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Abstract: A series of compounds based on a 4-phenyl-2-phenylaminopyridine scaffold that are potent and selective inhibitors of Traf2- and Nck-interacting kinase (TNIK) activity are described. These compounds were used as tools to test the importance of TNIK kinase activity in signaling and proliferation in Wnt-activated colorectal cancer cells. The results indicate that pharmacological inhibition of TNIK kinase activity has minimal effects on either Wnt/TCF4/β-catenin-driven transcription or viability. The findings suggest that the kinase activity of TNIK may be less important to Wnt signaling than other aspects of TNIK function, such as its putative role in stabilizing the TCF4/β-catenin transcriptional complex. [Copyright &y& Elsevier]

The ribosome accelerates the rate of peptide bond formation by at least 107-fold, but the catalytic mechanism remains controversial. Here we report evidence that a functional group on one of the tRNA substrates plays an essential catalytic role in the reaction. Substitution of the P-site tRNA A76 2'OH with 2'H or 2'F results in at least a 106-fold reduction in the rate of peptide bond formation, but does not affect binding of the modified substrates. Such substrate-assisted catalysis is relatively uncommon among modern protein enzymes, but it is a property predicted to be essential for the evolution of enzymatic function. These results suggest that substrate assistance has been retained as a catalytic strategy during the evolution of the prebiotic peptidyl transferase center into the modern ribosome. [ABSTRACT FROM AUTHOR]

The peptidyl transferase center of the ribosome is literally the mother of all protein enzymes, yet it was only recently that the content of its active site was found to be RNA and not protein. This review focuses on how this RNA enzyme orients its substrates and promotes the chemical reaction that is center stage in protein synthesis. [Copyright &y& Elsevier]

The crystal structure of the ribosomal 50S subunit from Haloarcula marismortui in complex with the transition state analog CCdAphosphate-puromycin (CCdApPmn) led to a mechanistic proposal wherein the universally conversed A2451 in the ribosomal active site acts as an "oxyanion hole" to promote the peptidyl transferase reaction [Nissen, P., Hansen, J., Ban, N., Moore, P.B., and Steitz, T.A. (2000) Science 289, 920-929]. In the model, close proximity (3 Å) between the A2451 N3 and the nonbridging phosphoramidate oxygen of CCdApPmn suggested that the carbonyl oxyanion formed during the tetrahedral transition state is stabilized by hydrogen bonding to the protonated A2451 N3, the pKa of which must be perturbed substantially. We characterize the contribution of the putative hydrogen bond between the N3 of A2451 and the nonbridging phosphoramidate oxygen by using chemical protection and peptidyl transfer inhibition assays. If this putative hydrogen bond makes a significant thermodynamic contribution, then CCdApPmn-binding affinity to the 50S ribosomal subunit should be strongly pH-dependent, with affinity increasing as the pH is lowered. We report that CCdApPmn binds 50S ribosomes with essentially equal affinity at all pH values between 5.0 and 8.5. These data argue against a mechanism for peptidyl transfer in which a residue with near neutral pKa stabilizes the transition-state oxyanion, at least to the extent that CCdApPmn accurately mimics the transition state. [ABSTRACT FROM AUTHOR]

A stratified, random sample of 344 White and Black adolescent females participated in a survey of ideal body size beliefs, which included responses to a questionnaire and a series of nine female and male body size drawings. Using SES and race as independent variables and BMI (kg/m2) as a covariate, Black females preferred a significantly heavier ideal female body size than Whites. They also perceived their parents and both male and female friends would select as ideal a significantly heavier female body size than White subjects. Black subjects' body size preferences were significantly more influenced by family members than were White subjects, who were significantly more influenced by their peer group. These findings suggest a greater social approval of increasing weight and body size for Black adolescent females, a desire for a smaller size by White adolescent females, and cultural differences in the influencing factors that help to communicate these body size preferences. [ABSTRACT FROM AUTHOR]

