Theophylline: Old Drug in a New Light,Application in COVID-19 through Computational Studies

Theophylline (3-methyxanthine) is a historically prominent drug used to treat respiratory diseases, alone or in combination with other drugs. The rapid onset of the COVID-19 pandemic urged the development of effective pharmacological treatments to directly attack the development of new variants of the SARS-CoV-2 virus and possess a therapeutical battery of compounds that could improve the current management of the disease worldwide. In this context, theophylline, through bronchodilatory, immunomodulatory, and potentially antiviral mechanisms, is an interesting proposal as an adjuvant in the treatment of COVID-19 patients. Nevertheless, it is essential to understand how this compound could behave against such a disease, not only at a pharmacodynamic but also at a pharmacokinetic level. In this sense, the quickest approach in drug discovery is through different computational methods, either from network pharmacology or from quantitative systems pharmacology approaches. In the present review, we explore the possibility of using theophylline in the treatment of COVID-19 patients since it seems to be a relevant candidate by aiming at several immunological targets involved in the pathophysiology of the disease. Theophylline down-regulates the inflammatory processes activated by SARS-CoV-2 through various mechanisms, and herein, they are discussed by reviewing computational simulation studies and their different applications and effects.     

Efficient Chemical and Enzymatic Syntheses of FAD Nucleobase Analogues and Their Analysis as Enzyme Cofactors**

Flavin adenine dinucleotide (FAD) is an essential redox cofactor in cellular metabolism. The organic synthesis of FAD typically involves coupling flavin mononucleotide (FMN) with adenosine monophosphate, however, existing synthesis routes present limitations such as multiple steps, low yields, and/or difficult-to-obtain starting materials. In this study, we report the synthesis of FAD nucleobase analogues with guanine/cytosine/uracil in place of adenine and deoxyadenosine in place of adenosine using chemical and enzymatic approaches with readily available starting materials, achieved in 1–3 steps with moderate yields (10–57 %). We find that the enzymatic route using Methanocaldococcus jannaschii FMN adenylyltransferase (MjFMNAT) is versatile and can produce these FAD analogues in high yields. Further, we demonstrate that Escherichia coli glutathione reductase is capable of binding and using these analogues as cofactors. Finally, we show that FAD nucleobase analogues can be synthesized inside a cell from cellular substrates FMN and nucleoside triphosphates by the heterologous expression of MjFMNAT. This lays the foundation for their use in studying the molecular role of FAD in cellular metabolism and as biorthogonal reagents in biotechnology and synthetic biology.     

Profiling hot isostatically pressed canister–wasteform interaction for Pu-bearing zirconolite-rich wasteforms

Zirconolite-rich full ceramic wasteforms designed to immobilize Pu-bearing wastes were produced via hot isostatic pressing (HIP) using stainless steel (SS) and nickel (Ni) HIP canisters. A detailed profiling of the elemental compositions of the major and minor phases over the canister–wasteform interaction zone was performed using scanning electron microscopy combined with energy-dispersive X-ray spectroscopy (SEM-EDS) characterization. Bulk sample analyses from regions near the center of the HIP canister were also conducted for both samples using X-ray diffraction and SEM-EDS. The sample with the Ni HIP canister showed almost no interaction zone with only minor diffusion of Ni from the inner wall of the canister into the near-surface region of the wasteform. The sample with the SS HIP canister showed ∼100–120 μm of interaction zone dominated by high-temperature Cr diffusion from canister materials to the wasteform with the Cr predominantly incorporated into the durable zirconolite phase. We also examined, for the first time, changes to the HIP canister wall thickness caused by HIPing and demonstrated that no canister wall thinning occurred. Instead, in the areas examined, the canister wall thickness was observed to increase (up to ∼20%) due to the compression occurring during the HIP cycle. Further, only sparse formation of (Cr, Mn)-rich oxide particles were noted within the HIP canister inner wall area immediately adjacent to the ceramic material, with no evidence for reverse diffusion of ceramic materials. Though the HIP canister–wasteform interaction extends to ∼120 μm when using an SS HIP canister for the system investigated, this translates to <<1 vol.% for an industrial scale HIPed wasteform. Importantly, the HIP canister–wasteform interactions did not produce any obviously less durable phases in the wasteform or had any detrimental impact on the HIP canister properties.     

