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In the post-COVID-19 era, treatment options for potential SARS-CoV-2 outbreaks remain limited. An increased incidence of central nervous system (CNS) disorders has been observed in long-term COVID-19 patients. Understanding the shared molecular mechanisms between these conditions may provide new insights for developing effective therapies. This study developed an integrative drug-repurposing framework for COVID-19, leveraging comorbidity data with CNS disorders, network-based modular analysis, and dynamic perturbation analysis to identify potential drug targets and candidates against SARS-CoV-2. We constructed a comorbidity network based on the literature and data collection, including COVID-19-related proteins and genes associated with Alzheimer's disease, Parkinson's disease, multiple sclerosis, and autism spectrum disorder. Functional module detection and annotation identified a module primarily involved in protein synthesis as a key target module, utilizing connectivity map drug perturbation data. Through the construction of a weighted drug–target network and dynamic network-based drug-repurposing analysis, ubiquitin–carboxy-terminal hydrolase L1 emerged as a potential drug target. Molecular dynamics simulations suggested pregnenolone and BRD-K87426499 as two drug candidates for COVID-19. This study introduces a dynamic-perturbation-network-based drug-repurposing approach to identify COVID-19 drug targets and candidates by incorporating the comorbidity conditions of CNS disorders. [ABSTRACT FROM AUTHOR]

Head and neck cancer ranks as the sixth-most common malignancy worldwide, characterized by high mortality and recurrence rates. Research studies indicate that molecular diagnostics play a crucial role in the early detection and prognostic evaluation of these diseases. This study aimed to identify potential biomarkers for head and neck cancer and elucidate their interactions with miRNAs and possible therapeutic drugs. Four drivers, namely, FN1, IL1A, COL1A1, and MMP9, were identified using network biology and machine learning approaches. Gene set variation analysis (GSVA) showed that these genes were significantly involved in different biological processes and pathways, including coagulation, UV-response-down, apoptosis, NOTCH signaling, Wnt-beta catenin, and other signal pathways. The diagnostic value of these hub genes was validated using receiver operating characteristic (ROC) curves. The top interactive miRNAs, including miR-128-3p, miR-218-5p, miR-214-3p, miR-124-3p, miR-129-2-3p, and miR-1-3p, targeted the key genes. Furthermore, the interaction between the key genes and drugs was also identified. In summary, the key genes and miRNAs or drugs reported in this study might provide valuable information for potential biomarkers to increase the prognosis and diagnosis of head and neck cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Head and neck squamous cell carcinoma (HNSCC) remains a global health concern due to the lack of precise early diagnostic biomarkers and often-delayed diagnosis. This study employs machine learning, weighted gene co-expression network analysis, and network biology to identify transcriptomic markers for HNSCC detection. We identified nine genes with significantly differentially expressed activity in samples from HNSCC patients. These gene signatures could greatly improve early HNSCC identification and warrant further investigation to confirm their predictive and therapeutic significance. The transcriptional landscape of platelets in head and neck cancer patients revealed distinct gene expression profiles compared to healthy controls, underscoring the systemic impact of the tumor on blood platelets. Additionally, the study emphasizes the role of tumor-educated platelets (TEPs), which carry RNA signatures indicative of tumor-derived material, offering a non-invasive source for early-detection biomarkers. Although there has been a reduction in head and neck squamous cell carcinoma occurrence, it continues to be a serious global health concern. The lack of precise early diagnostic biomarkers and postponed diagnosis in the later stages are notable constraints that contribute to poor survival rates and emphasize the need for innovative diagnostic methods. In this study, we employed machine learning alongside weighted gene co-expression network analysis (WGCNA) and network biology to investigate the gene expression patterns of blood platelets, identifying transcriptomic markers for HNSCC diagnosis. Our comprehensive examination of publicly available gene expression datasets revealed nine genes with significantly elevated expression in samples from individuals diagnosed with HNSCC. These potential diagnostic markers were further assessed using TCGA and GTEx datasets, demonstrating high accuracy in distinguishing between HNSCC and non-cancerous samples. The findings indicate that these gene signatures could revolutionize early HNSCC identification. Additionally, the study highlights the significance of tumor-educated platelets (TEPs), which carry RNA signatures indicative of tumor-derived material, offering a non-invasive source for early-detection biomarkers. Despite using platelet and tumor samples from different individuals, our results suggest that TEPs reflect the transcriptomic and epigenetic landscape of tumors. Future research should aim to directly correlate tumor and platelet samples from the same patients to further elucidate this relationship. This study underscores the potential of these biomarkers in transforming early diagnosis and personalized treatment strategies for HNSCC, advocating for further research to validate their predictive and therapeutic potential. [ABSTRACT FROM AUTHOR]

Chromatin conformation capture technologies permit the study of chromatin spatial organization on a genome-wide scale at a variety of resolutions. Despite the increasing precision and resolution of high-throughput chromatin conformation capture (Hi-C) methods, it remains challenging to conclusively link transcriptional activity to spatial organizational phenomena. We have developed a clique-based approach for analyzing Hi-C data that helps identify chromosomal hotspots that feature considerable enrichment of chromatin annotations for transcriptional start sites and, building on previously published work, show that these chromosomal hotspots are not only significantly enriched in RNA polymerase II binding sites as identified by the ENCODE project, but also identify a noticeable increase in FANTOM5 and GTEx transcription within our identified cliques across a variety of tissue types. From the obtained data, we surmise that our cliques are a suitable method for identifying transcription factories in Hi-C data, and outline further extensions to the method that may make it useful for locating regions of increased transcriptional activity in datasets where in-depth expression or polymerase data may not be available. [ABSTRACT FROM AUTHOR]

BackgroundComputational models of cell signaling networks are extremely useful tools for the exploration of underlying system behavior and prediction of response to various perturbations. By representing signaling cascades as executable Boolean networks, the previously developed rxncon ("reaction-contingency") formalism and associated Python package enable accurate and scalable modeling of signal transduction even in large (thousands of components) biological systems. The models are split into reactions, which generate states, and contingencies, that impinge on reactions; this avoids the so-called "combinatorial explosion" of system size. Boolean description of the biological system compensates for the poor availability of kinetic parameters which are necessary for quantitative models. Unfortunately, few tools are available to support rxncon model development, especially for large, intricate systems.ResultsWe present the kboolnet toolkit ( https://github.com/Kufalab-UCSD/kboolnet , complete documentation at https://github.com/Kufalab-UCSD/kboolnet/wiki ), an R package and a set of scripts that seamlessly integrate with the python-based rxncon software and collectively provide a complete workflow for the verification, validation, and visualization of rxncon models. The verification script VerifyModel.R checks for responsiveness to repeated stimulations as well as consistency of steady state behavior. The validation scripts TruthTable.R, SensitivityAnalysis.R, and ScoreNet.R provide various readouts for the comparison of model predictions to experimental data. In particular, ScoreNet.R compares model predictions to a cloud-stored MIDAS-format experimental database to provide a numerical score for tracking model accuracy. Finally, the visualization scripts allow for graphical representations of model topology and behavior. The entire kboolnet toolkit is cloud-enabled, allowing for easy collaborative development; most scripts also allow for the extraction and analysis of individual user-defined "modules".ConclusionThe kboolnet toolkit provides a modular, cloud-enabled workflow for the development of rxncon models, as well as their verification, validation, and visualization. This will enable the creation of larger, more comprehensive, and more rigorous models of cell signaling using the rxncon formalism in the future.

