Elena Goncharova

Female scent signals enhance the resistance of male mice to influenza.

Background The scent from receptive female mice functions as a signal, which stimulates male mice to search for potential mating partners. This searching behavior is coupled with infection risk due to sniffing both scent marks as well as nasal and anogenital areas of females, which harbor bacteria and viruses. Consideration of host evolution under unavoidable parasitic pressures, including helminthes, bacteria, viruses, etc., predicts adaptations that help protect hosts against the parasites associated with mating. Methods and Findings We propose that the perception of female signals by BALB/c male mice leads to adaptive redistribution of the immune defense directed to protection against respiratory infection risks. Our results demonstrate migration of macrophages and neutrophils to the upper airways upon exposure to female odor stimuli, which results in an increased resistance of the males to experimental influenza virus infection. This moderate leukocyte intervention had no negative effect on the aerobic performance in male mice. Conclusions Our data provide the first demonstration of the adaptive immunological response to female odor stimuli through induction of nonspecific immune responses in the upper respiratory tract.

Influenza virus inactivated by artificial ribonucleases as a prospective killed virus vaccine

The inactivation of viral particles with agents causing minimal damage to the structure of surface epitopes is a well-established approach for the production of killed virus vaccines. Here, we describe new agents for the inactivation of influenza virus, artificial ribonucleases (aRNases), which are chemical compounds capable of cleaving RNA molecules. Several aRNases were identified, exhibiting significant virucidal activity against the influenza A virus and causing a minimal effect on the affinity of monoclonal antibodies for the inactivated virus. Using a murine model of the influenza virus infection, a high protective activity of the aRNase-inactivated virus as a vaccine was demonstrated. The results of the experiments demonstrate the efficacy of novel chemical agents in the preparation of vaccines against influenza and, perhaps, against other infections caused by RNA viruses.

Novel amphiphilic compounds effectively inactivate the vaccinia virus

Recent studies demonstrated the ability of artificial ribonucleases (aRNases, small organic RNA cleaving compounds) to inactivate RNA‐viruses via the synergetic effect of viral RNA cleavage and disruption of viral envelope [1,2]. Herein, we describe the antiviral activity of aRNases against DNA‐containing vaccinia virus: screening of aRNases of various structures revealed that amphiphilic compounds built of positively charged 1,4‐diazabicyclo[2.2.2] octane substituted at the bridge nitrogen atoms with aliphatic residues efficiently inactivate this virus. The first stage was the destruction of viral membrane and structure of surface proteins (electron microscopy data). Thus, 1,4‐diazabicyclo[2.2.2] octane‐based aRNases are novel universal agents inactivating both RNA‐ and DNA‐containing viruses.

Chimeric antibodies against tick-borne encephalitis virus

Two chimeric antibodies (ch) 13D6 and 10C2 against the glycoprotein E of tick-borne encephalitis virus (TBEV) were constructed by fusing variable regions of murine monoclonal antibodies (Mabs) 13D6 and 10C2 to human constant regions. Monovalent analogues of these antibodies in format of single-chain antibodies (scFv or sc) were developed, as well. The ch13D6, ch10C2, sc13D6 and sc10C2 exhibited binding characteristics similar to parental Mabs. Only the ch13D6 and sc13D6 were able to neutralize TBEV infectivity in vitro. The in vitro neutralization provided by ch13D6 suggests that this antibody can be further developed into a potent prophylaxis and therapy for tick-borne encephalitis (TBE) infection.

BIRTH OF THE SHAPE OF A REACHABLE SET

We address a linear control system under geometric constraints on control and study its reachable sets starting at zero time from the origin. The main result is the existence of a limit shape of the reachable sets as the terminal time tends to zero. Here, a shape of a set stands for the set regarded up to an invertible linear transformation. Both autonomous and nonautonomous cases are considered.

