Human variation databases

More than 100 000 human genetic variations have been described in various genes that are associated with a wide variety of diseases. Such data provides invaluable information for both clinical medicine and basic science. A number of locus-specific databases have been developed to exploit this huge amount of data. However, the scope, format and content of these databases differ strongly and as no standard for variation databases has yet been adopted, the way data is presented varies enormously. This review aims to give an overview of current resources for human variation data in public and commercial resources

Deletion of the signalling molecule synthase ScbA has pleiotropic effects on secondary metabolite biosynthesis, morphological differentiation and primary metabolism in Streptomyces coelicolor A3(2)

Summary Streptomycetes have high biotechnological relevance as producers of diverse metabolites widely used in medical and agricultural applications. The biosynthesis of these metabolites is controlled by signalling molecules, +¦-butyrolactones, that act as bacterial hormones. In Streptomyces coelicolor, a group of signalling molecules called SCBs (S. coelicolorbutanolides) regulates production of the pigmented antibiotics coelicolor polyketide (CPK), actinorhodin and undecylprodigiosin. The +¦-butyrolactone synthase ScbA is responsible for the biosynthesis of SCBs. Here we show the results of a genome-wide transcriptome analysis of a scbA deletion mutant prior to and during the transition to antibiotic production. We report a strong perturbation in the expression of three pigmented antibiotic clusters in the mutant throughout the growth curve, thus providing a molecular explanation for the antibiotic phenotype observed previously. Our study also revealed, for the first time, that the secondary metabolite cluster responsible for synthesis of the siderophore desferrioxamine is under the control of SCB signalling. Moreover, expression of the genes encoding enzymes for primary metabolism pathways, which supply antibiotic precursors and genes for morphological differentiation, was found shifted earlier in time in the mutant. In conclusion, our time series analysis demonstrates new details of the regulatory effects of the butyrolactone system in Streptomyce

Cancer vaccine enhanced, non-tumor-reactive CD8(+) T cells exhibit a distinct molecular program associated with "division arrest anergy"

Immune-mediated tumor rejection relies on fully functional T-cell responses and neutralization of an adverse tumor microenvironment. In clinical trials, we detected peptide-specific but non-tumor-reactive and therefore not fully functional CD8(+) T cells post-vaccination against tumor antigens. Understanding the molecular mechanisms behind nontumor reactivity will be a prerequisite to overcome this CD8(+) T-cell deviation. We report that these non-tumor-reactive CD8(+) T cells are characterized by a molecular program associated with hallmarks of "division arrest anergy." Non-tumor-reactive CD8(+) T cells are characterized by coexpression of CD7, CD25, and CD69 as well as elevated levels of lck(p505) and p27(kip1). In vivo quantification revealed high prevalence of non-tumor-reactive CD8(+) T cells with increased levels during cancer vaccination. Furthermore, their presence was associated with a trend toward shorter survival. Dynamics and frequencies of non-target-reactive CD8(+) T cells need to be further addressed in context of therapeutic vaccine development in cancer, chronic infections, and autoimmune diseases