Emerging roles for WNK kinases in cancer

The subfamily of WNK protein kinases is composed of four human genes and is characterised by a typical sequence variation within the conserved catalytic domain. Although most research has focussed on the role of WNK1, WNK3 and WNK4 in regulating different ion transporters in both the kidney and extrarenal tissues, there is growing evidence for additional roles of WNK kinases in various signalling cascades related to cancer. Here, we review the connection between WNK kinases and tumorigenesis and describe existing experimental evidence as well as potential new links to major aspects of tumour biology. In particular, we discuss their role in G1/S cell cycle progression, metabolic tumour cell adaptation, evasion of apoptosis and metastasis.     

Physical characteristics of Blue Grouse winter use-trees and roost sites

Physical characteristics of winter use-trees and roost sites of Blue Grouse ( Dendragapus obscurus ) were studied in northeastern Utah. Blue Grouse selectively roosted in the largest Douglas-fir ( Pseudotsuga menziesii ) trees during the day and subalpine fir ( Abies lasiocarpa ) trees at night. Diurnal and nocturnal roosts were typically adjacent to tree trunks in the lower two-thirds of trees. Nocturnal roosts provided greater canopy and denser shelter than diurnal roosts. Roost site selection was consistent with occupation of favorable microhabitat, particularly at night, and foraging strategy during the day. Timber management strategies should perpetuate large trees within Douglas-fir-subalpine fir habitat in areas occupied by wintering Blue Grouse.     

Discovering Science from an Armchair: Popular Science in British Magazines of the Interwar Years

Analysing the contents of magazines published with the stated intention of conveying information about science and technology to the public provides a mechanism for evaluation what counted as ‘popular science’. This article presents numerical surveys of the contents of three magazines published in inter-war Britain (Discovery, Conquest and Armchair Science) and offers an evaluation of the results. The problem of defining relevant topic-categories is addressed, both direct and indirect strategies being employed to ensure that the topics correspond to what the editors and publishers took to be the principal areas of science and technology of interest to their readers. Analysis of the results of the surveys reveals different editorial policies depending on the backgrounds of the publishers and their anticipated readerships. The strong focus of the two most populist magazines on applied science and ‘hobbyist’ topics such as natural history, radio and motoring is noted and contrasted with the very limited coverage of theoretical science. In conclusion, a survey of changes in the contents over the periods of publication is used to identify trends in the coverage of science during this period.     

Improving Hull and White's Method of Estimating Portfolio Value‐at‐Risk

We propose a method approach. We use six international stock price indices and three hypothetical portfolios formed by these indices. The sample was observed daily from 1 January 1996 to 31 December 2006. Confirmed by the failure rates and backtesting developed by Kupiec (Technique for verifying the accuracy of risk measurement models. Journal of Derivatives 1995; 3 : 73–84) and Christoffersen (Evaluating interval forecasts. International Economic Review 1998; 39 : 841–862), the empirical results show that our method can considerably improve the estimation accuracy of value‐at‐risk. Thus the study establishes an effective alternative model for risk prediction and hence also provides a reliable tool for the management of portfolios. Copyright © 2011 John Wiley & Sons, Ltd.     

Genetic susceptibility to hypertensive renal disease

Hypertensive renal disease occurs at increased frequency among the relatives of patients with this disease compared to individuals who lack a family history of disease. This suggests a heritable risk in which genetic variation may play a role. These observations have motivated a search for genetic variation contributing to this risk in both experimental animal models and in human populations. Studies of animal models indicate the capacity of natural genetic variants to contribute to disease risk and have produced a few insights into the disease mechanism. In its current phase, human population genetic studies have sought to associate genetic variation with disease in large populations by testing genotypes at a large number of common genetic variations in the genome, expecting that common genetic variants contributing to renal disease risk will be identified. These genome-wide association studies (GWAS) have been productive and are a clear technical success; they have also identified narrowly defined loci and genes containing variation contributing to disease risk. Further extension and refinement of these GWAS are likely to extend this success. However, it is also clear that few additional variants with substantial effects accounting for the greatest part of heritability will be uncovered by GWAS. This raises an interesting biological question regarding where the remaining unaccounted heritable risk may be located. At present, much consideration is being given to this question and to the challenge of testing hypotheses that lead from the various alternative mechanisms under consideration. One result of the progress of GWAS is likely to be a renewed interest in mechanisms by which related individuals can share and transmit traits independently of Mendelian inheritance. This paper reviews the current progress in this area and considers other mechanisms by which familial aggregation of risk for renal disease may arise.     

The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat

Meckel-Gruber syndrome is a severe autosomal, recessively inherited disorder characterized by bilateral renal cystic dysplasia, developmental defects of the central nervous system (most commonly occipital encephalocele), hepatic ductal dysplasia and cysts and polydactyly. MKS is genetically heterogeneous, with three loci mapped: MKS1, 17q21-24 (ref. 4); MKS2, 11q13 (ref. 5) and MKS3 (ref. 6). We have refined MKS3 mapping to a 12.67-Mb interval (8q21.13-q22.1) that is syntenic to the Wpk locus in rat, which is a model with polycystic kidney disease, agenesis of the corpus callosum and hydrocephalus. Positional cloning of the Wpk gene suggested a MKS3 candidate gene, TMEM67, for which we identified pathogenic mutations for five MKS3-linked consanguineous families. MKS3 is a previously uncharacterized, evolutionarily conserved gene that is expressed at moderate levels in fetal brain, liver and kidney but has widespread, low levels of expression. It encodes a 995-amino acid seven-transmembrane receptor protein of unknown function that we have called meckelin.     

Common nonsynonymous variants in PCSK1 confer risk of obesity

Mutations in PCSK1 cause monogenic obesity. To assess the contribution of PCSK1 to polygenic obesity risk, we genotyped tag SNPs in a total of 13,659 individuals of European ancestry from eight independent case-control or family-based cohorts. The nonsynonymous variants rs6232, encoding N221D, and rs6234-rs6235, encoding the Q665E-S690T pair, were consistently associated with obesity in adults and children (P = 7.27 x 10(-8) and P = 2.31 x 10(-12), respectively). Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity.