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  • Public defence: 2017-02-25 10:15 Ihresalen, Engelska parken, Uppsala
    Thegel, Miriam
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Languages, Department of Modern Languages.
    ¿Opiniones, normas o pura necesidad?: La modalidad deóntica y la modalidad dinámica a través de deber tener que2017Doctoral thesis, monograph (Other academic)
    Abstract [en]

    This study focuses on the notions of deontic and dynamic modality in Spanish and how they are expressed through the modal verbs deber ‘must’ and tener que ‘have to’. The analysis is based on a corpus of political debates from the European Parliament, conducted 2010‒2011 by Spanish MEPs. In total, 578 occurrences of deber and 334 occurrences of tener que have been studied in detail, in order to understand their semantic and pragmatic behavior.

    Out of the 912 cases, 860 were classified as deontic necessity and 52 as dynamic necessity. When separating the deontic readings from the dynamic ones, the notions of volitivity and factuality proved to be crucial: whereas deontic cases are volitive and non-factual, dynamic cases can be described as non-volitive and, to a high extent, factual.

    In order to further examine the deontic uses, four classificatory variables were taken into account, namely, grammatical person, degree of agentivity, tense and source of the necessity. The distributions of deber and tener que were analyzed using Chi-square tests. Statistically significant differences were found for all four variables. The results show that deber is highly preferred in the third person, whereas tener que occurs equally often in the first and third person. Moreover, deber occurs more frequently in contexts which obscure the responsible agent, such as the impersonal se construction and inanimate subjects. As far as tense is concerned, the major difference between deber and tener que is found in the conditional tense, where tener que barely occurs, while deber is fairly frequent. A final difference between the two verbs is that the speaker usually is the source of the necessity when tener que is used, whereas deber is the first option when the speaker refers to another source or authority.

    In conclusion, it is argued, firstly, that there is a clear difference between deontic and dynamic modality in Spanish, and secondly, that deber and tener que display different semantic and pragmatic functions in deontic contexts, pointing towards an intersubjective use of deber and a subjective use of tener que.

  • Public defence: 2017-02-27 09:00 Polhemsalen, Uppsala
    Koumpouras, Konstantinos
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Theory.
    Atomistic spin dynamics and relativistic effects in chiral nanomagnets2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis, studies based on magnetization dynamics on atomic length scales are presented for a number of magnetic systems, where Dzyaloshinskii-Moriya (DM) interaction is present. First-principle methods, based on density functional theory (DFT), have been used to study the pairwise magnetic interactions, such as Heisenberg exchange and DM interaction, which are the crucial parameters for the helimagnetic systems. The first part of this thesis concerns the theoretical background: basics of DFT, atomistic spin dynamics and magnetic skyrmions. The second part concerns the ground state and dynamical properties of helimagnets.

    Magnetic interaction parameters have been calculated for heterostructures, such as Co/Ni/Co on heavy metal non-magnetic substrates. These parameters are strongly dependent on the material of the substrate. Furthermore, the magnetization dynamics of domain wall and skyrmion are studied and our results show that motion is influenced by the spin-Hall effect (SHE) which arises from the non-magnetic substrate. Similar studies of magnetic interaction parameters have been made for several half-Heusler compounds MnZSn (Z=Tc, Ru, Rh, Os, Ir and Pt) and the phase diagram of the MnPt0.99Ir0.01Sn alloy proves the existence of skyrmions in a wide range of temperature and external magnetic field. 

    The manipulation of low-dimensional magnetic structures (skyrmions and solitons) with spin transfer torques have been investigated. The nucleation and annihilation processes of skyrmion, by the use of spin polarised current, are essential and the impact of different edges (antiferromagnetic, magnetically softer and stiffer) on both processes is studied. When the edge is magnetically softer, less current is required for skyrmion nucleation and annihilation. Furthermore, one-dimensional magnetic solitons are used to explore concepts of logical operations in a prototype majority gate device, since they are stable and can be easily created and manipulated by spin currents.

    Lastly, edge dislocations in FeGe helimagnet have been studied. These dislocations described in terms of thermally driven dynamics by the use of atomistic spin dynamics approach and possibly explain some unusual jumps of the spiral wavelength observed by time-dependent experiments.

  • Public defence: 2017-02-28 09:00 Rudbecksalen, Uppsala
    Manivel, Vivek Anand
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    The role of anti-collagen type II antibodies in the pathogenesis and prognosis of rheumatoid arthritis2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Rheumatoid arthritis (RA) which affects 0.5-1% of the world population and is characterised by joint erosions and presence of the autoantibodies anti-citrullinated protein antibodies (ACPA) and rheumatoid factor. Collagen II (CII) is a joint-specific antigen and we have shown that antibodies against CII (anti-CII) are present in around 8% of RA patients. RA patients with anti-CII are characterized by acute RA onset with elevated CRP and early joint erosions at the time of RA onset. Polymorphonuclear granulocytes (PMN) and peripheral blood mononuclear cells (PBMC) are abundant in RA synovial fluids, where they can interact with anti-CII, thus forming immune complexes (IC) with CII. In my thesis I have shown that PMN upregulated the cell surface markers CD66b and CD11b and downregulated CD16 and CD32 after stimulation with anti-CII IC. These changes in CD66b and CD16 associated to joint erosions to a larger extent than did PBMC responses to anti-CII IC. PMN cocultured with PBMC and stimulated with anti-CII IC showed augmented chemokine production that was dependent on TLR4 and functionally active PMN enzymes. This mechanism can lead to accumulation of inflammatory cells in joints of RA patients who are anti-CII positive around the time of RA diagnosis, and may thus help explain the acute onset RA phenotype associated with anti-CII.

