Zugl.: München, Univ., Diss., 2009

Zugl.: Köln, Universiẗat, Diss., 2009.

Universiẗat, Diss., 2000--Köln.

Thesis (Ph. D.)--University of Chicago, Dept. of Neurobiology, Pharmacology and Physiology, December 2002. / Includes bibliographical references. Also available on the Internet.

Master-Arbeit Univ. St. Gallen, 2007.

Thesis (Ph.D.)--University of Delaware, 2007. / Principal faculty advisor: Eric B. Kmiec, Dept. of Biological Sciences. Includes bibliographical references.

Universiẗat, Diss., 2002--Bielefeld.

A targeted, stimuli-responsive, polymeric drug delivery vehicle has been developed to help alleviate the severe side-effects caused by narrow therapeutic window drugs. Doxorubicin, a commonly used chemotherapeutic agent has been conjugated to dextran by two different techniques. In the first method, doxorubicin and hepatocyte-targeting galactosamine were attached to dextran through amine bonds. Conjugation efficiency based on the amount loaded of each reactant varied from 1% to 50% for doxorubicin and from 2% to 20% for galactosamine, depending on various synthesis parameters. For the second conjugate, doxorubicin was attached to dextran through an acid-labile hydrazide bond. Fluorescence quenching indicated that all our conjugates can bind to DNA. The degree of binding was improved with increasing polymer molecular weight and substitution of doxorubicin, and also with hydrazide-bonded conjugate. In cell culture experiments, we have found that the uptake of conjugates was much lower than that of free doxorubicin. Lower uptake of conjugates decreased the toxicity of doxorubicin. Also, the uptake of non-galactosylated conjugate was lower than that of the galactosylated conjugate. Microscopy studies indicated that doxorubicin was localized almost exclusively at the nucleus, whereas the amine-bonded conjugates were present throughout the cell. Targeted amine-linked conjugates and hydrazide-bonded conjugates achieved greatly improved cytotoxicity. Following uptake, the doxorubicin was dissociated from the hydrazide conjugate in an endosomal compartment and diffused to the nucleus. The LC₅₀ values of non-targeted amine-linked, targeted amine-linked, and hydrazide-linked doxorubicin were 19.81 μg/mL, 7.33 μg/mL and 4.39 μg/mL, respectively. The amine-linked conjugates were also tested on a multidrug-resistant cell line; the LC₅₀ values of doxorubicin and the non-targeted amine-linked conjugate were 8.60 μg/mL and 36.02 μg/mL, respectively. / Singapore-MIT Alliance (SMA)

Peroxisomes are dynamic and multifunctional organelles, which are essential for human health and development. They are remarkably diverse, with functions that vary significantly between cells and organisms, and can dramatically change their size, shape and dynamics in response to cellular cues. In the past few years, several studies have significantly increased our understanding of the basic principles that enable peroxisome biogenesis and degradation, as well as their pivotal role in cellular signalling and homeostasis. However, several of these processes are still poorly understood. In this thesis we initially studied the peroxisome targeting mechanism of a group of C-terminally anchored membrane proteins, known as tail-anchored (TA) proteins. In order to investigate the molecular signals that enable TA protein targeting to cellular organelles, we analysed the physicochemical properties of a cohort of TA proteins both in silico and in vivo, and show that a combination of transmembrane domain (TMD) hydrophobicity and C-terminal tail charge determines organelle-specific targeting. Focusing on peroxisomes, we demonstrate that a balance between TMD hydrophobicity and high positive tail charge directs TA proteins to this organelle, and enables binding to the peroxisomal chaperone PEX19. These results allowed us to create a bioinformatical tool to predict the targeting of uncharacterised TA proteins and further develop our understanding of the molecular mechanisms involved in the targeting of this protein group. From our initial TA protein screen, we identified the TA protein MIRO1 at peroxisomes and looked at its role in the regulation of peroxisome motility. We show that endogenous MIRO1 localises to mitochondria and peroxisomes, and that dual targeting depends on the C-terminal tail. MIRO1 expression significantly increased peroxisome motility in several cell lines, and revealed a role for motility in peroxisome dynamics, by inducing organelle proliferation and elongation. These results reveal a new molecular complex at peroxisomes and provide us with a tool to further dissect the role of motility on peroxisome function.

A assimetria nas preferências dos Bancos Centrais é um assunto que vem sendo muito discutido no meio acadêmico, mas até o momento essa polêmica tem se restringido a economias desenvolvidas como a canadense e inglesa. O que o texto a seguir se propõe é, em parte, tentar trazer essa discussão para o campo dos países emergentes, tomando como centro da análise a economia brasileira. Preferências assimétricas consistem num comportamento por parte da autoridade monetária que atribui perdas diferentes a desvios da taxa de inflação observada em relação à meta definida, que embora sejam de mesma magnitude apresentam sinais opostos. Replicando os testes já usados em outros estudos, o regime de Metas de Inflação é aqui abordado, iniciando sua análise sob uma ótica mais geral e depois o particularizando para a economia brasileira, desde sua concepção (em 1999 após a crise cambial de janeiro desse ano) até os dias atuais. Este comportamento assimétrico parece, ainda, ocasionar um viés inflacionário diferente daquele proposto pelo modelo KPBG (Kydland-Prescott-Barro-Gordon) que surge da ambição do Banco Central em estabelecer uma taxa de desemprego que esteja abaixo da taxa natural, num ambiente no qual as preferências, ao contrário do proposto, são quadráticas. Infelizmente, os dados brasileiros ainda não apontam na direção da assimetria, talvez por causa do tempo de implantação do regime no Brasil, talvez devido às turbulências que a economia brasileira sofreu decorrentes de crises internacionais e de suas conseqüências sobre o desempenho da política de Metas de Inflação que gerou inúmeros insucessos. No entanto, o histórico de hiperinflações e sua influência sobre as expectativas e os comportamentos dos agentes econômicos nos faz suspeitar de que dentro em breve a assimetria será não só detectada em nossa economia como também será fruto de estudos para o desenho e direcionamento da política monetária. / Central Banks preferences asymmetry is a subject that has been discussed for quite some time in academic publications. However, such controversy has been restricted to developed economies, such as the English and Canadian ones, so far. The following text intends to bring about the discussion to emerging countries, using the brazilian economy as the focus of the analysis. Asymmetric preferences can be defined as a particular behaviour of the monetary authorities that weigh differently their losses concerning inflation deviations from its predetermined target that have the same magnitude but different signs. The main tests used in other studies have been repeated here and the inflation target regime is approached, initially from a broader outlook and then specifically to the brazilian case, ever since its conception in 1999 (after the exchange rate crash in the same year) to the present day. The asymmetric behaviour seems to cause an inflationary bias different from the one proposed by the KPBG model (Kydland-Prescott-Barro-Gordon) which derives from the Central Bank ambition to establish an unemployment rate lower than its natural rate, in an environment in which preferences are quadratic. Unfortunately, brazilian data do not suggest asymmetry yet, maybe because the inflation target regime has been installed for too little time, or because of all the turmoil in the brazilian economy in recent international crisis and their consequences on the regime performance, that has been usually compromised. Nevertheless, the history of hyperinflations and their impacts on expectations and the agents behaviour raises suspicions that soon not only will asymmetry be found in our economy but it will also be studied to design monetary policy directives.