Identification of Human Dihydroorotate Dehydrogenase Inhibitor by a Pharmacophore-Based Virtual Screening Study

Human dihydroorotate dehydrogenase (hDHODH) is an enzyme belonging to a flavin mononucleotide (FMN)-dependent family involved in de novo pyrimidine biosynthesis, a key biological pathway for highly proliferating cancer cells and pathogens. In fact, hDHODH proved to be a promising therapeutic target for the treatment of acute myelogenous leukemia, multiple myeloma, and viral and bacterial infections; therefore, the identification of novel hDHODH ligands represents a hot topic in medicinal chemistry. In this work, we reported a virtual screening study for the identification of new promising hDHODH inhibitors. A pharmacophore-based approach combined with a consensus docking analysis and molecular dynamics simulations was applied to screen a large database of commercial compounds. The whole virtual screening protocol allowed for the identification of a novel compound that is endowed with promising inhibitory activity against hDHODH and is structurally different from known ligands. These results validated the reliability of the in silico workflow and provided a valuable starting point for hit-to-lead and future lead optimization studies aimed at the development of new potent hDHODH inhibitors.     

Thermodynamic equilibrium between locally excited and charge-transfer states through thermally activated charge transfer in 1-(pyren-2′-yl)-o-carborane

Reversible conversion between excited-states plays an important role in many photophysical phenomena. Using 1-(pyren-2′-yl)-o-carborane as a model, we studied the photoinduced reversible charge-transfer (CT) process and the thermodynamic equilibrium between the locally-excited (LE) state and CT state, by combining steady state, time-resolved, and temperature-dependent fluorescence spectroscopy, fs- and ns-transient absorption, and DFT and LR-TDDFT calculations. Our results show that the energy gaps and energy barriers between the LE, CT, and a non-emissive ‘mixed’ state of 1-(pyren-2′-yl)-o-carborane are very small, and all three excited states are accessible at room temperature. The internal-conversion and reverse internal-conversion between LE and CT states are significantly faster than the radiative decay, and the two states have the same lifetimes and are in thermodynamic equilibrium.

Reversible conversion between excited-states is key to many photophysical phenomena. We studied the equilibrium between LE and CT states by time-resolved and temperature-dependent fluorescence, fs- and ns-transient absorption, and LR-TDDFT calculations.     

Anti-Inflammatory and Antinociceptive Activities of the Essential Oil of Tagetes parryi A. Gray (Asteraceae) and Verbenone

Tagetes parryi is a plant empirically used to treat gastrointestinal and inflammatory diseases, its essential oil (EOTP) was obtained from the aerial parts, and the composition was elucidated by GC-MS. The in vivo and in vitro anti-inflammatory activities and the antinociceptive activity of EOTP and (1S)-(-)-verbenone (VERB) were assessed. The major compounds identified for EOTP were verbenone (33.39%), dihydrotagetone (26.88%), and tagetone (20.8%). EOTP and VERB diminished the ear oedema induced with TPA by 93.77 % and 81.13 %, respectively. EOTP and VERB decreased inflammation in a 12-O-tetradecanoylphorbol-13-acetate (TPA) chronic model with ED₅₀ = 54.95 mg/kg and 45.24 mg/kg, respectively. EOTP (15 µg/mL) inhibited the in vitro production of the pro-inflammatory mediators NO (67.02%), TNF-α (69.21%), and IL-6 (58.44%) in LPS-stimulated macrophages. In the acetic induced writhing test, EOTP and VERB showed antinociceptive effects with ED₅₀ = 84.93 mg/kg and ED₅₀ = 45.24 mg/kg, respectively. In phase 1 of the formalin test, EOTP and VERB showed no antinociceptive effects, whereas in phase 2, EOTP (ED₅₀ = 35.45 mg/kg) and VERB (ED₅₀ = 24.84 mg/kg) showed antinociceptive effects. The antinociceptive actions of ETOP and VERB were blocked with the co-administration of L-NAME. This study suggests that EOTP and VERB might be used in the treatment of pain and inflammatory problems.     

Sobolev spaces on Lie groups: Embedding theorems and algebra properties

Let G be a noncompact connected Lie group, denote with ρ a right Haar measure and choose a family of linearly independent left-invariant vector fields X on G satisfying Hörmander's condition. Let χ be a positive character of G and consider the measure ${\mu }_{\chi }$ whose density with respect to ρ is χ. In this paper, we introduce Sobolev spaces $L_{\alpha }^p({\mu }_{\chi })$ adapted to X and ${\mu }_{\chi }$ ($1<p<\infty$, $\alpha \ge 0$) and study embedding theorems and algebra properties of these spaces. As an application, we prove local well-posedness and regularity results of solutions of some nonlinear heat and Schrödinger equations on the group.     

