The Increased Amyloidogenicity of Spike RBD and pH-Dependent Binding to ACE2 May Contribute to the Transmissibility and Pathogenic Properties of SARS-CoV-2 Omicron as Suggested by In Silico Study

SARS-CoV-2 is a rapidly evolving pathogen that has caused a global pandemic characterized by several consecutive waves. Based on epidemiological and NGS data, many different variants of SARS-CoV-2 were described and characterized since the original variant emerged in Wuhan in 2019. Notably, SARS-CoV-2 variants differ in transmissibility and pathogenicity in the human population, although the molecular basis for this difference is still debatable. A significant role is attributed to amino acid changes in the binding surface of the Spike protein to the ACE2 receptor, which may facilitate virus entry into the cell or contribute to immune evasion. We modeled in silico the interaction between Spike RBDs of Wuhan-Hu-1, Delta, and Omicron BA.1 variants and ACE2 at different pHs (pH 5 and pH 7) and showed that the strength of this interaction was higher for the Omicron BA.1 RBD compared to Wuhan-Hu-1 or Delta RBDs and that the effect was more profound at pH 5. This finding is strikingly related to the increased ability of Omicron variants to spread in the population. We also noted that during its spread in the population, SARS-CoV-2 evolved to a more charged, basic composition. We hypothesize that the more basic surface of the Omicron variant may facilitate its spread in the upper respiratory tract but not in the lower respiratory tract, where pH estimates are different. We calculated the amyloidogenic properties of Spike RBDs in different SARS-CoV-2 variants and found eight amyloidogenic regions in the Spike RBDs for each of the variants predicted by the FoldAmyloid program. Although all eight regions were almost identical in the Wuhan to Gamma variants, two of them were significantly longer in both Omicron variants, making the Omicron RBD more amyloidogenic. We discuss how the increased predicted amyloidogenicity of the Omicron variants RBDs may be important for protein stability, influence its interaction with ACE2 and contribute to immune evasion.     

Complex Diagnostics of Non-Specific Intellectual Developmental Disorder

Intellectual development disorder (IDD) is characterized by a general deficit in intellectual and adaptive functioning. In recent years, there has been a growing interest in studying the genetic structure of IDD. Of particular difficulty are patients with non-specific IDD, for whom it is impossible to establish a clinical diagnosis without complex genetic diagnostics. We examined 198 patients with non-specific IDD from 171 families using whole-exome sequencing and chromosome microarray analysis. Hereditary forms of IDD account for at least 35.7% of non-specific IDD, of which 26.9% are monogenic forms. Variants in the genes associated with the BAF (SWI/SNF) complex were the most frequently identified. We were unable to identify phenotypic features that would allow differential diagnosis of monogenic and microstructural chromosomal rearrangements in non-specific IDD at the stage of clinical examination, but due to its higher efficiency, exome sequencing should be the diagnostic method of the highest priority study after the standard examination of patients with NIDD in Russia.     

Hepatoprotective Activity of Lignin-Derived Polyphenols Dereplicated Using High-Resolution Mass Spectrometry,In Vivo Experiments,and Deep Learning

Chronic liver diseases affect more than 1 billion people worldwide and represent one of the main public health issues. Nonalcoholic fatty liver disease (NAFLD) accounts for the majority of mortal cases, while there is no currently approved therapeutics for its treatment. One of the prospective approaches to NAFLD therapy is to use a mixture of natural compounds. They showed effectiveness in alleviating NAFLD-related conditions including steatosis, fibrosis, etc. However, understanding the mechanism of action of such mixtures is important for their rational application. In this work, we propose a new dereplication workflow for deciphering the mechanism of action of the lignin-derived natural compound mixture. The workflow combines the analysis of molecular components with high-resolution mass spectrometry, selective chemical tagging and deuterium labeling, liver tissue penetration examination, assessment of biological activity in vitro, and computational chemistry tools used to generate putative structural candidates. Molecular docking was used to propose the potential mechanism of action of these structures, which was assessed by a proteomic experiment.     

How to reach 100% selectivity in H2O2-based oxidation of 2,3,6-trimethylphenol to trimethyl-p-benzoquinone over Ti,Si-catalysts

A comprehensive study of structure/activity/selectivity relationships and mechanistic aspects of the oxidation of 2,3,6-trimethylphenol (TMP) with aqueous H₂O₂ over a wide variety of titanium-silicate catalysts allowed us to infer requirements to an optimal catalyst and optimal reaction conditions for this reaction and to produce 2,3,5-trimethyl-1,4-benzoquinone (TMBQ, Vitamin E precursor) with nearly 100% selectivity at 100% substrate conversion. The main by-products in the TMP oxidation are C–C and C–O dimers, formed by coupling of intermediate phenoxyl radicals. The formation of TMBQ is favoured by (1) a poor coordinating solvent (MeCN), (2) elevated temperature (80 °C), (3) low TMP concentration (not higher than 0.1 M), (4) high H₂O₂/TMP molar ratio (ca. 3.5), and (5) low TMP/Ti ratio (<10–20). The crucial factors which determine the selectivity of Ti,Si-catalysts in TMP oxidation to TMBQ are mesoporosity and an optimal surface concentration (ca. 0.7–1.0 Ti atoms/nm²) of accessible highly dispersed, probably, dimeric Ti(IV) species. The catalysts prepared by a simple, affordable and cheap synthesis methodology via grafting titanium(IV) precursors onto the surface of commercial mesoporous silica completely fulfil these requirements and thus can be viewed as promising catalysts for environmentally benign TMBQ production.     

Hydrothermal Solubilization–Hydrolysis–Dehydration of Cellulose to Glucose and 5-Hydroxymethylfurfural Over Solid Acid Carbon Catalysts

Solid acid catalysts based on graphite-like mesoporous carbon material Sibunit were developed for the one-pot solubilization–hydrolysis–dehydration of cellulose into glucose and 5-hydroxymethylfurfural (5-HMF). The catalysts were produced by treating Sibunit surface with three different procedures to form acidic and sulfo groups on the catalyst surface. The techniques used were: (1) sulfonation by H₂SO₄ at 80–250 °C, (2) oxidation by wet air or 32 v/v% solution of HNO₃, and (3) oxidation-sulfonation what meant additional sulfonating all the oxidized carbons at 200 °C. All the catalysts were characterized by low-temperature N₂ adsorption, titration with NaOH, TEM, XPS. Sulfonation of Sibunit was shown to be accompanied by surface oxidation (formation of acidic groups) and the high amount of acidic groups prevented additional sulfonation of the surface. All the Sibunit treatment methods increased the surface acidity in 3–15 times up to 0.14–0.62 mmol g^?1 compared to pure carbon (0.042 mmol g^?1). The catalysts were tested in the depolymerization of mechanically activated microcrystalline cellulose at 180 °C in pure water. The main products 5-HMF and glucose were produced with the yields in the range of 8–22 wt% and 12–46 wt%, respectively. The maximal yield were achieved over Sibunit sulfonated at 200 °C. An essential difference in the composition of main products obtained with solid acid Sibunit carbon catalysts (glucose, 5-HMF) and soluble in water H₂SO₄ catalysts (formic and levulinic acids) as well as strong dependence of the reaction kinetics on the morphology of carbon catalysts argue for heterogenious mechanism of cellulose depolymerization over Sibunit.     

