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It is substantiated that the necessary institutional prerequisite for increasing the effectiveness of extended reproduction and economic development of natural resource potential is the modernization of the economic mechanism of nature use both at the national, regional and local levels, in particular in the part of the transformation of the system of fiscal regulation of the use of subsoil for the extraction of minerals. Studies have shown that the deepening of budget-fiscal decentralization requires more effective use of endogenous factors of socio-economic development of territorial communities, in the spectrum of which the increase in the effectiveness of fiscal regulation of subsoil use through the improvement of the methodology of extraction and distribution of rent for the use of subsoil is of particular importance. It was established that in the years 2007-2021, several phases of growth and decline are observed in the dynamics of rent payments for the use of subsoil to the local budgets of Ukraine, which correlates with the dynamics of socio-economic uplift, the impact of the global financial crisis on the national economy, changes in the percentages of deduction of mineral and raw materials rents to public financial funds of the respective territories. It has been proven that in the conditions of budgetary and fiscal decentralization, favorable conditions have been formed for increasing the share of rent deductions for subsoil use to local budgets, which will make it possible to form special financial funds for the reproduction of mineral and raw material potential and increase the interest of local self-government in its complex use. It is substantiated that the revision of the principles of subsoil use rents should be preceded by the modernization of the economic mechanism of nature use in terms of the diversification of payments for the extraction of minerals, and this will make it possible to ensure the equivalence of the extraction of mineral and raw material rents and its adequate distribution between public budgets of different taxonomic levels . Key words: economic mechanism of nature use, mineral and raw material rent, rent for subsoil use, local budgets, minerals, territorial community.

Modern development of territorial communities requires the creation of new modern approaches and the necessary conditions for their socioeconomic development on the basis of innovation and investment. The decentralization reform is aimed at creating additional financial resources in the regions, stimulating the management of local community development, launching new economic formations which are based on the transfer of power to the local government. The purpose of the study is to substantiate the theoretical and practical positions on the aim at the formation of agri-industrial parks in the territories of the United Territorial Communities (UTC) of Ukraine, which will promote the development of rural areas on an innovation and investment basis. The key tasks include: research of regional transformations of decentralization reform; analysis of factors of living standards and labor migration of the rural population; development of a human-centered model of development of territorial communities; analysis of ways to improve the social and financial situation in the community on the base of the results of a survey of local community deputies; determining the stages of implementation of the strategy of creating agri-industrial parks. The study is based on the following methods: monographic, graphic, abstract-logical, methods of analysis and synthesis. The authors propose mechanisms for launching a new type of entities formations in the territories of UTC of Ukraine – agri-industrial parks, which in the long run will promote the development of rural areas on an innovation and investment basis. The study of the field of common interests of stakeholders in this process confirmed the need for a joint dialogue between government and business structures in order to create a favorable innovation and investment climate in rural areas. A promising area of further research is the practical implementation of the proposed mechanisms in the context of regional development.

This article reveals the essence of the importance of involving modern youth in recreational activities, aspects of the formation of physical recreation in Ukraine, the concepts, forms, means and methods of physical recreation are characterized; features of use of motor activity within the limits of physical recreation are specified. Socio- economic changes in Ukraine have affected the health of the population. In addition to positive changes, there are negative phenomena in people's lives, in particular a decrease in life expectancy. Every year the number of students enrolled in special medical groups increases. Factors that negatively affect health should include the deterioration of socio-economic indicators, sanitary- epidemiological and environmental situation in our country, psycho-emotional overload, etc. Probably one of the main reasons for the deterioration of the health situation is the lack of financial and material support from the state to the recreational and health sphere, which leads to a certain physical inactivity. Most young people have a low level of physical activity and low interest in participating in recreational activities and fitness programs. The main reasons that prevent young people from engaging in physical activity are: lack of time, lack of interesting forms, financial problems, no friends for joint exercise, no knowledge for independent training, lack of desire, no sportswear, lack of reasoning for exercise. Most young people have severe hypokinesia, despite daily physical activity. Thus, it can be argued that in Ukraine, recreational and health activities have not become widespread and popular. Intensification of work in the direction of recreational and health activities of young people is extremely important, because the health of Ukrainians is getting worse, and the number of people involved in regular exercise and physical activity is getting smaller and smaller every year. Today, successful mastering of education is possible only with a sufficiently high level of health, and therefore taking into account the peculiarities of lifestyle, namely physical activity and a positive attitude to physical activity, is an important element of physical education for young people. [ABSTRACT FROM AUTHOR]

AlphaFold2 (AF2) models have had wide impact but mixed success in retrospective ligand recognition. We prospectively docked large libraries against unrefined AF2 models of the σ 2 and serotonin 2A (5-HT2A) receptors, testing hundreds of new molecules and comparing results with those obtained from docking against the experimental structures. Hit rates were high and similar for the experimental and AF2 structures, as were affinities. Success in docking against the AF2 models was achieved despite differences between orthosteric residue conformations in the AF2 models and the experimental structures. Determination of the cryo-electron microscopy structure for one of the more potent 5-HT2A ligands from the AF2 docking revealed residue accommodations that resembled the AF2 prediction. AF2 models may sample conformations that differ from experimental structures but remain low energy and relevant for ligand discovery, extending the domain of structure-based drug design.

