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.     

Structural Analysis of Partial and Total Esters of Glycerol Undecenoate and Diglycerol Undecenoate

The direct esterification reaction between glycerol and undecylenic acid or between diglycerol and undecylenic acid generates all the possible types of glycerol or diglycerol esters. Purification by silica gel chromatography resulted in the isolation of each of these types of ester in a pure form. The molecular structures of the compounds isolated were characterized and identified by mass spectrometry, ¹H NMR, ¹³C NMR and DEPT‐135. We then studied the composition of esters of undecylenic acid formed with glycerol or diglycerol as a function of their reaction conditions, which constitute a highly complex system. We purified undecylenic acid esters from each polyol family to allow the structural identification of each ester of glycerol and each ester of diglycerol with undecylenic acid. We found that the polarity of these non‐ionic amphiphilic esters directly affected their affinity for organic and inorganic solvents and that these esters behaved very differently from anionic amphiphilic molecules, such as undecylenic acid.     

新型短程硝化反硝化工艺处理高浓度氨氮废水

研发了一种新型短程硝化反硝化工艺——ANITATMShunt,它通过特殊的自控系统来控制N2O的释放。采用500 L的SBR中试装置处理消化污泥脱水上清液,经过18个月的稳定运行表明:通过短程硝化反硝化途径可以实现90%的脱氮率,并且释放的N2O不足总脱氮量的0.7%。将通过pH值、温度和在线监测的NO-2-N浓度实时计算的亚硝酸浓度与亚硝酸浓度设定值进行比对,以便对曝气过程进行调控,从而抑制了N2O的释放并实现了对SBR短程硝化反硝化工艺的自动控制。同时证实了在低溶解氧条件下,由氨氧化菌(AOB)在短程硝化反硝化过程中产生的N2O并非与高亚硝酸盐浓度有直接关系,而是与游离亚硝酸浓度有关。     

Values of the mass transfer coefficient of the linear driving force model for VOC adsorption on activated carbons

Modelling of activated carbon cartridges is essential in personal protective equipments against toxic gases in order to know the duration of protection. The linear driving force model seems to be more adapted than the actual Wheeler–Jonas model because it has more physical significance. The difficulty is that the mass transfer coefficient can not be calculated a priori. Values of the LDF mass transfer coefficient are disseminated in the literature and thus there is no overview of the range and variations with different adsorbents, adsorbates and concentrations. The object of this paper is thus twofold: obtaining values of the mass transfer coefficient at different concentrations and adsorbates in order to have a comprehensive view of variations and appreciating the validity of the LDF constant pattern model.     

An analytic method to predict the thermal map of cryosurgery iceballs in MR images

This paper presents a newly developed method to estimate, in magnetic resonance (MR) images, the temperatures reached within the volume of an iceball produced by a cryogenic probe. Building on the direct measurements of the MR signal intensity and its correlation with independent temperature variations at the phase transition from liquid to solid, the thermal information embedded in the images was accessed. The volume and diameter of the growing iceball were estimated from a time series of MR images. Using regressions over the volume in the time and thermal domains, this method predicted the cryogenic temperatures beyond the range of sensitivity of the MR signal itself. We present a validation of this method in samples of gelatin and ex vivo pig liver. Temperature predictions are shown to agree with independent thermosensor readings over a range extending from 20 degrees C down to -65 degrees C, with an average error of less than 6 degrees C.     

Parameter identification and computational simulation of polyurethane foaming process by finite pointset method

Numerical simulation of the polyurethane foaming process is a valuable method to analyze the molding process at an early stage of product development to shorten time-to-market cycles and cut costs by using fewer prototypes. However, this process involves highly coupled thermo-chemo-rheological modeling and needs adequate model parameters’ identification. A theoretical model including chemical reactions and thermo-rheological coupling of conservation equations was developed. Based on the theoretical model, three-dimensional numerical simulation for mold filling of the polyurethane foam was carried out by using Finite Pointset Method (FPM) to predict flow field, flow front advancement, temperature and density distributions during mold filling. A FOAMAT system was used to monitor foam height rise and reaction temperature on a cylindrical test tube and foam viscosity was measured by using a dynamic rotational rheometer with parallel-plate system. The parameters of the model were identified by an inverse analysis method which consists in determining the parameters by comparing the computed quantities to those measured experimentally. The overall modeling was validated by using short shot foams obtained with a panel mold cavity. Mold filling of an automotive underlay carpet cavity was investigated numerically. Flow front results were successfully compared to short shot foams obtained with the industrial mold cavity.     

Credible autocoding of convex optimization algorithms

The efficiency of modern optimization methods, coupled with increasing computational resources, has led to the possibility of real-time optimization algorithms acting in safety-critical roles. There is a considerable body of mathematical proofs on on-line optimization algorithms which can be leveraged to assist in the development and verification of their implementation. In this paper, we demonstrate how theoretical proofs of real-time optimization algorithms can be used to describe functional properties at the level of the code, thereby making it accessible for the formal methods community. The running example used in this paper is a generic semi-definite programming solver. Semi-definite programs can encode a wide variety of optimization problems and can be solved in polynomial time at a given accuracy. We describe a top-down approach that transforms a high-level analysis of the algorithm into useful code annotations. We formulate some general remarks on how such a task can be incorporated into a convex programming autocoder. We then take a first step towards the automatic verification of the optimization program by identifying key issues to be addressed in future work.     

The effect of copolymer composition on the surface properties of perfluoroalkylethyl acrylates

The surface properties of two perfluoroalkylethyl acrylic copolymers—aqueous, Zonyl^®329 and solvent‐based, Zonyl^®225—were studied. Zonyl^®329 is a water‐based dispersion and Zonyl^®225 a solvent‐based copolymer solution; both polymers have the same perfluoroalkyethyl side chains [F(CF₂)_nCH₂CH₂? ] but have different comonomer compositions. Thin films, prepared by dip coating onto mica and quartz, with and without annealing, were characterized by contact angle and by X‐ray photoelectron spectroscopy (XPS). The contact angle measurements showed little variation with polymer and with substrate, consistent with the supposition that the perfluoroalkylethyl chains aggregate on the surface and thus dominate surface properties, irrespective of the composition of the rest of the polymer. XPS revealed only small variations in surface chemistry for studied films. Annealed films showed improved segregation for solvent‐based Zonyl^®225, which has both hydrocarbon alkyl and perfluoroalkylethyl side chains; the presence of hydrocarbon alkyl chains enables the perfluoroalkylethyl chains to reorganize after annealing. Depending on the external conditions, this thermal treatment can enable more perfluoroalkylethyl chains to reach the film surface (solid/air interface), leading to a reduction in the dispersive‐dominant surface and enhancement in perfluoroalkylethyl segregation. This suggested that perfluoroalkylethyl side chains dominate the surface properties, which are thus not dependent on substrate, backbone composition, or formulation. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009