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In clinical practice, ovarian steroidogenesis is stimulated and ovulation is induced using such gonadotropin preparations as human chorionic gonadotropin (hCG) and luteinizing hormone (LH) which, however, have a number of side effects, including a reduction in ovarian sensitivity to endogenous LH and ovarian hyperstimulation syndrome. An alternative to hCG and LH could be allosteric LH/hCG receptor agonists, including the thieno[2,3-d]-pyrimidine derivative TP03 developed in our laboratory. This work was aimed to study the effect of TP03 (40 µg/kg, i.p.) versus hCG (30 IU/rat, s.c.) on ovarian steroidogenesis in mature female rats in the late proestrus phase, including those treated with the gonadotropin releasing hormone (GnRH) antagonist Orgalutran (100 µg/kg, s.c., 3 h before TP03 or hCG administration). Estradiol, progesterone and LH levels were measured in the blood, while expression levels of the steroidogenesis-related genes Star, Cyp11a1, Hsd3b, Cyp17a1, Hsd17b, Cyp19a1 and LH/hCG receptor gene Lhcgr were assessed in the ovaries. Three hours after administration, TP03 and hCG increased blood progesterone levels and stimulated the expression of genes encoding the cholesterol-transporting protein StAR, cytochrome P450c17, and aromatase (cytochrome P450c19), with these effects detected both in control rats with normal LH levels and in Orgalutran-treated rats with reduced LH levels. The effects of TP03 were comparable to those of hCG, but in contrast to hCG, TP03 did not reduce the activity of the hypothalamic–pituitary–gonadal axis, as indicated by the lack of its influence on blood LH levels and ovarian expression of LH/hCG receptors. Our data suggest the ability of TP03 to effectively stimulate ovarian steroidogenesis, as well as good prospects for the development of TP03-based drugs for controlled ovulation induction. [ABSTRACT FROM AUTHOR]

Human chorionic gonadotropin (hCG) and luteinizing hormone (LH) are widely used for the treatment of reproductive disorders and for controlled ovulation induction, but their use is limited by side effects. Allosteric agonists of the LH/hCG receptor, including thieno[2,3-d]thienopyrimidine TP03 developed by us, can become an alternative. TP03 (50 mg/rat, i.p.) when administered to immature female rats treated 48 h before with Follimag has been shown to increase progesterone levels (maximum 8 h post-treatment) and induce ovulation, as indicated by the appearance at 24 h corpus luteum (8.6 ± 0.5 per ovary). In terms of its activity, TP03 is comparable to hCG, although it acts more moderately. In the ovaries, unlike hCG, TP03 does not lead to an increase in the expression of vascular endothelial growth factor, which can cause ovarian hyperstimulation syndrome. Thus, TP03 is a promising drug as an ovulation inducer and ovarian steroidogenesis stimulator. [ABSTRACT FROM AUTHOR]

The level of spontaneous and radiation-induced DNA damage varies depending on genetic and environmental factors in human somatic cells. This variation may be associated with transcriptional changes in cells, allowing the use of gene expression levels as markers of individual sensitivity to mutagenic effects. This study aimed to identify and characterize differentially expressed genes (DEGs) in lymphocytes of individuals with various frequencies of endogenous γH2AX foci and radiation-induced micronuclei (n = 37). The low-focus group was characterized by 0.18 ± 0.02 endogenous γH2AX foci per cell and a 155.78 ± 47.19‰ radiation-induced micronucleus frequency. The high-focus group was characterized by 0.49 ± 0.07 foci/cell and a 78.44 ± 33.21‰ micronucleus frequency. Seven DEGs (ENST00000424415, CRNDE, ADAMTS1, ENST00000424084, EIF2A, PNPLA5, and FRG2C) (FDR < 0.2) were identified by gene expression analysis with microarrays. As the extracellular matrix metalloproteinase, ADAMTS1 is able to activate the latent form of TGFβ, and TGFβ is involved in radiation-induced cellular response; the effects of ADAMTS1 knockout and overexpression on the gene expression profile were further validated in adherent HeLa cells. Twenty-nine of 160 identified DEGs are involved in apoptosis, DNA DSB repair, G2/M cell cycle transition, and the TGFβ signaling pathway. Thus, ADAMTS1 may be useful as a potential target for antitumor therapy. [ABSTRACT FROM AUTHOR]

A brief history of the development of ideas about pleiotropy, its types, and the overall prevalence of pleiotropic loci in the human genome, as well as pleiotropic variants and genes within the same group of pathologies (disorders of psychomotor development) and between different diseases are discussed. Data on the association of the birth of a child with intellectual disability in a woman with a history of miscarriage are presented. The involvement of the same copy number variations (CNVs) in disorders of prenatal and postnatal development has been shown. The hypothesis is proposed that these CNVs are pleiotropic and manifested by one pathology or another, depending on additional modifying factors. [ABSTRACT FROM AUTHOR]

Flotation and assimilation of nonmetallic inclusions from metal slag in steel-pouring ladles and tundishes during pouring steels with increased aluminum and sulfur content are considered. The authors study the formation of nonmetallic inclusions in a steel-pouring ladle during steel extra-furnace treatment, the process of submerged nozzle clogging during continuous casting, the change in slag composition in a tundish, and development of an assimilation mixture composition for a steel-pouring ladle. Laboratory studies are made of the physicochemical properties of a developed SFM. It is established that use of the new SFM makes it possible to improve nonmetallic inclusion assimilation in a steel-pouring ladle and does not lead to a marked change in slag chemical composition and physical properties in a tundish. As a result of this, there is less steel contamination with nonmetallic inclusions and a reduction in submerged nozzle clogging. [ABSTRACT FROM AUTHOR]

