Effects of ML-236B (compactin) on sterol synthesis and low density lipoprotein receptor activities in fibroblasts of patients with homozygous familial hypercholesterolemia

金沢大学大学院医学系研究科　We studied biochemical genetics of low density lipoprotein (LDL) receptor mutations in fibroblasts from six homozygous and five heterozygous patients with familial hypercholesterolemia (FH). Three of six homozygotes are receptor-negative type and the other three homozygotes are receptor-defective type. In the cells from three receptor-negative homozygotes, the receptor binding, internalization, and degradation of 125I-LDL were 0.5 ± 0.3 ng/mg protein (mean ± SEM), 14 ± 8 and 8 ± 6 ng/mg protein per 6 h (four normal cells; 44 ± 3, 386 ± 32, and 1,335 ± 214 ng/mg protein per 6 h), respectively. In the cells from three receptor-defective homozygotes, the receptor binding, internalization, and degradation of 12:5I-LDL were 6 ± 2, 29 ± 8, and 90 ± 32 ng/mg protein per 6 h, respectively. In these six homozygotes, two pairs of siblings are included. Two siblings in the same family were classified as receptor-negative and two siblings in another family were classified as receptor-defective. The receptor-negative phenotypes and the receptor-defective phenotypes bred true in individual families. The cells from five heterozygotes showed ~46% of the normal activities of receptor. ML-236B, competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), completely inhibited the incorporation of [14C]acetate into digitonin-precipitable sterols in fibroblasts from normal subjects and heterozygous and homozygous patients with FH with the concentration of 0.5 μg/ml. However, at 0.05 μg/ml of ML-236 B sterol synthesis in fibroblasts from homozygotes was not completely suppressed in contrast to normal and heterozygous cells. Moreover, after preincubation with 0.05 μg/ml of ML-236B for 24 h in medium containing lipoproteins, sterol synthesis in the cells from receptor-negative homozygote showed 75% of the initial activity compared with that of 25% without preincubation. In the cells from a normal subject and heterozygote, sterol synthesis was inhibited even after preincubation. These results suggest that (a) the inhibitory effect of ML-236B is overcome in homozygote cells by their high intracellular levels of HMG-CoA reductase and (b) that a higher dose of ML-236B may be required to lower serum cholesterol levels in FH homozygotes than in heterozygotes

The ASTRO-H X-ray Observatory

The joint JAXA/NASA ASTRO-H mission is the sixth in a series of highly successful X-ray missions initiated by the Institute of Space and Astronautical Science (ISAS). ASTRO-H will investigate the physics of the high-energy universe via a suite of four instruments, covering a very wide energy range, from 0.3 keV to 600 keV. These instruments include a high-resolution, high-throughput spectrometer sensitive over 0.3-2 keV with high spectral resolution of Delta E < 7 eV, enabled by a micro-calorimeter array located in the focal plane of thin-foil X-ray optics; hard X-ray imaging spectrometers covering 5-80 keV, located in the focal plane of multilayer-coated, focusing hard X-ray mirrors; a wide-field imaging spectrometer sensitive over 0.4-12 keV, with an X-ray CCD camera in the focal plane of a soft X-ray telescope; and a non-focusing Compton-camera type soft gamma-ray detector, sensitive in the 40-600 keV band. The simultaneous broad bandpass, coupled with high spectral resolution, will enable the pursuit of a wide variety of important science themes.Comment: 22 pages, 17 figures, Proceedings of the SPIE Astronomical Instrumentation "Space Telescopes and Instrumentation 2012: Ultraviolet to Gamma Ray

Hitomi (ASTRO-H) X-ray Astronomy Satellite

The Hitomi (ASTRO-H) mission is the sixth Japanese x-ray astronomy satellite developed by a large international collaboration, including Japan, USA, Canada, and Europe. The mission aimed to provide the highest energy resolution ever achieved at E  >  2  keV, using a microcalorimeter instrument, and to cover a wide energy range spanning four decades in energy from soft x-rays to gamma rays. After a successful launch on February 17, 2016, the spacecraft lost its function on March 26, 2016, but the commissioning phase for about a month provided valuable information on the onboard instruments and the spacecraft system, including astrophysical results obtained from first light observations. The paper describes the Hitomi (ASTRO-H) mission, its capabilities, the initial operation, and the instruments/spacecraft performances confirmed during the commissioning operations for about a month

Myosin XI-i Links the Nuclear Membrane to the Cytoskeleton to Control Nuclear Movement and Shape in Arabidopsis.

