N-Terminal Fragment of Cardiac Myosin Binding Protein-C Increases the Duration of Actin-Myosin Interaction.

Cardiac myosin binding protein-C (cMyBP-C) located in the C-zone of myocyte sarcomere is involved in the regulation of myocardial contraction. Its N-terminal domains C0, C1, C2, and the m-motif between C1 and C2 can bind to the myosin head and actin of the thin filament and affect the characteristics of their interaction. Measurements using an optical trap showed that the C0-C2 fragment of cMyBP-C increases the interaction time of cardiac myosin with the actin filament, while in an in vitro motility assay, it dose-dependently reduces the sliding velocity of actin filaments.

CanB, a Druggable Cellular Target in .

Treatment against tuberculosis can lead to the selection of drug-resistant strains. To tackle this serious threat, new targets from are needed to develop novel effective drugs. In this work, we aimed to provide a possible workflow to validate new targets and inhibitors by combining genetic, , and enzymological approaches.

Dormancy: There and Back Again.

Many cells are capable of maintaining viability in a non-dividing state with minimal metabolism under unfavorable conditions. These are germ cells, adult stem cells, and microorganisms. Unfortunately, a resting state, or dormancy, is possible for tuberculosis bacilli in a latent form of the disease and cancer cells, which may later form secondary tumors (metastases) in different parts of the body.

[Dormancy: There and Back Again].

Many cells are capable of maintaining viability in a non-dividing state with minimal metabolism under unfavorable conditions. These are germ cells, adult stem cells, and microorganisms. Unfortunately, a resting state, or dormancy, is possible for tuberculosis bacilli in a latent form of the disease and cancer cells, which may later form secondary tumors (metastases) in different parts of the body.

Bioconversion of Renewable Plant Biomass. Second-Generation Biofuels: Raw Materials, Biomass Pretreatment, Enzymes, Processes, and Cost Analysis.

The review discusses various aspects of renewable plant biomass conversion and production of the second-generation biofuels, including the types of plant biomass, its composition and reaction ability in the enzymatic hydrolysis, and various pretreatment methods for increasing the biomass reactivity. Conversion of plant biomass into sugars requires the use of a complex of enzymes, the composition of which should be adapted to the biomass type and the pretreatment method. The efficiency of enzymatic hydrolysis can be increased by optimizing the composition of the enzymatic complex and by increasing the catalytic activity and operational stability of its constituent enzymes.

Tritium labelling to study humic substance-nanodiamond composites.

Nanodiamonds produced by the detonation method are used as lubricants, polishing compositions, polymer composites, etc. To reveal how nanodiamonds differ in terms of surface properties and interact with natural organic matter, we used tritium-labelled humic substances to quantitively describe their adsorption onto the nanodiamond surface. It was shown that the adsorption of humic substances onto nanodiamonds resulted in fractionation of humic substances that was strongly dependent on the zeta potential of nanodiamonds in water but did not significantly affect the uptake of nanodiamonds by wheat seedlings.

[Comprehensive study of the composition of fish fat extracts and quantitative criteria for distinguishing standardized omega-3 polyunsaturated fatty acids extracts].

Background Effects of drugs and biologically active supplements based on omega-3 polyunsaturated fatty acids (ω3 PUFA) considerably depend on the standardized content of eicosatetraenoic acid (EPA), docosahexaenoic acid (DHA), and other fatty acids in the extracts.Material and methods In this study, we comprehensively examined the composition of 10 ω3 PUFA samples with chromatographic measurement of more than 40 metabolites of fatty acids and other compounds. The data on extract composition were analyzed with current methods of intelligent data analysis (metric condensation method; multidimensional scaling; principal component analysis with axis identification; topology-metrical approach to recognition).

Optical Properties of Soil Dissolved Organic Matter Are Related to Acidic Functions of Its Components as Revealed by Fractionation, Selective Deuteromethylation, and Ultrahigh Resolution Mass Spectrometry.

The goal of this study was to establish a relationship between the optical properties of soil dissolved organic matter (DOM) and acidic functions carried out by its individual constituents. We obtained 12 fractions of DOM samples using sequential solid phase extraction on nonionic sorbent at steadily lowered pH values: 7, 5, 3, 2, which correspond to low bounds of p values of phenols, aliphatic, and aromatic carboxylic acids, and ketoacids. The structural studies were conducted with the use of NMR and selective deuteromethylation of isolated fractions coupled to ultrahigh resolution mass spectrometry.

