Molecular Networking for Drug Toxicities Studies: The Case of Hydroxychloroquine in COVID-19 Patients

Using drugs to treat COVID-19 symptoms may induce adverse effects and modify patient outcomes. These adverse events may be further aggravated in obese patients, who often present different illnesses such as metabolic-associated fatty liver disease. In Rennes University Hospital, several drug such as hydroxychloroquine (HCQ) have been used in the clinical trial HARMONICOV to treat COVID-19 patients, including obese patients. The aim of this study is to determine whether HCQ metabolism and hepatotoxicity are worsened in obese patients using an in vivo/in vitro approach. Liquid chromatography high resolution mass spectrometry in combination with untargeted screening and molecular networking were employed to study drug metabolism in vivo (patient’s plasma) and in vitro (HepaRG cells and RPTEC cells). In addition, HepaRG cells model were used to reproduce pathophysiological features of obese patient metabolism, i.e., in the condition of hepatic steatosis. The metabolic signature of HCQ was modified in HepaRG cells cultured under a steatosis condition and a new metabolite was detected (carboxychloroquine). The RPTEC model was found to produce only one metabolite. A higher cytotoxicity of HCQ was observed in HepaRG cells exposed to exogenous fatty acids, while neutral lipid accumulation (steatosis) was further enhanced in these cells. These in vitro data were compared with the biological parameters of 17 COVID-19 patients treated with HCQ included in the HARMONICOV cohort. Overall, our data suggest that steatosis may be a risk factor for altered drug metabolism and possibly toxicity of HCQ.     

Ionic conductivity of the Na1+xM x III Zr2−x(PO4)3 systems (M = Al,Ga, Cr,Fe, Sc,In, Y,Yb)

The existence and ionic conductivity of solid solutions Na_1+xM _x ^III Zr_2–x(PO₄)₃ with Nasicon-like structure have been investigated and the results compared with literature data. A limited range of solid solutions is formed with M^III = aluminium, gallium, yttrium, ytterbium, whereas a continuous series is obtained for M^III = chromium, iron, scandium, indium. The pure end member Na₃ln₂(PO₄)₃ is reported for the first time; according to powder diffraction data, it is hexagonal witha = 0.8966(1) andc = 2.2104(4) nm. The small monoclinic distortion already known for M^III = chromium, iron and scandium is restricted tox values very close to 2. Ionic conductivity measurements show that for a given value ofx, the mobility of the Na⁺ ions is strongly influenced both by the ionic radius and the type of electronic structure of the M^III ion. However, no simple correlation can be found.     

Effect of film structure on the electrochemical properties of gold electrodes for neural implants

The development of interfaces with low impedance is a prerequisite for long-term neural devices. A broad range of new materials has been developed for this purpose. Here we show how the performance of traditional gold electrodes can be improved by controlling the deposition parameters of the gold film. The morphology of the film was tuned from granular to columnar structure as shown by scanning electron microscopy of film cross sections. Electrochemical characterisation with impedance spectroscopy, chronoamperometry and cyclic voltammetry demonstrates that the dense columnar structure of the films effectively lowers the impedance of the interface and increases charge injection properties. The samples produced are also compared to titanium nitride films, a well-established electrode material with a columnar structure.     

Synthesis and properties of poly(methyl methacrylate)/carbon nanotube composites covalently integrated through in situ radical polymerization

Poly(methyl methacrylate) (PMMA)/single‐walled carbon nanotube (SWNT) composites were synthesized by the grafting of PMMA onto the sidewalls of SWNTs via in situ radical polymerization. The free‐radical initiators were covalently attached to the SWNTs by a well‐known esterification method and confirmed by means of thermogravimetric analysis and Fourier transform infrared spectroscopy. Scanning electron microscopy and transmission electron microscopy were used to image the PMMA–SWNT composites; these images showed the presence of polymer layers on the surfaces of debundled, individual nanotubes. The PMMA–SWNT composites exhibited better solubility in chloroform than the solution‐blended composite materials. On the other hand, compared to the neat PMMA, the PMMA–SWNT nanocomposites displayed a glass‐transition temperature up to 6.0°C higher and a maximum thermal decomposition temperature up to 56.6°C higher. The unique properties of the nanocomposites resulted from the strong interactions between the SWNTs and the PMMA chains. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Residual stress analysis of all perovskite oxide cantilevers

We have used a method to experimentally determine the curvature of thin film multilayers in all oxide cantilevers. This method is applicable for large deflections and enables the radius of curvature of the beam, at a certain distance from the anchor, to be determined accurately. The deflections of the suspended beams are measured at different distances from the anchor point using SEM images and the expression of the deflection curve is calculated for each cantilever. With this expression it is possible to calculate the value of the radius of curvature at the free end of the cantilever. Together with measured values for the Youngs Modulus, this enabled us to determine the residual stress in each cantilever. This analysis has been applied to SrRuO ₃/BaTiO ₃/SrRuO ₃, BaTiO ₃/MgO/SrTiO ₃ and BaTiO₃/SrTiO₃ piezoelectric cantilevers and the results compared to two models in which the stresses are determined by lattice parameter mismatch or differences in thermal expansion coefficient. Our analysis shows that the bending of the beams is mainly due the thermal stress generated during the cooling down stage subsequent to the film deposition.     

Some sources of variation in the bar-pressing versus freeloading phenomenon in rats.

Gave 40 albino rats a choice between barpressing for food or taking it freely from a dish. In Exp I Ss were given 3 days of free-food training and 6 days of barpress training before the choice. In Exp II the number of prechoice bar presses was varied within the choice sessions, and in Exp. III the choice sessions were extended over 10 days. In all 3 experiments the mean number of pellets obtained via bar pressing was over 70%. In Exp IV and V the amount of time spent and the number of pellets obtained in freeloading and barpressing were equalized. In both studies Ss greatly preferred to freeload. (PsycINFO Database Record (c) 2010 APA, all rights reserved)