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321.
Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans 总被引:2,自引:0,他引:2
Kathiresan S Melander O Guiducci C Surti A Burtt NP Rieder MJ Cooper GM Roos C Voight BF Havulinna AS Wahlstrand B Hedner T Corella D Tai ES Ordovas JM Berglund G Vartiainen E Jousilahti P Hedblad B Taskinen MR Newton-Cheh C Salomaa V Peltonen L Groop L Altshuler DM Orho-Melander M 《Nature genetics》2008,40(2):189-197
322.
Kozyrev SV Abelson AK Wojcik J Zaghlool A Linga Reddy MV Sanchez E Gunnarsson I Svenungsson E Sturfelt G Jönsen A Truedsson L Pons-Estel BA Witte T D'Alfonso S Barizzone N Barrizzone N Danieli MG Gutierrez C Suarez A Junker P Laustrup H González-Escribano MF Martin J Abderrahim H Alarcón-Riquelme ME 《Nature genetics》2008,40(2):211-216
323.
Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes 总被引:1,自引:0,他引:1
Zeggini E Scott LJ Saxena R Voight BF Marchini JL Hu T de Bakker PI Abecasis GR Almgren P Andersen G Ardlie K Boström KB Bergman RN Bonnycastle LL Borch-Johnsen K Burtt NP Chen H Chines PS Daly MJ Deodhar P Ding CJ Doney AS Duren WL Elliott KS Erdos MR Frayling TM Freathy RM Gianniny L Grallert H Grarup N Groves CJ Guiducci C Hansen T Herder C Hitman GA Hughes TE Isomaa B Jackson AU Jørgensen T Kong A Kubalanza K Kuruvilla FG Kuusisto J Langenberg C Lango H Lauritzen T Li Y Lindgren CM 《Nature genetics》2008,40(5):638-645
Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and approximately 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 x 10(-14)), CDC123-CAMK1D (P = 1.2 x 10(-10)), TSPAN8-LGR5 (P = 1.1 x 10(-9)), THADA (P = 1.1 x 10(-9)), ADAMTS9 (P = 1.2 x 10(-8)) and NOTCH2 (P = 4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D. 相似文献
324.
325.
Oddi S Fezza F Pasquariello N De Simone C Rapino C Dainese E Finazzi-Agrò A Maccarrone M 《Cellular and molecular life sciences : CMLS》2008,65(5):840-850
Anandamide is a lipid messenger that carries out a wide variety of biological functions. It has been suggested that anandamide
accumulation involves binding to a saturable cellular component. To identify the structure(s) involved in this process, we
analyzed the intracellular distribution of both biotinylated and radiolabeled anandamide, providing direct evidence that lipid
droplets, also known as adiposomes, constitute a dynamic reservoir for the sequestration of anandamide. In addition, confocal
microscopy and biochemical studies revealed that the anandamide-hydrolase is also spatially associated with lipid droplets,
and that cells with a larger adiposome compartment have an enhanced catabolism of anandamide. Overall, these findings suggest
that adiposomes may have a critical role in accumulating anandamide, possibly by connecting plasma membrane to internal organelles
along the metabolic route of this endocannabinoid.
S. Oddi, F. Fezza: These authors contributed equally to the study. 相似文献
326.
Protease-activated receptors (PARs) play a clear role in the burst of inflammatory reactions and immune responses. However,
for PAR-3, the most elusive member of the PAR family, the functional role is still largely unclear. It has been claimed that
PAR-3 does not signal autonomously, although the wide expression of human PAR-3 indicates its important physiological roles.
We demonstrate that in HEK-293 cells, stably transfected with human PAR-3, thrombin induced calcium signaling, IL-8 gene expression
and IL-8 release. We confirmed this finding using human lung epithelial and human astrocytoma cells that express endogenous
PAR-3. Moreover, thrombin exposure of HEK-293 cells resulted in ERK1/2 activation coinciding with IL-8 release. The effects
of thrombin were not dependent on PAR-1 activation, as confirmed by PAR-1 gene silencing. Thus, we propose that PAR-3 is able
to signal autonomously to induce IL-8 release mediated by ERK1/2 phosphorylation, which contributes actively to inflammatory
responses.
Received 9 December 2007; received after revision 16 January 2008; accepted 18 January 2008 相似文献
327.
Navarro S Aleu J Jiménez M Boix E Cuchillo CM Nogués MV 《Cellular and molecular life sciences : CMLS》2008,65(2):324-337
Human eosinophil cationic protein (ECP)/ ribonuclease 3 (RNase 3) is a protein secreted from the secondary granules of activated
eosinophils. Specific properties of ECP contribute to its cytotoxic activities associated with defense mechanisms. In this
work the ECP cytotoxic activity on eukaryotic cell lines is analyzed. The ECP effects begin with its binding and aggregation
to the cell surface, altering the cell membrane permeability and modifying the cell ionic equilibrium. No internalization
of the protein is observed. These signals induce cell-specific morphological and biochemical changes such as chromatin condensation,
reversion of membrane asymmetry, reactive oxygen species production and activation of caspase-3-like activity and, eventually,
cell death. However, the ribonuclease activity component of ECP is not involved in this process as no RNA degradation is observed.
In summary, the cytotoxic effect of ECP is attained through a mechanism different from that of other cytotoxic RNases and
may be related with the ECP accumulation associated with the inflammatory processes, in which eosinophils are present.
Received 26 October 2007; accepted 23 November 2007 相似文献
328.
329.
Src-family kinases (SFKs) regulate different granulocyte and monocyte/macrophage responses. Accumulating evidence suggests that members of this family are implicated in signal transduction pathways regulating phagocytic cell migration and recruitment into inflammatory sites. Macrophages with a genetic deficiency of SFKs display marked alterations in cytoskeleton dynamics, polarization and migration. This same phenotype is found in cells with either a lack of SFK substrates and/or interacting proteins such as Pyk2/FAK, c-Cbl and p190RhoGAP. Notably, SFKs and their downstream targets also regulate monocyte recruitment into inflammatory sites. Depending on the type of assay used, neutrophil migration in vitro may be either dependent on or independent of SFKs. Also neutrophil recruitment in in vivo models of inflammation may be regulated differently by SFKs depending on the tissue involved. In this review we will discuss possible mechanisms by which SFKs may regulate phagocytic cell migratory abilities. 相似文献
330.
Two major functions of the Golgi apparatus (GA) are formation of complex glycans and sorting of proteins destined for various
subcellular compartments or secretion. To fulfill these tasks proper localization of the accessory proteins within the different
sub-compartments of the GA is crucial. Here we investigate structural determinants mediating transition of the two glycosyltransferases
β-1,4- galactosyltransferase 1 (gal-T1) and the α-1,3-fucosyltransferase 6 (fuc-T6) from the trans-Golgi cisterna to the trans-Golgi network (TGN). Upon treatment with the ionophore monensin both glycosyltransferases are found in TGN-derived swollen
vesicles, as determined by confocal fluorescence microscopy and density gradient fractionation. Both enzymes carry a signal
consisting of the amino acids E5P6 in gal-T1 and D2P3 in fuc-T6 necessary for the transition of these glycosyltransferases from the trans-Golgi cisterna to the TGN, but not for their steady state localization in the trans-Golgi cisterna.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
Received 30 July 2008; received after revision 17 September 2008; accepted 29 September 2008 相似文献