Molecular Systems Biology最新文献

Transcriptomic profiling of shed cells enables spatial mapping of cellular turnover in human organs. 脱壳细胞的转录组学分析使人类器官中细胞周转的空间定位成为可能。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-10-02 DOI: 10.1038/s44320-025-00154-w

Tal Barkai, Oran Yakubovsky, Yael Korem Kohanim, Keren Bahar Halpern, Sapir Shir, Noa Oren, Michal Fine, Paz Kelmer, Amit Talmon, Alon Israeli, Niv Pencovich, Ron Pery, Ido Nachmany, Shalev Itzkovitz

{"title":"Transcriptomic profiling of shed cells enables spatial mapping of cellular turnover in human organs.","authors":"Tal Barkai, Oran Yakubovsky, Yael Korem Kohanim, Keren Bahar Halpern, Sapir Shir, Noa Oren, Michal Fine, Paz Kelmer, Amit Talmon, Alon Israeli, Niv Pencovich, Ron Pery, Ido Nachmany, Shalev Itzkovitz","doi":"10.1038/s44320-025-00154-w","DOIUrl":"https://doi.org/10.1038/s44320-025-00154-w","url":null,"abstract":"Single-cell atlases provide valuable insights into gene expression states but lack information on cellular dynamics. Understanding cell turnover rates-the time between a cell's birth and death-can shed light on stemness potential and susceptibility to damage. However, measuring turnover rates in human organs has been a significant challenge. In this study, we integrate transcriptomic data from both tissue and shed cells to assign turnover scores to individual cells, leveraging their expression profiles in spatially resolved expression atlases. By performing RNA sequencing on shed cells from the upper gastrointestinal tract, collected via nasogastric tubes, we infer turnover rates in the human esophagus, stomach, and small intestine. In addition, we analyze colonic fecal washes to map turnover patterns in the human large intestine. Our findings reveal a subset of short-lived, interferon-stimulated colonocytes within a distinct pro-inflammatory microenvironment. Our approach introduces a dynamic dimension to single-cell atlases, offering broad applicability across different organs and diseases.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213197","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

Fast and furious: mapping epithelial cellular turnover into intestinal transcriptomic atlases. 速度与激情：将上皮细胞转化成肠道转录组图谱。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-10-02 DOI: 10.1038/s44320-025-00156-8

Christoph Kilian, Lorenz Adlung

引用次数: 0

High-throughput 3D engineered paediatric tumour models for precision medicine. 高精度医学的高通量3D工程儿科肿瘤模型。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-10-01 DOI: 10.1038/s44320-025-00152-y

MoonSun Jung, Valentina Poltavets, Joanna N Skhinas, Gabor Tax, Alvin Kamili, Jinhan Xie, Sarah Ghamrawi, Philipp Graber, Jie Mao, Marie Wong-Erasmus, Louise Cui, Kathleen Kimpton, Pooja Venkat, Chelsea Mayoh, Angela Lin, Emmy D G Fleuren, Ashleigh M Fordham, Zara Barger, John Grady, David M Thomas, Eric Y Du, Nicole S Graf, Mark J Cowley, Andrew J Gifford, Jamie I Fletcher, Loretta M S Lau, M Emmy M Dolman, J Justin Gooding, Maria Kavallaris