Cytoscape is an open-source bioinformatics environment for the analysis, integration, visualization, and query of biological networks. In this perspective piece, we describe our project to bring the Cytoscape desktop application to the web while explaining our strategy in ways relevant to others in the bioinformatics community. We examine opportunities and challenges in developing bioinformatics software that spans both the desktop and web, and we describe our ongoing efforts to build a Cytoscape web application, highlighting the principles that guide our development.

BackgroundPancreatic adenocarcinoma (PDAC) persists as a malignancy with high morbidity and mortality that can benefit from new means to characterize and detect these tumors, such as radiogenomics. In order to address this gap in the literature, constructed a transcriptomic-CT radiogenomic (RG) map for PDAC.MethodsIn this Institutional Review Board approved study, a cohort of subjects (n = 50) with gene expression profile data paired with histopathologically confirmed resectable or borderline resectable PDAC were identified. Studies with pre-operative contrast-enhanced CT images were independently assessed for a set of 88 predefined imaging features. Microarray gene expression profiling was then carried out on the histopathologically confirmed pancreatic adenocarcinomas and gene networks were constructed using Weighted Gene Correlation Network Analysis (WCGNA) (n = 37). Data were analyzed with bioinformatics analyses, multivariate regression-based methods, and Kaplan-Meier survival analyses.ResultsSurvival analyses identified multiple features of interest that were significantly associated with overall survival, including Tumor Height (P = 0.014), Tumor Contour (P = 0.033), Tumor-stroma Interface (P = 0.014), and the Tumor Enhancement Ratio (P = 0.047). Gene networks for these imaging features were then constructed using WCGNA and further annotated according to the Gene Ontology (GO) annotation framework for a biologically coherent interpretation of the imaging trait-associated gene networks, ultimately resulting in a PDAC RG CT-transcriptome map composed of 3 stage-independent imaging traits enriched in metabolic processes, telomerase activity, and podosome assembly (P

In this white paper, we describe the founding of a new ELIXIR Community - the Systems Biology Community - and its proposed future contributions to both ELIXIR and the broader community of systems biologists in Europe and worldwide. The Community believes that the infrastructure aspects of systems biology - databases, (modelling) tools and standards development, as well as training and access to cloud infrastructure - are not only appropriate components of the ELIXIR infrastructure, but will prove key components of ELIXIR’s future support of advanced biological applications and personalised medicine. By way of a series of meetings, the Community identified seven key areas for its future activities, reflecting both future needs and previous and current activities within ELIXIR Platforms and Communities. These are: overcoming barriers to the wider uptake of systems biology; linking new and existing data to systems biology models; interoperability of systems biology resources; further development and embedding of systems medicine; provisioning of modelling as a service; building and coordinating capacity building and training resources; and supporting industrial embedding of systems biology. A set of objectives for the Community has been identified under four main headline areas: Standardisation and Interoperability, Technology, Capacity Building and Training, and Industrial Embedding. These are grouped into short-term (3-year), mid-term (6-year) and long-term (10-year) objectives.

Introduction: Enteric infections are a major cause of under-5 (age) mortality in low/middle-income countries. Although vaccines against these infections have already been licensed, unwavering efforts are required to boost suboptimalefficacy and effectiveness in regions that are highly endemic to enteric pathogens. The role of baseline immunological profiles in influencing vaccine-induced immune responses is increasingly becoming clearer for several vaccines. Hence, for the development of advanced and region-specific enteric vaccines, insights into differences in immune responses to perturbations in endemic and non-endemic settings become crucial. Materials and methods: For this reason, we employed a two-tiered system and computational pipeline (i) to study the variations in differentially expressed genes (DEGs) associated with immune responses to enteric infections in endemic and non-endemic study groups, and (ii) to derive features (genes) of importance that keenly distinguish between these two groups using unsupervised machine learning algorithms on an aggregated gene expression dataset. The derived genes were further curated using topological analysis of the constructed STRING networks. The findings from these two tiers are validated using multilayer perceptron classifier and were further explored using correlation and regression analysis for the retrieval of associated gene regulatory modules. Results: Our analysis reveals aggressive suppression of GRB-2, an adaptor molecule integral for TCR signaling, as a primary immunomodulatory response against S. typhi infection in endemic settings. Moreover, using retrieved correlation modules and multivariant regression models, we found a positive association between regulators of activated T cells and mediators of Hedgehog signaling in the endemic population, which indicates the initiation of an effector (involving differentiation and homing) rather than an inductive response upon infection. On further exploration, we found STAT3 to be instrumental in designating T-cell functions upon early responses to enteric infections in endemic settings. Conclusion: Overall, through a systems and computational biology approach, we characterized distinct molecular players involved in immune responses to enteric infections in endemic settings in the process, contributing to the mounting evidence of endemicity being a major determiner of pathogen/vaccine-induced immune responses. The gained insights will have important implications in the design and development of region/endemicity-specific vaccines. [ABSTRACT FROM AUTHOR]

Background: Previous pharmacovigilance studies and a retroactive review of cancer clinical trial studies identified that women were more likely to experience drug adverse events (i.e., any unintended effects of medication), and men were more likely to experience adverse events that resulted in hospitalization or death. These sex-biased adverse events (SBAEs) are due to many factors not entirely understood, including differences in body mass, hormones, pharmacokinetics, and liver drug metabolism enzymes and transporters. Methods: We first identified drugs associated with SBAEs from the FDA Adverse Event Reporting System (FAERS) database. Next, we evaluated sex-specific gene expression of the known drug targets and metabolism enzymes for those SBAE-associated drugs. We also constructed sex-specific tissue gene-regulatory networks to determine if these known drug targets and metabolism enzymes from the SBAE-associated drugs had sex-specific gene-regulatory network properties and predicted regulatory relationships. Results: We identified liver-specific gene-regulatory differences for drug metabolism genes between males and females, which could explain observed sex differences in pharmacokinetics and pharmacodynamics. In addition, we found that ~ 85% of SBAE-associated drug targets had sex-biased gene expression or were core genes of sex- and tissue-specific network communities, significantly higher than randomly selected drug targets. Lastly, we provide the sex-biased drug-adverse event pairs, drug targets, and drug metabolism enzymes as a resource for the research community. Conclusions: Overall, we provide evidence that many SBAEs are associated with drug targets and drug metabolism genes that are differentially expressed and regulated between males and females. These SBAE-associated drug metabolism enzymes and drug targets may be useful for future studies seeking to explain or predict SBAEs. [ABSTRACT FROM AUTHOR]

In this white paper, we describe the founding of a new ELIXIR Community - the Systems Biology Community - and its proposed future contributions to both ELIXIR and the broader community of systems biologists in Europe and worldwide. The Community believes that the infrastructure aspects of systems biology - databases, (modelling) tools and standards development, as well as training and access to cloud infrastructure - are not only appropriate components of the ELIXIR infrastructure, but will prove key components of ELIXIR’s future support of advanced biological applications and personalised medicine. By way of a series of meetings, the Community identified seven key areas for its future activities, reflecting both future needs and previous and current activities within ELIXIR Platforms and Communities. These are: overcoming barriers to the wider uptake of systems biology; linking new and existing data to systems biology models; interoperability of systems biology resources; further development and embedding of systems medicine; provisioning of modelling as a service; building and coordinating capacity building and training resources; and supporting industrial embedding of systems biology. A set of objectives for the Community has been identified under four main headline areas: Standardisation and Interoperability, Technology, Capacity Building and Training, and Industrial Embedding. These are grouped into short-term (3-year), mid-term (6-year) and long-term (10-year) objectives.