Effect of Impact Angle on Ceramic Deposition Behavior in Composite Cold Spray: A Finite-Element Study

During the cold spraying of particle-reinforced metal matrix composite coatings (ceramic and metal particles mixture) on metal substrates, ceramic particles may either get embedded in the substrate/deposited coating or may rebound from the substrate surface. In this study, the dependence of the ceramic rebounding phenomenon on the spray angle and its effect on substrate erosion have been analyzed using finite-element analysis. From the numerical simulations, it was found that the ceramic particle density and substrate material strength played the major roles in determining the embedding and ceramic retention behavior. Substrate material erosion also influenced the ceramic retention, and the material loss increased as the impact angles decreased from normal. In general, the results concluded that decreasing the impact angle promoted the retention possibility of ceramics in the substrate. This study provides new theoretical insights into the effect of spray angles on the ceramic retention and suggests a new route toward optimizing the spraying process to increase the ceramic retention in composite coatings cold spray.     

Vertical and Radial Consolidation Analysis of Multilayered Soil Using the Spectral Method

A new, easy to implement, solution to the consolidation of multilayered soil based on the spectral method is presented. Combined vertical and radial drainage under instantaneous or single ramp loading is considered, ignoring well resistance. Flow in the vertical direction is based on the average hydraulic gradient at a particular depth which allows smear effects to be included. The excess pore-water pressure profile across all soil layers is described by a single expression calculated with common matrix operations. Average excess pore pressures within or across any number of layers are easily calculated from the single expression. The new model is verified against other solutions from the current literature indicating that the more general spectral method model can replace the separate solutions developed for specific problems.     

Effects of perinatal testosterone on handedness of gerbils: Support for part of the Geschwind-Galaburda hypothesis.

When assuming their species-typical tripodal stance. male Mongolian gerbils (Meriones unguiculatus) use their right forepaw for support more frequently than do females. This experiment determined whether. as N. Geschwind and A. M. Galaburda (1987) have proposed, the direction of such sexualIy dimorphic lateral asymmetry of forelimb use is affected by perinatal exposure to testosterone (TP). It was found that male gerbils injected with TP when 4 days old were significantly less likely to rest on their right forepaw when in a tripodal stance than were their oil-injected siblings. Female gerbils injected with TP when 6 days old were more likely than oil-injected controls to use their right forepaws for support. The findings demonstrate effects of perinatal exposure to TP on handedness in gerbils and suggest that the relationship between TP exposure and asymmetrical forelimb use is not always as direct as Geschwind and Galaburda's model suggests. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Computational Analysis of Dissipative Heating Due to Impact Between a Micro-Particle Cluster and a Deformable Wall

Abstract:   A combined finite and discrete element method is used to examine the energetics of a micro-particle cluster that impacts a deformable planar wall. The method combines conservation principles with a penalty based, two-dimensional (2-D) distributed potential force algorithm, and an elastic-viscoplastic and friction constitutive theory, to predict thermomechanical fields within the wall and cluster resulting from both particle-wall and particle-particle contact. Emphasis is placed on characterizing the temporal and spatial partitioning of wall and cluster energy for both normal (θ= 0°, where θ is incidence angle) and oblique (θ= 45°) impact. Predictions for an initially close-packed cluster of well-resolved particles, each having an initial radius and speed of 50 μ m and 500 m/s, indicate that particles adjacent to the wall experience significant dissipative heating due to plastic and friction work. Frictionally induced temperature rises in excess of 2,000 K are predicted for cluster mass located in the immediate vicinity of sliding contact surfaces, even for normal impact, whereas temperature rises near 200 K are predicted for significantly larger cluster mass due to plastic work. Friction is shown to significantly affect cluster kinetic energy, and to weakly affect its elastic potential energy and plastic work. This analysis highlights the importance of friction as a viable heating mechanism that may trigger combustion of energetic clusters.     

Studies on structural,dielectric and charge transport properties of PVA:LiBr solid polymer electrolyte films

In the present study, solid polymer electrolytes (SPEs) based on poly (vinyl alcohol) (PVA) doped with lithium bromide (LiBr) were prepared by solution casting method. Fourier transform infrared spectroscopy results affirm the complexation of LiBr with PVA. X-ray diffraction results exhibit the increase of amorphous nature of the polymer electrolytes, which is also observed in scanning electron microscopy images and atomic force microscopy topographs. Thermogravimetric analysis thermographs endorse the increase of thermal stability of the polymer due to doping. Dielectric studies exhibit non-Debye nature of the polymer electrolytes. Conductivity spectra reveal the maximum ionic conductivity (1.15 × 10⁻⁴ S/cm) for 20 wt% LiBr/PVA electrolyte at ambient temperature. Impedance analysis reveals the decrease of ionic relaxation in the polymer electrolytes and the studied transport properties of the electrolyte show that the major contribution to the conduction in this polymer electrolyte is ions.