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Spinal Muscular Atrophy is caused by partial loss of survival of motoneuron (SMN) protein expression. The numerous interaction partners and mechanisms influenced by SMN loss result in a complex disease. Current treatments restore SMN protein levels to a certain extent, but do not cure all symptoms. The prolonged survival of patients creates an increasing need for a better understanding of SMA. Although many SMN-protein interactions, dysregulated pathways, and organ phenotypes are known, the connections among them remain largely unexplored. Monogenic diseases are ideal examples for the exploration of cause-and-effect relationships to create a network describing the disease-context. Machine learning tools can utilize such knowledge to analyze similarities between disease-relevant molecules and molecules not described in the disease so far. We used an artificial intelligence-based algorithm to predict new genes of interest. The transcriptional regulation of 8 out of 13 molecules selected from the predicted set were successfully validated in an SMA mouse model. This bioinformatic approach, using the given experimental knowledge for relevance predictions, enhances efficient targeted research in SMA and potentially in other disease settings., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

To better understand the potential of drug repurposing in COVID-19, we analyzed control strategies over essential host factors for SARS-CoV-2 infection. We constructed comprehensive directed protein-protein interaction (PPI) networks integrating the top-ranked host factors, the drug target proteins and directed PPI data. We analyzed the networks to identify drug targets and combinations thereof that offer efficient control over the host factors. We validated our findings against clinical studies data and bioinformatics studies. Our method offers a new insight into the molecular details of the disease and into potentially new therapy targets for it. Our approach for drug repurposing is significant beyond COVID-19 and may be applied also to other diseases., (© The Author(s) 2021. Published by Oxford University Press.)

The complex web of macromolecular interactions occurring within cells-the interactome-is the backbone of an increasing number of studies, but a clear consensus on the exact structure of this network is still lacking. Different genome-scale maps of human interactome have been obtained through several experimental techniques and functional analyses. Moreover, these maps can be enriched through literature-mining approaches, and different combinations of various 'source' databases have been used in the literature. It is therefore unclear to which extent the various interactomes yield similar results when used in the context of interactome-based approaches in network biology. We compared a comprehensive list of human interactomes on the basis of topology, protein complexes, molecular pathways, pathway cross-talk and disease gene prediction. In a general context of relevant heterogeneity, our study provides a series of qualitative and quantitative parameters that describe the state of the art of human interactomes and guidelines for selecting interactomes in future applications., (© The Author(s) 2021. Published by Oxford University Press.)

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., (© 2021 The Authors. Current Protocols published by Wiley Periodicals LLC.)

The human genetic dissection of clinical phenotypes is complicated by genetic heterogeneity. Gene burden approaches that detect genetic signals in case-control studies are underpowered in genetically heterogeneous cohorts. We therefore developed a genome-wide computational method, network-based heterogeneity clustering (NHC), to detect physiological homogeneity in the midst of genetic heterogeneity. Simulation studies showed our method to be capable of systematically converging genes in biological proximity on the background biological interaction network, and capturing gene clusters harboring presumably deleterious variants, in an efficient and unbiased manner. We applied NHC to whole-exome sequencing data from a cohort of 122 individuals with herpes simplex encephalitis (HSE), including 13 individuals with previously published monogenic inborn errors of TLR3-dependent IFN-α/β immunity. The top gene cluster identified by our approach successfully detected and prioritized all causal variants of five TLR3 pathway genes in the 13 previously reported individuals. This approach also suggested candidate variants of three reported genes and four candidate genes from the same pathway in another ten previously unstudied individuals. TLR3 responsiveness was impaired in dermal fibroblasts from four of the five individuals tested, suggesting that the variants detected were causal for HSE. NHC is, therefore, an effective and unbiased approach for unraveling genetic heterogeneity by detecting physiological homogeneity., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Background: The explosive growth of genomic, chemical, and pathological data provides new opportunities and challenges for humans to thoroughly understand life activities in cells. However, there exist few computational models that aggregate various bioentities to comprehensively reveal the physical and functional landscape of biological systems., Results: We constructed a molecular association network, which contains 18 edges (relationships) between 8 nodes (bioentities). Based on this, we propose Bioentity2vec, a new method for representing bioentities, which integrates information about the attributes and behaviors of a bioentity. Applying the random forest classifier, we achieved promising performance on 18 relationships, with an area under the curve of 0.9608 and an area under the precision-recall curve of 0.9572., Conclusions: Our study shows that constructing a network with rich topological and biological information is important for systematic understanding of the biological landscape at the molecular level. Our results show that Bioentity2vec can effectively represent biological entities and provides easily distinguishable information about classification tasks. Our method is also able to simultaneously predict relationships between single types and multiple types, which will accelerate progress in biological experimental research and industrial product development., (© The Author(s) 2020. Published by Oxford University Press.)

