In recent years, the genetic component of many general common diseases has been considered from the point of view of evolutionary context: asthma, chronic obstructive pulmonary disease, cancer, obesity, diabetes. The genetic history of populations leads to the accumulation of specific frequencies. Modern susceptibility to common pathological phenotypes could have had a certain adaptive significance in the past during the dispersal of humans across the globe. Of particular interest are diseases with phenotypes associated with cognitive impairment, such as schizophrenia, Alzheimer's disease, bipolar disorder, autism and others. Diseases associated with post-reproductive age (various types of dementia), as well as various manifestations of psychotic disorders, which were previously uncommon, are currently acquiring enormous socioeconomic significance throughout the world. Evolutionary hypotheses have also been proposed for schizophrenia and Alzheimer's disease. The indigenous ethnic groups of Northern Eurasia are of particular interest to the researcher. Until recently, populations were isolated, isolated both by geography of residence and by linguistic and cultural characteristics, which led to genetic isolation. In this regard, the gene pool of populations of Northern Eurasia is an important source of genetic information. In connection with all of the above, the goal of the work was to search for signals of natural selection in the loci of the genome associated with schizophrenia, Alzheimer's disease, in the populations of Northern Eurasia. In our work, a search was performed for signals of natural selection in the loci of the genome associated with diseases leading to cognitive impairment in humans in 16 populations of Northern Eurasia: Russians, Udmurts, Khanty, Khakasses, northern and southern Kyrgyz, Yakuts, Buryats, Nivkhs, Chukchi, Kazakhs, Uzbeks, Altaians, Yakuts, Tuvins. MALDI-TOF mass spectrometry technology (Matrix Assisted Laser Desorption/Ionization Time Of Flight Mass-Spectrometry) was used for multiplex genotyping of 28 SNP markers. In our work, when analyzing selective neutrality using the Ewens-Watterson neutrality test for 28 markers, deviation from neutrality was found in 10 SNPs: rs10273775 of the CNTNAP2 gene, rs1031381 of the NCAPD3 gene, rs12922317 of the SNX29 gene, rs1466662 of the DCHS2 gene, rs1532278 of the CLU gene, rs16887244 of the LSM1 gene, rs3826656 of the CD33 gene, rs433598 of the ACSM1 gene, rs561655 near the PICALM gene, rs6859 of the NECTIN2 gene. The maximum number of populations for markers that have a deviation from selective neutrality was found for the genetic locus rs1031381 of the NCAPD3 gene - 10 populations (southern Kyrgyz, Altaians, Buryats, Koryaks, Tuvins, Khanty, Kazakhs, Udmurts, Kets, Uzbeks), while the minimum number of populations was identified for the marker rs16887244 of the LSM1 gene - one population (Nivkhs). In the present study, signals of natural selection were detected in all 16 populations. Interestingly, for the populations of northern Kyrgyz, Buryats, Koryaks, Khakasses and Udmurts, the effect of selection was only directional, and for the Russian population, the effect of balancing selection was noted, in the remaining ten populations, the effect of two types of selection was shown. For individual markers, only balancing selection was observed (rs16887244 of the LSM1 gene), while exclusively directional selection was detected for rs1466662 of the DCHS2 gene and rs561655 near the PICALM gene. It should be noted that of all 10 polymorphic variants of genes that showed deviation from selective neutrality, six SNPs showed statistically significant associations with schizophrenia or Alzheimer's disease in our previous studies in association analysis: rs12922317 of the SNX29 gene, rs1466662 of the DCHS2 gene, rs1532278 of the CLU gene, rs16887244 of the LSM1 gene, rs561655 near the PICALM gene, rs6859 of the NECTIN2 gene. The results of our work indicate a significant role of natural selection in the populations of Northern Eurasia in the formation of genetic diversity in the genes of diseases associated with human cognitive impairment, such as schizophrenia and Alzheimer's disease. The Authors declare no conflict of interest.

