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Aldener-Cannavá, Anna. "HLA polymorphism : genomic typing and impact on unrelated stem cell transplantation /." Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4593-4/.
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Mandage, Rajendra 1984. "Understanding interactions between EBV and human genomic variation." Doctoral thesis, Universitat Pompeu Fabra, 2018. http://hdl.handle.net/10803/586328.
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The EBV has been linked to multiple human disease phenotypes and has been associated with cancers and other infections. Recently single gene analysis and genome-wide analysis studies have been exploited to uncover the human genetic variants that are linked with EBV diseases. It also suggested the substantial role of individual host genetics and also provided a clue in understanding the interaction between virus and human. Furthermore, the outcome of the EBV infection is a complex phenomenon governs by the variation in the genetic architecture of the viral and human genomes and/or the interacting environmental factors.
Therefore, this PhD work is mainly a large-scale effort towards the understanding of the human and EBV genetic architecture to uncover the role of genetic variation in EBV associated infections, disease susceptibility, immune recognition and invasion. Our results also provide a framework on the impact of human and EBV genetic variation and their unusual interactions that highlight the human genetic influence affecting viral load reflecting the clinical behavior of EBV in LCLs and the other side viral antigenic variation modulating immune response to sustain persistence infection. This EBV-human perturbation is essential to follow-up in the context of the susceptibility of individual populations to a specific EBV associated pathology.
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Pimentel-Santos, Fernando Manuel. "Ankylosing spondylitis: genomic and functional characterization of candidate genes and their repercussion in clinical practice." Doctoral thesis, Faculdade de Ciências Médicas. Universidade Nova de Lisboa, 2012. http://hdl.handle.net/10362/7806.
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RESUMO: Introdução: A espondilite anquilosante (EA) é uma doença inflamatória crónica caracterizada pela inflamação das articulações sacroilíacas e da coluna. A anquilose progressiva motiva uma deterioração gradual da função física e da qualidade de vida. O diagnóstico e o tratamento precoces podem contribuir para um melhor prognóstico. Neste contexto, a identificação de biomarcadores, assume-se como sendo muito útil para a prática clínica e representa hoje um grande desafio para a comunidade científica.
Objetivos: Este estudo teve como objetivos: 1 - caracterizar a EA em Portugal; 2 - investigar possíveis associações entre genes, MHC e não-MHC, com a suscetibilidade e as características fenotípicas da EA; 3 - identificar genes candidatos associados a EA através da tecnologia de microarray.
Material e Métodos: Foram recrutados doentes com EA, de acordo com os critérios modificados de Nova Iorque, nas consultas de Reumatologia dos diferentes hospitais participantes. Colecionaram-se dados demográficos, clínicos e radiológicos e colhidas amostras de sangue periférico. Selecionaram-se de forma aleatória, doentes HLA-B27 positivos, os quais foram tipados em termos de HLA classe I e II por PCR-rSSOP. Os haplótipos HLA estendidos foram estimados pelo algoritmo Expectation Maximization com recurso ao software Arlequin v3.11. As variantes alélicas dos genes IL23R, ERAP1 e ANKH foram estudadas através de ensaios de discriminação alélica TaqMan. A análise de associação foi realizada utilizando testes da Cochrane-Armitage e de regressão linear, tal como implementado pelo PLINK, para variáveis qualitativas e quantitativas, respetivamente. O estudo de expressão génica foi realizado por Illumina HT-12 Whole-Genome Expression BeadChips. Os genes candidatos foram validados usando qPCR-based TaqMan Low Density Arrays (TLDAs).
Resultados: Foram incluídos 369 doentes (62,3% do sexo masculino, com idade média de 45,4 ± 13,2 anos, duração média da doença de 11,4 ± 10,5 anos). No momento da avaliação, 49,9% tinham doença axial, 2,4% periférica, 40,9% mista e 7,1% entesopática. A uveíte anterior aguda (33,6%) foi a manifestação extra-articular mais comum. Foram positivos para o HLA-B27, 80,3% dos doentes. Os haplótipo A*02/B*27/Cw*02/DRB1*01/DQB1*05 parece conferir suscetibilidade para a EA, e o A*02/B*27/Cw*01/DRB1*08/DQB1*04 parece conferir proteção em termos de atividade, repercussão funcional e radiológica da doença. Três variantes (2 para IL23R e 1 para ERAP1) mostraram significativa associação com a doença, confirmando a associação destes genes com a EA na população Portuguesa. O mesmo não se verificou com as variantes estudadas do ANKH. Não se verificou associação entre as variantes génicas não-MHC e as manifestações clínicas da EA. Foi identificado um perfil de expressão génica para a EA, tendo sido validados catorze genes - alguns têm um papel bem documentado em termos de inflamação, outros no metabolismo da cartilagem e do osso.
Conclusões: Foi estabelecido um perfil demográfico e clínico dos doentes com EA em Portugal. A identificação de variantes génicas e de um perfil de expressão contribuem para uma melhor compreensão da sua fisiopatologia e podem ser úteis para estabelecer modelos com relevância em termos de diagnóstico, prognóstico e orientação terapêutica dos doentes. -----------ABSTRACT: Background: Ankylosing Spondylitis (AS) is a chronic inflammatory disorder characterized by inflammation in the spine and sacroiliac joints leading to progressive joint ankylosis and in progressive deterioration of physical function and quality of life. An early diagnosis and early therapy may contribute to a better prognosis. The identification of biomarkers would be helpful and represents a great challenge for the scientific community.
Objectives: The present study had the following aims: 1- to characterize the pattern of AS in Portuguese patients; 2- to investigate MHC and non-MHC gene associations with susceptibility and phenotypic features of AS and; 3- to identify candidate genes associated with AS by means of whole-genome microarray.
Material and Methods: AS was defined in accordance to the modified New York criteria and AS cases were recruited from hospital outcares patient clinics. Demographic and clinical data were recorded and blood samples collected. A random group of HLA-B27 positive patients and controls were selected and typed for HLA class I and II by PCR-rSSOP. The extended HLA haplotypes were estimated by Expectation Maximization Algorithm using Arlequin v3.11 software. Genotyping of IL23R, ERAP1 and ANKH allelic variants was carried out with TaqMan allelic discrimination assays. Association analysis was performed using the Cochrane-Armitage and linear regression tests as implemented in PLINK, for dichotomous and quantitative variables, respectively. Gene expression profile was carried out using Illumina HT-12 Whole-Genome Expression BeadChips and candidate genes were validated using qPCR-based TaqMan Low Density Arrays (TLDAs).
