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Aim: demonstration of basic molecular biological, metabolic and immunological effects of fecal microbiota transplantation (FMT), on the example of a rare case of acute graft-versus-host disease (GVHD) with intestinal damage in a patient after allogeneic hematopoietic stem cell transplantation (allo-HSCT).Materials and methods. To monitor the basic effects of FMT, we performed targeted DNA sequencing of 16S rRNA gene (V3–V4) using MiSeq platform as well as multiplex real-time PCR, MS/gas chromatography technique, immunophenotyping of blood lymphocytes, histological and immunohistochemical techniques.Clinical case. A 40-year-old female patient diagnosed with myelodysplastic syndrome, with a history of two unsuccessful allo-HSCTs due to graft failure, underwent the third haploidentical HSCT (haplo-HSCT) from her father as ‘salvage’ therapy. Due to early viral/bacterial colitis post-transplant associated with a multidrug-resistant strain of K. pneumoniae and herpes virus type 6, FMT was performed on days 46 and 47 after allo-HSCT. Complete resolution of the enteropathy symptoms was noted following FMT. However, immunosuppressive therapy was canceled on D+106 after haplo-HSCT due to the detection of minimal residual disease causing development of the ‘overlap’-type GVHD with damage skin lesions grade 4, and intestinal mucous membranes grade 3. This complication required resumption and subsequent intensification of immunosuppressive therapy with complete resolution of GVHD symptoms. Following FMT treatment, the patient showed complete resolution of clinical colitis symptoms. According to results of 16S rRNA sequencing, the species-specific diversity of fecal microbiota increased significantly, along with decreased relative contents of opportunistic bacteria (Klebsiella, Enterococcus, Streptococcus genera). A significant growth was revealed for commensal Bacteroidota, and re-emergence of Faecalibacterium, Blautia, Roseburia. Acute gastrointestinal GVHD promoted by tacrolimus withdrawal was associated with repeated depletion of intestinal microbiota. Upon resolution of GVHD and resumed immunosuppression, increased microbiota diversity (Shannon index) was again recorded, and the parameters of patient’s fecal microbiota reached the donor values. The microbiota shifts at all clinical stages (before and after FMT, at the peak of acute intestinal GVHD and intensive immunosuppressive therapy) showed some relations with metabolism of bile and fatty acids in blood plasma and immune parameters.Conclusions. FMT may be a component of complex therapy aimed at early reconstitution of immune system and organic acid metabolism in patients after allo-HSCT. The composition of fecal microbiota, metabolic profile and spectrum of lymphocyte subpopulations may be markers for monitoring complex rehabilitation after allo-HSCT.

This article aims to provide a comprehensive analysis of the role of British monarch George III in the events surrounding the American Revolution. The novelty of this research lies in its exploration of the English king’s actions, which have yet to be thoroughly examined in terms of assessing the counterrevolutionary response of the metropolis to the challenges posed by the colonists, as well as the objective factors influencing his critical decisions during the American War of Independence. The author investigates the nuances of the king’s political maturation, the concept of the patriot king as articulated by Viscount Bolingbroke, and the evolution of perceptions regarding the monarchy and George III within colonial society. The motivations behind the sovereign’s specific choices during the American crisis are analyzed through the lens of domestic politics and the characteristics of imperial governance. This article departs from the traditional portrayal of the British monarch as a tyrant, as established by the Declaration of Independence, which is examined in light of its allegations against the king’s tyranny. The conclusion drawn is that, in matters of imperial relations, George III was primarily guided by parliamentary interests and only after the outbreak of war, due to his character and sense of duty, did he become one of the most steadfast and obstinate proponents of suppressing the colonial rebellion through force.

