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The features of the coupled aldol condensation—hydrogenation processing of ethyl methyl ketone on a Pd/activated carbon catalyst were studied. The phase and chemical composition of activated carbon, as well as the carbon based catalyst, were studied using powder X-ray diffraction and electron microscopy. We established the influence of the reaction temperature, palladium mass content, contact time, and H2/EtC(O)Me molar ratio on the main parameters of the process, namely, on the conversion of the starting EtC(O)Me and the selectivity of the formation of 5-methylheptan-3-one and 3-methylheptane. The optimal process conditions were selected (0.3 wt.% of palladium, 300 °C, contact time 17 s, a 1.25 H2/EtC(O)Me molar ratio), allowing to achieve a 96% total selectivity for the target products. [ABSTRACT FROM AUTHOR]

Leptin, secreted by adipose tissue, indirectly stimulates the activity of GnRH-producing neurons in the hypothalamus and thus regulates the functional activity of the hypothalamic–pituitary–testicular (HPT) axis. Obesity is known to be accompanied by a systemic hyperleptinemia and impaired leptin transport in the central nervous system, which limits the use of full-length leptin as a drug. It was previously shown that the intranasally administered (i.n.) leptin fragment MA-[D-Leu4]-OB3 (LF) enhances the steroidogenic effect of human chorionic gonadotropin (hCG) in rats fed a standard diet. An even more urgent task is to assess its effect on testicular steroidogenesis in obesity that reduces reproductive functions in men. This work was aimed to study the ability of LF (200 µg/kg, i.n., for 3 days) to modulate the effect of hCG (10 IU/rat, s.c., once) on testicular steroidogenesis in male Wistar rats with obesity induced by a 20-week high-fat/high-carb diet (HFHCD), as well as to evaluate the impact of the GnRH receptor antagonist Cetrorelix (ANT, 75 µg/kg, s.c., for 3 days) on the effects of LF in these animals. Obese rats demonstrated reduced testicular levels of the luteinizing hormone receptor (LHR) and a compensatorily upregulated expression of the Cyp11a1 gene encoding the steroidogenic enzyme cytochrome P450scc. LF administration enhanced hCG effects on blood testosterone levels and testicular expression of the Star gene encoding the cholesterol transporter protein StAR, which suggests the ability of LF to positively modulate HPT axis activity under obesity. ANT and LF co-administration, by contrast, reduced the stimulatory effect of hCG on blood testosterone levels and testicular Star gene expression, which may be due to the testicular effects of LF. Our data indicate the ability of LF to influence different components of the male gonadal axis under conditions of diet-induced obesity. [ABSTRACT FROM AUTHOR]

