DiVA - Academic Archive On-line

Adsorption and Ordering of Surface Active Molecules and Particles at Solid Interfaces and in the Bulk

Maja S. Hellsing — Tue, 24 Apr 2012 10:22:31 +0200

Factors that influence the process of adsorption and order of dilute and concentrated systems of molecules and particles are explored in this thesis. The results are based largely on neutron scattering techniques. Study of the adsorption from dilute solutions of a common surfactant, AOT (sodium bis (2-ethylhexyl) sulfosuccinate), at a solid/liquid interface showed that AOT molecules adsorbed to the interface in a bilayer structure, with the hydrocarbon tails at maximum packing density even at very low concentrations. At higher AOT concentrations, a stack of fluctuating layers each separated by large amounts of water next to the dense bilayer was seen. The driving force for adsorption is dominated by self-assembly of AOT. It was found that an oriented lamellar phase wets the interface below the bulk concentration for formation of this phase.

Proteins can be viewed as polymeric surfactants. The adsorption of proteins from seeds of the Moringa oleifera tree to a silicon oxide surface was studied to elucidate the mechanism of the protein as a flocculent in water treatment processes. The protein was found to adsorb at the interface as dense layers with a thickness suggestive of co-adsorption rather than single isolated molecules. The strong adsorption and tendency to associate in solution suggest mechanisms for flocculating particulate impurities in water.

As with surfactants, dispersions of colloidal particles can assemble in regular structures by self-assembly. Polystyrene latex particles were studied and could form large three-dimensional crystals of about 1×1 cm² in a 2 mm path cell. The diffraction pattern indicated a close packed structure with the 110 axis perpendicular to the container wall. The crystal was well-aligned and oriented by the direction of flow. At the solid interface large two-dimensional domains of about 20 cm² of highly oriented particles were formed. The particle-particle separation at the surface and in the bulk was determined by the charge repulsion of the particles.

Macromolecular Matchmaking : Mechanisms and Biology of Bacterial Small RNAs

Erik Holmqvist — Tue, 24 Apr 2012 10:42:15 +0200

Cells sense the properties of the surrounding environment and convert this information into changes in gene expression. Bacteria are, in contrast to many multi-cellular eukaryotes, remarkable in their ability to cope with rapid environmental changes and to endure harsh and extreme milieus. Previously, control of gene expression was thought to be carried out exclusively by proteins. However, it is now clear that small regulatory RNAs (sRNA) also carry out gene regulatory functions. Bacteria such as E. coli harbor a large class of sRNAs that bind to mRNAs to alter translation and/or mRNA stability.

By identifying mRNAs that are targeted by sRNAs, my studies have broadened the understanding of the mechanisms that underlie sRNA-dependent gene regulation, and have shed light on the impact that this type of regulation has on bacterial physiology. Control of gene expression often relies on the interplay of many regulators. This interplay is exemplified by our discovery of mutual regulation between the sRNA MicF and the globally acting transcription factor Lrp. Through double negative feedback, these two regulators respond to nutrient availability in the environment which results in reprogramming of downstream gene expression. We have also shown that both the transcription factor CsgD, and the anti-sigma factor FlgM, are repressed by the two sRNAs OmrA and OmrB, suggesting that these sRNAs are important players in the complex regulation that allow bacteria to switch between motility and sessility. Bacterial populations of genetically identical individuals show phenotypic variations when switching to the sessile state due to bistability in gene expression. While bistability has previously been demonstrated to arise from stochastic fluctuations in transcription, our results suggest that bistability possibly may arise from sRNA-dependent regulatory events also on the post-transcriptional level.

Doing Things in Relation to Machines : Studies on Online Interactivity

Anders Olof Larsson — Tue, 24 Apr 2012 09:55:23 +0200

The Internet is often discussed in conjunction with various notions of interactivity. Recently, conceptualizations of a “Web 2.0″, mainly focusing on harnessing user-generated content, have grown increasingly common in both public discourse and among researchers interested in the continued growth and transformation of the Internet.

This thesis approaches the use and non-use of online interactive features by societal institutions. Specifically, the thesis focuses on online newspapers and online political actors, studying the practitioners working within those institutions and on their respective audiences. Consisting of four empirical studies, the thesis is informed theoretically by the application of conceptual tools pertaining to structuration theory. In Anthony Giddens’ original conception, structuration theory posits that social structure is recursively shaped (and possibly altered) as human agents choose to re-enact certain modalities of specific structures. By changing their uses of the rules and resources made available to them by structure, humans are given agency in relation to overarching, macro-level structures. Giddens’ writings have also been contextualized to the study of information technology use by Wanda Orlikowski, who has mostly focused on organizational research.

Combining insights from Giddens and Orlikowski, the thesis suggests that most Internet users are enacting a “structure of audiencehood”, entailing somewhat traditional consumer behavior, rather than a “structure of prosumerism”, which would entail extensive uses of the interactive features made available online. Similar traditional use patterns are discerned for practitioners. The thesis suggests that we should not be surprised at relatively low levels of use of interactive features by practitioners and audiences in these contexts. While the chosen areas of study are often surrounded by expectations and “hype” regarding the consequences of online interactivity, institutionalized news and politics can be said to represent stable structures – structures that have functioned in similar ways for extended periods of time, and, thus, are not so easily amended.

Studies on Phosphohistidine Phosphatase 1 : What? Where? Why?

Ulla Beckman Sundh — Wed, 25 Apr 2012 10:27:43 +0200

Phosphohistidine phosphatase 1 (PHPT1) is a small protein, consisting of 125 amino acids, that catalyzes the dephosphorylation of histidine but does not have any activity towards other phosphorylated amino acids. PHPT1 was identified in 2002, and is so far the only mammalian histidine phosphatase known, but still little is known about its physiological role. No mammalian histidine kinases have hitherto been identified.

Phosphorylation is one of the most important ways in which the structure and activity of a protein may be changed after translation. Proteins are phosphorylated on the side chain of amino acid residues. When a hydroxyl is phosphorylated the result is a phosphoester and when a nitrogen is phosphorylated the result is a phosphoamidate. Histidine may be phosphorylated on either of the two nitrogens of the imidazole ring of the side chain. The resulting phosphoamidate bond is labile and rich in energy, which makes histidine phosphorylation highly reversible and flexible. However, histidine phosphorylation is less studied than that of the phosphoesters due to the acid lability of the phosphoamidate bond.

The work described in this thesis was focused on further elucidating the physiological role of PHPT1. Amino acid residues of importance for the activity of PHPT1 were identified, and mutants with decreased phosphatase activity were produced. These mutants have been used in studies on the function of PHPT1. By using immunohistochemical methodology the localization of PHPT1 in both mouse and human tissues was determined, with mainly similar results. A general finding was that expression of PHPT1 was high in epithelial cells with short turnover time, indicating that PHPT1 may have an important role in proliferating cells. We have also developed a comparatively fast and simple screening method for determination of PHPT1 activity. Since research in this field has been hampered by the lack of efficient and practical methodology, hopefully this new method will be an asset in search of inhibitors for PHPT1, which in turn may be used for detection of the elusive mammalian histidine kinases, the finding of which may give major breakthroughs in the field.

Quantitative Tracer Based MRI Perfusion : Potentials and Limitations

Arvid Morell — Wed, 25 Apr 2012 12:00:37 +0200

Tracer based MRI perfusion measurements is a clinically useful tool to assess regional distributions of tissue blood flow and volume. The method may be based on any of the three relaxation mechanisms T1, T1 and T2*, the latter denoted DSC-MRI being the most common. The primary aim of this work was to study the feasibility of obtaining quantitative estimates using these methods.

1) Feasibility of DSC-MRI for kidneys using an iron oxide based contrast agent and the influence of secondary relaxation effects on the results, part of a clinical phase II trial: The method proved feasible and the underestimation induced by secondary relaxation can be corrected for by using a double echo sequence.

2) Influence of blood flow rate on risk factors for developing cerebral ischemia during cardio pulmonary bypass, measurements in pig with gadolinium based DSC-MRI: The results indicated an ischemic threshold level at a blood flow rate of approximately 6 ml/kg/min.

3) The ability of gadolinium based DSC-MRI to detect changes in global blood flow, experimental measurements in pig and numerical simulations: The results support that DSC-MRI can discriminate between global flow levels in the same subject given that all other parameters are kept constant. The results also indicate that calculated perfusion values are highly sensitive to the arterial deconvolution procedure.

4) Influence of differences in blood/tissue relaxivity and secondary relaxation for a gadolinium based contrast agent, measurements in pig and numerical simulations: The blood/tissue relaxivity ratio is not unity and the situation is complicated by secondary relaxation effects. Deconvolution regularization appears to partly counteract the overestimation induced by difference in blood/tissue relaxivity for DSC-MRI.

In summary, the fundamental assumption of equal blood and tissue relaxivity is experimentally shown to be invalid and the influence of this discrepancy is substantial. Several factors contribute to measurement errors, a combination of these factors can incidentally lead to additive errors or error cancellation based on a variety of experimental and analysis conditions. Given that the differences in blood/tissue relaxivity cannot readily be accounted for in a clinical setting, absolute perfusion quantification by tracer based MRI remains challenging if not impossible.

Outcome of Stroke Prevention : Analyses Based on Data from Riks-Stroke and Other Swedish National Registers

Signild Åsberg — Tue, 24 Apr 2012 14:14:34 +0200

The aim of this thesis was to explore variations in stroke prevention and the effect of prevention on outcome. The studies were based on patients registered in the Swedish Stroke Register between 2001 and 2009 and although used to different extents in each paper, additional information was retrieved through linkage to The National Patient Register, the Cause of Death Register, the Prescribed Drug Register and the Total Population Register.

Cardiovascular risk factors were prevalent among ischemic stroke (IS) patients; however, they were not always prescribed the drugs recommended, and increasing age was an important negative predictor (Paper I).

After IS, the rate of hemorrhage in patients prescribed antiplatelet agents (2.4 per 100 person-years) was double to results from randomized controlled trails, but was similar for patients prescribed warfarin (2.5 per 100 person-years). Age ≥75 years and previous hemorrhage were associated with a moderately increased risk of future hemorrhage (Paper II).

Among IS patients with atrial fibrillation, one-third was prescribed warfarin and two-thirds were prescribed antiplatelets. After adjustment for a propensity score (used to adjust for the non-randomized design), warfarin was associated with a reduced risk of death (0.67; 95% CI, 0.63-0.71) (Paper III). The rate of subsequent hemorrhagic stroke was 0.4 per 100 person-years and the risk did not change (HR 1.04; 95% CI, 0.73-1.48) when later years of the 2000s (inclusion period 2005-8: follow-up until 2009) was compared with earlier years (inclusion period 2001-4: follow-up until 2005) (Paper IV, cohort).

Although the risk of first-ever hemorrhagic stroke more than doubled with warfarin than without, the risk did not change between 2006 and 2009 (Paper IV, case-control).

In summary, the prescription of secondary preventive drugs varies with age, even though cardiovascular risk factors are prevalent in all ages. The risk of death and hemorrhage are affected by the type of antithrombotic prescribed. Therefore, it is important individual’s stroke and bleeding risks in stroke prevention are assessed.

Compression Mechanics of Powders and Granular Materials Probed by Force Distributions and a Micromechanically Based Compaction Equation

Foad Mahmoodi — Tue, 24 Apr 2012 13:59:00 +0200

The internal dynamics of powder systems under compression are as of yet not fully understood, and thus there is a necessity for approaches that can help in further clarifying and enhancing the level of understanding on this subject. To this end, the internal dynamics of powder systems under compression were probed by means of force distributions and a novel compaction equation.

The determination of force distributions hinged on the use of carbon paper as a force sensor, where the imprints transferred from it onto white paper where converted through calibration into forces. Through analysis of these imprints, it was found that the absence of friction and bonding capacity between the particles composing the powder bed had no effect on how the applied load was transferred through the system. Additionally, it was found that pellet strength had a role to play in the homogeneity of force distributions, where, upon the occurrence of fracture, force distributions became less homogenous.

A novel compaction equation was derived and tested on a series of systems composed of pellets with differing mechanical properties. The main value of the equation lay in its ability to predict compression behavior from single particle properties, and the agreement was especially good when a compact of zero porosity was formed.

The utility of the equation was tested in two further studies, using a series of pharmaceutically relevant powder materials. It was established that the A parameter of the equation was a measure of the deformability of the powder material, much like the Heckel 1/K parameter, and can be used as a means to rank powders according to deformability, i.e. to establish plasticity scale. The equation also provided insights into the dominating compression mechanisms through an invariance that could be exploited to determine the point, at which the powder system became constrained, i.e. the end of rearrangement. Additionally, the robustness of the equation was demonstrated through fruitful analysis of a set of diverse materials.

In summary, this thesis has provided insights and tools that can be translated into more efficient development and manufacturing of medicines in the form of tablets.

Imaging and Treatment Outcome of Potentially Curable Prostate Cancer

Sam Ladjevardi — Fri, 27 Apr 2012 09:55:49 +0200

The over-all aim of the present study was to compare the results of treatment with curative intent, with conservative treatment in men with prostate cancer (PCa) without distant metastases.

In a population-based cohort in Sweden, the predictive value of prostate-specific antigen (PSA) was evaluated and the relative survival of men considered plausible candidates for treatment with curative intent was investigated.

We also evaluated the association between curative treatment and cause-specific mortality, and over-all as well as relative survival in men diagnosed with PCa with a serum PSA level between 20 and 100 ng/ml.

