Alternative splicing provides the cell the ability to generate, from a single gene, multiple protein isoforms, sometimes with different or even antagonistic functions. This process is tightly regulated and alterations in the accurate balance of alternatively spliced mRNAs are a common cause of disease. The main objective of this thesis has been to understand the molecular mechanisms underlying disease-causing defective splicing. Skipping of Fas death receptor exon 6 leads to decreased Fas-ligand induced apoptosis. We have studied how this event is promoted by a mutation at the 3’ splice site and by the proto-oncogene SF2, leading to Autoimmune Lymphoproliferative Syndrome and possibly contributing to tumor progression, respectively. Moreover, we have determined the mechanism by which an antitumor drug, Spliceostatin A, alters 3’ splice site recognition and affects alternative splicing. This thesis underscores the importance of pre-mRNA splicing in disease and how the study of disease-causing aberrant splicing can be used as a tool to understand splicing mechanisms and vice versa. / El processament alternatiu del pre-ARNm proporciona a la cèl•lula l’habilitat de generar, a partir d’un únic gen, proteïnes amb funcions diferents i, fins i tot, antagòniques. Aquest procés està altament regulat i desequilibris en l’abundància de les diferent isoformes són causes comunes de malaltia. L’objectiu principal d’aquesta tesi ha estat entendre el mecanisme molecular a través del qual problemes en el processament del pre-ARNm causen malalties. L’exclusió de l’exó 6 del receptor de mort cel•lular Fas condueix a una disminució de l’apoptosi en resposta al lligand de Fas. Hem estudiat com una mutació al lloc de processament 3’ d’aquest exó i el proto-oncogén SF2 promouen aquest patró, causant el síndrome autoimmune lifoproliferatiu i possiblement contribuint a la progressió tumorogènica, respectivament. A més, hem estudiat el mecanisme pel qual la droga antitumoral Spliceostatin A altera el reconeixement del lloc de processament 3’ i causa canvis en el processament alternatiu de diversos gens. Aquesta tesi posa en evidència la importancia del processament del pre-ARNm en malalties i com l’estudi de mutacions que alteren aquest procés i són causa de malaties pot ser utilitzat con una eina per entendre el mecanisme d’aquest processament i viceversa.

This exegesis examines the landscape of heaven depicted in the contemporary novel, The Lovely Bones by Alice Sebold. I examine the various characteristics of the heaven (or 'afterlife') depicted in Sebold's novel, with the aim of ascertaining the narrative effects of using this device. Using Ingrid Daemmrich's analysis of the paradisiacal motif in literature as a framework (Daemmrich, I 1997, Studies on Themes and Motifs in Literature: Enigmatic Bliss, The Paradise Motif in Literature, Peter Lang, New York), I reveal characteristics in The Lovely Bones that are both consistent with and challenge traditional literary representations of heaven and which therefore demonstrate that the text utilises the established literary motif of heaven for symbolism and meaning, but in a contemporary context. I explore the growing trend of contemporary literary heavens by reviewing two other literary heavens that are relevant to this scholarship. I examine where as writers and readers, we ascertain our concept of heaven (in society's religious foundations and from prior literature), and for the relevance of the key text, I briefly discuss the author's likely cultural influences. Having established the novel's lack of alignment with a religious version of heaven, I then examine the nature of and the narrative effect of, the personalised heaven depicted in the novel, The Lovely Bones. In doing so, I explore one of the new portraits of heaven in literature, an example which represents a growing trend away from portraying a classic edenic heaven shared by all humanity (and traditional to literary representations of heaven), toward a contemporary, personalised heaven that seeks to meet the wants and desires of the individual in our modern society. With reference to literature's ability to reflect back to us, our society's beliefs and values, I examine what this new portrait of heaven reveals about society. Access to the project examined in conjunction with this exegesis has been restricted due to copyright.

