bioRxiv - Systems Biology最新文献_第10页

Inference of gene regulatory networks for overcoming low performance in real-world data 推断基因调控网络，克服真实世界数据性能低下的问题

bioRxiv - Systems Biology Pub Date : 2024-07-22 DOI: 10.1101/2024.07.16.603684

Yusuke Hiki, Yuta Tokuoka, Takahiro G Yamada, Akira Funahashi

{"title":"Inference of gene regulatory networks for overcoming low performance in real-world data","authors":"Yusuke Hiki, Yuta Tokuoka, Takahiro G Yamada, Akira Funahashi","doi":"10.1101/2024.07.16.603684","DOIUrl":"https://doi.org/10.1101/2024.07.16.603684","url":null,"abstract":"The identification of gene regulatory networks is important for understanding the mechanisms of various biological phenomena. Many methods have been proposed to infer networks from time-series gene expression data obtained by high-throughput next-generation sequencings. Such methods can effectively infer gene regulatory networks for in silico data, but inferring the networks accurately from in vivo data remiains a challenge because of the large noise and low time sampling rate. Here, we proposed a novel unsupervised learning method, Multi-view attention Long-short term memory for Network inference (MaLoN). It can infer gene regulatory networks with temporal changes in gene regulation using the multi-view attention Long Short-term memory model. Using in vivo benchmark datasets in Saccharomyces cerevisiae and Escherichia coli, we showed that MaLoN can infer gene regulatory networks more accurately than existing methods. The ablated models indicated that the multi-view attention mechanism suppressed false positives. The order of activation of gene regulations inferred by MaLoN was consistent with existing knowledge.","PeriodicalId":501213,"journal":{"name":"bioRxiv - Systems Biology","volume":"82 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141739567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DREAMER: Exploring Common Mechanisms of Adverse Drug Reactions and Disease Phenotypes through Network-Based Analysis DREAMER：通过网络分析探索药物不良反应和疾病表型的共同机制

bioRxiv - Systems Biology Pub Date : 2024-07-22 DOI: 10.1101/2024.07.20.602911

Farzaneh Firoozbakht, Maria L. Elkjaer, Diane Handy, Ruisheng Wang, Zoe Chervontseva, Matthias Rarey, Joseph Loscalzo, Jan Baumbach, Olga Tsoy

{"title":"DREAMER: Exploring Common Mechanisms of Adverse Drug Reactions and Disease Phenotypes through Network-Based Analysis","authors":"Farzaneh Firoozbakht, Maria L. Elkjaer, Diane Handy, Ruisheng Wang, Zoe Chervontseva, Matthias Rarey, Joseph Loscalzo, Jan Baumbach, Olga Tsoy","doi":"10.1101/2024.07.20.602911","DOIUrl":"https://doi.org/10.1101/2024.07.20.602911","url":null,"abstract":"Adverse drug reactions (ADRs) are a major concern in clinical healthcare, significantly affecting patient safety and drug development. This study introduces DREAMER, a novel network-based method for exploring the mechanisms underlying ADRs and disease phenotypes at a molecular level by leveraging a comprehensive knowledge graph obtained from various datasets. By considering drugs and diseases that cause similar phenotypes, and investigating their commonalities regarding their impact on specific modules of the protein-protein interaction network, DREAMER can robustly identify protein sets associated with the biological mechanisms underlying ADRs and unravel the causal relationships that contribute to the observed clinical outcomes. Applying DREAMER to 649 ADRs, we identified proteins associated with the mechanism of action for 67 ADRs across multiple organ systems. In particular, DREAMER highlights the importance of GABAergic signaling and proteins of the coagulation pathways for personality disorders and intracranial hemorrhage, respectively. We further demonstrate the application of DREAMER in drug repurposing and propose sotalol, ranolazine, and diltiazem as candidate drugs to be repurposed for cardiac arrest. In summary, DREAMER effectively detects molecular mechanisms underlying phenotypes.","PeriodicalId":501213,"journal":{"name":"bioRxiv - Systems Biology","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141781401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The guardians of mitochondrial dynamics: a novel role for intermediate filament proteins 线粒体动力学的守护者：中间丝蛋白的新作用

bioRxiv - Systems Biology Pub Date : 2024-07-22 DOI: 10.1101/2024.07.19.604282

Irene MGM Hemel, Carlijn Steen, Simon LIJ Denil, Gokhan Ertaylan, Martina Kutmon, Michiel Adriaens, Mike Gerards

