Search

Relevance . Monocytes are circulating immune cells which are traditionally divided into three subsets. The contribution of each subset to breast cancer pathogenesis is controversial. Moreover, there is no data regarding the programming of monocyte subsets towards antitumor activity induced by chemotherapy. Aim . To study the trajectories of monocyte subsets and transcriptomic changes in blood monocytes during neoadjuvant chemotherapy (NAC). Materials and Methods . Mononuclear cells were purified from the peripheral blood of nine triple-negative breast cancer (TNBC) patients before NAC and on the 3rd and 21st day after the first NAC cycle (AC regimen). Total cell concentration and viability (Calcein/DRAQ7) were assessed by flow cytometry. Single-cell RNA sequencing was performed on a Genolab M platform (GeneMind Biosciences) using the 10x Genomics technology for fixed samples. Data were analyzed using Seurat, SingleR, and the dynverse R package for trajectories. Results and Discussion . The trajectory analysis indicated that monocytes were clustered into three subsets: classical, non-classical, and intermediate. Classical monocytes were characterized by high expression of CD14 , CSF3R , S100A8 , S100A9 , VCAN , LYZ , SELL , and GRN genes, whereas non-classical monocytes expressed FCGR3A , MTSS1 , TCF7L2 , CSF1R , SPN , EVL , and LYN . The developmental trajectories of monocytes were significantly affected by chemotherapy. Transcriptionally, classical monocytes were subdivided into two clusters: one characterized by proliferative signals and the other by stress signals. By day 21st after NAC, developmental trajectories of monocytes and their subset composition were observed to recover. Chemotherapy promoted the pro-inflammatory activity of monocytes. Conclusion . Peripheral blood monocytes of TNBC patients are capable of recovering their subset composition after NAC by the 21st day after the first cycle of chemotherapy.

Abstract Caspase-2 is a unique and conserved cysteine protease that is involved in several cellular processes, including different forms of cell death, maintenance of genomic stability, and the response to reactive oxygen species. Despite advances in caspase-2 research in recent years, the mechanisms underlying its activation remain largely unclear. Although caspase-2 is activated in the PIDDosome complex, its processing could occur even in the absence of PIDD1 and/or RAIDD, suggesting the existence of an alternative platform for caspase-2 activation. Here, we show that caspase-2 undergoes ubiquitination and interacts with scaffolding protein p62/sequestosome-1 (SQSTM1) under normal conditions and in response to DNA damage. p62 promotes proteasomal but not autophagic caspase-2 degradation as well as its dimerization and activation that triggers the caspase cascade and, subsequently, cell death. Inhibition of p62 expression attenuates cisplatin-induced caspase-2 processing and apoptosis. Notably, the ZZ domain of p62 is critical for caspase-2 binding, whereas the UBA domain is seemingly required to stabilize the p62–caspase-2 complex. Thus, we have uncovered the dual role of p62 in regulating caspase-2 activity: it can foster the degradation of caspase-2 in the proteasome or facilitate its activation by acting as a scaffold platform.

Abstract Currently A(H5Nx) avian influenza viruses are globally widespread and continue to evolve. Since their emergence in 2020 novel highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b reassortant viruses have become predominant in the world and caused multiple infections in mammals. It was shown that some of A(H5N1) viruses mostly isolated from mammals contain an E627K mutation in the PB2 protein which can lead to adaptation of influenza viruses to mammalian cells. In 2023 in Russia we have isolated two highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b viruses from birds one of which contained an E627K mutation in the PB2 protein. This virus had increased virulence in mice. Limited airborne transmission of the virus with the PB2-E627K mutation was observed between ferrets, in which infectious virus was detected in the nasal washings of the three of the twelve recipient ferrets, and clinical symptoms of the disease were observed in one case. Both viruses showed dominant binding to avian-type sialoside receptors, which was most likely the reason for the limited transmissibility. Thus, this study indicates a possible limited increase in the pandemic potential of A(H5N1) 2.3.4.4b viruses and highlights the importance of continuous avian influenza surveillance for pandemic preparedness and response.

This study examines the invasion dynamics of ash-leaved maple (box elder, Acer negundo L.) in the ribbon forests of Altai Krai, Russia, where it has become one of the dominant invasive species over the past thirty years. Originally introduced as an ornamental plant in the early 20th century, A. negundo has rapidly proliferated in lowland, steppe, and forest-steppe regions, significantly impacting local ecosystems. Our research analyzes the ecological and phytocoenotic conditions that facilitate A. negundo's invasion, focusing on its distribution across various ribbon pine forests in the region. Through geobotanical surveys and forest management record analysis, we reveal the species' prevalence in diverse forest types and its effects on biodiversity, tree growth, and community dynamics. Key findings indicate that A. negundo flourishes in disturbed habitats, where it aggressively competes with native flora, suppressing their growth and altering successional pathways. This leads to low-diversity communities increasingly dominated by the invasive species and highlights the exacerbating role of logging and land-use changes. Using predictive modeling techniques, we assessed habitat suitability for A. negundo across Eurasia, identifying temperature as the primary limiting factor for its distribution. The model achieved a high AUC value of 0.97, indicating strong reliability. These findings suggest a significant potential for A. negundo's range expansion throughout Altai Krai, especially in areas with reduced competition from native species. This research underscores the urgent need for effective management strategies to mitigate the effects of A. negundo in Altai Krai and similar regions.

The Russian Federation has a great number of land plots to be used for a particular purpose, which depends on the category and type of the land. Agricultural land plots are of particular importance for the regional economy because they are subject to the local tax, established by the municipalities, i.e., land tax makes up a significant share of local budget revenues. Prompt and correct accounting of agricultural land improves the local budget. The authors determined the area of agricultural land in the Kemerovo Region and calculated the budget effect from their use. They also identified the potential income to the regional budget. The appropriate land measurement and classification proved to have a positive impact on the budget of the Kemerovo Region. The article contains an assessment of potential tax fees to the budget of the Kemerovo Region, as well as the amount of fines for irrational or improper use of agricultural lands.

The paper analyses the neutron data and covariance matrixes, which are crucial for the computational prediction of neutronic characteristics of fast neutron reactors with uranium-plutonium fuel and currently available in the state-of-the-art versions of evaluated nuclear data libraries: ENDF/B-VIII, JENDL-5, TENDL 2021, JEFF 4T1. The newly obtained covariance data are compared to the data that was presented in the Russian evaluated nuclear data library BROND 3.1. A simplified model of a fast neutron reactor with mixed dense nitride uranium-plutonium fuel and heavy liquid metal coolant was used to calculate the spread in neutronic performance values and their uncertainties due to neutron data using different evaluated nuclear data libraries for the following characteristics: effective multiplication factor, effective delayed neutron fraction, Doppler reactivity coefficient, breeding ratio and gain, reactivity margin for fuel burnup and other fuel burnup characteristics. It has been observed that, on the whole, the uncertainties of the reactor functionals have decreased when estimated using state-of-the-art versions of evaluated neutron data libraries, compared to previous releases of those libraries. The paper also examines changes in target accuracies for predicting the main neutronic characteristics of fast neutron reactors over the past decades, as well as evaluates the requirements for neutron data uncertainties to achieve the recently declared target accuracies. The main findings of this study are presented in two aspects: first, in terms of the effects evaluated neutron data from different libraries have on the accuracy of calculations for the key neutronic characteristics of fast reactors; and second, in terms of the potential for improving the accuracy of predicted neutronic characteristics of fast reactors by considering the results of reactor physics measurements.