Understanding disease comorbidity contributes to improved quality of life in patients who are suffering from multiple diseases. Therefore, to better explore comorbid diseases, the clarification of associations between diseases based on biological functions is essential. In our study, we propose a method for identifying disease comorbidity in a module-based network, named the module-module interaction (MMI) network, which represents how biological functions influence each other. To construct the MMI network, we detected gene modules - sets of genes that have a higher probability of taking part in specific functions - and established a link between these modules. Subsequently, we constructed disease-related networks in the MMI network to understand inherent disease mechanisms and calculated comorbidity scores of disease pairs using Gene Ontology (GO) terms. Our results show that we can obtain further information on disease mechanisms by considering interactions between functional modules instead of between genes. In addition, we verified that predicted comorbid relationships of disease pairs based on the MMI network are more significant than those based on the protein-protein interaction (PPI) network. This study can be useful to elucidate the mechanisms underlying comorbidities for further study, which will provide a broader insight into the pathogenesis of diseases.

Cytoscape is an open-source software used to analyze and visualize biological networks. In addition to being able to import networks from a variety of sources, Cytoscape allows users to import tabular node data and visualize it onto networks. Unfortunately, such data tables can only contain one row of data per node, whereas omics data often have multiple rows for the same gene or protein, representing different post-translational modification sites, peptides, splice isoforms, or conditions. Here, we present a new app, Omics Visualizer, that allows users to import data tables with several rows referring to the same node, connect them to one or more networks, and visualize the connected data onto networks. Omics Visualizer uses the Cytoscape enhancedGraphics app to show the data either in the nodes (pie visualization) or around the nodes (donut visualization), where the colors of the slices represent the imported values. If the user does not provide a network, the app can retrieve one from the STRING database using the Cytoscape stringApp. The Omics Visualizer app is freely available at https://apps.cytoscape.org/apps/omicsvisualizer., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Legeay M et al.)

The human interactome is instrumental in the systems-level study of the cell and the contextualization of disease-associated gene perturbations. However, reference organismal interactomes do not capture the cell-type-specific context in which proteins and modules preferentially act. Here, we introduce SCINET, a computational framework that reconstructs an ensemble of cell-type-specific interactomes by integrating a global, context-independent reference interactome with a single-cell gene-expression profile. SCINET addresses technical challenges of single-cell data by robustly imputing, transforming, and normalizing the initially noisy and sparse expression of data. Inferred cell-level gene interaction probabilities and group-level interaction strengths define cell-type-specific interactomes. We use SCINET to reconstruct and analyze interactomes of the major human brain and immune cell types, revealing specificity and modularity of perturbations associated with neurodegenerative, neuropsychiatric, and autoimmune disorders. We report cell-type interactomes for brain and immune cell types, together with the SCINET package., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

One key issue in the post-genomic era is how to systematically describe the associations between small molecule transcripts or translations inside cells. With the rapid development of high-throughput "omics" technologies, the achieved ability to detect and characterize molecules with other molecule targets opens the possibility of investigating the relationships between different molecules from a global perspective. In this article, a molecular association network (MAN) is constructed and comprehensively analyzed by integrating the associations among miRNA, lncRNA, protein, drug, and disease, in which any kind of potential associations can be predicted. More specifically, each node in MAN can be represented as a vector by combining two kinds of information including the attribute of the node itself (e.g., sequences of ncRNAs and proteins, semantics of diseases and molecular fingerprints of drugs) and the behavior of the node in the complex network (associations with other nodes). A random forest classifier is trained to classify and predict new interactions or associations between biomolecules. In the experiment, the proposed method achieved a superb performance with an area under curve (AUC) of 0.9735 under a five-fold cross-validation, which showed that the proposed method could provide new insight for exploration of the molecular mechanisms of disease and valuable clues for disease treatment., Competing Interests: The authors declare no conflict of interest.

Identification of effective drug combinations for patients is an expensive and time-consuming procedure, especially for in vitro experiments. To accelerate the synergistic drug discovery process, we present a new classification model to identify more effective anti-cancer drug pairs using in silico network biology approach. Based on the hypotheses that the drug synergy comes from the collective effects on the biological network, therefore, we developed six network biology features, including overlap and distance of drug perturbation network, that were derived by using individual drug-perturbed transcriptome profiles and the relevant biological network analysis. Using publicly available drug synergy databases and three machine-learning (ML) methods, the model was trained to discriminate the positive (synergistic) and negative (nonsynergistic) drug combinations. The proposed models were evaluated on the test cases to predict the most promising network biology feature, which is the network degree activity, i.e. the synergistic effect between drug pairs is mainly accounted by the complementary signaling pathways or molecular networks from two drugs.

