G,WAS going on? Putative regulatory function of GWAS-identified markers of susceptibility to acute appendicitis

Appendicitis affects 7-9% of Americans and is the most common diagnosis requiring hospitalization of both children and adults. Several etiologies of appendicitis have been hypothesized, but definitive mechanisms remain elusive – a critical review of the literature does not support a primary role of fecaliths or lymphoid hyperplasia, as is commonly believed. It is known that appendicitis has heritable components, and so we collaborated with 23andMe Inc., a personal genomics company, to identify genetic determinants of susceptibility to acute appendicitis. 23andMe performed a genome-wide association study (GWAS) of 18,773 appendectomy cases and 114,907 controls, and identified one locus with genome-wide significance. In addition, the GWAS identified eight highly significant SNPs that did not reach genome-wide significance. Most of the SNPs identified using this analysis fell outside of protein-coding genes, thus bioinformatic analysis using RegulomeDB was done to interrogate the SNPs’ putative regulatory capacity of nearby or distant genes, or proteins. This analysis identified 921 targets of putative regulatory elements in the same LD blocks as the four of nine lead SNPs identified in the GWAS and chosen for follow-up study. Of these, 299 targets were unique when targets from all four genomic regions were combined. These targets were organized according to the distance of their putatively egulatory SNP from the given lead SNP, and based on overlap of elements’ targets within one region with targets of elements within the rest of the genomic regions. Ultimately, the following list of 17 proteins was generated for priority in further studies: CEBPB, CTCF, EP300, EVI-1, FOS, FOXJ3, FOXP1, GATA1, HNF4A, JUN, MYC, NFKB, PPARG, RAD21, SPI1, STAT1, and STAT3. This list includes several proteins that directly interact with, or influence the expression of very specific inflammatory markers known to be strongly associated with appendicitis, including IL-8, IL-1B, and IL-6. This outcome supports the utility of RegulomeDB in the interpretation of GWAS-generated non-coding variants. This compiled resource and the ongoing parallel studies born of the appendectomy GWAS may help to elucidate the pathogenesis of acute appendicitis, thereby providing opportunities to improve the diagnosis, treatment, and prevention of this extremely common disease. The public health significance of appendicitis and its genetics are addressed, and a theoretical public health program that integrates the multiple factors involved in appendicitis etiology is proposed

Russian Vector in the Formation of a Common Social and Socio-Cultural Space in the South Caucasus

The article analyzes the phenomenon of “social space”, reveals the historical role of Russia in the formation of the unified social space on the South Caucasus, examines the doctrinal views of scientists and politicians of the Russian Federation and the Caucasian states on the process of formation social area in the Caucasus, assesses the prospects of the impact of the leading actors of foreign policy on the social space in the South Caucasus

Political Value of Contracts of the Russian Federation with the States of South Caucasus and their Influence on Regional Policy

The article investigates the influence of international military treaties on regional policy. Military contracts are considered as part of the implementation of the state’s military policy. It assesses the role of the military contracts to provide security. The article presents a classification of military contracts, the influence of the military agreements of the Russian Federation on the political situation in the South Caucasus

Approaches to classification of microembolic signals in patients recovering from ischemic stroke

Introduction. Microembolus detection by transcranial Doppler (TCD) is the only non-invasive modality for visualization of cerebral embolism. Currently, there is no unified classification of recorded microembolic signals (MES) that could be used in clinical practice. The aim of the study is to investigate biophysical MES parameters in patients with ischemic stroke, as well as to assess approaches to microemboli differentiation by structure and origin to improve the diagnostic accuracy of the method and to reduce the risk of recurrent ischemic events. Materials and methods. The inclusion criterion was TCD-detected signs of MES. We analyzed the data of 28 patients with ischemic stroke (9 women and 19 men; mean age was 58 years 13). We recorded power, duration, and frequency for each MES, and calculated an energy index. Results. A total of 938 MES were reported. In patients with cardioembolic stroke and all other pathogenetic stroke subtypes, biophysical parameter limits were as follows: 14.65 dB for the average power, 9.45 ms for the average duration, and 0.16 J for the average energy index. For patients with atrial fibrillation, characteristic MES power was found to be 13 dB. The MES frequency limit was determined to be 650 Hz for microemboli differentiation by acoustic density. Conclusion. The data obtained can be used to further search for optimal limit ranges for biophysical parameters of various MES in order to establish a single MES classification, which will increase the diagnostic value of microembolus detection by TCD in stroke treatment practice

VALIDATION OF THE QUALITATIVE DETERMINATION OF HPLC METODS FOR SUCROSE AND PEG-2000-DSPE IN A LIPOSOMAL FORM OF THE PHOTOSENSITIZER LIPOPHTHALOCYAN