Due to the uncertainly of transrectal ultrasound-guided biopsy in the diagnosis of PCa, we created a model for prostate imaging to increase the safety of guided Core Needle Biopsy (CNB) in men with suspect PCa, thereby improving staging.

Material and methods. The cohorts in the first three studies were prospectively included in a population-based register (the National Prostate Cancer Register). Study IV was a clinical study on patients included between 2010 and 2011.

Results. Regardless of Gleason Score, a positive relationship between survival and serum PSA level categories in patients with a PSA level> 4 ng/ml was found, but a paradoxical inverse relationship was observed in men with a PSA level < 4 ng/ml. Men with a well-differentiated tumour had a 5-year relative survival exceeding 100% regardless of treatment. The survival rate for moderately and poorly differentiated tumours was poor for men managed conservatively. The 10-year cause-specific mortality for patients with PSA 20-50 ng/ml was 36% for patients treated without and 13% for patients treated with curative intent. For patients with a PSA 50-100 ng/ml the 10-year cause-specific mortality was 55% for conservative and 20% for patients treated with curative intent.

PCa detection by CNB, magnetic resonance imaging (MR) with ADC (Apparent diffusion coefficient), magnetic resonance spectroscopic imaging (MRSI) and Positron Emission Tomography (PET/CT) ¹¹C Acetate imaging applied to 10 sections of the prostate demonstrated clear conformity between MRI ADC mapping and postoperative findings, showing high specificity (87%) and sensitivity (95%).

Conclusion. The inverse relationship between relative survival and PSA at levels below 4 ng/ml should be considered when choosing a PSA cut-off level. Outcome differs little between conservative management and treatment with curative intent in men with localised well- to moderately differentiated tumours over a 10-yr period. For men with poorly differentiated tumours, on the other hand, choice of treatment is crucial for outcome. Treatment with curative intent is beneficial in the group of men with prostate cancer and PSA levels between 20 and 100 ng/ml without distant metastases. A combination of MRI , diffusion ADC and MRSI may provide an improved model for imaging of the prostate for targeted biopsy.

Små lån, fattiga vänner : Om betydelsen av symboliskt och socialt kapital för mikrofinansanvändare i tre kenyanska organisationer, 2002 - 2006

Emilia Liljefrost — Wed, 25 Apr 2012 11:03:18 +0200

Emilia Liljefrost

Små lån, fattiga vänner.

Om betydelsen av symboliskt och socialt kapital för mikrofinansanvändare i tre kenyanska organisationer, 2002–2006

Dissertation presented at Uppsala University to be publicly examined in Room IV, University Main Building, Uppsala, Friday, May 18, 2012, at 13:15, for the degree of Doctor of Philosophy. The examination will be conducted in Swedish.

Abstract

Liljefrost, E. 2012. Små lån, fattiga vänner. Om betydelsen av symboliskt och socialt kapital för mikrofinansanvändare i tre kenyanska organisationer, 2002 – 2006. (Meager credit, deprived friends. The importance of symbolic and social capital among microfinance users belonging to three Kenyan organizations, 2002 – 2006) 198 pp. ISBN 978-91-87199-02-8. Sekel Bokförlag

The aim of the thesis is to investigate how poor people are viewed on an international policy level and what role the social context has for microfinance users. The study uses research methods such as text analysis, interviews and observations. To be able to achieve the aim of the thesis, a theoretical framework utilizing the concepts of symbolic and social capital and trust has been used.

Stakeholders expect that microfinance will improve poor people and their access to financial services. The idea is that this will strengthen people’s livelihoods through its empowering effects. The thesis demonstrates that it is crucial to the international aid stakeholders to identify the poor that are to be reached by microfinance. However, the categories that are utilized are limited when it comes to the extent they include the variety of dimensions regarding what it means to live under scarce circumstances.

At the same time, to live under scarce circumstances seems to be much more complex than what the international policies envisage. Poor people lack economic capital and many do not have access to convenient financial institutions, but they also lack other essential things. The thesis shows how the users’ need for trust is as important as the financial services as such. To be able to foresee other people’s behavior, which is necessary in the process aiming to establish trust, there are two enabling factors: firstly, the existence of shared norms and secondly, a social setting that guarantees their existence. Norms reduce the complexity that living with others brings. This means that there are aspects of inclusion and exclusion involved: exclusion, since a system that includes rules means that people who do not live according to the norms could be considered to have broken the rules and therefore are no longer accepted as full worthy members; inclusion, since living according the norms will be rewarded with recognition and acceptance by the others in the group and increased symbolic and social capital will be the outcome. If norms exist within a social setting it will be more effective and therefore useful for the establishment of trust.

Keywords: microfinance, poverty reduction, categorizing the poor, international discourse, Kenya, symbolic capital, social capital, habitus, taste, trust, norms, Christianity, social belonging, entrepreneurship,

Emilia Liljefrost, Department of Economic History, Uppsala University, Box 513, SE-751 20 Uppsala, Sweden

Identical, But Still Different : On Artistic Appropriation in Visual Art

Rikard Ekholm — Thu, 26 Apr 2012 10:55:43 +0200

In this dissertation about artistic appropriation I acknowledge that something indeed has happened in art. Visual art does not have to look in any special way anymore, or have historically validated content that can be visually grasped. Within this precondition artistic appropriation is situated. An artistic appropriation artwork is visually identical to a pre-existing artwork, but is still an independent artwork that is about something other than what the pre-existing artwork is about.The dissertation ties into, and separates itself from, two discussions: On the one hand, a discussion about the difference between a mere thing and an artwork that looks exactly like it. Duchamp’s Fountain is an example; it looks exactly like an ordinary urinal. On the other, the various ways artists have used pre-existing art throughout history to make new art. One historical example is the paraphrase. Previously, there has been no sufficient discussion about artists who make artworks that look exactly like pre-existing artworks and what this artistic practice says about the identity of art. I argue that artistic appropriation unveils the constitution of the artwork. In chapter one, a definition of artistic appropriation is introduced. Then there follows a discussion regarding previous research about appropriation and closely related concepts like adaptation and intertextuality. In chapter two, artistic appropriation is situated in relation to the historical avant-garde and later changes that made conceptual art possible. Present is also a discussion about how artistic appropriation both challenges and affirms traditional notions in art, such as originality, authorship and creativity. In chapter three there is a discussion about three artistic appropriators and their work: The artists are Elaine Sturtevant, Sherrie Levine and Michael Mandiberg. They must be understood in relation to a different set of backgrounds, which means that their artworks emerge differently.

Transmission Electron Microscopy of Graphene and Hydrated Biomaterial Nanostructures : Novel Techniques and Analysis

Sultan Akhtar — Thu, 26 Apr 2012 13:25:01 +0200

Transmission Electron Microscopy (TEM) on light element materials and soft matters is problematic due to electron irradiation damage and low contrast. In this doctoral thesis techniques were developed to address some of those issues and successfully characterize these materials at high resolution. These techniques were demonstrated on graphene flakes, DNA/magnetic beads and a number of water containing biomaterials. The details of these studies are given below.

A TEM based method was presented for thickness characterization of graphene flakes. For the thickness characterization, the dynamical theory of electron diffraction is used to obtain an analytical expression for the intensity of the transmitted electron beam as a function of thickness. From JEMS simulations (experiments) the absorption constant λ in a low symmetry orientation was found to be ~ 208 nm (225 ± 9 nm). When compared to standard techniques for thickness determination of graphene/graphite, the method has the advantage of being relatively simple, fast and requiring only the acquisition of bright-field (BF) images. Using the proposed method, it is possible to measure the thickness change due to one monolayer of graphene if the flake has uniform thickness over a larger area.

A real-space TEM study on magnetic bead-DNA coil interaction was conducted and a statistical analysis of the number of beads attached to the DNA-coils was performed. The average number of beads per DNA coil was calculated around 6 and slightly above 2 for samples with 40 nm and 130 nm beads, respectively. These results are in good agreement with magnetic measurements. In addition, the TEM analysis supported an earlier hypothesis that 40 nm beads are preferably attached interior of the DNA-coils while 130 nm beads closer to the exterior of the coils.

A focused ion-beam in-situ lift-out technique for hydrated biological specimens was developed for cryo-TEM. The technique was demonstrated on frozen Aspergillus niger spores which were frozen with liquid nitrogen to preserve their cellular structures. A thin lamella was prepared, lifted out and welded to a TEM grid. Once the lamella was thinned to electron transparency, the grid was cryogenically transferred to the TEM using a cryo-transfer bath. The structure of the cells was revealed by BF imaging. Also, a series of energy filtered images was acquired and C, N and Mn elemental maps were produced. Furthermore, 3 Å lattice fringes of the underlying Al support were successfully resolved by high resolution imaging, confirming that the technique has the potential to extract structural information down to the atomic scale. The experimental protocol is ready now to be employed on a large variety of samples e.g. soft/hard matter interfaces.

Clinically Unrecognized Myocardial Scars Detected by MRI

Raquel Espregueira Themudo — Thu, 26 Apr 2012 13:05:18 +0200

A high percentage of unrecognized myocardial infarctions (UMIs) seen at delayed-enhanced magnetic resonance imaging (DE-MRI) are not detected by ECG. DE-MRI-detected UMIs are independent predictors of cardiovascular events in patients with coronary artery disease. In an elderly population, subjects with DE-MRI-detected UMIs do not have increased Framingham risk score or increased prevalence of artery stenosis in whole-body MR angiography as patients with recognized myocardial infarctions (RMI). Further investigation on the pathogenesis of DE-MRI-detected UMIs focus on the need to decide the management of these subjects.

From the Prospective Investigation of the Vasculature in Uppsala Seniors, 248 subjects underwent cardiac MRI at age 70 and from these, 185 underwent a 5-year follow-up MR. DE-MRI-detected UMIs had lower signal intensity than RMIs probably reflecting different composition of their tissues. Subjects with UMI scar had increased levels of NT-proBNP, a predictor of increased risk of cardiovascular events. After 5 years, UMI scars were in their majority seen on the same location and with the same size, and their prevalence increased. Subjects with an UMI did not differ from subjects without a scar in terms of coronary stenosis assessed by computed tomography angiography or signs of ischemia on exercise test.

In conclusion, DE-MRI-detected UMI scars are a frequent finding in an elderly population and its prevalence increases with age. The increased levels of NT-proBNP indicate that subjects with an UMI might have an increased rate of future cardiovascular events but the findings that these scars might have a different contrast distribution volume on MRI and that they are not related to CAD are indicators that they probably have a different etiology from RMIs. The prognosis of DE-MRI detected UMI scars in the general population is still unknown and therefore the clinical management of these individuals is yet to be defined.

Theoretical Studies of Magnetism and Electron Correlation in Solids

Oscar Grånäs — Thu, 26 Apr 2012 14:24:58 +0200

This work presents new development and applications of ab-initio simulation tools for material science. Focus lies on materials with strong electronic correlation and strong spin-orbit coupling. Improvements on methods for solving the impurity problem in LDA+DMFT is presented, as well as a reliant method for charge self-consistency in a LMTO based electronic structure code. A new adaptive scheme for Brillouin zone integration is developed, where we show a strong reduction of numerical noise compared to standard techniques. A reformulation of the standard LDA+U method aiming to reduce the number of free parameters is introduced. Fast and realistic reduction of the number of free parameters provides the possibility of high throughput calculations and enabled us to study a large number of compounds. An analysis method for polarization in terms of coupled multipoles, and their corresponding energy contributions is developed and applied. This led to the formulation of Katt's rules, a set of rules complementary to Hund's rules. Katt's rules applies for occupying the orbitals of an electronic shell with strong spin-orbit coupling. The analysis is also used to investigate the unconventional Uranium based superconductors URu₂Si₂, UPt₃, UPd₂Al₃ and UNi₂Al₃, as well as the high temperature superconductor LaOFeAs. We also investigate the non-magnetic delta-phase of Plutonium, providing insight to the electronic structure and the branching ratios of 4d to 5f transitions seen in photo emission spectra.The influence of surface reconstruction on the magneto crystalline anisotropy is investigated in multilayer Fe/ZnSe, showing that Fe deposited on an unreconstructed interface strongly reduces the uniaxial component of the MAE. We provide a detailed understanding of the magnetic properties of Fe₂P, opening possible routes for enhancing the MAE in this system. A general route to strong MAE in nano-laminates is presented, we apply this to propose a candidate with extremely strong anisotropy energy density, 5Fe/2W_1-xRe_X for x=[0.6-0.8].

Understanding the Noise : Spliceosomal snRNA Profiling

Lei Liu Conze — Wed, 2 May 2012 09:49:10 +0200

The concept of the gene has been constantly challenged by new discoveries in the life sciences. Recent challenging observations include the high frequency of alternative splicing events and the common transcription of non-protein-coding-RNAs (ncRNAs) from the genome. The latter has long been considered noise in biological systems. Multiple lines of evidence from genomic studies indicate that alternative splicing and ncRNA play important roles in expanding proteome diversity in eukaryotes. Here, the aim is to find the link between alternative splicing and ncRNAs by studying the expression profile of the spliceosomal snRNAs (U snRNA).