The first data on the existence of multiple genomic rearrangements, such as copy number variation (CNV) and copy neutral loss of heterozygosity, in vascular tissues and peripheral blood leukocytes from patients with atherosclerosis, are presented. Compared to internal mammary arteries and peripheral blood leukocytes, right coronary arteries in the atherosclerotic plaque area presented with a higher CNV length and number of genes located in their vicinity. In each of the patients, 6-16% of CNVs were common to the three types of tissues examined. Therefore, most of the copy number variations in the tissues affected by atherosclerosis (from 68 to 91% in each of the patients) were of somatic origin. The gains in 3p21.31 ( CACNA2D2), 7q32.1 ( FLNC), 19p13.3 ( C19orf29, PIP5K1C), and 21q22.3 ( COL6A1) were detected in vascular tissues but not in peripheral blood leukocytes. Moreover, the gain in 7p15.2 ( SKAP2), detected in the patients with atherosclerosis, did not overlap with any CNV regions currently reported in The Database of Genomic Variants. The loss of heterozygosity in 12 out of 13 chromosomal regions was copy neutral and covered tumor suppressor genes ( SFRP1, CEBPD, RB1CC1, DIRAS3, TUSC3, and ZDHHC2). [ABSTRACT FROM AUTHOR]

We conducted an absolute paleointensity survey on 74 lava flows from the Okhotsk–Chukotka Volcanic Belt (NE Russia), emplaced 90–83 Ma toward the end of the Cretaceous Normal Superchron (CNS, 121–84 Ma). Relying on preliminary results, we restricted our analysis to eight lava flows (140 Thellier–Coe experiments), two of which also yielded successful Wilson determinations. A detailed analysis of the magneto‐mineralogy—based on X‐ray structural analysis, reflected‐light microscopy, and thermomagnetic curves—indicates that the determinations from solely two lava flows can be fully trusted, with remanence carriers (a) dominated by low‐titanium titanomagnetite, (b) showing unambiguous traces of high‐temperature oxidation, and (c) yielding partial thermoremanent magnetization (pTRM) tails representative of pseudo‐single‐domain grains. Recalculated in terms of geomagnetic dipole strength, our two successful flow‐mean determinations yield virtual dipole moments of 4.76 ± 0.26 × 1022 Am2 (N = 7) and 9.07 ± 0.84 × 1022 Am2 (N = 8). Using an updated version of the paleointensity database for the Cretaceous epoch, we stress that determinations based on nonglassy whole rocks, submarine basaltic glasses, and single crystals are mutually inconsistent, suggesting a separate analysis of their distributions is more appropriate. Despite statistically indistinguishable estimates of dipole strength before and after the onset of the CNS—in accord with recent studies refuting the existence of a strict correlation between chron duration and dipole moment—we found that the distribution of dipole moments during the CNS is slightly bimodal with a leptokurtic dominant mode, thus more inclined to produce outliers and suggesting distinct geomagnetic field behavior during the CNS. Plain Language Summary: The Cretaceous Normal Superchron (CNS, 121–84 Ma) is a salient feature of the geomagnetic field during the Phanerozoic, characterized by an anomalously long period of stable polarity whereas Earth's magnetic field stochastically reversed its polarity approximately 4 times per Myr during the last 5 million years. Deciphering the geomagnetic behavior during the CNS, in terms of average dipole strength and variability, is thus essential to better understand the modus operandi of the geodynamo and better constrain numerical models. To this end, we conducted absolute paleointensity (API) experiments on lava flows from the Okhotsk–Chukotka Volcanic Belt (NE Russia), yielding two estimates of the geomagnetic dipole strength toward the end of the CNS. Using an updated version of the API database, we show that average dipole strength is statistically indistinguishable before and after the onset of the CNS, suggesting the absence of a strict correlation between duration of polarity intervals and average dipole strength. In contrast, we also show that the distribution of dipole strength estimates is slightly bimodal, with the dominant mode being more peaked than a normal distribution. This feature may point to a higher propensity of the geodynamo to produce outliers and thus distinct geomagnetic behavior during the CNS. Key Points: We investigate geomagnetic field behavior during the Cretaceous Normal Superchron (CNS), a ∼40 Myr interval of stable polarityWe present new absolute paleointensity data from Chukotka (NE Russia) emplaced at high latitude toward the end of the CNS (∼87 Ma)We show that geomagnetic dipole strength during the CNS may be bimodal, yet with a similar average than during the whole Cretaceous epoch [ABSTRACT FROM AUTHOR]

Analysis of the prevalence of copy number variations of the CNTN6 gene, recently selected as a new candidate gene for intellectual disorders, was performed. Real-time PCR did not detect any change in the number of CNTN6 gene copies in a group of 200 patients with impaired intellectual development. However, taking into account our data from the previous aCGH analysis and published data, the overall frequency of microdeletions and microduplications of CNTN6 was estimated as 1: 265 (0.4%). The common phenotypic features of 40 patients with microdeletions and microduplications of CNTN6 appeared to be the autism spectrum disorders, developmental delay, intellectual disability, seizures, cognitive impairment, cardiological defects, and behavioral problems. [ABSTRACT FROM AUTHOR]