Heart failure of various etiologies, including diabetic cardiomyopathy (DCM), is a global problem. However, the features of DCM pathogenesis, including the role of the T-tubular system in this process, are not fully understood. The available literature data on T-system remodeling in diabetic rodent models are contradictory, with changes in this system being demonstrated in some of them already at the prediabetic stage. So, this work was aimed to assess changes in the T-system in a rat model of metabolic syndrome (MS) that precedes type 2 diabetes mellitus. MS was induced in Wistar rats by a high-carbohydrate (HC) and a combined high-carbohydrate high-fat (HCHF) diets for 10 weeks. The parameters to be finally estimated were body, abdominal fat, and heart weights, as well as fasting plasma glucose levels measured by a glucose tolerance test (GTT). The structure of the T-system was examined via confocal microscopy in isolated hearts stained with DI-8-ANEPPS. HCHF-fed rats developed more severe MS since their body and abdominal fat weights, as well as fasting plasma glucose levels, were significantly higher compared to the controls; moreover, GTT revealed the signs of glucose tolerance. HC-fed rats were characterized by a moderate MS, as manifested only in an increase in abdominal fat weight. The structural correlates of T-system remodeling were also found in HCHF-fed rats only, as manifested in a significant increase in the average interval between the rows of T-tubules. These findings differ from our results obtained in a model of type 1 prediabetes and diabetes. Thus, T-system remodeling in rat cardiomyocytes begins already at the stage of HCHF-induced MS and proceeds similarly to that described for type 2 diabetes, but differs from that in type 1 prediabetes and diabetes, suggesting different pathways of DCM pathogenesis in different diabetic types.

We propose a model of a light bridge as a current-carrying magnetic flux tube formed by convection. It is shown that convection in the sunspot penumbra provides the electric current necessary to heat the flux rope plasma and forms structures of a light bridge type. The steady-state heating mode of the light bridge is considered, since the light bridge life time (days) is much longer than the typical heating time (minutes). Radiation losses determine the current value I > 1011A required to heat the light bridge to a temperature up to 6800 K. The parameters of the light bridge plasma are presented, and the observed double structure of the light bridge emission is explained.

Impaired cardiovascular function in metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM) is not adequately studied, and data on changes in electrocardiogram (ECG) parameters, including in rodent models of MS and T2DM, are contradictory and ambiguous. Aim of the study was to investigate ECG parameters in models of MS and T2DM and to identify possible correlations between impaired glucose tolerance and the severity of changes in ECG parameters. Material and methods. Male Wistar rats were used in the experiments. MS was induced by a high-fat diet (HFD) for 17 weeks; T2DM was induced by a combination of HFD and streptozotocin injection (HFD + STZ): 11 weeks of HFD followed by an injection of streptozotocin and continued HFD for another 6 weeks. Control animals were kept on a standard diet. Results. The glucose tolerance test confirmed the development of impaired glucose tolerance to the prediabetic level in the HFD group and to the diabetic level in the HFD+STZ group. ECG changes were found only in the HFD+STZ group: a significant (compared to the control and HFD group) increase in the amplitude and area T wave on the ECG was shown. Conclusions. Pronounced ECG abnormalities develop only in the model of T2DM, but not in the MS model.

The decisive role of the neutral component of solar plasma in the dissipation of electric currents in magnetic flux tubes is shown. For the first time, the dependences of the Cowling resistivity and the rate of the Joule dissipation were obtained for various current magnitudes in a wide range of heights, from the photosphere to the corona. Based on the atmospheric model of Avrett and Loeser (2008) it was shown that the Cowling resistivity exceeds the classical (Spitzer) resistivity in the chromosphere and the transition region. The Spitzer resistivity prevails over the Cowling one at the altitudes less than 300–1000 km depending on the electric current magnitude. The Cowling resistivity plays the main role at the electric currents of more than 109 A in the corona with a relative density of neutral atoms ∼10–7. It was found that the maximum of the Joule dissipation is located at the altitude of about 2100 km, which creates favorable conditions for formation of the chromosphere-corona transition region and heating of the corona. Anomalous (turbulent) resistance requires a lot of tiny current filaments in a flux tube. The role of Joule dissipation in the heating of pre-flare plasma and in the formation of the sunspot light bridges is discussed.

