Lithium is the most effective mood stabilizer for the treatment of bipolar disorder, but it is toxic at only twice the therapeutic dosage and has many undesirable side effects. It is likely that a small molecule could be found with lithium-like efficacy but without toxicity through target-based drug discovery; however, lithium’s therapeutic target remains equivocal. Inositol monophosphatase is a possible target but no bioavailable inhibitors exist. Here we report that the antioxidant ebselen inhibits inositol monophosphatase and induces lithium-like effects on mouse behaviour, which are reversed with inositol, consistent with a mechanism involving inhibition of inositol recycling. Ebselen is part of the National Institutes of Health Clinical Collection, a chemical library of bioavailable drugs considered clinically safe but without proven use. Therefore, ebselen represents a lithium mimetic with the potential both to validate inositol monophosphatase inhibition as a treatment for bipolar disorder and to serve as a treatment itself.

SUMMARY The RNA polymerase II (RNAPII) carboxyl-terminal domain (CTD) heptapeptide repeats (Y1-S2-P3-T4-S5-P6-S7) undergo dynamic phosphorylation and dephosphorylation during the transcription cycle to recruit factors that regulate transcription, RNA processing and chromatin modification. We show here that RPRD1A and RPRD1B form homodimers and heterodimers through their coiled-coil domains and interact preferentially via CTD interaction domains (CIDs) with CTD repeats phosphorylated at S2 and S7. Our high resolution crystal structures of the RPRD1A, RPRD1B and RPRD2 CIDs, alone and in complex with CTD phosphoisoforms, elucidate the molecular basis of CTD recognition. In an interesting example of cross-talk between different CTD modifications, our data also indicate that RPRD1A and RPRD1B associate directly with RPAP2 phosphatase and, by interacting with CTD repeats where phospho-S2 and/or phospho-S7 bracket a phospho-S5 residue, serve as CTD scaffolds to coordinate the dephosphorylation of phospho-S5 by RPAP2.

RNA polymerase II transcribes both protein coding and non-coding RNA genes and, in yeast, different mechanisms terminate transcription of the two gene types. Transcription termination of mRNA genes is intricately coupled to cleavage and polyadenylation, whereas transcription of small nucleolar (sno)/small nuclear (sn)RNA genes is terminated by the RNA-binding proteins Nrd1, Nab3 and Sen1. The existence of an Nrd1-like pathway in humans has not yet been demonstrated. Using the U1 and U2 genes as models, we show that human snRNA genes are more similar to mRNA genes than yeast snRNA genes with respect to termination. The Integrator complex substitutes for the mRNA cleavage and polyadenylation specificity factor complex to promote cleavage and couple snRNA 3′-end processing with termination. Moreover, members of the associated with Pta1 (APT) and cleavage factor I/II complexes function as transcription terminators for human snRNA genes with little, if any, role in snRNA 3′-end processing. The gene-specific factor, proximal sequence element-binding transcription factor (PTF), helps clear the U1 and U2 genes of nucleosomes, which provides an easy passage for pol II, and the negative elongation factor facilitates termination at the end of the genes where nucleosome levels increase. Thus, human snRNA genes may use chromatin structure as an additional mechanism to promote efficient transcription termination in vivo.

This paper examines the economic efficiency of Russian special economic zones (SEZs) established by federal authorities since 2005. The results are mixed: the payback of SEZs is low, but they continue to attract residents; SEZs have greater attractiveness for foreign investment, but their sectoral structure is fundamentally no better than the country-wide structure; SEZs' enterprises have higher labour productivity than the country, but mainly owing to their recent creation. The common bottlenecks of SEZ development are the instability of legislation on SEZs, the low level of federal authorities' activity in SEZ development before the economic crisis, competition with other preferential regimes for investors and the long period of searching for the optimal system of SEZ management. Differences in the efficiency of particular SEZs are explained by the peculiarities of the territories where SEZs are established. SEZs are successful if they are created on sites that enjoy a favourable geographic position and in regions that have advanced levels of industrial development.