The biogenesis of the large (60S) ribosomal subunit in eukaryotes involves nucleolar, nucleoplasmic, and cytoplasmic steps. The cytoplasmic protein Rei1, found in all eukaryotes, was previously shown to be necessary for the nuclear reimport of 60S subunit export factor Arx1. In this study we investigate the function of Reh1, a protein with high sequence similarity to Rei1. We demonstrate an overlapping function for Reh1 and Rei1 in the cytoplasmic maturation of the 60S subunit that is independent of Arx1 recycling. We observe that strains lacking both Reh1 and Rei1 accumulate salt-labile 60S subunits, suggesting that Reh1/Rei1 is necessary for the cytoplasmic 60S subunit to adopt its mature, stable form. [ABSTRACT FROM AUTHOR]

The Holocene growth of fringing and nearshore reefs on the GBR is examined. A review of data from 21 reefs indicates that most grow upon Pleistocene reef, boulder, and gravel, or sand and clay substrates, with no cored examples growing directly over rocky headlands or shores. Dated microatolls and material from shallow reef-flat cores indicate that fringing and nearshore reefs have experienced several critical growth phases since the mid-Holocene: (1) from initiation to 5500 YBP, optimum conditions for reef and reef-flat growth prevailed; (2) from 5500–4800 YBP, reef-flat progradation stalls in almost 50% of the reefs examined; (3) of reefs prograding post-4800 YBP, approximately half ceased active progradation around 3000–2500 YBP; (4) reefs prograding to present do so at rates well below mid-Holocene rates; (5) a group of nearshore reefs has established since 3000 YBP, in conditions traditionally considered poor for reef establishment and growth. Importantly, many of the reefs that appear to have grown little for several millennia are veneered by well-developed coral communities. Although local conditions no doubt exert some influence over these growth patterns, the apparent synchronicity of these growth and quiescent phases over wide geographical areas suggests the involvement of broader scale influences, such as climate and sea-level change. Recognition and understanding these phases of active and moribund reef growth provides a useful longer term context in which to evaluate reported current declines in fringing and nearshore reef condition. [ABSTRACT FROM AUTHOR]

Abstract: This article reviews coastal geomorphological research published in New Zealand or international journals which has been carried out in New Zealand during the past ten years. All coastal environments are covered, including tidal inlets, estuaries and lagoons, beach, surfzone, nearshore and shelf environments, and rocky coasts. Applied coastal studies are also covered. While the New Zealand coastal science community remains relatively small, a significant body of work has been carried out, much of it innovative and unique. However, with 11 000 km of very diverse coastline covering 13 degrees of latitude available for study, there are many areas, geographical as well as disciplinary, that remain poorly researched. [ABSTRACT FROM AUTHOR]

Mangrove restoration requires the cultivation of healthy seedlings and propagules for transplantation. Nurseries established near the restoration sites provide local employment and involvement. Using a participatory action research methodology, this study showed the successful establishment and operation of a mangrove nursery on the landward side of a sea dyke, on acid sulphate soils normally considered unsuitable for mangrove growth. This nursery in Vam Ray area, Kien Giang province, Vietnam produced 37,500 seedlings of five mangrove species, Avicennia marina, Rhizophora apiculata, Bruguiera cylindrica, Sonneratia alba and Nypa fruticans. The seedlings had 100% survival and were available for transplantation within three months, at a reasonable cost. The nursery procedures and techniques were based on local practices and knowledge. The study showed that a successful nursery on acid sulphate soils was achievable. Key differences compared with other mangrove nursery projects were land-based location, use of sea-bed mud to improve acid sulphate soils, use of local resources and locally traded products to minimise cost, reduced waste, local livelihood improvement and planting of multiple individuals per pot for selected species. [ABSTRACT FROM AUTHOR]

Abstract: Activators of the pyruvate kinase M2 (PKM2) are currently attracting significant interest as potential anticancer therapies. They may achieve a novel antiproliferation response in cancer cells through modulation of the classic ‘Warburg effect’ characteristic of aberrant metabolism. In this Letter, we describe the optimization of a weakly active screening hit to a structurally novel series of small molecule 3-(trifluoromethyl)-1H-pyrazole-5-carboxamides as potent PKM2 activators. [Copyright &y& Elsevier]