Background: Understanding how cells and tissues respond to stress factors and perturbations during disease processes is crucial for developing effective prevention, diagnosis, and treatment strategies. Single-cell RNA sequencing (scRNA-seq) enables high-resolution identification of cells and exploration of cell heterogeneity, shedding light on cell differentiation/maturation and functional differences. Recent advancements in multimodal sequencing technologies have focused on improving access to cell-specific subgroups for functional genomics analysis. To facilitate the functional annotation of cell groups and characterization of molecular mechanisms underlying cell trajectories, we introduce the Pathways, Annotated Gene Lists, and Gene Signatures Electronic Repository for Single-Cell Functional Genomics Analysis (PAGER-scFGA).Results: We have developed PAGER-scFGA, which integrates cell functional annotations and gene-set enrichment analysis into popular single-cell analysis pipelines such as Scanpy. Using differentially expressed genes (DEGs) from pairwise cell clusters, PAGER-scFGA infers cell functions through the enrichment of potential cell-marker genesets. Moreover, PAGER-scFGA provides pathways, annotated gene lists, and gene signatures (PAGs) enriched in specific cell subsets with tissue compositions and continuous transitions along cell trajectories. Additionally, PAGER-scFGA enables the construction of a gene subcellular map based on DEGs and allows examination of the gene functional compartments (GFCs) underlying cell maturation/differentiation. In a real-world case study of mouse natural killer (mNK) cells, PAGER-scFGA revealed two major stages of natural killer (NK) cells and three trajectories from the precursor stage to NK T-like mature stage within blood, spleen, and bone marrow tissues. As the trajectories progress to later stages, the DEGs exhibit greater divergence and variability. However, the DEGs in different trajectories still interact within a network during NK cell maturation. Notably, PAGER-scFGA unveiled cell cytotoxicity, exocytosis, and the response to interleukin (IL) signaling pathways and associated network models during the progression from precursor NK cells to mature NK cells.Conclusion: PAGER-scFGA enables in-depth exploration of functional insights and presents a comprehensive knowledge map of gene networks and GFCs, which can be utilized for future studies and hypothesis generation. It is expected to become an indispensable tool for inferring cell functions and detecting molecular mechanisms within cell trajectories in single-cell studies. The web app (accessible at https://au-singlecell.streamlit.app/) is publicly available.

Wolbachia are gram-negative endosymbiotic bacteria residing in the nematode host Brugia malayi that causes lymphatic filariasis in humans. Wolbachia settle in the host environment for their survival, growth and reproduction by maintaining an obligate mutualism relationship. However, the mechanism used by Wolbachia to maintain its mutualistic relationship with the nematode is poorly understood. Therefore, to elucidate the host-pathogen interaction (HPI) mechanism of Wolbachia and Brugia malayi, we used interolog-based approach for identification of host-pathogen protein-protein interactions (HP-PPIs) network and domain-based approach for the validation. The inter-species HP-PPIs network contained 392 proteins (258 Brugia malayi and 134 Wolbachia proteins) connected by 829 edges. Further, based on interolog approach, we identified 24 pathogen (Wolbachia) and 33 host (Brugia malayi) proteins involved in HPI. This study also reported 8 hub genes namely bma-atp-1, Bm1_25145, A0A0K0JKQ9, fusA, bma-eef-2, rplB, Bma-rpl-2, and bma-eftu-2 involved in maintaining an endosymbiotic relationship between Wolbachia and Brugia malayi. Furthermore, we also reported six-pair of host-pathogen interactions containing numerous pairs of shared domains that might be crucial for the establishment of mutualistic relationship between Wolbachia and Brugia malayi. The functional analysis revealed most of the Brugia malayi proteins are involved in the generation of precursor metabolites showing catalytic activity in the intracellular anatomical structures and organelles. The subcellular localization reported host and pathogen proteins were located in mitochondria and cytoplasm respectively. The Brugia malayi pathways involved in HPI were metabolic pathway, oxidative phosphorylation pathway, and spliceosome pathways, indicates that for maintaining mutualism energy-yielding pathways are targeted. Overall, this work provides new insights into the mechanism of HPIs between Wolbachia and Brugia malayi, and will help researchers a deeper understanding of the intracellular pathogenic activity and endosymbiotic relationship of Wolbachia with its host Brugia malayi.

In the post-COVID-19 era, treatment options for potential SARS-CoV-2 outbreaks remain limited. An increased incidence of central nervous system (CNS) disorders has been observed in long-term COVID-19 patients. Understanding the shared molecular mechanisms between these conditions may provide new insights for developing effective therapies. This study developed an integrative drug-repurposing framework for COVID-19, leveraging comorbidity data with CNS disorders, network-based modular analysis, and dynamic perturbation analysis to identify potential drug targets and candidates against SARS-CoV-2. We constructed a comorbidity network based on the literature and data collection, including COVID-19-related proteins and genes associated with Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and autism spectrum disorder. Functional module detection and annotation identified a module primarily involved in protein synthesis as a key target module, utilizing connectivity map drug perturbation data. Through the construction of a weighted drug–target network and dynamic network-based drug-repurposing analysis, ubiquitin–carboxy-terminal hydrolase L1 emerged as a potential drug target. Molecular dynamics simulations suggested pregnenolone and BRD-K87426499 as two drug candidates for COVID-19. This study introduces a dynamic-perturbation-network-based drug-repurposing approach to identify COVID-19 drug targets and candidates by incorporating the comorbidity conditions of CNS disorders.

The Protein Kinase Ontology (ProKinO) is an integrated knowledge graph that conceptualizes the complex relationships among protein kinase sequence, structure, function, and disease in a human and machine-readable format. In this study, we have significantly expanded ProKinO by incorporating additional data on expression patterns and drug interactions. Furthermore, we have developed a completely new browser from the ground up to render the knowledge graph visible and interactive on the web. We have enriched ProKinO with new classes and relationships that capture information on kinase ligand binding sites, expression patterns, and functional features. These additions extend ProKinO's capabilities as a discovery tool, enabling it to uncover novel insights about understudied members of the protein kinase family. We next demonstrate the application of ProKinO. Specifically, through graph mining and aggregate SPARQL queries, we identify the p21-activated protein kinase 5 (PAK5) as one of the most frequently mutated dark kinases in human cancers with abnormal expression in multiple cancers, including a previously unappreciated role in acute myeloid leukemia. We have identified recurrent oncogenic mutations in the PAK5 activation loop predicted to alter substrate binding and phosphorylation. Additionally, we have identified common ligand/drug binding residues in PAK family kinases, underscoring ProKinO's potential application in drug discovery. The updated ontology browser and the addition of a web component, ProtVista, which enables interactive mining of kinase sequence annotations in 3D structures and Alphafold models, provide a valuable resource for the signaling community. The updated ProKinO database is accessible at https://prokino.uga.edu. [ABSTRACT FROM AUTHOR]

Understanding condition-specific biological mechanisms from RNA-seq data requires comprehensive analysis of gene expression data, from the gene to the network level. However, this requires computational expertise, which limits the accessibility of data analysis for understanding biological mechanisms. Therefore, the development of an easy-to-use and comprehensive analysis system is essential. In response to this issue, we present TFNetPropX, a user-friendly web-based platform designed to perform gene-level, gene-set-level, and network-level analysis of RNA-seq data under two different conditions. TFNetPropX performs comprehensive analysis, from DEG analysis to network propagation, to predict TF-affected genes with a single request, and provides users with an interactive web-based visualization of the results. To demonstrate the utility of our system, we performed analysis on two TF knockout RNA-seq datasets and effectively reproduced biologically significant findings. We believe that our system will make it easier for biological researchers to gain insights from different perspectives, allowing them to develop diverse hypotheses and analyses. [ABSTRACT FROM AUTHOR]

The liver, as a crucial metabolic organ, undergoes significant pathological changes during the aging process, which can have a profound impact on overall health. To gain a comprehensive understanding of these alterations, we employed data-driven approaches, along with biochemical methods, histology, and immunohistochemistry techniques, to systematically investigate the effects of aging on the liver. Our study utilized a well-established rat aging model provided by the National Institute of Aging. Systems biology approaches were used to analyze genome-wide transcriptomics data from liver samples obtained from young (4–5 months old) and aging (20–21 months old) Fischer 344 rats. Our findings revealed pathological changes occurring in various essential biological processes in aging livers. These included mitochondrial dysfunction, increased oxidative/nitrative stress, decreased NAD + content, impaired amino acid and protein synthesis, heightened inflammation, disrupted lipid metabolism, enhanced apoptosis, senescence, and fibrosis. These results were validated using independent datasets from both human and rat aging studies. Furthermore, by employing co-expression network analysis, we identified novel driver genes responsible for liver aging, confirmed our findings in human aging subjects, and pointed out the cellular localization of the driver genes using single-cell RNA-sequencing human data. Our study led to the discovery and validation of a liver-specific gene, proprotein convertase subtilisin/kexin type 9 (PCSK9), as a potential therapeutic target for mitigating the pathological processes associated with aging in the liver. This finding envisions new possibilities for developing interventions aimed to improve liver health during the aging process. [ABSTRACT FROM AUTHOR]

IntroductionEnteric infections are a major cause of under-5 (age) mortality in low/middle-income countries. Although vaccines against these infections have already been licensed, unwavering efforts are required to boost suboptimalefficacy and effectiveness in regions that are highly endemic to enteric pathogens. The role of baseline immunological profiles in influencing vaccine-induced immune responses is increasingly becoming clearer for several vaccines. Hence, for the development of advanced and region-specific enteric vaccines, insights into differences in immune responses to perturbations in endemic and non-endemic settings become crucial.Materials and methodsFor this reason, we employed a two-tiered system and computational pipeline (i) to study the variations in differentially expressed genes (DEGs) associated with immune responses to enteric infections in endemic and non-endemic study groups, and (ii) to derive features (genes) of importance that keenly distinguish between these two groups using unsupervised machine learning algorithms on an aggregated gene expression dataset. The derived genes were further curated using topological analysis of the constructed STRING networks. The findings from these two tiers are validated using multilayer perceptron classifier and were further explored using correlation and regression analysis for the retrieval of associated gene regulatory modules.ResultsOur analysis reveals aggressive suppression of GRB-2, an adaptor molecule integral for TCR signaling, as a primary immunomodulatory response against S. typhi infection in endemic settings. Moreover, using retrieved correlation modules and multivariant regression models, we found a positive association between regulators of activated T cells and mediators of Hedgehog signaling in the endemic population, which indicates the initiation of an effector (involving differentiation and homing) rather than an inductive response upon infection. On further exploration, we found STAT3 to be instrumental in designating T-cell functions upon early responses to enteric infections in endemic settings.ConclusionOverall, through a systems and computational biology approach, we characterized distinct molecular players involved in immune responses to enteric infections in endemic settings in the process, contributing to the mounting evidence of endemicity being a major determiner of pathogen/vaccine-induced immune responses. The gained insights will have important implications in the design and development of region/endemicity-specific vaccines.

Although there has been a reduction in head and neck squamous cell carcinoma occurrence, it continues to be a serious global health concern. The lack of precise early diagnostic biomarkers and postponed diagnosis in the later stages are notable constraints that contribute to poor survival rates and emphasize the need for innovative diagnostic methods. In this study, we employed machine learning alongside weighted gene co-expression network analysis (WGCNA) and network biology to investigate the gene expression patterns of blood platelets, identifying transcriptomic markers for HNSCC diagnosis. Our comprehensive examination of publicly available gene expression datasets revealed nine genes with significantly elevated expression in samples from individuals diagnosed with HNSCC. These potential diagnostic markers were further assessed using TCGA and GTEx datasets, demonstrating high accuracy in distinguishing between HNSCC and non-cancerous samples. The findings indicate that these gene signatures could revolutionize early HNSCC identification. Additionally, the study highlights the significance of tumor-educated platelets (TEPs), which carry RNA signatures indicative of tumor-derived material, offering a non-invasive source for early-detection biomarkers. Despite using platelet and tumor samples from different individuals, our results suggest that TEPs reflect the transcriptomic and epigenetic landscape of tumors. Future research should aim to directly correlate tumor and platelet samples from the same patients to further elucidate this relationship. This study underscores the potential of these biomarkers in transforming early diagnosis and personalized treatment strategies for HNSCC, advocating for further research to validate their predictive and therapeutic potential.

NDEx, the Network Data Exchange (https://www.ndexbio.org) is a web-based resource where users can find, store, share and publish network models of any type and size. NDEx is integrated with Cytoscape, the widely used desktop application for network analysis and visualization. NDEx and Cytoscape are the pillars of the Cytoscape Ecosystem, a diverse environment of resources, tools, applications and services for network biology workflows. In this article, we introduce researchers to NDEx and highlight how it can simplify common tasks in network biology workflows as well as streamline publication and access to). Finally, we show how NDEx can be used programmatically via Python with the ndex2 client library, and point readers to additional examples for other popular programming languages such as JavaScript and R. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Getting started with NDEx Basic Protocol 2: Using NDEx and Cytoscape in a publication-oriented workflow Basic Protocol 3: Manipulating networks in NDEx via Python.

