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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Estrutura e variabilidade da região 3’não-traduzida dos genes HLA-A, HLA-C e HLA-G e perfil de ligação de microRNAs

Porto, Iane de Oliveira Pires January 2018 (has links)
Orientador: Erick da Cruz Castelli / Resumo: O complexo gênico de Antígenos Leucocitário Humanos (HLA) é a região mais variável do genoma humano. Os genes HLA de classe I são divididos em clássicos e não clássicos, a depender de suas funções primárias, níveis de expressão e polimorfismos. Assim, HLA-A, HLA-B e HLA-C são loci clássicos e estão associados à apresentação antigênica para células T citotóxicas, enquanto HLA-E, HLA-G e HLA-F são loci não clássicos e estão associados à imunomodulação e inibição de células T e NK. No entanto, o HLA-C também apresenta propriedades imunomodulatórias a partir da interação com o TCR de células T CD8 (ativação) e com receptores KIR de células NK (principalmente inibição). A maioria dos estudos sobre variabilidade dos genes HLA têm como foco suas regiões codificadoras e negligenciam regiões regulatórias – região promotora e região 3’não-traduzida (3’NT). Esta última apresenta um papel essencial na estabilidade do mRNA e no controle pós-transcricional mediado pela ligação de microRNAs (miRNA). Neste trabalho, nós avaliamos a estrutura e a variabilidade das regiões 3’NTs dos genes HLA-A, HLA-C e HLA-G por sequenciamento de nova geração além do padrão de ligação de miRNAs observado para cada gene. A região 3’NT dos genes HLA-A e HLA-C são altamente variáveis, enquanto a de HLA-G apresenta poucos pontos de variação. No entanto, os três genes apresentaram números similares de haplótipos de 3’NT frequentes. Vários miRNAs possuem potencial de regular HLA-A, HLA-C e HLA-G tanto de modo espec... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The Human Leucocyte Antigen (HLA) gene complex is the most variable region of the human genome. The class I HLA genes are classified as classical or nonclassical depending on their primary function, expression levels and polymorphism rate. Thus, HLA-A, HLA-B, and HLA-C are classical loci, associated with antigen presentation to cytotoxic T cells, while HLA-E, HLA-G, and HLA-F are non-classical loci associated with immunomodulation inhibition of both T and NK cells. Nevertheless, HLA-C also presents immumodulatory features by interacting with TCR on CD8 T (activation) cells as well as KIR receptors on NK cells (mostly inhibition). Most studies on HLA variability focus on their coding sequences and neglects their regulatory sequences – promoter and 3’untranslated region (3’UTR). The last one plays a pivotal role on mRNA stability and post-transcriptional control by microRNA (miRNA) binding. Here we evaluated 3’UTR structure and variability for HLA-A, HLA-C, and HLA-G by using massively parallel sequencing in a Brazilian population sample. We also report the miRNA binding pattern observed for each locus. Both HLA-A and HLAC 3’UTR segments are highly variable, while HLA-G 3’UTR presents few variation sites. However, the three loci present a similar number of frequent 3’UTR haplotypes. Several miRNAs are potential regulators of HLA-A, HLA-C, and HLA-G on a specific manner as well as the three of them together. This fact may be associated with the fine regulation of HLA expression ... (Complete abstract click electronic access below) / Doutor
2

Transplantace ledvin - shoda mezi dárcem a příjemcem ve FN Hradec Králové / Kidney Transplantation: Donor-Recipient Pairing in University Hospital Hradec Králové