MicroRNAs (miRNAs) are small noncoding RNAs (ncRNAs) involved in several biological processes and diseases. MiRNAs regulate gene expression at the posttranscriptional level, mostly downregulating their targets by binding specific regions of transcripts through imperfect sequence complementarity. Prediction of miRNA-binding sites is challenging, and target prediction algorithms are usually based on sequence complementarity. In the last years, it has been shown that by adding miRNA and protein coding gene expression, we are able to build tissue-, cell line-, or disease-specific networks improving our understanding of complex biological scenarios. In this chapter, we present an application of a recently published software named SWIM, that allows to identify key genes in a network of interactions by defining appropriate "roles" of genes according to their local/global positioning in the overall network. Furthermore, we show how the SWIM software can be used to build miRNA-disease networks, by applying the approach to tumor data obtained from The Cancer Genome Atlas (TCGA).

Cells have traditionally been characterized using expression levels of a few proteins that are thought to specify phenotype. This requires a priori selection of proteins, which can introduce descriptor bias, and neglects the wealth of additional molecular information nested within each cell in a population, which often makes these sparse descriptors qualitative. Recently, more unbiased and quantitative cell characterization has been made possible by new high-throughput, information-dense experimental approaches and data-driven computational methods. This review discusses such quantitative descriptors in the context of three central concepts of cell identity: definition, creation, and stability. Collectively, these concepts are essential for constructing quantitative phenotypic landscapes, which will enhance our understanding of cell biology and facilitate cell engineering for research and clinical applications., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Diverse interactions occur between biomolecules, such as activation, inhibition, expression, or repression. However, previous network-based studies of drug repositioning have employed interaction on the binary protein-protein interaction (PPI) network without considering the characteristics of the interactions. Recently, some studies of drug repositioning using gene expression data found that associations between drug and disease genes are useful information for identifying novel drugs to treat diseases. However, the gene expression profiles for drugs and diseases are not always available. Although gene expression profiles of drugs and diseases are available, existing methods cannot use the drugs or diseases, when differentially expressed genes in the profiles are not included in their network., Results: We developed a novel method for identifying candidate indications of existing drugs considering types of interactions between biomolecules based on known drug-disease associations. To obtain associations between drug and disease genes, we constructed a directed network using protein interaction and gene regulation data obtained from various public databases providing diverse biological pathways. The network includes three types of edges depending on relationships between biomolecules. To quantify the association between a target gene and a disease gene, we explored the shortest paths from the target gene to the disease gene and calculated the types and weights of the shortest paths. For each drug-disease pair, we built a vector consisting of values for each disease gene influenced by the drug. Using the vectors and known drug-disease associations, we constructed classifiers to identify novel drugs for each disease., Conclusion: We propose a method for exploring candidate drugs of diseases using associations between drugs and disease genes derived from a directed gene network instead of gene regulation data obtained from gene expression profiles. Compared to existing methods that require information on gene relationships and gene expression data, our method can be applied to a greater number of drugs and diseases. Furthermore, to validate our predictions, we compared the predictions with drug-disease pairs in clinical trials using the hypergeometric test, which showed significant results. Our method also showed better performance compared to existing methods for the area under the receiver operating characteristic curve (AUC).

Background: Systems biology takes a holistic approach by handling biomolecules and their interactions as big systems. Network based approach has emerged as a natural way to model these systems with the idea of representing biomolecules as nodes and their interactions as edges. Very often the input data come from various sorts of omics analyses. Those resulting networks sometimes describe a wide range of aspects, for example different experiment conditions, species, tissue types, stimulating factors, mutants, or simply distinct interaction features of the same network produced by different algorithms. For these scenarios, synchronous visualization of more than one distinct network is an excellent mean to explore all the relevant networks efficiently. In addition, complementary analysis methods are needed and they should work in a workflow manner in order to gain maximal biological insights., Results: In order to address the aforementioned needs, we have developed a Synchronous Network Data Integration (SyNDI) framework. This framework contains SyncVis, a Cytoscape application for user-friendly synchronous and simultaneous visualization of multiple biological networks, and it is seamlessly integrated with other bioinformatics tools via the Galaxy platform. We demonstrated the functionality and usability of the framework with three biological examples - we analyzed the distinct connectivity of plasma metabolites in networks associated with high or low latent cardiovascular disease risk; deeper insights were obtained from a few similar inflammatory response pathways in Staphylococcus aureus infection common to human and mouse; and regulatory motifs which have not been reported associated with transcriptional adaptations of Mycobacterium tuberculosis were identified., Conclusions: Our SyNDI framework couples synchronous network visualization seamlessly with additional bioinformatics tools. The user can easily tailor the framework for his/her needs by adding new tools and datasets to the Galaxy platform.