The current knowledge on multiple epimutations in imprinted genes and their impact on the disturbance of human prenatal development and the emergence of hereditary diseases are reviewed and analyzed. Genetic mechanisms regulating the epigenetic state of imprinted loci in the human genome are discussed. [ABSTRACT FROM AUTHOR]

The functional restoration of the male reproductive system in type 2 diabetes mellitus (DM2) is one of the urgent global challenges in modern endocrinology. This problem can be solved through the application of both the drugs that improve glucose homeostasis and insulin sensitivity, primarily metformin, and the activators of luteinizing hormone receptor (LHR), such as human chorionic gonadotropin (hCG) and low-molecular-weight allosteric LHR agonists. The aim of the work was to study the effect of metformin therapy (4 weeks, 120 mg/kg/day) on steroidogenesis- and spermatogenesis-stimulating effects induced by the 5-day administration of 5-amino-N-tert-butyl-2-(methylsulfanyl)-4-(3-(nicotinamido)phenyl)thieno[2,3-d]pyrimidine-6-carboxamide (TP03), an allosteric LHR agonist (15 mg/kg/day), and hCG (20 IU/rat/day) to male Wistar rats with DM2. The DM2 was induced by a high-fat diet and a low-dose streptozotocin (25 mg/kg). Metformin therapy partially restored testosterone levels and normalized spermatogenesis in DM2 rats. On the first day, metformin treatment enhanced the steroidogenic effects of TP03 and hCG, however, in the following days its potentiating effect was not detected. After five days of treatment of diabetic rats with TP03 and hCG, epididymal sperm count was restored, including the spermatozoa with progressive motility, and the percentage of abnormal sperm was decreased. Spermatogenesis indices when treating with metformin or LHR agonists separately were comparable to those resulted from their co-administration. Thus, metformin therapy enhances TP03- and hCG-induced testosterone production on the first day of treatment with these drugs, however, later on, steroidogenic and spermatogenic effects of LHR agonists in the groups of diabetic rats treated and untreated with metformin did not differ significantly. [ABSTRACT FROM AUTHOR]

Single-nucleotide polymorphisms (SNPs) in the 9p21.3 locus have recently been demonstrated to be strongly associated with atherosclerosis. However, the pathophysiology of this locus is insufficiently studied. Here, the methylation profile of the nearest mapped genes for cyclin-dependent kinase inhibitors CDKN2A (p16, p14) and CDKN2B (p15) in the tissues of the carotid artery in patients with atherosclerosis was evaluated for the first time. Aberrant DNA methylation of the analyzed loci was not established in either the atherosclerotic plaques or in the tissues from the macroscopically intact vascular wall in the same patients. [ABSTRACT FROM AUTHOR]

Currently, the question of epigenetic mechanisms of gene regulation in the context of cardiovascular diseases is of considerable interest. Here, DNA methylation profiles of vascular tissues of atherosclerotic patients have been analyzed for the first time using the Infinium Human Methylation27 BeadChip microarray (Illumina, United States). As the result, within 286 genes, 314 CpG sites that varied significantly in the level of DNA methylation between the tissue samples of carotid (in the area of atherosclerotic plaques and nearby macroscopically intact tissues of the vascular wall) and mammary arteries, as well as saphenous veins have been identified. The most pronounced differences in the methylation level was registered for CpG sites of homeobox genes HOXA2 and HOXD4, as well as the imprinted MEST gene. In particular, these genes were found to be hypomethylated in the carotid atherosclerotic plaques compared to their methylation patterns in intact tissues of internal mammary arteries and saphenous veins. [ABSTRACT FROM AUTHOR]

For the first time, the epigenetic status of breast benign proliferative processes, malignant breast tumors, and metastases to regional lymph nodes has been studied using the GoldenGate Cancer Panel I DNA methylation microarray (Illumina, United States). The functional groups of differentially methylated genes were identified in each set of samples. The aberrant methylation of genes that regulate cell proliferation and mobility was found in the samples of benign proliferative breast processes. The aberrant methylation of genes responsible for cell differentiation and proliferation, as well as protein phosphorylation and cell mobility, was observed in the samples of malignant breast tumors. The differential methylation of the genes that regulate cell adhesion, the formation of anatomical structures, angiogenesis, immune response, signal transduction, and protein phosphorylation were found in samples with metastases to regional lymph nodes compared to the unaltered breast epithelium. It was found that tissues that range from benign proliferative processes and metastases to regional lymph nodes were generally characterized by a relatively lower level of epigenetic variability compared to the tissues of the primary tumor. [ABSTRACT FROM AUTHOR]

Mutation theory of atherogenesis proved by 'loss of heterozygosity' and microsatellite instability in the area of atherosclerotic plaques is complemented by data on epigenetic variability of genetic loci involved in the pathologic process. However, only recently large-scale analysis of epigenetic modifications in the human genome became possible. For the first time, the quantitative microarray-based methylation profiling of 1505 CpG-sites in 807 genes was performed in atherosclerotic plaques of aorta and carotid artery from humans using the GoldenGate Methylation Cancer Panel I (Illumina, United States). One hundred and three (7%) CpG-sites in 90 (11%) genes were differentially methylated between tissue samples. The most pronounced differences in DNA methylation levels were registered for a site located in CpG-island of the imprinted gene H19. By comparing 90 genes that were differentially methylated between tissue samples in our study, 10 genes ( ICAM1, GSTM1, IGFBP1, POMC, APOA1, IL1RN, INS, LTA, MMP3, THBS2) were overlapped with data in the Human Genome Epidemiology Network (HuGENet), in which they were identified as candidates for cardiovascular disease continuum. [ABSTRACT FROM AUTHOR]

