Rummagene: massive mining of gene sets from supporting materials of biomedical research publications.

Many biomedical research publications contain gene sets in their supporting tables, and these sets are currently not available for search and reuse. By crawling PubMed Central, the Rummagene server provides access to hundreds of thousands of such mammalian gene sets. So far, we scanned 5,448,589 articles to find 121,237 articles that contain 642,389 gene sets. These sets are served for enrichment analysis, free text, and table title search. Investigating statistical patterns within the Rummagene database, we demonstrate that Rummagene can be used for transcription factor and kinase enrichment analyses, and for gene function predictions. By combining gene set similarity with abstract similarity, Rummagene can find surprising relationships between biological processes, concepts, and named entities. Overall, Rummagene brings to surface the ability to search a massive collection of published biomedical datasets that are currently buried and inaccessible. The Rummagene web application is available at https://rummagene.com .

Pan-cancer proteogenomics characterization of tumor immunity.

Despite the successes of immunotherapy in cancer treatment over recent decades, less than <10%-20% cancer cases have demonstrated durable responses from immune checkpoint blockade. To enhance the efficacy of immunotherapies, combination therapies suppressing multiple immune evasion mechanisms are increasingly contemplated. To better understand immune cell surveillance and diverse immune evasion responses in tumor tissues, we comprehensively characterized the immune landscape of more than 1,000 tumors across ten different cancers using CPTAC pan-cancer proteogenomic data. We identified seven distinct immune subtypes based on integrative learning of cell type compositions and pathway activities. We then thoroughly categorized unique genomic, epigenetic, transcriptomic, and proteomic changes associated with each subtype. Further leveraging the deep phosphoproteomic data, we studied kinase activities in different immune subtypes, which revealed potential subtype-specific therapeutic targets. Insights from this work will facilitate the development of future immunotherapy strategies and enhance precision targeting with existing agents.

Toxicology knowledge graph for structural birth defects.

BACKGROUND: Birth defects are functional and structural abnormalities that impact about 1 in 33 births in the United States. They have been attributed to genetic and other factors such as drugs, cosmetics, food, and environmental pollutants during pregnancy, but for most birth defects there are no known causes. METHODS: To further characterize associations between small molecule compounds and their potential to induce specific birth abnormalities, we gathered knowledge from multiple sources to construct a reproductive toxicity Knowledge Graph (ReproTox-KG) with a focus on associations between birth defects, drugs, and genes. Specifically, we gathered data from drug/birth-defect associations from co-mentions in published abstracts, gene/birth-defect associations from genetic studies, drug- and preclinical-compound-induced gene expression changes in cell lines, known drug targets, genetic burden scores for human genes, and placental crossing scores for small molecules. RESULTS: Using ReproTox-KG and semi-supervised learning (SSL), we scored >30,000 preclinical small molecules for their potential to cross the placenta and induce birth defects, and identified >500 birth-defect/gene/drug cliques that can be used to explain molecular mechanisms for drug-induced birth defects. The ReproTox-KG can be accessed via a web-based user interface available at https://maayanlab.cloud/reprotox-kg . This site enables users to explore the associations between birth defects, approved and preclinical drugs, and all human genes. CONCLUSIONS: ReproTox-KG provides a resource for exploring knowledge about the molecular mechanisms of birth defects with the potential of predicting the likelihood of genes and preclinical small molecules to induce birth defects.

While birth defects are common, for most birth defects there are no known causes. During pregnancy, developing babies are exposed to drugs, cosmetics, food, and environmental pollutants that may cause birth defects. However, exactly how these environmental factors are involved in producing birth defects is difficult to discern. Also, birth defects can be a consequence of the genes inherited from the parents. We combined general data about human genes and drugs with specific data previously implicating genes and drugs in inducing birth defects to create a knowledge graph representation that connects genes, drugs, and birth defects. This knowledge graph can be used to explore new links that may explain why birth defects occur, particularly those that result from a combination of inherited and environmental influences.

Enrichr-KG: bridging enrichment analysis across multiple libraries.