The Cretaceous Normal Superchron (CNS, 84–121 Ma) is a singular period of the geodynamo's history, identified by a prolonged absence of polarity reversals. To better characterize the paleosecular variation (PSV) of the geomagnetic field at the end of this interval, we sampled seven continuous sequences of lava flows from the Okhotsk‐Chukotka Volcanic Belt, emplaced 84–89 Ma in the vicinity of the Kupol ore deposit (NE Russia). From a collection of 1,024 paleomagnetic cores out of 82 investigated lava flows, we successfully determined the paleodirections of 78 lava flows, which led to 57 directional groups after removing the serial correlations. The resulting paleomagnetic pole is located at 170.0°E, 76.8°N (A95 = 5.2°, N = 57), in good agreement with previous estimates for north‐eastern Eurasia. Aiming at quantifying PSV at a reconstructed paleolatitude (λ) of ∼80°N, we obtained a virtual geomagnetic pole (VGP) scatter Sb=21.5°|19.3°24.0°(N=57) ${{S}_{\mathrm{b}}=21.5{}^{\circ}\vert }_{19.3{}^{\circ}}^{24.0{}^{\circ}}\,(N=57)$, the value of which was corrected for within‐site dispersion and is little dependent on the choice of the selection criteria. Compared to previous paleodirectional data sets characterizing PSV at various paleolatitudes during the CNS, our Sb estimate confirms a relative latitudinal increase Sb(λ = 90°)/Sb(λ = 0°) on the order of 2–2.5. Focusing on PSV at high paleolatitude within the 70°–90° range, we show that Sb was ∼15% lower at the end of the CNS than during the past 10 Myr, confirming that the singular polarity regime of the geodynamo observed during the CNS is likely accompanied with reduced PSV. Plain Language Summary: Compared to the last 10 million years during which Earth's magnetic field stochastically reversed its polarity ∼4 times per million year, the Cretaceous Normal Superchron (CNS, 84–121 Ma) represents an anomalously long period of stable polarity, the understanding of which is crucial to constrain the working of the geodynamo. In this effort to better characterize the paleosecular variation (PSV) of the geodynamo, we investigated the paleomagnetic record of lava flow sequences from the Okhotsk‐Chukotka Volcanic Belt (NE Russia) emplaced 84–89 Ma at high paleolatitude. First, we obtained that the dispersion of virtual paleomagnetic poles (VGP), used as a proxy for PSV, is 2–2.5 times as high at the paleopole as at the paleoequator. Second, we showed that VGP scatter at high paleolatitude was ∼15% lower at the end of the CNS than during the last 10 million years, confirming a potential link between polarity regime and PSV. Key Points: We investigate geomagnetic field behavior at high paleolatitude (∼80°N) at the end of the Cretaceous Normal Superchron (CNS)We present a paleodirectional data set from 78 lava flows (resp. 57 directional groups), emplaced 84–89 Ma in north‐eastern EurasiaWe show that the dispersion of virtual geomagnetic poles at high latitude is ∼15% lower during the CNS than for the past 10 Myr [ABSTRACT FROM AUTHOR]

In this paper, a cellular automation model developed on the basis of Bezier curves with the use of a cellular automation approach for the creation of digital twins for porous nanostructures of different nature is proposed. Some numerical experiments on the creation of digital twins for the synthesized experimental samples of chitosan-based aerogels are carried out. The structural characteristics of the digital copies and experimental samples are compared, allowing us to conclude that the model is correct. The resulting digital twins can be used for predicting the properties of porous fiber materials, in particular, chitosan-based aerogels, to provide the partial replacement of real experiments by computational ones and, consequently, to decrease the expenditures on the development of new materials with specified properties. [ABSTRACT FROM AUTHOR]

The adipokine leptin plays an important role in the regulation of the reproductive system. It stimulates the activity of the hypothalamic–pituitary–gonadal axis by indirectly affecting gonadoliberin (GnRH)-secreting neurons and modulates testicular steroidogenesis via binding to leptin receptors in Leydig cells. The leptin fragment (LF) 116–122, which includes the main receptor-binding determinants of this adipokine, normalizes metabolic parameters in animals with a diet-induced obesity. However, its ability to influence the testicular steroidogenic function, including through interaction with hypothalamic GnRH neurons, has not been studied. The aim of this work was to study the effects of a single and 3-day intranasal LF administration (200 µg/rat) on blood testosterone levels and expression of steroidogenic genes in the testes of mature male Wistar rats, as well as to evaluate the steroidogenic activity of LF upon testosterone synthesis stimulation by human chorionic gonadotropin (hCG, 15 IU/rat, s.c.) and inhibition by the GnRH receptor antagonist Cetrorelix (75 µg/kg, s.c.). It was shown that a single LF administration increases blood testosterone levels, while a 3-day administration enhances the steroidogenic effect of hCG. LF and hCG increased the expression of the Star gene that encodes the key regulatory protein of steroidogenesis StAR. Cetrorelix administration reduced blood testosterone levels and Star expression, while compensatory increasing gene expression of the luteinizing hormone receptor. The potentiating effect of LF on hCG-induced stimulation of testosterone synthesis and Star expression was not detected after Cetrorelix treatment. Thus, LF is able to stimulate testicular steroidogenesis in rats by itself and potentiate the steroidogenic effects of hCG. Since its effects are suppressed in the presence of a GnRH antagonist, there are grounds to assume that they are implemented via stimulation of hypothalamic GnRH neurons. [ABSTRACT FROM AUTHOR]