Moravcová, Lucie January 2019 (has links)
8 ABSTRACT Author: Bc. Lucie Moravcová Supervisor: MUDr. Vít Řeháček Charles University, Faculty of Pharmacy in Hradec Králové Title of master's thesis: Kidney transplantation: donor-recipient pairing in University Hospital Hradec Králové Background: The aim of this study was to determine HLA, blood group, age and sex match in donor-recipient pairing in kidney transplantation. HLA alleles of deceased donors were typed in Transfusion Department of the University Hospital Hradec Králové. Methods: Donor's HLA-A*, HLA-B* and HLA-DRB1* alleles were typed by PCR - SSP method. Complex data evaluating and processing was then performed. Results: 97 deceased donors were tested between 2013 and 2018. A total of 98 kidneys received from them were subsequently transplanted to 98 recipients in University Hospital Hradec Králové. 60,2 % of the donors were men, 63,3 % of the recipients were men. Most of the donors, as well as the recipients, were 51-70 years old (50,0 % and 59,2 %, respectively). The most common diagnoses in the group of deceased donors were associated with brain damage (66,3 %), the most common cause of renal failure in the group of recipients was chronic inflammatory kidney disease (41,8 %). All 98 transplantations (100,0 %) were AB0 compatible. 74 transplantations (75,5 %) were RhD compatible. 5...
3

The phenotypic characterization of the monocyte in human sepsis

Perry, Sara Elizabeth January 2003 (has links)
No description available.
4

Epitope mapping in major histocompatibility systems

Marsh, Steven George Edward January 1997 (has links)
No description available.
5

Class II Human Leukocyte Antigen gene polymorphisms, cell surface expression and immunoglobulin E mediated disease

Standring, Peter January 1998 (has links)
No description available.
6

Epigenetická regulace genů HLA II. třídy a její modifikace během života / Epigenetic regulation of HLA class II genes and its modification during the lifetime

Lamborová, Věra January 2013 (has links)
Background: The major histocompatibility complex (MHC) molecules play an important role in the immune response regulation and in the maintenance of the immune homeostasis. Regulation of their expression is therefore a key factor influencing the adaptive immune response. DNA methylation of gene regulatory regions is one of the mechanisms of gene expression control that affects the accessibility of DNA to transcription factors. Ageing is connected with changes in DNA methylation and increased predisposition to autoimmune diseases in older age could be associated with changes in MHC class II genes methylation. Aims: The aim of this diploma thesis is to analyze the methylation profile of DQA1 and DQB1 genes regulatory regions and to compare its differences between the generations and between individual alleles. The next aim is to compare DQA1 mRNA expression between the generations and between single alleles. Methods: DNA and RNA were isolated from blood of three age group donors. DNA was converted by the bisulfite treatment and regulatory regions of HLA class II genes were amplified and cloned into bacteria. Positive clones were sequenced and then analyzed. RNA was reverse transcribed and its expression level was determined by real-time PCR. Results: Statistically significant differences were found by...
7

Improved Prediction-based Dynamic Load Balancing Systems for HLA-Based Distributed Simulations

Alkharboush, Raed January 2015 (has links)
Due to the dependency of High-Level Architecture (HLA)-Based simulations on the resources of distributed environments, simulations can face load imbalances and can suffer from low performance in terms of execution time. HLA is a framework that simplifies the implementation of distributed simulations; it also has been built with dedicated resources in mind. As technology is nowadays shifting towards shared environments, the following two weaknesses have become apparent in HLA: managing federates and reacting towards load imbalances on shared resources. Moreover, a number of dynamic load management systems have been designed in order to provide a solution to enable a balanced simulation environment on shared resources. These solutions use specific techniques depending on simulation characteristics or load aspects to perform the balancing task. Load prediction is one of such techniques that improves load redistribution heuristics by preventing load imbalances. In this thesis, a number of enhancements for a prediction technique are presented, and their efficiency are compared. The proposed enhancements solve the observed problems with Holt’s implementations on dynamic load balancing systems for HLA-Based distributed simulations and provide better forecasting. As a result, these enhancements provide better predictions for the load oscillations of the shared resources. Furthermore, a number of federate migration decision-making approaches are introduced to add more intelligence into the process of migrating federates. The approaches aim to solve a dependency problem in the prediction-based load balancing system on the prediction model, thus making similar systems adapt to any future system improvements.
8

Estudo in silico das bases moleculares responsáveis pela reatividade cruzada entre epitopos virais restritos ao alelo HLA-A*02:01

