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Loegler, Victor. "The genotype-phenotype relationship through the pangenome perspective". Electronic Thesis or Diss., Strasbourg, 2024. http://www.theses.fr/2024STRAJ071.
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La variation génomique au sein d'une espèce constitue la base de la variation phénotypique héréditaire sur laquelle agit la sélection naturelle. Cependant, explorer le rôle des variants structurels (SV, plus de 50 paires de bases) sur la variation des traits reste un défi en raison de la difficulté à les détecter. Cette thèse vise à étudier l'impact phénotypique de ces variants en utilisant une population de plus de 1000 isolats de la levure Saccharomyces cerevisiae. La construction du pangénome à l'aide d'assemblages quasi-télomères-à-télomères a permis la création d'un catalogue complet de variants génomiques. Des études d'association avec plus de 8 000 caractères ont révélé l'impact relativement plus important des SV sur la variation des caractères, ainsi que des divergences entre l’architecture génétique de différents types de caractères. L'ensemble de ces travaux met en évidence le large impact phénotypique des grands variants génomiques au niveau de l'espèceGenomic variation within a species provides the basis for the heritable phenotypic variation upon which natural selection acts. However, exploring the role of structural variants (SVs, more than 50 base pairs) on trait variation remains a challenge due to the difficulty of detecting them. This thesis research aims to address the phenotypic impact of such variants by leveraging a natural population of over a thousand isolates of the budding yeast Saccharomyces cerevisiae. Pangenome construction using near telomere-to-telomere assemblies enabled the creation of a comprehensive catalog of genomic variants. Association studies with more than 8,000 molecular and organismal traits revealed the relatively higher impact of SVs on traits variation, and discrepancies in the genomic basis of different types of traits. Together, this work highlights the strong phenotypic effect of large genomic variants at the species level
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Jorge, Susan Elisabeth Domingues Costa 1983. "Correlação estrutura-função de variantes da hemoglobina humana = Structure-function relations of human hemoglobin variants". [s.n.], 2013. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310885.
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Orientadores: Maria de Fatima Sonati, Munir Salomão SkafTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Doutorado
Ciencias Biomedicas
Doutora em Ciências Médicas
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Bruce, David. "Antithrombin : structural variants and thrombosis". Thesis, Open University, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.386084.
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Lecompte, Lolita. "Structural variant genotyping with long read data". Thesis, Rennes 1, 2020. http://www.theses.fr/2020REN1S054.
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Les variants de structure (SVs) sont des réarrangements génomiques de plus de 50 paires de base et restent encore aujourd'hui peu étudiés malgré les impacts importants qu'ils peuvent avoir sur le fonctionnement des génomes. Récemment, les technologies de séquençage de troisième génération ont été développées et produisent des données de longues lectures qui s'avèrent très utiles car elles peuvent chevaucher les réarrangements. À l'heure actuelle, les méthodes bioinformatiques se sont concentrées sur le problème de la découverte de SVs avec des données de longues lectures. Aucune méthode n'a cependant été proposée pour répondre spécifiquement à la question du génotypage de SVs avec ce même type de données. L'objectif du génotypage de SVs vise pour un ensemble de SVs donné à évaluer les allèles présents dans un nouvel échantillon séquencé. Cette thèse propose une nouvelle méthode pour génotyper des SVs avec des longues lectures et repose sur la représentation des séquences des allèles. Notre méthode a été implémentée dans l'outil SVJedi. Nous avons testé notre outil à la fois sur des données simulées et réelles afin de valider notre méthode. SVJedi obtient une précision élevée qui dépasse les performances des autres outils de génotypage de SVs, notamment des outils de détection de SVs et des outils de génotypage de SVs de lectures courtesStructural Variants (SVs) are genomic rearrangements of more than 50 base pairs. Since SVs can reach several thousand base pairs, they can have huge impacts on genome functions, studying SVs is, therefore, of great interest. Recently, a new generation of sequencing technologies has been developed and produce long read data of tens of thousand of base pairs which are particularly useful for spanning over SV breakpoints. So far, bioinformatics methods have focused on the SV discovery problem with long read data. However, no method has been proposed to specifically address the issue of genotyping SVs with long read data. The purpose of SV genotyping is to assess for each variant of a given input set which alleles are present in a newly sequenced sample. This thesis proposes a new method for genotyping SVs with long read data, based on the representation of each allele sequences. We also defined a set of conditions to consider a read as supporting an allele. Our method has been implemented in a tool called SVJedi. Our tool has been validated on both simulated and real human data and achieves high genotyping accuracy. We show that SVJedi obtains better performances than other existing long read genotyping tools and we also demonstrate that SV genotyping is considerably improved with SVJedi compared to other approaches, namely SV discovery and short read SV genotyping approaches
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Seabra, Catarina Morais. "Rare structural variants in severe spermatogenic impairment". Master's thesis, Universidade de Aveiro, 2012. http://hdl.handle.net/10773/9537.
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Mestrado em Biomedicina MolecularA azoospermia afeta aproximadamente 15% de todos os homens inférteis e é frequentemente causada por anomalias cromossómicas e microdeleções do cromossoma Y. No entanto, em aproximadamente 70% dos casos de azoospermia não-obstrutiva (NOA) as causas permanecem por identificar. Nos últimos anos, a descoberta de variantes genómicas de número de cópia (CNVs), como as causadas por deleções, revelou uma fonte de variação genómica que afecta a dosagem génica e que poderá resultar em haploinsuficiência. De facto, observa-se uma sobre-representação de CNVs raros (<1% na população), sobretudo de grandes deleções de novo, em pacientes com diferentes distúrbios do desenvolvimento, comparados com controlos saudáveis. Porém, uma possível contribuição, para a infertilidade masculina, de variantes estruturais ligados ao cromossoma X e aos autossomas foi ainda pouco explorada. Este estudo foca-se na validação de deleções encontradas apenas em pacientes inférteis, no cromossoma X e em 11p13, que contêm genes candidatos a participar na espermatogénese. Estas deleções, previamente identificadas por arrays de oligonucleótidos, de elevada densidade (Affymetrix 6.0 SNP Array), numa coorte de 171 pacientes Portugueses com disfunção severa da espermatogénese (NOA e oligozoospermia severa), foram agora confirmadas por técnicas convencionais de genética molecular. Adicionalmente, a caraterização dos locais de quebra nestas deleções foi realizada por aCGH. Ainda que não se tenham validado as deleções menos extensas (em Xq21.1, Xq25, Xp11.4, Xq22.1 e Xq26.3), confirmou-se a nulizigotia em Xq28 nestes indivíduos, que abrange genes candidatos com uma função sugestiva na espermatogénese: MAGE-A8, expresso em testículo e em alguns cancros e o microRNA hsa-miR-4330, envolvido na regulação pós-transcricional de vários genes com expressão na linha germinal. Foi ainda validada, por MLPA, uma deleção extensa num paciente infértil não-sindrómico da nossa coorte. Estes resultados apontam a haploinsuficiência de WT1 como a causa mais provável de azoospermia neste paciente, já que não foram detetadas mutações germinais no alelo restante. Mutações no gene WT1, que codifica um factor de transcrição muito conservado, crucial para o desenvolvimento e manutenção gonadal em mamíferos, geralmente interferem com a ligação desta proteína ao DNA e estão principalmente associadas a síndromes que envolvem anomalias reprodutivas. Motivados pela nossa descoberta de uma deleção de WT1 num homem infértil embora saudável, decidimos abordar a contribuição de mutações exónicas no gene WT1 para a azoospermia isolada. Testámos a hipótese de que mutações localizadas em domínios que não aqueles essenciais à ligação ao DNA pudessem resultar na disfunção não-sindrómica da espermatogénese. Assim, analisámos a sequência codificante de WT1 num subgrupo de 40 pacientes azoospérmicos. Como resultado, descrevemos uma nova variação missense c.185C>T (P130L; ENST00000332351) no primeiro exão de WT1, inserida no domínio proteico de auto-associação. A nova variante descrita deverá ter um impacto menos drástico na função da proteína WT1, comparativamente com as mutações descritas no mesmo exão até à data, as quais resultam em proteínas truncadas e fenótipos severos de disfunção gonadal, incluindo a formação de tumores renais. Estes resultados revelam novos genes candidatos a um papel na espermatogénese e sugerem que a haploinsuficiência de proteínas importantes para o desenvolvimento do sistema reprodutor masculino podem resultar em azoospermia. Estudos futuros poderão clarificar a utilidade dos nossos genes candidatos como biomarcadores da infertilidade masculina. A implementação de novos biomarcadores beneficiaria os doentes azoospérmicos através da melhoria do diagnóstico, aconselhamento genético e acompanhamento destes pacientes, podendo vir a limitar a necessidade de procedimentos invasivos.
Azoospermia affects approximately 15% of all infertile males and it is frequently caused by chromosomal abnormalities and Yq microdeletions. However, despite considerable research efforts in the last decades, in approximately 70% of the cases of non-obstructive azoospermia (NOA) the causes are yet to be identified. In the last years, the discovery of genomic copy number variants, such as those caused by deletions, revealed a source of genomic variation which impacts gene dosage and may result in haploinsufficiency. In fact, rare CNVs (<1% population), mainly large de novo deletions, are over-represented in patients with different developmental disorders, compared to healthy controls. However, a possible contribution of X-linked and autosomal structural variants to male infertility is still largely unexplored. This study focused on the validation of rare patient-specific deletions found on the X chromosome and at 11p13 of infertile patients, which harbor candidate spermatogenesis genes. These deletions had been previously identified by high density oligonucleotide arrays (Affymetrix 6.0 SNP Array), in a cohort of 171 Portuguese patients with severe spermatogenic impairment (non-obstructive azoospermia and severe oligozoospermia) and were now confirmed by conventional molecular genetics techniques. Additionally, breakpoint characterization was carried out by aCGH. In fact, even though the smaller deletions (at Xq21.1, Xq25, Xp11.4, Xq22.1 and Xq26.3) were not validated, we confirmed nullizygosity at Xq28 in two patients, spanning either MAGE-A8, a known cancer-testis antigen, or hsa-miR-4330, a microRNA involved in post-transcription regulation, both with a suggestive role in spermatogenesis pathways. We have also validated by MLPA a large deletion at 11p13, in a non-syndromic infertile patient from our cohort. These results support WT1 haploinsufficiency as the likely cause of azoospermia in this patient, as no other germline mutations were detected in the remaining WT1 copy. Mutations in WT1, an evolutionarily conserved transcription factor crucial for gonadal development and maintenance in mammals, typically interfere with the DNA-binding properties of the protein and are mainly associated with syndromes involving reproductive abnormalities. Motivated by our finding of a WT1 deletion in an infertile but otherwise healthy man we addressed the contribution of WT1 exonic mutations to isolated azoospermia. We reasoned that mutations located in domains not essential for DNA binding could result in non-syndromic spermatogenic impairment. Thus, we analyzed the WT1 coding sequence in a subgroup of 40 azoospermic patients. As a result of the exon screening, we report a novel c.185C>T (P130L; ENST00000332351) WT1 missense variant on exon 1, within the protein self-association domain. While all exon 1 mutations as yet reported result in truncated proteins and severe phenotypes, including the formation of renal tumors, this novel variant is expected to have a milder impact on WT1 function. These results reveal new candidate genes for a role in spermatogenesis and suggest that haploinsufficiency of proteins important for the development of the male reproductive system can lead to azoospermia. Further studies will clarify the utility of our candidate genes as biomarkers of male infertility. The implementation of new biomarkers would benefit azoospermic men by improving diagnosis, genetic counseling and patient care, eventually limiting the need for invasive procedures.
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Toyama, Brandon Hiroyuki. "The structural basis of yeast prion strain variants". Diss., Search in ProQuest Dissertations & Theses. UC Only, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3378511.
