Search

Inhibition of soluble epoxide hydrolase (sEH) is a promising therapeutic strategy for treating neuropathic pain. These inhibitors effectively reduce diabetic neuropathic pain and inflammation induced by Freund's adjuvant which makes them a suitable alternative to traditional opioids. This study showcased the notable analgesic effects of compound AMHDU (1,1'-(hexane-1,6-diyl)bis(3-((adamantan-1-yl)methyl)urea)) in both inflammatory and diabetic neuropathy models. While lacking anti-inflammatory properties in a paw edema model, AMHDU is comparable to celecoxib as an analgesic in 30 mg/kg dose administrated by intraperitoneal injection. In a diabetic tactile allodynia model, AMHDU showed a prominent analgesic activity in 10 mg/kg intraperitoneal dose (p < 0.05). The effect is comparable to that of gabapentin, but without the risk of dependence due to a different mechanism of action. Low acute oral toxicity (>2000 mg/kg) and a high therapeutic index makes AMHDU a promising candidate for further structure optimization and preclinical evaluation.

Series of 1,3-disubstituted ureas and diadamantyl disubstituted diureas with fluorinated and chlorinated adamantane residues were shown to inhibit human soluble epoxide hydrolase (sEH) with inhibition potency ranging from 40 pM to 9.2 nM. The measured IC50 values for some molecules were below the accuracy limit of the existing in vitro assays. Such an increase in activity was achieved by minimal structural modifications to the molecules of known inhibitors, including 4-[trans-4-(1-adamantylcarbamoylamino)cyclohexyl]oxybenzoic acid. For the chlorinated homologue of the latter the sharp jump in inhibitory activity can be (according to molecular dynamics data) the result of interactions - Cl-π interaction. Considering the extremely high inhibitory activity, acceptable solubility and partial blockage of metabolically sensitive centres in their structures, some compounds are of interest for further in vivo biotesting.

The purpose of the research is to study the features of the development of the market of industrial medical products in the context of digitalization and transition to Industry 5.0, as well as to analyze the impact of digital technologies on economic relations in this sector. The relevance of the work is due to the global processes of digital transformation and the need to adapt medical markets to new technological challenges, which is particularly important in the context of import substitution and the desire for technological sovereignty. The research methodology includes a mixed method of analysis, which combines quantitative and qualitative approaches. The authors used statistical data, analytical reports and materials covering current trends and dynamics in the global and Russian markets. Special attention is paid to analyzing the competitiveness of the Russian medtech market and the role of digital technologies in its development. The main results include: 1) characterization of the features of the global and Russian medtech markets in the conditions of digital transformation management and Industry 5.0; 2) identification of key trends, such as the active introduction of artificial intelligence, telemedicine and IoT, as well as their impact on the structure and dynamics of the market; 3) development of recommendations for managing the development of the medtech market, including the concepts of circular transformation and ecosystem approach; 4) proposal to use the Living Labs concept as an effective tool to accelerate the implementation of innovations. The scientific novelty of the work lies in the system analysis of the convergence of Industry 5.0 principles and digitalization in the medtech sector, as well as in the proposal of new approaches to market management, taking into account global and local challenges. The practical value of the paper lies in proposing recommendations for the strategic development of the medtech market in the context of the digital economy. The conclusions confirm that Industry 5.0 creates new opportunities for the development of the medtech sector, but also requires active actions in innovation management and cooperation between science and industry. Future research directions include in-depth analysis of the role of living labs and ecosystems in accelerating technovation in the medtech market.

A series of soluble epoxide hydrolase (sEH) inhibitors containing halogenated pyrazoles was developed. Inhibition potency of the obtained compounds ranges from 0.8 to 27.5 nM. 1-Adamantyl-3-[(4,5-dichloro-1-methyl-1Н-pyrazol-3-yl)methyl]urea (3f, IC50 = 0.8 nM) and 1-[(Adamantan-1-yl)methyl]-3-[(4,5-dichloro-1-methyl-1Н-pyrazol-3-yl)methyl]urea (4f, IC50 = 1.2 nM) were found to be the most potent sEH inhibitors within the described series.