Machine learning, a collection of data-analytical techniques aimed at building predictive models from multi-dimensional datasets, is becoming integral to modern biological research. By enabling one to generate models that learn from large datasets and make predictions on likely outcomes, machine learning can be used to study complex cellular systems such as biological networks. Here, we provide a primer on machine learning for life scientists, including an introduction to deep learning. We discuss opportunities and challenges at the intersection of machine learning and network biology, which could impact disease biology, drug discovery, microbiome research, and synthetic biology., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In situ sequencing methods generate spatially resolved RNA localization and expression data at an almost single-cell resolution. Few methods, however, currently exist to analyze and visualize the complex data that is produced, which can encode the localization and expression of a million or more individual transcripts in a tissue section. Here, we present InsituNet, an application that converts in situ sequencing data into interactive network-based visualizations, where each unique transcript is a node in the network and edges represent the spatial co-expression relationships between transcripts. InsituNet is available as an app for the Cytoscape platform at http://apps.cytoscape.org/apps/insitunet. InsituNet enables the analysis of the relationships that exist between these transcripts and can uncover how spatial co-expression profiles change in different regions of the tissue or across different tissue sections., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Efficient diagnosis of tuberculosis (TB) is met with multiple challenges, calling for a shift of focus from pathogen-centric diagnostics towards identification of host-based multi-marker signatures. Transcriptomics offer a list of differentially expressed genes, but cannot by itself identify the most influential contributors to the disease phenotype. Here, we describe a computational pipeline that adopts an unbiased approach to identify a biomarker signature. Data from RNA sequencing from whole blood samples of TB patients were integrated with a curated genome-wide molecular interaction network, from which we obtain a comprehensive perspective of variations that occur in the host due to TB. We then implement a sensitive network mining method to shortlist gene candidates that are most central to the disease alterations. We then apply a series of filters that include applicability to multiple publicly available datasets as well as additional validation on independent patient samples, and identify a signature comprising 10 genes - FCGR1A, HK3, RAB13, RBBP8, IFI44L, TIMM10, BCL6, SMARCD3, CYP4F3 and SLPI, that can discriminate between TB and healthy controls as well as distinguish TB from latent tuberculosis and HIV in most cases. The signature has the potential to serve as a diagnostic marker of TB., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

The mouse, Mus musculus, is a popular model organism for the study of human genes involved in development, immunology, and disease phenotypes. Despite recent revolutions in gene-knockout technologies in mouse, identification of candidate genes for functions of interest can further accelerate the discovery of novel gene functions. The collaborative nature of genetic functions allows for the inference of gene functions based on the principle of guilt-by-association. Genome-scale co-functional networks could therefore provide functional predictions for genes via network analysis. We recently constructed such a network for mouse (MouseNet), which interconnects over 88% of protein-coding genes with 788,080 functional relationships. The companion web server ( www.inetbio.org/mousenet ) enables researchers with no bioinformatics expertise to generate predictions that facilitate discovery of novel gene functions. In this chapter, we present the theoretical framework for MouseNet, as well as step-by-step instructions and technical tips for functional prediction of genes and pathways in mouse and other model vertebrates.

For over half a century, the field of developmental biology has leveraged computation to explore mechanisms of developmental processes. More recently, computational approaches have been critical in the translation of high throughput data into knowledge of both developmental and stem cell biology. In the past several years, a new subdiscipline of computational stem cell biology has emerged that synthesizes the modeling of systems-level aspects of stem cells with high-throughput molecular data. In this review, we provide an overview of this new field and pay particular attention to the impact that single cell transcriptomics is expected to have on our understanding of development and our ability to engineer cell fate., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Blood flow is an essential contributor to plaque growth, composition and initiation. It is sensed by endothelial cells, which react to blood flow by expressing > 1000 genes. The sheer number of genes implies that one needs genomic techniques to unravel their response in disease. Individual genomic studies have been performed but lack sufficient power to identify subtle changes in gene expression. In this study, we investigated whether a systematic meta-analysis of available microarray studies can improve their consistency. We identified 17 studies using microarrays, of which six were performed in vivo and 11 in vitro. The in vivo studies were disregarded due to the lack of the shear profile. Of the in vitro studies, a cross-platform integration of human studies (HUVECs in flow cells) showed high concordance (> 90 %). The human data set identified > 1600 genes to be shear responsive, more than any other study and in this gene set all known mechanosensitive genes and pathways were present. A detailed network analysis indicated a power distribution (e. g. the presence of hubs), without a hierarchical organisation. The average cluster coefficient was high and further analysis indicated an aggregation of 3 and 4 element motifs, indicating a high prevalence of feedback and feed forward loops, similar to prokaryotic cells. In conclusion, this initial study presented a novel method to integrate human-based mechanosensitive studies to increase its power. The robust network was large, contained all known mechanosensitive pathways and its structure revealed hubs, and a large aggregate of feedback and feed forward loops.

