Single Enantiomer Versus Racemate: Chiral Distinction in the Proton Pump Inhibitors Omeprazole and Esomeprazole

Chiral distinction in the proton pump inhibitor drugs omeprazole and in its chiral‐switch esomeprazole magnesium was studied employing the Density Functional Theory (DFT) method. At B3LYP/6‐311G(d,p), the 6‐methoxy???6‐methoxy and 5‐methoxy???5‐methoxy homochiral and heterochiral dimers were calculated. The chiral distinction free energies (ΔΔG_{298,(RS‐SS)}) between the cyclic C₂‐(S,S)‐ and C_i‐(R,S)‐dimers with two intermolecular hydrogen bonds are 3.8, 1.9 (with BSSE counterpoise correction), and –6.9 (with D3 dispersion and BSSE counterpoise corrections) kJ/mol. Adding water as an implicit solvent (polarized continuum model [PCM] model) resulted in a chiral distinction energy of –3.3 kJ/mol, indicating a reversal of the order of the relative stabilities of C₂‐(S,S)‐ and C_i‐(R,S)‐dimers. The chiral distinction free energies between the corresponding (less stable) C₁‐dimers with one intermolecular hydrogen bond are –9.3, –5.8 (with BSSE CC), 17.6 (D3 + BSSE CC), and –3.2 (H₂O) kJ/mol. The results highlight the contention that omeprazole is not just a superposition of its enantiomer constituents. They are consistent with the pharmacological evidence of enantiomer–enantiomer interactions in omeprazole versus esomeprazole and the differences between the drugs omeprazole and esomeprazole magnesium and support the lodged application for regulatory supplementary protection certificate (SPC) exclusivity for the esomeprazole‐related combination drug Vimovo. Chirality 26:214–227, 2014. © 2014 Wiley Periodicals, Inc.     

Transient binding of plastocyanin to its physiological redox partners modifies the copper site geometry

The transient complexes of plastocyanin with cytochrome f and photosystem I are herein used as excellent model systems to investigate how the metal sites adapt to the changes in the protein matrix in transient complexes that are involved in redox reactions. Thus, both complexes from the cyanobacterium Nostoc sp. PCC 7119 (former Anabaena sp. PCC 7119) have been analysed by X-ray absorption spectroscopy. Our data are consistent with a significant distortion of the trigonal pyramidal geometry of the Cu coordination sphere when plastocyanin binds to cytochrome f, no matter their redox states are. The resulting tetrahedral geometry shows a shortening of the distance between Cu and the S(delta) atom of its ligand Met-97, with respect to the crystallographic structure of free plastocyanin. On the other hand, when plastocyanin binds to photosystem I instead of cytochrome f, the geometric changes are not significant but a displacement in charge distribution around the metal centre can be observed. Noteworthy, the electronic density around the Cu atom increases or decreases when oxidised plastocyanin binds to cytochrome f or photosystem I, respectively, thus indicating that the protein matrix affects the electron transfer between the two partners during their transient interaction.     

Risk-Based Corrective Action of Hydrocarbon Contamination at a Former Major Urban Petroleum Storage Site in the U.K.

The former site of a major petroleum storage facility adjacent to a major urban watercourse was found to have potentially significant concentrations of hydrocarbons in soil and groundwater that needed to be addressed prior to redevelopment. A series of intrusive investigations were undertaken to collect physical and chemical data for a Quantitative Risk Assessment (QRA) of potential impacts on human health and the wider environment, in order to derive a remedial strategy for redevelopment of the site for light industrial use. A site-specific QRA methodology was devel oped using both U.K. and U.S. guidance to produce Risk-Based Clean-up Levels (RBCLs) for benzene, and other petroleum hydrocarbons. The U.K. has no nationally based guidance on risk assessment and studies are designed by the consultant for submission to the U.K. Environment Agency (EA) for their approval. It is the EA's role to determine whether the work has been undertaken satisfactorily. To achieve these RBCLs, ex situ bioremediation was identified as the best practicable remedial option. This was carried out in windrows using mechanical aeration (to achieve oxygenation with ammonia nitrate granule and woodchip addition) for a total of approximately 5291?m³ of soil. The bioremediation process was successful in achieving the site specific RBCLs for benzene and for other hydrocarbons within an average of 5 to 6 weeks. This article describes the successful implementation of Risk-Based Corrective Action (RBCA) at this petroleum release site as a demonstration of how risk-based remedial standards for contaminated sites can be achieved with regulatory approval.     

Interlinked bistable mechanisms generate robust mitotic transitions

The transitions between phases of the cell cycle have evolved to be robust and switch-like, which ensures temporal separation of DNA replication, sister chromatid separation, and cell division. Mathematical models describing the biochemical interaction networks of cell cycle regulators attribute these properties to underlying bistable switches, which inherently generate robust, switch-like, and irreversible transitions between states. We have recently presented new mathematical models for two control systems that regulate crucial transitions in the cell cycle: mitotic entry and exit,¹ Mochida S, Rata S, Hino H, Nagai T, Novák B. Two Bistable Switches Govern M Phase Entry. Curr Biol. 2016;26:3361-3367. doi:10.1016/j.cub.2016.10.022. PMID:27889260[Crossref], [PubMed], [Web of Science ®] [Google Scholar] and the mitotic checkpoint.² Mirkovic M, Hutter LH, Novák B, Oliveira RA. Premature sister chromatid separation is poorly detected by the spindle assembly checkpoint as a result of system-level feedback. Cell Rep. 2015;13:469-478. doi:10.1016/j.celrep.2015.09.020[Crossref], [PubMed], [Web of Science ®] [Google Scholar] Each of the two control systems is characterized by two interlinked bistable switches. In the case of mitotic checkpoint control, these switches are mutually activating, whereas in the case of the mitotic entry/exit network, the switches are mutually inhibiting. In this Perspective we describe the qualitative features of these regulatory motifs and show that having two interlinked bistable mechanisms further enhances robustness and irreversibility. We speculate that these network motifs also underlie other cell cycle transitions and cellular transitions between distinct biochemical states.     

