Molecular Systems Biology最新文献_第3页

Deciphering cross-cohort metabolic signatures of immune responses and their implications for disease pathogenesis. 解读免疫反应的跨队列代谢特征及其对疾病发病机制的影响。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-09-10 DOI: 10.1038/s44320-025-00146-w

Jianbo Fu, Nienke van Unen, Andrei Sarlea, Nhan Nguyen, Martin Jaeger, Javier Botey Bataller, Valerie A C M Koeken, L Charlotte de Bree, Vera P Mourits, Simone J C F M Moorlag, Godfrey Temba, Vesla I Kullaya, Quirijn de Mast, Leo A B Joosten, Cheng-Jian Xu, Mihai G Netea, Yang Li

{"title":"Deciphering cross-cohort metabolic signatures of immune responses and their implications for disease pathogenesis.","authors":"Jianbo Fu, Nienke van Unen, Andrei Sarlea, Nhan Nguyen, Martin Jaeger, Javier Botey Bataller, Valerie A C M Koeken, L Charlotte de Bree, Vera P Mourits, Simone J C F M Moorlag, Godfrey Temba, Vesla I Kullaya, Quirijn de Mast, Leo A B Joosten, Cheng-Jian Xu, Mihai G Netea, Yang Li","doi":"10.1038/s44320-025-00146-w","DOIUrl":"https://doi.org/10.1038/s44320-025-00146-w","url":null,"abstract":"The complex interplay between circulating metabolites and immune responses, which is pivotal to disease pathophysiology, remains poorly understood and understudied in systematic research. Here, we performed a comprehensive analysis of the immune response and circulating metabolome in two Western European cohorts (534 and 324 healthy individuals) and one from sub-Saharan Africa (323 healthy donors). At the metabolic level, our analysis revealed sex-specific differences in the correlation between phosphatidylcholine and cytokine responses following ex vivo stimulation. Notably, sphingomyelin exhibited a significant negative correlation with monocyte-derived cytokine production in response to Staphylococcus aureus stimulation, a finding that was validated through functional experiments. Subsequently, using Mendelian randomization analysis, we established a link between sphingomyelin and COVID-19 severity, providing compelling evidence for its modulatory role in immune responses during human infection. Collectively, our results represent a unique resource ( https://lab-li.ciim-hannover.de/apps/imetabomap/ ) for exploring metabolic signatures associated with immune function in different populations, highlighting sphingomyelin metabolism as a potential target in treating inflammatory and infectious diseases.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033634","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

Overflow metabolism in bacterial, yeast, and mammalian cells: different names, same game. 细菌、酵母和哺乳动物细胞的溢出代谢：不同的名字，相同的游戏。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-09-09 DOI: 10.1038/s44320-025-00145-x

Thomas Gosselin-Monplaisir, Brice Enjalbert, Sandrine Uttenweiler-Joseph, Jean-Charles Portais, Stéphanie Heux, Pierre Millard

{"title":"Overflow metabolism in bacterial, yeast, and mammalian cells: different names, same game.","authors":"Thomas Gosselin-Monplaisir, Brice Enjalbert, Sandrine Uttenweiler-Joseph, Jean-Charles Portais, Stéphanie Heux, Pierre Millard","doi":"10.1038/s44320-025-00145-x","DOIUrl":"https://doi.org/10.1038/s44320-025-00145-x","url":null,"abstract":"Overflow metabolism refers to the widespread phenomenon of cells excreting metabolic by-products into their environment. Although overflow is observed in virtually all living organisms, it has been studied independently and given different names in different species. This review highlights emerging evidence that overflow metabolism is governed by common principles in prokaryotic and eukaryotic organisms. We examine the similarities and specificities in the structure, function, and regulation of overflow pathways in bacterial, yeast, and mammalian cells, with a focus on model species and common by-products. Our reinterpretation of previous findings points to the existence of universal principles governing overflow fluxes. We also emphasize the need to reconsider the roles of overflow metabolites, not as cellular stress-inducing toxic waste, but as nutrients and regulators, influencing metabolism at both cellular and community levels, often to the benefit of the producing cells. Finally, we review prevailing theories of overflow metabolism and explore avenues toward a potential unified theory of overflow. This review offers fundamental insights into this widespread metabolic process and proposes a conceptual foundation for future research.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145030142","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

