Highly Significant Association between Two Common Single Nucleotide Polymorphisms in CORIN Gene and Preeclampsia in Caucasian Women

Preeclampsia is a frequent medical complication during pregnancy. Corin, a serine protease which activates pro-atrial natriuretic peptide, has recently been shown to be involved in the pathophysiology of preeclampsia. The aim of this study was to search for CORIN gene variations and their association to preeclampsia in Caucasian and African women. Our study population was composed of 571 pregnant women (295 with preeclampsia and 276 normotensive controls) matched for maternal and gestational age, and ethnic origin. The 22 exons of the CORIN gene were sequenced in a discovery sample (n = 260), where 31 single nucleotide polymorphisms were identified. In a replication sample (n = 311), 4 single nucleotide polymorphisms were tested. Two minor alleles (C for rs2271036 and G for rs2271037) were significantly associated to preeclampsia. Adjusted odds ratios [95% confidence interval] were 2.5 [1.2–3.8] (p = 0.007) and 2.3 [1.5–3.5] (p = 1.3×10⁻⁴), respectively. These associations were ethnic-specific, as only found in the Caucasian of subjects (odds ratio = 3.5 [1.8–6.6], p = 1.1×10⁻⁴; odds ratio = 3.1 [1.7–5.8], p = 2.1×10⁻⁴, for each single nucleotide polymorphism, respectively). The two single nucleotide polymorphisms are in almost perfect linkage disequilibrium (r² = 0.93). No specific association was found with severe preeclampsia, early-onset preeclampsia nor fetal growth retardation. In conclusion, this is the first report of a highly significant association between these two single nucleotide polymorphisms in CORIN gene and preeclampsia. Our findings further support the probability of a critical role of corin in preeclamspia pathophysiology at the uteroplacental interface.     

apoE3[K146N/R147W] acts as a dominant negative apoE form that prevents remnant clearance and inhibits the biogenesis of HDL

The K146N/R147W substitutions in apoE3 were described in patients with a dominant form of type III hyperlipoproteinemia. The effects of these mutations on the in vivo functions of apoE were studied by adenovirus-mediated gene transfer in different mouse models. Expression of the apoE3[K146N/R147W] mutant in apoE-deficient (apoE^−/−) or apoA-I-deficient (apoA-I^−/−)×apoE^−/− mice exacerbated the hypercholesterolemia and increased plasma apoE and triglyceride levels. In apoE^−/− mice, the apoE3[K146N/R147W] mutant displaced apoA-I from the VLDL/LDL/HDL region and caused the accumulation of discoidal apoE-containing HDL. The WT apoE3 cleared the cholesterol of apoE^−/− mice without induction of hypertriglyceridemia and promoted formation of spherical HDL. A unique property of the truncated apoE3[K146N/R147W]202 mutant, compared with similarly truncated apoE forms, is that it did not correct the hypercholesterolemia. The contribution of LPL and LCAT in the induction of the dyslipidemia was studied. Treatment of apoE^−/− mice with apoE3[K146N/R147W] and LPL corrected the hypertriglyceridemia, but did not prevent the formation of discoidal HDL. Treatment with LCAT corrected hypertriglyceridemia and generated spherical HDL. The combined data indicate that the K146N/R147W substitutions convert the full-length and the truncated apoE3[K146N/R147W] mutant into a dominant negative ligand that prevents receptor-mediated remnant clearance, exacerbates the dyslipidemia, and inhibits the biogenesis of HDL.     

Independent interaction of the acyltransferase HlyC with two maturation domains of the Escherichia coli toxin HlyA

The apparently unique fatty acylation mechanism that underlies activation (maturation) of Escherichia coli haemolysin and related toxins is further clarified by investigation of the interaction of protoxin with the specific acyltransferase HlyC. Using deleted protoxin variants and protoxin peptides as substrates in an in vitro maturation reaction dependent upon HlyC and acyl-acyl carrier protein, two independent HlyC recognition domains were identified on the 1024-residue protoxin, proA, and they were shown to span the two target lysine residues K₅₆₄ (KI) and K₆₉₀ (KII) that are fatty acylated. Each domain required 15–30 amino acids for basal recognition and 50–80 amino acids for wild-type acylation. The two domains (FAI and FAII) competed with each other in cis and in trans for HlyC. The affinity of FAI for HlyC is approximately four times greater than that of FAII resulting in an overall 80% acylation at KI and 20% acylation at KII in both whole toxin and peptide derivatives. No other proA sequences were required for toxin maturation, and excess Ca²⁺ prevented acylation of both lysines. The lack of primary sequence identity between FAI and FAll domains in proA and among corresponding sites on related protoxins currently precludes an explanation of the basis of HlyC recognition by proA.     

Increased plasma ghrelin levels in chronic renal failure are not associated with hemodynamic parameters.

