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Objective. Objectives. To assess the rates of antibiotic resistance, production of acquired carbapenemases, genotypes and prevalence of «international high-risk clones» among nosocomial strains of Pseudomonas aeruginosa isolated in various regions of Russia within the «MARATHON 2015–2016» study. Materials and Methods. A total of 1006 non-duplicate nosocomial isolates of P. aeruginosa collected in 44 hospitals from 25 cities in Russia in 2015–2016 were studied. Species identification of isolates was performed by means of MALDI-TOF mass-spectrometry. Antimicrobial susceptibility was determined using broth microdilution method according to ISO 20776-1:2006 and interpreted using EUCAST MIC clinical breakpoints v.9.0. The presence of acquired carbapenemase genes of VIM, IMP, NDM, GES-2 and GES-5 groups was determined using real-time PCR. Genotyping of isolates was performed by analysis of selected single nucleotide polymorphisms in 7 chromosomal loci used for multi-locus sequence typing (MLST) of this species. Results. P. aeruginosa comprised of 17.4% of all bacterial pathogens isolated within the «MARATHON 2015–2016» study. The resistance rates to antibiotics were (in decreasing order of in vitro activity): 1.4% to colistin, 41.5% to aztreonam, 41.6% to ceftazidime/avibactam, 47.7% to amikacin, 51.5% to cefepime, 54.2% to tobramycin, 55.5% to meropenem, 56.3% to gentamicin, 56.8% to ceftazidime, 62.0% to piperacillin/tazobactam, 63.3% to ciprofloxacin, 65.2% to piperacillin, 67.5% to imipenem, and 97,6% to ticarcillin/clavulanic acid. Acquired carbapenemase genes were detected in 35% of the isolates including those for metallo-β-lactamases of VIM- (30.5%) and IMP-type (0.3%) and for GES-5-like serine carbapenemases. MBL producers were highly resistant to all antibiotics except for aztreonam (49%) and polymyxins (0%); GES-5-producers were resistant to most antibiotics except for aztreonam (4.8%), ceftazidime/avibactam (11.9%) and polymyxins (0%). The majority of carbapenemase producing strains belonged to the international “high-risk” CC235 (76.3%) and CC654 (21%) clones. All CC235 isolates revealed the presence of specific variant of the gene encoding secreted phospholipase A2, ExoU, which is a major virulence factor of P. aeruginosa. Conclusions. The results of this study indicate an increase in resistance rates to most antibiotics, including carbapenems, and in prevalence of carbapenemase production in nosocomial strains of P. aeruginosa. This can be largely attributed to the expansion of “high-risk” clones.