Antunes, Dinler Amaral January 2011 (has links)
A apresentação de peptídeos endógenos pelo Complexo Principal de Histocompatibilidade (MHC, do inglês Major Histocompatibility Complex) e seu reconhecimento pelos Linfócitos T Citotóxicos representa a etapa final de uma importante via intracelular. Esta via permite ao sistema imune realizar uma constante vigilância acerca do conteúdo citoplasmático de todas as células nucleadas do organismo, sendo um mecanismo central na defesa antitumoral e antiviral. A compreensão dos detalhes moleculares que levam um dado complexo peptídeo:MHC (pMHC) a estimularem uma população de linfócitos é vital para o desenvolvimento de vacinas e imunoterapias, tendo especial aplicação no entendimento da resposta imune ao Vírus da Hepatite C (HCV, do inglês Hepatitis C Virus). Em um trabalho publicado em 2008, Paraskevi Fytili e colaboradores avaliaram a imunogenicidade de um conjunto de variantes do epitopo imunodominante HCV-NS31073 (CV/INGVCWTV) frente a uma população de linfócitos previamente estimulada com o epitopo selvagem. Foram utilizadas tanto variantes naturais quanto sintéticas, tendo sido observado uma grande variação na produção de IFN-gama pelas células específicas contra o epitopo selvagem. O presente trabalho pretende avaliar esta variabilidade em um nível molecular, através do uso de ferramentas de bioinformática. A prévia identificação de padrões alelo específicos, adotados pelos epitopos na fenda do MHC, permitiu o desenvolvimento de uma estratégia in silico para a construção de complexos pMHC, através do uso combinado de Docking Molecular e Minimização de Energia (D1-EM-D2). Esta abordagem inovadora foi aplicada para a construção de 10 complexos apresentando peptídeos sintéticos e 28 complexos apresentando variantes naturais, todos no contexto do alelo de MHC humano HLAA* 02:01. A superfície destes complexos foi posteriormente avaliada quanto à topologia, distribuição de cargas e área acessível ao solvente. Os resultados foram utilizados para agrupar as variantes de acordo com a similaridade com o complexo apresentando o peptídeo selvagem, sendo estes agrupamentos confrontados com os resultados previamente observados in vitro por Fytili e colaboradores. Esta análise, corroborada pela utilização de métodos estatísticos multivariados, permitiu evidenciar o compartilhamento de características estruturais entre os complexos que estimulavam resposta in vitro, bem como identificar possíveis aspectos moleculares responsáveis pela abolição da resposta imune celular contra determinadas variantes de HCV. Este trabalho sugere a análise estrutural in silico de complexos pMHC como uma importante ferramenta no desenvolvimento de vacinas, permitindo a predição do impacto de mutações de escape viral e a seleção de epitopos com potencial para induzir respostas imunes poli-específicas (cross-reactive immune responses). / Recognition of the Major Histocompatibility Complex (MHC) by Cytotoxic T Lymphocytes (CTLs) is the final step of an important intracellular pathway, responsible for presenting endogenous peptides. This route allows the Immune System to perform a persistent surveillance of the cytoplasmic content of all nucleated cells, being a pivotal mechanism in antiviral and antitumoral defense. The understanding of molecular issues underlying the stimulation of a given T cell population by a specific peptide:MHC (pMHC) complex is essential for vaccine development, having special application to study the immunity against Hepatits C Virus (HCV). In a recent work, Paraskevi Fytili and colleagues evaluated the immunogenicity of an HCV-NS31073 variants subset against a CTL population previously stimulated with the wild-type epitope. Both natural and synthetic variants were used, and a large variation of IFN-gamma production by wildtype- specific T cells was observed. In this work, we intend to evaluate this variability at molecular level, through bioinformatics approaches. The prior identification of allele-specific patterns, presented by epitopes in the MHC cleft, allowed the development of a strategy for in silico construction of pMHC complexes, combining Molecular Docking and Energy Minimization (D1- EM-D2). This innovative approach was used to build 10 complexes presenting synthetic peptides and 28 complexes presenting naturally occurring variants, all in the context of human MHC allele HLA-A*02:01. The molecular surface of these complexes was further evaluated regarding its topology, electrostatic potential and Accessible Surface Area (ASA). Resulting data was used to group the variants according to its similarity with the wild-type-presenting complex, being these groups confronted with in vitro data, previously published by Fytili et al. This analysis, corroborated by multivariate statistical methods, has highlighted the sharing of structural aspects among complexes that stimulate response in vitro, as well as possible molecular issues responsible for abrogation of cellular immune response against certain HCV variants. This work suggests structural in silico analysis of pMHC complexes as a reliable tool for vaccine development, affording to predict the impact of viral escape mutations and selection of epitopes with potential to induce cross-reactive immune responses.
9

Structural and electrostatic analysis of HLA B cell epitopes : inferences on immunogenicity and prediction of humoral alloresponses

Mallon, Dermot Henry January 2018 (has links)
Despite the use of potent immunosuppressive agents, injury secondary to the alloimmune response principally directed against mismatched HLA antigens, remains a significant cause of renal transplant dysfunction and loss. One of the principal ways to limit the detrimental effect of immune alloreactivity towards the graft is through minimisation of donor-recipient HLA mismatches, but this has not changed conceptually since the early period of clinical transplantation. The central hypothesis of the research described in this thesis is that assessment of histocompatibility based on evaluation of structural differences between donor and recipient HLA molecules has the potential to improve graft outcomes after kidney transplantation. Amino acid sequence analyses have been central to gaining an understanding of the relative immunogenicity of a mismatched donor HLA antigen in the context of a recipient's HLA repertoire. While these methods offer advantages over basic enumeration of HLA mismatches, regardless of how sophisticated they may be, they are unable to fully describe the intricate nature of the B cell epitope--BCR interaction that initiates a humoral response. This interaction requires, but is not limited to, structural and electrostatic potential complementarity. The aim of this thesis is to describe a fully structural description of HLA immunogenicity through analysis of the three-dimensional physicochemical environment at the surface of the HLA molecule. First, I describe the bioinformatic techniques that integrate HLA sequence and X-ray crystallographic data to produce accurate models of HLA molecular structure and, subsequently, calculate the electrostatic potential in the three-dimensional area surrounding the molecule. Through quantitative comparison of the three-dimensional electrostatic potential on the surface of each HLA molecule, Electrostatic Mismatch Score 3D (EMS-3D) is derived. EMS-3D represents the electrostatic disparity between a group of HLA molecules. Subsequently, I demonstrate, using examples of HLA mutagenesis studies described in the literature, that patterns of antigenicity are better explained through analysis of surface electrostatic potential than by analysis of sequence. Of greater clinical interest, the ability of EMS-3D to predict the development of \textit{de novo} alloantibody responses was assessed in a cohort of patients who received a standardised immunisation and had their antibody profile characterised using Luminex single-antigen beads. This analysis validated EMS-3D as a valuable predictor of the development and magnitude of an alloantibody response, and therefore as a potentially useful clinical tool in the allocation of donor organs. The clinical utility of EMS-3D was assessed in a national cohort of kidney transplants, which found EMS-3D to better predict transplant outcome than conventional, currently-employed, measures of histocompatibility. HLA polymorphisms are implicated in many disease processes, particularly in autoimmunity. In the last chapter, the methodology developed in this thesis is employed to analyse the association between particular HLA polymorphisms and Inflammatory Bowel Disease (IBD). Analyses of the electrostatic potential within the HLA peptide binding groove found that particular patterns of electrostatic potential within the HLA peptide binding groove were associated with disease phenotype. Future work will examine how the examination of multiple discrete regions, ostensibly epitopes, can further improve the prediction of the HLA alloimmune response.
10

Estudo in silico das bases moleculares responsáveis pela reatividade cruzada entre epitopos virais restritos ao alelo HLA-A*02:01