Gene and protein set enrichment analysis is a critical step in the analysis of data collected from omics experiments. Enrichr is a popular gene set enrichment analysis web-server search engine that contains hundreds of thousands of annotated gene sets. While Enrichr has been useful in providing enrichment analysis with many gene set libraries from different categories, integrating enrichment results across libraries and domains of knowledge can further hypothesis generation. To this end, Enrichr-KG is a knowledge graph database and a web-server application that combines selected gene set libraries from Enrichr for integrative enrichment analysis and visualization. The enrichment results are presented as subgraphs made of nodes and links that connect genes to their enriched terms. In addition, users of Enrichr-KG can add gene-gene links, as well as predicted genes to the subgraphs. This graphical representation of cross-library results with enriched and predicted genes can illuminate hidden associations between genes and annotated enriched terms from across datasets and resources. Enrichr-KG currently serves 26 gene set libraries from different categories that include transcription, pathways, ontologies, diseases/drugs, and cell types. To demonstrate the utility of Enrichr-KG we provide several case studies. Enrichr-KG is freely available at: https://maayanlab.cloud/enrichr-kg.

A multi-omic analysis of MCF10A cells provides a resource for integrative assessment of ligand-mediated molecular and phenotypic responses.

The phenotype of a cell and its underlying molecular state is strongly influenced by extracellular signals, including growth factors, hormones, and extracellular matrix proteins. While these signals are normally tightly controlled, their dysregulation leads to phenotypic and molecular states associated with diverse diseases. To develop a detailed understanding of the linkage between molecular and phenotypic changes, we generated a comprehensive dataset that catalogs the transcriptional, proteomic, epigenomic and phenotypic responses of MCF10A mammary epithelial cells after exposure to the ligands EGF, HGF, OSM, IFNG, TGFB and BMP2. Systematic assessment of the molecular and cellular phenotypes induced by these ligands comprise the LINCS Microenvironment (ME) perturbation dataset, which has been curated and made publicly available for community-wide analysis and development of novel computational methods ( synapse.org/LINCS_MCF10A ). In illustrative analyses, we demonstrate how this dataset can be used to discover functionally related molecular features linked to specific cellular phenotypes. Beyond these analyses, this dataset will serve as a resource for the broader scientific community to mine for biological insights, to compare signals carried across distinct molecular modalities, and to develop new computational methods for integrative data analysis.

Getting Started with LINCS Datasets and Tools.

The Library of Integrated Network-based Cellular Signatures (LINCS) was an NIH Common Fund program that aimed to expand our knowledge about human cellular responses to chemical, genetic, and microenvironment perturbations. Responses to perturbations were measured by transcriptomics, proteomics, cellular imaging, and other high content assays. The second phase of the LINCS program, which lasted 7 years, involved the engagement of six data and signature generation centers (DSGCs) and one data coordination and integration center (DCIC). The DSGCs and the DCIC developed several digital resources, including tools, databases, and workflows that aim to facilitate the use of the LINCS data and integrate this data with other publicly available data. The digital resources developed by the DSGCs and the DCIC can be used to gain new biological and pharmacological insights that can lead to the development of novel therapeutics. This protocol provides step-by-step instructions for processing the LINCS data into signatures, and utilizing the digital resources developed by the LINCS consortia for hypothesis generation and knowledge discovery. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Navigating L1000 tools and data in CLUE.io Basic Protocol 2: Computing signatures from the L1000 data with the CD method Basic Protocol 3: Analyzing lists of differentially expressed genes and querying them against the L1000 data with BioJupies and the Bulk RNA-seq Appyter Basic Protocol 4: Utilizing the L1000FWD resource for drug discovery Basic Protocol 5: KINOMEscan and the KINOMEscan Appyter Basic Protocol 6: LINCS P100 and GCP Proteomics Assays Basic Protocol 7: The LINCS Joint Project (LJP) Basic Protocol 8: The LINCS Data Portals and SigCom LINCS Basic Protocol 9: Creating and analyzing signatures with iLINCS.

SigCom LINCS: data and metadata search engine for a million gene expression signatures.

Millions of transcriptome samples were generated by the Library of Integrated Network-based Cellular Signatures (LINCS) program. When these data are processed into searchable signatures along with signatures extracted from Genotype-Tissue Expression (GTEx) and Gene Expression Omnibus (GEO), connections between drugs, genes, pathways and diseases can be illuminated. SigCom LINCS is a webserver that serves over a million gene expression signatures processed, analyzed, and visualized from LINCS, GTEx, and GEO. SigCom LINCS is built with Signature Commons, a cloud-agnostic skeleton Data Commons with a focus on serving searchable signatures. SigCom LINCS provides a rapid signature similarity search for mimickers and reversers given sets of up and down genes, a gene set, a single gene, or any search term. Additionally, users of SigCom LINCS can perform a metadata search to find and analyze subsets of signatures and find information about genes and drugs. SigCom LINCS is findable, accessible, interoperable, and reusable (FAIR) with metadata linked to standard ontologies and vocabularies. In addition, all the data and signatures within SigCom LINCS are available via a well-documented API. In summary, SigCom LINCS, available at https://maayanlab.cloud/sigcom-lincs, is a rich webserver resource for accelerating drug and target discovery in systems pharmacology.

