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| 2. |
- Akhras, Michael S., 1980-
(författare)
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Nucleic Acid Based Pathogen Diagnostics
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pathogenic organisms are transmitted to the host organism through all possible connected pathways, and cause a myriad of diseases states. Commonly occurring curable infectious diseases still impose the greatest health impacts on a worldwide perspective. The Bill & Melinda Gates Foundation partnered with RAND Corporation to form the Global Health Diagnostics Forum, with the goal of establishing and interpreting mathematical models for what effects a newly introduced point-of-care pathogen diagnostic would have in developing countries. The results were astonishing, with potentially millions of lives to be saved on an annual basis. Golden standard for diagnostics of pathogenic bacteria has long been cultureable medias. Environmental biologists have estimated that less than 1% of all bacteria are cultureable. Genomic-based approaches offer the potential to identify all microbes from all the biological kingdoms. Nucleic acid based pathogen diagnostics has evolved significantly over the past decades. Novel technologies offer increased potential in sensitivity, specificity, decreased costs and parallel sample management. However, most methods are confined to core laboratory facilities. To construct an ultimate nucleic acid based diagnostic for use in areas of need, potential frontline techniques need to be identified and combined. The research focus of this doctoral thesis work has been to develop and apply nucleic acid based methods for pathogen diagnostics. Methods and assays were applied to the two distinct systems i) screening for antibiotic resistance mutations in the bacterial pathogen Neisseria gonorrhoeae, and ii) genotype determination of the cancer causative Human Papillomavirus (HPV). The first part of the study included development of rapid, direct and multiplex Pyrosequencing nucleic acid screenings. With improved methodology in the sample preparation process, we could detect an existence of multiple co-infecting HPV genotypes at greater sensitivities than previously described, when using the same type of methodology. The second part of the study focused on multiplex nucleic acid amplification strategies using Molecular Inversion Probes with end-step Pyrosequencing screening. The PathogenMip assay presents a complete detection schematic for virtually any known pathogenic organism. We also introduce the novel Connector Inversion Probe, a padlock probe capable of complete gap-fill reactions for multiplex nucleic acid amplifications.
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| 3. |
- Andersson, Anders, 1957-
(författare)
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Numerical Conformal Mappings for Waveguides
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Acoustic or electro-magnetic scattering in a waveguide with varying direction and cross-section can be re-formulated as a two-dimensional scattering problem, provided that the variations take place in only one dimension at a time. By using the so-called Building Block Method, it is possible to construct the scattering properties of a combination of scatterers when the properties of each scatterer are known. Hence, variations in the waveguide geometry or in the boundary conditions can be treated one at a time. Using the Building Block Method, the problem takes the form of the Helmholtz equation for stationary waves in a waveguide of infinite length and with smoothly varying geometry and boundary conditions. A conformal mapping is used to transform the problem into a corresponding problem in a straight horizontal waveguide, and by expanding the field in Fourier trigonometric series, the problem can be reformulated as an infinite-dimensional ordinary differential equation. From this, numerically solvable differential equations for the reflection and transmission operators are derived. To be applicable in the Building Block Method, the numerical conformal mapping must be constructed such that the direction of the boundary curve can be controlled. At the channel ends ,it is an indispensable requirement, that the two boundary curves are (at least) asymptotically parallel and straight. Furthermore, to achieve bounded operators in the differential equations, the boundary curves must satisfy different regularity conditions, depending on the boundary conditions. In this work, several methods to accomplish such conformal mappings are presented. The Schwarz–Christoffel mapping, which is a natural starting point and for which also efficient numerical software exists, can be modified in different ways in order to achieve polygons with rounded corners. We present algorithms by which the parameters in the mappings can be determined after such modifications. We show also how the unmodified Schwarz–Christoffel mapping can be used for regions with a smooth boundary. This is done by constructing an appropriate outer polygon to the considered region.Finally, we introduce one method that is not Schwarz–Christoffel-related, by showing how one of the so-called zipper algorithms can be used for waveguides. Keywords: waveguides, building block method, numerical conformalmappings, Schwarz–Christoffel mapping, rounded corners method, approximate curve factors, outer polygon method, boundary curvature, zipper method, geodesic algorithm, acoustic wave scattering, electro-magnetic wave scattering
