Bulletin of RSMU

ISSN Print 2500–1094 ISSN Online 2542–1204

Bulletin of RSMU

BIOMEDICAL JOURNAL OF PIROGOV UNIVERSITY (MOSCOW, RUSSIA)

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Barykin AD, Chepurnykh TV, Osipova ZM

The deep learning technologies have become the driver of the revolutionary changes in scientific research in various fields. The AlphaFold-2 neural network software development that has solved the semicentennial problem of 3D protein structure prediction based on primary amino acid sequence is the most obvious example of using such technologies in structural biology and biomedicine. The use of deep learning methods for the prediction of protein–ligand interactions can considerably simplify predicting, speed up the development of new effective pharmaceuticals and change the concept of drug design.

Received: 2023-12-06

Published online: 2024-02-08

DOI: 10.24075/brsmu.2024.002

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VIEWS 269

Yurchenko DA, Markova ZhG, Minzhenkova ME, Vorontsova EO, Shilova NV

Small supernumerary marker chromosomes (sSMC) are structurally abnormal chromosomes that cannot be identified unambiguously by standard cytogenetic methods. A comprehensive approach involving the use of molecular cytogenetic methods is required for the more thorough morphological assessment of such chromosomes, as well as for the development of strategy for genetic counseling of the patients being the sSMC carriers. It is widely accepted that the development of abnormal phenotype by the patients having sSMC in their karyotype is associated with the presence of euchromatic region material in the marker chromosome. Therefore, it results from the presence of relatively large DNA copy number variations (CNVs) in the form of duplication, triplication, and more increased copy numbers; which are localized in the pericentromeric region of the appropriate chromosome. Pericentromeric CNVs can be involved in the chromosome imbalance in asymptomatic carriers of sSMC as well, however, the boundaries of such imbalance have not been clearly identified. The study was aimed to acquire additional information about the genomic topology of the DNA regions insensitive to the genes copy number increase. FISH analysis with commercial and homemade DNA probes was performed in 18 carriers of sSMC 15 and 22 having no clinically significant phenotypic abnormalities. The molecular cytogenetic testing showed that pericentromeric euchromatic regions sized 1.2 Mb and 714 kb, respectively, were found in 33% of cases (6 out of 18). We assume that these regions comprise no potentially dosage-sensitive genes.

Received: 2023-10-23

Published online: 2024-01-31

DOI: 10.24075/brsmu.2024.001

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VIEWS 240

Zakharova MV, Zagoskin AA, Ivanov RA, Nagornykh MO

Technologies underlying the production of synthetic mRNAs in vitro have significantly expanded the possibilities for research and therapeutic use of this class of molecules. The flagship application area has been the niche of mRNA vaccines, but this class of therapeutic molecules has the potential to be applied in a much broader range of situations. The process of in vitro production of artificial RNA molecules is based on an enzymatic synthesis reaction, one of the components of which is a ribonuclease inhibitor. This protein protects synthesized RNA from attacks by ribonucleases and prevents degradation of the molecules, which is critically important for RNA. Eukaryotic ribonuclease inhibitor synthesized as a recombinant protein in the cells of E. coli bacteria is the most common choice. However, the structure of this protein makes it a difficult product to make in bacteria. This study aimed to test the production of a recombinant ribonuclease inhibitor in various strains of E. coli, and to show the effect that helper polypeptides and cellular chaperones have on this process. Using genetic engineering approaches, we constructed plasmids, from which chimeric ribonuclease inhibitor molecules and helper polypeptides were produced. The influence of various components on solubility of the target recombinant protein was assessed with the help of densitometry, to which we have subjected products of the PAGE electrophoresis. It was determined that combinations of a vector with a strong promoter for the expression of the RNH1 ribonuclease inhibitor gene and helper polypeptides MBP and TIG against the background of increased expression of cellular chaperones dnaK, dnaJ, grpE give the target product yield of 45 mg/l and 60 mg/l, respectively. The selected conditions allow large-scale production of this protein for further use in in vitro RNA synthesis in the context of production of medicines.

Received: 2023-11-16

Published online: 2023-12-31

DOI: 10.24075/brsmu.2023.058

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VIEWS 367

Vladimirsky GM, Zhuravleva MA, Dashieva AE, Korneeva IE, Nazarenko TA

Currently, in vitro fertilization (IVF) with embryo transfer is the main method of treatment of all forms of infertility, but successful cases ending in pregnancy still account for only a third of all cycles performed. It is necessary to take into account many parameters and investigate the connections between them in order to properly evaluate the results of IVF. Over the past decades, a number of IVF prediction models have been developed with the aim at assessing the outcomes in individual cases, but, given the generally poor prognostic capacity, only a few of them have proven to be clinically significant. This study aimed to create nonlinear IVF outcomes prediction models and identify the most significant factors affecting the said outcomes. Using a database containing information on more than 700 indicators of 7004 women aged 18 to 45 years who participated in the IVF program in Russia from 2010 to 2020, we trained a random forest model that predicted pregnancy in the IVF cycle with ROC-AUC = 0.69. This paper describes 20 most successful predictors of the resulting model and interprets their contribution to the prognosis. Of these, body mass index (BMI) and the number of received and fertilized oocytes have been covered in the scientific literature previously as predictors of IVF outcomes, but other parameters, such as anamnestic data, previous participation in an IVF program (number of cases and their results), as well as serum concentration of AMH, rarely appear in foreign prognostic models.