Results: A total of 369 patients (62.3% male; mean age 45.4±13.2 years; mean disease duration 11.4±10.5 years), were included. Regarding clinical disease pattern, at the time of assessment, 49.9% had axial disease, 2.4% peripheral disease, 40.9% mixed disease and 7.1% isolated enthesopathic disease. Acute anterior uveitis (33.6%) was the most common extra-articular manifestation. 80.3% of AS patients were HLA-B27 positive. The haplotype A*02/B*27/Cw*02/DRB1*01/DQB1*05 seems to confer susceptibility to AS, whereas A*02/B*27/Cw*01/DRB1*08/DQB1*04 seems to provide protection in terms of disease activity, functional and radiological repercussion. Three markers (two for IL23R and one for ERAP1) showed significant single-locus disease associations. Association of these genes with AS in the Portuguese population was confirmed, whereas ANKH markers studied did not show an association with AS. No association was seen between non-MHC genes and clinical manifestations of AS. A gene expression signature for AS was established; among the fourteen validated genes, a number of them have a well-documented inflammatory role or in modulation of cartilage and bone metabolism.
Conclusions: A demographic and clinical profile of patients with AS in Portugal was established. Identification of genetic variants of target genes as well as gene expression signatures could provide a better understanding of AS pathophysiology and could be useful to establish models with relevance in terms of susceptibility, prognosis, and potential therapeutic guidance.
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Mendes, Fábio Henrique Kuriki. "Seleção natural em genes HLA e seu efeito sobre regiões adjacentes do genoma." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/41/41131/tde-02082013-161104/.
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O MHC é uma região genômica que contém genes de papel central na resposta imune adaptativa. Genes do MHC e, particularmente, genes HLA em humanos, estão envolvidos susceptibilidade e resistência a doenças infecciosas, na predisposição a doenças autoimunes e na rejeição de órgãos transplantados. Essas descobertas incentivaram uma série de estudos sobre padrões da variabilidade genética em genes HLA, que demonstraram possuir uma variação bastante distinta da expectativa neutra. Essa contundente evidência de seleção natural, ímpar no genoma humano, levanta uma série de perguntas a respeito das forças evolutivas específicas que agem nesses genes e as implicações genômicas para a evolução da região como um todo. O presente estudo investiga como a seleção natural afeta e é afetada pela diversidade de genes que estão ligados fisicamente a outros que constituem alvos de seleção. Nossa expectativa é que seleção balanceadora forte sobre genes HLA interfere na eficácia com que a seleção purificadora remove variantes deletérias em loci próximos. Especificamente, a partir da anotação funcional de variantes genéticas, testamos se grupos de genes ligados fisicamente aos genes HLA apresentam uma diversidade mais alta do que seria esperado na ausência de seleção balanceadora e de carona genética causada por ela, e se essa diversidade é enriquecida com variantes possivelmente deletérias. Por meio da análise de razão entre polimorfismos não-sinônimos e sinônimos (e diversas outras estatísticas relacionadas), fomos capazes de observar que loci próximos a genes HLA acumulam um excesso de variação não-sinônima (e portanto potencialmente deletéria). O grau de deleteriedade foi confirmado pelo emprego do software Polyphen 2, que utiliza como critério de classificação a conservação das sequências nucleotídicas e informação das estruturas protéicas, e pela análise de estatísticas como Pdel/Pn e Pdel/Ps. De acordo com testes de McDonald-Kreitman e o Índice de Neutralidade, entretanto, parte dessa variação deletéria se fixa em longo prazo, o que sugere que a seleção em genes HLA pode interferir tanto nos padrões de polimorfismos como de divergênciaThe MHC is a genomic region that contains genes with a central role in the adaptive immune response. Genes in the MHC region, in particular the HLA genes of humans, are involved in the differential susceptibility and resistance to infectious diseases, predisposition to autoimmune diseases and the rejection of transplanted organs. These findings have fueled a series of studies on patterns of genetic variation at HLA genes, which have conclusively demonstrated that their variation deviates from neutral expectations. Such strong evidence of natural selection, with few counterparts in the remainder of the human genome, raise a series of questions concerning the specific evolutionary forces acting on this region and their genomic implications for the evolution of the region as a whole. This work investigates how natural selection affects and is affected by the diversity of genes that are physically linked to those that are units of selection. Our expectation is that strong selection on HLA genes may interfere with the efficacy of selection in removing deleterious variants at closely linked loci. Specifically, by using functional annotations of genetic variants, we test whether sets of genes physically linked to the strongly selected HLA loci show a higher diversity than would be expected in the absence of balancing selection and genetic hitchhiking caused by it, and if this diversity is enriched for putatively deleterious variants. By analyzing the ratio of nonsynonymous to synonymous polymorphisms (and several related statistics) we were able to show that loci close to HLA genes are harboring an excess of nonsynonymous (and hence potentially deleterious) variation. The deleteriousness was confirmed by employing Polyphen 2 - a software that uses nucleotide sequence conservation and protein structure information to classify variants as deleterious or not - and computing statistics such as Pdel/Pn and Pdel/Ps. According to McDonald-Kreitman tests and the Neutrality Index, however, part of this putatively deleterious variation reaches fixation over long timespans, suggesting that selection at the HLA genes may be interfering with both the transient patterns of polymorphism and substitution processes
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Landry, Jonathan [Verfasser], and Stefan [Akademischer Betreuer] Wölfl. "The genomic and transcriptomic landscape of HeLa cells / Jonathan Landry. Betreuer: Stefan Wölfl." Heidelberg : Universitätsbibliothek Heidelberg, 2012. http://d-nb.info/1061054462/34.
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Xu, Huaigeng. "Targeted Disruption of HLA genes via CRISPR-Cas9 generates iPSCs with Enhanced Immune Compatibility." Kyoto University, 2019. http://hdl.handle.net/2433/242420.
