Expression of HLA-G in inflammatory bowel disease provides a potential way to distinguish between ulcerative colitis and Crohn's disease.

In addition to being involved in nutrient uptake, the epithelial mucosa constitute the first line of defense against microbial pathogens. A direct consequence of this physiological function is a very complex network of immunological interactions that lead to a strong control of the mucosal immune balance. The dysfunction of immunological tolerance is likely to be a cause of inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease (CD). HLA-G is a non-classical major histocompatibility complex (HLA) class I molecule, which is highly expressed by human cytotrophoblast cells. These cells play a role in immune tolerance by protecting trophoblasts from being killed by uterine NK cells. Because of the deregulation of immune system activity in IBD, as well as the immunoregulatory role of HLA-G, we have analyzed the expression of HLA-G in intestinal biopsies of patients with UC and CD. Our study shows that the differential expression of HLA-G provides a potential way to distinguish between UC and CD. Although the reason for this differential expression is unclear, it might involve a different mechanism of immune regulation. In addition, we demonstrate that in the lamina propria of the colon of patients with UC, IL-10 is strongly expressed. In conclusion, the presence of HLA-G on the surface of intestinal epithelial cell in patients with UC lends support to the notion that this molecule may serve as a regulator of mucosal immune responses to antigens of undefined origin. Thus, this different pattern of HLA-G expression may help to differentiate between the immunopathogenesis of CD and UC

Comportamento à flexão de vigas eco-eficientes de ultra elevada durabilidade

Atualmente, o ecossistema mundial tem vindo a ser confrontado com problemas de grande importância, a elevada poluição do meio ambiente e a limitação dos recursos energéticos. Estes problemas têm contribuído para que a sustentabilidade da construção seja uma prioridade cada vez maior no presente e no futuro. A manutenção e a reabilitação do património construído surge como uma das medidas mais eficazes para prevenir ou reduzir o consumo de energia no setor da construção. No caso da construção nova, a tendência é para verificar-se um aumento da utilização de elementos estruturais pré-fabricados com partes betonadas em obra, obtendose uma maior rapidez de execução associada a um maior controlo de qualidade. O betão de ultra elevada durabilidade, reforçado com fibras metálicas, é considerado um material inovador desenvolvido nas últimas décadas, apresentando um conjunto de caraterísticas especiais, como a durabilidade, a facilidade de aplicação, as elevadas resistências mecânicas, tornando-o num produto particularmente atraente para a reabilitação e reforço de estruturas de betão. No entanto, este betão não deve ser produzido em grandes quantidades devido ao elevado consumo de cimento e adições, resultando em elevados custos económicos e ambientais. Considerando estas desvantagens é proposto que o betão de ultra elevada durabilidade seja usado apenas na camada de recobrimento, formando-se assim uma superskin que protege o elemento estrutural dos ambientes mais agressivos, isto é, aumenta a durabilidade das estruturas de betão sem que, no entanto, seja criado um impacte ambiental muito significativo (a quantidade de CO2 libertada para a atmosfera é menor devido ao menor consumo de cimento e adições). A presente dissertação pretende explorar o conceito de superskin do ponto de vista do comportamento estrutural, nomeadamente, estudar o comportamento de vigas sujeitas a esforços de flexão, compostas por uma camada exterior de betão de ultra elevada durabilidade, associado a um núcleo com betão eco-eficiente, com baixa dosagem de cimento, de modo a obter uma solução mais durável e ao mesmo tempo, ecologicamente mais eficiente. Foram realizadas oito vigas com diferentes taxas de armadura: quatro vigas produzidas apenas com betão com baixa dosagem de cimento (usadas como vigas de referência) e quatro vigas produzidas com um betão de ultra elevada durabilidade na camada de recobrimento e com um betão com baixa dosagem de cimento no núcleo. As diferentes taxas de armadura longitudinal permitem avaliar a influência da superskin em vigas com roturas dúcteis e frágeis. Com base nos dados recolhidos durante os ensaios experimentais estudou-se: (i) relação cargadeslocamento; (ii) os valores teóricos e experimentais do momento resistente; (iii) a evolução da curvatura nas secções críticas; (iv) a evolução da rigidez à flexão com a carga aplicada; (v) a ductilidade; e (vi) a fendilhação e o tipo de rotura. Da análise de resultados foi possível verificar que o recobrimento em betão de ultra elevada durabilidade é uma solução com aspetos muito positivos, nomeadamente, aumenta a resistência à flexão das vigas

Enhanced genetic maps from family-based disease studies: population-specific comparisons