Modern multipolar world subject to economic and financial crises requires the creation of a new model of interaction and cooperation. The goals and priorities for economic systems development at the level of states and regions have recently undergone major changes. Under the leadership of the President of the Russian Federation Vladimir Putin, the development plans of the constituent entities of the Russian Federation are constantly revised depending on the current situation in the regions. In the modern sphere of regional policy, the task of ensuring sustainable development of the economic systems of the territories is becoming more and more urgent. Public administration bodies and scientific and expert communities pay more attention to the issues of state regional policy and its constituent part such as regional economic policy, which should ensure the interrelation of regional priorities of the country with the concepts, long-term strategies, and medium-term programs of socio-economic development at the regional level. The formation of effective mechanisms for Russian economic policy implementation at various levels of government requires special attention. Insufficient clarity of state policy objectives in individual subjects makes it difficult to determine strategic development priorities and reduces the forecasts effectiveness. In this regard, the study of the regional socio-economic development processes in modern Russia is relevant both in theoretical and practical terms and necessitates the improvement of scientific support for the mechanisms of forming and implementing modern effective regional economic policy. It is necessary to work hard on its adaptation in order to form long-term programs of the country’s socio-economic development. The basic thesis of the study is that the regions are the center of forming effective economy in Russia at any stage of its development. The purpose of the study is to develop the theoretical foundations for forming regional economic policy of the constituent entities of the Russian Federation and to develop practical recommendations to improve the effectiveness of its implementation in modern conditions.

Satellite remote sensing of ocean colour properties allows observation of the ocean with high temporal and spatial coverage, facilitating the better assessment of changes in marine primary production. Ocean productivity is often assessed using satellite-derived chlorophyll a concentrations, a commonly used proxy for phytoplankton concentration. We used the Copernicus GlobColour remote sensing chlorophyll a surface concentration to investigate seasonal and non-seasonal variability, temporal trends, and changes in spring bloom chlorophyll a magnitude. Complementary, we analysed the chlorophyll a relationship with sea surface temperature and mixed-layer depth in the German Bight from 1998 to 2020. Empirical orthogonal functions were employed in order to investigate dominant spatial and temporal patterns (modes) related to the main processes of chlorophyll a variability. Multi covariance analysis was used to extract the dominant structures that maximize the covariance between chlorophyll a and sea surface temperature mixed-layer depth fields. High levels of chlorophyll a were found near the coast, showing a decreasing gradient towards offshore waters. A significant chlorophyll a positive trend was observed close to the Elbe estuary and adjacent area, while 55 % of the German Bight was characterized by a significant chlorophyll a negative trend. The chlorophyll a non-seasonal variability showed that the first four modes explained around 45 %, with the first and second modes related to inter- and intra-annual variability, respectively, observed in the temporal principal components spectral analyses. Monthly chlorophyll a concentration anomalies co-varied by 45 % with sea surface temperature anomalies and 23 % with mixed-layer depth anomalies. The monthly averages of chlorophyll a anomaly fields were suitable to investigate long-term trends and variability. The rising water temperature, combined with its indirect effects on other variables, can partially explain the observed trends in chlorophyll a.

Введение. Статья посвящена обобщению опыта решения задач планирования работы машинистов городского рельсового транспорта, результаты которого оказывают существенное влияние на безопасность движения. Целью исследования является выявление общих черт в подходах к планированию работы производственных и человеческих ресурсов городского рельсового транспорта; анализ результатов, достигнутых в планировании работы машинистов; определение направления расширения сферы применения и дальнейших исследований, связанных с комбинированием различных методов при решении задач планирования.Материалы и методы. Объектом исследования является математическое обеспечение элементов интеллектуальных транспортных систем, связанных с планированием работы машинистов. Для формализации задачи построения графиков работы машинистов введено описание результатов построения в формате кортежей, т. е. последовательностей компонентов.Результаты. Анализ опыта создания сценариев управления различными видами ресурсов (производственными и человеческими) позволил выявить единство постановок задач и подходов к их решению при повышении комфортности получения транспортных услуг и условий работы людей, чему уделяется существенное внимание на этапе планирования перевозочного процесса. Проанализированы результаты функционирования созданных авторами систем, которые являются составными частями интеллектуальных транспортных систем, и достигаемые при этом эффекты. Предложен новый для отечественных железных дорог подход к формализации задачи планирования работы машинистов, иллюстрирующий предложенную классификацию задач планирования и позволяющий объединить результаты построения графиков работы машинистов, выполняющих разные типы работ. Показана возможность применения метода динамического программирования Беллмана и генетического алгоритма к решению поставленной задачи. Выполнена статистическая обработка полученных данных. Выявлены предпосылки для создания единой методологии интеллектуализации планирования работы ресурсов разных типов на городском рельсовом транспорте.Обсуждение и заключение. Полученные результаты могут быть использованы и при формировании графиков работы локомотивных бригад, например, для условий Московского центрального кольца, при дополнении существующей модели. Использование разработанных алгоритмов позволяет улучшить показатели равномерности автоматически построенных графиков работ по сравнению с построенными вручную применительно к реальным транспортным системам.

