Molecular Systems Biology最新文献_第7页

Essentiality and dynamic expression of the human tRNA pool during viral infection. 病毒感染过程中人类tRNA库的必要性和动态表达。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-04-01 Epub Date: 2026-01-20 DOI: 10.1038/s44320-025-00181-7

Noa Aharon-Hefetz, Michal Schwartz, Einav Aharon, Noam Stern-Ginossar, Orna Dahan, Yitzhak Pilpel

{"title":"Essentiality and dynamic expression of the human tRNA pool during viral infection.","authors":"Noa Aharon-Hefetz, Michal Schwartz, Einav Aharon, Noam Stern-Ginossar, Orna Dahan, Yitzhak Pilpel","doi":"10.1038/s44320-025-00181-7","DOIUrl":"10.1038/s44320-025-00181-7","url":null,"abstract":"Human viruses rely on host translation resources, including the cellular tRNA pool, because they lack tRNA genes. Using tRNA sequencing, we profiled mature tRNAs during infections with human cytomegalovirus (HCMV) and SARS-CoV-2. HCMV-induced alterations in mature tRNA levels were predominantly virus-driven, with minimal influence from the cellular immune response. Certain post-transcriptional modifications, correlated with tRNA stability, were actively manipulated by HCMV. By contrast, SARS-CoV-2 caused minimal changes in mature tRNA levels or modifications. Comparing viral codon usage with proliferation- versus differentiation-associated codon-usage signatures in human genes revealed striking divergence. HCMV genes aligned with differentiation codon usage, whereas SARS-CoV-2 genes matched proliferation codon usage. Structural and gene-expression genes in both viruses showed strong adaptation to host tRNA pools. Finally, a systematic CRISPR screen of human tRNA genes and tRNA-modifying enzymes identified specific tRNAs and enzymes that either enhanced or restricted HCMV infectivity and influenced cellular growth. Together, these data define a dynamic interplay between the host tRNA landscape and viral infection, illuminating the mechanisms governing host-virus interactions.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"519-536"},"PeriodicalIF":6.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13046961/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011481","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 the protein interaction landscape of a free-living bacterium with pooled-AlphaFold3. 用poole - alphafold3预测自由细菌的蛋白质相互作用景观。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-04-01 Epub Date: 2026-01-20 DOI: 10.1038/s44320-026-00189-7

Horia Todor, Lili M Kim, Jürgen Jänes, Hannah N Burkhart, Seth A Darst, Pedro Beltrao, Carol A Gross

{"title":"Predicting the protein interaction landscape of a free-living bacterium with pooled-AlphaFold3.","authors":"Horia Todor, Lili M Kim, Jürgen Jänes, Hannah N Burkhart, Seth A Darst, Pedro Beltrao, Carol A Gross","doi":"10.1038/s44320-026-00189-7","DOIUrl":"10.1038/s44320-026-00189-7","url":null,"abstract":"Accurate prediction of protein complex structures by AlphaFold3 and similar programs has been used to predict the presence of protein-protein interactions (PPIs), but this technique has never been applied to an entire genome due to onerous computational requirements and questionable utility. Here we present pooled-PPI prediction, a technique that dramatically improves the accuracy of genome-scale screens compared to a paired approach while simultaneously reducing inference time (~twofold) and the number of jobs (~100-fold). We use this technique to predict the structure of all 113,050 pairwise PPIs in Mycoplasma genitalium using only 2027 AlphaFold3 jobs. This unbiased and comprehensive dataset was highly predictive of known interactions, revealed a previously unappreciated but widespread size bias in AlphaFold interface scores, correctly identified protein-protein interfaces in macromolecular complexes, and uncovered new biology in M. genitalium. This work establishes pooled-PPI prediction as a highly scalable method for uncovering protein-protein interactions and a powerful addition to the functional genomics toolkit.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"497-518"},"PeriodicalIF":6.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13047044/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011445","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

Unlocking CRISPR-Cas9 editing for widely diverse Dictyostelid species. 解锁CRISPR-Cas9编辑广泛多样的盘基骨类物种。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-04-01 Epub Date: 2026-01-12 DOI: 10.1038/s44320-025-00180-8

Mireia Garriga-Canut, Nikki Cannon, Matt Benton, Andrea Zanon, Samuel T Horsfield, Jacob Scheurich, Kim Remans, John Lees, Alexandre Paix, Jordi van Gestel

