The predominant contribution of oligopeptide transporter PepT1 to intestinal absorption of beta-lactam antibiotics in the rat small intestine

Although recent evidence suggests that certain beta-lactam antibiotics are absorbed via a specific transport mechanism, its nature is unclear. To confirm whether peptide transport in the rat can be largely ascribed to the intestinal oligopeptide transporter PepT1, the transporter has been functionally characterized and its significance in the intestinal absorption of beta-lactam antibiotics was evaluated. For evaluation of transport activity complementary RNA (cRNA) of rat PepT1 was synthesized in-vitro and expressed in Xenopus laevis oocytes. cRNA induced uptake of several beta-lactam antibiotics and the dipeptide [14C]glycylsarcosine; this was specifically inhibited by various dipeptides and tripeptides but not by their constituent amino acids or by tetra- or pentapeptides. The transport activity of PepT1 for beta-lactam antibiotics correlated well with their in-vivo intestinal transport and absorption. Furthermore, mutual inhibitory effects on uptake were observed between glyclsarcosine and beta-lactam antibiotics. Hybrid depletion of the functional expression of rat PepT1 in oocytes injected with rat intestinal epithelial total mRNA was studied using an antisense oligonucleotide corresponding to the 5'-coding region of PepT1. In oocytes injected with rat mRNA pre-hybridized with the antisense oligonucleotide against rat PepT1, the uptake of [14C]glycylsarcosine was almost completely abolished, whereas its uptake was not influenced by a sense oligonucleotide for the same region of PepT1. Similarly, the uptake of beta-lactam antibiotics was also reduced by the antisense oligonucleotide against rat PepT1. These results demonstrate that the intestinal proton-coupled oligopeptide transporter PepT1 plays a predominant role in the carrier-mediated intestinal absorption of beta-lactam antibiotics and native oligopeptides in the rat.     

Studies on miscibility in homopolymer/ random copolymer blends by equation of state theory

The miscibility of poly(methyl methacrylate) (PMMA) and styrene-acrylonitrile random copolymers (SAN) blends was investigated on the basis of the Flory—Orwoll—Vrij equation of state theory. To obtain the equation of state parameters (P*, V*_sp, T*: characteristic parameters), the pressure—volume—temperature (PVT) behaviour was measured for PMMA and a series of SANs with various acrylonitrile contents. The exchange energy parameter X_ij was also calculated by fitting the theory to some phase diagrams of PMMA/SAN blends. The Flory—Huggins interaction parameter χ was separated into two contributions based on the equation of state theory for mixtures: the exchange energy term χ_inter and the free volume term χ_free. Both the temperature and copolymer composition dependences of χ_inter and χ_free were estimated by calculations using the equation of state parameters. There exists a region in which χ_inter is negative, leading to a miscibility window in PMMA/SAN blends. However, the immiscibility at high temperatures in the blends cannot be explained only by χ_inter; it is caused by the free volume contribution, χ_free. The miscibility window behaviour in PMMA/SAN blends may be explained within the framework of the equation of state theory.     

TEM characterization of Ge precipitates in an Al-1.6at% Ge alloy

The growth mechanism and morphology of Ge precipitates in an Al-Ge alloy was characterized by a combination of in-situ transmission electron microscopy, high-resolution transmission electron microscopy and three-dimensional electron tomography. Anisotropic growth of rod-shaped Ge precipitates was observed by in-situ transmission electron microscopy over different time periods, and faceting of the precipitates was clearly seen using high-resolution transmission electron microscopy and three-dimensional electron tomography. This anisotropic growth of rod-shaped Ge precipitates was enhanced by vacancy concentration as proposed previously, but also by surface diffusion as observed during the in-situ experiment. Furthermore, a variety of precipitate morphologies was identified by three-dimensional electron tomography.     

Orientation dependence of fracture toughness measured by indentation methods and its relation to surface energy in single crystal silicon

Fracture toughness of silicon crystals has been investigated using indentation methods, and their surface energies have been calculated by molecular dynamics (MD). In order to determine the most preferential fracture plane at room temperature among the crystallographic planes containing the 〈001〉, 〈110〉 and 〈111〉 directions, a conical indenter was forced into (001), (110) and (111) silicon wafers at room temperature. Dominant {110}, {111} and {110} cracks were introduced from the indents on (001), (011) and (111) wafers, respectively. Fracture occurs most easily along {110}, {111} and {110} planes among the crystallographic planes containing the 〈001〉, 〈011〉 and 〈111〉 directions, respectively. A series of surface energies of those planes were calculated by MD to confirm the orientation dependence of fracture toughness. The surface energy of the {110} plane is the minimum of 1.50 Jm⁻² among planes containing the 〈001〉 and 〈111〉 directions, respectively, and that of the {111} plane is the minimum of 1.19 Jm⁻² among the planes containing the 〈011〉 direction. Fracture toughness of those planes was also derived from the calculated surface energies. It was shown that the K _IC value of the {110} crack plane was the minimum among those for the planes containing the 〈001〉 and 〈111〉 directions, respectively, and that K _IC value of the {111} crack plane was the minimum among those for the planes containing the 〈011〉 direction. These results are in good agreement with that obtained conical indentation.     

