[The relationship between the relative length of leukocyte telomeres and mtDNA copy number and acute coronary syndrome in a 15-year follow-up.]

OBJECTIVE: to study the association of relative leukocyte DNA telomere length with death from natural causes during a 15-year follow-up in a middle-aged and elderly Siberian population. Study of the association of the relative length of leukocyte telomeres (LTL) with fatal outcomes during a 15-year follow-up of a random population sample formed in 2003-2005 (n=9 360, 45-69 years old, Novosibirsk, HAPIEE project). The main group included the persons died from natural causes (except external) without a previous history of CVD and cancer (n=609); controls were stratified by sex and age (n=799). The analysis of relative LTL at baseline was performed using quantitative real-time PCR. We estimated the odds ratio of all-cause death per 1 decile shortening of LTD as a continuous variable in a multivariable-adjusted logistic regression. The carriers of shorter telomere carriers had an increased risk of death from natural causes over the next 15 years (OR=1,37, 95% CI 1,31-1,44) per decile of LTL decrease, regardless of other factors. The risk coefficients were similar for death from CVD (1,39), cancer (1,42), and other non-external causes (1,51). In studied middle-aged and elderly Siberian (Caucasoid) population cohort the LTL was an independent inverse predictor of the 15-year risk of death from natural causes.

[Human placenta hydrolysates: from V.P. Filatov to the present day: Review].

Works of V.P. Filatov and his school laid the foundation for the study and clinical use of human placenta hydrolysates (HPH). To date, the PubMed database contains more than 5,000 publications on basic and clinical research on HPH. Studies of the peptide composition of HPH, carried out using the methods of modern proteomics, have made it possible to propose a complex of molecular mechanisms of the action of HPH in various pathologies. The article discusses the effects of HPH on the treatment of liver diseases, atopic dermatitis, viral infections (herpes, COVID-19, viral hepatitis), iron overload and chronic fatigue syndrome. Stimulation of HPH regenerative capabilities of the body is important for accelerating and improving the quality of wound healing, treatment of diseases of the joints and the reproductive system.

[The relationship between the relative length of leukocyte telomeres and mtDNA copy number and acute coronary syndrome in a 15-year follow-up.]

We studied the relationship between the leucocyte telomere length (LTL) and the copy number of mitochondrial DNA (CNmtDNA) and the development of acute coronary syndrome during 15 years of follow-up. A random population sample was examined at baseline in 2003-2005 (n=9 360, men and women 45-69 years old, Novosibirsk, the HAPIEE project) and followed-up for 15 years. In the frame of nested case-control design, we selected cases - incident myocardial infarction/acute coronary syndrome (MI/ACS) among those free from baseline CVD (n=256) and sex- and age-stratified control among those free from baseline CVD and cancer and alive by the end of follow-up (n=799). The relative LTL and CNmtDNA were assessed using quantitative real-time PCR. Results. The carriers of shorter telomeres had increased 15-year risk of MI/ACS with adjusted OR=1,87 (95% CI 1,70-2,06) per 1 LTL decile independent of other factors. Fewer CNmtDNA was associated with increased risk of MI/ACS with adjusted OR=1,19 (95% CI 1,12-1,26) per 1 CNmtDNA decile. The identified associations were confirmed in tertile analysis and in stepwise analysis with continuous variables of both biomarkers. All associations persisted after adjusting for gender, age, and traditional CVD risk factors. Conclusion. The LTL and CNmtDNA were independent predictors of the 15-year risk of MI/ACS in the middle- and elderly Siberian (Caucasoid) population cohort. These findings highlight the need for further research to elucidate the mechanisms by which LTL and mtDNA copy number may affect human health.

[Mitochondrial DNA copy number of leucocytes as ageing marker and risk factors for age-related diseases in human.]

