Transmissible spongiform encephalopathy (TSE) strains are defined by their biological properties on transmission to wild-type mice, specifically by their characteristic incubation periods and patterns of vacuolar pathology (‘lesion profiles’) in the brain. Whilst a single TSE strain has been identified in variant Creutzfeldt-Jakob disease (vCJD), the phenotypic heterogeneity observed in sporadic CJD (sCJD) implies the existence of multiple strains of agent. These distinct strains are proposed to be enciphered by the different conformers of abnormal prion protein (PrP), recognised as different protease resistant PrP (PrPres) types by Western blotting (type 1 or type 2) and are thought to be substantially influenced by the different prion protein gene (PRNP) codon 129 polymorphism (MM, MV and VV). To test the relationship between disease phenotype and agent strain, this study carried out a full characterisation of the sCJD agent by primary transmission of brain tissue from 27 sCJD cases (comprising all six possible combinations of PRNP codon 129 genotype and PrPres type) in panels of wild-type mice using the standard strain typing properties of incubation period and lesion profiles, plus a full analysis of PrP in the mouse brain and the PrPres molecular subtypes present. Results were directly compared with the transmission characteristics of brain tissue from 10 vCJD cases. The characterisation of the agent strain in sCJD and vCJD was extended to include analysis of subsequent mouse-to-mouse passages. In an additional investigation, wild-type mice were experimentally challenged with a wide-range of lymphoid tissues, neural tissues and biological fluids from vCJD and sCJD patients in order to investigate the extent of peripheral involvement in CJD and to determine whether the agent is subject to any tissue-specific modifications. Analysis of all 27 sCJD sources demonstrated the existence of two strains of agent, one associated with the MM1/MV1 subgroups and the other associated with the MM2 subgroup, which could be distinguished by their transmission properties in the mice. The lack of transmission in mice challenged with VV1, MV2 and VV2 tissues provided evidence of at least one further sCJD strain. In contrast, all 10 vCJD sources resulted in consistent incubation periods and lesion profiles, suggesting that all 10 patients investigated were infected with the same strain of agent. Overall, the observation that PrPres type in sCJD and vCJD was maintained on transmission is consistent with the proposition that PrPres type plays a role in enciphering strain-specific information. Experimental transmissions from peripheral tissues extended the evidence for a peripheral infection in vCJD. However, comparison of incubation periods and lesion profiles from transmission of brain and peripheral tissues showed no evidence of tissue-specific modification in the biological properties of the agent. Furthermore, the detection of low levels of infectivity in a sCJD buffy coat sample provides supporting evidence for a peripheral involvement in sCJD. This study highlights the complex relationship between disease phenotype, PRNP codon 129 genotype, PrPres type and agent strain in sCJD and vCJD. Overall, this study confirms that multiple strains of agent are associated with sCJD, some of which successfully propagate in wild-type mice but none of which are identical to the agent responsible for vCJD. Importantly, the sCJD strains identified here by their biological properties partially correlated with the current sub-classification system for sCJD which is based on the clinical and pathological phenotype of the disease.

This study suggests that Blake’s works can be understood as ‘conversion works,’ which seek to facilitate a broadly defined perceptual, spiritual, and intellectual conversion in the reader/viewer. This conversion is manifested in various ways in the texts, images, narrative structures, and style of Blake’s works. Part I discusses the genesis of the narrative of Blake’s own conversion and introduces critical discussions of the conversion narrative as a genre, showing how the predominant interpretative paradigm of the conversion narrative (as an autobiographical reportage describing a one-off experience) is challenged by the shapes that conversion narratives have taken throughout history, suggesting a broader definition of conversion literature. In Part II, I analyze Blake’s depictions of Christ in his illustrations to Night Thoughts in relation to eighteenth-century Moravian art, and the way in which they are later used in The Four Zoas. I discuss how Milton can be understood as a multilayered conversion narrative, how the manifestation of conversion in Jakob Boehme’s works might have influenced it, and how a related conversion is manifested in Jerusalem (1804-20). Finally, I show how Blake represents conversion in his illustrations to Pilgrim’s Progress and the Book of Job, emphasizing the importance of vision and the inclusion of protagonist and viewer in the divine body. Together, these analyses show conversion as a gradually developing presence in Blake’s works, exploring the conversion moment as a way into the shared salvific space of the body of Christ for fictive characters, author, and reader or viewer together.

