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Coming dissertations at Uppsala university

Please note that the date and time given on these pages is the time of electronic publication, and not the date of the public defense. To find the time and venue of the public defense, please follow the link to DiVA of the thesis in question.
  • Allogeneic dendritic cells as adjuvants in cancer immunotherapy

    Author: Grammatiki Fotaki
    Publication date: 2019-03-22 08:08

    In recent years, immunotherapeutic approaches have achieved remarkable successes through checkpoint blockade antibodies, advances in the use of chimeric antigen receptor (CAR) T cells and new insights into the immunosuppressive role of the tumor microenvironment (TME). Through the advances, the role of cancer vaccines based on ex vivo manipulated autologous dendritic cells (DC) has been challenged. The main aim of DC-based vaccination is the induction of tumor-specific T-cell responses through presentation of tumor-associated antigens. However, this process has been found to be highly dependent on the ability of the injected vaccine-DCs to activate endogenous bystander DCs.

    In this work, we examined the feasibility of having an allogeneic source of vaccine-DCs (alloDCs), not for direct antigen-presentation to T cells but as an immune primer aiming to activate bystander DCs. In paper I, we treated alloDCs with a T helper cell type 1 (Th1)-promoting maturation cocktail alone or combined with a replication-deficient, infection-enhanced adenoviral vector (Ad5M) as a potential gene delivery vehicle. We found that mature pro-inflammatory alloDCs, either non-transduced or transduced, created a cytokine- and chemokine-enriched milieu in vitro, and promoted the activation of co-cultured immune cells, including cytolytic NK cells, from unrelated donors. The emerged milieu induced the maturation of bystander DCs, which cross-presented antigens from their environment to autologous antigen-specific T cells. In paper II, we found that alloDCs promoted the migration of murine immune cells both to the site of injection and to the draining lymph node. When Ad5M was used for the delivery of the melanoma-associated antigen gp100, we found that gp100-expressing alloDCs were able to control tumor growth through gp100-specific T-cell responses and alteration of the TME. In paper III, we found that co-administration of alloDCs with an adenoviral vector encoding for HPV-antigens is effective in controlling the growth of HPV-related tumors and this may depend on a cross-talk between alloDCs and NK cells which leads to further recruitment of immune cells into the TME. In paper IV, we observed that concomitant targeting of immune checkpoint receptors or co-stimulatory molecules results in synergistic therapeutic effects in a murine colorectal model.

  • Congenital Recessive Ichthyosis : Studies of Gene Expressions Related to Keratinocyte Differentiation and Skin Barrier Repair

    Author: Hanqian Zhang
    Publication date: 2019-03-20 13:42

    Autosomal recessive congenital ichthyosis (ARCI) is a rare monogenetic disorder characterized by a defective skin barrier, hyperkeratosis, and dry, scaly skin. It affects keratinocyte differentiation and is caused by mutations in any of at least 12 genes believed to control the formation of ω-O-acylceramide and the corneocyte lipid envelope (CLE): ABCA12, ALOXE3, ALOX12B, CERS3, CYP4F22, ELOVL4, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, and TGM1.

    Studies of keratinocyte differentiation and gene expression in ARCI may help us better understand the pathobiology of skin barrier formation. One way to verify that ARCI-related gene products are operating in a chain of events essential for lipid barrier formation is to use immunofluorescence and in situ proximity ligation assays to demonstrate the proteins’ colocalizations in the epidermis. In paper I, a new method for the objective quantitative image analysis of protein expression and colocalization in different epidermal layers of skin sections was developed using free, open-source software, CellProfiler. Using this method and microarray analyses of skin biopsies from ARCI patients with TGM1 mutations (n = 5) compared with those of healthy controls (n = 4), many ARCI-related genes were found to be upregulated in patient epidermis (paper II). Because many other genes involved in keratinocyte differentiation and immune/inflammatory response, including PPARD, were also induced in the patients’ microarrays, the effects of a ligand-dependent transcription factor, PPARδ, encoded by PPARD, were studied on ARCI-related gene expression in cultured keratinocytes, usually showing the pronounced upregulation by PPARδ agonists (paper III). Furthermore, using previous array data obtained from cultured differentiated keratinocytes and from skin biopsies of patients with TGM1 mutations, nine novel candidate markers of differentiation were identified, and the upregulation was verified by qPCR of mRNA from cultured keratinocytes and skin biopsies. These transcripts were also induced by PPARδ agonists in cultured proliferating keratinocytes (paper IV).

