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Submitted by Suzana Dias (suzana.dias@famerp.br) on 2018-10-26T18:02:09Z No. of bitstreams: 1 MarlonFragaMattos_dissert.pdf: 1719909 bytes, checksum: 70d153012a84a6566276733a0ea859da (MD5) / Made available in DSpace on 2018-10-26T18:02:09Z (GMT). No. of bitstreams: 1 MarlonFragaMattos_dissert.pdf: 1719909 bytes, checksum: 70d153012a84a6566276733a0ea859da (MD5) Previous issue date: 2017-09-30 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Down syndrome (DS) is the most frequent human chromosomopathy with approximate incidence of the 1 to 850 live births, nearly 90-95% of these cases are characterized by the presence of three copies of chromosome 21 as a result of the meiotic nondisjunction. DS individuals present many clinic features, including immunological changes that result in altered inflammatory response. The immune response is modulated by pro- and anti-inflammatory cytokines whose expression could be influenced by genetic polymorphisms in the coding or promoter region within the gene. Objectives: The study aimed to evaluate the frequencies of the -174G/C, -572G/C e -597G/A polymorphisms in the interleukin (IL) 6 gene promoter region and of the -592C/A, -1082A/G e -819C/T polymorphisms in the IL-10 gene promoter region in individuals with DS, and a control group without 21 trisomy, as well as to investigate the impact of the studied genotypes in the interleukins serum levels. Material and Methods: DNA samples of 200 DS individuals and 200 controls without DS were submitted to Polymerase Chain Reaction – Restriction Fragment Length Polymorphism (PCR-RFLP) or real time PCR for evaluate to presence of the -174G>C, -572G>C, and -597G>A IL-6 and -592C>A, -1082A>G, and -819C>T IL-10 polymorphisms. The serum measurement of IL-6 and IL-10 was performed in a subgroup (54 cases and 54 controls) by ELISA essay. The genotypic distribution between groups was performed by multiple logistic regression by SNPStats, program, and the linkage disequilibrium evaluation and haplotype frequency was performed by Haploview program. The comparison of IL-6 and IL-10 serum level between the groups was performed by Mann Whitney test, the interleukins concentrations analyze in relation to genotypes was performed by Kruskal-Wallis test, using the GraphPad Prism version 6.0 software. The standard error of 5% was accept. Result: Either the frequency of IL-6 and IL-10 polymorphisms or their haplotypes did not show differences between the case and control groups. There was no association between the IL-6 and IL-10 serum levels and the IL-6 and IL-10 polymorphisms. IL-10 serum levels were increased in the case group in relation to control group. Conclusion: The frequencies of the polymorphisms and haplotypes evaluated are not different between individuals with and without DS. Genotypes show no effect on the IL-6 and IL-10 serum levels. The IL-10 serum levels are increased in DS individuals, but the IL-10 polymorphisms are not the main factors that influence in higher expression of the IL-10 in DS. / A síndrome de Down (SD) é a cromossomopatia humana mais frequente, com incidência aproximada de 1 em 850 nativivos e, em cerca de 90-95% dos casos, é atribuída à trissomia livre do cromossomo 21 resultante da não-disjunção meiótica. Os indivíduos com a síndrome apresentam várias características clínicas, incluindo alterações imunológicas que resultam em resposta inflamatória alterada. A resposta imune é modulada por citocinas pró e anti-inflamatórias cuja expressão pode ser influenciada por polimorfismos genéticos na região codificante ou promotora do gene. Objetivos: O presente estudo teve como objetivos avaliar as frequências dos polimorfismos -174G/C, -572G/C e -597G/A na região promotora do gene da interleucina (IL) 6 e dos polimorfismos -592C/A, -1082A/G e -819C/T na região promotora do gene da IL-10 em indivíduos com SD, e em um grupo controle sem a trissomia do cromossomo 21 e investigar o impacto dos genótipos estudados nos respectíveis