AlphaFold2 (AF2) and RosettaFold have greatly expanded the number of structures available for structure-based ligand discovery, even though retrospective studies have cast doubt on their direct usefulness for that goal. Here, we tested unrefined AF2 models prospectively , comparing experimental hit-rates and affinities from large library docking against AF2 models vs the same screens targeting experimental structures of the same receptors. In retrospective docking screens against the σ 2 and the 5-HT2A receptors, the AF2 structures struggled to recapitulate ligands that we had previously found docking against the receptors' experimental structures, consistent with published results. Prospective large library docking against the AF2 models, however, yielded similar hit rates for both receptors versus docking against experimentally-derived structures; hundreds of molecules were prioritized and tested against each model and each structure of each receptor. The success of the AF2 models was achieved despite differences in orthosteric pocket residue conformations for both targets versus the experimental structures. Intriguingly, against the 5-HT2A receptor the most potent, subtype-selective agonists were discovered via docking against the AF2 model, not the experimental structure. To understand this from a molecular perspective, a cryoEM structure was determined for one of the more potent and selective ligands to emerge from docking against the AF2 model of the 5-HT2A receptor. Our findings suggest that AF2 models may sample conformations that are relevant for ligand discovery, much extending the domain of applicability of structure-based ligand discovery., Competing Interests: Competing interests B.K.S. is co-founder of BlueDolphin, LLC, Epiodyne, and Deep Apple Therapeutics, Inc., serves on the SRB of Genentech, the SAB of Schrodinger LLC and of Vilya Therapeutics, and consults for Levator Therapeutics, Hyku Therapeutics, and for Great Point Ventures. J.J.I. cofounded Deep Apple Therapeutics, Inc., and BlueDolphin, LLC. B.L.R is a co-founder of Epiodyne and Onsero and on the SAB for Onsero, Epiodyne, Levator, Escient and Septerna. A.C.K. is a cofounder and consultant for biotechnology companies Tectonic Therapeutic and Seismic Therapeutic, and also for the Institute for Protein Innovation, a nonprofit research institute. X.B.A is now a senior scientist at Tectonic Therapeutics

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoproliferative disorders, accounting for about 10 % of all non-Hodgkin lymphomas. The most common subtype is peripheral T-cell lymphoma, unclassified (PTCL-NOS), accounting for about 26 % of all PTCLs. PTCL-NOS is associated with less favorable overall survival (OS) and progression-free survival (PFS) compared with aggressive B-cell lymphomas. The role of radiation therapy in the treatment of PTCL-NOS is still not definitively defined. The results of many studies show that the addition of radiation therapy to the treatment regimen is associated with a significant improvement in survival in patients with early-stage PTCL-NOS, but in the later stages, the benefit of radiation therapy is not obvious., Objective: peripheral T-cell lymphoma, unspecified is a clinically and biologically heterogeneous disease with a poor prognosis. Since the role of radiation therapy is still unclear, a study was conducted to evaluate the effectiveness of radiation therapy in peripheral T-cell lymphoma, unspecified., Materials and Methods: The work is based on clinical observations and treatment results of patients who were diagnosed between 2013 and 2023 at the National Cancer Institute (in the period from 2020 to 2023, patients were observed and treated as part of research). 56 patients were included in the study., Results: The work analyzed the immediate results of the treatment of patients with peripheral T-cell lymphoma, unspecified depending on the stage and type of treatment, as well as the overall survival of these patients. When analyzing the overall response to the treatment of patients with I/II stages of the disease, it was proven that this indicator is higher in the group of patients who received chemoradiotherapy, compared to patients who received only chemotherapy (100 % versus 83.3 %), and this indicator was higher due to patients who demonstrated a complete response to therapy (75 % vs. 50 %). Analyzing the response to treatment of patients with III/IV stages of the pathological process, it was established that there was no difference in the overall response to treatment, the level of complete and partial response to treatment. Analysis of the overall survival of patients with I/II stages of the disease, with a median follow-up of 60 months, demonstrated a significant improvement in overall survival in the group of patients who received chemoradiotherapy compared to the group of patients who received only radiation therapy (median 48 vs. 22 months). Overall 1-year (78 % vs. 69 %), 3-year (64 % vs. 40 %), and 5-year (48 % vs. 35 %) were also higher in the chemoradiotherapy group. In the group of patients with III/IV stages of the disease, there was no difference in overall survival between patients who received chemoradiotherapy and patients who received only chemotherapy (median 16 vs. 13 months, 1-year survival 54 vs. 52, 3-year survival 33 vs. 30 and 5-year overall survival of 23 vs. 20 %., Conclusions: The addition of radiation therapy to the treatment plan demonstrated a significant improvement in the overall response and overall survival of patients with peripheral T-cell lymphomas, unspecified with I and II stages of the pathological process, but in III and IV stages of the disease, the benefit of radiation therapy has not been proven., (I. Kriachok, O. Aleksyk, I. Tytorenko, M. Bushuieva, Y. Moroz.)