Introduction: Parkinson’s disease (PD) is a chronic neurodegenerative disease of the central nervous system, the pathogenesis of which is associated with the death of dopaminergic neurons of the midbrain substantia nigra. The mainstay of therapy for PD is levodopa. However, in the initial stages of PD or in case of levodopa intolerance, MAO B inhibitors are used. Purpose of the study was to determine antiparkinsonian activity of newly synthesized selective MAO-B inhibitors in vivo on the model of experimental parkinsonism in white mice. Materials and Methods: Parkinsonian syndrome in mice was modeled by systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). As the criteria for its evaluation, we used the determination of muscle rigidity severity by step length of mice and evaluation of oligokinesia severity and emotional and mental disturbances in the open field test. A total of 9 candidate compounds were studied, assigned with laboratory codes S1-S5, S9, S10, S14, and S15. Rasagiline was used as a comparison drug. Results and Discussion: Of the 9 compounds used at a dosage of 2mg/kg, the degree of rigidity was significantly reduced by compounds S1, S9, and S15; locomotor activity was restored to the level reached through rasagiline only by compound S9; the decline in exploratory activity was prevented only by S9 and to some extent by S5. Conclusion: Only compound S9 having benzenesulfonamide chemotype showed significant therapeutic potential in a model of experimental parkinsonism and only in relation to it additional studies can be planned.

Relevance. Non-small cell lung cancer (NSCLC) is the leading cause of cancer-­related mortality worldwide due to the high recurrence and metastasis rates. It is generally accepted that metastases and recurrences are formed by tumor cells with a highly invasive, stem and chemoresistant phenotype. Tumor hybrid cells (THCs) formed by the fusion of tumor cells with a wide range of normal cells: macrophages, fibroblasts, mesenchymal stem cells, etc. are considered to be potential metastasis and recurrence-­initiating cells. However, the phenotypic diversity of THCs, and their association with disease progression remain poorly understood. The aim of the study was to characterize the population composition of THCs in NSCLC and its association with clinicopathological characteristics, metastasis and recurrence. Materials and Methods. A total of 50 patients with NSCLC were included. Fresh frozen samples of tumor tissue obtained during resection and morphologically verified were used to analyze types and number of THCs. THCs were analyzed by flow cytometry in primary tumors using markers for tumor cells, cancer stem cells, leukocytes, macrophages and fibroblasts. Results and Discussion. THCs were detected in all NSCLC patients. Most THCs demonstrated leukocyte, macrophage and stem characteristics. The number and frequency of THCs depended on neoadjuvant chemotherapy. THCs with leukocyte and stem cell markers (pan-­CK+CD45+CD44+CD73+) were associated with locoregional recurrence, whereas THCs with macrophage and stem cell markers (EpCAM+CD45+CD44+CD73+CD163+) — with distant metastases. Conclusion. This study is the first to comprehensively describe the population composition of THCs in NSCLC, their association with clinicopathological characteristics, neoadjuvant chemotherapy and disease prognosis. Detection of prognostically relevant THCs could be an effective approach for predicting the risk of metastasis and recurrence of NSCLC and the basis for the development of therapy focused on the prevention of cancer progression.

This paper discusses the problems of improvement of product quality through the expansion of responsible management of human resources in the context of perspectives of operations research. According to this, we determined the essence and features of responsible HRM, outlined trends and factors defining the current state and development of this sphere, and characterised the directions and factors of the influence of SHRM on the quality of products within the quality management system. The goal of this paper was to substantiate further direction and prospects for the development of responsible HRM, based on operations research, which allows raising the quality of products and effectiveness of companies' activities. We also characterised the main methodological transformations that take place in the sphere of human resources management, identified spheres and operations that supplement human resources management within the application of the sustainable approach, offered a block scheme of the algorithm of analysis of a workplace based on SHRM, proposed the tools of integrating the elements of sustainability into this algorithm, characterised the direction for supplementing the corresponding algorithms with the elements of sustainability for each separate element of human resources management, and determined the promising directions for further research on the influence of sustainable HRM in an increase in product quality through the lens of operations research.

Product quality is the basis for demand at national and world industry markets and a precondition for the competitiveness of manufacturing companies. Modern conditions, predetermined by the insufficient volume of resources, problems with personal provision, and high requirements for physical, chemical, environmental, and exploitation indicators of products involve the focus on the capabilities of the digital economy. Digital economy markets offer a rather wide range of tools that allow solving various tasks faced by manufacturers in the sphere of management and improvement of the level of product quality. This research proved the hypothesis on the direct dependence between digitalisation and achievement of effectiveness in ensuring the main indicators of product quality in companies from various spheres of the economy. The scientific novelty of this research is due to the substantiation of the features of implementing innovative directions for product quality management with the use of digital tools in countries with various economic systems.

Introduction. Obtaining stabilized recombinant HIV-1 Env trimers that have a close to the native conformation is one of the directions in the field of development of vaccines against HIV-1. The aim of the study was to obtain and characterize the stabilized trimer Env of HIV-1 SOSIP.664 based on the circulating genetic variant of the recombinant form CRF63_02A6. Materials and methods. Bioinformatics resources were used to design the trimer Env gene based on the HIV-1 recombinant genetic variant CRF63_02A6. The designed gene was synthesized and cloned as part of an integration plasmid vector. A stable producer of trimer Env was obtained by transfection of the CHO-K1 cell line using the developed plasmid vector. Purification of the protein complex was performed using affinity chromatography and gel filtration. Antigenic properties of trimer Env were studied using immunochemical analysis using broadly neutralizing HIV-1 monoclonal antibodies (bnAbs). Results. A new variant of the stabilized trimer Env of the surface glycoprotein of the recombinant form CRF63_02A6 HIV-1 SOSIP.664 was designed, including additional stabilizing modifications. Based on the CHO-K1 cell line, a stable producer was obtained and a purification protocol for the designed trimer Env was developed. It was found that the trimer Env CRF63_02A6 SOSIP.664 is effectively recognized by bnAbs 2G12, VRC01 and PGT126. Conclusion. The obtained results indicate the prospects for further study of the structural features of the trimer Env CRF63_02A6 SOSIP.664, as well as its immunogenicity and the possibility of using it as a vaccine antigen.

Сopolymers and the methodology for their synthesis are presented. In order to protect metal products and structures from the effects of corrosion processes, various fillers for polymer coating were selected: silicon production waste (microsilica) and titanium dioxide, as well as their combined mixtures. The obtained copolymers exhibit good adhesion required for composite protective coatings. An experiment was conducted to evaluate the corrosion resistance of metals subjected to aggressive environment, as well as to determine the hardness and thickness of the obtained polymer coatings. Thus, the corrosion score of the polymer coating with titanium dioxide filler is 2 in 5% NaCl and 5% KOH aggressive media and is 3-4 in acidic media with 10% KOH. Polymer coating with microsilica filler has a corrosion score of 2 in salt and acid aggressive media, but in alkaline media such coating performed worse and has a corrosion score of 4. The best corrosion resistance values are for the series 2 combination polymer coating consisting of methyl methacrylate, styrene and vinyl butyl ether, with a corrosion score of 2 in salt and acid media and a corrosion score of 4 in alkaline media. Series 1, methyl methacrylate, maleic anhydride, and vinyl butyl ether combined coating has the worst corrosion resistance: corrosion score of 4, 5, 6 in 10% H2SO4 and in an alkaline media (5 and 10% KOH), respectively. At the same time, the developed polymer coatings exhibit satisfactory adhesion properties even after the exposure to aggressive media.