Technological advances in high-throughput techniques have resulted in tremendous growth of complex biological datasets providing evidence regarding various biomolecular interactions. To cope with this data flood, computational approaches, web services, and databases have been implemented to deal with issues such as data integration, visualization, exploration, organization, scalability, and complexity. Nevertheless, as the number of such sets increases, it is becoming more and more difficult for an end user to know what the scope and focus of each repository is and how redundant the information between them is. Several repositories have a more general scope, while others focus on specialized aspects, such as specific organisms or biological systems. Unfortunately, many of these databases are self-contained or poorly documented and maintained. For a clearer view, in this article we provide a comprehensive categorization, comparison and evaluation of such repositories for different bioentity interaction types. We discuss most of the publicly available services based on their content, sources of information, data representation methods, user-friendliness, scope and interconnectivity, and we comment on their strengths and weaknesses. We aim for this review to reach a broad readership varying from biomedical beginners to experts and serve as a reference article in the field of Network Biology.

Abstract Background Computational models of cell signaling networks are extremely useful tools for the exploration of underlying system behavior and prediction of response to various perturbations. By representing signaling cascades as executable Boolean networks, the previously developed rxncon (“reaction-contingency”) formalism and associated Python package enable accurate and scalable modeling of signal transduction even in large (thousands of components) biological systems. The models are split into reactions, which generate states, and contingencies, that impinge on reactions; this avoids the so-called “combinatorial explosion” of system size. Boolean description of the biological system compensates for the poor availability of kinetic parameters which are necessary for quantitative models. Unfortunately, few tools are available to support rxncon model development, especially for large, intricate systems. Results We present the kboolnet toolkit ( https://github.com/Kufalab-UCSD/kboolnet , complete documentation at https://github.com/Kufalab-UCSD/kboolnet/wiki ), an R package and a set of scripts that seamlessly integrate with the python-based rxncon software and collectively provide a complete workflow for the verification, validation, and visualization of rxncon models. The verification script VerifyModel.R checks for responsiveness to repeated stimulations as well as consistency of steady state behavior. The validation scripts TruthTable.R, SensitivityAnalysis.R, and ScoreNet.R provide various readouts for the comparison of model predictions to experimental data. In particular, ScoreNet.R compares model predictions to a cloud-stored MIDAS-format experimental database to provide a numerical score for tracking model accuracy. Finally, the visualization scripts allow for graphical representations of model topology and behavior. The entire kboolnet toolkit is cloud-enabled, allowing for easy collaborative development; most scripts also allow for the extraction and analysis of individual user-defined “modules”. Conclusion The kboolnet toolkit provides a modular, cloud-enabled workflow for the development of rxncon models, as well as their verification, validation, and visualization. This will enable the creation of larger, more comprehensive, and more rigorous models of cell signaling using the rxncon formalism in the future.

Abstract Background Elucidating compound mechanism of action (MoA) is beneficial to drug discovery, but in practice often represents a significant challenge. Causal Reasoning approaches aim to address this situation by inferring dysregulated signalling proteins using transcriptomics data and biological networks; however, a comprehensive benchmarking of such approaches has not yet been reported. Here we benchmarked four causal reasoning algorithms (SigNet, CausalR, CausalR ScanR and CARNIVAL) with four networks (the smaller Omnipath network vs. 3 larger MetaBase™ networks), using LINCS L1000 and CMap microarray data, and assessed to what extent each factor dictated the successful recovery of direct targets and compound-associated signalling pathways in a benchmark dataset comprising 269 compounds. We additionally examined impact on performance in terms of the functions and roles of protein targets and their connectivity bias in the prior knowledge networks. Results According to statistical analysis (negative binomial model), the combination of algorithm and network most significantly dictated the performance of causal reasoning algorithms, with the SigNet recovering the greatest number of direct targets. With respect to the recovery of signalling pathways, CARNIVAL with the Omnipath network was able to recover the most informative pathways containing compound targets, based on the Reactome pathway hierarchy. Additionally, CARNIVAL, SigNet and CausalR ScanR all outperformed baseline gene expression pathway enrichment results. We found no significant difference in performance between L1000 data or microarray data, even when limited to just 978 ‘landmark’ genes. Notably, all causal reasoning algorithms also outperformed pathway recovery based on input DEGs, despite these often being used for pathway enrichment. Causal reasoning methods performance was somewhat correlated with connectivity and biological role of the targets. Conclusions Overall, we conclude that causal reasoning performs well at recovering signalling proteins related to compound MoA upstream from gene expression changes by leveraging prior knowledge networks, and that the choice of network and algorithm has a profound impact on the performance of causal reasoning algorithms. Based on the analyses presented here this is true for both microarray-based gene expression data as well as those based on the L1000 platform.

Background: Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS) share phenotypic and molecular commonalities, including the fact that they can be caused by mutations in ubiquitous proteins involved in RNA metabolism, namely SMN, TDP-43 and FUS. Although this suggests the existence of common disease mechanisms, there is currently no model to explain the resulting motor neuron dysfunction. In this work we generated a parallel set of Drosophila models for adult-onset RNAi and tagged neuronal expression of the fly orthologues of the three human proteins, named Smn, TBPH and Caz, respectively. We profiled nuclear and cytoplasmic bound mRNAs using a RIP-seq approach and characterized the transcriptome of the RNAi models by RNA-seq. To unravel the mechanisms underlying the common functional impact of these proteins on neuronal cells, we devised a computational approach based on the construction of a tissue-specific library of protein functional modules, selected by an overall impact score measuring the estimated extent of perturbation caused by each gene knockdown. Results: Transcriptome analysis revealed that the three proteins do not bind to the same RNA molecules and that only a limited set of functionally unrelated transcripts is commonly affected by their knock-down. However, through our integrative approach we were able to identify a concerted effect on protein functional modules, albeit acting through distinct targets. Most strikingly, functional annotation revealed that these modules are involved in critical cellular pathways for motor neurons, including neuromuscular junction function. Furthermore, selected modules were found to be significantly enriched in orthologues of human neuronal disease genes. Conclusions: The results presented here show that SMA and ALS disease-associated genes linked to RNA metabolism functionally converge on neuronal protein complexes, providing a new hypothesis to explain the common motor neuron phenotype. The functional modules identified represent promising biomarkers and therapeutic targets, namely given their alteration in asymptomatic settings. [ABSTRACT FROM AUTHOR]

The rising issues of herpes simplex virus (HSV)-2 drug ramifications have encouraged the researchers to look for new and alternative approaches that pose minimum adversities in the host while efficiently reducing the HSV-2 infection. Although microRNAs (miRNAs), as unorthodox approaches, are gaining popularity due to eliciting highly reduced immunogenic reactions, their implications in HSV-2 research have been rarely explored. In this study, a pool of cellular miRNAs with significance in HSV-2-induced inflammatory and immune responses have been identified. Computationally recognizing the host targets of these miRNAs through network biology and machine learning, in vitro validation has been addressed along with the identification of their regulation in the HSV-2 infection. To signify the role of these identified miRNAs, they have been individually ectopically expressed in macrophages. The ectopic expression of the individual miRNAs was able to suppress HSV-2 viral gene expression. Taking a step forward, this study also highlights the Box–Behnken design-based combinatorial effect of ectopically expressed miRNAs on maximum suppression of HSV-2 infectivity. Therefore, the concentrations of each of the miRNAs optimized in a combination, predicted through expert systems biology tools were validated in vitro to not only recover the target expressions but also inhibit the HSV-2 infection in the macrophages. Overall, the study offers miRNAs as intriguing alternatives to commercially available medications against HSV-2. Moreover, the study illuminates the prophylactic potentiality of the miRNAs, which is significant since there are currently no vaccines available for HSV-2. Moving forward, the miRNAs are employed in an innovative strategy that incorporates intricate biological system models and in vitro confirmation methods to deliver a prospective combinatorial miRNA therapeutic against HSV-2 infection. [ABSTRACT FROM AUTHOR]

Simple Summary: This study focused on identifying cancer type-specific genes, which are crucial for improving the detection, diagnosis, and treatment of various types of cancer. We used a network biology framework to explore the expression of transcription factors in different types of cancer. By comparing gene networks in normal cells with those in cancer cells, we were able to identify cancer type-specific genes. This offers a resource for understanding transcriptional networks across various cancer types. Identifying cancer type-specific genes that define cell states is important to develop effective therapies for patients and methods for detection, early diagnosis, and prevention. While molecular mechanisms that drive malignancy have been identified for various cancers, the identification of cell-type defining transcription factors (TFs) that distinguish normal cells from cancer cells has not been fully elucidated. Here, we utilized a network biology framework, which assesses the fidelity of cell fate conversions, to identify cancer type-specific gene regulatory networks (GRN) for 17 types of cancer. Through an integrative analysis of a compendium of expression data, we elucidated core TFs and GRNs for multiple cancer types. Moreover, by comparing normal tissues and cells to cancer type-specific GRNs, we found that the expression of key network-influencing TFs can be utilized as a survival prognostic indicator for a diverse cohort of cancer patients. These findings offer a valuable resource for exploring cancer type-specific networks across a broad range of cancer types. [ABSTRACT FROM AUTHOR]

Breast cancer is a complex disease that is influenced by the concurrent influence of multiple genetic and environmental factors. Recent advances in genomics and other high throughput biomolecular techniques (-omics) have provided numerous insights into the molecular mechanisms underlying breast cancer development and progression. A number of these mechanisms involve multiple layers of regulation. In this review, we summarize the current knowledge on the role of multiple omics in the regulation of breast cancer, including the effects of DNA methylation, non-coding RNA, and other epigenomic changes. We comment on how integrating such diverse mechanisms is envisioned as key to a more comprehensive understanding of breast carcinogenesis and cancer biology with relevance to prognostics, diagnostics and therapeutics. We also discuss the potential clinical implications of these findings and highlight areas for future research. Overall, our understanding of the molecular mechanisms of multi-omic regulation in breast cancer is rapidly increasing and has the potential to inform the development of novel therapeutic approaches for this disease. [ABSTRACT FROM AUTHOR]

Biological entities are involved in complicated and complex connections; hence, discovering biological information using network biology ideas is critical. In the past few years, network biology has emerged as an integrative and systems-level approach for understanding and interpreting these complex interactions. Biological network analysis is one method for reducing enormous data sets to clinically useful knowledge for disease diagnosis, prognosis, and treatment. The network of biological entities can help us predict drug targets for several diseases. The drug targets identified through the systems biology approach help in targeting the essential biological pathways that contribute to the progression and development of the disease. The novel strategical approach of system biology-assisted pharmacology coupled with computer-aided drug discovery (CADD) can help drugs fight multifactorial diseases efficiently. In the present review, we have summarized the role and application of network biology for not only unfolding the mechanism of complex neurodevelopmental disorders but also identifying important drug targets for diseases like ADHD, Autism, Epilepsy, and Intellectual Disability. Systems biology has emerged as a promising approach to identifying drug targets and aiming for targeted drug discovery for the precise treatment of neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

Organophosphate pesticides (OPs) are toxic substances that contaminate aquatic environments, interfere with the development of the nervous system, and induce Neurodevelopmental Toxicity (NDT) in animals and humans. The canonical mechanism of OP neurotoxicity involves the inhibition of acetylcholinesterase (AChE), but other mechanisms non-AChE are also involved and not fully understood. We used network toxicology and molecular docking to identify molecular targets and toxicity mechanisms common to OPs. Targets related to diazinon-oxon, chlorpyrifos oxon, and paraoxon OPs were predicted using the Swiss Target Prediction and PharmMapper databases. Targets related to NDT were compiled from GeneCards and OMIM databases. In order to construct the protein–protein interaction (PPI) network, the common targets between OPs and NDT were imported into the STRING. Network topological analyses identified EGFR, MET, HSP90AA1, and SRC as hub nodes common to the three OPs. Using the Reactome pathway and gene ontology, we found that signal transduction, axon guidance, cellular responses to stress, and glutamatergic signaling activation play key roles in OP-induced NDT. [ABSTRACT FROM AUTHOR]

Introduction: Network-based methods are promising approaches in systems toxicology because they can be used to predict the effects of drugs and chemicals on health, to elucidate the mode of action of compounds, and to identify biomarkers of toxicity. Over the years, the network biology community has developed a wide range of methods, and users are faced with the task of choosing the most appropriate method for their own application. Furthermore, the advantages and limitations of each method are difficult to determine without a proper standard and comparative evaluation of their performance. This study aims to evaluate different network-based methods that can be used to gain biological insight into the mechanisms of drug toxicity, using valproic acid (VPA)-induced liver steatosis as a benchmark. Methods: We provide a comprehensive analysis of the results produced by each method and highlight the fact that the experimental design (how the method is applied) is relevant in addition to the method specifications. We also contribute with a systematic methodology to analyse the results of the methods individually and in a comparative manner. Results: Our results show that the evaluated tools differ in their performance against the benchmark and in their ability to provide novel insights into the mechanism of adverse effects of the drug. We also suggest that aggregation of the results provided by different methods provides a more confident set of candidate genes and processes to further the knowledge of the drug's mechanism of action. Discussion: By providing a detailed and systematic analysis of the results of different network-based tools, we aim to assist users in making informed decisions about the most appropriate method for systems toxicology applications. [ABSTRACT FROM AUTHOR]

The development of tools for the annotation of genes from newly sequenced species has not evolved much from homologous alignment to prior annotated species. While the quality of gene annotations continues to decline as we sequence and assemble more evolutionary distant gut microbiome species, machine learning presents a high quality alternative to traditional techniques. In this study, we investigate the relative performance of common classical and nonclassical machine learning algorithms in the problem of gene annotation using human microbiome-associated species genes from the KEGG database. The majority of the ensemble, clustering, and deep learning algorithms that we investigated showed higher prediction accuracy than CD-Hit in predicting partial KEGG function. Motif-based, machine-learning methods of annotation in new species were faster and had higher precision–recall than methods of homologous alignment or orthologous gene clustering. Gradient boosted ensemble methods and neural networks also predicted higher connectivity in reconstructed KEGG pathways, finding twice as many new pathway interactions than blast alignment. The use of motif-based, machine-learning algorithms in annotation software will allow researchers to develop powerful tools to interact with bacterial microbiomes in ways previously unachievable through homologous sequence alignment alone. [ABSTRACT FROM AUTHOR]