níveis séricos das interleucinas. Materiais e Métodos: Amostras de DNA de 200 indivíduos com SD e 200 controles sem a síndrome foram submetidas à reação em cadeia da polimerase - polimorfismo no comprimento dos fragmentos de restrição (PCR-RFLP) ou PCR em tempo real para avaliação da presença dos polimorfismos IL-6 -174G/C, -572G/C e -597G/A e IL-10 -592C/A, -1082A/G e -819C/T. A dosagem sérica de IL-6 e IL-10 foi realizada em um subgrupo de indivíduos (54 casos e 54 controles) pela técnica de ELISA. A distribuição genotípica entre os grupos foi realizada por regressão logística pelo programa SNPStats, e a avaliação do desequilíbrio de ligação e frequência dos haplótipos foram realizadas pelo programa Haploview. A comparação dos níveis séricos de IL-6 e IL-10 entre os grupos foi realizada pelo teste de Mann Whitney. A análise das concentrações de interleucinas em relação aos genótipos foi realizada com o teste de Kruskal-Wallis, utilizando o software GraphPad Prism versão 6.0. O erro aceito foi de 5%. Resultado: A frequência dos polimorfismos de IL-6 e IL-10 e dos seus haplótipos não mostrou diferenças entre os grupos caso e controle. Também não houve associação entre os níveis séricos de IL-6 e IL-10 e os polimorfismos de IL-6 e IL-10. Os níveis séricos de IL-10 foram aumentados no grupo caso em relação ao grupo controle. Conclusão: As frequências dos polimorfismos e haplótipos estudados não diferem entre indivíduos com SD e sem a síndrome e os genótipos não têm efeito nos níveis séricos de IL-6 e IL-10. Os níveis de IL-10 são aumentados em indivíduos com SD, mas os polimorfismos no gene IL-10 não são os principais fatores que influenciam a expressão aumentada da IL-10 na SD.

BACKGROUND:Subspecies B1 human adenoviruses (HAdV-B1) are prevalent respiratory pathogens. Compared to their species C (HAdV-C) counterparts, relatively little work has been devoted to the characterization of their unique molecular biology. The early region 3 (E3) transcription unit is an interesting target for future efforts because of its species-specific diversity in genetic content among adenoviruses. This diversity is particularly significant for the subset of E3-encoded products that are membrane glycoproteins and may account for the distinct pathobiology of the different human adenovirus species. In order to understand the role of HAdV-B-specific genes in viral pathogenesis, we initiated the characterization of unique E3 genes. As a continuation of our efforts to define the function encoded in the highly polymorphic ORF E3-10.9K and testing the hypothesis that the E3-10.9K protein orthologs with a hydrophobic domain contribute to the efficient release of viral progeny, we generated HAdV-3 mutant viruses unable to express E3-10.9K ortholog E3-9K and examined their ability to grow, disseminate, and egress in cell culture.RESULTS:No differences were observed in the kinetics of infected cell death, and virus progeny release or in the plaque size and dissemination phenotypes between cells infected with HAdV-3 E3-9K mutants or the parental virus. The ectopic expression of E3-10.9K orthologs with a hydrophobic domain did not compromise cell viability.CONCLUSIONS:Our data show that despite the remarkable similarities with HAdV-C E3-11.6K, HAdV-B1 ORF E3-10.9K does not encode a product with a "death-like" biological activity.

HSCR has been felt to be a polygeneic disease on the basis of an incompletely penetrant sex modified transmission, which may be either autosomal dominant or recessive in different kindred. During the 1990's several of the genes involved in this transmission have come to light. Other genes remain to be discovered.

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HSCR has been felt to be a polygeneic disease on the basis of an incompletely penetrant sex modified transmission, which may be either autosomal dominant or recessive in different kindred. During the 1990's several of the genes involved in this transmission have come to light. Other genes remain to be discovered.

FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico / Apesar do empenho do MinistÃrio da SaÃde para a eliminaÃÃo da hansenÃase, o Brasil à o segundo paÃs em nÃmero de casos no mundo, precedido pela Ãndia, e responsÃvel por 80% dos casos no continente americano, sendo o Nordeste do paÃs e, em especial, o Estado do Cearà considerado uma regiÃo de alta endemicidade. De acordo com a classificaÃÃo de Ridley e Jopling, as formas clÃnicas dividem-se em virchowiana, dimorfa-virchowiana, dimorfa-dimorfa, dimorfa-tuberculÃide e tuberculÃide. O trabalho foi realizado com 87 pacientes com hansenÃase, sendo 51,72% do sexo feminino e 48,3% do sexo masculino; destes 87 pacientes, 77,01% vacinados em algum perÃodo da vida entre a infÃncia a adolescÃncia. Os pacientes incluÃdos no estudo encontravam-se nÃo tratados (n=23) ou em tratamento (n=64), apresentando a maioria dos pacientes a hansenÃase pela primeira vez e alguns apresentavam recidiva (n=11). A sorologia de IgG sÃrica anti-PGL1 foi realizada em 83 pacientes, tendo sido as concentraÃÃes de maiores diferenÃas ocorridas entre os grupos com a forma tuberculÃide e dimorfa-tuberculÃide e o grupo com a forma dimorfa-virchowiana. As 87 amostras analisadas foram amplificadas quanto à seqÃÃncia de 171 pb de uma regiÃo altamente conservada dos aminoÃcidos 671-692 do C-terminal no domÃnio intracelular do receptor Toll-like 2 e foi aplicada a tÃcnica de AnÃlise do Polimorfismo Conformacional de Fita Ãnica (SSCP). O perfil eletroforÃtico das amostras testadas encontradas foram de duas e trÃs bandas, mostrando-se necessÃrio o sequenciamento,este apresentou heterozigose marcado pela presenÃa das bases C e T na posiÃÃo C2029T, e alÃm de dois outros perfis de heterozigose nas posiÃÃes C2006T (encontrado em todas as amostras sequenciadas) e T2008G (amostra 82). O trabalho sugere que houve heterozigose na regiÃo do Ãxon 3 do gene do receptor toll-like tipo 2, diferentemente do encontrado por Kang e Chae (2001) o que pode significar que o perfil de suscetibilidade em nossa populaÃÃo à distinta daqueles encontrados na Ãndia e na CorÃia. / Although several efforts from Ministry of Health have been made in order to eliminate leprosy, Brazil is still the second country with the highest number of cases in world after India and is responsible for 80% of the cases in the American continent, the Ceara state situated in the Norheastern region is considered to have high incidence rates of leprosy cases. According to Ridley and Jopling classification, the clinical forms of leprosy can be divided in lepromatous leprosy, borderline lepromatous leprosy, borderline borderline leprosy, borderline tuberculoid leprosy, and tuberculoid leprosy. This work was done with 87 patients with leprosy, being 51.72 % of the female gender and 48.3% of the male gender; from the total of patients, 77.0% had been vaccinated with BCG once in life. All the patients enrolled in the study were not treated (n=23) or in treatment (n=64). Most of the patients had suffered from leprosy for the first time and some (n=11) had suffered from leprosy recidive. The anti-PGL1 serum IgG serology has been performed in 83 patients, and the most significant differences were found comparing the tuberculoid leprosy and borderline tuberculoid leprosy groups with the borderline lepromatous leprosy group. All DNA samples (n=87) were amplified in respect to the 171 bp highly conserved sequence of the aminoacids 671-692 from the C-terminal intra-cellular domain of Toll-like 2 receptor, and they were submitted to a Single Strain Conformation Polymorphism Technique (SSCP). The eletrophoretic profile found of the samples showed two and three bands, it is essential to the sequencing, this showed heterozygosis at position C2029T, and in addition two other sections of heterozygosity at positions C2006T (found in all four sequenced samples) and 2008 (sample 82). The work showed that the heterozygosity found in the gene exon 3 of the tool-like receptor type 2, unlike the one found by Kang and Chae (2001) which may mean that the susceptibility profile from our population is distinct from those found in India and Korea.