Despite the remarkable progress achieved in the identification of specific genes involved in breast cancer (BC), our understanding of their complex functioning is still limited. In this manuscript, we systematically explore the existence of direct physical interactions between the products of BC core and associated genes. Our aim is to generate a protein interaction network of BC-associated gene products and suggest potential molecular mechanisms to unveil their role in the disease. In total, we report 599 novel high-confidence interactions among 44 BC core, 54 BC candidate/associated and 96 newly identified proteins. Our findings indicate that this network-based approach is indeed a robust inference tool to pinpoint new potential players and gain insight into the underlying mechanisms of those proteins with previously unknown roles in BC. To illustrate the power of our approach, we provide initial validation of two BC-associated proteins on the alteration of DNA damage response as a result of specific re-wiring interactions. Overall, our BC-related network may serve as a framework to integrate clinical and molecular data and foster novel global therapeutic strategies., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The totipotent zygote gives rise to cells with differing identities during mouse preimplantation development. Many studies have focused on analyzing the spatio-temporal dependencies during these lineage decision processes and much has been learnt by tracing transgenic marker gene expression up to the blastocyst stage and by analyzing the effects of genetic manipulations (knockout/ overexpression) on embryo development. However, until recently, it has not been possible to get broader overviews on the gene expression networks that distinguish one cell from the other within the same embryo. With the advent of whole genome amplification methodology and microfluidics-based quantitative RT-PCR it became possible to generate transcriptomes of single cells. Here we review the current state of the art of single-cell transcriptomics applied to mouse preimplantation embryo blastomeres and summarize findings made by pioneering studies in recent years. Furthermore we use the PluriNetWork and ExprEssence to investigate cell transitions based on published data., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

E. coli has been a critically important model research organism for more than 50 years, particularly in molecular biology. In 1997, the E. coli draft genome sequence was published. Post-genomic techniques and resources were then developed that allowed E. coli to become a model organism for systems biology. Progress made since publication of the E. coli genome sequence will be summarized.

Cellular information processing in signaling networks forms the basis of responses to environmental stimuli. At any given time, cells receive multiple simultaneous input cues, which are processed and integrated to determine cellular responses such as migration, proliferation, apoptosis, or differentiation. Protein phosphorylation events play a major role in this process and are often involved in fundamental biological and cellular processes such as protein-protein interactions, enzyme activity, and immune responses. Determining which kinases phosphorylate specific phospho sites poses a challenge; this information is critical when trying to elucidate key proteins involved in specific cellular responses. Here, methods to generate high-quality quantitative phosphorylation data from cell lysates originating from primary cells, and how to analyze the generated data to construct quantitative signaling network models, are presented. These models can subsequently be used to guide follow-up in vitro/in vivo validation studies., (Copyright © 2014 John Wiley & Sons, Inc.)

The past decade has seen a dramatic expansion in the number and range of techniques available to obtain genome-wide information and to analyze this information so as to infer both the functions of individual molecules and how they interact to modulate the behavior of biological systems. Here, we review these techniques, focusing on the construction of physical protein-protein interaction networks, and highlighting approaches that incorporate protein structure, which is becoming an increasingly important component of systems-level computational techniques. We also discuss how network analyses are being applied to enhance our basic understanding of biological systems and their disregulation, as well as how these networks are being used in drug development.

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]

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.

Cytoscape is an open-source software used to analyze and visualize biological networks. In addition to being able to import networks from a variety of sources, Cytoscape allows users to import tabular node data and visualize it onto networks. Unfortunately, such data tables can only contain one row of data per node, whereas omics data often have multiple rows for the same gene or protein, representing different post-translational modification sites, peptides, splice isoforms, or conditions. Here, we present a new app, Omics Visualizer, that allows users to import data tables with several rows referring to the same node, connect them to one or more networks, and visualize the connected data onto networks. Omics Visualizer uses the Cytoscape enhancedGraphics app to show the data either in the nodes (pie visualization) or around the nodes (donut visualization), where the colors of the slices represent the imported values. If the user does not provide a network, the app can retrieve one from the STRING database using the Cytoscape stringApp. The Omics Visualizer app is freely available at https://apps.cytoscape.org/apps/omicsvisualizer.

