N-nitroso compound exposure-associated transcriptomic profiles are indicative of an increased risk for colorectal cancer

Endogenous formation of N-nitroso compounds (NOCs), which are known animal carcinogens, could contribute to human carcinogenesis but definitive evidence is still lacking. To investigate the relevance of NOCs in human colorectal cancer (CRC) development, we analyzed whole genome gene expression modifications in human colon biopsies in relation to fecal NOC exposure. We had a particular interest in patients suffering from intestinal inflammation as this may stimulate endogenous NOC formation, and consequently predispose to CRC risk. Inflammatory bowel disease (IBD) patients diagnosed with ulcerative colitis and irritable bowel syndrome patients without inflammation, serving as controls, were therefore recruited. Fecal NOC were demonstrated in the majority of subjects. By associating gene expression levels of all subjects to fecal NOC levels, we identified a NOC exposure-associated transcriptomic response that suggests that physiological NOC concentrations may potentially induce genotoxic responses and chromatin modifications in human colon tissue, both of which are linked to carcinogenicity. In a network analysis, chromatin modifications were linked to 11 significantly modulated histone genes, pointing towards a possible epigenetic mechanism that may be relevant in comprehending NOC-induced carcinogenesis. In addition, pro-inflammatory transcriptomic modifications were identified in visually non-inflamed regions of the IBD colon. However, fecal NOC levels were slightly but not significantly increased in IBD patients, suggesting that inflammation did not strongly stimulate NOC formation. We conclude that NOC exposure is associated with gene expression modifications in the human colon that may suggest a potential role of these compounds in CRC development.

Red meat intake-induced increases in fecal water genotoxicity correlate with pro-carcinogenic gene expression changes in the human colon

Red meat consumption is associated with an increased colorectal cancer (CRC) risk, which may be due to an increased endogenous formation of genotoxic N-nitroso compounds (NOCs). To assess the impact of red meat consumption on potential risk factors of CRC, we investigated the effect of a 7-day dietary red meat intervention in human subjects on endogenous NOC formation and fecal water genotoxicity in relation to genome-wide transcriptomic changes induced in colonic tissue. The intervention showed no effect on fecal NOC excretion but fecal water genotoxicity significantly increased in response to red meat intake. Colonic inflammation caused by inflammatory bowel disease, which has been suggested to stimulate endogenous nitrosation, did not influence fecal NOC excretion or fecal water genotoxicity. Transcriptomic analyses revealed that genes significantly correlating with the increase in fecal water genotoxicity were involved in biological pathways indicative of genotoxic effects, including modifications in DNA damage repair, cell cycle, and apoptosis pathways. Moreover, WNT signaling and nucleosome remodeling pathways were modulated which are implicated in human CRC development. We conclude that the gene expression changes identified in this study corroborate the genotoxic potential of diets high in red meat and point towards a potentially increased CRC risk in humans.

Expression-system-dependent modulation of HIV-1 envelope glycoprotein antigenicity and immunogenicity.

Recombinant expression systems differ in the type of glycosylation they impart on expressed antigens such as the human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins, potentially affecting their biological properties. We performed head-to-head antigenic, immunogenic and molecular profiling of two distantly related Env surface (gp120) antigens produced in different systems: (a) mammalian (293 FreeStyle cells; 293F) cells in the presence of kifunensine, which impart only high-mannose glycans; (b) insect cells (Spodoptera frugiperda, Sf9), which confer mainly paucimannosidic glycans; (c) Sf9 cells recombinant for mammalian glycosylation enzymes (Sf9 Mimic), which impart high-mannose, hybrid and complex glycans without sialic acid; and (d) 293F cells, which impart high-mannose, hybrid and complex glycans with sialic acid. Molecular models revealed a significant difference in gp120 glycan coverage between the Sf9-derived and wild-type mammalian-cell-derived material that is predicted to affect ligand binding sites proximal to glycans. Modeling of solvent-exposed surface electrostatic potentials showed that sialic acid imparts a significant negative surface charge that may influence gp120 antigenicity and immunogenicity. Gp120 expressed in systems that do not incorporate sialic acid displayed increased ligand binding to the CD4 binding and CD4-induced sites compared to those expressed in the system that do, and imparted other more subtle differences in antigenicity in a gp120 subtype-specific manner. Non-sialic-acid-containing gp120 was significantly more immunogenic than the sialylated version when administered in two different adjuvants, and induced higher titers of antibodies competing for CD4 binding site ligand-gp120 interaction. These findings suggest that non-sialic-acid-imparting systems yield gp120 immunogens with modified antigenic and immunogenic properties, considerations that should be considered when selecting expression systems for glycosylated antigens to be used for structure-function studies and for vaccine use.