Conserved interfaces mediate multiple protein-protein interactions in a prokaryotic metabolon. 保守界面在原核代谢过程中介导多种蛋白质相互作用。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-09-03 DOI: 10.1038/s44320-025-00139-9

Sanchari Bhattacharyya, Srivastav Ranganathan, Sourav Chowdhury, Bharat V Adkar, Mark Khrapko, Eugene I Shakhnovich

{"title":"Conserved interfaces mediate multiple protein-protein interactions in a prokaryotic metabolon.","authors":"Sanchari Bhattacharyya, Srivastav Ranganathan, Sourav Chowdhury, Bharat V Adkar, Mark Khrapko, Eugene I Shakhnovich","doi":"10.1038/s44320-025-00139-9","DOIUrl":"10.1038/s44320-025-00139-9","url":null,"abstract":"Enzymes in a pathway often form metabolons through weak protein-protein interactions (PPI) that localize and protect labile metabolites. Due to their transient nature, the structural architecture of these enzyme assemblies has largely remained elusive, limiting our abilities to re-engineer novel metabolic pathways. Here, we delineate a complete PPI map of 1225 interactions in the E. coli 1-carbon metabolism pathway using bimolecular fluorescence complementation that can capture transient interactions in vivo and show strong intra- and inter-pathway clusters within the folate and purine biosynthesis pathways. Scanning mutagenesis experiments along with AlphaFold predictions and metadynamics simulations reveal that most proteins use conserved \"dedicated\" interfaces distant from their active sites to interact with multiple partners. Diffusion-reaction simulations with shared interaction surfaces and realistic PPI networks reveal a dramatic speedup in metabolic pathway fluxes. Overall, this study sheds light on the fundamental features of metabolon biophysics and structural aspects of transient binary complexes.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992971","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

LaGrACE: estimating gene program dysregulation with latent regulatory network. LaGrACE：用潜在调控网络估计基因程序失调。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-09-01 Epub Date: 2025-06-30 DOI: 10.1038/s44320-025-00115-3

Minxue Jia, Haiyi Mao, Mengli Zhou, Yu-Chih Chen, Panayiotis V Benos

{"title":"LaGrACE: estimating gene program dysregulation with latent regulatory network.","authors":"Minxue Jia, Haiyi Mao, Mengli Zhou, Yu-Chih Chen, Panayiotis V Benos","doi":"10.1038/s44320-025-00115-3","DOIUrl":"10.1038/s44320-025-00115-3","url":null,"abstract":"Gene expression programs that establish and maintain specific cellular states are orchestrated through a regulatory network composed of transcription factors, cofactors, and chromatin regulators. Dysregulation of this network can lead to a broad range of diseases by altering gene programs. This article presents LaGrACE, a novel method designed to estimate dysregulation of gene programs combining omics data with clinical information. This approach facilitates the grouping of samples exhibiting similar patterns of gene program dysregulation, thereby enhancing the discovery of underlying molecular mechanisms in disease subpopulations. We rigorously evaluated LaGrACE's performance using synthetic data, bulk RNA-seq clinical datasets (breast cancer, chronic obstructive pulmonary disease (COPD)), and single-cell RNA-seq drug perturbation datasets. Our findings demonstrate that LaGrACE is exceptionally robust in identifying biologically meaningful and prognostic molecular subtypes. In addition, it effectively discerns drug response signals at a single-cell resolution. Moreover, the COPD analysis uncovered a new role of LEF1 regulator in COPD molecular mechanisms associated with mortality. Collectively, these results underscore the utility of LaGrACE as a valuable tool for elucidating the underlying mechanisms of diseases.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1263-1281"},"PeriodicalIF":7.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405484/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528998","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

AlphaDesign: a de novo protein design framework based on AlphaFold. AlphaDesign：基于AlphaFold的全新蛋白质设计框架。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-09-01 Epub Date: 2025-06-17 DOI: 10.1038/s44320-025-00119-z

Michael A Jendrusch, Alessio L J Yang, Elisabetta Cacace, Jacob Bobonis, Carlos G P Voogdt, Sarah Kaspar, Kristian Schweimer, Cecilia Perez-Borrajero, Karine Lapouge, Jacob Scheurich, Kim Remans, Janosch Hennig, Athanasios Typas, Jan O Korbel, S Kashif Sadiq