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Ohadi, Mina. "Genome mapping of a locus for familial haemophagocytic lymphohistiocytosis." Thesis, King's College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.314048.
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Bianchi, I. "LE BASI GENETICHE DELLA CIRROSI BILIARE PRIMITIVA: DAGLI STUDI DI ASSOCIAZIONE SU SINGOLO GENE AGLI STUDI SULL'INTERO GENOMA." Doctoral thesis, Università degli Studi di Milano, 2011. http://hdl.handle.net/2434/151770.
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Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of unknown etiology. Genetic factors are critical in determining susceptibility to PBC, but there has not been a clear association with specific genes. A multicenter case-control study was performed and HLA class II DRB1 associations were analyzed using a large cohort of 664 cases of PBC and 1,992 controls of Italian ancestry; healthy controls were rigorously matched by age, sex, and also for the geographical origin of the proband four grandparents (Northern, Central, and Southern Italy). After correction for multiple testing, DRB1*08 [odds ratio (OR) 3.35] and DRB1*02 (OR 0.9) were significantly associated with PBC, whereas alleles DRB1*11 (OR 0.4) and DRB1*13 (OR 0.7) were protective. When subjects were stratified according to their grandparental geographical origin, only the associations with DRB1*08 and DRB1*11 were common to all three areas. No significant associations were detected between specific DRB1 alleles and relevant clinical features represented by the presence of cirrhosis or serum autoantibodies. To further define the genetic factors conferring risk for PBC a genome-wide association screen for PBC was performed in an Italian cohort of 453 patients and 945 controls. In particular, 610,000 and 1 milion common variants were evaluated in PBC cases and controls, respectively. The results confirmed also by genome-wide approach a significant association at the HLA region. In addition a combined meta-analysis using a Canadian dataset showed a strong IL12A and IL12RB associations and identified newly associated loci at SPIB (OR 1.46), IRF5-TNPO3 (OR 1.63) and 17q12-21 (OR 1.38)
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Fries, Jonna. "Hela Jaget : en analys av Anna Rydstedts Genom nålsögat." Thesis, Växjö University, School of Humanities, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:vxu:diva-1061.
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Gregoracci, Gustavo Bueno. "Terapia experimental com bacteriófagos." [s.n.], 2010. http://repositorio.unicamp.br/jspui/handle/REPOSIP/317028.
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Orientador: Marcelo BrocchiTese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: Bacteriófagos são vírus que infectam bactérias e arqueias, representando as entidades biológicas mais abundantes do mundo e influenciando de maneira marcante populações naturais de seus hospedeiros. A terapia com bacteriófagos, que representa uma das primeiras formas modernas de combate a infecções bacterianas, foi recentemente redescoberta e vem sendo reavaliada seguindo metodologias atuais quanto à sua viabilidade terapêutica. Para completar a caracterização dos fagos de nossa coleção, sequenciamos completamente o genoma da maior parte destes, através da metodologia multiplex pair-ended utilizando a plataforma Illumina. Visando contribuir para verificação da viabilidade terapêutica de bacteriófagos testamos os efeitos protetor e terapêutico dos fagos Shfl1, Saen1v2 e Saen1v4, pertencentes à coleção de nosso laboratório, em modelos biológicos relevantes. O fago Shfl1, lítico contra Shigella flexneri, foi testado em ensaio de invasão em células HeLa. A redução de bactérias intracelulares foi mensurada independentemente através de plaqueamento e citometria de fluxo, além da observação direta por microscopia de fluorescência. O fago Saen1v2, lítico contra Salmonella Typhimurium, foi estudado quanto à biodistribuição e meia-vida em modelo murino, e uma variante viral com maior persistência in vivo foi selecionada. Essa variante, denominada Saen1v2p5, e o fago Saen1v4, lítico contra Salmonella Typhi, foram testados em modelo murino de infecção tifoide, contra seus respectivos hospedeiros. Encontramos similaridade genômica a fagos conhecidos, como T4, T7, T1 entre outros, em maior ou menor grau. Obtivemos um efeito protetor e terapêutico contra Shigella flexneri utilizando o fago Shfl1 em ensaio de invasão em cultura de células HeLa, verificado por todas as metodologias empregadas. Não verificamos efeito antimicrobiano in vivo do fago Saen1v2p5 em modelo murino de infecção por Salmonella Typhimurium. Por outro lado, observamos efeito terapêutico e protetor dose dependente utilizando o fago Saen1v4 em modelo murino de infecção por Salmonella Typhi. O sucesso obtido com baixas multiplicidades de infecção sugere um possível efeito indireto ou estimulação imune inespecífica
Abstract: Bacteriophages are viruses that infect Bacteria and Achaea, representing the most abundant biological entities in the world and markedly influencing natural host populations. Phage therapy, which represents one of the first modern ways to fight bacterial infections, was recently rediscovered and is being re-evaluated according to current methodologies regarding its therapeutic viability. In order to complete phage characterization in our collection, we sequenced completely the genomes of most of these, through the multiplex pair-ended methodology using the Illumina platform. Aiming to contribute to the therapeutic viability verification of bacteriophages we tested phage protective and therapeutic effects of Shfl1, Saen1v2 and Saen1v4, which belong to our collection, in biologically relevant models. Phage Shfl1, lytic against Shigella flexneri, was tested in a HeLa invasion assay. Intracellular bacteria reduction was measured independently through plating and flow cytometry, besides direct observation through fluorescent microscopy. Phage Saen1v2, lytic against Salmonella Typhimurium, was studied about its bio-distribution and half-life in murine model, and a viral variant with longer in vivo persistence was selected. This variant, denominated Saen1v2p5, and phage Saen1v4, lytic against Salmonella Typhi, were tested in murine typhoid model, against their respective hosts. Genomic similarity to known phages such as T4, T7, T1 among others, was found, in various degrees. We obtained both protective and therapeutic effect against Shigella flexneri using phage Shfl1 in the HeLa invasion assay, through all methodologies utilized. We could not verify in vivo antimicrobial effect of phage Saen1v2p5 in the murine model of Salmonella Typhimurium infection. On the other hand, we observed both therapeutic and protective dose dependent effect using phage Saen1v4 in Salmonella Typhi murine infection model. The success obtained with low multiplicities of infection may suggest a possible indirect effect or unspecific immune stimulation
Doutorado
Microbiologia
Doutor em Genetica e Biologia Molecular
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Sooda, Anuradha. "Discovery of novel HLA-B*57:01 restricted T-cell antigens through genome-wide screening of Epstein-Barr virus." Thesis, Sooda, Anuradha (2020) Discovery of novel HLA-B*57:01 restricted T-cell antigens through genome-wide screening of Epstein-Barr virus. PhD thesis, Murdoch University, 2020. https://researchrepository.murdoch.edu.au/id/eprint/54110/.
