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PURPOSE: Increased glucocorticoid receptor (GR) signaling is a proposed compensatory mechanism of resistance to androgen receptor (AR) inhibition in metastatic castration-resistant prostate cancer (mCRPC). ORIC-101 is a potent and selective orally-bioavailable GR antagonist. PATIENTS AND METHODS: Safety, pharmacokinetic/pharmacodynamic, and antitumor activity of ORIC-101 in combination with enzalutamide were studied in patients with mCRPC progressing on enzalutamide. ORIC-101 doses ranging from 80 to 240 mg once daily were tested in combination with enzalutamide 160 mg once daily. Pharmacokinetics/pharmacodynamics was assessed after a single dose and at steady state. Disease control rate (DCR) at 12 weeks was evaluated at the recommended phase 2 dose (RP2D). RESULTS: A total of 41 patients were enrolled. There were no dose-limiting toxicities and the RP2D was selected as 240 mg of ORIC-101 and 160 mg of enzalutamide daily. At the RP2D, the most common treatment-related adverse events were fatigue (38.7%), nausea (29.0%), decreased appetite (19.4%), and constipation (12.9%). Pharmacokinetic/pharmacodynamic data confirmed ORIC-101 achieved exposures necessary for GR target engagement. Overall, for 31 patients treated at the RP2D, there was insufficient clinical benefit based on DCR (25.8%; 80% confidence interval: 15.65-38.52) which did not meet the prespecified target rate, leading to termination of the study. Exploratory subgroup analyses based on baseline GR expression, presence of AR resistance variants, and molecular features of aggressive variant prostate cancer suggested possible benefit in patients with high GR expression and no other resistance markers, although this would require confirmation. CONCLUSIONS: Although the combination of ORIC-101 and enzalutamide demonstrated an acceptable tolerability profile, GR target inhibition with ORIC-101 did not produce clinical benefit in men with metastatic prostate cancer resistant to enzalutamide.

Cow’s milk is an important food product for humans since it has a complex chemical composition and high nutritional value. Over 140 fatty acids, including linoleic, linolenic and arachidonic acids, were found in milk’s lipid profile. Milk is rich in minerals and contains almost all fat-soluble and water-soluble vitamins. Milk proteins are a complete source of all essential amino acids for humans. Approximately 78 % of the total amount of protein in milk is casein. Beta-casein is one of the most important proteins in cow’s milk, accounting for up to 35 % of all milk proteins. It is believed that the A2A2 allele of the β-casein gene allows animals to produce а more nutritionally valuable milk since in this case, during the cleavage of β-casein in the human gastrointestinal tract, β-casomorphin-7 is either not produced or is produced in much smaller (trace) amounts than in the case of the А1А1 allele, which makes the process of milk digestion more physiological. Research has shown a link between β-casomorphin-7 and a variety of negative effects that occur both directly in the gastrointestinal tract and throughout the human body, contributing to the development of numerous pathologies, in particular type 1 diabetes mellitus, cardiac diseases, and various neurological disorders. A comprehensive study involving preschool children demonstrated that replacing regular milk with milk containing only A2А2 β-casein led to a significant reduction in complications associated with gastrointestinal intolerance as well as to improved cognitive functions.

Urbanisation presents both challenges and opportunities for bat populations. Understanding the composition and distribution of urban bat species is the first step toward their effective conservation. However, comprehensive studies on urban bat diversity remain scarce in Bulgaria. To address this gap, we conducted a year-long acoustic survey on five different habitats in the urbanised territory of Veliko Tarnovo. Our study identified the presence of eight bat species and other distinct acoustic groups within the urban environment. Bats were found to utilise various habitats across the urban landscape. Although the activity was highest during May and September, bats remained active all year round, including the winter. Our study provides insights into synanthropic bats’ seasonal and microhabitat-dependent use of urban areas. These findings will establish a baseline for future research focusing on habitat preferences, population dynamics, and interactions with urbanisation. Such research is essential for the effective management and conservation of bat populations in urban environments.

Oral non-tobacco nicotine products have gained enormous popularity in recent years. The countries of the Eurasian Economic Union also produce and sell this type of innovative but poorly studied goods. As a result, the safety profile and quality of such products as nicotine poaches require urgent comprehensive research. This study featured the changes in quality of nicotine poaches during storage, i.e. nicotine content, water activity, and microbiological index. The research featured nicotine poaches of several popular brands. The authors used standard research methods; the experiments were performed in the laboratory for chemistry and quality control, Institute of Tobacco, Makhorka, and Tobacco Products, Krasnodar, and at the Department of Bioorganic Chemistry and Technical Microbiology, Kuban State Technological University, Krasnodar. The water activity was 0.8911–0.9502 Aw at the initial stage and remained stable in most samples even after six months of storage. Velo Freeze was the only brand to show significant variations in water activity. The nicotine content was 10.115–12.950 mg/g at the initial stage. Only four samples maintained the initial values after six months of storage. The fluctuations of nicotine content were also mentioned by the manufacturer. The microbiological profile remained stable during the six months of storage and met the requirements for similar products, i.e., chewing gum and unglazed caramel. The project needs further research because the qualitative characteristics of nicotine poaches provided rather unambiguous results. Our study will help develop state standards for oral nicotine products. The results obtained will be used to formulate proposals to the organizations responsible for the future Technical Regulations of the Eurasian Economic Union for nicotine products.

