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Y Kimura T Hanami Y Tanaka MJ de Hoon T Soma M Harbers A Lezhava Y Hayashizaki K Usui 《Biochemistry》2012,51(31):6056-6067
Nucleic acid oligonucleotides are widely used in hybridization experiments for specific detection of complementary nucleic acid sequences. For design and application of oligonucleotides, an understanding of their thermodynamic properties is essential. Recently, exciton-controlled hybridization-sensitive fluorescent oligonucleotides (ECHOs) were developed as uniquely labeled DNA oligomers containing commonly one thymidine having two covalently linked thiazole orange dye moieties. The fluorescent signal of an ECHO is strictly hybridization-controlled, where the dye moieties have to intercalate into double-stranded DNA for signal generation. Here we analyzed the hybridization thermodynamics of ECHO/DNA duplexes, and thermodynamic parameters were obtained from melting curves of 64 ECHO/DNA duplexes measured by ultraviolet absorbance and fluorescence. Both methods demonstrated a substantial increase in duplex stability (ΔΔG°(37) ~ -2.6 ± 0.7 kcal mol(-1)) compared to that of DNA/DNA duplexes of the same sequence. With the exception of T·G mismatches, this increased stability was mostly unaffected by other mismatches in the position opposite the labeled nucleotide. A nearest neighbor model was constructed for predicting thermodynamic parameters for duplex stability. Evaluation of the nearest neighbor parameters by cross validation tests showed higher predictive reliability for the fluorescence-based than the absorbance-based parameters. Using our experimental data, a tool for predicting the thermodynamics of formation of ECHO/DNA duplexes was developed that is freely available at http://genome.gsc.riken.jp/echo/thermodynamics/ . It provides reliable thermodynamic data for using the unique features of ECHOs in fluorescence-based experiments. 相似文献
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Kamata M Yamashita T Kina A Tawada M Endo S Mizukami A Sasaki M Tani A Nakano Y Watanabe Y Furuyama N Funami M Amano N Fukatsu K 《Bioorganic & medicinal chemistry letters》2012,22(14):4769-4772
Spiro-pyrazolidinedione derivatives without quaternary chiral center were discovered by structure-based drug design and characterized as potent acetyl-CoA carboxylase (ACC) inhibitors. The high metabolic stability of the spiro-pyrazolo[1,2-a]pyridazine scaffold and enhancement of the activity by incorporation of a 7-methoxy group on the benzothiophene core successfully led to the identification of compound 4c as an orally bioavailable and highly potent ACC inhibitor. Oral administration of 4c significantly decreased the values of the respiratory quotient in rats, indicating the stimulation of fatty acid oxidation. 相似文献
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Somatic nuclear transfer is a cloning technique that shows great promise in the application to regenerative medicine. Although cloned animals are genetically identical to their donor counterparts, abnormalities in phenotype and gene expression are frequently observed. One hypothesis is that the cause of these abnormalities is due to epigenetic aberration. In this report, we focused our analysis on the acetylation of histone H3 at lysine9 (H3K9Ac). Through the use of whole genome tiling arrays and quantitative PCR, we examined this epigenetic event and directly compared and assessed the differences between a cloned mouse (C1) and its parental nuclear donor (D1) counterpart. We identified 4720 regions of chromosomal DNA that showed notable differences in H3K9Ac and report here many genes identified in these hyper- and hypo-acetylated regions. Analysis of a second clone (C2) and its parental donor counterpart (D2) for H3K9Ac showed a high degree of similarity to the C1/D1 pair. This conservation of aberrant acetylation is suggestive of a reproducible epigenetic phenomenon that may lead to the frequent abnormalities observed in cloned mice, such as obesity. Furthermore, we demonstrated Crp which was identified as a hyper-acetylated gene in this study is related to the body mass, suggesting that Crp is a possible candidate of a cause for the abnormal obesity in cloned mice. In this, one of the first reports describing genome-wide epigenetic aberration between parental and nuclear transfer-cloned mammals, we propose that aberrant acetylation of histones (H3K9Ac) flanking promoter regions highly correlates with gene-expression and may itself be an epigenetic change that accounts for variable expression patterns observed in cloned animals. 相似文献