Hugo Wolf drew the strands of form, rhythm, and other elements together to form tightly woven songs, each element of which can be traced to the text as its original inspiration. Truly this was a genius of romantic expression, who took the tools developed by his predecessors in song, tempered them with his own sensitive personality, and used them to the fullest in setting the meaning and the mood, as well as the words, of the poems he had chosen.

Jakob van Hoddis, Georg Trakl together with Else Lasker-Schüler belong to the leading representatives of early expressionist poetry. This thesis deals with translation analysis of their selected poems into the Czech language. The first part of the thesis describes the birth, evolution and essential ideas of expressionism, but also significant centres of literary course of events of that period and reception of expressionism in Bohemia and Moravia. The issue of artistic translation is further outlined with focus on the question of equivalence. The second part of the thesis includes analysis of selected poems, which are ordered according to the author and date of issue. One chapter is devoted to each poet, it briefly introduces his life to help point out aspects which have influenced his production, followed by analysis of poems that document the circumstances of their creation and comparisons of their translations. Key words: expressionist poetry, translation analysis, Jakob van Hoddis, Georg Trakl, Else Lasker-Schüler

Les maladies à prions sont des pathologies neurodégénératives d’évolution fatale, transmissibles, pour lesquelles aucun traitement efficace n’existe. Elles associent sur le plan neuropathologique une spongiose, une gliose astrocytaire, une perte neuronale, et une accumulation de la forme anormalement repliée (PrPsc) de la protéine prion cellulaire codée par l’hôte. Certaines formes de cette maladie sont associées à une tauopathie et présentent des lésions neuropathologiques similaires à celles retrouvées dans la maladie d’Alzheimer (MA).Nous avons utilisé un modèle de cultures primaires de neurones afin d’explorer d’une part la relation entre la protéine prion et la physiopathologie de la protéine tau, et d’étudier d’autre part la propagation de souches humaines et l’effet de composés anti-prions sur cette propagation. Nos résultats indiquent que l’hyperphosphorylation de tau en réponse à l’exposition de PrP recombinantes est mutation dépendante, conformation dépendante, partiellement dépendante de la PrPc et est médiée par la kinase PDK1. Nous avons aussi démontré pour la première fois que la propagation d’isolats humains de maladie de Creutzfeldt-Jakob est possible dans un modèle in vitro et permet une évaluation rapide de l’efficacité de composés anti-prions, confirmée in vivo. Ces travaux ont permis de mieux caractériser la relation protéine amyloïde-physiopathologie de tau, d’ouvrir des perspectives de recherche dans la compréhension des mécanismes impliqués dans la MA, et d’apporter un modèle unique permettant d’évaluer rapidement les effets de molécules anti-prions vis-à-vis des souches les plus pertinentes, dans une stratégie de repositionnement thérapeutique. / Prion diseases are fatal transmissible neurodegenerative disorders, with no effective treatment. Brain lesions include neuronal vacuolization, astrogliosis, neuronal loss and the accumulation of PrPSc, an abnormal isoform of the host-encoded cellular prion protein (PrPc). Some forms of prion diseases are associated with tau fibrillar pathology similar to that observed in Alzheimer’s disease except that Abeta peptides are replaced by PrPsc. Here we used a primary neuronal cultures to first explore the interplay between the formation of prion protein assemblies and the occurrence of tau pathology, and secondly to evaluate in vitro human strain propagation and the efficiency of some antiprion compounds towards human prions. We showed that tau hyperphosphorylation in response to recombinant PrPs exposition was mutation-dependent, conformation-dependent and varied with the PrPc expression level of exposed neurons. This effect was mediated by PDK1 kinase. We also demonstrated for the first time that human prion isolates could propagate in an in vitro model. This model was also useful to evaluate the efficacy of antiprion compounds that was further validated in vivo. Our results help us to better understand the amyloid protein-tau physiopathology interplay and provide a useful and unique tool for fast evaluation of therapeutic compounds active against human prion strains in a repositioning strategy in such rare but devastating diseases.

