Chemical Genetics Reveals an RGS/G-Protein Role in the Action of a Compound

We report here on a chemical genetic screen designed to address the mechanism of action of a small molecule. Small molecules that were active in models of urinary incontinence were tested on the nematode Caenorhabditis elegans, and the resulting phenotypes were used as readouts in a genetic screen to identify possible molecular targets. The mutations giving resistance to compound were found to affect members of the RGS protein/G-protein complex. Studies in mammalian systems confirmed that the small molecules inhibit muscarinic G-protein coupled receptor (GPCR) signaling involving G-αq (G-protein alpha subunit). Our studies suggest that the small molecules act at the level of the RGS/G-αq signaling complex, and define new mutations in both RGS and G-αq, including a unique hypo-adapation allele of G-αq. These findings suggest that therapeutics targeted to downstream components of GPCR signaling may be effective for treatment of diseases involving inappropriate receptor activation

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Use of Direct Fed Microbials to Alleviate Subacute Acidosis

Direct fed rnicrobials are feed additives composed of live cultures of microorganisms that are currently being used in the feedlot industry to improve animal performance. Reported beneficial effects include increased feed intake and weight gain. The efficacy of these supplements have been associated with their abilities to alter rumen function, such as volatile fatty acid production, stabilization of pH, and reduction of the amount of lactate produced. This experiment was conducted to determine the effect of the direct fed microbials on rumen steady state and to evaluate their ability to alleviate subacute acidosis

Digestibility of Wet and Dry Distillers Grains from the Fermentation of Corn or Sorghum

Research conducted at the University of Nebraska has evaluated wet and dry distillers byproducts as energy sources for cattle. The majority of the research has been conducted with distillers byproducts resulting from the fermentation of corn. However, in the dry milling industry various cereal grains may be used to produce ethanol and distillers byproducts. The resulting byproducts have the potential to have a different feeding value when compared to byproducts produced from corn. A Nebraska trial (1995 Nebraska Beef Report, pp. 25-26) conducted by Lodge et al. indicated steers consuming diets containing distillers byproducts (40% of diet DM) produced from the fermentation of primarily sorghum gained less and were less efficient than previous research with coin byproducts would have predicted. These data imply that distillers byproducts produced from grain sorghum may have a lower feeding value than corn based distillers byproducts. One explanation for this difference in performance may be related to differences in digestibility between corn and sorghum distillers byproducts. Therefore, a lamb digestibility trial was conducted to evaluate the digestibility of wet and dried distillers byproducts produced from the fermentation of corn or sorghum

Evaluation of Wet Distillers Byproducts Composite for Finishing Ruminants

Demand for ethanol and coin sweeteners is on the rise and is predicted to increase in the future. This trend will result in an abundance of byproducts that are potentially economical alternatives to corn. Wet distillers grains and wet corn gluten feed are currently used as sources of protein and energy in feedlot diets. Previous research indicates that wet corn byproducts (distillers grains and thin stillage) are higher in net energy than corn grain; however, wet corn gluten feed (WCGF) is similar in net energy to corn. Potential differences between wet distillers byproducts and WCGF include lipid content, escape protein level, and NDF level. Therefore, two finishing trials evaluated the effect of a composite of feed ingredients formulated to be similar in nutrient composition as wet distillers byproducts