Doctor of Philosophy (PhD) / The toxicity of platinum anticancer drugs presents a major obstacle in the effective treatment of tumours. Much of the toxicity stems from a lack of specificity of the drugs for the sites at which they are able to exert maximum anticancer activity. An improved understanding of the behaviour of the drugs in the tumour environment may assist in the rational design of future platinum anticancer agents with enhanced specificity and reduced toxicity. In the work presented herein, the specificity of two classes of platinum anticancer agents was assessed (platinum(IV) cisplatin analogues and platinum(II) anthraquinone complexes). The interaction of the platinum(IV) agents with DNA, believed to be their main cellular target, was examined using XANES spectroscopy. This experiment was designed to assess the ability of the drugs to interact with DNA and thus exert their anticancer activity. It was shown that the platinum(IV) complexes were not reduced by DNA during 48 hr incubation. It was not possible to conclusively determine whether the interaction of the complexes with DNA was direct or platinum(II) catalysed, or whether interaction had occurred at all. The distribution of platinum(II) anthraquinone complexes and their corresponding anthraquinone ligands in tumour cells (A2780 ovarian and DLD-1 colon cancer cell lines) was investigated. The cytotoxicity of the compounds in DLD-1 cells was also assessed. It was found that the compounds were efficiently taken up into the cells and entered the lysosomal compartments almost exclusively. This suggested that the cytotoxicity of the drugs was caused by lysosomal disruption, or that the platinum complexes were degraded, leaving a platinum species to enter the cell nuclei and interact with DNA. Alternatively, the complexes may bind to proteins and transport into the nuclei of the cells, though with their fluorescence quenched by the protein. The penetration and distribution of platinum(IV) complexes was assessed in DLD-1 multicellular tumour spheroids (established models of solid tumours) using a number of synchrotron techniques, including micro-tomography, micro-SRIXE, and micro-XANES. The complexes were found to be capable of penetrating throughout the entire volume of the spheroids. Micro-XANES indicated that in central and peripheral spheroidal regions, bound platinum species were present largely as platinum(II).

<p>This thesis focuses on host and pathogen specific interactions during invasive disease. We have investigated the role and impact of different virulence factors of <i>Neisseria gonorrhoeae, N. meningitidis</i> and <i>Streptococcus pyogenes</i> on host epithelial cells and <i>in vivo</i>. </p><p><i>N. gonorrhoeae</i> cause the sexually transmitted disease gonorrhoea and <i>N. meningitidis</i> is the most common cause of bacterial meningitis and may be leathal to the host within hours of infection. The neisserial type IV pili were shown to have an important impact on host cells for the induction of pro-inflammatory and other cellular defence transcriptional responses. Furthermore, <i>N. meningitidis</i> generally induced an earlier response compared to <i>N. gonorrhoeae</i>, probably as a result of the meningococcal capsule. The role of <i>N. meningitidis</i> serogroup B lipooliogsaccharide was investigated during invasive disease. Bacterial invasion of host cells and blood survival as well as virulence in vivo was dependent on the integrity of the LOS structure. </p><p><i>S. pyogenes</i> may cause a variety of diseases ranging from uncomplicated diseases such as 'strep-throat' to more severe invasive diseases such as necrotizing fasciitis and streptococcal toxic shock syndrome. <i>S. pyogenes</i> ScpC protease degrade interleukin 8 during necrotizing fasciitis. We investigated the role of ScpC in systemic disease and observed enhanced virulence by bacteria unable to degrade IL-8. Following an intravenous infection of mice pro-inflammatory cytokines and complement activation was induced by the ScpC negative mutant compared to the wild-type and correlated with higher bacteremia. These data indicate that the precense of the ScpC protease has an important impact on the host for the outcome of streptococcal sepsis. Another phagocytic escape mechanism of <i>S. pyogenes</i> is their ability to coat themselves with host proteins. We observed that released complement control protein, CD46, bound to the streptococcal cell surface. CD46 has been shown to interact with the streptococcal M protein and have now been found to bind to the surface of the bacteria in a growth phase dependent manner. We observed a more aggressive disease development in CD46 transgenic mice after an intravenous infection with an M6 serotype, resulting in higher mortality of CD46 transgenic mice compared with control mice. These data indicate that CD46 may confer a protection to the streptococci during early stage of systemic infection and contributes to the understanding of immune evsion of <i>S. pyogenes</i>.</p>