Most copy number variations (CNV) of pathogenetic significance are associated with neurodevelopmental phenotypes and characterized by incomplete penetrance and variable expressivity. However, the nature of these phenomena has not yet been disclosed. As a result, this leads to the uncertainty of prognosis in families with affected children having a genetic variant associated with the disease that was, however, inherited from apparently healthy parents, which is a problem for genetic counseling in medicine. This review discusses the evidence for the contribution of interloci interaction between different CNVs to variability of clinical manifestations of neuropsychiatric and intellectual disorders. [ABSTRACT FROM AUTHOR]

Abstract—A paleomagnetic study of the Okhotsk–Chukotka belt volcanics exposed in the region of the Kupol field (~66.9° N, 170.1° E) has been carried out. The studied rocks were formed between 85 and 95 Ma during the Cretaceous Normal Superchron (CNS). In most of the studied samples, the characteristic magnetization component is isolated. Its primary origin is supported by the positive fold test, magnetic mineralogy data, and similarity of the calculated paleomagnetic pole with that of coeval rocks from the same region. It is shown that the studied rocks were formed in high polar latitudes close to 80° N. The amplitude of paleosecular variation (PSV) of the geomagnetic field during CNS has been estimated. Depending on the calculation method, the estimates (and their confidence intervals) for ~81° N are Sb = 22.1° (19.5°; 24.7°) in case of using a fixed cut-off angle of 45° and Sb = 23.1° (20.3°; 25.7°) in case of the cut-off angle calculated by the Vandamme method. The obtained estimates generally support the existing models of PSV latitudinal dependence for CNS. At the same time, the estimates are less consistent with the model (McFadden et al., 1991) where PSV values are low at the equator and sharply increase with latitude than with the model (Biggin et al., 2008) predicting higher PSV values at the equator and their more gentle increase towards polar latitudes. Irrespective of the calculation method, the obtained estimates almost perfectly fit the PSV latitudinal dependences for the last 5 Ma. This means that the amplitude of secular geomagnetic variation during CNS, at least at high latitudes, was the same as it was during the last 5 Ma. The obtained result does not support the hypothesis that geodynamo regimes change at the transition from the periods of frequent geomagnetic reversals to superchrons (e.g., (Gallet and Pavlov, 2016)), which suggests, in particular, that the modern numerical models are not fully adequate to the real processes of generation of the geomagnetic field. [ABSTRACT FROM AUTHOR]

U–Pb and 40Ar/39Ar age data obtained for volcanic rocks of the Okhotsk–Chukotka Belt in the headwaters of the Malyi Anyui River (the vicinity of Kupol deposit) indicate at least two main pulses of volcanic activity, 98–93 Ma and 90–84 Ma. The conventional stratigraphic models are not consistent with the new data on the age and composition of volcanic units. The spatial relations between volcanic complexes of different ages imply that volcanic units accumulated under conditions of dissected topography. In the absence of obvious petrographic distinctions between the volcanic sequences of different ages, the composition of detailed geological and paleovolcanological maps requires representative precise isotopic age data. [ABSTRACT FROM AUTHOR]

New U–Pb and 40Ar/39Ar isotopic dates on volcanic rocks of the East Chukotka segment of the Okhotsk–Chukotka Belt correspond to 76–71 Ma span, which is partially beyond the conventional lifetime of this volcanic province. This could result from the migration of magmatic loci along the strike of the volcanic belt, and/or from the overprint by a younger magmatic event. [ABSTRACT FROM AUTHOR]

