Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Three-dimensional investigation of void growth leading to fracture in commercially pure titanium

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Systematic characterization of human CD8(+) T cells with natural killer cell markers in comparison with natural killer cells and normal CD8(+) T cells

We investigated the function of CD56(+) CD8(+) T cells (CD56(+) T cells) and CD56(−) CD57(+) CD8(+) T cells (CD57(+) T cells; natural killer (NK)-type T cells) and compared them with those of normal CD56(−) CD57(−) CD8(+) T cells (CD8(+) T cells) and CD56(+) NK cells from healthy volunteers. After the stimulation with immobilized anti-CD3 antibodies, both NK-type T cells produced much larger amounts of interferon-γ (IFN-γ) than CD8(+) T cells. Both NK-type T cells also acquired a more potent cytotoxicity against NK-sensitive K562 cells than CD8(+) T cells while only CD56(+) T cells showed a potent cytotoxicity against NK-resistant Raji cells. After the stimulation with a combination of interleukin (IL)-2, IL-12 and IL-15, the IFN-γ amounts produced were NK cells ≥ CD56(+) T cells ≥ CD57(+) T cells > CD8(+) T cells. The cytotoxicities against K562 cells were NK cells > CD56(+) T cells ≥ CD57(+) T cells > CD8(+) T cells while cytotoxicities against Raji cells were CD56(+) T cells > CD57(+) T cells ≥ CD8(+) T cells ≥ NK cells. However, the CD3-stimulated proliferation of both NK-type T cells was smaller than that of CD8(+) T cells partly because NK-type T cells were susceptible to apoptosis. In addition to NK cells, NK-type T cells but not CD8(+) T cells stimulated with cytokines, expressed cytoplasmic perforin and granzyme B. Furthermore, CD3-stimulated IFN-γ production from peripheral blood mononuclear cells (PBMC) correlated with the proportions of CD57(+) T cells in PBMC from donors. Our findings suggest that NK-type T cells play an important role in the T helper 1 responses and the immunological changes associated with ageing

Characterization of extrathymic CD8αβ T cells in the liver and intestine in TAP-1 deficient mice

TAP-1 deficient (−/−) mice cannot transport MHC class I antigens onto the cell surface, which results in failure of the generation of CD8(+) T cells in the thymus. In a series of recent studies, it has been proposed that extrathymic T cells are generated in the liver and at other extrathymic sites (e.g. the intestine). It was therefore investigated whether CD8(+) extrathymic T cells require an interaction with MHC class I antigens for their differentiation in TAP-1(−/−) mice. Although CD8(+) thymically derived T cells were confirmed to be absent in the spleen as well as in the thymus, CD8αβ(+) T cells were abundant in the livers and intestines of TAP-1(−/−) mice. These CD8(+) T cells expanded in the liver as a function of age and were mainly confined to a NK1·1(−)CD3(int) population which is known to be truly of extrathymic origin. Hepatic lymphocytes, which contained CD8(+) T cells and which were isolated from TAP-1(−/−) mice (H-2(b)), responded to neither mutated MHC class I antigens (bm1) nor allogeneic MHC class I antigens (H-2(d)) in in vitro mixed lymphocyte cultures. However, the results from repeated in vivo stimulations with alloantigens (H-2(d)) were interesting. Allogeneic cytotoxicity was induced in liver lymphocytes in TAP-1(−/−) mice, although the magnitude of cytotoxicity was lower than that of liver lymphocytes in immunized B6 mice. All allogeneic cytotoxicity disappeared with the elimination of CD8(+) cells in TAP-1(−/−) mice. These results suggest that the generation and function of CD8(+) extrathymic T cells are independent of the existence of the MHC class I antigens of the mouse but have a limited allorecognition ability