This thesis focuses on host and pathogen specific interactions during invasive disease. We have investigated the role and impact of different virulence factors of Neisseria gonorrhoeae, N. meningitidis and Streptococcus pyogenes on host epithelial cells and in vivo. N. gonorrhoeae cause the sexually transmitted disease gonorrhoea and N. meningitidis is the most common cause of bacterial meningitis and may be leathal to the host within hours of infection. The neisserial type IV pili were shown to have an important impact on host cells for the induction of pro-inflammatory and other cellular defence transcriptional responses. Furthermore, N. meningitidis generally induced an earlier response compared to N. gonorrhoeae, probably as a result of the meningococcal capsule. The role of N. meningitidis serogroup B lipooliogsaccharide was investigated during invasive disease. Bacterial invasion of host cells and blood survival as well as virulence in vivo was dependent on the integrity of the LOS structure. S. pyogenes may cause a variety of diseases ranging from uncomplicated diseases such as 'strep-throat' to more severe invasive diseases such as necrotizing fasciitis and streptococcal toxic shock syndrome. S. pyogenes ScpC protease degrade interleukin 8 during necrotizing fasciitis. We investigated the role of ScpC in systemic disease and observed enhanced virulence by bacteria unable to degrade IL-8. Following an intravenous infection of mice pro-inflammatory cytokines and complement activation was induced by the ScpC negative mutant compared to the wild-type and correlated with higher bacteremia. These data indicate that the precense of the ScpC protease has an important impact on the host for the outcome of streptococcal sepsis. Another phagocytic escape mechanism of S. pyogenes is their ability to coat themselves with host proteins. We observed that released complement control protein, CD46, bound to the streptococcal cell surface. CD46 has been shown to interact with the streptococcal M protein and have now been found to bind to the surface of the bacteria in a growth phase dependent manner. We observed a more aggressive disease development in CD46 transgenic mice after an intravenous infection with an M6 serotype, resulting in higher mortality of CD46 transgenic mice compared with control mice. These data indicate that CD46 may confer a protection to the streptococci during early stage of systemic infection and contributes to the understanding of immune evsion of S. pyogenes.

This dissertation examines the effect of fiscal decentralization on poverty reduction and explores potential transmission channels through pro-poor sectoral outcomes such as basic education, basic healthcare and agricultural productivity. We first develop a theoretical model to explain the interaction between decentralization and poverty reduction outcomes. In particular, we show that the marginal effect of fiscal decentralization on pro-poor sectors depends largely on the outcome of the trade-off between potential benefits derived from better matching of local preference due to local proximity, and the lack of technical capacity at the local level. This finding provides, in a way, a theoretical explanation of the different outcomes observed in fiscal decentralization programs around the world. This inconclusive theoretical result motivates an empirical analysis to assess whether there is any statistical significant relationship between fiscal decentralization and poverty. We implement this estimation using the Generalized Method of Moment Instrumental Variable (GMM-IV) methodology on 97 countries spanned over the period 1975-2000. Our estimation results reveal a statistically significant, but non-linear relationship between fiscal decentralization and poverty. In addition, we empirically explore potential transmission mechanism of the effect of fiscal decentralization on poverty through three sectors (basic education, basic healthcare and agricultural extension) that have been shown in the literature on basic needs and also by development practitioners to have significant bearing on the well-being of the poor. Finally, given the relatively high level of poverty in addition to the fact that most African countries are far behind in attaining their Millennium Development Goals (MDGs) targets, we investigate whether the effect of fiscal decentralization on poverty will be greater in Sub-Saharan Africa (SSA) relative to other regions.

No description available.

This thesis presents an architecture and an FPGA implementation of the two dimensional discrete wavelet transformation (DWT) for applications where row-based raw image data is streamed in at high bandwidths and local buffering of the entire image is not feasible. The architecture is especially suited for multi-spectral imager systems, such as on board an imaging satellite, however can be used in any application where time to next image constraints require real-time processing of multiple images. The latency that is introduced as the images stream through the iii DWT module and the amount of locally stored image data, is a function of the image and tile size. For an n1 &times / n2 size image processed using (n1/k1) &times / (n2/k2) sized tiles the latency is equal to the time elapsed to accumulate a (1/k1) portion of one image. In addition, a (2/k1) portion of each image is buffered locally. The proposed hardware has been implemented on an FPGA and is part of a JPEG 2000 compression system designed as a payload for a low earth orbit (LEO) micro-satellite to be launched in September 2003. The architecture can achieve a throughput of up to 160Mbit/s. The latency introduced is 0.105 sec (6.25% of total transmission time) for tile sizes of 256&times / 256. The local storage size required for the tiling operation is 2 MB. The internal storage requirement is 1536 pixels. Equivalent gate count for the design is 292,447.