{"title":"High-throughput 3D engineered paediatric tumour models for precision medicine.","authors":"MoonSun Jung, Valentina Poltavets, Joanna N Skhinas, Gabor Tax, Alvin Kamili, Jinhan Xie, Sarah Ghamrawi, Philipp Graber, Jie Mao, Marie Wong-Erasmus, Louise Cui, Kathleen Kimpton, Pooja Venkat, Chelsea Mayoh, Angela Lin, Emmy D G Fleuren, Ashleigh M Fordham, Zara Barger, John Grady, David M Thomas, Eric Y Du, Nicole S Graf, Mark J Cowley, Andrew J Gifford, Jamie I Fletcher, Loretta M S Lau, M Emmy M Dolman, J Justin Gooding, Maria Kavallaris","doi":"10.1038/s44320-025-00152-y","DOIUrl":"https://doi.org/10.1038/s44320-025-00152-y","url":null,"abstract":"Precision medicine for paediatric and adult cancers that incorporates drug sensitivity profiling can identify effective therapies for individual patients. However, obtaining adequate biopsy samples for high-throughput (HTP) screening remains challenging, with tumours needing to be expanded in culture or patient-derived xenografts, this is time-consuming and often unsuccessful. Herein, we have developed paediatric patient-derived tumour models using an engineered extracellular matrix (ECM) tissue mimic hydrogel system and HTP 3D bioprinting. Gene expression analysis from a neuroblastoma and sarcoma paediatric patient cohort identified key components of the ECM in these tumour types. Engineered hydrogels with ECM-mimic peptides were used to bioprint and create patient-specific tumouroids using patient-derived cells from xenograft models, and the approach was further confirmed on direct patient tumour samples. Bioprinted tumouroids from the PDX models recapitulated the genetic and phenotypic characteristics of the original tumours and retained tumourigenicity. HTP drug screening of these models identified individualised drug sensitivities. Our approach offers a timely and clinically relevant technology platform for precision medicine in paediatric cancers, potentially transforming preclinical testing across multiple cancer types.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206934","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

Compensatory evolution to DNA replication stress is robust to nutrient availability. DNA复制胁迫的代偿性进化对营养物质的可利用性是稳健的。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-10-01 Epub Date: 2025-06-26 DOI: 10.1038/s44320-025-00127-z

Mariana Natalino, Marco Fumasoni

{"title":"Compensatory evolution to DNA replication stress is robust to nutrient availability.","authors":"Mariana Natalino, Marco Fumasoni","doi":"10.1038/s44320-025-00127-z","DOIUrl":"10.1038/s44320-025-00127-z","url":null,"abstract":"Evolutionary repair refers to the compensatory evolution that follows perturbations in cellular processes. While evolutionary trajectories are often reproducible, other studies suggest they are shaped by genotype-by-environment (GxE) interactions. Here, we test the predictability of evolutionary repair in response to DNA replication stress-a severe perturbation impairing the conserved mechanisms of DNA synthesis, resulting in genetic instability. We conducted high-throughput experimental evolution on Saccharomyces cerevisiae experiencing constitutive replication stress, grown under different glucose availability. We found that glucose levels impact the physiology and adaptation rate of replication stress mutants. However, the genetics of adaptation show remarkable robustness across environments. Recurrent mutations collectively recapitulated the fitness of evolved lines and are advantageous across macronutrient availability. We also identified a novel role of the mediator complex of RNA polymerase II in adaptation to replicative stress. Our results highlight the robustness and predictability of evolutionary repair mechanisms to DNA replication stress and provide new insights into the evolutionary aspects of genome stability, with potential implications for understanding cancer development.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1325-1350"},"PeriodicalIF":7.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12494895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144506866","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

Variant scoring tools for deep mutational scanning. 用于深度突变扫描的变体评分工具。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-10-01 Epub Date: 2025-08-08 DOI: 10.1038/s44320-025-00137-x

Hasan Çubuk, Xinyi Jin, Belinda Phipson, Joseph A Marsh, Alan F Rubin

{"title":"Variant scoring tools for deep mutational scanning.","authors":"Hasan Çubuk, Xinyi Jin, Belinda Phipson, Joseph A Marsh, Alan F Rubin","doi":"10.1038/s44320-025-00137-x","DOIUrl":"10.1038/s44320-025-00137-x","url":null,"abstract":"Deep mutational scanning (DMS) can systematically assess the effects of thousands of genetic variants in a single assay, providing insights into protein function, evolution, host-pathogen interactions, and clinical impacts. Accurate scoring of variant effects is crucial, yet the diversity of tools and experimental designs contributes considerable heterogeneity that complicates data analysis. Here, we review and compare 12 computational tools for processing DMS sequencing data and scoring variant effects. We systematically outline each tool's statistical approaches, supported experimental designs, input/output requirements, software implementation, visualisation capabilities, and key assumptions. By highlighting the strengths and limitations of these tools, we hope to guide researchers in selecting methods appropriate for their specific experiments. Furthermore, we discuss current challenges, including the need for standardised analysis protocols and sustainable software maintenance, as well as opportunities for future methods development. Ultimately, this review seeks to advance the application and adoption of DMS, facilitating deeper biological understanding and improved clinical translation.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1293-1305"},"PeriodicalIF":7.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12494760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804452","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 input signals of transcription factors in Escherichia coli. 预测大肠杆菌转录因子的输入信号。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-10-01 Epub Date: 2025-07-16 DOI: 10.1038/s44320-025-00132-2