Risks related to occupational exposure of humans to ionizing radiation remains a focus of attention. Of special importance is the poorly understood effect of ionizing radiation on the rate of numerical chromosome aberrations in human somatic cells. The purpose of this study was characterization of a radiation-induced increase in the rate of aneuploidy induced by incorporated plutonium-239 (Pu) in somatic cells of chemonuclear industry workers. Significant differences in the chromosome 2, 7, 8, 12, and Y aneuploidy rate have been found between subjects with incorporated Pu and control subjects have been demonstrated. Chromosome nondisjunction has been found to be the main mechanism of aneuploidy induced by incorporated Pu. [ABSTRACT FROM AUTHOR]

Aneuploidy is among the most serious impairments of hereditary material in somatic and germline cells of living organisms. Chromosome loss or the appearance of an extra homolog in the chromosome set can result in either cell death or the development of various neoplasms with high probability of malignancy. It was traditionally believed that ionizing radiation produces primarily a clastogenic effect. However, there is apparently an aneugenic component of radiation, with mechanism different from that of structural chromosome damage. The present review focuses on the evidence for the existence of the aneugenic effect of ionizing radiation in mammalian and human somatic cells. [ABSTRACT FROM AUTHOR]

In most cases, the cause of embryo and fetus death remains unclear although the multifactorial reasons are suspected. The polymorphic C677T and A1298C variants of the MTHFR gene are associated with hyperhomocysteinemia, which is a risk factor of early pregnancy loss. The aim of this study is analysis of genotypes and haplotypes of C677T and A1298C polymorphic variants of MTHFR genes in the groups of spontaneous abortions with normal karyotype and newborns in the Tomsk population. Between these groups, no statistically significant differences were determined in the allele, genotype, and haplotype distributions of C677T and A1298C polymorphisms of the MTHFR gene. The haplotype frequencies of C677T and A1298C polymorphic variants of MTHFR gene in the Russian populations, which proved to be similar to those in most European populations, are presented for the first time. [ABSTRACT FROM AUTHOR]

The effect of knockout and overexpression of the ADAMTS1 on the radiation-induced response in HeLa cell line was analyzed. The cell line with the ADAMTS1 gene knockout was created using the CRISPR/Cas9 genome editing technology. The ADAMTS1 gene overexpression was ensured by transient transfection of the plasmid containing the gene of interest. Clonogenic survival, micronuclei frequency, and the γH2AX and 53BP1 foci level after irradiation with 2–8 Gy of γ rays were assessed. It was shown that the HeLa cell line with the ADAMTS1 gene knockout was characterized by a 1.9-fold decrease in clonogenic survival after an irradiation dose of 2 Gy (p < 0.05) and an increase in micronuclei frequency (55.3 ± 8.3‰) in comparison with intact HeLa (36.0 ± 7.2‰, p < 0.05), but did not differ in the DNA repair foci level. Transfection of the plasmid carrying the ADAMTS1 gene into HeLa cell line with the ADAMTS1 gene knockout led to a decrease in the radiation-induced micronuclei frequency from 55.3 ± 8.3 to 28.7 ± 10.3‰ (p < 0.05), which was comparable with the micronuclei frequency in the original HeLa cell line after irradiation (36.0 ± 7.2‰). Our results indicate that the ADAMTS1 gene is involved in radiation-induced cellular response in the HeLa cell line. [ABSTRACT FROM AUTHOR]

Human ring chromosomes are often unstable during mitosis, and daughter cells can be partially or completely aneuploid. We studied the mitotic stability of four ring chromosomes, 8, 13, 18, and 22, in long-term cultures of skin fibroblasts and induced pluripotent stem cells (iPSCs) by GTG karyotyping and aCGH. Ring chromosome loss and secondary aberrations were observed in all fibroblast cultures except for r(18). We found monosomy, fragmentation, and translocation of indexed chromosomes. In iPSCs, aCGH revealed striking differences in mitotic stability both between iPSC lines with different rings and, in some cases, between cell lines with the same ring chromosome. We registered the spontaneous rescue of karyotype 46,XY,r(8) to 46,XY in all six iPSC lines through ring chromosome loss and intact homologue duplication with isoUPD(8)pat occurrence, as proven by SNP genotype distribution analysis. In iPSCs with other ring chromosomes, karyotype correction was not observed. Our results suggest that spontaneous correction of the karyotype with ring chromosomes in iPSCs is not universal and that pluripotency is compatible with a wide range of derivative karyotypes. We conclude that marked variability in the frequency of secondary rearrangements exists in both fibroblast and iPSC cultures, expanding the clinical significance of the constitutional ring chromosome. [ABSTRACT FROM AUTHOR]

Detection of translocations in subtelomeric regions of chromosomes is a serious diagnostic problem, because they are difficult to determine by conventional cytogenetics with G banding. The aim of this work was the development of the technology of DNA probe synthesis for unique sequences of subtelomeric chromosome regions based on long-range PCR using the clinical case of determining the parental origin of unbalanced translocation between chromosomes 5 and 8. The unbalanced translocation der(5)t(5;8)(р15.33;q24.22) in a proband with physical, motor, intellectual, and speech development delay and in his sibling with speech and intellectual development delay as well, which was previously identified by array comparative genomic hybridization (aCGH), was confirmed by FISH. A balanced translocation 46,XX,t(5;8)(p15.33;q24.22) was detected in the mother's karyotype using the created locus-specific DNA probe. This chromosome aberration was not detected by G banding of metaphase chromosomes. The father's karyotype was normal according to FISH results. The method presented here makes it possible to create locus-specific DNA probes in a molecular cytogenetic laboratory using long-range PCR for the rapid diagnosis of cryptic chromosomal rearrangements. [ABSTRACT FROM AUTHOR]

