Mutações inativadoras do receptor de GnRH (GNRHR) são a causa genética mais frequente de hipogonadismo hipogonadotrófico isolado (HHI) normósmico. Os genes envolvidos da patogênese do HHI, incluindo o GNRHR, estão associados a um amplo espectro fenotípico, variando de HHI parcial a completo. O atraso constitucional do crescimento e desenvovimento (ACCD) poderia constituir uma variante fenotípica leve do HHI. Neste estudo avaliamos a frequência de mutações no gene GNRHR em pacientes com HHI normósmico e ACCD, bem como correlacionamos o genótipo/fenótipo nesses pacientes. Além disso, avaliamos o efeito fundador de uma mutação do GNRHR (p.R139H) frequente na população brasileira com HHI normósmico. Para esse estudo, selecionamos 116 pacientes com HHI normósmico e 51 com ACCD. Um grupo de 130 indivíduos com desenvolvimento puberal normal foi utilizado como controle. A região codificadora do gene GNRHR foi amplificada por PCR e sequenciada. Análises in silico e in vitro foram realizadas nas duas novas variantes (p.V134G e p.Y283H). Três marcadores de microssatélites (D4S409, D4S2387, D4S3018) foram amplificados e analisados nos pacientes portadores da mutação p.R139H, familiares e controles. No grupo de HHI normósmico, nove mutações (p.N10K,p.Q11K, p.Q106R, p.R139H, p.C200Y, p.R262Q, p.Y284C, p.Y283H, p.V134G) foram identificadas em onze pacientes (9,5%). Entre as mutações identificadas no GNRHR, duas foram descritas pela primeira vez no estudo atual: p.Y283H e p.V134G, cuja análise in vitro demonstrou inativação completa do receptor. Em geral, uma boa correlação genótipo-fenótipo foi observada. Pacientes portadores de mutações inativadoras apresentavam HHI completo e mutações com perda parcial de função causavam HHI parcial, incluindo dois pacientes que evoluíram com reversão do hipogonadismo após reposição androgênica. Por outro lado, não houve diferença fenotípica entre os casos com e sem mutação do GNRHR. Análise de ancestralidade genética da mutação p.R139H demonstrou que todos os casos brasileiros apresentaram o mesmo haplótipo, sugerindo que a mutação p.R139H possui um ancestral comum na população brasileira. Por outro lado o caso familial proveniente da Polônia apresentou apenas um marcador em comum com as famílias brasileiras e estudos mais abrangentes seriam necessários para determinar a origem da mutação p.R139H em indivíduos não Brasileiros. Na casuística de ACCD apenas a mutação p.Q106R foi identificada no gene GNRHR em heterozigose em um paciente. Em conclusão, o GNRHR foi o gene mais comumente afetado, apresentando uma boa correlação genótipo-fenótipo, e deve ser o primeiro candidato para análise genética em HHI normósmico. Os resultados sugerem que a mutação p.R139H possui um ancestral comum na população brasileira. Mutações no GNRHR parecem não estar envolvidas na patogênese do ACCD / GnRH receptor (GNRHR) inactivating mutations are the most common genetic cause of normosmic IHH. The genes involved in the IHH, including GNRHR, have been associated with a large phenotypic spectrum, varying from partial to complete IHH. Constitutional delay of growth and puberty (CDGP) might represent a mild phenotypic variant of IHH. In this study we investigated novel variants and characterized the frequency and phenotype-genotype correlation of GNRHR mutations in normosmic IHH and CDGP patients. Additionally, we determined de cause of the recurrence of GNRHR p.R139H mutation in patients with normosmic IHH. We studied 116 patients with normosmic IHH and 51 with CDGP. The control group was composed by 130 adults with normal pubertal development. The coding region of GNRHR was amplified and automatically sequenced. The two novel variants identified (p.Y283H, p.V134G) were submitted to in silico and in vitro analysis. Three microsatellite markers (D4S409, D4S2387, D4S3018) were amplified by PCR and analyzed in the patients with the p.R139H mutation. In the CDGP group, the previously described mutation p.Q106R was identified in the heterozygous state in one boy. The p.Q106R mutation has been identified in heterozygous state in individuals with normal pubertal development and does not appear be involved on the CDGP phenotype in this patient. In the normosmic IHH group, nine variants were identified (p.N10K, p.Q11K, p.Q106R, p.R139H, p.C200Y, p.R262Q, p.Y284C, p.Y283H, p.V134G) in eleven patients (9.5%). In vitro analysis of the novel variants p.Y283H and the p.V134G demonstrated that both of them cause complete loss of function of the receptor. The