The article develops strategic recommendations for improving the management practices of integrating modern scientific achievements into the processes of sustainable development of industrial ecosystems, adapted to the requirements and challenges of Industry 5.0. The concept of industrial EICSG-ecosystem in the context of Industry 5.0 is developed, combining elements of environmental (E - environmental), intellectual (I - intelligent), cyber-social (CS - cyber-social) and governance (G - governance) resilience. The conceptual components of effective development of industrial EICSG ecosystems, which form the organisational basis of Industry 5.0, are proposed. The prerequisites of strategic management of the industrial EICSG ecosystem of Industry 5.0 are defined.

For efficient business functioning, the organisation's management needs to adopt and approve the organisation's strategy based on the ability to reduce or completely bypass possible risks associated with the influence of the external environment. The development of technology has facilitated the emergence of completely new business models that have seriously simplified the consumption process by reducing the time it takes to transfer goods from multiple sellers to the customer. But from the point of view of organisations specialising in a narrow segment of goods the situation can be more complex, because with the simplification of communication there are many competitors within one site, the strategic behaviour of a limited number of competitors can be calculated with the help of existing mathematical models or with the help of game theory, but when there are so many competitors that we cannot identify them all, one of the most difficult types of uncertainty appears - the uncertainty of ignorance. The solution to this problem is to increase the interconnectedness in the different fields of action of the organisation. By increasing the interconnections, namely their number, firstly, there is an opportunity to expand the activities of the organisation in several subsystems, thus allowing diversification of risks, and secondly, we acquire a large number of stakeholders in different subsystems, who will be interested in the long-term retention of the organisation at a sufficient level of efficiency. It is the increased interconnectedness that contributes to the necessary sustainability in the strategic perspective, as well as compensating and distributing the growing external uncertainty between the activities in the different subsystems.

Adamantyl ureas are good soluble epoxide hydrolase (sEH) inhibitors; however they have limited solubility and rapid metabolism, thus limiting their usefulness in some therapeutic indications. Herein, we test the hypothesis that nodal substitution on the adamantane will help solubilize and stabilize the compounds. A series of compounds containing adamantane derivatives and isoxazole functional groups were developed. Overall, the presence of methyl on the nodal positions of adamantane yields higher water solubility than previously reported urea-based sEH inhibitors while maintaining high inhibition potency. However, it did not improve microsomal stability.

The main purpose of this study was the comparison of the results of quantification obtained via different sample preparation approaches such as microwave‐assisted wet digestion (MAWD) and suspension preparation. Two total reflection x‐ray fluorescence (TXRF) spectrometers equipped with Mo x‐ray tubes were used to compare results obtained via two different paths of sample preparations which would further be compared to the conventional way of analysis by inductively coupled plasma optical emission spectrometry (ICP‐OES) including MAWD. Three dietary supplement samples with different sets and concentrations of elements were analyzed. The benefits and limitations of the simplified path of sample preparation were highlighted. A round‐robin test between TXRF and ICP‐OES was discussed. Accuracy as the percentage of recovery in all measurements ranged from 80 to 120. Precision for all results did not exceed 8% for TXRF and 5% for ICP‐OES. Limits of quantification by TXRF are ranged from 1 to 0.01 mg/pill for different elements. It was shown that suspension preparation of samples might be a useful response to increasing demand for quality control of dietary supplements since it is less time consuming and cost efficient. [ABSTRACT FROM AUTHOR]

We assessed the effect of ground fires on the success of advanced regeneration of tree species on gentle hilly ridges of terminal moraines of the North-Eastern part of the Leningrad Region. To study the juvenile generation of tree species, we carried out a reconnaissance survey of transects in the forest areas affected by wildfires. The forest stands were 10–12 years old. The stem numbers and heights of the regenerating tree species were recorded. The correlation analysis was used to determine the degree of influence of external factors on forest regeneration, including soil conditions and the burnt area size. We found differences in the species composition of stands with a predominance of deciduous and coniferous species depending on soil and hydrological conditions. We also found a relationship between soil factors and spruce and pine regeneration size in stands with a predominance of coniferous and deciduous species. The soil granulometric composition influenced proportions of coniferous and deciduous trees in post-fire stands. Using the knowledge obtained about the stand composition, we can forecast the future development of forest stands and prescribe the optimal forest management regimes.

Soluble epoxide hydrolase (sEH) is an enzyme involved in the metabolism of bioactive lipid signaling molecules. sEH converts epoxyeicosatrienoic acids (EET) to virtually inactive dihydroxyeicosatrienoic acids (DHET). The first acids are "medicinal" molecules, the second increase the inflammatory infiltration of cells. Mitogen-activated protein kinases (p38 MAPKs) are key protein kinases involved in the production of inflammatory mediators, including tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2). p38 MAPK signaling plays an important role in the regulation of cellular processes, especially inflammation. The proto-oncogenic serine/threonine protein kinase Raf (c-Raf) is a major component of the mitogen-activated protein kinase (MAPK) pathway: ERK1/2 signaling. Normal cellular Raf genes can also mutate and become oncogenes, overloading the activity of MEK1/2 and ERK1/2. The development of multitarget inhibitors is a promising strategy for the treatment of socially dangerous diseases. We synthesized 1,3-disubstituted ureas and diureas containing a dichloroadamantyl moiety. The results of computational methods show that soluble epoxide hydrolase inhibitors can act on two more targets in different signaling pathways of mitogen-activated protein kinases p38 MAPK and c-Raf. The two chlorine atoms in the adamantyl moiety may provide additional Cl-π interactions in the active site of human sEH. Molecular dynamics studies have shown that the stability of ligand–protein complexes largely depends on the "spacer effect." The compound containing a bridge between the chloroadamantyl fragment and the ureide group forms more stable ligand–protein complexes with sEH and p38 MAPK, which indicates a better conformational ability of the molecule in the active sites of these targets. In turn, a compound containing two chlorine atoms forms a more stable complex with c-Raf, probably due to the presence of additional halogen bonds of chlorine atoms with amino acid residues. [ABSTRACT FROM AUTHOR]

The objects of research were potato meristem plants of the Charoite variety, mass and the number of mini-tubers grown on the “Agrobalt S” peat fertilizer and in a mixture of “ORVI” and biochar substrate in a closed greenhouse. A statistically significant effect of the use of this substrate and biochar on the increase in the number of standard mini-tubers relative to the control variant using only peat soil was established. The yield of standard tubers (9 – 60 mm) was 78 % when using “Agrobalt S” peat soil; 10 % of the substrate "ORVI" and 5 % of biochar, 78 %; 20 % of the substrate “ORVI” and 5 % of biochar, 77 %. A decrease in the standard material of mini-tubers of the Charoite variety against the background of an increase in quantitative indicators does not occur when using the substrate and biochar. Evaluation of latent viral infection of meristem plants and mini-tubers grown from them was performed by ELISA (Sandwich variant) in July and February and did not reveal latent infection in any of the variants. The determination of growing parameters was carried out a month after harvesting and showed that mini-tubers in all variants had no signs of the late blight disease, rhizoctonia disease, common scab, etc.

In Northwest Russia, creation and introduction of new varieties of cereals characterized by early maturity, high adaptive potential and ecological plasticity is one of the most important tasks. A new generation of barley varieties is needed that combines high yields with early maturity, high feed qualities of grain, and resistance to lodging and grain shedding. We carried out field and laboratory studies of a new variety of spring barley Fermerskiy in an experimental field of the Leningrad Research Institute of Agriculture "Belogorka". In 2021, Fermersky was transferred for state variety testing. The variety is midseason and the growing season is 72–87 days. Over three years of competitive variety testing (2018–2020), the yield increase was 1.25 t/ha relative to the Suzdalets standard (3.12 t/ha). The highest yield of 5.27 t/ha was obtained in 2019, under conditions of low moisture supply. The average index of ecological plasticity (Jsp) was 1.48 (min 1.11, max 1.94). The adaptive potential (ds/dk) was 7.91 (min 6.92, max 9.08), The Fermerskiy variety consistently formed a high yield and was characterized by ecological plasticity, early maturity, and resistance to diseases and lodging.

The formation of primary experimental material was carried out in the form of production seeding and field experiments. Among a large number of indicators assessing certain parameters of soil fertility from the point of view of fertility reproduction, stable characteristics determining agronomic soil value are of the highest importance For sod-podzolic soils, such characteristics are the granulometric composition, the content of organic matter and available forms of mineral nutrition elements, the acidity level. The impact on these indicators determines the effectiveness of soil improvement measures. Based on the generalization of experimental data, on the mathematical and statistical methods, the optimal parameters of these properties for specific crops were determined. To improve and manage soil fertility, it is also necessary to further develop special regulations related to soil enrichment with elements aimed at mineral nutrition of plants and humus. There are complex relationships between the doses of fertilizers and the specific accumulation of the relevant substances, which should be studied in special experiments.

