Disease-associated genetic variants in the regulatory regions of human genes: mechanisms of action on transcription and genomic resources for dissecting these mechanisms

Whole genome and whole exome sequencing technologies play a very important role in the studies of the genetic aspects of the pathogenesis of various diseases. The ample use of genome-wide and exome-wide association study methodology (GWAS and EWAS) made it possible to identify a large number of genetic variants associated with diseases. This information is accumulated in the databases like GWAS central, GWAS catalog, OMIM, ClinVar, etc. Most of the variants identified by the GWAS technique are located in the noncoding regions of the human genome. According to the ENCODE project, the fraction of regions in the human genome potentially involved in transcriptional control is many times greater than the fraction of coding regions. Thus, genetic variation in noncoding regions of the genome can increase the susceptibility to diseases by disrupting various regulatory elements (promoters, enhancers, silencers, insulator regions, etc.). However, identification of the mechanisms of influence of pathogenic genetic variants on the diseases risk is difficult due to a wide variety of regulatory elements. The present review focuses on the molecular genetic mechanisms by which pathogenic genetic variants affect gene expression. At the same time, attention is concentrated on the transcriptional level of regulation as an initial step in the expression of any gene. A triggering event mediating the effect of a pathogenic genetic variant on the level of gene expression can be, for example, a change in the functional activity of transcription factor binding sites (TFBSs) or DNA methylation change, which, in turn, affects the functional activity of promoters or enhancers. Dissecting the regulatory roles of polymorphic loci have been impossible without close integration of modern experimental approaches with computer analysis of a growing wealth of genetic and biological data obtained using omics technologies. The review provides a brief description of a number of the most well-known public genomic information resources containing data obtained using omics technologies, including (1) resources that accumulate data on the chromatin states and the regions of transcription factor binding derived from ChIP-seq experiments; (2) resources containing data on genomic loci, for which allele-specific transcription factor binding was revealed based on ChIP-seq technology; (3) resources containing in silico predicted data on the potential impact of genetic variants on the transcription factor binding sites

Preventing and masking Trojan Circuits triggering out of working area

Inserting malicious sub-circuits that may cause

Effect of the Frequency of Probiotic Use on the Productivity and Incubation Properties of Eggs of the Meat Production Direction

The use of probiotics Levisel SB Plus and Cellobacterin-T in the amount of 0.50 kg/t of mixed fodder in the diet of young herd replacement of the meat direction during the growing period from 3 to 45 days allowed to get homogeneity by 20.9 and 13.1 % above the analogues of the control group. Probiotic feed additive Levisel SB Plus increased the number of fertilized eggs by 1.96 %, hatchability – by 0.90 %, hatchery waste decreased by 2.7 %, feed costs decreased by 9.6 %. However, the best production results were shown by the group with a similar rate of probiotic Cellobacterin-T introduction, which had these indicators, respectively, of 2.0 %, 1.28, 4.2 and 10.4 %

Joint effect of the mycotoxins T-2 toxin, deoxynivalenol and zearalenone on the weaner pigs against a background of the infection load

Currently, among more than 100 000 known species of fungi about 250 species produce mycotoxins, secondary metabolites which are dangerous to human and animal health. Most of these toxins are highly resistant to physical and chemical factors, and are not destroyed even after prolonged heating of feed contaminated with mycotoxins. The aim of the present study was to investigate the joint effects of T-2 toxin, zearalenone, deoxynivalenol and infectious agents on pigs. The study was conducted inthe Federal Center for Toxicological, Radiation and BiologicalSafety. Studies have shown that the jointdietary intake T-2 toxin at a dose of 70 mg/kg, zearalenoneat a dose of 50 mg/kg and deoxynivalenolat a dose of 1000 mg/kg for 30 days against a background of the simulated Clostridium infection load causes symptomatic mycotoxicosis which is accompanied by activation of lipoperoxidation, decrease in hematological, biochemical and immunological parameters: a reduction in the number of T and B lymphocytes, titers of specific protective antibodies and the development of pathological processes in the tissues and organs of weaner pigs, slow weight gain, increase in feed conversion ratio and the development of infectious disease, confirmed with laboratory tests. The result was different in the group of animals with the same infection load but without introducing mycotoxins into the animal diet. The findings provide strong evidence that chronic intake of fuzariotoxins even at the level of permissible concentrations against a background of infection load predisposes to infectious diseases

Количественная оценка магнитной восприимчивости (QSM) в подкорковых структурах головного мозга как маркер нейродегенерации при ремиттирующем и вторично-прогрессирующем рассеянном склерозе

