Mineralogical identification of macxrocomponents of inorganic part of Kansk-Achinsk coals

The results of research of mineral formation in composition of coal samples with different ash level using expanded complex of physical chemical methods allowing increase of reliability of revealing ash-forming components in coal to estimate variants of their transformation as applied to techniques of coal preparation and burning, interaction with gaseous products of these techniques are presented

COMBINED EFFECT OF ANTIBODIES TO BENZO[A]PYRENE, ESTRADIOL AND PROGESTERONE UPON SEX HORMONE CONCENTRATIONS IN BLOOD SERUM OF PREGNANT WOMEN WITH CONGENITAL MALFORMATIONS OF FETUS

Specific antibodies against environmental chemical gene toxicants and endogenous steroid hormones are shown to modulate concentrations of these compounds in blood serum and their biological effects in experimental models. However, probable hazards of such antibodies in human teratogenesis are still unknown. In particular, potential correlations between specific serum antibodies, sex hormone levels in pregnant women, and congenital malformations in newborns are not clear. The aim of this study was to identify possible associations between occurrence of antibodies to benzo[a]pyrene, estradiol and progesterone (Bp, Es and Pg, respectively), and congenital malformations, and effects of these antibodies upon Es and Pg concentrations in blood serum of pregnant women. We have included into the study 182 women with normal pregnancy and 101 females with congenital malformations of fetus. A non-competitive solid phase immunoassay was performed using Bp, Es and Pg conjugated to bovine serum albumin as antigens. Es and Pg serum concentrations were measured using immunoassay test-systems of “Immunotech” (Moscow). Results: strong positive correlations were revealed between the levels of studied antibodies in the both groups. High IgA-Bp/IgA-Es (> 3) and IgA-Bp/IgA-Pg ratios (> 3) were associated with congenital malformations (OR = 2.2, p = 0.013 and OR = 6.8, p < 0.0001). Positive correlations were revealed between Pg/Es and IgA-Bp/IgA-Es (rS = 0.62, p < 0.0001), and IgA-Bp/IgA-Pg ratios (rS = 0.77, p < 0.0001) in cases with inborn malformations. Similar correlations were found for the women who had normal pregnancy (rS = 0.4, p = 0.0001, and rS = 0.23, p = 0.026, respectively). The Pg/Es proportion correlated with IgG-Bp/IgG-Es (rS = 0.46, p = 0.002), and with IgG-Bp/IgG-Pg ratio (rS = 0.5, p = 0.0009) in cases of malformations, but not in women with normal pregnancy. Conclusion: we have revealed novel associations between congenital malformations of fetus and ratios of IgA-Bp/IgA-Es, as well as IgA-Bp/IgA-Pg, like as positive correlations between hormonal Pg/Es proportions, and ratios of specific antibodies in pregnant women

THE ASSOCIATION OF IMMUNE RESPONSE TO XENOAND ENDOBIOTIKS AND THEIRS BIOTRANSFORMATION ENZYME GENE POLYMORPHISM WITH CONGENITAL MALFORMATIONS OF THE FETUS

The correlation between immune response to benzo(a)pyrene and progesterone in combination with detoxification enzyme gene polymorphism (CYPIA2*1F and GSTTI) and the occurrence of congenital malformations of the fetus was revealed. It is shown that at high ratio of IgA-antibodies to benzo(a)pyrene and to progesterone in conjunction with the mutant allele of the gene CYPIA2*1F and the deletion genotype of the gene GSTTI chance of the reproductive pathology developing increases to 41 times

Approbation of a prognostic model of commodity turnover of a pharmacy organization on the example of the Sysert urban district

The purpose of the study is to test the predictive model of the turnover of a pharmacy organization on the example of the Sysert urban district.Цель исследования – апробация прогностической модели товарооборота аптечной организации на примере Сысертского городского округа

The first and only combination of basal and prandial insulin analogs degludec and aspart: the position of Russian endocrinologists