The bloody epoch of the Thirty Years' War and the wide spread decline of German culture and social life is the major topic in Simplicissimus, the first High German novel written by Hans Jacob Christoph von Grimmelshausen in 1668. The purpose of this thesis is to summarize the development of this novel and to find Grimmelshausen's intention in writing his book which was immensely popular upon its publication, but disappeared into obscurity during the German classical period. Since its rediscovery in the middle of the 19th century, scholars have puzzled over the satirical meaning of Simplicissimus as well as the identity of its author. By concentrating on the sources available to Grimmelshausen, researchers have proposed a variety of interpretations of the text. Some see the book as Germany's best example of the Spanish picaresque novel, others include it in the genre of "Bildungsroman", whose classic example is Goethe's Wilhelm Meister. Many readers marvel over the satirical and witty language of the novel, while others admire its sophisticated structures. It is evident that scholars have yet to reach a consensus on a comprehensive interpretation of Simplicissimus. Valuable insight could be gained from discovering Grimmelshausen's intentions. By searching the text carefully for statements made by the author about his opinion on social customs, war, family, religion etc., a composite picture of Grimmelshausen's world view was constructed. By combining these assumed attitudes and opinions with his personal development and the social and historical influences of his time, the conclusion emerged that the author wrote his novel out of an ethical didactic urge to confront his readers with the ills of their time. The economic, political and religious changes of the 17th century uprooted the established medieval structures of European life, causing millions of deaths and devastation in large parts of Germany. Grimmelshausen saw the deterioration of life directly related to the changes in the beliefs and behaviors of his contemporaries and felt compelled to alarm his fellow men. A second motivational force for his literary endeavors was the necessity to supplement his small income as tavern owner, although he certainly could not have anticipated the astonishing success of his book. The confusing array of literary forms in Simplicissimus is the result of the author's concern with his message which subordinated the adherence to a specific genre, but nevertheless produced a masterpiece of German literature.

Le diagnostic biologique des maladies à prions du vivant du patient repose sur la recherche de protéine 14.3.3 dans le liquide céphalo-rachidien. Le dosage conjoint de la néoptérine permet d'améliorer nettement sa spécificité. Cependant, les performances analytiques ne sont pas suffisantes pour établir un diagnostic de certitude. Dans la quête d'un marqueur supposé plus spécifique, nous avons recherché la protéine prion pathologique résistante à la protéinase K (PrPres) dans le nerf péronier. Malgré l'optimisation de notre méthode, nous ne l'avons détecté que dans un cas sur trois. Cela nous a conduit à utiliser et valider la streptomycine comme ligand exogène pour concentrer la PrPres. Nous avons démontré sa capacité à concentrer la PrPres d'origine cérébrale et amygdalienne; sa sensibilité analytique s'avère être équivalente, pour une faible quantité de tissu initiale (5 mg), à celle de l'acide phosphotungstique. Par ailleurs, nous avons pu correctement classer, à partir d'un nombre significatif d'échantillons cérébraux, les patients EST des patients non atteints d'une EST avec une sensibilité et une spécificité de 100 %. Ainsi, nous disposons d'un outil susceptible d'augmenter la sensibilité des techniques initialement utilisées pour détecter la PrPres dans des nerfs facilement accessibles par biopsie.

Le diagnostic de la maladie d'Alzheimer (MA) est tardif et présente un manque de fiabilité en regard de l'examen neuropathologique postmortem permettant de confirmer ce diagnostic. En effet, les présentations cliniques de la MA peuvent être multiples et parfois atypiques. Des anomalies dans les concentrations des protéines tau, tau phosphorylées et amyloïdes bêta, au sein du liquide céphalorachidien (LCR), ont permis d'améliorer le diagnostic du vivant du patient. Nous avons évalué la performance de ces marqueurs, dans le LCR, utilisés pour le diagnostic de la MA dans les formes syndromiques atypiques. L'utilisation de ces marqueurs augmente la précision du diagnostic lors de ces différentes présentations cliniques. De plus, nous avons mis au point un test diagnostic biochimique postmortem des différentes tauopathies permettant de mieux les caractériser en complément de l'examen neuropathologique. Enfin, nous avons conçu et caractérisé des anticorps spécifiquement dirigés contre la protéine tau phosphorylée en position 231. Cet outil nous a permis de développer un test ELISA dans le LCR. Des résultats préliminaires suggéreraient une interaction in vivo entre les protéines tau et Prion. Ces résultats, décrits pour la première fois, sont corrélés à nos observations histologiques.

