Molecular Systems Biology最新文献_第8页

Author Correction: Bacterial expression of a designed single-chain IL-10 prevents severe lung inflammation. 作者更正：细菌表达设计的单链 IL-10 可预防严重的肺部炎症。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2024-03-01 DOI: 10.1038/s44320-023-00008-3

Ariadna Montero-Blay, Javier Delgado Blanco, Irene Rodriguez-Arce, Claire Lastrucci, Carlos Piñero-Lambea, Maria Lluch-Senar, Luis Serrano

引用次数: 0

Detection of PatIent-Level distances from single cell genomics and pathomics data with Optimal Transport (PILOT). 利用优化传输（PILOT）从单细胞基因组学和病理组学数据中检测专利级距离。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2024-02-01 Epub Date: 2023-12-19 DOI: 10.1038/s44320-023-00003-8

Mehdi Joodaki, Mina Shaigan, Victor Parra, Roman D Bülow, Christoph Kuppe, David L Hölscher, Mingbo Cheng, James S Nagai, Michaël Goedertier, Nassim Bouteldja, Vladimir Tesar, Jonathan Barratt, Ian Sd Roberts, Rosanna Coppo, Rafael Kramann, Peter Boor, Ivan G Costa

{"title":"Detection of PatIent-Level distances from single cell genomics and pathomics data with Optimal Transport (PILOT).","authors":"Mehdi Joodaki, Mina Shaigan, Victor Parra, Roman D Bülow, Christoph Kuppe, David L Hölscher, Mingbo Cheng, James S Nagai, Michaël Goedertier, Nassim Bouteldja, Vladimir Tesar, Jonathan Barratt, Ian Sd Roberts, Rosanna Coppo, Rafael Kramann, Peter Boor, Ivan G Costa","doi":"10.1038/s44320-023-00003-8","DOIUrl":"10.1038/s44320-023-00003-8","url":null,"abstract":"Although clinical applications represent the next challenge in single-cell genomics and digital pathology, we still lack computational methods to analyze single-cell or pathomics data to find sample-level trajectories or clusters associated with diseases. This remains challenging as single-cell/pathomics data are multi-scale, i.e., a sample is represented by clusters of cells/structures, and samples cannot be easily compared with each other. Here we propose PatIent Level analysis with Optimal Transport (PILOT). PILOT uses optimal transport to compute the Wasserstein distance between two individual single-cell samples. This allows us to perform unsupervised analysis at the sample level and uncover trajectories or cellular clusters associated with disease progression. We evaluate PILOT and competing approaches in single-cell genomics or pathomics studies involving various human diseases with up to 600 samples/patients and millions of cells or tissue structures. Our results demonstrate that PILOT detects disease-associated samples from large and complex single-cell or pathomics data. Moreover, PILOT provides a statistical approach to find changes in cell populations, gene expression, and tissue structures related to the trajectories or clusters supporting interpretation of predictions.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"57-74"},"PeriodicalIF":9.9,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10883279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139098306","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

Derailed protein turnover in the aging mammalian brain. 哺乳动物大脑衰老过程中的蛋白质周转失调。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2024-02-01 Epub Date: 2024-01-05 DOI: 10.1038/s44320-023-00009-2

Nalini R Rao, Arun Upadhyay, Jeffrey N Savas

{"title":"Derailed protein turnover in the aging mammalian brain.","authors":"Nalini R Rao, Arun Upadhyay, Jeffrey N Savas","doi":"10.1038/s44320-023-00009-2","DOIUrl":"10.1038/s44320-023-00009-2","url":null,"abstract":"Efficient protein turnover is essential for cellular homeostasis and organ function. Loss of proteostasis is a hallmark of aging culminating in severe dysfunction of protein turnover. To investigate protein turnover dynamics as a function of age, we performed continuous in vivo metabolic stable isotope labeling in mice along the aging continuum. First, we discovered that the brain proteome uniquely undergoes dynamic turnover fluctuations during aging compared to heart and liver tissue. Second, trends in protein turnover in the brain proteome during aging showed sex-specific differences that were tightly tied to cellular compartments. Next, parallel analyses of the insoluble proteome revealed that several cellular compartments experience hampered turnover, in part due to misfolding. Finally, we found that age-associated fluctuations in proteasome activity were associated with the turnover of core proteolytic subunits, which was recapitulated by pharmacological suppression of proteasome activity. Taken together, our study provides a proteome-wide atlas of protein turnover across the aging continuum and reveals a link between the turnover of individual proteasome subunits and the age-associated decline in proteasome activity.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"120-139"},"PeriodicalIF":9.9,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10897147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139106318","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