Case study part 1: how to calculate appropriate deterministic long-term toxicity to exposure rates (TERs) for birds and mammals

In the European Union, first-tier assessment of the long-term risk to birds and mammals from pesticides is based on calculation of a deterministic long-term toxicity/exposure ratio(TERlt). The ratio is developed from generic herbivores and insectivores and applied to all species. This paper describes two case studies that implement proposed improvements to the way long-term risk is assessed. These refined methods require calculation of a TER for each of five identified phases of reproduction (phase-specific TERs) and use of adjusted No Observed Effect Levels (NOELs)to incorporate variation in species sensitivity to pesticides. They also involve progressive refinement of the exposure estimate so that it applies to particular species, rather than generic indicators, and relates spraying date to onset of reproduction. The effect of using these new methods on the assessment of risk is described. Each refinement did not necessarily alter the calculated TER value in a way that was either predictable or consistent across both case studies. However, use of adjusted NOELs always reduced TERs, and relating spraying date to onset of reproduction increased most phase-specific TERs. The case studies suggested that the current first-tier TERlt assessment may underestimate risk in some circumstances and that phase-specific assessments can help identify appropriate risk-reduction measures. The way in which deterministic phase-specific assessments can currently be implemented to enhance first-tier assessment is outlined.

Case study part 2: probabilistic modelling of long-term effects of pesticides on individual breeding success in birds and mammals

Abstract: Long-term exposure of skylarks to a fictitious insecticide and of wood mice to a fictitious fungicide were modelled probabilistically in a Monte Carlo simulation. Within the same simulation the consequences of exposure to pesticides on reproductive success were modelled using the toxicity-exposure-linking rules developed by R.S. Bennet et al. (2005) and the interspecies extrapolation factors suggested by R. Luttik et al.(2005). We built models to reflect a range of scenarios and as a result were able to show how exposure to pesticide might alter the number of individuals engaged in any given phase of the breeding cycle at any given time and predict the numbers of new adults at the season’s end.

En analys av Joseph Conrads roman Heart of Darkness samt novell An outpost of progress

Denna studie är en analys av romanen Heart of Darkness (1902) och novellen An outpost ofprogress (1898) av Joseph Conrad (1857-1924) i syfte att undersöka berättelsernashuvudsakliga tematik ur en postkolonial infallsvinkel samt vad Conrads avsikt tycks ha varitmed porträtteringen av elfenbensagenten Kurtz. För att genomföra denna analys har jag gjorten närläsning av Heart of Darkness samt An outpost of progress och samtidigt tolkathändelseförloppen.Tolkningarna är delvis mina egna samt delvis baserat på tidigare forskning. Efter att hagenomfört dessa närläsningar är min slutsats att Conrads huvudsakliga avsikt var att skildaden mänskliga moralens förfall genom den ondskefulla girigheten. Det är denna girighet somhan definierar som det mörka i en människas hjärta. Genom framställningen av Kurtz visarhan exempel på detta samt hur farlig en skicklig retoriker kan vara.

Performance analysis and analysis for performance : a study of Villa-Lobos's Bachianas Brasileiras No. 9

This study of Villa-Lobos’s Bachianas Brasileiras No. 9 aims at gaining insight into the decision-making processes of translating a score into a musical performance. Chapter I presents a discussion of selected issues related to interpretative analysis. Chapter II is an overview of the approaches to recording comparison deemed relevant to the present study. Chapter III is a comparative study of the vocal and string versions of Bachianas Brasileiras No. 9, while Chapter IV offers a structural analysis of the work. Chapter V compares four recordings: the composer’s own with the Orchestre National de La Radiodiffusion Française—EMI 7243 5 66964 2 6; Odaline de la Martinez and the BBC Singers, LNT 102; Michael Tilson Thomas and the New World Symphony —RCA 09026-68538-2; and my own CD, Construção, Orquestra de Câmara Theatro São Pedro- Limited Edition (live recording made on December 11, 1995 in Bayreuth, Germany). This comparison utilizes data obtained with the software Tempo. The tabulation of these results is shown in graphs that compare how matters of tempo flexibility affect each performance. This multi-faceted study shows that although painstaking analysis can lead to insightful solutions, the fleeting nature of musical performance requires an open mind and imagination to deal with the often contradictory directives of the score.

