Mutations in Francisella tularensis, decreasing the virulence of these bacteria and leading to a change in the immune response upon infection of experimental animals with them]

The research was aimed at isolation of Francisella tularensis mutants possessing the decreased virulence for experimental animals and mediating the changes in the animal immune response. A number of spontaneous and induced mutants of the American and European subtypes of Francisella tularensis were selected for antibiotics resistance or detergent sensitivity. All the obtained mutants have the decreased virulence and differ in their ability to induce the protective antitularemia immunity or ability to induce the humoral immune response in the laboratory animals. The dimeric immunoprecipitation in gel as well as immunoblotting have shown the mutations decreasing the virulence to cause the loss by bacteria of a number of antigenic structures (in case the virulence is completely lost) or changes in antigenic structure resulting in inability of bacteria to induce the humoral immune response when immunizing the laboratory animals. The latter occurs in partially virulent mutants of the vaccine mutant type. The concomitant changes in virulence, ability to cause protective immunity or humoral immune response of the mutants is discussed.     

Change in distribution of mobile genetic elements in genome of <Emphasis Type="Italic">Drosophila melanogaster</Emphasis>: Cause or consequence of selection for quantitative traits?

The distribution pattern of the hobo transposon and Dm412 retrotransposon hybridization sites on the salivary gland polytene chromosomes from larvae of the Drosophila melanogaster isogenic strain 51 used to analyze the effect of the transposition of transposable elements (TEs) on selection for quantitative traits was studied. It was shown that no more than half of the Dm412 hybridization sites were retained 15 years after isogenization; the frequency of the Dm412 transposition varied from 2.0 × 10⁻⁴ to 8.8 × 10⁻⁵ sites per genome for generation depending on whether the appearance of the same hybridization sites in a part of individuals was considered as independent events or as the manifestation of the appearing sample heterogeneity. The distribution patterns of hobo hybridization sites in two isofemale strains derived from the isogenic strain 51 differed much more markedly; the number of the hobo sites in one of the derivative strains was threefold smaller than in the other one and only some of the sites were common. Within each derivative strain, the TE distribution was uniform, which suggests that inbreeding had no effect on Dm412 activity in this strain. The rates of change in the distribution patterns of various TE in the strain 51 corresponded to their spontaneous transposition rates. Since the isogenic strain accumulates polymorphism in the TE distribution without selection, the TEs are more likely to be the markers of selection events rather than their inducers. Thus, when studying the effects of various environmental factors on TE transposition even in isogenic strains, it is necessary to perform additional close inbreeding to reduce the potential polymorphism.     

Improved procedure of the search for poly(ADP-Ribose) polymerase-1 potential inhibitors with the use of the molecular docking approach

A search for poly(ADP-ribose) polymerase-1 inhibitors by virtual screening of a chemical compound database and a subsequent experimental verification of their activities have been performed. It was shown that the most efficient method to predict inhibitory properties implies a combinatorial approach joining molecular docking capabilities with structural filtration. Among more than 300000 low molecular chemical compounds, 9 PARP1 inhibitors were revealed; the most active ones, namely, STK031481, STK056130, and STK265022, displayed biological effect at a micromolar concentration (IC₅₀ = 2.0, 1.0, and 2.6 μM, respectively).     

Usnic acid derivatives are effective inhibitors of tyrosyl-DNA phosphodiesterase 1

The synthesis of (+)-usnic acid derivatives is described. The derivatives contain one or two cyano groups, connected to the acetophenone fragment of dibenzofuran core by linkers of different length and character, or some other modifications. The influence of these compounds on the activity of recombinant human tyrosyl-DNA phosphodiesterase 1 and MCF-7 tumor cells’ viability has been estimated. The data indicate a distinct dependence of functional characteristics of the compounds on their structure.     

Seasonal changes in the levels of various metabolites and proteins in cow milk and colostrum

The studies on lactating black-and-white cows have shown that the content of albumins as well as of lactate, ammonia and glutamate in colostrum and milk of cows is higher in winter and spring but the level of beta- and gamma-globulins, citrate and urea is lower than the analogous indices in cows in summer. The concentration of alpha-globulins, oxaloacetate, malate and pyruvate in colostrum and milk did not change with the season.     

Synthesis of a series of NAD<Superscript>+</Superscript> analogues,potential inhibitors of PARP 1, using ADP conjugates functionalized at the terminal phosphate group

A convenient approach has been proposed to the synthesis of nicotinamide adenine dinucleotide (NAD⁺) mimetics, which comprise morpholino analogues of nucleosides. The approach is based on the use of ADP conjugates containing an amino group, which is tethered to the terminal phosphate through the aliphatic linker by the phosphodiester bond. We have synthesized four series of the NAD⁺ mimetics, which differ in the type of the modified nucleoside (2-aminomethylmorpholine (Mor) or 2-aminomethyl-4-carboxymethylmorpholine (MorGly) derivatives), in the linker length, and in the manner of the nucleoside attachment to the ADP derivative. We have studied the efficiency of NAD⁺ mimetics in the inhibition of the auto-poly(ADP-ribosyl)ation by the PARP 1 enzyme. The linker length, the mode of the attachment of the morpholino nucleoside analogue, and the nature of the heterocyclic base of the modified nucleoside were shown to inf luence the inhibition efficiency.