eLife最新文献_第4页

To be, or not to be, part-time in academia.

IF 6.4 1区生物学

eLife Pub Date : 2025-02-20 DOI: 10.7554/eLife.106336

Sinead English, M Emília Santos, Clare Buckley, Chrissy L Hammond, Sarah Lloyd-Fox, Nina F Ockendon-Powell

引用次数: 0

AI-enabled alkaline-resistant evolution of protein to apply in mass production.

IF 6.4 1区生物学

eLife Pub Date : 2025-02-19 DOI: 10.7554/eLife.102788

Liqi Kang, Banghao Wu, Bingxin Zhou, Pan Tan, Yun Kenneth Kang, Yongzhen Yan, Yi Zong, Shuang Li, Zhuo Liu, Liang Hong

{"title":"AI-enabled alkaline-resistant evolution of protein to apply in mass production.","authors":"Liqi Kang, Banghao Wu, Bingxin Zhou, Pan Tan, Yun Kenneth Kang, Yongzhen Yan, Yi Zong, Shuang Li, Zhuo Liu, Liang Hong","doi":"10.7554/eLife.102788","DOIUrl":"10.7554/eLife.102788","url":null,"abstract":"Artificial intelligence (AI) models have been used to study the compositional regularities of proteins in nature, enabling it to assist in protein design to improve the efficiency of protein engineering and reduce manufacturing cost. However, in industrial settings, proteins are often required to work in extreme environments where they are relatively scarce or even non-existent in nature. Since such proteins are almost absent in the training datasets, it is uncertain whether AI model possesses the capability of evolving the protein to adapt extreme conditions. Antibodies are crucial components of affinity chromatography, and they are hoped to remain active at the extreme environments where most proteins cannot tolerate. In this study, we applied an advanced large language model (LLM), the Pro-PRIME model, to improve the alkali resistance of a representative antibody, a VHH antibody capable of binding to growth hormone. Through two rounds of design, we ensured that the selected mutant has enhanced functionality, including higher thermal stability, extreme pH resistance, and stronger affinity, thereby validating the generalized capability of the LLM in meeting specific demands. To the best of our knowledge, this is the first LLM-designed protein product, which is successfully applied in mass production.","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/PMC11839161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448466","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}

引用次数: 0

Synovial macrophage diversity and activation of M-CSF signaling in post-traumatic osteoarthritis.

IF 6.4 1区生物学

eLife Pub Date : 2025-02-19 DOI: 10.7554/eLife.93283

Alexander J Knights, Easton C Farrell, Olivia M Ellis, Michelle J Song, C Thomas Appleton, Tristan Maerz

{"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":"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.","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}

引用次数: 0

Cortico-striatal action control inherent of opponent cognitive-motivational styles.

IF 6.4 1区生物学

eLife Pub Date : 2025-02-19 DOI: 10.7554/eLife.100988

Cassandra Avila, Martin Sarter

{"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":"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.","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}

引用次数: 0

Catalytic growth in a shared enzyme pool ensures robust control of centrosome size.

IF 6.4 1区生物学

eLife Pub Date : 2025-02-19 DOI: 10.7554/eLife.92203

Deb Sankar Banerjee, Shiladitya Banerjee

{"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":"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.","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}

引用次数: 0

An adaptable, reusable, and light implant for chronic Neuropixels probes.

IF 6.4 1区生物学

eLife Pub Date : 2025-02-18 DOI: 10.7554/eLife.98522

Célian Bimbard, Flóra Takács, Joana A Catarino, Julie M J Fabre, Sukriti Gupta, Stephen C Lenzi, Maxwell D Melin, Nathanael O'Neill, Ivana Orsolic, Magdalena Robacha, James S Street, José M Gomes Teixeira, Simon Townsend, Enny H van Beest, Arthur M Zhang, Anne K Churchland, Chunyu A Duan, Kenneth D Harris, Dimitri Michael Kullmann, Gabriele Lignani, Zachary F Mainen, Troy W Margrie, Nathalie L Rochefort, Andrew Wikenheiser, Matteo Carandini, Philip Coen