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Bc. Michal Rataj Supervisor: Doc. PharmDr. Martin Beránek Ph.D. Title of diploma thesis: Genetic polymorphism in the NBS1 gene for diagnosis and treatment of patients with cervical carcinoma The aim of this diploma thesis is to find optimal methods for screening of mutation 657del5 and estimate frequency of heterozygotes and homozygotes for the mutation 657del5 in population of the Czech republic. In the first section of the theoretical part is comprehensively pointed out the effect of factors affecting the integrity of genetic information and the formation of mutations in DNA. On the contrary, the second section devotes to the ability of cells to respond to this damage. In detail, the thesis devotes to the NBS1 gene and its product nibrin. In the complex MRE11/Rad50/NBN nibrin is an important member of the mechanisms of repair of double strand breaks NHEJ (non-homologous end joining) and HR (homologous recombination). The thesis is focused on nibrin and its functions, but also to mutations that prevent these functions and causes genetic disease Nijmegen breakage syndrome. Nibrin is translated from the sequence of the NBS1 gene. Gene NBS1 appears in population with several various...

O objetivo do presente estudo foi avaliar, em humanos, a associação entre polimorfismos genéticos no sistema RANK/RANKL/OPG com as dimensões craniofaciais. Foram incluídos neste estudo um total de 100 indivíduos caucasianos brasileiros não relacionados. O DNA foi extraído da saliva de cada um dos participantes e os polimorfismos rs3826620, rs9594738 e rs2073618 em RANK, RANKL e OPG, respectivamente, foram analisados por PCR em tempo real. Para avaliação das dimensões craniofaciais foram avaliadas três medidas angulares (SNA, SNB e ANB) e quatro medidas lineares (Co-Gn, Go-Pg, Co-Go e PTM-A), obtidas de traçados cefalométricos. Para avaliar a distribuição dos genótipos de acordo com os padrões esqueléticos faciais (Classe I, Classe II e Classe III) foi utilizado o teste do qui-quadrado. Para comparar as médias das dimensões maxilares e mandibulares de acordo com os genótipos utilizou-se o teste de Kruskal-Wallis, com o pós-teste de Dunn para comparações múltiplas, ou ANOVA com pós-teste de Tukey. Foi utilizada a análise de regressão linear multivariada para ajustar a possível influência da idade e do gênero em cada medida. O equilíbrio de Hardy-Weinberg foi avaliado utilizando o teste do qui-quadrado para cada polimorfismo. O nível de significância adotado para todas as análises foi 5%. Os resultados obtidos evidenciaram que não houve associação estatisticamente significante entre a distribuição genotípica de RANK, RANKL e OPG com as médias dos ângulos SNA e SNB, nem com a distribuição fenotípica (padrão esquelético Classe I, II ou III) (p>0,05). Observou-se diferença estatisticamente significante entre a distribuição das medidas do comprimento da base mandibular, de acordo com os genótipos de RANK, onde o genótipo GG apresentou maior medida de Go-Pg (p=0,039). Na análise multivariada, observou-se associação significante para os polimorfismos em RANK e medidas mandibulares (Go-Pg e Co-Gn) (p<0,05). A medida da maxila não foi associada a nenhum polimorfismo. Conclui-se que houve associação entre o polimorfismo genético rs3826620 em RANK com maiores dimensões mandibulares, onde o comprimento da mandíbula (Co-Gn) e o comprimento da base da mandíbula (Go-Pg) estavam aumentados. / The objective of the present study was to evaluate, in humans, the association between genetic polymorphisms in the RANK/ RANKL/OPG system with alterations in craniofacial dimensions. A total of 100 unrelated Brazilian Caucasians were included in this study. DNA was extracted from the saliva of each of the participants and the polymorphisms rs3826620, rs9594738 and rs2073618 in RANK, RANKL and OPG, respectively, were analyzed by real-time PCR. To evaluate the craniofacial dimensions, three angular measurements (SNA, SNB and ANB) and four linear measurements (Co-Gn, Go-Pg, Co-Go and PTM-A) were obtained from cephalometric tracings. To compare the difference between the means of the linear and angular measurements according to the genotype, Kruskal-Wallis followed by Dunn post test or ANOVA followed by the Tukey post test was used. Linear regression analysis was also used to adjust the possible influence of age and gender on each linear maxillary and mandibular measure. The Hardy-Weinberg equilibrium was also evaluated using the chi-square test within each polymorphism. The level of significance was 5%. The results demonstrated that there were no statistically significant association between the genotypic distribution of RANK, RANKL, OPG, and the angules SNA, SNB and according to the phenotypic distribution (Class I, Class II or Class III of skeletal pattern) (p> 0.05). A statistically significant difference was observed between the distribution of mandibular base length measurements according to the RANK genotypes, where the GG genotype showed a higher Go-Pg measurement (p=0.039). In the multivariate analysis, a statistically significant association was found for RANK and mandibular (Go-Pg and Co-Gn) polymorphisms (p<0.05). Measurement of the maxilla was not associated with any polymorphism. It was concluded that there was an association between genetic polymorphism rs3826620 in RANK with a greater mandibular dimension, in which the length of the mandible (Co-Gn) and the length of the base of the mandible (Go-Pg) were increased.