Spliceosomal snRNAs are essential for pre-mRNA splicing in eukaryotes. They participate in splice site selection, recruitment of protein factors and catalyzing the splicing reaction. Because of this, both the abundance and diversity of U snRNAs were expected to be large. In our study we deeply analyzed the U snRNA population in primates using a combination of bioinformatical, biochemical and high throughput sequencing approaches. This transcriptome profiling has revealed that human, chimpanzee and rhesus have similar U snRNA populations, i.e. the vast majority of U snRNAs originate from few well-defined gene loci and the heterogeneity observed in U snRNA populations was largely due to the presence of SNPs at these loci. It seems that the gene loci that could potentially encode a significantly heterogeneous population of U snRNAs are mostly silent. Only few minority transcripts were detected in our study, and among them three U1-like snRNAs might play a role in the regulation of alternative splicing by recognizing non-canonical splicing sites.

Mutations of U snRNA have been shown to impact the splicing process. Therefore, our study provides a reference to study the biological significance of SNPs in U snRNA genes and their association with diseases.

Magnetic Order in Artificial Structures

Unnar B. Arnalds — Thu, 3 May 2012 10:50:36 +0200

The topic of this thesis is the investigation of the magnetic properties of artificially created magnetic structures. Applying different characterization techniques, ranging from direct imaging methods to reciprocal space techniques, the properties of lithographically patterned arrays of magnetic thin film and multilayer elements are investigated by exploring their magnetic state, extending from the atomic scale up to collective ordering phenomena of nano-magnetic elements.

Laterally patterned amorphous multilayer arrays of combined circular and ellipsoidal islands were investigated. The arrays contain a variety of length scales, ranging from their nanometer scale multilayer structure to their lateral periodicity in the micrometer range. The attributes of these arrays are explored using different techniques, applicable for addressing the magnetization at different length scales, including magneto-optical techniques, micromagnetic simulations and x-ray resonant magnetic scattering.

Arrays of dipole interacting elongated magnetic elements composed of Pd(Fe) thin films were investigated. Pd(Fe) films have a low Curie temperature which can be tuned by the thickness of the Fe layer embedded in Pd. By this, the interaction and the shape anisotropy energies can be brought down to energy scales comparable to room temperature enabling the possibility of investigating the effect of thermal excitations on such arrays. The temperature dependent magnetization of an artificial square spin ice array was investigated by magneto-optical measurements demonstrating the possibility of observing an order-disorder transition in an artificial square spin ice system. The role of dipolar interactions and the possibility of achieving thermal ground state ordering was then further investigated by magnetically sensitive photoemission electron microscopy imaging of ring arrangements of elongated Pd(Fe) elements. The results reveal a high probability of achieving a thermal ground state ordering of the magnetization of the islands.

A Study of Jupiter Trojans

Ola Karlsson — Fri, 27 Apr 2012 14:20:02 +0200

Jupiter Trojan asteroid dynamics have been studied for a long time but it is only within the last decades that the known population has become large enough to make other studies meaningful. In four articles I have been scratching the surface of the unknown Trojan knowledge space.

Paper I presents photometric observations confirming a larger variety in surface redness for the smaller Trojans compared to the larger ones, in line with the groups in the outer main asteroid belt. However, the largest Trojans are significantly redder compared to the largest Cybele and Hilda asteroids.

Paper II is an investigation of the Trojan discovery completeness. The analysis shows that all Trojans down to a limiting absolute magnitude of H=11.5 mag have been discovered. Missing Trojans in the almost discovery-completed section should have inclinations above the mean of the same group. The faintest Trojans are discovery biased due to orbit orientations similar to the Milky Way.

Paper III is a general review of dynamical and physical properties of the discovery-completed sample of Jupiter Trojans found in Paper II. The two Trojan swarms are often treated as being equal, but are different in a number of details. Two known facts are that the L₅ swarm is less rich, while the L₄ swarm has a larger fraction of low inclination Trojans. Trojans are in general red objects but the mean redness is higher for Trojans which have not collided compared to Trojans in families.

Paper IIII is an investigation of Trojan collisions, family detection and evolution. Collision circumstances were mapped using numerical simulations and recorded Trojan close approaches. Synthetic families were created and evolved numerically. The result suggests that the HCM family detection technique can find Trojan families even in a densely populated parameter space. However, interlopers cannot be avoided at any level but their contribution should be less than 30%. Synthetic families can be identified with backwards orbital integrations for times up to a Gyr-scale. However, there are discrepancies between real Trojan families and my synthetic families.

Cytoreductive Surgery and Intraperitoneal Chemotherapy in Patients with Peritoneal Metastases from Colorectal Cancer : Aspects of loco-regional treatment outcome, patient selection, and chemo-sensitivity

Peter H Cashin — Fri, 4 May 2012 10:12:56 +0200

Previously, peritoneal metastases(PM) from colorectal cancer(CRC) have been considered a terminal and generalised form of cancer. A new treatment strategy combining cytoreductive surgery(CRS) and intraperitoneal chemotherapy(IPC) has recently shown promising results. The aim of this thesis was to investigate different aspects of this treatment in order to optimise the treatment and to clarify its potential as a new treatment option. Treatment outcome, patient selection, method of IPC (hyperthermic intraperitoneal chemotherapy-HIPEC vs. sequential postoperative intraperitoneal chemotherapy-SPIC) and choice of drugs for IPC were the aspects covered in this thesis.

The treatment outcome of CRS and IPC according to the median overall survival ranged from 24 to 34 months with 5-year overall survival ranging from 20 to 40% depending on the IPC treatment administered. Furthermore, the 5-year disease-free survival was impressive at 32% for patients receiving HIPEC. This establishes the curative potential of this treatment. Due to current inadequacies of radiological imaging, a score (Corep score) was developed for patient selection purposes. This score had a sensitivity of 80% and specificity of 100% in identifying patients with short cancer-specific survival after the treatment (<12 months). Further studies are needed to elucidate the clinical usefulness of the Corep score. HIPEC was associated with better survival than the SPIC method at similar morbidity and mortality rates, suggesting that HIPEC be the method of preference. Concerning the choice of drugs, the last study investigated the chemo-sensitivity of different PM tumour-types with a special focus on CRC. While CRC samples were generally more resistant, the ratio of the in vivo concentration compared to the ex vivo concentration giving a 50% tumour cell death showed that oxaliplatin had the best profile across all PM tumour types as well as for CRC. This needs further confirmation in a clinical trial.

Design and Synthesis of Enzyme Inhibitors Against Infectious Diseases : Targeting Hepatitis C Virus NS3 Protease and Mycobacterium tuberculosis Ribonucleotide Reductase

Johan Gising — Thu, 3 May 2012 14:17:45 +0200

Infectious diseases, including hepatitis C and tuberculosis, claim the lives of over 15 million people each year. Hepatitis C is caused by the hepatitis C virus (HCV) which infects the liver and can ultimately result in liver transplantation. HCV is very adaptive as a result of its high mutation rate. Thus, there is a potential high risk for the development of drug resistance and also a possible cross-resistance due to a structural similarity between many of the HCV NS3 protease inhibitors currently in clinical trial and on the market, that all are based on a P2-proline or a proline mimic. Thus, part of the research behind this thesis was to explore a new structural P3-P2 unit for the NS3 protease inhibitors, a 2(1H)-pyrazinone moiety. A microwave-assisted protocol was developed, and the 2(1H)-pyrazinone core was synthesized in only 2 × 10 min. A series of optimization steps resulted in several submicromolar 2(1H)-pyrazinone-containing NS3 protease inhibitors that performed well against drug-resistant NS3 protease variants. The key modifications were: exchanging the unstable carbamate P3 capping group for a stable urea functionality, transferring the P2 group from the amino acid residue to the pyrazinone ring and elongating the substituent, and using an aromatic acyl sulfonamide in the P1-P1' position.

The causative agent of tuberculosis is Mycobacterium tuberculosis (Mtb), which currently infects one third of the world's population. No new TB drugs have been approved in nearly 50 years and drug resistance has been observed for all of the current first-line drugs. Because of the importance of identifying novel drug targets, the ribonucleotide reductase (RNR) enzyme was investigated. The RNR enzyme consists of two R1 and two R2 subunits and is essential for Mtb replication. Starting from hits identified in a virtual screening program, a small library of low molecular weight inhibitors of the association between the R1 and R2 subunits was designed and synthesized. The compounds with the strongest affinity for the R1 subunit of RNR were further evaluated in an orthogonal activity assay. Two RNR inhibitors with promising antimycobacterial effects were identified, which can serve as leads in the further optimization of this class of compounds.

Exploring the Molecular Dynamics of Proteins and Viruses

Daniel Larsson — Fri, 4 May 2012 09:02:04 +0200

Knowledge about structure and dynamics of the important biological macromolecules — proteins, nucleic acids, lipids and sugars — helps to understand their function. Atomic-resolution structures of macromolecules are routinely captured with X-ray crystallography and other techniques. In this thesis, simulations are used to explore the dynamics of the molecules beyond the static structures.

Viruses are machines constructed from macromolecules. Crystal structures of them reveal little to no information about their genomes. In simulations of empty capsids, we observed a correlation between the spatial distribution of chloride ions in the solution and the position of RNA in crystals of satellite tobacco necrosis virus (STNV) and satellite tobacco mosaic virus (STMV). In this manner, structural features of the non-symmetric RNA could also be inferred.

The capsid of STNV binds calcium ions on the icosahedral symmetry axes. The release of these ions controls the activation of the virus particle upon infection. Our simulations reproduced the swelling of the capsid upon removal of the ions and we quantified the water permeability of the capsid. The structure and dynamics of the expanded capsid suggest that the disassembly is initiated at the 3-fold symmetry axis.

Several experimental methods require biomolecular samples to be injected into vacuum, such as mass-spectrometry and diffractive imaging of single particles. It is therefore important to understand how proteins and molecule-complexes respond to being aerosolized. In simulations we mimicked the dehydration process upon going from solution into the gas phase. We find that two important factors for structural stability of proteins are the temperature and the level of residual hydration. The simulations support experimental claims that membrane proteins can be protected by a lipid micelle and that a non-membrane protein could be stabilized in a reverse micelle in the gas phase. A water-layer around virus particles would impede the signal in diffractive experiments, but our calculations estimate that it should be possible to determine the orientation of the particle in individual images, which is a prerequisite for three-dimensional reconstruction.

Application of Proximity Ligation Assay for Multidirectional Studies on Transforming Growth Factor-β Pathway

Agata Zieba — Wed, 2 May 2012 13:03:47 +0200

A comprehensive understanding of how the body and all its components function is essential when this knowledge is exploited for medical purposes. The achievements in biological and medical research during last decades has provided us with the complete human genome and identified signaling pathways that governs the cellular processes that facilitates the development and maintenance of higher order organisms. This has brought about the realization that diseases such as cancer is a consequence of genomic aberrations that effects these signaling pathways, endowing cancer cells with the capacity to circumvent homeostasis by acquiring features like self-sustained proliferation and insensitivity to apoptosis. The increased understanding of biology and medicine has been made possible by the development of advanced methods to carry out biological and clinical analyses. The demands of a method often differ regarding in what context it will be applied. It may be acceptable for method to be laborious and time consuming if it is used in basic research, but for medical purposes molecular methods need to be fast and straightforward to perform. Innovative technologies should preferentially address the demands of both researchers and clinicians and provide data not possible to obtain by other methods. An example of such a method is the in situ proximity ligation assay (in situ PLA). In this thesis I have used this method to determine the activity status, at the single-cell level, of the transforming growth factor-β (TGF-β) signaling pathway and activating protein-1 (AP-1) family of transcription factors. Both of these pathways are frequently involved in cancer development and progression. In addition to this research I herein also present further modifications of in situ PLA, and analyses thereof, to increase the utility and resolution of this assay.

On the Formation and Structure of the Ionosphere of Titan

Karin Ågren — Fri, 4 May 2012 10:04:14 +0200

We present results on the ionospheric structure around Titan observed during numerous deep (<1000 km) flybys by the Cassini spacecraft. Our results are based on measurements by the radio and plasma wave science instrument, in particular the Langmuir probe. In addition, data from the magnetometer and electron spectrometer have contributed.

The ionosphere of Titan is created when the atmosphere of the moon becomes ionised. There are several mechanisms that contribute to this, the most important of which are considered to be photoionisation by EUV from the Sun with associated photoelectron ionisation, and particle impact ionisation by electrons and ions from Saturn’s corotating magnetosphere.

We investigate the influence of the solar zenith angle on the electron number density at the ionospheric peak. The results show on average four times more plasma on the dayside compared to the nightside, with typical densities of 2500 – 3500 cm^-3 and 400 – 1000 cm^-3, respectively. In a complementary study, we make a case study of a nightside flyby and show that the altitude structure of the deep ionosphere is reproducible by a simple electron impact ionisation model. Taken together, this leads to the conclusion that solar photons are the main ionisation source of the dayside ionosphere. However, magnetospheric particle precipitation also contributes and can explain the electron densities seen on the nightside.

As Titan does not exhibit any large intrinsic magnetic field, the fact that it is embedded in the magnetosphere of Saturn means that the Kronian field drapes around the moon and gives rise to an induced magnetosphere. We show that there are currents of the order of 10 – 100 nA m^-2 flowing in the ionosphere of the moon. Associated with the currents are perpendicular electric fields ranging from 0.5 to 3 µV m^-1.

Finally, we investigate measurements obtained during T70, the deepest Titan flyby performed to date. We show that there is a substantial amount of negative ions present below an altitude of 900 km. This confirms previous result by the electron spectrometer, showing negative ions at higher altitudes in Titan’s ionosphere.