In this study, the effect of the THBS1 gene knockout on the survival of human tumor cells, the frequency of spontaneous and radiation-induced micronuclei, and the expression profile of genes in the HeLa cell line was investigated. It was shown that the THBS1 gene knockout led to a decrease in the plating efficiency before and after irradiation (1.4-fold, p = 0.0002 and 1.7-fold, p = 0.00009, respectively) and an increase in the frequency of spontaneous and radiation-induced micronuclei (1.9-fold, p = 0.02 and 2.5-fold, p = 0.01, respectively). In addition, expression of genes involved in the DNA repair processes, apoptosis, and G2/M cell cycle checkpoint was changed after THBS1 knockout in comparison with the intact HeLa cell line. Thus, the THBS1 gene knockout leads to an increase in the radiosensitivity of the HeLa cell line. This indicates the possible role of the THBS1 gene in the regulation of a radiation-induced cellular response. [ABSTRACT FROM AUTHOR]

Purpose: To study the contribution of embryo chromosomal abnormalities in primary and secondary recurrent pregnancy loss (RPL) and to analyze the recurrence of chromosomal constitution in miscarriages from the same couple. Methods: Retrospective study of abortion karyotypes in RPL families based on the mother's primary or secondary RPL status (563 embryo specimens, 335 samples from primary, and 228 samples from secondary RPL). RPL was defined as two or more consecutive miscarriages. One hundred eight cases of recurrent embryo/fetal loss in 51 families were analyzed to assess the probability of having the same karyotype pattern (recurrent normal or recurrent abnormal) in both previous and subsequent pregnancy loss. The karyotypes of abortions were established using standard cytogenetic analysis, as well as interphase fluorescence in situ hybridization (FISH) and comparative genomic hybridization (CGH). Results: The frequency of aberrations was 43.9% in abortions from primary RPL versus 52.6% in secondary RPL (p = 0.041). Women 35 years of age or older were the main contributors to this difference. The odds ratio of a subsequent abortion having the same karyotype pattern (normal or abnormal) as the previous one was 6.98 (p = 0.0013). Conclusion: The frequency of abnormalities is higher in abortions from the secondary RPL versus primary RPL group, and this difference is due to the relative deficiency of miscarriages with abnormal karyotypes in older women with primary RPL. The probability of having the same karyotype pattern (recurrent normal or recurrent abnormal) in the previous and subsequent abortion is increased significantly compared with chance. [ABSTRACT FROM AUTHOR]

The scale and age of extreme hydrological events that have been manifested over the past 2000 years on the coast of Valentin Bay is established based on stratigraphic study and radiocarbon dating of different facies deposits. The deposits of four major historical tsunamis (1993, 1983, 1644, and the 12th century) and a paleo-tsunami, which occurred between 1700–1800 cal yr BP. BP, were found. Sedimentation zones were mapped. The composition of diatoms in tsunami sands has been studied in detail. Along with marine and brackish water species tsunami waves also carried most freshwater forms that were redeposited from the coastal lake. Much of the material was supplied from depths up to 5 m. The correlation of events with data for the Japanese Islands is carried out. It has been suggested that the most dangerous tsunamis for this part of the Eastern Primorye coast are caused by submarine earthquakes with epicenters located near the Okushiri Island. The tsunamis associated with earthquakes with epicenters located near the northwestern Honshu Island, were less pronounced. Data on the irregular frequency of extreme floods during the last millennium has been obtained. It was established that the pluvial phase of the Warm Medieval Period ended in the early to mid-12th century. During the Little Ice Age, the water content of the rivers was insignificant, only two events, comparable to the catastrophic floods of the late 20th to early 21st century, are known to correspond to the warm phase of the mid-14th century to early 15th century. Only two of the modern floods have left traces recorded in the sedimentary sequences of the Valentin Bay coast. [ABSTRACT FROM AUTHOR]

Using chromosome microarray analysis, 52 samples of placental tissues from first trimester human spontaneous abortions were examined. One hundred twenty copy number variations (CNVs) were identified, affecting one or more genes (total of 427 genes). Using enrichment analysis with the mammalian phenotype ontology, all genes were divided into 183 categories (p ≤ 0.05). The embryogenesis category included 22 genes: AIP, BMP4, BMP5, CDKN1C, EXT1, GAB1, H19, HOXD13, IGF2, KIT, LDHA, NKX2-5, NRK, PEG3, PHLDA2, SMCHD1, SMN1, TBX3, TGIF1, TH, TLX2, and TRR. In this paper, the functions of each of the above genes and pathological phenotypes associated with mutations in them are discussed. A hypothesis of the pleiotropic effect of genes involved in CNVs in spontaneous abortions is proposed. [ABSTRACT FROM AUTHOR]