    In a large Swedish RA cohort, anti-CII associated with elevations in clinical and laboratory measures of disease activity at diagnosis and until 6 months, whereas ACPA associated with late inflammation. Anti-CII seropositive RA was associated with improvements in clinical measurements and was negatively associated with smoking in contrast to ACPA that was associated with worseneing of clinical symptoms and associated positively with smoking. Anti-CII levels associated to  HLADRB1*03 and  HLADRB1*01 whereas ACPA showed negative association to HLA-DRB1*03. In a Malaysian RA cohort anti-CII also associated to elevated CRP at the time of diagnosis.

    Anti-CII seropositive RA represents a distinct phenotype, in many respects representing the converse  to the clinical, genetic and smoking associations described for ACPA. Early determinations of anti-CII in parallel to ACPA predict the inflammatory outcome in RA.

  • Public defence: 2017-03-03 09:00 B42, Biomedicinskt Centrum, Uppsala
    Karlsson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Characterization and Engineering of Protein-Protein Interactions Involving PDZ Domains2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The work presented in this thesis has contributed with knowledge to several aspects of protein-protein interaction involving PDZ domains. A substantial amount of our proteome contains regions that are intrinsically disordered but fold upon ligand interaction. The mechanism by which disordered regions bind to their ligands is one important piece of the puzzle to understand why disorder is beneficial. A region in the PDZ domain of nNOS undergoes such a disorder-to-order transition to form a b-sheet in the binding pocket of its partner. By studying the kinetics of interaction, in combination with mutations that modulate the stability of the aforementioned region, we demonstrate that the binding mechanism consists of multiple steps in which the native binding interactions of the b-sheet are formed cooperatively after the rate-limiting transition state. These mechanistic aspects may be general for the binding reactions of intrinsically disordered protein regions, at least upon formation of β-sheets.  

                The second part of this thesis deals with the engineering of proteins for increasing affinity in protein-protein interaction. Infection by high-risk human papillomavirus (hrHPV) can lead to cancer, and the viral E6 protein is an attractive drug target. E6 from hrHPV natively interacts with the well-characterized PDZ2 domain in SAP97, which we used as a scaffold to develop a high affinity bivalent binder of hrHPV E6. We initially increased PDZ2's affinity for E6 6-fold, but at the cost of decreased specificity. Attaching a helix that binds E6 at a distant site, increasing the affinity another14-fold, completed the design.

                The final work of this thesis investigates if binding studies conducted with isolated PDZ domains is representative of the full-length proteins they belong to. It has been suggested that ligand binding in PDZ domains can be influenced by factors such as adjacent domains and interactions outside of the binding pocket. We studied these aspects for the three PDZ domains of PSD-95 and found that they on the whole function in an independent manner with short peptides as ligands, but that interactions outside of the PDZ binding-pocket may be present. The representative length of the PDZ interaction partner should therefore be considered.

  • Public defence: 2017-03-03 09:00 Rosénsalen, Uppsala
    Christersson, Albert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Fractures of the distal radius: Factors related to radiographic evaluation, conservative treatment and fracture healing2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Distal radius fractures (DRFs) are one of the most common injuries encountered in orthopaedic practise. Such fractures are most often treated conservatively, but surgical treatment has become increasingly common. This trend is not entirely scientifically based

    The aims of this thesis were threefold: to increase measurement precision in dorsal angulation (DA) on radiographs and computer tomographies (CTs); to assess the results after shortened plaster cast fixation time in reduced DRFs; and to evaluate the feasibility and safety of applying Augment® (rhPDGF-BB/β-TCP) in DRFs.

    In Paper I and Appendix 1 and 2, a semi-automatic CT-based three-dimensional method was developed to measure change in DA over time in DRFs. This approach proved to be a better (more sensitive) method than radiography in determining changes in DA in fractures of the distal radius.

    In Paper II, a CT model was used to simulate lateral radiographic views of different radial directions in relation to the X-ray. Using an alternative reference point on the distal radius, precision and accuracy in measuring DA was increased.

    Paper III and IV are based on a prospective and randomised clinical study (the GitRa trial) that compares clinical and radiographic outcomes after plaster cast removal at 10 days versus 1 month in 109 reduced DRFs. Three patients in the early mobilised group were excluded because of fracture dislocation (n=2) or a feeling of fracture instability (n=1). For the remaining patients in the early mobilised group (51/54) a limited but temporary gain in range of motion, but a slight increase in radiographic displacement were observed. Our results suggest that plaster cast removal at 10 days after reduction of DRFs is not feasible.

    Paper V is based on a prospective, randomised clinical study (the GEM trial) in which 40 externally fixated DRFs were randomised to rhPDGF-BB/β-TCP into the fracture gap or to the control group. Augment® proved to be convenient and safe during follow-up (24 weeks). However, because of the nature of the study design, the effect on fracture healing could not be determined. A decrease in pin infections was seen in the Augment® group, a finding we could not explain.

  • Public defence: 2017-03-03 09:15 Polhemsalen, Uppsala
    Asfaw, Habtom Desta
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Structural Chemistry.
    Multifunctional Carbon Foams by Emulsion Templating: Synthesis, Microstructure, and 3D Li-ion Microbatteries2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Carbon foams are among the existing electrode designs proposed for use in 3D Li-ion microbatteries. For such electrodes to find applications in practical microbatteries, however, their void sizes, specific surface areas and pore volumes need be optimized. This thesis concerns the synthesis of highly porous carbon foams and their multifunctional applications in 3D microbatteries. The carbon foams are derived from polymers that are obtained by polymerizing high internal phase water-in-oil emulsions (HIPEs).