abstract: Telomerase is a special reverse transcriptase that extends the linear chromosome termini in eukaryotes. Telomerase is also a unique ribonucleoprotein complex which is composed of the protein component called Telomerase Reverse Transcriptase (TERT) and a telomerase RNA component (TR). The enzyme from most vertebrate species is able to utilize a short template sequence within TR to synthesize a long stretch of telomeric DNA, an ability termed "repeat addition processivity". By using human telomerase reconstituted both in vitro (Rabbit Reticulocyte Lysate) and in vivo (293FT cells), I have demonstrated that a conserved motif in the reverse transcriptase domain of the telomerase protein is crucial for telomerase repeat addition processivity and rate. Furthermore, I have designed a "template-free" telomerase to show that RNA/DNA duplex binding is a critical step for telomere repeat synthesis. In an attempt to expand the understanding of vertebrate telomerase, I have studied RNA-protein interactions of telomerase from teleost fish. The teleost fish telomerase RNA (TR) is by far the smallest vertebrate TR identified, providing a valuable model for structural research. / Dissertation/Thesis / Ph.D. Biochemistry 2010

Une étude théorique et expérimentale de la convection de Rayleigh-Bénard pour un fluide non-Newtonien rhéofluidifiant a été effectuée. L’approche théorique consiste en une analyse linéaire et faiblement non linéaire de l’instabilité thermo-convective d’une couche horizontale d’un fluide non-Newtonien, d’étendue supposée infinie dans le plan horizontal, chauffée par le bas et refroidie par le haut. Le comportement rhéofluidifiant est décrit par le modèle de Carreau. Pour ce modèle, les conditions critiques d’instabilité du régime conductif sont les mêmes que pour un fluide Newtonien. L’objectif de l’analyse faiblement non linéaire consiste à déterminer d’une part la valeur critique du degré de rhéofluidification à partir duquel la bifurcation primaire devient sous critique et d’autre part l’influence de rhéofluidification sur la sélection du motif de convection au voisinage des conditions critiques, en tenant compte d’un éventuel glissement à la paroi, d’une conductivité thermique finie de celle-ci et de la thermodépendance de la viscosité. Les conséquences sur le champ de viscosité et l’évolution du nombre de Nusselt sont caractérisées. L’approche expérimentale consiste à visualiser par ombroscopie les motifs de convection qui se développent dans une cellule cylindrique. Deux rapports d’aspect ont été considérés : AR = 3 et AR = 4. Les fluides utilisés sont des solutions aqueuses de Xanthan à différentes concentrations. L’influence du degré de rhéofluidification combiné avec la thermodépendance de la viscosité sur le domaine de stabilité des rouleaux et des hexagones ainsi que sur la zone de transitions rouleaux hexagones est mise en évidence / Theoretical and experimental study of Rayleigh-Bénard convection in a non-Newtonian shear-thinning fluid was performed. The theoretical approach consists in a linear and a weakly nonlinear of thermo-convective instability in a horizontal layer of a non-Newtonian fluid, assumed infinite in extent, heated from below and cooled from above. The rheological behavior of the fluid is described by the Carreau model. For this rheological model, the critical threshold is the same as for a Newtonian fluid. The objective of the weakly non linear analysis is to determine on one hand the critical value of the shear-thinning degree above which the bifurcation becomes subcritical and on the other hand, the influence of shear-thinning effects on the pattern selection near the onset, taking into account the possibility of wall slip, a finite thermal conductivity of the walls as well as the thermo-dependency of the viscosity. The impact on the viscosity field and on the evolution of the Nusselt number are characterized. The experimental approach consists in visualizing the convection patterns using the shadowgraph method in a cylindrical cell. Two aspect ratios were considered : AR = 3 and AR = 4. The fluids used are aqueous solutions of xanthan-gum at different concentrations. The influence of shear-thinning effects combined with the thermo-dependency of the viscosity on the stability domain of rolls and hexagons as well as on the transition between rolls and hexagons is highlighted

The presented master thesis on the project theme called The Chair, for art lessons on higher primary school is composed of two interconnected parts - theoretical and practical. The theoretical part, intended as a source of inspiration for the application of the topic in the educational process at the primary school, focuses on the characteristics of the seating furniture in the context of historical development and the chair as a motif in art. The practical part contains brief schema of project teaching, captures the preparatory and implementation phase, documentation and reflection of particular art lessons associated with the thematic unit of study. The master thesis contains a representative photographic documentation in the annex.

