I argue against the halfer response to the Sleeping Beauty case by presenting a new problem for halfers. When the original Sleeping Beauty case is generalized, it follows from the halfer’s key premise that Beauty must update her credence in a fair coin’s landing heads in such a way that it becomes arbitrarily close to certainty. This result is clearly absurd. I go on to argue that the halfer’s key premise must be rejected on pain of absurdity, leaving the halfer response to the original Sleeping Beauty case unsupported. I consider two ways that halfers might avoid the absurdity without giving up their key premise. Neither way succeeds. My argument lends support to the thirder response, and, in particular, to the idea that agents may be rationally compelled to update their beliefs despite not having learned any new evidence.

This essay examines gender normative and patriarchal elements of the popular fairy            tale Sleeping Beauty in order to expose how patriarchal ideals are upheld. The reason for this is that children may internalize the values taught in these stories, which may lead to them perpetuating patriarchal ideals and gender normative behavior. The popular version of this fairy tale, made by Disney, follows many of the typical patriarchal ideals with a strong male hero, a wicked female witch and a weak and submissive young female, close to nature. This is contrasted by a modern retelling by Cameron Dokey that is, in many ways, gender subversive and challenges the traditional gender roles and attributes. This essay finds that the version made by Disney is a product of its time, and portrays ideals from that period that could affect children of today into internalizing archaic patriarchal ideals. Dokey’s version is better adapted to the current socio-cultural environment and succeeds in aligning the story with modern values and provides a better option to teach children the actual values and gender roles of our society. / Denna uppsats undersöker könsnormativa och patriarkala element i den populära sagan Törnrosa, för att blottlägga hur patriarkala ideal upprätthålls. Anledningen till detta är att barn kan internalisera de värderingar som lärs ut i dessa sagor, vilket kan leda till att de upprätthåller patriarkala ideal och könsnormativa beteenden. Disneys populära version av sagan följer många av de typiska patriarkala idealen, med en stark manlig hjälte, en ond kvinnlig häxa och en svag och undergiven ung kvinna, som är nära kopplad till naturen. Denna version kontrasteras av en modern återberättelse av sagan skriven av Cameron Dokey som på många sätt utmanar traditionella patriarkala könsnormer och sttribut. Disneys version är en produkt av sin tid, och porträtterar ideal från den tiden som kan påverka dagens barn att internalisera ålderdomliga könsideal. Dokeys version är bättre anpassad till den nuvarande socio-kulturella miljön och lyckas med att justera historian till att bättre passa moderna värderingar, och framstår som ett bättre alternativ för att lära barn vårat samhälles könsroller och värderingar.

Thesis (M.A.)--York University, 2004. Graduate Programme in Interdisciplinary Studies. / Typescript. Includes bibliographical references (leaves 117-123). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://wwwlib.umi.com/cr/yorku/fullcit?pMQ99392

About a decade ago, Adam Elga introduced philosophers to an intriguing puzzle. In it, Sleeping Beauty, a perfectly rational agent, undergoes an experiment in which she becomes ignorant of what time it is. This situation is puzzling for two reasons: First, because there are two equally plausible views about how she will change her degree of belief given her situation and, second, because the traditional rules for updating degrees of belief don't seem to apply to this case. In this dissertation, my goals are to settle the debate concerning this puzzle and to offer a new rule for updating some types of degrees of belief. Regarding the puzzle, I will defend a view called "the Lesser view," a view largely favorable to the Thirders' position in the traditional debate on the puzzle. Regarding the general rule for updating, I will present and defend a rule called "Shifted Jeffrey Conditionalization." My discussions of the above view and rule will complement each other: On the one hand, I defend the Lesser view by making use of Shifted Jeffrey Conditionalization. On the other hand, I test Shifted Jeffrey Conditionalization by applying it to various credal transitions in the Sleeping Beauty problem and revise that rule in accordance with the results of the test application. In the end, I will present and defend an updating rule called "General Shifted Jeffrey Conditionalization," which I suspect is the general rule for updating one's degrees of belief in so-called tensed propositions.