Objective. To assess rates of antimicrobial resistance and production of the clinically important acquired resistance mechanisms (extended spectrum beta-lactamases [ESBL] and carbapenemases) in nosocomial strains of Enterobacterales, and to determine genotypes and prevalence of “international high-risk clones” among carbapenemase-producing Klebsiella pneumoniae isolated in various Russian regions within the “MARATHON 2015–2016“ study. Materials and Methods. A total of 2786 non-duplicate nosocomial isolates of Enterobacterales, including 1316 isolates of K. pneumoniae and 837 isolates of Escherichia coli isolated in 49 hospitals from 25 cities in Russia in 2015–2016 were studied. Species identification of isolates was performed using MALDI-TOF mass-spectrometry. Broth microdilution method was used for susceptibility testing and phenotypic ESBL detection. The presence of acquired carbapenemase genes of VIM, IMP, NDM, KPC and OXA-48-groups was determined using real-time PCR. Genotyping of K. pneumoniae isolates was performed by multi-locus sequence typing (MLST) according to the Pasteur institute database and Diancourt et al. method. Results. A total of 48.2% of all bacterial pathogens isolated within the “MARATHON 2015–2016“ study comprised of Enterobacterales. The most common pathogens were K. pneumoniae (47.2%) and E. coli (30.0%). The majority of Enterobacterales isolates were resistant to oxyimino-β-lactam compounds: cefotaxime (78.4%), ceftazidime (67.2%), cefepime (68.4%) and aztreonam (71.5%). ESBL production was determined in 67.8% of isolates. Resistance to carbapenems (imipenem, meropenem and ertapenem) was observed in 6.9%, 6.5% and 23.6% of all Enterobacterales isolates, respectively. A total of 14.4% of Enterobacterales isolates carried the genes of class D carbapenemases OXA-48 (11.4%), class B carbapenemases NDM-1 (2.7%) and class A carbapenemases KPC (< 0.1%). Eight isolates (0.3%) of K. pneumoniae carried the genes of NDM- and OXA-48-like carbapenemases simultaneously and one isolate (< 0.1%) of Proteus mirabilis carried the genes of NDM and VIM metallo-β-lactamases. Most of the 57 genotyped carbapenemase-producing K. pneumoniae isolates belonged to the “international high-risk clones”: CG395 (45.6%), CG11 (12.3%), CG147 (10.5%) and CG307 (10.5%). The most active agents were ceftazidime/avibactam (3.5% of resistant isolates) and aztreonam/avibactam (MIC50 and MIC90 were 0.06 and 0.25 mg/L respectively). Colistin was the most active agent in vitro (18.6% of resistant isolates) among non-β-lactam antibiotics. The only 3.9% of E. coli isolates were resistant to tigecycline. The MIC50/MIC90 values of tigecycline for K. pneumoniae were 0.5 and 2 mg/L and did not exceed ECOFF value (≤ 2 mg/L). Conclusions. The results of this study showed an extremely high prevalence of resistance to most antibiotics, including carbapenems, and a variety of carbapenemase genes in nosocomial isolates of Enterobacterales. It makes a selection of empiric antibiotic treatment extremely difficult and warrants the need for regular resistance surveillance in every hospital.

Objective. Objectives. To assess the rates of antibiotic resistance and production of acquired carbapenemases in nosocomial strains of Acinetobacter spp., and to determine the genotypes and prevalence of “international high-risk clones” among nosocomial strains of Acinetobacter baumannii isolated in various regions of Russia within the “MARATHON 2015–2016” study. Materials and Methods. A total of 1005 non-duplicate nosocomial isolates of Acinetobacter spp., including 975 isolates of A. baumannii, collected in 44 hospitals from 25 cities in Russia in 2015– 2016 were studied. Species identification of isolates was performed by means of MALDI-TOF massspectrometry. Antimicrobial susceptibility was determined using broth microdilution method according to ISO 20776-1:2006 and interpreted using EUCAST MIC clinical breakpoints v.9.0. The presence of acquired carbapenemase genes of OXA-23, OXA-24/40, OXA-58, VIM, IMP, NDM, GES-2 and GES-5 groups was determined using real-time PCR. Genotyping of A. baumannii isolates was performed by analysis of selected single nucleotide polymorphisms in 10 chromosomal loci used for multi-locus sequence tying (MLST) of this species. Results. Acinetobacter spp. and A. baumannii comprised of 17.4% and 16.8% of all bacterial pathogens isolated within the “MARATHON 2015–2016” study. Resistance rates to carbapenems (imipenem and meropenem) were 77.4% and 77.1% of A. baumannii isolates, respectively. In 76.2% of A. baumannii isolates, the genes of acquired carbapenemases of molecular class D were detected, which belonged to the following groups: OXA-24/40 (57.5%), OXA-23 (18.4%) and OXA-58 (0.1%). Two isolates (0.2%) carried the genes of OXA-24/40- and OXA-23-like carbapenemases simultaneously. Most carbapenemaseproducing isolates belonged to the «international high-risk clones»: CC92/208OXF/CC2PAS (60.3%), CC944OXF/CC78PAS (25.4%) and CC109/231OXF/CC1PAS (11.6%). The vast majority of A. baumannii isolates exhibited resistance to ciprofloxacin (99.0%), amikacin (89.2%) and gentamicin (77.4%). The prevalence of resistance to tobramycin and trimethoprim/sulfamethoxazole was variable among strains of different genotypes. Colistin was the most active agent in vitro (0.9% of resistant isolates). Isolates of other Acinetobacter species were more susceptible to most antibiotics. However, two isolates of Acinetobacter ursingii and Acinetobacter baylyi carried the genes of NDM metallo-beta-lactamases. Conclusions. The results of this study indicate a very high prevalence of resistance to most antibiotics, including carbapenems, in nosocomial strains of Acinetobacter spp. This makes the selection of empiric antibiotic treatment extremely difficult and urges the need for regular local surveillance of resistance in every hospital.