Abstract—Identification of the hereditary basis of preeclampsia remains a relevant area for medical genetics. Despite numerous attempts to search for the main predetermining factors, due to the multifactorial nature of the preeclampsia no generally accepted hypotheses for the pathogenesis of this pregnancy complication exists. One of the progressive approaches to the study of complex diseases is an analysis of gene–gene interactions, which makes it possible to isolate factors that can determine a high or low risk of predisposition within the pathology from a large array of combinations. In the presented work, analysis of gene–gene interactions was used to create a model that predicts the risk of severe preeclampsia and find key combinations of genes predisposing one to the development of preeclampsia in the Russian population. For the first time the prognostic potential of combinations of the rs3774298 BCL6 and rs2071045 LEP loci in the development of a severe form of preeclampsia (OR = 2.97) was demonstrated. Additionally, it was found that the rs3774298 polymorphic variant of the BCL6 gene is located in a functionally active region of the genome located in the binding site of the transcription factor CTCF, which can function as both a transcription activator and a repressor. This emphasizes the role of cell regulatory systems in the mechanisms of the formation and course of preeclampsia.

The Nivkhs are a small ethnic group indigenous of the Russian Far East, living in the Khabarovsk Territory and on Sakhalin Island, descending from the ancient inhabitants of these territories. In the Nivkhs, a specific Sakhalin-Amur anthropological type is prevalent. They are quite isolated, due to long isolation from contacts with other peoples. The gene pool of the Nivkhs and other Far Eastern and Siberian populations was characterized using a genome-wide panel of autosomal single-nucleotide polymorphic markers and Y chromosome haplogroups. Bioinformatic processing of frequencies of autosomal SNPs, Y chromosome haplogroups and YSTR haplotypes showed that the Nivkh gene pool is very different from the other populations’. Analysis of the SNP frequencies using the PCA method divided the Far Eastern populations in full accordance with the territories of their residence into the northern group of the Chukchi and Koryaks and the southern group, including the Nivkhs and Udege. The remoteness of the Nivkhs coincides with their geographic localization, with the Nivkhs and Udege demonstrating the greatest kinship. The Nivkhs have a specific component of their gene pool, which is present with much less frequency in the Udege and Transbaikal Evenks. According to the IBD blocks, the genotypes of the Nivkhs show a very small percentage of coincidence with the Udege, Koryaks, Evenks and Chukchi, the value of which is the lowest compared to the IBD blocks among all other Siberian populations. The Nivkh-specific composition of haplogroups and YSTR haplotypes was shown. In the Nivkhs, the C2a1 haplogroup is divided into three sublines, which have a fairly ancient origin and are associated with the ancestors of modern northern Mongoloids. The Nivkh haplogroup O2a1b1a2a-F238 is found among residents of China and Myanmar. The Q1a1a1-M120 line is represented among the Nivkhs, Koryaks, Evenks and Yukaghirs. Phylogenetic analysis of individual Y chromosomal haplogroups demonstrated the closeness of the Nivkh gene pool with the ancient population of the Amur and Okhotsk regions, the Koryaks, the Tungus peoples and the population of Southeast Asia. The Nivkh gene pool confirms the relative smallness of their ancestral groups without mixing with other populations.