    To conclude, the upregulation of other ARCI-related genes in patients with TGM1 mutations might reflect a feedback mechanism in ω-O-acylceramide biosynthesis, which, however, is unable to restore the patients’ skin barrier. In theory, substitution therapy with ω-O-acylceramide and recombinant TGm-1 may be required. Because PPARδ activation appears involved in upregulating ARCI-related genes and nine novel differentiation marker genes, all potentially important for barrier repair, this approach could become a treatment option for several types of ichthyosis and wound healing.

  • Kulturgeografin tar plats i välfärdsstaten : Vetenskapliga modeller och politiska reformer under efterkrigstidens första decennier

    Author: Wikman Pär
    Publication date: 2019-03-20 10:04

    The aim of this study is to explain why human geography in Sweden became a planning science during the postwar period. Human geography had developed a sophisticated use of abstract models. The proliferation of models within in the social sciences was an international phenomenon during the postwar period. Actors within human geography in Sweden embraced this trend and strived towards making the constructions of models the methodological core of the discipline. Human geography, as an independent discipline, was being defined during this period. Simultaneously, human geography’s position within Swedish society was also being defined. This led a group of geographers, who were very much in favor of human geography as a science of models, to align themselves with the needs of the expanding welfare state.

    The group of actors, who reformed their discipline by making a specific form of geographical expertise essential to the welfare state, are referred to as geographers of planning. The most important actors within this group was, the not yet world famous, Torsten Hägerstrand and his colleague Sven Godlund. During the crucial years of the mid-1950s to the early-1960s, Hägerstrand held a position at Lund University while Godlund was engaged in a number of public investigations. Godlund regularly hired Hägerstran’s students and those same students used their experiences working for the public investigations to write their term papers. Through Godlund’s and Hägerstrand’s relationship a generations of human geographers was trained in planning practices and human geography was defined, within the public administration, by the works of Godlund and Hägerstrand.

    The most widely disseminated models were constructed from the German geographer Walter Christaller’s central place theory. By translating the general arguments of the theory into codified models, the theory was turned into a tool for planners. Thus the theoretical skills of human geographers where embedded in the practices of practical planning. This process turned the difference between research and planning into a difference of degree, rather than a difference of practice. During the municipal reforms of the 1960s the Swedish municipalities were remade to closer resemble the ideal of the central place theory. Through that reform the relationship between human geography and social planning was consolidated, making human geographers experts of planning. A labor market was created for geographers but it also placed an onus on the geographical institutions to supply the labor force for that market.

  • On Virtual Surgical Planning in Cranio-Maxillofacial Surgery

    Author: Johanna Nilsson
    Publication date: 2019-03-19 12:56

    The complex three-dimensional (3D) anatomy of the cranio-maxillofacial (CMF) region makes surgery a challenging task. Virtual surgical planning (VSP) has the potential to increase accuracy, reproducibility and shorten operation time. Key challenges in VSP are to accurately separate, or segment, certain structures of interest, such as the orbit, from the rest of the image, as well as to create an accurate 3D model of the facial bones and dentition for orthognathic surgery planning. The time required for planning and fabrication of guides for trauma surgery is another challenge. The overall aim of this thesis was to develop and evaluate new virtual planning tools for CMF-surgery and to investigate their usefulness. Study I, II discuss and evaluate image fusion of CT/CBCT and intraoral scanning for orthognathic surgery. A method for virtual bite registration in centric relation (CR) was also proposed. The workflow has the potential to eliminate traditional laboratory work, and may facilitate 3D computer-assisted-planning in orthognathic surgery. Study III deals with orbit segmentation and presents a semi-automatic method, using a deformable model tracing the inside of the orbit via haptic 3D interaction. The method was validated in retrospective unilateral orbital fracture cases. The fractured orbits were compared to the intact side by volume and shape analyses. The method showed high accuracy, precision, time-efficiency and thereby potential to be a powerful tool for planning and evaluating reconstruction of orbital fractures. Study IV evaluates an in-house haptic-assisted VSP system for complex mandibular fractures on a series of retrospective cases and an artificial case. The system showed high precision and time-efficiency, but relatively low accuracy. This study proposes a novel, fast and user-friendly way of integrating VSP into planning mandible trauma surgery and could help in reducing operating time and increase accuracy. Study V is a systematic review and meta-analysis studying potential time benefits using VSP in CMF surgery. The study suggests that VSP shortens the operating time and ischemia time for reconstructive surgery. VSP also appears to shorten the preoperative planning time for orthognathic surgery.