Technological advancement, data democratisation, and decreasing costs have led to a revolution in molecular biology in which the entire set of DNA, RNA, proteins, and various other molecules – the 'multi-omic' profile – can be measured in humans. Sequencing 1 million bases of human DNA now costs US$0.01, and emerging technologies soon promise to reduce the cost of sequencing the whole genome to US$100. These trends have made it feasible to sample the multi-omic profile of millions of people, much of which is publicly available for medical research. Can anaesthesiologists use these data to improve patient care? This narrative review brings together a rapidly growing literature in multi-omic profiling across numerous fields that points to the future of precision anaesthesiology. Here, we discuss how DNA, RNA, proteins, and other molecules interact in molecular networks that can be used for preoperative risk stratification, intraoperative optimisation, and postoperative monitoring. This literature provides evidence for four fundamental insights: (1) Clinically similar patients have different molecular profiles and, as a consequence, different outcomes. (2) Vast, publicly available, and rapidly growing molecular datasets have been generated in chronic disease patients and can be repurposed to estimate perioperative risk. (3) Multi-omic networks are altered in the perioperative period and influence postoperative outcomes. (4) Multi-omic networks can serve as empirical, molecular measurements of a successful postoperative course. With this burgeoning universe of molecular data, the anaesthesiologist-of-the-future will tailor their clinical management to an individual's multi-omic profile to optimise postoperative outcomes and long-term health. [ABSTRACT FROM AUTHOR]

Biological systems are by nature multiscale, consisting of subsystems that factor into progressively smaller units in a deeply hierarchical structure. At any level of the hierarchy, an ever-increasing diversity of technologies can be applied to characterize the corresponding biological units and their relations, resulting in large networks of physical or functional proximities-e.g., proximities of amino acids within a protein, of proteins within a complex, or of cell types within a tissue. Here, we review general concepts and progress in using network proximity measures as a basis for creation of multiscale hierarchical maps of biological systems. We discuss the functionalization of these maps to create predictive models, including those useful in translation of genotype to phenotype, along with strategies for model visualization and challenges faced by multiscale modeling in the near future. Collectively, these approaches enable a unified hierarchical approach to biological data, with application from the molecular to the macroscopic.

Single-cell RNA-sequencing (scRNA-seq) has revolutionized molecular biology and medicine by enabling high-throughput studies of cellular heterogeneity in diverse tissues. Applying network biology approaches to scRNA-seq data can provide useful insights into genes driving heterogeneous cell-type compositions of tissues. Here, we present scNetViz-  a Cytoscape app to aid biological interpretation of cell clusters in scRNA-seq data using network analysis. scNetViz calculates the differential expression of each gene across clusters and then creates a cluster-specific gene functional interaction network between the significantly differentially expressed genes for further analysis, such as pathway enrichment analysis. To automate a complete data analysis workflow, scNetViz integrates parts of the Scanpy software, which is a popular Python package for scRNA-seq data analysis, with Cytoscape apps such as stringApp, cyPlot, and enhancedGraphics. We describe our implementation of methods for accessing data from public single cell atlas projects, differential expression analysis, visualization, and automation. scNetViz enables users to analyze data from public atlases or their own experiments, which we illustrate with two use cases. Analysis can be performed via the Cytoscape GUI or CyREST programming interface using R (RCy3) or Python (py4cytoscape).

Abstract Background A key histopathological hallmark of Alzheimer’s disease (AD) is the presence of neurofibrillary tangles of aggregated microtubule-associated protein tau in neurons. Anle138b is a small molecule which has previously shown efficacy in mice in reducing tau aggregates and rescuing AD disease phenotypes. Methods In this work, we employed bioinformatics analysis—including pathway enrichment and causal reasoning—of an in vitro tauopathy model. The model consisted of cultured rat cortical neurons either unseeded or seeded with tau aggregates derived from human AD patients, both of which were treated with Anle138b to generate hypotheses for its mode of action. In parallel, we used a collection of human target prediction models to predict direct targets of Anle138b based on its chemical structure. Results Combining the different approaches, we found evidence supporting the hypothesis that the action of Anle138b involves several processes which are key to AD progression, including cholesterol homeostasis and neuroinflammation. On the pathway level, we found significantly enriched pathways related to these two processes including those entitled “Superpathway of cholesterol biosynthesis” and “Granulocyte adhesion and diapedesis”. With causal reasoning, we inferred differential activity of SREBF1/2 (involved in cholesterol regulation) and mediators of the inflammatory response such as NFKB1 and RELA. Notably, our findings were also observed in Anle138b-treated unseeded neurons, meaning that the inferred processes are independent of tau pathology and thus represent the direct action of the compound in the cellular system. Through structure-based ligand-target prediction, we predicted the intracellular cholesterol carrier NPC1 as well as NF-κB subunits as potential targets of Anle138b, with structurally similar compounds in the model training set known to target the same proteins. Conclusions This study has generated feasible hypotheses for the potential mechanism of action of Anle138b, which will enable the development of future molecular interventions aiming to reduce tau pathology in AD patients.

Abstract Inference and analysis of gene regulatory networks (GRNs) require software that integrates multi-omic data from various sources. The Network Zoo (netZoo; netzoo.github.io) is a collection of open-source methods to infer GRNs, conduct differential network analyses, estimate community structure, and explore the transitions between biological states. The netZoo builds on our ongoing development of network methods, harmonizing the implementations in various computing languages and between methods to allow better integration of these tools into analytical pipelines. We demonstrate the utility using multi-omic data from the Cancer Cell Line Encyclopedia. We will continue to expand the netZoo to incorporate additional methods.

Abstract Background Pancreatic adenocarcinoma (PDAC) persists as a malignancy with high morbidity and mortality that can benefit from new means to characterize and detect these tumors, such as radiogenomics. In order to address this gap in the literature, constructed a transcriptomic-CT radiogenomic (RG) map for PDAC. Methods In this Institutional Review Board approved study, a cohort of subjects (n = 50) with gene expression profile data paired with histopathologically confirmed resectable or borderline resectable PDAC were identified. Studies with pre-operative contrast–enhanced CT images were independently assessed for a set of 88 predefined imaging features. Microarray gene expression profiling was then carried out on the histopathologically confirmed pancreatic adenocarcinomas and gene networks were constructed using Weighted Gene Correlation Network Analysis (WCGNA) (n = 37). Data were analyzed with bioinformatics analyses, multivariate regression-based methods, and Kaplan-Meier survival analyses. Results Survival analyses identified multiple features of interest that were significantly associated with overall survival, including Tumor Height (P = 0.014), Tumor Contour (P = 0.033), Tumor-stroma Interface (P = 0.014), and the Tumor Enhancement Ratio (P = 0.047). Gene networks for these imaging features were then constructed using WCGNA and further annotated according to the Gene Ontology (GO) annotation framework for a biologically coherent interpretation of the imaging trait-associated gene networks, ultimately resulting in a PDAC RG CT-transcriptome map composed of 3 stage-independent imaging traits enriched in metabolic processes, telomerase activity, and podosome assembly (P

