Discovery of heteroaryl sulfonamides as new EP1 receptor selective antagonists

4-({2-[Isobutyl(phenylsulfonyl)amino]-5-(trifluoromethyl)phenoxy}methyl)benzoic acid (1) is a functional PGE2 antagonist selective for EP1 receptor subtype. Analogs of 1, in which the phenyl-sulfonyl moiety has been replaced with more hydrophilic heteroarylsulfonyl moieties, exhibited more optimized antagonist activity, while some of them showed in vivo antagonist activity. Structure-activity relationship (SAR) studies are also presented.     

Ribosome biogenesis factor OLI2 and its interactor BRX1-2 are associated with morphogenesis and lifespan extension in Arabidopsis thaliana

Mutations that reduce the expression of ribosomal proteins (RPs) or limit the activity of ribosome biogenesis-related factors frequently cause physiological and morphological changes in Arabidopsis. Arabidopsis OLI2/NOP2A, a homolog of yeast Nop2, encodes a nucleolar methyltransferase that is required for the maturation of the 25S ribosomal RNA of the 60S large ribosomal subunit. Mutant oli2 plants exhibit pointed leaves and shortened primary roots. In this study, detailed phenotypic analysis of oli2 mutant and OLI2 overexpressor lines revealed a range of phenotypes. Seeds produced by oli2 mutant and OLI2 overexpressor plants were lighter and heavier than wild-type seeds, respectively. Seeds of the oli2 mutant also showed delayed germination, whereas seeds from the OLI2 overexpressor lines germinated earlier than the wild type. The oli2 mutant also had fewer and shorter lateral roots than the wild type. The lateral root development phenotype in the oli2 mutant was similar to that of auxin-related mutants, but was not enhanced by exogenously supplied auxin. Furthermore, the oli2 mutant and OLI2 overexpressor lines were hypersensitive and less sensitive to high concentrations of sugar, respectively. Split-GFP-based bimolecular fluorescence complementation analysis revealed that OLI2 interacted with a nucleolar protein, BRX1-2, which is involved in rRNA processing for the large ribosomal subunit. Moreover, overexpression of OLI2 and BRX1-2 caused similar morphological changes, including extension of plant lifespans. These results suggest that the functions of OLI2 and its interactor BRX1-2 are intimately associated with a range of developmental events in Arabidopsis.     

Molecular phylogeny of the yellow peach moth,Conogethes punctiferalis (Lepidoptera: Crambidae): distribution of two genetic lineages across Japan

Mating disruption using synthetic sex pheromones is an effective pest-control method to prevent the evolution of insecticide resistance. Although the sex pheromone of the yellow peach moth Conogethes punctiferalis (Guenée) (Lepidoptera, Crambidae) has already been identified and artificially synthesized, mating disruption in the field has been less successful than expected. Such ineffectiveness may be caused by genetic variation in the attractiveness of the sex pheromone across moth populations. To evaluate this possibility, we evaluated the genetic population structure of this species across 10 populations in Japan. We found that two clades were present at the mtDNA COI region, each clade was sympatrically distributed, and no genetic structure was detected among the populations. In addition, the frequencies of the two clades did not differ between the samples in pheromone traps using two types of blend and those hand collected from infested fruit. Our mating experiment revealed random mating between the two clades. Our results strongly suggest that the genetic variation in the attractiveness of the sex pheromone is minimal and symmetrical gene flow likely occurs between the clades in the field.

     

4D modeling in a gimbaled linear accelerator by using gold anchor markers

Purpose

The purpose of this study was to verify whether the dynamic tumor tracking (DTT) feature of a Vero4DRT system performs with 10-mm-long and 0.28 mm diameter gold anchor markers.

