Design and development of a two‐dimensional system based on hydrophilic and reversed‐phase liquid chromatography with on‐line sample treatment for the simultaneous separation of excreted xenobiotics and endogenous metabolites in urine

In the present work we describe a two‐dimensional liquid chromatographic system (2D‐LC) with detection by mass spectrometry (MS) for the simultaneous separation of endogenous metabolites of clinical interest and excreted xenobiotics deriving from exposure to toxic compounds. The 2D‐LC system involves two orthogonal chromatographic modes, hydrophilic interaction liquid chromatography (HILIC) to separate polar endogenous metabolites and reversed‐phase (RP) chromatography to separate excreted xenobiotics of low and intermediate polarity. Additionally, the present proposal has the novelty of incorporating an on‐line sample treatment based on the use of restricted access materials (RAMs), which permits the direct injection of urine samples into the system. The work is focused on the instrumental coupling, studying all possible options and attempting to circumvent the problems of solvent incompatibility between the RAM device and the two chromatographic columns, HILIC and RP. The instrumental configuration developed, RAM‐HILIC‐RPLC‐MS/MS, allows the simultaneous assessment of urinary metabolites of clinical interest and excreted compounds derived from exposure to toxic agents with minimal sample manipulation. Thus, it may be of interest in areas such as occupational and environmental toxicology in order to explore the possible relationship between the two types of compounds. Copyright © 2015 John Wiley & Sons, Ltd.     

Study of Endogen Substrates,Drug Substrates and Inhibitors Binding Conformations on MRP4 and Its Variants by Molecular Docking and Molecular Dynamics

Multidrug resistance protein-4 (MRP4) belongs to the ABC transporter superfamily and promotes the transport of xenobiotics including drugs. A non-synonymous single nucleotide polymorphisms (nsSNPs) in the ABCC4 gene can promote changes in the structure and function of MRP4. In this work, the interaction of certain endogen substrates, drug substrates, and inhibitors with wild type-MRP4 (WT-MRP4) and its variants G187W and Y556C were studied to determine differences in the intermolecular interactions and affinity related to SNPs using protein threading modeling, molecular docking, all-atom, coarse grained, and umbrella sampling molecular dynamics simulations (AA-MDS and CG-MDS, respectively). The results showed that the three MRP4 structures had significantly different conformations at given sites, leading to differences in the docking scores (DS) and binding sites of three different groups of molecules. Folic acid (FA) had the highest variation in DS on G187W concerning WT-MRP4. WT-MRP4, G187W, Y556C, and FA had different conformations through 25 ns AA-MD. Umbrella sampling simulations indicated that the Y556C-FA complex was the most stable one with or without ATP. In Y556C, the cyclic adenosine monophosphate (cAMP) and ceefourin-1 binding sites are located out of the entrance of the inner cavity, which suggests that both cAMP and ceefourin-1 may not be transported. The binding site for cAMP and ceefourin-1 is quite similar and the affinity (binding energy) of ceefourin-1 to WT-MRP4, G187W, and Y556C is greater than the affinity of cAMP, which may suggest that ceefourin-1 works as a competitive inhibitor. In conclusion, the nsSNPs G187W and Y556C lead to changes in protein conformation, which modifies the ligand binding site, DS, and binding energy.     

The Influence of Silicon Dioxide on the Stability of the Phase Composition and Mechanical Properties of Alumina-Toughened Zirconia-Based Ceramics

Technical Physics - The influence of SiO2 impurity (with a concentration varying from 0 to 10 mol %) on the stability of tetragonal ZrO2 (t-ZrO2) and on a set of micro- and macromechanical...     

Vibration Properties of Thin Films of Transition 3d-Metals on the Cu (111) Surface

Russian Physics Journal - Using the potentials, generated by a tight binding approximation, the equilibrium atomic structure and the phonon spectra of Cr and Ni thin films (one monolayer) deposited...     

Gradient structure of polypropylene composites filled with carbon black

Russian Chemical Bulletin - Gradient polymer composites were prepared by melt-mixing of carbon black and polypropylene in a compounder and subsequent hot pressing of pellets. The thermally treated...     

Thermodynamic and structural characteristics of aqueous alkanolamine solutions

Journal of Structural Chemistry - Thermodynamic characteristics are calculated for aqueous alkanolamine solutions that are obtained by substituting alkyl radicals for the protons in the amino group...     

Microelectromechanical Systems for Nanomechanical Testing: Electrostatic Actuation and Capacitive Sensing for High-Strain-Rate Testing

Experimental Mechanics - There have been relatively few studies on mechanical properties of nanomaterials under high strain rates, mainly due to the lack of capable nanomechanical testing devices....