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A relationship between latent viral infections and drug hypersensitivity reactions (HSR) has been observed in several clinical situations. Abacavir hypersensitivity has been shown by several groups to be an HLA-B*57:01 restricted CD8+ T cell dependent process. Although compelling evidence suggests that carriage of HLA-B*57:01 is necessary, it is not sufficient for abacavir hypersensitivity. Based on previous structural and functional studies, it was hypothesised that heterologous immune responses of the pre-existing anti-viral T cell responses mediate abacavir hypersensitivity. Human herpesviruses (HHV) have been posited to be associated with the development of HSR because they have co-evolved with the human major histocompatibility complex and they persist in most people as lifelong latent, asymptomatic infections. In addition, they are reactivated in immunocompromised individuals and have been implicated in drug-viral interactions such as associated with Epstein-Barr virus (EBV). EBV is the most common HHV infecting more than 95% of the world’s population. The EBV genome is approximately 172 kb in length and encodes 89 proteins. However, the extent to which these proteins are surveyed by host-derived T cells has not been fully explored. The objective of this body of work was to generate ORFeome-wide map of memory CD8+ T cell responses for the identification of HLA-B*57:01 restricted antigens which could be involved in the cross-reactivity of abacavir drug hypersensitivity. Mapping revealed 14 novel HLA-B*57:01 restricted EBV antigens and confirmed the previously identified epitopes EBNA3B (VSFIEFVGW), EBNA2 (LASAMRML), and LMP1 (IALYLQQNW). A novel immunodominant epitope was detected in EBNA3C (QSRGDENRGW). To identify cross-reactive anti-viral T cell receptors, single cells specific for the immunodominant epitopes of EBNA3B (VSF) and EBNA3C (QSR) were sorted based on tetramer staining. Antigen-specific T cells were sequenced for the T cell receptors cloned into Jurkat cells. A modified heterologous T cell receptor reporter assay was developed to study the T cell responses against HLA-B*57:01 restricted EBV immunodominant epitopes. Dose-dependent T cell responses were detected against each EBV epitope, however, the TCRs were not cross-reactive to abacavir plus self-peptide presented in the context of HLA-B*57:01. The presence of abacavir was shown to modulate the EBV-specific TCR responses to the two EBV epitopes, which suggested the non-covalent binding of abacavir to HLA-B*57:01 may have down modulated the TCR responses. Although unable to demonstrate cross-reactivity of the EBV-specific TCRs with the abacavir plus self-peptide, this work has provided a road map for future experiments to elucidate the role of heterologous immunity in the immunopathogenesis of drug hypersensitivity and other aberrant acquired immune responses in humans.
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N'Guyen, Yohan. "Détection moléculaire des formes complètes et tronquées en région 5’non codante des Entérovirus et conséquences sur la réponse inflammatoire chez des patients souffrant de myocardite ou de cardiomyopathie dilatée Virus detection and semiquantitation in explanted heart tissues of idiopathic dilated cardiomyopathy adult patients by use of PCR coupled with mass spectrometry analysis Enterovirus but not Parvovirus B19 is associated with idiopathic dilated cardiomyopathy and endomyocardial CD3, CD68, or HLA-DR expression Major Persistent 5' Terminally Deleted Coxsackievirus B3 Populations in Human Endomyocardial Tissues Enterovirus Persistence in Cardiac Cells of Patients With Idiopathic Dilated Cardiomyopathy Is Linked to 5' Terminal Genomic RNA-Deleted Viral Populations With Viral-Encoded Proteinase Activities." Thesis, Reims, 2019. http://www.theses.fr/2019REIMM203.
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Des ARN génomiques d’Enterovirus (EV) tronqués en région 5’ Non-Codante ont été détectés dans les tissus cardiaques de cas de myocardite aigue et de cardiomyopathie dilatée (CMD). La cinétique d’apparition de ces formes virales cardiaques et leurs conséquences sur la réponse inflammatoire sont inconnues. Une technique de PCR-MS a permis de détecter des ARN d’EV seuls (32%) ou associés à l’ADN du PVB19 (48%) chez des patients souffrant de CMD idiopathique. Chez ces patients, la présence exclusive d’ARN EV était associée avec un immunomarquage endomyocardique positif pour CD3, CD68 ou HLA-DR. Dans ces cas de CMD, une stratégie de « RACE-PCR » a montré que les populations EV tronquées de 37 à 50 nucleotides (nt) représentaient les formes persistantes majoritaires (80%) associées à des formes tronquées intermédiaires (19%) et complètes (1%). Dans des cas de myocardite à EVs, les proportions des ARN tronqués de 37 à 50 nt (84%) étaient supérieures à celles des formes intermédiaires et complètes (P<10-3). Dans le sous groupe des patients avec une myocardite sévère, les proportions des populations tronquées de 8 à 36 nt étaient supérieures (P=0.02) et associées à des niveaux plus élevés d’ARNm d’IFN-β (P=0.02). La transfection de cardiomyocytes par des ARN viraux synthétiques tronquées de 8 à 36 nt dans des proportions identiques à celles des cas sévères, induit des niveaux supérieurs d’ARNm (P<10-3) et protéiques d’IFN-β (P=0.02). Les populations EV tronquées en région 5‘NC sont majoritaires dès la phase de myocardite aigue et les proportions des formes minoritaires tronquées de 15 à 36 nt pourraient moduler l’activation de la voie des IFN-β et la sévérité de la pathologieMajor enterovirus (EV) populations characterized by 5’ terminal genomic RNA deletions (TD) ranging up to 50 nucleotides were previously identified in cardiac tissues from acute myocarditis and chronic dilated cardiomyopathy (DCM) patients. Dynamics of emergence and impact of various EV-TD populations onto the inflammatory response remains unknown. Using a PCR-MS approach EV-RNAs were detected alone (32%) or with PVB19 genomes in 48 % of patients with an idiopathic DCM. Among these patients, EV- RNA was associated with a positive endomyocardial CD3, CD68 ou HLA-DR immunostaining. In these EV-DCM cases, a quantitative "RACE-PCR" system showed that 37 to 50 nt EV-TD forms were the major persistant viral populations (80%) in association with 15 to 36 nt EV-TD (19%) and full-length (FL) (1%) forms. In samples from myocarditis cases, levels of 37 to 50 nt EVB-TD forms (84%) appeared to be statistically higher than other EV-TD (8%) and FL forms (8%) (P<10-3). Among severe myocarditis cases subgroup, levels of 15 to 36 nt EV-TD forms were significantly higher (P=0.02)) and associated with higher IFN-β mRNA levels (P=0.02)) than in non-severe myocarditis patients. HCM transfection of synthetic 8 to 36 nt EV-TD forms induced higher IFN-β mRNA (P<10-3) and cytokine levels (P=0.02) comparatively to those obtained after transfection by others deleted EV RNA forms. EV-RNA TD populations appeared to be major in acute myocarditis and DCM cases. Moreover, the proportions of minor 15 to 36nt EV-TD forms could modulate the innate immune sensing mechanisms in cardiomyocytes and therefore the clinical severity of cardiac infection
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Odenbrink, Viktor, and Viktor Johansson. "Utveckla kassaflödet genom hela affärsprocessen : En fallstudie hos en hustillverkare." Thesis, Linnéuniversitetet, Institutionen för ekonomistyrning och logistik (ELO), 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-66053.
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Bakgrund och problem: Bostadsmarknaden är en viktig del av samhället där ökad bebyggelse är en förutsättning för att säkerställa framtida bostäder. Dessvärre tenderar befolkningstillväxten att öka i en snabbare takt gentemot antalet bostäder som byggs. Vidare är det inte alltid enkelt att motivera ett byggprojekt då det sträcker sig över en lång tid, kräver stort kapital och således innebär risker. Kapitalkrävande projekt kräver därför eftertänksamhet då det kan påverka kassaflödet negativt. Då studier saknas på hur kapitalbehovet och kassaflödet förhåller sig till affärsprocessen för byggföretag och hustillverkare vill vi tillsammans med vårt fallföretag titta närmare på detta. Ett stabilt kassaflöde är viktigt för framtida överlevnad och därmed också för framtida bebyggelse. Syfte: Syftet med detta arbete är att kartlägga vårt fallföretags affärsprocess och kartlägga kapitalbehovet genom hela affärsprocessen. Vidare syftar studien till att utifrån kartläggningen ge förslag på hur företaget kan styra och effektivisera kassaflödet genom affärsprocessen. Studien syftar också till att bidra med kunskap om hur hustillverkare och byggföretag kan styra och effektivisera sina kassaflöden genom hela affärsprocessen. Metod: Under denna studie har fallstudien som metod legat till grund för den forskning som bedrivits. Det empiriska underlaget har inhämtats med hjälp av ostrukturerade och semistrukturerade intervjuer. Vidare har även observationer och dokument utgjort delar av det empiriska underlaget.Background: The housing market is an important part of society, where increased housing is a prerequisite for ensuring future housing. Unfortunately, population growth tends to increase at a faster pace compared to the number of homes being built. Furthermore, it is not always easy to justify a construction project as it extends over a long time, requires large capital and thus involves risks. Capital intensive projects therefore require thoughtfulness as it may tend to affect cash flow negatively. As studies are lacking in how the capital requirements and cash flow relate to the business process for construction companies and house manufacturers, we want to look closer with our business case. A stable cash flow is important for future survival and therefore also for future housing. Purpose: The purpose of this work is to map the business process of our business case and map the capital requirement throughout the business process. Furthermore, the purpose of this study is to provide on the basis of the survey, suggestions on how the company can control and streamline the cash flow through the business process. This study also aims to provide knowledge about how house manufacturers and construction companies can control and streamline their cash flows throughout the business process. Method: During this study, case study has been the basis of the research conducted as a method. The empirical basis has been obtained through unstructured and semi- structured interviews. Furthermore, observations and documents have also been part of the empirical basis.
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Persson, Julia, Jenny Runnqvist, and Rebecca Waernulf. "Legitimitet i ideella elitidrottsföreningar Möjligheten att spegla hela verksamheten genom redovisningen." Thesis, Örebro universitet, Handelshögskolan vid Örebro Universitet, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-56015.
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Kallin, Eric Michael Zhang Yi. "Epigenetic regulation of gene transcription Jhdm1b characterization and genome-wide localization of H2A ubiquitylation /." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2009. http://dc.lib.unc.edu/u?/etd,2871.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2009.Title from electronic title page (viewed Jun. 4, 2010). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Genetics and Molecular Biology." Discipline: Genetics and Molecular Biology; Department/School: Medicine.
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Ali, Zhian. "Jag behöver språk som ett verktyg genom hela livet! : En kvalitativ studie om förskollärarnas arbetssätt med flerspråkiga barns språkutveckling genom modersmål." Thesis, Uppsala universitet, Institutionen för pedagogik, didaktik och utbildningsstudier, 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-412547.
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Kronvall, Eva. ""Kränkningar går som i en cirkel hela tiden!" : Elever undersöker begreppet kränkningar i en fokusgrupp genom drama." Thesis, Högskolan i Gävle, Avdelningen för kultur-, religions- och utbildningsvetenskap, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:hig:diva-14820.
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Kyllergård, Olivia. "”Vi sopade hela dagen igår säger vi…" : En jämförande studie över barns sätt att kommunicera genom lek." Thesis, Högskolan i Borås, Akademin för bibliotek, information, pedagogik och IT, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:hb:diva-12326.