Julian Trouillon, Alexandra E Huber, Yannik Trabesinger, Uwe Sauer

{"title":"Predicting input signals of transcription factors in Escherichia coli.","authors":"Julian Trouillon, Alexandra E Huber, Yannik Trabesinger, Uwe Sauer","doi":"10.1038/s44320-025-00132-2","DOIUrl":"10.1038/s44320-025-00132-2","url":null,"abstract":"The activity of bacterial transcription factors (TFs) is typically modulated through direct interactions with small molecules. However, these input signals remain unknown for most TFs, even in well-studied model bacteria. Identifying these signals typically requires tedious experiments for each TF. Here, we develop a systematic workflow for the identification of TF input signals in bacteria based on metabolomics and transcriptomics data. We inferred the activity of 173 TFs from published transcriptomics data and determined the abundance of 279 metabolites across 40 matched experimental conditions in Escherichia coli. By correlating TF activities with metabolite abundances, we successfully identified previously known TF-metabolite interactions and predicted novel TF effector metabolites for 41 TFs. To validate our predictions, we conducted in vitro assays and confirmed a predicted effector metabolite for LeuO. As a result, we established a network of 80 regulatory interactions between 71 metabolites and 41 E. coli TFs. This network includes 76 novel interactions that encompass a diverse range of chemical classes and regulatory patterns, bringing us closer to a comprehensive TF regulatory network in E. coli.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1371-1387"},"PeriodicalIF":7.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12494820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649932","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

When biomedical discovery faces data barriers: building a governance-empowered framework for resilient collaboration. 当生物医学发现面临数据障碍时：为弹性协作建立治理授权框架。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-10-01 Epub Date: 2025-08-26 DOI: 10.1038/s44320-025-00138-w

Zefeng Wang, Guoqing Zhang, Guoping Zhao

引用次数: 0

Transition between cell states of sensitivity reveals molecular vulnerability of drug-tolerant cells. 细胞敏感状态之间的转变揭示了耐药细胞的分子脆弱性。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-10-01 DOI: 10.1038/s44320-025-00150-0

Ludovic Peyre, Marielle Péré, Mickael Meyer, Benjamin Bian, Marina Moureau-Barbato, Walid Djema, Bernard Mari, Georges Vassaux, Jérémie Roux

{"title":"Transition between cell states of sensitivity reveals molecular vulnerability of drug-tolerant cells.","authors":"Ludovic Peyre, Marielle Péré, Mickael Meyer, Benjamin Bian, Marina Moureau-Barbato, Walid Djema, Bernard Mari, Georges Vassaux, Jérémie Roux","doi":"10.1038/s44320-025-00150-0","DOIUrl":"https://doi.org/10.1038/s44320-025-00150-0","url":null,"abstract":"Drug-tolerant cells to pro-apoptotic treatments exhibit transient resistance to subsequent challenges, which can be sustained via transcriptional and translational regulations. Although persister cells have been described in other cell death modalities, how they respond to subsequent treatments that are different from the one they originate from remains less explored. Here we show that drug-tolerant cells to pro-apoptotic treatments exhibit a reduced capacity to activate caspase-8, as well as higher levels of RIPK3 protein expression. As this apoptosis-tolerant cell state exhibits features of vulnerability to necroptosis, we show that alternating from apoptotic to necroptotic treatments increases cell response compared to drug holiday or sustained treatment. To gain insights on these transitions between states of vulnerability to cell death, we developed a compartmental model explaining the emergence of drug-tolerant cell populations, and the fluxes between drug-sensitivity states. We found that drug-sensitivity states coexist in a clonal population of cancer cells with continuous transitions between them, which are sufficient to explain both the sustained resistance to repeated treatments and how alternating drug treatments ameliorates the overall treatment efficacy.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145206929","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

