Polymorphism of glyoxalase I in Vienna.

Phenotype and gene frequencies of the GLO I polymorphism in Vienna are given. No exception to the postulated rule of inheritance could be found in 23 families with 51 children and 132 mother-child pairs. Linkage with the HLA system is confirmed, but no linkage disequilibrium between GLO alleles and HLA-A, B, C genes was detected. The use of the GLO I polymorphism in paternity cases is discussed.     

Drice restrains Diap2-mediated inflammatory signalling and intestinal inflammation

The Drosophila IAP protein, Diap2, is a key mediator of NF-κB signalling and innate immune responses. Diap2 is required for both local immune activation, taking place in the epithelial cells of the gut and trachea, and for mounting systemic immune responses in the cells of the fat body. We have found that transgenic expression of Diap2 leads to a spontaneous induction of NF-κB target genes, inducing chronic inflammation in the Drosophila midgut, but not in the fat body. Drice is a Drosophila effector caspase known to interact and form a stable complex with Diap2. We have found that this complex formation induces its subsequent degradation, thereby regulating the amount of Diap2 driving NF-κB signalling in the intestine. Concordantly, loss of Drice activity leads to accumulation of Diap2 and to chronic intestinal inflammation. Interestingly, Drice does not interfere with pathogen-induced signalling, suggesting that it protects from immune responses induced by resident microbes. Accordingly, no inflammation was detected in transgenic Diap2 flies and Drice-mutant flies reared in axenic conditions. Hence, we show that Drice, by restraining Diap2, halts unwanted inflammatory signalling in the intestine.Subject terms: Ubiquitins, Gene regulation, Antimicrobial responses, Chronic inflammation, Signal transduction     

PrPc on the road: trafficking of the cellular prion protein

The glycosylphosphatidylinositol (GPI)-anchored cellular prion protein (PrPc) has a fundamental role in prion diseases. Intracellular trafficking of PrPc is important in the generation of protease resistant PrP species but little is known of how endocytosis affects PrPc function. Here, we discuss recent experiments that have illuminated how PrPc is internalized and what are the possible destinations taken by the protein. Contrary to what would be expected for a GPI-anchored protein there is increasing evidence that clathrin-mediated endocytosis and classical endocytic organelles participate in PrPc trafficking. Moreover, the N-terminal domain of PrPc may be involved in sorting events that can direct the protein during its intracellular journey. Indeed, the concept that the GPI-anchor determines PrPc trafficking has been challenged. Cellular signaling can be triggered or be regulated by PrPc and we suggest that endocytosis of PrPc may influence signaling in several ways. Definition of the processes that participate in PrPc endocytosis and intracellular trafficking can have a major impact on our understanding of the mechanisms involved in PrPc function and conversion to protease resistant conformations.     

Single amino acid substitutions and deletions that alter the G protein coupling properties of the V2 vasopressin receptor identified in yeast by receptor random mutagenesis

To facilitate structure-function relationship studies of the V2 vasopressin receptor, a prototypical G(s)-coupled receptor, we generated V2 receptor-expressing yeast strains (Saccharomyces cerevisiae) that required arginine vasopressin-dependent receptor/G protein coupling for cell growth. V2 receptors heterologously expressed in yeast were unable to productively interact with the endogenous yeast G protein alpha subunit, Gpa1p, or a mutant Gpa1p subunit containing the C-terminal G alpha(q) sequence (Gq5). In contrast, the V2 receptor efficiently coupled to a Gpa1p/G alpha(s) hybrid subunit containing the C-terminal G alpha(s) sequence (Gs5), indicating that the V2 receptor retained proper G protein coupling selectivity in yeast. To gain insight into the molecular basis underlying the selectivity of V2 receptor/G protein interactions, we used receptor saturation random mutagenesis to generate a yeast library expressing mutant V2 receptors containing mutations within the second intracellular loop. A subsequent yeast genetic screen of about 30,000 mutant receptors yielded four mutant receptors that, in contrast to the wild-type receptor, showed substantial coupling to Gq5. Functional analysis of these mutant receptors, followed by more detailed site-directed mutagenesis studies, indicated that single amino acid substitutions at position Met(145) in the central portion of the second intracellular loop of the V2 receptor had pronounced effects on receptor/G protein coupling selectivity. We also observed that deletion of single amino acids N-terminal of Met(145) led to misfolded receptor proteins, whereas single amino acid deletions C-terminal of Met(145) had no effect on V2 receptor function. These findings highlight the usefulness of combining receptor random mutagenesis and yeast expression technology to study mechanisms governing receptor/G protein coupling selectivity and receptor folding.     