{"title":"The guardians of mitochondrial dynamics: a novel role for intermediate filament proteins","authors":"Irene MGM Hemel, Carlijn Steen, Simon LIJ Denil, Gokhan Ertaylan, Martina Kutmon, Michiel Adriaens, Mike Gerards","doi":"10.1101/2024.07.19.604282","DOIUrl":"https://doi.org/10.1101/2024.07.19.604282","url":null,"abstract":"Mitochondria are dynamic organelles and the main source of cellular energy. Their dynamic nature is crucial to meet cellular requirements. However, the processes and proteins involved in mitochondrial dynamics are not fully understood. Using a computational protein-protein interaction approach, we identified ITPRIPL2, which caused mitochondrial elongation upon knockdown. ITPRIPL2 co-localizes with the intermediate filament protein vimentin and interacts with vimentin according to protein simulations. ITPRIPL2 knockdown alters vimentin processing, disrupts intermediate filaments and transcriptomics analysis revealed changes in vimentin-related pathways. Our data illustrates that ITPRIPL2 is essential for vimentin related intermediate filament structure. Interestingly, like ITPRIPL2 knockdown, vimentin knockdown results in mitochondrial elongation. Our data highlights ITPRIPL2 as a vimentin-associated protein and reveals a role for intermediate filaments in mitochondrial dynamics, improving our understanding of mitochondrial dynamics regulators. Moreover, our study demonstrates that protein-protein interaction analysis is a powerful approach for identifying novel mitochondrial dynamics proteins.","PeriodicalId":501213,"journal":{"name":"bioRxiv - Systems Biology","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141781264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CoDIAC: A comprehensive approach for interaction analysis reveals novel insights into SH2 domain function and regulation CoDIAC：一种用于相互作用分析的综合方法揭示了有关 SH2 结构域功能和调控的新见解

bioRxiv - Systems Biology Pub Date : 2024-07-22 DOI: 10.1101/2024.07.18.604100

Alekhya Kandoor, Gabrielle Martinez, Julianna M. Hitchcock, Savannah Angel, Logan Campbell, Saqib Rizvi, Kristen M. Naegle

{"title":"CoDIAC: A comprehensive approach for interaction analysis reveals novel insights into SH2 domain function and regulation","authors":"Alekhya Kandoor, Gabrielle Martinez, Julianna M. Hitchcock, Savannah Angel, Logan Campbell, Saqib Rizvi, Kristen M. Naegle","doi":"10.1101/2024.07.18.604100","DOIUrl":"https://doi.org/10.1101/2024.07.18.604100","url":null,"abstract":"Protein domains are conserved structural and functional units and are the functional building blocks of proteins. Evolutionary expansion means that domain families are often represented by many members in a species, which are found in various configurations with other domains, which have evolved new specificity for interacting partners. Here, we develop a structure-based interface analysis to comprehensively map domain interfaces from available experimental and predicted structures, including interfaces with other macromolecules and intraprotein interfaces (such as might exist between domains in a protein). We hypothesized that a comprehensive approach to contact mapping of domains could yield new insights. Specifically, we use it to gain information about how domains selectivity interact with ligands, whether domain-domain interfaces of repeated domain partnerships are conserved across diverse proteins, and identify regions of conserved post-translational modifications, using relationship to interaction interfaces as a method to hypothesize the effect of post-translational modifications (and mutations). We applied this approach to the human SH2 domain family, an extensive modular unit that is the foundation of phosphotyrosine-mediated signaling, where we identified a novel approach to understanding the binding selectivity of SH2 domains and evidence that there is coordinated and conserved regulation of multiple SH2 domain binding interfaces by tyrosine and serine/threonine phosphorylation and acetylation, suggesting that multiple signaling systems can regulate protein activity and SH2 domain interactions in a regulated manner. We provide the extensive features of the human SH2 domain family and this modular approach, as an open source Python package for COmprehensive Domain Interface Analysis of Contacts (CoDIAC).","PeriodicalId":501213,"journal":{"name":"bioRxiv - Systems Biology","volume":"70 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141781266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Multimodal screen reveals noise regulatory proteins 多模式筛选发现噪声调控蛋白

bioRxiv - Systems Biology Pub Date : 2024-07-21 DOI: 10.1101/2024.07.17.603871

Oscar Garcia-Blay, Xinyu Hu, Christin L. Wassermann, Tom van Bokhoven, Frederique M.B. Struijs, Maike M.K. Hansen

引用次数: 0

Perturbed pediatric serum metabolome in mild and severe dengue disease 轻度和重度登革热病儿科血清代谢组紊乱

bioRxiv - Systems Biology Pub Date : 2024-07-19 DOI: 10.1101/2024.07.16.603788

Paul S Soma, Rebekah C Gullberg, Barbara Graham, M Nurul Islam, Angel Balmaseda, Carol D Blair, Barry Beaty, John T Belisle, Eva Harris, Rushika Perera