  • Exact Results in Supersymmetric Field Theories : A dissertation on the defect and deformed

    Author: Erik Widen
    Publication date: 2019-03-12 13:45

    Quantum field theories (QFTs) are the most precise descriptions of the physical reality that humanity has found. Yet exact predictions are often missing as most computations are notoriously difficult to carry out. One generally resorts to perturbation theory which immediately limits the regime of validity. The need of better computational techniques and a deeper understanding of quantum field theory is evident.

    The highly symmetric N=4 SYM theory offers guidance in this quest. The theory's maximal supersymmetry and conformal invariance have allowed for the development of several computational techniques, most notably the AdS/CFT correspondence, supersymmetric localization and applications of integrability. These methods provide the rarity of exact results in a fully interacting QFT and shine light on regimes inaccessible by traditional computations.

    The insights drawn from N=4 SYM can be extended into more general settings through deformations and modifications. Three such modifications are the β-deformation, the massive deformation N=2* and N=4 SYM with a defect. This thesis summarizes a number of exact results for these three settings through: i) a spin-chain analogy for two-point functions in the defect N=4 SYM, ii) a vacuum solution for the β-deformed defect N=4 SYM and its spin-chain interpretation of one-point functions, iii) a detailed study of the phase transitions in N=2* applying localization and iv) an adaptation of the Quantum Spectral Curve to explicit calculations of anomalous dimensions in β-deformed N=4 SYM.

  • Laga efter läge : Statsråds föreställningar om styrning i Regeringskansliet

    Author: Lena Noreland
    Publication date: 2019-03-11 08:23

    This thesis concentrates on two questions: What beliefs do ministers have of appropriate steering in the Swedish core executive Regeringskansliet (RK)? Do they believe that RK is a politically steered organization as it is usually described, or as a throughout political organization, as some political scientists have recently depicted it? RK embraces two institutional subcultures: one non-political with permanent civil servants and firm rules and regulations for work processes, the other one political, where work conditions are more adaptive. Analyses of beliefs that ministers may have, build on information from interviews with 35 ministers in governments from 1991 to 2014. They answered questions about their steering of preparation work in cases, performed by civil servants. They described their choice of strategies and means for steering. Their explicit memories of actual steering activities have been used for inferences of their beliefs. The research method is typically qualitative. Two organizational theories serve as basis for the analyses. One is the legal bureaucratic model, mainly according to Max Weber. Either ministers steer the work of civil servants hierarchically, giving instructions directly to them. Or else, they steer with political advisers as proxies, thereby involving them in the hierarchical steering. The other one is a cadre theory - an unorthodox choice, which reflects a recent idea saying that RK is a throughout political cadre organization where ministers, staff members as well as civil servants are political office holders. All ministers stressed that work processes in RK ministries are steered by them, i.e. they believe RK to be a politically steered organization. Ministers chose steering strategies according to institutional demands and possibilities and according to their beliefs of what strategies match their individual ambitions for the government position. Most ministers stated that they gave instructions directly to civil servants. But approximately three out of ten ministers said that they steered using political advisors as proxies, in some cases with far-reaching mandates to act independently. The ministers focused both on steering formulation of the matter per se and preparation procedures when it was important for the political outcome.