BACKGROUND: Chronic generalized periodontitis takes the second place by the occurrence rate worldwide among the diseases of the maxillofacial area. High significance of preventing and early diagnostics for chronic generalized periodontitis is defined by the early tooth loss, by the decrease in chewing efficiency and by the development of chronic infection foci. It is known that the main etiology factor of chronic periodontitis is the microbial one, including the representative of the oral cavity microbiota — Tannerella forsythia, which is a Gram-negative, anaerobic bacterium. AIM: To verify the presence of T. forsythia in cases of chronic generalized periodontitis depending on the disease severity. METHODS: The research included 126 patients with chronic generalized periodontitis of various severity degree, for which, an analysis of the content of periodontal recess was carried out. In the control group, consisting of individuals with no periodontal tissue abnormalities (n=39), the content of gingival sulcus was analyzed. The samples were examined using the method of polymerase chain reaction following the real time mode by means of employing the DT-96 detection thermocycler (DNA-Tekhnologia NPO) and the «ParadontoScreen» test kit. RESULTS: The findings included a high direct correlation between the rate of detecting T. forsythia and the severity degree of the course of chronic periodontitis (the correlation coefficient value was found to be 0.997; p 0.05). A strong direct relation (0.948; p 0.05) was demonstrated between the concentration of T. forsythia genomic equivalent and the severity degree of chronic periodontitis. CONCLUSION: The conducted research has shown that the concentration of T. forsythia is a predictor for severity degree of chronic periodontitis.

Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has shown wastewater (WW) surveillance to be an effective means of tracking the emergence of viral lineages which arrive by many routes of transmission including via transportation hubs. In the Canadian province of Ontario, numerous municipal wastewater treatment plants (WWTPs) participate in WW surveillance of infectious disease targets such as SARS-CoV-2 by qPCR and whole genome sequencing (WGS). The Greater Toronto Airports Authority (GTAA), operator of Toronto Pearson International Airport (Toronto Pearson), has been participating in WW surveillance since January 2022. As a major international airport in Canada and the largest national hub, this airport is an ideal location for tracking globally emerging SARS-CoV-2 variants of concern (VOCs). In this study, WW collected from Toronto Pearson’s two terminals and pooled aircraft sewage was processed for WGS using a tiled-amplicon approach targeting the SARS-CoV-2 virus genome. Data generated was analyzed to monitor trends of SARS-CoV-2 lineage frequencies. Initial detections of emerging lineages were compared between Toronto Pearson WW samples, municipal WW samples collected from the surrounding regions, and Ontario clinical data as published by Public Health Ontario. Results enabled the early detection of VOCs and individual mutations emerging in Ontario. On average, the emergence of novel lineages at the airport preceded clinical detections by 1–4 weeks, and up to 16 weeks in one case. This project illustrates the efficacy of WW surveillance at transitory transportation hubs and sets an example that could be applied to other viruses as part of a pandemic preparedness strategy and to provide monitoring on a mass scale.

Introduction. Human cytomegalovirus (Orthoherpesviridae: Herpesvirales: Cytomegalovirus: Cytomegalovirus humanbeta 5) (HCMV) is one of the most commonly detected viruses in recipients of allogeneic hematopoietic stem cell (allo-HSCT) transplants. However, the emergence of resistance to antiviral drugs such as ganciclovir (GCV) poses a challenge in managing these patients. This study aims to investigate the prevalence and impact of mutations in the HCMV UL97 gene associated with resistance to GCV on the course of infection among allo-HSCT patients. Materials and methods. The study examined the association between UL97 mutations and the clinical course of HCMV infection in allo-HSCT patients. Genetic sequencing was performed to identify mutations, and their impact on viral replication and resistance to GCV was assessed. Results and discussion. Six mutations were identified (D490A, T502A, C592G, C592F, E596G, C603W). C592G, C592F, E596G, and C603W are associated with resistance to antiviral drugs, while D490A and T502A described for the first time. When comparing patients with wild-type and those carrying the mutant variant, several parameters of peripheral blood were significantly lower in the former group. The median time to peak viral load following allo-HSCT, duration of viremia, and rate of virological response to high-dose therapy also differed significantly between the two groups. Conclusion. It was shown that approximately one third (4 out of 14) of allogeneic stem cell transplant recipients had mutations associated with resistance to GCV. Patients carrying the mutant variant of HCMV had longer viremia and took longer to achieve a negative virological test result after starting high-dose therapy. Performing genotyping may help make more evidence-based therapeutic decisions.

BackgroundCervical screening, aimed at detecting precancerous lesions and preventing cancer, is based on cytology and HPV testing. Both methods have limitations, the main ones being the variable diagnostic sensitivity of cytology and the moderate specificity of HPV testing. Various molecular biomarkers are proposed in recent years to improve cervical cancer management, including a number of mRNAs encoded by human genes involved in carcinogenesis. Many scientific papers have shown that the expression patterns of cellular mRNAs reflect the severity of the lesion, and their analysis in cervical smears may outperform HPV testing in terms of diagnostic specificity. However, such analysis has not yet been implemented in broad clinical practice. Our aim was to devise an assay detecting severe cervical lesions (≥HSIL) via analysis of cellular mRNA expression in cytological smears.MethodsThrough logistic regression analysis of a reverse-transcription quantitative PCR (RT-qPCR) dataset generated from analysis of six mRNAs in 167 cervical smears with various cytological diagnoses, we generated a family of linear classifiers based on paired mRNA concentration ratios. Each classifier outputs a dimensionless decision function (DF) value that increases with lesion severity. Additionally, in the same specimens, the HPV genotyping, viral load assessment, diagnosis of cervicovaginal microbiome imbalance and profiling of some relevant mRNAs and miRNAs were performed by qPCR-based methods.ResultsThe best classifiers were obtained with pairs of mRNAs whose expression changes in opposite directions during lesion progression. With this approach based on a five-mRNA combination (CDKN2A, MAL, TMPRSS4, CRNN, and ECM1), we generated a classifier having ROC AUC 0.935, diagnostic sensitivity 89.7%, and specificity 87.6% for ≥HSIL detection. Based on this classifier, a two-tube RT-qPCR based assay was developed and it confirmed the preliminary characteristics on 120 cervical smears from the test sample. DF values weakly correlated with HPV loads and cervicovaginal microbiome imbalance, thus being independent markers of ≥HSIL risk.ConclusionThus, we propose a high-throughput method for detecting ≥HSIL cervical lesions by RT-qPCR analysis of several cellular mRNAs. The method is suitable for the analysis of cervical cytological smears prepared by a routine method. Further clinical validation is necessary to clarify its clinical potential.

Predatory insects play an important role in the regulation of arthropod’s numbers. When they counteract with the diseased prey, the entomopathogenic microorganisms may be disseminated mechanically or parasitize such secondary hosts. Microsporidia are wide-spread pathogens of insects with diverse host ranges, and infection of entomophagous hosts is not uncommon. In the present study, the spined soldier bug nymphs were fed with the adzuki bean borer larvae infected with Nosema pyrausta (A. Paillot) J. Weiser, 1961 or the silkworm larvae infected with N. bombycis Nägeli, 1857. Both pathogens were infective to the predator at the prevalence level of 15-30%. The former pathogen displayed a decrease of prevalence level in the filial generation to as low as 5 % and no infection in consequent generations. The latter could only be transmitted to bugs horizontally and no infections in the filial generation was found. This indicates low (or no) risk of vertical transmission of these two pathogens, making them suitable for combined application with the predatory bug in the integrated pest management programmes.

Alaskan English (AE), or the regional variety of English used by Native Alaskans, is a unique yet largely underinvestigated phenomenon. Specific conditions in which Alaskan English and its distinct characteristics have emerged remain significantly understudied. The aim of this article is to explore these conditions as well as their long-term effects on the regional native language communities. The present work gives an overview of historical and sociolinguistic factors, the influence of which can be considered crucial as far as the variety and the language situation in Alaska are concerned. The article primarily focuses on the contacts between linguacultural communities during colonization, language policy in various periods of time, the English language acquisition in local educational context as well as language shift. Data from the personal narratives of Upper Kuskokwim Athabaskans is used in the study. Twenty six interviews were recorded during the fieldwork in the Inner Alaskan settlement Nikolai by one of the authors in 2001 and 2019. To describe the consequences of language shift and the process of “shaping” the local variety of English, comparative analysis of the interview transcripts has been employed. This method enabled us to compare and contrast the linguistic realities and the conditions of language acquisition between and within generations. Apart from that, some elements of discourse analysis have been used to reconstruct the sociolinguistic context behind the narrators’ statements. The obtained data sheds light on the sociolinguistic and cultural processes that took part in the region and their influence on the language situation and Alaskan English, and it lays basis for future research into the topic.