In the era of Big Data, data collection underpins biological research more than ever before. In many cases, this can be as time-consuming as the analysis itself. It requires downloading multiple public databases with various data structures, and in general, spending days preparing the data before answering any biological questions. Here, we introduce Sherlock, an open-source, cloud-based big data platform ( https://earlham-sherlock.github.io/) to solve this problem. Sherlock provides a gap-filling way for computational biologists to store, convert, query, share and generate biology data while ultimately streamlining bioinformatics data management. The Sherlock platform offers a simple interface to leverage big data technologies, such as Docker and PrestoDB. Sherlock is designed to enable users to analyze, process, query and extract information from extremely complex and large data sets. Furthermore, Sherlock can handle different structured data (interaction, localization, or genomic sequence) from several sources and convert them to a common optimized storage format, for example, the Optimized Row Columnar (ORC). This format facilitates Sherlock’s ability to quickly and efficiently execute distributed analytical queries on extremely large data files and share datasets between teams. The Sherlock platform is freely available on GitHub, and contains specific loader scripts for structured data sources of genomics, interaction and expression databases. With these loader scripts, users can easily and quickly create and work with specific file formats, such as JavaScript Object Notation (JSON) or ORC. For computational biology and large-scale bioinformatics projects, Sherlock provides an open-source platform empowering data management, analytics, integration and collaboration through modern big data technologies.

In the era of Big Data, data collection underpins biological research more than ever before. In many cases, this can be as time-consuming as the analysis itself. It requires downloading multiple public databases with various data structures, and in general, spending days preparing the data before answering any biological questions. Here, we introduce Sherlock, an open-source, cloud-based big data platform (https://earlham-sherlock.github.io/) to solve this problem. Sherlock provides a gap-filling way for computational biologists to store, convert, query, share and generate biology data while ultimately streamlining bioinformatics data management. The Sherlock platform offers a simple interface to leverage big data technologies, such as Docker and PrestoDB. Sherlock is designed to enable users to analyze, process, query and extract information from extremely complex and large data sets. Furthermore, Sherlock can handle different structured data (interaction, localization, or genomic sequence) from several sources and convert them to a common optimized storage format, for example, the Optimized Row Columnar (ORC). This format facilitates Sherlock’s ability to quickly and efficiently execute distributed analytical queries on extremely large data files and share datasets between teams. The Sherlock platform is freely available on GitHub, and contains specific loader scripts for structured data sources of genomics, interaction and expression databases. With these loader scripts, users can easily and quickly create and work with specific file formats, such as JavaScript Object Notation (JSON) or ORC. For computational biology and large-scale bioinformatics projects, Sherlock provides an open-source platform empowering data management, analytics, integration and collaboration through modern big data technologies.

In the era of Big Data, data collection underpins biological research more than ever before. In many cases, this can be as time-consuming as the analysis itself. It requires downloading multiple public databases with various data structures, and in general, spending days preparing the data before answering any biological questions. Here, we introduce Sherlock, an open-source, cloud-based big data platform ( https://earlham-sherlock.github.io/) to solve this problem. Sherlock provides a gap-filling way for computational biologists to store, convert, query, share and generate biology data while ultimately streamlining bioinformatics data management. The Sherlock platform offers a simple interface to leverage big data technologies, such as Docker and PrestoDB. Sherlock is designed to enable users to analyze, process, query and extract information from extremely complex and large data sets. Furthermore, Sherlock can handle different structured data (interaction, localization, or genomic sequence) from several sources and convert them to a common optimized storage format, for example, the Optimized Row Columnar (ORC). This format facilitates Sherlock’s ability to quickly and efficiently execute distributed analytical queries on extremely large data files and share datasets between teams. The Sherlock platform is freely available on GitHub, and contains specific loader scripts for structured data sources of genomics, interaction and expression databases. With these loader scripts, users can easily and quickly create and work with specific file formats, such as JavaScript Object Notation (JSON) or ORC. For computational biology and large-scale bioinformatics projects, Sherlock provides an open-source platform empowering data management, analytics, integration and collaboration through modern big data technologies.

Preeclampsia is a hypertensive disorder of pregnancy, which complicates up to 15% of US deliveries. It is an idiopathic disorder associated with several different phenotypes. We sought to determine if the genetic architecture of preeclampsia can be described by clusters of patients with variants in genes in shared protein interaction networks. We performed a case-control study using whole exome sequencing on early onset preeclamptic mothers with severe clinical features and control mothers with uncomplicated pregnancies between 2016 and 2020. A total of 143 patients were enrolled, 61 women with early onset preeclampsia with severe features based on ACOG criteria, and 82 control women at term, matched for race and ethnicity. A network analysis and visualization tool, Proteinarium, was used to confirm there are clusters of patients with shared gene networks associated with severe preeclampsia. The majority of the sequenced patients appear in two significant clusters. We identified one case dominant and one control dominant cluster. Thirteen genes were unique to the case dominated cluster. Among these genes, LAMB2, PTK2, RAC1, QSOX1, FN1, and VCAM1 have known associations with the pathogenic mechanisms of preeclampsia. Using bioinformatic analysis, we were able to identify subsets of patients with shared protein interaction networks, thus confirming our hypothesis about the genetic architecture of preeclampsia. [ABSTRACT FROM AUTHOR]

