Thesis--University of Washington. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves [433]-474).

Originally presented as the author's thesis (Ph. D.). / Includes bibliographical references (p. [304]-306).

Thesis (M.A.)--Guo li Taiwan da xue. / Reproduced from typescript. Includes bibliographical references (p. 165-170).

Thesis (M.A.)--Fu ren da xue. / Reproduced from typescript copy. Bibliography: p. [125-127]

Texte remanié de: Thèse de doctorat--Littérature française--Paris 3, 2005. / Bibliogr. p. 383-394.

Thesis (M.A.)--University of Hong Kong, 2009. / Includes bibliographical references.

Thesis (M.A.)--Fu ren da xue. / Reproduced from typescript. Includes bibliographical references (p. 159-161).

Les facteurs de transcription ETS sont divisés en sous-familles en fonction de leurs similitudes en matière de séquence protéique, de séquences de liaison à l'ADN et d’interactions avec différents cofacteurs. Ils sont régulés par des signaux extracellulaires et contribuent à divers processus cellulaires, dont la prolifération cellulaire et la transformation tumorale. Les gènes de la famille ETS sont fréquemment ciblés par des processus oncogéniques que ce soit des translocations chromosomiques ou des gains du nombre de leurs copies. Le gène PU.1/SPI1 est également ciblé par des mutations ponctuelles inactivatrices dans les hémopathies myéloïdes humaines. Nous avons étudié une mutation somatique récurrente du gène PU.1/SPI1 (c.676C>G, p.Q226E), identifiée chez environ 6% des patients atteints d’une macroglobulinémie de Waldenström (MW), un syndrome lymphoprolifératif B chronique rare. La mutation modifie les caractéristiques de liaison à l'ADN de la protéine mutante, passant des séquences classiques reconnues par SPI1 à des séquences reconnues par d’autres protéines ETS comme ETS1, et d’une liaison à des régions enhancer à une liaison à des régions promotrices. La liaison accrue du mutant de SPI1 aux régions promotrices active des programmes transcriptionnels impliquant des voies de signalisation intracellulaire généralement favorisées par d'autres membres de la famille ETS. Les conséquences fonctionnelles de cette mutation sont une augmentation de la prolifération cellulaire et une diminution de la différenciation lymphoïde B terminale dans une lignée cellulaire modèle et des échantillons primaires de MW. Nous décrivons ici un mécanisme de subversion oncogénique de la fonction d’un facteur de transcription suite à la modification subtile de la spécificité de liaison à l'ADN de la protéine mutante, menant à un arrêt de différenciation. La démonstration qu'une mutation somatique ponctuelle peut modifier l'équilibre de liaison d’un facteur de transcription à l’échelle du génome fournit un paradigme mécanistique sur la façon dont les mutations faux sens dans les gènes codant pour des facteurs de transcription pourraient être oncogéniques dans les tumeurs humaines. / The ETS-domain transcription factors are divided into subfamilies based on protein similarities, DNA binding sequences and interaction with cofactors. They are regulated by extracellular clues and contribute to a variety of cellular processes, including proliferation and transformation. ETS genes are targeted by oncogenic processes through chromosomal translocations and copy number gains. The PU.1/SPI1 gene is also targeted by inactivating point mutations in human myeloid malignancies. We investigated a recurrent somatic missense mutation (Q226E) of the PU.1/SPI1 gene in Waldenström macroglobulinemia, a human B-cell lymphoproliferative disorder. The mutation changes DNA binding of the mutant protein from classical SPI1 to ETS1-like sequences, shifting the balance from binding to promoter regions from enhancers. Increased binding by mutant SPI1 at promoters activates gene expression of intracellular signaling pathways typically promoted by other ETS factor family members. The functional consequences are decreased terminal B-cell differentiation in a model cell line and primary samples. In summary, we describe oncogenic subversion of transcription factor function through subtle alteration DNA binding specificity leading to differentiation arrest. The demonstration that a somatic point mutation subtly changes the balance of genome binding provides a mechanistic paradigm for how missense mutations in transcription factor genes may be oncogenic in human tumors.

Speaking to the erotological fiction, people would often refer to Rou Pu Tuan. Besides Jin Ping Mei, Rou Pu Tuan is also frequently mentioned by people when it comes to the classic in those sexual stories. The book was even translated to many different languages in other countries. However, according to the prosperous publishing business during the Ming and Cing dynasties, Rou Pu Tuan is obviously not the only erotological fiction that had been published during those years. Why the Rou Pu Tuan can become such a famous erotological fiction? People would definitely curious about it. Therefore, my research is mainly focused on the Rou Pu Tuan itself. First step, I summarize the whole story. I also make a brief introduction to illustrate the dissemination and editions of Rou Pu Tuan. Moreover, I mention the background about the author and the time that Rou Pu Tuan had been written. Second step, I analyze male and female characters and discuss the power from both genders in the story. Finally, I try to find out the subjects of the whole story. According to my observation, the attraction of Rou Pu Tuan is based on its exquisite characterization and subjects that emphasize by some narrative way. This fiction does improve its value by giving different images and personalities to every role, but its main power is still possessed by the male. Retributive justice and appropriate sex are the subjects of the story. The story emphasized the subjects by using the coincidences that based on daily life, corresponding clues and the illustration from active narrator. Therefore, exquisite characterization and unique narrative for subjects are the factors that make Rou Pu Tuan a famous erotological fiction.

B cells are capable of producing antibodies of diverse antigen specificities and effector functions to counter infection by a wide range of pathogens. The diversification of immunoglobulin (Ig) is achieved through a series of programmed DNA recombination and mutagenic events during B cell maturation. A key factor involved in the Ig diversification process is Activation Induced Cytidine Deaminase (AID). AID is a B cell specific enzyme that is critical for three distinct pathways of Ig diversification: class switch recombination, somatic hypermutation and Ig gene conversion. AID functions by deaminating cytosine to uracil in target DNA at the Ig loci. Although essential for effective immunity, the mutagenic activity of AID needs to be confined to the Ig loci in order to protect genomic integrity, but the underlying mechanism is not fully understood. In this study, I show that two lymphoid specific transcription factors, PU.1 and IRF4, play important roles in regulating AID function in chicken B cells. PU.1 and IRF4 have been implicated in many aspects of B cell development and function. The two factors could form a heterodimer and regulate target gene expression cooperatively. However, we found that PU.1 and IRF4 appear to have different impacts on AID function. We show that PU.1 is important for the expression of AID gene in chicken B cells, and the regulation appears to involve direct interaction of PU.1 with the AID gene. By comparison, IRF4 plays a minor role in AID expression. On the other hand, both PU.1 and IRF4 are required for efficient gene conversion that is mediated by AID at the Igλ locus. Moreover, the gene dosage of PU.1 is critical for AID function, since a severe gene conversion defect is observed in PU.1+/- cells. The function of PU.1 and IRF4 in AID-mediated gene conversion involves binding sites for the PU.1/IRF4 complex within a regulatory element at the Igλ locus. Future studies will be directed at understanding how PU.1 and IRF4 regulate AID-mediated gene conversion. / text