founder effect study revealed that all the p.R139H affected Brazilian patients presented the same haplotype, suggesting that the this mutation has a common ancestor in the Brazilian population. Nevertheless the affected Polish family presented a different haplotype, with only one marker in common with the Brazilian families and further studies would be necessary to determine the origin of the p.R139H mutation in the European population. In conclusion this study demonstrated that GNRHR was the most commonly affected gene in normosmic IHH, with a good genotype-phenotype correlation, and should be the first candidate gene for genetic screening in this condition. The results of the founder effect study suggested that the p.R139H mutation has a common ancestor in the Brazilian population. Finally, mutations in the GNRHR do not appear to be involved in the pathogenesis of CDGP

Orientador: Suzy Lagazzi Rodrigues / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Estudos da Linguagem / Made available in DSpace on 2018-08-10T13:44:28Z (GMT). No. of bitstreams: 1 Pitombo-Oliveira_Tania_D.pdf: 3921299 bytes, checksum: b0e6240ebc5a18633cdb285711df93f6 (MD5) Previous issue date: 2007 / Resumo: Nesta minha reflexão, que se inscreve na perspectiva teórica da Análise de Discurso fundada nos trabalhos de Michel Pêcheux na França e Eni Orlandi e o grupo de pesquisadores por ela formados no Brasil, tenho como objeto a compreensão da constituição histórica do conflito posto no Estado de Mato Grosso pelo processo migratório instaurado na década de setenta, na perspectiva discursiva de análise do discurso jornalístico. Através dessa análise pretendo compreender a divisão que se mostra na língua e circula na mídia, principalmente nas diferentes posições-sujeito observadas. Para esta reflexão e compreensão dos sentidos que afloram e circulam na região norte do Estado de Estado de Mato Grosso, a análise do material constituído por entrevistas e depoimentos a partir de recortes de jornais locais impressos, virtuais e revistas; representativos da região norte do Estado do Mato Grosso, produziu recortes específicos, marcados, a partir das relações imaginárias constitutivas dos processos discursivos, por um forte posicionamento favorável à proposta de divisão territorial do Estado. Essa prática discursiva favorável ao processo divisionista, estabelece, por defender esse posicionamento, uma situação de confronto com os habitantes da região sul do Estado. Para entender esse confronto, foi necessário me deter também na prática discursiva jornalística representativa dos habitantes da região sul do Estado de Mato Grosso que compreende a capital Cuiabá e seu entorno, região esta toda ela à luz de mais de 200 anos de colonização e que devido às grandes distâncias, falta de estradas e comunicação com os grandes centros do País, viveu um grande período de isolamento sócio-econômico e cultural até a instauração do processo migratório no Estado. Tomando o discurso como local privilegiado de observação, encontro práticas discursivas que reforçam o ser de Mato Grosso, nascido aqui, em posição de enfrentamento aos paus-rodados e paus-fincados, formulações essas ancoradas no acontecimento discursivo da primeira divisão estadual, no movimento da construção de fundar sentidos postos pela Declaração da Amazônia, e, ainda, nos efeitos de uma incerteza em relação a um futuro marcados pelo tempo verbal do futuro do pretérito. A análise do discurso em relação ao confronto não dividir x criar um novo Estado deu visibilidade a processos de identificação que definem as relações imaginárias postas no Estado de Mato Grosso pelos seus habitantes / Abstract: This reflection is inscribed in the theoretical outlook of the analysis of the discourse based on productions by Michel Pêcheux in France and Erni Orlandi and the team of researchers formed by it in Brazil. I aim the understanding of the historical constitution of the conflict brought about by the migratory process in the state of Mato Grosso in the 80¿s, under the discursive analysis of the journalist discourse. Through this analysis I intend to understand the division shown in the language that circulates in the mass media, mainly in the different subject-positions observed. For this reflection and understanding of the meanings that emerge and circulate in the North region of the state of Mato Grosso, the analysis of the material made up of interviews and depositions from local newspaper clippings virtual news and magazines