HVEM study of crack-tip dislocations in Si crystals prepared by FIB and twin-blade cutting method

Crack-tip dislocations in silicon crystals have been examined by using high-voltage electron microscopy. Cracks were introduced by the Vickers indentation method at room temperature and the indented specimens were annealed at high temperatures to induce dislocations around crack tips under the presence of residual stress due to the indentation. A selected area around a crack tip was thinned by a focused ion beam (FIB) technique. Specimens were thinned in advance by a twin-blade cutting (TBC) method, which is a simple cutting process for saving FIB machine time. A combination of FIB and TBC can be a useful thinning procedure for the efficient preparation of transmission electron microscopy specimens. Characteristic dislocation structures were observed around the tip of a crack, aiding the elucidation of dislocation processes, which is essential to increase the fracture toughness of materials.     

Orientation of nanowires consisting of poly(3-hexylthiophene) using strong magnetic field

Nanowires consisting of regioregular poly(3-hexylthiophene) (P3HT) as a conducting polymer were prepared using p-xylene. Magnetic processing of the nanowires was carried out using two superconducting magnets with horizontal (B_max = 8 T) and vertical (B_max = 10 T) directions. The formation of the nanowires was confirmed by atomic force microscopy (AFM) measurement. The results from the AFM images and the polarized absorption spectra on glass plates indicated that the nanowires partly oriented themselves with their long axes, which are parallel to the π–π stacking direction, being perpendicular to the magnetic field. The magnetic orientation is most likely ascribed to anisotropy in the magnetic susceptibilities of the ordered P3HT in the nanowires.     

Asymmetric Hydrogenation of 3‐Amido‐2‐arylpyridinium Salts by Triply Chloride‐Bridged Dinuclear Iridium Complexes Bearing Enantiopure Diphosphine Ligands: Synthesis of Neurokinin‐1 Receptor Antagonist Derivatives

We describe a most straightforward synthetic method for preparing neurokinin‐1 (NK1) receptor antagonist derivatives by asymmetric hydrogenation of 3‐amido‐2‐arylpyridinium salts using dinuclear iridium complexes with enantiopure diphosphine ligands, affording the corresponding chiral piperidines in high cis‐diastereoselectivity (>95:5) and moderately high enantioselectivity (up to 86%). Deprotection treatments afforded the NK‐1 receptor antagonist (+)‐CP‐99,994 (83% ee). In addition, we observed unique additive effects of 10‐camphorsulfonic acid in the asymmetric hydrogenation of 3‐amido‐2‐arylpyridinium salts.

     

Iridium‐Catalyzed Asymmetric Hydrogenation of Tosylamido‐Substituted Pyrazines for Constructing Chiral Tetrahydropyrazines with an Amidine Skelton

Dinuclear triply chloro‐bridged iridium(III) complexes bearing chiral diphosphine ligands catalyze the asymmetric hydrogenation of tosylamido‐substituted pyrazines to give the corresponding chiral tetrahydropyrazines with an amidine skeleton in high yield and with high enantioselectivity. Addition of N,N‐dimethylanilinium bromide enhanced the catalytic activity of the iridium complexes and also increased the enantioselectivity of the products by trapping the hydrogenated amine products with HBr from N,N‐dimethylanilinium bromide. The amidine skeleton of the products could be transformed to give chiral piperazinones and piperazines without loss of enantioselectivity.

     

Antiatherogenic effects of the antioxidant BO-653 in three different animal models

Antioxidants have been proposed to have antiatherogenic potential by their inhibition of low density lipoprotein (LDL) oxidation. Here, we report an antioxidant, BO-653 (2,3-dihydro-5-hydroxy-2, 2-dipentyl-4,6-di-tert-butylbenzofuran), designed to exhibit antioxidative potency comparable to that of alpha-tocopherol, but yet possess a high degree of lipophilicity comparable to that of probucol. BO-653 exhibits a high affinity for LDL and is well distributed in aortic vessels in vivo. In atherosclerosis models of rabbits and mice, BO-653 has been shown to be able to suppress the formation of atherosclerotic lesions without untoward side effects. Specifically, there was no reduction of high density lipoprotein levels. This antioxidant provides additional evidence in support of the oxidized-LDL hypothesis, and itself is a promising candidate antioxidant for clinical use.