The optimal formation and selection strategies for ensuring environmental safety is a key topical aspect of the first half of the XXI century. In conditions of limited economic resources and a disturbed ecological balance, is especially important to take into account inter-sectoral externalities that determine the choice of optimal mechanisms, both stimulating and restraining positive and negative external effects from institutional approach standpoint. The article provides an overview of the existing and substantiation of the author’s directions for the strategy of ensuring environmental safety in regional socio-economic systems, taking into account inter-sectoral externalities. The article analyzes the possibility of forming a platform for the system of responsible education in ensuring the ecological balance for present and future generations, aimed at using optimal strategies that allow to gently, without creating tension, regulate the responsible consumption of all types of resources. It is assumed that on the platform of responsible education system, the formation of a personality is carried out, based on: 1) awareness of equal access right of every person to a favorable environment; 2) understanding and accepting responsible resource use; 3) the obligation to adopt the institution of “soft environmental tax mechanisms”; 4) a responsible approach to cross-sectoral positive and negative externalities.

The article is devoted to the formation of financial policy in the field of agro-industrial complex, in its economic and social aspects, the main goals, elements and directions of development at the present stage. The article considers the main directions of financial policy in the agricultural sector using the example of the Volgograd region, which is one of the leading regions of the southern Federal district in terms of agricultural planning, economics and engineering. The article concludes that at the moment, the region has chosen a liberal model of financial policy that offers the maximum package of incentives for agribusiness. At the same time, the article also identified existing problems in the system of formation and implementation of financial and legal policy in the agricultural sector of the region, as well as outlined possible ways to solve them by modernizing the budget process, ensuring the stability of the regional budget and its balance in the long term, improving the efficiency of Executive authorities and stateinstitutions.

Worldwide globalization and the development of market relations in Russia is accompanied by toughening the competition between foreign and Russian producers. In these conditions, enterprise managers are forced to look for new ways to increase their products competitiveness, taking into account the changing market situation. As practice shows, in modern business conditions, only those solutions that are based on a deep understanding of the competitive market struggle nature and mechanisms are effective. The stability of the meat market is determined by the stability of the market entities activities. This stability is achieved by combining the effective implementation of their competitive strategy with the scientifically sound economic and social policies of the state, aimed at ensuring favorable conditions for the economic entities functioning and improving the population living standards.