This diploma thesis offers insight into the issue of window, into the variability of the issue and its usage during art lessons in the lower secondary schools. The first chapter of the theoretical part of the thesis focuses on the form and the function of window in course of the historical development of architecture. Next chapters deal with the usage of the motif of the window in painting in the course of history and the usage of the motif of the window in art during the last century. The end of theoretical part of the thesis deals with motif of the window in Czech language and literature and the last chapter defines the project in education and its history. The practical part is based on the findings in the theoretical part that become the source of inspiration for the application of the topic in the art lessons. This part focuses on preparation, process and the reflection of author's own art lessons that have been realised in the lower secondary school.

L'endosymbiose racinaire entre les plantes et les champignons mycorhiziens à arbuscules (CMA) permet aux plantes d'avoir un meilleur accès aux nutriments du sol. Pour cette raison, cette endosymbiose joue un rôle majeur dans les écosystèmes et pour l'agriculture durable. Les étapes clés de la colonisation des racines par les CMA sont: 1) la pénétration des CMA dans le système racinaire à travers les cellules de l'épiderme et du cortex externe, et 2) la formation dans les cellules du cortex interne d'une structure ramifiée appelée arbuscule, qui permet des échanges entre les cellules végétales et les hyphes fongiques. L'établissement de cette symbiose implique une communication entre les deux partenaires. Les plantes produisent des hormones, les strigolactones qui induisent chez les CMA la production de signaux symbiotiques : des lipo-chitooligosaccharides (Myc-LCO) et des chitooligosaccharides courts (Myc-COs). Les Myc-LCO et les Myc-CO induisent des réponses moléculaires et physiologiques chez les plantes qui sont capables de former des mycorhizes à arbuscules. Cependant, leur rôle exact dans l'établissement des mycorhizes à arbuscules n'est pas connu. La difficulté à cultiver et transformer le partenaire fongique de cette symbiose rend la recherche compliquée du côté fongique. Du côté des plantes, on sait que des membres de la famille des récepteurs kinases à domaines lysin (LysM-RLK) perçoivent des LCO et des CO produits par divers microorganismes et sont donc de bons candidats pour percevoir des Myc-LCO et des Myc-CO. La plupart des recherches sur les mycorhizes à arbuscules sont réalisées chez des légumineuses, espèces chez lesquelles plusieurs duplications de gènes codant les LysM-RLK ont eu lieu. J'ai donc utilisé lors de mon doctorat des Solanaceae (Solanum lycopersicum, Petunia hybrida et Nicotiana benthamiana) pour étudier le rôle de deux récepteurs putatifs de Myc- LCO, codés par les gènes LYK10 et LYK4. Ces deux gènes, physiquement proches l'un de l'autre dans les génomes de la plupart des dicotylédones, proviennent probablement d'une ancienne duplication en tandem. En utilisant une approche biochimique, nous avons montré que SlLYK10 de S. lycopersicum est capable de lier des LCO avec une haute affinité. De plus, j'ai montré que le promoteur de SlLYK10 est exprimé dans l'épiderme et le cortex externe avant la colonisation par les CMA, puis dans des cellules contenant des arbuscules au cours de la colonisation par les CMA. Enfin, des approches de génétique inverse chez la tomate et le pétunia ont permis de démontrer que LYK10 contrôle la pénétration des CMA dans les racines et la formation des arbuscules. Ces résultats suggèrent que LYK10 perçoit les LCO et active chez les plantes la machinerie nécessaire à la pénétration de CMA dans les cellules végétales et à la formation des arbuscules. / The root endosymbiosis between plants and arbuscular mycorrhizal fungi (AMF) allows the plants to have a better access to soil nutrients. For this reason this endosymbiosis plays a major role in ecosystems and in sustainable agriculture. The key steps for AMF colonization are: 1) the AMF penetration in the root system through crossing epidermal/outer cortical cells, and 2) the formation of a branched inner cortex structure called arbuscules that permits