Sleeping Beauty (SB) Transposon-basierte Vektoren werden als Alternative zu viralen Vektoren für T-Zell-Gentherapie erforscht und ermöglichen eine schnelle und kostengünstige Genmanipulation von T-Zellen. Die Verwendung von Transposon-Vektoren erfordert jedoch die DNA-Elektroporation von T-Zellen, die sich schädlich auf T-Zellen auswirkt. DNA-elektroporierte T-Zellen weisen eine verringerte Lebensfähigkeit und eine verzögerte Aktivierung nach Stimulation des T-Zell-Rezeptors (TCR) auf. Um die Nachteile der Transposon-basierten T-Zell-Genmanipulation zu überwinden, haben wir neuartige SB-Vektoren entwickelt. Durch die Kombination von SB Transposon-basierten Minicircle-Vektoren mit SB100X Transposase-mRNA konnten T-Zellen effizient genmodifiziert werden. Unser Ansatz reduzierte die T-Zell-Mortalität und steigerte gleichzeitig die Transfektionseffizienz. Mit diesen neuartigen Vektoren wurde die stabile Expression verschiedener TCRs und CARs in über 50% der eingesetzten T-Zellen erreicht. Gentechnisch manipulierte T-Zellen konnten Antigen-spezifisch stimuliert werden und zeigten effiziente Zytokin-Sekretion und Tumorzell-Lyse. Weiterhin haben wir miRNAs entwickelt, die die Expression der endogenen TCR-Ketten unterdrücken. Der Einbau dieser miRNAs in die TCR-Expressionskassette erhöhte die Oberflächenexpression des therapeutischen TCRs, verringerte die Fehlpaarung mit endogenen TCR-Ketten und erhöhte die T-Zell-Funktionalität. Ein direkter Vergleich von SB- und Virus-modifizierten T-Zellen zeigte sowohl in vitro als auch in vivo eine vergleichbare Wirksamkeit der modifizierten T-Zellen hinsichtlich Zytokin-Sekretion, Tumorzell-Lyse und Tumorkontrolle. In dieser Arbeit konnte gezeigt werden, dass SB Minicircle-Vektoren die Herstellung von genetisch modifizierten T-Zellen ermöglichen und diese Tumor-spezifische Wirksamkeit aufweisen. Dieser Ansatz könnte die Herstellung therapeutischer T-Zellen für die personalisierte T-Zell-Gentherapie vereinfachen und beschleunigen. / Sleeping Beauty (SB) transposon-based vectors have entered clinical trials as an alternative to viral vectors for T cell gene therapy, offering time- and cost-efficient engineering of therapeutic T cells. However, transposon vectors require DNA electroporation into T cells, which we found to cause adverse effects. T cell viability was decreased, and DNA-transfected T cells showed delayed activation upon T cell receptor (TCR) stimulation regarding blast formation and proliferation. To overcome the limitations of transposon-based T cell engineering, we investigated the effect of DNA electroporation on T cells and developed novel SB vectors. T cells could efficiently be engineered with Sleeping Beauty vectors by combining SB transposon minicircles and SB100X transposase mRNA. Our approach reduced T cell mortality and substantially enhanced transfection efficiency. We achieved stable expression of several TCRs and CARs in more than 50% of the transfected T cells compared to 15% when conventional plasmids were used. T cells engineered to express a tumor-specific TCR mediated effective tumor cell lysis and cytokine secretion upon antigen-specific stimulation. Furthermore, we developed miRNAs to silence the expression of the endogenous TCR chains. Incorporation of these miRNAs into the TCR expression cassette increased surface expression of the therapeutic TCR, diminished mispairing with endogenous TCR chains, and enhanced T cell functionality. Importantly, a direct comparison of SB minicircle- and RV-engineered T cells in vitro as well as in vivo demonstrated equal T cell efficacy with regards to cytokine release, tumor cell lysis and tumor control. We demonstrated that SB minicircles enable the generation of gene-modified T cells with tumor-specific reactivity. Our approach facilitates the manufacturing of therapeutic T cells with superior biosafety and accelerates the generation of patient-specific T cell products for personalized T cell gene therapy.