Synthesis and applications of theranostic oligonucleotides carrying multiple fluorine atoms.

The use of various oligonucleotide (ON) syntheses and post-synthetic strategies for targeted chemical modification enables improving their efficacy as potent modulators of gene expression levels in eukaryotic cells. However, the search still continues for new approaches designed for increasing internalization, lysosomal escape, and tissue specific delivery of ON. In this review we emphasized all aspects related to the synthesis and properties of ON derivatives carrying multifluorinated (MF) groups.

Effect of Interchain Disulfide Crosslinking in the Tropomyosin Molecule on Actin-Myosin Interaction in the Atrial Myocardium.

Tropomyosin (Tpm) is one of the main regulatory proteins in the myocardium. In some heart pathologies, interchain disulfide crosslinking in the Tpm molecule occurs. In the ventricle, this change in the structural properties of the Tpm molecule affects calcium regulation of the actin-myosin interaction.

Structural-functional diversity of the natural oligopeptides.

Natural oligopeptides may regulate nearly all vital processes. To date, the chemical structures of many oligopeptides have been identified from >2000 organisms representing all the biological kingdoms. We have considered a number of mathematical (sequence length), chemical, physical, and biological features of an array of natural oligopeptides on the basis of the oligopeptide EROP-Moscow database (http://erop.

NOS2-deficient mice with hypoxic necrotizing lung lesions predict outcomes of tuberculosis chemotherapy in humans.

During active TB in humans a spectrum of pulmonary granulomas with central necrosis and hypoxia exists. BALB/c mice, predominantly used in TB drug development, do not reproduce this complex pathology thereby inaccurately predicting clinical outcome. We found that Nos2 mice incapable of NO-production in immune cells as microbial defence uniformly develop hypoxic necrotizing lung lesions, widely observed in human TB.

The antibacterial prodrug activator Rv2466c is a mycothiol-dependent reductase in the oxidative stress response of .

The gene encodes an oxidoreductase enzyme annotated as DsbA. It has a CPWC active-site motif embedded within its thioredoxin fold domain and mediates the activation of the prodrug TP053, a thienopyrimidine derivative that kills both replicating and nonreplicating bacilli. However, its mode of action and actual enzymatic function in have remained enigmatic.

Discovery of prenylated flavonoids with dual activity against influenza virus and Streptococcus pneumoniae.

Influenza virus neuraminidase (NA) is the primary target for influenza therapeutics. Severe complications are often related to secondary pneumonia caused by Streptococcus pneumoniae (pneumococci), which also express NAs. Recently, a NA-mediated lethal synergism between influenza A viruses and pneumococci was described.

Biocatalytic conversion of poultry processing leftovers: Optimization of hydrolytic conditions and peptide hydrolysate characterization.

Peptide hydrolysate (PH) was produced by deep controllable bioconversion of poultry processing leftovers (broiler necks), by means of a multienzyme composition, containing four commercially available enzyme preparations (Alcalase, Neutrase, Flavourzyme, Protamex). The design of multienzyme composition (MEC) was applied to yield a hydrolysate with adjusted properties, including minimized antigenicity and bitterness. The protein recovery was optimized using Box-Behnken response surface design.

Dormant non-culturable Mycobacterium tuberculosis retains stable low-abundant mRNA.

Background: Dormant Mycobacterium tuberculosis bacilli are believed to play an important role in latent tuberculosis infection. Previously, we have demonstrated that cultivation of M. tuberculosis in K(+)-deficient medium resulted in generation of dormant cells.

The Redox State Regulates the Conformation of Rv2466c to Activate the Antitubercular Prodrug TP053.

Rv2466c is a key oxidoreductase that mediates the reductive activation of TP053, a thienopyrimidine derivative that kills replicating and non-replicating Mycobacterium tuberculosis, but whose mode of action remains enigmatic. Rv2466c is a homodimer in which each subunit displays a modular architecture comprising a canonical thioredoxin-fold with a Cys(19)-Pro(20)-Trp(21)-Cys(22) motif, and an insertion consisting of a four α-helical bundle and a short α-helical hairpin. Strong evidence is provided for dramatic conformational changes during the Rv2466c redox cycle, which are essential for TP053 activity.

