Rational in silico design of aptamers for organophosphates based on the example of paraoxon

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Poisoning by organophosphates (OPs) takes one of the leading places in the total number of exotoxicoses. Detoxication of OPs at the first stage of the poison entering the body could be achieved with the help of DNA- or RNA-aptamers, which are able to bind poisons in the bloodstream. The aim of the research was to develop an approach to rational in silico design of aptamers for OPs based on the example of paraoxon. From the published sequence of an aptamer binding organophosphorus pesticides, its threedimensional model has been constructed. The most probable binding site for paraoxon was determined by molecular docking and molecular dynamics (MD) methods. Then the nucleotides of the binding site were mutated consequently and the values of free binding energy have been calculated using MD trajectories and MM-PBSA approach. On the basis of the energy values, two sequences that bind paraoxon most efficiently have been selected. The value of free binding energy of paraoxon with peripheral anionic site of acetylcholinesterase (AChE) has been calculated as well. It has been revealed that the aptamers found bind paraoxon more effectively than AChE. The peculiarities of paraoxon interaction with the aptamers nucleotides have been analyzed. The possibility of improving in silico approach for aptamer selection is discussed

Recovery of a potential on a quantum star graph from Weyl's matrix

The problem of recovery of a potential on a quantum star graph from Weyl's matrix given at a finite number of points is considered. A method for its approximate solution is proposed. It consists in reducing the problem to a two-spectra inverse Sturm-Liouville problem on each edge with its posterior solution. The overall approach is based on Neumann series of Bessel functions (NSBF) representations for solutions of Sturm-Liouville equations, and, in fact, the solution of the inverse problem on the quantum graph reduces to dealing with the NSBF coefficients. The NSBF representations admit estimates for the series remainders which are independent of the real part of the square root of the spectral parameter. This feature makes them especially useful for solving direct and inverse problems requiring calculation of solutions on large intervals in the spectral parameter. Moreover, the first coefficient of the NSBF representation alone is sufficient for the recovery of the potential. The knowledge of the Weyl matrix at a set of points allows one to calculate a number of the NSBF coefficients at the end point of each edge, which leads to approximation of characteristic functions of two Sturm-Liouville problems and allows one to compute the Dirichlet-Dirichlet and Neumann-Dirichlet spectra on each edge. In turn, for solving this two-spectra inverse Sturm-Liouville problem a system of linear algebraic equations is derived for computing the first NSBF coefficient and hence for recovering the potential. The proposed method leads to an efficient numerical algorithm that is illustrated by a number of numerical tests.Comment: arXiv admin note: substantial text overlap with arXiv:2210.1250

Inhibition of protein tyrosine phosphatases unmasks vasoconstriction and potentiates calcium signalling in rat aorta smooth muscle cells in response to an agonist of 5-HT2B receptors BW723C86

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.In blood vessels, serotonin 5-HT2B receptors mainly mediate relaxation, although their activation by the selective agonist BW723C86 is known to exert contraction of aorta in deoxycorticosterone acetate (DOCA)-salt and N(omega)-nitro-L-arginine (L-NAME) hypertensive rats [Russel et al., 2002; Banes et al., 2003] and in mice with type 2 diabetes [Nelson et al., 2012]. The unmasking effect on vasoconstriction can be caused by a shift in the balance of tyrosine phosphorylation in smooth muscle cells (SMC) due to oxidative stress induced inhibition of protein tyrosine phosphatases (PTP). We have demonstrated that BW723C86 which does not cause contraction of rat aorta and mesenteric artery rings, evoked a vasoconstrictor effect in the presence of PTP inhibitors sodium orthovanadate (Na3VO4) or BVT948. BW723C86 induced a weak rise of [Ca2+]i in the SMC isolated from rat aorta; however, after pre-incubation with Na3VO4 the response to BW723C86 increased more than 5-fold. This effect was diminished by protein tyrosine kinase (PTK) inhibitor genistein, inhibitor of Src-family kinases PP2, inhibitor of NADPH-oxidase VAS2870 and completely suppressed by N-acetylcysteine and 5-HT2B receptor antagonist RS127445. Using fluorescent probe DCFH-DA we have shown that Na3VO4 induces oxidative stress in SMC. In the presence of Na3VO4 BW723C86 considerably increased formation of reactive oxygen species while alone had no appreciable effect on DCFH oxidation. We suggest that oxidative stress causes inhibition of PTP and unmasking of 5-HT2B receptors functional activity