This paper examines the theoretical foundations and provisions for the formation of balanced economic growth and development of the region considering its territorial, socio-economic, resource, and structural features and using the Republic of Tatarstan as an example. The paper analyses the theoretical and methodological apparatus proposed by scientists and specialists in ensuring the economic growth and development of the region. The purpose is to identify the main risks, factors and problems in the economic sectors of the Republic of Tatarstan, which to one degree or another are capable of influencing the processes of forming the balanced economic growth and development of the region. Based on the analysis, the paper identifies common problems for the regions and formulates the main directions for improving the economic situation in the region, and also submits for consideration the authors’ model of interaction between enterprises, state and municipal entities in order to reduce the negative impact of previously identified threats and problems, which considers new global challenges, transformations and restructures in economic processes associated with the introduction of restrictive measures, political isolation, various economic sanctions, and with the unresolved internal problems in the field of the economic growth and development of the Republic of Tatarstan.

A novel split-explicit (SE) external mode solver for the Finite volumE Sea ice–Ocean Model (FESOM2) and its sub-versions is presented. It is compared with the semi-implicit (SI) solver currently used in FESOM2. The split-explicit solver for the external mode utilizes a dissipative asynchronous (forward–backward) time-stepping scheme that does not require additional filtering during the barotropic sub-cycling. Its implementation with arbitrary Lagrangian–Eulerian vertical coordinates like Z star (z*) and Z tilde (z̃) is explored. The comparisons are performed through multiple test cases involving idealized and realistic global simulations. The SE solver demonstrates lower phase errors and dissipation, while maintaining a simulated mean ocean state very similar to the SI solver. The SE solver is also shown to possess better run-time performance and parallel scalability across all workloads tested.

Aim of the study. Genetic analysis of Streptococcus pneumoniae serogroups 15 and 11 circulating in Russia according to the following parameters: serotype affiliation; clonal complex (CC); presence of resistance and virulence determinants; relatedness to genetic lineages circulating in the world, and justification of inclusion of the actual serotypes of serogroups 15 and 11 in the future conjugate vaccine composition. Materials and methods. The study included whole genome data of S. pneumoniae serogroups 11 and 15. Results. Genomes of serogroup 15 strains from Russia are represented mainly by serotypes 15B and 15C, the majority of which belong to CC-1025 and CC-1262. CC-1025 is characterized by a more frequent association with invasive diseases. Representatives of CC-1025 and CC-1262 contain virulence determinants unique to these genetic lineages within the studied population of serogroup 15: oligopeptide transporters, fructose-specific PTS system, unique hydrolase variants, additional iron ion transporters, the gene of zinc metalloprotease ZmpC (activating human MMP9). The genomes of serogroup 11 are represented mainly by serotype 11A, the majority belong to CC-62 and CC-1012. The virulence determinants unique to CC-62 (within the studied serogroup 11) include bacteriocins, components of oligopeptide transport, flavin reductase-like protein (adhesin, also protects bacteria from oxidative stress), fucose processing operon, PsaA (adhesin, also a component of the ATP-binding cassette transporter that imports manganese ions). Conclusion. In the Russian Federation, serogroups 15 and 11 are the most common non-vaccine serogroups. No antimicrobial resistance determinants have been identified in the genomes of representatives of these serogroups. For each of the genetic lineages prevalent in Russia and associated with serogroups 15 and 11, unique virulence determinants within the studied serogroup have been identified, which may contribute to the success of these lineages. It is advisable to include serotypes 15B and 11A in vaccines promising for the Russian Federation.

