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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
41

Rôle de l'isoforme p35 de la chaîne invariante humaine dans la formation et le transport de complexes de CMH II

Gauthier, Catherine 08 1900 (has links)
La présentation antigénique par les molécules de classe II du complexe majeur d’histocompatibilité (CMH II) est un mécanisme essentiel au contrôle des pathogènes par le système immunitaire. Le CMH II humain existe en trois isotypes, HLA-DP, DQ et DR, tous des hétérodimères composés d’une chaîne α et d’une chaîne β. Le CMH II est entre autres exprimé à la surface des cellules présentatrices d’antigènes (APCs) et des cellules épithéliales activées et a pour fonction de présenter des peptides d’origine exogène aux lymphocytes T CD4+. L’oligomérisation et le trafic intracellulaire du CMH II sont largement facilités par une chaperone, la chaîne invariante (Ii). Il s’agit d’une protéine non-polymorphique de type II. Après sa biosynthèse dans le réticulum endoplasmique (ER), Ii hétéro- ou homotrimérise, puis interagit via sa région CLIP avec le CMH II pour former un complexe αβIi. Le complexe sort du ER pour entamer son chemin vers différents compartiments et la surface cellulaire. Chez l’homme, quatre isoformes d’Ii sont répertoriées : p33, p35, p41 et p43. Les deux isoformes exprimées de manière prédominante, Iip33 et p35, diffèrent par une extension N-terminale de 16 acides aminés portée par Iip35. Cette extension présente un motif de rétention au réticulum endoplasmique (ERM) composé des résidus RXR. Ce motif doit être masqué par la chaîne β du CMH II pour permettre au complexe de quitter le ER. Notre groupe s’est intéressé au mécanisme du masquage et au mode de sortie du ER des complexes αβIi. Nous montrons ici que l’interaction directe, ou en cis, entre la chaîne β du CMH II et Iip35 dans une structure αβIi est essentielle pour sa sortie du ER, promouvant la formation de structures de haut niveau de complexité. Par ailleurs, nous démontrons que NleA, un facteur de virulence bactérien, permet d’altérer le trafic de complexes αβIi comportant Iip35. Ce phénotype est médié par l’interaction entre p35 et les sous-unités de COPII. Bref, Iip35 joue un rôle central dans la formation des complexes αβIi et leur transport hors du ER. Ceci fait d’Iip35 un régulateur clef de la présentation antigénique par le CMH II. / Antigen presentation by the major histocompatibility complex class II molecules (MHCII) is a pathway essential to the immune system control over pathogens. There are three MHCII isotypes in humans, which are HLA-DP, DQ and DR. These are all heterodimers made of an α and a β chain. MHCII is expressed at the cell surface of antigen presenting cells (APCs) and activated epithelial cells and its role is mainly to present peptides of exogenous origin to CD4+ T lymphocytes. MHCII oligomerization and trafficking are largely favored by its chaperone, the invariant chain (Ii). Ii is a non-polymorphic type II protein. It hetero- or homotrimerizes right after biosynthesis in the endoplasmic reticulum (ER), and then its CLIP region interacts with MCHII to form a αβIi structure. This multimer exits the ER and starts its journey towards numerous compartments and the cell surface. Humans have four Ii isoforms: p33, p35, p41 et p43. The two most predominantly expressed are Ii p33 and p35. They differ in a N-terminal extension long of 16 amino acids that is displayed by Iip35. This extension bears an ER retention motif (ERM) made of the RXR residues. The RXR motif must be masked by the MHCII β chain in order for the αβIi multimer to exit the ER. Our group investigated the masking and ER exit mechanisms of the αβIi structures. Here we show that a direct (cis) interaction between the MHCII β chain and Iip35 is essential for ER exit, thus promoting the formation of high order αβIi structures. Moreover, we demonstrate that the bacterial virulence factor NleA impairs the trafficking of Iip35-containing αβIi multimers. This observation is mediated by an interaction between COPII subunits and Iip35. Altogether, Iip35 plays a crucial role in the αβIi multimer formation and ER exit. Iip35 is therefore a key regulator for MHCII antigen presentation.
42