{"title":"An adaptable, reusable, and light implant for chronic Neuropixels probes.","authors":"Célian Bimbard, Flóra Takács, Joana A Catarino, Julie M J Fabre, Sukriti Gupta, Stephen C Lenzi, Maxwell D Melin, Nathanael O'Neill, Ivana Orsolic, Magdalena Robacha, James S Street, José M Gomes Teixeira, Simon Townsend, Enny H van Beest, Arthur M Zhang, Anne K Churchland, Chunyu A Duan, Kenneth D Harris, Dimitri Michael Kullmann, Gabriele Lignani, Zachary F Mainen, Troy W Margrie, Nathalie L Rochefort, Andrew Wikenheiser, Matteo Carandini, Philip Coen","doi":"10.7554/eLife.98522","DOIUrl":"10.7554/eLife.98522","url":null,"abstract":"Electrophysiology has proven invaluable to record neural activity, and the development of Neuropixels probes dramatically increased the number of recorded neurons. These probes are often implanted acutely, but acute recordings cannot be performed in freely moving animals and the recorded neurons cannot be tracked across days. To study key behaviors such as navigation, learning, and memory formation, the probes must be implanted chronically. An ideal chronic implant should (1) allow stable recordings of neurons for weeks; (2) allow reuse of the probes after explantation; (3) be light enough for use in mice. Here, we present the 'Apollo Implant', an open-source and editable device that meets these criteria and accommodates up to two Neuropixels 1.0 or 2.0 probes. The implant comprises a 'payload' module which is attached to the probe and is recoverable, and a 'docking' module which is cemented to the skull. The design is adjustable, making it easy to change the distance between probes, the angle of insertion, and the depth of insertion. We tested the implant across eight labs in head-fixed mice, freely moving mice, and freely moving rats. The number of neurons recorded across days was stable, even after repeated implantations of the same probe. The Apollo implant provides an inexpensive, lightweight, and flexible solution for reusable chronic Neuropixels recordings.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11835385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448479","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}

引用次数: 0

The conserved ATPase PCH-2 controls the number and distribution of crossovers by antagonizing their formation in Caenorhabditis elegans.

IF 6.4 1区生物学

eLife Pub Date : 2025-02-18 DOI: 10.7554/eLife.102409

Bhumil Patel, Maryke Grobler, Alberto Herrera, Elias Logari, Valery Ortiz, Needhi Bhalla

{"title":"The conserved ATPase PCH-2 controls the number and distribution of crossovers by antagonizing their formation in Caenorhabditis elegans.","authors":"Bhumil Patel, Maryke Grobler, Alberto Herrera, Elias Logari, Valery Ortiz, Needhi Bhalla","doi":"10.7554/eLife.102409","DOIUrl":"10.7554/eLife.102409","url":null,"abstract":"Meiotic crossover recombination is essential for both accurate chromosome segregation and the generation of new haplotypes for natural selection to act upon. This requirement is known as crossover assurance and is one example of crossover control. While the conserved role of the ATPase, PCH-2, during meiotic prophase has been enigmatic, a universal phenotype when pch-2 or its orthologs are mutated is a change in the number and distribution of meiotic crossovers. Here, we show that PCH-2 controls the number and distribution of crossovers by antagonizing their formation. This antagonism produces different effects at different stages of meiotic prophase: early in meiotic prophase, PCH-2 prevents double-strand breaks from becoming crossover-eligible intermediates, limiting crossover formation at sites of initial double-strand break formation and homolog interactions. Later in meiotic prophase, PCH-2 winnows the number of crossover-eligible intermediates, contributing to the designation of crossovers and ultimately, crossover assurance. We also demonstrate that PCH-2 accomplishes this regulation through the meiotic HORMAD, HIM-3. Our data strongly support a model in which PCH-2's conserved role is to remodel meiotic HORMADs throughout meiotic prophase to destabilize crossover-eligible precursors and coordinate meiotic recombination with synapsis, ensuring the progressive implementation of meiotic recombination and explaining its function in the pachytene checkpoint and crossover control.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11835387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448556","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}

引用次数: 0

Visual homogeneity computations in the brain enable solving property-based visual tasks.

IF 6.4 1区生物学

eLife Pub Date : 2025-02-18 DOI: 10.7554/eLife.93033

Georgin Jacob, R T Pramod, S P Arun

引用次数: 0

The relationship between gut and nasopharyngeal microbiome composition can predict the severity of COVID-19.

IF 6.4 1区生物学

eLife Pub Date : 2025-02-18 DOI: 10.7554/eLife.95292

Benita Martin-Castaño, Patricia Diez-Echave, Jorge García-García, Laura Hidalgo-García, Antonio Jesús Ruiz-Malagon, José Alberto Molina-Tijeras, María Jesús Rodríguez-Sojo, Anaïs Redruello-Romero, Margarita Martínez-Zaldívar, Emilio Mota, Fernando Cobo, Xando Díaz-Villamarin, Marta Alvarez-Estevez, Federico García, Concepción Morales-García, Silvia Merlos, Paula Garcia-Flores, Manuel Colmenero-Ruiz, José Hernández-Quero, Maria Nuñez, Maria Elena Rodriguez-Cabezas, Angel Carazo, Javier Martin, Rocio Moron, Alba Rodríguez Nogales, Julio Galvez