INTRODUÇÃO: Os fatores genéticos que influenciam o início da puberdade precoce ainda não são totalmente conhecidos. Assim, investigar os mecanismos gênicos que estariam envolvidos na sua gênese é muito importante, pois, além de possibilitar o diagnóstico em fases iniciais, pode contribuir para o desenvolvimento de novas terapias, com melhora do prognóstico. Para alguns investigadores, o estradiol também seria um fator contribuinte no determinismo da puberdade. OBJETIVOS: Estudar três genes que codificam enzimas relacionadas à esteroidogênese (CYP1A1, CYP1B1 e CYP17) em meninas com puberdade precoce central. Avaliar a associação entre variações na sequência desses genes e a puberdade precoce central. MÉTODOS: Foram incluídas 177 pacientes, divididas em dois grupos: Grupo Controle - formado por 104 meninas sem puberdade precoce, acompanhadas no Setor de Ginecologia da Infância e da Adolescência da Divisão de Clínica Ginecológica do HC-FMUSP por outros diagnósticos; Grupo Caso - composto por 73 meninas com diagnóstico de puberdade precoce central, acompanhadas no mesmo setor. Foi avaliada a presença de mutação em genes envolvidos no metabolismo do estrogênio (CYP1A1, CYP1B1 e CYP17) pela técnica de RFLP (Restriction Fragment Length Polymorphism), utilizando DNA obtido a partir de sangue periférico. RESULTADOS: A distribuição dos genótipos de CYP1A1 MspI (p=0,86) e CYP17 (p=0,12) não apresentou diferença significante entre os grupos. Para o CYP1B1 Eco571, o genótipo mutado C/C foi mais frequente no Grupo Controle que no Grupo Caso (p=0,03). CONCLUSÃO: Nossos dados sugerem que a variação do gene CYP1B1 Eco571 poderia estar associada ao determinismo da puberdade / INTRODUCTION: The genetic factors influencing onset of precocious puberty are not as yet fully known. Therefore, it is very important to investigate the genetic mechanisms involved in its genesis, for the resulting knowledge would not only enable diagnosis in the early stages but also contribute to the development of new therapies for improvement in prognosis. According to some researchers, estradiol would also be a contributory factor in puberty timing. OBJECTIVES: To investigate three genes which codify enzymes associated with steroidogenesis (CYP1A1, CYP1B1, and CYP17) in girls with central precocious puberty by focusing on the association between the sequence variation of these genes and central precocious puberty. METHODS: A total of 177 patients was included and divided into two groups: Control Group with 104 girls without precocious puberty who were being treated for other diagnoses at the Sector of Gynecology of Childhood and Adolescence, Division of Gynecology Clinic, HC-FMUSP; Case Group with 73 girls diagnosed with central precocious puberty. Mutations in genes involved in estrogen metabolism (CYP1A1, CYP1B1, and CYP17) were assessed by the RFLP (restriction fragment length polymorphism) technique using DNA obtained from peripheral blood. RESULTS: No significant difference in the distribution of the CYP1A1 MspI (p=0.86) and CYP17 (p=0.12) genotypes was detected between the two study groups. As for CYP1B1 Eco571, the mutated C/C genotype was found to be more frequent in the Control Group than in the Case Group (p=0.03). CONCLUSION: Our data suggest the CYP1B1 Eco571 gene variation is associated with puberty timing