The Role of Six1 in Transcriptional Regulation during Myogenesis

Liu, Yubing January 2017 (has links)
Skeletal myogenesis is under the control of a combinatorial network of transcription factors. It has been shown that the homeobox protein Six1 is required for embryonic myogenesis. Using functional genomics approaches, I determined that Six1 is required for myoblasts differentiation through direct binding to a cluster of genes that are related to muscle function and muscle structure during my Master’s studies. However, it was still not fully understood how Six1 selects its genomic targets and whether Six1 regulates the expression of Myod directly. I devoted my PhD work to study three central aspects of Six1 function: through what DNA motif it binds to DNA, how it regulates the expression of the myogenic regulatory factor MyoD, and how it might regulate chromatin structure at the enhancer regions of muscle genes. A more degenerate MEF3-like DNA sequence consensus has been identified from Six1 ChIP-on-chip experiments. This MEF3 motif was further optimized using bioinformatic methods and was proved to discover Six1 binding sites with improved specificity and sensitivity. Myod, a member of myogenic regulatory factors (MRFs), is a master regulator in the myogenic lineage. Multiple MEF3 sites were identified on the regulatory regions of Myod, including two MEF3 sites within its core enhancer region (CER). Six1 was able to bind to the CER directly through these two MEF3 sites and regulated the Myod expression in cultured primary myoblasts. Previous work has suggested that the CER is also bound by Myod in myoblasts. I demonstrated that the binding of Myod to the CER depended on the presence of Six1. Six1 was also involved in maintaining a relatively ‘open’ chromatin structure at the CER, suggesting that Six1 may play a direct or indirect role in chromatin remodeling. During my Master’s studies, I demonstrated a synergistic regulation by the Six and MRF families. This synergistic function gains potential importance by the fact that ~25% of Six1 genomic targets are also bound by Myod. I decided to study whether the co-occupancy of Six1 and Myod was essential to maintain the proper global chromatin structure at these loci. Six1 and Myod co-bound genomic regions correlated with more accessible chromatin, which was detected by the formaldehyde-assisted isolation of regulatory elements (FAIRE) assay followed by DNA deep sequencing (FAIRE-seq). When combined with small interfering RNA-mediated gene knockdown of Six1 or Myod, FAIRE-seq data suggested that Six1, but not Myod, was involved in regulating the chromatin accessibility at these co-bound DNA loci. To shed light on the mechanism by which Six1 functions, proteomics approaches were used and revealed that proteins involved in “regulation of transcription” and “chromatin organization” were enriched among Six1-bound proteins. Cdk9 and its partner cyclin T have been shown to stimulate gene expression by releasing RNA polymerase II from transcriptional pause, but they can also function at gene enhancers. I determined that Six1 and Cdk9 participated in the same protein complex, and that the Cdk9 activity appeared to mediate the effect of Six1 on the chromatin accessibility at the CER to regulate the Myod expression. Taken together, these results demonstrate that Six1 regulates the expression of Myod through its direct binding on the CER which facilitates transcriptional elongation.
43

Analysis, expression profiling and characterization of hsa-miR-5698 target genes as putative dynamic network biomarkers for prostate cancer: a combined in silico and molecular approach

Lombe, Chipampe Patricia January 2019 (has links)
Philosophiae Doctor - PhD / 2018, the International Agency for Research on Cancer (IARC) estimated that prostate cancer (PCa) was the second leading cause of death in males worldwide. The number of deaths are expected to raise by 50 % in the next decade. This rise is attributed to the shortcomings of the current diagnostic, prognostic, and therapeutic biomarkers used in the management of the disease. Therefore, research into more sensitive, specific and effective biomarkers is a requirement. The use of biomarkers in PCa diagnosis and management takes advantage of the genetic alterations and abnormalities that characterise the disease. In this regard, a microRNA, hsa-miR-5698 was identified in a previous study as a differentiating biomarker between prostate adenocarcinoma and bone metastasis. Six putative translational targets (CDKN1A, CTNND1, FOXC1, LRP8, ELK1 and BIRC2) of this microRNA were discovered using in silico approaches. The aim of this study was to analyse via expression profiling and characterization, the target genes of hsa-miR-5698 in order to determine their ability to act as putative dynamic network biomarkers for PCa. The study was conducted using a combined in silico and molecular approach. The in silico part of the study investigated the putative transcriptional effects of hsa-miR-5698 on the promotors of its translational targets, the correlation between hsa-miR-5698 and mRNA expression profiles as well as the co-expression analysis, pathway analysis and prognostic ability of the target genes. A number of computational software were employed for these purposes, including, R Studio, Trident algorithm, STRING, KEGG, MEME Suite, SurvExpress and ProGgene. The molecular part of the study involved expression profiling of the genes in two PCa cell line LNCaP and PC3 via qPCR.
44

