Pathway-Based Analysis of a Melanoma Genome-Wide Association Study: Analysis of Genes Related to Tumour-Immunosuppression

Systemic immunosuppression is a risk factor for melanoma, and sunburn-induced immunosuppression is thought to be causal. Genes in immunosuppression pathways are therefore candidate melanoma-susceptibility genes. If variants within these genes individually have a small effect on disease risk, the association may be undetected in genome-wide association (GWA) studies due to low power to reach a high significance level. Pathway-based approaches have been suggested as a method of incorporating a priori knowledge into the analysis of GWA studies. In this study, the association of 1113 single nucleotide polymorphisms (SNPs) in 43 genes (39 genomic regions) related to immunosuppression have been analysed using a gene-set approach in 1539 melanoma cases and 3917 controls from the GenoMEL consortium GWA study. The association between melanoma susceptibility and the whole set of tumour-immunosuppression genes, and also predefined functional subgroups of genes, was considered. The analysis was based on a measure formed by summing the evidence from the most significant SNP in each gene, and significance was evaluated empirically by case-control label permutation. An association was found between melanoma and the complete set of genes (pemp = 0.002), as well as the subgroups related to the generation of tolerogenic dendritic cells (pemp = 0.006) and secretion of suppressive factors (pemp = 0.0004), thus providing preliminary evidence of involvement of tumour-immunosuppression gene polymorphisms in melanoma susceptibility. The analysis was repeated on a second phase of the GenoMEL study, which showed no evidence of an association. As one of the first attempts to replicate a pathway-level association, our results suggest that low power and heterogeneity may present challenges

Gaseous emissions during the fattening of pigs kept either on fully slatted floor or on straw flow

The aim of this study was to compare the environmental impact of the straw-flow system for fattening pigs with the slatted-floor system by measuring pollutant gas emissions such as ammonia (NH3), nitrous oxide (N2O), methane (CH4) and carbon dioxide (CO2), manure nitrogen (N) content and emissions of water vapour (H2O). Three successive batches of 32 pigs were fattened. For each batch, pigs were allotted to two groups raised in separated rooms fitted either with a concrete totally slatted-floor system (0.75 m(2) per pig) or with a straw-flow system (0.79 m(2) per pig). With this last system, pigs were kept on a sloped floor, straw being provided daily at the top of the pen. Throughout the fattening period, about 34.4 kg of straw were supplied per pig. The straw, mixed with dung, travelled down the slope by pig motion and went out of the pen to a scraped passage. The solid fraction was scraped every day, stored in a heap in the room and removed every month, 1 week before each period of gaseous emission measurement. The liquid fraction was automatically pumped from the scraped passage into a hermetic tank, which was emptied at the end of each fattening period. Rooms were ventilated mechanically in order to maintain a constant ambient temperature. Once a month, the emissions of NH3, N2O, CH4, CO2 and H2O were measured hourly for 6 consecutive days via infrared photoacoustic detection. Mean daily emissions per pig fattened on the slatted floor or on the sloped floor were, respectively, 4.98 and 13.31 g NH3, 0.67 and 0. 68 g N2O, 15.2 and 8.88 g CH4, 548 g and 406 g CO2 equivalents, 1.61 and 1.77 kg CO2 and 2.33 and 2.95 kg H2O. Except for N2O emissions, all the differences were statistically significant (P < 0.001). From the slatted-floor system, the amount of slurry removed per fattening period was on average 256 kg per pig. From the straw-flow system, solid manure amounted on average to 209 kg per pig and liquid manure to 53 kg per pig. The total N-content of the manure was 2.23 kg N per pig with the straw-flow system (solid and liquid manure) v. 3.26 kg N per pig for slurry from the slatted-floor system. This reduction of 30% observed with the sloped floor was mainly explained by the higher level of NH3-N emissions

Governing Lisbon: evolving forms of city governance

For Lisbon, a dominant national capital and increasingly internationalized city, the last 30 years have witnessed a period of dramatic growth, modernization and dynamism. As the socioeconomic landscape has changed, so too has the political and institutional one, with a significant evolution in the nature of systems of governance to manage, respond to and lead the city through this period of intense transition. Whilst increased global and particularly European integration has been an important driver to change, critically it has been the interplay of these global forces with the role and constitution of the national state and political developments at the level of the city, region and municipality that has shaped the evolutionary path of governance change. This article analyses recent governance change within Lisbon to argue that governance transition within Lisbon is characterized by significant change with regard to the relationships between public and private sectors, but also by strong continuities with regard to the dominant role of the central state in the absence of political devolution. The result is a governance system marked by structural constraints that limit the city's capacity to deal with current strategic challenges in an integrated, coordinated and inclusionary manner