{"title":"Perturbed pediatric serum metabolome in mild and severe dengue disease","authors":"Paul S Soma, Rebekah C Gullberg, Barbara Graham, M Nurul Islam, Angel Balmaseda, Carol D Blair, Barry Beaty, John T Belisle, Eva Harris, Rushika Perera","doi":"10.1101/2024.07.16.603788","DOIUrl":"https://doi.org/10.1101/2024.07.16.603788","url":null,"abstract":"Dengue viruses (DENVs) are the most prevalent arboviruses affecting humans. Four billion people are at risk of infection and this burden is rapidly increasing due to geographic expansion of the mosquito vector. Infection with any of the four serotypes of DENV can result in a self-limiting disease but debilitating febrile illness (DF), and some infections progress to severe disease with manifestations such as hemorrhage and shock. DENV infection drives the metabolic state of host cells for viral benefit and induces a host-immune response that has metabolic implications that link to disease. In this study, a dynamic metabolic response to DENV infection and disease was measured in 535 pediatric patient sera using liquid chromatography-mass spectrometry. The metabolome was interrogated to discover biochemical pathways and identify key metabolites perturbed in severe dengue disease. A biomarker panel of thirty-two perturbed metabolites was utilized to classify DF, and severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) with high sensitivity and specificity equating to a balanced accuracy of 96.9%. Some metabolites that were structurally confirmed here belong to important biochemical pathways of omega-3 and omega-6 fatty acids, sphingolipids, purines, and tryptophan metabolism. A previously reported trend between serotonin and platelets in DHF patients has been expanded upon here to reveal a major depletion of serotonin, but not platelets, in DSS patients. This study differentiated and classified DF and DHF/DSS using a serum metabolic biomarker panel based on perturbed biochemical pathways that have potential implications for severe dengue disease.","PeriodicalId":501213,"journal":{"name":"bioRxiv - Systems Biology","volume":"61 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141739602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Analysis of the Modulation of RAF Signaling by 14-3-3 Proteins 14-3-3 蛋白质对 RAF 信号的调控分析

bioRxiv - Systems Biology Pub Date : 2024-07-19 DOI: 10.1101/2024.07.16.603736

Peter Carlip, Edward C Stites

{"title":"Analysis of the Modulation of RAF Signaling by 14-3-3 Proteins","authors":"Peter Carlip, Edward C Stites","doi":"10.1101/2024.07.16.603736","DOIUrl":"https://doi.org/10.1101/2024.07.16.603736","url":null,"abstract":"The regulation of cellular biochemical signaling reactions includes the modulation of protein activity through a variety of processes. For example, signaling by the RAF kinases, which are key transmitters of extracellular growth signals downstream from the RAS GTPases, is modulated by dimerization, protein conformational changes, post-translational modifications, and protein-protein interactions. 14-3-3 proteins are known to play an important role in RAF signal regulation, and have the ability to stabilize both inactive (monomeric) and active (dimeric) states of RAF. It is poorly understood how these antagonistic roles ultimately modulate RAF signaling. To investigate, we develop a mathematical model of RAF activation with both roles of 14-3-3, perform algebraic and numeric analyses, and compare with available experimental data. We derive the conditions necessary to explain experimental observations that 14-3-3 overexpression activates RAF, and we show that strong binding of 14-3-3 to Raf dimers alone is not generally sufficient to explain this observation. Our integrated analysis also suggests that RAF-14-3-3 binding is relatively weak for the reasonable range of parameter values, and suggests the Raf dimer-14-3-3 interactions are stabilized primarily by avidity. Lastly we find that in the limit of paired weak/avidity driven interactions between RAF and 14-3-3, the paired binding interactions may be reasonably approximated with a strong, single, equilibrium reaction. Overall, our work presents a mathematical model that can serve as a foundational piece for future, extended, studies of signaling reactions involving regulated RAF kinase activity.","PeriodicalId":501213,"journal":{"name":"bioRxiv - Systems Biology","volume":"86 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141739603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Expanded Genome and Proteome Reallocation in a Novel, Robust Bacillus coagulans Capable of Utilizing Pentose and Hexose Sugars 能利用五糖和六糖的新型健壮凝结芽孢杆菌的基因组扩展和蛋白质组重组

bioRxiv - Systems Biology Pub Date : 2024-07-18 DOI: 10.1101/2024.07.15.603586

David Dooley, Seunghyun Ryu, Richard J Giannone, Jackson Edwards, Bruce S Dien, Patricia Slininger, Cong T. Trinh