Antitumor effect of the LIVP-GFP recombinant vaccinia virus

248 Virotherapy using genetically modified viruses is a rapidly progressing field of research in the treatment of neoplastic diseases [1]. Genetically modified viruses, notably herpes simplex virus, adenovirus, vaccinia virus (VACV), and others have been obtained that can replicate only in tumor cells under artificial conditions and, therefore, have no effect on normal cells [1]. Cur rently, clinical trials of the different recombinant onc olytic viruses are carried out: phase I of the clinical tri als of recombinant adenovirus has been completed, phases I and II of the clinical trials of recombinant oncolytic vaccinia viruses are under research, and phase III of the clinical trials of recombinant herpes simplex virus has started [2]. As a result, the antitumor effect of the recombinant viruses and the safety for the patients was demonstrated.

LIMIT SHAPES OF REACHABLE SETS FOR LINEAR IMPULSE CONTROL SYSTEMS

Abstract The main purpose of the paper is to study the asymptotic behavior of reachable sets to linear time-invariant impulsive control systems. The issue is analyzed within the framework of shapes of reachable sets. This approach enables an exhaustive description of attractors arising in the space of shapes and the related dynamics. The results are compared with (Ovseevich, 1991; Figurina and Ovseevich, 1999).

Design, RNA cleavage and antiviral activity of new artificial ribonucleases derived from mono-, di- and tripeptides connected by linkers of different hydrophobicity

A novel series of metal-free artificial ribonucleases (aRNases) was designed, synthesized and assessed in terms of ribonuclease activity and ability to inactivate influenza virus WSN/A33/H1N1 in vitro. The compounds were built of two short peptide fragments, which include Lys, Ser, Arg, Glu and imidazole residues in various combinations, connected by linkers of different hydrophobicity (1,12-diaminododecane or 4,9-dioxa-1,12-diaminododecane). These compounds efficiently cleaved different RNA substrates under physiological conditions at rates three to five times higher than that of artificial ribonucleases described earlier and displayed RNase A-like cleavage specificity. aRNases with the hydrophobic 1,12-diaminododecane linker displayed ribonuclease activity 3-40 times higher than aRNases with the 4,9-dioxa-1,12-diaminododecane linker. The assumed mechanism of RNA cleavage was typical for natural ribonucleases, that is, general acid-base catalysis via the formation of acid/base pairs by functional groups of amino acids present in the aRNases; the pH profile of cleavage confirmed this mechanism. The most active aRNases under study exhibited high antiviral activity and entirely inactivated influenza virus A/WSN/33/(H1N1) after a short incubation period of viral suspension under physiological conditions.

Nonsmooth mechanical systems with impactively blockable degrees of freedom and active holonomic constraints

The talk is devoted to control dynamical systems obtained as a mathematical formalization of mechanical systems driven by fast vibrations of systems coordinates and impactive blocking the system degrees of freedom. The idealized model is described by a measure differential equation with square and affine impulses, and the latter are subjected to a mixed constraint relating the affine control measure and the one-sided limits of a state solution. We propose a scheme for approximation of the impulsive control dynamical system by ordinary control processes, and design a constructive trajectory compactification (relaxation of solutions). We establish the existence of a minimizer of a related optimal control problem.

Virtual screening, synthesis and biological evaluation of DNA intercalating antiviral agents

This paper describes computer-aided design of new anti-viral agents against Vaccinia virus (VACV) potentially acting as nucleic acid intercalators. Earlier obtained experimental data for DNA intercalation affinities and activities against Vesicular stomatitis virus (VSV) have been used to build, respectively, pharmacophore and QSAR models. These models were used for virtual screening of a database of 245 molecules generated around typical scaffolds of known DNA intercalators. This resulted in 12 hits which then were synthesized and tested for antiviral activity against VaV together with 43 compounds earlier studied against VSV. Two compounds displaying high antiviral activity against VaV and low cytotoxicity were selected for further antiviral activity investigations.