Seaward Landward : Investigations on the archaeological source value of the landing site category in the Baltic Sea region

Kristin Ilves — Fri, 4 May 2012 11:14:47 +0200

There is a tendency in archaeology dealing with watercraft landing sites in a wider context to assume a direct relationship between sites in coastal and shore-bound areas and the practise of landing, without any deeper practical or theoretical exploration of the reality of any such relationship. This problem has its origins in the poor archaeological and conceptual definitions of watercraft landing sites obstructing any real understanding of the role of these sites in the maritime cultural landscape. Landing sites are taken for granted and they are undervalued as an archaeological source of explanation; notwithstanding, the concept of the landing site is readily used in archaeology in order to underpin archaeological interpretations on the maritime activities of past societies.

In order to break away from the simplified understandings of past water-bound strategies based on the undefined concept of the landing site, this dissertation suggests a definition of watercraft landing sites in a wider social sense as water-bound contact zones; places of social interaction that can be archaeologically identified and investigated. This perspective integrates the understanding of the intentional character of human activity related to watercraft landing with the remaining archaeological traces. Archaeological definitions of landing sites that can be tested against the archaeological data are provided, and thereby, the dissertation contributes with the possibility to archaeologically evaluate and approach the social function of watercraft landing sites. This dissertation demonstrates that there can be an archaeology of landing sites.

Dismantling the Conflict Trap : Essays on Civil War Resolution and Relapse

Joakim Kreutz — Thu, 3 May 2012 11:07:30 +0200

Countries that have experienced civil war suffer a greater risk for new conflict than countries with no prior history of civil war. This empirical finding has been called a conflict trap where the legacy of previous war - unsolved issues, indecisive outcomes, and destruction – leads to renewed fighting. Yet, countries like Cambodia, El Salvador, Indonesia, and Mozambique have managed to overcome decade-long conflicts without relapse. This dissertation addresses this empirical puzzle by seeking to dismantle the conflict trap and look at microlevel explanations for civil war resolution and relapse. It adds to existing scholarship in three ways: first, by using disaggregated empirics on war termination and how fighting resumes; second, by exploring government agency in conflict processes; and third, by disaggregating rebel organizations. Essay I present original data on the start and end dates and means of termination for all armed conflicts, 1946-2005. Contrary to previous work, this data reveal that wars does not always end through victory or peace agreement, but commonly end under unclear circumstances. Essay II addresses how developments exogenous to the conflict influence governments’ decision to engage in a peace process. The results show that after natural disasters when state resources need to be allocated towards disaster relief, governments are more willing to negotiate and conclude ceasefires with insurgents. Essay III focuses on the post-conflict society, and posits that security concerns among former war participants will push them towards remobilizing into rebellion. The findings indicate that if ex-belligerent elite’s security is compromised, the parties of the previous war will resume fighting, while insecurity among former rank-and-file leads to the formation of violent splinter rebel groups. Finally, Essay IV seeks to explain why governments sometimes launch offensives on former rebels in post-conflict countries. The results show that internal power struggles provide leaders with incentives to use force against domestic third parties to strengthen their position against intra-government rivals. Taken together, this dissertation demonstrates that there is analytical leverage to be had by disaggregating the processes of violence in civil war and post-conflict societies, as well as the actors involved – both the government and rebel sides.

Population Pharmacodynamic Modeling and Methods for D2-receptor Antagonists

Klas Petersson — Thu, 3 May 2012 14:10:30 +0200

Early predictions of a potential drug candidate’s time-course of effect and side-effects, based on models describing drug concentrations, drug effects and disease progression, would be valuable to make drug development more efficient. Pharmacodynamic modeling can incorporate and propagate prior knowledge and be used for simulations of different scenarios.

In this thesis three population pharmacodynamic models were developed to describe the antipsychotic effects and the side-effects prolactin elevation and Extra Pyramidal Symptoms (EPS) following administration of D₂-receptor antagonists, commonly used in the treatment of schizophrenia.

Model parameter estimates of prolactin elevating potencies of six compounds correlated with in vitro values of receptor affinities, and parameters related to diurnal prolactin variation and tolerance were similar for the different compounds. The developed prolactin model can thereby be used to predict the time-course of prolactin elevation in patients for a drug candidate using information on in vitro affinity to the D₂-receptor. Furthermore, the clinical antipsychotic effect and the prolactin elevation was found to correlate on the individual level for the three antipsychotic compounds investigated and a quantitative relation between D₂-receptor occupancy in the brain and prolactin elevation was established. These results support the use of prolactin concentrations as a biomarker in drug development or for individual dose adjustments in clinical care.

The developed model for spontaneously reported EPS adverse events, following treatment with one of five antipsychotics drugs, characterized both the duration and severity of EPS. The model successfully described both the proportions and number of transitions between severity grades and was shown to adequately simulate longitudinal categorical EPS data.

Complex pharmacodynamic models are often associated with long estimation times and non-normal distributions of individual parameters. A method for shortening computation times by substituting differential equations for difference equations was evaluated and shown to be valuable for some models. In addition, transformation of distributions allowed for non-normal distributions of between-subject variability to be better characterized and thereby simulation properties were improved.

In conclusion, population pharmacodynamic models for a range of D₂-receptor antagonists were developed and together with the investigated methods the models can facilitate prediction of effects and side-effects in drug development.

Growth in Aging Colonies : The Importance of Being Different

Marie Wrande — Fri, 4 May 2012 11:23:13 +0200

The accumulation of rifampicin resistant (Rif^R) mutants in aging bacterial colonies has previously been attributed to stress-induced mutagenesis. Mutations giving rise to Rif^R are located in the rpoB gene, coding for the β subunit of RNA polymerase, RpoB. We showed that these mutants accumulate because they grow faster than the wild-type in the aging colonies. We found no evidence of increased mutagenesis in the Rif^R cells and their distribution, as localized clones in the aging colonies, indicated that they accumulated by selection and growth rather than by an increased rate of mutagenesis. Colony competition experiments with reconstructed strains showed that the Rif^R mutations were responsible for the growth advantage. We also found that deletion of rpoS, coding for the stationary phase sigma factor (RpoS), also gives a growth advantage on bacterial cells in aging colonies.

We suggest that mutants lacking RpoS, having a different transcription pattern than the wild-type, may override the signals to enter stationary phase together with the rest of the population and instead keep growing for as long as possible. We found that the rpoB mutants mimicked the transcription pattern of the rpoS deletion mutant, thereby displaying a similar phenotype in the aging colonies. The pathways used in acetate metabolism (consisting of the enzymes Acs, AckA-Pta, PoxB and AceBAK) were shown to be important for the growth advantage mutants suggesting that acetate is one of the main carbon sources used to support their prolonged growth in the aging colonies.

Rifampicin is a first-line drug used to treat M. tuberculosis infections. We used S. enterica as a model system for experimental evolution to ask whether compensatory mutations might be important in Rif^R mutants. In every lineage evolved compensatory mutations arose without any significant reduction in resistance. These mutations altered genes for the α, β, and β’ subunits of RNA polymerase.

Purification Processes for Complex Biomacromolecules

Hans Blom — Fri, 4 May 2012 11:25:21 +0200

This thesis details various techniques and considerations for the purification of complex biomacromolecules.

Initially an α-mannosidase from babaco fruit was purified using anion exchange-, lectin affinity- and size exclusion chromatography. The enzyme was approximately 260-280 kDa in size with an apparent an unusual octagonal stoichiometry and displayed properties similar to other known plant α-mannosidases.

Mucins were fractionated by ion exchange and size exclusion chromatography to assess the properties that govern the mucin surface coating interactions in biomaterial research. Commercially available mucins, of bovine and porcine origin, as wells as crude human mucin were tested. All showed to consist of a population of molecules which differ in size, charge and composition.

The third part of the thesis concerns different aspects of plasmid DNA purification processes.

A two-step method for analysis of plasmid DNA consisting of size exclusion followed by thiophilic adsorption chromatography was evaluated. It allowed determination of the supercoiled plasmid DNA concentration in all process steps without requirement for extensive sample preparation. This method was shown to be fully comparable in terms of accuracy to capillary gel electrophoresis, considered as the industry standard.

Purification of plasmid DNA generally involves bacterial cell alkaline lysis, which creates a solution with flocculate material which needs to be removed prior to further processing. The addition of ammonium hydrogen carbonate to the suspension was evaluated to clarify the solution. The released carbon dioxide and ammonium lifts the flocculate to the surface and allows draining of a clear solution. The method is fully scalable, does not affect the plasmid DNA quality and requires no special equipment.

Thiophilic adsorption chromatography was evaluated for simplification of an existing commercial large scale purification process and was shown to increase both product purity and yields of several tested plasmids. Also, implementation of this step significantly reduced overall production process time.

Bending, Twisting and Turning : Protein Modeling and Visualization from a Gauge-Invariance Viewpoint

Martin Lundgren — Fri, 4 May 2012 11:27:33 +0200

Proteins in nature fold to one dominant native structure. Despite being a heavily studied field, predicting the native structure from the amino acid sequence and modeling the folding process can still be considered unsolved problems. In this thesis I present a new approach to this problem with methods borrowed from theoretical physics. In the first part I show how it is possible to use a discrete Frenet frame to define the discrete curvature and torsion of the main chain of the protein. This method is then extended to the side chains as well. In particular I show how to use the discrete Frenet frame to produce a statistical distribution of angles that works in similar fashion as the commonly used Ramachandran plot and side chain rotamers. The discrete Frenet frame displays a gauge symmetry, in the choice of basis vectors on the normal plane, that is reminiscent of features of Abelian-Higgs theory. In the second part of the thesis I show how this similarity with Abelian-Higgs theory can be translated into an effective energy for a protein. The loops of the proteins are shown to correspond to solitons so that the whole protein can be constructed by gluing together any number of solitons. I present results of simulating proteins by minimizing the energy, starting from a real line or straight helix, where the correct native fold is attained. Finally the model is shown to display the same phase structure as real proteins.

Nutrition and Oxidative Parameters in Pregnancy, Size at Birth and Metabolic Status of the Offspring at 4.5 Years : The MINIMat Trial in Rural Bangladesh

Emma Lindström — Fri, 4 May 2012 10:31:34 +0200

Undernutrition and oxidative stress in fetal life and infancy may lead to adverse health outcomes in the offspring. We studied nutrition and oxidative parameters in pregnancy and their associations with birth anthropometry and metabolic status in the children.

In Matlab in rural Bangladesh, women were randomized to either early (Early) invitation to food supplementation or to start at their own liking (Usual). Women were also allocated to either; 1) 60 mg iron and 400 µg folic acid (Fe60F), 2) multiple micronutrients including 30 mg iron and folic acid (MMS), or 3) 30 mg iron and folic acid (Fe30F). Micronutrients (hemoglobin, iron, zinc, folic acid, vitamin B-12) were assessed in pregnancy week 14, lipid peroxidation in week 14 and 30, and DNA oxidation in week 19. The offspring were assessed for anthropometric measurements at birth and metabolic status at 4.5 years.

Micronutrient deficiencies were common with zinc and vitamin B-12 deficiency being most prevalent. Anemia was present in approximately one third of women, however, iron deficiency was uncommon seen in only 2%.

Maternal Early food supplementation group resulted in an improved lipid status in the children at 4.5 years compared to Usual food group. Prenatal use of MMS lowered the children’s glucose, insulin, HOMA-IR, and growth factors compared to Fe60F.

Lipid peroxidation in early pregnancy was associated with size at birth and insulin and HOMA-IR levels in the children. Lipid peroxidation in late pregnancy, however, was associated with the children’s lipid status. Both increasing lipid peroxidation and increasing DNA oxidation was associated with decreasing IGF-1 levels.

The beneficial effects of an Early start of food supplementation show that an improved prenatal nutrition may have lasting effects in the offspring and highlights the importance of early timing food supplementation. Use of MMS, however, resulted in lower insulin levels, which, considering the already low level of insulin in these children, may be a cause of concern. MMS also resulted in growth factors indicative of slower growth and further research appears to be needed before scaling up the use of MMS. Oxidative parameters in pregnancy were associated with longer-term outcomes in the offspring, suggesting that oxidative stress may be involved in the development of later metabolic disease.

Role of GABA and GABAA Channels in T lymphocytes and Stem cells

Suresh Kumar Mendu — Mon, 7 May 2012 10:16:36 +0200

GABA (gamma-aminobutyric acid) is best known for its physiological function in the central nervous system. In the brain GABA is the main inhibitory neurotransmitter where it decreases excitability of neurons and neuronal networks. The balance between excitation evoked by glutamate and inhibition evoked by GABA is the base from where the brain works. It is fair to say that glutamate is like the gas-pedal and GABA the brake that keeps the brain running at a normal speed. But, it is not only in the brain that GABA is taking a part in a physiological process vital to life. GABA is present in blood and is even released in the pancreatic islets. What function GABA has in these tissues is still being examined and is the focus of this thesis. The GABA concentration in the peripheral tissues is in the submicromolar concentration range.

The studies in this thesis support the idea that GABA reduces the proliferation and cytokine secretion from immune cells by activating high-affinity GABA_A channels in the cells. In contrast, in retinal progenitor stem cells GABA promotes cell proliferation. These studies demonstrate that the effect of GABA on proliferation is cell-type specific. The GABA_A channel subunit isoforms expressed in human, mice and rats T cells differ between the species. This interspecies variability will result in different pharmacological profile of the subtypes of GABA_A channels expressed whereas the physiological process most likely is the same. Clearly, GABA is not only a neurotransmitter molecule but is also an immunomodulator and an important signal molecule in peripheral tissues.

