| 1. |
- Andersson, Ida E., 1982-
(författare)
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Modified Glycopeptides Targeting Rheumatoid Arthritis : Exploring molecular interactions in class II MHC/glycopeptide/T-cell receptor complexes
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that leads to degradation of cartilage and bone mainly in peripheral joints. In collagen-induced arthritis (CIA), a mouse model for RA, activation of autoimmune CD4+ T cells depends on a molecular recognition system where T-cell receptors (TCRs) recognize a complex between the class II MHC Aq protein and CII259-273, a glycopeptide epitope from type II collagen (CII). Interestingly, vaccination with the Aq/CII259-273 complex can relieve symptoms and cause disease regression in mice. This thesis describes the use of modified glycopeptides to explore interactions important for binding to the Aq protein and recognition by autoimmune T-cell hybridomas obtained from mice with CIA. The CII259-273 glycopeptide was modified by replacement of backbone amides with different amide bond isosteres, as well as substitution of two residues that anchor the glycopeptide in prominent pockets in the Aq binding site. A three-dimensional structure of the Aq/glycopeptide complex was modeled to provide a structural basis for interpretation of the modified glycopeptide’s immunological activities. Overall, it was found that the amide bond isosteres affected Aq binding more than could be explained by the static model of the Aq/glycopeptide complex. Molecular dynamics (MD) simulations, however, revealed that the introduced amide bond isosteres substantially altered the hydrogen-bonding network formed between the N-terminal 259-265 backbone sequence of CII259-273 and Aq. These results indicated that the N-terminal hydrogen-bonding interactions follow a cooperative model, where the strength and presence of individual hydrogen bonds depended on the neighboring interactions. The two important anchor residues Ile260 and Phe263 were investigated using a designed library of CII259-273 based glycopeptides with substitutions by different (non-)natural amino acids at positions 260 and 263. Evaluation of binding to the Aq protein showed that there was scope for improvement in position 263 while Ile was preferred in position 260. The obtained SAR understanding provided a valuable basis for future development of modified glycopeptides with improved Aq binding. Furthermore, the modified glycopeptides elicited varying T-cell responses that generally could be correlated to their ability to bind to Aq. However, in several cases, there was a lack of correlation between Aq binding and T-cell recognition, which indicated that the interactions with the TCRs were determined by other factors, such as presentation of altered epitopes and changes in the kinetics of the TCR’s interaction with the Aq/glycopeptide complex. Several of the modified glycopeptides were also found to bind well to the human RA-associated DR4 protein and elicit strong responses with T-cell hybridomas obtained from transgenic mice expressing DR4 and the human CD4 co-receptor. This encourages future investigations of modified glycopeptides that can be used to further probe the MHC/glycopeptide/TCR recognition system and that also constitute potential therapeutic vaccines for treatment of RA. As a step towards this goal, three modified glycopeptides presented in this thesis have been identified as candidates for vaccination studies using the CIA mouse model.
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| 2. |
- Andersson, Jonas E, 1964-
(författare)
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Architecture and Ageing : On the Interaction between Frail Older People and the Built Environment
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This doctoral thesis deals with the type of architecture that materializes when age-related problems become a long-term condition (LTC) and gradually restrain the individual’s ability to perform activities in daily life (ADL). Their life situation necessitates a support from relatives or municipal eldercare staff in order for them to continue to participate in everyday living. In addition, the architectural space requires a close adjustment to the personal panorama of cognitive or functional impairments. The habitat can be a flat appropriated many years previously or in a residential care home for dependent and frail seniors. Architecture for ageing with dependency demonstrates how space can be used either to affirm or oppress the older person’s attempts to maintain an independent life style. By use of design theory, case study methodology and a heterogeneous research strategy, this study uses a threefold approach—a retrospective, a contemporaneous, and a future-oriented approach—to explore frail older people’s interaction with the architectural space of residential care homes. This has resulted in seven papers that focus on aspects of these human interactions with the built environment. Based on twelve exemplary models, the research paper I concludes that national guidelines result in a homelike, a hotel-like or a hospital-like environment. Research paper II is a retrospective study that examines the use of architecture competitions as a socio-political instrument to define architectural guidelines. Research paper III focuses on dependent seniors’ spatial appropriation of the communally shared space of a ward in a residential care home. Research paper IV employs two environmental assessment methods from the architecture profession and gerontological research (TESS-NH) in order to evaluate the use of interior colouring when refurbishing two residential care homes while the residents remained in place. Research paper V displays a municipal organizer’s considerations to opt for an architecture competition as a means of renewing architecture for the ageing population. Research paper VI examines competition documentation of three municipal architecture competitions organized during the period of 2006 to 2009. Research paper VII, the final study, explores notions concerning the appropriate space for ageing found among a group of municipal representatives, and people from organizations defending older people’s right. It supplies a model for understanding the appropriate space for ageing. This study illustrates the absence of older people with frailties in the public discussion about appropriate architecture for ageing. During the 20th century, the multi-dimensional idea of an architectural space with a homelike appearance has been used to contrast the negatively charged opposite—the complete and austere institution. The overarching conclusion of this study is that architecture for dependent and frail seniors constitutes a particular type of built space that requires an extended dialogue involving dependent seniors, architects, building contractors and care planners in order to conceive appropriate architecture for the ageing society.