The research presents the development of a heterogeneous graph neural network model for predicting gene-disease using existing genomic and medical data. The novelty of the approach is in integrating the principles of graph neural networks and heterogeneous information networks for efficient processing of structured data and consideration of complex genepathology interactions. The solution proposed is a heterogeneous graph neural network which utilizes a heterogeneous graph structure for representing genes, diseases, and their relationships. The performance of the developed model was evaluated on the DisGeNET, LASTFM, YELP datasets. On these datasets, a comparison was made with current SOTA models. The comparison results demonstrated that the proposed model outperforms other models in terms of Average Precision (AP), F1-measure (F1@S), Hit@k, Area Under Receiver Operating Characteristic curve (AUROC) in predicting “gene-disease” associations. The model developed serves as a tool for bioinformatics analysis and can aid researchers and doctors in studying genetic diseases. This could expedite the discovery of new drug targets and the advancement of personalized medicine.

Abstract Cancer treatment with vascular disrupting agents (VDAs) causes rapid and extensive necrosis in solid tumors. However, these agents fall short in eliminating all malignant cells, ultimately leading to tumor regrowth. Here, we investigated whether the molecular changes in the tumor microenvironment induced by VDA treatment sensitize the tumors for secondary nanotherapy enhanced by clinical-stage tumor penetrating peptide iRGD. Treatment of peritoneal carcinomatosis (PC) and breast cancer mice with VDA combretastatin A-4 phosphate (CA4P) resulted in upregulation of the iRGD receptors αv-integrins and NRP-1, particularly in the peripheral tumor tissue. In PC mice treated with CA4P, coadministration of iRGD resulted in an approximately threefold increase in tumor accumulation and a more homogenous distribution of intraperitoneally administered nanoparticles. Notably, treatment with a combination of CA4P, iRGD, and polymersomes loaded with a novel anthracycline Utorubicin (UTO-PS) resulted in a significant decrease in the overall tumor burden in PC-bearing mice, while avoiding overt toxicities. Our results indicate that VDA-treated tumors can be targeted therapeutically using iRGD-potentiated nanotherapy and warrant further studies on the sequential targeting of VDA-induced molecular signatures.

The creation of new and improvement of existing machines and mechanisms requires the development of drive engineering and the creation of new drive systems capable of competing with currently known circuit solutions. Under these conditions, the creation of combined pneumatic-mechanical drives is an important scientific and technical task. The purpose of this work is to increase the speed at a given accuracy of auxiliary movements of the target mechanisms of technological machines by creating a pneumatic-mechanical drive with improved energy and dynamic characteristics. The technical solution of a positioning pneumatic-mechanical drive of executive movements of technological equipment is presented, mathematical and computer models are developed. In this case, the method of solving the differential equation in the SimInTech program is used. As a result, an oscillogram of transients is obtained. The developed models allow for dynamic analysis of pneumatic-mechanical systems.

Intraventricular hemorrhage (IVH)4 is one of the most threatening neurological complications associated with preterm birth which can lead to long-term sequela such as cerebral palsy. Early recognition of IVH risk may prevent its occurrence and/or reduce its severity. Using multivariate logistic regression analysis, risk factors significantly associated with IVH were identified and integrated into risk scales. A special aspect of this study was the inclusion of mathematically calculated cerebral blood flow (CBF) as an independent predictive variable in the risk score. Statistical analysis was based on clinical data from 254 preterm infants with gestational age between 23 and 30 weeks of pregnancy. Several risk scores were developed for different clinical situations. Their efficacy was tested using ROC analysis, and validation of the best scores was performed on an independent cohort of 63 preterm infants with equivalent gestational age. The inclusion of routinely measured clinical parameters significantly improved IVH prediction compared to models that included only obstetric parameters and medical diagnoses. In addition, risk assessment with numerically calculated CBF demonstrated higher predictive power than risk assessments based on standard clinical parameters alone. The best performance in the validation cohort (with AUC = 0.85 and TPR = 0.94 for severe IVH, AUC = 0.79 and TPR = 0.75 for all IVH grades and FPR = 0.48 for cases without IVH) was demonstrated by the risk score based on the MAP, pH, CRP, CBF and leukocytes count.