Molecular Systems Biology最新文献_第4页

A 'rich-get-richer' mechanism drives patchy dynamics and resistance evolution in antibiotic-treated bacteria. 富者愈富 "的机制推动了抗生素处理过的细菌的斑块动态和耐药性进化。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-08-01 Epub Date: 2024-06-14 DOI: 10.1038/s44320-024-00046-5

Emrah Şimşek, Kyeri Kim, Jia Lu, Anita Silver, Nan Luo, Charlotte T Lee, Lingchong You

{"title":"A 'rich-get-richer' mechanism drives patchy dynamics and resistance evolution in antibiotic-treated bacteria.","authors":"Emrah Şimşek, Kyeri Kim, Jia Lu, Anita Silver, Nan Luo, Charlotte T Lee, Lingchong You","doi":"10.1038/s44320-024-00046-5","DOIUrl":"10.1038/s44320-024-00046-5","url":null,"abstract":"Bacteria in nature often form surface-attached communities that initially comprise distinct subpopulations, or patches. For pathogens, these patches can form at infection sites, persist during antibiotic treatment, and develop into mature biofilms. Evidence suggests that patches can emerge due to heterogeneity in the growth environment and bacterial seeding, as well as cell-cell signaling. However, it is unclear how these factors contribute to patch formation and how patch formation might affect bacterial survival and evolution. Here, we demonstrate that a 'rich-get-richer' mechanism drives patch formation in bacteria exhibiting collective survival (CS) during antibiotic treatment. Modeling predicts that the seeding heterogeneity of these bacteria is amplified by local CS and global resource competition, leading to patch formation. Increasing the dose of a non-eradicating antibiotic treatment increases the degree of patchiness. Experimentally, we first demonstrated the mechanism using engineered Escherichia coli and then demonstrated its applicability to a pathogen, Pseudomonas aeruginosa. We further showed that the formation of P. aeruginosa patches promoted the evolution of antibiotic resistance. Our work provides new insights into population dynamics and resistance evolution during surface-attached bacterial growth.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"880-897"},"PeriodicalIF":8.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141321261","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

Molecular causality in the advent of foundation models. 基础模型出现时的分子因果关系。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-08-01 Epub Date: 2024-06-18 DOI: 10.1038/s44320-024-00041-w

Sebastian Lobentanzer, Pablo Rodriguez-Mier, Stefan Bauer, Julio Saez-Rodriguez

引用次数: 0

µPhos: a scalable and sensitive platform for high-dimensional phosphoproteomics. μPhos：高维磷酸化蛋白质组学的可扩展灵敏平台。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-08-01 Epub Date: 2024-06-21 DOI: 10.1038/s44320-024-00050-9

Denys Oliinyk, Andreas Will, Felix R Schneidmadel, Maximilian Böhme, Jenny Rinke, Andreas Hochhaus, Thomas Ernst, Nina Hahn, Christian Geis, Markus Lubeck, Oliver Raether, Sean J Humphrey, Florian Meier

{"title":"µPhos: a scalable and sensitive platform for high-dimensional phosphoproteomics.","authors":"Denys Oliinyk, Andreas Will, Felix R Schneidmadel, Maximilian Böhme, Jenny Rinke, Andreas Hochhaus, Thomas Ernst, Nina Hahn, Christian Geis, Markus Lubeck, Oliver Raether, Sean J Humphrey, Florian Meier","doi":"10.1038/s44320-024-00050-9","DOIUrl":"10.1038/s44320-024-00050-9","url":null,"abstract":"Mass spectrometry has revolutionized cell signaling research by vastly simplifying the analysis of many thousands of phosphorylation sites in the human proteome. Defining the cellular response to perturbations is crucial for further illuminating the functionality of the phosphoproteome. Here we describe µPhos ('microPhos'), an accessible phosphoproteomics platform that permits phosphopeptide enrichment from 96-well cell culture and small tissue amounts in <8 h total processing time. By greatly minimizing transfer steps and liquid volumes, we demonstrate increased sensitivity, >90% selectivity, and excellent quantitative reproducibility. Employing highly sensitive trapped ion mobility mass spectrometry, we quantify ~17,000 Class I phosphosites in a human cancer cell line using 20 µg starting material, and confidently localize ~6200 phosphosites from 1 µg. This depth covers key signaling pathways, rendering sample-limited applications and perturbation experiments with hundreds of samples viable. We employ µPhos to study drug- and time-dependent response signatures in a leukemia cell line, and by quantifying 30,000 Class I phosphosites in the mouse brain we reveal distinct spatial kinase activities in subregions of the hippocampal formation.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"972-995"},"PeriodicalIF":8.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141437256","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

