1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine as a substrate of cytochrome P450 2D6: allosteric effects of NADPH-cytochrome P450 reductase

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that produces Parkinsonism symptoms in man, has been examined as a substrate of recombinant human cytochrome P450 2D6. When cumene hydroperoxide is used as an oxygen and electron donor, a single product is formed, identified as 4-phenyl-1,2,3,6-tetrahydropyridine. The K(m) for formation of this product (130 microM) is in agreement with the dissociation constants for MPTP binding to the enzyme determined by optical and nuclear magnetic resonance (NMR) spectroscopy. When the reaction is carried out with nicotinamide adenine dinucleotide phosphate (reduced) (NADPH) and recombinant human NADPH-cytochrome P450 reductase, a second product, identified as 1-methyl-4-(4'-hydroxyphenyl)-1,2,3,6-tetrahydropyridine, is formed in addition to 4-phenyl-1,2,3,6-tetrahydropyridine. The K(m) values for formation of these two products are 19 microM and 120 microM, respectively. Paramagnetic relaxation experiments have been used to measure distances between the protons of bound MPTP and the heme iron, and these have been used to construct models for the position and orientation of MPTP in the active site. For the cytochrome alone, a single mode of binding was observed, with the N-methyl close to the heme iron in a position appropriate for the observed N-demethylation reaction. In the presence of the reductase, the data were not consistent with a single mode of binding but could be explained by the existence of two alternative orientations of MPTP in the active site. One of these, characterized by a dissociation constant of 150 microM, is essentially identical to that observed in the absence of the reductase. In the second, which has a K(d) of 25 microM, the MPTP is oriented so that the aromatic ring is close to the heme iron, in a position appropriate for p-hydroxylation leading to the formation of the product seen only in the presence of the reductase. In the case of codeine, another substrate for cytochrome P450 2D6, the addition of reductase had no effect on the nature of the product formed, the dissociation constant, or the orientation in the binding site. These observations show that NADPH-cytochrome P450 reductase has an allosteric effect on the active site of cytochrome P450 2D6 that affects the binding of some substrates but not others.     

Mössbauer spectroscopic studies of Fe-substituted YIG

Compositional dependence of hyperfine parameters, determined through Mössbauer spectral analysis has been studied for Y_3−xFe_5+xO₁₂ (x = 0.0, 0.1, 0.3 and 0.5) garnet system at 300 K. The Mössbauer spectra have been fitted with three sextets in the ferrimagnetic state corresponding to Fe³⁺ ions at tetrahedral (d), octahedral (a) and dodecahedral (c) sites of the crystal structure. It is observed that isormershift, quadrupole shift and hyperfine field of d-site show no significant variation with Fe³⁺ concentration. The change in hyperfine fields of a- and c-sites with composition (x) has been explained on the basis of strength of exchange integrals, change in isomershift can be understood due to s-electron charge distribution and asymmetric displacement of oxygen ions surrounding the a- and c-sites seems to be responsible for observable quadrupole shift. The magneton number values obtained from magnetization and Mossbauer data are in agreement to those calculated using Neel's three sublattice model of ferrimagnetism.     

A design advisor for the optimal inspection of circularity tolerance

In the wake of growing importance for quality and the need to reduce inspection costs simultaneously, the need for a scientific method of selecting an optimum inspection strategy for coordinate measuring machine (CMM) based inspection has become very important. The inspection error resulting from CMM inspection is greatly affected by the profile irregularities and the sampling strategy, which includes sample size, sampling methods, and algorithms used for form evaluation. This paper describes a system that can recommend an optimal inspection plan based on the needs of the user. A design of experiments (DOE) based approach is used to relate the inspection error with sampling strategies. Surface irregularities are included in the form of lobes formed on the profile. A new two-way model is proposed that works in both directions between the sampling strategy and the performance metrics. The results indicate that the number of lobes and the sampling method used have little impact on the inspection error, while the sample size and form evaluation algorithms have a significant influence. An inspection plan advisor is presented, which provides an inspection plan based on the estimated shape and acceptable measurement error.     

