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The pathogenesis, investigation and management of mitochondrial DNA diseaseChinnery, Patrick Francis January 1999 (has links)
No description available.
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Genotype-phenotype correlation using phylogenetic treesHabib, Farhat 14 September 2007 (has links)
No description available.
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Genetic and cellular studies of familial hemophagocytic lymphohistiocytosis /Rudd, Eva, January 2007 (has links)
Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.
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Diversity and persistence of Helicobacter pylori /Lundin, Annelie, January 2004 (has links)
Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.
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Functional and structural studies on CYP21 mutants in congenital adrenal hyperplasia /Robins, Tiina, January 2005 (has links)
Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 5 uppsatser.
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An Exploration of the Molecular Pathogenesis of the Autism Component of PTEN Hamartoma Tumor Syndrome (PHTS): Towards an Understanding of PTEN Variation on PHTS Phenotype DiversityThacker, Stetson Thomas 21 June 2021 (has links)
No description available.
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SYNTHESIS AND CHARACTERIZATION OF RESVERATROL AND ITS CONJUGATED METABOLITES AND CONTRIBUTION OF METABOLISM TO ITS DECREASED BIOVAILABILITYOkpor, Otito Iwuchukwu January 2011 (has links)
The purported chemopreventive and chemotherapeutic properties of the dietary phytochemical resveratrol continue to undergo active investigations. Systemic pharmacokinetics of this compound revealed that it was rapidly and extensively metabolized into its sulfate and glucuronide conjugates. This extensive metabolism leads to high plasma levels of resveratrol sulfates and glucuronides and very low levels of the parent compound (low bioavailability). These observations raised many questions, some of which this body of work examined and has helped to explain. Chapter 1 presents a detailed introduction to resveratrol and its role in colorectal cancer chemoprevention. It also lays the foundation for the hypotheses generated and the studies presented in succeeding chapters. In chapter 2, we explored the possibility that resveratrol metabolites possess intrinsic activity and thus contribute to the observed effects of the parent. The mono-sulfated and glucuronidated conjugates of trans-resveratrol were synthesized and tested for antiproliferative activity in a panel of mammalian cell lines. Their activity was then compared with the parent compound. Resveratrol was shown to be antiproliferative in all cell lines studied while no discernible antiproliferative activity was observed for the metabolites. Chapter 3 details the results of the glucuronidation kinetics of cis and trans-resveratrol isomers across a wide concentration range chosen to mimic blood levels following high dose consumption. Human tissue microsomes and recombinant supersomes over-expressing the enzymes (UGTs) of interest were used for these studies. Our results show the presence of atypical kinetics for the formation of resveratrol glucuronides across most of the protein sources used. Prior to this study, the full glucuronidation kinetics of total resveratrol had not been conducted. In chapter 4, we examined the association between genetic polymorphisms in the major enzymes (UGT1A1 and UGT1A6) and rates of glucuronidation of trans and cis-resveratrol. We set out to correlate functional genetic variations in these UGTs with their catalytic rates and a positive association was made for cis-resveratrol and UGT1A6 where the UGT1A6 variants mediated higher glucuronidation rates compared to the reference genotype. Chapter 5 explored the inherent ability of resveratrol to induce its own glucuronidation upon chronic dosing. Enzyme induction has been proposed as a mechanism that may contribute to the low bioavailability of resveratrol. Since dietary polyphenols like resveratrol are not consumed in isolation, we also studied the effects of combining resveratrol with two dietary polyphenols (curcumin and chrysin) on two chemoprevention endpoints - i) antiproliferation and ii) UGT enzyme induction. Our results indicate that resveratrol is capable of inducing UGT1A1 expression and activity in a non-concentration dependent manner and this induction as well as its antiproliferative effects are enhanced by both curcumin and chrysin. In summary, en route to probing the activity of resveratrol metabolites, we optimized two synthetic routes and generated measurable quantities of these compounds for future use. While the in vitro kinetics of resveratrol did not allow for any in vivo predictions, we were able to show alterations in resveratrol metabolism with respect to genotypic differences and enzyme induction that may contribute to the observed low bioavailability profile. / Pharmaceutical Sciences
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On the significance of neutral spaces in adaptive evolutionSchaper, Steffen January 2012 (has links)
Evolutionary dynamics arise from the interplay of mutation and selection. Fundamentally, these two processes operate at different levels: Mutations modify genetic information (the genotype), which is passed from parent to offspring. Selection is triggered by variation in reproductive success, which depends on the physical properties (the phenotype) of an organism and its environment. Thus the genotype-phenotype map determines if and how mutations can lead to selection. The aim of this dissertation is to incorporate this map explicitly into a theoretical description of evolutionary dynamics. The first part of the analysis presented here is concerned with the static properties of simple models of these maps, which are studied using exhaustive enumeration. The two most important observations are phenotypic bias – some phenotypes are realized by many more genotypes than most other phenotypes – and the existence of neutral spaces – genotypes with the same phenotype can often be reached from each other by single mutational steps. The remainder of the dissertation provides a theoretical description of evolutionary dynamics on and across neutral spaces. Two different mean-field approximations lead to simple analytic results for the first discovery of alternative phenotypes, highlighting the importance of phenotypic bias: Rare phenotypes are hard to find by evolutionary search. These results are used to discuss the relationship of robustness, the ability to withstand mutational change, and evolvability, the ability to create variation through mutation. Several types of fluctuations beyond the mean-field limit are studied, both theoretically and in simulations. The discrete structure of genotype spaces can lead to strong correlations in the spectra of phenotypes produced, increasing the probability that a particular phenotype is fixed in the population quickly after its discovery. Structural correlations between genotypes can increase the effect of phenotypic bias, while the qualitative features of the mean-field description remain valid. All these results highlight that neutral spaces impact evolutionary dynamics in many non-trivial ways, in particular by favouring phenotypes of high accessibly, but comparably low fitness over those phenotypes that are highly fit, but very hard to discover.