Processes of trans–cis isomerization of azobenzene (AZB), 4,4′-azopyridine (AZP), and azoxybenzene (AZOB) are studied using quantum chemical calculations at the DFT/B3LYP/cc-pvTZ level of theory. The chosen objects can serve as reference points when studying intramolecular rearrangements of numerous compounds containing an azo group and an azoxy bridging group. Geometric and electronic characteristics of trans and cis isomers AZB and AZP and four AZOB isomers, as well as transition states (TSs) between them, are determined. It is established that two AZOB isomers containing a semi-polar bond N→O have a significantly lower energy than two isomers with a cyclic NON bridging group. The transition between the low-energy trans–cis isomers proceeds via a TS while preserving the N→O bond so that the oxygen atom does not migrate between the nitrogen atoms. The NBO analysis of the electronic structure is performed, the factors stabilizing the obtained geometric configurations of all isomers and transition states are determined. [ABSTRACT FROM AUTHOR]

The identification of the cybersecurity (CS) state of Internet of things (IoT) devices determines the necessity to search for and improve approaches to detecting various threat types. The unification used in the mass development of IoT devices facilitates software and hardware modification to block certain built-in protective functions from the side of a potential intruder. A need arises to develop universal methods for identifying the cybersecurity state of devices using comprehensive approaches to analyzing data from internal and external information channels. The article presents an approach to identifying the cybersecurity of IoT devices based on processing time series recorded from sensors during various processes, and internal and external (thirdparty) sources. The approach is based on classification methods. The presented solution uses template sequences containing synchronized time series showing numerical values obtained from various probes and sensors during process execution. The proposed approach makes it possible to identify IoT device cybersecurity states without increasing the volume of information stored and processed in internal resources. [ABSTRACT FROM AUTHOR]

This review is devoted to a comprehensive analysis of DNA copy number variations (CNVs) identified in patients with neurodevelopmental disorders (NDDs) from the literature. The selection of publications was conducted using specifically developed criteria. CNVs were characterized based on their clinical significance, type of copy number alteration (microdeletion/microduplication), size, origin, and gene content. The study sample comprised 3375 patients with NDDs. Pathogenic and likely pathogenic CNVs, as well as variants of uncertain clinical significance, were identified in 395 individuals (12%). Chromosomal variations of each category were identified in 89 (3%), 56 (2%), and 241 (7%) patients, respectively. Nine individuals exhibited combinations of CNVs with different clinical significance. The number of duplications slightly exceeded the number of deletions (250 and 204, respectively). The size of most CNVs ranged from 193 bp to 400 kb and from 1 to 3 Mb (237 and 96, respectively). Seventy-two variants originated de novo, while 165 were inherited. Eighty-six CNVs were associated with 33 known microdeletion/microduplication syndromes. The most prevalent syndromes were 1q21.1 duplication (7/395, 1.8%) (OMIM: 612475), 2p16.3 deletion (9/395, 2.3%) (OMIM: 614332), 15q13.3 deletion (7/395, 1.8%) (OMIM: 612001), 16p11.2 deletion (9/395, 2.3%) (OMIM: 611913), and 22q11.2 duplication (7/395, 1.8%) (OMIM: 608363) syndromes. Enrichment analysis revealed that pathogenic CNVs, as well as variants of uncertain clinical significance, are enriched in genes associated with abnormal behavioral and neurological phenotypes. Likely pathogenic CNVs included genes associated with disorders of the nervous system and homeostasis/metabolism. [ABSTRACT FROM AUTHOR]

