Genetic predictors of chronic heart failure in obese patients

BACKGROUND: the study of molecular genetic markers and pathogenetic mechanisms of neurohormonal activation, as well as their importance in the formation of heart failure in obesity, is an urgent problem of modern medicine, the solution of which will allow effective prevention of cardiovascular complications, optimize treatment and improve the prognosis of obese patients. AIMS: search for genetic markers presumably involved in the pathogenesis of secondary diastolic heart failure in patients with obesity. MATERIALS AND METHODS: PCR-diagnostics of whole blood of 104 patients with obesity was carried out, which were divided into 2 groups, depending on the presence of diastolic heart failure. The following candidate genes were analyzed: angiotensinogen AGT gene (C521T and T704C), angiotensin II receptor gene of the first type AGTR1 (A1166C), angiotensin II receptor gene of the second type AGTR2 (G1675A), aldosterone synthase gene CYP11B2 (C (-344) T). RESULTS: It is shown that the development of secondary diastolic heart failure in obese individuals of both sexes is associated with the mutation of the aldosterone synthase gene CYP11B2, namely, with the replacement of the C allele at the -344 position by the T allele and the presence of the T / T genotype. The relative risk of developing the disease with the T / T genotype was 5.93 times higher in men (p = 0.008) and 4.57 times in women (p = 0.014). For men, the mutation of the angiotensinogen AGT gene, namely the replacement of the allele C at position 521 by the T allele, is important. At the same time, the relative risk of development of SDS in the T / T genotype is increased by 4.26 times (p = 0.039). Mutations of the genes of the angiotensin II receptor of the first type AGTR1 (A1166C) and the angiotensin II receptor of the second type AGTR2 (G1675A) are not associated with the development of diastolic heart failure in obese patients. CONCLUSIONS: The data presented can be used to stratify the risk of secondary heart failure in obese individuals

Creation of development zones in the Arctic: methodology and practice

The article describes the basic principles and methodological bases of formation and development of the supporting areas of the Russian Arctic. The work emphasizes that the basis of the methodological approach in the formation of the supporting areas is a vector of development of the territory as an integral project on the principle of coordination of all "industrial" activities in the planning, goal-setting, financing and implementation, which will allow to reduce all kinds of costs and expenses, as well as all the projects included in the supporting areas should be aimed at the development of the macro-region as a whole, not just to solve individual tasks of the industry. The article underlines that the formation of the supporting areas is aimed at achieving a single global goal — to encourage efficiency and diversification of the economy of the Arctic zone, oriented to the preservation and development of the Northern Sea Route

Na,K-ATPase Acts as a Beta-Amyloid Receptor Triggering Src Kinase Activation

Beta-amyloid (Aβ) has a dual role, both as an important factor in the pathology of Alzheimer’s disease and as a regulator in brain physiology. The inhibitory effect of Aβ42 oligomers on Na,K-ATPase contributes to neuronal dysfunction in Alzheimer’s disease. Still, the physiological role of the monomeric form of Aβ42 interaction with Na,K-ATPase remains unclear. We report that Na,K-ATPase serves as a receptor for Aβ42 monomer, triggering Src kinase activation. The co-localization of Aβ42 with α1- and β1-subunits of Na,K-ATPase, and Na,K-ATPase with Src kinase in SH-SY5Y neuroblastoma cells, was observed. Treatment of cells with 100 nM Aβ42 causes Src kinase activation, but does not alter Na,K-ATPase transport activity. The interaction of Aβ42 with α1β1 Na,K-ATPase isozyme leads to activation of Src kinase associated with the enzyme. Notably, prevention of Na,K-ATPase:Src kinase interaction by a specific inhibitor pNaKtide disrupts the Aβ-induced Src kinase activation. Stimulatory effect of Aβ42 on Src kinase was lost under hypoxic conditions, which was similar to the effect of specific Na,K-ATPase ligands, the cardiotonic steroids. Our findings identify Na,K-ATPase as a Aβ42 receptor, thus opening a prospect on exploring the physiological and pathological Src kinase activation caused by Aβ42 in the nervous system

Crystal structure, Fermi surface calculations and Shubnikov-de Haas oscillations spectrum of the organic metal θ\theta-(BETS)4_4HgBr4_4(C6_6H5_5Cl) at low temperature

The organic metal \theta$-(BETS)$_4$HgBr$_4$(C$_6$H$_5$Cl) is known to undergo a phase transition as the temperature is lowered down to about 240 K. X-ray data obtained at 200 K indicate a corresponding modification of the crystal structure, the symmetry of which is lowered from quadratic to monoclinic. In addition, two different types of cation layers are observed in the unit cell. The Fermi surface (FS), which can be regarded as a network of compensated electron and hole orbits according to band structure calculations at room temperature, turns to a set of two alternating linear chains of orbits at low temperature. The field and temperature dependence of the Shubnikov-de Haas oscillations spectrum have been studied up to 54 T. Eight frequencies are observed which, in any case, points to a FS much more complex than predicted by band structure calculations at room temperature, even though some of the observed Fourier components might be ascribed to magnetic breakdown or frequency mixing. The obtained spectrum could result from either an interaction between the FS's linked to each of the two cation layers or to an eventual additional phase transition in the temperature range below 200 K.Comment: accepted for publication in Solid State Science

Number Sense and Mathematics: Which, When and How?

Individual differences in number sense correlate with mathematical ability and performance, although the presence and strength of this relationship differs across studies. Inconsistencies in the literature may stem from heterogeneity of number sense and mathematical ability constructs. Sample characteristics may also play a role as changes in the relationship between number sense and mathematics may differ across development and cultural contexts. In this study, 4,984 16-year-old students were assessed on estimation ability, one aspect of number sense. Estimation was measured using two different tasks: number line and dot-comparison. Using cognitive and achievement data previously collected from these students at ages 7, 9, 10, 12, and 14 years of age, the study explored for which of the measures and when in development these links are observed; how strong these links are and how much these links are moderated by other cognitive abilities. The two number sensemeasures correlated modestly with each other (r = .22), but moderately with mathematics at age 16. Both measures were also associated with earlier mathematics; but this association was uneven across development and was moderated by other cognitive abilities

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Introduction: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive as

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.

We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.352

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk