Association of Polymorphic Variants of TCF7L2 and PPARG Genes with Metabolic Markers in Patients with Early Disorders of Carbohydrate Metabolism.

We performed complex analysis of the association of polymorphic variants rs7903146 of the TCF7L2 gene and rs1801282 of the PPARG gene with metabolic parameters, insulin resistance, and ß-cell function in a group of patients with early signs of carbohydrate metabolism disturbances in a sample of Tyumen citizens. The study group consisted of 64 people (39 women, 25 men) aged 40-70 years. The distribution of frequencies of alleles and genotypes of the polymorphic markers rs7903146 and rs1801282 was analyzed and associations of carriage of major homozygous polymorphisms with various phenotypic traits were identified. Genotyping for polymorphic variants of TCF7L2 and PPARG genes was performed using allele-specific PCR with primers provided by Synthol company. Carriers of homozygotes for allele C of the polymorphic marker rs7903146 significantly differed from other respondents by a higher level of C-peptide, as well as by the presence of associations with waist circumference, elevated level of glycated hemoglobin, and arterial hypertension. Carriers of homozygotes for the allele C of the rs1801282 polymorphism of the PPARG gene differed from the group of carriers of homozygotes for the allele G and the group of heterozygote carriers by higher levels of triglycerides, as well as the presence of associations with waist circumference and the level of glycated hemoglobin.

Effect of Gonadotropin-Releasing Hormone Antagonist on the Expression Patterns of Insulin-Like Growth Factor 1, Androgen Receptor, and Luteinizing Hormone Receptor in an Experimental Rat Model of Functional Ovarian Cysts.

We studied the expression of insulin-like growth factor 1 (IGF-1), androgen receptor (AR) and luteinizing hormone receptor (LHR) in the ovaries under the conditions of the modeling and subsequent treatment of functional ovarian cysts with gonadotropin-releasing hormone antagonist (ant-GnRH). The intensity of IGF-1, LHR, and AR expression in the generative elements of rat ovaries changed under conditions of functional ovarian cysts simulation, as well as during treatment with ant-GnRH. In both experimental groups, the expression levels of the studied markers in preantral follicles and epithelial lining of cysts were found to be related to the number of growing follicles and cysts. A divergence of LHR and AR expression indices and a more pronounced decrease in the number of cystic cavities were observed in the group receiving ant-GnRH. These changes demonstrate a positive effect of ant-GnRH on intra-ovarian regulatory factors and a therapeutic effect in functional ovarian cysts.

Morphofunctional State of the Ovaries in Rats with Experimental Model of Functional Cysts and Their Treatment with Gonadotropin-Releasing Hormone Antagonist.

The morphofunctional features of the ovaries were evaluated in rats with functional ovarian cysts model treated with gonadotropin-releasing hormone antagonist. Administration of the antagonist significantly (p=0.009) reduced the number of cysts and the growth of follicles in the ovaries. The obtained results attest to a possibility of successful treatment of functional ovarian cysts with gonadotropin-releasing hormone antagonist.

Performance of a cryo-cooled crystal monochromator illuminated by hard X-rays with MHz repetition rate at the European X-ray Free-Electron Laser.

Due to the high intensity and MHz repetition rate of photon pulses generated by the European X-ray Free-Electron Laser, the heat load on silicon crystal monochromators can become large and prevent ideal transmission in Bragg diffraction geometry due to crystal deformation. Here, we present experimental data illustrating how heat load affects the performance of a cryogenically cooled monochromator under such conditions. The measurements are in good agreement with a depth-uniform model of X-ray dynamical diffraction taking beam absorption and heat deformation of the crystals into account.

Materials Imaging and Dynamics (MID) instrument at the European X-ray Free-Electron Laser Facility.

The Materials Imaging and Dynamics (MID) instrument at the European X-ray Free-Electron Laser (EuXFEL) facility is described. EuXFEL is the first hard X-ray free-electron laser operating in the MHz repetition range which provides novel science opportunities. The aim of MID is to enable studies of nano-structured materials, liquids, and soft- and hard-condensed matter using the bright X-ray beams generated by EuXFEL. Particular emphasis is on studies of structure and dynamics in materials by coherent scattering and imaging using hard X-rays. Commission of MID started at the end of 2018 and first experiments were performed in 2019.

[The role of nutritional factors in the formation of cardiovascular risk in patients with type 2 diabetes mellitus].

Cardiovascular diseases are the most common complications of type 2 diabetes mellitus (T2DM) and remain the main cause of mortality in this category of patients. Currently, there is more and more data that confirm the influence of nutritional factors not only on the achievement of target values of metabolic parameters in diabetes, but also on predictors of cardiovascular risk, and also demonstrate their role as independent predictors. In this regard, the study of the role of nutritional factors in the formation of high cardiovascular risk in patients with T2DM is of high practical importance and relevance. The aim was to assess the role of nutritional factors in the formation of high total cardiovascular risk in patients with T2DM. Material and methods. An open clinical controlled prospective observation was carried out for one year in 110 patients with T2DM (87 women and 23 men, mean age 56.7±8.6 years). The average value of glycated hemoglobin (HbA1c) in the group was 8.95±2.09%, the av erage value of the body mass index was 32.3±6.2 kg/m2. All patients were assessed for traditional cardiovascular risk factors, markers of systemic inflammation and endothelial dysfunction, nutritional status was assessed by analyzing the frequency of consumption and a general semi-quantitative assessment of the intake of nutrients, food groups, and energy. During a one-year prospective follow-up, total cardiovascular endpoints were recorded and the effect of patient education on metabolic parameters, nutritional factors, and cardiovascular risk was assessed. Results. In patients with T2DM who had various clinical forms of cardiovascular diseases, the diet had an increased level of fats, which exceeded the intake in individuals without complications (p=0.013), and saturated fatty acids (SFA) (p=0.003). The risk of developing cardiovascular events in patients with T2DM increased by 5 times under excessive consumption of products containing SFA (meat, animal fats, sausages) (OR 5.34; CI 3.05-10.22, p=0.001). The decrease in body weight in the target range (by 7-10% during the year) was characterized by a decrease in the HbA1c by 11.9%, postprandial glycemia by 25.7%, total cholesterol by 20.4%, atherogenic coefficient by 25.0%, plasminogen activator inhibitor-1 by 8.5%, highly sensitive C-reactive protein by 27.4%, systolic blood pressure by 6.9%, and also was accompanied by significant decrease in unfavorable total cardiovascular events during the year (p=0.024). In addition, in the group of patients who underwent training, there was a decrease in the total amount of calories consumed (p=0.018), consumption of SFA (p=0.021) and mono- and disaccharides (p=0.001), an increase in dietary fiber in the diet (p=0.015). Conclusion. In the course of the study, an imbalance in the nutritional components of the diet in patients with T2DM was revealed. The significant role of alimentary factors in the formation of high cardiovascular risk has been demonstrated, as well as the effectiveness of therapeutic education of patients in terms of managing behavioral risk factors.

Angle-Resolved Auger Spectroscopy as a Sensitive Access to Vibronic Coupling.

In the angle-averaged excitation and decay spectra of molecules, vibronic coupling may induce the usually weak dipole-forbidden transitions by the excitation intensity borrowing mechanism. The present complementary theoretical and experimental study of the resonant Auger decay of core-to-Rydberg excited CH_{4} and Ne demonstrates that vibronic coupling plays a decisive role in the formation of the angle-resolved spectra by additionally involving the decay rate borrowing mechanism. Thereby, we propose that the angle-resolved Auger spectroscopy can in general provide very insightful information on the strength of the vibronic coupling.

Preventive Salpingectomy and Ovarian Reserve: Experimental Study.