Endothelial cell laminin isoforms, laminins 8 and 10, play decisive roles in T cell recruitment across the blood-brain barrier in experimental autoimmune encephalomyelitis

An active involvement of blood-brain barrier endothelial cell basement membranes in development of inflammatory lesions in the central nervous system (CNS) has not been considered to date. Here we investigated the molecular composition and possible function of the extracellular matrix encountered by extravasating T lymphocytes during experimental autoimmune encephalomyelitis (EAE).Endothelial basement membranes contained laminin 8 (alpha4beta1gamma1) and/or 10 (alpha5beta1gamma1) and their expression was influenced by proinflammatory cytokines or angiostatic agents. T cells emigrating into the CNS during EAE encountered two biochemically distinct basement membranes, the endothelial (containing laminins 8 and 10) and the parenchymal (containing laminins 1 and 2) basement membranes. However, inflammatory cuffs occurred exclusively around endothelial basement membranes containing laminin 8, whereas in the presence of laminin 10 no infiltration was detectable. In vitro assays using encephalitogenic T cell lines revealed adhesion to laminins 8 and 10, whereas binding to laminins 1 and 2 could not be induced. Downregulation of integrin alpha6 on cerebral endothelium at sites of T cell infiltration, plus a high turnover of laminin 8 at these sites, suggested two possible roles for laminin 8 in the endothelial basement membrane: one at the level of the endothelial cells resulting in reduced adhesion and, thereby, increased penetrability of the monolayer; and secondly at the level of the T cells providing direct signals to the transmigrating cells.     

Inefficient clearance of dying cells in patients with SLE: anti-dsDNA autoantibodies,MFG-E8, HMGB-1 and other players

Systemic lupus erythematosus (SLE) is a complex disease resulting from inflammatory responses of the immune system against several autoantigens. Inflammation is conditioned by the continuous presence of autoantibodies and leaked autoantigens, e.g. from not properly cleared dying and dead cells. Various soluble molecules and biophysical properties of the surface of apoptotic cells play significant roles in the appropriate recognition and further processing of dying and dead cells. We exemplarily discuss how Milk fat globule epidermal growth factor 8 (MFG-E8), biophysical membrane alterations, High mobility group box 1 (HMGB1), C-reactive protein (CRP), and anti-nuclear autoantibodies may contribute to the etiopathogenesis of the disease. Up to date knowledge about these key elements may provide new insights that lead to the development of new treatment strategies of the disease.     

Nitrate uptake and carbon exudation – do plant roots stimulate or inhibit denitrification?

Plant and Soil - Plant growth affects soil moisture, mineral N and organic C availability in soil, all of which influence denitrification. With increasing plant growth, root exudation may stimulate...     

Premature Mortality from Cardiovascular Disease in the Americas – Will the Goal of a Decline of “25% by 2025” be Met?

Background

Cardiovascular diseases (CVD) are the underlying cause 1.6 million deaths per year in the Americas, accounting for 30% of total mortality and 38% of by non-communicable deaths diseases (NCDs). A 25% reduction in premature mortality due four main NCDs was targeted by the 2011 High-level Meeting of the General Assembly on the Prevention and Control of NCDs. While overall CVD mortality fell in the Americas during the past decade, trends in premature CVD mortality during the same period have not been described, particularly in the countries of Latin America and the Caribbean.

Methods

This is a population-based trend-series study based on a total of 6,133,666 deaths to describe the trends and characteristics of premature mortality due to CVD and to estimates of the average annual percentage of change during the period 2000–2010 in the Americas.

Findings

Premature mortality due to CVD in the Americas fell by 21% in the period 2000–2010 with a -2.5% average annual rate of change in the last 5 year—a statistically significant reduction of mortality—. Mortality from ischemic diseases, declined by 25% - 24% among men and 26% among women. Cerebrovascular diseases declined by 27% -26% among men and 28% among women. Guyana, Trinidad and Tobago, the Dominican Republic, Bahamas, and Brazil had CVD premature mortality rates over 200 per 100,000 population, while the average for the Region was 132.7. US and Canada will meet the 25% reduction target before 2025. Mexico, Costa Rica, Venezuela, Dominican Republic, Panama, Guyana, and El Salvador did not significantly reduce premature mortality among men and Guyana, the Dominican Republic, and Panama did not achieve the required annual reduction in women.

Conclusions

Trends in premature mortality due to CVD observed in last decade in the Americas would indicate that if these trends continue, the Region as a whole and a majority of its countries will be able to reach the goal of a 25% relative reduction in premature mortality even before 2025.