Abstract Background Accurate genetic maps are required for successful and efficient linkage mapping of disease genes. However, most available genome-wide genetic maps were built using only small collections of pedigrees, and therefore have large sampling errors. A large set of genetic studies genotyped by the NHLBI Mammalian Genotyping Service (MGS) provide appropriate data for generating more accurate maps. Results We collected a large sample of uncleaned genotype data for 461 markers generated by the MGS using the Weber screening sets 9 and 10. This collection includes genotypes for over 4,400 pedigrees containing over 17,000 genotyped individuals from different populations. We identified and cleaned numerous relationship and genotyping errors, as well as verified the marker orders. We used this dataset to test for population-specific genetic maps, and to re-estimate the genetic map distances with greater precision; standard errors for all intervals are provided. The map-interval sizes from the European (or European descent), Chinese, and Hispanic samples are in quite good agreement with each other. We found one map interval on chromosome 8p with a statistically significant size difference between the European and Chinese samples, and several map intervals with significant size differences between the African American and Chinese samples. When comparing Palauan with European samples, a statistically significant difference was detected at the telomeric region of chromosome 11p. Several significant differences were also identified between populations in chromosomal and genome lengths. Conclusions Our new population-specific screening set maps can be used to improve the accuracy of disease-mapping studies. As a result of the large sample size, the average length of the 95% confidence interval (CI) for a 10 cM map interval is only 2.4 cM, which is considerably smaller than on previously published maps.http://deepblue.lib.umich.edu/bitstream/2027.42/112826/1/12881_2010_Article_748.pd

Genetic variants in FGFR2 and FGFR4 genes and skin cancer risk in the Nurses' Health Study

<p>Abstract</p> <p>Background</p> <p>The human fibroblast growth factor (FGF) and its receptor (FGFR) play an important role in tumorigenesis. Deregulation of the <it>FGFR2 </it>gene has been identified in a number of cancer sites. Overexpression of the <it>FGFR4 </it>protein has been linked to cutaneous melanoma progression. Previous studies reported associations between genetic variants in the <it>FGFR2 </it>and <it>FGFR4 </it>genes and development of various cancers.</p> <p>Methods</p> <p>We evaluated the associations of four genetic variants in the <it>FGFR2 </it>gene highly related to breast cancer risk and the three common tag-SNPs in the <it>FGFR4 </it>gene with skin cancer risk in a nested case-control study of Caucasians within the Nurses' Health Study (NHS) among 218 melanoma cases, 285 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases, and 870 controls.</p> <p>Results</p> <p>We found no evidence for associations between these seven genetic variants and the risks of melanoma and nonmelanocytic skin cancer.</p> <p>Conclusion</p> <p>Given the power of this study, we did not detect any contribution of genetic variants in the <it>FGFR2 </it>or <it>FGFR4 </it>genes to inherited predisposition to skin cancer among Caucasian women.</p

Identification and Replication of Loci Involved in Camptothecin-Induced Cytotoxicity Using CEPH Pedigrees

To date, the Centre d'Etude Polymorphism Humain (CEPH) cell line model has only been used as a pharmacogenomic tool to evaluate which genes are responsible for the disparity in response to a single drug. The purpose of this study was demonstrate the model's ability to establish a specific pattern of quantitative trait loci (QTL) related to a shared mechanism for multiple structurally related drugs, the camptothecins, which are Topoisomerase 1 inhibitors. A simultaneous screen of six camptothecin analogues for in vitro sensitivity in the CEPH cell lines resulted in cytotoxicity profiles and orders of potency which were in agreement with the literature. For all camptothecins studied, heritability estimates for cytotoxic response averaged 23.1±2.6%. Nonparametric linkage analysis was used to identify a relationship between genetic markers and response to the camptothecins. Ten QTLs on chromosomes 1, 3, 5, 6, 11, 12, 16 and 20 were identified as shared by all six camptothecin analogues. In a separate validation experiment, nine of the ten QTLs were replicated at the significant and suggestive levels using three additional camptothecin analogues. To further refine this list of QTLs, another validation study was undertaken and seven of the nine QTLs were independently replicated for all nine camptothecin analogues. This is the first study using the CEPH cell lines that demonstrates that a specific pattern of QTLs could be established for a class of drugs which share a mechanism of action. Moreover, it is the first study to report replication of linkage results for drug-induced cytotoxicity using this model. The QTLs, which have been identified as shared by all camptothecins and replicated across multiple datasets, are of considerable interest; they harbor genes related to the shared mechanism of action for the camptothecins, which are responsible for variation in response