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Följande studie inleds genom att nämna några framstående forskare, historiska och aktuella, vars teorier och perspektiv gällande barns kommunikation genom lek har haft betydande inverkan på dagens förskola. Några exempel på forskningsområden som framhävs är bland annat barns förmåga till metakommunikation, metakognition, leksignaler men även ickeverbala och verbala strategier. Samtidigt hävdar en forskare att förskollärare tenderar ha en förenklad syn på kommunikationens betydelse gällande barns lek. Av den anledningen är studiens syfte att synliggöra hur yngre barn (1-3 år) kommunicerar med varandra genom lek i jämförelse med äldre barn (4-6 år) och deras sätt att kommunicera genom lek.Den kvalitativa metod som har funnits lämpligast i avseende med studiens syfte och frågeställningar är observationer i form av löpande protokoll. En av flera fördelar med observationer är att det ger en tydlig och verklighetstrogen bild över barns sätt att kommunicera genom lek men även vad som är utmärkande inom varje ålderskategori. Observationsmaterialet har bearbetats utifrån tre olika kategorier; metakognition/metakommunikation, leksignaler och ickeverbal/verbal kommunikation med avsikt att avgränsa och förtydliga områden som ska undersökas. Dessutom har insamling och bearbetning av observationsmaterial handskats med största varsamhet utifrån Vetenskapsrådets forskningsetiska principer.Sammanfattningsvis visar resultatet att 1-3 åringar föredrar att kommunicera med varandra genom kroppsspråk, ansiktsuttryck och gester medan 4-6 åringar inte har samma behov på grund av ett mer utvecklat språk. Samtidigt visar de äldsta barnen behov av att ibland kommunicera vad de kommunicerar eller tänker under en lek, trots att deras metakognitiva och metakommunikativa förmågor är välutvecklade. Vidare framkommer det att metakognition och metakommunikation inte nödvändigtvis är utvecklade vid en specifik ålder som det har förmodats enligt tidigare forskning. Däremot tyder resultatet på åldersskillnader gällande barns förmåga att skilja mellan lek och verklighet genom att byta tempus under en pågående lek. Tid är nämligen ännu ett abstrakt och svårbegripligt fenomen hos 1-3 åringarna jämfört med 4-6 åringarna. Avslutningsvis synliggör resultatet att kommunikativa leksignaler som exempelvis skratt, leenden och ljudeffekter är vanligt förekommande inom samtliga ålderskategorier.
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Henrik, Strand, and Oskar Östlund. ""Vi säljer upplevelser" : En studie om hur motorcykelbranschen kan stärka sitt erbjudande över hela året genom en omnikanalstrategi." Thesis, Linnéuniversitetet, Institutionen för marknadsföring (MF), 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-88149.
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Titel ”Vi säljer upplevelser” - En studie om hur motorcykelbranschen kan stärka sitt erbjudande över hela året genom en omnikanalstrategi Nyckelord Omnikanalstrategi, säsongsförsäljning, upplevelseekonomi, motorcykelbransch, touchpoints, CEM, CRM Forskningsfråga På vilka sätt kan motorcykelbranschen med säsongsbetonad försäljning använda sig av en omnikanalstrategi för att stärka sitt varumärke och skapa erbjudanden genom hela året? Syfte Syftet med studien är att öka kunskapen om hur MC-branschen kan använda en omnikanalstrategi som hjälper motorcykelåterförsäljare att stärka sitt varumärke och öka försäljningen och sina erbjudanden under hela året oberoende av säsong. Metod Studien har använt en kvalitativ forskningsstrategi med ett abduktivt angreppssätt. Studien bygger på relevant teori som skapat frågor till sju semistrukturerade intervjuer med representanter av ett kvoturval. Slutsats För att motorcykel återförsäljare ska stärka sitt varumärke och skapa relevanta erbjudanden genom hela året bör en omnikanalstrategi implementeras. Inom denna strategi bör företaget prioritera kundbemötande och skapa upplevelser samt långsiktiga och lojala kundrelationer. Synkronisera alla kanaler för en sömlös upplevelse, skapa en varrumärkesupplevelse och engagemang genom hela året med kreativa erbjudanden. Utforma servicelandskap både traditionellt och virtuellt som bidrar till varimärkesupplevelse, värdeskapande och gemenskap.Abstract Title “We sell experiences” - A study on how the motorcycle industry can strengthen its offering throughout the year through an omnichannel strategy Keyword Omni-Channel Strategy, Seasonal Sales, Experience Economi, Motorcycle Industry, Touchpoints, CEM, CRM Research Question In what ways can the motorcycle industry with seasonal sales use an omnichannel strategy to strengthen its brand and create offers throughout the year? Purpose The purpose of the study is to increase knowledge of how the MC industry can use an omnichannel strategy that helps motorcycle dealers strengthen their brand and increase sales and offers throughout the year regardless of season. Method The study has used a qualitative research strategy with an abductive approach. The study is based on relevant theory that created questions for seven semi-structured interviews with representatives of a quota selection. Conclusion In order for motorcycle dealers to strengthen their brand and create relevant offers throughout the year, an omnichannel strategy should be implemented. In this strategy, the company should prioritize customer service and create experiences as well as long-term and loyal customer relationships. Synchronize all channels for a seamless experience, create a brand experience and commitment throughout the year with creative offerings. Design service landscapes both traditional and virtual that contribute to brand experience, value creation and community.
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Rundgren, Klara, and Elin Svensson. "Högläs skönlitteratur för att lära med hela kroppen : En aktionsforskningsstudie om att bearbeta högläsning genom drama i årskurs tre." Thesis, Högskolan i Halmstad, Akademin för lärande, humaniora och samhälle, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:hh:diva-28953.