Antunes, Dinler Amaral January 2011 (has links)
A apresentação de peptídeos endógenos pelo Complexo Principal de Histocompatibilidade (MHC, do inglês Major Histocompatibility Complex) e seu reconhecimento pelos Linfócitos T Citotóxicos representa a etapa final de uma importante via intracelular. Esta via permite ao sistema imune realizar uma constante vigilância acerca do conteúdo citoplasmático de todas as células nucleadas do organismo, sendo um mecanismo central na defesa antitumoral e antiviral. A compreensão dos detalhes moleculares que levam um dado complexo peptídeo:MHC (pMHC) a estimularem uma população de linfócitos é vital para o desenvolvimento de vacinas e imunoterapias, tendo especial aplicação no entendimento da resposta imune ao Vírus da Hepatite C (HCV, do inglês Hepatitis C Virus). Em um trabalho publicado em 2008, Paraskevi Fytili e colaboradores avaliaram a imunogenicidade de um conjunto de variantes do epitopo imunodominante HCV-NS31073 (CV/INGVCWTV) frente a uma população de linfócitos previamente estimulada com o epitopo selvagem. Foram utilizadas tanto variantes naturais quanto sintéticas, tendo sido observado uma grande variação na produção de IFN-gama pelas células específicas contra o epitopo selvagem. O presente trabalho pretende avaliar esta variabilidade em um nível molecular, através do uso de ferramentas de bioinformática. A prévia identificação de padrões alelo específicos, adotados pelos epitopos na fenda do MHC, permitiu o desenvolvimento de uma estratégia in silico para a construção de complexos pMHC, através do uso combinado de Docking Molecular e Minimização de Energia (D1-EM-D2). Esta abordagem inovadora foi aplicada para a construção de 10 complexos apresentando peptídeos sintéticos e 28 complexos apresentando variantes naturais, todos no contexto do alelo de MHC humano HLAA* 02:01. A superfície destes complexos foi posteriormente avaliada quanto à topologia, distribuição de cargas e área acessível ao solvente. Os resultados foram utilizados para agrupar as variantes de acordo com a similaridade com o complexo apresentando o peptídeo selvagem, sendo estes agrupamentos confrontados com os resultados previamente observados in vitro por Fytili e colaboradores. Esta análise, corroborada pela utilização de métodos estatísticos multivariados, permitiu evidenciar o compartilhamento de características estruturais entre os complexos que estimulavam resposta in vitro, bem como identificar possíveis aspectos moleculares responsáveis pela abolição da resposta imune celular contra determinadas variantes de HCV. Este trabalho sugere a análise estrutural in silico de complexos pMHC como uma importante ferramenta no desenvolvimento de vacinas, permitindo a predição do impacto de mutações de escape viral e a seleção de epitopos com potencial para induzir respostas imunes poli-específicas (cross-reactive immune responses). / Recognition of the Major Histocompatibility Complex (MHC) by Cytotoxic T Lymphocytes (CTLs) is the final step of an important intracellular pathway, responsible for presenting endogenous peptides. This route allows the Immune System to perform a persistent surveillance of the cytoplasmic content of all nucleated cells, being a pivotal mechanism in antiviral and antitumoral defense. The understanding of molecular issues underlying the stimulation of a given T cell population by a specific peptide:MHC (pMHC) complex is essential for vaccine development, having special application to study the immunity against Hepatits C Virus (HCV). In a recent work, Paraskevi Fytili and colleagues evaluated the immunogenicity of an HCV-NS31073 variants subset against a CTL population previously stimulated with the wild-type epitope. Both natural and synthetic variants were used, and a large variation of IFN-gamma production by wildtype- specific T cells was observed. In this work, we intend to evaluate this variability at molecular level, through bioinformatics approaches. The prior identification of allele-specific patterns, presented by epitopes in the MHC cleft, allowed the development of a strategy for in silico construction of pMHC complexes, combining Molecular Docking and Energy Minimization (D1- EM-D2). This innovative approach was used to build 10 complexes presenting synthetic peptides and 28 complexes presenting naturally occurring variants, all in the context of human MHC allele HLA-A*02:01. The molecular surface of these complexes was further evaluated regarding its topology, electrostatic potential and Accessible Surface Area (ASA). Resulting data was used to group the variants according to its similarity with the wild-type-presenting complex, being these groups confronted with in vitro data, previously published by Fytili et al. This analysis, corroborated by multivariate statistical methods, has highlighted the sharing of structural aspects among complexes that stimulate response in vitro, as well as possible molecular issues responsible for abrogation of cellular immune response against certain HCV variants. This work suggests structural in silico analysis of pMHC complexes as a reliable tool for vaccine development, affording to predict the impact of viral escape mutations and selection of epitopes with potential to induce cross-reactive immune responses.

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