Ingenuity Pathways Analysis (IPA)

Ingenuity's Knowledge Base

	Overview Ingenuity's knowledge base is a repository of molecular interactions, regulatory events, gene-to-phenotype associations, and chemical knowledge that provides the building blocks for pathway construction. It is the largest knowledge base of its kind, with millions of findings pulled from the full text of the life sciences literature by Ph.D.-level life scientists, and features the most descriptive and detailed structure, and the highest degree of accuracy. Ingenuity's knowledge base is used as a starting point for exploration of biological and chemical systems and a bridge between novel discovery and known biology. It provides researchers with a tremendous resource for searching relevant and substantiated knowledge from the literature, and for interpreting experimental results in the context of larger biological systems for greater confidence with research decisions. Ingenuity's knowledge base provides: Integrated, broad coverage of systems biology knowledge including relationships between proteins, genes, protein complexes, cells, cellular components, tissues, organs, small molecules, cellular phenotypes, and disease processes Gene View pages with comprehensive, species-specific knowledge about gene function and regulation, tissue and cell line expression patterns, subcellular location, mutations, and disease associations Chemical and drug information for clinical candidates and FDA-approved drugs Millions of physical interactions and regulatory events extracted from literature Semantic and linguistic consistency based on Ingenuity's comprehensive ontology Synonym and homonym mapping to maintain object identity and remove duplicate objects Representation of biological context, including species specificity, localization, mutations, epigenetic modifications, and experimental conditions Systematic capture of canonical pathway relationships

	Highlights Expert Extraction: All relationships are manually curated and modeled by a team of Ph.D. scientists, and are supported by experimental evidence published in the peer-reviewed literature. Breadth of Knowledge: The knowledge base houses millions of relationships between proteins, genes, complexes, cells, tissues, drugs, and diseases. Biological Context: Strict content extraction protocols require inclusion of details regarding cellular context, mutations, protein and promoter domains, species, tissues, and the net effect on the process or phenotype being studied. Consistent Modeling: Ingenuity's proprietary ontology tools and protocols ensure consistent modeling of biological and chemical knowledge, enabling rapid development of computational solutions. Frequent Updates: Regular updates provide customers with high-impact content from over 300 journals, review articles, textbooks, and external databases such as OMIM, GO, and EntrezGene, as well as manually curated canonical pathways and drug/target/disease relationships.

Quality Content
The information in Ingenuity's knowledge base includes modeled relationships between proteins, genes, complexes, cells, tissues, drugs, and diseases. Each modeled relationship originates from reported experimental findings from various primary literature sources, including peer-reviewed journal articles, review articles, and textbooks. In addition to literature findings, Ingenuity's knowledge base includes many other types of content including findings and annotations from major NCBI databases (EntrezGene, RefSeq, OMIM disease associations), targets and pharmacological relevance of FDA approved and clinical trial drugs, Gene Ontology annotations, a normal gene expression body atlas for over 30 tissues and the NCI-60 panel of cancer cell lines, KEGG and LIGAND metabolic pathways and reactions, cell signaling pathways, and more.

New Updates
With the release of IPA 6, the content in Ingenuity's knowledge base has been updated to incorporate new expert-extracted biological and chemical information from the scientific literature on the following pathways:

• PXR/RXR Activation
• TR/RXR Activation
• Tight Junction Signaling
• Regulation of Actin-based Motility by Rho GTPases
• Ceramide Signaling

IPA 6 contains additional content curated from customer-requested bibliographies, including:

• Women's Health Topics o Folliculogenesis
  • Luteinizing Hormone
• Drug-Protein Adducts and Drug Metabolism Content
• Gene-to-Disease Associations o Alzheimer's and Bipolar Disorder
  • Hypereosinophilia
  • Obesity

Ingenuity's content team of Ph.D. scientists has also curated additional knowledge on clinical candidates:

• Over 3100 new clinical candidate-to-disease pairings, and 170 new clinical candidates supported by evidence from ClinicalTrials.gov

Chemical Content
Ingenuity's knowledge base contains knowledge on thousands of compounds, including endogenous chemicals and metabolites, FDA-approved drugs and clinical candidates, and exogenous chemicals and toxicants. This information allows researchers to understand and visualize the biological impact of these compounds, including:

• Interaction with target proteins, regulation of target protein activity, phosphorylation, and expression
• Impact on non-target proteins and on molecular, cellular and disease processes
• Participation in signaling and metabolic pathways
• Toxicity and therapeutic information
• Compound regulation of P450 enzyme expression and activity
• Bioavailability, plasma binding, LD50, IC50, PK/PD, AUC, and metabolism
• Mutagenicity data
• CAS number
• Synonyms (including systematic name and brand names)
• Chemical formula and SMILES notation

Toxicology Content
Ingenuity's knowledge base features a large collection of knowledge from the molecular toxicology literature describing the pharmacological and toxicological effects of chemicals in vitro and in vivo.

Here are a few highlights from the collection of toxicity pathways and lists in Ingenuity's knowledge base:  

Manual Curation
To obtain each finding, Ph.D.-level scientists read the full text primary source, then extract findings substantiated by experimental evidence and report each finding using a highly descriptive, controlled vocabulary. This process involves breaking down a finding into its logical components, then modeling each component and the reported relationship between components along with the contextual experimental parameters (e.g., species type, cell type, experimental method, etc.). The components, relationships, and contextual details are then deposited within Ingenuity's knowledge base, where they are computationally accessed to drive the features and solutions in IPA.

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