This study examines the impact of digitalization on the formation and development of the regulatory subsystem, which is a key component of the human psyche. The findings reveal that digitalization has a significant and complex influence on this subsystem, operating at two complementary levels: analytical and structural. The analytical level reflects a profound decrease in the development of the subsystem’s individual components, including essential regulatory processes and their associated qualities. This decline raises concerns about the capacity of individuals to effectively manage their cognitive and emotional resources in a digital context. In contrast, the structural level involves meaningful transformations in the organization, structuring, and integration of these components. These changes indicate a shift in how the regulatory subsystem operates, suggesting that digitalization is reshaping the very foundation of psychological regulation. As a result of this complex influence, a new phenomenon emerges, referred to as the syndrome of reduced personality regulation. This syndrome holds significant implications for overall personality development and regulatory potential, sharing similarities with previously identified syndromes of decreased cognition and metacognition. The structural transformations in the regulatory subsystem, influenced by digitalization, primarily manifest as changes in the degree of organization and integration, rather than qualitative alterations. The qualitative aspects remain invariant and resist the pervasive effects of digitalization, suggesting the subsystem’s resilience that may offer avenues for further exploration and intervention.

Abstract Reproducibility of Al/AlOx/Al Josephson junctions is a challenge for scaling up superconducting quantum processors. The frequency uncertainty of the transmon qubits arising from the fabrication process is attributed to deviations in the Josephson junction microstructure and electrical properties. Here, we present a solution for this problem using the post-fabrication Josephson junction thermal annealing process. The developed thermal post-exposure method allows not only to increase the junction resistance by 175%, but also to decrease by 60% with a step of 10% in Rn, which opens up new possibilities for tuning the frequency of qubits. The resistance is shown to be strongly temperature dependent, and is weakly dependent on the holding time. The linear dimensions of the electrodes and the sidewalls contribution to the total JJ area also have a significant impact on the final resistance after annealing. Finally, a theoretical model of the structure modification in a tunnel barrier with changes in oxygen concentration gradient is proposed. The proposed thermal annealing approach can be used to form stable and reproducible tunnel barriers and scalable frequency trimming for widely used fixed-frequency transmon qubits.

Available and reliable energy supply is essential for the consumers in the Arctic regions that are characterized by a climate. The importance of the energy infrastructure is emphasized in the strategic planning documents. However, projects of constructing energy capacities are not always implemented. In the study an analysis of some energy development projects implementation in the regions of the Western Russian Arctic was performed; promising areas of energy development are also examined. In the medium term, fossil fuels and hydropower will continue to be the main sources of energy supply to consumers in the Western Arctic, while a significant share of nuclear power will remain in the Murmansk region. Under these circumstances, in the regions the tasks of providing gas supplies and increasing the use of local energy resources are set. Gas supplies methods as well as types of local energy resources may differ for different regions. Purpose of the study it to find out trends in the development of energy supply in the regions of the Western Arctic of Russia in the medium term. Methodology includes information analysis on the research topic, generalization, comparison, systematization. Results: it was found that the trends in the development of energy supply in the regions of the Western Arctic were an increase in gas supplies and the use of local energy sources. The formulated criteria for choosing energy resources are accessibility, economic feasibility, and environmental acceptability. Practical implications. The obtained results can be applied in making decisions on energy development in the Western Arctic regions, as well as to prepare courses on energy economics and regional economics.

This paper considered theoretical aspects of the concept of knowledge management as a factor in the technological and innovative development of the country and organisation. In this context, the essence of knowledge and its role in the economic and technological development were disclosed, the specifics and character of the process of knowledge management were considered, and the expedience and necessity of managing knowledge to ensure high competitiveness of organisations in the conditions of the market environment and technological conditions that change quickly were studied. The research methodology is based on the systemic approach, the general scientific methods of analysis, synthesis, generalisation, and systematisation, content analysis, and correlation analysis of table data. The theoretical basis of the research is philosophical and conceptual provisions of the cognition of reality and capabilities of the human brain, which are implemented through the tools of the management of knowledge and intellectual capital, and the e-HRM and HR Tech concepts. The value of this work lies in the generalisation of scientific approaches to the use of digital HRM from the position of knowledge management in the conditions of the state programme “The Decade of Science and Technology” in the Russian Federation and the development of a model of knowledge management that characterises the structure of the system and determines the points and capabilities of digital processes and tools to raise the level of organisations’ competitiveness.

This paper elaborates on the issue of digitalisation of labour, development of digital competencies, and integration of digital technologies into production and managerial processes of companies in combination with the problem of knowledge management in high-tech companies. In the context of this research, the problems of hiring and involving employees with ICT competencies are analysed, the problem of involving intellectual resources by companies of the high-tech sector is considered, and expectations from digital transformation of the labour market in the context of the development of digital programme solutions, which can partially replace workforce, are studied. The research methodology is based on the concepts of digital personnel from the position of a combination of digital technologies and human labour (digitalisation of labour, digital workplace, automatized digital system, autonomous intelligent platform, etc.). It involves the study of the environment of the development of digital personnel and knowledge management in high-tech companies, which are based on the methods of statistical and mathematical analysis, as well as general scientific methods of observation and generalisation. The main contribution of this work lies in the systemic consideration of the conditions of digitalisation of companies' work from the position of search and hiring of employees, substantiation of the need for high-tech production for intelligent resources, and description of trends and expectations from the integration of digital technologies and systems of knowledge management into the systems of high-tech companies’ management.

This article investigates the processes of knowledge and information systems management from the position of the dataset approach, which focuses on the specifics of the digital economy and the role of Big Data and AI in the processes of labour intellectualisation. According to this, the paper discloses theoretical foundations and features of the key definitions of the research, such as knowledge, knowledge management, and Big Data, and analyses challenges and opportunities that are connected with the possibility of using digital technologies for the collection and processing of data and their usage in management. Special attention is paid to the ability of Big Data and tools of AI to transform non-structured data into a clear information flow or knowledge. The methodological basis of the research is formed by the dataset approach, which determines regularities and principles of work with large arrays of data, and the complex approach, which agrees theoretical concepts of knowledge management and the practical aspects of using digital technologies to raise the effectiveness of information systems of knowledge management. The paper uses the methods of analysis, comparative analysis, synthesis, empirical overview of literature, comparison, observation, and generalisation. The chief value of this work lies in the study of the practical aspects of knowledge management with the use of Big Data and AI, which is based on the identification of the effect of these technologies on the processes of knowledge management, determination of the sequence of operations, and generalisation of the practical experience of such systems’ functioning and their characteristics from the position of the ability to ensure deep processing of non-structured and other information.

This study presents the synthesis, characterization and Hirshfeld surface analysis of 1-[6-bromo-2-(3-bromophenyl)-1,2,3,4-tetrahydroquinolin-4-yl]pyrrolidin-2-one, C19H18Br2N2O. In the title compound, the pyrrolidine ring adopts a distorted envelope configuration. In the crystal, molecules are linked by intermolecular N—H...O, C—H...O and C—H...Br hydrogen bonds, forming a three-dimensional network. In addition, pairs of molecules along the c axis are connected by C—H...π interactions. According to a Hirshfeld surface study, H...H (36.9%), Br...H/H...Br (28.2%) and C...H/H...C (24.3%) interactions are the most significant contributors to the crystal packing.

Background. There is a large body of empirical evidence supporting the positive effects of systematic exercise on cognitive development of children and adolescents. However, the results on the immediate effect of physical activity on cognitive functions (in particular attention and memory) which can potentially come immediately after exercise, are practically lacking or quite contradictory. Objective. The study had its purpose to investigate the immediate effect of physical activity on the measures of attention span and working memory capacity in adolescents. Study Participants. The study involved 190 schoolchildren (54% girls) aged 13–17 (M = 14.73, SD = 1.61) from several regions of Russian Federation. Methods. The “Schulte's tables” were used for diagnostics of attention stability. Working memory scores were measured by means of “Memorization of 10 words”. Results. Comparison of averages demonstrated no significant differences in the indicators of attention stability before and after physical activity (t = 9401, p = 0.131). In contrast, working memory indices were significantly lower after exercise (W = 7257, p < 0.001). Apart from that, girls were shown to memorize and reproduce on average more material than boys. Conclusions. Thus, the obtained results indicate that there is no immediate positive effect of physical activity on the attention span and working memory capacity in adolescents. This may mean that the relationship between the indicators of attention stability, working memory capacity and physical activity is more complex and nonlinear, which requires further study.

Aim. To evaluate the clinical effectiveness, safety and compare the incidence of hospitalization during treatment with antiviral drugs with a direct mechanism of action (riamilovir and umifenovir) in people with acute respiratory viral infections (ARVI) in an outpatient setting. Materials and methods. The study included 150 outpatients with ARVI aged 18–27 years: 50 patients received riamilovir 250 mg 3 times a day for 5 days, the second group included 50 patients who received umifenovir 200 mg 4 times a day for 5 days, 50 individuals received only pathogenetic treatment. Results. The use of direct-acting antiviral drugs was characterized by the least severity of pain and aches in the body, general weakness, and in the group of patients receiving riamilovir, the lowest severity of rhinitis, cough, and the lowest morning body temperature were recorded compared to other groups. In riamilovir group reduction in the duration of the disease was observed. The lowest frequency of ARVI pathogens detection was observed on the 6th day in riamilovir group. Outpatient treatment with riamilovir was accompanied by a minimal number of cases of the disease requiring hospitalization. Conclusion. The use of direct antiviral drugs contributes to the rapid relief of ARVI symptoms in patients receiving medical care on an outpatient basis. The antiviral drug riamilovir showed the most pronounced effectiveness (clinical and laboratory).

Background. Torsional deformities of the long bones in children are usually treated using correcting detorsional osteotomies with different types of osteosynthesis. However, this method is highly traumatic and can cause severe complications. Guided growth is the gold standard for frontal and sagittal planes deformities treatment in growing children. The technique is effective, minimally invasive, enables early weight-bearing and has lower complication rate. Recently, application of guided growth technique has been actively studied for horizontal plane deformities correction as well. The aim of the review — based on a scientific literature analysis, to present possibilities of using guided growth technique for correcting torsional deformities of the long bones, as well as to define the ways of its improvement for further clinical application. Methods. The search was performed in PubMed/MEDLINE, Google Scholar and eLIBRARY databases. For review, we included 8 articles (five animal experimental studies and three clinical studies), which were published from 2013 to 2023. Results. Analyzed studies demonstrated the possibility of applying detorsional guided growth for horizontal plane deformities correction in growing children. Three main surgical techniques were suggested. Correction efficiency mainly depends on the interplate angle, proper plate positioning and longitudinal growth potential. Limitations of these studies were: a small group number; absence of preoperative CT scans in animal studies; torsional profile measurement using computed tomography was performed only in one of three clinical studies. There was also no preoperative planning of deformity correction/creation amount, so it was not possible to evaluate the accuracy of the suggested methods. The main complications were secondary deformities and limb length discrepancy. Conclusions. Further clinical application of detorsional guided growth in children may be possible after solving the problem of secondary deformities and shortening and providing preoperative planning of the deformity correction amount.

The article deals with mobiliary art objects found in the cultural layers of the complex of archaeological sites " Koksharovskiy Kholm sanctuary – Yuryinskoye settlement", located in the mountain forest zone of the Middle Trans-Urals. The archaeological site contains artifacts from the Neolithic, Chalcolithic, Late Bronze Age, and Middle Ages. But the main part of the collection includes artifacts, made of clay and stone, from the Neolithic, known in the literature as cross-grooved items, spherical and biconical findings, ornithomorphic and zoomorphic artefacts, including plastic on vessels, talc rods of segmented shape with and without impression, a drilled stone mace, a fragment of a polished slate knife, back part of which is designed in the form of an ornithomorphic image, flint and ground arrowheads, clay disks without a hole, etc. Some of these artifacts can be considered as cultic ones, because, it is likely that they were used in the rituals held on the sanctuary, which apparently had the status of an interregional cult center.

In the article, transformation of the foreign policy and security strategies of the Benelux countries – Belgium, the Netherlands and Luxembourg – is analyzed against the exacerbating conflict in Ukraine. Using the comparative historical method, we outline the evolution of strategic trends of Europeanism – seeking deeper integration within the European institutional framework – and Atlanticism – pursuing a general strategic orientation towards the United States – in the three countries. As smaller-sized countries, they initially combined Europeanism and «moderate» Atlanticism, which left them some space for foreign policy maneuver. Since the 1990s, the Dutch foreign policy more closely follows the Atlanticist paradigm, while those of Belgium and Luxembourg are characterized more by Europeanism. The analysis of the EU strategic autonomy debate as a case study has shown that Belgium, the Netherlands and Luxembourg seek the greatest possible economic benefits from the autonomy initiatives. Besides, the balance between the strategic trends remains; Belgium and Luxembourg positively view deeper EU defense cooperation, while the Netherlands mostly sees security guarantees in Euro-Atlantic cooperation. The current state in European security has thus not fundamentally changed the Benelux countries’ approaches to balancing Europeanism and Atlanticism that have been characteristic for them since the 1990s. Besides, for Belgium, support for deeper integration has become a key identity feature, while the Netherlands relies on special relations with the United States and ad hoc coalitions in the EU; Luxembourg’s foreign policy can be described to follow a free rider strategy.

Immunotherapy represents a groundbreaking therapeutic approach, based on the immune system’s intrinsic capacity to interfere with tumor progression, that opens the horizons in the treatment of endometrial cancer. However, the clinical efficacy of immunotherapy is hampered by the development of resistance in patients. The resistance to immunotherapy is multifactorial mechanism, encompassed genetic and epigenetic alterations in tumor cells modulating immune checkpoint molecules, resulted in escaping immune surveillance. The tumor microenvironment can orchestrate an immunosuppressive milieu, attenuating the immune response and facilitating tumor progression. To overcome immunotherapeutic resistance in endometrial cancer we must bring to light the mechanisms of intricate interplay between neoplastic cells, the host immune system, and the tumor microenvironment. The identification of predictive biomarkers for immunotherapeutic response and the innovative agents capable of reversing resistance pathways must be developed. Our review summarizes accumulated data on the role of cells of the tumor microenvironment and their regulatory molecules in the mechanisms underlying therapeutic effects of immune checkpoint inhibitors, including resistance to therapy. Major question we raise here – which group of patients is the most favorable to achieve durable immunotherapy response in endometrial cancer?