The levels of anti-Müllerian hormone, follicle-stimulating hormone, and testosterone were studied in rats after removal of the uterine horns, oviducts, or combined surgery. The effects of preventive salpingectomy on ovarian reserve were studied. After preventive salpingectomy, the level of anti-Müllerian hormone was low throughout the experiment, follicle-stimulating hormone increased only by the end of observation (on day 40), and testosterone level decreased only on day 10. Hysterectomy alone caused no changes in the concentrations of the studied hormones on day 10 after surgery. Salpingectomy alone reduced the concentrations of anti-Müllerian hormone and testosterone and did not change the level of follicle-stimulating hormone during this period.

Personified strategy for the correction of cardiometabolic risk factors in the alien population of the Arctic.

Aim. To estimate the efficacy and prognostic value of individual consulting in Far North inhabitants during a 5 year survey. Materials and methods. 125 patients with metabolic syndrome were included in the study (24.8% women, 24.8% men, age median 45 years (39-48); p > 0.05). All the participants were divided into 2 groups dependence on the consulting frequency in the framework of the non-surgical body mass reduction programs (group 1 - single consulting, group 2 - repeated consultings in 12 months). Results. Individual consulting of patients with MS within 3 months after the onset of the study allowed the target body mass to be achieved in 50% of the patients in association with the reduction of atherogenic lipid fractions (p < 0,05), insulin resistance (p < 0,05), inflammation markers, hemostasis disorders markers (p < 0,05) and decrease in the number of patients with behavioral risk factors. Repeated educational module increased the relative probability 1,9 (95% CI 1,03-3,6) and odds ratio - 2.4 (95% CI 1,01-5,4) of body mass maintenance within 24 months and also reduced the risk of type 2 DM development (Cox's F-Test: F = 2,7; p = 0,041) and atherogenicity of lipid profile after 5 year observations. Conclusion. Our results proves the necessity of active utilization of educational modules at least as often as once a year. For the successful use of these modules based at outpatient facilities of the Far North it is necessary to include a dietologist in the staff of prophylactic departments which encounters difficulty under the modern funding mode.

[Group preventive consulting influence on body mass correction and nutrition disorders. 5-year prospective survey].

The aim of the work was to analyze education technologies efficacy using group methods of prevention (body mass correction school) in patients with overweight and obesity, living in Extreme North, according to a 5-year prospective survey. 181 Extreme North alien inhabitants have been investigated (23.2% men, 76.8% women) with overweight and obesity. 144 of them were surveyed during 5 years. Age median was 37 (29-49) years, including men - 33 (29-43) and women - 39.5 (27.5-48) (p=0.123). All participants were divided into 2 groups depending on preventive group education compliance. Group 1 received brief recommendations for the inspection, Group 2 was trained with the group of preventive counseling. Within 3 months of surveillance target body mass reduction was achieved by 11.3% of patients of the group 1 and 31.5% of patients of the group 2 (p=0.0018). By the end of the first year these parameters proved to be 7% and 16.4% (p=0.0453). After that there was no significant difference between groups, although about 5-6% of responders kept the achieved target of BM reduction even in group 1. Group prevention consulting is associated with short time reduction of such risk factors prevalence as low physical activity (from 86.3 to 61.1% during 3 months, p<0.005), insufficient fruits and vegetables consumption and violation of macro- and micronutrient composition of the daily diet. It is also accompanied with lower cumulative proportion of patients without all metabolic syndrome components (Cox's F-Test: F=2.61; p=0.0178) and a significant reduction of percent of patients having SCORE-risk >5% (p=0.0461) after 5 years of surveillance. Thus, group preventive consulting raises awareness of patients about their health status, leads to daily meal ratio impairment reduction, decreases prevalence of obesity and low physical activity in short time period and reduces MS - risk. During 3 months after consulting body mass reduction (of 5% or more) was observed in 30% of patients. Achieved result is stable within following 12 months in less than 16% of patients. In the longer term, education is accompanied by a decrease in MS risk and some reduction in SCORE-risk.

[Content of heavy metals and petroleum products in the soil on the territory of oilproducing areas of the Republic of Tatarstan].