which represent the North region of the state of Mato Grosso has produced specific meanings, which are marked by a strong favorable stand to the proposal of the territorial division of the state and imaginary constitutive relations of the discursive processes. This discursive practice which is favorable to the divisional process stablishes a confronting situation towards the inhabitants of the south region of the state for defending this position. In order to understand this confrontation I also had to detain in the journalistic discursive practice which represents the inhabitants of the south region of the state of Mato Grosso which comprises the capital city Cuiabá and its surroundings. A region subject to over 200 years of colonization and which, due to large distances, lack of roads and communication with the large cities in Brazil, has faced a great period of socio-economical and financial isolation until the instauration of the migratory process in the state. Taking the discourse a privileged observation spot I find discursive practices which reinforce the Mato Grosso being. Born here, facing the ¿pau-rodados¿ and ¿pau-fincados¿, formulations anchored the discursive discourse of the first state division, to the construction movement of founding meanings imposed by the Declaration of the Amazonia and also to the effects of an incertaintly concerning a future marked by the conditional verbal tense. The discourse analysis related to the confrontation no division x creation of a new state enlighted the identification processes that define the imaginary relations inflicted in the state of Mato Grosso by its inhabitants / Doutorado / Mestre em Linguística

Made available in DSpace on 2016-03-15T19:26:50Z (GMT). No. of bitstreams: 1 Matheus Fernandes Junior.pdf: 862744 bytes, checksum: 7ae0f1de3ba158af12066864631a3dad (MD5) Previous issue date: 2010-02-10 / Fundo Mackenzie de Pesquisa / Family control and management can be considered efficient and beneficial to corporate performance by reducing conflicts between shareholders and managers, lowering administrative myopia, reducing information asymmetry and profiting from social and political family influence. On the other hand, they may also be inefficient and harmful to performance by bringing conflicts between majority and minority shareholders, by being subject to nepotism and particularism, by obstructing takeovers and by extending family conflicts into the firm. It ends in doubts about positive, negative or null correlation of family control and management and corporate performance. This study investigated this issue, bringing two main contributions: the analysis of family or individual control, founding family control and founder CEO administration and its relation with performance for the Brazilian environment, and the deployment of a specific measurement index for corporate governance, which is usually approached via proxies in existing literature. Empirical analysis evaluating the performance of 230 companies with higher liquidity (on the Sao Paulo stock exchange BM&FBOVESPA) in the years of 2006, 2007 and 2008 and evaluated taking into consideration family control, founding family control and CEO position occupied by the person who founded the company (CEO founder). They were compared with control groups without such characteristics. Econometric models showed no evidence of different market performance for family or founding family control. However, CEO founder showed superior market performance compared with non CEO founder firms. Operational performance measured by accountancy parameters of family controlled, founding family controlled and founder CEO managed companies was lower than operational performance of other companies. Such results differ from the ones obtained in the US and Western Europe, which showed both superior market and operational performance for family, founding family control and founder CEO administration. / As estruturas de controle e administração familiares são apontadas, por um lado, como eficientes e benéficas ao desempenho das empresas pelo seu potencial de redução de conflitos entre acionistas e administradores, menor miopia administrativa, reduzida assimetria de informação e possível influência social e política das famílias, entre outros fatores. Por outro, são apontadas como estruturas prejudiciais ao desempenho, por serem fonte de conflitos entre os acionistas majoritários e minoritários, estarem sujeitas ao nepotismo e particularismo, pela inibição