Abstract—Fetal growth restriction is a complication of pregnancy that is defined as the inability of the fetus to realize its genetically determined growth potential. Despite the high social and medical significance of this problem the exact pathogenesis of fetal growth restriction is not known. Therefore, the analysis of the molecular genetics mechanisms of this pathology within the framework of approaches using modern high-performance technologies of next generation sequencing is of undoubted interest. In this review we focused on the analysis of data obtained in studies of the genetics component of fetal growth restriction. The authors of these studies used next generation sequencing technologies and carried out whole transcriptome profiling. The results of the gene expression genome-wide analysis in placental tissue allow us to identify 1430 differentially expressed genes between fetal growth restriction and normal pregnancy, of which only 1

Metabolic syndrome (MetS) is common among schizophrenia patients, and one of MetS’s causes may be an imbalance in nitric oxide regulation. In this study, we examined associations of three polymorphic variants of the nitric oxide synthase 1 adapter protein (NOS1AP) gene with MetS in schizophrenia. NOS1AP regulates neuronal nitric oxide synthase, which controls intracellular calcium levels and may influence insulin secretion. The aim of the investigation was to study polymorphic variants of the NOS1AP gene as possible markers of MetS in patients with schizophrenia. A total of 489 Caucasian patients with schizophrenia (ICD-10) from Siberia (Russia) were included in the study, and 131 (26.8%) patients had MetS (IDF classification, 2007). The participants were genotyped for three single-nucleotide polymorphisms in NOS1AP (rs12143842, rs10494366, and rs12029454). Logistic regression was used for association analysis. Single-nucleotide polymorphisms, sex, and age served as covariates; the dependent variable was the coded parameter of the presence/absence of MetS. Polymorphisms rs12143842 and rs10494366 showed a stable association even after Bonferroni’s correction for multiple comparisons (p = 0.005 and 0.002, respectively), indicating a statistically significant contribution of these polymorphic variants to the pathogenesis of MetS. Our results suggest that in patients with schizophrenia, NOS1AP may be involved in MetS pathophysiology.

We aimed to explore the potential link of maternal age at menarche (mAAM) gene polymorphisms with risk of the fetal growth restriction (FGR). This case (FGR)–control (FGR free) study included 904 women (273 FGR and 631 control) in the third trimester of gestation examined/treated in the Departments of Obstetrics. For single nucleotide polymorphism (SNP) multiplex genotyping, 50 candidate loci of mAAM were chosen. The relationship of mAAM SNPs and FGR was appreciated by regression procedures (logistic/model-based multifactor dimensionality reduction [MB-MDR]) with subsequent in silico assessment of the assumed functionality pithy of FGR-related loci. Three mAAM-appertain loci were FGR-linked to genes such as KISS1 (rs7538038) (effect allele G-odds ratio (OR)allelic = 0.63/pperm = 0.0003; ORadditive = 0.61/pperm = 0.001; ORdominant = 0.56/pperm = 0.001), NKX2-1 (rs999460) (effect allele A-ORallelic = 1.37/pperm = 0.003; ORadditive = 1.45/pperm = 0.002; ORrecessive = 2.41/pperm = 0.0002), GPRC5B (rs12444979) (effect allele T-ORallelic = 1.67/pperm = 0.0003; ORdominant = 1.59/pperm = 0.011; ORadditive = 1.56/pperm = 0.009). The haplotype ACA FSHB gene (rs555621*rs11031010*rs1782507) was FRG-correlated (OR = 0.71/pperm = 0.05). Ten FGR-implicated interworking models were founded for 13 SNPs (pperm ≤ 0.001). The rs999460 NKX2-1 and rs12444979 GPRC5B interplays significantly influenced the FGR risk (these SNPs were present in 50% of models). FGR-related mAAM-appertain 15 polymorphic variants and 350 linked SNPs were functionally momentous in relation to 39 genes participating in the regulation of hormone levels, the ovulation cycle process, male gonad development and vitamin D metabolism. Thus, this study showed, for the first time, that the mAAM-appertain genes determine FGR risk.

