eLife最新文献_第2页

Cytosolic S100A8/A9 promotes Ca²⁺ supply at LFA-1 adhesion clusters during neutrophil recruitment.

IF 6.4 1区生物学

eLife Pub Date : 2024-12-19 DOI: 10.7554/eLife.96810

Matteo Napoli, Roland Immler, Ina Rohwedder, Valerio Lupperger, Johannes Pfabe, Mariano Gonzalez Pisfil, Anna Yevtushenko, Thomas Vogl, Johannes Roth, Melanie Salvermoser, Steffen Dietzel, Marjan Slak Rupnik, Carsten Marr, Barbara Walzog, Markus Sperandio, Monika Pruenster

{"title":"Cytosolic S100A8/A9 promotes Ca2+ supply at LFA-1 adhesion clusters during neutrophil recruitment.","authors":"Matteo Napoli, Roland Immler, Ina Rohwedder, Valerio Lupperger, Johannes Pfabe, Mariano Gonzalez Pisfil, Anna Yevtushenko, Thomas Vogl, Johannes Roth, Melanie Salvermoser, Steffen Dietzel, Marjan Slak Rupnik, Carsten Marr, Barbara Walzog, Markus Sperandio, Monika Pruenster","doi":"10.7554/eLife.96810","DOIUrl":"https://doi.org/10.7554/eLife.96810","url":null,"abstract":"S100A8/A9 is an endogenous alarmin secreted by myeloid cells during many acute and chronic inflammatory disorders. Despite increasing evidence of the proinflammatory effects of extracellular S100A8/A9, little is known about its intracellular function. Here, we show that cytosolic S100A8/A9 is indispensable for neutrophil post-arrest modifications during outside-in signaling under flow conditions in vitro and neutrophil recruitment in vivo, independent of its extracellular functions. Mechanistically, genetic deletion of S100A9 in mice caused dysregulated Ca2+ signatures in activated neutrophils resulting in reduced Ca2+ availability at the formed LFA-1/F-actin clusters with defective β2 integrin outside-in signaling during post-arrest modifications. Consequently, we observed impaired cytoskeletal rearrangement, cell polarization, and spreading, as well as cell protrusion formation in S100a9-/- compared to wildtype (WT) neutrophils, making S100a9-/- cells more susceptible to detach under flow, thereby preventing efficient neutrophil recruitment and extravasation into inflamed tissue.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853425","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}

引用次数: 0

Endosomal sorting protein SNX4 limits synaptic vesicle docking and release.

IF 6.4 1区生物学

eLife Pub Date : 2024-12-19 DOI: 10.7554/eLife.97910

Josse Poppinga, Nolan J Barrett, L Niels Cornelisse, Matthijs Verhage, Jan R T van Weering

引用次数: 0

Full-length direct RNA sequencing uncovers stress granule-dependent RNA decay upon cellular stress.

IF 6.4 1区生物学

eLife Pub Date : 2024-12-19 DOI: 10.7554/eLife.96284

Showkat Ahmad Dar, Sulochan Malla, Vlastimil Martinek, Matthew John Payea, Christopher Tai-Yi Lee, Jessica Martin, Aditya Jignesh Khandeshi, Jennifer L Martindale, Cedric Belair, Manolis Maragkakis

{"title":"Full-length direct RNA sequencing uncovers stress granule-dependent RNA decay upon cellular stress.","authors":"Showkat Ahmad Dar, Sulochan Malla, Vlastimil Martinek, Matthew John Payea, Christopher Tai-Yi Lee, Jessica Martin, Aditya Jignesh Khandeshi, Jennifer L Martindale, Cedric Belair, Manolis Maragkakis","doi":"10.7554/eLife.96284","DOIUrl":"10.7554/eLife.96284","url":null,"abstract":"Cells react to stress by triggering response pathways, leading to extensive alterations in the transcriptome to restore cellular homeostasis. The role of RNA metabolism in shaping the cellular response to stress is vital, yet the global changes in RNA stability under these conditions remain unclear. In this work, we employ direct RNA sequencing with nanopores, enhanced by 5' end adapter ligation, to comprehensively interrogate the human transcriptome at single-molecule and -nucleotide resolution. By developing a statistical framework to identify robust RNA length variations in nanopore data, we find that cellular stress induces prevalent 5' end RNA decay that is coupled to translation and ribosome occupancy. Unlike typical RNA decay models in normal conditions, we show that stress-induced RNA decay is dependent on XRN1 but does not depend on deadenylation or decapping. We observed that RNAs undergoing decay are predominantly enriched in the stress granule transcriptome while inhibition of stress granule formation via genetic ablation of G3BP1 and G3BP2 rescues RNA length. Our findings reveal RNA decay as a key component of RNA metabolism upon cellular stress that is dependent on stress granule formation.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853389","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}

引用次数: 0

Statistical analysis supports pervasive RNA subcellular localization and alternative 3' UTR regulation.