An isostatic hot-pressing technique for the fabrication of dense W samples' is presented. The samples’ microstructure and chemical content were analyzed. The most compact samples were received at 5 GPa pressure and 1500 and 2000 °C temperatures, with densities of 18.50 and 19.07 g/cm3, respectively. It has been established that high temperature exposure has a positive effect on both the microstructure and density. It is shown that as the sintering temperature increases, the porosity of the samples decreases from 32.31% to 0.94%, and their relative density increases from 67.69% to 99.06%. The crystal structure investigation revealed that all the samples contain the main body-centered cubic W phase, and the availability of the WO2 phase is observed just after the temperature of sintering increases above 1000 °C, which is confirmed by the appearance of 111 and 22-2 reflections. A study of the shielding effectiveness against gamma-radiation was carried out using the Phy-X/PSD software. A gamma-ray source of Co60 with energies of 0.8–2.5 MeV was applied for the calculations. The results were calculated for the sample with the highest density (19.07 g/cm3) and compared with the calculations for Pb. The W shielding effectiveness main parameters are determined: linear attenuation coefficient (at 0.8 MeV–1.46 cm-1), mean free path (at 2.5 MeV–1.2 cm) and half value layer (at 2.5 MeV–0.86 cm). These values turned out to be higher than for Pb, which makes shields based on W promising for use in the field of radiation protection.

IntroductionModification of natural enzymes to introduce new properties and enhance existing ones is a central challenge in bioengineering. This study is focused on the development of Taq polymerase mutants that show enhanced reverse transcriptase (RTase) activity while retaining other desirable properties such as fidelity, 5′- 3′ exonuclease activity, effective deoxyuracyl incorporation, and tolerance to locked nucleic acid (LNA)-containing substrates. Our objective was to use AI-driven rational design combined with multiparametric wet-lab analysis to identify and validate Taq polymerase mutants with an optimal combination of these properties.MethodsThe experimental procedure was conducted in several stages: 1) On the basis of a foundational paper, we selected 18 candidate mutations known to affect RTase activity across six sites. These candidates, along with the wild type, were assessed in the wet lab for multiple properties to establish an initial training dataset. 2) Using embeddings of Taq polymerase variants generated by a protein language model, we trained a Ridge regression model to predict multiple enzyme properties. This model guided the selection of 14 new candidates for experimental validation, expanding the dataset for further refinement. 3) To better manage risk by assessing confidence intervals on predictions, we transitioned to Gaussian process regression and trained this model on an expanded dataset comprising 33 data points. 4) With this enhanced model, we conducted an in silico screen of over 18 million potential mutations, narrowing the field to 16 top candidates for comprehensive wet-lab evaluation.Results and DiscussionThis iterative, data-driven strategy ultimately led to the identification of 18 enzyme variants that exhibited markedly improved RTase activity while maintaining a favorable balance of other key properties. These enhancements were generally accompanied by lower Kd, moderately reduced fidelity, and greater tolerance to noncanonical substrates, thereby illustrating a strong interdependence among these traits. Several enzymes validated via this procedure were effective in single-enzyme real-time reverse-transcription PCR setups, implying their utility for the development of new tools for real-time reverse-transcription PCR technologies, such as pathogen RNA detection and gene expression analysis. This study illustrates how AI can be effectively integrated with experimental bioengineering to enhance enzyme functionality systematically. Our approach offers a robust framework for designing enzyme mutants tailored to specific biotechnological applications. The results of our biological activity predictions for mutated Taq polymerases can be accessed at https://huggingface.co/datasets/nerusskikh/taqpol_insilico_dms

In the title compound, C19H18BrFN2O, the pyrrolidine ring adopts an envelope conformation. In the crystal, molecules are linked by intermolecular N—H...O, C—H...O, C—H...F and C—H...Br hydrogen bonds, forming a three-dimensional network. In addition, C—H...π interactions connect molecules into ribbons along the b-axis direction, consolidating the molecular packing. The intermolecular interactions in the crystal structure were quantified and analysed using Hirshfeld surface analysis.

Abstract In this paper, we propose a fluorescence-lifetime imaging microscopy (FLIM) multiplexing system based on the fluorogen-activating protein FAST. This genetically encoded fluorescent labeling platform employs FAST mutants that activate the same fluorogen but provide different fluorescence lifetimes for each specific protein-dye pair. All the proposed probes with varying lifetimes possess nearly identical and the smallest-in-class size, along with quite similar steady-state optical properties. In live mammalian cells, we target these chemogenetic tags to two intracellular structures simultaneously, where their fluorescence signals are clearly distinguished by FLIM. Due to the unique structure of certain fluorogens under study, their complexes with FAST mutants display a monophasic fluorescence decay, which may facilitate enhanced multiplexing efficiency by reducing signal cross-talks and providing optimal prerequisites for signal separation upon co-localized and/or spatially overlapped labeling.

Introduction. The amino acid substitution A62V in reverse transcriptase was identified as a mutation correlated with virologic failure in patients on first-line therapy including tenofovir (TDF) and tenofovir alafenamide (TAF). A62V is a typically polymorphic mutation in HIV-1 sub-subtype A6, which is the most widespread virus variant in Russia. Materials and methods. The European EuResist (EIDB) database was queried to form two equivalent groups of patients: group 1 ‒ patients with A62V at baseline treated with TDF or TAF on the first-line therapy, group 2 ‒ patients without A62V at baseline treated with TDF or TAF on the first-line therapy. Each group included 23 patients. Results. There was no statistical difference between the two groups in virologic efficacy in 4, 12, and 24 weeks after the start of antiretroviral therapy (ART) and in the frequency of virologic failures. Conclusion. This study has some limitations, and the exact role of A62V in the efficacy of the first-line ART based on tenofovir deserves further investigation.

Abstract Background Among the non-traditional antibacterial agents in development, only a few targets critical Gram-negative bacteria such as carbapenem-resistant Pseudomonas aeruginosa, Acinetobacter baumannii or cephalosporin-resistant Enterobacteriaceae. Endolysins and their genetically modified versions meet the World Health Organization criteria for innovation, have a novel mode of antibacterial action, no known bacterial cross-resistance, and are being intensively studied for application against Gram-negative pathogens. Methods The study presents a multidisciplinary approach, including genetic engineering of LysECD7-SMAP and production of recombinant endolysin, its analysis by crystal structure solution following molecular dynamics simulations and evaluation of antibacterial properties. Two types of antimicrobial dosage forms were formulated, resulting in lyophilized powder for injection and hydroxyethylcellulose gel for topical administration. Their efficacy was estimated in the treatment of sepsis, and pneumonia models in BALB/c mice, diabetes-associated wound infection in the leptin receptor-deficient db/db mice and infected burn wounds in rats. Results In this work, we investigate the application strategies of the engineered endolysin LysECD7-SMAP and its dosage forms evaluated in preclinical studies. The catalytic domain of the enzyme shares the conserved structure of endopeptidases containing a putative antimicrobial peptide at the C-terminus of polypeptide chain. The activity of endolysins has been demonstrated against a range of pathogens, such as Klebsiella pneumoniae, A. baumannii, P. aeruginosa, Staphylococcus haemolyticus, Achromobacter spp, Burkholderia cepacia complex and Haemophylus influenzae, including those with multidrug resistance. The efficacy of candidate dosage forms has been confirmed in in vivo studies. Some aspects of the interaction of LysECD7-SMAP with cell wall molecular targets are also discussed. Conclusions Our studies demonstrate the potential of LysECD7-SMAP therapeutics for the systemic or topical treatment of infectious diseases caused by susceptible Gram-negative bacterial species and are critical to proceed LysECD7-SMAP-based antimicrobials trials to advanced stages.

Monoclonal antibodies are widely used in all fields of biology and medicine. The emergence and development of the technology for their production revolutionized immunology and allowed the creation of not only new diagnostic methods, but also many effective drugs. The purpose of our review is to analyze and summarize relevant data concerning the technology of obtaining monoclonal antibodies. We have analyzed information from 70 modern literary sources devoted to various methods of obtaining them. In this review, we tried to cover the entire range of methods used to obtain monoclonal antibodies today.