Certification of nitrate in spinach powder reference material SPIN-1 by high-precision isotope dilution GC–MS

A high-precision exact-matching quadruple isotope dilution method (ID⁴MS) was employed for the quantitation of nitrate in an air-dried spinach powder Certified Reference Material (CRM). The analyte was extracted in hot water following addition of ¹⁵NO\({}_{3}^{-}\) internal standard. The blend was then treated with sulfamic acid to remove nitrite and with triethyloxonium tetrafluoroborate to promote aqueous conversion of nitrate into volatile EtONO₂. The derivative was analyzed by headspace GC–MS with 3-min elution time. The method performance was validated with a series of tests which demonstrated adequate selectivity and ruggedness. This method supported the development of novel SPIN-1 CRM giving a modest contribution to its uncertainty (u_char = 0.85%). With respect to previous attempts, the SPIN-1 was proven stable, homogeneous (u_hom = 0.44%), and suitable for spinach monitoring under EU regulations. On dried basis, the nitrate content of SPIN-1 was found to be 22.53 ± 0.43 mg/g (U_c = 1.9%, k = 2). The material was also used in an inter-laboratory study where four laboratories employed a total of ten measurement methods.

SPIN-1 Certified Reference Material for nitrate in spinach powder

     

Emergent biaxiality in nematic microflows illuminated by a laser beam

Anisotropic fluids (e.g. liquid crystals) offer a remarkable promise as optofluidic materials owing to the directional, tunable, and coupled interactions between the material, flow, and the optical fields. Here we present a comprehensive in silico treatment of this anisotropic interaction by performing nonequilibrium molecular dynamics simulations. We quantify the response of a nematic liquid crystal (NLC) undergoing a Poiseuille flow in the Stokes regime, while being illuminated by a laser beam incident perpendicular to the flow direction. We adopt a minimalistic model to capture the interactions, accounting for two features: first, the laser heats up the NLC locally; and second, the laser polarises the NLC and exerts an optical torque that tends to reorient molecules of the nematic phase. Because of this reorientation the liquid crystal exhibits small regions of biaxiality, where the nematic director is one symmetry axis and the axis of rotation for the reorientation of the molecules is the other one. We find that the relative strength of the viscous and the optical torques mediates the flow-induced response of the biaxial regions, thereby tuning the emergence, shape and location of the regions of enhanced biaxiality. The mechanistic framework presented here promises experimentally tractable routes toward novel optofluidic applications based on material-flow-light interactions.     

Fractional powers of the noncommutative Fourier's law by the S‐spectrum approach

Let e_?, for ? = 1,2,3, be orthogonal unit vectors in and let be a bounded open set with smooth boundary ?Ω. Denoting by a point in Ω, the heat equation, for nonhomogeneous materials, is obtained replacing the Fourier law, given by the following: into the conservation of energy law, here a, b, are given functions. With the S‐spectrum approach to fractional diffusion processes we determine, in a suitable way, the fractional powers of T. Then, roughly speaking, we replace the fractional powers of T into the conservation of energy law to obtain the fractional evolution equation. This method is important for nonhomogeneous materials where the Fourier law is not simply the negative gradient. In this paper, we determine under which conditions on the coefficients a, b, the fractional powers of T exist in the sense of the S‐spectrum approach. More in general, this theory allows to compute the fractional powers of vector operators that arise in different fields of science and technology. This paper is devoted to researchers working in fractional diffusion and fractional evolution problems, partial differential equations, and noncommutative operator theory.     

Modelling and design of a novel air-spring for a suspension seat

Air-springs used in conjunction with auxiliary volumes provide both spring stiffness and damping. The damping is introduced through the flow restriction connecting the two air volumes. This article presents a simplified model of an air-spring with an auxiliary volume derived from first principles for simulation and design of an air-spring coupled to an auxiliary volume for a suspension seat. Tests were performed on an experimental apparatus to validate the model. The simulation model of the air-spring and auxiliary volume followed the trend predicted by the literature but showed approximately 27% lower transmissibility amplitude and 21% lower system natural frequency than that obtained by tests when using large diameter flow restrictions. This inaccuracy is assumed to be introduced by the simplified mass transfer equations defining the flow restriction between air-spring and auxiliary volume. The model showed closer correlation to the experimental results when the auxiliary volume size was decreased by two-thirds of the volume actually used for the experiment. A procedure, using the developed simulation model, for the design of a prototype air-spring and auxiliary volume, is presented for application in a typical articulated or rigid frame dump truck. The goal of the study was to design a suspension seat for this application and to obtain a SEAT value below 1.1. The design was optimised by varying auxiliary volume size and flow restriction diameters for different loads. A SEAT value of less than 0.9 was achieved, clearly indicating the effectiveness of using an auxiliary volume with an air-spring as seat suspension.     

M?ssbauer spectroscopic study of iron�Cnickel nitrides thin films prepared by ion beam assisted deposition

An overview is given of the present status of parity violation tests in neutron decay and nuclear beta decay. Prospects for improved and new measurements are discussed as well.