The paper presents data on the hygienic assessment of the content of heavy metals and petroleum products in the soil on the territory of oil-producing areas of the Republic of Tatarstan. The average total content of lead (10,1 mg/kg), cadmium (0.073 mg/kg), manganese (792.4 mg/kg), cobalt (14.2 mg/kg), chromium (87.6 mg/kg), nickel (65.2 mg/ kg), arsenic (8.0 mg/kg), copper (36.6 mg/kg) and zinc (521 mg/kg) in soil for agricultural purposes near objects oil production was shown not to exceed the established hygienic standards. Soil contamination with oil products leads to an increase in its toxicity and mutagenicity. Soil contamination with oil products at the level of as low as 30 mg/ kg leads to the gain in its toxicity (low toxicity) and mutagenicity (average) (specific gravity of germinated seeds was 70.7±0.67%, aberrations - 1.78±0.19%).

Delta deletion 4977 in mitochondrial DNA in patients with idiopathic Parkinson's disease.

AIM: To determine the presence of delta deletion 4977 in mitochondrial DNA in patients with Idiopathic Parkinson's disease (IPD). MATERIAL AND METHODS: This has been a prospective, clinically genetic study, lasting for whole two years. The clinical part of this study was made at the University Clinic of Neurology in Skopje, Unit for extrapyramidal diseases. The laboratory-genetic part of the study was elaborated at the Laboratory for molecular biology at the Institute for Biology, Faculty of Sciences, University "Sts. Cyril and Methodius". This study comprised a total of 32 subjects with a clinically verified diagnosis for idiopathic Parkinson's disease; 18 men and 14 women (with mean age of 52.7 years). Control group consisted of 31 randomly selected, literally healthy persons, at similar age, with similar gender distribution, and no clinical and anamnestic data for parkinsonism or similar clinical entities. RESULTS: Objective neurologic results of all 32 investigated subjects (100%) showed presence of rigor, tremor and bradykinesia.The difference tested between the investigated and control group, concerning the present or absent deletion and heteroplasmia, has been highly statistically significant (p=0.001). CONCLUSION: It could be concluded with a great statistical significance that deletion 4977 in mitochondrial genome has been registered more frequently in the group of patients with IPD (Tab. 10, Fig. 6, Ref. 36).

[Proinflammatory cytokine levels depending on the stage of hepatic fibrosis in patients with metabolic syndrome and non-alcoholic fatty liver disease].

AIM: To study levels of systemic inflammation markers and plasminogen activator inhibitor-1 (PAL-1) in patients with metabolic syndrome (MS) and establish their relationship with the progress of selected stages of non-alcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: 129 patients aged 18-59 yr with abdominal obesity and MS underwent elastometry for the assessment of the degree of fibrosis depending on concomitant metabolic disorders and measurement of proinflammatory cytokine levels. RESULTS: Disorders of carbohydrate metabolism in MS patients are associated with the high levels of systemic inflammation markers (CRP, TNF-α, IL-6) and a two-fold rise in the PAI-1 level. The progress of fibrosis is associated with the increase of cytokine levels. CONCLUSION: Patients with MS and NAFLD associated with disorders of carbohydrate metabolism need to be examined by elastometry for the detection of fibrosis with simultaneous measurement of IL-6 and PAI-1 levels as cardiovascular risk factors.

The persistence of seroprotective levels of antibodies after vaccination with PreHevbrio, a 3-antigen hepatitis B vaccine.

Prevention of hepatitis B virus (HBV) infection by vaccination can potentially eliminate HBV-related diseases. PreHevbrio™/PreHevbri® is a 3-antigen (S, preS1, preS2) HBV vaccine (3A-HBV) recently licensed for adults in the US, EU and Canada. This study evaluated antibody persistence in a subset of fully vaccinated and seroprotected (anti-HBs ≥ 10 mIU/mL) Finnish participants from the phase 3 trial (PROTECT) of 3A-HBV versus single-antigen HBV vaccine (1A-HBV). 465/528 eligible subjects were enrolled (3A-HBV: 244; 1A-HBV: 221). Baseline characteristics were balanced. After 2.5 years, more 3A-HBV subjects remained seroprotected (88.1 % [95 %CI: 84.1,92.2]) versus 1A-HBV (72.4 % [95 %CI: 66.6,78.3)], p < 0.0001) and had higher mean anti-HBs [1382.9 mIU/mL (95 %CI: 1013.8,1751.9) versus 252.6 mIU/mL (95 %CI: 127.5,377.6), p < 0.0001]. In multiple variable logistic regression analysis including age, vaccine, initial vaccine response, sex and BMI, only higher post dose 3 (Day 196) antibody titers significantly reduced the odds of losing seroprotection.