BACKGROUND/AIMS: Hardly anything is known about the effect of renal function on plasma ghrelin levels. Ghrelin is an orexigenic hormone with important hemodynamic effects. We examined differences in plasma ghrelin levels between chronic renal failure (CRF) patients and healthy subjects, and ghrelin's relationship with indices of left ventricular (LV) function. METHODS: Fasting total plasma ghrelin levels were measured in 122 CRF patients (57 on, 65 not on hemodialysis) and 57 control subjects. Indices of LV function were evaluated using echocardiography. RESULTS: Total plasma ghrelin levels were higher in patients with CRF compared to controls, but were not different between patients on and those not on hemodialysis. In a multivariate linear regression model, presence of kidney dysfunction explained 41 % of the variability of ghrelin values. The etiology of renal failure (diabetic nephropathy or not) had no influence on ghrelin levels in the renal patients. Ghrelin levels were not associated with indices of LV systolic function or blood pressure in these patients. CONCLUSION: Fasting plasma ghrelin concentrations are higher in CRF patients regardless of their need for hemodialysis compared to controls. The etiology of renal failure does not have any effect on plasma ghrelin levels. In addition, ghrelin levels are not associated with hemodynamic parameters in patients with CRF.     

Spectrophotometric assays for measuring redox biomarkers in blood

The assessment of redox status is most frequently performed by measuring redox biomarkers. The spectrophotometer is the most commonly used analytical instrument in biochemistry. There is a huge number of spectrophotometric redox biomarkers and assays, thus distinguishing the most appropriate biomarkers and protocols is overwhelming. The aim of the present review is to propose valid and reliable spectrophotometric assays for measuring redox biomarkers in blood. It is hoped that this work will help researchers to select the most suitable redox biomarkers and assays.     

Projections of the availability and cost of residues from agriculture and forestry

By‐products of agricultural and forestry processes, known as residues, may act as a primary source of renewable energy. Studies assessing the availability of this resource offer little insight on the drivers and constraints of the available potential as well as the associated costs and how these may vary across scenarios. This study projects long‐term global supply curves of the available potential using consistent scenarios of agriculture and forestry production, livestock production and fuel use from the spatially explicit integrated assessment model IMAGE. In the projections, residue production is related to agricultural and forestry production and intensification, and the limiting effect of ecological and alternative uses of residues are accounted for. Depending on the scenario, theoretical potential is projected to increase from approximately 120 EJ yr^?1 today to 140–170 EJ yr^?1 by 2100, coming mostly from agricultural production. To maintain ecological functions approximately 40% is required to remain in the field, and a further 20–30% is diverted towards alternative uses. Of the remaining potential (approximately 50 EJ yr^?1 in 2100), more than 90% is available at costs <10By‐products of agricultural and forestry processes, known as residues, may act as a primary source of renewable energy. Studies assessing the availability of this resource offer little insight on the drivers and constraints of the available potential as well as the associated costs and how these may vary across scenarios. This study projects long‐term global supply curves of the available potential using consistent scenarios of agriculture and forestry production, livestock production and fuel use from the spatially explicit integrated assessment model IMAGE. In the projections, residue production is related to agricultural and forestry production and intensification, and the limiting effect of ecological and alternative uses of residues are accounted for. Depending on the scenario, theoretical potential is projected to increase from approximately 120 EJ yr^?1 today to 140–170 EJ yr^?1 by 2100, coming mostly from agricultural production. To maintain ecological functions approximately 40% is required to remain in the field, and a further 20–30% is diverted towards alternative uses. Of the remaining potential (approximately 50 EJ yr^?1 in 2100), more than 90% is available at costs <10$₂₀₀₅ GJ^?1. Crop yield improvements increase residue productivity, albeit at a lower rate. The consequent decrease in agricultural land results in a lower requirement of residues for erosion control. The theoretical potential is most sensitive to baseline projections of agriculture and forestry demand; however, this does not necessarily affect the available potential which is relatively constant across scenarios. The most important limiting factors are the alternative uses. Asia and North America account for two‐thirds of the available potential due to the production of crops with high residue yields and socioeconomic conditions which limit alternative uses.     

Presence of a p70 IL-2-binding peptide on leukemic cells from various hemopoietic lineages

Recent studies have shown that IL-2R are composed of at least two polypeptide chains of 55 kDa (Tac or alpha-chain) and 70 to 75 kDa (p70 or beta-chain). The association of both chains forms high affinity IL-2R, whereas each chain alone binds IL-2 with a low (alpha-chain) or intermediate (beta-chain) affinity. So far, the p70 peptide has been found, in the absence of the Tac peptide, on the surface of lymphoid cells of T, B, or NK lineage. In this study, we investigated whether leukemic cells of various hemopoietic lineages expressed the p70 IL-2-binding protein. We found that both fresh leukemic cells obtained from patients, and cells from established leukemic lines of T cells, B cell, and myeloid origin constitutively expressed a p70 IL-2-binding protein on their surface, as detected by affinity cross-linking of radioiodinated IL-2. IL-2 binding and cross-linking to these cells was completely inhibited in the presence of an excess unlabeled rIL-2, but not with an anti-Tac mAb. Binding experiments on pre-B and myeloid cell lines revealed intermediate affinity IL-2R, whereas both high and intermediate affinity IL-2R were detected in T leukemic cells. The intermediate affinity binding of 125I-rIL-2 to the leukemic cell lines MOLT4 and Reh6 was inhibited by the TU27 mAb, which recognized the p75 chain of IL-2R. Moreover, the TU27 mAb could stain the K562, KM3, and MOLT4 (weakly) cell lines by indirect immunofluorescence. A high dose of rIL-2 (400 U/ml) enhanced the proliferation of cells from one out of three patients with acute myeloblastic leukemia, but it did not induce differentiation of the cells in any of three cases. Thus the finding of p70 IL-2-binding molecules on immature lymphoid and nonlymphoid hemopoietic cells should disclose new biologic functions for IL-2.