IF 6.4 1区生物学

eLife Pub Date : 2024-12-19 DOI: 10.7554/eLife.87517

Rob Bierman, Jui M Dave, Daniel M Greif, Julia Salzman

{"title":"Statistical analysis supports pervasive RNA subcellular localization and alternative 3' UTR regulation.","authors":"Rob Bierman, Jui M Dave, Daniel M Greif, Julia Salzman","doi":"10.7554/eLife.87517","DOIUrl":"https://doi.org/10.7554/eLife.87517","url":null,"abstract":"Targeted low-throughput studies have previously identified subcellular RNA localization as necessary for cellular functions including polarization, and translocation. Furthermore, these studies link localization to RNA isoform expression, especially 3' Untranslated Region (UTR) regulation. The recent introduction of genome-wide spatial transcriptomics techniques enables the potential to test if subcellular localization is regulated in situ pervasively. In order to do this, robust statistical measures of subcellular localization and alternative poly-adenylation (APA) at single-cell resolution are needed. Developing a new statistical framework called SPRAWL, we detect extensive cell-type specific subcellular RNA localization regulation in the mouse brain and to a lesser extent mouse liver. We integrated SPRAWL with a new approach to measure cell-type specific regulation of alternative 3' UTR processing and detected examples of significant correlations between 3' UTR length and subcellular localization. Included examples, Timp3, Slc32a1, Cxcl14, and Nxph1 have subcellular localization in the mouse brain highly correlated with regulated 3' UTR processing that includes the use of unannotated, but highly conserved, 3' ends. Together, SPRAWL provides a statistical framework to integrate multi-omic single-cell resolved measurements of gene-isoform pairs to prioritize an otherwise impossibly large list of candidate functional 3' UTRs for functional prediction and study. In these studies of data from mice, SPRAWL predicts that 3' UTR regulation of subcellular localization may be more pervasive than currently known.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"12 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853528","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}

引用次数: 0

The geometric basis of epithelial convergent extension.

IF 6.4 1区生物学

eLife Pub Date : 2024-12-19 DOI: 10.7554/eLife.95521

Fridtjof Brauns, Nikolas H Claussen, Matthew F Lefebvre, Eric F Wieschaus, Boris I Shraiman

{"title":"The geometric basis of epithelial convergent extension.","authors":"Fridtjof Brauns, Nikolas H Claussen, Matthew F Lefebvre, Eric F Wieschaus, Boris I Shraiman","doi":"10.7554/eLife.95521","DOIUrl":"10.7554/eLife.95521","url":null,"abstract":"Shape changes of epithelia during animal development, such as convergent extension, are achieved through the concerted mechanical activity of individual cells. While much is known about the corresponding large-scale tissue flow and its genetic drivers, fundamental questions regarding local control of contractile activity on the cellular scale and its embryo-scale coordination remain open. To address these questions, we develop a quantitative, model-based analysis framework to relate cell geometry to local tension in recently obtained time-lapse imaging data of gastrulating Drosophila embryos. This analysis systematically decomposes cell shape changes and T1 rearrangements into internally driven, active, and externally driven, passive, contributions. Our analysis provides evidence that germ band extension is driven by active T1 processes that self-organize through positive feedback acting on tensions. More generally, our findings suggest that epithelial convergent extension results from the controlled transformation of internal force balance geometry which combines the effects of bottom-up local self-organization with the top-down, embryo-scale regulation by gene expression.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853525","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}

引用次数: 0

Dysfunctional S1P/S1PR1 signaling in the dentate gyrus drives vulnerability of chronic pain-related memory impairment.

IF 6.4 1区生物学

eLife Pub Date : 2024-12-19 DOI: 10.7554/eLife.99862

Mengqiao Cui, Xiaoyuan Pan, Zhijie Fan, Shulin Wu, Ran Ji, Xianlei Wang, Xiangxi Kong, Zhou Wu, Lingzhen Song, Weiyi Song, Jun-Xia Yang, Hongjie Zhang, Hongxing Zhang, Hai-Lei Ding, Jun-Li Cao