Effects of Enterovirus Infection on Innate Immunity and Beta Cell Function in Human Islets of Langerhans

Oskar Skog — Wed, 9 May 2012 11:19:01 +0200

This thesis focuses on enteroviral effects on human pancreatic islets. Most knowledge of viral effects on host cells relies on studies of immortalized cell lines or animal models. The islets represent a fundamentally different and less well studied cellular host. Also, enterovirus has been implicated in the etiology of type 1 diabetes (T1D). We show that when enterovirus replicates in human islets it activates innate immunity genes and induces secretion of the chemokines MCP-1 and IP-10. An important difference in activation of innate immunity by replicating EV and synthetic dsRNA is suggested, since the chemokine secretion induced by EV infection but not by dsRNA is reduced by female sex hormone. We also demonstrate a direct antiviral effect of nicotinamide, and even though this substance failed to prevent T1D in a large-scale study, this finding could have implications for the treatment/prevention of virus- and/or immune-mediated disease.

We also had access to human pancreata from two organ donors with recent onset T1D and several donors with T1D-related autoantibodies, which gave us the opportunity to study ongoing pathogenic processes at and before the onset of T1D. Despite this, we could neither confirm nor reject the hypothesis that EV is involved in T1D development. Several observations, such as ultrastructural remodeling of the beta cell, activation of innate immunity, and immunopositivity to EV capsid protein 1, supported an ongoing virus infection, but direct evidence is still lacking.

An interesting finding in the donors with recent onset T1D was that the islets were positively stained for insulin, but did not secrete insulin in response to glucose-stimulation. A similar effect was observed in EV-infected islets in vitro; EV destroyed islet function and insulin gene expression, but the islets still stained positive for insulin. This may be indicative of that a functional block in addition to beta cell destruction is involved in T1D pathogenesis.

In conclusion, these studies of EV in isolated human islets in vitro support that this virus can cause T1D in vivo, but future studies will have to show if and how frequently this happens.

Kriminaldårar : Sinnessjuka brottslingar och straffrihet i Sverige, ca 1850–1930

Lars Garpenhag — Wed, 9 May 2012 10:39:34 +0200

The aim of this thesis is to explain how the management of insane offenders operated and changed in Sweden in the approximate period 1850–1930. The investigation concerns primarily a level of practice, i.e. how insane offenders were treated in courts and insane asylums as a part of the everyday activities of these institutions. Their treatment depended on a double set of social categorizations. In the courts the insane had to be discerned from the sane, and at asylums criminals were distinguished from non-criminal patients. Asylum patient records and other sources are used to examine different aspects of the the trial and post-trial treatment of insane offenders, as well as their social composition as a group.

It is shown that during the period of study, the management of criminal cases of this kind went through important changes. One important change was that the boundaries of criminal responsibility shifted when new kinds of deviant mental conditions came to be taken into consideration as grounds for exemption from punishment. An important observation is that the division of labor in trials, between lawyers and physicians, as well as between medical professionals, was a harmonious one. No conflicts of a more general nature are noticeable in the studied cases. In contemporary discussions criminals were often described as a problematic type of psychiatric patients, characterized by traits making them unsuitable for care in regular asylums. The investigation shows that insane offenders were subject to different kinds of special treatment, regarding e.g. their release from asylum care, attempts to religious and moral reform, and through considerations surrounding security and discipline. However, despite the frequent portrayal of criminal patients as troublesome, most of them remained in regular psychiatric institutions, and there is ample evidence that individual criminals could enjoy the same liberties and privileges as other patients.

Reducing Attrition via Improved Strategies for Pre-clinical Drug Discovery : SPR-biosensor Aided Interaction Studies

Johan Winquist — Fri, 4 May 2012 14:23:47 +0200

The efficacy of a drug is tightly intertwined with its interaction mechanism with the drug target. The mechanism is dependent on the physicochemical and structural characteristics of both target and drug molecule.

Drug discovery is plagued by a high attrition rate, whereas in the clinic, a major issue is drug resistance. To improve the quality of the lead compounds in the pre-clinical phase of drug discovery, and thereby reducing the attrition, a deeper understanding of interaction mechanisms is needed. We have adopted new strategies and techniques for this purpose.

A compound library was compiled for the purpose of fragment-based drug discovery. Its compatibility with the SPR platform, along with its interaction profile, was validated. The library was subsequently used in a screening campaign for novel scaffolds of human immunodeficiency virus-1 protease, not sensitive to common resistance mutations. This was achieved by the use of a target panel containing signature resistance mutations towards already approved HIV-1 protease inhibitors. 10 scaffolds were identified and deemed novel. These constitute interesting starting points for development of a new generation of HIV-1 protease inhibitors with different resistance mechanisms, which is very valuable in combination therapies.

The cause of difference in anti-viral potency in cell cultures was investigated for two iso-affinity compounds acting on the hepatitis C viral polymerase, NS5B. By SPR-aided interaction analysis with chemo- and thermodynamic characterization, filibuvir and VX-222, both same-site allosteric inhibitors in phase II clinical trials, were identified to have two different interaction mechanisms. This was ultimately suggested to cause the differences in potency.

A structure-kinetic relationship study, with a thermodynamic characterization, was performed for an approved thrombin inhibitor and five close P3-analogues. This study had the aim to better understand the basic mechanisms of the interactions. Stopped-flow spectroscopy, SPR, and calorimetry were used in parallel and their results compared before evaluation with x-ray crystallography data.

Thus, this thesis has demonstrated successful use of fragment-based drug discovery and high resolution techniques to advance projects in most stages of pre-clinical drug discovery with the aim to reduce the future drug attrition and to understand molecular interactions on a fundamental level.

The Neurological Wake-up Test in Neurocritical Care

Karin Skoglund — Wed, 9 May 2012 09:33:28 +0200

The neurological wake-up test, NWT, is a clinical monitoring tool that can be used to evaluate the level of consciousness in patients with traumatic brain injury (TBI) and subarachnoid haemorrhage (SAH) during neurocritical care (NCC). Since patients with severe TBI or SAH are often treated with mechanical ventilation and sedation, the NWT requires that the continuous sedation is interrupted. However, interruption of continuous sedation may induce a stress response and the use of the NWT in NCC is controversial.

The effects of the NWT on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) were evaluated in 21 patients with TBI or SAH. Compared to baseline when the patients were sedated with continuous propofol sedation, the NWT resulted in increased ICP and CPP (p<0.05). Next, the effects of the NWT on the stress hormones adrenocorticotrophic hormone (ACTH), cortisol, epinephrine and norepinephrine were evaluated in 24 patients. Compared to baseline, the NWT caused a mild stress response resulting in increased levels of all evaluated stress hormones (p<0.05). To compare the use of routine NCC monitoring tools, the choice of sedation and analgesia and the frequency of NWT in Scandinavian NCC units, a questionnaire was used. The results showed that all 16 Scandinavian NCC units routinely use ICP and CPP monitoring and propofol and midazolam were primary choices for patient sedation in an equal number of NCC units. In 2009, the NWT was not routinely used in eight NCC units whereas others used the test up to six times daily.

Finally, intracerebral microdialysis (MD), brain tissue oxygenation (PbtiO₂) and jugular bulb oxygenation (SjvO₂) were used in 17 TBI patients to evaluate the effect of the NWT procedure on focal neurochemistry and cerebral oxygenation. The NWT did not negatively alter interstitial markers of energy metabolism or cerebral oxygenation.

In conclusion, the NWT induced a mild stress response in patients with TBI or SAH that did not result in a detectable, significant secondary insult to the injured brain. These results suggest that the NWT may safely be used as a clinical monitoring tool in the NCC of severe TBI and SAH in a majority of patients.

Subcultures and Small Groups : A Social Movement Theory Approach

Ugo Corte — Thu, 10 May 2012 13:45:03 +0200

This dissertation uses social movement theory to analyze the emergence, activities and development of subcultures and small groups. The manuscript is comprised of an Introduction followed by three journal articles and one book chapter. The introduction discusses: 1) the concept of theoretical extension whereby a theory developed for one purpose is adapted to another; 2) it identifies the social movement theories used to analyze subcultures and small groups; 3) it describes the data used in the analyses included here. The data for this work derives from two distinct research projects conducted by the author between 2002 and 2012 and relies on multiple sources of qualitative data. Data collection techniques used include fieldwork, archival research, and secondary data. Paper I uses resource mobilization (RM) theory to analyze the origin, development, and function of White Power music in relation to the broader White Power Movement (WPM). The research identifies three roles played by White Power music: (1) recruit new adherents, (2) frame issues and ideology for the construction of collective identity, (3) obtain financial resources. Paper II gives an overview of the subculture of Freestyle BMX, discussing its origins and developments—both internationally as a wider subcultural phenomenon, and locally, through a three-year ethnographic case study of a subcultural BMX scene known as “Pro Town USA.” Paper III conceptualizes BMX as a social movement using RM theory to identify and explain three different forms of commercialization within this lifestyle sport in “Pro Town.” The work sheds light on the complex process of commercialization within lifestyle sports by identifying three distinct forms of commercialization: paraphernalia, movement, and mass market, and analyses different impacts that each had on the on the development of the local scene. Findings reveal that lifestyle-sport insiders actively collaborate in each form of commercialization, especially movement commercialization which has the potential to build alternative lifestyle-sport institutions and resist adverse commercial influences. Paper IV refines the small group theory of collaborative circles by: (1) further clarifying its concepts and relationships, (2) integrating the concepts of flow and idioculture, and (3) introducing a more nuanced concept of resources from RM. The paper concludes by demonstrating that circle development was aided by specific locational, human, moral, and material resources as well as by complementary social-psychological characteristics of its members.

Distressing Symptoms in Children with Cancer in General; During Needle Procedures in Particular

Lena Hedén — Thu, 10 May 2012 14:57:01 +0200

The main aims of this thesis were to investigate the effect of distraction, midazolam and morphine on fear, distress, and pain during needle procedures, and to longitudinally describe parents’ perceptions of their children’s symptom burden during and after cancer treatment.

The design in Study I-III was that of a randomized controlled trial (RCT) conducted in a medical setting; Studies II-III were placebo controlled. Study IV has a longitudinal design, and data were collected at three times during treatment and three times after the end of successful treatment. Participants in Study I were children aged 1 to 7 (n=28), in Study II children aged 1 to 19 (n=50), in Study III children aged 1 to 19 (n=50), and in Study IV parents (n=160) of children aged 1 to 19.

Blowing soap bubbles or having a heated pillow reduces children’s fear and distress in connection with needle procedures. Low-dose oral midazolam 0.3mg/kg body weight is effective in reducing fear and distress, especially in younger children. Interestingly, oral morphine at a dose of 0.25mg/kg body weight does not reduce fear, distress or pain.

These studies have evaluated interventions that may be of help for the most frightened children during needle procedures. We suggest that the first-line intervention against procedural fear, distress, and/or pain should be standard care (i.e. EMLA) in addition to distraction interventions when needed, and only when this is insufficient to add pharmacological interventions.

According to parents, feeling drowsy, pain, and lack of energy are initially the most prevalent symptoms in their children, whereas less hair than usual is the most prevalent symptom during treatment. Pain, feeling sad, and nausea are initially the most distressing symptoms. Pain is both prevalent and distressing throughout treatment. The child’s symptom burden, as reported by parents, decreases over time. Information about distressing symptoms and when they can be expected may increase acceptance and adaptation in children and parents during and after cancer treatment.

Die ,schwedische‘ Lösung : Eine kultursemiotisch orientierte Untersuchung der audiovisuellen Werbespots von IKEA in Deutschland

Jennie Mazur — Fri, 11 May 2012 11:26:34 +0200

The Swedish furniture company IKEA is famous worldwide for its successful advertising and communication strategies. In the years 1997–2007, the company attained a very prominent status in Germany through audiovisual advertisements in the mass media of television and the Internet, including YouTube. A striking example of this phenomenon is the campaign launched by IKEA on St. Knut’s Day, the date that traditionally ends the Christmas holidays in Sweden. In its advertising, IKEA invented a Swedish tradition of throwing out the Christmas tree through the window in order to create more space for IKEA furniture at home.

The present study examines the process of establishing IKEA as a Swedish brand in Germany through audiovisual advertising. This is done within an interdisciplinary framework of primarily cultural semiotics, communication theory and advertising research. The theoretical concepts of Ego and Alter cultures are employed in order to grasp the interaction between the Swedish company and the German consumer culture. IKEA constructs a model of itself and enters into a dialogue with the German market.

The analysis of 48 audiovisual advertisements, published by IKEA during the period 1997–2007 for a German target audience, shows that the company very consciously draws on various notions of ‘Swedishness’ and Nordic stereotypes. In the last few years, however, the advertising has also included typical German topics that concern domestic, everyday life themes, including equality issues such as parental leave after the birth of a child, women’s careers, and wealthy men being interested in home styling. Over the years, the messages have moved from being indirect and humorous/self-ironic to becoming more serious and direct. The in-depth analyses of six selected audiovisual advertisements explore in detail how IKEA’s presentation of itself as a Swedish company on the German furniture market functions.

Filantropi under konstruktion : En undersökning av Sällskapet DBW:s samhällsengagemang 1814–1876

Mikael Karlsson — Fri, 11 May 2012 09:58:36 +0200

The 19^th century was a time when a large number of voluntary associations were being formed both in Sweden and in Europe as a whole. Their ambition was to engage in health care and poor relief issues as well as in the educational system. Furthermore, the general idea was to promote temperance and foster a sense of thrift among the poor and the working class population.