Abstract: 2-Arylamino-4-aryl-pyrimidines were found to be potent inhibitors of PAK1 kinase. The synthesis and SAR are described. The incorporation of a bromide at the 5-position of the pyrimidine core and in combination with a 1,2-dimethylpiperazine pendant domain yielded a lead compound with potent PAK1 inhibition and anti-proliferative activity in various colon cancer cell lines. [Copyright &y& Elsevier]

AIMS: Common polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are strongly associated with Type 2 diabetes. Many studies include a large proportion of cases enriched for family history or young age of diagnosis and may therefore provide an overestimation of the general population risk. We aimed to compare the impact of TCF7L2 in UK community-based Type 2 diabetic subjects with that in subjects ascertained for genetic studies. METHODS: We genotyped the TCF7L2 polymorphism rs7903146 in 1068 cases from two sources: 487 from 10 GP practices and 601 ascertained for genetic studies, and 2099 control subjects from two sources: 1099 parents from a birth cohort (population control subjects) and 300 subjects with normal fasting glucose aged > or = 45 years (community control subjects). RESULTS: When compared with Type 2 diabetes cases ascertained for genetic studies, the risk allele frequency in community-based cases was lower (40 vs. 36%, P = 0.04), but there was no difference in risk allele frequency between community-based control and population-based control subjects (31 vs. 30%, P = 0.61). The T allele of rs7903146 increased Type 2 diabetes risk with an odds ratio (OR) of 1.32 (95% CI: 1.13-1.52; P = 0.0002) in community-based cases, but this OR was lower than the OR of cases enriched for genetic studies [1.58 (95% CI: 1.38-1.80), P = 1.4 x 10(-11)] and the combined OR of meta-analysis of 10 studies to date on rs7903146 [1.48 (95% CI: 1.41-1.54), P < 10(-20)]. CONCLUSION: Common variation in the TCF7L2 gene contributes to Type 2 diabetes risk in UK patients recruited in general practice, but the risk allele frequency may be lower than that in subjects enriched for genetic effects. [ABSTRACT FROM AUTHOR]

Aims Common polymorphisms in the transcription factor 7-like 2 ( TCF7L2) gene are strongly associated with Type 2 diabetes. Many studies include a large proportion of cases enriched for family history or young age of diagnosis and may therefore provide an overestimation of the general population risk. We aimed to compare the impact of TCF7L2 in UK community-based Type 2 diabetic subjects with that in subjects ascertained for genetic studies. Methods We genotyped the TCF7L2 polymorphism rs7903146 in 1068 cases from two sources: 487 from 10 GP practices and 601 ascertained for genetic studies, and 2099 control subjects from two sources: 1099 parents from a birth cohort (population control subjects) and 300 subjects with normal fasting glucose aged ≥ 45 years (community control subjects). Results When compared with Type 2 diabetes cases ascertained for genetic studies, the risk allele frequency in community-based cases was lower (40 vs. 36%, P = 0.04), but there was no difference in risk allele frequency between community-based control and population-based control subjects (31 vs. 30%, P = 0.61). The T allele of rs7903146 increased Type 2 diabetes risk with an odds ratio (OR) of 1.32 (95% CI: 1.13–1.52; P = 0.0002) in community-based cases, but this OR was lower than the OR of cases enriched for genetic studies [1.58 (95% CI: 1.38–1.80), P = 1.4 × 10−11] and the combined OR of meta-analysis of 10 studies to date on rs7903146 [1.48 (95% CI: 1.41–1.54), P < 10−20]. Conclusion Common variation in the TCF7L2 gene contributes to Type 2 diabetes risk in UK patients recruited in general practice, but the risk allele frequency may be lower than that in subjects enriched for genetic effects. [ABSTRACT FROM AUTHOR]