Deposits of the two strongest tsunamis of the 20th century have been found on the eastern coast of Primorye. The tsunamis had epicenters in the Sea of Japan west of the coast of Hokkaido. The distribution and preservation of deposits in bays of different geomorphological structure have been analyzed. The best defined sedimentary covers occur in the upper part of sections in low-lying areas of bay shores, where the wave runup was more than 3 m. The best preserved deposits have been observed in bays attributed to loworder streams. Variations of the structural composition of tsunami deposits formed by traction processes associated with the tsunamis have been analyzed depending on distance from the shoreline; the sources of material have been identified. Tsunami waves transported sand not only from beaches, ancient storm ridges, and terraces, but also from the underwater coastal slope; waves also grabbed material from estuarine lagoons and lakes located in the shore inundation zone. Deposits include marine diatoms with dominant sublittoral planktonic and benthic species, which suggests that the material was transported from a depth no more than 15 m. Deep-sea species of diatoms and their fragments have been encountered. Among freshwater diatoms are species with different ecological identities, indicating erosion and redeposition of material transported from various sources. [ABSTRACT FROM AUTHOR]

An analysis of differential methylation of 47 imprinted genes in placenta tissues of spontaneous abortions at the first trimester of pregnancy from women with recurrent pregnancy loss or with one sporadic abortion was performed using the DNA-microarray approach. We showed that epimutations of the imprinted genes were registered significantly more often in abortions from women with recurrent miscarriage in contrast to the embryos from women with sporadic pregnancy loss with frequency of 6.2 and 3.7% per locus, respectively (p < 0.01). The predominant type of epimutation appeared to be a postzygotic hypomethylation of the imprinted genes on chromosomes of maternal origin, which was observed in the examined samples in 5.1 and 2.89% of cases, respectively. Replicative study of the methylation status of seven imprinted genes ( DLK1, PEG10, PLAGL1, KCNQ1OT1, PEG3, GRB10, and PEG1/MEST) in the enlarged embryo samples supported the results of microarray analysis in respect to both epimutation frequency and predominance of somatic hypomethylation of maternal alleles. It was also demonstrated that pregnancy loss was associated with multilocus methylation defects of imprinted genes, the frequency of which was also significantly increased in the placental tissues of spontaneous abortions in women with recurrent miscarriage. [ABSTRACT FROM AUTHOR]

A set of algorithms for simultaneous localization and mapping in industrial television systems is discussed. A probabilistic model of this problem is described with the FastSLAM algorithm as an example. The possibility of using a sigma-point Kalman filter for estimating the movement of spatial landmarks, a key feature of images characterized by stable detection and recognition within the video stream, is considered. A general model of the camera motion and a method for evaluating its spatial position using a particle filter are presented. [ABSTRACT FROM AUTHOR]

A procedure is described for qualitative evaluation of the effect of binders on granulated slag-forming mixture (SFM) strength. A relationship is established for slip density and finished granulate bulk density on water content. Industrial tests are conducted for a new binder and a test batch of granulated SFM is prepared with a low proportion of dusty fraction for pouring steel in a CBCM at MMK. [ABSTRACT FROM AUTHOR]

The discovery of cell-free DNA in blastocoele fluid opens new perspectives for the development of preimplantation genetic diagnosis of human chromosomal and genetic diseases. In this review we analyzed the results of the first studies, which made it possible to evaluate the effectiveness of the application of a new source of biological material and showed a high degree of agreement between the results of molecular karyotyping with cell-free DNA and blastocyst cells. The results suggest the possibility of developing a noninvasive method of preimplantation genetic diagnosis, which may open a new round of progress in the field of assisted reproductive technologies and the genetics of early stages of human ontogenesis. [ABSTRACT FROM AUTHOR]

Early stages of human embryonic development are characterized by the spatiotemporal coincidence of events of total epigenetic genome reprogramming and elevated level of mosaic forms of numerical chromosome abnormalities. It is possible that the abnormal reprogramming of various regions of the genome can lead to violations of local epigenetic chromatin organization and gene expression, which affect the correct chromosome segregation during mitosis. In this study, a comparative analysis of the methylation index of LINE-1 retrotransposon, which largely reflects the methylation profile of the genome, is performed in placental tissues of spontaneous abortions with complete and mosaic forms of aneuploidy and with a normal karyotype, as well as in the control group of induced abortions of the first trimester of pregnancy. It was shown that extraembryonic mesoderm and chorionic cytotrophoblast of spontaneous abortions with chromosomal mosaicism are characterized by the highest index of LINE-1 methylation among all studied groups. At the same time, the excessive hypomethylation of transposable genetic element was registered in spontaneous abortions with normal karyotype. We hypothesize that violations of parental genome demethylation during epigenetic reprogramming at preimplantation stages of development may be associated with an increased frequency of mitotic errors in chromosome segregation, which leads to the formation of a mosaic karyotype. [ABSTRACT FROM AUTHOR]

The present work was aimed at generating the dynamic standard reference intervals (DSRI) and their application for chromosomal-aberration (CA) analysis. The evaluation of the generated DSRI was performed using the DNA samples from four patients with already known CA. High-resolution comparative genomic hybridization analysis (HR-CGH) allowed us to not only identify all of the CAs that were not revealed by CGH, but also to detect the breakpoints and to determine the size of chromosomal imbalance. [ABSTRACT FROM AUTHOR]

The methylation profiles of the placental tissues of human embryos with normal karyotype and trisomy 16 were compared using an Infinium HumanMethylation27 BeadChip array (Illumina, United States). Numerous differences between the extraembryonic tissues with diploid and aneuploid karyotypes were observed. The extraembryonic mesoderm of embryos with trisomy 16 appeared to be less methylated than the diploid tissue, whereas the cytotrophoblast of aneuploid embryos was hypermethylated. The presence of the supernumerary chromosome was shown to influence the epigenetic profile of the genome by changing the level of methylation of CpG sites of all chromosomes. However, the largest number of differentially methylated loci was found on chromosome 16. Furthermore, more often, the epimutations were tissuespecific. In both tissues, the hypomethylated genes belong to the groups of genes responsible for different metabolic processes, whereas the hypermethylated genes control the processes of development, cell adhesion, immune response, and response to stimulus. [ABSTRACT FROM AUTHOR]