While the starting-point of the thesis was the question as to why the voluntary associations founded various charitable activities as well as how the philanthropy was designed, organised and modified throughout the century, the aim has been to elucidate the motive force and incentives for their social reforms. In order to answer the two main questions of the dissertation, the association De Badande Wännerna (the DBW), which engaged in several philanthropic activities in the Swedish province of Gotland as early as the 1810s, has been selected for a case study.

In the literature a number of different reasons have been stressed as to why voluntary associations chose to engage in charitable activities. In order to shed light on what factors that underlay their philanthropic work, the process of negotiation regarding the various institutions established by the DBW, as well as the practical layout of the establishments, have been analysed from the perspectives of a theoretical model based on affinity groups.

The study has shown that the incentives of philanthropy were complex. Furthermore, the incentives changed concurrently with the expansion of the public poor relief and educational system, which from the middle of the 19^th century took over many of the humanitarian efforts hitherto run by the voluntary associations. The result of this development was that the voluntary associations created new spheres of activity. They continued to fulfil important societal functions, but their establishments also fulfilled a more internal desire for pleasure and delights.

Characterization of Male Breast Cancer : From Molecule to Clinical Outcome

Cecilia Nilsson — Fri, 11 May 2012 10:48:42 +0200

The aim of this thesis was to investigate different aspects of male breast cancer (MBC), and to compare these with findings in female breast cancer (FBC). In paper I, a population–based study was performed to investigate possible differences in treatment and outcome between MBC and FBC patients. MBC and FBC presented with a similar distribution of stage. Although no differences in primary treatment strategy were demonstrated, MBC patients had significantly poorer overall and relative survival, indicating a more aggressive disease. Paper II aimed to assess the value of clinicopathological factors and molecular subtypes in MBC. One hundred and ninety-seven MBC tumors were characterized using immunohistochemistry (IHC) and the findings were correlated to outcome. Lymph node positivity, larger tumor size and ER-negativity were independent risk factors for breast cancer death. Tumor grade, HER2, Ki 67 or IHC classification into molecular subtypes did not demonstrate any prognostic information. In paper III, the same patient material as in paper II was used for evaluation of proliferation markers. High levels of cyclin A and cyclin B expression and an elevated mitotic count were predictive of breast cancer death. Ki-67 was re-evaluated using different cut-offs, but no prognostic value could be demonstrated. Contrarily, overexpression of cyclin D1 was associated with a lower risk of breast cancer death. In papers IV-V, the molecular background of MBC tumors was investigated. Global GEX analyses were performed and two novel subgroups of MBC tumors were identified; luminal M1 and luminal M2. When comparing the degree of similarity with the “intrinsic” subtypes in FBC tumors, more than half of the MBC tumors remained unclassified. Comparative genomic hybridization was used to investigate DNA aberrations. Two MBC subgroups were identified, of which one did not resemble any of the female subgroups. In both studies on the molecular level, a majority of patients were classified into the subgroup with a more aggressive tumor behavior. In conclusion, MBC seems to be a unique tumor entity. The established molecular subtypes in FBC are not applicable in MBC. Other prognostic profiles, specific for MBC, need to be identified.

Brownian Dynamics Simulations of Macromolecules : Algorithm Development and Polymers under Confinement

Tobias Carlsson — Mon, 14 May 2012 09:43:07 +0200

In this thesis I have used computer simulations to study the structure and dynamics of grafted polymers during confinement. These systems are of importance for understanding e.g. colloidal stability and surface coatings. We have used Brownian dynamics simulations with the polymers modeled as discrete wormlike chains allowing for a variable persistence length as well as different non-bonded interactions. The size and shape of the chains are characterized by the radius of gyration and the degree of oblateness/prolateness, and the entanglement is followed by calculating the mean overcrossing number. Starting in the dilute regime with a single polymer mushroom we have investigated how the rate of compression and solvent quality effects the behaviour of a compressed chain. In the brush regime, we investigated how the surface coverage effects the behaviour during compression. For low coverages the chains have the possibilty to increase their lateral extension during confinement but in general, the chains have a low inter-entanglement, as they strive to keep their integrity during the confinement process.

To go from a polymer brush to the construction of a connected network, we have developed a method to construct a closed network without using periodic boundary conditions by building the network on a sphere in R⁴. In this way we avoid the restrictions of periodicity at the cell boundaries. We finally also show how to develop the idea of using spherical boundary conditions, by presenting a novel algorithm for simulating diffusion on a spherical surface. The method is more stable and allows for larger time steps, compared to commonly used methods in computer simulations.

On the Machinability of High Performance Tool Steels

Natalia Sandberg — Tue, 8 May 2012 08:49:57 +0200

The continuous development of hot forming tool steels has resulted in steels with improved mechanical properties. A change in alloying composition, primarily a decreased silicon content, makes them tougher and more wear resistant at elevated temperatures. However, it is at the expense of their machinability. The aim of this study is to explain the mechanisms behind this negative side effect.

Hot work tool steels of H13 type with different Si content were characterised mechanically, and evaluated analytically and by dedicated machining tests. Machining tests verified that materials with low Si content displayed reduced machinability due to their stronger tendency to adhere to the cutting edge. Three hypotheses were tested.

The first hypothesis, that the improved toughness of the low Si steels is the reason behind their relatively poor machinability, was rejected after machining tests with one low Si steel heat treated to the same relatively low toughness as conventional hot work tool steels.

The second hypothesis, that a change in oxidation properties, also associated with the change in Si composition, lies behind the reduced machinability was investigated by dedicated tests and evaluations. It was found that the oxide thickness increased with reduced Si content and that there was an enrichment of Cr at the oxide/steel interface. The differences in oxide thickness and the possible differences in oxidation properties may influence the machinability of the materials through their different abilities to adhere to the cutting edge.

The third hypothesis, that a high enough temperature to initiate phase transformation from ferrite to austenite is generated during machining of the tool steels, was also investigated. This may lead to a reduced machinability because higher austenite content is directly related to higher compressive stresses and higher cutting forces. This causes accelerated tool wear. This hypothesis was verified by ThermoCalc calculation of austenite content in the steels, which showed a good agreement with Gleeble compression tests and cutting force measurements.

This thesis confirms that a reduced Si content in conventional H13 steel improves the toughness, reduces the oxidation resistance and lowers the ferrite-to-austenite transformation temperature. The reduction in austenite temperature is probably the most important factor behind the reduced machinability.

In vitro Studies of Genodermatoses Affecting Cytoskeletal Integrity and Lipid Processing in Human Epidermis : Pathogenic Mechanisms and Effects of Retinoid Therapy

Hao Li — Mon, 14 May 2012 10:53:25 +0200

Autosomal dominant epidermolytic ichthyosis (EI) is a rare disease characterized by intra-epidermal blistering due to mutations in either of two keratin genes, KRT1 and KRT10, expressed by suprabasal keratinocytes. Autosomal recessive congenital ichthyosis (ARCI) is a non-blistering, hyperkeratotic disease caused by mutations in one of the following genes: ABCA12, ALOX12B, ALOXE3, TGM1, CYP4F22, NIPAL4 and SLC27A4, which are all essential for skin barrier homeostasis. ARCI and EI often respond well to treatment with retinoids, but the mechanism of action is unclear. The aim of this thesis was to increase the knowledge of pathogenic pathways in ichthyosis and to find new explanations to the effect of retinoids.

In vitro studies of immortalized keratinocytes from EI patients showed an abnormal keratin aggregation after heat stress, that could be partially inhibited by pre-treatment with all-trans retinoic acid (ATRA) or retinoic acid receptor α-agonists. ATRA treatment also reduced the relative expression of mutated vs wildtype KRT10. The clearance of ATRA in human keratinocytes was found to be mediated by CYP26B1.

In skin biopsies from ARCI patients, immunofluorescence analysis of 12R-LOX, eLOX-3, TGM1, ichthyin and FATP4 showed altered expression, not only of the mutated protein, but also of the other proteins. These observations are consistent with a feedback regulatory mechanism by which the loss of one protein results in an up-regulation of other proteins. Furthermore, 12R-LOX, eLOX-3 and TGM1 were intimately co-localized in stratum corneum, as were ichthyin and FATP4, suggesting that the proteins are linked to the same metabolic pathway. When treated with a CYP26 inhibitor known to raise the endogenous ATRA level of the skin, two patients with NIPAL4 mutations, initially exhibiting increased co-localization signals for 12R-LOX and eLOX-3, displayed normalized lipoxygenase expressions and showed clinical improvement.

In conclusion, mechanisms are proposed by which pathogenic keratin aggregations in EI and epidermal protein deficiencies in ARCI patients may be mitigated by retinoids. Furthermore, the vivid crosstalk between proteins incriminated in ARCI suggests that these enzymes operate along a common metabolic pathway essential for producing barrier lipids in stratum corneum. Any abrogation of this production may cause barrier failure, hence resulting in a compensatory hyperkeratosis characteristic of congenital ichthyosis.

Dynamics and Mechanisms of Adaptive Evolution in Bacteria

Song Sun — Mon, 14 May 2012 09:17:20 +0200

Determining the properties of mutations is fundamental to understanding the mechanisms of adaptive evolution. The major goal of this thesis is to investigate the mechanisms of bacterial adaptation to new environments using experimental evolution. Different types of mutations were under investigations with a particular focus on genome rearrangements. Adaptive evolution experiments were focused on the development of bacterial resistance to antibiotics.

In paper I, we performed stochastic simulations to examine the role of gene amplification in promoting the establishment of new gene functions. The results show that gene amplification can contribute to creation of new gene functions in nature. In paper II, the evolution of β-lactam resistance was studied by evolving S. typhimurium carrying a β-lactamase gene towards increased resistance against cephalosporins. Our results suggest that gene amplification is likely to provide an immediate solution at the early stage of adaptive evolution and subsequently facilitate further stable adaptation. In paper III, we isolated spontaneous deletion mutants with increased competitive fitness, which indicated that genome reduction could be driven by selection. To test this hypothesis, independent lineages of wild type S. typhimurium were serially passaged for 1000 generations and we observed fixation of deletions that significantly increased bacterial fitness when reconstructed in wild type genetic background. In paper IV, we developed a new strategy combining 454 pyrosequencing technology and a ‘split mapping’ computational method to identify unique junction sequences formed by spontaneous genome rearrangements. A high steady-state frequency of rearrangements in unselected bacterial populations was suggested from our results. In paper V, the rates, mechanisms and fitness effects of colistin resistance in S. typhimurium were determined. The high mutation rate and low fitness costs suggest that colistin resistance could develop in clinical settings. In paper VI, a novel Metallo-β-lactamase (MBL) with low resistance against β-lactam antibiotics was employed as the ancestral protein in a directed evolution experiment to examine how an enzyme evolves towards increased resistance. For most isolated mutants, in spite of their significantly increased resistance, both mRNA and protein levels were decreased as compared with the parental protein, suggesting that the catalytic activity had increased.

On the Prediction of Warfarin Dose

Niclas Eriksson — Mon, 14 May 2012 10:10:23 +0200

Warfarin is one of the most widely used anticoagulants in the world. Treatment is complicated by a large inter-individual variation in the dose needed to reach adequate levels of anticoagulation i.e. INR 2.0 – 3.0. The objective of this thesis was to evaluate which factors, mainly genetic but also non-genetic, that affect the response to warfarin in terms of required maintenance dose, efficacy and safety with special focus on warfarin dose prediction.

Through candidate gene and genome-wide studies, we have shown that the genes CYP2C9 and VKORC1 are the major determinants of warfarin maintenance dose. By combining the SNPs CYP2C9 *2, CYP2C9 *3 and VKORC1 rs9923231 with the clinical factors age, height, weight, ethnicity, amiodarone and use of inducers (carbamazepine, phenytoin or rifampicin) into a prediction model (the IWPC model) we can explain 43 % to 51 % of the variation in warfarin maintenance dose. Patients requiring doses < 29 mg/week and doses ≥ 49 mg/week benefitted the most from pharmacogenetic dosing. Further, we have shown that the difference across ethnicities in percent variance explained by VKORC1 was largely accounted for by the allele frequency of rs9923231. Other novel genes affecting maintenance dose (NEDD4 and DDHD1), as well as the replicated CYP4F2 gene, have small effects on dose predictions and are not likely to be cost-effective, unless inexpensive genotyping is available.

Three types of prediction models for warfarin dosing exist: maintenance dose models, loading dose models and dose revision models. The combination of these three models is currently being used in the warfarin treatment arm of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) study. Other clinical trials aiming to prove the clinical validity and utility of pharmacogenetic dosing are also underway.

The future of pharmacogenetic warfarin dosing relies on results from these ongoing studies, the availability of inexpensive genotyping and the cost-effectiveness of pharmacogenetic driven warfarin dosing compared with new oral anticoagulant drugs.

Ground and Excited State Aromaticity : Design Tools for π-Conjugated Functional Molecules and Materials

Christian Dahlstrand — Mon, 14 May 2012 14:49:02 +0200

The main focus of this thesis is on the aromaticity of the ground state and electronically excited states of π-conjugated molecules and polymers, as well as how aromaticity is connected to their properties.

The electronic structures of polybenzenoid hydrocarbons (PBHs) were explored through density functional theory (DFT) calculations and the π-component of the electron localization function (ELF_π). The study revealed how the π-electronic structure is influenced by the fusion of double bonds or benzene rings to the PBHs. We also demonstrated that the π-electrons of benzene extend to accommodate as much aromaticity as possible when bond length distorted.

