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京都大学 / 新制・課程博士 / 博士(医学) / 甲第23806号 / 医博第4852号 / 新制||医||1058(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 森信 暁雄, 教授 上野 英樹, 教授 椛島 健治 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Early mammalian development before the oocyte-to-embryo transition is under 'maternal control' from factors deposited in the cytoplasm during oocyte growth, synthesized independent of de novo transcription. Maternal mRNAs encode proteins necessary for early embryo development. Two elements in the mRNA 3’untranslated region (UTR), the cytoplasmic polyadenylation element (CPE) and the hexanucleotide (AAUAAA) are involved in the control of translation of specific mRNAs during meiotic maturation. Despite advances in understanding the translational regulation during meiotic maturation, regulation at the 1-cell stage has not been explained. More studies are required to explain this complex mechanism of temporal mRNA recruitment after fertilization. Maternal mRNAs translated at different stages were examined to understand how specific maternal mRNAs are synthesized and stored, what are these maternal mRNAs, which maternal mRNAs are translated, and how these maternal mRNAs are temporally regulated. Polysomal mRNAs from eggs and 1-cell embryos were analyzed by microarray analysis and this indicated that temporally significant biological activities were encoded by mRNAs recruited at different stages of development. The mRNAs recruited in eggs were involved in homeostasis and transport mechanisms and those recruited in zygotes were involved in biosynthesis and metabolic activities. These data indicated that there is a temporal regulation of maternal mRNAs to meet the different biological requirements of the embryos. After the identification of temporally translated mRNAs, experiments were performed to understand the mechanism underlying temporal translation. The prevalence of the CPE differed between the two mRNA populations translated i.e., egg and 1-cell stage polysomal mRNAs. CPEs were present in ~53% of transcripts at the 1-cell stage compared to ~86% at the MII stage. This indicated that novel motifs other than CPEs regulate translation of mRNAs at the 1-cell stage. Truncation and deletion experiments were conducted using chimeric mRNAs based on one mRNA that was enriched in the 1- cell polysomes (Bag4). These experiments led to the identification of two regulatory regions that control translation at the 1-cell stage, an 80 nt region and a 43 nt region with different regulatory motifs. The 80 nt region is involved in activation of translation and the 43 nt region has an inhibitory effect on translation at the MII and early 1-cell stage. These results provide a detailed picture of how specific maternal mRNAs are prevented from undergoing translation at the MII stage and how the effect of inhibition is eliminated by the late 1-cell stage. / Biochemistry

<p> Identifying motifs that are "close" to one or more substrings in each sequence in a given set of sequences and hence characterize that set is an important problem in computational biology. The target motif identification problem requires motifs that characterize one given set of sequences but are far from every substring in another given set of sequences. This problem is N P-hard and hence is unlikely to have efficient optimal solution algorithms. In this thesis, we propose a set of modifications to one of the most popular stochastic heuristics for finding motifs, Gibbs Sampling [LAB+93], which allow this heuristic to detect target motifs. We also present the results of four simulation studies and tests on real protein datasets which suggest that these modified heuristics are very good at (and are even, in some cases, necessary for) detecting target motifs.</p> / Thesis / Master of Science (MSc)

This thesis is missing page 157, the other copies of the thesis did not have the page either. -Digitization Centr / The polyomavirus enhancer is organized into three elements. One of these elements, Element 2, is particularly interesting because the activities of the factors which interact with it are highly regulated. There are at least three cellular proteins, PEA1, PEA2, and PEA3, which bind to adjacent sites in Element 2. These proteins are differentially active in mouse cells at different developmental stages and their activity is modulated by serum, tumor promoting agents and the products of several oncogenes. It is likely, therefore, that these cellular proteins play an important role in interpreting growth stimuli and other physiological cues in the mouse. A plasmid was contructed which can be used to test enhancer elements for their ability to activate both transcription and DNA replication. This plasmid includes the Py origin of replication and a minimal promoter, consisting of a TATA box only, controlling expression of a reporter gene. The activity of the PEA factors was studied by cloning the binding sites for these factors into this reporter plasmid as monomers, multiple tandem copies, and in paired combinations, and testing their ability to activate transcription and DNA replication in vivo. The results of these studies show that PEA1 and PEA3 can function independently and cooperatively to activate both replication and transcription. By contrast, PEA2 is unable to independently activate transcription and represses PEA1-activated transcription when the binding sites for these factors are located adjacent to one another. However, PEA2 functions cooperatively with PEA1 to activate DNA replication, and can weakly activate replication on its own. / Thesis / Master of Science (MS)

