GWAS Explorer: an open-source tool to explore, visualize, and access GWAS summary statistics in the PLCO Atlas.

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is a prospective cohort study of nearly 155,000 U.S. volunteers aged 55-74 at enrollment in 1993-2001. We developed the PLCO Atlas Project, a large resource for multi-trait genome-wide association studies (GWAS), by genotyping participants with available DNA and genomic consent. Genotyping on high-density arrays and imputation was performed, and GWAS were conducted using a custom semi-automated pipeline. Association summary statistics were generated from a total of 110,562 participants of European, African and Asian ancestry. Application programming interfaces (APIs) and open-source software development kits (SKDs) enable exploring, visualizing and open data access through the PLCO Atlas GWAS Explorer website, promoting Findable, Accessible, Interoperable, and Re-usable (FAIR) principles. Currently the GWAS Explorer hosts association data for 90 traits and >78,000,000 genomic markers, focusing on cancer and cancer-related phenotypes. New traits will be posted as association data becomes available. The PLCO Atlas is a FAIR resource of high-quality genetic and phenotypic data with many potential reuse opportunities for cancer research and genetic epidemiology.

PLCOjs, a FAIR GWAS web SDK for the NCI Prostate, Lung, Colorectal and Ovarian Cancer Genetic Atlas project.

MOTIVATION: The Division of Cancer Epidemiology and Genetics (DCEG) and the Division of Cancer Prevention (DCP) at the National Cancer Institute (NCI) have recently generated genome-wide association study (GWAS) data for multiple traits in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Genomic Atlas project. The GWAS included 110 000 participants. The dissemination of the genetic association data through a data portal called GWAS Explorer, in a manner that addresses the modern expectations of FAIR reusability by data scientists and engineers, is the main motivation for the development of the open-source JavaScript software development kit (SDK) reported here. RESULTS: The PLCO GWAS Explorer resource relies on a public stateless HTTP application programming interface (API) deployed as the sole backend service for both the landing page's web application and third-party analytical workflows. The core PLCOjs SDK is mapped to each of the API methods, and also to each of the reference graphic visualizations in the GWAS Explorer. A few additional visualization methods extend it. As is the norm with web SDKs, no download or installation is needed and modularization supports targeted code injection for web applications, reactive notebooks (Observable) and node-based web services. AVAILABILITY AND IMPLEMENTATION: code at https://github.com/episphere/plco; project page at https://episphere.github.io/plco.

COMETS Analytics: An Online Tool for Analyzing and Meta-Analyzing Metabolomics Data in Large Research Consortia.

Consortium-based research is crucial for producing reliable, high-quality findings, but existing tools for consortium studies have important drawbacks with respect to data protection, ease of deployment, and analytical rigor. To address these concerns, we developed COnsortium of METabolomics Studies (COMETS) Analytics to support and streamline consortium-based analyses of metabolomics and other -omics data. The application requires no specialized expertise and can be run locally to guarantee data protection or through a Web-based server for convenience and speed. Unlike other Web-based tools, COMETS Analytics enables standardized analyses to be run across all cohorts, using an algorithmic, reproducible approach to diagnose, document, and fix model issues. This eliminates the time-consuming and potentially error-prone step of manually customizing models by cohort, helping to accelerate consortium-based projects and enhancing analytical reproducibility. We demonstrated that the application scales well by performing 2 data analyses in 45 cohort studies that together comprised measurements of 4,647 metabolites in up to 134,742 participants. COMETS Analytics performed well in this test, as judged by the minimal errors that analysts had in preparing data inputs and the successful execution of all models attempted. As metabolomics gathers momentum among biomedical and epidemiologic researchers, COMETS Analytics may be a useful tool for facilitating large-scale consortium-based research.

An investigation of factors affecting elementary school students' BMI values based on the system dynamics modeling.

This study used system dynamics method to investigate the factors affecting elementary school students' BMI values. The construction of the dynamic model is divided into the qualitative causal loop and the quantitative system dynamics modeling. According to the system dynamics modeling, this study consisted of research on the four dimensions: student's personal life style, diet-relevant parenting behaviors, advocacy and implementation of school nutrition education, and students' peer interaction. The results of this study showed that students with more adequate health concepts usually have better eating behaviors and consequently have less chance of becoming obese. In addition, this study also verified that educational attainment and socioeconomic status of parents have a positive correlation with students' amounts of physical activity, and nutrition education has a prominent influence on changing students' high-calorie diets.

Ginkgo biloba extract attenuates oxLDL-induced endothelial dysfunction via an AMPK-dependent mechanism.

Atherosclerosis is a complex inflammatory arterial disease, and oxidized low-density lipoprotein (oxLDL) is directly associated with chronic vascular inflammation. Previous studies have shown that Ginkgo biloba extract (GbE) acts as a therapeutic agent for neurological and cardiovascular disorders. However, the mechanisms mediating the actions of GbE are still largely unknown. In the present study, we tested the hypothesis that GbE protects against oxLDL-induced endothelial dysfunction via an AMP-activated protein kinase (AMPK)-dependent mechanism. Human umbilical vein endothelial cells were treated with GbE, followed by oxLDL, for indicated time periods. Results from Western blot showed that GbE inhibited the membrane translocation of the NADPH oxidase subunits p47(phox) and Rac-1 and attenuated the increase in protein expression of membrane subunits gp91 and p22(phox) caused by oxLDL-induced AMPK dephosphorylation and subsequent PKC activation. AMPK-α(1)-specific small interfering RNA-transfected cells that had been exposed to GbE followed by oxLDL revealed elevated levels of PKC and p47(phox). In addition, exposure to oxLDL resulted in reduced AMPK-mediated Akt/endothelial nitric oxide (NO) synthase signaling and the induction of phosphorylation of p38 mitogen-activated protein kinase, which, in turn, activated NF-κB-mediated inflammatory responses, such as the release of interleukin-8, the expression of the adhesion molecule, and the adherence of monocytic cells to human umbilical vein endothelial cells. Furthermore, oxLDL upregulated the expression of inducible NO synthase, thereby augmenting the formation of NO and protein nitrosylation. Pretreatment with GbE, however, exerted significant cytoprotective effects in a dose-dependent manner. Results from this study may provide insight into a possible molecular mechanism by which GbE protects against oxLDL-induced endothelial dysfunction.

EGCG protects against oxidized LDL-induced endothelial dysfunction by inhibiting LOX-1-mediated signaling.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), originally identified as the major receptor for oxidized low-density lipoprotein (oxLDL) in endothelial cells, plays a major role in the pathology of vascular diseases. Green tea consumption is associated with reduced cardiovascular mortality in some epidemiological studies. In the present study, we hypothesized that the most abundant polyphenolic compound in tea, epigallocatechin-3-gallate (EGCG), can downregulate parameters of endothelial dysfunction by modulating LOX-1-regulated cell signaling. In cultured human umbilical vein endothelial cells (HUVECs), exposure to oxLDL (130 microg/ml), which led to an increase in LOX-1 expression at the RNA and protein levels, was abrogated by addition of EGCG or DPI, a well-known inhibitor of flavoproteins, suggesting the involvement of NADPH oxidase. Furthermore, oxLDL rapidly activated the membrane translocation of Rac-1 and p47phox and the subsequent induction of ROS generation, which was suppressed markedly by pretreatment with EGCG or anti-LOX-1 monoclonal antibody. OxLDL also increased p38 MAPK phosphorylation and decreased phosphorylation of the amino-terminal region of Akt, with maximal induction at about 30 min, and NF-kappaB phosphorylation within 1 h, resulting in redox-sensitive signaling. In addition, oxLDL diminished the expression of endothelial nitric oxide synthase (eNOS), enhanced the expression of endothelin-1 and adhesion molecules (ICAM, E-selectin, and monocyte chemoattractant protein-1), and increased the adherence of monocytic THP-1 cells to HUVECs. Pretreatment with EGCG, however, exerted significant cytoprotective effects in all events. These data suggest that EGCG inhibits the oxLDL-induced LOX-1-mediated signaling pathway, at least in part, by inhibiting NADPH oxidase and consequent ROS-enhanced LOX-1 expression, which contributes to further ROS generation and the subsequent activation of NF-kappaB via the p38 MAPK pathway. Results from this study may provide insight into a possible molecular mechanism by which EGCG suppresses oxLDL-mediated vascular endothelial dysfunction.