Cancer is the second most common cause of death in the United States. It is a complex disease with environmental, genetic, and lifestyle factors influencing the likelihood of getting cancer and the development of any resulting tumor. Understanding the genetics of cancer is integral to developing novel patient-specific treatments. However, due to complexity, hundreds to thousands of tumors are required for sufficient power to identify the network of relationships among these genes. Animal models of cancer are commonly used to reduce cost and to control experimental variables allowing for more specific hypothesis testing. The Sleeping Beauty transposon mutagenesis system can be used to model cancer in mice. While the Sleeping Beauty mutagenesis system is an important tool in understanding cancer, it has specific computational needs. Experiments need to be analyzed in a fast, unbiased, and efficient manner. A computational method must also accurately model the system allowing for validation and interpretation. Here I present an updated Integration Analysis System and use this system to validate the assumptions present in forward genetic screens of cancer using the Sleeping Beauty. This system allows for rapid identification of cancer genes, but does not directly aid in understanding the relationship between the genes. Given the complexity of cancer, understanding the relationship between cancer genes is very difficult. I have created a connectedness network utilizing the STRING database to better derive an understanding of cancer genes. STRING is a database of known and predicted protein-protein interactions. The connectedness between pairs of genes is calculated using a network reliability metric. This database allows for increased power to detect known pathways when compared to STRING alone. Combining this connectivity network with the set of cancer genes identified by the Integration Analysis System is a strategy for rapid and efficient interpretation of the genetic results.

Gynecological cancers present a tremendous disease burden worldwide. Endometrial cancer, the most common gynecological malignancy, is predominantly a disease of deranged glandular function. The mechanisms by which known environmental risk factors influence the mutational profile of endometrial cancer are poorly understood. Non-HPV vulvar cancer, on the other hand, is a very rare gynecological malignancy of vulvar squamous cells with little known about its pathogenesis. Surgical resection of vulvar cancer is associated with high post-surgical morbidity. Pivotal to improving treatment and outcomes for patients with gynecological cancers is an understanding of the molecular drivers unique to each tumor type. To inform our understanding of endometrial gland regulation, I began my investigations with an assessment of normal endometrial adenogenesis in vivo and present the first evidence implicating the necessity of Sox17 in endometrial gland development. My data suggest Sox17 mediates adenogenesis via a non-cell autonomous mechanism from within the stromal compartment of the endometrium. I then interrogated the contribution of SOX17 to dysregulated glandular function in Type I endometrial adenocarcinoma in vitro. My findings reveal an oncogenic role of SOX17 in the Ishikawa Type 1 endometrial cancer cell line, with homozygous loss of SOX17 impairing cellular proliferation, blunting the cancer phenotype of these cells. The majority of cancers, including gynecological cancers, develop from the accumulation of genetic mutations that occur sporadically in cells over time. The complexity and heterogeneity of solid tumors, however, renders the identification of mutations responsible for driving tumorigenesis difficult. The Sleeping Beauty (SB) insertional mutagenesis system can be used to streamline sporadic tumor formation and driver mutation identification. I present results from an initial attempt to develop an SB model of endometrial cancer and discuss ways in which the SB system can be harnessed to evaluate tumorigenesis in a variety of tissue types and microenvironmental contexts. Finally, I present an SB model of metastatic vulvar cancer. Primary tumors from this model resulted in the identification of 76 novel candidate drivers of vulvar cancer, with the ubiquitin-specific peptidase, Usp9x, the most commonly disrupted gene in our screen. I show data suggesting that differential expression of Usp9x isoforms may underlie Usp9x-mediated tumorigenesis and preliminary data demonstrating the relevance of USP9X to human vulvar cancer. Taken as a whole, these data contribute to our scientific understanding of gynecological tissue homeostasis and cancers, lay the foundation for the development of an SB model of endometrial cancer, and describe the first reported model system for studying HPV-naive vulvar cancer in vivo.

