We discovered a nonpeptidic compound, TAK-070, that inhibited BACE1, a rate-limiting protease for the generation of A␤ peptides that are considered causative for Alzheimer's disease (AD), in a noncompetitive manner. TAK-070 bound to full-length BACE1, but not to truncated BACE1 lacking the transmembrane domain. Short-term oral administration of TAK-070 decreased the brain levels of soluble A␤, increased that of neurotrophic sAPP␣ by ϳ20%, and normalized the behavioral impairments in cognitive tests in Tg2576 mice, an APP transgenic mouse model of AD. Six-month chronic treatment decreased cerebral A␤ deposition by ϳ60%, preserving the pharmacological efficacy on soluble A␤ and sAPP␣ levels. These results support the feasibility of BACE1 inhibition with a noncompetitive inhibitor as disease-modifying as well as symptomatic therapy for AD.

Homoepitaxial hydride vapor phase epitaxy (HVPE) growth on GaN substrates grown with a Na-flux method, which is the most promising approach for fabrication of large-diameter, low-dislocation-density, fast-growing GaN wafers, was attempted for the first time. We found that, when different growth methods are combined, the differences in oxygen concentrations between a seed and grown crystal must be eliminated to maintain the crystallographic quality of the seed. Two kinds of Na-flux-grown seed crystals were prepared; one had a surface composed of c, {101̅2}, and {101̅1} planes, the other a surface composed entirely of c-planes. Both crystals were sliced, ground, mirror-polished, and applied for 500-μm-thick HVPE growth. In the former sample, the seed crystal generated fine cracks, and the epitaxially grown layer had a rough surface and included many dislocations; the latter sample showed no fault. For clarifying the mechanism of crystal degradation, we investigated the lattice constants of each growth sector using an X-ray microbeam and found that lattice constants in the {101̅1}-growth sector were expanded compared to those in other growth sectors due to oxygen impurities. These values were estimated to be much larger than those of HVPE crystals, resulting in the crystal degradation after the HVPE growth by a lattice mismatch.

Dislocation-free InP and GaAs crystals have been grown by liquid encapsulation by means of an ’’impurity doping’’ procedure. It was found that grown-in dislocations were diminished when the crystals were pulled from melts to which certain kinds of impurities were added. The impurity effect on grown-in dislocation density was examined for Zn, S, and Te in InP, and Zn, S, Te, Al, and N in GaAs. It was found that these impurities were effective for reducing the grown-in dislocation density, except for Zn in GaAs. The effectiveness of impurities for reducing the dislocation density of the crystals was ascribed to the strength of the bonds formed between the substitutional impurity atoms and host crystal atoms surrounding the impurity atoms. The anomaly of Zn in GaAs was presumed to originate from the interstitial Zn.

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Synchrotron radiation total reflection X-ray fluorescence spectroscopy (SR-TXRF) was utilized to analyze various trace elements in small amounts of drugs of abuse. Sample amounts of 1 L solutions containing 10 g of drugs (methamphetamine, amphetamine, 3,4-methylene-dioxymethamphetamine, cocaine, and heroin) were spotted on silicon wafers for direct analysis. In addition, a leaflet of marijuana was set directly on a silicon wafer, and opium in the form of a soft lump was smeared on another silicon wafer for analysis. In these experiments, about 10 pg of contaminant elements could be detected. For example, in a seized methamphetamine sample, iodine was found, which could be indicative of syn-thetic route. In seized 3,4-methylenedioxymethamphetamine samples, variable amounts of phosphorus, calcium, sulfur, and potassium were found, which could not be detected in a control 3,4-methylenedioxymethamphetamine sample. For marijuana and opium, two spectral patterns were ob-tained that were far different from each other and could be easily discriminated. Using SR-TXRF, pg amounts of each trace element in 10 g of var-ious drugs can be easily detected, which is not the case either for a standard TXRF experimental system or for other elemental analysis techniques.

Results of phase-contrast X-ray imaging are presented. The optical system employed consisted of a successive arrangement of horizontal and vertical (+, -) double crystals taking asymmetric Bragg reflection with an asymmetry factor of ∼0.2. The original beam size was thus expanded in both directions and the field of view actually obtained was ∼5×5 mm2. Boundary structures in samples were clearly observed with much higher contrast than those obtained in conventional absorption-contrast imaging. Since this method works in real time, it will provide a new X-ray imaging diagnosis technique for in situ observation over a large area of the samples.

A thin silicon nano-overlayer (SNOL) fabricated by oxidation and etchback in a separation by implantation of oxygen wafer was investigated by grazing incident x-ray diffraction at incident angles between 0.01° and 0.1° below the critical angle of total reflection (0.18° ). We measured {220} reflections by probing the sample in depth and found that the SNOL has finite domains under strain close to the surface. We also found that annealing the sample up to 1000 °C significantly reduced inhomogeneous in depth strain and increased the size of the domains in the surface region of the SNOL.

Two topography experimental stations are presently available at SPring-8. The first, constructed at the short-length bending magnet beam line BL28, is designed to perform white- and selected wide-energy-range x-ray topography. The other is a high-resolution diffraction topography station located on the medium-length bending magnet beam line BL20, where the incoming beam displays a large cross section and high degree of parallelism. This allows us to observe fine structures of three-dimensionally large crystals used in industry if high energy is employed. The construction concepts, as well as first, selected experimental results are presented.