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Investigação de Polimorfismos nos Genes IGF2 e CYP21 em Bovinos de Raças Zebuínas e Análise das Possíveis Associações com Características de Interesse Econômico / Investigation of Polimorphisms in IGF2 and CYP21 Genes in Zebu Breeds and Possible Associations with Economic Interest TraitsSilva, Andrea Martins da 05 July 2010 (has links)
Existe um relevante interesse em pesquisar a ocorrência de polimorfismos no genoma bovino por diferentes motivos, e mais recentemente, com a finalidade de agregar mais informações ao estudo de características quantitativas visando selecionar animais geneticamente superiores com considerável valor comercial. Os polimorfismos de base única (SNPs) neste estudo foram identificados como RFLP/MboII e RFLP/HpaII sendo que o polimorfismo RFLP/MboII está situado no exon 6 do gene IGF2 (insulin-like growth factor 2), localizado no cromossomo 29 em bovinos, e desempenha um papel importante na proliferação e diferenciação celular para o crescimento e desenvolvimento dos mamíferos. O polimorfismo RFLP/HpaII encontra-se no elemento Bov-A2 (considerado um elemento SINE - Short Interspersed Nucleotide Element) presente na região promotora do gene CYP21 (Steroid 21-hydroxylase gene) no cromossomo 23 em bovinos. Para avaliar a ocorrência dos SNPs utilizou-se a técnica de PCR-RFLP em amostras de DNA a partir de sangue/sêmen de cerca de 300 animais bovinos das raças zebuínas Gir, Guzerá e Nelore. As frequências alélicas mostraram maior incidência do alelo T quando comparado ao C enquanto que as frequências genotípicas apresentaram alta ocorrência do heterozigoto TC em comparação aos homozigotos CC e TT para o polimorfismo IGF2 - RFLP/MboII. Com relação ao polimorfismo CYP21 RFLP/HpaII, a frequência alélica revelou alto valor do alelo T. A população encontrou-se em equilíbrio de Hardy-Weinberg para os SNPs estudados. Ferramentas de bioinformática foram utilizadas para investigações in silico revelando que os sítios polimórficos estão em regiões com potencial regulatório. A associação desses polimorfismos com DEPs das características reprodutivas e produtivas foram investigadas, entretanto mostrou-se significativas apenas para DP550 (IGF2 - RFLP/MboII) e DP450 (CYP21 - RFLP/HpaII). Os resultados obtidos sugerem que protocolos de Biologia Molecular in vitro podem ser usados para identificar novos marcadores moleculares, como SNPs funcionais adicionando informações que certamente contribuirão para estratégias de melhoramento dessas raças bovinas de grande importância para a produção de carne e leite em nosso país. Este foi o primeiro estudo sobre a ocorrência desses polimorfismos em raças zebuínas criadas no Brasil. / There is a considerable interest in researching the occurrence of polymorphisms in the bovine genome for different reasons, and more recently, in order to add more information to the study of quantitative traits to select genetically superior animals with considerable commercial value. The single nucleotide polymorphisms (SNPs) in this study were identified as RFLP/MboII and RFLP/HpaII polymorphisms being the RFLP/MboII is situated in exon 6 of the IGF2 gene (insulin-like growth factor 2), located on chromosome 29 in cattle, perform an important role in cell proliferation, differentiation for growth and in the development of mammals. Polymorphism RFLP/HpaII is the element Bov-A2 (considered an element SINE - Short Interspersed Nucleotide Element) present in the promoter region of CYP21 gene (Steroid 21-hydroxylase gene) on chromosome 23 in cattle. To evaluate the occurrence of SNPs, we used the PCR-RFLP method on DNA samples from blood/semen of about 300 cattle breeds from Zebu Gyr, Guzerat and Nellore. The allele frequencies showed a higher incidence of T allele compared to C while the genotype frequencies showed high incidence of heterozygous CT compared to CC and TT homozygous for the IGF2 polymorphism - RFLP/MboII. On the subject of the CYP21 polymorphism - RFLP/HpaII, the allele frequency showed high value T. The population was found in Hardy-Weinberg equilibrium for the SNPs studied. Bioinformatics tools, used for in silico investigations, revealed that the polymorphic sites are in regions with regulatory potential. The association of these polymorphisms with EPDs of reproductive and productive traits were investigated, but proved to be significant only for DP550 (IGF2 - RFLP/MboII) and DP450 (CYP21 - RFLP/HpaII). The results suggest that protocols of molecular biology in vitro can be used to identify new molecular markers, such as functional SNPs adding information that certainly will contribute to the improvement strategies of these breeds of great importance for the production of meat and milk in our country. It has been the first study on the occurrence of these polymorphisms in Zebu breeds raised in Brazil.