Identifying Spatial Co-occurrence in Healthy and InflAmed tissues (ISCHIA). 在健康和炎症组织中识别空间共现（ISCHIA）。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2024-02-01 Epub Date: 2024-01-15 DOI: 10.1038/s44320-023-00006-5

Atefeh Lafzi, Costanza Borrelli, Simona Baghai Sain, Karsten Bach, Jonas A Kretz, Kristina Handler, Daniel Regan-Komito, Xenia Ficht, Andreas Frei, Andreas Moor

{"title":"Identifying Spatial Co-occurrence in Healthy and InflAmed tissues (ISCHIA).","authors":"Atefeh Lafzi, Costanza Borrelli, Simona Baghai Sain, Karsten Bach, Jonas A Kretz, Kristina Handler, Daniel Regan-Komito, Xenia Ficht, Andreas Frei, Andreas Moor","doi":"10.1038/s44320-023-00006-5","DOIUrl":"10.1038/s44320-023-00006-5","url":null,"abstract":"Sequencing-based spatial transcriptomics (ST) methods allow unbiased capturing of RNA molecules at barcoded spots, charting the distribution and localization of cell types and transcripts across a tissue. While the coarse resolution of these techniques is considered a disadvantage, we argue that the inherent proximity of transcriptomes captured on spots can be leveraged to reconstruct cellular networks. To this end, we developed ISCHIA (Identifying Spatial Co-occurrence in Healthy and InflAmed tissues), a computational framework to analyze the spatial co-occurrence of cell types and transcript species within spots. Co-occurrence analysis is complementary to differential gene expression, as it does not depend on the abundance of a given cell type or on the transcript expression levels, but rather on their spatial association in the tissue. We applied ISCHIA to analyze co-occurrence of cell types, ligands and receptors in a Visium dataset of human ulcerative colitis patients, and validated our findings at single-cell resolution on matched hybridization-based data. We uncover inflammation-induced cellular networks involving M cell and fibroblasts, as well as ligand-receptor interactions enriched in the inflamed human colon, and their associated gene signatures. Our results highlight the hypothesis-generating power and broad applicability of co-occurrence analysis on spatial transcriptomics data.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"98-119"},"PeriodicalIF":9.9,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10897385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139472182","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

Systematic discovery of protein interaction interfaces using AlphaFold and experimental validation. 利用 AlphaFold 系统发现蛋白质相互作用界面并进行实验验证。

IF 8.5 1区生物学

Molecular Systems Biology Pub Date : 2024-02-01 Epub Date: 2024-01-15 DOI: 10.1038/s44320-023-00005-6

Chop Yan Lee, Dalmira Hubrich, Julia K Varga, Christian Schäfer, Mareen Welzel, Eric Schumbera, Milena Djokic, Joelle M Strom, Jonas Schönfeld, Johanna L Geist, Feyza Polat, Toby J Gibson, Claudia Isabelle Keller Valsecchi, Manjeet Kumar, Ora Schueler-Furman, Katja Luck

{"title":"Systematic discovery of protein interaction interfaces using AlphaFold and experimental validation.","authors":"Chop Yan Lee, Dalmira Hubrich, Julia K Varga, Christian Schäfer, Mareen Welzel, Eric Schumbera, Milena Djokic, Joelle M Strom, Jonas Schönfeld, Johanna L Geist, Feyza Polat, Toby J Gibson, Claudia Isabelle Keller Valsecchi, Manjeet Kumar, Ora Schueler-Furman, Katja Luck","doi":"10.1038/s44320-023-00005-6","DOIUrl":"10.1038/s44320-023-00005-6","url":null,"abstract":"Structural resolution of protein interactions enables mechanistic and functional studies as well as interpretation of disease variants. However, structural data is still missing for most protein interactions because we lack computational and experimental tools at scale. This is particularly true for interactions mediated by short linear motifs occurring in disordered regions of proteins. We find that AlphaFold-Multimer predicts with high sensitivity but limited specificity structures of domain-motif interactions when using small protein fragments as input. Sensitivity decreased substantially when using long protein fragments or full length proteins. We delineated a protein fragmentation strategy particularly suited for the prediction of domain-motif interfaces and applied it to interactions between human proteins associated with neurodevelopmental disorders. This enabled the prediction of highly confident and likely disease-related novel interfaces, which we further experimentally corroborated for FBXO23-STX1B, STX1B-VAMP2, ESRRG-PSMC5, PEX3-PEX19, PEX3-PEX16, and SNRPB-GIGYF1 providing novel molecular insights for diverse biological processes. Our work highlights exciting perspectives, but also reveals clear limitations and the need for future developments to maximize the power of Alphafold-Multimer for interface predictions.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"75-97"},"PeriodicalIF":8.5,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10883280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139472172","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

