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81.
In the yeast Saccharomyces cerevisiae, triacylglycerol mobilization for phospholipid synthesis occurs during growth resumption from stationary phase, and this metabolism is essential in the absence of de novo fatty acid synthesis. In this work, we provide evidence that DGK1-encoded diacylglycerol kinase activity is required to convert triacylglycerol-derived diacylglycerol to phosphatidate for phospholipid synthesis. Cells lacking diacylglycerol kinase activity (e.g. dgk1Δ mutation) failed to resume growth in the presence of the fatty acid synthesis inhibitor cerulenin. Lipid analysis data showed that dgk1Δ mutant cells did not mobilize triacylglycerol for membrane phospholipid synthesis and accumulated diacylglycerol. The dgk1Δ phenotypes were partially complemented by preventing the formation of diacylglycerol by the PAH1-encoded phosphatidate phosphatase and by channeling diacylglycerol to phosphatidylcholine via the Kennedy pathway. These observations, coupled to an inhibitory effect of dioctanoyl-diacylglycerol on the growth of wild type cells, indicated that diacylglycerol kinase also functions to alleviate diacylglycerol toxicity. 相似文献
82.
Human microRNA-155 on chromosome 21 differentially interacts with its polymorphic target in the AGTR1 3' untranslated region: a mechanism for functional single-nucleotide polymorphisms related to phenotypes
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Sethupathy P Borel C Gagnebin M Grant GR Deutsch S Elton TS Hatzigeorgiou AG Antonarakis SE 《American journal of human genetics》2007,81(2):405-413
Animal microRNAs (miRNAs) regulate gene expression through base pairing to their targets within the 3' untranslated region (UTR) of protein-coding genes. Single-nucleotide polymorphisms (SNPs) located within such target sites can affect miRNA regulation. We mapped annotated SNPs onto a collection of experimentally supported human miRNA targets. Of the 143 experimentally supported human target sites, 9 contain 12 SNPs. We further experimentally investigated one of these target sites for hsa-miR-155, within the 3' UTR of the human AGTR1 gene that contains SNP rs5186. Using reporter silencing assays, we show that hsa-miR-155 down-regulates the expression of only the 1166A, and not the 1166C, allele of rs5186. Remarkably, the 1166C allele has been associated with hypertension in many studies. Thus, the 1166C allele may be functionally associated with hypertension by abrogating regulation by hsa-miR-155, thereby elevating AGTR1 levels. Since hsa-miR-155 is on chromosome 21, we hypothesize that the observed lower blood pressure in trisomy 21 is partially caused by the overexpression of hsa-miR-155 leading to allele-specific underexpression of AGTR1. Indeed, we have shown in fibroblasts from monozygotic twins discordant for trisomy 21 that levels of AGTR1 protein are lower in trisomy 21. 相似文献
83.
Autosomal dominant nonsyndromic cleft lip and palate: significant evidence of linkage at 18q21.1
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Beiraghi S Nath SK Gaines M Mandhyan DD Hutchings D Ratnamala U McElreavey K Bartoloni L Antonarakis GS Antonarakis SE Radhakrishna U 《American journal of human genetics》2007,81(1):180-188
Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common congenital facial defects, with an incidence of 1 in 700-1,000 live births among individuals of European descent. Several linkage and association studies of NSCL/P have suggested numerous candidate genes and genomic regions. A genomewide linkage analysis of a large multigenerational family (UR410) with NSCL/P was performed using a single-nucleotide-polymorphism array. Nonparametric linkage (NPL) analysis provided significant evidence of linkage for marker rs728683 on chromosome 18q21.1 (NPL=43.33 and P=.000061; nonparametric LOD=3.97 and P=.00001). Parametric linkage analysis with a dominant mode of inheritance and reduced penetrance resulted in a maximum LOD score of 3.61 at position 47.4 Mb on chromosome 18q21.1. Haplotype analysis with informative crossovers defined a 5.7-Mb genomic region spanned by proximal marker rs1824683 (42,403,918 bp) and distal marker rs768206 (48,132,862 bp). Thus, a novel genomic region on 18q21.1 was identified that most likely harbors a high-risk variant for NSCL/P in this family; we propose to name this locus "OFC11" (orofacial cleft 11). 相似文献
84.