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POLIMORFISMOS DO GENE DGAT1 (REGIÃO 5’UTR) EM BOVINOS NELORES (PO) E MESTIÇOS (SRD), E SUA RELAÇÃO COM A CIRCUNFERÊNCIA ESCROTAL E ABERTURA BI ISQUIÁTICA.Freire, Kelia Margarida Barros 15 March 2017 (has links)
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Previous issue date: 2017-03-15 / After the opening of diverse branches of Genetics Science, and the decoding of human
and animal (bovine) genome, our production animals are being evaluated by molecular
markers, which read the genome and translate it in four letters: AT-CG. The variations are
analyzed as monomorphic and polymorphic regions. The aim of this research was to evaluate
the “polymorphisms of the gene DGAT1 and its relation to the external sciatic bi opening and
the scrotal circumference”. 109 animals have been analyzed, n= 73 Nelores bovines and n=
36 with no determined breed (NDB), with the age adjusted to 550 days, owned by breeders
from the state of Goiás. In the morphometric data analysis through the test T of Student,
comparing the groups Nelores PO and Bovine NDB, The analysis of morphometric data
through the test T of Student comparing the groups Nelore PO and Bovine NDB does not
indicate that the identified differences are substantially important to the variables ABi and CE
(p ≤ 0,0001). In the genomic analysis, the test Chi-square was not relevant (p ≥ 0,05),
revealing, this, that the groups of Nelore PO and of animals of NDB do not differ when it
comes to the obtained genotypic and allelic frequencies. In this situation, we have observed so
far variations in the allelic and genotypic frequencies for the sampled animals and the three
SNP used in the study: rs471462296, rs456245081 and rs438495570. The genotype of the
sampled bovines did not affect the evaluated characteristics, revealing there are, this, other
genetic and non-genetic effects which affect the characteristics studied in Nelore, which deserve to be investigated. / Com o desenvolvimento dos vários ramos da Ciência Genética e a decodificação do
genoma humano e animal (bovinos), nossos animais de produção estão sendo avaliados por
marcadores moleculares, que fazem a leitura do genoma e o traduz em quatro letras: AT-CG.
As variações são analisadas como regiões monomórficas e polimórficas. O objetivo desta
pesquisa foi avaliar os “Polimorfismos do Gene DGAT1 e sua relação com a abertura bi
isquiática externa (ABI) e o circunferência escrotal (CE)”. Foram analisados 109 bovinos,
sendo73 bovinos daraça Nelore (PO) e36 bovinos sem raça definida (SRD), com idade
ajustada para 550 dias, pertencentes a diferentes criadores do Estado de Goiás. A análise dos
dados morfométricos pelo teste T de Student, comparando os grupos Nelore PO e bovinos
SRD, não indica que as diferenças encontradas são substantivamente importantes para as
variáveis ABI e CE (p ≤ 0,0001).Na análise genômica, o teste do Qui-quadrado não foi
significativo (p ≥ 0,05), revelando, portanto, que os grupos de Nelore PO e de animais SRD
não diferem quanto às frequências genotípicas e alélicas encontradas. Nessa situação, não
foram observados até o momento variações na frequência alélica e genotípica para os animais
amostrados e para os três SNPs usados no estudo: rs471462296, rs456245081 e
rs438495570. O genótipo dos bovinos amostrados não apresentou influência sobre as
características avaliadas, existindo, portanto, outros efeitos genéticos e não genéticos que afetam as características estudadas em Nelore, as quais merecem ser investigadas.
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