Enantioselective Pharmacokinetics of α-Lipoic Acid in Rats

α-Lipoic acid (LA) is widely used for nutritional supplements as a racemic mixture, even though the R enantiomer is biologically active. After oral administration of the racemic mixture (R-α-lipoic acid (RLA) and S-α-lipoic acid (SLA) mixed at the ratio of 50:50) to rats, RLA showed higher plasma concentration than SLA, and its area under the plasma concentration-time curve from time zero to the last (AUC) was significantly about 1.26 times higher than that of SLA. However, after intravenous administration of the racemic mixture, the pharmacokinetic profiles, initial concentration (C₀), AUC, and half-life (T_1/2) of the enantiomers were not significantly different. After oral and intraduodenal administration of the racemic mixture to pyrolus-ligated rats, the AUCs of RLA were significantly about 1.24 and 1.32 times higher than that of SLA, respectively. In addition, after intraportal administration the AUC of RLA was significantly 1.16 times higher than that of SLA. In conclusion, the enantioselective pharmacokinetics of LA in rats arose from the fraction absorbed multiplied by gastrointestinal availability (F_aF_g) and hepatic availability (F_h), and not from the total clearance.     

DL-alpha-tocopherol acetate mitigates maternal hyperthermia-induced pre-implantation embryonic death accompanied by a reduction of physiological oxidative stress in mice

Maternal hyperthermia induces pre-implantation embryo death, which is accompanied by enhanced physiological oxidative stress. We evaluated whether the administration of DL-alpha-tocopherol acetate (TA) to hyperthermic mothers mitigated pre-implantation embryo death. Mice were exposed to heat stress (35 degrees C, 60% relative humidity) for 12 h or not heated (25 degrees C) on the day of mating. Twelve hours before the beginning of temperature treatment, TA was injected intraperitoneally at a dose of 1 g/kg body weight. After the treatment, zygotes were recovered and the developmental abilities and intracellular glutathione (GSH) levels were evaluated. Another set of mice, with or without TA treatment, was exposed to heat stress for 12, 24 and 36 h, and the urinary levels of the oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured. Heat stress significantly decreased the blastocyst development rate and the GSH content in zygotes, as compared with the non-heat-stressed embryos, while TA administration significantly mitigated the deleterious effects of heat stress with regard to both parameters. Moreover, although the urinary levels of 8-OHdG gradually increased according to the duration of heat exposure, with or without TA administration, the levels were lower in the TA-administered group than in the placebo-injected mice. These results suggest that heat stress enhances physiological oxidative stress, and that TA administration alleviates the hyperthermia-induced death of pre-implantation embryos by reducing physiological oxidative stress.     

Structure-Based Design,Synthesis, and Biological Evaluation of Imidazo[4,5-b]pyridin-2-one-Based p38 MAP Kinase Inhibitors: Part 1

We identified a lead series of p38 mitogen-activated protein kinase inhibitors using a structure-based design strategy from high-throughput screening of hit compound 1 . X-ray crystallography of 1 with the kinase showed an infrequent flip of the peptide bond between Met109 and Gly110, which was considered to lead to high kinase selectivity. Our structure-based design strategy was to conduct scaffold transformation of 1 with maintenance of hydrogen bond interactions with the flipped hinge backbone of the enzyme. In accordance with this strategy, we focused on scaffold transformation to identify imidazo[4,5-b]pyridin-2-one derivatives as potent inhibitors of the p38 MAP kinase. Of the compounds evaluated, 21 was found to be a potent inhibitor of the p38 MAP kinase, lipopolysaccharide-induced tumor necrosis factor-α (TNF-α) production in human monocytic leukemia cells, and TNF-α-induced production of interleukin-8 in human whole blood cells. Herein we describe the discovery of potent and orally bioavailable imidazo[4,5-b]pyridin-2-one-based p38 MAP kinase inhibitors that suppressed cytokine production in a human whole blood cell-based assay.     

电磁搅拌下Cr钢柱状晶向等轴晶转变准则(二)

在枝晶破碎理论基础上,分析了电磁搅拌强度及合金元素碳、铬含量对钢凝固组织的影响。对柱状晶向等轴晶转变(CET)的准则进行讨论。发现线性电磁搅拌下的CET准则对Cr钢仍然有效。得到了临界固相分率、枝晶间流速和液体平均流速关系。发现铬含量提高使柱状晶向等轴晶转变更难。     

Thermal decomposition of alkaline-earth metal hydride and ammonia borane composites

We demonstrate a method to improve the promising hydrogen storage capabilities of ammonia borane by making composites with alkaline-earth metal hydrides using ball-milling technique. The ball-milling for the mixtures of alkaline-earth metal hydride (MgH₂ or CaH₂) and ammonia borane (AB) yields a destabilization compared with the ingredient of the mixture, showing the hydrogen capacity of 8.7 and 5.8 mass% at easily accessible dehydrogenation peak temperatures of 78 and 72 °C, respectively, without the unwanted by-product borazine. Through detailed analyses on the dehydrogenation performance of the composite at various ratios in the hydride and AB, we proposed a different chemical activation mechanism from that in the LiH/AB and NaH/AB systems reported in a previous literature.     