In Vivo Activity of the Benzothiazinones PBTZ169 and BTZ043 against Nocardia brasiliensis.

Background: Mycetoma is a neglected, chronic, and deforming infectious disease caused by fungi and actinomycetes. In Mexico, N. brasiliensis is the predominant etiologic agent.

Molecular mechanism of a specific capsid binder resistance caused by mutations outside the binding pocket.

Enteroviruses cause various acute and chronic diseases. The most promising therapeutics for these infections are capsid-binding molecules. These can act against a broad spectrum of enteroviruses, but emerging resistant virus variants threaten their efficacy.

Efflux-mediated resistance to a benzothiadiazol derivative effective against Burkholderia cenocepacia.

Burkholderia cenocepacia is a major concern for people suffering from cystic fibrosis as it contributes to serious respiratory tract infections. The lack of drugs effective against this opportunistic pathogen, along with the high level of resistance to multiple antibiotics, render the treatment of these infections particularly difficult. Here a new compound, belonging to the 2,1,3-benzothiadiazol-5-yl family (10126109), with a bactericidal effect and a minimal inhibitory concentration (MIC) of 8 μg/ml against B.

Heat-induced conformational changes of TET peptidase from crenarchaeon Desulfurococcus kamchatkensis.

The effects of heating on the structure and stability of multimeric TET aminopeptidase (APDkam589) were studied by differential scanning calorimetry, tryptophan fluorescence quenching, and dynamic light scattering. Thermally induced structural changes in APDkam589 were found to occur in two phases: local conformational changes, which occur below 70 °C and are not associated with thermal denaturation of the protein, and global structural changes (above 70 °C) induced by irreversible thermal unfolding of the protein accompanied by its spontaneous aggregation. These results may explain the bell-shaped temperature dependence with a maximum at ~70 °C previously observed for enzymatic activity of APDkam589.

Thiophenecarboxamide Derivatives Activated by EthA Kill Mycobacterium tuberculosis by Inhibiting the CTP Synthetase PyrG.

To combat the emergence of drug-resistant strains of Mycobacterium tuberculosis, new antitubercular agents and novel drug targets are needed. Phenotypic screening of a library of 594 hit compounds uncovered two leads that were active against M. tuberculosis in its replicating, non-replicating, and intracellular states: compounds 7947882 (5-methyl-N-(4-nitrophenyl)thiophene-2-carboxamide) and 7904688 (3-phenyl-N-[(4-piperidin-1-ylphenyl)carbamothioyl]propanamide).

The 8-Pyrrole-Benzothiazinones Are Noncovalent Inhibitors of DprE1 from Mycobacterium tuberculosis.

8-Nitro-benzothiazinones (BTZs), such as BTZ043 and PBTZ169, inhibit decaprenylphosphoryl-β-d-ribose 2'-oxidase (DprE1) and display nanomolar bactericidal activity against Mycobacterium tuberculosis in vitro. Structure-activity relationship (SAR) studies revealed the 8-nitro group of the BTZ scaffold to be crucial for the mechanism of action, which involves formation of a semimercaptal bond with Cys387 in the active site of DprE1. To date, substitution of the 8-nitro group has led to extensive loss of antimycobacterial activity.

Role of inter-domain cavity in the attachment of the orange carotenoid protein to the phycobilisome core and to the fluorescence recovery protein.

Using molecular modeling and known spatial structure of proteins, we have derived a universal 3D model of the orange carotenoid protein (OCP) and phycobilisome (PBS) interaction in the process of non-photochemical PBS quenching. The characteristic tip of the phycobilin domain of the core-membrane linker polypeptide (LCM) forms the attachment site on the PBS core surface for interaction with the central inter-domain cavity of the OCP molecule. This spatial arrangement has to be the most advantageous one because the LCM, as the major terminal PBS-fluorescence emitter, accumulates energy from the most other phycobiliproteins within the PBS before quenching by OCP.

2-Carboxyquinoxalines kill mycobacterium tuberculosis through noncovalent inhibition of DprE1.

Phenotypic screening of a quinoxaline library against replicating Mycobacterium tuberculosis led to the identification of lead compound Ty38c (3-((4-methoxybenzyl)amino)-6-(trifluoromethyl)quinoxaline-2-carboxylic acid). With an MIC99 and MBC of 3.1 μM, Ty38c is bactericidal and active against intracellular bacteria.