    In general, the carbonization of the sulfonated polymers yielded hierarchically porous structures with void sizes ranging from 2 to 35 µm and a BET specific surface area as high as 630 m2 g-1. Thermogravimetric and spectroscopic evidence indicated that the sulfonic acid groups, introduced during sulfonation, transformed above 250 oC to thioether (-C-S-) crosslinks which were responsible for the thermal stability and charring tendency of the polymer precursors. Depending on the preparation of the HIPEs, the specific surface areas and void-size distributions were observed to vary considerably. In addition, the pyrolysis temperature could also affect the microstructures, the degree of graphitization, and the surface chemistry of the carbon foams.

    Various potential applications were explored for the bespoke carbon foams. First, their use as freestanding active materials in 3D microbatteries was studied. The carbon foams obtained at 700 to 1500 oC suffered from significant irreversible capacity loss during the initial discharge. In an effort to alleviate this drawback, the pyrolysis temperature was raised to 2200 oC. The resulting carbon foams were observed to deliver high, stable areal capacities over several cycles. Secondly, the possibility of using these structures as 3D current collectors for various active materials was investigated in-depth. As a proof-of-concept demonstration, positive active materials like polyaniline and LiFePO4 were deposited on the 3D architectures by means of electrodeposition and sol-gel approach, respectively. In both cases, the composite electrodes exhibited reasonably high cyclability and rate performance at different current densities. The syntheses of niobium and molybdenum oxides and their potential application as electrodes in microbatteries were also studied. In such applications, the carbon foams served dual purposes as 3D scaffolds and as reducing reactants in the carbothermal reduction process. Finally, a facile method of coating carbon substrates with oxide nanosheets was developed. The approach involved the exfoliation of crystalline VO2 to prepare dispersions of hydrated V2O5, which were subsequently cast onto CNT paper to form oxide films of different thicknesses.

  • Public defence: 2017-03-03 10:00 Hamberg, Uppsala
    Muhamad, Harbe
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, Geophysics.
    Geophysical studies in the western part of the Siljan Ring Impact Crater2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis utilizes several geophysical methods to study the Siljan Ring impact structure, focusing on the western part of the structure. This thesis, and the three papers upon which it is based, reports on attempts to delineate the Paleozoic rocks at depth within the annular ring graben and characterize their structure. In addition, the nature of the basement, which underlies these sedimentary rocks is investigated.

    Papers I and III focus on analysis of the down-hole logging and borehole core data. As well as the acquisition, processing and interpretation of 2D high-resolution reflection seismic data from the Mora area. The borehole log responses were compared with the core lithology from the Mora 001 borehole and information from two other cores (Mora VM 2 and Mora MV 3) in order to interpret the logs. The logs reveal significant changes in the lithology between boreholes, indicating a very high level of structural complexity, which is attributed to impact tectonics. In addition, the log data revealed a high sonic velocity contrast between the Silurian and Ordovician successions and a higher apparent temperature gradient than in the northern part of the structure. The interpretation of the high-resolution 2D seismic data suggest that the Mora area has been significantly affected by the impact. Several potential faults were identified in the area and interpreted to be post depositional and related to the impact. In paper II, a 2D seismic profile from the Orsa area (12 km) located in the northwestern part of the Siljan Ring was re-processed. To compliment this seismic line, first break traveltime tomography results, vintage seismic OPAB profiles, new and pre-existing gravity data, aeromagnetic data and the bedrock geological map were used to present a geological model along the Orsa profile. Reprocessing of the seismic data resulted in improved stacked and migrated sections and better imaging of the top of the crystalline basement than the original processing. Integrated interpretation of the seismic profiles suggests that the area has been significantly affected by faulting and that the depth to the basement varies greatly along the different profiles.

  • Public defence: 2017-03-03 10:15 Geijersalen, Uppsala
    Ekoluoma, Mari-Elina
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of Cultural Anthropology and Ethnology.
    Everyday Life in a Philippine Sex Tourism Town2017Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Sabang used to be a small, marginalized Philippine fishing village that in the span of three decades became a well-known international sex tourism site. This thesis deals with the implications of tourism (including sex tourism) and how it has become embedded in the daily life in today’s Sabang. The thesis highlights the local populations’ diverse reactions to the various changes associated with tourism growth, in particular how various symbolic, moral, and spatial boundaries are constructed and maintained.

    The ethnographic material examined in this thesis builds on several periods of fieldwork, in total 18 months, that were carried out between 2003 and 2015. Analytical tools found in tourism anthropology and in particular the branch of postcolonial tourism studies has guided the discussion and analysis of the socio-cultural effects of becoming a tourism town.

    This thesis argues that complex networks of boundaries are significant in maintaining a sense of order and social cohesion in times of change. Notions of cultural differences are expressed through the narratives and behaviors of the various inhabitants, and contribute to the maintaining of boundaries within and between groups. From the beginning of tourism growth commercial sex has been central and has become a significant factor in the tourism economy. While residents acknowledge their dependency on the go-go bars, the business of the night is framed so as not to defeat the inhabitants’ struggles to maintain local community’s sense of morality, or at least to set up boundaries between the outsiders’ immorality and insiders’ morality. Tourism has also offered opportunities to challenge conventional social hierarchies and local seats of power, and there are also recurrent discussions about who has the right to control resources and who can claim entitlement to a place now shared by people from all over the world.  