Creation of productive and plastic varieties of spring barley (Hordeum vulgare L.) resistant to adverse weather factors will improve the efficiency of grain production in conditions of low fertility of sodpodzolic soils in the Leningrad region in Russia. The purpose of the study was to determine the environmental plasticity and adaptation features of the new line of spring barley in comparison with the standards: Suzdalets variety (nutans variety) and Leningradsky variety (pallidum variety). The main abiotic stressors for spring barley plants are increased acidity and low supply with plant nutrients, drought followed with excess moisture at the end of the growing season. Field, laboratory, and statistical methods generally accepted for these studies were used in this work. Using the ecological plasticity index (Isp) and the generative to reproductive organs length ratio ds /dk simplifies the task of evaluating hybrids, lines, and varieties. Genotype-environment interaction is a complex process both in its nature and in intensity. The selection of promising variety samples is aimed at isolating genotypes for which the influence of this interaction is minimal. Of particular importance in the selection of spring barley is the creation of varieties with a genetically determined mechanism of protection against adverse environmental factors.

The article presents the analysis of the results of a long-term experiment on studying the effectiveness of the combination of the doses of lime and mineral fertilizers on sod-podzolic sandy loam soil in crop rotation in the Leningrad region. Research experiments are carried out in the six-field crop rotation. The data obtained in the course of long-term stationary field experiments are more reliable and accurate compared to the results of model experiments. The liming and long-term uses of mineral fertilizers affect the crop nutrition pattern and the migration capacity of substances in soils. The application of moderate doses of mineral fertilizers during soil liming increases the number of bacterial microflora. Liming significantly increases the nitrification capacity of the soil. Liming of strongly acidic sod-podzolic soils increases the amount of phosphorus and fertilizers the crops take from soil. Calcium, which is a part of phosphorus fertilizers, is essential for acid-sensitive crops. The optimal reaction level for crop development is not constant. In case of a good crops supply with nutrients, the optimal reaction level shifts to a more assiduous area. As a result, the knowledge of the process patterns occurring in the soil under the influence of anthropogenic agricultural activity was obtained. The data obtained are the key to control the soil evolution during its agricultural use.

A one-stage method for the preparation of 1-[isocyanato(phenyl)methyl]adamantane containing a phenylmethylene fragment located between the adamantane fragment and the isocyanate group, and 1-[isocyanato(phenyl)methyl]-3,5-dimethyladamantane with additional methyl groups at the nodal positions of adamantane, with a yield of 95% and 89%, respectively, is described. The method includes the direct inclusion of an adamantane moiety through the reaction of phenylacetic acid ethyl ester with 1,3-dehydroadamantane or 3,5-dimethyl-1,3-dehydroadamantane followed by the hydrolysis of the obtained esters. The reaction of 1-[isocyanato(phenyl)methyl]adamantane with fluorine(chlorine)-containing anilines gave a series of 1,3-disubstituted ureas with 25–85% yield. 1-[Isocyanato(phenyl)methyl]-3,5-dimethyladamantane was involved in the reactions with fluorine(chlorine)-containing anilines and trans-4-amino-(cyclohexyloxy)benzoic acid to obtain another series of ureas with a yield of 29–74%. The resulting 1,3-disubstituted ureas are promising inhibitors of the human soluble epoxide hydrolase (hsEH). [ABSTRACT FROM AUTHOR]

In econometrics the same data set is typically used to select the model and to estimate the parameters in the selected model. In applied econometrics practice, however, one typically acts as if the model had been given a priori, thus ignoring the fact that the estimators are in fact pretest estimators. Hence one assumes incorrectly that the estimator is unbiased, and that the reported variance, conditional on the selected model, is equal to its unconditional variance. In this paper, we find the unconditional first and second moments of the pretest estimator (in fact, of a more general estimator, the WALS estimator), taking full account of the fact that model selection and estimation are an integrated procedure, and show that the error in not reporting the correct moments can be large. We also show that this error can vary substantially between different model selection procedures. Finally, we ask how the error increases when the number of auxiliary regressors increases. JEL classification: C13; C51 Keywords': Pretest estimator; Model selection; Mean squared error

In econometrics the same data is usually selected for both model selection and forecasting. The flaws in the methodology are explained and a better alternative, the 'neutral Laplace estimator' is presented for stock market forecasting.