Modeling of cis-elements in the upstream regions of genes is a challenging computational problem. A set of regulatory motifs present in the promoters of a set of genes can be modeled by a biclique. Combinations of cis-elements play a vital role in ascertaining that the correct co-action of transcription factors binding to the gene promoter, results in appropriate gene expression in response to various stimuli. Geometrical and spatial constraints in transcription factor binding also impose restrictions on order and separation of cis-elements. Not all regulatory elements that coexist are biologically significant. If the set of genes in which a set of regulatory elements co-occur, are tightly correlated with respect to gene expression data over a set of treatments, the regulatory element combination can be biologically directed. The system developed in this work, XcisClique, consists of a comprehensive infrastructure for annotated genome and gene expression data for Arabidopsis thaliana. XcisClique models cis-regulatory elements as regular expressions and detects maximal bicliques of genes and motifs, called itemsets. An itemset consists of a set of genes (called a geneset) and a set of motifs (called a motifset) such that every motif in the motifset occurs in the promoter of every gene in the geneset. XcisClique differs from existing tools of the same kind in that, it offers a common platform for the integration of sequence and gene expression data. Itemsets identified by XcisClique are not only evaluated for statistical over-representation in sequence data, but are also examined with respect to the expression patterns of the corresponding geneset. Thus, the results produced are biologically directed. XcisClique is also the only tool of its kind for Arabidopsis thaliana, and can also be used for other organisms in the presence of appropriate sequence, expression, and regulatory element data. The web-interface to a subset of functionalities, source code and supplemental material are available online at http://bioinformatics.cs.vt.edu/xcisclique. / Master of Science

L’emploi atypique constitue une forme d’emploi de plus en plus présente sur le marché du travail, particulièrement chez les étudiants. Certaines études ont démontré que l’engagement organisationnel de ces travailleurs étudiants serait différent de celui des travailleurs occupant des emplois dits traditionnels. Cela implique également des différences sur le plan de la satisfaction au travail, des comportements de citoyenneté organisationnelle ainsi que de l’intention de quitter l’emploi. Toutefois, la compréhension de ces différences reste anecdotique. Les études s’étant penchées sur la question ont relevé l’importance de tenir compte des motifs poussant les employés atypiques à occuper, sur une base volontaire ou non, un emploi atypique. Dans cette perspective, 119 étudiants occupant un emploi atypique ont été sondés afin de répondre aux deux principaux objectifs de la présente thèse : 1) connaître les motifs expliquant le choix des travailleurs étudiants d’occuper un emploi atypique et 2) vérifier l’existence d’un effet de médiation partielle de la forme d’engagement affectif des travailleurs atypiques sur la relation unissant les motifs d’occuper un emploi atypique à la satisfaction au travail, aux comportements de citoyenneté organisationnelle et à l’intention de quitter l’emploi. Les résultats confirment l’existence de seize motifs d’occupation d’un emploi atypique chez les travailleurs étudiants. De même, on observe un effet de médiation partielle de l’engagement affectif sur la relation entre les motifs volontaires et la satisfaction au travail, l’intention de quitter l’emploi et les comportements de citoyenneté organisationnelle, ainsi qu’un effet de médiation partielle de l’engagement normatif sur la relation unissant les motifs volontaires et la satisfaction au travail. L’étude se conclut sur une discussion des implications de ces résultats pour l’avancement des connaissances et la pratique professionnelle.