KEA3: improved kinase enrichment analysis via data integration.

Phosphoproteomics and proteomics experiments capture a global snapshot of the cellular signaling network, but these methods do not directly measure kinase state. Kinase Enrichment Analysis 3 (KEA3) is a webserver application that infers overrepresentation of upstream kinases whose putative substrates are in a user-inputted list of proteins. KEA3 can be applied to analyze data from phosphoproteomics and proteomics studies to predict the upstream kinases responsible for observed differential phosphorylations. The KEA3 background database contains measured and predicted kinase-substrate interactions (KSI), kinase-protein interactions (KPI), and interactions supported by co-expression and co-occurrence data. To benchmark the performance of KEA3, we examined whether KEA3 can predict the perturbed kinase from single-kinase perturbation followed by gene expression experiments, and phosphoproteomics data collected from kinase-targeting small molecules. We show that integrating KSIs and KPIs across data sources to produce a composite ranking improves the recovery of the expected kinase. The KEA3 webserver is available at https://maayanlab.cloud/kea3.

Appyters: Turning Jupyter Notebooks into data-driven web apps.

Jupyter Notebooks have transformed the communication of data analysis pipelines by facilitating a modular structure that brings together code, markdown text, and interactive visualizations. Here, we extended Jupyter Notebooks to broaden their accessibility with Appyters. Appyters turn Jupyter Notebooks into fully functional standalone web-based bioinformatics applications. Appyters present to users an entry form enabling them to upload their data and set various parameters for a multitude of data analysis workflows. Once the form is filled, the Appyter executes the corresponding notebook in the cloud, producing the output without requiring the user to interact directly with the code. Appyters were used to create many bioinformatics web-based reusable workflows, including applications to build customized machine learning pipelines, analyze omics data, and produce publishable figures. These Appyters are served in the Appyters Catalog at https://appyters.maayanlab.cloud. In summary, Appyters enable the rapid development of interactive web-based bioinformatics applications.

Towards Intelligent Integration and Sharing of Stem Cell Research Data.

Advancements in regenerative medicine have brought to the fore the need for increased standardization and sharing of stem cell product characterization to help drive these innovative interventions toward public availability. Although numerous attempts have been made to store this data, there is still a lack of a platform that incorporates heterogeneous stem cell information into a harmonized project-based framework. The aim of this project was to introduce and pilot-test an intelligent informatics solution which integrates diverse stem cell product characteristics with study subject and omics information. In the resulting platform, heterogeneous data is validated using predefined ontologies and stored in a NoSQL repository. Pilot-testing was performed on nine sponsored stem cell projects conducting preclinical and intervention evaluations. The pilot-testing demonstrated the robustness of the proposed platform, by seamlessly harmonizing diverse common data elements, and the potential of this platform for driving knowledge generation from the aggregation of this shared data.

LINCS Data Portal 2.0: next generation access point for perturbation-response signatures.

The Library of Integrated Network-Based Cellular Signatures (LINCS) is an NIH Common Fund program with the goal of generating a large-scale and comprehensive catalogue of perturbation-response signatures by utilizing a diverse collection of perturbations across many model systems and assay types. The LINCS Data Portal (LDP) has been the primary access point for the compendium of LINCS data and has been widely utilized. Here, we report the first major update of LDP (http://lincsportal.ccs.miami.edu/signatures) with substantial changes in the data architecture and APIs, a completely redesigned user interface, and enhanced curated metadata annotations to support more advanced, intuitive and deeper querying, exploration and analysis capabilities. The cornerstone of this update has been the decision to reprocess all high-level LINCS datasets and make them accessible at the data point level enabling users to directly access and download any subset of signatures across the entire library independent from the originating source, project or assay. Access to the individual signatures also enables the newly implemented signature search functionality, which utilizes the iLINCS platform to identify conditions that mimic or reverse gene set queries. A newly designed query interface enables global metadata search with autosuggest across all annotations associated with perturbations, model systems, and signatures.