Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis

Variants associated with meconium ileus in cystic fibrosis were identified in 3,763 affected individuals by genome-wide association study (GWAS). Five SNPs at two loci near SLC6A14 at Xq23-24 (minimum P = 1.28 × 10(-12) at rs3788766) and SLC26A9 at 1q32.1 (minimum P = 9.88 × 10(-9) at rs4077468) accounted for ~5% of phenotypic variability and were replicated in an independent sample of affected individuals (n = 2,372; P = 0.001 and 0.0001, respectively). By incorporating the knowledge that disease-causing mutations in CFTR alter electrolyte and fluid flux across surface epithelium into a hypothesis-driven GWAS (GWAS-HD), we identified associations with the same SNPs in SLC6A14 and SLC26A9 and established evidence for the involvement of SNPs in a third solute carrier gene, SLC9A3. In addition, GWAS-HD provided evidence of association between meconium ileus and multiple genes encoding constituents of the apical plasma membrane where CFTR resides (P = 0.0002; testing of 155 apical membrane genes jointly and in replication, P = 0.022). These findings suggest that modulating activities of apical membrane constituents could complement current therapeutic paradigms for cystic fibrosis.     

The effectiveness of imprecise probability forecasts

In this paper we investigate the feasibility of algorithmically deriving precise probability forecasts from imprecise forecasts. We provide an empirical evaluation of precise probabilities that have been derived from two types of imprecise probability forecasts: probability intervals and probability intervals with second-order probability distributions. The minimum cross-entropy (MCE) principle is applied to the former to derive precise (i.e. additive) probabilities; expectation (EX) is used to derive precise probabilities in the latter case. Probability intervals that were constructed without second-order probabilities tended to be narrower than and contained in those that were amplified by second-order probabilities. Evidence that this narrowness is due to motivational bias is presented. Analysis of forecasters' mean Probability Scores for the derived precise probabilities indicates that it is possible to derive precise forecasts whose external correspondence is as good as directly assessed precise probability forecasts. The forecasts of the EX method, however, are more like the directly assessed precise forecasts than those of the MCE method.     

Book reviews

Affiliated to Astrophysics Div., Space Science Department, European Space Agency.     

Comparative successional roles of trembling aspen and lodgepole pine in the Southern Rocky Mountains

Normal 0 false false false EN-US X-NONE X-NONE MicrosoftInternetExplorer4 st1\:*{behavior:url(#ieooui) } /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;} A review of the ecological distribution and successional roles of lodgepole pine and trembling aspen in the Southern Rocky Mountains suggests that the two species have different strategies for occupying disturbed sites. Lodgepole pine’s easily dispersed seeds and faster growth from seed in unsuppressed conditions allows it to colonize severe burns, even from remote seed sources. Aspen appears to compensate for ineffective development from seed by vegetative reproduction from durable root stocks, which promotes geographic persistence. Such persistence is achieved by the maintenance of a forest structure conducive to light surface fires, which stimulate suckering and retard conifer invasion, and by the accumulation of soil organic matter, which improves site nutrient retention and water availability.       

Regulation of the bacterial cell cycle by an integrated genetic circuit

How bacteria regulate cell cycle progression at a molecular level is a fundamental but poorly understood problem. In Caulobacter crescentus, two-component signal transduction proteins are crucial for cell cycle regulation, but the connectivity of regulators involved has remained elusive and key factors are unidentified. Here we identify ChpT, an essential histidine phosphotransferase that controls the activity of CtrA, the master cell cycle regulator. We show that the essential histidine kinase CckA initiates two phosphorelays, each requiring ChpT, which lead to the phosphorylation and stabilization of CtrA. Downregulation of CckA activity therefore results in the dephosphorylation and degradation of CtrA, which in turn allow the initiation of DNA replication. Furthermore, we show that CtrA triggers its own destruction by promoting cell division and inducing synthesis of the essential regulator DivK, which feeds back to downregulate CckA immediately before S phase. Our results define a single integrated circuit whose components and connectivity can account for the cell cycle oscillations of CtrA in Caulobacter.