Thesis (Ph. D.)--University of Chicago, Dept. of Biochemistry and Molecular Biology, June 2003. / Includes bibliographical references. Also available on the Internet.

Würzburg, Univ., Diss., 2004. / Erscheinungsjahr an der Haupttitelstelle: 2004

Thesis (Ph. D.)--University of Hong Kong, 2010. / Includes bibliographical references (leaves 92-100). Also available in print.

Thesis (M. Sc.)--University of Canterbury, 2006. / Typescript (photocopy). Includes bibliographical references (leaves 103-111). Also available via the World Wide Web.

Thesis (Ph. D.)--Virginia Commonwealth University, 2006. / Prepared for: Dept. of Human Genetics. Bibliography: leaves 111-135.

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Orientador: José Roberto Bosqueiro / Banca: Mirtes Costa / Banca: Célia Regina Nogueira / Resumo: Os glicocorticóides são amplamente utilizados na prática clínica como agentes antiinflamatórios e imunossupressores, e estão entre as drogas utilizadas nos tratamentos de cânceres, como o de próstata. Contudo, seu uso prolongado ou excessivo pode desencadear o diabetes mellitus tipo 2, caracterizado pela hiperglicemia devido à resistência periférica à insulina. Recente estudo do nosso grupo de pesquisa, utilizando modelo de diminuição da sensibilidade periférica à insulina pela administração de dexametasona (DEX, 1 mg/kg, ip) por 5 dias, demonstrou, na próstata ventral de ratos, atrofia epitelial e das células musculares lisas, além de alterações de elementos celulares do estroma prostático, como os fibroblastos. A partir deste estudo, inúmeras perguntas surgiram acerca dos mecanismos de sinalização presentes no tecido prostático neste modelo, especialmente em relação à insulina. Assim, neste trabalho investigamos as vias de sinalização da insulina e a proliferação celular epitelial na próstata ventral de ratos no modelo de resistência à insulina induzida pelo tratamento com dexametasona, buscando possível correlação com a expressão dos receptores de glicocorticóides (GR) e de andrógenos (AR). A resistência à insulina foi induzida em ratos Wistar machos adultos (n=4) pela administração de dexametasona (DEX, 1 mg/kg, ip), durante 5 dias, enquanto os ratos controles (CTL) receberam solução salina. O tratamento com a dexametasona resultou em diminuição significativa no peso corporal, mas não do peso prostático. Reduções na expressão das proteínas IRS-1/AKT/mTOR, constituintes da via de sinalização da insulina, e nos níveis das proteínas AR e GR foram observados nas próstatas de ratos resistentes à insulina, comparados com o grupo CTL.A frequência de células ARpositivas no epitélio acinar da próstata diminuiu no grupo tratado... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Glucocorticoids are widely used in clinical practice as anti-inflammatory and immunosuppressants agents, and are among the drugs used in treatment of cancers, such as the prostate. However, excessive or prolonged use can trigger diabetes mellitus type 2, characterized by hyperglycemia due to peripheral insulin resistance. Recent study of our research group, using model of decreased peripheral insulin sensitivity by administration of dexamethasone (DEX, 1 mg / kg, ip) for 5 days, showed, in rat ventral prostate, epithelial atrophy and of smooth muscle cells, in addition to alterations of cellular elements of the prostatic stroma, such as fibroblasts. From this study, many questions have arisen about the signaling mechanisms present in prostate tissue in this model, especially in relation to insulin. Thus, this study investigated the insulin signaling pathway and epithelial cell proliferation in the rat prostate in a model of insulin resistance induced by treatment with dexamethasone, searching for possible correlation with the expression of glucocorticoid (GR) and androgen (AR) receptors. Insulin resistance was induced in adult male Wistar rats (n=4) by the administration of dexamethasone (DEX, 1 mg/kg, ip) for 5 days, while the control (CTL) rats received saline. Dexamethasone treatment resulted in a significant decrease in body weight, but not of prostatic weight. Reductions in the expression of proteins IRS-1/AKT/mTOR, constituents of the signaling pathway of insulin, AR and GR levels protein were observed in the prostate of insulin resistant rats, compared with the CTL group. The frequency of ARpositive cells in the acinar epithelium of the prostate decreased in the group treated with DEX. Furthermore, the intensity of reaction for this receptor in the cell nuclei was lower in this group. The treatment with glucocorticoid reduced the frequency of PCNA-positive cells by 30-fold... (Complete abstract click electronic access below) / Mestre

For over a decade, we have heard alarming statements about the spread of cyber weapons from senior policymakers and experts. Yet, the dynamics of cyber proliferation are still under-studied and under-theorized. This study offers a theoretical and empirical account of what causes the spread and restraint of cyber weapons and argues that the world is not at the brink of mass cyber proliferation. Whilst almost forty states are exploring and pursuing the development of cyber weapons, I indicate that only few have so far acquired a meaningful capability. This is due both to supply and demand factors. On the supply-side, most states have a latent capacity to develop relatively simple offensive cyber capabilities, but are unable to develop sophisticated cyber weapons. Moreover, the incentives for knowledge transfer and thus exporting offensive cyber capabilities between states are weak. On the demand-side, I show that national security considerations do not provide the best explanation of variance. Instead, domestic politics and prestige considerations are paramount. Moreover, and unlike nuclear proliferation, I argue that it is not the possession of cyber weapons but the intention of possession signalled through visible initiatives which matters. Ultimately, I note that cyber weapons can have strategic value - but only under certain conditions.

Doctor of Philosophy / Security Studies Interdepartmental Program / David R. Stone / Best known for being a ‘rollercoaster’ and a ‘marriage of convenience’, various scholars have tried to reflect upon the true nature of Pak-U.S. relationship under this banner. However, no matter how one examines this relationship one thing is certain –– the experience for both countries has been harrowing. After India settled for non-alignment early in the Cold War, Pakistan seized the opportunity and aligned itself with the United States in the East-West struggle and pledged allegiance to fight communism in Asia. But that was not the only motive –– Pakistan secretly hoped that an alliance with the U.S. would provide it security against India with whom Pakistan had an antagonistic relationship over their outstanding territorial dispute of Kashmir. When the U.S. did not rescue Pakistan as it had hoped for during its war with India in 1965 and sanctioned both countries with an arms embargo, Pakistan felt betrayed. From that period onwards, Pakistan’s list of grievances against the U.S. developed into a narrative of betrayal and abandonment fed by several episodes in their relationship during and after the Cold War –– a period in which Pakistan developed and tested its nuclear weapons –– duly exploited by Pakistani leaders as a tool for populist politics. This dissertation provides the first scholarly account of Pakistan’s narrative and tests its merit against the U.S. non-proliferation policy towards Pakistan under five administrations from Ford to Clinton and finds that Pakistan’s narrative of betrayal and abandonment is uneven and misleading with respect to the objectives and successes of U.S. non-proliferation policy. This dissertation uses multi-archival documents to offer a counter-narrative which argues that Pakistan, although a small state, was able to brilliantly maneuver its way through restricted spaces in its relationship with the U.S. in the past five decades to not only acquire a decent conventional capability through U.S. military assistance but also nuclear weapons due to the fickleness of U.S. non-proliferation policy. This research concludes that the compromises made by the U.S. to accommodate Pakistan and its inconsistency in enforcement of non-proliferation laws has implications for the efficacy and success of U.S. non-proliferation policy with prospective proliferants.

Made available in DSpace on 2014-06-11T19:23:00Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-03-02Bitstream added on 2014-06-13T20:49:45Z : No. of bitstreams: 1 costa_mm_me_botib.pdf: 483607 bytes, checksum: 289e5910d4e9921c925d107cc827b1eb (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Os glicocorticóides são amplamente utilizados na prática clínica como agentes antiinflamatórios e imunossupressores, e estão entre as drogas utilizadas nos tratamentos de cânceres, como o de próstata. Contudo, seu uso prolongado ou excessivo pode desencadear o diabetes mellitus tipo 2, caracterizado pela hiperglicemia devido à resistência periférica à insulina. Recente estudo do nosso grupo de pesquisa, utilizando modelo de diminuição da sensibilidade periférica à insulina pela administração de dexametasona (DEX, 1 mg/kg, ip) por 5 dias, demonstrou, na próstata ventral de ratos, atrofia epitelial e das células musculares lisas, além de alterações de elementos celulares do estroma prostático, como os fibroblastos. A partir deste estudo, inúmeras perguntas surgiram acerca dos mecanismos de sinalização presentes no tecido prostático neste modelo, especialmente em relação à insulina. Assim, neste trabalho investigamos as vias de sinalização da insulina e a proliferação celular epitelial na próstata ventral de ratos no modelo de resistência à insulina induzida pelo tratamento com dexametasona, buscando possível correlação com a expressão dos receptores de glicocorticóides (GR) e de andrógenos (AR). A resistência à insulina foi induzida em ratos Wistar machos adultos (n=4) pela administração de dexametasona (DEX, 1 mg/kg, ip), durante 5 dias, enquanto os ratos controles (CTL) receberam solução salina. O tratamento com a dexametasona resultou em diminuição significativa no peso corporal, mas não do peso prostático. Reduções na expressão das proteínas IRS-1/AKT/mTOR, constituintes da via de sinalização da insulina, e nos níveis das proteínas AR e GR foram observados nas próstatas de ratos resistentes à insulina, comparados com o grupo CTL.A frequência de células ARpositivas no epitélio acinar da próstata diminuiu no grupo tratado... / Glucocorticoids are widely used in clinical practice as anti-inflammatory and immunosuppressants agents, and are among the drugs used in treatment of cancers, such as the prostate. However, excessive or prolonged use can trigger diabetes mellitus type 2, characterized by hyperglycemia due to peripheral insulin resistance. Recent study of our research group, using model of decreased peripheral insulin sensitivity by administration of dexamethasone (DEX, 1 mg / kg, ip) for 5 days, showed, in rat ventral prostate, epithelial atrophy and of smooth muscle cells, in addition to alterations of cellular elements of the prostatic stroma, such as fibroblasts. From this study, many questions have arisen about the signaling mechanisms present in prostate tissue in this model, especially in relation to insulin. Thus, this study investigated the insulin signaling pathway and epithelial cell proliferation in the rat prostate in a model of insulin resistance induced by treatment with dexamethasone, searching for possible correlation with the expression of glucocorticoid (GR) and androgen (AR) receptors. Insulin resistance was induced in adult male Wistar rats (n=4) by the administration of dexamethasone (DEX, 1 mg/kg, ip) for 5 days, while the control (CTL) rats received saline. Dexamethasone treatment resulted in a significant decrease in body weight, but not of prostatic weight. Reductions in the expression of proteins IRS-1/AKT/mTOR, constituents of the signaling pathway of insulin, AR and GR levels protein were observed in the prostate of insulin resistant rats, compared with the CTL group. The frequency of ARpositive cells in the acinar epithelium of the prostate decreased in the group treated with DEX. Furthermore, the intensity of reaction for this receptor in the cell nuclei was lower in this group. The treatment with glucocorticoid reduced the frequency of PCNA-positive cells by 30-fold... (Complete abstract click electronic access below)