Illuminating phenotypic drug responses of sarcoma cells to kinase inhibitors by phosphoproteomics. 通过磷酸蛋白组学阐明肉瘤细胞对激酶抑制剂的表型药物反应。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2024-01-01 Epub Date: 2023-12-18 DOI: 10.1038/s44320-023-00004-7

Chien-Yun Lee, Matthew The, Chen Meng, Florian P Bayer, Kerstin Putzker, Julian Müller, Johanna Streubel, Julia Woortman, Amirhossein Sakhteman, Moritz Resch, Annika Schneider, Stephanie Wilhelm, Bernhard Kuster

{"title":"Illuminating phenotypic drug responses of sarcoma cells to kinase inhibitors by phosphoproteomics.","authors":"Chien-Yun Lee, Matthew The, Chen Meng, Florian P Bayer, Kerstin Putzker, Julian Müller, Johanna Streubel, Julia Woortman, Amirhossein Sakhteman, Moritz Resch, Annika Schneider, Stephanie Wilhelm, Bernhard Kuster","doi":"10.1038/s44320-023-00004-7","DOIUrl":"10.1038/s44320-023-00004-7","url":null,"abstract":"Kinase inhibitors (KIs) are important cancer drugs but often feature polypharmacology that is molecularly not understood. This disconnect is particularly apparent in cancer entities such as sarcomas for which the oncogenic drivers are often not clear. To investigate more systematically how the cellular proteotypes of sarcoma cells shape their response to molecularly targeted drugs, we profiled the proteomes and phosphoproteomes of 17 sarcoma cell lines and screened the same against 150 cancer drugs. The resulting 2550 phenotypic profiles revealed distinct drug responses and the cellular activity landscapes derived from deep (phospho)proteomes (9-10,000 proteins and 10-27,000 phosphorylation sites per cell line) enabled several lines of analysis. For instance, connecting the (phospho)proteomic data with drug responses revealed known and novel mechanisms of action (MoAs) of KIs and identified markers of drug sensitivity or resistance. All data is publicly accessible via an interactive web application that enables exploration of this rich molecular resource for a better understanding of active signalling pathways in sarcoma cells, identifying treatment response predictors and revealing novel MoA of clinical KIs.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"20 1","pages":"28-55"},"PeriodicalIF":9.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10883282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139098308","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

Hotspot propensity across mutational processes. 不同突变过程中的热点倾向

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2024-01-01 Epub Date: 2023-12-20 DOI: 10.1038/s44320-023-00001-w

Claudia Arnedo-Pac, Ferran Muiños, Abel Gonzalez-Perez, Nuria Lopez-Bigas

{"title":"Hotspot propensity across mutational processes.","authors":"Claudia Arnedo-Pac, Ferran Muiños, Abel Gonzalez-Perez, Nuria Lopez-Bigas","doi":"10.1038/s44320-023-00001-w","DOIUrl":"10.1038/s44320-023-00001-w","url":null,"abstract":"The sparsity of mutations observed across tumours hinders our ability to study mutation rate variability at nucleotide resolution. To circumvent this, here we investigated the propensity of mutational processes to form mutational hotspots as a readout of their mutation rate variability at single base resolution. Mutational signatures 1 and 17 have the highest hotspot propensity (5-78 times higher than other processes). After accounting for trinucleotide mutational probabilities, sequence composition and mutational heterogeneity at 10 Kbp, most (94-95%) signature 17 hotspots remain unexplained, suggesting a significant role of local genomic features. For signature 1, the inclusion of genome-wide distribution of methylated CpG sites into models can explain most (80-100%) of the hotspot propensity. There is an increased hotspot propensity of signature 1 in normal tissues and de novo germline mutations. We demonstrate that hotspot propensity is a useful readout to assess the accuracy of mutation rate models at nucleotide resolution. This new approach and the findings derived from it open up new avenues for a range of somatic and germline studies investigating and modelling mutagenesis.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":"20 1","pages":"6-27"},"PeriodicalIF":9.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10883281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139098307","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

What we can learn from deep space communication for reproducible bioimaging and data analysis 我们能从深空通信中学到什么，以实现可重现的生物成像和数据分析

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-12-13 DOI: 10.1038/s44320-023-00002-9

Tatiana Woller, Christopher J Cawthorne, Romain Raymond Agnes Slootmaekers, Ingrid Barcena Roig, Alexander Botzki, Sebastian Munck

引用次数: 0

A multi-layered network model identifies Akt1 as a common modulator of neurodegeneration. 多层网络模型确定Akt1是神经退行性变的共同调节剂。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-12-06 Epub Date: 2023-11-20 DOI: 10.15252/msb.202311801