We used quantitative real-time PCR method to analyse mtDNA copy number in a random subsample (n=996; 358 men aged 66,31±7,24 years; 468 women aged 67,62±7,1 years) selected from a population cohort (n=9 630) examined at baseline in international project HAPIEE in Novosibirsk, Russia, in 2003-2005. The participants were re-examined after 12 years in 2015-2017. The average relative number of mtDNA copies in peripheral blood leukocytes was greater in women than in men, independently of age and smoking (p=0,001). mtDNA copy number was inversely correlated with age both in men (p=0,005) and women (p<0,001). In age adjusted analysis, mtDNA copy number was inversely associated with waist, hip and heart rate in both sexes. In addition, mtDNA copy number in women was inversely associated with triglycerides and glucose, aterogenity index and positively with HDL cholesterol. In men, mtDNA copy number was positively associated with physical activity. The age-adjusted mean of mtDNA copy number among male never-smokers was greater than in smokers (p=0,003), and the mean mtDNA copy number was lower in women with diabetes than in women without diabetes (p=0,005). In both sexes, subjects with baseline history of hypertension had lower mtDNA copy number after 12-year follow-up than those without hypertension (p=0,05). This broadly supports the hypothesis that mtDNA copy number may act as biomarker of ageing.

A high-accuracy complex-phase method of simulating X-ray propagation through a multi-lens system.

The propagation of X-ray waves through an optical system consisting of many X-ray refractive lenses is considered. For solving the problem for an electromagnetic wave, a finite-difference method is applied. The error of simulation is analytically estimated and investigated. It was found that a very detailed difference grid is required for reliable and accurate calculations of the propagation of X-ray waves through a multi-lens system. The reasons for using a very detailed difference grid are investigated. It was shown that the wave phase becomes a function, very quickly increasing with increasing distance from the optical axis, after the wave has passed through the multi-lens system. If the phase is a quickly increasing function of the coordinates perpendicular to the optical axis, then the electric field of the wave is a quickly oscillating function of these coordinates, and thus a very detailed difference grid becomes necessary to describe such a wavefield. To avoid this difficulty, an equation for the phase function is proposed as an alternative to the equation of the electric field. This allows reliable and accurate simulations to be carried out when using the multi-lens system. An equation for the phase function is derived and used for accurate simulations. The numerical error of the suggested method is estimated. It is shown that the equation for the phase function allows efficient simulations to be fulfilled for the multi-lens system.

[Length telomere leukocytes as ageing markers and risk factors for age-related diseases in humans].

The purpose of the research was studying of leukocyte telomere length association with age, sex, risk factors for age-related diseases in Russian people of pre-retirement and retirement age. By quantitative real-time PCR method we studied the leukocyte telomere length in 398 men (56,3±7,2 years) and 365 women (56,6±7,1 years) selected from a population sample of 45-69 year-old residents of the Oktyabrsky and Kirovsky districts of Novosibirsk (9 400 people). The selection was formed in the course of work on the international project HAPIEE. As a result, an inverse correlation of telomere length with age (r=-0,159, р<0,001), with the ratio waist / hips (r=-0,107, p=0,003) was found out. The average length of telomeres in women significantly more than in men, p=0,031.The correlation of telomere length in males with weight (r=0,140, p=0,005), waist size (r=0,111, p=0,027) was found out. In women, there is an inverse correlation of telomere length with a waist size (r=-0,127, p=0,015), the ratio of waist / hips (r=-0,141, p=0,007). The length of telomeres is an inverse correlation with correlation with quantity of the cigarettes smoked (r=-0,121, р=0,024). The length of telomeres leukocytes correlates with age, smoking, and a number of phenotypical signs. In men with the family anamnesis burdened by malignancies leucocytes telomere length was found to be greater than in men without such anamnesis.

FEATURES OF GILBERT'S SYNDROME IN PATIENTS WITH DIFFERENT GENOTYPES UGT1AI.

The aim; to evaluate the clinical manifestations and data of instrumental methods in patients with Gilbert's syndrome and different genotype UGT1A1. MATERIALS AND METHODS: Clinical manifestations and results of instrumental methods were studies in 104 patients with Gilbert's syndrome (UGIlAl gene mutation rs8175347), including 75 with the homozygous variant (genotype 7TA*7TA) and 29 - with heterozygous variant (genotypes 6TA*7TA or 6TA*STA). RESULTS: The most frequent clinical manifestation was asthenovegetative syndrome. The promoter of the appearance/intensification ofjaundice were physical activity, stress and viral infections. Homozygotes exhibit an earlier manifestation of the disease, higher rates of bilirubin (sometimes not only due to deconjugating), a greater variety of stigmas undifferentiated dysplasia of connective tissue, more frequent detection of biliary sludge or gallstones. The clinical observation of a family case of Gilbert's syndrome where the mother is a homozygote, and the son - heterozygotes on UGT1A1 mutation is presented, which shows the above differences associated with genotype. CONCLUSION: Patients with asthenic constitution and the stigma dysplasia of connective tissue have to be examined by the presence of mutations rs8175347 gene UGT1A1. The carrier not only homozygous but with the heterozygous variant mutations may require changes in the interpretation of symptoms, lifestyle, medication, etc.