Men with obesity demonstrate not only various metabolic disorders and insulin resistance, but also reduced testosterone levels and reproductive system dysfunctions. Although one of the ways for pharmacological correction of these abnormalities may be the use of luteinizing hormone receptor (LHR) agonists and antidiabetic drugs (specifically, metformin, MF), the mechanisms of their effects on the hypothalamic–pituitary–gonadal axis have not been sufficiently investigated. The aim of this work was to study the effects of long-term MF therapy (5 weeks, 120 mg/kg) and five-day treatment with LHR agonists, such as human chorionic gonadotropin (hCG, 20 IU/rat/day, s.c.) and allosteric agonist TP03 (15 mg/kg/day, i.p.), on blood testosterone levels and the expression of testicular and pituitary genes in male Wistar rats with long-term diet-induced obesity (DIO). TP03 moderately stimulated testosterone production in male rats with DIO without having an inhibitory effect on testicular LHR expression and only insignificantly reducing the pituitary expression of the LH β-subunit gene. After a single TP03 administration to DIO rats, its steroidogenic effect was comparable to that in the control group, but after a five-day administration, it was significantly inferior to it. In DIO rats, the steroidogenic effect of hCG after a single administration was lower than that in the control but comparable to that after a five-day administration, significantly exceeding the corresponding effects of TP03. Unlike TP03, hCG significantly reduced testicular LHR expression and more pronouncedly inhibited pituitary LH expression. MF treatment restored the androgenic status without significantly affecting the testicular expression of steroidogenic genes. In MF-treated groups, there was no increase in the steroidogenic effects of both LHR agonists. The results suggest the prospects for the use of TP03 and hCG to stimulate testicular steroidogenesis and increase the effectiveness of MF therapy in order to normalize testosterone production in DIO, which can be used to correct reproductive disorders in obesity. At the same time, a co-administration of MF and LHR agonists in DIO appears to be inappropriate. [ABSTRACT FROM AUTHOR]

The biased expression of parental alleles plays a fundamental role in the formation of the placenta as a multifunctional organ necessary for the development and survival of the fetus. First of all, this is expressed in the phenomenon of imprinting, where only a maternal or paternal allele is expressed in placental cells. The placenta uses an extended range of imprinting mechanisms compared to the embryo: histone modifications that suppress or, conversely, activate the expression of nearby genes, regulatory sequences and genes derived from retroviruses or retrotransposons, which are microRNAs that function as antisense RNAs and participate in transcriptional and post-transcriptional regulation of gene expression. In addition, incomplete suppression of the activity of one of the parental alleles is detected in the placenta, leading to a biased imprinted expression of some genes. This review shows the role of biased expression of parental alleles in the development of placental structures of an embryo, discusses the mechanisms of epigenetic control of parental alleles, mainly expressed in the placenta. [ABSTRACT FROM AUTHOR]

The review considers monogenic and chromosomal mutations associated with X-linked intellectual disability. Peculiarities of the development of the clinical phenotype in cases of different mutations were described. Special attention is paid to X-linked CNVs (microdeletions and microduplications). Chromosomal microaberrations most frequently found in patients with intellectual disability are presented. A modifying effect of X chromosome inactivation on the phenotype of carriers of X-linked mutations is discussed. The problems of interpretation of the clinical significance of X-linked CNVs are considered. [ABSTRACT FROM AUTHOR]

The results of calculations and experimental determination of the neutronics characteristics of the IRT-T research reactor are presented. The IRT-T reactor is a pool reactor with rated thermal power 6 MW(t). The neutronics characteristics of the reactor were determined during the 2016–2017 runs. The calculations were performed using the precision software MCU-PTR with the MDBPT50 baseline nuclear constants. The experimental determination of the reactivity parameters was obtained by analyzing the current values of the reactor's standard control and protection system. Different approaches and methods for determining the efficiency of the reactor controls were considered. The calculations and experimental work were conducted in order to assess the effects of reactivity. [ABSTRACT FROM AUTHOR]

