2D SMARTCyp reactivity-based site of metabolism prediction for major drug-metabolizing cytochrome P450 enzymes

Cytochrome P450 (CYP) 3A4, 2D6, 2C9, 2C19, and 1A2 are the most important drug-metabolizing enzymes in the human liver. Knowledge of which parts of a drug molecule are subject to metabolic reactions catalyzed by these enzymes is crucial for rational drug design to mitigate ADME/toxicity issues. SMARTCyp, a recently developed 2D ligand structure-based method, is able to predict site-specific metabolic reactivity of CYP3A4 and CYP2D6 substrates with an accuracy that rivals the best and more computationally demanding 3D structure-based methods. In this article, the SMARTCyp approach was extended to predict the metabolic hotspots for CYP2C9, CYP2C19, and CYP1A2 substrates. This was accomplished by taking into account the impact of a key substrate-receptor recognition feature of each enzyme as a correction term to the SMARTCyp reactivity. The corrected reactivity was then used to rank order the likely sites of CYP-mediated metabolic reactions. For 60 CYP1A2 substrates, the observed major sites of CYP1A2 catalyzed metabolic reactions were among the top-ranked 1, 2, and 3 positions in 67%, 80%, and 83% of the cases, respectively. The results were similar to those obtained by MetaSite and the reactivity + docking approach. For 70 CYP2C9 substrates, the observed sites of CYP2C9 metabolism were among the top-ranked 1, 2, and 3 positions in 66%, 86%, and 87% of the cases, respectively. These results were better than the corresponding results of StarDrop version 5.0, which were 61%, 73%, and 77%, respectively. For 36 compounds metabolized by CYP2C19, the observed sites of metabolism were found to be among the top-ranked 1, 2, and 3 sites in 78%, 89%, and 94% of the cases, respectively. The computational procedure was implemented as an extension to the program SMARTCyp 2.0. With the extension, the program can now predict the site of metabolism for all five major drug-metabolizing enzymes with an accuracy similar to or better than that achieved by the best 3D structure-based methods. Both the Java source code and the binary executable of the program are freely available to interested users.     

Analysis of biomarkers characteristic of porcine liver injury--from biomolecular logic gates to an animal model

A biocatalytic cascade for the analysis of the simultaneous increase in the concentration of two biomarkers characteristic of liver injury (alanine transaminase, ALT, and lactate dehydrogenase, LDH) was tested on real samples acquired from an animal model (domestic pigs, Sus scrofa domesticus) suffering from traumatic liver injury. A two-step reaction biocatalyzed in the presence of both enzyme-biomarkers resulted in the oxidation of NADH followed by optical absorbance measurements. A simple qualitative, YES/NO, test allowed for distinction between animals with and without the presence of liver injury with the probability of 92%. These data represent the first demonstration of applying binary logic systems for the analysis of real biomedical samples.     

Optimized thermal desorption for improved sensitivity in trace explosives detection by ion mobility spectrometry

In this work we evaluate the influence of thermal desorber temperature on the analytical response of a swipe-based thermal desorption ion mobility spectrometer (IMS) for detection of trace explosives. IMS response for several common high explosives ranging from 0.1 ng to 100 ng was measured over a thermal desorber temperature range from 60 °C to 280 °C. Most of the explosives examined demonstrated a well-defined maximum IMS signal response at a temperature slightly below the melting point. Optimal temperatures, giving the highest IMS peak intensity, were 80 °C for trinitrotoluene (TNT), 100 °C for pentaerythritol tetranitrate (PETN), 160 °C for cyclotrimethylenetrinitramine (RDX) and 200 °C for cyclotetramethylenetetranitramine (HMX). By modifying the desorber temperature, we were able to increase cumulative IMS signal by a factor of 5 for TNT and HMX, and by a factor of 10 for RDX and PETN. Similar signal enhancements were observed for the same compounds formulated as plastic-bonded explosives (Composition 4 (C-4), Detasheet, and Semtex). In addition, mixtures of the explosives exhibited similar enhancements in analyte peak intensities. The increases in sensitivity were obtained at the expense of increased analysis times of up to 20 seconds. A slow sample heating rate as well as slower vapor-phase analyte introduction rate caused by low-temperature desorption enhanced the analytical sensitivity of individual explosives, plastic-bonded explosives, and explosives mixtures by IMS. Several possible mechanisms that can affect IMS signal response were investigated such as thermal degradation of the analytes, ionization efficiency, competitive ionization from background, and aerosol emission.     