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Bruno L Diaz Hiroshi Fujishima Yoshihide Kanaoka Yoshihiro Urade Jonathan P Arm 《Journal of immunology (Baltimore, Md. : 1950)》2002,168(3):1397-1404
Mouse bone marrow-derived mast cells (BMMC), stimulated with stem cell factor, IL-1beta, and IL-10, secrete IL-6 and demonstrate a delayed phase of PGD(2) generation that is dependent upon the induced expression of PG endoperoxide synthase (PGHS)-2. We have examined the potential for exogenous prostanoids, acting in a paracrine fashion, and endogenous prostanoids, acting in an autocrine fashion, to regulate PGHS-2 induction and IL-6 secretion in mouse BMMC. Exogenous PGE(2), which acts through G protein-coupled receptors, and 15-deoxy-Delta(12,14)-PGJ(2), which is a ligand for peroxisome proliferator-activated receptor (PPAR)gamma, elicited a 2- to 3-fold amplification of PGHS-2 induction, delayed-phase PGD(2) generation, and IL-6 secretion in response to stem cell factor, IL-1beta, and IL-10. The effect of PGE(2) was reproduced by the E prostanoid (EP)1 receptor agonist 17-trinor-PGE(2), and the EP1/EP3 agonist, sulprostone, but not the EP2 receptor agonist, butaprost. Although BMMC express PPARgamma, the effects of 15-deoxy-Delta(12,14)-PGJ(2) were not reproduced by the PPARgamma agonists, troglitazone and ciglitazone. PGHS-2 induction, but not IL-6 secretion, was impaired in cPLA(2)-deficient BMMC. However, there was no impairment of PGHS-2 induction in BMMC deficient in hematopoietic PGD synthase or PGHS-1 in the presence or absence of the PGHS-2 inhibitor, NS-398. Thus, although exogenous prostanoids may contribute to amplification of the inflammatory response by augmenting PGD(2) generation and IL-6 secretion from mast cells, endogenous prostanoids do not play a role. 相似文献
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Mitsunori Kono Tsuneo Oda Michiko Tawada Takashi Imada Yoshihiro Banno Naohiro Taya Tetsuji Kawamoto Hidekazu Tokuhara Yoshihide Tomata Naoki Ishii Atsuko Ochida Yoshiyuki Fukase Tomoya Yukawa Shoji Fukumoto Hiroyuki Watanabe Keiko Uga Akira Shibata Hideyuki Nakagawa Satoshi Yamamoto 《Bioorganic & medicinal chemistry》2018,26(2):470-482
A series of tetrahydroisoquinoline derivatives were designed, synthesized, and evaluated for their potential as novel orally efficacious retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of Th17-driven autoimmune diseases. We carried out cyclization of the phenylglycinamide core by structure-based drug design and successfully identified a tetrahydroisoquinoline carboxylic acid derivative 14 with good biochemical binding and cellular reporter activity. Interestingly, the combination of a carboxylic acid tether and a central fused bicyclic ring was crucial for optimizing PK properties, and the compound 14 showed significantly improved PK profile. Successive optimization of the carboxylate tether led to the discovery of compound 15 with increased inverse agonistic activity and an excellent PK profile. Oral treatment of mice with compound 15 robustly and dose-dependently inhibited IL-17A production in an IL23-induced gene expression assay. 相似文献
70.
We propose that growth bar size may indicate the quality of individuals in Styan's Grasshopper Warblers Locustella pleskei . Positive correlations of an individual's standardized growth bar width between years showed that some individuals of both sexes were usually in better condition than others. The survival rate of males with wider growth bars was higher than that of other males. These survivors might have survived better because of a better body condition. We also examined the relationships between growth bar width and reproductive parameters (arrival date, pairing date and reproductive success). Males with wider growth bars arrived earlier, acquired a mate earlier and achieved higher total reproductive success by breeding twice. In females, growth bar width was correlated with reproductive parameters (arrival date, pairing date and total reproductive success), but not with survival. These results suggest that males with wider growth bars were of higher quality than those with narrower bars. The contrasting results for the two sexes may be explained by differences in their breeding tactics. 相似文献