We report the occurrence of superconductivity, with maximum Tc = 40 K, in superlattices (SLs) based on two insulating oxides, namely CaCuO 2 and SrTiO 3/sub>. In these (CaCuO2)n/(SrTiOsub>3)m SLs, the CuO2 planes belong only to CaCuO2 lock, which is an antiferromagnetic insulator. Superconductivity, confined within a few unit cells at the CaCuO2/SrTi O3 interface, shows up only when the SLs are grown in a highly oxidizing atmosphere, because of extra oxygen ions entering at the interfaces. The hole doping is obtained by charge transfer from the interface layers, which thus act as charge reservoir. [ABSTRACT FROM AUTHOR]

Genomic imprinting is one of the key epigenetic phenomena involved in embryonic development of eutherians and humans. Molecular mechanisms of imprinting disturbances in the pathology of prenatal and postnatal onthogenesis are to a great extent related to methylation abnormalities of the imprinted genes. Over recent years, data are accumulating on multiple abnormalities of methylation simultaneously in several imprinted loci in the development of various pathologies that raises the issue of deciphering the structural and functional organization of imprintome and the interaction of imprinted genes. The present work analyzes DNA methylation of 51 imprinted genes in the placental tissues of human spontaneous abortions. We revealed multiple epimutations in from four to 12 imprinted genes in every embryo. Most of the epimutations (78%) were of a postzygotic origin. It has been established for the first time that the total incidence of methylation disturbance in maternal and paternal alleles of the imprinted genes leading to embryo development suppression is significantly higher than the incidence of epimutations, which stimulate embryogenesis. This fact supports at the epigenetic level the hypothesis of parent-offspring conflict that describes the occurrence of a monoallelic expression of imprinted genes in mammalian evolution. [ABSTRACT FROM AUTHOR]

For the first time, DNA methylation patterns in the human cytotrophoblast and the extraembryonic mesoderm were determined using a genome-wide Infinium HumanMethylation27 BeadChip Array (Illumina, United States). These tissues are derivatives of the trophectoderm and the inner cell mass of the blastocyst and have substantial differences in the dynamics of epigenetic genome reprogramming during early stages of differentiation. It was shown that the genome of the extraembryonic mesoderm cells was more methylated than that of the cytotrophoblast, similarly to the findings in other mammalian species. There were differences in the methylation patterns of single CpG dinucleotides and dinucleotides located within promoter CpG islands: in both tissues most single CpG dinucleotides were methylated, promoters CpG island sites were not. A comparative analysis revealed 202 differentially methylated genes in the extraembryonic mesoderm and 40 such genes in the cytotrophoblast. These genes are responsible for a number of diverse biological processes. However, in the extraembryonic mesoderm, a majority of genes identified were responsible for DNA binding and transcriptional factor activity, whereas those identified in the cytotrophoblast were responsible for transport and protein and cytokine secretion. [ABSTRACT FROM AUTHOR]

Epigenetic mechanisms of cell cycle regulation providing for maintenance of genome stability and precise transmission of hereditary information to the daughter cells attract considerable interest. Up-to-date molecular technologies allow the genome-wide methylation pattern to be determined in a single experiment. In this work, we pioneered in determining the epigenetic status of the placental tissues of the human embryos with mosaic karyotype using a genome-wide Illumina Infinium HumanMethylation27 BeadChip array (Illumina, United States), comprising 27578 CpG dinucleotides contained in 14475 genes. The groups of genes associated with the cell cycle and its regulation that contain differentially methylated CpG sites in their promoter regions have been determined. It was demonstrated that the methylation level most frequently changed in oncogenes ( ARHGEF1 and FGF5), tumor suppressors ( APC2, BRACA2, DCC, GRLF1, RB1, TP73, TSPYL2, and VHL), and the genes involved in the regulation of chromosome segregation ( CNTROB, GMNN, PROCR, and TACC1). [ABSTRACT FROM AUTHOR]

The sex ratio and X-chromosome inactivation were analyzed in placental tissues of human spontaneous abortuses with pure and mosaic forms of chromosome 16 trisomy. The sex ratio value was found to decrease with an increase in the share of cells with the trisomic karyotype, which suggests differential survival of embryos belonging to different sexes. The pattern of X-chromosome inactivation in cells of extraembryonic mesoderm in the control group of embryos and in spontaneous abortuses with the level of trisomy 16 below 80% corresponded to random X-inactivation, whereas in most embryos with a frequency of trisomy 16 exceeding 80% skewed inactivation was observed. Our results support the hypothesis about the existence of an autosomal transfactor influencing the initiation of X-chromosome inactivation and suggest its possible localization on chromosome 16. [ABSTRACT FROM AUTHOR]

The methylation status of the promoter region of the cell cycle gene P14ARF was studied in the extraembryonic mesoderm and in the cytotrophoblast of 46 human spontaneous abortions with chromosomal mosaicism. Aberrant methylation of alleles of this gene was revealed for the first time in placental tissues of 9% of embryos. The identified epimutations were found to be characteristic of embryos with aneuploid cell clones of postzygotic origin. It is suggested that epigenetic inactivation of loci responsible for the regulation of cell division and for segregation of chromosomes is associated with the origin of mosaic forms of the karyotype at early stages of human embryonic development. [ABSTRACT FROM AUTHOR]