The aromatic chameleon property displayed by fulvenes, isobenzofulvenes, fulvalenes, bis(fulvene)s, and polyfulvenes were investigated using DFT calculations. The tria-, penta-, and heptafulvenes were shown to possess ionization energies and electron affinities which can be tuned extensively by substitution, some of which even outperform TTF and TCNQ, the prototypical electron donor and acceptor, respectively. The singlet-triplet energy gap of pentafulvenes can be tuned extensively by substitution to the point that the triplet state is lower than the singlet state and thus becomes the ground state. The ELF_π of isobenzofulvene shows that the benzene ring in an electronically excited state can be more aromatic than the corresponding ring in the ground state. We have shown that the 6-ring of [5.6.7]quinarene is influenced by a Hückel aromatic resonance structure with 4n+2 π-electrons in the excited quintet state. The bis(fulvene)s which are composed of a donor type heptafulvene and an acceptor type pentafulvene, retain the basic donor-acceptor properties of the two fragments and could function as compact donor-acceptor dyads. A few of the designed polyfulvenes were found to have band gaps below 1 eV at the PBC-B3LYP/6-31G(d) level.

Various 2,7-disubstituted fluorenones and dibenzofulvenes were synthesized and their excited state properties were investigated by absorption spectroscopy and time-dependent DFT calculations. It was found that the ¹A → ¹B transition of ππ* character can be tuned by substitution in the 2,7-positions. The 2,7-bis(N,N-dimethyl) derivatives of fluorenone and dibenzofulvene displayed low energy transitions at 2.18 and 1.61 eV, respectively, in toluene.

Advanced MEMS Pressure Sensors Operating in Fluids

Emil Anderås — Tue, 15 May 2012 09:45:58 +0200

Today’s MEMS technology allows manufacturing of miniaturized, low power sensors that sometimes exceeds the performance of conventional sensors. The pressure sensor market today is dominated by MEMS pressure sensors.

In this thesis two different pressure sensor techniques are studied. The first concerns ways to improve the sensitivity in the most commonly occurring pressure sensor, namely such based on the piezoresistive technique. Since the giant piezoresistive effect was observed in silicon nanowires, it was assumed that a similar effect could be expected in nano-thin silicon films. However, it turned out that the conductivity was extremely sensitive to substrate bias and could therefore be controlled by varying the backside potential. Another important parameter was the resistivity time drift. Long time measurements showed a drastic variation in the resistance. Not even after several hours of measurement was steady state reached. The drift is explained by hole injection into the buried oxide as well as existence of mobile charges. The piezoresistive effect was studied and shown to be of the same magnitude as in bulk silicon. Later research has shown the existence of such an effect where the film thickness has to be less than around 20 nm.

The second area that has been studied is the pressure sensitivity of in acoustic resonators. Aluminium nitride thin film plate acoustic resonators (FPAR) operating at the lowest-order symmetric (S0), the first-order asymmetric (A1) as well as the first-order symmetric (S1) Lamb modes have been theoretically and experimentally studied in a comparative manner. The S0 Lamb mode is identified as the most pressure sensitive FPAR mode. The theoretical predictions were found to be in good agreement with the experiments. Additionally, the Lamb modes have been tested for their sensitivities to mass loading and their ability to operate in liquids, where the S0 mode showed good results.

Finally, the pressure sensitivity in aluminium nitride thin film bulk wave resonators employing c- and tilted c-axis texture has been studied. The c-axis tilted FBAR demonstrates a substantially higher pressure sensitivity compared to its c-axis oriented counterpart.

Traits & Talks : Lessons about Personality and Deliberation from the Negotiations between Nelson Mandela and FW de Klerk

Julia Jennstål — Mon, 14 May 2012 13:56:38 +0200

Compelling research in political psychology and personality psychology points to the significance of personality as a determinant of political behavior. Within a comprehensive framework for the study of personality in politics, the so-called Five-level Model (FLM), this thesis primarily focuses on the level of personality traits, where the well-established Five-factor model (the ‘Big Five’) is applied.

Specifically, the objective is to examine the role of personality in deliberation. The current trend in research on deliberation is to take a systemic, institutional perspective. In contrast, the argument here is that a comprehensive examination of the individual level is suitable if we want to counteract the ongoing ‘concept stretching’ of deliberation.

A Deliberative Behavioral Repertoire (DBR) is compiled consisting of four distinct behavioral expectations on deliberative participants (reason-giving, inner moral reasoning, open-mindedness and respect for others) and suggested as a functional approach to measuring and evaluating deliberative processes on an individual level of analysis.

While the DBR is an approximation of deliberative conduct, it remains silent on the matter of personality. In order to determine the role of personality in deliberative conduct, the DBR is linked to the five factors. In a secondary analysis, a set of hypotheses on the links between the DBR and the five factors (drawing on both trait and facet levels) is proposed for empirical validation. The analysis ends with a presentation of a personality profile of the ’genuine’ deliberator, which evokes a discussion on normative, conceptual and empirical implications of bringing personality into the study of deliberation.

Empirically, the peace negotiations in South Africa, 1989-94, between Nelson Mandela and FW de Klerk, are used to substantiate the impact of personality in deliberation. This crucial case of naturally occurring political-leadership deliberation is explored in depth. Based on the two leaders’ personality profile – assessed in a qualitative analysis of each leader’s behavior evident across situations and over time – it is demonstrated how deliberative features of the negotiations are linked to vital personality attributes of the leaders. Through this close scrutiny of how personality might influence negotiation processes and outcomes, the study also contributes to the broader field of negotiation research.

Experimental Studies of Charge Transport in Single Crystal Diamond Devices

Saman Majdi — Tue, 15 May 2012 10:45:19 +0200

Diamond is a promising material for high-power, high-frequency and high- temperature electronics applications, where its outstanding physical properties can be fully exploited. It exhibits an extremely high bandgap, very high carrier mobilities, high breakdown field strength, and the highest thermal conductivity of any wide bandgap material. It is therefore an outstanding candidate for the fastest switching, the highest power density, and the most efficient electronic devices obtainable, with applications in the RF power, automotive and aerospace industries. Lightweight diamond devices, capable of high temperature operation in harsh environments, could also be used in radiation detectors and particle physics applications where no other semiconductor devices would survive.

The high defect and impurity concentration in natural diamond or high-pressure-high-temperature (HPHT) diamond substrates has made it difficult to obtain reliable results when studying the electronic properties of diamond. However, progress in the growth of high purity Single Crystal Chemical Vapor Deposited (SC-CVD) diamond has opened the perspective of applications under such extreme conditions based on this type of synthetic diamond.

Despite the improvements, there are still many open questions. This work will focus on the electrical characterization of SC-CVD diamond by different measurement techniques such as internal photo-emission, I-V, C-V, Hall measurements and in particular, Time-of-Flight (ToF) carrier drift velocity measurements. With these mentioned techniques, some important properties of diamond such as drift mobilities, lateral carrier transit velocities, compensation ratio and Schottky barrier heights have been investigated. Low compensation ratios (N_D/N_A) < 10^-4 have been achieved in boron-doped diamond and a drift mobility of about 860 cm²/Vs for the hole transit near the surface in a lateral ToF configuration could be measured. The carrier drift velocity was studied for electrons and holes at the temperature interval of 80-460 K. The study is performed in the low-injection regime and includes low-field drift mobilities. The hole mobility was further investigated at low temperatures (10-80 K) and as expected a very high mobility was observed.

In the case of electrons, a negative differential mobility was seen in the temperature interval of 100-150K. An explanation for this phenomenon is given by the intervally scattering and the relation between hot and cold conduction band valleys. This was observed in direct bandgap semiconductors with non-equivalent valleys such as GaAs but has not been seen in diamond before.

Furthermore, first steps have been taken to utilize diamond for infrared (IR) radiation detection. To understand the fundamentals of the thermal response of diamond, Temperature Coefficient of Resistance (TCR) measurements were performed on diamond Schottky diodes which are a candidate for high temperature sensors. As a result, very high TCR values in combination with a low noise constant (K_1/f) was observed.

Mechanisms for Quantitative Regulation of TGF-ß Signaling

Markus Dahl — Mon, 14 May 2012 13:38:04 +0200

Cancer is a widely spread disease, and many cancer variants are today still difficult to treat. Efforts are being made to understand the complexity of cancer, both at a clinical level but also at a pre-clinical level. The aim is of course to merge the research from both disciplines, as an example, find out how to treat a tumour in a patient and what molecular mechanisms are behind the origin of the tumour. Basic research provides a platform that in the long run will help to create treatments for many cancer variants that exist today. Transforming Growth Factor Beta (TGF-ß) is a cytokine that regulates many cellular events such as cell differentiation, cell proliferation and migration. TGF-ß signaling is important to study since many studies show that patients with cancer actually have accumulated mutations in proteins connected to the pathway. In this thesis I try to enhance the knowledge of the TGF-ß signaling pathway, looking in more detail how the signaling output is regulated by the response to the ligand, explained in paper four. Furthermore I try to reveal the protein network that control transmission of the signal from the cell surface to the nucleus. We found that PARP-1 (paper one and two) and PARP-2 (paper three) associates with the signaling pathway to regulate the Smad proteins and to negatively regulate the transcription of Smad target genes.

Correlated Electronic Structure of Materials : Development and Application of Dynamical Mean Field Theory

Patrik Thunström — Wed, 16 May 2012 13:13:25 +0200

This thesis is dedicated to the development, implementation and application of a combination of Density Functional Theory and Dynamical Mean Field Theory. The resulting program is shown through several examples to be a powerful and flexible tool for calculating the electronic structure of strongly correlated materials. The main part of this work is focused on the development and implementation of three methods for solving the effective impurity model arising in the Dynamical Mean Field Theory: Hubbard-I approximation (HIA), Exact Diagonalization (ED), and Spin-Polarized T-matrix Fluctuation-exchange (SPTF). The Hubbard-I approximation is limited to systems where the hybridization between the 4f-orbitals and the rest of the material can be completely neglected, and can therefore not capture any Kondo physics. It has been used to study the atomic-like multiplet spectrum of the strongly localized 4f-electrons in the Lanthanide compounds YbInCu₄, YbB₁₂, Yb₂Pd₂Sn, YbPd₂Sn, SmB₆, SmSn₃, and SmCo₅. The calculated spectral properties are shown to be in excellent agreement with experimental direct and inverse photoemission data, clearly affirming the applicability of the Hubbard-I approximation for this class of systems if we are not focusing on Kondo physics. Full self-consistence in both self-energy and electron density is shown to be of key importance in the extraction of the magnetic properties of the hard permanent magnet SmCo₅. The Exact Diagonalization solver is implemented as an extension of the Hubbard-I approximation. It takes into account a significant part of the hybridization between the correlated atom and the host through the use of a few effective bath orbitals. This approach has been applied to the long-standing problem of the electronic structure of NiO, CoO, FeO, and MnO. The resulting spectral densities are favorably compared to photoemission spectroscopy. Apart from predicting the correct spectral properties, the Exact Diagonalization solver also provides full access to the many-body density operator. This feature is used to make an in-depth investigation of the correlations in the electronic structure, and two measures of the quantum entanglement of the many-body ground-states are presented. It is shown that CoO possesses the most intricate entanglement properties, due to a competition between crystal field effects and Coulomb interaction, and such a mechanism likely carries over to several classes of correlated electron systems. The Exact Diagonalization solver has also been applied to the prototypical dilute magnetic semiconductor Mn doped GaAs, a material of great importance in the study of future spintronics applications. The problem of Fe impurities in Cs has been used to study the dependence of the spectral properties on the local environment. Finally, the Spin-polarized T-matrix Fluctuation-exchange solver has been implemented and applied to more delocalized electron systems where the effective impurity problem can be solved as a perturbation with respect to the strength of the local Coulomb interaction. This approach has been used to study the magnetic and spectral properties of the late transition metals, Fe, Co and Ni, and NiS.

Entanglement and Quantum Computation from a Geometric and Topological Perspective

Markus Johansson — Mon, 14 May 2012 10:14:25 +0200

In this thesis we investigate geometric and topological structures in the context of entanglement and quantum computation.

A parallel transport condition is introduced in the context of Franson interferometry based on the maximization of two-particle coincidence intensity. The dependence on correlations is investigated and it is found that the holonomy group is in general non-Abelian, but Abelian for uncorrelated systems. It is found that this framework contains a parallel transport condition developed by Levay in the case of two-qubit systems undergoing local SU(2) evolutions.

Global phase factors of topological origin, resulting from cyclic local SU(2) evolution, called topological phases, are investigated in the context of multi-qubit systems. These phases originate from the topological structure of the local SU(2)-orbits and are an attribute of most entangled multi-qubit systems. The relation between topological phases and SLOCC-invariant polynomials is discussed. A general method to find the values of the topological phases in an n-qubit system is described.

A non-adiabatic generalization of holonomic quantum computation is developed in which high-speed universal quantum gates can be realized by using non-Abelian geometric phases. It is shown how a set of non-adiabatic holonomic one- and two-qubit gates can be implemented by utilizing transitions in a generic three-level Λ configuration. The robustness of the proposed scheme to different sources of error is investigated through numerical simulation. It is found that the gates can be made robust to a variety of errors if the operation time of the gate can be made sufficiently short. This scheme opens up for universal holonomic quantum computation on qubits characterized by short coherence times.

Aphasia and Communication in Everyday Life : Experiences of persons with aphasia, significant others, and speech-language pathologists

Monica Blom Johansson — Wed, 16 May 2012 08:36:16 +0200

The aims of this thesis were to describe the experiences of persons with aphasia and their significant others of their conversations and use of communication strategies, examine current practice of family-oriented speech-language pathology (SLP) services, and test a family-oriented intervention in the early phase of rehabilitation.

