed in the <i>Smn^2B/-</i> mouse at P19. However, mild liver steatosis was observed, although no changes in liver function were detected. Notably, pancreatic alterations resembled that of <i>Smn^2B/-</i>mice, with a decrease in insulin-producing β-cells and an increase in glucagon-producingα-cells, accompanied by a reduction in blood glucose and an increase in plasma glucagon and glucagon-like peptide (GLP-1). These changes were transient, as mice at P60 exhibited recovery of liver and pancreatic function. While the mosaic pattern of the Cre-mediated excision precludes definitive conclusions regarding the contribution of liver-specific SMN depletion to overall tissue pathology, our findings highlight an intricate connection between liver function and pancreatic abnormalities in SMA.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457255","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":"Systems genomics of salinity stress response in rice.","authors":"Sonal Gupta, Simon Niels Groen, Maricris L Zaidem, Andres Godwin C Sajise, Irina Calic, Mignon Natividad, Kenneth McNally, Georgina V Vergara, Rahul Satija, Steven J Franks, Rakesh K Singh, Zoé Joly-Lopez, Michael D Purugganan","doi":"10.7554/eLife.99352","DOIUrl":"10.7554/eLife.99352","url":null,"abstract":"<p><p>Populations can adapt to stressful environments through changes in gene expression. However, the fitness effect of gene expression in mediating stress response and adaptation remains largely unexplored. Here, we use an integrative field dataset obtained from 780 plants of <i>Oryza sativa</i> ssp. <i>indica</i> (rice) grown in a field experiment under normal or moderate salt stress conditions to examine selection and evolution of gene expression variation under salinity stress conditions. We find that salinity stress induces increased selective pressure on gene expression. Further, we show that <i>trans</i>-eQTLs rather than <i>cis</i>-eQTLs are primarily associated with rice's gene expression under salinity stress, potentially via a few master-regulators. Importantly, and contrary to the expectations, we find that <i>cis-trans</i> reinforcement is more common than <i>cis-trans</i> compensation which may be reflective of rice diversification subsequent to domestication. We further identify genetic fixation as the likely mechanism underlying this compensation/reinforcement. Additionally, we show that <i>cis</i>- and <i>trans</i>-eQTLs are under balancing and purifying selection, respectively, giving us insights into the evolutionary dynamics of gene expression variation. By examining genomic, transcriptomic, and phenotypic variation across a rice population, we gain insights into the molecular and genetic landscape underlying adaptive salinity stress responses, which is relevant for other crops and other stresses.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457273","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":"Reduced discrimination between signals of danger and safety but not overgeneralization is linked to exposure to childhood adversity in healthy adults.","authors":"Maren Klingelhöfer-Jens, Katharina Hutterer, Miriam A Schiele, Elisabeth J Leehr, Dirk Schümann, Karoline Rosenkranz, Joscha Böhnlein, Jonathan Repple, Jürgen Deckert, Katharina Domschke, Udo Dannlowski, Ulrike Lueken, Andreas Reif, Marcel Romanos, Peter Zwanzger, Paul Pauli, Matthias Gamer, Tina B Lonsdorf","doi":"10.7554/eLife.91425","DOIUrl":"10.7554/eLife.91425","url":null,"abstract":"<p><p>Childhood adversity is a strong predictor of developing psychopathological conditions. Multiple theories on the mechanisms underlying this association have been suggested which, however, differ in the operationalization of 'exposure.' Altered (threat) learning mechanisms represent central mechanisms by which environmental inputs shape emotional and cognitive processes and ultimately behavior. 1402 healthy participants underwent a fear conditioning paradigm (acquisition training, generalization), while acquiring skin conductance responses (SCRs) and ratings (arousal, valence, and contingency). Childhood adversity was operationalized as (1) dichotomization, and following (2) the specificity model, (3) the cumulative risk model, and (4) the dimensional model. Individuals exposed to childhood adversity showed blunted physiological reactivity in SCRs, but not ratings, and reduced CS+/CS- discrimination during both phases, mainly driven by attenuated CS+ responding. The latter was evident across different operationalizations of 'exposure' following the different theories. None of the theories tested showed clear explanatory superiority. Notably, a remarkably different pattern of increased responding to the CS- is reported in the literature for anxiety patients, suggesting that individuals exposed to childhood adversity may represent a specific sub-sample. We highlight that theories linking childhood adversity to (vulnerability to) psychopathology need refinement.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"12 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457297","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":"To be, or not to be, part-time in academia.","authors":"Sinead English, M Emília Santos, Clare Buckley, Chrissy L Hammond, Sarah Lloyd-Fox, Nina F Ockendon-Powell","doi":"10.7554/eLife.106336","DOIUrl":"10.7554/eLife.106336","url":null,"abstract":"<p><p>Part-time working can be beneficial for individual academics, and also for academia as a whole. In addition to improving work-life balance and well-being, the benefits of part-time working include increased motivation, reduced burnout, and workplaces that are more diverse and inclusive. Here, six researchers who have experience of working part-time discuss what individuals, employers and funders can do to promote and support part-time working in academia.