[ALLELES C282Y AND H63D HFE GENE, INSULIN RESISTANCE AND SUSCEPTIBILITY TO DISTURBANCE OF PORPHYRIN METABOLISM IN NON-ALCOHOLIC FATTY LIVER DISEASE].

THE PURPOSE OF THE STUDY: The aim of the present work was to study the frequency of genotypes and alleles of C282Y and H63D HFE gene that may be associated with impaired porphyrin metabolism, as well as possible reasons for the formation of dysmetabolism porphyrins with NAFLD. MATERIALS AND METHODS: The study involved 65 patients (52 men and 13 women) aged 21 to 69 years (mean age 48.5±1.5 years). Excretion uroporphyrin, coproporphyrin, 6-aminolevulinic acid of porphobilinogen in urine was determined by chromatography and spectrophotometry calculated total excretion of porphyrins. Allele frequencies C282Y and H63D were determined during the molecular genetic analysis of DNA using the polymerase chain reaction followed by analysis of length polymorphism restraktsionnyh fragments. Condition of carbohydrate metabolism was evaluated by the level of fasting blood glucose and standard glucose tolerance test. Diagnosis of insulin resistance was performed according to the criteria proposed by the European Group for the Study of insulin resistance (EGIR). RESULTS: Skill test for the C282Y mutation carriage and H63D in the HFE gene in 65 patients with non-alcoholic fatty liver disease. Disturbances in the metabolism of porphyrins were recorded in 43 (66.2%) patients. H63D and C282Y mutations were found in 18 (27.7%) patients, of whom 13 (72.2%) people with different options dismetabolism porphyrins and signs of insulin resistance. In 47 (72.3%) patients without mutations studied porphyrin metabolism disorders were detected in 30 (63.8 %), of which insulin resistance is registered only in 16 (34.0 %). CONCLUSION: Detection of mutations C282Y and H63D in the HFE gene in combination with disorders of porphyrin metabolism on the background of insulin resistance is likely to allow such patients considered as candidates for inclusion in the higher risk of formation of diabetes.

Threefold Increase of the Bulk Electron Temperature of Plasma Discharges in a Magnetic Mirror Device.

This Letter describes plasma discharges with a high temperature of bulk electrons in the axially symmetric high-mirror-ratio (R=35) open magnetic system gas dynamic trap (GDT) in the Budker Institute (Novosibirsk). According to Thomson scattering measurements, the on-axis electron temperature averaged over a number of sequential shots is 660±50 eV with the plasma density being 0.7×10^{19} m^{-3}; in few shots, electron temperature exceeds 900 eV. This corresponds to at least a threefold increase with respect to previous experiments both at GDT and at other comparable machines, thus, demonstrating the highest quasistationary (about 1 ms) electron temperature achieved in open traps. The breakthrough is made possible by application of a new 0.7 MW/54.5 GHz electron cyclotron resonance heating system in addition to standard 5 MW heating by neutral beams, and application of a radial electric field to mitigate the flute instability.

[VISCOELASTISITY AND ELECTRICAL PARAMETERS OF ERYTHROCYTES IN GILBERT SYNDROME].

Results of viscoelastic and electrical properties of erythrocytes study in patients with genetically confirmed Gilbert's syndrome (n = 81) are presented. Dielectrophoresis of erythrocytes in a nonuniform an alterning electric field was performed in81 patients with Gilbert's syndrome and in 20 persons of the comparison group without of the pathology identified by thelaboratory and instrumental examination. The significant differences in viscoelasticity properties of erythrocytes in Gilbert'ssyndrome were obtained. The amplitude of the deformation, the speed of movement to the electrodes and the polarizability on electric field's of all frequencies were significantly lower, but generalized rigidity index, viscosity, index of aggregationand degradation on electric field's of all frequencies were higher than in the comparison group. A number of electricalparameters (conductivity, the capacity of the cells and the relative polarizability) were also higher than in the comparisongroup. Some differences in the parameters of erythrocytes were obtained from homozygous and heterozygous carriers of A(TA), TAA of gene UGT1A1 promotor.