In the era of Big Data, data collection underpins biological research more than ever before. In many cases, this can be as time-consuming as the analysis itself. It requires downloading multiple public databases with various data structures, and in general, spending days preparing the data before answering any biological questions. Here, we introduce Sherlock, an open-source, cloud-based big data platform (https://earlham-sherlock.github.io/) to solve this problem. Sherlock provides a gap-filling way for computational biologists to store, convert, query, share and generate biology data while ultimately streamlining bioinformatics data management. The Sherlock platform offers a simple interface to leverage big data technologies, such as Docker and PrestoDB. Sherlock is designed to enable users to analyze, process, query and extract information from extremely complex and large data sets. Furthermore, Sherlock can handle different structured data (interaction, localization, or genomic sequence) from several sources and convert them to a common optimized storage format, for example, the Optimized Row Columnar (ORC). This format facilitates Sherlock’s ability to quickly and efficiently execute distributed analytical queries on extremely large data files and share datasets between teams. The Sherlock platform is freely available on GitHub, and contains specific loader scripts for structured data sources of genomics, interaction and expression databases. With these loader scripts, users can easily and quickly create and work with specific file formats, such as JavaScript Object Notation (JSON) or ORC. For computational biology and large-scale bioinformatics projects, Sherlock provides an open-source platform empowering data management, analytics, integration and collaboration through modern big data technologies.

Preeclampsia is a hypertensive disorder of pregnancy, which complicates up to 15% of US deliveries. It is an idiopathic disorder associated with several different phenotypes. We sought to determine if the genetic architecture of preeclampsia can be described by clusters of patients with variants in genes in shared protein interaction networks. We performed a case-control study using whole exome sequencing on early onset preeclamptic mothers with severe clinical features and control mothers with uncomplicated pregnancies between 2016 and 2020. A total of 143 patients were enrolled, 61 women with early onset preeclampsia with severe features based on ACOG criteria, and 82 control women at term, matched for race and ethnicity. A network analysis and visualization tool, Proteinarium, was used to confirm there are clusters of patients with shared gene networks associated with severe preeclampsia. The majority of the sequenced patients appear in two significant clusters. We identified one case dominant and one control dominant cluster. Thirteen genes were unique to the case dominated cluster. Among these genes, LAMB2, PTK2, RAC1, QSOX1, FN1, and VCAM1 have known associations with the pathogenic mechanisms of preeclampsia. Using bioinformatic analysis, we were able to identify subsets of patients with shared protein interaction networks, thus confirming our hypothesis about the genetic architecture of preeclampsia.

In the era of Big Data, data collection underpins biological research more so than ever before. In many cases this can be as time-consuming as the analysis itself, requiring downloading multiple different public databases, with different data structures, and in general, spending days before answering any biological questions. To solve this problem, we introduce an open-source, cloud-based big data platform, called Sherlock ( https://earlham-sherlock.github.io/). Sherlock provides a gap-filling way for biologists to store, convert, query, share and generate biology data, while ultimately streamlining bioinformatics data management. The Sherlock platform provides a simple interface to leverage big data technologies, such as Docker and PrestoDB. Sherlock is designed to analyse, process, query and extract the information from extremely complex and large data sets. Furthermore, Sherlock is capable of handling different structured data (interaction, localization, or genomic sequence) from several sources and converting them to a common optimized storage format, for example to the Optimized Row Columnar (ORC). This format facilitates Sherlock’s ability to quickly and easily execute distributed analytical queries on extremely large data files as well as share datasets between teams. The Sherlock platform is freely available on Github, and contains specific loader scripts for structured data sources of genomics, interaction and expression databases. With these loader scripts, users are able to easily and quickly create and work with the specific file formats, such as JavaScript Object Notation (JSON) or ORC. For computational biology and large-scale bioinformatics projects, Sherlock provides an open-source platform empowering data management, data analytics, data integration and collaboration through modern big data technologies.