Rats kept on a high-fat/high-sucrose diet (HFSD) for 10–12 weeks demonstrated the development of hyperglycemia and signs of visceral obesity. Compared to the control, extracellular action potentials (eAP) of subepicardial myocytes of the left ventricle (LV) of HFSD rats characterized by a significantly increased fraction of signals with a pronounced afterhyperpolarization (AHP) phase and an accelerated decline. Local delivery of apamin (a blocker of small conductance Ca2+-activated K+ channels (IKCa, SK channels) to the eAP registration cite at a concentration of 500 nM in the solution inside the pipette was accompanied by suppression of the AHP phase and prolongation of the eAP decline. The obtained data suggest that HFSD leads to an increase in the expression and/or activity of SK channels and, as a result, to the development of AHP and shortening of eAP in epicardial cardiomyocytes of the LV of the rat heart.

ObjectiveEpidermolysis bullosa simplex (EBS) is a common, well-characterized type of epidermolysis bullosa. However, some rare syndromic EBS phenotypes are not well described. The accumulation of clinical descriptions of patients with syndromic subtypes of EBS is important for understanding the natural history of the disease and assessing genotype–phenotype correlations.Case summaryWe present a series of case reports of the syndromic subtype of EBS associated with mutations in the KLHL24 gene in seven patients from four unrelated families. The clinical features of this rare phenotype in children and adult patients are described in detail. In two families, we revealed pathogenic variant c.1A > G (p.Met1?) in the KLHL24 gene. The third family had c.3G > A (p.Met1?) mutation, and the fourth family had a novel de novo variant c.23del (p.Arg8AsnfsTer2).ConclusionThe description of the clinical manifestations of the disease in two generations of EBS families with different genetic variants allows the assessment and prediction of the natural course and severity of the disease in these families, the risk of complications, and the planning of the amount of medical care necessary.

The gene pool of the Koryaks was studied in comparison with other Far Eastern and Siberian peoples using a genome-wide panel of autosomal single-nucleotide polymorphic markers and Y-chromosome markers. The results of analyzing the frequencies of autosomal SNPs using various methods, the similarity in the composition of Y-chromosome haplogroups and YSTR haplotypes indicate that the gene pool of the Koryaks is as close as possible to the Chukchi one and was formed as a result of the unification of several groups whose ancestors had moved from the territory of modern Yakutia and the Amur region. The two dominant Y-chromosome haplogroups of the Koryaks with different sublines of haplotype clusters demonstrate their contacts with the Chukchi, Evens, Yukaghirs, and Eskimos. Analysis of the composition of genetic components and IBD blocks on autosomes indicates the maximum genetic proximity of the Koryaks to the Chukchi. Among the Siberian populations, the Chukchi, Koryaks, and Nivkhs form a cluster separate from the main group of Siberian populations, while the Chukchi and Koryaks are more closely related. Far Eastern populations are divided in full accordance with geographic localization into the northern group (Chukchi and Koryaks) and the southern group, including the Nivkhs and Udege. A more detailed analysis of the component composition of gene pools in some populations reveals components specific to them. The isolation of such components is associated with founder effects and a shift in allele frequencies for these populations. The Koryaks and Chukchi represent one of the most striking examples of long-standing genetic kinship. Their populations demonstrate maximum values of the level of genomic inbreeding FROH > 1.5 (0.0422, 0.0409), which is natural due to their relative isolation.

The role of small-conductance Ca2+-activated K+-channels (SK channels) in the pathogenesis of cardiomyopathies of various etiologies remains poorly understood. The purpose of this work was to evaluate the effect of the blocker of SK channels, apamin, on the extracellularly recorded action potentials (eAPs) of subepicardial myocytes in the left ventricles of sham-operated rats and rats with myocardial infarction caused by ischemia-reperfusion. It was found that local delivery of the SK channel blocker apamin at a concentration of 500 nM to the eAP recording area did not affect the eAP profiles in the group of sham-operated rats but caused a significant slowdown in the repolarization time and a decrease in the afterhyperpolarization phase of eAPs in the group of rats with myocardial infarction. These data suggest that changes in the waveform of eAPs after infarction are associated with increased expression and/or activity of SK channels in subepicardial myocytes. The possible role of these channels in the structural and functional remodeling of the myocardium of the left ventricle of the heart after ischemia-reperfusion is discussed.