Single-bubble sonoluminescence spectra of the following samples were recorded in the modes of standing and moving bubble in liquid near the center of its levitation under the action of ultrasound: water contaminated with additives of commercial gasoline (1.5 - 38 mg·L - 1 ), water with additives of individual gasoline components (hexane, benzene, toluene, p-xylene, naphthalene, anthracene, and p-terphenyl), and solutions of these gasoline components in hexane. Characteristic bands λ max of gasoline component emitters are recorded in the sonoluminescence spectra of a moving bubble for water samples contaminated with additives of commercial gasoline: 290 (p-xylene), 340 (p-terphenyl), 381, 399, 424, 449 (anthracene), and 438, 474, 516, 564 nm (C 2 , a hydrocarbon decomposition product during sonolysis).These bands are as a spectral portrait of gasoline contamination of water: they make it possible to identify gasoline in water in the above mentioned range of its content and to find a quantitative content of individual gasoline components., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Interleukin-6 (IL-6) is a multifunctional cytokine that controls the immune response, and its role has been described in the development of autoimmune diseases. Signaling via its cognate IL-6 receptor (IL-6R) complex is critical in tumor progression and, therefore, IL-6R represents an important therapeutic target., Methods: An albumin-binding domain-derived highly complex combinatorial library was used to select IL-6R alpha (IL-6Rα)-targeted small protein binders using ribosome display. Large-scale screening of bacterial lysates of individual clones was performed using ELISA, and their IL-6Rα blocking potential was verified by competition ELISA. The binding of proteins to cells was monitored by flow cytometry and confocal microscopy on HEK293T-transfected cells, and inhibition of signaling function was examined using HEK-Blue IL-6 reporter cells. Protein binding kinetics to living cells was measured by LigandTracer, cell proliferation and toxicity by iCELLigence and Incucyte, cell migration by the scratch wound healing assay, and prediction of binding poses using molecular modeling by docking., Results: We demonstrated a collection of protein variants called NEF ligands, selected from an albumin-binding domain scaffold-derived combinatorial library, and showed their binding specificity to human IL-6Rα and antagonistic effect in HEK-Blue IL-6 reporter cells. The three most promising NEF108, NEF163, and NEF172 variants inhibited cell proliferation of malignant melanoma (G361 and A2058) and pancreatic (PaTu and MiaPaCa) cancer cells, and suppressed migration of malignant melanoma (A2058), pancreatic carcinoma (PaTu), and glioblastoma (GAMG) cells in vitro. The NEF binders also recognized maturation-induced IL-6Rα expression and interfered with IL-6-induced differentiation in primary human B cells., Conclusion: We report on the generation of small protein blockers of human IL-6Rα using directed evolution. NEF proteins represent a promising class of non-toxic anti-tumor agents with migrastatic potential., (© 2024. The Author(s).)

Background: Programmed cell death 1 (PD-1) belongs to immune checkpoint proteins ensuring negative regulation of the immune response. In non-small cell lung cancer (NSCLC), the sensitivity to treatment with anti-PD-1 therapeutics, and its efficacy, mostly correlated with the increase of tumor infiltrating PD-1 + lymphocytes. Due to solid tumor heterogeneity of PD-1 + populations, novel low molecular weight anti-PD-1 high-affinity diagnostic probes can increase the reliability of expression profiling of PD-1 + tumor infiltrating lymphocytes (TILs) in tumor tissue biopsies and in vivo mapping efficiency using immune-PET imaging., Methods: We designed a 13 kDa β-sheet Myomedin scaffold combinatorial library by randomization of 12 mutable residues, and in combination with ribosome display, we identified anti-PD-1 Myomedin variants (MBA ligands) that specifically bound to human and murine PD-1-transfected HEK293T cells and human SUP-T1 cells spontaneously overexpressing cell surface PD-1., Results: Binding affinity to cell-surface expressed human and murine PD-1 on transfected HEK293T cells was measured by fluorescence with LigandTracer and resulted in the selection of most promising variants MBA066 (hPD-1 KD = 6.9 nM; mPD-1 KD = 40.5 nM), MBA197 (hPD-1 KD = 29.7 nM; mPD-1 KD = 21.4 nM) and MBA414 (hPD-1 KD = 8.6 nM; mPD-1 KD = 2.4 nM). The potential of MBA proteins for imaging of PD-1 + populations in vivo was demonstrated using deferoxamine-conjugated MBA labeled with 68 Galium isotope. Radiochemical purity of 68 Ga-MBA proteins reached values 94.7-99.3% and in vitro stability in human serum after 120 min was in the range 94.6-98.2%. The distribution of 68 Ga-MBA proteins in mice was monitored using whole-body positron emission tomography combined with computerized tomography (PET/CT) imaging up to 90 min post-injection and post mortem examined in 12 mouse organs. The specificity of MBA proteins was proven by co-staining frozen sections of human tonsils and NSCLC tissue biopsies with anti-PD-1 antibody, and demonstrated their potential for mapping PD-1 + populations in solid tumors., Conclusions: Using directed evolution, we developed a unique set of small binding proteins that can improve PD-1 diagnostics in vitro as well as in vivo using PET/CT imaging., (© 2024. The Author(s).)