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| 4. |
- Babiker, Adil Abdelgadir, 1962-
(författare)
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Prostasome Modulation of Blood Cascade System and Phosphoprotein Reactions with Focus on Prostate Cancer
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prostasomes are extracellularly occurring submicron, membrane-surrounded organelles produced by the epithelial cells of the prostate and present in semen. Their precise physiological role is not known, although some of their properties assign them to important physiological and patho-physiological functions. In this thesis, some new properties of seminal and malignant cell line (DU145, PC-3 and LNCaP) prostasomes have been identified. Differences in the expressions and activities of prostasomal CD59, ATPase, protein kinases and tissue factor (TF) have been characterized. The transfer of prostasomal CD59 to CD59-deficient erythrocytes (rabbit and human PNH erythrocytes) has been established. CD59, protein kinases and TF were overexpressed by malignant cell prostasomes. ATPase activity was highest on seminal prostasomes with minimal expression by malignant cell prostasomes resulting in more residual ATP available for phosphorylation reactions. Several proteins were phosphorylated by prostasomal protein kinases, viz. complement component C3, fibrinogen, vitronectin and E-cadherin. Furthermore, TF was identified as the main endogenous phosphorylation substrate on prostasomes. In addition, prothrombotic effects of prostasomes were established. DU145 and PC-3-derived prostasomes exerted a higher clotting effect on whole blood and plasma compared to LNCaP and seminal prostasomes.In conclusion, malignant cell prostasomes showed higher ability to interact with the biological system in favor of prostate cancer cell promotion and survival. The roles played by prostasomes in this context may improve the understanding of the mechanisms that help the prostate cancer cells to avoid the complement attack (CD59 transfer and phosphorylation of C3), to promote angiogenesis (TF) and to metastasize. It may also provide a better understanding of some of the complications usually seen in some terminal prostate cancer patients like thrombotic events and tendency to develop disseminated intravascular coagulation.
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| 5. |
- Boustedt, Jonas, 1965-
(författare)
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On the Road to a Software Profession : Students’ Experiences of Concepts and Thresholds
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Research has shown that there are gaps in knowledge between newly hired and experienced professionals and that some of these gaps are related to concepts, such as the concepts of object orientation. This problem, and the fact that most computer science majors want to work in the software industry, leads to questions regarding why these gaps exist and how students can be better prepared for their future careers. Against this background, this thesis addresses two theme-based perspectives that focus on students' views of concepts in Computer Science. The first theme-based perspective investigated the existence of potential Threshold Concepts in Computer Science. Such concepts should be troublesome, transformative, irreversible, and integrative. Qualitative methods have been mainly used and empirical data have been collected through semi-structured interviews, concept maps, and written stories. The results identified two Threshold Concepts, suggested several more, and then described the ways in which these concepts have transformed students. The second theme-based perspective took a phenomenographic approach to find the variation in how students understand concepts related to the software profession. Data were collected via semi-structured interviews. In one study the interviews were held in connection with role-playing where students took on the role of a newly hired programmer. The results show a variety of ways to experience the addressed phenomena in the student collective, ranging from superficial views that often have a practical nature to more sophisticated understandings that reflect a holistic approach, including a professional point of view. Educators can use the results to emphasize concepts that are important from students' perspectives. The phenomenographic outcome spaces can help teachers to reflect upon their own ways of seeing contrasted with student conceptions. I have indicated how variation theory can be applied to open more sophisticated ways of seeing, which in this context stresses the professional aspects to help students prepare for becoming professional software developers.