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Viñas, Jornet Marina. "Identificació de variants en nombre de còpies i correlació clínica en una població adulta amb discapacitat intel·lectual i trastorns psiquiàtrics i/o conductuals". Doctoral thesis, Universitat Autònoma de Barcelona, 2016. http://hdl.handle.net/10803/369041.
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El genoma humà està constituït per 3 bilions de parells de bases, que inclouen aproximadament 20.000-25.000 gens, i presenta una variabilitat en forma de variants en la seqüència i variants estructurals. L’aparició de noves tecnologies moleculars han revelat l’existència d’una gran quantitat de variants en nombre de còpies (CNVs) que representen canvis de dosi (guanys i pèrdues de material) descrits en el 4,8%-9,5% del genoma. Tot i identificar-se en població sana, s’ha reconegut que tenen una contribució en l’expressió gènica, l’estructura proteica i l’estabilitat cromosòmica i, en conseqüència, ha incrementat l’interès per entendre el paper que tenen les CNVs en malalties com la discapacitat intel·lectual i els trastorns psiquiàtrics. La discapacitat intel·lectual afecta entre l’1-3% dels individus i les millores en el seguiment mèdic dels pacients han contribuït en una major supervivència fins a etapes adultes, en les que es posa de manifest una gran incidència de trastorns psiquiàtrics i de la conducta associats.
Amb l’objectiu de determinar l’etiologia genètica del diagnòstic dual de discapacitat intel·lectual i trastorns psiquiàtrics i/o de la conducta en una cohort de 100 adults i identificar CNVs de susceptibilitat per aquesta patologia, s’ha aplicat una estratègia d’anàlisi genètica seqüencial. Inicialment es realitza un cariotip amb bandes G, un cribatge de la síndrome X fràgil i estudis moleculars dirigits a la confirmació de la sospita clínica d’una síndrome específica. Per aquells casos que són negatius, es realitza un cribatge de CNVs submicroscòpiques de les regions subtelomèriques mitjançant multiplex ligation dependent probe amplification i posteriorment un cribatge del genoma amb un array d’hibridació genòmica comparada(aCGH) d’alta resolució (400k).
S’ha establert una elevada freqüència diagnòstica (38%) en la cohort d’adults amb diagnòstic dual. La co-morbiditat d’un segon trastorn psiquiàtric augmenta la probabilitat de causa genètica. S’ha determinat un alt rendiment diagnòstic del cariotip molecular, pel que es proposa l’aCGH com a primera tècnica per l’estudi del diagnòstic dual. Mitjançant la caracterització de les CNVs, s’han identificat gens candidats que predisposen a discapacitat intel·lectual i trastorns psiquiàtrics, majoritàriament implicats en les primeres etapes del desenvolupament, amb expressió a sistema nerviós i de localització sinàptica. Hi ha gens que participen en les vies glutamatèrgiques i de les ubiquitines i gens implicats en mecanismes oxidatius. La valoració del grau de discapacitat intel·lectual, dels trastorns psiquiàtrics, dels trastorns de la conducta i la dismorfologia presents en els pacients ha permès establir una correlació genotip-fenotip, identificant CNVs associades al diagnòstic dual en el 19% dels casos i CNVs en regions candidates: dup3q29 (FBXO45, PAK2), del7q31.1 (IMMP2L), del8p23.1 (MSRA), del8q21.13 (STMN2), dup9p24.2p24.1 (SLC1A1), del10q21.3 (CTNNA3), dup15q14q15.1 (SPRED1), del15q26.2 (MCTP2), dup17q24.1q24.2 (PRKCA). Es determina que la deleció 2p16.3 és un factor de risc per discapacitat intel·lectual i trastorns psiquiàtrics amb una expressivitat variable. Es descriu per primer cop un fenotip dismòrfic comú entre els adults afectats i l’avaluació clínica dels familiars portadors identifica un patró cognitiu i psiquiàtric comú amb diferents nivells de severitat a tots els portadors de la deleció.
L’estudi d’una població adulta aporta nombrosos avantatges, tant als pacients com als familiars, per adequar el pronòstic, seguiment, tractament i consell genètic. A més a més, el coneixement obtingut en pacients adults amb trastorns psiquiàtric pot ser de gran utilitat pels infants amb discapacitat intel·lectual, ja que el diagnòstic precoç n’afavoreix la prevenció mitjançant un seguiment i tractaments específics.ABSTRACT The human genome contains nearly 3 billion base pairs that include around 20.000-25.000 genes. There are two sources of genetic variation among individuals: single nucleotide variants and structural variants. The improvement of molecular technologies has revealed a large amount of copy number variants (CNVs), which represents dose changes (gains and losses) in about 4,8%-9,5% of the genome. The CNVs contribute to the gene expression, protein structure and chromosome stability even if they are found in healthy people. Consequently, there has been a significant increase in the interest to understand the role of CNVs in diseases, such as intellectual disability and psychiatric disorders. Intellectual disability affects between 1¬3% of human population. With improvement in paediatric care, patients are most likely to survive into adulthood, in which is revealed a high incidence of psychiatric and behaviouraldisorders associated. In order to identify the genetic aetiology of dual diagnosis of intellectual disability and psychiatric and/or behavioural disorders in a cohort of 100 adults and to identify CNVs of disease susceptibility, a sequential genetic test workflow was performed. Firstly, G-banded karyotype, Fragile X syndrome screening and specific molecular technologies targeted to confirm a clinical suspicious of a syndrome were applied. In those negative cases, subtelomeric region screening by multiplex ligation dependent probe amplification and then a whole genome screening by high resolution (400k) comparative genomic hybridization array (CGHa) were performed. A high genetic diagnosis frequency (38%) has established in the adult cohort with dual diagnosis. The co-morbidity of a second psychiatric disorder increases the likelihood of genetic cause. The CNV characterization has identified candidate genes for intellectual disability and psychiatric disorder, mostly involved in the early stages of development, high expression in nervous system and synaptic localization. Some genes identified are involved in glutamatergic and ubiquitin pathways or in oxidative status. The assessment of the intellectual disability degree, psychiatric/behavioural disorders and dismorphology allowed us to establish a genotype-phenotype correlation. It has been identified CNVs associated with dual diagnosis in 19% of cases and CNVs in candidate regions: dup3q29 (FBXO45, PAK2) del7q31.1 (IMMP2L) del8p23.1 (MSRA) del8q21.13 (STMN2) dup9p24.2p24.1 (SLC1A1) del10q21.3 (CTNNA3) dup15q14q15.1 (SPRED1) del15q26.2 (MCTP2) dup17q24.1q24.2 (PRKCA). The 2p16.3 deletion is an intellectual disability and a psychiatric disorder risk factor with variable expressivity. For the first time, it has been described a common dysmorphic phenotype on those patients affected by a 2p16.3 deletion in addition to a common cognitive and psychiatric profile with different levels of severity among all carriers. Studies in an adult population provide numerous advantages in both patients and family members. Genetic diagnosis allows to adequate the prognosis, monitoring, treatment and genetic counselling. Moreover, the knowledge obtained in adult patients with psychiatric disorders can be useful for children affected by intellectual disability. The early diagnosis promotes prevention through monitoring and specific treatments.
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Masciangioli, Tina Marie. "Structural and dynamic studies of bacteriorhodopsin and its variants". Diss., Georgia Institute of Technology, 1999. http://hdl.handle.net/1853/30551.
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NASCIMENTO, JÚNIOR Francisco do. "ScreenVar - a biclustering-based methodology for evaluating structural variants". Universidade Federal de Pernambuco, 2017. https://repositorio.ufpe.br/handle/123456789/25375.
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The importance of structural variants as a source of phenotypic variation has grown in recent years. At the same time, the number of tools that detect structural variations using Next- Generation Sequencing (NGS) has increased considerably with the dramatic drop in the cost of sequencing in last ten years. Then evaluating properly the detected structural variants has been featured prominently due to the uncertainty of such alterations, bringing important implications for researchers and clinicians on scrutinizing thoroughly the human genome. These trends have raised interest about careful procedures for assessing the outcomes from variant calling tools. Here, we characterize the relevant technical details of the detection of structural variants, which can affect the accuracy of detection methods and also we discuss the most important caveats related to the tool evaluation process. This study emphasizes common assumptions, a variety of possible limitations, and valuable insights extracted from the state-of-the-art in CNV (Copy Number Variation) detection tools. Among such points, a frequently mentioned and extremely important is the lack of a gold standard of structural variants, and its impact on the evaluation of existing detection tools. Next, this document describes a biclustering-based methodology to screen a collection of structural variants and provide a set of reliable events, based on a defined equivalence criterion, that is supported by different studies. Finally, we carry out experiments with the proposed methodology using as input data the Database of Genomic Variants (DGV). We found relevant groups of equivalent variants across different studies. In summary, this thesis shows that there is an alternative approach to solving the open problem of the lack of gold standard for evaluating structural variants.
A importância das variantes estruturais como fonte de variação fenotípica tem se proliferado nos últimos anos. Ao mesmo tempo, o número de ferramentas que detectam variações estruturais usando Next-Generation Sequencing (NGS) aumentou consideravelmente com a dramática queda no custo de seqüenciamento nos últimos dez anos. Neste cenário, avaliar corretamente as variantes estruturais detectadas tem recebido destaque proeminente devido à incerteza de tais alterações, trazendo implicações importantes para os pesquisadores e clínicos no exame minucioso do genoma humano. Essas tendências têm impulsionado o interesse em procedimentos criteriosos para avaliar os variantes identificados. Inicialmente, caracterizamos os detalhes técnicos relevantes em torno da detecção de variantes estruturais, os quais podem afetar a precisão. Além disso, apresentamos advertências fundamentais relacionadas ao processo de avaliação de uma ferramenta. Desta forma, este estudo enfatiza questões como suposições comuns à maioria das ferramentas, juntamente com limitações e vantagens extraídas do estadoda- arte em ferramentas de detecção de variantes estruturais. Entre esses pontos, há uma muito questão bastante citada que é a falta de um gold standard de variantes estruturais, e como sua ausência impacta na avaliação das ferramentas de detecção existentes. Em seguida, este documento descreve uma metodologia baseada em biclustering para pesquisar uma coleção de variantes estruturais e fornecer um conjunto de eventos confiáveis, com base em um critério de equivalência definido e apoiado por diferentes estudos. Finalmente, realizamos experimentos com essa metodologia usando o Database of Genomic Variants (DGV) como dados de entrada e encontramos grupos relevantes de variantes equivalentes em diferentes estudos. Desta forma, esta tese mostra que existe uma abordagem alternativa para o problema em aberto da falta de gold standard para avaliar variantes estruturais.
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Lee, Seung-Joo. "Structural and functional consequences of disease-related protein variants". Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1269545015.
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ROQUEPLO, GIMENEZ ANNE-PAULE. "Structure et fonction de l'angiotensionogene humain : etude des variants naturels et des variants obtenus par mutagenese dirigee". Paris 6, 1999. http://www.theses.fr/1999PA066440.
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L'angiotensinogene est le substrat unique et specifique de la renine. Il a ete recemment mis en evidence une relation positive entre le gene de l'angiotensinogene humain et l'hypertension arterielle essentielle. Nous avons realise l'etude des mutations naturelles du gene et caracterise la mutation y248c qui induit une glycosylation anormale de la proteine et un diminution de sa production in vitro et in vivo. Nous avons etudie certaines proprietes biochimiques de la proteine recombinante. La glycosylation de la proteine est entierement responsable de son heterogeneite. Nous avons produit un angiotensinogene mutant recombinant, homogene, completement deglycosyle, fonctionnel et utilise ce mutant pour demontrer que l'angiotensinogene presente un pont disulfure entre la cys 1 8 et la cys 1 3 8. La purification de l'angiotensinogene humain recombinant a conduit a montrer un clivage c-terminal entre la gln 4 1 2 et la leu 4 1 3, suggerant l'existence d'une fonction serpin-like pour l'angiotensinogene. La capacite de l'angiotensinogene de former un complexe covalent avec la proforme de la proteine majeure basique des granules eosinophiles (prombp) a ete recemment demontree. Nous avons produit in vitro le complexe angiotensinogene-prombp et montre que l'hydrolyse du complexe par la renine est 7 fois plus lente que l'hydrolyse de la forme monomerique. La liaison disulfire reliant les deux proteines fait intervenir la cys 2 3 2 de l'angiotensinogene. Le polymorphisme m235t de l'nagiotensinogene influe sur la formation du complexe avec une proportion plus faible du rapport complexe/monomere pour l'angiotensinogene 235t suggerant une nouvelle explication physiopathologique pour son association avec l'hta gravidique. Le clivage de l'angiotensinogene par la renine libere d'une part l'angiotensine i, fondamentale pou le fonctionnement du systeme renine-angiotensine, et d'autre part le des-angiotensine i-angiotensinogene, par l'intermediaire du clivage de la region c-terminal et la cys 2 3 2 hyperreactive dont la relevance physiologique reste a demontrer.
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Suliman, Muna. "Identifying Sortase A Variants With Higher Catalytic Effeciency". VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/383.
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In the past two decades, the field of protein engineering has evolved rapidly to include new genetic and chemical techniques to alter protein function. Protein engineering seeks to improve enzyme properties through powerful methods that specifically incorporate novel or improved function in proteins. One such method is protein ligation, which is used to selectively link synthetic and recombinant polypeptides. Due to the limitations of current protein labeling techniques, simple site-specific modification methods remain in high demand. Use of enzyme-based labeling has been the focus of various studies because of its substrate specificity. Sortase-mediated transpeptidation is one approach that has been well documented. Staphylococcus aureus sortase A (SrtAstaph), a membrane-anchored cysteine transpeptidase present in gram-positive bacteria, covalently anchors virulence-associated surface proteins to the peptidoglycan cross bridge of the cell wall. SrtAstaph, one of the most characterized sortases, has found numerous applications in the semi-synthesis of protein and peptide conjugates. While current studies have demonstrated the growing range of applications for sortase A, the enzyme itself has seen very few improvements. In steady-state kinetic analysis, the calculated K cat value of SrtAstaph was 2.27 × 10−5 s−1 indicative of its slow in-vitro turnover rate. Due to sortase’s relative inefficiency, several studies documented the use of excessive amounts of the enzyme in vitro (>30μM) or reactions were incubated for long periods. Through the use of directed evolution, we aimed to improve the catalytic activity of sortase A. Using random mutagenesis and an in vivo bacterial-based screen we isolated a variant that showed a 13-fold increase in its catalytic efficiency when compared to wild-type. This sortase mutant will enable more efficient labeling of LPETG-tagged substrates and will provide further insight into the enzyme’s molecular mechanism of catalysis, which is currently limited.
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Obri, Arnaud. "Etude structurale et fonctionnelle de la variante d'histone H2AZ". Phd thesis, Université de Strasbourg, 2012. http://tel.archives-ouvertes.fr/tel-00912335.
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La variante d'histone H2AZ joue un rôle important dans l'activation de la transcription, la prolifération cellulaire, le développement et la différentiation. H2AZ orne les promoteurs de la majorité des gènes, mais les mécanismes de bases de cette localisation sont inconnus. La compréhension de l'assemblage et du désassemblage du nucléosome passe par la caractérisation de la dynamique du nucléosome et des chaperonnes d'histones. L'objectif de ma thèse était d'identifier des chaperonnes spécifiques impliqués dans la dynamique de H2AZ en utilisant une approche de protéomique. Pour élucider les mécanismes de déposition/éviction de H2AZ, j'ai purifié le complexe prénucléosomale de H2AZ et j'ai caractérisé toutes les protéines associées. J'ai trouvé que Anp32e fait partie du complexe p400/TIP60 qui est présumée pour être responsable de l'échange d'H2AZ sur la chromatine. Anp32e présente une spécificité pour le dimère H2AZ-H2B, car il n'interagit pas avec le dimère H2A-H2B. L'interaction est accomplie au niveau d'une petite région dans le domaine d'ancrage sur H2AZ et au niveau d'un nouveau domaine ZID sur Anp32e. Finalement, j'ai montré que la suppression d'Anp32e entraine : un défaut dans la dé-répression des gènes dont l'expression est contrôlée par une hormone et une accumulation sur les promoteurs de ces derniers. Dans l'ensemble ces résultats identifient Anp32e comme une nouvelle chaperonne de la variante d'histoneH2AZ impliquée dans l'éviction de H2AZ chez les mammifères.
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Boulding, Hannah. "Identifying causative elements within structural variants associated with developmental disorders". Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:d9af47cc-1c91-4a66-a6ac-86655f1ff375.
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It has been well established that copy number variation contributes substantially to genetic variation within human populations. However, the extent to which de novo and inherited copy number variants (CNVs) underlie human disease is not well known. In this thesis, I investigate the role of de novo and inherited CNVs in a wide range of developmental abnormalities. First, I compare disease associated and apparently benign CNVs for structural differences, with the aim of identifying distinguishing features of disease causing CNVs. I identified significant enrichments of protein-coding genes, protein-coding genes associated with disease in OMIM and miRNAs amongst disease associated disease. Conversely, inherited CNVs observed in healthy individuals show depletions of these features. Following this, I employ functional enrichment approaches to identify the copy number variable genes within these de novo CNVs that contribute to the patient’s developmental abnormalities. I predict candidate genes for 143 different developmental abnormalities, with 65% of the candidate genes not having been previously associated with disease in OMIM. Through examining the distribution of these candidate genes within the patient’s CNVs, I found evidence of extensive pleiotropy and epistasis as well as a small number of simple additive effects. Finally, I extend my analyses to examine the role of inherited CNVs as the underlying cause of human developmental disorders. I implicate inherited CNVs and their overlapping copy number variable genes in the underlying causes of 45 human developmental abnormalities. Additionally, I re-examine the patients possessing both de novo CNVs and inherited CNVs using functional enrichment analyses. I reveal significant enrichments for a greater number of human developmental abnormalities when combining both the de novo and inherited CNVs, suggesting it is de novo mutations in combination with the inherited genomic background that are responsible for many instances of human developmental abnormalities.
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Aziz, Ali Barkat. "A comparison of a Lazy PageRank and variants for common graph structures". Thesis, Mälardalens högskola, Akademin för utbildning, kultur och kommunikation, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:mdh:diva-38435.
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The thesis first reviews the mathematics behind the Google’s PageRank, which is the state-of-the-art webpage ranking algorithm. The main focus of the thesis is on exploring a lazy PageRank and variants, related to a random walk, and by realizing that, they can be computed using the very same algorithm, find lazy PageRank and variants' expressions for some common graph structures, for example, a line-graph, a complete-graph, a complete-bipartite graph including a star graph, and try to get some understanding of the behavior of the PageRank, when a network evolves, for example either by a contraction or an expansion of graphs’ nodes or links.
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Bönisch, Clemens. "Structure/function analyses of mammalian histone H2A and H3 variants". Diss., lmu, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-154109.
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Cholombitko, A. V. "Features of variants of the structure of the arterial bed". Thesis, Sumy State University, 2017. http://essuir.sumdu.edu.ua/handle/123456789/54059.
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Introduction. Intraspecific features of topography and a branching of arteries pelvic to a belt and a free back extremity are important for experimenters, especially those which are engaged in transplantation of an extremity. At the same time, the available data of literature insufficiently fully display the listed above questions. Work purpose. To investigate intraspecific features of options of a structure of the arterial course and their value for transplantation of her back extremity.
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Karagyozova, Tina. "Spatio-temporal organisation of histone variants : from nucleosomes to nuclei". Electronic Thesis or Diss., Université Paris sciences et lettres, 2023. http://www.theses.fr/2023UPSLS030.
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Les multiples échelles d'organisation de la chromatine dans le noyau, de l'empaquetage en nucléosomes distincts à la formation de structures à l'échelle du kilo (kb) ou de la mégabase (Mb), contribuent à la régulation de la fonction du génome tout au long du cycle cellulaire et pendant les changements de destin cellulaire. Les travaux de notre équipe ont notamment démontré que le dépôt de variants H3 distincts dans la chromatine contribue à la définition des régions de réplication précoce. Cependant, la manière dont la distribution des variants H3 est liée au repliement du génome à un niveau supérieur, et ses implications pour l'initiation de la réplication précoce, restent des questions ouvertes. Au cours de mon projet de doctorat, j'ai étudié comment les nucléosomes, avec des variants H3 distincts, sont liés au repliement du génome en structures d’ordre supérieur, et quelles sont les implications pour l'initiation précoce de la réplication. Pour ce faire, j'ai d'abord intégré des données de ChIP-seq spécifiques à certains variants H3, provenant de cellules dans lesquelles le chaperon HIRA spécifique à H3.3 était présent (WT) ou knockout (KO), avec des données Hi-C publiques pour établir le profil de distribution des variants H3 dans les compartiments. Par la suite, j'ai généré des données Hi-C appariées pour évaluer l'effet de la perte d'HIRA sur l'organisation du génome en 3D. Enfin, j'ai réalisé des expériences de sauvetage pour vérifier si le fait de restaurer HIRA permet de rétablir les schémas de variants H3 et, à son tour, restaurer l'initiation précoce de la réplication et/ou l'organisation 3D du génome, simultanément ou séparément. J'ai montré que HIRA est nécessaire au dépôt ciblé de H3.3 dans les régions du compartiment A et au maintien de leurs contacts avec le reste du génome d'une manière indépendante des PTM H3. En outre, l'incorporation de H3.3 médiée par HIRA était essentielle pour maintenir l'identité du compartiment A et les niveaux de PTM dans les ZI précoces non transcrites, sans affecter leur conformation 3D locale. La restauration de HIRA a suffi à rétablir l'enrichissement en H3.3 à l'échelle du génome entier dans les compartiments A, ainsi que leur modèle d'interaction, et à l'échelle locale dans les sites H3.3 préexistants, quelle que soit leur activité transcriptionnelle. Cela s'est accompagné d'un sauvetage partiel de l'initiation précoce de la réplication au niveau de ces sites, mais pas d'une inversion de compartiment à cette échelle de temps. Mes résultats suggèrent que HIRA est important pour l'organisation 3D de la chromatine à l'échelle des compartiments, d'une manière indépendante des PTM d'histones et distincte de son rôle dans la définition des ZI de réplication précoceThe multiple scales of chromatin organization in the nucleus: from packaging into distinct nucleosomes up to forming structures on the scale of kilo- (kb) to megabases (Mb), contribute to the regulation of genome function throughout the cell cycle and during cell fate transitions. Notably, work from our team demonstrated that deposition of distinct H3 variants on chromatin contributes to the definition of early-replicating regions. However, how the distribution of H3 variants relates to higher-order genome folding and its implications for early replication initiation remain open questions. During my PhD project, I explored how nucleosomes with distinct H3 variants relate to higher-order genome folding and what their implications for early replication initiation are. To achieve this, I integrated unique H3 variant-specific ChIP-seq data from cells in which the H3.3-specific chaperone HIRA was present (WT) or knocked-out (KO) with publicly available Hi-C data to profile H3 variant distribution with respect to compartments. Secondly, I generated matched Hi-C data to assess the effect of HIRA loss on 3D genome organization. Finally, I performed rescue experiments to test whether supplying back HIRA can re-establish H3 variant patterns, and in turn restore either early replication initiation and/or 3D genome organization simultaneously or separately. I showed that HIRA is required for targeted H3.3 deposition in compartment A regions and maintenance of their contacts with the rest of the genome in a manner independent of H3 PTMs. Furthermore, HIRA-mediated H3.3 incorporation was essential for maintaining A compartment identity and PTM levels at non-transcribing early IZs without affecting their local 3D conformation. Strikingly, re-supplying HIRA was sufficient to restore H3.3 enrichment globally in A compartments along with their interaction pattern, as well as locally at H3.3 pre-existing sites regardless of their transcriptional activity. This was accompanied by a partial rescue of the impaired early replication initiation at these sites, but not by reversal of compartment on this timescale. My results suggest that HIRA is important for 3D chromatin organization on the scale of compartments in a manner that is independent of histone PTMs and separate from its role in defining early replication IZs
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Ueda, Yoshihide. "New p73 variants with altered C-terminal structures have varied transcriptional activities". Kyoto University, 2001. http://hdl.handle.net/2433/150540.
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Boopathy, Sivakumar. "Investigating Structural and Functional Defects in ALS-causing Profilin 1 Variants". eScholarship@UMMS, 2009. http://escholarship.umassmed.edu/gsbs_diss/923.
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Mutations in profilin 1 (PFN1) cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease that targets motor neurons. PFN1 is a 15 kDa protein that is best known for its role in actin dynamics. However, little is known about the pathological mechanisms of PFN1 in ALS. In this dissertation, it is demonstrated that certain familial ALS-linked mutations severely destabilize the native conformation of PFN1 in vitro and cause accelerated turnover of the PFN1 protein in neuronal cells. This mutation-induced destabilization can account for the high propensity of ALS-linked variants to aggregate and also provides rationale for their reported functional defects in cell-based assays. The source of this destabilization is illuminated by the crystal structures of several PFN1 proteins, revealing an expanded cavity near the protein core of one ALS variant and predicting a non-surface exposed cavity in another. Functional biochemical experiments point to abnormalities in actin filament nucleation and elongation caused by PFN1 mutants. In HeLa cells, PFN1 is essential for the generation of actin-rich filopodia and expression of mutant PFN1 alters filopodia density further supporting a pathogenesis mechanism involving actin cytoskeleton. Taken together, this dissertation infers that the pathogenesis of ALS due to mutations in PFN1 can be mediated at least by two possibly related mechanisms, a destabilization of the native PFN1 structure and an impact on the actin assembly processes.
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Boopathy, Sivakumar. "Investigating Structural and Functional Defects in ALS-causing Profilin 1 Variants". eScholarship@UMMS, 2017. https://escholarship.umassmed.edu/gsbs_diss/923.
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Mutations in profilin 1 (PFN1) cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease that targets motor neurons. PFN1 is a 15 kDa protein that is best known for its role in actin dynamics. However, little is known about the pathological mechanisms of PFN1 in ALS. In this dissertation, it is demonstrated that certain familial ALS-linked mutations severely destabilize the native conformation of PFN1 in vitro and cause accelerated turnover of the PFN1 protein in neuronal cells. This mutation-induced destabilization can account for the high propensity of ALS-linked variants to aggregate and also provides rationale for their reported functional defects in cell-based assays. The source of this destabilization is illuminated by the crystal structures of several PFN1 proteins, revealing an expanded cavity near the protein core of one ALS variant and predicting a non-surface exposed cavity in another. Functional biochemical experiments point to abnormalities in actin filament nucleation and elongation caused by PFN1 mutants. In HeLa cells, PFN1 is essential for the generation of actin-rich filopodia and expression of mutant PFN1 alters filopodia density further supporting a pathogenesis mechanism involving actin cytoskeleton. Taken together, this dissertation infers that the pathogenesis of ALS due to mutations in PFN1 can be mediated at least by two possibly related mechanisms, a destabilization of the native PFN1 structure and an impact on the actin assembly processes.
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Bowley, Sheryl Rubio Lord Susan T. "Insights from structure-function studies of variant fibrinogen". Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2008. http://dc.lib.unc.edu/u?/etd,1992.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2008.Title from electronic title page (viewed Feb. 17, 2009). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry with Emphasis in Biological Chemistry." Discipline: Chemistry; Department/School: Chemistry.
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Freywald, Ulrike, Katharina Mayr, Sören Schalowski e Heike Wiese. "Linguistic Fieldnotes II: Information structure in different variants of written German". Universität Potsdam, 2010. http://opus.kobv.de/ubp/volltexte/2010/3683/.
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Dieser Band versammelt Originaldaten aus einer Erhebung, die im Rahmen des SFB-Teilprojekts B6 „Kiezdeutsch“ im Frühjahr 2010 in Berlin und İzmir, Türkei, durchgeführt wurde. Sämtliche hier dokumentierten Daten wurden schriftlich produziert; sie stammen von drei verschiedenen Sprechergruppen: Jugendliche aus einem multiethnischen Berliner Wohngebiet, die untereinander Kiezdeutsch sprechen, Jugendliche aus einem monoethnischen Berliner Wohngebiet, in dem der traditionelle Berliner Dialekt vorherrscht, und türkische Jugendliche in İzmir, die Deutsch als Fremdsprache gesteuert erworben haben.
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Romain, Sandra. "Identification, génotypage et représentation des variants de structure dans les pangénomes". Electronic Thesis or Diss., Université de Rennes (2023-....), 2024. https://ged.univ-rennes1.fr/nuxeo/site/esupversions/71b8c90f-bac9-4948-9bb1-a4b6d953f322.
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Les variants structuraux (SVs), des variations génomiques de plus de 50 pb, contribuent de manière significative à la diversité génétique et à l'évolution des espèces. La détection et le génotypage précis des SVs est crucial pour comprendre leur rôle dans la variation phénotypique et l'adaptation. Les graphes de variation (VGs) et graphes de pangénomes (PGs), qui représentent les variations génomiques comme des chemins alternatifs dans un graphe, offrent une approche prometteuse pour l'analyse des SVs. Cette thèse explore l'utilisation des VGs et PGs pour la détection et le génotypage des SVs, en se concentrant sur un complexe de quatre espèces de papillons Coenonympha alpins. Deux outils bio-informatiques ont été développés au cours de cette thèse : (1) SVJedi-graph, le premier génotypeur de SVs à partir de lectures longues utilisant un VG pour représenter les SVs, fournissant une précision de génotypage supérieure aux outils de l’état de l’art, en particulier pour les SVs proches et chevauchants, et (2) INVPG-annot, un outil d’identification des inversions dans les PGs, qui a permi de démontrer que les inversions sont représentées par différentes topologies dans les PGs selon l’outil de construction utilisé. L'analyse comparative des génomes des papillons Coenonympha a permis d'identifier douze grandes inversions (≥ 100 kbp) entre les quatre espèces, dont certaines pourraient jouer un rôle dans l'isolement reproductif et l'adaptation locale de deux de ces espèces. Bien que l'approche basée sur les PGs présente des avantages pour la comparaison de génomes, des défis restent à relever pour l'analyse des grands variants comme les inversionsStructural variants (SVs), genomic variations of more than 50 bp, contribute significantly to genetic diversity and species evolution. Accurate detection and genotyping SVs is crucial to understanding their role in phenotypic variation and adaptation. Variation graphs (VGs) and pangenome graphs (PGs), which represent genomic variations as alternative paths in a graph, offer a promising approach for the analysis of SVs. This thesis explores the use of VGs and PGs for the detection and genotyping of SVs, focusing on a complex of four species of alpine Coenonympha butterflies. Two bioinformatics tools were developed during this thesis: (1) SVJedi-graph, the first long-read SV genotyper using a VG to represent SVs, providing a genotyping accuracy superior to state-of-the-art tools, particularly for close and overlapping SVs, and (2) INVPG-annot, a tool for identifying inversions in PGs, which demonstrated that inversions are represented by different topologies in PGs depending on the construction tool used. Comparative analysis of the Coenonympha butterfly genomes identified twelve large inversions (≥ 100 kbp) between the four species, some of which could play a role in the reproductive isolation and local adaptation of two of these species. While the PG-based approach offers advantages for genome comparison, challenges remain for the analysis of large variants such as inversions
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Roulland, Yohan. "Fonctions des extrémités flexibles de l’ADN du nucléosome CENP-A dans l'organisation de la chromatine centromérique". Thesis, Université Grenoble Alpes (ComUE), 2016. http://www.theses.fr/2016GREAV087/document.
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CENP-A est le variant d’histone qui remplace spécifiquement l’histone H3 au niveau des centromères et confère ses propriétés uniques à la chromatine centromérique. La cristallographie aux rayon X, ainsi que la digestion à la MNase des nucléosomes contenant CENP-A suggèrent une flexibilité de l’ADN entrant et sortant de ce nucléosome. Néanmoins ces déductions restent aujourd’hui au stade hypothétique, en particulier, rien n’est connu sur le rôle éventuelle de cette particularité dans la fonction du nucléosome CENP-A. L’utilisation de la cryo-électromicroscopie nous a permis de déterminer les caractéristiques de la dynamique de l’ADN sortant du nucléosome CENP-A. Nos analyses biochimiques, de protéomiques et de pseudo-génétiques révèlent que la flexibilité élevée de l’ADN du nucléosome CENP-A ne permet pas l’interaction avec l’histone de liaison H1. In vitro, remplacer les 2 tours de l’hélice aN de CENP-A avec les 3 tours de l’hélice aN de H3 permet de restaurer l’interaction de l’histone H1. In vivo, le replacement des nucléosomes CENP-A par des nucléosomes contenant ce même nucléosome hybride aN-CENP-A permet également le recrutement de H1, mais cela conduit également à la délocalisation d’un certain nombre de protéines du kinétochore. Ce kinétochore ne permet pas une ségrégation correcte des chromosomes et il conduit à des phases de mitose et de cytokinèse défectueuses. L’ensemble de ces données montre que la conservation au cours de l’évolution de la flexibilité de l’ADN dans le nucléosome CENP-A est essentielle pour l’accomplissement de la division cellulaireCENP-A is a histone variant, which replaces histone H3 at centromeres and confers unique properties to centromeric chromatin. The crystal structure and MNase digestion of CENP-A nucleosome suggests flexible nucleosomal DNA ends but their dynamics in solution remains elusive and their implication in centromere function is unknown. Using electron cryo-microscopy we determined the dynamic solution properties of the CENP-A nucleosome. Our biochemical, proteomic and genetic data reveal that the high flexibility of the DNA ends impairs histone H1 binding to the CENP-A nucleosome. Substituting the 2-turn aN-helix of CENP-A with the 3-turn N-helix of H3 results in particles able to bind histone H1. In vivo replacement of CENP-A nucleosomes with the same NH3-CENP-A hybrid nucleosomes leads to H1 recruitment, delocalization of kinetochore proteins and significant mitotic and cytokinesis defects. Put together, ourdata reveal that the evolutionarily conserved flexible ends of the CENP-A nucleosomes are essential to ensure the fidelity of the mitotic pathway
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Simpson, Jared Thomas. "Efficient sequence assembly and variant calling using compressed data structures". Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607828.
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Ross, Gordon Andrew. "Biomedical applications of capillary electrophoresis : including the analysis of structural haemoglobin variants". Thesis, Queen Mary, University of London, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.364283.
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Awan, Sarah Jabeen. "Structural and mechanistic studies on E. coli porphobilinogen deaminase and mutant variants". Thesis, University College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244212.
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Nalin, Venkat Sameera. "Network Structural Equation Modeling of PV Minimodule Variants Under Indoor Accelerated Exposures". Case Western Reserve University School of Graduate Studies / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1619711989919366.
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SIXTO, TAPIA ARTUR, e M. GOLDBERG. "Structure-fonction des variants m et z de l'alpha-1-antitrypsine humaine". Paris 7, 1994. http://www.theses.fr/1994PA077304.
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L'alpha-1-antitrypsine (aat) est une glycoproteine monomerique appartenant a la superfamille des inhibiteurs de serine-proteases ou serpines. L'aat normale (ou aat m) est abondante dans le serum. Le variant z d'aat differe du variant m par un seul acide amine, qui se trouve a un endroit cle pour la structure de la boucle contenant le centre actif. La modification de la structure de cette boucle entraine un phenomene de polymerisation moyennant l'insertion de la boucle dans le feuillet beta d'une deuxieme molecule d'aat. L'aat z est retenue dans le reticulum endoplasmique des hepatocytes sous forme de polymeres, et son defaut de secretion est associee a diverses pathologies. L'objectif du travail a ete de mieux comprendre et d'etudier les moyens de prevenir le defaut de secretion de l'aat z. La traduction in vitro de l'aat a permis d'etudier la glycosylation et l'agregation des deux variants dans des membranes microsomales. Les variants m et z ont ete purifies a partir de plasma et divers pics d'aat ont ete caracterises. L'effet d'inhibition de divers peptides homologues de la boucle sur la polymerisation de l'aat purifiee a ete analyse. La fluorescence intrinseeque des variants m et z a servi a etudier la structure de la boucle et le mecanisme de polymerisation, ainsi que l'interaction des peptides avec l'aat
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Boulard, Matthieu. "Variants d'histones H2BFWT et macroH2A1: de la structure à la fonction épigénétique". Phd thesis, Grenoble 1, 2007. http://www.theses.fr/2007GRE10149.
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Les eucaryotes expriment des variants d'histones non-alléliques en faible quantité en plus des histones conventionnels. De récentes données ont montré que ces variants d'histones sont impliqués dans de nombreuses fonctions cellulaires dont la réparation de l'ADN, la ségrégation des chromosomes ou encore le contrôle de la transcription. L'objectif de cette étude est d'améliorer la compréhension du rôle biologique des variants d'histones. Les travaux rapportés dans ce manuscrit abordent plus spécifiquement la fonction de deux variants: H2BFWT, qui joue un rôle dans la spermatogenèse chez l'homme; et macroH2A1 qui semble impliqué dans la répression transcriptionnelle. Nous avons montré que malgré sa grande divergence avec H2B, l'incorporation de H2BFWT ne modifie pas la structure globale du nucléosome. Néanmoins, contrairement à l'histone somatique H2B, H2BFWT n'a pas la capacité de recruter les facteurs d'assemblage du chromosome et n'est pas requis pour la condensation du chromosome mitotique. Cette différence de comportement vis-à-vis de l'assemblage des chromosomes suggère que H2BFWT pourrait être impliqué dans l'architecture de structure d'ordre supérieur de la chromatine. Dans le but d'élucider le rôle biologique de macroH2A1 in vivo, nous avons généré une lignée de souris invalidées pour macroH2A1. Malgré l'abondance des investigations portant sur macroH2A1, sa fonction reste inconnue. MacroH2A1 a la particularité d'être trois fois plus grand que H2A, il comporte ainsi une extension C-terminale de fonction inconnue. Initialement macroH2A1 avait été décrit comme principalement localisé sur le chromosome X inactif. La signification biologique de cet enrichissement n'est pas comprise. In vitro, la présence de macroH2A1 interfère avec la transcription. De récentes études ont montré que certaines séquences d'ADN méthylées, incluant les gènes soumis à l'empreinte et les rétrotransposons sont enrichies en nucléosomes contenant macroH2A1. Il a également été démontré que c'est la méthylation de l'ADN, nécessaire pour la répression transcriptionnelle, qui permet le recrutement de macroH2A1 sur les rétrotransposons. Nous émettons l'hypothèse que la méthylation de l'ADN aboutirait à la répression des rétrotransposons via le recrutement de macroH2A1. L'étude du phénotype des souris déficientes en macroH2A1 permet de conclure que contrairement au consensus actuel, macroH2A1 n'est pas nécessaire pour réprimer la transcription des séquences répétées incluant les rétrotransposons. Les examens anatomopathologiques suggèrent que macroH2A1 pourrait être impliqué dans la régulation du métabolisme des acides grasIn addition to conventional histones, non-allelic variants are also expressed in low amount in eukaryotic cells. Recent data have revealed that histone variants assume roles in various processes within the cell including DNA repair, chromosome segregation and transcriptional control. The aim of my study was to highlight some biological functions harbored by histone variants. My investigations focused on two variants: the uncharacterized H2BFWT, which plays a role in human spermatogenesis and macroH2A1, which has an unclear function in transcriptional silencing. We show that, despite its huge divergence with H2B, the presence of H2BFWT does not affect the overall structure of the nucleosome. Importantly, in contrast to somatic H2B, H2BFWT was unable to recruit chromosome condensation factors and to participate in the assembly of mitotic chromosomes. This difference towards chromosome assembly suggests that H2BFWT might be involved in chromatin architecture. In order to bring new insights about macroH2A1 function in vivo we have disrupted macroH2A1 expression in mice by gene targeting. Many studies have been addressed macroH2A1 function, however its biological role remains unclear. MacroH2A1 is three times bigger than H2A and carries a C-terminal extension of unknown function. Initially macroH2A1 had been reported to be predominantly located on the inactive X chromosome in female. The biological significance of this enrichment is totally unknown. In vitro, the presence of macroH2A1 interferes with transcription. Recent studies show that methylated DNA sequences including imprinted genes and retrotransposons are enriched in macroH2A1. It has been reported that macroH2A recruitment on retrotransposons is mediated by DNA methylation, which is absolutely required for their silencing. We hypothesized that methylation of CpG dinucleotides in retrotransposons might achieve transcriptional repression through recruitment of macroH2A1. The study of the mice phenotype shows that contrary to the current view, macroH2A1 is not able on its own, to repress transcription of repetitive sequences including transposon in vivo. Anatomopathological examinations reveal that macroH2A1 could be involved in fatty acid metabolism
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Boulard, Matthieu. "Variants d'histones H2BFWT et macroH2A1: de la structure à la fonction épigénétique". Phd thesis, Université Joseph Fourier (Grenoble), 2007. http://tel.archives-ouvertes.fr/tel-00175842.
Texto completo da fonteResumo:
Les eucaryotes expriment des variants d'histones non-alléliques en faible quantité en plus des histones conventionnels. De récentes données ont montré que ces variants d'histones sont impliqués dans de nombreuses fonctions cellulaires dont la réparation de l'ADN, la ségrégation des chromosomes ou encore le contrôle de la transcription. L'objectif de cette étude est d'améliorer la compréhension du rôle biologique des variants d'histones. Les travaux rapportés dans ce manuscrit abordent plus spécifiquement la fonction de deux variants: H2BFWT, qui joue un rôle dans la spermatogenèse chez l'homme; et macroH2A1 qui semble impliqué dans la répression transcriptionnelle.Nous avons montré que malgré sa grande divergence avec H2B, l'incorporation de H2BFWT ne modifie pas la structure globale du nucléosome. Néanmoins, contrairement à l'histone somatique H2B, H2BFWT n'a pas la capacité de recruter les facteurs d'assemblage du chromosome et n'est pas requis pour la condensation du chromosome mitotique. Cette différence de comportement vis-à-vis de l'assemblage des chromosomes suggère que H2BFWT pourrait être impliqué dans l'architecture de structure d'ordre supérieur de la chromatine.
Dans le but d'élucider le rôle biologique de macroH2A1 in vivo, nous avons généré une lignée de souris invalidées pour macroH2A1.
Malgré l'abondance des investigations portant sur macroH2A1, sa fonction reste inconnue. MacroH2A1 a la particularité d'être trois fois plus grand que H2A, il comporte ainsi une extension C-terminale de fonction inconnue. Initialement macroH2A1 avait été décrit comme principalement localisé sur le chromosome X inactif. La signification biologique de cet enrichissement n'est pas comprise. In vitro, la présence de macroH2A1 interfère avec la transcription. De récentes études ont montré que certaines séquences d'ADN méthylées, incluant les gènes soumis à l'empreinte et les rétrotransposons sont enrichies en nucléosomes contenant macroH2A1. Il a également été démontré que c'est la méthylation de l'ADN, nécessaire pour la répression transcriptionnelle, qui permet le recrutement de macroH2A1 sur les rétrotransposons. Nous émettons l'hypothèse que la méthylation de l'ADN aboutirait à la répression des rétrotransposons via le recrutement de macroH2A1.
L'étude du phénotype des souris déficientes en macroH2A1 permet de conclure que contrairement au consensus actuel, macroH2A1 n'est pas nécessaire pour réprimer la transcription des séquences répétées incluant les rétrotransposons.
Les examens anatomopathologiques suggèrent que macroH2A1 pourrait être impliqué dans la régulation du métabolisme des acides gras.
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Baldan, Nikita <1996>. "Computational analysis of NaV1.7 protein variants and tool for 3D visualization of protein structures". Master's Degree Thesis, Università Ca' Foscari Venezia, 2020. http://hdl.handle.net/10579/17572.
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This thesis is composed of two parts. The first part explores the possibility to use Graph Kernels to discriminate pathogenic versus non-pathogenic variants of a specific protein.
All variants are represented as Residue Interaction Networks (RIN), where nodes are amino acids and edges represent non-covalent bonds between atoms of the two involved amino acids.
This part is guided by a previous Master degree thesis that considered protein NaV1.7, which is responsible for the transmission of the pain signal from the peripheral nervous system to the brain. The thesis considered 85 genetic variants of the human NaV1.7, among which 30 are known to cause neuropathic diseases and 55 are instead neutral.
The results of the first part highlight that some Graph Kernels are actually able to discriminate between pathogenic and neutral variants.
This prompted the idea of realizing a 3D viewer able to show the three-dimensional structure of a protein and also its non-covalent bonds.
The second part of the thesis describes Spheremole, an application for the visualization of the three-dimensional structure of a protein. In particular, Spheremole allows the visualization of two proteins structures and their visual comparison, also based on their non-covalent bonds.
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Mercati, Oriane. "Etude fonctionnelle et structurale de variants rares des contactines et vulnérabilité à l’autisme". Thesis, Paris 5, 2013. http://www.theses.fr/2013PA05T069/document.
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Les troubles du spectre autistique (TSA) affectent un individu sur 100 et sont caractérisés par des déficits de la communication et des interactions sociales, et par des comportements restreints et répétitifs. Les TSA présentent une forte composante génétique ; les premiers gènes impliqués ont été identifiés au laboratoire et codent des protéines d’adhérence ou d’échafaudage localisées à la synapse : les neuroligines (NLGN) et SHANK. Nous nous sommes intéressés à l’implication dans les TSA des contactines (CNTN), un groupe de six molécules d’adhérence neurales de la superfamille des immunoglobulines. Ces protéines sont ancrées à la membrane plasmique par un groupement glycosyl phosphatidylinositol (GPI) et peuvent être sécrétées par clivage du GPI. Elles interviennent dans des processus variés du développement neuronal comme la croissance neuritique, le guidage et la fasciculation des axones ou la myélinisation. Des études génétiques ont suggéré l’implication des contactines 4 à 6 dans les TSA, mais aucune étude fonctionnelle n’a confirmé cette hypothèse. Ce travail de thèse associe une analyse génétique, une analyse fonctionnelle sur des cultures de neurones primaires de rat et une analyse structurale par modélisation moléculaire. Nous avons identifié plusieurs "Copy-Number Variants" (CNV) dans les gènes CNTN (essentiellement des délétions affectant CNTN5 et CNTN6) et observé une tendance à l’enrichissement chez les patients par rapport aux individus témoins. Le séquençage des exons codants de CNTN5 et CNTN6 chez plus de 200 patients et 200 témoins nous a ensuite permis d’identifier des variants ponctuels non synonymes. Les variants privés (présents chez un seul individu ou dans une seule famille) sont plus fréquents chez les patients que chez les témoins. Les CNV et les variants ponctuels sont hérités, de parents pour la plupart non atteints, ce qui suggère que les altérations des contactines constituent des facteurs de vulnérabilité aux TSA plutôt que des facteurs causaux. Afin de déterminer l’effet fonctionnel des variants ponctuels rares, nous avons comparé l’effet sur la neuritogenèse des CNTN mutées à celui des CNTN sauvages. Nous avons ainsi analysé, sur plusieurs centaines de neurones par condition, la longueur et la ramification des neurites dans un système de co-culture avec des cellules HEK surexprimant la CNTN. La plupart des protéines CNTN5 et CNTN6 mutées présentent des effets différents de ceux des protéines sauvages (inhibition ou augmentation des effets positifs de celles-ci). Le dernier objectif de cette étude consistait à évaluer l’influence de certains de ces variants sur l’interaction des CNTN, via les domaines immunoglobuline (Ig) 2 et 3, avec l’un de leurs ligands, le récepteur à activité tyrosine phosphatase PTPRG. Par homologie avec la structure cristallographique déjà résolue pour les quatre premiers domaines Ig de CNTN4 de souris, nous avons modélisé cette région pour les CNTN5 et 6 humaines, sauvages et mutées. Nous avons ainsi pu prédire que certains variants étaient susceptibles de modifier les liaisons ioniques ou l’encombrement stérique dans cette région d’interaction. L’ensemble de nos résultats démontre l’existence d’effets fonctionnels délétères de plusieurs variants rares des contactines retrouvés chez les patients atteints de TSA. La présence de ces variants rares chez des apparentés non atteints indique que les altérations des CNTN s’inscrivent dans un modèle de "multiple hit", qui propose que l’autisme puisse résulter de la combinaison de plusieurs atteintes génétiques, chacune représentant un facteur de risque à effet modéré et n’entraînant pas, à elle seule, le développement du trouble. Le séquençage d’exomes et de génomes entiers, en cours au laboratoire, permettra une meilleure compréhension de ces atteintes génétiques multiplesAutism Spectrum Disorders (ASDs) affect one individual out of 100 and are characterised by deficits in communication and social interactions, and by restricted and repetitive behaviours. ASDs display a strong genetic component ; the first genes involved were identified in our laboratory and encode for cell-adhesion or scaffolding proteins localised at the synapse : neuroligins (NLGNs) and SHANKs. We were interested in the implication, in the ASDs, of contactins (CNTNs), a group of six neural cell-adhesion molecules of the immunoglobulin superfamily. These proteins are anchored to the plasma membrane by a glycosyl phosphatidylinositol (GPI) and can be secreted by cleavage of this anchor. They participate in various processes of neuronal development such as neurite outgrowth, axon guidance and fasciculation, and myelination. Genetic studies have suggested the involvement of contactins 4, 5 and 6 in the ASDs, but no functional study has confirmed this hypothesis. The present work combines a genetic analysis, a functional analysis on cultured primary rat cortical neurons and a structural analysis by molecular modelling. We identified several "Copy-Number Variants" (CNVs) in CNTN genes (mainly deletions affecting CNTN5 and CNTN6) and observed a trend of enrichment in patients compared to control individuals. Subsequent sequencing of CNTN5 and CNTN6 coding exons in more than 200 patients and 200 controls allowed us to identify non synonymous single-nucleotide variants (SNVs). Private variants (present only in one individual or one family) are enriched in patients compared to controls. CNVs and SNVs are inherited, mainly from unaffected parents, which suggests that impairments in contactins represent susceptibility factors for ASDs, rather than causal factors. In order to determine the functional effects of rare SNVs, we compared the effect on neuritogenesis of mutant CNTNs to that of WT CNTNs. We therefore analysed, on several hundreds of neurons per condition, the length and branching of neurites in a co-culture system with HEK cells overexpressing a CNTN protein. Most of CNTN5 and CNTN6 mutant proteins either inhibited or increased the positive effects of WT proteins. The last aim of the present study consisted in evaluating the influence of some of these variants on the interaction of CNTNs, via their immunoglobulin (Ig) domains 2 and 3, with one of their ligands, the protein tyrosine phosphatase receptor PTPRG. Using homology with the crystal structure that had already been solved for the first four Ig domains Ig of mouse CNTN4, we modelled this region for human CNTN5 and CNTN6, WT and mutated. We have thus been able to predict that some variants were likely to alter ionic bonds or steric constraints in this interaction module. Taken as a whole, our results demonstrate that several rare CNTN variants found in patients with ASD have deleterious functional effects. The presence of these rare variants in unaffected relatives indicates that CNTN impairments fit into a "multiple hit" model, according to which autism may result from the combination of several genetic defects, each being a risk factor with moderate effect but not triggering, in itself, the development of the disorder. Sequencing of exomes and whole genomes, ongoing in the laboratory, will allow better understanding of those multiple genetic impairments
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Heller, David [Verfasser]. "Structural variant calling using third-generation sequencing data / David Heller". Berlin : Freie Universität Berlin, 2021. http://d-nb.info/122534946X/34.
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Santos, Fellipe Bronze dos. "Análise bioquímica e estrutural das proteínas dermicidina-1L e sua splice variante em sistema biomimético". Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/42/42136/tde-26062014-170711/.
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Dermicidina (DCD) é um gene mapeado no cromossomo 12, lócus 12q13.1, e codifica uma proteína de 110 aminoácidos, que sofre um processamento proteolítico, gerando peptídeos ativos. O peptídeo C-terminal (DCD-1L) de 48 aminoácidos tem uma carga -2, e exerce função antibacteriana e antifúngica, e o peptídeo C-terminal splice variante, denominado DCD-SV de 59 aminoácidos, tem carga neutra, e suas propriedades ainda não foram estabelecidas. Neste trabalho são apresentados os resultados da expressão, purificação e sequenciamento da DCD nativa produzida em E. coli BL21 transformada com o vetor pAE-DCD. Na segunda parte são descritas as análises físico-químicas e bioquímicas da interação dos peptídeos sintéticos DCD-1L e DCD-SV com vesículas lipídicas gigantes e vesículas unilamelar grandes sintetizadas com palmitoil-oleoil-fosfatidilcolina. As preferenciais estruturais dos peptídeos foram investigadas por espectroscopia de Dicroísmo Circular. Nossos resultados sugerem que a DCD-SV tem alta propensão para adotar uma estrutura helicoidal permitindo sua inserção e oligomerização em membranas biomiméticas, e possível formação de canais de condutância molecular.Dermicidin (DCD) is mapped a gene on chromosome 12, locus 12q1.13 whose 110 amino acids protein is proteolytically processed to N and C-terminal peptides. The 48-amino acid C-terminal peptide (DCD-1L) has -2 net charges and display antibacterial and antifungal properties and the 59-amino acid splice variant C-terminal peptide (DCD-SV) has neutral net charge; however, its structure and biological function are unknown. Here we show the results of expression, purification and amino acid sequencing of recombinant DCD protein produced in E.coli transformed with pAE-DCD vector. We also describe the results of physical-chemical and biochemical analyses showing the visible differences between the interactions of DCD-1LL and DCD-SV synthetic peptides with giant unilamellar vesicles and large unilamellar vesciles made of palmitoyl-oleoyl phosphatidylcholine, used as biomimetic membranes. The structural preferences of peptides were analyzed by circular dichroism spectroscopy. Our results suggest that DCD-SV peptide has higher propensity to adopt helicoidal structure enabling it to insert into mimetic membranes, undergo oligomerization and formation of conductance channel.
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Pyon, Yoon Soo. "Variant Detection Using Next Generation Sequencing Data". Case Western Reserve University School of Graduate Studies / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1347053645.
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Frandsen, Jane K. "Non-canonical T box riboswitch-tRNA recognition in ileS variants". The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1560863957375393.
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Marin, Luciano Heitor Gallegos. "Statistical decision making for stochastic damage localization approaches". Thesis, Rennes 1, 2013. http://www.theses.fr/2013REN1S059/document.
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Les systèmes mécaniques soumis et excités par vibrations sont les candidats naturels à être modélisé par des systèmes linéaires invariables dans le temps. La localisation de dommages utilisant les paramètres modaux évalués à partir de données de vibration ambiantes mesurées grâce à de capteurs est possible notamment par l'approche nommée Stochastic Dynamic Damage Location Vector (SDDLV), où l'emplacement des dommages est empiriquement relié aux positions où le stress est proche de zéro. La première contribution dans cette thèse montre comment l'incertitude sur les paramètres du système d'état peut être utilisée pour déduire des bornes d'incertitude sur les résidus de localisation de dommages, ceci afin de décider de l'emplacement de dommage utilisant un test d'hypothèse. Dans la deuxième contribution, la méthode de localisation de dommages est étendue pour être robuste au choix des variables de Laplace utilisées dans cette méthode. Ceci est obtenue en agrégeant statistiquement les résultats à valeurs différentes dans le domaine de Laplace. L'influence Line Damage Location (ILDL) est une approche complémentaire du SDDLV où l'angle entre les sous-espaces principaux est calculé et les dommages sont empiriquement localisés aux points près du zéro. L'approche développée pour la SDDLV est étendue à cette nouvelle approche, l'ILDL. Les méthodes proposées sont validées et appliquées avec succès pour la localisation de dommages dans des structures civilesMechanical systems under vibration excitation are prime candidate for being modeled by linear time invariant systems. Damage localization using both finite element information and modal parameters estimated from ambient vibration data collected from sensors is possible by the Stochastic Dynamic Damage Location Vector (SDDLV) approach, where the damage location is empirically related to positions where the stress is close to zero. The first contribution in this thesis shows how the uncertainty in the estimates of the state space system can be used to derive uncertainty bounds on the damage localization residuals to decide about the damage location with a hypothesis test using one chosen Laplace value. In the second contribution, the damage localization method is extended with a statistical framework and robustness of the localization information is achieved by aggregating results at different values in the Laplace domain. The Influence Line Damage Location (ILDL) is a complementary approach of the SDDLV where the subspace angle is computed and damage is empirically located at points near zero. The last contribution describes how robustness of the localization information is achieved by aggregating results at different values in the Laplace domain based on the previous two contributions. The proposed methods are validated and successfully applied to damage localization of several applications in civil structures
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MIGGIANO, RICCARDO. "Biochemical and structural studies of the Mycobacterium tuberculosis O6-Methylguanine Methyltransferase and mutated variants". Doctoral thesis, Università del Piemonte Orientale, 2014. http://hdl.handle.net/11579/41372.
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Wälchli, Chantal. "Structure and distribution of three novel collagenous proteins and of the alternatively spliced variants /". Zürich, 1994. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=10715.
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Yan, Haile. "Crystal structure, martensitic transformation crystallography, mechanical and magnetocaloric performance of Ni(Co)MnIn multifunctional alloys". Thesis, Université de Lorraine, 2016. http://www.theses.fr/2016LORR0105/document.
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Les alliages à base de Ni-Mn-In ont attiré une attention considérable en raison de leurs propriétés multifonctionnelles depuis leur découverte en 2004, telles que l’effet de mémoire de forme métamagnétique (Metamagnetic shape memory effect MMSME), l'effet magnétocalorique (MCE) et l'effet de magnétorésistance (MR). Cependant, certaines connaissances fondamentales sur ces alliages manquent toujours jusqu'à présent, telles que la structure cristalline de la martensite, les caractéristiques cristallographiques de microstructure et de transition magnétostructurale. Dans cette thèse, les caractéristiques cristallographiques, les comportements mécaniques et les propriétés magnétiques des alliages Ni-Mn-In base ont été étudiés théoriquement et expérimentalement. Tout d'abord, les structures cristallines des alliages Ni-Mn-In ont été déterminées avec précision par la méthode de Rietveld dans le cadre de la théorie du superespace. Ensuite, la microstructure de la martensite, notamment l'organisation et l'interface des variantes, ainsi que les caractéristiques cristallographiques de la transformation martensitique, telles que les relations d'orientation (OR), le chemin de déformation de la transformation et la compatibilité géométrique entre l'austénite et la martensite, ont été systématiquement étudiés. Enfin, avec cette connaissance fondamentale sur les alliages Ni-Mn-In, les comportements et les mécanismes de sélection /réarrangement des variantes de martensite sous deux types de stratégies de chargement mécanique, à savoir le chargement à l'état martensitique et le chargement durant la transition structurelle, et les effets du recuit sur l'effet MCE et les pertes d'hystérésis associées ont été explorées. Les principaux résultats sont les suivants. La martensite modulé a une structure cristalline incommensurable avec la structure cristalline 6M et le groupe de superespace I2/m(α0γ)00 qui peut être approximée par un modèle de superstructure de multiplicité 3 dans l'espace à tridimensionnel. La microstructure de martensite est en forme de plaques et auto-organisée en colonies. Chaque colonie a quatre variantes d'orientations distinctes. Le maximum de 6 colonies distinctes et 24 variantes peut être généré à l'intérieur d'un grain austénitique. Bien que jusqu'à 14 types de relations de maclage sont proposées dans le cadre des théories cristallographiques de transformation martensitique, seuls trois types de relations de maclage sont généralement observés, à savoir des macles de type I, type II et composées. Les interfaces des variantes sont définies à l'échelle mésoscopique par leur plan de maclage K1 correspondant. Cependant, à l'échelle atomique, la macle de type I a une interface cohérente, alors que celles de type-II et les macles composées ont des interfaces étagées. Les deux relations d'orientations K-S et Pitsch sont appropriés pour décrire la correspondance de réseau entre austénite et martensite dans les alliages Ni-Mn-In. Cependant, le chemin de déformation lié à la relation de Pitsch est mis en évidence pour être efficace pour la déformation de la structure. Avec le chemin de transformation déterminé, le mécanisme sous-jacent de l'organisation des variantes est révélé. À travers la transformation martensitique, en dépit de l'existence d'une relativement large couche contrainte (de l'ordre de 20 nm), le plan d'habitat est bordé par une variante de martensite simple avec l'austénite plutôt que la structure généralement observée "en sandwich", ce qui suggère une relativement bonne compatibilité géométrique entre les phases correspondantes. Pour le chargement en compression à l'état martensitique, l'arrangement des variantes est réalisé par des processus de démaclage. Il est démontré que l'état de variante unique dans certaines colonies pourrait être obtenu lorsque l'orientation de chargement est située dans la zone de Facteur de Schmid (SF) positif commune pour les trois systèmes de démaclage. [...]Ni-Mn-In based alloys have attracted considerable attention due to their multifunctional properties since its discovery in 2004, such as metamagnetic shape memory effect (MMSME), magnetocaloric effect (MCE) and magnetoresistance (MR) effect. However, some fundenmental knowledge on these alloys is still missing until now, such as crystal structure of martensite, crystallographic features of microstructure and magnetostructural transition. In this dissertation, the crystallographic features, mechanical behaviors and magnetic properties of Ni-Mn-In based alloys were studied theoretically and experimentally. First, the crystal structures of Ni-Mn-In alloys were accurately determined by Rietveld method in the frame of superspace theory (Chapter 3). Then, the microstructure of martensite (Chapter 4), such as variant organization and interface structure, and the crystallographic features of martensitic transformation, such as orientation relationship (OR), transformation strain path and geometrical compatibility between austenite and martensite, were systematically studied (Chapter 5). Finally, with this fundamental knowledge on Ni-Mn-In alloys, the behaviors and mechanisms of martensite variant rearrangement/ selection under two kinds of mechanical loading strategies, i.e. loading at martensite state and loading across the structural transition, and the effects of annealing on MCE and its related hysteresis loss were explored (Chapter 6). The main results are as follows. The modulated martensite has an incommensurate 6M crystal structure with superspace group I2/m(α0γ)00 that can be approximated by a three-fold superstructure model in the three-dimensional space. The microstructure of martensite is in plate shape and self-organized in colonies. Each colony has four distinct orientation variants. The maximum of 6 distinct colonies and 24 variants can be generated within one austenite grain. Although as many as 14 kinds of twin relations are suggested in the frame of crystallographic theories of martensitic transformation, only three types of twin relations are generally detected, i.e. type-I, type-II and compound twin. Variant interfaces are defined by their corresponding twinning plane K1 at mesoscopic scale. However, at atomic scale, the type-I twin has a coherent interface, whereas type-II and compound twins have “stepped” interfaces. Both the K-S and Pitsch ORs are appropriate to describe the lattice correspondence between austenite and martensite in Ni-Mn-In alloys. However, the strain path related to the Pitsch relation is evidenced to be the effective for the structural distortion. With the determined transformation path, the underlying mechanism of variant organization is revealed. Across the martensitic transformation, despite the existence of a relative wide stressed layer (around 20 nm), the habit plane is bordered by single martensite variant with austenite rather than the generally observed “sandwich-like” structure, implying a relative good geometrical compatibility between the corresponding phases. For compressive loading at martensite, variant arrangement is realized by the detwinning process. It is evidenced that a single variant state in some colonies can be obtained when the loading orientation is located in the common positive Schmid factor (SF) zone of the three detwinning systems. For loading across the structural transition, the prestrain is obtained by variant selection in which the number of colonies is significantly reduced and the variant organization within colony is greatly changed. The SF for transformation strain path is introduced to evaluate the possible selection of variants. Heat treatment can significantly enhance the magnetic entropy change ΔSM but simultaneously increase the magnetic hysteresis loss. For ΔSM, the chemical ordered degree should play a prominent role [...]
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Saleem, Fozia. "Structure/function analysis and hypoxic regulation of STREX variant BK channels". Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/25146.
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Hypoxia sensitivity of STREX has previously been shown to be dependent upon a cysteine motif (-CSC-) in the STREX insert that is also within a putative phosphorylation motif. This thesis thus had three main aims: 1) to develop a high throughput assay to allow discrimination of different BK channel splice variants and their modulation 2) to characterise the role of cysteine residues within the STREX exon that may determine hypoxia sensitivity of the channel, and finally 3) to examine the modulation of the hypoxia response by intracellular ATP. During the course of these experiments the monovalent ion lithium (Li+) was observed to robustly block the STREX response to hypoxia. Li+ shares physiochemical properties with the divalent magnesium (Mg2+) ion hence the role of Mg2+ in the STREX hypoxia response was also investigated. Mg2+ modulated the response in a similar fashion to ATP. In addition it was seen that Li+ and Mg2+ decreased the single channel conductance of STREX and ZERO variants, Mg2+ also increased STREX channel open probability. However, while Li+ and Mg2+ may share similar mechanisms/sites to modulate channel conductance the differential effect of Li+ and Mg2+ on the hypoxia response suggest Li+ acts via a site/mechanism distinct from that of Mg2+. Taken together, these data suggest that alternative pre-mRNA splicing is an important determinant of BK channel pharmacology and that cysteine and other residues within the STREX insert play a key role in function of the channel and its response to hypoxia.
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Chen, Yuh-Ing. "Nonparametric procedures for structured effects in analysis of variance /". The Ohio State University, 1989. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487671108307997.
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Manceur, Marc Ameur. "Separable variance-covariance structure: estimation, testing and environmental application". Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=110384.
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Multi-dimensional, univariate or multivariate datasets arise when one or several random variables are observed on a spatio-temporal domain. A parsimonious model is often used to facilitate the estimation of variance-covariance parameters. This is the case in particular with the matrix and tensor normal distribution models, which imply a simply and doubly separable variance-covariance structure, respectively. A separable variance-covariance matrix is the Kronecker product of two, three, or more component variance-covariance matrices, each representing variability and dependencies in one dimension (e.g. 1-D space and time; multivariate, 1-D space, and time; 3-D space and time). In this thesis, the focus is on parameter estimation by maximum likelihood (ML), the likelihood ratio test (LRT) of separability, and the application to an original dataset. First, the empirical bias of the ML estimator of a simply separable variance-covariance matrix is shown to follow a non-monotonic 'peak-trough' pattern with increasing sample size, a result apparently not conform to theory. This atypical pattern is explained by decomposing the ergodic (empirical) bias into an estimation bias and a fluctuation bias minus a non-orthogonality factor. Then, an unbiased modified LRT for simple separability of a variance-covariance structure, without or with modeling of the mean, is proposed. A penalty factor improves the chi-square distribution of the LRT statistic in finite samples, which represents a simpler and more general procedure to obtain a valid LRT of separability than existing methods. Thereafter, the tensor normal distribution model is presented in detail, with a decomposition of the bias of the ML estimator of a doubly separable variance-covariance matrix and an unbiased modified LRT for double separability. Finally, an original multi-dimensional dataset of wood density in trunk sections of white spruce (Picea glauca (Moench) Voss), as measured from computed tomography scanning data, is used to test and accept the hypothesis of double separability on the variance-covariance structure and to assess direction, height and year effects on mean wood density using modified analysis-of-variance F-tests based on Box's 'epsilon'.Les jeux de données multidimensionnels, univariés ou multivariés, se présentent lorsqu'une ou plusieurs variables aléatoires sont observées sur un domaine spatio-temporel. Un modèle parcimonieux est souvent utilisé pour faciliter l'estimation de la matrice de variance-covariance. C'est le cas en particulier des modèles de la matrice et du tenseur aléatoires normaux, qui impliquent une structure de variance-covariance simplement ou doublement séparable, respectivement. Une matrice de variance-covariance séparable est le produit de Kronecker de deux, trois, ou plus de matrices de variance-covariance, chacune représentant la variabilité et les dépendances dans une dimension (p. ex. espace 1-D et temps; plusieurs variables, espace 1-D, et temps; espace 3-D et temps). Dans cette thèse, le focus est sur l'estimation des paramètres par maximum de vraisemblance (MV), le test du rapport de vraisemblances (TRV), et l'application des modèles à un jeu de données original. Tout d'abord, il est montré que le biais empirique de l'estimateur MV d'une matrice de variance-covariance simplement séparable décroît de manière non-monotone en suivant un patron 'pic-creux' lorsque la taille d'échantillon augmente, un résultat non conforme à la théorie en apparence. Ce patron atypique est expliqué en décomposant le biais ergodique (empirique) en un biais d'estimation et un biais de fluctuation, moins un facteur de non-orthogonalité. Ensuite, un TRV modifié non-biaisé de séparabilité simple pour une structure de variance-covariance, sans ou avec modélisation de la moyenne, est proposé. Un facteur de pénalité améliore la distribution chi-deux de la statistique TRV en échantillons finis, ce qui représente une procédure plus simple et plus générale d'obtenir un TRV valide de séparabilité que les méthodes existantes. Par après, le modèle du tenseur aléatoire normal est présenté en détail, avec une décomposition du biais de l'estimateur MV d'une matrice de variance-covariance doublement séparable et un TRV modifié non-biaisé de séparabilité double. Enfin, un jeu de données multidimensionnel, fait de mesures de densité du bois obtenues à partir de données de tomodensitométrie pour des sections de troncs d'épinette blanche (Picea glauca (Moench) Voss), est utilisé pour tester et accepter l'hypothèse de séparabilité double de la matrice de variance-covariance et pour évaluer les effets de la direction, de la hauteur et de l'année sur la densité moyenne du bois à l'aide de tests F d'analyse de variance modifiés sur base du 'epsilon' de Box.
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Bönisch, Clemens [Verfasser], e Peter [Akademischer Betreuer] Becker. "Structure/function analyses of mammalian histone H2A and H3 variants / Clemens Bönisch. Betreuer: Peter Becker". München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2012. http://d-nb.info/1031879870/34.
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Louie, Gordon V. "Structural studies of wild-type and variant yeast iso-1-cytochromes c". Thesis, University of British Columbia, 1991. http://hdl.handle.net/2429/30997.
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The crystal structure of yeast (Saccharomyces cerevisiae) iso-1- cytochrome c has been determined through molecular replacement techniques, and refined against X-ray diffraction data in the resolution range 6.0-1.23 Å to a crystallographic R-factor of 0.192. The yeast iso-1-cytochrome c molecule has the typical cytochrome c fold, with the polypeptide chain organized into five α-helices and a series of loops which serve to enclose almost completely the heme prosthetic group within a hydrophobic pocket Comparison of the structures of yeast iso-1-, tuna and rice cytochromes c shows that the polypeptide backbone fold, intramolecular hydrogen bonding, conformation of side chains and particularly packing within the heme crevice of protein groups against the heme moiety are very similar in the three proteins. Significant structural differences among the three cytochromes c can be explained by differences in amino acid sequence.
X-ray crystallographic techniques have also been used to study the effect of single-site amino acid substitutions at Phe82 and at Arg38 in iso-1-cytochrome c. The structures of the various variant iso-1-cytochromes c have been determined at nominal resolutions in the range 2.8 to 1.76 Å. Conspicuous structural perturbations in the neighborhood of the substituted side chain are evident in all of the variant proteins. In wild-type iso-1-cytochrome c, the phenyl ring of Phe82 is positioned adjacent and approximately parallel to the heme group, and occupies a non-polar cavity within the heme crevice. In the Ser82 variant, a channel extending from the surface of the molecule down into the heme crevice is created. In the Gly82 variant, the polypeptide backbone has refolded into the space formerly occupied by the phenyl ring of Phe82. Steric conflicts prevent both the phenolic ring of Tyr82 and the side chain of Ile82 from being completely accommodated within the pocket normally occupied by a phenyl ring. Substitution of alanine at position 38 causes a slight reorganization of the hydrogen bonding network in which Arg38 normally participates, and also exposes to external solvent a normally buried propionic acid group of the heme.
The altered functional properties of the position 82 variant proteins have been interpreted with respect to the observed structural perturbations. The drop in reduction potential, most notably for the Ser82 and Gly82 variants, can be explained by the elevated heme environment polarity arising from the increased access of solvent or polar protein groups to the heme pocket The reduced stability of the heme crevice, as indicated by lowered pKa's for alkaline isomerization, is likely due to the disruption of stabilizing packing forces formed by the Phe82 phenyl ring within its hydrophobic cavity. The lowered activity, in comparison to the wild-type protein and the Tyr82 variant, for electron transfer with Zn+-cytochrome c peroxidase is attributed to the loss of an aromatic group positioned adjacent to the heme group. The altered surface topography of the variant proteins (particularly the Gly82, Tyr82 and Ile82 variants) may further hinder productive complex formation between cytochrome c and its redox partners. These results suggest that the invariant Phe82 contributes in at least three ways to the proper functioning of cytochrome c. It has an important structural role in maintaining the integrity of the heme crevice and in establishing the appropriate heme environment The phenyl ring of Phe82 may also be required for efficient movement of an electron to and from the heme of cytochrome c. Finally, Phe82 may have a role in forming intermolecular interactions with enzymic redox partners of cytochrome c.Medicine, Faculty of
Biochemistry and Molecular Biology, Department of
Graduate
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Trappe, Kathrin [Verfasser]. "Computational Methods for Integrative Structural Variant Analysis Across Species Boundaries / Kathrin Trappe". Berlin : Freie Universität Berlin, 2018. http://d-nb.info/1176705679/34.
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Iraola, Guzmán Susana. "AnáIisis de la herencia epigenética en trastornos neurológicos". Doctoral thesis, Universitat de Barcelona, 2012. http://hdl.handle.net/10803/101096.
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Las enfermedades neurodegenerativas, como la enfermedad de Alzheimer (EA) y la enfermedad de Parkinson (EP), representan un grave problema de salud pública, sobre todo en los países occidentales, donde el envejecimiento creciente de la población augura un incremento sustancial de la prevalencia de estas patologías. A pesar de que ciertos tratamientos proporcionan una disminución de las manifestaciones clínicas, el avance del proceso neurodegenerativo es irreversible. La identificación de los mecanismos, como la interacción entre factores genéticos y medio-ambientales, implicados en la etiología y evolución de estas patologías es de importancia capital. En el presente trabajo de tesis se explora el papel de la metilación del ADN genómico y el mosaicismo genético en enfermedades neurodegenerativas. El análisis del perfil de metilación del ADN se realizó empleando dos arrays de metilación: “HumanMethylation” (27K y 450K, IlIumina), cuyas sondas distribuidas estratégicamente por todo el genoma, permiten detectar cuantitativamente el estado de mutilación de unos 27.000 y 450.000 dinucleótidos CpG, respectivamente. La comparación de un total de 60 individuos (28 con enfermedad de Alzheimer, 3 con enfermedad de Parkinson y 29 controles) ha permitido identificar el perfil de metilación del genoma de distintas áreas del sistema nervioso central (SNC) (corteza, amígdala, hipocampo, hipotálamo, protuberancia, sustancia negra y cerebelo), mostrando la existencia de un patrón diferencial entre hombres y mujeres, asociado a la inactivación del cromosoma X, un patrón independiente para cerebelo, y un patrón de metilación de un conjunto de dianas característico de los estadíos 3 y 4 de Braak de la EA. Asimismo, se observaron diferencias significativas de metilación (1.112 CpGs, p<0,0l) en el cerebelo asociadas a la EA, confirmando su implicación en la enfermedad. El análisis del mosaicismo somático del cerebro se realizó empleando el "SurePrint G3 human CGH array 400K" (Agilent). Tomando como área de referencia el cerebelo se detectaron ganancias o pérdidas de material genómico entre áreas del cerebro de un mismo individuo. Dos muestras de corteza, pertenecientes a dos controles, presentaron una ganancia de material genómico en el gen WWOX, mientras que tan solo una muestra mostró una ganancia de material genómico en el gen ADAM5P3A. La elevada frecuencia de variantes en el número de copia en WWOX y su posible implicación en EA llevó a genotipar un mayor número de individuos, aunque ninguno mostró mosaicismo somático. El análisis del estado de metilación de las sondas ubicadas en WWOX permitió observar una disminución significativa de la metilación entre pacientes y controles en 14 sondas (T-student, p<0,05), sugiriendo que la regulación epigenética de WWOX puede estar alterada en la EA. En conjunto, estos resultados muestran la alteración de los perfiles de mutilación del SNC en relación con la EA tardía (estadíos 3 y 4 de Braak). Principalmente, en una de las regiones cuya afectación patológica en la EA ha sido más controvertida, cerebelo. Es especialmente interesante remarcar que la aparición de las lesiones características de cerebelo tienen lugar en estadíos más avanzados, indicando la posibilidad de que la alteraciones epigenéticas observadas podrían corresponder a un evento prematuro en la progresión de la patología.Neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD), represent a major issue of public health in developing countries where the aging of the population is leading to a progressive increase of its prevalence rates. Currently, several therapeutic strategies help to palliate clinical symptoms, but the neurodegeneration is progressive and irreversible. Identification of underlying mechanisms leading to these disorders is essential to improve patient's life expectancy and quality. In this context, many efforts have been focused on identifying genetics and environment causes of these disorders with little success, highlighting the need to evaluate new mechanisms and factors involved. The present thesis project has explored the implication of new mechanisms, such as DNA methylation and somatic mosaicism in AD and PD. The analysis of DNA methylation was performed with a new methylation array technology: 'HumanMethylation' (27K and 450K, IlIumina), whose probes strategically distributed along the human genome, enables to quantify the methylation state of around 27,000 and 450,000 CpG sites, respectively. The pattern of methylation of 60 subjects (28 AD, 3 PD and 29 unaffected) with four to seven brain regions (cortex, amygdala, hippocampus, hypothalamus, pons, substantia nigra and cerebellum) has been assessed. The study has shown three ma in clusters depending on gender (female/male), brain area (cerebellum vs others) and disease stage (AD3 vs AD4). In addition, a' differential analysis performed in individual CpG sites proved the presence of significant differences associated to AD patient's cerebellum (1112 CpG sites, p<0.01). Somatic mosaicism analysis has been carried out with a 'SurePrint G3 human CGH array 400K' (Agilent) to detect intra-individual genomic gains and losses compared to cerebellum. A total of two cortex samples showed a genomic gain in the WWOX gene, whereas only one sample showed a gain on ADAM5P3A. WWOX has been considered as a potential candidate gene in previous AD studies, and was further analyzed in a larger cohort of human brain samples. Genotyping assays did not confirm the presence of new somatic mosaicism cases, but it was possible to determine the genotype distribution and compared data between samples. A significant hypomethylation of the WWOX promoter region was observed in AD patients compared to controls subjects (T-test, p<0.05) in 14 probes, suggesting a potential regulation of expression by methylation. Overall, these results highlight the implication of epigenetic mechanisms in neurodegenerative disorders, as AD. In particular, it is remarkable the specific pattern of methylation in the cerebellum in intermediate stages of AD, suggesting an overlap with early modifications, which could contribute to unraveling new mechanisms implicated in AD.
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Flatt, Joanna Frances. "A study of human erythrocyte membrane structure and function using variant erythrocytes". Thesis, University of Bristol, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.560498.
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Human erythrocytes are highly specialised cells boasting numerous features to maximise gas carriage, exchange and delivery around the body. The role of the highly proteinaceous red cell membrane in these processes is vital. Some membrane proteins such as the Rh-associated glycoprotein (RhAG) and aquaporin-1 (AQP1) are postulated to form gas channels, and disorders affecting membrane proteins can have extensive effects on normal red cell function. In this work, the role and interactions of Rh proteins are probed using rare variant Rh-deficient erythrocytes. The RhCE polypeptide is required for normal expression of other members of the Rh complex. Lack of RhCE is associated with depressed expression of CD44, an adhesion molecule, and may alter expression of proteins involved in complement such as decay acceleration factor and Iymphocyte function-associated antigen 3. Absence of RhAG prevents Rh complex expression and is found to affect band 3 macrocomplex proteins GPA and protein 4.2, highlighting the important role for RhAG in the macrocomplex. AQP1 is increased in the absence of RhAG, which supports the hypothesis that they share similar functions. The hereditary stomatocytoses are disorders that affect the ion permeability of red cell membranes. This work comprises a study of the pleiotropic disorder stomatin-deficient cryohydrocytosis (sdCHC), which is caused by mutations in the red cell glucose transporter, glut1. The mutant proteins show minimal glucose transport and increased permeability to cations when expressed heterologously in Xenopus laevis oocytes - consistent with the disease phenotype. sdCHC erythrocytes have very reduced amounts of stomatin, a monotopic membrane protein, a feature shared by other very leaky red cells. This is accompanied by a concomitant increase in stomatin-like protein 2, whose function in red cells is currently unknown. The fates of stomatin proteins in normal and leaky cells are investigated throughout erythropoiesis and found to differ between cation-leaky phenotypes.