Well-being and health of the nation - the higher value of the state

Алкоголизм не перестаёт быть одновременно и медицинской и нравственной проблемой.Alcoholism does not cease to be both a medical and a moral problem. The main purpose of the article is to study the impact of alcohol consumption on development and health

The issues of prevention of addictive behavior among students

В статье анализируются методы профилактика аддиктивного поведения в студенческой среде.The article analyzes the methods of prevention of addictive behavior among students

Protein engineering of a ubiquitin-variant inhibitor of APC/C identifies a cryptic K48 ubiquitin chain binding site.

Ubiquitin (Ub)-mediated proteolysis is a fundamental mechanism used by eukaryotic cells to maintain homeostasis and protein quality, and to control timing in biological processes. Two essential aspects of Ub regulation are conjugation through E1-E2-E3 enzymatic cascades and recognition by Ub-binding domains. An emerging theme in the Ub field is that these 2 properties are often amalgamated in conjugation enzymes. In addition to covalent thioester linkage to Ub's C terminus for Ub transfer reactions, conjugation enzymes often bind noncovalently and weakly to Ub at "exosites." However, identification of such sites is typically empirical and particularly challenging in large molecular machines. Here, studying the 1.2-MDa E3 ligase anaphase-promoting complex/cyclosome (APC/C), which controls cell division and many aspects of neurobiology, we discover a method for identifying unexpected Ub-binding sites. Using a panel of Ub variants (UbVs), we identify a protein-based inhibitor that blocks Ub ligation to APC/C substrates in vitro and ex vivo. Biochemistry, NMR, and cryo-electron microscopy (cryo-EM) structurally define the UbV interaction, explain its inhibitory activity through binding the surface on the APC2 subunit that recruits the E2 enzyme UBE2C, and ultimately reveal that this APC2 surface is also a Ub-binding exosite with preference for K48-linked chains. The results provide a tool for probing APC/C activity, have implications for the coordination of K48-linked Ub chain binding by APC/C with the multistep process of substrate polyubiquitylation, and demonstrate the power of UbV technology for identifying cryptic Ub-binding sites within large multiprotein complexes

Controlling opioid receptor functional selectivity by targeting distinct subpockets of the orthosteric site

Controlling receptor functional selectivity profiles for opioid receptors is a promising approach for discovering safer analgesics; however, the structural determinants conferring functional selectivity are not well understood. Here, we used crystal structures of opioid receptors, including the recently solved active state kappa opioid complex with MP1104, to rationally design novel mixed mu (MOR) and kappa (KOR) opioid receptor agonists with reduced arrestin signaling. Analysis of structure-activity relationships for new MP1104 analogs points to a region between transmembrane 5 (TM5) and extracellular loop (ECL2) as key for modulation of arrestin recruitment to both MOR and KOR. The lead compounds, MP1207 and MP1208, displayed MOR/KOR Gi-partial agonism with diminished arrestin signaling, showed efficient analgesia with attenuated liabilities, including respiratory depression and conditioned place preference and aversion in mice. The findings validate a novel structure-inspired paradigm for achieving beneficial in vivo profiles for analgesia through different mechanisms that include bias, partial agonism, and dual MOR/KOR agonism

The issues of prevention of addictive behavior among students

В статье анализируются методы профилактика аддиктивного поведения в студенческой среде.The article analyzes the methods of prevention of addictive behavior among students

Well-being and health of the nation - the higher value of the state

Алкоголизм не перестаёт быть одновременно и медицинской и нравственной проблемой.Alcoholism does not cease to be both a medical and a moral problem. The main purpose of the article is to study the impact of alcohol consumption on development and health

Antimicrobial Potential of the Alkalophilic Fungus Sodiomyces alkalinus and Selection of Strains–Producers of New Antimicotic Compound

Abstract The ability of alkalophilic micromycetes of the species Sodiomyces alkalinus to produce antimicrobial compounds was studied. As a result of the determination of the spectrum and yield of antibiotic compounds, a promising producer of the antimycotics Sodiomyces alkalinus was selected from the most active strains 8KS17-10. The producer exhibited antifungal activity against opportunistic fungi, as well as pathogenic clinical isolates of molds and yeasts—pathogens of systemic mycoses. The isolated active compound can be attributed to the group of antimicrobial glycopeptides based on the totality of the identified structural features (molecular weight, absorption ratio at certain wavelengths). </jats:sec