Objective: This study assessed the patterns and clinical significance of potential drug–drug interactions (pDDIs) in patients with diseases of the cardiovascular system. Methods: Electronic health records (EHRs), established in 2018–2023, were selected using the probability serial nested sampling method (n = 1030). Patients were aged 27 to 95 years (65.0% men). Primary diagnosis of COVID-19 was present in 17 EHRs (1.7%). Medscape Drug Interaction Checker was used to characterize pDDIs. The Mann–Whitney U test and chi-square test were used for statistical analysis. Results: Drug numbers per record ranged from 1 to 23 in T-List and from 1 to 20 in P-List. In T-List, 567 drug combinations resulted in 3781 pDDIs. In P-List, 584 drug combinations resulted in 5185 pDDIs. Polypharmacy was detected in 39.0% of records in T-List versus 65.9% in P-List (p-value < 0.05). The rates of serious and monitor-closely pDDIs due to ‘aspirin + captopril’ combinations were significantly higher in P-List than in T-List (p-value < 0.05). The rates of serious pDDIs due to ‘aspirin + enalapril’ and ‘aspirin + lisinopril’ combinations were significantly lower in P-List compared with the corresponding rates in T-List (p-value < 0.05). Serious pDDIs due to administration of aspirin with fosinopril, perindopril, and ramipril were detected less frequently in T-List (p-value < 0.05). Conclusions: Obtained data may suggest better patient adherence to ‘aspirin + enalapril’ and ‘aspirin + lisinopril’ combinations, which are potentially superior to the combinations of aspirin with fosinopril, perindopril, and ramipril. An abundance of high-order pDDIs in real-world clinical practice warrants the development of a decision support system aimed at reducing pharmacotherapy-associated risks while integrating patient pharmacokinetic, pharmacodynamic, and pharmacogenetic information.

The effects of the demographic history of mankind have led to the fact that the indigenous peoples of Dagestan and Siberia are inferior in terms of genetic diversity to the populations of Europe, which affects the level of identification informativeness of standard forensic autosomal markers in these populations. In our study, we evaluated the effectiveness of two standard sets of autosomal STRs (13 CODIS, 20 CODIS, Combined DNA Index System) for the genetic testing of parent-child relatedness in four highly inbred populations of the Russian Federation and the Russian population, using two types of reference frequencies. The results of the study confirmed the assumption that the level of identification informativity of standard autosomal markers in highly inbred populations of Siberia and Dagestan is lower than in the Russian population. The total information content of markers of the new CODIS standard exceeds the threshold values required in the order of the Ministry of Health and Social Development of the Russian Federation (No. 346n). At the same time, the probability of a false positive result increases with an increase in the inbreeding coefficient in the population.

We analyze electron acceleration by a large-scale electric field E in a collisional hydrogen plasma under the solar flare coronal conditions based on approaches proposed by Dreicer and Spitzer for the dynamic friction force of electrons. The Dreicer electric field E(Dr )is determined as a critical electric field at which the entire electron population runs away. Two regimes of strong (E less than or similar to E-Dr) and weak (E << E-Dr) electric field are discussed. It is shown that the commonly used formal definition of the Dreicer field leads to an overestimation of its value by about five times. The critical velocity at which the electrons of the "tail" of the Maxwell distribution become runaway under the action of the sub-Dreiser electric fields turns out to be underestimated by root 3 times in some works because the Coulomb collisions between runaway and thermal electrons are not taken into account. The electron acceleration by sub-Dreicer electric fields generated in the solar corona faces difficulties.