A molecular orbital study on the interaction between the cytochrome P-450 and its substrates.

Models for the interaction of the cytochrome P-450 with its substrates, namely for the type I interaction are proposed in which the molecular planes of the aromatic substrate and the porphyrins of P-450 are in parallel. Optical values such as transition energies and oscillator strengths for the isolated P-450 and P-450-substrate complex are calculated by means of molecular orbital method (ASMO SCF CI method), and they are compared with the observed values. The fact that no appreciable shift in the absorption peak of Soret band of P-450 was observed upon addition of substrate is reflected well in the calculation. Similarly, the well-known fact that the absorbance of the P-450 was decreased by mixing it with the substrate is also explained well by the calculated oscillator strength for the isolated P-450 and the stacked complexes. From the good agreement between the calculated results and the observed ones, it is suggested that the proposed models might be true reflections of the interactions between the P-450 and its substrates.     

Fine-Scale Genetic Structure and Demographic History in the Miyako Islands of the Ryukyu Archipelago

The Ryukyu Archipelago is located in the southwest of the Japanese islands and is composed of dozens of islands, grouped into the Miyako Islands, Yaeyama Islands, and Okinawa Islands. Based on the results of principal component analysis on genome-wide single-nucleotide polymorphisms, genetic differentiation was observed among the island groups of the Ryukyu Archipelago. However, a detailed population structure analysis of the Ryukyu Archipelago has not yet been completed. We obtained genomic DNA samples from 1,240 individuals living in the Miyako Islands, and we genotyped 665,326 single-nucleotide polymorphisms to infer population history within the Miyako Islands, including Miyakojima, Irabu, and Ikema islands. The haplotype-based analysis showed that populations in the Miyako Islands were divided into three subpopulations located on Miyakojima northeast, Miyakojima southwest, and Irabu/Ikema. The results of haplotype sharing and the D statistics analyses showed that the Irabu/Ikema subpopulation received gene flows different from those of the Miyakojima subpopulations, which may be related with the historically attested immigration during the Gusuku period (900 − 500 BP). A coalescent-based demographic inference suggests that the Irabu/Ikema population firstly split away from the ancestral Ryukyu population about 41 generations ago, followed by a split of the Miyako southwest population from the ancestral Ryukyu population (about 16 generations ago), and the differentiation of the ancestral Ryukyu population into two populations (Miyako northeast and Okinawajima populations) about seven generations ago. Such genetic information is useful for explaining the population history of modern Miyako people and must be taken into account when performing disease association studies.     

Continuously applied compressive pressure induces bone resorption by a mechanism involving prostaglandin E2 synthesis

In previous research, we devised a specific culture chamber to examine the effect of continuously applied compressive pressure (CCP) on bone formation and resorption. The chamber was infused with compressed mixed gases with different O2 and CO2 composition to maintain the pO2, pCO2, and pH in the culture medium under pressures of +0.5 atm (1.5 atm total) to +2.0 atm (3.0 atm total) at the same levels as those at the ordinary pressure (1 atm). Using the specific culture chamber, we demonstrated that CCP greatly suppressed the differentiation of mouse osteoblast-like MC3T3-E1 cells. The inhibition by CCP appeared to be mediated by prostaglandin E2 (PGE2). In the present study, we examined the effect of CCP on osteoclastic bone resorption. CCP treatment of mouse bone marrow culture markedly increased both the PGE2 production and the number of tartrate-resistant acid phosphatase (TRACP)-positive mononuclear cells (possibly precursors of multinucleated osteoclasts). An autoradiographic study using [125I]-salmon calcitonin showed clearly that those TRACP-positive cells had calcitonin receptors. The CCP effect was the greatest at +1.0 atm (2.0 atm total). Isobutylmethylxanthine potentiated the production of TRACP-positive cells induced by CCP. Adding indomethacin completely inhibited both the TRACP-positive cell formation and the PGE2 production induced by CCP. CCP also increased the release of 45Ca from prelabeled mouse calvaria during later stages (2-6 days) of the 6-day culture period. CCP markedly increased PGE2 but not interleukin 1 in the culture media of mouse calvaria. These results indicate that, besides inhibiting osteoblast differentiation, CCP stimulates bone resorption by generating new osteoclasts through a mechanism involving PGE2 production.     

Discovery of novel serine palmitoyltransferase inhibitors as cancer therapeutic agents

We pursued serine palmitoyltransferase (SPT) inhibitors as novel cancer therapeutic agents based on a correlation between SPT inhibition and growth suppression of cancer cells. High-throughput screening and medicinal chemistry efforts led to the identification of structurally diverse SPT inhibitors 4 and 5. Both compounds potently inhibited SPT enzyme and decreased intracellular ceramide content. In addition, they suppressed cell growth of human lung adenocarcinoma HCC4006 and acute promyelocytic leukemia PL-21, and displayed good pharmacokinetic profiles. Reduction of 3-ketodihydrosphingosine, the direct downstream product of SPT, was confirmed under in vivo settings after oral administration of compounds 4 and 5. Their anti-tumor efficacy was observed in a PL-21 xenograft mouse model. These results suggested that SPT inhibitors might have potential to be effective cancer therapeutics.     

A Transient Rise in Free Mg2+ Ions Released from ATP-Mg Hydrolysis Contributes to Mitotic Chromosome Condensation

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Two new species of deepwater flathead <Emphasis Type="Italic">Bembras</Emphasis> Cuvier, 1829 from the Andaman Sea,eastern Indian Ocean

Two new species of Bembras Cuvier 1829, Bembras leslieknappi sp. nov. and Bembras andamanensis sp. nov., are described from single specimens collected from the Andaman Sea off Myanmar, eastern Indian Ocean, in 2015. The two new species are distinguished from each other and five known congeners by the numbers of anal-fin rays and pectoral-fin rays (15 and 20 in B. leslieknappi vs. 14 and 20–21 in B. andamanensis), forward-slanting body scale rows above the lateral line (80 vs. 74) and upper limb gill rakers (3 vs. 4), as well as by head (41.5 vs. 42.1% SL), snout (14.3 vs. 13.8% SL) and orbit (10.4 vs. 10.9% SL) proportions, and color of the second dorsal (dusky, with blackish spots only on first spine and bases of many soft rays vs. pale, with many scattered blackish spots), pectoral (with a blotch vs. without it) and caudal (both with a broad band) fins.     

<Emphasis Type="Italic">Angiostoma namekuji</Emphasis> n. sp. (Nematoda: Angiostomatidae) from terrestrial slugs on Oshiba Island in the Seto Inland Sea,Japan

A new species of nematode, Angiostoma namekuji n. sp. (Angiostomatidae: Rhabditida), is described from the intestinal lumen of the terrestrial slug Philomycidae gen. sp. collected from Oshiba Island in the Seto Inland Sea, Hiroshima Prefecture, Japan. The new species is recognized by the following characteristics: body length 2,782–3,599 (mean 3,240) μm (male); 4,666–5,532 (5,030) μm (female); lateral field present; pharyngeal corpus with valves in the bulb; male with short tail, c = 35–57 (48), with one denticle; and seven pairs of genital papillae arranged as 1+2/3+1; female with tail having small denticles on distal tip; uterus c.50% of the body size; each ovary long, starting near vulva, not coiled, reflexed and reaching uterus; ovaries not crossing each other. Our phylogenetic tree based on sequences of the nuclear 28S ribosomal RNA gene supported the generic allocation of the new species in Angiostoma Dujardin, 1845.     

Analysis of helicase gene mutations in Japanese Werner’s syndrome patients

The profile of helicase gene mutations was studied in 89 Japanese Werner’s syndrome (WRN) patients by examining the previously described mutations 1– 4 as well as a new mutation found during this study, designated mutation 5. Of 178 chromosomes (89 patients), 89 chromosomes (50%) had mutation 4, 11 (6.2%) chromosomes had mutation 1, and two chromosomes (1.1%) contained mutation 5. Mutations 2 and 3 were not observed in this patient population. The remaining 76 (42.7%) chromosomes had none of these mutations. A significant fraction of all patients (22 total patients, 24.7%) appear to be compound heterozygotes, including those carrying mutations of both types 1 and 4. The genotype analysis of the markers surrounding the WRN helicase gene strongly suggests that most of the chromosomes carrying either mutation 1 or 4 were derived from two single founders. Received: 25 July 1996 / Revised: 20 September 1996     

A new species of deepwater flathead,Bembras adenensis (Scorpaeniformes: Bembridae) from the western Indian Ocean

A new bembrid,Bembras adenensis, is described on the basis of specimens collected from the Gulf of Aden, western Indian Ocean. This species is easily distinguished fromB. japonica, the only known congener of the genus, by the following combination of characters: larger orbital diameter, longer head length, pectoral-fin with a small black blotch near tip of upper rays, 3 gill rakers on upper gill arch, 19 pectoral-fin rays, and 15 anal-fin rays (vs. smaller orbital diameter, shorter head length, pectoral-fin with several small spots forming irregular bands, 2 gill rakers on upper gill arch, usually 17 pectoral-fin rays, and 14 anal-fin rays inB. japonica).