Dokyun Na, Do-Hwan Lim, Jae-Sang Hong, Hyang-Mi Lee, Daeahn Cho, Myeong-Sang Yu, Bilal Shaker, Jun Ren, Bomi Lee, Jae Gwang Song, Yuna Oh, Kyungeun Lee, Kwang-Seok Oh, Mi Young Lee, Min-Seok Choi, Han Saem Choi, Yang-Hee Kim, Jennifer M Bui, Kangseok Lee, Hyung Wook Kim, Young Sik Lee, Jörg Gsponer

{"title":"A multi-layered network model identifies Akt1 as a common modulator of neurodegeneration.","authors":"Dokyun Na, Do-Hwan Lim, Jae-Sang Hong, Hyang-Mi Lee, Daeahn Cho, Myeong-Sang Yu, Bilal Shaker, Jun Ren, Bomi Lee, Jae Gwang Song, Yuna Oh, Kyungeun Lee, Kwang-Seok Oh, Mi Young Lee, Min-Seok Choi, Han Saem Choi, Yang-Hee Kim, Jennifer M Bui, Kangseok Lee, Hyung Wook Kim, Young Sik Lee, Jörg Gsponer","doi":"10.15252/msb.202311801","DOIUrl":"10.15252/msb.202311801","url":null,"abstract":"The accumulation of misfolded and aggregated proteins is a hallmark of neurodegenerative proteinopathies. Although multiple genetic loci have been associated with specific neurodegenerative diseases (NDs), molecular mechanisms that may have a broader relevance for most or all proteinopathies remain poorly resolved. In this study, we developed a multi-layered network expansion (MLnet) model to predict protein modifiers that are common to a group of diseases and, therefore, may have broader pathophysiological relevance for that group. When applied to the four NDs Alzheimer's disease (AD), Huntington's disease, and spinocerebellar ataxia types 1 and 3, we predicted multiple members of the insulin pathway, including PDK1, Akt1, InR, and sgg (GSK-3β), as common modifiers. We validated these modifiers with the help of four Drosophila ND models. Further evaluation of Akt1 in human cell-based ND models revealed that activation of Akt1 signaling by the small molecule SC79 increased cell viability in all models. Moreover, treatment of AD model mice with SC79 enhanced their long-term memory and ameliorated dysregulated anxiety levels, which are commonly affected in AD patients. These findings validate MLnet as a valuable tool to uncover molecular pathways and proteins involved in the pathophysiology of entire disease groups and identify potential therapeutic targets that have relevance across disease boundaries. MLnet can be used for any group of diseases and is available as a web tool at http://ssbio.cau.ac.kr/software/mlnet.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"e11801"},"PeriodicalIF":9.9,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10698508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138176810","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

Evaluating E. coli genome-scale metabolic model accuracy with high-throughput mutant fitness data. 评估E。大肠杆菌基因组规模代谢模型的准确性与高通量突变适应度数据。

IF 9.9 1区生物学

Molecular Systems Biology Pub Date : 2023-12-06 Epub Date: 2023-10-27 DOI: 10.15252/msb.202311566

David B Bernstein, Batu Akkas, Morgan N Price, Adam P Arkin

{"title":"Evaluating E. coli genome-scale metabolic model accuracy with high-throughput mutant fitness data.","authors":"David B Bernstein, Batu Akkas, Morgan N Price, Adam P Arkin","doi":"10.15252/msb.202311566","DOIUrl":"10.15252/msb.202311566","url":null,"abstract":"The Escherichia coli genome-scale metabolic model (GEM) is an exemplar systems biology model for the simulation of cellular metabolism. Experimental validation of model predictions is essential to pinpoint uncertainty and ensure continued development of accurate models. Here, we quantified the accuracy of four subsequent E. coli GEMs using published mutant fitness data across thousands of genes and 25 different carbon sources. This evaluation demonstrated the utility of the area under a precision-recall curve relative to alternative accuracy metrics. An analysis of errors in the latest (iML1515) model identified several vitamins/cofactors that are likely available to mutants despite being absent from the experimental growth medium and highlighted isoenzyme gene-protein-reaction mapping as a key source of inaccurate predictions. A machine learning approach further identified metabolic fluxes through hydrogen ion exchange and specific central metabolism branch points as important determinants of model accuracy. This work outlines improved practices for the assessment of GEM accuracy with high-throughput mutant fitness data and highlights promising areas for future model refinement in E. coli and beyond.","PeriodicalId":18906,"journal":{"name":"Molecular Systems Biology","volume":" ","pages":"e11566"},"PeriodicalIF":9.9,"publicationDate":"2023-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10698504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54230090","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