Purpose. The aim of the study was to investigate changes in iron distribution in the brain of patients with multiple sclerosis (MS) using magnetic resonance imaging (MRI) technique – quantitative susceptibility mapping (QSM) – in comparison with clinical data.Materials and methods. Three groups of patients were included in this prospective study: 47 patients with relapsing-remitting MS (RRMS), 20 patients with secondary progressive MS (SPMS) and 39 healthy controls. For all patients we collected clinical data, including history of present illness (H&P) and disability degree, and performed brain MRI followed by QSM maps obtaining and assessing relative magnetic susceptibility in subcortical structures.Results. We found an increase in magnetic susceptibility in the heads of the caudate nuclei and in putamen in patients with SPMS as compared to RRMS. At the same time, a decrease in magnetic susceptibility in the thalamic pulvinar was detected in patients with MS in the long term, but a sharp hyperintensity in conjunction with decreasing volume was observed in some patients.Conclusion. Increased magnetic susceptibility on the QSM in subcortical structures of the brain, reflecting iron content, is more typical for patients with SPMS, which may indicate the prognostic value of these changes.Цель исследования: изучение изменений в распределении железа в веществе головного мозга с помощью методики магнитно-резонансной томографии (МРТ) – количественного картирования восприимчивости (quantitative susceptibility mapping – QSM) – в сопоставлении с клиническими данными у пациентов с рассеянным склерозом (РС).Материал и методы. В данное проспективное исследование вошло три группы пациентов: 47 пациентов с ремиттирующим РС (РРС), 20 – с вторично-прогрессирующим РС (ВПРС) и 39 здоровых добровольцев (группа контроля). Для всех пациентов были собраны анамнестические данные и проведена МРТ головного мозга, включающая последовательность мульти-эхо 3D Т2* GRE, после чего были получены карты QSM и рассчитана относительная магнитная восприимчивость в области подкорковых структур.Результаты. Были выявлены более высокие показатели магнитной восприимчивости в скорлупе у пациентов с ВПРС по сравнению с РРС, что может отражать избыточное накопление железа в данных структурах. При этом было выявлено понижение магнитной восприимчивости в подушке таламуса у пациентов с ВПРС, однако у части пациентов отмечалось ее резкое повышение при уменьшении объема подушки таламуса.Заключение. Повышение магнитной восприимчивости на карте QSM в области подкорковых структур головного мозга, преимущественно в области скорлупы, отражающее накопление железа, а также ее снижение в области подушки таламуса, являются более характерными для пациентов с ВПРС, что может иметь прогностическую значимость в оценке прогрессирования заболевания

Femtosecond pulse generation with a diode-pumped Yb3+:YVO4 laser

A diode-pumped Yb:YVO4 laser has been passively mode locked for the first time, to our knowledge. 120 fs pulses with an average output power of 300 mW and a peak power as high as 14.5 kW are obtained by use of a semiconductor saturable-absorber mirror for passive mode locking. The optical spectrum has a 10 nm bandwidth (full width at half-maximum) and is centered at 1021 nm

The potential to encode sex, age, and individual identity in the alarm calls of three species of Marmotinae

In addition to encoding referential information and information about the sender’s motivation, mammalian alarm calls may encode information about other attributes of the sender, providing the potential for recognition among kin, mates, and neighbors. Here, we examined 96 speckled ground squirrels (Spermophilus suslicus), 100 yellow ground squirrels (Spermophilus fulvus) and 85 yellow-bellied marmots (Marmota flaviventris) to determine whether their alarm calls differed between species in their ability to encode information about the caller’s sex, age, and identity. Alarm calls were elicited by approaching individually identified animals in live-traps. We assume this experimental design modeled a naturally occurring predatory event, when receivers should acquire information about attributes of a caller from a single bout of alarm calls. In each species, variation that allows identification of the caller’s identity was greater than variation allowing identification of age or sex. We discuss these results in relation to each species’ biology and sociality

Resolution on the results of Advisory Board “Searching the effective methods of testing and treating patients with NSCLC caused by <i>NTRK</i> gene fusions“

The Advisory Board was held on December 24, 2021. The molecular genetic research lead specialists and national lead oncologists discussed issues of diagnosis of NTRK gene translocations in patients with non-small cell lung cancer (NSCLC), as well as current opportunities for the treatment of patients with NSCLC caused by NTRK gene fusions. The experts reaffirmed the necessity to identify timely patients with NSCLC caused by NTRK gene fusions, as the correct diagnosis of the disease, including the use of modern diagnostic methods of NTRK gene fusion (NGS is the most sensitive and specific method) determines the success of patient treatment. In this regard, it is critical that physicians know the advantages and disadvantages of each molecular diagnostic method used to have the opportunity to choose the best approach in each clinical case. In order to have a clear, well-functioning strategy for managing patients with suspected NSCLC caused by NTRK gene fusion, it is necessary to use molecular genetic tests, as well as include TRK inhibitors (in particular, the drug larotrectinib; at the time publication of the Resolution, the drug larotrectinib is not registered in the territory of the Russian Federation) in the clinical guidelines for the treatment of lung cancer. Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor. The clinical studies on larotrectinib have demonstrated high response rates and durable responses in adults and children with tumours associated with NTRK gene fusions, including primary CNS tumours and brain metastases. The objective response rate observed with larotrectinib was 79%, with 16% achieving a complete response and 64% achieving a partial response. At the same time, the median progression-free survival on larotrectinib was 28.3 months, and the median overall survival was 44.4 months