    From minister perspectives the political staff can be identified as a cadre. Evidence for civil servants being seen as political cadres was scarce. One minister had practiced typical cadre steering in specific task forces, parallel to hierarchical steering in the ordinary ministry organization. Some ministers had used detached cadre-oriented means. In their opinion, informality in steering procedures promoted the performance of civil servants. One minister mentioned that all work in RK ultimately results in government decisions, and that is why RK may be characterized as an outright political organization. Almost all ministers who used political advisors as proxies, belonged to coalition governments. Their choice of steering strategy can be understood as an adjustment to the heavy workload that coordination of politics imposes on them.

  • Micro-grids supplied by renewable energy : Improving technical and social feasibility

    Author: Caroline Bastholm
    Publication date: 2019-03-08 14:06

    Universal access to electricity stands high on the global agenda and is regarded as essential for positive development in sectors such as health care, education, poverty reduction, food production and climate change. Decentralized, off-grid electrification is deemed an important complement to centralized grid extension. By utilizing a renewable energy source, solar technology for the generation of electricity, photovoltaics (PV) is being considered as a way forward to minimize the environmental problems related to energy use.

    This thesis aims to contribute to improving the technical and social feasibility of PV and PV-diesel hybrid micro-grids for the purpose of providing access to electricity to people in rural areas of countries with low level access to electricity. In line with these general aims, the focus has been to address three questions related to challenges in three phases of rural electrification. The work has a multi-disciplinary approach, addressing mainly technical and social aspects of long-term sustainability of micro-grids, in a local context, and the changes these are intended to generate. One specific micro-grid in Tanzania has been used as a major case study.

    The thesis is developed through three papers, all presenting methodologies or aspects for investigation in rural electrification projects and studies in general, and for PV-diesel hybrid micro-grids in particular. Paper I puts forward a methodology to facilitate non-social scientific researchers to take social aspects increasingly into consideration. Paper II is a guideline to support system users to increasingly apply an evaluation based system operation. Paper III specifically highlights the importance to consider blackouts when investigating how an existing off-grid PV-diesel hybrid system shall be utilized when a national grid becomes available.

  • The Ambassador's Letter : On the Less Than Nothing of Diplomacy

    Author: Alexander Stagnell
    Publication date: 2019-03-08 12:38

    The principal aim of this dissertation is to answer the age-old question What is diplomacy? But this study approaches the question in what might, on first look, appear oblique. By employing Slavoj Žižek’s reworked notion of Ideologiekritik with respect to the history, science, and artistic explorations of diplomacy, this work begins by extracting three of its essential problems: the name, death, and representation. A presentation of the central concepts and theoretical perspectives at play in Žižek’s work is elaborated upon, focusing on his understanding of politics, ideology, and the core of the conceptual apparatus of Lacanian psychoanalysis.

    The overarching argument of the thesis is that diplomacy constitutes an Ideological State Apparatus, i.e. that it offers a symbolic link destined to, through ideology, repress the fundamental inconsistencies of the modern nation state, in order to secure its continuous functioning. Diplomacy is shown to constitute the name that points to the impossibility of the state to become One with itself, and the thesis aims to capture how this impossibility, and that which must be excluded from the state to keep the fantasy of fulness alive, always returns to haunt it. Empirically, this is explored by way of re-reading the history of the word diplomacy, whose modern birth coincided with the events of the French Revolution. The study seeks to retrace diplomacy through three distinct historical formations, which here are referred to as the archi-political, ultra-political, and post-political. Each of theses formations functions as a covering over of the fundamental impossibility of the state. Readings of Immanual Kant, Henry James, André Brink, Mads Brügger, and 20th century IR-theory and Diplomacy Studies are presented in order to elaborate the way in which these formations are constituted as ideological fantasies protecting the state and, for that matter, diplomacy from their abyssal ground.

  • Toward fully automatic earthquake detection and processing for tomography in the Hengill area

    Author: Frederic Wagner
    Publication date: 2019-03-05 09:38

    This thesis focuses on the automation of seismic data analysis, in particular, event detection, quality assessment of detected events, and preparation of an earthquake catalogue for seismic tomography.