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Att inneha ett rikt språk är betydelsefullt för attleva och verka i dagens samhälle som omges av text och samtal. Barns läsförmågaoch intresse för litteratur har senaste decenniet försämrats. Därför är det avstor vikt att lärare applicerar högläsning i undervisningen och bearbetar denpå ett varierat sätt, exempelvis genom drama. Ansatsen är baserad påaktionsforskning där fokus låg på att utveckla VFU-verksamhetens praktik. Syftet med studien är attbidra med kunskap omspråkutvecklande arbetssätt för bearbetning av högläst skönlitteratur. Aktionerna genomfördes med högläsning, dramabearbetning i grupper,dramapresentation och en enskild reflektion. Data samlades in med hjälp avvideoinspelning och loggboksskrivande som sedan analyserades. I resultatetsynliggjordes fyra kategorier: Eleverbearbetar genom upprepning, elever bearbetar genom koppling till sin omvärld, eleverbearbetar genom koppling till känslomässiga erfarenheter och elever bearbetar genom att fantisera.Studiens centrala slutsats äratt dramatisering vid bearbetning av skönlitteratur har bidragit tillengagemang i textens innehåll, vilket i sin tur underlättade för eleverna attrelatera innehållet till sin omvärld eller uttrycka emotionella erfarenheter. Genomdenna studie vill vi uppmärksamma och inspirera lärare kring hur bearbetning avhögläsning kan utformas. Framtida forskning bör inriktas kring andra kreativasätt högläsning kan bearbetas för att gynna elevers språkutveckling.
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Klint, Axel, and Fabian Strand. "Utmaningar med implementering av BIM genom hela värdekedjan : en analys av informationsgap i BIM-projekt med stöd av innovationsteori." Thesis, KTH, Fastigheter och byggande, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-297636.
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Digitalisering är ett ämne som ständigt diskuteras och har på senare år utvecklats på många plan. Inom byggbranschen har BIM (Byggnadsinformationsmanagement) länge setts som en digital lösning vilken kan tänkas utveckla branschen inom flera områden, men trots det är den digitala utvecklingen inom branschen relativt låg vilket kan ge indikation på lägre produktivitet. Särskilt om man jämför med vad som faktiskt kan uppnås vid implementering av BIM fullt ut genom värdekedjan i projekt. Det finns en brist på tidigare studier kring varför det finns ett informationsgap mellan aktörer genom hela värdekedjan som delvis kan förklara denna låga produktivitet. Syftet med denna studie är därmed att undersöka vilka utmaningar som finns vid implementeringen av BIM i hela värdekedjan av projekt och vad utmaningarna skapar för informationsgap mellan design/konstruktion- och förvaltningssidan inom ett projekt. För att besvara syfte och frågeställningar har innovationsteori samt investeringsteori använts, där fokus främst riktats på innovationsteori. Med hjälp av teorierna kunde utmaningar med implementeringen av BIM och eventuella informationsgap som uppstår studeras djupare. I studien genomfördes åtta semistrukturerade intervjuer med fastighetsbolag, arkitekturbolag, konsultbolag och intresseorganisation. De existerande utmaningarna vid implementering av BIM hos olika aktörer, som kan ligga till grund för försämrad interoperabilitet, kan förklaras med att avsaknad av gemensamma branschstandarder, avsaknad av en central BIM-samordnare och generellt sett låg utbildningsnivå kring vad BIM är. Det noteras att ett informationsgap finns mellan aktörer som arbetar på förvaltningssidan kontra design/konstruktion och detta kan dels förklaras på grund av motvilja att anpassa sig till nya lösningar enligt innovationsteori, dels på grund av avsaknad av gemensamma branschstandarder. Att en aktör i projektskedet inte anser det lämpligt att använda BIM kan förklaras eftersom kostnaden hittills inte alltid understiger nyttan. Implementeringsfasen hos olika aktörer genom värdekedjan varierar och därmed kan branschen i vissa fall tolkas som trögflytande, bland annat på grund av frånvaro av öppna standarder och de språkbarriärer mellan program som kan uppstå vid användning av olika BIM-system. För att vidareutveckla arbetet kring ämnesfrågan behöver ytterligare studier genomföras kring proprietära rättigheter och problem vid anbudskalkylering, offentlig sektors påverkan på utveckling kring gemensamma branschstandarder, extern och intern BIM-samordning kopplat till effektivare projektledning och även hur gemensamma branschstandarder påverkar olika aktörer i hela värdekedjan av ett projekt.Digitalization is constantly being discussed and has in recent years developed on many levels. Building information management, further described as BIM, has long been considered a digital solution in the construction and management industry. A solution that suitably would develop the industry in several areas. Despite this, digital development is relatively low which may indicate lower productivity than can be achieved. There is a lack of previous studies on why there is an information gap between stakeholders throughout the value chain that can partly explain low productivity and low effective stakeholder efficiency. The purpose of this study is thus to investigate the existing difficulties in the implementation of BIM in the entire value chain and what these difficulties lead to, such as information gaps between the design, construction and management side within a project. The findings of the study are explained with support of innovation theory and investment theory, with main focus on innovation theory. With support of the theories, difficulties with implementation of BIM for stakeholders and any information gaps that arise have been studied more deeply. This study conducted eight semi-structured interviews with real estate companies, architecture companies, one consulting company and one interest group. Existing challenges regarding implementation of BIM among different stakeholders, which may be the basis for impaired interoperability, can be explained in the absence of common industry standards, absence of a central BIM coordinator and generally low level of education about the subject BIM. It is noted that there is an information gap between stakeholders working on the administrative side versus design/construction and can be partly explained due to reluctance to adapt to new solutions according to innovation theory and partly due to the absence of common industry standards. The fact that the cost so far is not always less than the benefit of investing in BIM may explain why stakeholders in the project phase choose that BIM does not have to be appropriate to implement. The implementation phase through the value chain of a project varies a lot for different stakeholders and because of that the industry may in some cases be interpreted as conservative. This could be explained due to the language barriers that can arise when using different BIM systems and due to absence of open standards. To further develop understanding on the subject issue, studies need to be carried out on proprietary rights and problems in tender calculation estimates. Moreover, studies on public sector impact regarding development around common industry standards, external and internal BIM coordination linked to more effective project management and how common industry standards affect different stakeholders in the whole value chain of a project may develop understanding on the subject issue.
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Bhrigu, Vipul. "Replication of Adeno-Associated Virus in Murine Fibroblasts with Mouse Adenovirus Provided Helper Functions." University of Toledo Health Science Campus / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=mco1242316433.
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Konstantinidis, Michalis. "Preimplantation genetic diagnosis : new methods for the detection of genetic abnormalities in human preimplantation embryos." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:28611f65-7729-4293-9c3f-4fc3f0cc39d7.