引用次数: 0

Author Correction: Estrogen receptor activation remodels TEAD1 gene expression to alleviate hepatic steatosis. 作者更正：雌激素受体激活重塑TEAD1基因表达，减轻肝脂肪变性。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-09-01 DOI: 10.1038/s44320-025-00126-0

Christian Sommerauer, Carlos J Gallardo-Dodd, Christina Savva, Linnea Hases, Madeleine Birgersson, Rajitha Indukuri, Joanne X Shen, Pablo Carravilla, Keyi Geng, Jonas Nørskov Søndergaard, Clàudia Ferrer-Aumatell, Grégoire Mercier, Erdinc Sezgin, Marion Korach-André, Carl Petersson, Hannes Hagström, Volker M Lauschke, Amena Archer, Cecilia Williams, Claudia Kutter

引用次数: 0

Orthogonal replication with optogenetic selection evolves yeast JEN1 into a mevalonate transporter. 光遗传选择的正交复制使酵母菌JEN1成为甲羟戊酸转运蛋白。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-09-01 Epub Date: 2025-06-11 DOI: 10.1038/s44320-025-00113-5

Scott A Wegner, Virginia Jiang, Jeremy D Cortez, José L Avalos

{"title":"Orthogonal replication with optogenetic selection evolves yeast JEN1 into a mevalonate transporter.","authors":"Scott A Wegner, Virginia Jiang, Jeremy D Cortez, José L Avalos","doi":"10.1038/s44320-025-00113-5","DOIUrl":"10.1038/s44320-025-00113-5","url":null,"abstract":"The in vivo continuous evolution system OrthoRep (orthogonal replication) is a powerful strategy for rapid enzyme evolution in Saccharomyces cerevisiae that diversifies genes at a rate exceeding the endogenous genome mutagenesis rate by several orders of magnitude. However, it is difficult to neofunctionalize genes using OrthoRep partly because of the way selection pressures are applied. Here we combine OrthoRep with optogenetics in a selection strategy we call OptoRep, which allows fine-tuning of selection pressure with light. With this capability, we evolved a truncated form of the endogenous monocarboxylate transporter JEN1 (JEN1t) into a de novo mevalonate importer. We demonstrate the functionality of the evolved JEN1t (JEN1tY180C/G) in the production of farnesene, a renewable aviation biofuel, from mevalonate fed to fermentation media or produced by microbial consortia. This study shows that the light-induced complementation of OptoRep may improve the ability to evolve functions not currently accessible for selection, while its fine tunability of selection pressure may allow the continuous evolution of genes whose desired function has a restrictive range between providing effective selection and cellular viability.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1190-1213"},"PeriodicalIF":7.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275372","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

Predicting natural variation in the yeast phenotypic landscape with machine learning. 用机器学习预测酵母表型景观的自然变异。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-09-01 DOI: 10.1038/s44320-025-00136-y

Sakshi Khaiwal, Matteo De Chiara, Benjamin P Barré, Inigo Barrio-Hernandez, Simon Stenberg, Pedro Beltrao, Jonas Warringer, Gianni Liti

{"title":"Predicting natural variation in the yeast phenotypic landscape with machine learning.","authors":"Sakshi Khaiwal, Matteo De Chiara, Benjamin P Barré, Inigo Barrio-Hernandez, Simon Stenberg, Pedro Beltrao, Jonas Warringer, Gianni Liti","doi":"10.1038/s44320-025-00136-y","DOIUrl":"10.1038/s44320-025-00136-y","url":null,"abstract":"Most organismal traits result from the complex interplay of many genetic and environmental factors, making their prediction difficult. Here, we used machine learning (ML) models to explore phenotype predictions for 223 traits measured across 1011 genome-sequenced Saccharomyces cerevisiae strains isolated worldwide. We benchmarked a ML pipeline with multiple linear and non-linear models to predict phenotypes from genotypes and gene expression, and determined gradient boosting machines as the best-performing model. Gene function disruption scores and gene presence/absence emerged as best predictors, suggesting a considerable contribution of the accessory genome in controlling phenotypes. The prediction accuracy broadly varied among phenotypes, with stress resistance being easier to predict compared to growth across nutrients. ML identified relevant genomic features linked to phenotypes, including high-impact variants with established relationships to phenotypes, despite these being rare in the population. Near-perfect accuracies were achieved when other phenomics data mostly in similar conditions were used, suggesting that useful information can be conveyed across phenotypes. Overall, our study underscores the power of ML to interpret the functional outcome of genetic variants.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961961","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