术中使用画线法与量角法测量股骨截骨旋转角度的对比分析研究

目的:探讨应用两种股骨截骨旋转角度测量方法矫正股骨颈前倾角(FNA)在儿童发育性髋关节脱位(DDH)治疗中的价值。方法:回顾性分析我科自2006年1月~2015年6月行手术治疗的DDH 32例(32髋),其中,股骨旋转截骨时,2006年1月~2009年12月的16例(16髋)采用画线法;2010年1月~2015年6月的16例(16髋)采用量角法。术前及术后进行X线及三维CT检查测量FNA。两组的一般资料及术前健侧及患侧FNA角度的差异无统计学意义(P0.05)。结果:本组病例均获得随访,随访时间12~48个月,平均28个月。两组术后患侧FNA与术前相比,均差异明显(P0.01);而与健侧相比,差异不明显(P0.05),说明术后FNA较术前明显改善,达到与健侧大致相等的FNA。两组间术后健侧、患侧FNA比较,无显著性差异(P0.05),故,目前尚不足以证明行股骨旋转截骨术时后期采用的量角法优于画线法。结论:采用量角法及画线法进行股骨旋转截骨术均可获得满意疗效。     

Improved estimates of digestion correction factors and passage rates for harbor seal (Phoca vitulina) prey in the northeast Atlantic

Diet composition in pinnipeds is widely estimated using hard prey remains recovered from feces. To estimate the size and number of prey represented in fecal samples accurately, digestion correction factors (DCFs) must be applied to measurements and counts of fish otoliths and cephalopod beaks. In this study, 101 whole prey feeding trials were conducted with six harbor seals (Phoca vitulina) and 18 prey species. We derived species‐ and grade‐specific estimates of digestion coefficients (DCs) and species‐specific recovery rates (RRs) to account for partial and complete digestion, respectively. Greater than 98% of otoliths were passed within three days of consumption. RRs were smallest for Atlantic salmon smolts (RR = 0.306, SE = 0.031) and increasingly larger for sandeels (RR = 0.494, SE = 0.017), flatfish (RR = 0.789, SE = 0.033), and large gadoids (RR = 0.944, SE = 0.034). Species‐specific otolith width DCs were smallest for Trisopterus species (DC = 1.14, SE = 0.015) and increasingly larger for flatfish (DC = 1.27, SE = 0.045), large gadoids (DC = 1.32, SE = 0.067) and sandeels (DC = 1.57, SE = 0.035). RRs were similar to those from gray seals (Halichoerus grypus), but harbor seal species‐ and grade‐specific DCs were generally smaller. Differences in partial and complete digestion rates among prey species and between seal species highlight the importance of applying DCFs when reconstructing diet.     

Noise‐Corrected Principal Component Analysis of fluorescence lifetime imaging data

Fluorescence Lifetime Imaging (FLIM) is an attractive microscopy method in the life sciences, yielding information on the sample otherwise unavailable through intensity‐based techniques. A novel Noise‐Corrected Principal Component Analysis (NC‐PCA) method for time‐domain FLIM data is presented here. The presence and distribution of distinct microenvironments are identified at lower photon counts than previously reported, without requiring prior knowledge of their number or of the dye's decay kinetics. A noise correction based on the Poisson statistics inherent to Time‐Correlated Single Photon Counting is incorporated. The approach is validated using simulated data, and further applied to experimental FLIM data of HeLa cells stained with membrane dye di‐4‐ANEPPDHQ. Two distinct lipid phases were resolved in the cell membranes, and the modification of the order parameters of the plasma membrane during cholesterol depletion was also detected.

Noise‐corrected Principal Component Analysis of FLIM data resolves distinct microenvironments in cell membranes of live HeLa cells.     

Correction for contaminant fluorescence in frequency-domain fluorometry

We describe a general method to correct for contaminant fluorescence when using the technique of frequency-domain fluorometry. The method can be applied regardless of the origin of the background signal, from scattered light, impurity fluorescence, or both. The procedure requires measurement of the frequency-dependent phase and modulation of the background at enough frequencies to approximate the decay law of the background. We also describe a general method to propagate the uncertainties in the measured phase and modulation values into the corrected values. This propagation is necessary to ensure proper weighting of the frequency-dependent data in the least-squares fitting algorithms. The practical usefulness of this correction method is demonstrated using frequency-domain data for one and two component mixtures which were deliberately contaminated with scattered light and/or other fluorophores.     

基于6S模型的FY-3A/MERSI可见光到近红外波段大气校正

基于山西省太原市及其周边区域气象台站观测数据,为6S模型提供所需的大气状态参数,对晴空状况下FY-3A/MERSI可见光到近红外波段（250 m分辨率）数据进行大气校正.结果表明：大气校正后,MERSI可见光到近红外波段数据范围加宽、反射率数据普遍增大,波峰高移,各波段反射率的分布更趋平滑;校正后,反映植被状况的归一化植被指数的值域比校正前增大、峰值变高,更接近实际情况;校正后彩色合成图显现出更丰富的地物信息,亮度增大,层次变强,对比度增强,地物信息更接近实际.