Optoacoustic monitoring of cerebral venous blood oxygenation though intact scalp in large animals.

Monitoring (currently invasive) of cerebral venous blood oxygenation is a key to avoiding hypoxia-induced brain injury resulting in death or severe disability. Noninvasive, optoacoustic monitoring of cerebral venous blood oxygenation can potentially replace existing invasive methods. To the best of our knowledge, we report for the first time noninvasive monitoring of cerebral venous blood oxygenation through intact scalp that was validated with invasive, "gold standard" measurements. We performed an in vivo study in the sheep superior sagittal sinus (SSS), a large midline cerebral vein, using our novel, multi-wavelength optoacoustic system. The study results demonstrated that: 1) the optoacoustic signal from the sheep SSS is detectable through the thick, intact scalp and skull; 2) the SSS signal amplitude correlated well with wavelength and actual SSS blood oxygenation measured invasively using SSS catheterization, blood sampling, and measurement with "gold standard" CO-Oximeter; 3) the optoacoustically predicted oxygenation strongly correlated with that measured with the CO-Oximeter. Our results indicate that monitoring of cerebral venous blood oxygenation may be performed in humans noninvasively and accurately through the intact scalp using optoacoustic systems because the sheep scalp and skull thickness is comparable to that of humans whereas the sheep SSS is much smaller than that of humans.

Influence of the SCN1A IVS5N + 5 G>A Polymorphism on Therapy with Carbamazepine for Epilepsy.

Carbamazepine (CBZ) blocks neuronal sodium channels in a voltage- and frequency-dependent manner, delaying the recovery of the channels from the inactivated state, reducing the number of action potentials within a burst, and decreasing burst duration. The α-subunit of the first neuronal sodium channel (SCN1A) is a major gene in different epilepsies. A synonymous polymorphism (SCN1A IVS5N + 5 G>A or rs3812718) is common in exon 5 of this gene. Mutations in the α-unit of this gene are associated with CBZ-resistant epilepsy and a higher maintenance dose of CBZ. We have investigated the association of this single nucleotide polymorphism (SNP) and epilepsy, efficacy and dose-dependence of CBZ therapy in 147 adult Macedonian patients and 137 non epileptic controls. No significant differences in allelic frequencies and genotype distribution were found between patients and controls (p = 0.94278), or between CBZ-responsive and unresponsive patients (p = 0.55449). An association between the A allele and a higher maintenance dose in CBZ-responsive patients was detected. No statistical difference was found between the plasma levels of CBZ and genotype of patients receiving the same dose, indicating that the variant exerts its effect at the level of receptor responsiveness. The predictive value of pretreatment testing showed a minor insignificant difference between patients with different genotypes, primarily due to a small number of patients.

Dense, single-phase, hard, and stress-free Ti0.32Al0.63W0.05N films grown by magnetron sputtering with dramatically reduced energy consumption.

