NPJ Systems Biology and Applications最新文献

{"title":"Understanding flux switching in metabolic networks through an analysis of synthetic lethals","authors":"Sowmya Manojna Narasimha, Tanisha Malpani, Omkar S. Mohite, J. Saketha Nath, Karthik Raman","doi":"10.1038/s41540-024-00426-5","DOIUrl":"https://doi.org/10.1038/s41540-024-00426-5","url":null,"abstract":"<p>Biological systems are robust and redundant. The redundancy can manifest as alternative metabolic pathways. Synthetic double lethals are pairs of reactions that, when deleted simultaneously, abrogate cell growth. However, removing one reaction allows the rerouting of metabolites through alternative pathways. Little is known about these hidden linkages between pathways. Understanding them in the context of pathogens is useful for therapeutic innovations. We propose a constraint-based optimisation approach to identify inter-dependencies between metabolic pathways. It minimises rerouting between two reaction deletions, corresponding to a synthetic lethal pair, and outputs the set of reactions vital for metabolic rewiring, known as the synthetic lethal cluster. We depict the results for different pathogens and show that the reactions span across metabolic modules, illustrating the complexity of metabolism. Finally, we demonstrate how the two classes of synthetic lethals play a role in metabolic networks and influence the different properties of a synthetic lethal cluster.</p>","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimal performance objectives in the highly conserved bone morphogenetic protein signaling pathway","authors":"Razeen Shaikh, Nissa J. Larson, Jayden Kam, Donny Hanjaya-Putra, Jeremiah Zartman, David M. Umulis, Linlin Li, Gregory T. Reeves","doi":"10.1038/s41540-024-00430-9","DOIUrl":"https://doi.org/10.1038/s41540-024-00430-9","url":null,"abstract":"<p>Throughout development, complex networks of cell signaling pathways drive cellular decision-making across different tissues and contexts. The transforming growth factor β (TGF-β) pathways, including the BMP/Smad pathway, play crucial roles in determining cellular responses. However, as the Smad pathway is used reiteratively throughout the life cycle of all animals, its systems-level behavior varies from one context to another, despite the pathway connectivity remaining nearly constant. For instance, some cellular systems require a rapid response, while others require high noise filtering. In this paper, we examine how the BMP-Smad pathway balances trade-offs among three such systems-level behaviors, or “Performance Objectives (POs)”: response speed, noise amplification, and the sensitivity of pathway output to receptor input. Using a Smad pathway model fit to human cell data, we show that varying non-conserved parameters (NCPs) such as protein concentrations, the Smad pathway can be tuned to emphasize any of the three POs and that the concentration of nuclear phosphatase has the greatest effect on tuning the POs. However, due to competition among the POs, the pathway cannot simultaneously optimize all three, but at best must balance trade-offs among the POs. We applied the multi-objective optimization concept of the Pareto Front, a widely used concept in economics to identify optimal trade-offs among various requirements. We show that the BMP pathway efficiently balances competing POs across species and is largely Pareto optimal. Our findings reveal that varying the concentration of NCPs allows the Smad signaling pathway to generate a diverse range of POs. This insight identifies how signaling pathways can be optimally tuned for each context.</p>","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tipping-point transition from transient to persistent inflammation in pancreatic islets","authors":"Thomas Holst-Hansen, Pernille Yde Nielsen, Mogens H. Jensen, Thomas Mandrup-Poulsen, Ala Trusina","doi":"10.1038/s41540-024-00427-4","DOIUrl":"https://doi.org/10.1038/s41540-024-00427-4","url":null,"abstract":"<p>Type 2 diabetes (T2D) is associated with a systemic increase in the pro-inflammatory cytokine IL-1β. While transient exposure to low IL-1β concentrations improves insulin secretion and β-cell proliferation in pancreatic islets, prolonged exposure leads to impaired insulin secretion and collective β-cell death. IL-1 is secreted locally by islet-resident macrophages and β-cells; however, it is unknown if and how the two opposing modes may emerge at single islet level. We investigated the duality of IL-1β with a quantitative in silico model of the IL-1 regulatory network in pancreatic islets. We find that the network can produce either transient or persistent IL-1 responses when induced by pro-inflammatory and metabolic cues. This suggests that the duality of IL-1 may be regulated at the single islet level. We use two core feedbacks in the IL-1 regulation to explain both modes: First, a fast positive feedback in which IL-1 induces its own production through the IL-1R/IKK/NF-κB pathway. Second, a slow negative feedback where NF-κB upregulates inhibitors acting at different levels along the IL-1R/IKK/NF-κB pathway—IL-1 receptor antagonist and A20, among others. A transient response ensues when the two feedbacks are balanced. When the positive feedback dominates over the negative, islets transit into the persistent inflammation mode. Consistent with several observations, where the size of islets was implicated in its inflammatory state, we find that large islets and islets with high density of IL-1β amplifying cells are more prone to transit into persistent IL-1β mode. Our results are likely not limited to IL-1β but are general for the combined effect of multiple pro-inflammatory cytokines and chemokines. Generalizing complex regulations in terms of two feedback mechanisms of opposing nature and acting on different time scales provides a number of testable predictions. Taking islet architecture and cellular heterogeneity into consideration, further dynamic monitoring and experimental validation in actual islet samples will be crucial to verify the model predictions and enhance its utility in clinical applications.