The nonstructural protein 3 (NSP3) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contains a conserved macrodomain enzyme (Mac1) that is critical for pathogenesis and lethality. While small molecule inhibitors of Mac1 have great therapeutic potential, at the outset of the COVID-19 pandemic there were no well-validated inhibitors for this protein nor, indeed, the macrodomain enzyme family, making this target a pharmacological orphan. Here, we report the structure-based discovery and development of several different chemical scaffolds exhibiting low- to sub-micromolar affinity for Mac1 through iterations of computer-aided design, structural characterization by ultra-high resolution protein crystallography, and binding evaluation. Potent scaffolds were designed with in silico fragment linkage and by ultra-large library docking of over 450 million molecules. Both techniques leverage the computational exploration of tangible chemical space and are applicable to other pharmacological orphans. Overall, 160 ligands in 119 different scaffolds were discovered, and 152 Mac1-ligand complex crystal structures were determined, typically to 1 Å resolution or better. Our analyses discovered selective and cell-permeable molecules, unexpected ligand-mediated protein dynamics within the active site, and key inhibitor motifs that will template future drug development against Mac1.

The unparalleled global effort to combat the continuing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic over the last year has resulted in promising prophylactic measures. However, a need still exists for cheap, effective therapeutics, and targeting multiple points in the viral life cycle could help tackle the current, as well as future, coronaviruses. Here, we leverage our recently developed, ultra-large-scale in silico screening platform, VirtualFlow, to search for inhibitors that target SARS-CoV-2. In this unprecedented structure-based virtual campaign, we screened roughly 1 billion molecules against each of 40 different target sites on 17 different potential viral and host targets. In addition to targeting the active sites of viral enzymes, we also targeted critical auxiliary sites such as functionally important protein-protein interactions., Competing Interests: M.C. and V.D. report working for Innophore. C.C.G. reports being a shareholder and CEO of Innophore, an enzyme and drug discovery company. G.W. and C.G. report being co-founders of the company Virtual Discovery, Inc., which provides virtual screening services. G.W. reports serving as the director of this company. G.W. reports being a co-founder of PIC Therapeutics, Cellmig Biolabs, and Skinap Therapeutics. H.A. reports being an equity holder in PIC Therapeutics. I.I. and D.R. report working for Enamine, a company that is involved in the synthesis and distribution of chemical building blocks, fragments, and screening compounds. Y.M. reports being a scientific advisor for Enamine. Y.M., O.T., and A.P. report working for Chemspace, a company that is involved in the distribution of chemical building blocks, fragments, and screening compounds. I.D. reports working for UkrOrgSyntez Ltd. (UORSY), a company that is involved in the synthesis of chemical building blocks, fragments, and screening compounds. G.T., S.P., A.S., M.G., N.L., C.H., E.Y., R.L., R.Y., D.P., and J.K. report working for Google, a company that also provides cloud computing services. The research described here is scientifically and financially independent of the efforts in any of the above mentioned companies., (© 2020 The Author(s).)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), previously known as 2019 novel coronavirus (2019-nCoV), has spread rapidly across the globe, creating an unparalleled global health burden and spurring a deepening economic crisis. As of July 7th, 2020, almost seven months into the outbreak, there are no approved vaccines and few treatments available. Developing drugs that target multiple points in the viral life cycle could serve as a strategy to tackle the current as well as future coronavirus pandemics. Here we leverage the power of our recently developed in silico screening platform, VirtualFlow, to identify inhibitors that target SARS-CoV-2. VirtualFlow is able to efficiently harness the power of computing clusters and cloud-based computing platforms to carry out ultra-large scale virtual screens. In this unprecedented structure-based multi-target virtual screening campaign, we have used VirtualFlow to screen an average of approximately 1 billion molecules against each of 40 different target sites on 17 different potential viral and host targets in the cloud. In addition to targeting the active sites of viral enzymes, we also target critical auxiliary sites such as functionally important protein-protein interaction interfaces. This multi-target approach not only increases the likelihood of finding a potent inhibitor, but could also help identify a collection of anti-coronavirus drugs that would retain efficacy in the face of viral mutation. Drugs belonging to different regimen classes could be combined to develop possible combination therapies, and top hits that bind at highly conserved sites would be potential candidates for further development as coronavirus drugs. Here, we present the top 200 in silico hits for each target site. While in-house experimental validation of some of these compounds is currently underway, we want to make this array of potential inhibitor candidates available to researchers worldwide in consideration of the pressing need for fast-tracked drug development., Competing Interests: Alexander Chuprina, Dmytro Radchenko,  and Iryna Iavniuk work for Enamine, Kyiv Ukraine. Igor Dziuba works for UkrOrgSyntez Ltd, Kyiv Ukraine. Olga Tarkhanova, Alla Plekhova, and Yurii Moroz work for Chemspace Kyiv, Ukraine. Enamine, UkrOrgSyntez, and Chemspace are companies that are involved in the synthesis and distribution of drug-like compounds. Yurii Moroz is a scientific advisor for Enamine.