Laggner H Muellner MK Schreier S Sturm B Hermann M Exner M Gmeiner BM Kapiotis S 《Free radical research》2007,41(7):741-747
Hypochlorite (HOCl), the product of the activated myeloperoxidase/H2O2/chloride (MPO/H2O2/Cl- ) system is favored as a trigger of LDL modifications, which may play a pivotal role in early atherogenesis. As HOCl has been shown to react with thiol-containing compounds like glutathione and N-acetylcysteine protecting LDL from HOCl modification, we have tested the ability of hydrogen sulfide (H2S)—which has recently been identified as an endogenous vasorelaxant—to counteract the action of HOCl on LDL. The results show that H2S could inhibit the atherogenic modification of LDL induced by HOCl, as measured by apolipoprotein alterations. Beside its HOCl scavenging potential, H2S was found to inhibit MPO (one may speculate that this occurs via H2S/heme interaction) and destroy H2O2. Thus, H2S may interfere with the reactants and reaction products of the activated MPO/H2O2/Cl- system. Our data add to the evidence of an anti-atherosclerotic action of this gasotransmitter taking the role of HOCl in the atherogenic modification of LDL into account. 相似文献
85.
Laggner H Schreier S Hermann M Exner M Mühl A Gmeiner BM Kapiotis S 《Free radical research》2007,41(2):234-241
Hypericin and pseudohypericin are polycyclic-phenolic structurally related compounds found in Hypericum perforatum L. (St John's wort). As hypericin has been found to bind to LDL one may assume that it can act as antioxidant of LDL lipid oxidation, a property which is of prophylactic/therapeutic interest regarding atherogenesis as LDL oxidation may play a pivotal role in the onset of atherosclerosis. Therefore, in the present paper hypericin, pseudohypericin and hyperforin, an other structurally unrelated constituent in St John's wort were tested in their ability to inhibit LDL oxidation. LDL was isolated by ultracentrifugation and oxidation was initiated either by transition metal ions (copper), tyrosyl radical (myeloperoxidase/hydrogen peroxide/tyrosine) or by endothelial cells (HUVEC). LDL modification was monitored by conjugated diene and malondialdehyde formation. The data show that all compounds (hypericin, pseudohypericin and hyperforin) at doses as low as 2.5 μmol/l are potent antioxidants in the LDL oxidation systems used. The results indicate that the derivatives found in Hypericum perforatum have possible antiatherogenic potential. 相似文献
86.
Djebali S Lagarde J Kapranov P Lacroix V Borel C Mudge JM Howald C Foissac S Ucla C Chrast J Ribeca P Martin D Murray RR Yang X Ghamsari L Lin C Bell I Dumais E Drenkow J Tress ML Gelpí JL Orozco M Valencia A van Berkum NL Lajoie BR Vidal M Stamatoyannopoulos J Batut P Dobin A Harrow J Hubbard T Dekker J Frankish A Salehi-Ashtiani K Reymond A Antonarakis SE Guigó R Gingeras TR 《PloS one》2012,7(1):e28213
87.
Adams D Altucci L Antonarakis SE Ballesteros J Beck S Bird A Bock C Boehm B Campo E Caricasole A Dahl F Dermitzakis ET Enver T Esteller M Estivill X Ferguson-Smith A Fitzgibbon J Flicek P Giehl C Graf T Grosveld F Guigo R Gut I Helin K Jarvius J Küppers R Lehrach H Lengauer T Lernmark Å Leslie D Loeffler M Macintyre E Mai A Martens JH Minucci S Ouwehand WH Pelicci PG Pendeville H Porse B Rakyan V Reik W Schrappe M Schübeler D Seifert M Siebert R Simmons D Soranzo N Spicuglia S Stratton M 《Nature biotechnology》2012,30(3):224-226
88.