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| 3. |
- Karlsson, Peter S.
(författare)
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Issues of incompleteness, outliers and asymptotics in high dimensional data
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis consists of four individual essays and an introduction chapter. The essays are in the field of multivariate statistical analysis of High dimensional data. The first essay presents the issue of estimating the inverse covariance matrix alone and when it is used within the Mahalanobis distance in High-dimensional data. Three types of ridge-shrinkage estimators of the inverse covariance matrix are suggested and evaluated through Monte Carlo simulations. The second essay deals with incomplete observations in empirical applications of the Arbitrage Pricing Theory model and the interest is to model the underlying covariance structure among the variables by a few common factors. Two possible solutions to the problem are considered and acase study using the Swedish OMX data is conducted for demonstration. In the third essay the issue of outlier detection in High-dimensional data is treated. A number of point estimators of the Mahalanobis distance are suggested and their properties are evaluated. In the fourth and last essay the relation between the second central moment of a distribution to its first raw moment is considered in an financial context. Three possible estimators are considered and it is shown that they are consistent even when the dimension increases proportionally to the number of observations.
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| 4. |
- Kunz, Barbara, 1980-
(författare)
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Kind words, cruise missiles and everything in between : A neoclassical realist study of the use of power resources in U.S. policies towards Poland, Ukraine and Belarus 1989–2008
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This study intends to explain why the United States led entirely different policies towards Poland, Ukraine and Belarus under circumstances where realist theory would predict otherwise. Realism being an “environment based theory”, it would indeed predict a state to lead highly similar foreign policies under identical conditions. Yet, within the overall context of managing unipolarity, the US has clearly led different policies toward these three countries from the demise of the Soviet Union to the end of the second Bush Administration (i.e., in the years 1989 to 2008). In seeking to explain that puzzle, this study follows a path hitherto neglected by neoclassical realist scholarship: a strong emphasis on the bilateral dimension in all foreign policies. Poland, Ukraine and Belarus are friendly, undecided and non-friendly states, respectively, as seen from a Washington perspective. What type of power resources seems appropriate in addressing them is likely to depend on this status. The study subsequently shows that different types of power resources or “base values” underlie the various foreign policy tools employed with respect to the studied countries. For that reason, it argues that perceptions of states’ friend, non-friend or undecided statuses should be considered an element of the missing link neoclassical realists identified between states’ power resources and their foreign policy output.
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| 5. |
- Nilsson, Pia
(författare)
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Price Formation in Real Estate Markets
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis includes an introductory chapter and four individual papers. The papers are held together by concepts associated with price formation in real estate markets, differentiated goods and the local character of land and housing markets. The first two papers focus on the markets for land and agricultural property and the two succeeding studies on housing markets. The first study examines regional variations of Swedish agricultural land prices. The associated empirical model follows the form of earlier literature in testing the influence of expected returns from the current agricultural use of land and the potential for non-agricultural use on prices. The use of market transacted land and the inclusion of decoupled income support to farmers, among a set of agricultural and non-agricultural factors, distinguishes this study from earlier empirical work.The second paper relates to the first by its focus on decoupled income support, but here the analysis extends to the micro level and to the study of price formation in the market for agricultural property. The study applies a spatial multilevel model to study variations in price determinants across and within local and regional markets.The third paper is devoted to the analysis of housing prices and their relation to open landscape amenities. The spatial analysis employs two geographical databases containing single-family home sales and preserved open spaces. In order to address the local character of urban housing markets and intraurban heterogeneity in amenity valuations the study applies a geographically weighted regression approach.The last paper focuses on the market for second homes with a particular emphasis on urban-rural interrelations. The paper is motivated by a growing demand for natural amenities and by the awareness that urban areas are becoming increasingly attractive markets for second homes.
