Activation of the carcinogen N-hydroxy-2-acetylaminofluorene by rat mammary peroxidase

A peroxidase preparation from rat mammary gland parenchymal cells, a target tissue of arylamine carcinogens, was shown to activate the carcinogen N-hydroxy-2-acetylaminofluorene via a nitroxyl free radical intermediate to the more active carcinogens nitrosofluorene and N-acetoxy-2-acetylaminofluorene. Hydrogen peroxide, cumene hydroperoxide, and linoleic acid hydroperoxide were effective as substrates. The antioxidants ascorbate, propyl gallate and reduced glutathione prevented the free radical activation route.     

Gene regulation: ancient microRNA target sequences in plants

MicroRNAs are an abundant class of small RNAs that are thought to regulate the expression of protein-coding genes in plants and animals. Here we show that the target sequence of two microRNAs, known to regulate genes in the class-III homeodomain-leucine zipper (HD-Zip) gene family of the flowering plant Arabidopsis, is conserved in homologous sequences from all lineages of land plants, including bryophytes, lycopods, ferns and seed plants. We also find that the messenger RNAs from these genes are cleaved within the same microRNA-binding site in representatives of each land-plant group, as they are in Arabidopsis. Our results indicate not only that microRNAs mediate gene regulation in non-flowering as well as flowering plants, but also that the regulation of this class of plant genes dates back more than 400 million years.     

Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis

In addition to the HLA locus, six genetic risk factors for primary biliary cirrhosis (PBC) have been identified in recent genome-wide association studies (GWAS). To identify additional loci, we carried out a GWAS using 1,840 cases from the UK PBC Consortium and 5,163 UK population controls as part of the Wellcome Trust Case Control Consortium 3 (WTCCC3). We followed up 28 loci in an additional UK cohort of 620 PBC cases and 2,514 population controls. We identified 12 new susceptibility loci (at a genome-wide significance level of P < 5 × 10??) and replicated all previously associated loci. We identified three further new loci in a meta-analysis of data from our study and previously published GWAS results. New candidate genes include STAT4, DENND1B, CD80, IL7R, CXCR5, TNFRSF1A, CLEC16A and NFKB1. This study has considerably expanded our knowledge of the genetic architecture of PBC.     

Free radicals produced in a nitrosofluorene-unsaturated lipid reaction

Summary We report here the first demonstration that the carcinogen 2-nitrosofluorene reacts directly with lipid molecules containing carbon-carbon double bonds to yield free radicals which appear to be the nitroxyl free radical of the carcinogen covalently bound to the lipid.This investigation was supported in part by the U.S. Public Health Service Grant 5 RO1 CA18591-01 from the National Institutes of Health.     

Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.     

Marmot distribution and habitat associations in the Great Basin

In this study I describe the distribution and habitat associations of yellow-bellied marmots ( Marmota flaviventris ) in the Great Basin, compare my findings with those of E.R. Hall during his 1929-1936 survey and later surveys, and discuss potential reasons for changes in marmot distribution over time. I found 62 marmot burrow sites in 18 mountain ranges, mostly in rocky meadows situated on well-drained slopes between 2100 m and 3000 m elevation. Marmots were generally found near burrows dug within talus slopes, talus-like rock piles, or clusters of massive boulders. Oceanspray ( Holodiscus discolor ) was the shrub most commonly associated with occupied rock formations. Marmots were most abundant in the Ruby/East Humboldt Range and were common in the Desatoya, Shoshone, Toiyabe, Toquima, Cherry Creek, Schell Creek, Deep Creek, and Stansbury Ranges. Marmots appeared to be uncommon in the Monitor Range and rare in the Clan Alpine, Roberts, and Snake Ranges. I was unable to find marmots in the Diamond, Egan, Spruce-Pequop, White Pine, and Oquirrh Ranges, although I located old, weathered marmot scats in all but the latter 2 ranges. Other evidence confirms that marmots do actually occur in the Oquirrh Range, but extensive searches of the White Pine Range, including some of the same rock formations where E.R. Hall collected marmots, revealed no sign of marmots. My distribution data suggest that marmots may have gone extinct in some Great Basin mountain ranges during the last century. These disappearances may represent a natural extinction-recolonization dynamic, but a more alarming possibility is a recent die-off linked to climate change, which is predicted to force montane vegetation zones further upslope, shrinking the habitat of associated faunas. However, marmots in this study were observed as low as 1550 m elevation, indicating an altitudinal flexibility that may allow this species to survive climatic change better than more specialized boreal species such as pikas ( Ochotona princeps ) and water shrews ( Sorex palustris ).     

Evidence for fault weakness and fluid flow within an active low-angle normal fault.

Determining the composition and physical properties of shallow-dipping, active normal faults (dips < 35 degrees with respect to the horizontal) is important for understanding how such faults slip under low resolved shear stress and accommodate significant extension of the crust and lithosphere. Seismic reflection images and earthquake source parameters show that a magnitude 6.2 earthquake occurred at about 5 km depth on or close to a normal fault with a dip of 25-30 degrees located ahead of a propagating spreading centre in the Woodlark basin. Here we present results from a genetic algorithm inversion of seismic reflection data, which shows that the fault at 4-5 km depth contains a 33-m-thick layer with seismic velocities of about 4.3 km s(-1), which we interpret to be composed of serpentinite fault gouge. Isolated zones exhibit velocities as low as approximately 1.7 km s(-1) with high porosities, which we suggest are maintained by high fluid pressures. We propose that hydrothermal fluid flow, possibly driven by a deep magmatic heat source, and high extensional stresses ahead of the ridge tip have created conditions for fault weakness and strain localization on the low-angle normal fault.