Insulin therapy for diabetes mellitus is the most effective way to control glycemia with the progression of the disease and the ineffectiveness of other sugar-lowering drugs. At the same time, the existing limitations of traditional insulin preparations, along with increasing attention to the individualized treatment of this disease, are pushing developers to create drugs that most closely reproduce the effect of natural human insulin. In this regard, the appearance of a combination of insulin analogs, the action profile of which practically imitates insulin secretion by a healthy pancreas, presents new possibilities in the treatment of diabetes mellitus. Insulin degludec / insulin aspart (IDegAsp, Ryzodeg®, Novo Nordisk, Denmark) is the first and only soluble combination preparation containing 70% of the ultra-long-acting insulin analogue degludec and 30% of the ultra-short-acting insulin analogue aspart in one injection, which meets the need for both basal and prandial insulin. The combined drug has nothing in common with traditional mixed insulin preparations (both human and analog) and provides doctors and patients with significant advantages over the latter. The article presents the position of Russian experts-diabetologists with extensive experience in the use of IDegAsp regarding the role and place of the drug in real clinical practice. Data from real clinical practice confirm that IDegAsp is a reasonable choice for starting and intensifying insulin therapy for type 2 diabetes mellitus when basal and prandial glycemic control is required. The use of the drug is most appropriate in patients who are on basal, biphasic, basal-plus/basal-bolus regimens and who do not achieve the goals of glycemic control during prior therapy. One of the leading reasons for choosing IDegAsp may also be a lower risk of developing hypoglycemia compared to insulin analogues of previous generations — biphasic insulin aspart and basal insulin glargine 100 U/ml. In addition, IDegAsp is a simple, flexible and safe insulin therapy for patients on premix therapy and basal-plus/basis-bolus regimens who require basal and prandial glycemic control. IDegAsp is a simple, flexible and safe insulin therapy. The greatest benefit of this drug use can be obtained by patients for whom adherence to a complex therapy regimen is difficult (the elderly, with cognitive impairment, after a stroke, with dementia), as well as patients who have an active lifestyle, accompanied by irregular food intake. It is important to note that since January 1, 2021, there is no need for a decision by a special medical commission to prescribe (IDegAsp) Ryzodeg®. This fact, as well as a significant price reduction at the end of 2020, opens up broader prospects for using the drug in the routine practice of a Russian endocrinologist

Progressive GAA·TTC Repeat Expansion in Human Cell Lines

Trinucleotide repeat expansion is the genetic basis for a sizeable group of inherited neurological and neuromuscular disorders. Friedreich ataxia (FRDA) is a relentlessly progressive neurodegenerative disorder caused by GAA·TTC repeat expansion in the first intron of the FXN gene. The expanded repeat reduces FXN mRNA expression and the length of the repeat tract is proportional to disease severity. Somatic expansion of the GAA·TTC repeat sequence in disease-relevant tissues is thought to contribute to the progression of disease severity during patient aging. Previous models of GAA·TTC instability have not been able to produce substantial levels of expansion within an experimentally useful time frame, which has limited our understanding of the molecular basis for this expansion. Here, we present a novel model for studying GAA·TTC expansion in human cells. In our model system, uninterrupted GAA·TTC repeat sequences display high levels of genomic instability, with an overall tendency towards progressive expansion. Using this model, we characterize the relationship between repeat length and expansion. We identify the interval between 88 and 176 repeats as being an important length threshold where expansion rates dramatically increase. We show that expansion levels are affected by both the purity and orientation of the repeat tract within the genomic context. We further demonstrate that GAA·TTC expansion in our model is independent of cell division. Using unique reporter constructs, we identify transcription through the repeat tract as a major contributor to GAA·TTC expansion. Our findings provide novel insight into the mechanisms responsible for GAA·TTC expansion in human cells

Disruption of Higher Order DNA Structures in Friedreich's Ataxia (GAA)n Repeats by PNA or LNA Targeting