{"title":"Unlocking CRISPR-Cas9 editing for widely diverse Dictyostelid species.","authors":"Mireia Garriga-Canut, Nikki Cannon, Matt Benton, Andrea Zanon, Samuel T Horsfield, Jacob Scheurich, Kim Remans, John Lees, Alexandre Paix, Jordi van Gestel","doi":"10.1038/s44320-025-00180-8","DOIUrl":"10.1038/s44320-025-00180-8","url":null,"abstract":"Dictyostelids are a species-rich clade of cellular slime molds that are widely found in soils and have been studied for over a century. Due to a lack of genome editing methods, most molecular research in Dictyostelids has focused on only a single species, Dictyostelium discoideum, which has severely limited broad-scale comparative analyses. Here, we introduce the first CRISPR-Cas9 editing approach that is cloning-free, selection-free, highly efficient, and effective across Dictyostelid species that diverged millions of years ago. Depending on the CRISPR-Cas9 target site, our editing approach generates knock-out efficiencies of up to 90% and knock-in efficiencies of up to 50% without a selective marker. We show that mutants can be isolated as soon as one day post-transfection, vastly outpacing existing methods for generating knock-outs, fusion proteins, and expression reporters. Leveraging single-cell sorting and fluorescent microscopy, we could readily apply our CRISPR-Cas9 editing approach to phylogenetically distant Dictyostelid species, including those that have never been genome edited before. Our methods therefore open the door to performing broad-scale genetic interrogations across the Dictyostelids.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"599-619"},"PeriodicalIF":6.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13046832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959318","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

Protein buffering of aneuploidy is driven by coordinated factors identified through machine learning. 非整倍体的蛋白质缓冲是由通过机器学习识别的协调因素驱动的。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-04-01 Epub Date: 2026-01-22 DOI: 10.1038/s44320-026-00187-9

Erik Marcel Heller, Karen Barthel, Markus Räschle, Klaske M Schukken, Jason M Sheltzer, Zuzana Storchová

{"title":"Protein buffering of aneuploidy is driven by coordinated factors identified through machine learning.","authors":"Erik Marcel Heller, Karen Barthel, Markus Räschle, Klaske M Schukken, Jason M Sheltzer, Zuzana Storchová","doi":"10.1038/s44320-026-00187-9","DOIUrl":"10.1038/s44320-026-00187-9","url":null,"abstract":"Aneuploidy, a hallmark of cancer, alters chromosome copy numbers and with that the abundance of hundreds of proteins. Evidence suggests that levels of proteins encoded on affected chromosomes are often buffered toward their abundances observed in diploids. Despite its prevalence, the molecular mechanisms driving this protein dosage compensation remain largely unknown. It is unclear whether all proteins are buffered similarly, what factors determine buffering, and whether dosage compensation varies across different cell lines or tumor types. Moreover, its potential adaptive advantage and therapeutic relevance remain unexplored. We established a novel approach to quantify protein dosage buffering in a gene copy number-dependent manner, showing that dosage compensation is widespread but variable in cancer samples. By developing multifactorial machine learning models, we identify gene dependency, protein complex participation, haploinsufficiency, and mRNA decay as key predictors of buffering. We show that dosage compensation affects oncogenic potential and that higher buffering correlates with reduced proteotoxic stress and increased drug resistance. These findings highlight protein dosage compensation as a crucial regulatory mechanism with therapeutic potential in aneuploid cancers.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"563-598"},"PeriodicalIF":6.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13046899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030393","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

Chromosome length is constrained by spindle scaling to ensure faithful mitosis in mammals. 哺乳动物的染色体长度受纺锤体缩放的限制，以确保有丝分裂忠实。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-04-01 Epub Date: 2026-01-15 DOI: 10.1038/s44320-026-00188-8

Yu-Long Zhao, Yi-Ming Zhao, Yi-Fang Yan, Ning Yang, Si-Nan Ma, Rui-Jia Wang, Gui-Hai Feng, Zhi-Kun Li, Wei Li, Li-Bin Wang

引用次数: 0

Proteome-wide AlphaFold pool party. 蛋白质组范围的AlphaFold泳池派对。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-04-01 Epub Date: 2026-02-17 DOI: 10.1038/s44320-026-00198-6

Kevin Drew

引用次数: 0

Pooled single-cell screen in colorectal cancer defines transcriptional modules linked to oncogenes. 结直肠癌的汇总单细胞筛选定义了与癌基因相关的转录模块。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-03-01 Epub Date: 2026-01-19 DOI: 10.1038/s44320-025-00186-2

Viola Hollek, Francisca Böhning, Catalina Florez Vargas, Anja Sieber, Markus Morkel, Nils Blüthgen

{"title":"Pooled single-cell screen in colorectal cancer defines transcriptional modules linked to oncogenes.","authors":"Viola Hollek, Francisca Böhning, Catalina Florez Vargas, Anja Sieber, Markus Morkel, Nils Blüthgen","doi":"10.1038/s44320-025-00186-2","DOIUrl":"10.1038/s44320-025-00186-2","url":null,"abstract":"Oncogenic mutations shape colorectal cancer (CRC) biology, yet their impact on transcriptional phenotypes remains incompletely understood, and their individual prognostic value is limited. Here, we perform a pooled single-cell transcriptomic screen of over 100,000 CRC cells with a comprehensive barcoded library of oncogenic variants across genetically diverse CRC lines. Using a variational autoencoder-based interpretable factor model, we identify ten conserved oncogene-driven transcriptional modules (TMOs) representing core cancer phenotypes such as cellular plasticity, inflammatory response, replicative stress, and epithelial-to-mesenchymal transition. Engagement of these modules can be context-dependent, reflecting interactions between oncogene-induced driver pathways and background genetics. TMO activity in patient tumors stratifies CRC cohorts into high- and low-risk groups, improving relapse-free survival prediction beyond existing classification systems. Our study systematically links oncogenic signaling to transcriptional states and clinical outcomes, establishing a functional framework for module-based patient stratification in precision oncology.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"435-460"},"PeriodicalIF":6.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12954089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003796","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