  • Public defence: 2017-03-03 10:15 Hörsal 1, Ekonomikum, Uppsala
    Pasay, Sarah Linden
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Economic History.
    Stable Media in the Age of Revolutions: Depictions of Economic Matters in British and Swedish State Newspapers, 1770–18202017Doctoral thesis, monograph (Other academic)
    Abstract [en]

    The dissertation examines how economic matters were depicted between 1770 and 1820 in two European kingdoms. Britain and Sweden are studied during this Age of Revolutions from the state’s perspective; state-managed newspapers are examined, one from Britain, the London Gazette, and two from Sweden, Stockholms Post-Tidningar and Inrikes Tidningar. These were stable types of media that transformed slowly alongside the changing popular press. State-managed newspapers were produced both to inform and manage the loyalty of populations. Aside from the continued development of the centralized state, this was also the time when Enlightenment ideals were spreading, the public sphere was transforming, notions of the nation and nationalism were developing, and communication strategies were changing; these concepts are the basis for the model of the development of modernity used in this study.

    Economic matters are seen as existing in a value-realm model that gradually disintegrated over time, expressing the birth of the modern world. This model included political, social-cultural, and technological values, in addition to economic matters. This disintegration involved a sense of uniformity. In both Britain and Sweden, economic objects, practices, ideas, and discourses received similar treatments over time. This process was, however, non-linear and not complete by the dawn of industrial transformation.  

    The first two chapters discuss the theory and methodological approaches. The form, order, and content of the newspapers are analyzed to show how economic matters became separate or unembedded to varying degrees over a fifty-year time span. British and Swedish descriptions are compared, as well as how the other state was portrayed in the opposing newspapers. These observations are described in three empirical chapters, relating events and analyses from 1770 to 1775, 1790 to 1795, and 1815 to 1820.

    The results of this dissertation show how early modern economic matters can be viewed beyond quantitative contents as an expression of becoming modern, offering complimentary context. Advances in thinking about data generated modern numerical indicators, also reflected by form and order qualities. The unembeddedness of economic matters was an ongoing and non-linear process that was expressed by increased abstractness, separation, and emphasis.

  • Public defence: 2017-03-03 13:15 B/B42, Uppsala
    Mehić, Merima
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Regulation of Hyaluronan Synthesis and Signaling via CD44 in Cancer2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Hyaluronan is a ubiquitous glycosaminoglycan which is an important constituent of the extracellular matrix (ECM). In addition to organizing the extracellular matrix and regulating tissue homeostasis, hyaluronan, by binding to its main cell surface receptor CD44, is involved in intracellular signaling pathways regulating major cellular processes during development, wound healing, inflammation and cancer. Accumulation of hyaluronan in cancer promotes progression of the disease and correlates with poor prognosis. This thesis focuses on the regulation of hyaluronan synthesis and its signaling in normal and cancer cells.

    Cancer cells in solid tumors are surrounded by stroma, which has an essential role in the growth and metastasis of tumors. Prominent members of the tumor stroma are fibroblasts, which synthesize ECM components, such as hyaluronan, and secrete growth factors, and activate intracellular signaling pathways. We demonstrate a cross-talk between the receptors for platelet-derived growth factor BB (PDGF-BB), transforming growth factor β (TGFβ) and CD44 in dermal fibroblasts. We found that PDGF-BB can activate the Smad signaling pathway downstream of the TGFβ receptor I (TβRI), and that PDGF-BB-induced migration depends on TβRI. CD44 forms a ternary complex with the receptors for PDGF-BB and TGFβ, and negatively regulates their signaling. Furthermore, we demonstrate that TGFβ stimulation of mammary epithelial cells transcriptionally upregulates hyaluronan synthase 2 (HAS2), which is essential for TGFβ-induced epithelial-mesenchymal transition (EMT); in this process, polarized epithelial cells adapt a mesenchymal phenotype which facilitates migration and invasion.

    HAS2 protein activity and stability is regulated by posttranslational modifications, including ubiquitination. We investigated the ubiquitination of HAS2 in aggressive breast cancer cells, whose metastasizing capability depends on HAS2-synthesized hyaluronan. We identified two deubiquitinating enzymes, USP4 and USP17, which target HAS2 and affect its activity and stability.

    In summary, these studies increase the knowledge about the regulation of hyaluronan production and its role in cancer progression.

  • Public defence: 2017-03-06 13:15 Uppsala
    Bai, Wensong
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Business Studies.
    The Best of Both Worlds: The Effects of Knowledge and Network Relationships on Performance of Returnee Entrepreneurial Firms2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In an increasingly globalized business world, international human mobility and its association with entrepreneurship presents attractive opportunities for business research. One increasingly important phenomenon in the field is returnee entrepreneurship, which is the reverse flow of migrants who acquired skills in developed countries back to their emerging-market home countries. In this way, knowledge from developed countries transfers back to, and fills technological and entrepreneurial gaps in, emerging countries. This thesis aims to explain returnee entrepreneurship by examining what factors differentiate innovation, internationalization and business performance of returnee entrepreneurial firms.

    The empirical investigation uses a mixed method approach comprising a qualitative single case study and four quantitative studies of a recent sample of 200 Chinese returnee entrepreneurial firms, and focusses on factors such as knowledge and network relationships, which are two advantages that returnee entrepreneurial firms are thought to have. By distinguishing among types of knowledge from various sources, and network relationships from both international and domestic origins, the findings show that international opportunity knowledge and domestic business relationships influence the innovation performance of returnee entrepreneurial firms. The structural characteristics of the international network of a returnee entrepreneurial firm are related to that firm’s international networking capability, which in turn influence its opportunity-driven internationalization. Additionally, the international experiential knowledge of returnee entrepreneurs nurtures their firms’ international market knowledge, and these experiences also indirectly affect firm internationalization by being transmitted through that market knowledge. Finally, international networking capability and innovation performance positively influence the business performance of returnee entrepreneurial firms, whereas the international business knowledge has a negative impact on business performance.

