Identification of the New Metabolite of Nebivolol Using Liquid Chromatography Coupled with High-Resolution Mass Spectrometry and Chemometrics

In this study, the phase I hepatic metabolism pathway of a cardiovascular drug nebivolol was proposed on the basis of a human liver microsomes assay with the use of LC-HR-MS coupled with the chemometric method. Six biotransformation products were found with the assistance of chemometric analysis. Five of them were identified as the previously reported products of alicyclic hydroxylation and dihydroxylation, aromatic hydroxylation, as well as alicyclic oxidation of the parent compound. Moreover, one metabolite, not reported so far, was found to be a product of N-dealkylation of nebivolol—2-amino-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)ethan-1-ol. The novel metabolite was submitted to an in silico toxicity analysis to assess its biological properties. The applied computational methods indicated a significantly elevated risk of its mutagenic activity, compared to the parent molecule. Several metabolites of the nebivolol described in the literature were not detected in this study, indicating their non-hepatic origin.     

Stress-resultant plasticity theories for composite laminated plates

Constitutive laws are presented for the inelastic analysis of laminated composite plates. The implications of using an elastoplastic theory, applied in a stress-resultant formulation, are discussed and investigated. Two different stress-resultant plasticity theories are proposed, both of which overlook the matrix and fiber inelastic behavior and describe the inelastic response of the laminate as a function of overall laminate properties. Results from numerical experiments with the proposed models are compared with results obtained using a micromechanical elastoplastic composite constitutive model.     

C, N CPMAS NMR and GIAO DFT calculations of stereoisomeric oxindole alkaloids from Cat's Claw (Uncaria tomentosa)

Oxindole alkaloids, isolated from the bark of Uncaria tomentosa [Willd. ex Schult.] Rubiaceae, are considered to be responsible for the biological activity of this herb. Five pentacyclic and two tetracyclic alkaloids were studied by solid-state NMR and theoretical GIAO DFT methods. The ¹³C and ¹⁵N CPMAS NMR spectra were recorded for mitraphylline, isomitraphylline, pteropodine (uncarine C), isopteropodine (uncarine E), speciophylline (uncarine D), rhynchophylline and isorhynchophylline. Theoretical GIAO DFT calculations of shielding constants provide arguments for identification of asymmetric centers and proper assignment of NMR spectra. These alkaloids are 7R/7S and 20R/20S stereoisomeric pairs. Based on the ¹³C CP MAS chemical shifts the 7S alkaloids (δ C3 70–71 ppm) can be easily and conveniently distinguished from 7R (δC3 74.5–74.9 ppm), also 20R (δC20 41.3–41.7 ppm) from the 20S (δC20 36.3–38.3 ppm). The epiallo-type isomer (3R, 20S) of speciophylline is characterized by a larger ¹⁵N MAS chemical shift of N4 (64.6 ppm) than the allo-type (3S, 20S) of isopteropodine (δN4 53.3 ppm). ¹⁵N MAS chemical shifts of N1–H in pentacyclic alkaloids are within 131.9–140.4 ppm.     

Mechanochemical synthesis and thermal stability of phases in the Y2O3–Yb2O3 system

Substitutional, continuous solid solution of the general formula Y_2–xYb_xO₃ was obtained from the mixture of Y₂O₃ and Yb₂O₃ oxides, for the first time by the mechanochemical method in a high-energy ball milling. The monophasic samples of nanocrystalline solid solution for x?>?0.00 and x?<?2.00 were examined by the methods: XRD, DTA, SEM, IR and UV–Vis–DR. As follows from the results, the solid solution crystallizes in cubic system and is isostructural with Y₂O₃ and Yb₂O₃. The solution is stable in the air atmosphere up to at least 900°C, and its decomposition temperature decreases with the increase in x, that is, with decreasing number of Yb³⁺ ions replacing Y³⁺ ions in the crystal lattice of Y₂O₃. The energy band gap estimated for the solid solution varies from?~?5.30 eV for x?=?0.50 to?~?4.90 eV for x?=?1.50, which means that it is an insulator.

     

Searching for extremal PPT entangled states

We study extremality in various sets of states that have positive partial transposes. One of the tools we use for this purpose is the recently formulated criterion allowing to judge if a given state is extremal in the set of PPT states. First we investigate qubit-ququart states and show that the only candidates for extremal PPT entangled states (PPTES) have ranks of the state and its partial transposition (5, 5) or (5, 6) (equivalently (6, 5)). Then, examples of extremal states of (5, 5) type and the so-called edge states of type (5, 6) are provided. We also make an attempt to explore the set of PPT states with ranks (5, 6). Finally, we discuss what are the possible configurations of ranks of density matrices and their respective partial transposition in general three-qubit and four-qubit symmetric states for which there may exist extremal entangled PPT states. For instance in the first case we show that the only possibilities are (4, 4, 4) and (4, 4, 5).     

Consensus,Polarization and Hysteresis in the Three-State Noisy q-Voter Model with Bounded Confidence

In this work, we address the question of the role of the influence of group size on the emergence of various collective social phenomena, such as consensus, polarization and social hysteresis. To answer this question, we study the three-state noisy q-voter model with bounded confidence, in which agents can be in one of three states: two extremes (leftist and rightist) and centrist. We study the model on a complete graph within the mean-field approach and show that, depending on the size q of the influence group, saddle-node bifurcation cascades of different length appear and different collective phenomena are possible. In particular, for all values of q>1, social hysteresis is observed. Furthermore, for small values of q∈(1,4), disagreement, polarization and domination of centrists (a consensus understood as the general agreement, not unanimity) can be achieved but not the domination of extremists. The latter is possible only for larger groups of influence. Finally, by comparing our model to others, we discuss how a small change in the rules at the microscopic level can dramatically change the macroscopic behavior of the model.     

Recording 2-D Nutation NQR Spectra by Random Sampling Method

The method of random sampling was introduced for the first time in the nutation nuclear quadrupole resonance (NQR) spectroscopy where the nutation spectra show characteristic singularities in the form of shoulders. The analytic formulae for complex two-dimensional (2-D) nutation NQR spectra (I = 3/2) were obtained and the condition for resolving the spectral singularities for small values of an asymmetry parameter η was determined. Our results show that the method of random sampling of a nutation interferogram allows significant reduction of time required to perform a 2-D nutation experiment and does not worsen the spectral resolution.     

Parameterization of the approximate valence bond (AVB) method to describe potential energy surface in the reaction catalyzed by HIV‐1 protease

The approximate valence bond (AVB) method was parameterized to obtain the potential energy surface for ongoing classical and further quantum classical molecular dynamics simulations describing the enzymatic reaction of the human immunodeficiency virus type 1 protease (HIV‐1 PR). The parameterized AVB method allows to describe the complete enzymatic reaction, including a proton transfer between a water molecule and an aspartic acid, nucleophilic attack of a hydroxy anion on the substrate peptide bond, conformational changes of an intermediate, two proton transfers between the intermediate and aspartic acids, and cleavage of the intermediate into reaction products. The AVB method was parameterized based on density functional theory (DFT) calculations performed for small molecular systems. © 2001 John Wiley & Sons, Inc. Int J Quant Chem 82: 86–103, 2001