Longitudinal big biological data in the AI era. AI时代的纵向生物大数据。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-09-01 Epub Date: 2025-08-05 DOI: 10.1038/s44320-025-00134-0

Adil Mardinoglu, Hasan Turkez, Minho Shong, Vishnuvardhan Pogunulu Srinivasulu, Jens Nielsen, Bernhard O Palsson, Leroy Hood, Mathias Uhlen

{"title":"Longitudinal big biological data in the AI era.","authors":"Adil Mardinoglu, Hasan Turkez, Minho Shong, Vishnuvardhan Pogunulu Srinivasulu, Jens Nielsen, Bernhard O Palsson, Leroy Hood, Mathias Uhlen","doi":"10.1038/s44320-025-00134-0","DOIUrl":"10.1038/s44320-025-00134-0","url":null,"abstract":"Generating longitudinal and multi-layered big biological data is crucial for effectively implementing artificial intelligence (AI) and systems biology approaches in characterising whole-body biological functions in health and complex disease states. Big biological data consists of multi-omics, clinical, wearable device, and imaging data, and information on diet, drugs, toxins, and other environmental factors. Given the significant advancements in omics technologies, human metabologenomics, and computational capabilities, several multi-omics studies are underway. Here, we first review the recent application of AI and systems biology in integrating and interpreting multi-omics data, highlighting their contributions to the creation of digital twins and the discovery of novel biomarkers and drug targets. Next, we review the multi-omics datasets generated worldwide to reveal interactions across multiple biological layers of information over time, which enhance precision health and medicine. Finally, we address the need to incorporate big biological data into clinical practice, supporting the development of a clinical decision support system essential for AI-driven hospitals and creating the foundation for an AI and systems biology-based healthcare model.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1147-1165"},"PeriodicalIF":7.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144789604","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

A transient mutational burst occurs during yeast colony development. 在酵母菌落发育过程中会发生短暂的突变爆发。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-09-01 Epub Date: 2025-06-09 DOI: 10.1038/s44320-025-00117-1

Nicolas Agier, Nina Vittorelli, Louis Ollivier, Frédéric Chaux, Alexandre Gillet-Markowska, Samuel O'Donnell, Fanny Pouyet, Gilles Fischer, Stéphane Delmas

{"title":"A transient mutational burst occurs during yeast colony development.","authors":"Nicolas Agier, Nina Vittorelli, Louis Ollivier, Frédéric Chaux, Alexandre Gillet-Markowska, Samuel O'Donnell, Fanny Pouyet, Gilles Fischer, Stéphane Delmas","doi":"10.1038/s44320-025-00117-1","DOIUrl":"10.1038/s44320-025-00117-1","url":null,"abstract":"Characterizing the contribution of mutators to mutation accumulation is essential for understanding cellular adaptation and diseases like cancer. By measuring single and double mutation rates, including point mutations, segmental duplications, and reciprocal translocations, we found that wild-type yeast colonies exhibit double mutation rates up to 17 times higher than expected from experimentally determined single mutation rates. These double mutants retained wild-type mutation rates, indicating they originated from genetically normal cells that transiently expressed a mutator phenotype. Numerical simulations suggest that transient mutator subpopulations likely consist of less than a few thousand cells, and experience high-intensity mutational bursts for less than five generations. Most double mutations accumulated sequentially across cell cycles, with simultaneous acquisition being rare and likely linked to systemic genomic instability. Additionally, we explored the genetic control of transient hypermutation and found that the excess of double mutants can be modulated by replication stress and the DNA damage tolerance pathway. Our findings suggest that transient mutators play a significant role in genomic instability and contribute to the mutational load accumulating in growing isogenic populations.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1214-1236"},"PeriodicalIF":7.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144258610","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