    The thesis challenges the enthusiastic view of returnee entrepreneurial firms by refining the heterogeneity of both the returnee entrepreneurs themselves, and the performance variances of their ventures. Empirically, this thesis suggests a combination of knowledge and resources from both ‘worlds’ that can best benefit the performance of a returnee entrepreneurial firm. This thesis also contributes to theory by providing new insights into the combined effect of (1) an individual entrepreneur’s international experience, and (2) a new venture’s knowledge base and capabilities; furthermore it also describes what that combined effect will be on the new venture’s performance.

  • Public defence: 2017-03-10 09:00 Enghoffsalen, Uppsala
    Farkhooy, Amir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Lung function in relation to exercise capacity in health and disease2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Exercise capacity (EC) is widely recognized as a strong and independent predictor of mortality and disease progression in various diseases, including cardiovascular and pulmonary diseases. Furthermore, it is generally accepted that exercise capacity in healthy individuals and in patients suffering from cardiovascular diseases is mainly limited by the maximum cardiac output.

    Objectives: This thesis investigated the impact of different lung function indices on EC in healthy individuals, patients with cardiovascular disease (e.g., pulmonary hypertension (PH)) and patients with pulmonary disease (e.g., chronic obstructive pulmonary disease (COPD)).

    Methods: The present thesis is based on cross-sectional and longitudinal analyses of patients suffering from COPD, attending pulmonary rehabilitation at Uppsala University Hospital (studies I and II), and healthy men enrolled in the “Oslo ischemia study” (study IV). Study III is a cross-sectional study of patients suffering from PH attending the San Giovanni Battista University Hospital in Turin. EC was assessed using a bicycle ergometer in studies I and IV, with 12-minute walk tests (12MWT) in study II and with 6-minute walk tests (6MWT) in study III. Extensive pulmonary function tests, including diffusing capacity of the lung (DLCO), were performed in studies I-III and dynamic spirometry was used to assess lung function in study IV.

    Results: DLCO is more closely linked to decreased levels of EC than airway obstruction in COPD patients. Furthermore, the decline in 12MWT over a 5-year period was mainly explained by deterioration in DLCO in COPD patients. Spirometric parameters indicating airway obstruction significantly related to EC and exercise-induced desaturation in PH patients. A significant, but weak association between lung function parameters and EC was found in healthy subjects and this association is strengthened with increasing age.

    Conclusion: DLCO is the strongest predictor of low EC and EC decline in COPD. In PH, airway obstruction is strongly related to reduced 6MWT. Therefore, extensive analysis of lung function, including measurements of diffusing capacity, along with standard assessment of airway obstruction, gives a more comprehensive assessment of the functional exercise capacity in patients suffering from pulmonary hypertension or COPD. Lung function is also significantly linked to EC even in healthy subjects, lacking evident cardiopulmonary diseases.

  • Public defence: 2017-03-10 09:00 Fåhraeussalen, Uppsala
    Bergman, Julia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Aspects of Gene Expression Profiling in Disease and Health2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aim of this thesis is to in various ways explore protein expression in human normal tissue and in cancer and to apply that knowledge in biomarker discovery.

    In Paper I the prognostic significance of RNA-binding motif protein 3 (RBM3) is explored in malignant melanoma. To further evaluate the prognostic significance of RBM3 expression was assessed in 226 incident cases of malignant melanoma from the prospective populationbased cohort study Malmö Diet and Cancer Study using tissue microarray technique (TMA). RBM3 was shown to be down regulated in metastatic melanoma and high nuclear expression in the primary tumor was an independent marker of prolonged over all survival. As a tool to facilitate clinical biomarker studies the Human Protein Atlas has created a tissue dictionary as an introduction to human histology and histopathology. In Paper II this work is introduced.

    A cancer diagnosis can be a complex process with difficulties of establishing tumor type in localized disease or organ of origin in generalized disease. Immunohistochemically assisted diagnosis of cancer is common practice among pathologists where its application combined with known protein expression profiles of different cancer types, can strengthen or help dismiss a suspected diagnosis. In Paper III the diagnostic performance of 27 commonly used antibodies are tested in a predominantly metastatic, multicancer cohort using TMA technique. Overall these 27 diagnostic markers showed a low sensitivity and specificity for its intended use, highlighting the need for novel, more specific markers.

    Breast, ovarian, endometrial and ovarian cancers affect predominantly women. Differential diagnostics between these cancer types can be challenging. In Paper IV an algorithm, based on six different IHC markers, to differentiate between these cancer types is presented. A new diagnostic marker for breast cancer, namely ZAG is also introduced.

    In Paper V the transcriptomic landscape of the adrenal gland is explored by combining a transcriptomic approach with a immunohistochemistry based proteomic approach. In the adrenal gland we were able to detect 253 genes with an elevated pattern of expression in the adrenal gland, as compared to 31 other normal human tissue types analyzed. This combination of a transcriptomic and immunohistochemical approach provides a foundation for a deeper understanding of the adrenal glands function and physiology.

  • Public defence: 2017-03-10 09:15 Siegbahnsalen, Uppsala
    Vannestål, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics.
    Optimal timing decisions in financial markets2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis consists of an introduction and five articles. A common theme in all the articles is optimal timing when acting on a financial market. The main topics are optimal selling of an asset, optimal exercising of an American option, optimal stopping games and optimal strategies in trend following trading. In all the articles, we consider a financial market different from the standard Black-Scholes market. In two of the articles this difference consists in allowing for jumps of the underlying process. In the other three, the difference is that we have incomplete information about the drift of the underlying process. This is a natural assumption in many situations, including the case of a true buyer of an American option, trading in a market which exhibits trends, and optimal liquidation of an asset in the presence of a bubble. These examples are all addressed in this thesis.