Porous α-Al2O3 ceramics are a highly sought-after material with a multitude of applications; for example, they are used as filters, substrates, biomedicine materials, etc. Despite the availability of raw materials, a challenge associated with this technology is the high energy budget caused by sintering above 1500 °C. For the cold sintering processing (CSP) of ceramics, lowering the α-Al2O3 sintering temperature is one of the most urgent challenges in the background of its rapid development. This paper is the first to demonstrate a solution to this problem using the CSP of α-alumina ceramics in the presence of pure water as a transient liquid. The manufactured materials were examined using XRD analysis; the evolution of their microstructures during CSP was revealed by SEM; and the porosity was evaluated using the Archimedes method. Ceramics with an open porosity up to 36% were produced at 380–450 °C and 220 MPa in 30 min. An increase in the pressure was found to impede α-Al2O3 formation from γ-AlOOH. The development of the microstructure was discussed within the framework of the dissolution–precipitation model and homogenous nucleation. The results of the SEM study pointed to the coalescence of γ-AlOOH grains during CSP.

Carboxymethyl cellulose sodium salt is a common water-soluble derivative of cellulose. It serves as a bioinert mucoadhesive material extensively used in biomedicine, particularly for crafting targeted drug delivery systems. In our study, we demonstrate that graft copolymers of sodium carboxymethyl-cellulose with poly(N-vinylimidazole) can function as carriers for the antibacterial drug metronidazole. Non-covalent associations form between the components, excluding the involvement of the nitro groups of the drug in the interaction. These loaded copolymers exhibit the capability to release the drug under conditions mimicking the stomach environment for up to 48 h. This renders the obtained associations promising candidates for the development of a metronidazole-targeted delivery system.

This article explores the bureaucratic, legal and economic dimensions of the neonatal care. Drawing analytically on the neo-Weberian approach in the sociology of professions [Freidson 2001] and the anthropology of bureaucracy in medicine [Berg 1996; Berg & Bowker 1997], we propose to analyse the medical documents and the practices of its composition as both a constitutive element of medical practice and as organisational infrastructure that ensures the coordination of different professional groups and their interactions with patients. Specifically, we define this part of the work of doctors, nursing staff and health care managers in the context of neonatal resuscitation care as a process of creating and modifying a 'paper body' for their patients, i.e. all the document flow that accompanies the processes of treating and routing the patient. Empirically, the study relies on qualitative data collected within ‘the Birth of the Patient’ project: diaries of included observations of a neonatal intensive care physician, ethnographic observations by social researchers, focus groups with neonatal intensive care unit staff and interviews with medical professionals and healthcare managers. As a result of this data analysis, we find that the documentary history of the newborn patient is shaped by multiple negotiations between different medical professionals and representatives of different health care institutions. In some cases, the patient's 'paper body' turns out to be a major determinant of his or her future trajectory of (de)hospitalisation. We also find that the formation of such a documentary biography of a newborn patient does not directly correlate with his or her clinical condition, but reflects the complex system of distribution of material and non-material resources that constitute the newborn care service and in some cases goes beyond it.

Introduction: Elevated intraocular pressure (IOP) has been identified as a major risk factor for the progression of primary open-angle glaucoma (POAG). However, the continued progression of POAG in some patients, despite the successful IOP reduction, indicates that IOP-independent mechanisms contribute to the development of optical neuropathy. Thus, it is relevant to further determine the molecular mechanisms of retinal ganglion cells (RGCs) death in order to develop therapeutic approaches independent of IOP in order to stop the progression of the disease. The aim: to research the correction possibility of experimental POAG induced by intracameral (i.c.) administration of hyaluronic acid using 2-ethyl-6-methyl-3-hydroxypyridinium N-acetyltaurinate. Materials and Methods: The study of the correction of neuroretinal changes on a model of POAG was carried out on Wistar rats. In order to correct POAG, 2-ethyl-6-methyl-3-hydroxypyridinium N-acetyltaurinate (EHMP-NAT) was used at doses of 27.5 mg/kg intramuscularly (i.m.) and 0.5 mg/kg instillationally. Further, the effectiveness of the combination of timolol eye drops with i.m. EHMP-NAT was studied. The effectiveness of the studied agents was evaluated on the 67th day of the experiment using ophthalmoscopic semi-quantitative assessment of the fundus condition, ocular tonometry, estimation of oxidative stress markers and markers involved in retinal apoptosis pathway using enzyme-linked immunosorbent assay (ELISA). Results: On the model of POAG, it was shown that 2-ethyl-6-methyl-3-hydroxypyridinium N-acetyltaurinate with the laboratory code EHMP-NAT has a pronounced neuro-, retinoprotective action based on the data of ophthalmoscopy, semi-quantitative assessment of the fundus condition, ocular tonometry, estimation of oxidative stress markers (GSH, CAT, SOD) and markers involved in retinal apoptosis (BAX, BCL-2, Caspase-3). On the 67th day of the experiment, the results of a comprehensive analysis revealed that the combination of EHMP-NAT 27.5 mg/kg i.m. + timolol 0.04 mg/kg instillationally has a more pronounced protective effect than EHMP-NAT 27.5 mg/kg i.m. in monotherapy in the POAG model. Conclusion: The data obtained indicate the need for the combined use of drugs with a hypotensive effect to normalize IOP with neuroretinoprotective agents in the correction of POAG.

Abstract In this work we focus on the study of RG flows of conformal field theories that are holographically dual to Poincaré domain wall solutions in $$D=3$$ D = 3 , $$\mathcal {N}=(2,0)$$ N = ( 2 , 0 ) gauged supergravity coupled to a sigma model with target space $$\textrm{SU}(1, 1)/\textrm{U}(1) = \mathbb {H}^2$$ SU ( 1 , 1 ) / U ( 1 ) = H 2 . This theory is truncated to a subsector where the vector field and phase of the scalar field vanish and we consider different boundary conditions for the remaining real scalar field. The RG flows, which are mostly non-superysymmetric, are analyzed by treating the supergravity field equations as a dynamical system for the scalar field and its derivative with respect to the scale factor. Phase diagrams are constructed for different values of the parameter $$a^2$$ a 2 , which is related to the curvature of the scalar manifold. The behavior of solutions near the boundary is used to determine their type based on the expansion of the corresponding fake superpotential. By incorporating information on the boundary conditions, the obtained RG flows are interpreted using the holographic dictionary. Numerical solutions and plots of the fake superpotential are also provided.

The paper is concerned with the possibilities of using innovative technologies at enterprises in the logistics industry. During the studying of this topic the authors of the article come to the conclusion that introduction of modern technologies presented in this article should not be limited exclusively to enterprises in the logistics industry. They can be used in different industries and fields of activity well. In examining the problem the authors point out that the practical realization of these techniques in combination can lead to significant positive structural changes in the company, to increase the motivation of employees to further use the implemented technologies and constantly search for new ways to reduce costs. In general, it can increase the efficiency of the company significantly. Purpose. The aim of the research is to study modern technologies which are used at enterprises of the logistics and other industries. The objectives of the study are to determine their main directions. Methodology. The article applies theoretical analysis, generalization of scientific literature, content analysis, systematization. Results. There are directions of research in logistics by both foreign authors and domestic researchers. The authors point tо significant potential for their implementation in the modern period. It is the basis for further research in this area. Practical implications. The scope of the results: managers of enterprises operating in the logistics industry can use the materials of the presented research. They can use it to make the choice of building the company development strategy and solving more specific tasks for example during personnel training.