de takeovers, por estenderem os conflitos familiares à empresa e assim por diante. As conclusões sobre a correlação (positiva, negativa ou inexistente) destes fatores com o desempenho das empresas seguem dúbias. Este trabalho investigou esta questão, trazendo duas contribuições principais: o estudo da relação entre controle familiar ou individual, famílias fundadoras e administração do fundador no contexto nacional e o uso de um índice específico para a medida da governança corporativa como variável de controle, o qual usualmente é tratado pela literatura estrangeira através de proxies. Na análise empírica foi investigado o desempenho das 230 empresas mais líquidas listadas na BM&FBOVESPA, nos anos de 2006, 2007 e 2008 frente ao controle familiar, ao controle da família fundadora da empresa e ao fato do cargo de CEO ser ocupado pela pessoa que fundou a firma, comparandoas aos grupos de controle não familiares ou não geridos pelo fundador. Modelos econométricos indicaram que, sob o ponto de vista de mercado, não há evidências claras de diferenças de desempenho entre empresas cujo controle é familiar ou individual e das famílias fundadoras e as empresas em geral. Já as empresas administradas pelo fundador (CEO fundador) apresentaram desempenho de mercado (Valor de Mercado sobre o Valor Contábil e Q de Tobin) superior às demais. Por outro lado, o desempenho operacional, medido por critérios contábeis, foi menor para o controle familiar, da família fundadora e para a administração do CEO fundador, comparado às empresas em geral. Os resultados referentes ao desempenho operacional diferem dos obtidos em estudos realizados nos Estados Unidos e Europa Ocidental que apontam relações positivas entre o desempenho de mercado e operacional - e o controle e administração familiares.

My diploma thesis is focused on the evaluation of headmasters by their school founders. It deals mainly with identifying the ways of evaluation, defining evaluation criteria and the overall approach to the assessment of the quality of headmasters' work. The aim is to create for a school founder an overview of the most commonly used forms of evaluation of headmasters. My work seeks to identify and compare different approaches to evaluation of headmasters by different school founders in the Prague region. My goal is to map and compare which criteria are considered to be crucial in evaluation of headmasters. Firstly, I would like to determine whether school founders have determined criteria for assessment of headmasters; secondly whether these criteria are familiar to headmasters, or whether they are possibly published. Next, I would like to present the schedule in which evaluation of headmasters is carried out and which forms of assessment are considered as motivational. The theoretical part of the work is focused on defining and describing basic concepts which are directly related to the issue regarding evaluation of headmasters. This part of the work is dedicated to theoretical pieces of knowledge concerning methods and possibilities of evaluation, its types, forms and tools. Furthermore, it...

1 ABSTRACT The dissertation is focused on analysis of the preschool education in the kindergartens founded by private founders on the territory of the capital city of Prague in 2001-2015 with emphasis on performance indicators, trends in development and specific aspects of this level of education. During the mentioned period, the number of new private kindergartens considerably increased. The private kindergartens represent a segment of preschool education which has been absent in the Czech Republic for a long time and which could secure varied offer of education including alternative approach, above-standard or non- standard concepts of the preschool education. Kindergartens represent the very first educational institution, which any child normally faces to, and which serves as a systematic field for education. The capital city of Prague has been chosen as a key-region of the Czech Republic with high level of dynamic changes and economic potential which also have influence on development of the preschool education.

This thesis analyzes the current state of the selected Kindergarten. Based on the analysis made a proposal to extend kindergarten, due to lack of capacity building. The thesis is designed to address deficiencies occurring in kindergarten. It created a proposal to extend the new kindergarten class together with the calculation of the costs incurred and revenues.

La maladie de Niemann-Pick type C (NP-C) est une maladie autosomal récessive rare neurodégénérative, pan-ethnique et avec variabilité phénotypique. La forme classique se trouve chez les patients juvéniles, mais des patients de tous les âges existent. Les symptômes incluent des signes viscéraux, moteurs et neurologiques. La maladie est causée par une mutation dans le gène NPC1 ou NPC2. La prévalence mondiale se trouve à environ un cas par 100 000 naissances, mais varie beaucoup selon les populations. Pour cette raison, nous avons voulu identifier et classifier des variants qui se trouve dans la population québécoise pour faire une estimation de la prévalence de NP-C au Québec. Nous croyons que cette maladie neurodégénérative est sous-diagnostiquée. Pour identifier le pool génétique de la population québécoise, nous avons utilisé une approche bio-informatique. À l’aide des données de séquençage des 1109 participants sains de la cohorte CARTaGENE, nous avons identifié des variants rares, ayant des fréquences alléliques inférieures à 1%, dans les gènes NPC1 et NPC2. Les données de séquençage de l’ARN et d’exome ont été alignées, les variants ont été détectés et annotés avec différents scores de pathogénicité. Les variants ont ensuite été classifiés à l’aide des lignes directrices de l’ACMG. À l’aide de notre pipeline bio-informatique, nous avons identifié 37 variants rares. Parmi ces variants, un, p.I1061T, a été classifié comme pathogénique comme il l’est dans d’autres bases de données et un, p.P543L, initialement classifié comme potentiellement pathogénique a été classifié comme pathogénique dans notre population. Le variant p.P543L est d’ailleurs possiblement une mutation fondatrice chez les Canadiens-Français. La prévalence mesurée à l’aide des fréquences alléliques de ces deux variants est de 0,61 cas par 100 000 naissances. Cette étude a permis d’identifier deux variants pathogéniques dans une population saine, c’est-à dire sans maladie neurodégénérative connue. Nous avons ensuite pu estimer pour la première fois la prévalence minimale de NP-C au Québec. Les résultats suggèrent que NP-C est sous-diagnostiquée dans notre population. Avec ces informations, les méthodes de diagnostic pourront être ajustées pour accélérer la détection de NP-C au Québec et ainsi aider les patients en donnant accès au traitement disponible pour réduire les symptômes neurologiques. / Niemann-Pick type C disease (NP-C) is a rare autosomal recessive neurodegenerative, pan-ethnic disease with heterogenous symptoms. The classical form mainly affects juvenile patients, but patients of varying ages exist. The main symptoms are visceral, motor and neurological. The disease is caused by mutations in the NPC1 or NPC2 gene. The worldwide prevalence is approximately one case per 100 000 births but varies between populations. Therefore, we wanted to identify and classify rare variants found in Quebec’s population to estimate the prevalence of NP-C in this population. We hypothesized that NP-C is under-diagnosed in Quebec. To determine the genetic pool of NP-C in Quebec’s population, we used a bioinformatics pipeline. With the sequencing data of 1109 healthy individuals of the CARTaGENE cohort, we identified rare variants, with a minor allele frequency inferior to 1%, in the NPC1 and NPC2 genes. The sequencing data from RNA and exome sequencing was aligned and the variants were found and annotated with different pathogenicity scores. The variants were then classified using the ACMG guidelines. Using our bioinformatics pipeline, we identified a total of 37 rare variants. In those variants, one, p.I1061T, was directly classified as pathogenic since it was classified as that in all databases. The other one, p.P543L, was initially classified as likely pathogenic, but we were able to reclassify it as pathogenic in our population. The p.P543L variant is possibly a founder mutation in the French-Canadian population. Next, we estimated the prevalence based on the allelic frequencies of those two variants in our cohort. We found a prevalence of 0,61 case per 100 000 births. This study allowed us to identify two pathogenic variants in a healthy population, without known neurodegenerative disease. We were also able to estimate the first ever minimal prevalence for NP-C in Quebec. Our results suggests that NP-C is underdiagnosed in our population. With the information collected here, we would be able to adjust the diagnostic methods of NP-C in Quebec to then be able to help the patients by giving them access to the available treatment to reduce neurological symptoms.

No description available.