exchanges between plant cells and fungal hyphae. The establishment of this symbiosis involves communication between the two partners of the symbiosis. Plants produce strigolactones, hormones that induce in AMF the production of symbiotic signals : lipo-chitooligosaccharides (Myc-LCOs) and short chitooligosaccharides (Myc-COs). Both Myc-LCOs and Myc-COs induce plant molecular and physiological responses known to be associated with the formation of arbuscular mycorrhiza (AM). However, theit exact role in AM establishment is unknown. The difficulty to grow and transform the fungal partner of this symbiosis makes the research complicated on the fungal side. On the plant side, members of the lysin motif receptor-like kinase (LysM-RLK) family are known to perceive LCOs and COs produced by various microorganisms and are thus good candidates to perceive Myc-LCOs and Myc-COs. Most of the laboratory researches on AM conducted worldwide are performed on legumes where the LysM-RLK family has encountered several gene duplications. During my PhD I used Solanaceae species (Solanum lycopersicum, Petunia hybrida and Nicotiana benthamiana) to study the role of two candidate Myc-LCO receptors encoded by the genes LYK10 and LYK4. These two genes are physically close to each other in genomes of most of the dicotyledons and likely originate from of an ancient tandem duplication. By using a biochemical approach, we showed that S. lycopersicum SlLYK10 is able to bind LCOs with high affinity. Moreover, I showed that SlLYK10 promoter is expressed in epidermis/outer cortex before AMF colonization and also in arbuscule-containing cells during colonization. Finally, reverse genetic approaches in tomato and petunia allowed demonstrating that LYK10 controls AMF penetration into the roots and arbuscule formation. Taken together, these results suggest that LYK10 perceive LCOs and induce/activate the plant machinery required for AMF penetration into plant cells. Altogether this strongly suggests that LCOs play a role in AMF perception by plant during AM establishment. By using the same approaches, we found that N. benthamiana NbLYK4, as its orthologs in legumes and other dicotyledons, also binds LCOs with high affinity and is involved in AM establishment and plant defence. NbLYK4-silenced plants showed reduced responses to defence elicitors and increased colonization by pathogens and AMF. This led to the hypothesis that LYK4 perceives LCOs and locally inhibits plant defence during AMF colonization. This strongly suggests that Myc-LCOs are able to regulate plant defence. In conclusion, at least two proteins are involved non-redundantly in LCO perception in Solanaceae, LYK10 and LYK4 and regulates complementary plant machineries required for AMF colonization.

Nuclear factor erythroid-2-related factor 1 (NRF1) and NRF2 are essential for maintaining redox homeostasis and coordinating cellular stress responses. They are highly homologous transcription factors that regulate the expression of genes bearing antioxidant-response elements (AREs). Genetic ablation of NRF1 or NRF2 results in vastly different phenotypic outcomes, implying that they play different roles and may be differentially regulated. Kelch-like ECH-associated protein 1 (KEAP1) is the main negative regulator of NRF2 and mediates ubiquitylation and degradation of NRF2 through its NRF2-ECH homology-like domain 2 (Neh2). Here, we report that KEAP1 binds to the Neh2-like (Neh2L) domain of NRF1 and stabilizes it. Consistently, NRF1 is more stable in KEAP1(+/+) than in KEAP1(-/-) isogenic cell lines, whereas NRF2 is dramatically stabilized in KEAP1(-/-) cells. Replacing NRF1's Neh2L domain with NRF2's Neh2 domain renders NRF1 sensitive to KEAP1-mediated degradation, indicating that the amino acids between the DLG and ETGE motifs, not just the motifs themselves, are essential for KEAP1-mediated degradation. Systematic site-directed mutagenesis identified the core amino acid residues required for KEAP1-mediated degradation and further indicated that the DLG and ETGE motifs with correct spacing are insufficient as a KEAP1 degron. Our results offer critical insights into our understanding of the differential regulation of NRF1 and NRF2 by KEAP1 and their different physiological roles.