An attempt was made to test the hypothesis that regular physical activity at the anaerobic thresh old can stimulate an increase in the amount of brown or beige body fat, which can manifest itself in increased lactate utilization during exercise and increased reactivity in response to acute regional cooling. The methods used in the study included the ramp test; regional acute cold exposure; measurement of gas exchange; lactate and glucose in the blood; heart rate; heart rate, blood pressure, and respiration variability at rest and during standard functional tests; infrared thermal imaging; and statistical methods of analysis of results. Training of ten physically active volunteers (7 males and 3 females) on a treadmill at a speed corresponding to 75-80% of personal maximum oxygen consumption ( ) for 30 min 3 times per week at a fixed ambient temper ature of 21-22°C for 6 weeks resulted in a significant (from 19 to 39%) increase in exercise duration in the ramp test, whereas changed, on average, only slightly. The increase in the anaerobic threshold power was associated with a sharp slowdown in the accumulation of lactate during the ramp test. The lactate utili zation rate during the recovery period, on the contrary, increased. In general, work efficiency during test load significantly increased. Noticeable changes in the condition and responses to the standard functional tests of the autonomic system were not found, as judged by the heart rate variability, blood pressure, and respiration variability at rest and during orthostatic tests and imposed breathing rhythm. The functional response of the body to acute cold exposure (1 min cooling of the feet in ice water) did not change after a cycle of training, both in terms of metabolism (oxygen consumption, etc.) and the skin temperature dynamics in the areas of most probable location of brown adipose tissue (BAT). These data do not confirm our previous hypothesis (2010) about the function of BAT as a universal homeostatic instrument in the body. Probably, if the forma tion of the beige adipose tissue is stimulated by physical activity and hormone irisin, produced by muscles, this tissue is involved in lactate utilization but is not involved in the thermoregulatory responses.

The impact of coronavirus on the socio-economic development of Russian regions inevitably depends on the structure of their economy, which is analyzed in the article on the basis of official data on the employment structure. The contribution of different sectors of the economy (primary, secondary, and tertiary), the role of informal employment and the budget sector, and the share of employment in the most affected industries are evaluated. Not only short-term, but also long-term structural problems of the regional economy are highlighted. It is shown that the negative impact of coronavirus mainly on the service sector in the context of the Russian Federation subjects is evident in federal cities, in economically underdeveloped regions with an underdeveloped real sector of the economy, as well as regions that specialize in certain types of services (tourism, foreign trade, complex services). For economically underdeveloped regions, the impact of coronavirus is deepened by a high share of the informal sector (which limits the possibility of obtaining state support), but is softened by an increased share of employees who receive wages from the budget system. The reduced share of the service sector in agricultural regions means that they are less dependent on coronavirus, but it confirms the need to develop the service sector as a basis for improving the quality of life of the population. At the same time, almost everywhere there is a need to restructure the service sector: reducing the role of simple services (primarily trade), in favor of complex ones related to high technologies and innovations and to the social sphere, especially health.

We use hand-collected data on a sample of German public firms during 2011-2014 to show that firms use currency derivatives more often when they export or import, and especially when exchange-rate fluctuations are larger, but to a lesser extent when having high export and import shares simultaneously. We interpret this finding as evidence of operational hedging that arises as foreign-denominated revenues and costs match, and substitutes for financial hedging. Our identification strategy uses both cross-sectional heterogeneity in exchange-rate exposures and time-series variation in exchange-rate fluctuations. We highlight the importance of examining operating strategies as integral determinants of corporate financing policies.

Introduction. Extract of goji berries (Lycium Barbarum L.) and buckwheat flour (Fagopýrum esculéntum L.) possess antioxidant and antimicrobial properties. As a result, they can be used to improve traditional Kazakh horse-meat formulations to obtain functional cooked and smoked meat products. These natural biologically active substances can improve the oxidative stability of pigments, lipids, and proteins of finished products. The research objective was to assess the potential of goji extract and buckwheat flour as additives that can improve the oxidative stability and general quality of Kanagat, a national Kazakh cooked and smoked horse-meat product. Goji extract and buckwheat flour were used in two concentrations – 0.5% and 1.0%. Study objects and methods. The research featured sensory evaluation of taste, smell, color, determination of color parameters (L*, a*, b*), pH, free amine nitrogen, total carbonyl proteins, acid value, peroxide value and thiobarbituric acid reactive substances (TBARS), as well as a histological analysis. Results and discussion. When 1.0% of goji extract and 1.0% of buckwheat flour were added to the traditional formulation, it improved the oxidative stability and quality of the modified horse-meat product while preserving its sensory properties and colour parameters. A set of microstructural studies showed that the processing of meat products with 1.0% of goji extract and 1.0% of buckwheat flour had a destructive effect on most fibers. The affected fibers showed multiple decays of myofibrillar substance, which turned into a finegrained protein mass. The abovementioned concentration caused effective inhibition of hydrolytic changes, as well as oxidation of proteins and lipids. Conclusion. The new technology made it possible to produce a new national horse-meat product fortified with 1.0% of goji extract and 1.0% of buckwheat flour. The specified amount of biologically active additives improved the oxidative stability and quality of the product, while maintaining its sensory and color characteristics.