Introduction. Traction calculations take into account additional resistance to train motion from the action of undercarriage generators using statistical data from field tests of rolling stock samples. Comparative analysis of calculated and actual results shows system deviations with real fuel and energy consumption exceeding the calculated values.Materials and methods. The analysis and detailing involved data of the memory block of the electric locomotives microprocessor control and diagnostic system, transcripts of the integrated train safety system and locomotive technical radio communication system. The authors applied methods of data array approximation and extrapolation, numerical integration, statistical data processing, and the method of energy-optimal traction calculation.Results. Traction calculation of the influence of undercarriage generators on resistance to movement shows that fuel and energy consumption exceeds the consumption without the influence of generators by 15% in average. The researchers found that the intensity of electrical equipment use in passenger cars has a variable effect on the performance of undercarriage generators. Most notably, the research prompted a new way of determining the resistance to motion from undercarriage generators.Discussion and conclusion. This method of estimating the additional resistance to train motion from undercarriage generators can be scaled to various train movement problems solved with statistical data using mathematical models. The algorithm developed by the authors would find its application in the systems of calculation, analysis and planning of fuel and energy resources consumption.

The relations of the UK with the majority of Latin American and Caribbean states are not marked by traumatic narratives directly related to colonial dependence, but in recent years the problem of repatriation of cultural objects has become more acute: indigenous communities and civil activists are putting pressure on the British government and museums to return cultural property to the countries of origin. The factor that mitigates the confrontational nature of the problem is the proactive policy of British museums aimed at implementing joint projects with indigenous communities of Latin American and Caribbean states. Nevertheless, many of them are aimed at promoting Western narratives and approaches to the «decolonization of art». British museums also make a major contribution to the dissemination of information about the history and culture of Latin American peoples, both to tourists from around the world and to South American diasporas in the UK. At the same time, as a multipolar international order is being formed, the impact of the problem of repatriation of cultural objects on the UK’s relations with Latin American and Caribbean states will increase: the lack of an effective international legal framework to resolve these contradictions will become more and more acute. A potential method of reducing the resulting tension in the bilateral relations between London and Latin American and Caribbean states may be the transfer of objects on long-term lease or voluntary withdrawal of the British side from the possession of artifacts — in case appropriate changes in the domestic legislation of Great Britain are made.

Introduction. The structure of dihydroquercetin (DHQ) is characterized by two chiral centers at positions 2 and 3 of the benzopyran cycle, resulting in possible diastereomers: trans- and cis-isomers. Therefore, the development of methods for qualitative and quantitative control of DHQ diastereomers in analyzed samples is essential for patient safety management. Nuclear magnetic resonance (NMR) spectroscopy is one of the physicochemical methods that can be used for this purpose.Aim. The study objective was to accumulate the analytical and structural characteristics of cis-DHQ by NMR spectroscopy of the spheroidal form of this flavonoid (DHQs).Materials and Methods. 1D 1H, 1H,1H-COSY, 1H,1H-NOESY, and 1H,13C-HSQC NMR spectra were acquired at 298 K on an 800 MHz NMR spectrometer equipped with a TXI triple resonance probe. The number of scans was 32. The mixing time in the NOESY experiment was 400 ms. The 1H and 13C were analyzed using CcpNmr software. The dihedral angles were calculated by applying the Karplus equation.Results and discussion. In trans-DHQ, the chemical shift values for H2 and H3 are 4.93 ppm and 4.52 ppm, respectively, and in cis-DHQ they are 5.31 ppm and 4.20 ppm, respectively. The spin-spin coupling constants between H2 and H3 of trans- and cis-DHQ are 12.00 Hz and 2.40 Hz, respectively. Thus, the dihedral angles for the trans- and cis-isomers are 154° and 64°, respectively. We found that DHQs contains 12.5 % of the cis-isomer.Conclusion. Our experiments confirmed that NMR spectroscopy can discriminate between trans- and cis-DHQ based on the chemical shift values for the cross-peaks of H2 and H3. The second major finding was that this method can be considered as a more selective quantitative analysis than HPLC with UV detection without reference. One of the most important results of this study for drug development is the updated information on the structural parameters of DHQ diastereomers in the liquid phase.