The level of chromosomal abnormalities in the somatic cells of adult individuals is characterized by significant interindividual variability, which may be partly affected by the genetic and epigenetic background. The epigenetic landscape in cells is largely determined by genome methylation. This study aimed to analyze the relationships between global genome methylation and the frequencies of chromosome abnormalities in lymphocytes of plutonium workers. The frequencies of chromosome aberrations, micronuclei, aneuploidy of chromosomes 2, 7, 8, 12, X, and Y and sister chromatid exchanges were analyzed in the lymphocytes of 40 male workers from a nuclear chemical facility (Seversk, Russia) with incorporated plutonium-239 and 49 healthy male volunteers who had no occupational exposure to ionizing radiation. The long interspersed nuclear elements-1 (LINE-1) methylation index was assessed as a well-known marker of global genome methylation. The frequencies of centromere-negative micronuclei (4.74 ± 2.26 vs. 3.02 ± 1.69‰), chromosome-type aberrations (0.81 ± 0.79 vs. 0.44 ± 0.69%), and total chromosome non-disjunction (0.93 ± 0.43 vs. 0.50 ± 0.25%) were significantly higher in the group of workers than in controls (p < 0.05). The LINE-1 methylation index did not differ significantly between the worker and control groups (74.93 ± 3.63 vs. 73.92 ± 4.62%). Correlations between LINE-1 methylation and the frequency of micronuclei (R = –0.35, p = 0.031) were observed in the control group, whereas correlations of LINE-1 methylation with chromatid-type aberrations (R = –0.42, p = 0.012) (but not chromosome-type aberrations) and with sister chromatid exchanges (R = –0.53, p = 0.004) were observed only in the group of plutonium workers. Thus, LINE-1 hypomethylation after plutonium exposure is associated mainly with chromatid breaks, either repaired or misrepaired. [ABSTRACT FROM AUTHOR]

An analysis of the prevalence of the CNTN6 gene microdeletions and microduplications in patients with neurodevelopmental disorders and healthy individuals was performed. Array comparative genomic hybridization and real-time PCR were used for screening of the CNTN6 gene copy number variations among 1070 patients with intellectual disability, 86 schizophrenia patients, and 200 healthy individuals. According to our current results and published data, the overall frequency of microdeletions and microduplications of the CNTN6 gene was estimated as 1 : 711 (0.14%) in patients with neurodevelopmental disorders and 1 : 917 (0.11%) in healthy individuals. CNTN6 microduplication in a control group was statistically significant in comparison with patient's group (p = 0.0372). For 43 out of 100 CNTN6 chromosomal mutations described in the literature, the inheritance from one of the parents was shown. In 12 cases out of 18 (67%), CNTN6 gene microdeletions and microduplications were inherited from a apparently healthy parent without phenotypic manifestations of the chromosomal mutation. [ABSTRACT FROM AUTHOR]

Autoimmune hyperthyroidism (Graves' disease), which is caused by stimulating autoantibodies to the thyroid-stimulating hormone receptor (TSHR), and thyroid tumors, caused by a constitutively increased activity of this receptor, are widespread and have a poor prognosis. The drugs used to treat them are low effective and have many side effects. One of the therapeutic approaches to these thyroid diseases may be the use of TSH receptor allosteric regulators with an activity of inverse agonists. This work was aimed to study the effects of the compound TP48, previously synthesized in our laboratory, and a newly synthesized compound TPY5, with both of them referring to thieno[2,3-d]-pyrimidines, on basal and thyrotropin-releasing hormone (TRH)-stimulated levels of thyroid hormones (THs) in the rat blood and on the expression of genes responsible for TH synthesis in the rat thyroid gland. TP48 and TPY5 effectiveness was studied upon both intraperitoneal (20 mg/kg) and peroral (40 mg/kg) administration. Using ELISA, blood levels of free (fT4) and total (tT4) thyroxine, as well as free (fT3) and total (tT3) triiodothyronine, were assessed, including during stimulation with intranasal TRH (300 µg/kg). Gene expression for thyroid peroxidase (Tpo), thyroglobulin (Tg), Na+/I– symporter (Nis), type 2 deiodinase (Dio2), and TSH receptor (Tshr) in the thyroid gland was assessed by PCR. TPY5, administered via both routes, reduced both basal and TRH-stimulated plasma TH levels, while TP48 suppressed TH production only after intraperitoneal administration. Peroral TPY5 significantly reduced basal Tpo expression, as well as TRH-stimulated Tg and Dio2 expression. Intraperitoneal TP48 reduced only TRH-stimulated Tg and Dio2 expression. Quite surprisingly, peroral TPY5 and intraperitoneal TP48 reduced basal Tshr expression but did not prevent its inhibition by TRH. Thus, the novel compound TPY5 exhibits the activity of a TSH receptor inverse agonist and is effective when administered perorally, which is more in demand in medicine; it can be considered as a prototype of drugs to treat autoimmune hyperthyroidism and thyroid tumors. [ABSTRACT FROM AUTHOR]

