Polyamine-dependent regulation of spermidine-spermine N-1-acetyltransferase mRNA translation

Spermidine-spermine N-1-acetyltransferase (SSAT) is induced in response to an elevation in intracellular polyamine pools. The increased enzyme activity is the result of an increase in gene transcription, mRNA translation, and protein stability. Induction of SSAT by polyamine analogues can lead to intracellular polyamine depletion and apoptosis. The mechanism by which polyamines alter the translational efficiency of SSAT mRNA is not well understood. In this study, we investigated the regulation of SSAT translation by the polyamine analogue N-1,N-11-diethylnorspermine ( DENSPM). DENSPM induced expression of both FLAG-tagged SSAT and SSAT fused to Renilla luciferase in a time- and concentration-dependent manner. This effect was not inhibited by actinomycin D indicating that changes in gene transcription did not explain the enhanced expression in the presence of DENSPM. Furthermore, because FLAG-SSAT did not contain the 5'- or 3'-untranslated regions of SSAT, translational regulation involved the coding sequence only. By contrast, cycloheximide completely inhibited induction by DENSPM, indicating a requirement for new protein synthesis. Deletion constructs identified two regions of the SSAT protein-coding RNA sequence that conferred polyamine responsiveness. Using these regions as probes in RNA electrophoretic mobility shift assays, we observed specific binding of a cytoplasmic protein. In addition, we found that the interaction between the RNA probes and the binding protein could be inhibited by DENSPM in a concentration-dependent manner. These results suggest that polyamines regulate SSAT mRNA translational efficiency by inhibiting a repressor protein from binding to regions of the coding sequence of the SSAT transcript

Post-conflict Statebuilding and State Legitimacy: From Negative to Positive Peace?

This version of this article has the following title: Statebuilding 3.0: building local legitimacy, essential security and global governance. This is the peer reviewed version of the following article: ROBERTS, D., 2008. Post-conflict statebuilding and state legitimacy: from negative to positive peace? Development and Change, 39 (4), pp. 537-555, which has been published in final form at: http://dx.doi.org/10.1111/j.1467-7660.2008.00495.x. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for self-archiving.This article is concerned with the potential that statebuilding interventions have to institutionalize social justice, in addition to their more immediate 'negative' peace mandates, and the impact this might have, both on local state legitimacy and the character of the 'peace' that might follow. Much recent scholarship has stressed the legitimacy of a state's behaviour in relation to conformity to global governance norms or democratic 'best practice'. Less evident is a discussion of the extent to which post-conflict polities are able to engender the societal legitimacy central to political stability. As long as this level of legitimacy is absent (and it is hard to generate), civil society is likely to remain distant from the state, and peace and stability may remain elusive. A solution to this may be to apply existing international legislation centred in the UN and the ILO to compel international organizations and national states to deliver basic needs security through their institutions. This has the effect of stimulating local-level state legitimacy while simultaneously formalizing social justice and positive peacebuilding

Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Objective To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. Results In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. Conclusions Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so

Selected issues in Pacific Island development: papers from the Islands/Australia Project

R.V. Cole and T.G. Parry, editors.viii, 264 p. : ill. ; 25 cm

A Second-Generation Genomewide Screen for Asthma-Susceptibility Alleles in a Founder Population

A genomewide screen for asthma- and atopy-susceptibility loci was conducted, using 563 markers, in 693 Hutterites who are members of a single 15-generation pedigree, nearly doubling the sample size from the authors' earlier studies. The resulting increase in power led to the identification of 23 loci in 18 chromosomal regions showing evidence for linkage that is, in general, 10-fold more significant (P<.001 vs. P<.01) than the linkages reported previously in this population. Moreover, linkages to loci in 11 chromosomal regions were identified for the first time in the Hutterites in this report, including five regions (5p, 5q, 8p, 14q, and 16q) showing evidence both of linkage, by the likelihood ratio (LR) χ(2), and of disequilibrium, by the transmission/disequilibrium test. A region on chromosome 19 continues to show evidence for linkage, by both tests, in this study. Studies of 17 candidate genes provide evidence for association with variation in the IL4RA gene (16p12), the HLA class II genes (6p21), and the interferon-α gene cluster (9p22), but the lack of evidence for linkage in these regions by the LR χ(2) test suggests that these are minor susceptibility loci. A polymorphism in the CD14 gene is in linkage disequilibrium with an as yet unidentified susceptibility allele in the 5q cytokine cluster, a region showing evidence for linkage among the Hutterites. Finally, 10 of the regions showing evidence for linkage in the Hutterites have shown evidence of linkage to related phenotypes in other genome screens, suggesting that these regions may contain common alleles that have relatively large effects on asthma and atopy phenotypes in diverse populations

Variance components for FST calculation

This file contains the variance components estimated using hierfstat. There is one set of components for each SNP. Components are: population (Pop), individual (Ind), and error (Error). The first column is the SNP identifier (SNP_id)

Exploratory Data Analysis Script

This R script was used to explore patterns within the data. Comments are used to briefly describe the analysis. A header gives contact information for the script author

Input and Output Files for Berg & Coop

The zipped archive contains a directory in which input files and output files from the method of Berg & Coop (2014) are housed. Please refer to Jeremy Berg's GitHub repository (cited in the associated manuscript) for detailed instructions on how to execute these files with his scripts

Geographic Locations

This file contains the geographic coordinates for each sampled population. It is a tab-delimited text file