  • Public defence: 2017-03-10 10:00 Ång/10132, Häggsalen, Uppsala
    Fowler, Nina
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Industrial Engineering & Management.
    Walking the Plank of the Entrepreneurial University: The little spin-out that could?2017Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Creating spinout companies (USOs) from university research is one focus of innovation policy. The phenomenon features in two main fields of enquiry: academic entrepreneurship studies, and literature on academic capitalism and the entrepreneurial university. Studies have explored the academic entrepreneur, the development stages of these nascent ventures, and the tools universities can provide to encourage and assist in the spinout process. This literature is however limited in that it is overwhelmingly concerned with resources, and little is known about how the USO relates to the parent research institution over time.

    The purpose of this study is therefore to explore social forces in research linked to a USO, and the main research question is: how can a social lens help us to understand some of the forces at play in research commercialisation, specifically through the early development of a USO from a parent research organisation?

    The case study is based on interviews and observations of university researchers, USO actors, and representatives from state agencies and a multinational corporation involved in a technology demonstration project. The sociologist Robert Park’s concepts of social groups, the individual within the collective, and social forces are used to explore the experiences of actors involved in academic research and industrial development throughout the changing relationship of a research group and USO.

    Five social forces were identified around the border between academia and industry, based on some of the concepts that seem to inform the actors’ understandings of the case at hand.

    An exploration of these forces helps to develop an understanding of how actors experience and negotiate various forces, and positions the results of the study in relation to the dominant models in academic entrepreneurship and academic life. Park’s concepts of specialised roles moves the discussion forward by considering how social forces might be handled within research and research commercialisation, and how such forces might in turn motivate the movement of individuals within and out of a particular social group. This discussion leads into the metaphor of the theatre, connected to project management literature, and research commercialisation as a performance by actors to safeguard the collective’s interests. 

  • Public defence: 2017-03-10 10:15 Ihresalen, Uppsala
    Bellander, Henrik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Rättegångskostnader: Om kostnadsbördan i dispositiva tvistemål2017Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Rättegångskostnader – Costs in Civil Procedure

    The rules on costs in Chapter 18 of the Swedish Code of Legal Procedure (Sw: Rättegångsbalken) have an impact on several procedural questions but have rarely been thoroughly discussed in legal practice or theory since their adoption in 1942. On the other hand, since the Code was adopted civil procecedure scholars have considerably focused on the development and changes in society and how they affect civil procedure.

    This thesis aims at examining both these lines of development. The impact of the theoretical discussions during the 20th century is critically addressed, with special attention to cost-related questions, and the application of rules on costs in some current and actual situations are examined and evaluated from a pragmatic perspective.

    The inquiry shows that costs have been of indirect relevance for the theoretical discussion in procedural law and that this theoretical development in turn has had effects on cost rules. Changing views on civil procedure have led to altered framings of cost problems and to shifts in how the rules have been comprehended and applied. The inquiry covers questions on cost assessment and cost shifting between the parties, as well as problems connected to possibilities to spread costs and risk on legal representatives, funders and others.

    It is argued that a more compromising and pluralistic application of the rules combined with more explicit communication in cost issues between the parties and the court during early stages of the proceedings may facilitate and lead to more nuanced cost decisions without burdening the final stages of the proceedings with extensive legal argumentation.

  • Public defence: 2017-03-10 13:15 C2:301, Uppsala
    Staaf, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Childhood Obesity and Islet Function2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The prevalence of childhood obesity and Type 2 Diabetes Mellitus (T2DM) has increased during recent decades. T2DM is accompanied with functional changes in the islets of Langerhans, which can be identified early in the pathogenesis. The aim of this thesis was to explore how metabolic changes caused by obesity early in life relate to islet function prior to overt T2DM.

    To address this, Uppsala Longitudinal Study of Childhood Obesity (ULSCO) was established (paper I). Initially, the association between palmitate and insulin secretion was investigated using a translational approach with obese and lean normoglycemic juveniles and isolated human islets (paper II). Secondly, dynamics of islet-hormones insulin and glucagon, and gut-hormones glucagon like-peptide 1 (GLP-1) and glicentin (paper III) and magnetic resonance imaging of pancreatic fat fraction (PFF) (paper IV) were studied in association to glucose tolerance and beta-cell function. Finally, a novel method of analysing shape features of oral glucose tolerance test (OGTT) curves was introduced and evaluated (paper V).

    Obese subjects had high prevalence of prediabetes and metabolic syndrome (MetS) (paper I). In obese pre-pubertal children with elevated palmitate levels, hyperinsulinemia was observed (paper II). In contrast, obese pubertal adolescents with similar palmitate levels showed moderate insulin levels during OGTT with delayed first phase insulin response. To explore mechanisms for these variations, isolated human islets were exposed to palmitate for different time periods in vitro. After 2 days accentuated insulin response was observed. Impaired beta-cell function and apoptosis were evident after 7 days, however. Hyperglucagonemia and disturbed GLP-1 and glicentin levels were associated with obesity and glycaemic status, with fasting glicentin being predictive of prediabetes (paper III). Furthermore, PFF was increased in obese subjects and associated to MetS and visceral adipose tissue, but not to beta-cell function (paper IV). OGTT curves were converted into geometric centres, centroids, which correlated with differences in glucose tolerance (paper V).

    In conclusion, the islet function in obese children was associated with elevated levels of palmitate, but not pancreatic fat. Fasting palmitate and glicentin levels, as well as centroid analyses of OGTT curves, could potentially identify obese children at risk of prediabetes and subsequent T2DM.