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| 6. |
- Brogårdh, Christina, 1968-
(författare)
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Constraint Induced Movement Therapy : influence of restraint and type of training on performance and on brain plasticity
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Partial paralysis of the hand is one of the main impairments after stroke. Constraint Induced Movement Therapy (CIT) is a new treatment technique that appears to improve upper extremity function after stroke. CIT consists of 6 hours of training/day for the affected arm (mainly with shaping exercises) and of restraint (mitt) of the non affected arm for two weeks. There are concerns about the practicality and resource issues in carrying out CIT according to the original model. In this thesis the benefit of modifications of CIT, of an assessment tool and of two common types of hand training have been evaluated. CIT (n=16) administered in groups for two weeks (paper I) seems to be a feasible alternative to improve upper limb motor function after chronic stroke. The arm/hand motor performance improved significantly on Motor Assessment Scale (MAS; p= 0.003) and on Sollerman hand function test (p= 0.037). The median self reported motor ability (MAL) also improved (p < 0.001). No additional effect was seen from wearing a mitt for an extended period of three months. The reliability of the Sollerman hand function test (paper II) was studied in patients with chronic stroke. Three examiners observed 24 patients at three experimental sessions. There was agreement (kappa ≥ 0.4) between the examiners for 15/20 subtests. Using total sum scores, the agreement within the examiners was higher than 0.96 (for Spearman’s rhos and ICCs) and agreement between the examiners was higher than 0.96 (Spearman’s rhos) and 0.92 (ICCs), respectively. In a cohort of 24 patients with subacute stroke (paper III) forced use therapy (FUT; mitt use and 3 hours of training/day for 2 weeks) improved arm/hand function, but not more than regular arm therapy given to the control group. Significant improvements in arm/hand motor performance were found in the FUT group (n=12) as well as in the control group (n=12) on the Sollerman hand function test (p= 0.001), on MAS (p< 0.05) and on MAL (p < 0.05). No significant differences were seen between the groups pre- or post training or at three months follow up, demonstrating that the mitt had limited importance. In a separate study on 30 healthy subjects (paper IV), employing transcranial magnetic brain stimulation (TMS), we found that shaping exercises but not general activity training increased dexterity (p<0.05; Purdue peg board test) of the trained non dominant hand. After shaping exercises the cortical motor map shifted forwardly into the premotor area but did not expand. After general activity training the cortical motor map expanded significantly (p=0.03) in the posterior (sensory) direction. Shift of location of active TMS positions rather than their numbers might therefore be a critical factor for the interpretation of cortical plasticity. In conclusion, the studies in this thesis have shown that less resource consuming modifications of CIT may be feasible to improve upper limb motor function after stroke. The type and amount of training for the more affected arm seems to be an important factor rather than the mitt use in itself. Shaping exercises, at least in healthy people, are effective in improving dexterity and the Sollerman hand function test reliable to evaluate arm/hand function after stroke.
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| 7. |
- Broomé, Sara, 1989-
(författare)
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Atlantic Water in the Nordic Seas : A satellite altimetry perspective on ocean circulation
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Atlantic Water in the Nordic Seas contributes to the mild climate of Northern Europe and is the main oceanic source of heat for the Arctic. The northward bound transport of the warm and saline Atlantic Water is mediated by a topographically constrained cyclonic boundary current along the Norwegian continental slope. The analysis within this thesis is based on satellite observations of dynamic Sea Surface Heights (SSH) from 1993 to the recent present, combined with both hydrographic observations and modelling. It provides some new perspectives and results, as well as corroborates the essential role of bottom topography for the circulation in the Nordic Seas.In the first part of the thesis, the topographic constraint is used in the analysis by examining the satellite-derived SSH along topographic contours. We find stationary along-contour anomalies that indicate deviations from strict topographic steering. However, we show that these deviations are dynamically consistent with, and can be explained by, potential vorticity conservation in an adiabatic steady-state model for flow over a topographic slope. The analysis along topographic contours is further developed to study northward-propagating, low-frequency ocean temperature signals. These signals have an expression in the SSH and their propagation speed is remarkably slow compared to the current speed. We propose a conceptual model of shear dispersion effects, in which the effective advection speed of a tracer is determined not only by the rapid current core, but by a mean velocity taken over the cross-flow extent of Atlantic Water. The model predicts a reduced effective tracer advection velocity, comparable to the one observed.The close connection between anomalies in SSH and heat content is further used to study decadal variability in the Nordic Seas. There is a shift in decadal trends in the mid-2000s, from a period of strong increase in SSH and heat content to a more stagnant period. We find this variability to be forced remotely, rather than by local air-sea heat fluxes. By developing a conceptual model of ocean heat convergence, we are able to explain the broad features of the decadal changes with the temperature variability of the inflowing Atlantic Water from the subpolar North Atlantic.In the final part of the thesis, satellite-derived surface geostrophic velocity fields are used as input to a Lagrangian trajectory model. Based on this, we study the fractionation of the Atlantic Water in the Nordic Seas between the two straits towards the Arctic Ocean: the Barents Sea Opening and the Fram Strait. This Lagrangian approach also provides insights on the origin of the water that reach the straits. We find that it is the frontal current branch, rather than the slope current, that contributes to the variability of the Barents Sea Opening inflow of warm Atlantic Water, and thus potentially to the climate of the Barents Sea and its sea ice cover.
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| 8. |
- Cabric, Sanja, 1977-
(författare)
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Pancreatic Islet Transplantation : Modifications of Islet Properties to Improve Graft Survival
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- During the past decade clinical islet transplantation has become a viable strategy for curing type 1 diabetes. The limited supply of organs, together with the requirement for islets from multiple donors to achieve insulin independence, has greatly limited the application of this approach. The islets are infused into the liver via the portal vein, and once exposed to the blood, the grafted tissue has been shown to be damaged by the instant blood-mediated inflammatory reaction (IBMIR), which is characterized by coagulation and complement activation as well as leukocyte infiltration into the islets. Islet revascularization is a subsequent critical step for the long-term function of the transplanted graft, which may partially be impeded by the IBMIR. In this thesis, we have explored novel strategies for circumventing the effects of the IBMIR and facilitating islet revascularization. Systemic inhibitors of the IBMIR are typically associated with an increased risk of bleeding. We therefore evaluated alternative strategies for modulating the islets prior to transplantation. We demonstrated, using an adenoviral vector, that a high level of expression and secretion of the anticoagulant hirudin could be induced in human islets. An alternative approach to limiting the IBMIR was developed in which anticoagulant macromolecular heparin complexes were conjugated to the islet surface. This technique proved effective in limiting the IBMIR in both an in vitro blood loop model and an allogeneic porcine model of islet transplantation. An increased adhesion of endothelial cells to the heparin-coated islet surface was demonstrated, as was the capacity of the heparin conjugate to bind the angiogenic factors VEGF and FGF; these results have important implications for the revascularization process. The outcome of the work in this thesis suggests that modulation of the islet surface is an attractive alternative to systemic therapy as a strategy for preventing the IBMIR. Moreover, the same techniques can be employed to induce revascularization and improve the engraftment of the transplanted islets. Ultimately, improved islet viability and engraftment will make islet transplantation a more effective procedure and increase the number of patients whose diabetes can be cured.
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| 9. |
- Davoodpour, Padideh, 1966-
(författare)
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2-ME-Induced Apoptotic Signalling in Prostate Cancer PC3 Cells
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prostate cancer is common in the Western society and current treatments are often associated with side effects, therefore improved therapeutic strategies are desired. 2-methoxyestradiol (2-ME), an endogenous metabolite of estradiol-17β inhibits tumor growth in vivo as it prevents angiogenesis. 2-ME has also direct cytotoxic effects on tumor cells. In this study, we have investigated the potential use of PET to record effects 2-ME on prostate cancer cell (PC3) aggregates. The anti-proliferative and pro-apoptotic effects of 2-ME on PC3 cell aggregates in vitro were correlated with the uptake of deoxy-D-glucose, FMAU and choline labeled with 18F, 11C or 3H. 2-ME clearly reduced growth of PC3 aggregates and induced apoptosis in a dose-dependent manner. However, the PET tracers failed to record the cytotoxicity of 2-ME on PC3 aggregates. Further, the signaling events responsible for 2-ME induced prostate cancer cell death were investigated. We found that Smad7, previously implicated in TGF-β-induced responses, is required for 2-ME-induced p38 MAPK activation and subsequent apoptosis in PC-3U cells, as shown by the use of antisense or siRNA techniques and a specific inhibitor of p38 MAPK (SB203580). Interestingly, Smad7 also regulated the expression of the pro-apoptotic Bim protein. Shb is a Src Homology 2 domain adapter protein with pro-apoptotic effects. PC3 clones overexpressing Shb exhibited increased rates of apoptosis, both in the presence or absence of 2-ME, as they failed to activate survival mechanisms through ERK and Akt in response to 2-ME. Notably, Shb cells displayed increased activity of the pro-apoptotic kinase c-Abl. Pre-treatment with SB203580 or c-Abl (STI-571) inhibitors completely blocked the apoptotic response to 2-ME. In conclusion, Smad7 and Shb appear to be crucial for 2-ME-induced PC3 cell apoptosis via their activation of p38 MAPK and c-Abl. Future therapies exploring these pathways can be envisaged as treatment of prostate cancer.
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| 10. |
- Eriksson Sörman, Daniel, 1974-
(författare)
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The influence of social relationships and leisure activity on adult cognitive functioning and risk of dementia : Longitudinal population-based studies
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Today, as we live longer, dementia diseases are becoming more prevalent around the world. Thus, further knowledge of how to maintain levels of cognitive functioning in old age and how to identify factors that postpone the onset of dementia are of acute interest. Lifestyle patterns and social life are important aspects to consider in this regard.This thesis includes three studies. Study I investigated the association between participation in various leisure activities in old age (≥65 years) and risk of incident all-cause dementia. Analyses of the total follow-up time period (15 years) showed that higher levels of “Social” and “Total” leisure activity were associated with decreased risk of dementia. In Study II, the aim was to investigate the association between various aspects of social relationships in old age (≥65 years) and risk of incidents of all-cause dementia and Alzheimer's disease. Results showed that over the total follow-up period (16 years) higher values on the relationship index were associated with reduced risk of both dementia and Alzheimer's disease. Visiting/visits of friends and acquaintances more than once a week was related to decreased risk for all-cause dementia, but not for Alzheimer's disease. However, in neither Study I nor II did any of these factors alter the risk of all-cause dementia or Alzheimer's disease when near-onset dementias were removed from the analyses (Study I, up to five years; Study II, up to three years).In Study III the aim was to investigate the association between social network size and cognitive ability in a middle-aged (40–60 years) sample. The idea was that if social network size can moderate negative age-related influence on memory functions, it might also put an individual on a cognitive trajectory that is beneficial in old age. Results from longitudinal analyses showed that baseline network size was positively related to five-year changes in semantic memory and with changes in both semantic and episodic memory at the ten-year follow-up. Social network size was unrelated to changes in visuospatial performance.Taken together, enrichment factors measured in old age (≥ 65 years) did not alter the risk of all-cause dementia or Alzheimer's disease when near-onset dementias were removed from the analyses. These results might reflect protective short-term effects or reverse causality, meaning that in the prodromal phase of dementia individuals tend to withdraw from activity. Social network size in middle age (40-60 years), however, appears to have beneficial long-term effects on cognitive functioning. The results highlight the importance of long follow-up periods and the need to adjust for the influences of reverse causality when investigating the impact of a socially and mentally active life on cognitive functioning.
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