Quantitative essentiality in a reduced genome: a functional, regulatory and structural fitness map. 减少基因组的定量重要性：功能、调控和结构适应度图。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-10-01 Epub Date: 2025-08-13 DOI: 10.1038/s44320-025-00133-1

Samuel Miravet-Verde, Raul Burgos, Eva Garcia-Ramallo, Marc Weber, Luis Serrano

{"title":"Quantitative essentiality in a reduced genome: a functional, regulatory and structural fitness map.","authors":"Samuel Miravet-Verde, Raul Burgos, Eva Garcia-Ramallo, Marc Weber, Luis Serrano","doi":"10.1038/s44320-025-00133-1","DOIUrl":"10.1038/s44320-025-00133-1","url":null,"abstract":"Essentiality studies have traditionally focused on coding regions, often overlooking other small genetic regulatory elements. To address this, we combined transposon libraries containing promoter or terminator sequences to obtain a high-resolution essentiality map of a genome-reduced bacterium, at near-single-nucleotide precision when considering non-essential genes. By integrating temporal transposon-sequencing data by k-means unsupervised clustering, we present a novel essentiality assessment approach, providing dynamic and quantitative information on the fitness contribution of different genomic regions. We compared the insertion tolerance and persistence of the two engineered libraries, assessing the local impact of transcription and termination on cell fitness. Essentiality assessment at the local base-level revealed essential protein domains and small genomic regions that are either essential or inaccessible to transposon insertion. We also identified structural regions within essential genes that tolerate transposon disruptions, resulting in functionally split proteins. Overall, this study presents a nuanced view of gene essentiality, shifting from static and binary models to a more accurate perspective. Additionally, it provides valuable insights for genome engineering and enhances our understanding of the biology of genome-reduced cells.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1388-1416"},"PeriodicalIF":7.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12494982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144847664","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

Impact of drugs and environmental contaminants on amine production by gut bacteria. 药物和环境污染物对肠道细菌产生胺的影响。

IF 7.7 1区生物学

Molecular Systems Biology Pub Date : 2025-10-01 Epub Date: 2025-06-30 DOI: 10.1038/s44320-025-00130-4

Stephan Kamrad, Tara F Davis, Kiran R Patil

{"title":"Impact of drugs and environmental contaminants on amine production by gut bacteria.","authors":"Stephan Kamrad, Tara F Davis, Kiran R Patil","doi":"10.1038/s44320-025-00130-4","DOIUrl":"10.1038/s44320-025-00130-4","url":null,"abstract":"Xenobiotics like drugs are recognised as key influencers of gut bacterial growth. Yet, their impact on the production of metabolites involved in microbiota-host interactions is largely unknown. Here, we report the impact of commonly ingested xenobiotics-therapeutic drugs, pesticides, industrial chemicals, and sweeteners-on gut bacterial amine metabolism. We tested >13,000 interactions between >1700 compounds and 4 amine-producing bacteria, uncovering 747 xenobiotic-species-metabolite interactions involving 275 compounds. These compounds span all tested classes, with the majority being antimicrobial drugs. In 66% of the cases, amine production was correlated with growth, while the rest showed xenobiotic-induced decoupling between growth and metabolite production. The latter includes transient bursts in polyamine production by Escherichia coli in response to β-lactam antibiotics, and overproduction of aromatic amines by Ruminococcus gnavus treated with 15 diverse chemicals. Xenobiotics thus can disrupt metabolic homeostasis in both growth-dependent and -independent manner. We also find that metabolic responses have non-monotonic dose-dependency, resulting in lower doses sometimes having stronger effects. Our results bring forward the potential of common xenobiotics to disrupt the amine metabolism of gut bacteria.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"1351-1370"},"PeriodicalIF":7.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12494721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528997","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