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| 6. |
- Zaremba-Niedźwiedzka, Katarzyna
(författare)
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Microbial Metagenomics : A Tale of the Dead and the Living
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- It is a microbial world we live in: microbes outnumber other organisms by several orders of magnitude, and they have great importance for the environment. However, environmental microbes are notoriously difficult to grow in the laboratory, and using culture independent techniques is necessary to expand our view. In this thesis, I apply metagenomics and single-cell genomics to environmental samples from ancient human remains and lakes.First, I used metagenomics to learn about bacteria from a Neanderthal’s bone and the gut of Ötzi, a frozen natural mummy. Both were exploratory studies where the main question was what kind of bacteria are present. I found out that Streptomyces dominated this particular Neanderthal fossil, and the DNA lacked the damage that is often seen in ancient samples. Ötzi's gut sample was dominated by Clostridia and fungi belonging to Basidiomycota.Second, ten single-cell amplified genomes of freshwater Alphaproteobacterium LD12 and three metagenomes from Swedish lakes were sequenced. Comparative metagenomics allowed hypothesizing about which functions are important for microbe proliferation in freshwater, pointing to osmoregulation and transport proteins and, possibly, to different strategies of metabolizing sugars. I also focused on SAR11 sister-groups in oceans and lakes. Phylogenies and sequence evolutionary distance estimates indicated the existence of microclusters within LD12, showing variation in abundance between lakes. The most striking difference was the relative amount of recombination compared to mutation, the estimated r/m ratio. SAR11 marine and their freshwater cousins are found at the opposite extremes of the r/m range, lowest and highest, respectively. The genetic background or sequence diversity did not explain the observed dramatic difference, so it is possibly connected to environmental adaptation or population dynamics.In addition, I have spent a substantial amount of effort benchmarking available metagenomic methods, for example fragment recruitment of metagenomes to reference genomes.In conclusion, my exploratory metagenomic studies have shed some light on the bacteria present in ancient human remains; comparative metagenomics has suggested the importance of substrate preference on functional differences between lakes and oceans; finally, single-cell genomes have allowed some insight into molecular evolutionary processes taking place in the freshwater LD12 bacterium.
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| 7. |
- Åstrand, Anders P, 1961-
(författare)
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A Tactile Resonance Sensor System for Detection of Prostate Cancer ex vivo : Design and Evaluation on Tissue Models and Human Prostate
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background The most common form of cancer among males in Europe and the USA is prostate cancer, PCa. Surgical removal of the prostate is the most common form of curative treatment. PCa can be suspected by a blood test for a specific prostate antigen, a PSA-test, and a digital rectal examination, DRE where the physician palpates the prostate through the rectum. Stiff nodules that can be detected during the DRE, and elevated levels of PSA are indications for PCa, and a reason for further examination. Biopsies are taken from the prostate by guidance of a transrectal ultrasound. Superficial cancer tumours can indicate that the cancer has spread to other parts of the body. Tactile resonance sensors can be used to detect areas of different stiffness in soft tissue. Healthy prostate tissue is usually of different stiffness compared to tissue with PCa.AimThe general aim of this doctoral thesis was to design and evaluate a flexible tactile resonance sensor system (TRSS) for detection of cancer in soft human tissue, specifically prostate cancer. The ability to detect cancer tumours located under the surface was evaluated through measurements on tissue phantoms such as silicone and biological tissues. Finally measurements on resected whole prostate glands were made for the detection of cancer tumours.Methods The sensor principle was based on an oscillating piezoelectric element that was indented into the soft tissue. The measured parameters were the change in resonance frequency, Δf, and the contact force F during indentation. From these, a specific stiffness parameter was obtained. The overall accuracy of the TRSS was obtained and the performance of the TRSS was also evaluated on tissue models made of silicone, biological tissue and resected whole human prostates in order to detect presence of PCa. Prostate glands are generally spherical and a special rotatable sample holder was included in the TRSS. Spherically shaped objects and uneven surfaces call for special attention to the contact angle between the sensor-tip and the measured surface, which has been evaluated. The indentation velocity and the depth sensitivity of the sensor were evaluated as well as the effect on the measurements caused by the force with which spherical samples were held in place in the sample holder. Measurements were made on silicone models and biological tissue of chicken and pork muscles, with embedded stiff silicone nodules, both on flat and spherical shaped samples. Finally, measurements were made on two excised whole human prostates.ResultsA contact angle deviating ≤ 10° from the perpendicular of the surface of the measured object was acceptable for reliable measurements of the stiffness parameter. The sensor could detect stiff nodules ≤ 4 mm under the surface with a small indentation depth of 0.4 to 0.8 mm.Measurements on the surface of resected human prostate glands showed that the TRSS could detect stiff areas (p < 0.05), which were confirmed by histopathological evaluation to be cancer tumours on, and under the surface.Conclusions A flexible resonance sensor system was designed and evaluated on soft tissue models as well as resected whole prostate glands. Evaluations on the tissue models showed that the TRSS can detect stiffer volumes hidden below the surface on both flat and spherical samples. The measurements on resected human prostate glands showed that PCa could be detected both on and under the surface of the gland. Thus the TRSS provides a promising instrument aimed for stiffness measurements of soft human tissue that could contribute to a future quantitative palpation method with the purpose of diagnosing cancer.
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