The methylation status of the cell cycle control gene RB1 has been studied in placental tissues of spontaneous abortions of the first trimester of pregnancy with mosaic variants of numerical chromosomal abnormalities verified by a molecular cytogenetic examination. Aberrant methylation of the gene promoter region has been revealed for the first time in 20% of embryos with chromosomal mosaicism that died in utero. A maximum frequency of epimutations was recorded in a group of embryos with a low level of abnormal cells for which mitotic errors are most likely to determine the formation of mosaic aneuploidy in primary euploid zygotes. It has been suggested that aberrant epigenetic genomic modifications at early stages of human embryonic development can be one of the mechanisms promoting genomic instability realized in the form of mosaic abnormalities of the karyotype that are incompatible with the normal course of embryogenesis. [ABSTRACT FROM AUTHOR]

Abstract: On basis of the theorem of a universal shower development stating that a hadronically generated extensive air shower is completely described by the primary energy, the position of the shower maximum and a parameter related to the total muon number, the so-called correlation curve method is developed and applied to KASCADE data. Correlation information of the muon and electron content of showers measured by the KASCADE experiment are used for the reconstruction of energy and mass of primary cosmic rays. Systematic uncertainties of the method and the results are discussed in detail. It is shown that by this method general tendencies in spectrum and composition indeed can be revealed, but the absolute normalization in energy and mass scale requires much more detailed simulations. [Copyright &y& Elsevier]

This article presents information on optical dispersion in standardization and quality control of medicinal preparations. The increasing number of heterogeneous medicinals (including falsified preparations) stimulates extensive basic research and effort toward the implementation of more perfect methods for the standardization and quality control of such medicinal preparations. In modern pharmacy, problems related to the standardization and quality control of heterogeneous medicinals are solved by various methods, including microscopy, sedimentation analysis nephelometry, and granulometric sieving analysis. The main disadvantage of the microscopic examination is that the investigation is performed only for a very restricted amount of the given preparation, which decreases the reliability of analysis.

We carried out systematic studies of the contribution of uniparental disomy for eight human chromosomes, 2, 9, 11, 15, 16, 19, 20, and 21, to the etiology of embryolethality. Most of these chromosomes have regions with orthologous imprinted genes syntenic with those on mouse chromosomes, the disturbed expression of which is related to embryolethality in mice. Screening of uniparental disomy in spontaneous abortuses of 5–16 weeks of pregnancy was performed by evaluation of the pattern of inheritance of alleles of polymorphic microsatellite loci located in the studied chromosomes. A total of 100 human embryos with cytogenetically determined normal karyotype were studied, in which arrest at the early stages of intrauterine development was determined by ultrasound examination of pregnant women. During this study, 13 embryos were discarded due to revealed karyotype anomalies or nonpaternity. No cases of uniparental disomy were found among the 87 studied abortuses for any of chromosomes studied. The analysis of the results of this study and four other studies concerning the search for uniparental disomy in dead embryos and fetuses did not reveal its elevated frequency in spontaneous abortuses as compared to the theoretically expected value based on evaluation of the probable combination of meiotic errors in human gametes. The data we obtained suggest that, first, uniparental disomies for human chromosomes that have regions with orthologous imprinted genes syntenic with mouse chromosomes do not contribute noticeably to the death of human embryos at the early developmental stages and, second, the mechanisms underlying embryolethality as a result of disturbed expression of imprinted loci differ markedly in evolutionarily remote mammals. [ABSTRACT FROM AUTHOR]

Introduction: Genetic disorders underlie a significant number of cases of mental retardation (MR). However, the traditionally used routine karyotyping is not able to detect small but often clinically relevant aberrations. High-resolution genome-wide microarray technologies may help to increase the detectability of MR etiology. Objectives: To improve MR diagnostics. Aims: To identify the novel CNV regions and susceptibility genes in MR patients. Methods: Large chromosomal rearrangements, biochemical defects, and known monogenic syndromes accompanied by MR were ruled out for 71 patients. Further the genome-wide analysis using CGH Microarray Kits 4×44K and 8×60K (Agilent Technologies, USA) was performed. Results: Eight novel CNVs in 9 patients not described in healthy individuals and not associated with any disease were indentified implicating regions at 11q22.3, 5q33.1, 3p26.3, 15q11.1-q11.2, 15q22.2, 1q25.1-q25.2, 7q21.3, 2q12.3. They include candidate genes DDX10 (putative RNA helicase), IL17B (cytokine, primarily localized to neuronal cell bodies), CNTN6 (may play a role in the formation of axon connections), TLN2 (plays a role in cell adhesion and recycling of synaptic vesicles), TNR (an extracellular matrix protein, expressed primarily in the central nervous system), ASTN1 (a neuronal adhesion molecule), PON1 (detoxifies organophosphate neurotoxicants), and SLC5A7 (choline transporter in the brain and periphery). Conclusions: Previously unknown CNVs, containing genes responsible for proper central nervous system functioning, were detected in 13% of patients. The novel CNVs and genes identified by aCGH may help discovering new etiological mechanisms of MR. This study was supported by European Community's Seventh Framework Programme, CHERISH (project 223692) and by Federal Program (grant 8727). [ABSTRACT FROM AUTHOR]