Analysis of Factors That Determine Weight Gain during Smoking Cessation Therapy

Cigarette smokers are generally known to gain weight after quitting smoking, and such weight gain is thought to contribute to the worsening of glucose tolerance. While smoking cessation therapy such as nicotine replacement is useful to minimize post-cessation weight gain, substantial gain occurs even during the therapy. The purpose of the present study was to identify factors associated with weight gain during smoking cessation therapy. We evaluated 186 patients(132 males and 54 females)who visited our outpatient clinic for smoking cessation, and successfully achieved smoking abstinence. We performed gender-adjusted regression analysis for the rate of BMI increase from the beginning of cessation to 3 months after initiation. Furthermore, we performed multivariate analysis to investigate factors that determine the BMI increase after smoking cessation. The mean BMI significantly (p<0.0001) increased from 23.5±3.6 kg/m² at the initial consultation to 23.9±3.8 kg/m² at 3 months after the start of therapy. There was no significant difference in the extent of BMI increase between nicotine patch and varenicline therapy groups. Factors significantly correlated with the %BMI increase at 3 months after the start of therapy were triglyceride (p = 0.0006, βa = 0.260), high-density lipoprotein cholesterol (p = 0.0386, βa = −0.168), daily cigarette consumption (p = 0.0385, βa = 0.154), and the Fagerström Test for Nicotine Dependence (FTND) score (p = 0.0060, βa = 0.203). Stepwise multivariate analysis demonstrated that triglyceride and the FTND score were the factors determining the post-cessation BMI increase and that the FTND score was the strongest one. The present study demonstrated that smokers with a high FTND score are more likely to gain weight during smoking cessation therapy. Thus, smokers with a high nicotine dependency may require intervention against weight gain in the cessation clinic.     

Properties of Glycomacropeptide and Para-K-casein Derived from Human K-Casein and Comparison of Human and Bovine K-Caseins as to Susceptibility to Chymosin and Pepsin

The nutritional efficiency of quinolinic acid as a substitute for nicotinic acid was investigated using weanling rats Of the Sprague Dawley strain (3-weeks old) fed a nicotinic acid-free, tryptophan-limited diet containing various amounts of nicotinic acid or quinolinic acid. Judging from the growth response, food efficiency ratio, levels of NAD activity in the blood, liver, brain and upper small intestine, and urinary excretion of niacin we have concluded that exogenous quinolinic acid is approximately 1/9 as active as nicotinic acid. As many foods contain quinolinic acid, dietary quinolinic acid cannot be ignored from the standpoint of tryptophan and nicotinic acid replacement.     

cDNA and deduced amino acid sequences of apolipophorin-IIIs from Bombyx mori and Bombyx mandarina

The cDNA sequence for apolipophorin-III from two strains of Bombyx mori (N4 and P50) and the Japanese and Chinese strains of Bombyx mandarina were determined. Both the cDNA and deduced amino acid sequences of the four apolipophorin-IIIs were highly similar (95-98%). The four Bombyx sequences also showed significant similarity to the sequence of apolipophorin-III from another lepidopteran, Manduca sexta (83-84%), particularly in the five amphipathic alpha-helices that are proposed to play a critical role in the binding of apolipophorin-III to lipophorin. In the coding region, the nucleotide sequences for the Chinese strain of B. mandarina and the P50 strain of B. mori were identical, supporting the suggestion that P50 is the current strain most closely related to the original domesticated strain. The N4 strain of B. mori is more closely related to these two strains than is the Japanese strain of B. mandarina, suggesting that Japanese strain of B. mandarina separated from the Chinese strain of B. mandarina before domestication of B. mori. Arch.     

Conformational behavior of oxygenated mycobacterial mycolic acids from Mycobacterium bovis BCG

Phase diagrams of Langmuir monolayers of oxygenated mycolic acids, i.e. methoxy mycolic acid (MeO-MA), ketomycolic acid (Keto-MA), and artificially obtained deoxo-mycolic acid (deoxo-MA) from Mycobacterium bovis BCG were obtained by thermodynamic analysis of the surface pressure (pi) vs. average molecular area (A) isotherms. At lower temperatures and lower surface pressures, both Keto- and MeO-MAs formed rigid condensed monolayers where each MA molecule was considered to be in a 4-chain form, in which the three carbon chain segments due to bending of the 3-hydroxy aliphatic carboxylate chain and the 2-side chain were in compact parallel arrangement. At higher temperatures and surface pressures, MeO-MA and deoxo-MA tended to take stretched-out conformations in which the 3-hydroxy aliphatic carboxylate chain was more or less in an extended form, but Keto-MA retained the original 4-chain structure. The thickness measurement of the monolayers in situ by ellipsometry at different pi values and temperatures supported the above conclusions derived from the phase diagrams. The enthalpy changes associated with the phase transitions of MeO-MA and deoxo-MA implied that the MeO-MA needed larger energy to change from a compact conformation to an extended one, possibly and partly due to the dehydration of the methoxy group from water surface involved. Molecular dynamics studies of MA models derived from Monte Carlo calculations were also performed, which confirmed the conformational behavior of MAs suggested by the thermodynamic studies on the Langmuir monolayers.