The present Ph.D. dissertation proceeds from poetry on the theme of the Virgin Mary which blossomed for several decades during the Romantic era and is dedicated to the use of its virgin and maternal themes in the work of C.J.L. Almqvist and P.D.A. Atterbom. The first chapter discusses Almqvist's description of the perfect complementary unity of male and female - and divine and human - in his juvenile work Murnis (1819). In this sexually explicit work, theology and religious experience is eroticized while sexuality is sacralized. In Amorina (1822), a burgeoning transformation of Almqvist's "wholeness" vision can be observed. While wholeness can only be achieved through the perfect union of man and woman in Murnis, Amorina emerges as a perfect figure in and of herself. In the second chapter, the figure of Tintomara in Drottningens juvelsmycke (1835) is analyzed. In this novel, the dream of the merging of "twoness" into "oneness" seems to have been abandoned in favour of an experiment, wherein the unity of masculinity and femininity is realized in one single individual, the androgynous Tintomara. Despite the fact that the novel's androgynous idea is formulated with direct reference to Plato's Symposium, the significance of Jakob Böhme's speculations on androgyny are also emphasized here. The third chapter deals with the poetry about Mary written by Almqvist, especially Isidoros av Tadmor and Marjam (1839). Almqvist's image of Mary is characterized in terms of "perfection" and "complexity". In Marjam, this complexity is expressed both through the drama's upholding of the paradoxical content of the dogma of the Virgin Mary and the main theme of the double drama, the tension between the earthly and the eschatological family. The fourth and fifth chapters of this dissertation are dedicated to the maternal theme in the work of P.D.A. Atterbom. I proceed from the hypothesis that the transformations which the figure of Mary undergoes reflect a tension between Romantic syncretism and classic Christianity. I analyze four texts by Atterbom in which this conflict is particularly apparent. In Atterbom's prose draft for his fairy play Fågel blå (1818), as in his sonnets dedicated to Mary (1817-18), I discern a shift away from Romantic syncretism and toward more Biblical patterns. In the fairy play Lycksalighetens ö (1824-27), this tension emerges anew in the two Nyx epiphanies in the piece. The elegy "Ave Maria" (1831) comprises the clearest example of the shift in Atterbom's writing toward classical Mariology. In the conclusion, Almqvist's and Atterbom's respective thematic use of Mary - where she is portrayed as a complex, transgressive figure - is contrasted with an early example of Swedish Biedermeier poetry, Carl von Zeipel's "Jesus Christus. Evangeliska romanser" (1822), where Mary is placed in the context of the little, idyllic family. / digitalisering@umu

Les encéphalopathies spongiformes transmissibles (EST) constituent de graves maladies neurodégéneratives atypiques, affectant aussi bien l'homme que l'animal. Ces maladies ont une origine infectieuse, génétique ou sporadique. On distingue chez l'homme la maladie de Creutzfeldt-Jakob, le syndrome de Gerstmann-Sträussler-Sheinker, le nouveau variant de la maladie de Creutzfeldt-Jakob dû à l'ingestion d'aliments contaminés, et les formes iatrogènes, qui surviennent le plus souvent à la suite d'une contamination contractée lors d'interventions chirurgicales. Les maladies à prions animales les plus courantes sont l'encéphalopathie spongiforme bovine et la tremblante du mouton. Le facteur commun à toutes ces maladies est la protéine prion ou PrP, présente de façon ubiquitaire dans l'organisme et de manière prépondérante dans le cerveau. La PrP existe sous deux états conformationnels qui ont la même séquence en acides aminés, mais qui possèdent des propriétés physicochimiques différentes. La forme anormale du prion appelée "scrapie" ou "PrPsc " est partiellement résistante aux protéases et plus riche en feuillets b que la PrPc, ce qui lui confère une susceptibilité exacerbée à l'agrégation. L'hypothèse de "la protéine seule" proposée par Prusiner prédit que le titre infectieux serait composé uniquement de la PrPsc, capable de se répliquer de manière autocatalytique en se servant de la PrPc endogène comme matrice de conversion. Les mécanismes moléculaires régissant ce processus sont encore mal connus. Cependant ce phénomène de conversion apparaît comme l'évènement central contrôlant l'infection et sa propagation vers le système nerveux central. Ces processus nécessitent la présence de la PrPc endogène, puisqu'il a été montré que des souris invalidées pour la protéine prion résistent à l'infection et sont viables. Ces observations ouvrent de nouvelles perspectives en terme d'approches thérapeutiques théoriquement envisageables dans le domaine des EST. La PrPc, après une étape de maturation, subit un clivage physiologique à la membrane plasmique en position 111/112 qui conduit à la formation d'un fragment sécrété appelé N1. Des travaux effectués dans notre laboratoire ont montré que ce clivage est constitutif et régulé par la PKC et nécessite l'activité des disintégrines ADAM10 et ADAM17, respectivement. Mon travail de thèse à consisté à étudier ce clivage en identifiant les isoformes de la PKC impliquées, et à démontrer sa régulation par les récepteurs muscariniques.