The advent of global phosphoproteome profiling has led to wide phosphosite coverage and therefore the opportunity to predict kinase-substrate associations from these datasets. However, the regulatory kinase is unknown for most substrates, due to biased and incomplete database annotations. In this study we compare the performance of six pairwise measures to predict kinase-substrate associations using a data driven approach on publicly available time resolved and perturbation mass spectrometry-based phosphoproteome data. First, we validated the performance of these measures using as a reference both a literature-based phosphosite-specific protein interaction network and a predicted kinase–substrate (KS) interactions set. The overall performance in predicting kinase-substrate associations using pairwise measures across both these reference sets was poor. To expand into the wider interactome space, we applied the approach on a network comprising pairs of substrates regulated by the same kinase (substrate-substrate associations) but found the performance to be equally poor. However, the addition of a sequence similarity filter for substrate–substrate associations led to a significant boost in performance. Our findings imply that the use of a filter to reduce the search space, such as a sequence similarity filter, can be used prior to the application of network inference methods to reduce noise and boost the signal. We also find that the current gold standard for reference sets is not adequate for evaluation as it is limited and context-agnostic. Therefore, there is a need for additional evaluation methods that have increased coverage and take into consideration the context-specific nature of kinase–substrate associations.

Background: A common task in molecular network analysis is the detection of community structures or modules. Such modules are frequently associated with shared biological functions and are often disrupted in disease. Detection of community structure entails clustering nodes in the graph, and many algorithms apply a clustering algorithm on an input node embedding. Graph representation learning offers a powerful framework to learn node embeddings to perform various downstream tasks such as clustering. Deep embedding methods based on graph neural networks can have substantially better performance on machine learning tasks on graphs, including module detection; however, existing studies have focused on social and citation networks. It is currently unclear if deep embedding methods offer any advantage over shallow embedding methods for detecting modules in molecular networks. Methods: Here, we investigated deep and shallow graph representation learning algorithms on synthetic and real cell-type specific gene interaction networks to detect gene modules and identify pathways affected by sequence nucleotide polymorphisms. We used multiple criteria to assess the quality of the clusters based on connectivity as well as overrepresentation of biological processes. Results: On synthetic networks, deep embedding based on a variational graph autoencoder had superior performance as measured by modularity metrics, followed closely by shallow methods, node2vec and Graph Laplacian embedding. However, the performance of the deep methods worsens when the overall connectivity between clusters increases. On real molecular networks, deep embedding methods did not have a clear advantage and the performance depended upon the properties of the graph and the metrics. Conclusions: Deep graph representation learning algorithms for module detection-based tasks can be beneficial for some biological networks, but the performance depends upon the metrics and graph properties. Across different network types, Graph Laplacian embedding followed by node2vec are the best performing algorithms.

Phenotypic heterogeneity in cancer is often caused by different patterns of genetic alterations. Understanding such phenotype-genotype relationships is fundamental for the advance of personalized medicine. We develop a computational method, named NETPHIX (NETwork-to-PHenotype association with eXclusivity) to identify subnetworks of genes whose genetic alterations are associated with drug response or other continuous cancer phenotypes. Leveraging interaction information among genes and properties of cancer mutations such as mutual exclusivity, we formulate the problem as an integer linear program and solve it optimally to obtain a subnetwork of associated genes. Applied to a large-scale drug screening dataset, NETPHIX uncovered gene modules significantly associated with drug responses. Utilizing interaction information, NETPHIX modules are functionally coherent and can thus provide important insights into drug action. In addition, we show that modules identified by NETPHIX together with their association patterns can be leveraged to suggest drug combinations.

Breast cancer is a complex disease that is influenced by the concurrent influence of multiple genetic and environmental factors. Recent advances in genomics and other high throughput biomolecular techniques (-omics) have provided numerous insights into the molecular mechanisms underlying breast cancer development and progression. A number of these mechanisms involve multiple layers of regulation. In this review, we summarize the current knowledge on the role of multiple omics in the regulation of breast cancer, including the effects of DNA methylation, non-coding RNA, and other epigenomic changes. We comment on how integrating such diverse mechanisms is envisioned as key to a more comprehensive understanding of breast carcinogenesis and cancer biology with relevance to prognostics, diagnostics and therapeutics. We also discuss the potential clinical implications of these findings and highlight areas for future research. Overall, our understanding of the molecular mechanisms of multi-omic regulation in breast cancer is rapidly increasing and has the potential to inform the development of novel therapeutic approaches for this disease.

Introduction: Network-based methods are promising approaches in systems toxicology because they can be used to predict the effects of drugs and chemicals on health, to elucidate the mode of action of compounds, and to identify biomarkers of toxicity. Over the years, the network biology community has developed a wide range of methods, and users are faced with the task of choosing the most appropriate method for their own application. Furthermore, the advantages and limitations of each method are difficult to determine without a proper standard and comparative evaluation of their performance. This study aims to evaluate different network-based methods that can be used to gain biological insight into the mechanisms of drug toxicity, using valproic acid (VPA)-induced liver steatosis as a benchmark.Methods: We provide a comprehensive analysis of the results produced by each method and highlight the fact that the experimental design (how the method is applied) is relevant in addition to the method specifications. We also contribute with a systematic methodology to analyse the results of the methods individually and in a comparative manner.Results: Our results show that the evaluated tools differ in their performance against the benchmark and in their ability to provide novel insights into the mechanism of adverse effects of the drug. We also suggest that aggregation of the results provided by different methods provides a more confident set of candidate genes and processes to further the knowledge of the drug’s mechanism of action.Discussion: By providing a detailed and systematic analysis of the results of different network-based tools, we aim to assist users in making informed decisions about the most appropriate method for systems toxicology applications.

Pulmonary fibrosis (PF) is a heterogeneous disease with a poor prognosis. Therefore, identifying additional therapeutic modalities is required to improve outcome. However, the lack of biomarkers of disease progression hampers the preclinical to clinical translational process. Here, this work assesses and identifies progressive alterations in pulmonary function, transcriptomics, and metabolomics in the mouse lung at 7, 14, 21, and 28 days after a single dose of oropharyngeal bleomycin. By integrating multi‐omics data, this work identifies two central gene subnetworks associated with multiple critical pathological changes in transcriptomics and metabolomics as well as pulmonary function. This work presents a multi‐omics‐based framework to establish a translational link between the bleomycin‐induced PF model in mice and human idiopathic pulmonary fibrosis to identify druggable targets and test therapeutic candidates. This work also indicates peripheral cannabinoid receptor 1 (CB1R) antagonism as a rational therapeutic target for clinical translation in PF. Mouse Lung Fibrosis Atlas can be accessed freely at https://niaaa.nih.gov/mouselungfibrosisatlas. [ABSTRACT FROM AUTHOR]