Cancer is one of the leading causes of death in the world. Approximately one fifth of deaths in the western industrial nations are caused by cancer. Every year several hundreds of thousands of new patients are diagnosed with cancer and several thousands die of cancer. Scientists have been conducting research from different angles for effective prevention, diagnosis and cure of Cancer. Ever since the genetic basis of cancer has been demonstrated, a race has been ignited globally in the scientific community to identify potential oncogenes and tumor suppressor genes. The genetics of the tumors are complex in nature where combinations of loss of function mutations in tumor suppressor genes and gain of function mutations in oncogenes cause cancers. The identification of these genes is extremely important to devise effective therapies to treat cancer. Insertional mutagenesis systems such as sleeping beauty provide an elegant way to identify genes involved in cancers. More and more researchers are adopting the Sleeping Beauty system for their insertional mutagenesis experiments to identify potential cancer causing genes. Given next generation sequence technologies and the vast amount of data they generate requires novel bioinformatics techniques to process, analyze and meaningfully interpret the data. The goal of this project is to develop a publicly available system for researchers worldwide to analyze the sequence data resulting from insertional mutagenesis experiments. This system will identify and annotate all the insertion sites resulting from the sequencing of the experiment. It will also identify the Common Insertion sites (CIS) and genes with Common Insertion Sites (gCIS). The Common Insertion Sites being the regions in the genome that are targeted more often than by chance. The whole system is accessible as a web application for use by researchers worldwide performing insertional mutagenesis experiments.

<p>When attempting to convey certain political or ideological agendas in literary texts maintaining specific writing strategies can work as a useful tool. From a feminist perspective the use of <em>écriture feminine</em> as a means of undermining patriarchy has been largely neglected as well as misunderstood by many feminists. However, as argued in this essay, <em>écriture feminine</em> is not only a useful tool for pursuing a feminist agenda, but is also something that needs to be discussed due to the many misunderstandings of it. Resting on the theoretical perspectives of Judith Butler, Hélène Cixous, Antonio Gramsci, Eve Kosofsky Sedgwick and Richard Slotkin this essay investigates Angela Carter’s short story “The Lady of the House of Love” in relation to <em>écriture feminine</em> by exploring how the text rejects patriarchy and its idea of the gender binary. In this short story Carter re-works the classic Sleeping Beauty fairy tale and provides us with a feminist’s version of it. The main thesis of this essay is therefore that Carter challenges the gender binary by de-victimizing “woman” and by engaging in a style of writing that overturns western culture’s definitions of “woman” Carter provides a version of Sleeping Beauty that radically differs from the hegemonic/patriarchal versions.</p>

Glioblastoma multiforme (GBM), the most common and malignant brain tumor, is characterized by high molecular and cellular heterogeneity within and among tumors. Parameters such as invasive growth, infiltration of immune cells and endothelial proliferation contribute in a systemic manner to maintain the malignancy. Studies in this thesis show that the expression of Sox2 is correlated with Sox21 in human gliomas. We demonstrate that an upregulation of Sox21 induces loss of proliferation, apoptosis and differentiation in glioma cells in vitro and in vivo and seems to correlate with decreased Sox2 expression. Induced expression of Sox21 in vivo significantly reduces the tumor size and increase the survival extensively, suggesting that Sox21 can act as a tumor suppressor Our studies indicate that the balance of Sox21-Sox2 in glioma cells is decisive of either a proliferative or a non-proliferative state. Several TGFß family members have an important role in glioma development. TGFß promotes proliferation and tumorigenicity whereas BMPs mostly inhibit proliferation. We demonstrate that BMP7 can induce the transcription factor Snail in glioma cells and that this reduces the tumorigenicity with a concomitant increase in invasiveness. Thus, we have identified a mechanism to the double-edged sword of proliferation versus invasiveness in GBM, the latter contributing to relapse in patients. Experimental gliomas were induced with the Sleeping Beauty (SB) model in mice with different immunological status of their T cells. The tumors that developed were either GBMs or highly diffuse in their growth, reminiscent of gliomatosis cerebri (GC). GC is a highly uncommon form of glioma characterized by extensive infiltrative growth in large parts of the brain. It is an orphan disease and today there is practically a total lack of relevant experimental models. The SB system would constitute a novel experimental model to study the mechanisms behind the development of diffusely growing tumors like GC. The presence or absence of T cells did not affect tumor development. The work in this thesis demonstrates that the proliferative and the invasive capacities of glioma cells can be dissociated and that the SB model constitutes an excellent model to study the highly proliferative cells in GBMs versus the highly invasive cells in diffuse tumors like .GC.