Differentiation of induced pluripotent stem cells (iPSCs) from patients and healthy donors allows in vitro study of genetic disorders. The authors have previously reported a clinical case of recurrent pregnancy loss in a patient with skewed X-chromosome inactivation in peripheral blood lymphocytes, endometrium, and buccal epithelium. A 239 kb microdeletion at Xq24 that affected eight genes, including UBE2A, has been found. In this work, an iPSC line iTAF15Xsk4 was produced from the patient's skin fibroblasts using nonintegrating episomal vectors. The iPSC line had a normal karyotype, expressed pluripotency markers, and expressed markers of all three germ layers upon differentiation in embryoid bodies. This cell line could be used for the UBE2A deficiency syndrome study. [ABSTRACT FROM AUTHOR]

Miscarriage is potentially associated with abnormal epigenetic regulation of genes responsible for the development of the embryo and placenta. The aim of this work was to analyze the methylation level of various subfamilies of the LINE-1 retrotransposon, which makes up about 17% of the entire genome, in chorionic villi of spontaneous abortions of the first trimester of pregnancy with different karyotypes, including the most common aneuploidies. The methylation profile in the LINE-1 retrotransposon promoter was analyzed using targeted bisulfite massive parallel sequencing in chorionic villi of induced abortions (n = 39), spontaneous abortions with normal karyotype (n = 173), trisomy 16 (n = 62) and monosomy X (n = 46), and peripheral blood lymphocytes of healthy volunteers (n = 17). The level of methylation of the LINE-1 retrotransposon subfamilies in the control groups of adult lymphocytes and chorionic villi of induced abortions was the highest for evolutionarily young L1HS subfamilies, lower for the more ancient L1PA2 and L1PA3 subfamilies, and the lowest for the even more ancient L1PA4 subfamily. In the groups of spontaneous abortions, an increased level of LINE-1 methylation was observed, and this effect was more pronounced for the older LINE-1 subfamilies. The revealed patterns indicate less control over the older subfamilies of the LINE-1 retrotransposon in the human genome, which can potentially be used as regulatory elements for nearby genes involved in embryonic development. An increase in the level of methylation of such sequences can disrupt the development of the placenta and embryo and make a certain contribution to miscarriage. [ABSTRACT FROM AUTHOR]

Central precocious puberty (СPP) is caused by premature reactivation of the hypothalamic–pituitary–gonadal axis. Genetic, epigenetic, and environmental factors play a crucial role in determining the timing of puberty. In recent years, the KISS1, KISS1R, MKRN3, and DLK1 variants have been identified as hereditary causes of CPP. The MKRN3 and DLK1 genes are imprinted, and therefore epigenetic modifications that alter the expression of these genes are also considered as a cause of precocious puberty. With the progression of CPP, epigenetic factors such as DNA methylation, posttranslational modifications of histones and noncoding RNAs can mediate the relationship between the influence of genetic variants and the environment. CPP is also associated with other short- and long-term adverse health effects. This is the basis for research aimed at understanding the genetic and epigenetic causes of СPP. The purpose of this review is to summarize the published data on the molecular genetic and epigenetic mechanisms of the formation of СPP. [ABSTRACT FROM AUTHOR]

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]

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]

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]

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]