Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of >10 million SNPs in 43,303prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three novel susceptibility loci were revealed at P<5×10-8; 15 variants were identified among men of European ancestry, 7 from multiethnic analyses and one was associated with early-onset prostate cancer. These 23 variants, in combination with the known prostate cancer risk variants, explain 33% of the familial risk of the disease in European ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the utility of combining ancestrally diverse populations to discover risk loci for disease.

Background: An impediment to the rational development of novel drugs against tuberculosis (TB) is a general paucity of knowledge concerning the metabolism of Mycobacterium tuberculosis, particularly during infection. Constraint-based modeling provides a novel approach to investigating microbial metabolism but has not yet been applied to genome-scale modeling of M. tuberculosis.

Streptomycetes sense and respond to the stress of phosphate starvation via the two-component PhoR–PhoP signal transduction system. To identify the in vivo targets of PhoP we have undertaken a chromatin-immunoprecipitation-on-microarray analysis of wild-type and phoP mutant cultures and, in parallel, have quantified their transcriptomes. Most (ca. 80%) of the previously in vitro characterized PhoP targets were identified in this study among several hundred other putative novel PhoP targets. In addition to activating genes for phosphate scavenging systems PhoP was shown to target two gene clusters for cell wall/extracellular polymer biosynthesis. Furthermore PhoP was found to repress an unprecedented range of pathways upon entering phosphate limitation including nitrogen assimilation, oxidative phosphorylation, nucleotide biosynthesis and glycogen catabolism. Moreover, PhoP was shown to target many key genes involved in antibiotic production and morphological differentiation, including afsS, atrA, bldA, bldC, bldD, bldK, bldM, cdaR, cdgA, cdgB and scbR-scbA. Intriguingly, in the PhoP-dependent cpk polyketide gene cluster, PhoP accumulates substantially at three specific sites within the giant polyketide synthase-encoding genes. This study suggests that, following phosphate limitation, Streptomyces coelicolor PhoP functions as a ‘master’ regulator, suppressing central metabolism, secondary metabolism and developmental pathways until sufficient phosphate is salvaged to support further growth and, ultimately, morphological development.

The biochemical reaction networks include elementary reactions differing by many orders of magnitude in the numbers of molecules involved. The kinetics of reactions involving small numbers of molecules can be studied by exact stochastic simulation. This approach is not practical for the simulation of metabolic processes because of the computational cost of accounting for individual molecular collisions. We present the "maximal time step method," a novel approach combining the Gibson and Bruck algorithm with the Gillespie tau-leap method. This algorithm allows stochastic simulation of systems composed of both intensive metabolic reactions and regulatory processes involving small numbers of molecules. The method is applied to the simulation of glucose, lactose, and glycerol metabolism in Escherichia coli. The gene expression, signal transduction, transport, and enzymatic activities are modeled simultaneously. We show that random fluctuations in gene expression can propagate to the level of metabolic processes. In the cells switching from glucose to a mixture of lactose and glycerol, random delays in transcription initiation determine whether lactose or glycerol operon is induced. In a small fraction of cells severe decrease in metabolic activity may also occur. Both effects are epigenetically inherited by the progeny of the cell in which the random delay in transcription initiation occurred.

Using dynamic light scattering we show that aqueous super- to undersaturated solutions of NaCl, (NH4)2SO4, and Na-citrate contain submicrometer size clusters at room temperature. The particle size distributions deduced by Laplace inversion of the spectra contain two predominant components. The smaller components with radii below 1 nm are attributed to mixtures of solvated ions and the larger with radii between 50−500 nm to ion clusters. Knowledge of the mesoscale structure of concentrated electrolyte solutions may be necessary to describe effective protein−protein interactions which are of importance in biochemical applications such as protein crystallization.