  • Public defence: 2017-03-10 13:15 Polhemsalen, Uppsala
    Nordlander, Thomas
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Observational Astronomy.
    Galactic archaeology with metal-poor stars2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The chemical fingerprints of old, metal-poor stars can be used to unravel the events of the newborn Universe and help us understand the properties of the first stars and star clusters. The study of nearby stars to infer properties in the distant past is often referred to as Galactic archaeology. However, the chemical composition of stars cannot be observed directly, but must be inferred by means of spectroscopic modelling. Traditionally, this modelling utilises one-dimensional (1D) stellar atmospheres in hydrostatic and local thermodynamic equilibrium (LTE). Today, we know that departures from LTE (known as NLTE), and differences between 1D model atmospheres and their hydrodynamical three-dimensional (3D) counterparts, become increasingly severe at lower metallicity. The development of NLTE modelling of spectral line formation in 3D atmospheres is still in its infancy, but constitutes a remarkable step forward that has been made possible by parallelised codes and supercomputers. The central theme of this thesis is the application of NLTE analyses to metal-poor stars, to help usher the field of Galactic archaeology forward with important consequences for the nature of the first stellar generations.

    I present a theoretical NLTE study of aluminium, where I validate the analysis using a set of bright standard stars and provide calculated NLTE effects for a large parameter space. I perform 3D NLTE calculations for the solar spectrum to better constrain the zero-point of the cosmic abundance scale, and find excellent agreement with the meteoritic aluminium abundance.

    I also present NLTE analyses of metal-poor stars in the globular clusters NGC 6397 and M4. While globular cluster stars were long expected to form from a chemically homogeneous medium, star-to-star abundance variations of light elements indicate multiple epochs of star formation. Massive first-generation stars polluted the interstellar medium from which later generations formed, and I use the observed abundance variations to deduce the properties of the polluting stars. Among the heavier elements, I uncover evolutionary abundance variations that match predictions of stellar evolution models with atomic diffusion. The results indicate that the chemical abundance ratios of unevolved metal-poor stars are affected by gravitational settling, with a bias of the order 25-50 %, increasing towards lower metallicity. This atmospheric depletion mechanism is a probable explanation to why the stellar abundances of lithium fall short of the predictions from standard Big Bang nucleosynthesis.

    Finally, I apply a 3D NLTE abundance analysis to the red giant SMSS 0313-6708, which is the most iron-deficient star known. The chemical abundance pattern of this star indicates that it formed from gas affected only by Big Bang nucleosynthesis and a single faint supernova. Comparison of the inferred abundance pattern to theoretical predictions leads to constraints on the explosion mechanism and the mass of the metal-free progenitor star.

  • Public defence: 2017-03-16 09:15 Rudbeck Hall, Uppsala
    Alzrigat, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Targeted Inhibition of Polycomb Repressive Complexes in Multiple Myeloma: Implications for Biology and Therapy2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Multiple myeloma (MM) is a hematological malignancy of antibody producing plasmablasts/plasma cells. MM is characterized by extensive genetic and clonal heterogeneity, which have hampered the attempts to identify a common underlying mechanism for disease establishment and development of appropriate treatment regimes. This thesis is focused on understanding the role of epigenetic regulation of gene expression mediated by the polycomb repressive complexes 1 and 2 (PRC1 and 2) in MM and their impact on disease biology and therapy.

    In paper I the genome-wide distribution of two histone methylation marks; H3K27me3 and H3K4me3 were studied in plasma cells isolated from newly diagnosed MM patients or age-matched normal donors. We were able to define targets of H3K27me3, H3K4me3 and bivalent (carry both marks) which are, when compared to normal individuals, unique to MM patients. The presence of H3K27me3 correlated with silencing of MM unique H3K27me3 targets in MM patients at advanced stages of the disease. Notably, the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also showed that inhibition of the PRC2 enzymatic subunit EZH2 using highly selective inhibitors (GSK343 and UNC1999) demonstrated anti-myeloma activity using relevant in vitro models of MM. These data suggest an important role for gene repression mediated by PRC2 in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.

    In paper II we further explored the therapeutic potential of UNC1999, a highly selective inhibitor of EZH2 in MM. We showed that EZH2 inhibition by UNC1999 downregulated important MM oncogenes; IRF-4, XBP-1, BLIMP-1and c-MYC. These oncogenes have been previously shown to be crucial for disease establishment, growth and progression. We found that EZH2 inhibition reactivated the expression of microRNAs genes previously found to be underexpressed in MM and which possess potential tumor suppressor functions. Among the reactivated microRNAs we identified miR-125a-3p and miR-320c as predicted negative regulators of the MM-associated oncogenes. Notably, we defined miR-125a-3p and miR-320c as targets of EZH2 and H3K27me3 in MM cell lines and patients samples.  These findings described for the first time PRC2/EZH2/H3K27me3 as regulators of microRNA with tumor suppressor functions in MM. This further strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.

    In paper III we evaluated the therapeutic potential of targeting PRC1 in MM using the recently developed chemical PTC-209; an inhibitor targeting the BMI-1 subunit of PRC1. Using MM cell lines and primary cells isolated from newly diagnosed or relapsed MM patients, we found that PTC-209 has a potent anti-MM activity. We showed, for the first time in MM, that PTC-209 anti-MM effects were mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, but that other subunits of the PRC1 complex were not affected. We showed that PTC-209 reduced MM cell viability via significant induction of apoptosis. More importantly, we demonstrated that PTC-209 shows synergistic anti-MM activity with other epigenetic inhibitors targeting EZH2 (UNC1999) and BET-bromodomains (JQ1). This work highlights the potential use of BMI-1 and PRC1 as potential therapeutic targets in MM alone or in combination with other anti-MM agents including epigenetic inhibitors.