A probabilistic static fatigue model for transverse cracking in CFRP cross-ply laminates

This paper presents a delayed-fracture model for transverse cracking in CFRP cross-ply laminates under static fatigue loading. First, a delayed-fracture model for a crack in a brittle material was established on the basis of the slow crack growth (SCG) concept in conjunction with a probabilistic fracture model using the three-parameter Weibull distribution. Second, the above probabilistic SCG model was applied to transverse cracking in cross-ply laminates under static fatigue loading. The stress and the length of the unit element in the transverse layers were calculated with the aid of a shear-lag analysis, taking the residual stress into account. The transverse crack density was expressed as a function of applied stress and time with the parameters in the Paris law and the Weibull distribution function specified, in addition to the mechanical and geometrical properties. Unknown parameters were determined from experiment data gathered in static tensile and static fatigue tests. The reproduced transverse crack density at various applied loads agreed well with the experiment results.     

A 1/2-in 1.3 M-pixel progressive-scan IT-CCD for digital stillcamera applications

A 1/2-in 1.3 M-pixel progressive-scan interline-transfer charge-coupled-device (IT-CCD) image sensor has been developed for small, low-power mega-pixel digital still cameras (DSCs). The pixel size as small as 5 μm square makes small-size progressive-scan IT-CCD (8.3×7.1 mm²) for the SXGA format. A two-phase-drive horizontal-CCD with phosphorus-implanted storage regions helps reduce the driving voltage to 2.5 V, resulting in the power consumption of the device being as low as 146 mW. A new source-follower amplifier with separate p-well driver transistors achieves 12% higher gain than that obtained using a conventional amplifier. An overflow drain with a self-adjusting potential barrier can instantly remove superfluous charges in vertical-CCDs just before an exposure period, which enables DSCs to perform such functions as quick auto-focusing and dark-current removal. New dual operation modes for still and motion pictures can provide not only high-resolution color signals in a 15-frame/s 1050-line progressive mode but also wide-dynamic-range color signals in a 30-frame/s 525-line progressive mode. The latter mode employs a pixel-exchange-and-mix readout operation that helps halve the number of scanning lines with no loss in sensitivity and color information     

Preparation of partly hydrophobized,crosslinked polyacrylamide particles by terpolymerization of acrylamide/ N,N‐methylenebisacrylamide/styrene in inverse microemulsion

Free‐radical polymerization of a termonomer system comprising acrylamide (AAm) N,N ′‐methylenebisacrylamide (MBAAm) and styrene (S) initiated by water‐soluble ammonium peroxodisulphate (APS) or by toluene‐soluble dibenzoyl peroxide (DBP) in inverse microemulsion (toluene/S/AOT//water//AAm/MBAAm), leads to the formation of partly hydrophobized crosslinked polymer particles of tailored chemical composition, degree of crosslinking and polymer particle size. Styrene strongly decreases the rate of terpolymerization, while the presence of MBAAm has almost no effect on the polymerization rates observed. This conclusion is valid for both APS and DBP initiators. Increase of the S/T mass ratio (T is toluene) in inverse microemulsion leads to an increase of polymer particle diameter from about 20 nm to about 50 nm attributed to toluene swelling of the styrene‐rich structural moieties of AAm‐co‐S copolymer located on the surface of polymer particles. Polymerization kinetics measurements pointed to the important role of exiting water soluble AAm and MBAAm monomer radicals generated by thermal decomposition of APS in water pools of inverse micelles for initiation of polymerization reactions of sparingly water‐soluble S monomer in the oil‐phase of the inverse microemulsion. It was shown that the polymerization and copolymerization reactions of S in the presence of AAm and/or MBAAm are effectively initiated by water‐soluble APS and also by oil‐soluble DBP initiators. During dialysis the polymerized single‐phase water/oil Winsor IV inverse microemulsion gradually converts itself into a two‐phase oil/water Winsor I dispersion system with volume fraction of aqueous phase Φ_aw ≈ 0.950. The water phase contains water swelled, crosslinked polymer particles of diameters 80–300 nm. During dialysis, toluene and the sodium salt of bis(2‐ethyl hexyl)sulphosuccinic acid (AOT) partition between the oil phase of the dialysed dispersion system and the water dialysate. After evaporation of water from the dialysed inverse microemulsion, solid, dried, crosslinked polymer particles in the form of a transparent film, almost uncontaminated by AOT surfactant, were obtained. © 2000 Society of Chemical Industry     

Peptide-Mediated Gene Transfer into Marine Purple Photosynthetic Bacteria

Use of photosynthetic organisms is one of the sustainable ways to produce high-value products. Marine purple photosynthetic bacteria are one of the research focuses as microbial production hosts. Genetic transformation is indispensable as a biotechnology technique. However, only conjugation has been determined to be an applicable method for the transformation of marine purple photosynthetic bacteria so far. In this study, for the first time, a dual peptide-based transformation method combining cell penetrating peptide (CPP), cationic peptide and Tat-derived peptide (dTat-Sar-EED) (containing D-amino acids of Tat and endosomal escape domain (EED) connected by sarcosine linkers) successfully delivered plasmid DNA into Rhodovulum sulfidophilum, a marine purple photosynthetic bacterium. The plasmid delivery efficiency was greatly improved by dTat-Sar-EED. The concentrations of dTat-Sar-EED, cell growth stage and recovery duration affected the efficiency of plasmid DNA delivery. The delivery was inhibited at 4 °C and by A22, which is an inhibitor of the actin homolog MreB. This suggests that the plasmid DNA delivery occurred via MreB-mediated energy dependent process. Additionally, this peptide-mediated delivery method was also applicable for E. coli cells. Thus, a wide range of bacteria could be genetically transformed by using this novel peptide-based transformation method.