Objective: This study was undertaken with the aim of the validate the simple isocratic metods high-performance liquid chromatographic (HPLC) for the estimation of PEG-2000-DSPE and sucrose in liposomal medicinal formulations of the phthalocyanine photosensitizer Lipophthalocyan. Methods: HPLC quantification was carried out by using of YMC-Pack Polyamine II column. The mobile phase (for sucrose: acetonitrile: water: ethyl acetate in the ratio of 450: 200: 20; for PEG-2000-DSPE: water in the ratio 10: 90) was pumped at a flow rate of 1 ml/min. Following the guidelines of the International Conference on Harmonization (ICH), the methods was validated for various analytical parameters like specificity, linearity, detection limit, quantitative limit, correctness, and accuracy. Results: The obtained results of the analysis were validated statistically. The correlation coefficient for the linearity was 0.999292, for sucrose, and 0.997650 for PEG-2000-DSPE. The methods can be assessed as correct, as the results obtained are close to the true value and the confidence interval for both methods include 100%. The coefficients of variation in both methods in determining the accuracy were less than 3%. Conclusion: The proposed HPLC methods were validated according to the ICH guidelines and results and statistical parameters demonstrated that the developed methods are sensitive, precise, reliable and simple for the estimation of PEG-2000-DSPE and sucrose in Lipophthalocyan

Structural basis for DNA strand separation by a hexameric replicative helicase

Hexameric helicases are processive DNA unwinding machines but how they engage with a replication fork during unwinding is unknown. Using electron microscopy and single particle analysis we determined structures of the intact hexameric helicase E1 from papillomavirus and two complexes of E1 bound to a DNA replication fork end-labelled with protein tags. By labelling a DNA replication fork with streptavidin (dsDNA end) and Fab (5′ ssDNA) we located the positions of these labels on the helicase surface, showing that at least 10 bp of dsDNA enter the E1 helicase via a side tunnel. In the currently accepted ‘steric exclusion’ model for dsDNA unwinding, the active 3′ ssDNA strand is pulled through a central tunnel of the helicase motor domain as the dsDNA strands are wedged apart outside the protein assembly. Our structural observations together with nuclease footprinting assays indicate otherwise: strand separation is taking place inside E1 in a chamber above the helicase domain and the 5′ passive ssDNA strands exits the assembly through a separate tunnel opposite to the dsDNA entry point. Our data therefore suggest an alternative to the current general model for DNA unwinding by hexameric helicases

Menstrual function and mental health of medical students during the COVID-19 pandemic: a continuous cross-sectional study

Aim. To assess the impact of new coronavirus infection (NCI) and COVID-19 vaccination on menstrual function in comparison with the frequency of depressive disorders during the COVID-19 pandemic among female students of a medical university. Materials and methods. Data for a continuous transverse (cross-sectional) study were obtained using an online survey. The questions included demographics, characteristics of menstrual function, the history of COVID-19 and vaccinations against it, and the standard CES-D (Center for Epidemiologic Studies Depression Scale) questionnaire. The survey included 1.879 female medical students. The exclusion criteria were age under 18 and over 25 years, hormonal contraceptives, pregnancy, childbirth during the last year, and vaccination after COVID-19. After applying the exclusion criteria, three study groups were formed. Group 1 included female students with a history of NCI (n=140), group 2 included students with no history of NCI, who were initially vaccinated against COVID-19 (n=647), group 3 (control group) included unvaccinated students with no history of NCI (n=55). Results. There were no differences in the prevalence of changes in menstrual function in female students after the NCI (49.3%) and after COVID-19 vaccination (39.6%) compared to the control group (43.6%); p=0.477. The rate of depression in the overall study cohort was 43.3%, without any significant differences between the study groups. Significant predictors of changes in menstrual function during the pandemic were marriage (odds ratio OR 2.33 [1.513.61]), depression (OR 1.72 [1.282.3]), a history of menstrual dysfunction (OR 1.5 [0.121.99]), and later menarche (OR 1.76 [1.023.04]). Multivariate analysis did not show the significance of the history of NCI and vaccination as factors of menstrual dysfunction (OR 1.61 [0.892.90] and OR 0.91 [0.591.41], respectively). Conclusion. During the COVID-19 pandemic, female medical students reported frequent changes in menstrual function and depressive disorders. During the pandemic, the most significant predictors of menstrual disorders in female students were depression, a history of menstrual dysfunction, and marriage. A multicenter prospective study is necessary to clarify the mechanisms of the pandemic's impact on menstrual function