    The developed event detector uses back-propagation and stacking of a seismic trace attribute with a known velocity model to detect and locate events. A four-dimensional volume in space and time is probed for local maxima of coherently stacking signals. These local maxima define event location and origin time. Application of the detection algorithm to data from a dense 26-station 3-component seismic network in the Hengill area, SW Iceland, produced an increased true-to-false detection ratio compared to the local detection routine.

    The detected events were analysed using inter-event cross-correlation with a manually picked reference catalogue to determine their similarity with real events. Automatic P- and S-phase picks were derived using the time delay information from highly correlated events. Relocation with the determined phase picks improves hypocentre uncertainty. A multi-stage selection process is implemented to categorise the detected events into different classes of varying priority for a potential manual analysis. Depending on the used parameters, the top quality category of events can be used in e.g. local-earthquake tomography without manual inspection. Iterative application of the algorithm improved the reference catalogue by almost 40% with events of at least equal quality.

    The final local-earthquake tomography with the updated reference catalogue confirms the success of the implemented workflow. The resulting Vp, Vs, and Vp/Vs models show structures that can be associated with the local geothermal activity. A higher resolution and extended ray coverage was achieved compared to previous tomographic studies. Double-difference location of the events using differential times from waveform correlation significantly improved event hypocentres revealing detailed fault geometry in the known seismicity pattern. A preliminary double-difference tomography shows promising results for high resolution imaging.

  • Multidisciplinary Near-Surface Investigation of a Quick-Clay Landslide Prone Area in Southwest Sweden

    Author: Silvia Salas Romero
    Publication date: 2019-03-05 09:37

    Quick-clay landslides are considered one of the most important geohazards in Sweden, Norway, and Canada. The deposits involved are glacial and postglacial clays and silty clays, which are very sensitive to increased stress that may collapse their structure and cause liquefaction.

    A multidisciplinary approach was adopted in this study of quick clays in an area of southwest Sweden that is prone to landslides. It was mainly based on geophysical methods, but was complemented and validated with geotechnical, geological, and hydrological data. Downhole geophysics, land and river reflection seismics, radio magnetotellurics, P-wave refraction tomography, magnetics, and multichannel analysis of surface waves comprised the main geophysical methods used in this research. Laboratory measurements of core samples, such as grain size analysis, mineral magnetic properties, fossil content, X-ray fluorescence, cation exchange capacity, X-ray powder diffraction, electrical conductivity, and pH were also taken. Hydrological modelling was used to obtain information on the properties of groundwater within a coarse-grained layer, given the importance of this information in the formation of quick clays.

    The evaluation of the physico-chemical properties of the coarse-grained layer revealed high values of magnetic susceptibility, probably as a result of fluvial sorting, which tends to accumulate denser minerals such as magnetite. Potential quick clays were visually observed above this layer, and their presence was also confirmed by geotechnical data acquired in previous studies. Marine fossils identified within the coarse-grained layer confirmed the glaciomarine origin of the clays. Geophysical results revealed the presence of large-scale structures, an undulating fractured bedrock and a coarse-grained layer sandwiched between clay deposits, with leached sediments on top and unleached sediments below. This layer, important for the development of quick clays in the area, was 3D modelled in a regional context. Magnetic data also revealed that the coarse-grained layer together with quick clays, have the potential to act as a sliding prone layer. Multichannel analysis of surface waves helped to geotechnically characterize the area. Although the results could not reach the deeper layers, it did yield information about the shallower layers of clay, silt and sand. The VS30 values indicated the presence of soft soils, as well as soft clays/silts with high plasticity index and high water content.

    This PhD is expected to improve the current knowledge of quick-clay landslides and how they are preconditioned. Climate change will probably affect the study area in the near future, most likely increasing landslide risk, therefore, research should continue and advance to new levels. Application of other geophysical methods such as borehole or geophysical monitoring, and induced polarization, could provide more information about the formation of quick clays and associated landslides.

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