{"title":"The relationship between gut and nasopharyngeal microbiome composition can predict the severity of COVID-19.","authors":"Benita Martin-Castaño, Patricia Diez-Echave, Jorge García-García, Laura Hidalgo-García, Antonio Jesús Ruiz-Malagon, José Alberto Molina-Tijeras, María Jesús Rodríguez-Sojo, Anaïs Redruello-Romero, Margarita Martínez-Zaldívar, Emilio Mota, Fernando Cobo, Xando Díaz-Villamarin, Marta Alvarez-Estevez, Federico García, Concepción Morales-García, Silvia Merlos, Paula Garcia-Flores, Manuel Colmenero-Ruiz, José Hernández-Quero, Maria Nuñez, Maria Elena Rodriguez-Cabezas, Angel Carazo, Javier Martin, Rocio Moron, Alba Rodríguez Nogales, Julio Galvez","doi":"10.7554/eLife.95292","DOIUrl":"10.7554/eLife.95292","url":null,"abstract":"Coronavirus disease 2019 (COVID-19) is a respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that displays great variability in clinical phenotype. Many factors have been described to be correlated with its severity, and microbiota could play a key role in the infection, progression, and outcome of the disease. SARS-CoV-2 infection has been associated with nasopharyngeal and gut dysbiosis and higher abundance of opportunistic pathogens. To identify new prognostic markers for the disease, a multicentre prospective observational cohort study was carried out in COVID-19 patients divided into three cohorts based on symptomatology: mild (n = 24), moderate (n = 51), and severe/critical (n = 31). Faecal and nasopharyngeal samples were taken, and the microbiota was analysed. Linear discriminant analysis identified Mycoplasma salivarium, Prevotella dentalis, and Haemophilus parainfluenzae as biomarkers of severe COVID-19 in nasopharyngeal microbiota, while Prevotella bivia and Prevotella timonensis were defined in faecal microbiota. Additionally, a connection between faecal and nasopharyngeal microbiota was identified, with a significant ratio between P. timonensis (faeces) and P. dentalis and M. salivarium (nasopharyngeal) abundances found in critically ill patients. This ratio could serve as a novel prognostic tool for identifying severe COVID-19 cases.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11835386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440227","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}

引用次数: 0

Multiplexed assays of human disease-relevant mutations reveal UTR dinucleotide composition as a major determinant of RNA stability.

IF 6.4 1区生物学

eLife Pub Date : 2025-02-18 DOI: 10.7554/eLife.97682

Jia-Ying Su, Yun-Lin Wang, Yu-Tung Hsieh, Yu-Chi Chang, Cheng-Han Yang, YoonSoon Kang, Yen-Tsung Huang, Chien-Ling Lin

{"title":"Multiplexed assays of human disease-relevant mutations reveal UTR dinucleotide composition as a major determinant of RNA stability.","authors":"Jia-Ying Su, Yun-Lin Wang, Yu-Tung Hsieh, Yu-Chi Chang, Cheng-Han Yang, YoonSoon Kang, Yen-Tsung Huang, Chien-Ling Lin","doi":"10.7554/eLife.97682","DOIUrl":"10.7554/eLife.97682","url":null,"abstract":"Untranslated regions (UTRs) contain crucial regulatory elements for RNA stability, translation and localization, so their integrity is indispensable for gene expression. Approximately 3.7% of genetic variants associated with diseases occur in UTRs, yet a comprehensive understanding of UTR variant functions remains limited due to inefficient experimental and computational assessment methods. To systematically evaluate the effects of UTR variants on RNA stability, we established a massively parallel reporter assay on 6555 UTR variants reported in human disease databases. We examined the RNA degradation patterns mediated by the UTR library in two cell lines, and then applied LASSO regression to model the influential regulators of RNA stability. We found that UA dinucleotides and UA-rich motifs are the most prominent destabilizing element. Gain of UA dinucleotide outlined mutant UTRs with reduced stability. Studies on endogenous transcripts indicate that high UA-dinucleotide ratios in UTRs promote RNA degradation. Conversely, elevated GC content and protein binding on UA dinucleotides protect high-UA RNA from degradation. Further analysis reveals polarized roles of UA-dinucleotide-binding proteins in RNA protection and degradation. Furthermore, the UA-dinucleotide ratio of both UTRs is a common characteristic of genes in innate immune response pathways, implying a coordinated stability regulation through UTRs at the transcriptomic level. We also demonstrate that stability-altering UTRs are associated with changes in biobank-based health indices, underscoring the importance of precise UTR regulation for wellness. Our study highlights the importance of RNA stability regulation through UTR primary sequences, paving the way for further exploration of their implications in gene networks and precision medicine.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11835390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448555","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}

引用次数: 0