Expansion of (GAA)n repeats in the first intron of the Frataxin gene is associated with reduced mRNA and protein levels and the development of Friedreich’s ataxia. (GAA)n expansions form non-canonical structures, including intramolecular triplex (H-DNA), and R-loops and are associated with epigenetic modifications. With the aim of interfering with higher order H-DNA (like) DNA structures within pathological (GAA)n expansions, we examined sequence-specific interaction of peptide nucleic acid (PNA) with (GAA)n repeats of different lengths (short: n=9, medium: n=75 or long: n=115) by chemical probing of triple helical and single stranded regions. We found that a triplex structure (H-DNA) forms at GAA repeats of different lengths; however, single stranded regions were not detected within the medium size pathological repeat, suggesting the presence of a more complex structure. Furthermore, (GAA)4-PNA binding of the repeat abolished all detectable triplex DNA structures, whereas (CTT)5-PNA did not. We present evidence that (GAA)4-PNA can invade the DNA at the repeat region by binding the DNA CTT strand, thereby preventing non-canonical-DNA formation, and that triplex invasion complexes by (CTT)5-PNA form at the GAA repeats. Locked nucleic acid (LNA) oligonucleotides also inhibited triplex formation at GAA repeat expansions, and atomic force microscopy analysis showed significant relaxation of plasmid morphology in the presence of GAA-LNA. Thus, by inhibiting disease related higher order DNA structures in the Frataxin gene, such PNA and LNA oligomers may have potential for discovery of drugs aiming at recovering Frataxin expression

Friedreich's Ataxia (GAA)n•(TTC)n Repeats Strongly Stimulate Mitotic Crossovers in Saccharomyces cerevisae

Expansions of trinucleotide GAA•TTC tracts are associated with the human disease Friedreich's ataxia, and long GAA•TTC tracts elevate genome instability in yeast. We show that tracts of (GAA)230•(TTC)230 stimulate mitotic crossovers in yeast about 10,000-fold relative to a “normal” DNA sequence; (GAA)n•(TTC)n tracts, however, do not significantly elevate meiotic recombination. Most of the mitotic crossovers are associated with a region of non-reciprocal transfer of information (gene conversion). The major class of recombination events stimulated by (GAA)n•(TTC)n tracts is a tract-associated double-strand break (DSB) that occurs in unreplicated chromosomes, likely in G1 of the cell cycle. These findings indicate that (GAA)n•(TTC)n tracts can be a potent source of loss of heterozygosity in yeast

Expression of Human Frataxin Is Regulated by Transcription Factors SRF and TFAP2

Friedreich ataxia is an autosomal recessive neurodegenerative disease caused by reduced expression levels of the frataxin gene (FXN) due to expansion of triplet nucleotide GAA repeats in the first intron of FXN. Augmentation of frataxin expression levels in affected Friedreich ataxia patient tissues might substantially slow disease progression.We utilized bioinformatic tools in conjunction with chromatin immunoprecipitation and electrophoretic mobility shift assays to identify transcription factors that influence transcription of the FXN gene. We found that the transcription factors SRF and TFAP2 bind directly to FXN promoter sequences. SRF and TFAP2 binding sequences in the FXN promoter enhanced transcription from luciferase constructs, while mutagenesis of the predicted SRF or TFAP2 binding sites significantly decreased FXN promoter activity. Further analysis demonstrated that robust SRF- and TFAP2-mediated transcriptional activity was dependent on a regulatory element, located immediately downstream of the first FXN exon. Finally, over-expression of either SRF or TFAP2 significantly increased frataxin mRNA and protein levels in HEK293 cells, and frataxin mRNA levels were also elevated in SH-SY5Y cells and in Friedreich ataxia patient lymphoblasts transfected with SRF or TFAP2.We identified two transcription factors, SRF and TFAP2, as well as an intronic element encompassing EGR3-like sequence, that work together to regulate expression of the FXN gene. By providing new mechanistic insights into the molecular factors influencing frataxin expression, our results should aid in the discovery of new therapeutic targets for the treatment of Friedreich ataxia

SND@LHC: The Scattering and Neutrino Detector at the LHC

SND@LHC is a compact and stand-alone experiment designed to perform measurements with neutrinos produced at the LHC in the pseudo-rapidity region of ${7.2 < \eta < 8.4}$. The experiment is located 480 m downstream of the ATLAS interaction point, in the TI18 tunnel. The detector is composed of a hybrid system based on an 830 kg target made of tungsten plates, interleaved with emulsion and electronic trackers, also acting as an electromagnetic calorimeter, and followed by a hadronic calorimeter and a muon identification system. The detector is able to distinguish interactions of all three neutrino flavours, which allows probing the physics of heavy flavour production at the LHC in the very forward region. This region is of particular interest for future circular colliders and for very high energy astrophysical neutrino experiments. The detector is also able to search for the scattering of Feebly Interacting Particles. In its first phase, the detector will operate throughout LHC Run 3 and collect a total of 250 $\text{fb}^{-1}$