{"title":"Dysfunctional S1P/S1PR1 signaling in the dentate gyrus drives vulnerability of chronic pain-related memory impairment.","authors":"Mengqiao Cui, Xiaoyuan Pan, Zhijie Fan, Shulin Wu, Ran Ji, Xianlei Wang, Xiangxi Kong, Zhou Wu, Lingzhen Song, Weiyi Song, Jun-Xia Yang, Hongjie Zhang, Hongxing Zhang, Hai-Lei Ding, Jun-Li Cao","doi":"10.7554/eLife.99862","DOIUrl":"10.7554/eLife.99862","url":null,"abstract":"Memory impairment in chronic pain patients is substantial and common, and few therapeutic strategies are available. Chronic pain-related memory impairment has susceptible and unsusceptible features. Therefore, exploring the underlying mechanisms of its vulnerability is essential for developing effective treatments. Here, combining two spatial memory tests (Y-maze test and Morris water maze), we segregated chronic pain mice into memory impairment-susceptible and -unsusceptible subpopulations in a chronic neuropathic pain model induced by chronic constrictive injury of the sciatic nerve. RNA-Seq analysis and gain/loss-of-function study revealed that S1P/S1PR1 signaling is a determinant for vulnerability to chronic pain-related memory impairment. Knockdown of the S1PR1 in the dentate gyrus (DG) promoted a susceptible phenotype and led to structural plasticity changes of reduced excitatory synapse formation and abnormal spine morphology as observed in susceptible mice, while overexpression of the S1PR1 and pharmacological administration of S1PR1 agonist in the DG promoted an unsusceptible phenotype and prevented the occurrence of memory impairment, and rescued the morphological abnormality. Finally, the Gene Ontology (GO) enrichment analysis and biochemical evidence indicated that downregulation of S1PR1 in susceptible mice may impair DG structural plasticity via interaction with actin cytoskeleton rearrangement-related signaling pathways including Itga2 and its downstream Rac1/Cdc42 signaling and Arp2/3 cascade. These results reveal a novel mechanism and provide a promising preventive and therapeutic molecular target for vulnerability to chronic pain-related memory impairment.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853442","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}

引用次数: 0

Mapping spatial patterns to energetic benefits in groups of flow-coupled swimmers.

IF 6.4 1区生物学

eLife Pub Date : 2024-12-19 DOI: 10.7554/eLife.96129

Sina Heydari, Haotian Hang, Eva Kanso

{"title":"Mapping spatial patterns to energetic benefits in groups of flow-coupled swimmers.","authors":"Sina Heydari, Haotian Hang, Eva Kanso","doi":"10.7554/eLife.96129","DOIUrl":"https://doi.org/10.7554/eLife.96129","url":null,"abstract":"The coordinated motion of animal groups through fluids is thought to reduce the cost of locomotion to individuals in the group. However, the connection between the spatial patterns observed in collectively moving animals and the energetic benefits at each position within the group remains unclear. To address this knowledge gap, we study the spontaneous emergence of cohesive formations in groups of fish, modeled as flapping foils, all heading in the same direction. We show in pairwise formations and with increasing group size that (1) in side-by-side arrangements, the reciprocal nature of flow coupling results in an equal distribution of energy requirements among all members, with reduction in cost of locomotion for swimmers flapping inphase but an increase in cost for swimmers flapping antiphase, and (2) in inline arrangements, flow coupling is non-reciprocal for all flapping phase, with energetic savings in favor of trailing swimmers, but only up to a finite number of swimmers, beyond which school cohesion and energetic benefits are lost at once. We explain these findings mechanistically and we provide efficient diagnostic tools for identifying locations in the wake of single and multiple swimmers that offer opportunities for hydrodynamic benefits to aspiring followers. Our results imply a connection between the resources generated by flow physics and social traits that influence greedy and cooperative group behavior.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863827","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}

引用次数: 0

N-terminus of Drosophila melanogaster MSL1 is critical for dosage compensation.

IF 6.4 1区生物学

eLife Pub Date : 2024-12-19 DOI: 10.7554/eLife.93241

Valentin Babosha, Natalia Klimenko, Anastasia Revel-Muroz, Evgeniya Tikhonova, Pavel Georgiev, Oksana Maksimenko