CANTAO: guiding clustering and annotation in single-cell RNA sequencing using average overlap. CANTAO：利用平均重叠指导单细胞RNA测序的聚类和注释。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-03-01 Epub Date: 2025-12-08 DOI: 10.1038/s44320-025-00176-4

Christopher Thai, Amartya Singh, Daniel Herranz, Hossein Khiabanian

{"title":"CANTAO: guiding clustering and annotation in single-cell RNA sequencing using average overlap.","authors":"Christopher Thai, Amartya Singh, Daniel Herranz, Hossein Khiabanian","doi":"10.1038/s44320-025-00176-4","DOIUrl":"10.1038/s44320-025-00176-4","url":null,"abstract":"Single-cell RNA sequencing allows defining cellular identities based on transcriptional similarity using unsupervised clustering. However, a single clustering resolution may not yield groups of cells that represent both broad, well-defined populations and smaller subpopulations simultaneously. Therefore, when cell identities are not known prior to sequencing, robust comparison and annotation of inferred de novo clusters remains a challenge. Here, we introduce CANTAO, in which we propose the average overlap metric to define the distance between single-cell clusters by comparing ranked lists of differentially expressed genes in a top-weighted manner. We benchmark CANTAO in truth-known datasets comprised of similar yet distinct cell populations and show that evaluating clusters with average overlap results in a consistent, precise, and biologically meaningful recapitulation of true cell identities. We then analyze unsorted mouse thymocytes and characterize stages of T-cell development in the thymus, including minor populations of double-negative (CD4-CD8-) T cells that are difficult to confidently detect among unsorted single cells. We demonstrate that CANTAO enables robust, reproducible characterization of single-cell data and clarifies biological interpretation of underlying identities in homogeneous populations.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"461-475"},"PeriodicalIF":6.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12954110/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145708582","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

Single-cell analysis reveals critical toxin/antitoxin ratio triggering persister resuscitation. 单细胞分析显示关键的毒素/抗毒素比触发持久性复苏。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-03-01 Epub Date: 2026-01-03 DOI: 10.1038/s44320-025-00174-6

Lina Wu, Qingqing Wang, Xinyi Hong, Xueer Cai, Litinghui Zhang, Min Li, Mingkai Wu, Thomas K Wood, Xiaomei Yan

{"title":"Single-cell analysis reveals critical toxin/antitoxin ratio triggering persister resuscitation.","authors":"Lina Wu, Qingqing Wang, Xinyi Hong, Xueer Cai, Litinghui Zhang, Min Li, Mingkai Wu, Thomas K Wood, Xiaomei Yan","doi":"10.1038/s44320-025-00174-6","DOIUrl":"10.1038/s44320-025-00174-6","url":null,"abstract":"Persisters represent a transient, antibiotic-tolerant subpopulation within isogenic bacterial populations, contributing to infection relapses. However, the mechanisms driving persister formation and resuscitation remain elusive. Here, we developed nano-flow cytometry (nFCM)-based methods for single-cell quantification of toxin (T) RelE and antitoxin (A) RelB levels, as well as for monitoring persister states through cell wall growth. We demonstrate that bacteria elevate the T/A ratio through two distinct TA expression modalities to withstand bacteriostatic antibiotic challenge, with T/A = 1.0 as a critical threshold. Intriguingly, single-cell resuscitation dynamics revealed that subinhibitory antibiotic exposure promotes entry into a deeper dormant state characterized by elevated T/A ratios, underscoring the importance of maximizing therapeutic antibiotic concentrations. Crucially, we uncovered a triphasic detoxification process during resuscitation where progressive toxin depletion drives T/A ratio reduction to a critical proliferation-permissive threshold. Proteomic profiling unveiled that persisters with high RelE production have increased transmembrane transporter levels linked to stress response and drug efflux. Our findings offer pivotal molecular insights underlying persister transitions and underscore the need for high-throughput, single-cell analysis of these heterogeneity phenotypes.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"395-411"},"PeriodicalIF":6.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12953861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896166","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

Multimodal AI agents for capturing and sharing proteomics laboratory practice. 用于捕获和共享蛋白质组学实验室实践的多模式人工智能代理。

IF 6.7 1区生物学

Molecular Systems Biology Pub Date : 2026-03-01 Epub Date: 2025-12-15 DOI: 10.1038/s44320-025-00179-1

Patricia Skowronek, Anant Nawalgaria, Matthias Mann

引用次数: 0