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11841984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457291","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":"Synovial macrophage diversity and activation of M-CSF signaling in post-traumatic osteoarthritis.","authors":"Alexander J Knights, Easton C Farrell, Olivia M Ellis, Michelle J Song, C Thomas Appleton, Tristan Maerz","doi":"10.7554/eLife.93283","DOIUrl":"10.7554/eLife.93283","url":null,"abstract":"<p><p>Synovium is home to immune and stromal cell types that orchestrate inflammation following a joint injury; in particular, macrophages are central protagonists in this process. We sought to define the cellular and temporal dynamics of the synovial immune niche in a mouse model of post-traumatic osteoarthritis (PTOA), and to identify stromal-immune crosstalk mechanisms that coordinate macrophage function and phenotype. We induced PTOA in mice using a non-invasive tibial compression model of anterior cruciate ligament rupture (ACLR). Single-cell RNA-sequencing and flow cytometry were used to assess immune cell populations in healthy (Sham) and injured (7 and 28 days post-ACLR) synovium. Characterization of synovial macrophage polarization states was performed, alongside computational modeling of macrophage differentiation, as well as implicated transcriptional regulators and stromal-immune communication axes. Immune cell types are broadly represented in healthy synovium, but experience drastic expansion and speciation in PTOA, most notably in the macrophage portion. We identified several polarization states of macrophages in synovium following joint injury, underpinned by distinct transcriptomic signatures, and regulated in part by stromal-derived macrophage colony-stimulating factor signaling. The transcription factors Pu.1, Cebpα, Cebpβ, and Jun were predicted to control differentiation of systemically derived monocytes into pro-inflammatory synovial macrophages. In summary, we defined different synovial macrophage subpopulations present in healthy and injured mouse synovium. Nuanced characterization of the distinct functions, origins, and disease kinetics of macrophage subtypes in PTOA will be critical for targeting these highly versatile cells for therapeutic purposes.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"12 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11839164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448560","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":"Cortico-striatal action control inherent of opponent cognitive-motivational styles.","authors":"Cassandra Avila, Martin Sarter","doi":"10.7554/eLife.100988","DOIUrl":"10.7554/eLife.100988","url":null,"abstract":"<p><p>Turning on cue or stopping at a red light requires attending to such cues to select action sequences, or suppress action, in accordance with learned cue-associated action rules. Cortico-striatal projections are an essential part of the brain's attention-motor interface. Glutamate-sensing microelectrode arrays were used to measure glutamate transients in the dorsomedial striatum (DMS) of male and female rats walking a treadmill and executing cued turns and stops. Prelimbic-DMS projections were chemogenetically inhibited to determine their behavioral necessity and the cortico-striatal origin of cue-evoked glutamate transients. Furthermore, we investigated rats exhibiting preferably goal-directed (goal trackers, GTs) versus cue-driven attention (sign-trackers, STs), to determine the impact of such cognitive-motivational biases on cortico-striatal control. GTs executed more cued turns and initiated such turns more slowly than STs. During turns, but not missed turns or cued stops, cue-evoked glutamate concentrations were higher in GTs than in STs. In STs, turn cue-locked glutamate concentrations frequently peaked twice or three times, contrasting with predominately single peaks in GTs. In GTs, but not STs, inhibition of prelimbic-DMS projections attenuated turn rates and turn cue-evoked glutamate concentrations and increased the number of turn cue-locked glutamate peaks. These findings indicate that turn cue-evoked glutamate release in GTs is tightly controlled by cortico-striatal neuronal activity. In contrast, in STs, glutamate release from DMS glutamatergic terminals may be regulated by other striatal circuitry, preferably mediating cued suppression of action and reward tracking. As cortico-striatal dysfunction has been hypothesized to contribute to a wide range of disorders, including complex movement control deficits in Parkinson's disease and compulsive drug taking, the demonstration of phenotypic contrasts in cortico-striatal control implies the presence of individual vulnerabilities for such disorders.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11839163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448551","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":"Catalytic growth in a shared enzyme pool ensures robust control of centrosome size.","authors":"Deb Sankar Banerjee, Shiladitya Banerjee","doi":"10.7554/eLife.92203","DOIUrl":"10.7554/eLife.92203","url":null,"abstract":"<p><p>Accurate regulation of centrosome size is essential for ensuring error-free cell division, and dysregulation of centrosome size has been linked to various pathologies, including developmental defects and cancer. While a universally accepted model for centrosome size regulation is lacking, prior theoretical and experimental works suggest a centrosome growth model involving autocatalytic assembly of the pericentriolar material. Here, we show that the autocatalytic assembly model fails to explain the attainment of equal centrosome sizes, which is crucial for error-free cell division. Incorporating latest experimental findings into the molecular mechanisms governing centrosome assembly, we introduce a new quantitative theory for centrosome growth involving catalytic assembly within a shared pool of enzymes. Our model successfully achieves robust size equality between maturing centrosome pairs, mirroring cooperative growth dynamics observed in experiments. To validate our theoretical predictions, we compare them with available experimental data and demonstrate the broad applicability of the catalytic growth model across different organisms, which exhibit distinct growth dynamics and size scaling characteristics.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"12 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11839165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448558","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}