The cell nucleus communicates with the cytoplasm through a nucleocytoplasmic linker that maintains the shape of the nucleus and mediates its migration. In contrast to animal nuclei, which are moved by motor proteins (kinesins and dyneins) along the microtubule cytoskeleton [1, 2], plant nuclei move rapidly and farther along an actin filament cytoskeleton [3]. This implies that plants use a distinct nucleocytoplasmic linker for nuclear dynamics, although its molecular identity is unknown. Here, we describe a new type of nucleocytoplasmic linker consisting of a myosin motor and nuclear membrane proteins. In the Arabidopsis thaliana mutant kaku1, nuclear movement was impaired and the nuclear envelope was abnormally invaginated. The responsible gene was identified as myosin XI-i, which encodes a plant-specific myosin. Myosin XI-i is specifically localized on the nuclear membrane, where it physically interacts with the outer-nuclear-membrane proteins WIT1 and WIT2. Both WIT proteins are required for anchoring myosin XI-i to the nuclear membrane and for nuclear movement. A striking feature of plant cells is dark-induced nuclear positioning in mesophyll cells. A deficiency of either myosin XI-i or WIT proteins diminished dark-induced nuclear positioning. The unique nucleocytoplasmic linkage in plants might enable rapid nuclear positioning in response to environmental stimuli

Effects of ML-236b (compactin) on sterol synthesis and low density lipoprotein receptor activities in fibroblasts of patients with homozygous familial hypercholesterolemia. J Clin Invest

A B S T R A C T We studied biochemical genetics of low density lipoprotein (LDL) receptor mutations in fibroblasts from six homozygous and five heterozygous patients with familial hypercholesterolemia (FH 29 December 1980. 1532 tion of 0.5 Ag/ml. However, at 0.05 ,ug/ml of sterol synthesis in fibroblasts from homozygotes was not completely suppressed in contrast to normal and heterozygous cells. Moreover, after preincubation with 0.05 ,ug/ml of ML-236B for 24 h in medium containing lipoproteins, sterol synthesis in the cells from receptornegative homozygote showed 75% of the initial activity compared with that of 25% without preincubation. In the cells from a normal subject and a heterozygote, sterol synthesis was inhibited even after preincubation. These results suggest that (a) the inhibitory effect of ML-236B is overcome in homozygote cells by their high intracellular levels of HMG-CoA reductase and (b) that a higher dose of ML-236B may be required to lower serum cholesterol levels in FH homozygotes than in heterozygotes

Alexia due to the left posterior inferior temporal lobe lesion : Examination of lexical and orthographic properties

1. はじめに 2. 方法 3. 結果・考察 4. まとめ50周年記念寄稿論文We reported a case of alexia due to the left posterior inferior temporal lobe lesion. The results of systematic language assessment, which was undertaken in 8 weeks after traumatism using Standard Language Test of Aphasia revealed relatively intact reading ability of kana and kanji one character. Nevertheless, she exhibited many errors when she read two-word kanji compounds. To test her orthographic input processing ability, lexical decision task in SALA (Sophia Analysis of Language in Aphasia) test battery was used. Also, we performed a reading aloud task for the same materials. Furthermore, we examined effects on linguistic variables: lexical properties and orthographic properties. As a result of close examination of linguistic variables revealed orthographic familiarity (for words and for one character) was associated with correct reading. Moreover, her responses of nonword reading task showed that she selected a reading with high pronunciation plausibility