Diss. (sammanfattning) Stockholm : Karolinska institutet, 2009. / Härtill 5 uppsatser.

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Research report presented to the SBL, Unisa, Midrand. / This report proposes to make a contribution in the area of governance by critically analyzing the governance structure of SNV (The Netherlands Development Organization) in implementing projects. This study is motivated by the scarcity of published documentation on corporate and project governance practices specific to the African and particularly Kenyan context which organisations interested in pursuing good governance and managerial practices can use as a reference point.

Essential genes are involved in control of the basic metabolism of their host. These genes encode elements involved is such crucial processes as DNA replication, transcription, translation or biosynthesis of important molecules. What makes essential genes unique is the fact that they cannot be lost from the genome. If any of them becomes inactivated it would result in inevitable death of an organism. Because of their role they can be efficiently used to control the survival of genetically modified organisms. Specific regulatory mechanisms can be applied to modulate the activity of essential genes, which prevents an organism from growing at determined conditions. Such mechanisms are called “kill switches” and have been developed in recent years as a response to significant development in the field of molecular biology. Proteins encoded by psychrophilic organisms are characterized by decreased resistance to thermal denaturation. This is believed to be a result of adaptation to low-temperature environment, where mutations that destabilize the protein structure are not selected against. For these reasons they often cannot perform their functions at moderate temperatures, which are typical for mesophilic organisms. At the same time psychrophilic proteins do not display any inhibition at permissive conditions. Use of psychrophilic alleles of essential genes has been proposed as a method of rendering modified organisms incapable of surviving at elevated temperatures. This allows generation of attenuated strains of pathogenic bacteria or generally safe versions of laboratory organisms. A temperature-sensitive organism can be created by substituting a single essential gene in mesophilic organism with its psychrophilic homologue. This can be facilitated by using the host’s native recombination system or through the use of plasmid based allele shuffling mechanisms. The objective of this work was to analyze a number of psychrophilic alleles of various essential genes for their ability to cause temperature-sensitive phenotype in mesophilic bacterium Francisella novicida. The special attention has been placed on investigating psychrophilic alleles of bacterial DNA ligase. Furthermore a selected psychrophilic strain has been characterized as a potential source of multiple temperature-sensitive alleles of essential genes. Finally the secondary focus was to develop a simple and robust mechanism allowing efficient exchange of alleles of essential genes in the mesophilic host. / Graduate

A series of investigations were conducted in order to characterise the GIT microbiota of salmonids and to determine the effect of microbial modulating feed additives on the intestinal microbiota, immunity and growth of salmonids. The first experiment, Chapter three, used PCR-DGGE and 16S rRNA gene sequence analysis of cultivable bacteria were used to investigate the GIT microbiota of brown trout. 16S rRNA gene sequence analysis demonstrated that Citrobacter freundii and Carnobacterium maltaromaticum were the predominant culturable viable bacteria and lactic acid bacteria, respectively in all regions of the GIT. DGGE revealed complex communities with a diverse range of microbes from the Firmicutes and Proteobacteria phyla. The latter chapters focused not only identifying the gut microbiota of salmonids, but also on the ability of probiotics and prebiotics to modulate these communities. In Chapter four, rainbow trout were fed a commercial diet supplemented with P. acidilactici for four weeks. P. acidilactici was detected in the GIT of the probiotic group by multiple methods and P. acidilactici was able to persist for at least 24h at the cessation of probiotic feeding. Histological appraisal on the intestine revealed significantly higher microvilli density in the posterior mucosa and a higher density of goblet cells in the anterior mucosa of the probiotic fed fish. RT-PCR results demonstrated that IL-1β, IL-8 and IgT gene expression were up-regulated in the P. acidilactici fed fish at the end of the study. Whilst mRNA of PCNA, HSP70 and casp-3 were down-regulated in the probiotic group at both sampling points. In Chapter five, the efficacy of dietary administration of P. acidilactici and short chain fructooligosaccharide (scFOS) on Atlantic salmon (Salmo salar L.) was evaluated at 63 and 132 days. Compared to the control group, total bacterial cell counts in all regions of the intestine with exception of the anterior digesta were significantly lower in the synbiotic group at the mid sampling point. PCR-DGGE revealed that species richness, diversity and the number of OTUs were significantly higher in the synbiotic group in the anterior digesta at the mid sampling point. Intestinal microvilli and villi length were increased in the anterior intestine of the synbiotic fed group at the end sampling point. IEL levels were increased in the synbiotic group in the posterior intestine at both sampling points. The expression of immunological genes were significantly up-regulated in the synbiotic fed salmon. In Chapter six, rainbow trout were fed three diets fishmeal (FM), soybean meal (SBM) and PlantMix diets supplemented with or without P. acidilactici for 12 weeks. At both sampling points, with exception of fish fed FM, LAB levels were significantly higher in all probiotic groups compared to the control groups. Serum lysozyme activity was significantly higher in fish fed FM and SBM diets containing P. acidilactici than that of fish fed the control diets. This body of research demonstrates that P. acidilactici can modulate immune response via up-regulation of immune genes as well as modulate IEL and goblet cell levels. Despite these benefits, P. acidilactici had no detrimental effects on growth performance.

The thesis presents novel formulations of hereditary cohesive zone models able to capture rate-dependent crack propagation along a defined interface. The formulations rely on the assumption that the measured fracture energy is the sum of an intrinsic fracture energy, related to the rupture of primary bonds at the atomic or molecular level, and an additional dissipation caused by any irreversible mechanisms present in the material and occurring simultaneously to fracture. The first contribution can be accounted for by introducing damage-type internal variables, which are to be driven by a rateindependent evolution law in order to be coherent with the definition as intrinsic energy. It is then proposed that the additional dissipation can be satisfactorily characterised by the same continuum-type material constitutive law obeyed by the interface material considered as a continuum: it is postulated that the dimensional reduction whereby a three-dimensional thin layer is idealized as a surface does not qualitatively alter the functional description of the free energy. The specific application considered is mode-I crack propagation along a rubber interface. After focusing on viscoelasticity as a suitable candidate to reproduce rubber’s behaviour, firstly the most common relaxation function, namely a single exponential term, is considerd after which the attention is turned to the use of fractional calculus and the related fractional integral kernel. A comparison with experimental results is presented. A shortcoming of the proposed approach is then noted, in that certain features of experimentally measured responses (i.e.the non-monotonicity of the critical energy-release rate with respect to crack speed) will be shown to be out of reach for the described modelling paradigm. A novel micromechanical formulation is then sketched in an attempt to qualitatively understand the phenomenon. An additional interface damaging mode is introduced, physically inspired by the desire to reproduce the formation of fibrils in a neighbourhood of the crack tip. Fibril formation is then driven by a variational argument applied to the whole of the interface, yielding its non-local character. Upon the introduction of an anisotropic fracture energy, motivated by experimental considerations, it is noted how the model can predict a non-monotonic energy-release rate vs crack speed behaviour, at least for a simple loading mode.