{"title":"N-terminus of Drosophila melanogaster MSL1 is critical for dosage compensation.","authors":"Valentin Babosha, Natalia Klimenko, Anastasia Revel-Muroz, Evgeniya Tikhonova, Pavel Georgiev, Oksana Maksimenko","doi":"10.7554/eLife.93241","DOIUrl":"10.7554/eLife.93241","url":null,"abstract":"The male-specific lethal complex (MSL), which consists of five proteins and two non-coding roX RNAs, is involved in the transcriptional enhancement of X-linked genes to compensate for the sex chromosome monosomy in Drosophila XY males compared with XX females. The MSL1 and MSL2 proteins form the heterotetrameric core of the MSL complex and are critical for the specific recruitment of the complex to the high-affinity 'entry' sites (HAS) on the X chromosome. In this study, we demonstrated that the N-terminal region of MSL1 is critical for stability and functions of MSL1. Amino acid deletions and substitutions in the N-terminal region of MSL1 strongly affect both the interaction with roX2 RNA and the MSL complex binding to HAS on the X chromosome. In particular, substitution of the conserved N-terminal amino-acids 3-7 in MSL1 (MSL1GS) affects male viability similar to the inactivation of genes encoding roX RNAs. In addition, MSL1GS binds to promoters such as MSL1WT but does not co-bind with MSL2 and MSL3 to X chromosomal HAS. However, overexpression of MSL2 partially restores the dosage compensation. Thus, the interaction of MSL1 with roX RNA is critical for the efficient assembly of the MSL complex on HAS of the male X chromosome.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853456","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}

引用次数: 0

Discarded sequencing reads uncover natural variation in pest resistance in Thlaspi arvense.

IF 6.4 1区生物学

eLife Pub Date : 2024-12-19 DOI: 10.7554/eLife.95510

Dario Galanti, Jun Hee Jung, Caroline Müller, Oliver Bossdorf

{"title":"Discarded sequencing reads uncover natural variation in pest resistance in Thlaspi arvense.","authors":"Dario Galanti, Jun Hee Jung, Caroline Müller, Oliver Bossdorf","doi":"10.7554/eLife.95510","DOIUrl":"https://doi.org/10.7554/eLife.95510","url":null,"abstract":"Understanding the genomic basis of natural variation in plant pest resistance is an important goal in plant science, but it usually requires large and labor-intensive phenotyping experiments. Here, we explored the possibility that non-target reads from plant DNA sequencing can serve as phenotyping proxies for addressing such questions. We used data from a whole-genome and -epigenome sequencing study of 207 natural lines of field pennycress (Thlaspi arvense) that were grown in a common environment and spontaneously colonized by aphids, mildew, and other microbes. We found that the numbers of non-target reads assigned to the pest species differed between populations, had significant SNP-based heritability, and were associated with climate of origin and baseline glucosinolate contents. Specifically, pennycress lines from cold and thermally fluctuating habitats, presumably less favorable to aphids, showed higher aphid DNA load, i.e., decreased aphid resistance. Genome-wide association analyses identified genetic variants at known defense genes but also novel genomic regions associated with variation in aphid and mildew DNA load. Moreover, we found several differentially methylated regions associated with pathogen loads, in particular differential methylation at transposons and hypomethylation in the promoter of a gene involved in stomatal closure, likely induced by pathogens. Our study provides first insights into the defense mechanisms of Thlaspi arvense, a rising crop and model species, and demonstrates that non-target whole-genome sequencing reads, usually discarded, can be leveraged to estimate intensities of plant biotic interactions. With rapidly increasing numbers of large sequencing datasets worldwide, this approach should have broad application in fundamental and applied research.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853439","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}

引用次数: 0

Conformational dynamics of a nicotinic receptor neurotransmitter site.

IF 6.4 1区生物学

eLife Pub Date : 2024-12-18 DOI: 10.7554/eLife.92418

Mrityunjay Singh, Dinesh C Indurthi, Lovika Mittal, Anthony Auerbach, Shailendra Asthana

{"title":"Conformational dynamics of a nicotinic receptor neurotransmitter site.","authors":"Mrityunjay Singh, Dinesh C Indurthi, Lovika Mittal, Anthony Auerbach, Shailendra Asthana","doi":"10.7554/eLife.92418","DOIUrl":"10.7554/eLife.92418","url":null,"abstract":"Agonists enhance receptor activity by providing net-favorable binding energy to active over resting conformations, with efficiency (η) linking binding energy to gating. Previously, we showed that in nicotinic receptors, η-values are grouped into five structural pairs, correlating efficacy and affinity within each class, uniting binding with allosteric activation (Indurthi and Auerbach, 2023). Here, we use molecular dynamics (MD) simulations to investigate the low-to-high affinity transition (L→H) at the Torpedo α-δ nicotinic acetylcholine receptor neurotransmitter site. Using four agonists spanning three η-classes, the simulations reveal the structural basis of the L→H transition where: the agonist pivots around its cationic center ('flip'), loop C undergoes staged downward displacement ('flop'), and a compact, stable high-affinity pocket forms ('fix'). The η derived from binding energies calculated in silico matched exact values measured experimentally in vitro. Intermediate states of the orthosteric site during receptor activation are apparent only in simulations, but could potentially be observed experimentally via time-resolved structural studies.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846132","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}

引用次数: 0