Wstęp: Badanie przeprowadzono w celu wyjaśnienia wpływu Z56822977 na biosyntezę serotoniny w mózgu szczurów z otyłością wy-wołaną podawaniem glutaminianu sodu (monosodium glutamate, MSG). Materiał i metody: W badaniu wykorzystano 18 samców szczura. Zwierzęta podzielono na trzy grupy: 1 - grupa kontrolna, 2 - grupa MSG, 3 - grupa MSG + Z56822977. Szczurzym oseskom w grupie 2 i 3 podawano podskórnie MSG rozpuszczony w soli fizjologicznej w dawce 4 mg/g masy ciała w objętości 8 μl/g w 2., 4., 6., 8. i 10. dniu życia. Grupie 3 podawano doustnie wodny roztwór Z56822977 w dawce 25 mg/kg w objętości 1 ml/kg. Pierwszą dawkę Z56822977 podawano po ukończeniu 4 tygodni życia, a następnie kontynuowa-no podawanie badanej substancji cyklicznie wedlug schematu tydzień podawania substancji badanej/3 tygodnie przerwy. Zwierzętom z grupy MSG podawano odpowiednio 1 ml/kg wody doustnie. Przez pierwsze 4 miesiące życia szczury otrzymywały standardową karmę. Zmierzono zawartość serotoniny, tryptofanu i 5-hydroksytryptofanu (5-HTr) oraz aktywność hydroksylazy tryptofanowej (tryptophan hydroxylase, TRH), dekarboksylazy aminokwasów (amino acid decarboxylase, AADC) i monoaminooksydazy (MAO) w tkance mózgowej. WYNIKI: Wykazano, że podawanie Z56822977 ma pozytywny wpływ na główne wskaźniki otyłości, co odzwierciedlają zmiany podsta-wowych parametrów fizjologicznych i biochemicznych [zmniejszenie masy ciała o 13% vs. MSG (p < 0,05); zmniejszenie wskaźnika masy ciała (body mass index, BMI), wskaźnika Lee oraz masy tkanki tłuszczowej trzewnej odpowiednio o 18%, 7% i 55%, (p < 0,05) w porównaniu z grupą MSG]. Zawartość tryptofanu i serotoniny była istotnie niższa (p < 0,05) u szczurów z otyłością wywołaną przez MSG. W badaniach wykazano, że u otyłych szczurów aktywność MAO zwiększa się o 97% (p < 0,05), a aktywność TRH i AADC odpowiednio o 44% i 53% (p < 0,05). Podawanie Z56822977 powodowało zwiększenie zawartości serotoniny i tryptofanu w mózgach szczurów i przywracało poziom aktywności enzymów (MAO, TRH, AADC) do wartości mierzonych u zwierząt kontrolnych. WNIOSKI: Wiadomo, że otyłość wiąże się z zaburzeniem syntezy serotoniny w mózgu szczurów. Jednak podawanie Z56822977 prowadzi do normalizacji stężenia serotoniny i tryptofanu oraz przywrócenia prawidłowej aktywności enzymów uczestniczących w biosynte-zie i degradacji serotoniny. Podawanie Z56822977, cząsteczki wpływającej na układ serotoninergiczny, może powodować korzystne efekty w leczeniu otyłości wywołanej przez MSG u szczurów. Można rozważać zastosowanie cząsteczki Z56822977 jako nowego leku stosowanego w otyłości, jednak konieczne są dalsze badania w celu potwierdzenia jej działania.