  • Public defence: 2017-03-17 10:00 Hambergsalen, Uppsala
    Andersson, Andreas
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences, LUVAL.
    Air-sea exchange of O2 and CO2: Processes controlling the transfer efficiency2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    World oceans cover more than 70% of the earth surface and constitutes a major sink of atmospheric CO2. Two of the most important gases in the marine carbon cycling are O2 and CO2 and hence accurate descriptions of the air-sea gas exchange of these gases are crucial. Still there is a lack of knowledge of the relative importance of processes controlling the efficiency of the air-sea gas transfer. This is especially true for Arctic and high latitude seas were studies on air-sea gas exchange are few. By studying processes causing water-side turbulence, using gases of different solubility and various measurement techniques, more knowledge on the governing processes can be obtained.

    Here we present the very first air-sea fluxes of O2 using atmospheric eddy covariance measurements and investigate the dependence between the gas transfer velocity of O2 and turbulence generated by the mean wind. The instrument was found to suffer from the limited precision and time response, causing significant corrections on the O2 flux. After correcting for this, the O2 fluxes displays an anti-correlation with the air-sea fluxes of CO2 in agreement with the measured air-sea gradient of O2. The transfer velocities for O2 indicates a stronger wind dependence than other commonly used parameterizations of the transfer velocity for CO2 and O2, this especially for wind speeds > 5 m s-1 where the typical onset of wave breaking occur.

    During two winter months eddy covariance measurements were taken over a high Arctic fjord. The data revealed a significant enhancement of the gas transfer velocity for CO2 from water-side convection, generated by cooling of surface waters. The dependence between water-side convection and gas transfer velocity were found for winds as high as 9 m s-1, but were strongest for wind speeds< 7  m s-1.  The data also showed on enhanced air-sea gas transfer of CO2 when conditions were unstable very close to neutral. This enhanced transfer were associated to increased contribution to the CO2 flux from downdraft of air with higher concentrations of CO2.  The combined effect of water-side convection and turbulence generated by wind results in a very effective transfer, thus the air-sea gas exchange at these latitudes may be significantly underestimated.

  • Public defence: 2017-03-17 23:15 Polhemsalen, Uppsala
    Li, Hu
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences.
    Covalent Graphene Functionalization for the Modification of Its Physical Properties2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Graphene, a two dimensional monolayer carbon sheet with the atoms tightly packed in a hexagonal lattice, has exhibited so many excellent properties, which enable graphene to break several material records with regard to carrier mobility, strength yield and thermal conductivity to name a few. Therefore, graphene has been placed as a potential candidate to allow truly next-generation material. Graphene is a zero band gap material, implying that an energy band gap around the Dirac point is supposed to be open to make graphene applicable as a semiconductor. Covalent bond graphene functionalization becomes an essential enabler to open the energy gap in graphene and extend graphene applications in electronics, while the densely packed hexagonal carbon atoms as well as the strong sp2 hybridization carbon-carbon bonds jointly result in a changeling topic of allowing graphene to be decorated with functional groups.

    Here in this thesis, different routes to realize graphene functionalizations are implemented by using physical and chemical ways. The physical functionalization methods are the ion/electron beam induced graphene fluorination as well as local defect insertion and the chemical ways correspond to the photochemistry techniques to approach hydrogenation and hydroxypropylation of graphene. Furthermore, to incorporate graphene into devices, the tuning of mechanical properties of graphene is desired. Towards this aim, the structure modification of graphene is employed to investigate the nanometer size-effect of crystalline size of graphene on the mechanical properties, namely Young’s modulus and surface energy. In the process of the graphene hydrogenation project, we discovered a high yield way to synthesis high quality graphene nanoscroll (GNS). Interestingly, the GNS shows superadhesion property through our atomic force microscopy measurements. This superadhesion is around 6-order stronger than van der Waals interaction and even higher than the hydrogen bonding enhanced and solid/liquid interfaces.

  • Public defence: 2017-03-24 13:15 Brusewitz-salen, Uppsala
    Ahlskog, Rafael
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Government.
    Essays on the collective action dilemma of vaccination2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Vaccines famously possess positive externalities that make them susceptible to the collective action dilemma: when I get vaccinated, I protect not only myself, but also those who I might otherwise have infected. Thus, some people will have an incentive to free ride on the immunity of others. In a population of rational agents, the critical level of vaccination uptake required for herd immunity will therefore be difficult to attain in the long run, which poses difficulties for disease eradication.

    In this doctoral dissertation, I explore different implications of the collective action dilemma of vaccination, and different ways of ameliorating it. First: given that coercion or force could solve the dilemma, and democracies may be less likely to engage in policies that violate the physical integrity of citizens, democracies may also be at a disadvantage compared to non-democracies when securing herd immunity. In essay I, I show that this is, empirically, indeed the case. Barring the use of extensive coercion therefore necessitates other solutions.

    In essay II, I highlight the exception to individual rationality found in other-regarding motivations such as altruism. Our moral psychology has likely evolved to take other's welfare into account, but the extent of our prosocial motivations vary: a wider form of altruism that encompasses not just family or friends, but strangers, is likely to give way to a more narrow form when humans pair-bond and have children. This dynamic is shown to apply to the sentiments underlying vaccination behavior as well: appeals to the welfare of society of getting vaccinated have positive effects on vaccination propensity, but this effect disappears in people with families and children. On this demographic, appeals to the welfare of close loved ones instead appears to have large effects.

    In essay III, I investigate whether the prosocial motivations underlying vaccination behavior are liable to be affected by motivation crowding - that is, whether they are crowded out when introducing economic incentives to get vaccinated. I find that on average, economic incentives do not have adverse effects, but for a small minority of highly prosocially motivated people, they might.