This paper explores the effect of internal technological defects on the fatigue life of carbon fiber reinforced plastic (CFRP) under simple loading waveforms. One conducted experiments on CFRP specimens with embedded artificial defects, including delamination’s (circular dry-spot) and wrinkling. Following quasi-static tests, one developed a fatigue testing program using triangular and sine waveforms. The findings indicate that these simple waveforms do not significantly affect the fatigue resistance of defect-free CFRP or CFRP with internal technological defects. The presence of the wrinkling defect significantly diminishes the fatigue resistance of CFRP. However, constructing fatigue life curves in relative terms reveals that the reduction in fatigue properties is directly related to a decrease in strength properties. In the case of delamination (dry-spot) defects, a reduction in fatigue life by approximately 2.5 times was observed across the tested range.

Проаналізовано критичне ставлення Г. Сковороди до масового суспільства з характерним йому антропологічним типом «плотської людини». Доведено, що осуд і прагнення витіснити спільноту «рабів плоті» доповнюється прагненням до її духовної трансформації з метою єднання з Богом у духовному середовищі серця. Осудження «плотського роду» разом із «плотською людиною» в обрії християнської думки визнається одним з аспектів персоналізації людини і суспільства. Виконане дослідження поширює й поглиблює трактування християнського персоналізму як фундаменту філософії Г. Сковороди у зв’язку з її співвіднесеністю з аскетичною критикою масового суспільства.

To accelerate the implementation of zero-emission power installations based on proton-exchange membrane fuel cells, it is necessary to maximize the power characteristics of these devices. For this purpose, we have obtained and tested a new N-doped carbon support and a synthesized Pt/C catalyst based on it with a platinum loading of about 37.3 %. A comparison of the degradation resistance of the initial support and the N-doped one has shown greater stability of the latter. At the same time, Raman spectroscopy has confirmed the presence of the C–N bond, which indicates the successful doping of carbon with nitrogen. The resulting Pt/C catalyst based on an N-doped support is characterized by a substantially narrow size dispersion and an ultra-small nanoparticle size of about 2.6 nm. The high-angle annular dark-field scanning transmission electron microscopy images of the synthesized catalyst have confirmed the presence of individual platinum atoms/clusters uniformly distributed over the surface of the support, and their presence is due to nitrogen embedded into the carbon structure. This material is characterized by a 50 m2 gPt-1 larger electrochemically active surface area and a 227 A gPt-1 greater mass activity compared to the commercial JM40 analog (40 % platinum loading). Meanwhile, the electrochemical parameters remaining after the accelerated stress testing are almost 2 times higher than those of JM40. And the power characteristics in the membrane electrode assembly for the catalyst synthesized by the facile one-pot synthesis method are 13 % (575 mW cm-2) higher than those of the commercial analog (500 mW cm-2). The Pt/C catalyst obtained during the research is deemed promising for commercial use in proton-exchange membrane fuel cells.

The subject of mathematical study and modelling in this paper is an inbound call center that receives calls initiated by customers. A closed exponential queueing network with customer retrials and impatient customers is used as a stochastic model of call processing. A brief review of published results on the application of queueing models in the mathematical modeling of customer service processes in call centers is discussed. The network model is described. The possible customer states, customer routing, parameters, and customer service features are given. The allocation of customers by network nodes at a fixed time fully describes the situation in the call center at that time. The state of the network model under study is represented by a continuous-time Markov chain on finite state space. The model is studied in the asymptotic case under the critical assumption of a large number of customers in the queueing network. The mathematical approach used makes it possible to use the passage to the limit from a Markov chain to a continuous-state Markov process. It is proved that the probability density function of the model state process satisfies the Fokker – Planck – Kolmogorov equation. Using the drift coefficients of the Fokker – Planck – Kolmogorov equation, a system of ordinary differential equations for calculating the expected number of customers in each network node over time can be written. The solution of this system allows for predicting the dynamics of the expected number of customers at the model nodes and regulating the parameters of the call center operation. The asymptotic technique used is applicable both in transient and steady states. The areas of implementation of research results are the design of call centers and the analysis of their workload.

The paper studies the concept of «virtual real estate», the market of which is developing against the backdrop of the emergence of metaverses. The current trend in the development of the Internet involves the merging of gaming and social life, which forms a huge, rapidly growing economy of consumption of virtual goods. The main factor in adjusting the trend of digital development is the evolution of the interaction between the Internet and users, therefore, the article initially considered the features and distinctive features of web 1.0, web 2.0, web 3.0. The technical solutions that distinguish web 3.0 are shown, contributing to the expansion of opportunities for involving consumers in the virtual world and the formation of their own virtual economy. Further, the concept of «metaverse» is investigated, key characteristics are highlighted. It has been established that the metaverse is a hybrid of the virtual and physical worlds, creating a space for communication, life and work. The metaverse market is growing, which makes it attractive to investors, one of the ways to invest for which is to purchase virtual land and real estate. Virtual real estate cannot be touched, but it has value, increases in price, which makes it an attractive investment. The purchase of virtual real estate is carried out for real money. Virtual real estate is a piece of land in a virtual space on which it is possible to build objects and participate in the game. The article is an opportunity to understand what virtual real estate is – another global scam or an attractive investment.