</p>","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142206520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EpiScan: accurate high-throughput mapping of antibody-specific epitopes using sequence information","authors":"Chuan Wang, Jiangyuan Wang, Wenjun Song, Guanzheng Luo, Taijiao Jiang","doi":"10.1038/s41540-024-00432-7","DOIUrl":"https://doi.org/10.1038/s41540-024-00432-7","url":null,"abstract":"<p>The identification of antibody-specific epitopes on virus proteins is crucial for vaccine development and drug design. Nonetheless, traditional wet-lab approaches for the identification of epitopes are both costly and labor-intensive, underscoring the need for the development of efficient and cost-effective computational tools. Here, EpiScan, an attention-based deep learning framework for predicting antibody-specific epitopes, is presented. EpiScan adopts a multi-input and single-output strategy by designing independent blocks for different parts of antibodies, including variable heavy chain (V_H), variable light chain (V_L), complementary determining regions (CDRs), and framework regions (FRs). The block predictions are weighted and integrated for the prediction of potential epitopes. Using multiple experimental data samples, we show that EpiScan, which only uses antibody sequence information, can accurately map epitopes on specific antigen structures. The antibody-specific epitopes on the receptor binding domain (RBD) of SARS coronavirus 2 (SARS-CoV-2) were located by EpiScan, and the potentially valuable vaccine epitope was identified. EpiScan can expedite the epitope mapping process for high-throughput antibody sequencing data, supporting vaccine design and drug development. Availability: For the convenience of related wet-experimental researchers, the source code and web server of EpiScan are publicly available at https://github.com/gzBiomedical/EpiScan.</p>","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142206521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Codon usage and expression-based features significantly improve prediction of CRISPR efficiency.","authors":"Shaked Bergman, Tamir Tuller","doi":"10.1038/s41540-024-00431-8","DOIUrl":"10.1038/s41540-024-00431-8","url":null,"abstract":"<p><p>CRISPR is a precise and effective genome editing technology; but despite several advancements during the last decade, our ability to computationally design gRNAs remains limited. Most predictive models have relatively low predictive power and utilize only the sequence of the target site as input. Here we suggest a new category of features, which incorporate the target site genomic position and the presence of genes close to it. We calculate four features based on gene expression and codon usage bias indices. We show, on CRISPR datasets taken from 3 different cell types, that such features perform comparably with 425 state-of-the-art predictive features, ranking in the top 2-12% of features. We trained new predictive models, showing that adding expression features to them significantly improves their r² by up to 0.04 (relative increase of 39%), achieving average correlations of up to 0.38 on their validation sets; and that these features are deemed important by different feature importance metrics. We believe that incorporating the target site's position, in addition to its sequence, in features such as we have generated here will improve our ability to predict, design and understand CRISPR experiments going forward.</p>","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11372048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142126288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Boolean model explains phenotypic plasticity changes underlying hepatic cancer stem cells emergence.","authors":"Alexis Hernández-Magaña, Antonio Bensussen, Juan Carlos Martínez-García, Elena R Álvarez-Buylla","doi":"10.1038/s41540-024-00422-9","DOIUrl":"10.1038/s41540-024-00422-9","url":null,"abstract":"<p><p>In several carcinomas, including hepatocellular carcinoma, it has been demonstrated that cancer stem cells (CSCs) have enhanced invasiveness and therapy resistance compared to differentiated cancer cells. Mathematical-computational tools could be valuable for integrating experimental results and understanding the phenotypic plasticity mechanisms for CSCs emergence. Based on the literature review, we constructed a Boolean model that recovers eight stable states (attractors) corresponding to the gene expression profile of hepatocytes and mesenchymal cells in senescent, quiescent, proliferative, and stem-like states. The epigenetic landscape associated with the regulatory network was analyzed. We observed that the loss of p53, p16, RB, or the constitutive activation of β-catenin and YAP1 increases the robustness of the proliferative stem-like phenotypes. Additionally, we found that p53 inactivation facilitates the transition of proliferative hepatocytes into stem-like mesenchymal phenotype. Thus, phenotypic plasticity may be altered, and stem-like phenotypes related to CSCs may be easier to attain following the mutation acquisition.</p>","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Network topology and interaction logic determine states it supports.","authors":"Tomáš Gedeon","doi":"10.1038/s41540-024-00423-8","DOIUrl":"https://doi.org/10.1038/s41540-024-00423-8","url":null,"abstract":"<p><p>In this review paper we summarize a recent progress on the problem of describing range of dynamics supported by a network. We show that there is natural connection between network models consisting of collections of multivalued monotone boolean functions and ordinary differential equations models. We show how to construct such collections and use them to answer questions about prevalence of cellular phenotypes that correspond to equilibria of network models.</p>","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11358538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142093646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recovering biomolecular network dynamics from single-cell omics data requires three time points.","authors":"Shu Wang, Muhammad Ali Al-Radhawi, Douglas A Lauffenburger, Eduardo D Sontag","doi":"10.1038/s41540-024-00424-7","DOIUrl":"10.1038/s41540-024-00424-7","url":null,"abstract":"<p><p>Single-cell omics technologies can measure millions of cells for up to thousands of biomolecular features, enabling data-driven studies of complex biological networks. However, these high-throughput experimental techniques often cannot track individual cells over time, thus complicating the understanding of dynamics such as time trajectories of cell states. These \"dynamical phenotypes\" are key to understanding biological phenomena such as differentiation fates. We show by mathematical analysis that, in spite of high dimensionality and lack of individual cell traces, three time-points of single-cell omics data are theoretically necessary and sufficient to uniquely determine the network interaction matrix and associated dynamics. Moreover, we show through numerical simulations that an interaction matrix can be accurately determined with three or more time-points even in the presence of sampling and measurement noise typical of single-cell omics. Our results can guide the design of single-cell omics time-course experiments, and provide a tool for data-driven phase-space analysis.</p>","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11350189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142081061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Constraint-based modelling predicts metabolic signatures of low and high-grade serous ovarian cancer.","authors":"Kate E Meeson, Jean-Marc Schwartz","doi":"10.1038/s41540-024-00418-5","DOIUrl":"10.1038/s41540-024-00418-5","url":null,"abstract":"<p><p>Ovarian cancer is an aggressive, heterogeneous disease, burdened with late diagnosis and resistance to chemotherapy. Clinical features of ovarian cancer could be explained by investigating its metabolism, and how the regulation of specific pathways links to individual phenotypes. Ovarian cancer is of particular interest for metabolic research due to its heterogeneous nature, with five distinct subtypes having been identified, each of which may display a unique metabolic signature. To elucidate metabolic differences, constraint-based modelling (CBM) represents a powerful technology, inviting the integration of 'omics' data, such as transcriptomics. However, many CBM methods have not prioritised accurate growth rate predictions, and there are very few ovarian cancer genome-scale studies. Here, a novel method for CBM has been developed, employing the genome-scale model Human1 and flux balance analysis, enabling the integration of in vitro growth rates, transcriptomics data and media conditions to predict the metabolic behaviour of cells. Using low- and high-grade ovarian cancer, subtype-specific metabolic differences have been predicted, which have been supported by publicly available CRISPR-Cas9 data from the Cancer Cell Line Encyclopaedia and an extensive literature review. Metabolic drivers of aggressive, invasive phenotypes, as well as pathways responsible for increased chemoresistance in low-grade cell lines have been suggested. Experimental gene dependency data has been used to validate areas of the pentose phosphate pathway as essential for low-grade cellular growth, highlighting potential vulnerabilities for this ovarian cancer subtype.</p>","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11344801/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SignalingProfiler 2.0 a network-based approach to bridge multi-omics data to phenotypic hallmarks.","authors":"Veronica Venafra, Francesca Sacco, Livia Perfetto","doi":"10.1038/s41540-024-00417-6","DOIUrl":"10.1038/s41540-024-00417-6","url":null,"abstract":"<p><p>Unraveling how cellular signaling is remodeled upon perturbation is crucial for understanding disease mechanisms and identifying potential drug targets. In this pursuit, computational tools generating mechanistic hypotheses from multi-omics data have invaluable potential. Here, we present a newly implemented version (2.0) of SignalingProfiler, a multi-step pipeline to draw mechanistic hypotheses on the signaling events impacting cellular phenotypes. SignalingProfiler 2.0 derives context-specific signaling networks by integrating proteogenomic data with the prior knowledge-causal network. This is a freely accessible and flexible tool that incorporates statistical, footprint-based, and graph algorithms to accelerate the integration and interpretation of multi-omics data. Through a benchmarking process on three proof-of-concept studies, we demonstrate the tool's ability to generate hierarchical mechanistic networks recapitulating novel and known perturbed signaling and phenotypic outcomes, in both human and mice contexts. In summary, SignalingProfiler 2.0 addresses the emergent need to derive biologically relevant information from complex multi-omics data by extracting interpretable networks.</p>","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11343843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}