Extraction de motifs séquentiels dans les flux de données

Marascu, Alice 14 September 2009 (has links) (PDF)
Ces dernières années ont vu apparaître de nombreuses applications traitant des données générées en continu et à de grandes vitesses. Ces données sont désormais connues sous le nom de flux de données. Leurs quantités de données potentiellement infinies ainsi que les contraintes qui en dérivent posent de nombreux problèmes de traitement. Parmi ces contraintes, citons par exemple l'impossibilité de bloquer un flux de données, ou encore le besoin de produire des résultats en temps réel. Néanmoins, les multiples domaines d'application de ces traitements (comme les transactions bancaires, l'usage du Web, la surveillance des réseaux, etc) ont suscité beaucoup d'intérêt tant dans les milieux industriels qu'académiques. Ces quantités potentiellement infinies de données interdisent tout espoir de stockage complet ; toutefois, on a besoin de pouvoir interroger l'historique des flux. Cela a conduit au compromis des « résumés » des flux de données et des résultats « approximatifs ». Aujourd'hui, un grand nombre de méthodes propose différents types de résumés des flux de données. Mais le développement incessant de la technologie et des applications afférentes demande un développement au moins équivalent des méthodes d'analyse et de résumé. De plus, l'extraction de motifs séquentiels y est encore peu étudiée: au commencement de cette thèse, il n'existait aucune méthode d'extraction de motifs séquentiels dans les flux de données. Motivés par ce contexte, nous nous sommes intéressés à une méthode qui résume les flux de données d'une manière efficace et fiable et qui permet principalement d'en extraire des motifs séquentiels. Dans cette thèse, nous proposons l'approche CLARA (CLAssification, Résumés et Anomalies). CLARA permet d'obtenir des clusters à partir d'un flux de séquences d'itemsets, de calculer et gérer des résumés de ces clusters et d'y détecter des anomalies. Les différentes contributions détaillées dans ce mémoire concernent: - La classification non supervisée de séquences d'itemsets sous forme de flux. A notre connaissance, cette technique est la première à permettre une telle classification. - Les résumés de flux de données à l'aide de l'extraction de motifs. Les résumés de CLARA sont composés de motifs séquentiels alignés représentant les clusters associés à leur historique dans le flux. L'ensemble de ces motifs permet de résumer le flux de manière fiable à un instant t. La gestion de l'historique de ces motifs est un point essentiel dans l'analyse des flux. CLARA introduit une nouvelle gestion de la granularité temporelle afin d'optimiser cet historique. - La détection d'anomalies. Cette détection, quand elle concerne les flux, doit être rapide et fiable. En particulier, les contraintes liées aux flux interdisent de consulter l'utilisateur final pour ajuster des paramètres (une anomalie détectée trop tard peut avoir de graves conséquences). Avec CLARA, cette détection est automatique et auto-adaptative. Nous proposerons également un cas d'étude sur des données réelles, réalisé en collaboration avec Orange Labs.
45