Identification of novel toxins associated with the extracellular contractile injection system using machine learning. 利用机器学习识别与细胞外收缩注射系统相关的新型毒素。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-08-01 Epub Date: 2024-07-28 DOI: 10.1038/s44320-024-00053-6

Aleks Danov, Inbal Pollin, Eric Moon, Mengfei Ho, Brenda A Wilson, Philippos A Papathanos, Tommy Kaplan, Asaf Levy

{"title":"Identification of novel toxins associated with the extracellular contractile injection system using machine learning.","authors":"Aleks Danov, Inbal Pollin, Eric Moon, Mengfei Ho, Brenda A Wilson, Philippos A Papathanos, Tommy Kaplan, Asaf Levy","doi":"10.1038/s44320-024-00053-6","DOIUrl":"10.1038/s44320-024-00053-6","url":null,"abstract":"Secretion systems play a crucial role in microbe-microbe or host-microbe interactions. Among these systems, the extracellular contractile injection system (eCIS) is a unique bacterial and archaeal extracellular secretion system that injects protein toxins into target organisms. However, the specific proteins that eCISs inject into target cells and their functions remain largely unknown. Here, we developed a machine learning classifier to identify eCIS-associated toxins (EATs). The classifier combines genetic and biochemical features to identify EATs. We also developed a score for the eCIS N-terminal signal peptide to predict EAT loading. Using the classifier we classified 2,194 genes from 950 genomes as putative EATs. We validated four new EATs, EAT14-17, showing toxicity in bacterial and eukaryotic cells, and identified residues of their respective active sites that are critical for toxicity. Finally, we show that EAT14 inhibits mitogenic signaling in human cells. Our study provides insights into the diversity and functions of EATs and demonstrates machine learning capability of identifying novel toxins. The toxins can be employed in various applications dependently or independently of eCIS.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"859-879"},"PeriodicalIF":8.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297309/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788702","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

Alternative proteoforms and proteoform-dependent assemblies in humans and plants. 人类和植物中的替代蛋白形式和蛋白形式依赖性组装。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-08-01 Epub Date: 2024-06-25 DOI: 10.1038/s44320-024-00048-3

Claire D McWhite, Wisath Sae-Lee, Yaning Yuan, Anna L Mallam, Nicolas A Gort-Freitas, Silvia Ramundo, Masayuki Onishi, Edward M Marcotte