Biological entities are involved in intricate and complex interactions, in which uncovering the biological information from the network concepts are of great significance. Benefiting from the advances of network science and high-throughput biomedical technologies, studying the biological systems from network biology has attracted much attention in recent years, and networks have long been central to our understanding of biological systems, in the form of linkage maps among genotypes, phenotypes, and the corresponding environmental factors. In this review, we summarize the recent developments of computational network biology, first introducing various types of biological networks and network structural properties. We then review the network-based approaches, ranging from some network metrics to the complicated machine-learning methods, and emphasize how to use these algorithms to gain new biological insights. Furthermore, we highlight the application in neuroscience, human disease, and drug developments from the perspectives of network science, and we discuss some major challenges and future directions. We hope that this review will draw increasing interdisciplinary attention from physicists, computer scientists, and biologists. [ABSTRACT FROM AUTHOR]

It is increasingly appreciated that alternative splicing plays a key role in generating functional specificity and diversity in cancer. However, the mechanisms by which cancer mutations perturb splicing remain unknown. Here, we developed a network-based strategy, DrAS-Net, to investigate more than 2.5 million variants across cancer types and link somatic mutations with cancer-specific splicing events. We identified more than 40,000 driver variant candidates and their 80,000 putative splicing targets deregulated in 33 cancer types and inferred their functional impact. Strikingly, tumors with splicing perturbations show reduced expression of immune system-related genes and increased expression of cell proliferation markers. Tumors harboring different mutations in the same gene often exhibit distinct splicing perturbations. Further stratification of 10,000 patients based on their mutation-splicing relationships identifies subtypes with distinct clinical features, including survival rates. Our work reveals how single-nucleotide changes can alter the repertoires of splicing isoforms, providing insights into oncogenic mechanisms for precision medicine.

Current technology is producing high throughput biomedical data at an ever-growing rate. A common approach to interpreting such data is through network-based analyses. Since biological networks are notoriously complex and hard to decipher, a growing body of work applies graph embedding techniques to simplify, visualize, and facilitate the analysis of the resulting networks. In this review, we survey traditional and new approaches for graph embedding and compare their application to fundamental problems in network biology with using the networks directly. We consider a broad variety of applications including protein network alignment, community detection, and protein function prediction. We find that in all of these domains both types of approaches are of value and their performance depends on the evaluation measures being used and the goal of the project. In particular, network embedding methods outshine direct methods according to some of those measures and are, thus, an essential tool in bioinformatics research. [ABSTRACT FROM AUTHOR]

Primary mitochondrial diseases form one of the most common and severe groups of genetic disease, with a birth prevalence of at least 1 in 5000. These disorders are multi-genic and multi-phenotypic (even within the same gene defect) and span the entire age range from prenatal to late adult onset. Mitochondrial disease typically affects one or multiple high-energy demanding organs, and is frequently fatal in early life. Unfortunately, to date there are no known curative therapies, mostly owing to the rarity and heterogeneity of individual mitochondrial diseases, leading to diagnostic odysseys and difficulties in clinical trial design. This review aims to discuss recent advances and challenges of systems approaches for the study of primary mitochondrial diseases. Although there has been an explosion in the generation of omics data, few studies have progressed toward the integration of multiple levels of omics. It is evident that the integration of different types of data to create a more complete representation of biology remains challenging, perhaps due to the scarcity of available integrative tools and the complexity inherent in their use. In addition, "bottom-up" systems approaches have been adopted for use in the iterative cycle of systems biology: from data generation to model prediction and validation. Primary mitochondrial diseases, owing to their complex nature, will most likely benefit from a multidisciplinary approach encompassing clinical, molecular and computational studies integrated together by systems biology to elucidate underlying pathomechanisms for better diagnostics and therapeutic discovery. Just as next generation sequencing has rapidly increased diagnostic rates from approximately 5% up to 60% over two decades, more recent advancing technologies are encouraging; the generation of multi-omics, the integration of multiple types of data, and the ability to predict perturbations will, ultimately, be translated into improved patient care. [ABSTRACT FROM AUTHOR]

Summary It is increasingly appreciated that alternative splicing plays a key role in generating functional specificity and diversity in cancer. However, the mechanisms by which cancer mutations perturb splicing remain unknown. Here, we developed a network-based strategy, DrAS-Net, to investigate more than 2.5 million variants across cancer types and link somatic mutations with cancer-specific splicing events. We identified more than 40,000 driver variant candidates and their 80,000 putative splicing targets deregulated in 33 cancer types and inferred their functional impact. Strikingly, tumors with splicing perturbations show reduced expression of immune system-related genes and increased expression of cell proliferation markers. Tumors harboring different mutations in the same gene often exhibit distinct splicing perturbations. Further stratification of 10,000 patients based on their mutation-splicing relationships identifies subtypes with distinct clinical features, including survival rates. Our work reveals how single-nucleotide changes can alter the repertoires of splicing isoforms, providing insights into oncogenic mechanisms for precision medicine. [ABSTRACT FROM AUTHOR]