The reactome pathway knowledgebase.

The Reactome Knowledgebase (https://reactome.org) provides molecular details of signal transduction, transport, DNA replication, metabolism and other cellular processes as an ordered network of molecular transformations in a single consistent data model, an extended version of a classic metabolic map. Reactome functions both as an archive of biological processes and as a tool for discovering functional relationships in data such as gene expression profiles or somatic mutation catalogs from tumor cells. To extend our ability to annotate human disease processes, we have implemented a new drug class and have used it initially to annotate drugs relevant to cardiovascular disease. Our annotation model depends on external domain experts to identify new areas for annotation and to review new content. New web pages facilitate recruitment of community experts and allow those who have contributed to Reactome to identify their contributions and link them to their ORCID records. To improve visualization of our content, we have implemented a new tool to automatically lay out the components of individual reactions with multiple options for downloading the reaction diagrams and associated data, and a new display of our event hierarchy that will facilitate visual interpretation of pathway analysis results.

VaximmutorDB: A Web-Based Vaccine Immune Factor Database and Its Application for Understanding Vaccine-Induced Immune Mechanisms.

Vaccines stimulate various immune factors critical to protective immune responses. However, a comprehensive picture of vaccine-induced immune factors and pathways have not been systematically collected and analyzed. To address this issue, we developed VaximmutorDB, a web-based database system of vaccine immune factors (abbreviated as "vaximmutors") manually curated from peer-reviewed articles. VaximmutorDB currently stores 1,740 vaccine immune factors from 13 host species (e.g., human, mouse, and pig). These vaximmutors were induced by 154 vaccines for 46 pathogens. Top 10 vaximmutors include three antibodies (IgG, IgG2a and IgG1), Th1 immune factors (IFN-γ and IL-2), Th2 immune factors (IL-4 and IL-6), TNF-α, CASP-1, and TLR8. Many enriched host processes (e.g., stimulatory C-type lectin receptor signaling pathway, SRP-dependent cotranslational protein targeting to membrane) and cellular components (e.g., extracellular exosome, nucleoplasm) by all the vaximmutors were identified. Using influenza as a model, live attenuated and killed inactivated influenza vaccines stimulate many shared pathways such as signaling of many interleukins (including IL-1, IL-4, IL-6, IL-13, IL-20, and IL-27), interferon signaling, MARK1 activation, and neutrophil degranulation. However, they also present their unique response patterns. While live attenuated influenza vaccine FluMist induced significant signal transduction responses, killed inactivated influenza vaccine Fluarix induced significant metabolism of protein responses. Two different Yellow Fever vaccine (YF-Vax) studies resulted in overlapping gene lists; however, they shared more portions of pathways than gene lists. Interestingly, live attenuated YF-Vax simulates significant metabolism of protein responses, which was similar to the pattern induced by killed inactivated Fluarix. A user-friendly web interface was generated to access, browse and search the VaximmutorDB database information. As the first web-based database of vaccine immune factors, VaximmutorDB provides systematical collection, standardization, storage, and analysis of experimentally verified vaccine immune factors, supporting better understanding of protective vaccine immunity.

Perform Pathway Enrichment Analysis Using ReactomeFIViz.

Modern large-scale biological data analysis often generates a set of significant genes, frequently associated with scores. Pathway-based approaches are routinely performed to understand the functional contexts of these genes. Reactome is the most comprehensive open-access biological pathway knowledge base, widely used in the research community, providing a solid foundation for pathway-based data analysis. ReactomeFIViz is a Cytoscape app built upon Reactome pathways to help users perform pathway- and network-based data analysis and visualization. In this chapter we describe procedures on how to perform pathway enrichment analysis using ReactomeFIViz for a gene score file. We describe two types of analysis: pathway enrichment based on a set of significant genes and GSEA analysis using gene scores without cutoff. We also describe a feature to overlay gene scores onto pathway diagrams, enabling users to understand the underlying mechanisms for up- or down- regulated pathways collected from pathway analysis.

Automation of ReactomeFIViz via CyREST API.

Pathway- and network-based approaches project seemingly unrelated genes onto the context of pathways and networks, enhancing the analysis power that cannot be achieved via gene-based approaches. Pathway and network approaches are routinely applied in large-scale data analysis for cancer and other complicated diseases. ReactomeFIViz is a Cytoscape app, providing features for researchers to perform pathway- and network-based data analysis and visualization by leveraging manually curated Reactome pathways and highly reliable Reactome functional interaction network. To facilitate adoption of this app in bioinformatics software pipeline and workflow development, we develop a CyREST API for ReactomeFIViz by exposing some major features in the app. We describe a use case to demonstrate the use of this API in a Python-based notebook, and believe the new API will provide the community a convenient and powerful tool to perform pathway- and network-based data analysis and visualization using our app in an automatic way.