{"title":"Alternative proteoforms and proteoform-dependent assemblies in humans and plants.","authors":"Claire D McWhite, Wisath Sae-Lee, Yaning Yuan, Anna L Mallam, Nicolas A Gort-Freitas, Silvia Ramundo, Masayuki Onishi, Edward M Marcotte","doi":"10.1038/s44320-024-00048-3","DOIUrl":"10.1038/s44320-024-00048-3","url":null,"abstract":"The variability of proteins at the sequence level creates an enormous potential for proteome complexity. Exploring the depths and limits of this complexity is an ongoing goal in biology. Here, we systematically survey human and plant high-throughput bottom-up native proteomics data for protein truncation variants, where substantial regions of the full-length protein are missing from an observed protein product. In humans, Arabidopsis, and the green alga Chlamydomonas, approximately one percent of observed proteins show a short form, which we can assign by comparison to RNA isoforms as either likely deriving from transcript-directed processes or limited proteolysis. While some detected protein fragments align with known splice forms and protein cleavage events, multiple examples are previously undescribed, such as our observation of fibrocystin proteolysis and nuclear translocation in a green alga. We find that truncations occur almost entirely between structured protein domains, even when short forms are derived from transcript variants. Intriguingly, multiple endogenous protein truncations of phase-separating translational proteins resemble cleaved proteoforms produced by enteroviruses during infection. Some truncated proteins are also observed in both humans and plants, suggesting that they date to the last eukaryotic common ancestor. Finally, we describe novel proteoform-specific protein complexes, where the loss of a domain may accompany complex formation.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"933-951"},"PeriodicalIF":8.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141450929","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 proximity proteomics pipeline with improved reproducibility and throughput. 可提高重现性和通量的近距离蛋白质组学管道。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-08-01 Epub Date: 2024-07-01 DOI: 10.1038/s44320-024-00049-2

Xiaofang Zhong, Qiongyu Li, Benjamin J Polacco, Trupti Patil, Aaron Marley, Helene Foussard, Prachi Khare, Rasika Vartak, Jiewei Xu, Jeffrey F DiBerto, Bryan L Roth, Manon Eckhardt, Mark von Zastrow, Nevan J Krogan, Ruth Hüttenhain

{"title":"A proximity proteomics pipeline with improved reproducibility and throughput.","authors":"Xiaofang Zhong, Qiongyu Li, Benjamin J Polacco, Trupti Patil, Aaron Marley, Helene Foussard, Prachi Khare, Rasika Vartak, Jiewei Xu, Jeffrey F DiBerto, Bryan L Roth, Manon Eckhardt, Mark von Zastrow, Nevan J Krogan, Ruth Hüttenhain","doi":"10.1038/s44320-024-00049-2","DOIUrl":"10.1038/s44320-024-00049-2","url":null,"abstract":"Proximity labeling (PL) via biotinylation coupled with mass spectrometry (MS) captures spatial proteomes in cells. Large-scale processing requires a workflow minimizing hands-on time and enhancing quantitative reproducibility. We introduced a scalable PL pipeline integrating automated enrichment of biotinylated proteins in a 96-well plate format. Combining this with optimized quantitative MS based on data-independent acquisition (DIA), we increased sample throughput and improved protein identification and quantification reproducibility. We applied this pipeline to delineate subcellular proteomes across various compartments. Using the 5HT2A serotonin receptor as a model, we studied temporal changes of proximal interaction networks induced by receptor activation. In addition, we modified the pipeline for reduced sample input to accommodate CRISPR-based gene knockout, assessing dynamics of the 5HT2A network in response to perturbation of selected interactors. This PL approach is universally applicable to PL proteomics using biotinylation-based PL enzymes, enhancing throughput and reproducibility of standard protocols.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"952-971"},"PeriodicalIF":8.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476993","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

Multicellular dynamics and wealth distribution in bacteria. 细菌的多细胞动力学和财富分配。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-08-01 Epub Date: 2024-07-15 DOI: 10.1038/s44320-024-00056-3

Kyle R Allison

引用次数: 0

A new way of looking at transcription factor assays. 转录因子检测的新视角。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-07-01 Epub Date: 2024-06-07 DOI: 10.1038/s44320-024-00044-7

Alan F Rubin

引用次数: 0

Deep mutational scanning quantifies DNA binding and predicts clinical outcomes of PAX6 variants. 深度突变扫描可量化 DNA 结合并预测 PAX6 变体的临床结果。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-07-01 Epub Date: 2024-06-07 DOI: 10.1038/s44320-024-00043-8