Homing Endonucleases and Horizontal Gene Transfer in Bacteria and Bacteriophages

Nord, David January 2007 (has links)
<p>Homing endonuclease genes (HEGs) are selfish genetic elements that mediate their own super-Mendelian inheritance. This is mediated by the homing endonuclease cleavage of a HEG<sup>- </sup>allele followed by recombination-repair with a HEG<sup>+</sup> allele.</p><p>The majority of the HEGs are encoded in intervening sequences (IVSs). The insertion of the IVS interrupts the endonuclease recognition site, making the genome with the IVS resistant to further cleavage by homing endonucleases with specificity for that particular sequence, but susceptible for homing endonucleases with a target not affected by the IVS insert. In 39 studied strains of the <i>Bacillus cereus</i> group, 28 IVSs were found in the <i>nrdIEF</i> operon. Phylogenetic studies of these sequences showed a scattered distribution of the IVSs, indicating a frequent horizontal gene transfer and that there might be competition between the different IVSs in the <i>nrdIEF</i> operon in the <i>Bacillaceae</i> family. One novel group I intron was shown to encode a functional homing endonuclease with a GIY-(X)<sub>8</sub>-YIG motif, expanding the family motif to GIY-(X)<sub>8</sub>-<sub>11</sub>-YIG. Interestingly, by studying the known insertion sites for IVSs in the ribonuclotide reductase genes, we show that the majority of the insertions are at conserved motifs, indicating that conservation is important for IVS survival.</p><p>Most freestanding HEGs in bacteriophage T4 cleave both HEG<sup>+</sup> and HEG<sup>-</sup> alleles, possibly providing a competitive advantage for the host organism when two phages infect the same bacterium. Two novel freestanding HEGs replace two putative HEGs in T4 in some T-even-like phages. The characterisation of these HEGs showed that both cleave double stranded DNA. SegH was shown to promote homing of its gene. Hef showed no homing, possibly due to general exclusion of other phages. The <i>mobE</i> putative HEG was shown to be homing proficient and showed strong general DNA degradation when expressed in <i>Escherichia coli.</i></p>
46

Homing Endonucleases and Horizontal Gene Transfer in Bacteria and Bacteriophages

Nord, David January 2007 (has links)
Homing endonuclease genes (HEGs) are selfish genetic elements that mediate their own super-Mendelian inheritance. This is mediated by the homing endonuclease cleavage of a HEG- allele followed by recombination-repair with a HEG+ allele. The majority of the HEGs are encoded in intervening sequences (IVSs). The insertion of the IVS interrupts the endonuclease recognition site, making the genome with the IVS resistant to further cleavage by homing endonucleases with specificity for that particular sequence, but susceptible for homing endonucleases with a target not affected by the IVS insert. In 39 studied strains of the Bacillus cereus group, 28 IVSs were found in the nrdIEF operon. Phylogenetic studies of these sequences showed a scattered distribution of the IVSs, indicating a frequent horizontal gene transfer and that there might be competition between the different IVSs in the nrdIEF operon in the Bacillaceae family. One novel group I intron was shown to encode a functional homing endonuclease with a GIY-(X)8-YIG motif, expanding the family motif to GIY-(X)8-11-YIG. Interestingly, by studying the known insertion sites for IVSs in the ribonuclotide reductase genes, we show that the majority of the insertions are at conserved motifs, indicating that conservation is important for IVS survival. Most freestanding HEGs in bacteriophage T4 cleave both HEG+ and HEG- alleles, possibly providing a competitive advantage for the host organism when two phages infect the same bacterium. Two novel freestanding HEGs replace two putative HEGs in T4 in some T-even-like phages. The characterisation of these HEGs showed that both cleave double stranded DNA. SegH was shown to promote homing of its gene. Hef showed no homing, possibly due to general exclusion of other phages. The mobE putative HEG was shown to be homing proficient and showed strong general DNA degradation when expressed in Escherichia coli.
47

Motif Finding in Biological Sequences

Liao, Ying-Jer 21 August 2003 (has links)
A huge number of genomic information, including protein and DNA sequences, is generated by the human genome project. Deciphering these sequences and detecting local residue patterns of multiple sequences are very difficult. One of the ways to decipher these biological sequences is to detect local residue patterns from them. However, detecting unknown patterns from multiple sequences is still very difficult. In this thesis, we propose an algorithm, based on the Gibbs sampler method, for identifying local consensus patterns (motifs) in monomolecular sequences. We first designed an ACO (ant colony optimization) algorithm to find a good initial solution and a set of better candidate positions for revising the motif. Then the Gibbs sampler method is applied with these better candidate positions as the input. The required time for finding motifs using our algorithm is reduced drastically. It takes only 20 % of time of the Gibbs sampler method and it maintains the comparable quality.
48

The Role of ERK2 in Regulating Epithelial-Mesenchymal Transition

Ilter, Didem January 2014 (has links)
Epithelial-mesenchymal transition (EMT) is a fundamental developmental program, which is believed to be reactivated during the progression of in situ carcinoma to aggressive metastatic cancers. Ras-ERK pathway has been shown to play a crucial role in EMT. We have previously shown that ERK2, but not ERK1, is necessary for RasV12-induced EMT and overexpression of ERK2 is sufficient to promote EMT. ERK2 promotes EMT by regulating several factors, including the upregulation of transcription factors ZEB1/2. ZEB1/2 repress expression of E-cadherin, which is necessary for polar epithelial tissue formations.
49