[The Role of Transcriptional Factor Gene TBX5 in Development of Disorders of Cadiac Conduction].

In order to study relationship between development of idiopathic atrioventricular (AV) and intraventricular disorders of cardiac conduction (DCC) with single nucleotide polymorphism (SNP) of TBX5 gene we examined 260 persons with primary DCC (71 patients with abnormal AV conduction, 84 and 105 patients with disordered conduction along right and left brunches of His bundle, respectively) as well as 257 individuals without cardiovascular diseases (control group). Patients were divided into subgroups depending on nosology, age, and sex. Diagnosis was verified by standard cardiological methods and retrospective analysis of available results of previous examinations. Molecular-genetic study of DNA was used for identification of genotype of TBX5 gene SNP. The results indicated significant preponderance of rare GG genotype (CNP-marker rs3825214) of TBX5 gene in the group of patients with left bundle branch block and in the subgroup of women with this pathology. These data suggest that presence of GG genotype (rs3825214) of TBX5 gene increases probability of development of idiopathic DCC along left bundle branch mainly in women.

Progress in Mirror-Based Fusion Neutron Source Development.

The Budker Institute of Nuclear Physics in worldwide collaboration has developed a project of a 14 MeV neutron source for fusion material studies and other applications. The projected neutron source of the plasma type is based on the gas dynamic trap (GDT), which is a special magnetic mirror system for plasma confinement. Essential progress in plasma parameters has been achieved in recent experiments at the GDT facility in the Budker Institute, which is a hydrogen (deuterium) prototype of the source. Stable confinement of hot-ion plasmas with the relative pressure exceeding 0.5 was demonstrated. The electron temperature was increased up to 0.9 keV in the regime with additional electron cyclotron resonance heating (ECRH) of a moderate power. These parameters are the record for axisymmetric open mirror traps. These achievements elevate the projects of a GDT-based neutron source on a higher level of competitive ability and make it possible to construct a source with parameters suitable for materials testing today. The paper presents the progress in experimental studies and numerical simulations of the mirror-based fusion neutron source and its possible applications including a fusion material test facility and a fusion-fission hybrid system.

Transport-limited electrochemical formation of long nanosharp probes from tungsten.

We show that electrochemical formation of long probes with nanosharp tips can be controlled by choosing an appropriate thermodynamic pathway of metal to metal oxide and hydroxide transformation. Currently, convection-limited electropolishing (CLE) is extensively used. Nanosharp probes are produced by electrochemically etching a wire until it breaks into two pieces. This process is difficult to control because of the complexity of the associated hydrodynamic flows. We introduce transport-limited electropolishing (TLE), where the electrochemical reaction results in the formation of metal oxides and hydroxides which form a porous surface layer hindering the flow of electrolyte. The developed TLE method enables one to make long tapered needles. The taper can spread over more than 6 mm while the radius of tip curvature can be decreased down to 30 nm. These needles are strong and were successfully applied for piercing single smooth vascular muscle cells.

Spatial pattern formation in external noise: theory and simulation.

Spatial pattern formation in fluctuating media is researched analytically from the point of view of the order parameters concept. A reaction-diffusion system with external noise is considered as a model of such media. Stochastic equations for unstable mode amplitudes (order parameters), the dispersion equation for averaged amplitudes of unstable modes, and the Fokker-Planck equation for the order parameters are obtained. The theory developed makes it possible to analyze different noise-induced effects including the variation of boundaries of ordering and disordering phase transitions depending on the parameters of external noise.

Protein-nanoparticle conjugates as potential therapeutic agents for the treatment of hyperlipidemia.