Received: 2023-11-24

Published online: 2023-12-31

DOI: 10.24075/brsmu.2023.057

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VIEWS 305

Radaeva OA, Simbirtsev AS, Kostina YuA, Iskandiarova MS, Negodnova EV, Mashnina SV, Yeremeev VV, Krasnoglazova KA, Babushkin IO

In spite of a vast number of trials devoted to quantitative characteristics of the cytokine profile in patients with various diseases, no exact reference intervals are presented. It is just as important that there is a limited number of trials analyzing circadian rhythms of cytokine synthesis in patients with arterial hypertension. The purpose of the work was to analyze the characteristics of circadian rhythms of cytokines (IL18, IL18 BP, LIF, sLIFr, M-CSF, MCSFR) in patients with Grade II essential arterial hypertension, and to detect pathogenetically significant characteristics developed following Covid-19. Blood samples were taken at 7.00–8.00, 12.00–13.00, 19.00–20.00.00, 00.00–1.00 to determine the levels of IL18, IL18 BP, LIF, sLIFr, M-CSF, MCSFR in 18 patients (56 (95% CI (54–69) years) with essential arterial hypertension (EAH) within three days prior to and following Covid-19. For this, the immunoenzyme method was used. The obtained data demonstrated altered circadian expression of cytokines in the peripheral blood of patients with essential hypertension depending on whether they have EAH or not, and their additional distortion following Covid-19, which is stable in the majority of cases. It is preserved for six months as low IL18 BP (р < 0.001), and twofold increase of sLIFr and MCSF (р < 0,001) at 18.00. A significant association is determined between the circadian rhythms of sLIFr and altered systolic BP resulting in the abnormal rhythm with BP rise at night (night peaker) in patients with EAH following COVID-19. The obtained fundamental data offer prospects for new research of immunopathogenesis following COVID-19 in patients with hypertension taking into account circadian rhythms of cytokines in the blood.

Received: 2023-11-29

Published online: 2023-12-31

DOI: 10.24075/brsmu.2023.056

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VIEWS 310

Macular rupture is among major vitreoretinal disorders resulting in significant visual function decline. In recent years, the use of platelet-rich autoplasma in the macular rupture surgery is considered to be promising. However, despite high rate of macular rupture closure (78–96%), the development of new technology for foveal microarchitectonics restoration and visual function improvement currently remains a pressing issue. The study was aimed to develop a new foveal reconstruction technique for macular rupture involving the use of autologous conditioned plasma. The reported study involved 9 patients (10 eyes) with idiopathic macular hole, who underwent standard three-port 27G vitrectomy involving the use of autologous conditioned plasma in accordance with the technique developed. The proposed technique makes it possible to achieve good clinical and functional surgical treatment outcome and ensures optimal and more manageable reconstruction of foveal microarchitectonics.

Received: 2023-12-04

Published online: 2023-12-31

DOI: 10.24075/brsmu.2023.055

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VIEWS 324

Minasov BSh, Yakupov RR, Bilyalov AR, Minasov TB, Valeev MM, Mavlyutov TR, Nigamedzanov IE, Akbashev VN, Karimov KK

Preoperative planning of hip arthroplasty provides surgeons with a unique opportunity of thorough investigation of the patient’s anatomy, allows them to determine optimal implant size and position, as well as to prevent potential complication. Advances in digital technology enable expansion of opportunities of preoperative planning due to using three-dimensional modeling. The study was aimed to compare precision of the three-step preoperative planning of hip arthroplasty and the standard method. Methods: The study involved 224 patients with various forms of degenerative and dystrophic diseases of the hip joint, who were divided into the index and control groups based on the planning method. In the index group, preoperative planning of arthroplasty was conducted in three steps: assessment of bone density in the zones of fixation based on CT; virtual design involving the use of automated programs; 3D model construction based on the computer model. X-ray images and endoprosthesis templates were used in the comparison group. The results showed that there were no significant differences between planning methods in patients with osteoarthrosis and avascular necrosis of the femoral head (p > 0.05), in contrast to the group with traumatic hip joint pathology showing significant differences (рс = 0.002). Conclusions: the three-step algorithm for preoperative planning of hip arthroplasty showed higher efficacy in patients with various nosological forms of degenerative and dystrophic diseases of the hip joint compared to the standard method.

Received: 2023-11-12

Published online: 2023-12-31

DOI: 10.24075/brsmu.2023.052

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VIEWS 327

Shepelkova GS, Reshetnikov VV, Avdienko VG, Sheverev DV, Yeremeev VV, Ivanov RA

Vaccination is among the most effective measures to reduce tuberculosis morbidity and mortality. In 1974, BCG vaccination was included in the Expanded Program on Immunization. Today, it covers 80% of all children around the globe. Unfortunately, BCG vaccine provides no protection against pulmonary tuberculosis, the most prevalent form of tuberculosis. It is necessary to urgently develop new vaccination strategies to stop large-scale dissemination of infection caused by the multidrugresistant pathogen. The study was aimed to compare the capabilities of three variants of mRNA vaccines encoding Esat6 epitopes of stimulating adaptive immune response formation in C57BL/6 mice (ELISpot, delayed hypersensitivity, IgG titers), as well as of protecting I/St mice against M. tuberculosis infection. Efficacy of mRNA vaccines comprising different untranslated regions packaged in lipid nanoparticles was compared with that of BCG vaccine. The 5'-TPL-Esat6-3'-Mod vaccine demonstrated the highest efficacy in our experimental model. Thus, the 5'-TPL-Esat6-3'-Mod mRNA vaccine can be considered as a candidate vaccine for further optimization, improving efficacy and subsequent use for prevention of tuberculosis.

Received: 2023-11-17

Published online: 2023-12-31

DOI: 10.24075/brsmu.2023.054

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VIEWS 329