The development of resistance measurement techniques is very important for characterization of future nanoelectronics. Pulsed IV measurement techniques are very useful for accurate resistance measurements on nanoscale samples because of the efficient removal of e.g. EMF errors. In the project we have designed a pulsed IV-setup based on a state-of-the art current source (6221) and nanovoltmeter (2182A) from Keithley, and used the setup for resistance measurements on ferromagnetic samples. Two different samples were investigated using the pulsed IV system – ferromagnetic wires with a central nanoconstriction and amorphous microwires. We have tested the pulse delta system with different pulse widths, duty cycles and voltage levels. The results show a successful integration of the setup. From the measurement results we confirm that the pulse delta system provides accurate measurements with a low noise of about 0.02Ω. The resistance of the samples increases approximately quadratically with bias which is interpreted as a heating effect due to the very high current density of about 107A∙cm-2.

Examensarbete 15 poäng i lärarutbildningen höstterminen 2007 Sammanfattning Författare: Robert Grandén ”Man är trygg här på nåt sätt” En fallstudie om gymnasieskolans individuella program. ”You feel secure here in some kind of way” A study about the individual program in high school. Antal sidor: 35 Mitt ämnesval tog sin bakgrund i att jag arbetat fem år som högstadielärare och var nyfiken på vad som händer med de elever som inte tar sig in på ett nationellt gymnasieprogram. Den heta debatt som pågår om det individuella programmets vara eller inte vara var ännu ett skäl för mig att lyfta ämnet. Syftet med det här examensarbetet var att undersöka om det individuella programmet hade en större betydelse för eleverna som gick där än att bara läsa upp sina betyg. Jag ville även undersöka vad dessa elever hade för erfarenhet av sina tre år på högstadiet samt hur lärarna på det individuella programmet såg på sin lärarroll. Metodvalet för min undersökning var kvalitativ och bestod i semistrukturerade intervjuer med fyra elever och två lärare. Det resultat som studien kom fram till visade att eleverna hade en negativ bild av sin tid på högstadiet och att det individuella programmet erbjöd dem en positivare skolupplevelse.

Catalase-peroxidase (KatG) of Mycobacterium tuberculosis is a bifunctional heme enzyme that has been shown to play an important role in the activation of a first line drug, isoniazid (INH), used in the treatment of tuberculosis infection. Mutations in the katG gene have been found to be associated with INH resistance. The most commonly encountered mutation is the Ser315Thr point mutation. In this dissertation, the x-ray crystallographic structures of MtbKatG and the mutant enzyme KatG[S315T] are presented to explore the molecular basis of the INH activation and resistance. The structure is dimeric and contains a heme cofactor in each subunit of the dimer. The most important change in KatG[S315T] is due to the presence of the methyl group of the threonine 315 side chain, which is located at the narrowest part of the substrate channel. The protruding methyl group effectively constricts the accessibility to the heme by closing down the dimensions of the channel, constraining the substrate entrance. VirB11 of Brucella abortus is a hexameric ATPase that belongs to the type IV secretion system. The crystal structure of BaVirB11 was found to contain six molecules per asymmetric unit. The Walker A (P loop), His box, and Glu box from the C-terminal domain are located at the interface of the N- and C-terminal domain. A large conformational change was found in the linker region when compared with that of HP0525 structure, the VirB11 analogous from H. pylori. To elucidate the functional role of each domain, seven functional mutations were generated and used for biochemical studies. The GER motif and the linker region were found to be crucial for ATP hydrolysis activity of BaVirB11. Mutations in the GER motif (R101Q) and the linker region (R120E) of BaVirB11 completely abolish the ATP hydrolysis activity of the enzyme. The binding affinities of the two mutants to the ATP; however, are similar to that of the wild-type enzyme, indicating that mutation in the GER motif or the linker region has no effect on ATP binding.

<p>Examensarbete 15 poäng</p><p>i lärarutbildningen</p><p>höstterminen 2007</p><p>Sammanfattning</p><p>Författare: Robert Grandén</p><p>”Man är trygg här på nåt sätt”</p><p>En fallstudie om gymnasieskolans individuella program.</p><p>”You feel secure here in some kind of way”</p><p>A study about the individual program in high school.</p><p>Antal sidor: 35</p><p>Mitt ämnesval tog sin bakgrund i att jag arbetat fem år som högstadielärare och var nyfiken på vad som händer med de elever som inte tar sig in på ett nationellt gymnasieprogram. Den heta debatt som pågår om det individuella programmets vara eller inte vara var ännu ett skäl för mig att lyfta ämnet. Syftet med det här examensarbetet var att undersöka om det individuella programmet hade en större betydelse för eleverna som gick där än att bara läsa upp sina betyg. Jag ville även undersöka vad dessa elever hade för erfarenhet av sina tre år på högstadiet samt hur lärarna på det individuella programmet såg på sin lärarroll. Metodvalet för min undersökning var kvalitativ och bestod i semistrukturerade intervjuer med fyra elever och två lärare. Det resultat som studien kom fram till visade att eleverna hade en negativ bild av sin tid på högstadiet och att det individuella programmet erbjöd dem en positivare skolupplevelse.</p>