Thapa A Morris L Xu J Ma H Michalakis S Biel M Ding XQ 《The Journal of biological chemistry》2012,287(22):18018-18029
Cyclic nucleotide-gated (CNG) channels play a pivotal role in phototransduction. Mutations in the cone CNG channel subunits CNGA3 and CNGB3 account for >70% of all known cases of achromatopsia. Cones degenerate in achromatopsia patients and in CNGA3(-/-) and CNGB3(-/-) mice. This work investigates the molecular basis of cone degeneration in CNG channel deficiency. As cones comprise only 2-3% of the total photoreceptor population in the wild-type mouse retina, we generated mouse lines with CNG channel deficiency on a cone-dominant background, i.e. CNGA3(-/-)/Nrl(-/-) and CNGB3(-/-)/Nrl(-/-) mice. The retinal phenotype and potential cell death pathways were examined by functional, biochemical, and immunohistochemical approaches. CNGA3(-/-)/Nrl(-/-) and CNGB3(-/-)/Nrl(-/-) mice showed impaired cone function, opsin mislocalization, and cone degeneration similar to that in the single knock-out mice. The endoplasmic reticulum stress marker proteins, including Grp78/Bip, phospho-eIF2α, phospho-IP(3)R, and CCAAT/enhancer-binding protein homologous protein, were elevated significantly in CNGA3(-/-)/Nrl(-/-) and CNGB3(-/-)/Nrl(-/-) retinas, compared with the age-matched (postnatal 30 days) Nrl(-/-) controls. Along with these, up-regulation of the cysteine protease calpains and cleavage of caspase-12 and caspase-7 were found in the channel-deficient retinas, suggesting an endoplasmic reticulum stress-associated apoptosis. In addition, we observed a nuclear translocation of apoptosis-inducing factor (AIF) and endonuclease G in CNGA3(-/-)/Nrl(-/-) and CNGB3(-/-)/Nrl(-/-) retinas, implying a mitochondrial insult in the endoplasmic reticulum stress-activated cell death process. Taken together, our findings suggest a crucial role of endoplasmic reticulum stress in cone degeneration associated with CNG channel deficiency. 相似文献
89.
90.
Plasma pro- and anti-inflammatory cytokine levels and outcome prediction in unselected critically ill patients 总被引:2,自引:0,他引:2
Dimopoulou I Orfanos S Kotanidou A Livaditi O Giamarellos-Bourboulis E Athanasiou C Korovesi I Sotiropoulou C Kopterides P Ilias I Kanellakopoulou K Armaganidis A 《Cytokine》2008,41(3):263-267
Purpose. To determine the inter-relationships between cytokine levels and physiological scores in predicting outcome in unselected, critically ill patients. Methods. To this end, 127 patients (96 men), having a mean ± SD age of 45 ± 20 years, with a wide range in admission diagnoses (medical, surgical, and multiple trauma patients) were prospectively investigated. Severity of critical illness and organ dysfunction were graded by acute physiology and chronic health evaluation (APACHE II) and sequential organ failure assessment (SOFA) scores, respectively. Blood samples were drawn on admission in the ICU to determine pro- and anti-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, and IL-10. The main outcome measure was 28-day mortality. Results. Overall, 88 patients survived and 39 patients died. Univariate logistic regression analysis showed that SOFA, APACHE II, IL-8, IL-6, and IL-10 on admission in the ICU were related to mortality. Multiple logistic regression analysis in the entire cohort of critically ill patients revealed that SOFA (OR = 1.341, p < 0.001) and IL-6 (OR = 1.075, p = 0.01) constituted independent outcome predictors. receiver operator characteristics curve analysis showed that SOFA, APACHE II, and IL-6 had the highest area under the curve values. IL-6 correlated with APACHE II (rs = 0.44, p < 0.0001) and SOFA (rs = 0.40, p < 0.0001) scores. Conclusions. In mixed ICU patients cytokine concentrations on admission in the ICU represent independent outcome predictors in the presence of disease severity scores. 相似文献