Implementation of bubble sort and the odd-even transposition sort on a rack of transputers

In this short note we discuss implementation of bubble sort and its variant the odd-even transposition sort in a parallel environment consisting of a network of transputers, with the accompanying OCCAM language.     

Revolutionizing supply chain management the theory of constraints way: a case study

This research describes in detail an application of theory of constraints (TOC) and its resulting benefits on the supply chain performance of India's largest lock manufacturing company over a period of seven years. Using TOC's thinking process, the core constraints that had limited the company's performance in the areas of production, distribution, supply group and projects were identified and eliminated. TOC's unique approach helped the company achieve a significant reduction in its finished goods, raw material and work-in-process inventories at various levels across the supply chain. The stock-outs and excess in the distribution system nearly disappeared. The existing lead times saw a drastic reduction while the availability of items increased to nearly 100% despite significant decrease in inventory levels in the supply chain. The inventory turns of the distributors and retailers more than tripled and their profitability increased significantly. The overall sales of the company grew nearly three times during the six years post TOC implementation. TOC's holistic approach helped the company to double its profits and improve its cash position during the Great Recession.     

Co-processing as a tool to improve aqueous dispersibility of cellulose ethers

Cellulose ethers are important materials with numerous applications in pharmaceutical industry. They are widely employed as stabilizers and viscosity enhancers for dispersed systems, binders in granulation process and as film formers for tablets. These polymers, however, exhibit challenge during preparation of their aqueous dispersions. Rapid hydration of their surfaces causes formation of a gel that prevents water from reaching the inner core of the particle. Moreover, the surfaces of these particles become sticky, thus leading to agglomeration, eventually reducing their dispersion kinetics. Numerous procedures have been tested to improve dispersibility of cellulose ethers. These include the use of cross-linking agents, alteration in the synthesis process, adjustment of water content of cellulose ether, modification by attaching hydrophobic substituents and co-processing using various excipients. Among these, co-processing has provided the most encouraging results. This review focuses on the molecular mechanisms responsible for the poor dispersibility of cellulose ethers and the role of co-processing technologies in overcoming the challenge. An attempt has been made to highlight various co-processing techniques and specific role of excipients used for co-processing.     

规范供电企业劳务外包合同文本的必要性

针对国家电网公司组织的历次审计、巡查工作中,劳务外包管理方面出现的"核心业务外包"、"假外包、真派遣"、无安全协议、无保密协议等问题,进行了深入调查分析,提出了规范供电企业劳务外包标准合同文本的主要做法,通过细化工作内容、要求、标准,明确发包方与承包方的义务和费用支付,增加安全、保密协议条款以及考核评价,进一步规范市县...     

Effect of pH on the detailed chemical nature and metal-carbonate species in as synthesized zirconia alumina composites

Zirconia was deposition precipitated on γ-alumina in pH range 7-10 from zirconium oxy-nitrate and soda ash. Zirconium formed its hydroxycarbonate as deduced from ICP-EOS, CHN, and TGA-MS. Higher pH favored formation of carbonate species of zirconium over its hydroxide. TGA-MS indicated formation of three different types of carbonate species. FTIR results corroborated this. Monodentate metal carbonate was observed irrespective of pH of preparation. In addition, bridged bidentate species formed at pH ≤ 8 which changed to chelating bidentate at pH > 8. XRD indicated that all the samples formed tetragonal-zirconia upon calcination irrespective of pH of preparation. Higher pH resulted in smaller crystallites of t-ZrO₂. Changes in chemical moiety with pH reflected on acidity and the deactivation rate for 2-methyl-3-butyn-2-ol which decreased by two orders of magnitude in samples prepared at higher pH. Surface area and pore volume benefited from deposition precipitation. SEM-EDAX showed reasonable distribution of zirconia over γ-Al₂O₃.