Les ataxies spastiques héréditaires forment une famille hétérogène de désordres qui ont des points communs avec les ataxies héréditaires et les paraplégies spastiques héréditaires. Un de ces éléments est une ataxie, soit une difficulté de coordination des membres souvent due à un dommage au cervelet. L’autre est une spasticité des membres inférieurs, souvent due à des dommages à la voie cortico-spinale. Une seule ataxie spastique à hérédité autosomique dominante a été rapportée dans la littérature, et il s’agit de SPAX1. À l’aide de trois familles de Terre-Neuve présentant ce phénotype, le locus a été identifié en 2002. Dans ce mémoire, c’est de la découverte du gène causal dont il est question. La mutation a été trouvée dans le gène VAMP1, qui encode la protéine synaptobrévine 1, une protéine synaptique impliquée dans l’exocytose des neurotransmetteurs. Il est aussi question de la caractérisation fonctionnelle de la mutation sur l’ARN et des conséquences possibles sur la protéine, concordant avec les symptômes de la maladie. / Hereditary spastic ataxias comprise a family of heterogeneous disorders resembling both hereditary ataxias and hereditary spastic paraplegias. The similar symptoms are ataxia, which is a problem with limb coordination due to cerebellar damage, and lower-limb spasticity due to corticospinal tract degeneration. Only one spastic ataxia inherited in an autosomal dominant fashion has been reported in the literature: SPAX1. The locus was identified in 2002 using three families from Newfoundland with the specific phenotype. This thesis reports the discovery of the causative mutation in the VAMP1 gene, which encodes VAMP1/synaptobrevin 1, a synaptic protein involved in neurotransmitter exocytosis. Experiments characterizing the effect of the mutation on RNA were conducted, leading to a possible molecular explanation of the symptoms.

Les événements fondateurs et les expansions territoriales peuvent promouvoir une cascade de changements génétiques et ont ainsi pu jouer un rôle important au cours de l’histoire évolutive de l’Homme moderne. Or, chez les populations humaines, les conséquences évolutives et la dynamique démographique des processus de colonisation demeurent largement méconnues et difficiles à étudier. Dans cette thèse, nous avons utilisé les généalogies de la population fondatrice canadienne-française ainsi que des données génomiques pour étudier ces questions. Les analyses génomiques et généalogiques, remarquablement concordantes, ont dévoilé un nouveau portrait détaillé de la structure de la population du Québec, incluant un continuum de diversité génétique dans l’axe ouest/est et des sous-populations significativement différenciées. L’analyse de l’immigration fondatrice a montré que virtuellement tous les Canadiens français sont métissés. Allant à l’encontre d’une prétendue homogénéité génétique de la population, nos résultats démontrent que le peuplement des régions a engendré une rapide différentiation génétique et expliquent certaines signatures régionales de l’effet fondateur. De plus, en suivant les changements évolutifs dans les généalogies, nous avons montré que les caractéristiques des peuplements fondateurs peuvent affecter les traits liés à la fécondité et au succès reproducteur. Cette thèse offre une meilleure compréhension du patrimoine génétique du Québec et apporte des éléments de réponse sur les conséquences évolutives des événements fondateurs. / Founding events and range expansions can promote a cascade of genetic changes and may have played an important role in the evolutionary history of modern humans. Yet the evolutionary consequences and demographic dynamics of these colonization processes remain poorly documented and challenging to study in human populations. In this thesis, we used deep-rooted genealogies from the French Canadian founder population in addition to genomic data to address these questions. Genomic and genealogical analyses were remarkably concordant and revealed a new portrait of Quebec fine-scale population structure, including a continuum of genetic diversity in the west/east axis and sub-populations significantly differentiated. The analysis of the founding immigration showed that virtually all French Canadians are admixed. Contrary to the idea of homogeneity of the population, our results demonstrate that the regional settlement histories led to a rapid genetic differentiation and explain some regional signatures of the founder effect. By monitoring evolutionary changes in real genealogies, we show that founding events impact fertility traits and reproductive success. This thesis leads to a better understanding of the genetic heritage of Quebec and provides insights on how peopling of new territories shaped human evolution.