Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex.

Cyclic peptide natural products have evolved to exploit diverse protein targets, many of which control essential cellular processes. Inspired by a series of cyclic peptides with partially elucidated structures, we designed synthetic variants of ternatin, a cytotoxic and anti-adipogenic natural product whose molecular mode of action was unknown. The new ternatin variants are cytotoxic toward cancer cells, with up to 500-fold greater potency than ternatin itself. Using a ternatin photo-affinity probe, we identify the translation elongation factor-1A ternary complex (eEF1A·GTP·aminoacyl-tRNA) as a specific target and demonstrate competitive binding by the unrelated natural products, didemnin and cytotrienin. Mutations in domain III of eEF1A prevent ternatin binding and confer resistance to its cytotoxic effects, implicating the adjacent hydrophobic surface as a functional hot spot for eEF1A modulation. We conclude that the eukaryotic elongation factor-1A and its ternary complex with GTP and aminoacyl-tRNA are common targets for the evolution of cytotoxic natural products

Gas flows in galaxies: the relative importance of mergers and bars

Galaxy-galaxy interactions and large scale galaxy bars are usually considered as the two main mechanisms for driving gas to the centres of galaxies. By using large samples of galaxy pairs and visually classified bars from the Sloan Digital Sky Survey (SDSS), we compare the relative efficiency of gas inflows from these two processes. We use two indicators of gas inflow: star formation rate (SFR) and gas phase metallicity, which are both measured relative to control samples. Whereas the metallicity of galaxy pairs is suppressed relative to its control sample of isolated galaxies, galaxies with bars are metal-rich for their stellar mass by 0.06 dex over all stellar masses. The SFRs of both the close galaxy pairs and the barred galaxies are enhanced by ~60%, but in the bars the enhancement is only seen at stellar masses M* >10^10 M_solar. Taking into account the relative frequency of bars and pairs, we estimate that at least three times more central star formation is triggered by bars than by interactions.Comment: Proceedings of "Tracing the Ancestry of Galaxies on the Land of our Ancestors", Eds Carignan, Freeman & Combe

Galaxy pairs in the Sloan Digital Sky Survey - IV: Interactions trigger AGN

Galaxy-galaxy interactions are predicted to cause gas inflows leading to enhanced nuclear star formation. In this paper we test the further prediction that the gas inflows lead to enhanced accretion onto the central supermassive black hole, triggering activity in the nucleus. Based on a sample of 11,060 SDSS galaxies with a close companion (rp < 80 kpc, Delta V < 200 km/s), we classify AGN based either on emission line ratios or on spectral classification as a quasar. The AGN fraction in the close pairs sample is compared to a control sample of 110,600 mass- and redshift-matched control galaxies with no nearby companion. We find a clear increase in the AGN fraction in close pairs of galaxies with projected separations < 40 kpc by up to a factor of 2.5 relative to the control sample (although the enhancement depends on the chosen S/N cut of the sample). The increase in AGN fraction is strongest in equal mass galaxy pairings, and weakest in the lower mass component of an unequal mass pairing. The increased AGN fraction at small separations is accompanied by an enhancement in the number of `composite' galaxies whose spectra are the result of photoionization by both AGN and stars. Our results indicate that AGN activity occurs (at least in some cases) well before final coalescence and concurrently with ongoing star formation. Finally, we find a marked increase at small projected separations of the fraction of pairs in which BOTH galaxies harbour AGN. We demonstrate that the fraction of double AGN exceeds the expected random fraction, indicating that some pairs undergo correlated nuclear activity. Taken together with complimentary studies, we favour an interpretation where interactions trigger AGN, but are not the only cause of nuclear activity.Comment: Accepted for publication in MNRA

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC

Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex.

Cyclic peptide natural products have evolved to exploit diverse protein targets, many of which control essential cellular processes. Inspired by a series of cyclic peptides with partially elucidated structures, we designed synthetic variants of ternatin, a cytotoxic and anti-adipogenic natural product whose molecular mode of action was unknown. The new ternatin variants are cytotoxic toward cancer cells, with up to 500-fold greater potency than ternatin itself. Using a ternatin photo-affinity probe, we identify the translation elongation factor-1A ternary complex (eEF1A·GTP·aminoacyl-tRNA) as a specific target and demonstrate competitive binding by the unrelated natural products, didemnin and cytotrienin. Mutations in domain III of eEF1A prevent ternatin binding and confer resistance to its cytotoxic effects, implicating the adjacent hydrophobic surface as a functional hot spot for eEF1A modulation. We conclude that the eukaryotic elongation factor-1A and its ternary complex with GTP and aminoacyl-tRNA are common targets for the evolution of cytotoxic natural products

Discovery and in Vivo Evaluation of Dual PI3Kβ/δ Inhibitors

Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue <b>63</b> was a potent and selective PI3Kβ/δ dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue <b>63</b> was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis. These studies highlight the potential therapeutic value of inhibiting both the PI3Kβ and δ isoforms in the treatment of a number of inflammatory diseases

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC