Connectivity mapping is a method used in the pharmaceutical industry to find connections between small molecules, disease states, and genes. The concept can be applied to a predictive toxicology paradigm to find connections between chemicals, adverse events, and genes. In order to assess the applicability of the technique for predictive toxicology purposes, we performed gene array experiments on 34 different chemicals: bisphenol A, genistein, ethinyl-estradiol, tamoxifen, clofibrate, dehydorepiandrosterone, troglitazone, diethylhexyl phthalate, flutamide, trenbolone, phenobarbital, retinoic acid, thyroxine, 1α,25-dihydroxyvitamin D3, clobetasol, farnesol, chenodeoxycholic acid, progesterone, RU486, ketoconazole, valproic acid, desferrioxamine, amoxicillin, 6-aminonicotinamide, metformin, phenformin, methotrexate, vinblastine, ANIT (1-naphthyl isothiocyanate), griseofulvin, nicotine, imidacloprid, vorinostat, 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) at the 6-, 24-, and 48-hour time points for 3 different concentrations in the 4 cell lines: MCF7, Ishikawa, HepaRG, and HepG2 GEO (super series accession no.: GSE69851). The 34 chemicals were grouped in to predefined mode of action (MOA)-based chemical classes based on current literature. Connectivity mapping was used to find linkages between each chemical and between chemical classes. Cell line-specific linkages were compared with each other and to test whether the method was platform and user independent, a similar analysis was performed against publicly available data. The study showed that the method can group chemicals based on MOAs and the inter-chemical class comparison alluded to connections between MOAs that were not predefined. Comparison to the publicly available data showed that the method is user and platform independent. The results provide an example of an alternate data analysis process for high-content data, beneficial for predictive toxicology, especially when grouping chemicals for read across purposes.

Background: The insulinotropic effect of whey protein is not fully understood and has clinical implications in the regulation of chronic and acute hyperglycemia. Summary: This review describes the composition of whey protein and potential mechanisms through which whey exerts an insulinotropic effect, including increasing the gastric emptying rate, effect on incretin hormones particularly gastric inhibitory peptide and glucagon-like polypeptide-1, and whey's role as a dipeptidyl peptidase IV inhibitor. Recent clinical evidence on the use of whey protein concentrate, isolate and hydrolysate in the management of type 2 diabetes and in the acute care adult population is reviewed. Key Messages: The mechanism through which whey protein exerts its insulinotropic effect is multifactorial. Increasing evidence supports the potential use of whey protein in medical/nutritional therapy to manage glycemia; however, additional research is needed to determine the most appropriate dose, form and delivery method for whey supplementation.

p24 proteins comprise a family of type-I transmembrane proteins of ~24kD that are present in yeast and plants as well as metazoans ranging from Drosophila to humans. These proteins are most commonly localized to the endoplasmic reticulum (ER)-Golgi interface and are incorporated in anterograde and retrograde transport vesicles. Little is known about how disruption of p24 signaling affects individual tissue function or whole animals. Drosophila melanogaster express nine p24 genes, grouped into four subfamilies. Based upon our mRNA and protein expression data, Drosophila p24 family members are expressed in a variety of tissues. To identify functions for particular Drosophila p24 proteins, we used RNA interference (RNAi) to reduce p24 expression. Ubiquitous reduction of most p24 genes resulted in complete or partial lethality during development. We found that reducing p24 levels in adults caused defects in female fecundity (egg laying) and also reduced male fertility. We attributed reduced female fecundity to decreased neural p24 expression. These results provide the first genetic analysis of all p24 family members in a multicellular animal and indicate vital roles for Drosophila p24s in development and reproduction, implicating neural expression of p24s in the regulation of female behavior.

Our data establish CNP/NPR2 signaling as a novel regulator of aortic valve development and disease and elucidate the therapeutic potential of targeting this pathway to arrest disease progression.