Cette thèse consiste à étudier le motif de la lumière dans l’œuvre poétique de Verlaine. La notion de motif dans la perspective thématique que nous avons adoptée et qui est définie principalement par Jean-Pierre Richard dans L’univers imaginaire de Mallarmé et dans Microlectures s’étend à un ensemble de termes qui, de par leur sens et leur référence, entretiennent entre eux des rapports variés et assurent à une œuvre sa cohésion. Ces termes, tout en renvoyant à une même notion, en l’occurrence la lumière, se métamorphosent au fil du texte et apparaissent sous des formes variées. Nous nous sommes fixés pour objectif de les repérer et d’étudier leur variation et leurs fonctions. Le poète adopte face à la réalité une attitude négative se caractérisant par le repliement sur soi et l’abandon. L’espace chez lui qu’il soit ouvert ou fermé est oppressant et le temps, associé souvent au passé, est synonyme de perte et de déception. De nombreux poèmes, surtout au début de l’œuvre, reflètent cette impression d’inertie et de défaillance. Mais malgré la forte présence lyrique, l’expression toujours suggestive ne se laisse pas dominer par le discours. A cette négativité, le poète associe la noirceur. Toutes les lumières dans ces poèmes sont sombres ou faibles. Les occurrences qui relèvent de cette tonalité sont de loin les plus nombreuses. Leur mise en œuvre et leur fréquence témoigne de l’importance que Verlaine accorde à l’esthétique. Mais le lyrisme de Verlaine est aussi celui de la célébration. La plus grande partie de son œuvre est composée de portraits et d’autoportraits. Dans cet ensemble où sont célébrés Dieu, les héros, les femmes, etc. Verlaine choisit l’envers de la discrétion. Il emploie des procédés qui favorisent l’exagération. Les portraits idéalisés sont sa manière de manifester sa quête d’altérité. L’expression exagérée caractéristique de ces poèmes engage des lumières fortes, lumineuses, blanches…Mais dans un certain nombre de poèmes, Verlaine rompt entièrement avec tout héritage poétique et a écrit une poésie qui tente de saisir la réalité dans sa fuite et dans sa métamorphose. Il adopte une voie intermédiaire qui soumet le langage aux exigences de l’artiste. Certaines lumières elles-mêmes changeantes et indéterminées peuvent en effet répondre à ce besoin. Ce besoin d’interroger le langage est en réalité commun aux poètes de la deuxième moitié du XIXème siècle. L’époque se caractérise par une évolution des goûts et des idées, mais aussi par un sentiment d’inquiétude face à la modernité naissante. Cette évolution et ce malaise sont perceptibles chez Verlaine. Celui-ci atteste de sa modernité en plaçant son art sur la frontière de ce qui est dit et de ce qui est tout simplement suggéré. L’existence de cet art dépend en fait de la complicité qui s’instaure par-delà les mots entre le poète et le lecteur. Si Verlaine semble gagner le pari d’une réception large, c’est grâce à cette poétique de l’indétermination et de la suggestion. / This thesis consists in studying the motif of the light in the poetry of Verlaine. The concept of motif in the thematic approach we have adopted and which is defined principally by Jean-Pierre Richard in L’univers imaginaire de Mallarmé and in Microlectures extends to a set of terms which, by their sense and reference, have various connections between them and ensure the work cohesion. These terms, while referring to a same notion, in this case the light, are transformed in the text and appear under various forms. We have set as a target to identify them and to study their changes and their functions.In the face of the reality, the poet adopts a negative attitude characterized by self-absorption and abandonment. The space that is open or closed is oppressive and the time, often associated with the past, means loss and disappointment. Many poems, especially at the beginning of the work, reflect this sense of inertia and failure. But despite the strong lyrical presence, the constantly suggestive expression cannot be dominated by the speech. The poet combines the dark with this abandonment. All the lights in these poems are dark and low. Occurrences that are related to this tone are by far the most numerous. Their use and their frequency reflect the importance that Verlaine attaches to the forms.But the lyricism of Verlaine is also the lyricism of celebration. The major part of his work is composed of portraits and self-portraits. In this set where God, heroes, women… are celebrated, Verlaine chooses the explicit expression. He uses processes that support the exaggeration. The idealized portraits are his way of showing his quest for otherness. The expression in these poems involves bright, shining and white lights.But in some poems, Verlaine breaks completely with poetic legacy and wrote a poetry that attempts to grasp the reality in its movement and its metamorphosis. He adopts a middle way that meets the needs of the artist. Some lights, themselves unstable and indeterminate, can meet this need. The need of asking language is in fact common to the poets of the second half of the nineteenth century. The era is characterized by changing tastes and ideas, but also by a concern about the emerging modernity. This development and this discomfort can be perceived in the poetry of Verlaine. The Verlaine modernity appears between what is said and what is just suggested.In fact, the existence of this art depends on the complicity that exists beyond the words between the poet and the reader. Verlaine seems to meet the challenge of a large reception thanks to the poetics of indeterminacy and suggestion.