Hyperlipidemia, a condition associated with atherosclerosis, can develop because of the lack of low density lipoprotein (LDL) receptors in hepatocytes. Since injected polymeric nanoparticles are quickly taken up by the liver Kupffer cells, we hypothesize that it is possible to enhance LDL delivery to the liver through the use of LDL-absorbing nanoparticles. Here, we demonstrate the feasibility of the proposed approach in vitro. We used biodegradable and biocompatible polylactide nanoparticles (approximately 100 nm in diameter) with covalently attached apolipoprotein B100 antibody to adsorb LDLs at physiologically relevant concentrations. We showed that up to sixfold decreases of LDL levels can be achieved in vitro upon treatment of LDL suspensions (500 mg dl( - 1)) with anti-apoB100-nanoparticle conjugates. The study of the uptake of the antibody-nanoparticle-LDL complexes by cells was performed using a mouse macrophage cell line (RAW 264.7) as a model for liver Kupffer cells. We found that macrophages can quickly take up antibody-nanoparticle-LDL complexes and digest them within 24 h. No evidence of cytotoxicity was observed for the experimental conditions used in this study.

Mitochondria and blood supply of chicken skeletal muscle fibers in ontogenesis.

Skeletal muscles have been studied during ontogenesis to reveal morphological and functional parameters that at most influence the formation of muscles with different levels of oxygen consumption. Development of oxidative red gastrocnemius muscle (RGM) and glycolytic white pectoralis muscle (WPM) has been studied at a period from being 10-day-old chicken embryos until they become 6-month-old chickens. By morphometry, we measured diameter, length, and numerical density of capillaries; muscle fibers diameter; as well as mitochondria's size, density, and volume fraction in muscle fibers. During the post-embryonic period, the blood flow was estimated by hydrogen clearance method. The data obtained were compared to previously published data on O2 consumption rate in fibers being at the same stages of ontogenesis [Microvasc. Res. 60 (2000) 168]. As shown, relationships between the parameters in the muscles studied appear at different ages. They are described by exponential equations with varying slopes. Beginning with the middle stages of embryogenesis, the clear dependency is seen in both types of muscles between O2 consumption rate in a fiber and summarized perimeter of mitochondria at a fiber section. Capillary bed during embryonal period is superfluous. The clear dependency between capillary-to-fiber number ratio and oxygen consumption in fibers becomes apparent in chickens only 10 days after birth, when the fiber diameter amounts to 20 microm. Since that period, redistribution of mitochondria toward the periphery of a fiber takes place, being especially pronounced in RGM. The regularities found between oxygen delivery and consumption systems enable to search for the leading factors of specialization of skeletal muscles in accordance with the level of oxidative metabolism. These factors may be used for calculation and numerical simulation of the parameters of oxygen transport in skeletal muscles.

Experimental evidence of high-beta plasma confinement in an axially symmetric gas dynamic trap.

In the axially symmetric magnetic mirror device gas dynamic trap (GDT), on-axis transverse beta (ratio of the transverse plasma pressure to magnetic field pressure) exceeding 0.4 in the fast ion turning points has been first achieved. The plasma has been heated by injection of neutral beams, which at the same time produced anisotropic fast ions. Neither enhanced losses of the plasma nor anomalies in the fast ion scattering and slowing down were observed. This observation confirms predicted magnetohydrodynamic stability of plasma in the axially symmetric mirror devices with average min-B, like the GDT is. The measured beta value is rather close to that expected in different versions of the GDT based 14 MeV neutron source for fusion materials testing.

Mitochondrial 16S rRNA gene encodes a functional peptide, a potential drug for Alzheimer's disease and target for cancer therapy.

New functions of well-known genes have been revealed frequently. A new example is described in this report. Earlier we have detected an up-regulation of expression of the mitochondrial 16S rRNA gene in non-Hodgkin's lymphomas. Here we demonstrate that the human mitochondrial 16S rRNA gene encodes a potential oncopeptide, Humanin described recently. This peptide suppresses neuronal cell death induced by mutant genes responsible for familial Alzheimer's disease (AD). Analysis of the gene coding site structure showed that Humanin mRNA is translated most likely in the cytosol, but not in the mitochondrion in vivo. This led us to suppose that AD could be caused by a block of Humanin mRNA transport from mitochondria into the cytosol. Moreover, our data and reports by others an mitochondrial 16S rRNA transcription and characteristic of transcript structure suggests that Humanin is a potential oncopeptide. Thus, the use of Humanin for the treatment of AD may increase the risk for the development of malignant diseases.