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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