The quest for lowering energy consumption during thin film growth, as by magnetron sputtering, becomes of particular importance in view of sustainable development goals. A recently proposed solution combining high power impulse and direct current magnetron sputtering (HiPIMS/DCMS) relies on the use of heavy metal-ion irradiation, instead of conventionally employed resistive heating, to provide sufficient adatom mobility, in order to obtain high-quality dense films. The major fraction of process energy is used at the sputtering sources rather than for heating the entire vacuum vessel. The present study aims to investigate the W+ densification effects as a function of increasing Al content in (Ti1-yAly)1-xWxN films covering the entire range up to the practical solubility limits (y ~ 0.67). Layers with high Al content are attractive to industrial applications as the high temperature oxidation resistance increases with increasing Al concentration. The challenge is, however, to avoid precipitation of the hexagonal wurtzite AlN phase, which is softer. We report here that (Ti1-yAly)1-xWxN layers with y = 0.66 and x = 0.05 grown by a combination of W-HiPIMS and TiAl-DCMS with the substrate bias Vs synchronized to the W+-rich fluxes (to provide mobility in the absence of substrate heating) possess single-phase NaCl-structure, as confirmed by XRD and SAED patterns. The evidence provided by XTEM images and the residual oxygen content obtained from ERDA analyses reveals that the alloy films are dense without discernable porosity. The nanoindentation hardness is comparable to that of TiAlN films grown at 400-500 °C, while the residual stresses are very low. We established that the adatom mobility due to the heavy ion W+ irradiation (in place of resistive heating) enables the growth of high-quality coatings at substrate temperatures not exceeding 130 °C provided that the W+ momentum transfer per deposited metal atom is sufficiently high. The benefit of this novel film growth approach is not only the reduction of the process energy consumption by 83%, but also the possibility to coat temperature-sensitive substrates.

[The position of cleavage furrow in cultivated cells on the example of lines L-929 and CHO].

The aim of the study carried out on cells of lines L-929 (NCTC a clone 929) and CHO was to examine whether the position of cleavage furrow is random or not. CHO cells were seeded in the traditional way (evenly across the surface of a Petri dish), and L-cell were put as colonies to monitor the migration of cells emanating from them. The time-lapse filming (imaging) was used for registration of behavior of cells. Analyzing the obtained images of cells, the angle between the axis of polarization of a cell and its cleavage furrow was measured. Besides, the angle between an axis of cell polarization or its cleavage furrow and the horizontal axis of image field was measured. It was shown that position of CHO cells in a dish plane was random as well as the value of the angle between the axis of polarization of these cells and their cleavage furrows. The L-929 cells migrating from colony were orientated so, that their polarization axis was directed to the colony center, and the cleavage furrow was perpendicular with this axis. Assumptions about nonrandom position of both cultivated cells during mitosis and their cleavage furrows were made.

Symmetry-forbidden electronic state interference observed in angularly resolved NO+ (A 1Π) deexcitation spectra of the N*O(2σ(-1)2π(2)) resonance.

Quantum mechanical interference between different pathways in inner-shell resonance excitation-deexcitation spectra is a realization of a double-slit experiment on the atomic scale. If the intermediate inner-shell resonances are of different symmetries, this interference is symmetry forbidden in the solid-angle-averaged or magic-angle-recorded deexcitation spectra. It has, however, been suggested that interference may by observable in off-magic-angle-recorded spectra. Here, we prove this interference in angularly resolved deexcitation spectra of the 2σ(-1)2π(2)(2Δ,2Σ±) resonances of N*O by a quantitative comparison between ab initio calculations and experiment.

Dislocation-driven surface dynamics on solids.

Dislocations are line defects that bound plastically deformed regions in crystalline solids. Dislocations terminating on the surface of materials can strongly influence nanostructural and interfacial stability, mechanical properties, chemical reactions, transport phenomena, and other surface processes. While most theoretical and experimental studies have focused on dislocation motion in bulk solids under applied stress and step formation due to dislocations at surfaces during crystal growth, very little is known about the effects of dislocations on surface dynamics and morphological evolution. Here we investigate the near-equilibrium dynamics of surface-terminated dislocations using low-energy electron microscopy. We observe, in real time, the thermally driven nucleation and shape-preserving growth of spiral steps rotating at constant temperature-dependent angular velocities around cores of dislocations terminating on the (111) surface of TiN in the absence of applied external stress or net mass change. We attribute this phenomenon to point-defect migration from the bulk to the surface along dislocation lines. Our results demonstrate that dislocation-mediated surface roughening can occur even in the absence of deposition or evaporation, and provide fundamental insights into mechanisms controlling nanostructural stability.