Using C-Alpha Geometry to Describe Protein Secondary Structure and Motifs

Williams, Christopher Joseph January 2015 (has links)
<p>X-ray crystallography 3D atomic models are used in a variety of research areas to understand and manipulate protein structure. Research and application are dependent on the quality of the models. Low-resolution experimental data is a common problem in crystallography which makes solving structures and producing the reliable models that many scientists depend on difficult.</p><p>In this work, I develop new, automated tools for validation and correction of low-resolution structures. These tools are gathered under the name CaBLAM, for C-alpha Based Low-resolution Annotation Method. CaBLAM uses a unique, C-alpha-geometry-based parameter space to identify outliers in protein backbone geometry, and to identify secondary structure that may be masked by modeling errors.</p><p>CaBLAM was developed in the Python programming language as part of the Phenix crystallography suite and the open CCTBX Project. It makes use of architecture and methods available in the CCTBX toolbox. Quality-filtered databases of high-resolution protein structures, especially the Top8000, were used to construct contours of expected protein behavior for CaBLAM. CaBLAM has also been integrated into the codebase for the Richardson Lab's online MolProbity validation service.</p><p>CaBLAM succeeds in providing useful validation feedback for protein structures in the 2.5-4.0A resolution range. This success demonstrates the relative reliability of the C-alpha; trace of a protein in this resolution range. Full mainchain information can be extrapolated from the C-alpha; trace, especially for regular secondary structure elements.</p><p>CaBLAM has also informed our approach to validation for low-resolution structures. Moderation of feedback, to reduce validation overload and to focus user attention on modeling errors that are both significant and correctable, is one of our goals. CaBLAM and the related methods that have grown around it demonstrate the progress towards this goal.</p> / Dissertation
50

Characterization and Molecular Targeting of the Bcl-2 i-Motif for Modulation of Gene Expression and Induction of Chemosensitivity in Lymphoma

Kendrick, Samantha Lynn January 2010 (has links)
The nature of DNA has captivated scientists for more than fifty years. The discovery of the double-helix model of DNA by Watson and Crick in 1953 not only established the primary structure of DNA, but also provided the mechanism behind DNA function. Since then, the demonstration of DNA secondary structure formation has allowed for the proposal that the dynamics of DNA itself can function to modulate transcription. We demonstrate for the first time the i-motif DNA secondary structure formed from an element within the Bcl-2 promoter region has potential to serve as a cellular molecular target for modulation of gene expression. Unlike typical oncogenes, Bcl-2 acts by promoting cellular survival rather than increasing cellular proliferation. The over-expression of Bcl-2, most notably in lymphomas, has been associated with the development of chemoresistance.Transcriptional regulation of Bcl-2 is highly complex and a guanine- and cytosine-rich (GC-rich) region directly upstream of the P1 site has been shown to be integral to Bcl-2 promoter activity. We have demonstrated that the C-rich strand is capable of forming an intramolecular i-motif DNA secondary structure with a transition pH of 6.6 and a predominant 8:5:7 loop using mutational studies coupled with circular dichroic spectra and thermal stability analyses. In addition, a novel assay involving the sequential incorporation of a fluorescent thymine analog at each thymine position provided evidence of a capping structure within the top loop region of the i-motif. Two different classes of steroids either stabilize or destabilize the i-motif structure and this differential interaction results in the activation or repression of Bcl-2 expression. The i-motif stabilizing steroid significantly up-regulated Bcl-2 gene and protein expression in BJAB Burkitt's lymphoma cells while the destabilizing steroid down-regulated Bcl-2 expression in B95.8 Burkitt's and Granta-519 mantle cell lymphoma cells, as well as in a SCID mouse lymphoma model. More importantly, the down-regulation of Bcl-2 led to chemosensitization of etoposide-resistant lymphoma cells demonstrating that Bcl-2 i-motif interactive small molecules can act as chemosensitizing agents. Conversely, compounds that up-regulate Bcl-2 by stabilization of the i-motif have potential for use as neuroprotective agents.

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