{"title":"Expanded Genome and Proteome Reallocation in a Novel, Robust Bacillus coagulans Capable of Utilizing Pentose and Hexose Sugars","authors":"David Dooley, Seunghyun Ryu, Richard J Giannone, Jackson Edwards, Bruce S Dien, Patricia Slininger, Cong T. Trinh","doi":"10.1101/2024.07.15.603586","DOIUrl":"https://doi.org/10.1101/2024.07.15.603586","url":null,"abstract":"Bacillus coagulans is recognized for its probiotic properties and recent development as a cell factory. Despite its importance for biotechnological applications, current understanding of B. coagulans’ robustness is limited. To fill this knowledge gap, we characterized metabolic capability and performed functional genomics and systems analysis of a novel, robust strain, B. coagulans B-768. Genome sequencing revealed that B-768 has the largest B. coagulans genome (3.94 Mbp), about 0.63 Mbp larger than the average genome of sequenced B. coagulans strains, with expanded carbohydrate metabolism and mobilome. Functional genomics identified a well-equipped genetic portfolio for utilizing a wide range of C5 (xylose, arabinose), C6 (glucose, mannose, galactose), and C12 (cellobiose) sugars present in biomass hydrolysates. For growth on individual xylose and glucose, the dominant sugars in biomass hydrolysates, B-768 exhibited distinct phenotypes and proteome profiles. Faster growth and glucose uptake rates resulted in lactate overflow metabolism, which makes B. coagulans a lactate overproducer; however, slower growth and xylose uptake diminished overflow metabolism due to the high energy demand for sugar assimilation. Carbohydrate Transport and Metabolism (COG-G), Translation (COG-J), and Energy Conversion and Production (COG-C) made up 60–65% of the measured proteomes but were allocated differently when growing on xylose and glucose. The trade-off in proteome reallocation, with high investment in COG-C over COG-G, explains the xylose growth phenotype with significant upregulation of xylose metabolism, pyruvate metabolism, and TCA cycle. Strain B-768 tolerates and effectively utilizes inhibitory biomass hydrolysates containing mixed sugars and exhibits hierarchical sugar utilization with glucose as the preferential substrate.","PeriodicalId":501213,"journal":{"name":"bioRxiv - Systems Biology","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141739609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Simulations of the infant gut microbiota suggest that complex ecological interactions regulate effects of human milk oligosaccharides on microbial mucin consumption 对婴儿肠道微生物群的模拟表明，复杂的生态相互作用调节着母乳低聚糖对微生物粘蛋白消耗的影响

bioRxiv - Systems Biology Pub Date : 2024-07-18 DOI: 10.1101/2024.07.15.603541

David M. Versluis, Clair Wijtkamp, Ellen Looijesteijn, Jan M.W. Geurts, Roeland M.H. Merks

{"title":"Simulations of the infant gut microbiota suggest that complex ecological interactions regulate effects of human milk oligosaccharides on microbial mucin consumption","authors":"David M. Versluis, Clair Wijtkamp, Ellen Looijesteijn, Jan M.W. Geurts, Roeland M.H. Merks","doi":"10.1101/2024.07.15.603541","DOIUrl":"https://doi.org/10.1101/2024.07.15.603541","url":null,"abstract":"Intestinal mucin acts as a barrier protecting the infant gut wall against diseases such as colitis and rotavirus. In vitro experiments have shown that the gut microbiota of breastfed infants consumes less mucin than the microbiota of non-breastfed infants, but the mechanisms are incompletely understood. The main difference between human milk and most infant formulas is the presence of human milk oligosaccharides (HMOs) in human milk. We hypothesize that HMOs protect mucin by stimulating non-mucin consuming bacteria. To understand the underlying mechanisms we developed a computational model that describes the metabolism and ecology of the infant gut microbiota. Model simulations suggest that extracellular digestion of the HMO 2'-fucosyllactose by the mucin-consumer Bifidobacterium bifidum may make this species vulnerable to competitors. The digestion products of HMOs become `public goods' that can be consumed by competing species such as Bacteroides vulgatus instead. Bifidobacterium longum, which does not consume mucin or produce public goods, can then become dominant, despite growing less efficiently on HMOs in monocultures than B. bifidum. In conclusion, our model simulations suggest that, through complex ecological interactions, HMOs may help lower mucin consumption by stimulating the non-mucin consumer B. longum at the expense of the mucin consumer B. bifidum.","PeriodicalId":501213,"journal":{"name":"bioRxiv - Systems Biology","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141739608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mathematical model of transcription loss due to accumulated DNA damage DNA 累积损伤导致转录丢失的数学模型

bioRxiv - Systems Biology Pub Date : 2024-07-18 DOI: 10.1101/2024.07.15.603615

Marko Raseta, Jacinta van de Grint, Shannon Dealy, Jiang Chang, Jan Hoeijmakers, Joris Pothof

引用次数: 0