MC1R gene polymorphisms analysis associated with human pigmentation phenotypes on the brazilian population

Dentre os genes conhecidos por infl uenciarem a variação normal de pigmentação de olhos, pele e cabelos em humanos, o gene MC1R (receptor de melanocortina 1) é o mais bem caracterizado até o momento. A atuação do MC1R ocorre pela produção de uma proteína transmembrana nos melanócitos, responsável pela regulação da produção de melanina nos mesmos. Sabe-se que a atuação do MC1R determina a proporção entre eumelanina (coloração castanha/preta) e feomelanina (amarela/vermelha) presente nos melanócitos. O presente trabalho tem como objetivo analisar os SNPs conhecidos do gene MC1R com o propósito de se avaliar a infl uência da diversidade deste gene em características como a presença de sardas e variação da pigmentação dos olhos, pele e cabelos em humanos. Foram analisados 29 SNPs conhecidos da região codifi cadora do gene MC1R em 296 indivíduos da região de Ribeirão Preto, SP. A extração do DNA foi feita pela técnica de salting-out. A região codifi cadora do gene MC1R (951pb) foi amplifi cada em uma única reação de PCR, a qual foi sequenciada em um analisador genético ABI-PRISM 310 por eletroforese capilar, utilizando-se os mesmos primers empregados para a amplifi cação. Dos 29 SNPs avaliados, 22 deles mostraram variação nas amostras estudadas, sendo que metade deles demonstrou estar associados a características de pigmentação. Observou-se um conjunto de SNPs associados claramente à fenótipos relacionados à feomelanina (+1645 A, +1831 T,+1858 T e +2260 C), enquanto outros se relacionam à ocorrência de eumelanina (+1558 G, +2322 G, +2346 A). O presente trabalho apresenta associações signifi cativas entre SNPs individuais e pigmentação de olhos, cabelos e pele, sendo que nosso dados confi rmam que tal gene também desempenha papel relevante na variação de pigmentação na população Brasileira.Among the known genes infl uencing eye, skin and hair normal pigmentation variation, the MC1R (melanocortin 1-receptor) gene is the best characterized so far. The activity of MC1R occurs due the production of a transmembrane protein in melanocytes, responsible for regulating the production of melanin. It is known that the performance of MC1R determines the ratio of eumelanin (brown /black color) and pheomelanin (yellow/ red) present in melanocytes. This study aims to analyze known SNPs of the MC1R gene in order to evaluate the infl uence of this gene diversity on features like freckles and pigmentation variation of eyes, skin and hair in humans. We analyzed 29 known SNPs in the coding region of MC1R gene in 296 individuals from the region of Ribeirão Preto, Brazil. DNA extraction was performed using the salting-out technique. The MC1R gene coding region (951pb) was amplifi ed in a single PCR reaction, which was sequenced on a ABI PRISM-310 genetic analyzer by capillary electrophoresis, using the same primers used for amplifi cation. Of the 29 SNPs evaluated, only 22 showed variation in the samples studied, half of them showing to be associated with pigmentation characteristics. We observed a set of SNPs clearly associated to pheomelanin (+1645 A, +1831 T,+1858 T e +2260 C), while others related to eumelanin occurrence (+1558 G, +2322 G, +2346 A). Our study shows signifi cant associations between individual SNPs and eyes, hair and skin pigmentation. The results presented here confi rm that this gene also plays a relevant role in the pigmentation variation in the Brazilian population

Inhibition of CDK4/6 as a novel therapeutic option for neuroblastoma

Background: Neuroblastoma is a neural crest-derived tumor and is the most common cancer in children less than 1 year of age. We hypothesized that aberrations in genes that control the cell cycle could play an important role in the pathogenesis of neuroblastoma and could provide a tractable therapeutic target. Methods: In this study, we screened 131 genes involved in cell cycle regulation at different levels by analyzing the effect of siRNA-mediated gene silencing on the proliferation of neuroblastoma cells. Results: Marked reductions in neuroblastoma cellular proliferation were recorded after knockdown of CCND1 or PLK1. We next showed that pharmacological inhibition of cyclin D1 dependent kinases 4/6 (CDK4/6) with PD 0332991 (palbociclib) reduced the growth of neuroblastoma cell lines, induced G1 cell cycle arrest, and inhibited the cyclin D1-Rb pathway. Conclusion: Selective inhibition of CDK4/6 using palbociclib may provide a new therapeutic option for treating neuroblastoma

Human predisposition to cognitive impairment and its relation with environmental exposure to potentially toxic elements

New lines of evidence suggest that less than 10% of neurodegenerative diseases have a strict genetic aetiology and other factors may be prevalent. Environmental exposures to potentially toxic elements appear to be a risk factor for Parkinson’s, Alzheimer’s and sclerosis diseases. This study proposes a multidisciplinary approach combining neurosciences, psychology and environmental sciences while integrating socio-economic, neuropsychological, environmental and health data. We present the preliminary results of a neuropsychological assessment carried out in elderly residents of the industrial city of Estarreja. A battery of cognitive tests and a personal questionnaire were administered to the participants. Multivariate analysis and multiple linear regression analysis were used to identify potential relationships between the cognitive status of the participants and environmental exposure to potentially toxic elements. The results suggest a relationship between urinary PTEs levels and the incidence of cognitive disorders. They also point towards water consumption habits and profession as relevant factors of exposure. Linear regression models show that aluminium (R2 = 38%), cadmium (R2 = 11%) and zinc (R2 = 6%) are good predictors of the scores of the Mini-Mental State Examination cognitive test. Median contents (µg/l) in groundwater are above admissible levels for drinking water for aluminium (371), iron (860), manganese (250), and zinc (305). While the World Health Organization does not provide health-based reference values for aluminium, results obtained from this study suggest that it may have an important role in the cognitive status of the elderly. Urine proved to be a suitable biomarker of exposure both to elements with low and high excretion rates

A large outbreak of Legionnaires’ Disease in an industrial town in Portugal

Background We describe the investigation and control of an outbreak of Legionnaires’ disease in Portugal in October, November and December 2014. Methods Confirmed cases were individuals with pneumonia, laboratory evidence of Legionella pneumophila serogroup 1 and exposure, by residence, occupational or leisure to the affected municipalities. 49 possible sources were reduced to four potential sources, all industries with wet cooling system, following risk assessment. We geo-referenced cases’ residences and the location of cooling towers defining four study areas 10 km buffer centered on each cooling tower system. We compared the number of cases with expected numbers, calculated from the outbreak's attack rates applied to 2011 census population. Using Stones’ Test, we tested observed to expected ratios for decline in risk, with distance up to 10 km four directions. Isolates of Legionella pneumophila were compared using molecular methods. Results We identified 403 cases, 377 of which were confirmed, 14 patients died. Patients became ill between 14 October and 2 December. A NE wind and thermal inversion were recorded during the estimated period of exposure. Disease risk was highest in people living south west from all of the industries identified and decreased with distance (p < 0.001). 71 clinical isolates demonstrated an identical SBT profile to an isolate from a cooling tower. Whole genome sequencing identified an unusual L. pneumophila subsp. fraseri serogroup 1 as the outbreak causative strain, and confirmed isolates’ relatedness. Conclusions Industrial wet cooling systems, bacteria with enhanced survival characteristics and a combination of climatic conditions contributed to the second largest outbreak of Legionnaires’ disease recorded internationally.info:eu-repo/semantics/publishedVersio