Towards Si-based electrically injected group-IV lasers

Approaches towards Si-based lasers are discussed using lattice-matched group-IV heterostructures that can be deposited strain free on Si substrates with either Ge or GeSn buffer layers. Several strain-free designs are presented that include Ge/GeSiSn quantum cascade structure, GeSn/GeSiSn double heterostructure, and GeSn/GeSiSn multiple quantum wells.     

Comparative analysis of photoluminescence and Raman enhancement by metal nanoparticles

We present a comparative study on the enhancement of photoluminescence and Raman processes by a single metal nanoparticle. Taking an analytical approach, we show the physics behind strikingly different orders of magnitude in enhancement that have been observed, provide fundamental explanation for not observing quenching of Raman processes, and outline the path to optimization of both photoluminescence and Raman enhancement.     

Determination of vitamin A in infant formula and adult nutritionals by UPLC-UV: First Action 2011.07

Vitamin A, a fat-soluble vitamin, is essential for health and plays an important part in vision, bone growth, reproduction, regulating the immune system, cell function, and skin health. Due to the advances in technology and the expansion of its uses, LC technologies are being studied for effectiveness in detecting and quantifying vitamin A in an effort to help determine the amount of vitamin A in various types of samples. For this reason, an Expert Review Panel agreed on June 29, 2011, at the "Standards Development and International Harmonization: AOAC INTERNATIONAL Mid-Year Meeting," to approve "Determination of Vitamin A in Infant Formula and Adult Nutritionals by UPLC-UV" as AOAC Official Method 2011.07. To move from First to Final Action status, it was recommended that additional information be generated for all types of infant formulas and adult nutritional formula matrixes at varied concentration levels, as indicated in the standard method performance requirements. International units or retinol equivalents typically represent the concentration of vitamin A in food and supplements. However, for the purpose of this method, the concentration represented is presented in microg/100 g.     

Thermal stability of brominated poly(isobutylene‐co‐isoprene)

The thermal stability of brominated isobutylene–isoprene rubber (BIIR) was investigated through studies of the elastomer and a model compound that accurately represented the reactive functionality within the polymer. An analysis of commercial BIIR and reaction products of brominated 2,2,4,8,8‐pentamethyl‐4‐nonene (BPMN) by NMR demonstrated that bromination of isobutylene–isoprene rubber by 1,3‐dibromo‐5,5‐dimethylhydantoin yielded a kinetically favored exomethylene substitution product, 3‐bromo‐6,6‐dimethyl‐2‐(2,2‐dimethylpropyl)‐1‐heptene ( 2 ), as opposed to the more stable endo‐isomer, (E,Z)‐4‐(bromomethyl)‐2,2,8,8‐tetramethyl‐4‐nonene ( 3 ). The exposure of BIIR and the brominated model compound BPMN to vulcanization temperatures led to the isomerization of 2 to 3 at a rate strongly dependent on HBr concentration. The elimination of HBr from these allylic bromides to produce exo‐ and endo‐conjugated dienes proceeded concurrently with isomerization, and the kinetics of these processes could be rationalized on the basis of a polar reaction mechanism. The product distributions obtained from both the model system and BIIR were consistent, thereby justifying an extension of the model compound approach to an analysis of BIIR vulcanization chemistry. © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 39: 2019–2026, 2001     

Measurements of L-shell X-ray emission lines of neonlike europium on an electron beam ion trap

We report a measurement of the two X-ray transitions that proceed from the and (1s²2s_1/22p⁶3p_1/2)_{J = 1} upper levels to the (1s²2s²2p⁶)_{J = 0} ground level in neonlike Eu⁵³⁺ (Z = 63), that is,  near the previously documented avoided crossing of the two upper levels at Z = 68. The measurement was carried out using the calorimeter spectrometer on the Livermore EBIT-I electron beam ion trap. It affirms the trends set by the neighboring neonlike ions both in terms of the relative intensity of the two lines and in terms of the magnitude of disagreement with theoretical energy level predictions.