Abstract Human reproduction is an imperfect process despite years of evolution. It is estimated that only 30% of conceived pregnancies end up with a live birth (Hum Reprod Update 8:333-343, 2002). Although the IVF cycle clinical pregnancy rate is estimated to be above 60%, the actual live birth rate is still well below 50% (Reprod Biomed Online 40:201-206, 2004). Errors of implantation, embryonic genetic mutations, structural as well as chromosomal abnormalities, endometrial aberrances as well as abnormal sites of implantation are all conditions that could be associated with a positive pregnancy test yet a non-viable pregnancy outcome. In this extensive literature review, we detailed the different risk factors hindering a successful reproductive outcome post-IVF in terms of early pregnancy loss. We also reviewed the different treatment modalities available to improve the prognosis of such patients.

Clinical observations of three patients aged 26, 43 and 37 years with severe psoriasis and psoriatic arthritis are presented. Clinical examples show the experience of effective treatment of patients with psoriasis and psoriatic arthritis using anti-cytokine therapy with an interleukin-17 inhibitor, initiated when the disease progresses. The clinical picture of the presented observations was characterized by an aggressive course of the skin and articular process, torpidity to basic therapy, despite the young age of the patients. It has been shown that the early termination of the progression of the inflammatory process in psoriasis with the use of genetically engineered biological therapy with secukinumab leads to a decrease in symptoms, both on the part of the skin and manifestations of the disease on the part of the musculoskeletal system. The high efficacy and safety of the drug allow complete control of the disease and improve the quality of life in patients suffering from severe forms of dermatosis.

Background: The present study investigates the feasibility of using three previously published genome-wide association studies (GWAS) results on blood lipids to develop polygenic risk scores (PRS) for population samples from the European part of the Russian Federation. Methods: Two population samples were used in the study – one from the Ivanovo region (n = 1673) and one from the Vologda region (n = 817). We investigated three distinct approaches to PRS development: using the straightforward PRS approach with original effect sizes and fine-tuning with PRSice-2 and LDpred2. Results: In total, we constructed 56 PRS scales related to four lipid phenotypes: low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol, and triglyceride levels. Compared with previous results for the Russian population, we achieved an additional R2 increase of 2–4%, depending on the approach and lipid phenotype studied. Overall, the R2 PRS estimates approached those described for other populations. We also evaluated the clinical utility of blood lipid PRS for predicting carotid and femoral artery atherosclerosis. Specifically, we found that PRS for total cholesterol, low-density lipoprotein cholesterol, and triglycerides were positively correlated with ultrasound parameters of carotid and femoral artery atherosclerosis (ρ = 0.09–0.13, p < 0.001), whereas PRS for high-density lipoprotein cholesterol were inversely correlated with the number of plaques in the femoral arteries (ρ = −0.08, p = 8.71 × 10−3). Conclusions: PRS fine-tuning using PRSice-2 add LDpred2 improves the performance of blood lipid PRS. Our study demonstrates the potential for further use of blood lipid PRS for prediction of atherosclerosis risk.

Relevance. The need to dentify the characteristics of the distribution of radioactive elements in the groundwater of Northern Kazakhstan. Aim. Generalization of available data on the geochemistry of groundwater and uranium and radon distribution in them using the example of the northern regions of the Republic of Kazakhstan. Methods. Generalization of long-term hydrogeochemical research and compilation of an electronic data bank on the territory of Northern Kazakhstan. A laboratory study of the chemical composition of groundwater was carried out at the Research Laboratory of Hydrogeochemistry of the School of Natural Resources Engineering of Tomsk Polytechnic University. Measurements of 222Rn contents in waters were carried out using the Alfarad Plus complex in the Laboratory of Hydrogeology of Sedimentary Basins of Siberia, Institute of Geology and Geography, Siberian Branch, Russian Academy of Sciences. Results. The groundwater of aquifers of different ages, distributed in the territory of Northern Kazakhstan (North Kazakhstan uranium province), was studied. Two geochemical sets of groundwater were identified. The first is characterized by the dominance of HCO3– and Mg2+ in the water composition, and the second by Cl– and Na+. A change in composition and an increase in the value of total mineralization from 0,1 to 49 g/dm3, in the direction from north to south, indicate the development of continental salinization. In natural waters of the first group, uranium content varies from 0.065 to 16000 μg/dm3 and radon activity from 4 to 3885 Bq/dm3. For sodium chloride waters of the second set, concentrations can reach 32500 μg/dm3, and radon activity is 6–59 Bq/dm3, since the emanating reservoir (granitoids) is located to the north – at a distance of 80–100 km. Naturally, granitoid massifs of the studied region are sources of uranium. Their drainage by the river network leads to its removal and concentration on geochemical barriers in the groundwater of the Neogene-Quaternary aquifer. This distribution of radioactive elements is associated with the high migration ability of uranium in solution in the form of uranyl ion in oxidizing geochemical conditions.

Background: Endogenous antimicrobial peptides (AMPs) are evolutionarily ancient molecular factors of innate immunity that play a key role in host defense. The study of the diversity of animal defense peptides has important applications in the context of the growing global antimicrobial resistance. Methods: In this study using a transcriptome mining approach, we found three novel thanatin-like β-hairpin AMPs in the bean bug Riptortus pedestris, named Rip-2, Rip-3, and Rip-4. The peptides were expressed in the bacterial system, and their antimicrobial activities were evaluated both in vitro and in vivo. Results: Homologs of the discovered AMPs are widely distributed among different members of the infraorder Pentatomomorpha. Rip-2 was shown to have the most similar structure and LptA-targeting mechanism of action to those of thanatin, but the former peptides demonstrated a higher activity against key Gram-negative ESKAPE pathogens and also displayed a significant efficacy in a lethal model of septicemia caused by E. coli in mice at daily doses greater than 5 mg/kg. In contrast, Rip-3 and Rip-4 peptides caused bacterial membrane damage, did not induce bacterial resistance, and exhibited a strong selectivity against Bacillus and Mycobacterium spp. Conclusions: This study extends the knowledge of the structure and functions of insect host defense AMPs. Each of the novel β-hairpin peptides has a potential to be a template for the development of selective antibiotic drugs.

The aim of the study – to identify the factors associated with the development of chronic post-traumatic pain (CPTP) in patients with knee joint (KJ) injury.Materials and methods. The study group consisted of 136 patients (51.5% women, age 38.7±12.4 years) who suffered a KJ injury with damage to the anterior cruciate ligament and/or menisci. The inclusion criterion was the presence of pain in KJ ≥4 on a numerical rating scale (NRS 0–10) for at least 1 month after injury. Surgical intervention (plastic surgery of the anterior cruciate ligament, meniscus suture, meniscus resection, combined operations) was performed immediately after injury in 48.5% of patients. The incidence of CPTP was assessed (persistence of pain during movement ≥4 on NRS after 3 and 6 months of follow-up) and factors related to the development of CPTP. All patients were recommended to use orthoses of KJ, physical therapy and taking nonsteroidal anti-inflammatory drugs in the “on-demand” mode. Results. CPTP was detected after 3 months in 33.1%, and after 6 months in 32.4% of patients. Surgical treatment did not affect the development of CPTP: odds ratio (OR) – 1.241, 95% confidence interval (95% CI): 0.775–1.986 (p=0.474). The risk of CPTP after 6 months was statistically significantly higher in women, persons with a high body mass index (≥30 kg/m2), initially severe pain (≥7 on NRS), in the presence of initial signs of depression and anxiety (HADS (Hospital Anxiety and Depression Scale) ≥8) and highly probable central sensitization (CSI (Central Sensitization Inventory) ≥40): OR=2,152, 95% CI: 1,383–3,348 (p=0,002); OR=1,243, 95% CI: 1,054–1,465 (p=0,05); OR=3,567, 95% CI: 1,717–5,708 (p=0,001); OR=2,330, 95% CI: 1,070–5,726 (p=0.0044); OR=2,446, 95% CI: 1,220–4,905 (p=0,016); OR=2,584, 95% CI: 1,101–8,133 (p=0.043), respectively.