One current approach in the treatment of cancer is the inhibition of cyclin dependent kinase (CDK) enzymes with small molecules. Here the discovery and development of 2-anilino-4-(thiazol-5-yl)pyrimidine CDK inhibitors is described, including details of the design and successful synthesis of novel ring-constrained thiazolylpyrimidines. The structure-activity relationship (SAR) trends exhibited by this constrained thiazolylpyrimidine family of CDK inhibitors are presented and compared with those from an unconstrained series of analogues. One significant finding from this aspect of the project was that ring-constrained thiazolylpyrimidines in general inhibit CDK2-cyclin E with greater potency than the corresponding unconstrained forms. Furthermore, an X-ray crystal structure of 2-methyl-N-[3-nitrophenyl]-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amine, a representative from the constrained thiazolylpyrimidine series, in complex with CDK2-cyclin A is reported; confirming the binding mode within the CDK2 ATP binding pocket. A further assessment of SARs through the synthesis of control compounds and an extended study into the synthesis of N-substituted derivatives is described. The identification of CDK inhibitors that possess a strong selectivity profile across the CDK family is important. For example, the identification of highly CDK4-selective inhibitors should enable researchers to study the biological role of this important enzyme and to enable a block of cell division in the G1 phase. Here synthetic attempts to prepare a potentially CDK4 selective inhibitor compound, namely 5-methyl-N8-[4-(piperazin-1-yl)phenyl]thiazolo[4,5-h]quinazoline-2,8-diamine, are described. This approach was inspired by SAR data published on a structurally related inhibitor, 8-cyclopentyl-5-methyl-2-[4-(piperazin-1-yl)phenylamino]pyrido[2,3-d]pyrimidin-7(8H)-one.

published_or_final_version / Nursing Studies / Master / Master of Nursing

published_or_final_version / Medicine / Master / Master of Philosophy

Mixing of miscible gas with oil in a reservoir decreases the effective strength of the gas, which can adversely affect miscibility and recovery efficiency. The mixing that occurs in a reservoir, however, is widely debated and often ignored in reservoir simulation, where very large grid blocks are used. Large grid blocks create artificially large mixing that can cause errors in predicted oil recovery. Reservoir mixing, or dispersion, is caused by diffusion of particles across streamlines of varying velocities. Mixing is enhanced by any mechanism that increases the area of contact between the gas and the oil, thereby allowing the effects of diffusion to be magnified. This is, in essence, the cause of scale-dependent dispersion. The contact area grows primarily because of variations in streamlines and their velocities around grains and through layers of various permeabilities (heterogeneity). Mixing can also be enhanced by crossflow, such as that caused by gravity and by the effects of other neighboring wells. This dissertation focuses on estimation of the level of effective local mixing at the field scale and its impact on oil recovery from miscible gas floods. Pore-level simulation was performed using the Navier-Stokes and convection-diffusion equations to examine the origin of scale dependent dispersion. We then estimated dispersivity at the macro scale as a function of key scaling groups in heterogeneous reservoirs. Lastly, we upscaled grid blocks to match the level of mixing at the pattern scale. Once the contact area ceases to grow with distance traveled, dispersion has reached its asymptotic limit. This generally occurs when the fluids are well mixed in transverse direction. We investigated a variety of pore-scale models to understand the nature of scale dependency. From the pore-scale study, we found that reservoir mixing or dispersion is caused by diffusion of particles across streamlines. Diffusion can be significantly enhanced if the surface area of contact between the reservoir and injected fluid are increased as fluids propagate through the reservoir. Echo and transmission dispersivities are scale dependent. They may or may not reach an asymptotic limit depending on the scale of heterogeneities encountered. The scale dependence results from an increase in the contact area between solute (gas) and resident fluid (oil) as heterogeneities are encountered, either at the pore or pattern-scale. The key scaling groups for first-contact miscible (FCM) flow are derived and their impact on mixing is analyzed. We examine only local mixing, not apparent mixing caused by variations in streamline path lengths (convective spreading). Local mixing is important because it affects the strength of the injected fluid, and can cause an otherwise multicontact miscible (MCM) flood to become immiscible. We then showed how to upscale miscible floods considering reservoir mixing. The sum of numerical dispersion and physical dispersion associated with the reservoir heterogeneities, geometry and fluid properties must be equal at both the fine- and large-scales. The maximum grid-block size allowed in both the x- and z-directions is determined from the scaling groups. Small grid-blocks must be used for reservoirs with uncorrelated permeabilities, while larger grid blocks can be used for more layered reservoirs. The predicted level of mixing for first-contact miscible floods can be extended with good accuracy to multicontact miscible (MCM) gas floods. / text