Emprego de uma metodologia multicritério na avaliação do estudo de impacto ambiental de hidrelétricas

Esta pesquisa parte da constatação expressa na literatura analisada de que os métodos e técnicas utilizados na elaboração do Estudo de Impacto Ambiental - EIA de empreendimentos hidrelétricos têm se mostrado inadequados para apoiar o complexo processo de tomada de decisão, tanto no âmbito das empresas de consultoria, que elaboram o Estudo, como no dos órgãos ambientais, que analisam o EIA. Para investigar e confirmar esta questão, foram analisados a legislação vigente, Termos de Referência para a elaboração de EIAs e nove EIAs de hidrelétricas. Dentre eles, foram selecionados dois para estudo de caso. Constatou-se que são necessários três processos de avaliação na elaboração do EIA: dos impactos, das medidas mitigadoras e dos programas. Na avaliação de impactos, a técnica mais utilizada é a Matriz de Leopold, aplicada de forma correta em apenas um dos EIAs. Tornou-se evidente que os pontos fracos dessa avaliação podem ser reduzidos e até eliminados desde que o órgão ambiental melhore algumas exigências no Termo de Referência, de tal forma que levem a consultora a utilizar a referida técnica de forma correta ou a adotar um método ou técnica mais adequada. As avaliações das medidas mitigadoras e dos programas não são realizadas, invariavelmente. As razões para esta situação podem ser atribuídas tanto aos órgãos ambientais como às empresas de consultoria. Os primeiros, porque nem sempre elaboram o Termo de Referência integralmente de acordo com a Resolução CONAMA nº 001/86, deixando de especificar que as avaliações devem ser realizadas com métodos e técnicas válidos e confiáveis. Os segundos, porque não tomam a iniciativa de atender à legislação vigente, independente das instruções expressas no Termo de Referência. Essas avaliações constituemse nos pontos fracos mais relevantes a serem melhorados por órgãos ambientais e consultores. Ao considerar a avaliação dos programas ambientais como a problemática prioritária, a pesquisa investiga e reconhece que as metodologias multicritério, em especial as de apoio à tomada de decisão, pertencentes ao grupo Multicriteria Decision Aid - MCDA, apresentam grande potencialidade para a solução da problemática detectada. A escolha recaiu sobre a abordagem proposta por Ensslin, Montibeller Neto e Noronha (2001), que foi adaptada e submetida a um teste para investigar a sua validade e exeqüibilidade na avaliação dos programas do EIA de duas hidrelétricas no rio Ijuí – RS. Para isso, foram envolvidos quatro especialistas da empresa consultora que elaborou o EIA, para atuarem como avaliadores. Os resultados foram submetidos à apreciação dos próprios avaliadores, de técnicos do órgão ambiental estadual e de técnicos do órgão ambiental federal, que se manifestaram favoráveis à metodologia, em sua maioria.

Avaliação dos impactos ambientais gerados por uma industria cerâmica típica da Região do Seridó/RN

The present work deals with an evaluation of the environmental impacts arised from a typical ceramics industry located in the Seridó region of Rio Grande do Norte State. That region contains the largest State s producing basin of red ceramics. The district of Parelhas stands out as the largest producing nucleus. The studied company is located in the rural zone of Parelhas, it was selected as study object because it possesses a great part of the representative characteristics of the Region s ceramics park as a whole. Impacts produced at the implantation and operation phases of the Company had been evaluated, being this last phase subdivided in stages of the productive process. Among found adverse impacts, they are distinguished: losses in air quality, undesirable noises, microclimatic alterations, impoverishment of the ground, elimination of the vegetal covering, agricultural exodus, crisis in cattle agriculture and, superficial and underground water contamination, beyond risks ocupational diseases and industrial accidents. The Leopold s interactive matrix, that summarizes results of the work, was presented in form of 15 (fifteen) tables that display impacts classified in qualitative and quantitative way. Totally, 175 (one hundred and seventy-five) significant impacts produced by this Company had been identified, being 114 (one hundred and fourteen) negative, 38 (thirty-eight) positive and 23 (twenty-three) among mixed, indefinite and inert ones. In the work, before the evaluation of impacts properly said, it was constructed a diagnostic table of the ambient situation at a previous moment to implantation of the Company, elaborated on basis of inferences and historical researches. It was proposed still, mitigative steps for adverse impacts identified, as also elaborated a program to accompaniment and observing that the fulfilment of indicated mitigative steps guarantees. The final part of the work contemplates conclusions and suggestions that aim to influence positively the presented sight in terms of environmental management

Lucien Febvre e a Europa: as fronteiras da história

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Formulação de um índice de qualidade de gestão de resíduos sólidos urbanos

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Análise de impactos ambientais gerados pela implantação de loteamentos fechados de alto padrão

Pós-graduação em Engenharia Civil - FEIS