Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression

Improved Algorithms for Network Topology Discovery

peer reviewedTopology discovery systems are starting to be introduced in the form of easily and widely deployed software. However, little consideration has been given as to how to perform large-scale topology discovery efficiently and in a network-friendly manner. In prior work, we have described how large numbers of traceroute monitors can coordinate their efforts to map the network while reducing their impact on routers and end-systems. The key is for them to share information regarding the paths they have explored. However, such sharing introduces considerable communication overhead. Here, we show how to improve the communication scaling properties through the use of Bloom filters to encode a probing stop set. Also, any system in which every monitor traces routes towards every destination has inherent scaling problems. We propose capping the number of monitors per destination, and dividing the monitors into clusters, each cluster focusing on a different destination list

Effects of body condition on buoyancy in endangered North Atlantic right whales

Buoyancy is an important consideration for diving marine animals, resulting in specific ecologically relevant adaptations. Marine mammals use blubber as an energy reserve, but because this tissue is also positively buoyant, nutritional demands have the potential to cause considerable variation in buoyancy. North Atlantic right whales Eubalaena glacialis are known to be positively buoyant as a result of their blubber, and the thickness of this layer varies considerably, but the effect of this variation on buoyancy has not been explored. This study compared the duration and rate of ascending and descending glides, recorded with an archival tag, with blubber thickness, measured with an ultrasound device, in free-swimming right whales. Ascending whales with thicker blubber had shorter portions of active propulsion and longer passive glides than whales with thinner blubber, suggesting that blubber thickness influences buoyancy because the buoyant force is acting in the same direction as the animal’s movement during this phase. Whales with thinner layers also used similar body angles and velocities when traveling to and from depth, while those with thicker layers used shallower ascent angles but achieved higher ascent velocities. Such alterations in body angle may help to reduce the cost of transport when swimming against the force of buoyancy in a state of augmented positive buoyancy, which represents a dynamic response to reduce the energetic consequences of physiological changes. These results have considerable implications for any diving marine animal during periods of nutritional stress, such as during seasonal migrations and annual variations in prey availability

The role of non-need factors in individual GP utilisation analysis and their implications for the pursuance of equity: a cross-country comparison

GP services, Utility model, C3, I1,