Kinase CDK2 in Mammalian Meiotic Prophase I: Screening for Hetero- and Homomorphic Sex Chromosomes

Cyclin-dependent kinases (CDKs) are crucial regulators of the eukaryotic cell cycle. The critical role of CDK2 in the progression of meiosis was demonstrated in a single mammalian species, the mouse. We used immunocytochemistry to study the localization of CDK2 during meiosis in seven rodent species that possess hetero- and homomorphic male sex chromosomes. To compare the distribution of CDK2 in XY and XX male sex chromosomes, we performed multi-round immunostaining of a number of marker proteins in meiotic chromosomes of the rat and subterranean mole voles. Antibodies to the following proteins were used: RAD51, a member of the double-stranded DNA break repair machinery; MLH1, a component of the DNA mismatch repair system; and SUN1, which is involved in the connection between the meiotic telomeres and nuclear envelope, alongside the synaptic protein SYCP3 and kinetochore marker CREST. Using an enhanced protocol, we were able to assess the distribution of as many as four separate proteins in the same meiotic cell. We showed that during prophase I, CDK2 localizes to telomeric and interstitial regions of autosomes in all species investigated (rat, vole, hamster, subterranean mole voles, and mole rats). In sex bivalents following synaptic specificity, the CDK2 signals were distributed in three different modes. In the XY bivalent in the rat and mole rat, we detected numerous CDK2 signals in asynaptic regions and a single CDK2 focus on synaptic segments, similar to the mouse sex chromosomes. In the mole voles, which have unique XX sex chromosomes in males, CDK2 signals were nevertheless distributed similarly to the rat XY sex chromosomes. In the vole, sex chromosomes did not synapse, but demonstrated CDK2 signals of varying intensity, similar to the rat X and Y chromosomes. In female mole voles, the XX bivalent had CDK2 pattern similar to autosomes of all species. In the hamster, CDK2 signals were revealed in telomeric regions in the short synaptic segment of the sex bivalent. We found that CDK2 signals colocalize with SUN1 and MLH1 signals in meiotic chromosomes in rats and mole voles, similar to the mouse. The difference in CDK2 manifestation at the prophase I sex chromosomes can be considered an example of the rapid chromosome evolution in mammals.     

Folding of Right- and Left-Handed Three-Helix Proteins

We are the first to investigate the relationship between protein handedness and the rate of protein folding. Our findings demonstrate that small three-helix, left-handed proteins are less densely packed and should result in faster folding than that of right-handed, three-helix proteins. At the same time, right-handed, three-helix proteins have higher mechanical stability than the left-handed proteins. Moreover, from our analysis we have revealed that bacterial three-helix proteins have some advantages in packing over eukaryotic right-handed, three-helix proteins, which should result in faster folding.     

Co(II,III) Hydroxides Supported on Zeolite Acting as an Efficient and Robust Catalyst for Catalytic Water Oxidation with Ru(bpy)33+

Topics in Catalysis - A novel highly efficient and stable for many cycles catalyst (1% Со-ZSM-5(17)) for water oxidation was developed using the method of polycondensation for...     

New Investigations with Lupane Type A-Ring Azepane Triterpenoids for Antimycobacterial Drug Candidate Design

Twenty lupane type A-ring azepano-triterpenoids were synthesized from betulin and its related derivatives and their antitubercular activity against Mycobacterium tuberculosis, mono-resistant MTB strains, and nontuberculous strains Mycobacterium abscessus and Mycobacterium avium were investigated in the framework of AToMIc (Anti-mycobacterial Target or Mechanism Identification Contract) realized by the Division of Microbiology and Infectious Diseases, NIAID, National Institute of Health. Of all the tested triterpenoids, 17 compounds showed antitubercular activity and 6 compounds were highly active on the H37Rv wild strain (with MIC 0.5 µM for compound 7), out of which 4 derivatives also emerged as highly active compounds on the three mono-resistant MTB strains. Molecular docking corroborated with a machine learning drug-drug similarity algorithm revealed that azepano-triterpenoids have a rifampicin-like antitubercular activity, with compound 7 scoring the highest as a potential M. tuberculosis RNAP potential inhibitor. FIC testing demonstrated an additive effect of compound 7 when combined with rifampin, isoniazid and ethambutol. Most compounds were highly active against M. avium with compound 14 recording the same MIC value as the control rifampicin (0.0625 µM). The antitubercular ex vivo effectiveness of the tested compounds on THP-1 infected macrophages is correlated with their increased cell permeability. The tested triterpenoids also exhibit low cytotoxicity and do not induce antibacterial resistance in MTB strains.