Alexander F McDonnell, Marcin Plech, Benjamin J Livesey, Lukas Gerasimavicius, Liusaidh J Owen, Hildegard Nikki Hall, David R FitzPatrick, Joseph A Marsh, Grzegorz Kudla

{"title":"Deep mutational scanning quantifies DNA binding and predicts clinical outcomes of PAX6 variants.","authors":"Alexander F McDonnell, Marcin Plech, Benjamin J Livesey, Lukas Gerasimavicius, Liusaidh J Owen, Hildegard Nikki Hall, David R FitzPatrick, Joseph A Marsh, Grzegorz Kudla","doi":"10.1038/s44320-024-00043-8","DOIUrl":"10.1038/s44320-024-00043-8","url":null,"abstract":"Nonsense and missense mutations in the transcription factor PAX6 cause a wide range of eye development defects, including aniridia, microphthalmia and coloboma. To understand how changes of PAX6:DNA binding cause these phenotypes, we combined saturation mutagenesis of the paired domain of PAX6 with a yeast one-hybrid (Y1H) assay in which expression of a PAX6-GAL4 fusion gene drives antibiotic resistance. We quantified binding of more than 2700 single amino-acid variants to two DNA sequence elements. Mutations in DNA-facing residues of the N-terminal subdomain and linker region were most detrimental, as were mutations to prolines and to negatively charged residues. Many variants caused sequence-specific molecular gain-of-function effects, including variants in position 71 that increased binding to the LE9 enhancer but decreased binding to a SELEX-derived binding site. In the absence of antibiotic selection, variants that retained DNA binding slowed yeast growth, likely because such variants perturbed the yeast transcriptome. Benchmarking against known patient variants and applying ACMG/AMP guidelines to variant classification, we obtained supporting-to-moderate evidence that 977 variants are likely pathogenic and 1306 are likely benign. Our analysis shows that most pathogenic mutations in the paired domain of PAX6 can be explained simply by the effects of these mutations on PAX6:DNA association, and establishes Y1H as a generalisable assay for the interpretation of variant effects in transcription factors.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"825-844"},"PeriodicalIF":8.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11219921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141288337","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 continuum of zinc finger transcription factor retention on native chromatin underlies dynamic genome organization. 锌指转录因子在原生染色质上的连续保留是动态基因组组织的基础。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-07-01 Epub Date: 2024-05-14 DOI: 10.1038/s44320-024-00038-5

Siling Hu, Yangying Liu, Qifan Zhang, Juan Bai, Chenhuan Xu

{"title":"A continuum of zinc finger transcription factor retention on native chromatin underlies dynamic genome organization.","authors":"Siling Hu, Yangying Liu, Qifan Zhang, Juan Bai, Chenhuan Xu","doi":"10.1038/s44320-024-00038-5","DOIUrl":"10.1038/s44320-024-00038-5","url":null,"abstract":"Transcription factor (TF) residence on chromatin translates into quantitative transcriptional or structural outcomes on genome. Commonly used formaldehyde crosslinking fixes TF-DNA interactions cumulatively and compromises the measured occupancy level. Here we mapped the occupancy level of global or individual zinc finger TFs like CTCF and MAZ, in the form of highly resolved footprints, on native chromatin. By incorporating reinforcing perturbation conditions, we established S-score, a quantitative metric to proxy the continuum of CTCF or MAZ retention across different motifs on native chromatin. The native chromatin-retained CTCF sites harbor sequence features within CTCF motifs better explained by S-score than the metrics obtained from other crosslinking or native assays. CTCF retention on native chromatin correlates with local SUMOylation level, and anti-correlates with transcriptional activity. The S-score successfully delineates the otherwise-masked differential stability of chromatin structures mediated by CTCF, or by MAZ independent of CTCF. Overall, our study established a paradigm continuum of TF retention across binding sites on native chromatin, explaining the dynamic genome organization.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"799-824"},"PeriodicalIF":8.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11220090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140922704","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