Le travail de recherche porte sur la réécriture des contes de fées chez Ana Maria Matute. Toute réécriture d’un modèle narratif suppose une interprétation particulière du monde : le message transmis par les romans et les contes de la romancière s’avère en effet ambivalent en fonction du public visé, subvertissant ou non la morale traditionnelle des contes. Si je schéma narratif du genre est respecté lorsqu’elle s’adresse aux enfants, ce schéma est entièrement subverti dans les ouvrages destinés aux adultes, offrant de la sorte une vision paradisiaque et nostalgique d’une enfance perdue. Resituée dans le contexte plus vaste de la littérature espagnole de l’après guerre et étayée à l’aune de différents modèles critiques, notre recherche nous amène à montrer comment dans une structure sociale traditionnelle, les contes de fées et leur subversion motif récurrent ans l’univers romanesque de l’Espagne franquiste, peuvent alors constituer une remise en cause de l’ordre établi. / Our research is about the reelaboration of Fairy Tales in the contemporary Spanish Literature, and most particularly in the works of Ana Maria Matute. Any rewriting of a known narrative model implies a particular interpretation of the world : The message conveyed of a known narrative novels and tales is ambivalent, and dépends on te target audience, subvertin or not the traditional morals of fairy tales. If the tarrative scheme of this genre is respected when she addresses children, this scheme is entirely subverted in books aimed at adult, thus giving a heavenly and nostalgic vision of a lost childhood. Placed int the larger context of post-war how, in a traditional social structure, fairy tales and their subversion, which are recurrent patterns in the novelistic universe of franquist Spain, an then turn out to question the establishment.

La présente recherche propose une réflexion sur les possibilités de concevoir un langage analytique approprié aux musiques du ţba‛ et traîte essenciellement deux ţbū‛ tunisiens: le nūā et le mħaīyar sika à travers le répertoire de la nūba. La problématique consiste à différencier deux ţbū‛ ayants en commun certains éléments de leurs échelles. L’analyse de ces deux ţbū‛ est basée sur la méthode paradigmatique avec une conception motivique ainsi que sur un travail de réduction inspiré de l’approche Schenkérienne. Cette recherche est composée de trois parties principales : La première porte sur l’analyse comparative des motifs principaux de fin. La deuxième consiste à analyser et comparer les motifs secondaires de fin et la troisième partie traite les motifs de début. La recherche s’achève par une conclusion répartie en deux; la première relève et commente les résultats de l’analyse; quant à la seconde, elle discute l’efficacité des procédures analytiques adoptées. / This research proposes a reflection on the possibilities to conceive an analytical procedure adapted to musical works based on the system of ţba‛; it deals mainly with two Tunisian ţbū‛, nūā and mħaīyar sika, considered through the nūba repertody. The aim is to differentiate two ţbū‛ sharing some elements of their scale. The analysis of these ţbū‛ is based on the paradigmatic method, envisaged in a motivic conception, and on a procedure of musical reduction inspired by Schenkerian theory. The research consists in three main parts: the first devoted to a comparative analysis of the main final motives; the second analyses and compares secondary final motives, and the third deals with initial motives.The thesis concludes in two parts: the first synthesizes and comments the results of the analysis, and the second discusses the validity of the analytical procedures.