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Preimplantation genetic diagnosis (PGD) refers to the testing of embryos produced through in vitro fertilization (IVF) in order to identify those unaffected by a specific genetic disorder or chromosomal abnormality. In this study, different methodologies were examined and developed for performance of PGD. Investigation of various whole genome amplification (WGA) methods identified multiple displacement amplification as a reliable method for genotyping single cells. Furthermore, this technology was shown to be compatible with subsequent analysis using single nucleotide polymorphism (SNP) microarrays. Compared to conventional methods used in this study to perform single cell diagnosis (e.g. multiplex PCR), WGA techniques were found to be advantageous since they streamline the development of PGD protocols for couples at high risk of transmitting an inherited disorder and simultaneously offer the possibility of comprehensive chromosome screening (CCS). This study also aimed to develop a widely applicable protocol for accurate typing of the human leukocyte antigen (HLA) region with the purpose of identifying embryos that will be HLA-identical to an existing sibling affected by a disorder that requires haematopoietic stem cell transplantation. Additionally, a novel microarray platform was developed that, apart from accurate CCS, was capable of reliably determining the relative quantity of mitochondrial DNA in polar bodies removed from oocytes and single cells biopsied from embryos. Mitochondria are known to play an important role in oogenesis and preimplantation embryogenesis and their measurement may therefore be of clinical relevance. Moreover, real-time PCR was used for development of protocols for CCS, DNA fingerprinting of sperm samples and embryos and the relative quantitation of telomere length in embryos (since shortened telomeres might be associated with reduced viability). As well as considering the role of genetics in terms of oocyte and embryo viability assessment and the diagnosis of inherited genetic disorders, attention was given to a specific gene (Phospholipase C zeta) of relevance to male infertility. A novel mutation affecting the function of the resulting protein was discovered highlighting the growing importance of DNA sequence variants in the diagnosis and treatment of infertility.
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Jha, Rajesh. "Combined Computational-Experimental Design of High-Temperature, High-Intensity Permanent Magnetic Alloys with Minimal Addition of Rare-Earth Elements." FIU Digital Commons, 2016. http://digitalcommons.fiu.edu/etd/2621.
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AlNiCo magnets are known for high-temperature stability and superior corrosion resistance and have been widely used for various applications. Reported magnetic energy density ((BH) max) for these magnets is around 10 MGOe. Theoretical calculations show that ((BH) max) of 20 MGOe is achievable which will be helpful in covering the gap between AlNiCo and Rare-Earth Elements (REE) based magnets. An extended family of AlNiCo alloys was studied in this dissertation that consists of eight elements, and hence it is important to determine composition-property relationship between each of the alloying elements and their influence on the bulk properties.
In the present research, we proposed a novel approach to efficiently use a set of computational tools based on several concepts of artificial intelligence to address a complex problem of design and optimization of high temperature REE-free magnetic alloys. A multi-dimensional random number generation algorithm was used to generate the initial set of chemical concentrations. These alloys were then examined for phase equilibria and associated magnetic properties as a screening tool to form the initial set of alloy. These alloys were manufactured and tested for desired properties. These properties were fitted with a set of multi-dimensional response surfaces and the most accurate meta-models were chosen for prediction. These properties were simultaneously extremized by utilizing a set of multi-objective optimization algorithm. This provided a set of concentrations of each of the alloying elements for optimized properties. A few of the best predicted Pareto-optimal alloy compositions were then manufactured and tested to evaluate the predicted properties. These alloys were then added to the existing data set and used to improve the accuracy of meta-models. The multi-objective optimizer then used the new meta-models to find a new set of improved Pareto-optimized chemical concentrations. This design cycle was repeated twelve times in this work. Several of these Pareto-optimized alloys outperformed most of the candidate alloys on most of the objectives. Unsupervised learning methods such as Principal Component Analysis (PCA) and Heirarchical Cluster Analysis (HCA) were used to discover various patterns within the dataset. This proves the efficacy of the combined meta-modeling and experimental approach in design optimization of magnetic alloys.
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Farrell, John J. "The prediction of HLA genotypes from next generation sequencing and genome scan data." Thesis, 2014. https://hdl.handle.net/2144/14694.
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Genome-wide association studies have very successfully found highly significant disease associations with single nucleotide polymorphisms (SNP) in the Major Histocompatibility Complex for adverse drug reactions, autoimmune diseases and infectious diseases. However, the extensive linkage disequilibrium in the region has made it difficult to unravel the HLA alleles underlying these diseases. Here I present two methods to comprehensively predict 4-digit HLA types from the two types of experimental genome data widely available.
The Virtual SNP Imputation approach was developed for genome scan data and demonstrated a high precision and recall (96% and 97% respectively) for the prediction of HLA genotypes. A reanalysis of 6 genome-wide association studies using the HLA imputation method identified 18 significant HLA allele associations for 6 autoimmune diseases: 2 in ankylosing spondylitis, 2 in autoimmune thyroid disease, 2 in Crohn's disease, 3 in multiple sclerosis, 2 in psoriasis and 7 in rheumatoid arthritis. The EPIGEN consortium also used the Virtual SNP Imputation approach to detect a novel association of HLA-A*31:01 with adverse reactions to carbamazepine.
For the prediction of HLA genotypes from next generation sequencing data, I developed a novel approach using a naïve Bayes algorithm called HLA-Genotyper. The validation results covered whole genome, whole exome and RNA-Seq experimental designs in the European and Yoruba population samples available from the 1000 Genomes Project. The RNA-Seq data gave the best results with an overall precision and recall near 0.99 for Europeans and 0.98 for the Yoruba population. I then successfully used the method on targeted sequencing data to detect significant associations of idiopathic membranous nephropathy with HLA-DRB1*03:01 and HLA-DQA1*05:01 using the 1000 Genomes European subjects as controls.
Using the results reported here, researchers may now readily unravel the association of HLA alleles with many diseases from genome scans and next generation sequencing experiments without the expensive and laborious HLA typing of thousands of subjects. Both algorithms enable the analysis of diverse populations to help researchers pinpoint HLA loci with biological roles in infection, inflammation, autoimmunity, aging, mental illness and adverse drug reactions.