The persons with aphasia valued having conversations despite perceiving their aphasia as a serious social disability. They acknowledged the importance of the communication partners’ knowledge and understanding of aphasia and their use of supporting conversation strategies. Their own use of communication strategies varied considerably. The persons with aphasia longed to regain language ability and to be active participants in society.

A majority of the significant others perceived their conversations with the person with aphasia as being less stimulating and enjoyable than conversations before stroke onset. Aphasia was considered a serious problem. The significant others took on increased communicative responsibility, where two thirds had changed their communicative behaviour to facilitate conversations. Type and severity of aphasia were especially related to the communicative experiences of the significant others and their motivation to be involved in SLP services.

Thirty percent of the speech-language pathologists worked with people with aphasia and typically met with their families. They considered the involvement of significant others in SLP services as very important, especially in providing information about aphasia and communication partner training (CPT). However, involvement of significant others was restricted because of a time shortage and perceived limited skills and knowledge. In addition, there were national differences regarding aphasia rehabilitation services.

The intervention consisted of three sessions directed to significant others (primarily emotional support and information) and three directed to the dyads (a person with aphasia and a significant other) (primarily CPT). All six participants (three dyads) felt that their knowledge and understanding of aphasia had increased and that their conversations had improved. These improvements were also evident to some extent with formal assessments.

These results suggest the following: CPT should be an integral part of SLP services, national clinical guidelines are needed, and further education of speech-language pathologists and implementation of new knowledge into clinical practice requires consideration.

Microstructural, Mechanical and Tribological Characterisation of CVD and PVD Coatings for Metal Cutting Applications

Mikael Fallqvist — Tue, 15 May 2012 11:42:52 +0200

The present thesis focuses on characterisation of microstructure and the resulting mechanical and tribological properties of CVD and PVD coatings used in metal cutting applications. These thin and hard coatings are designed to improve the tribological performance of cutting tools which in metal cutting operations may result in improved cutting performance, lower energy consumption, lower production costs and lower impact on the environment. In order to increase the understanding of the tribological behaviour of the coating systems a number of friction and wear tests have been performed and evaluated by post-test microscopy and surface analysis. Much of the work has focused on coating cohesive and adhesive strength, surface fatigue resistance, abrasive wear resistance and friction and wear behaviour under sliding contact and metal cutting conditions.

The results show that the CVD deposition of accurate crystallographic phases, e.g. α-Al₂O₃ rather than κ-Al₂O₃, textures and multilayer structures can increase the wear resistance of Al₂O₃. However, the characteristics of the interfaces, e.g. topography as well as interfacial porosity, have a strong impact on coating adhesion and consequently on the resulting properties. Through the deposition of well designed bonding and template layer structures the above problems may be eliminated.

Also, the presence of macro-particles in PVD coatings may have a significant impact on the interfacial adhesive strength, increasing the tendency to coating spalling and lowering the surface fatigue resistance, as well as increasing the friction in sliding contacts.

Finally, the CVD-Al₂O₃coating topography influences the contact conditions in sliding as well as in metal cutting.

In summary, the work illuminates the importance of understanding the relationships between deposition process parameters, composition and microstructure, resulting properties and tribological performance of CVD and PVD coatings and how this knowledge can be used to develop the coating materials of tomorrow.

Perfectly Matched Layers and High Order Difference Methods for Wave Equations

Kenneth Duru — Mon, 14 May 2012 10:03:49 +0200

The perfectly matched layer (PML) is a novel technique to simulate the absorption of waves in unbounded domains. The underlying equations are often a system of second order hyperbolic partial differential equations. In the numerical treatment, second order systems are often rewritten and solved as first order systems. There are several benefits with solving the equations in second order formulation, though. However, while the theory and numerical methods for first order hyperbolic systems are well developed, numerical techniques to solve second order hyperbolic systems are less complete.

We construct a strongly well-posed PML for second order systems in two space dimensions, focusing on the equations of linear elasto-dynamics. In the continuous setting, the stability of both first order and second order formulations are linearly equivalent. We have found that if the so-called geometric stability condition is violated, approximating the first order PML with standard central differences leads to a high frequency instability at most resolutions. In the second order setting growth occurs only if growing modes are well resolved. We determine the number of grid points that can be used in the PML to ensure a discretely stable PML, for several anisotropic elastic materials.

We study the stability of the PML for problems where physical boundaries are important. First, we consider the PML in a waveguide governed by the scalar wave equation. To ensure the accuracy and the stability of the discrete PML, we derived a set of equivalent boundary conditions. Second, we consider the PML for second order symmetric hyperbolic systems on a half-plane. For a class of stable boundary conditions, we derive transformed boundary conditions and prove the stability of the corresponding half-plane problem. Third, we extend the stability analysis to rectangular elastic waveguides, and demonstrate the stability of the discrete PML.

Building on high order summation-by-parts operators, we derive high order accurate and strictly stable finite difference approximations for second order time-dependent hyperbolic systems on bounded domains. Natural and mixed boundary conditions are imposed weakly using the simultaneous approximation term method. Dirichlet boundary conditions are imposed strongly by injection. By constructing continuous strict energy estimates and analogous discrete strict energy estimates, we prove strict stability.

Electronic and Geometric Structure of Phthalocyanines on Metals

Masumeh-Nina Shariati — Wed, 16 May 2012 10:25:48 +0200

Adsorption of monolayers and multilayers of metal-free and metal phthalocyanines molecules on metal surfaces has been investigated using complementary microscopic and synchrotron-based spectroscopic techniques. It was observed by STM measurements that at monolayer coverage the adsorption direction of the metal-free phthalocyanine molecules with respect to the gold surface vary as a function of temperature, i.e. at room temperature (RT) and low temperature (LT). It was explained by the difference in strength of intermolecular and adsorbate-substrate interactions at room and low temperatures. Nature of the interaction between adsorbed species and the surfaces as a function of coverage has been further characterized by XPS measurements. Binding energy shifts as a function of coverage have been attributed to initial- and final-state effects, the latter being due to different core-hole screening for the different molecular coverage. The alignment of molecular films at both monolayer and multilayer coverages, which has been determined by XAS measurements in several cases, is also dependent upon the relative strength of molecule-molecule versus molecule-substrate interaction. Parallel alignment of the molecular film with respect to the surface is the result of significant interaction between the adsorbate and the substrate, whilst standing geometry of the molecular film is due to more significant intermolecular interactions. DFT simulations have provided further information on the nature of the adsorbate-substrate interaction as well as contribution of different molecular orbitals in XPS and XAS spectra. Moreover, investigation of alkali interaction with the phthalocyanine films revealed a significant modification in their geometric and electronic structures due to charge transfer from the alkali metal to the molecular film. However, no sign of metallization of the molecules has been observed by spectroscopic and microscopic studies.

Asymmetric Hydrogenations using N, P - Ligated Iridium Complexes

Alexander Paptchikhine — Tue, 15 May 2012 14:15:37 +0200

The research described in this thesis focuses on the catalytic asymmetric hydrogenation of prochiral olefins using N, P – chelated iridium catalysts. This catalytic system is tolerant to a wide range of substrates and performs better than the well-known ruthenium- and rhodium-catalytic systems for substrates devoid of coordinating groups in proximity of the olefin. Low catalytic loadings (often <1 %) and the high atom efficiency of this reaction make it a synthetically useful method of chiral molecule synthesis. The primary aim of this thesis was to develop new catalysts that rapidly and efficiently hydrogenate a broad range of alkenes asymmetrically. Papers I and II describe the synthesis and evaluation of new, highly efficient, chiral N, P – ligated iridium complexes. These catalysts were obtained in relatively few steps, while leaving open possibilities to modify and fine-tune their structure. Their versatility is ideally suited to both industrial uses and to equip any catalyst box. Paper III deals with a common problem of defluorination of vinylic fluorides during the hydrogenation. The catalyst designed in that work performs well for several substrates giving very low defluorination rates making it a good starting point for further improvements to cover a broader scope of vinyl fluorides. The structures of the catalysts from papers I and III also offers an easy approach to attach the catalyst ligands to a solid support. Paper IV explores hydrogenation of vinyl boronates, which gives synthetically interesting borane compounds with high enantioselectivities. Taking into account the rich chemistry of organic boranes, these compounds are very important. Paper V deals with hydrogenation of diphenylvinylphosphine oxides and vinyl phosphonates, another important classes of substrates that give chiral phosphorous containing compounds of interest in many fields of chemistry: such as medicinal chemistry and organocatalysis. In papers VI and VII we explore the Birch reaction as a source of prochiral olefins. By combining asymmetric hydrogenation with it, we obtain a powerful method to create chiral compounds with excellent enantioselectivities that are next to impossible to make by other routes. The products of the asymmetric hydrogenation are further modified by other well-known transformation to create other induced stereogenic centres.

Presenting the Absent : An Account of Undocumentedness in Sweden

Erika Sigvardsdotter — Wed, 16 May 2012 10:51:13 +0200

This thesis provides an ethnography and critical phenomenology of undocumentedness in the Swedish context. By attending to the forces and processes that circumscribe the life-worlds of undocumented persons, as well as the phenomenology and essential experiences of their condition, a complex and multi-layered illustration of what undocumentedness is and means is successively presented. Employing a dual conceptualization of the state, as a juridico-political construct as well as a practiced and embodied set of institutions, the undocumented position emerges as a legal category defined only through omission, produced and reproduced through administrative routine and practice. The health care sector provides empirical examples of state-undocumented interaction where the physical and corporeal presence of the officially absent becomes irrefutable. This research suggests that the Swedish welfare state – universalistic, comprehensive and with digitized administrative routines – becomes a particularly austere environment in which to be undocumented.

Drawing on interviews with regional and local health care administrators, NGO-clinics’ representatives and health professionals, as well as extensive participatory observation and interviews with undocumented persons, I argue that the undocumented condition is characterized by simultaneous absence and presence, and a correspondingly paradoxical spatiality. I suggest that the official absence and deportability of undocumented persons deprives them of the capacity to define space and, in an Arendtian sense, appear as themselves to others. There are, however, some opportunities for embodied political protest and dissensus. The paradoxical qualities of the absent-present condition manipulate the undocumented mode of being-in-the-world and I argue that alienation and disorientation are essential experiences of the undocumented situation.

Palladium-Catalysed Couplings in Organic Synthesis : Exploring Catalyst-Presenting Strategies and Medicinal Chemistry Applications

Alejandro Trejos — Wed, 16 May 2012 14:15:13 +0200

Palladium-catalysed coupling reactions have been embraced by synthetic chemists as one of the preferred means for smooth formation of new carbon-carbon bonds: a truly ubiquitous methodology of synthesizing complex molecules.

This thesis describes the study of a series of palladium(0)-catalysed C2-arylations of a 1-cyclopentenyl ether, equipped with a chiral (S)-N-methyl-pyrrolidine auxiliary. The investigated olefin was demonstrated to undergo Si-face insertion, providing (R)-configuration of the arylated C2-carbon.

In addition, the mild and novel palladium(II)-catalysed dominoHeck/Suzuki β,α-diarylation-reduction of a dimethylaminoethyl-substituted chelating vinyl ether was developed using arylboronic acids as arylating agents in combination with 1,4-benzoquinone (BQ). Further, highly regioselective palladium(II)-catalysed α-and β-monoarylation of the chelating vinyl ether was achieved using either a bidentate ligand or by employing ligand-less conditions. These studies demonstrate that the choice of ligands has a profound effect on the reaction outcome, as productive β,α-diarylation could only be obtained by suppressing the competing β-hydride elimination using BQ as the stabilising ligand and terminal reoxidant.

The pivotal role of BQ in the reaction was studied using computer-aided density functional theory calculations. The calculations highlight the crucial role of BQ as a Pd(II)-ligand. In addition of serving as an oxidant of palladium, the calculations support the view that the coordination of BQ to the Pd(II)-centre in the key σ-alkyl complex leads to a low-energy pathway, aided by a strong η²Pd-BQ donation-back-donation interaction.

Furthermore, an investigation of the scope and limitations of novel stereoselective and BQ-mediated palladium(II)-catalysed domino Heck/Suzuki β,α-diarylation reactions, involving metal coordinating cyclic methylamino vinyl ethers and a number of electronically diverse arylboronic acids, conducted.

In addition, a set of 4-quinolone-3-carboxylic acids, structurally related to elvitegravir and bearing different substituents on the condensed benzene ring, was designed and synthesized as potential HIV-1 integrase inhibitors.

Finally, in an effort to identify a new class of HIV-1 protease inhibitors, four different stereopure β-hydroxy γ-lactam-containing inhibitors were synthesized, biologically evaluated, and co-crystallized with the enzyme.

Phosphorus Centers in π-conjugated Systems

Elisabet Öberg — Tue, 15 May 2012 08:29:20 +0200

Single-molecular electronics and organic material electronics are expanding research fields that ultimately aim for a vast variety of different applications, ranging from organic light-emitting diodes, to novel ways to improve the performance and decrease the size of electronics components. To achieve these goals, research has to be focused both on the development of functional molecules, but also on device fabrication. The work of this thesis is focused on the development of synthetic routes towards novel molecules for potential organic electronics applications, together with an investigation of their optical and electronic properties.

The first part of the thesis describes the synthesis of butadiyne-substituted and diacetylenic phosphaalkenes. Theoretical, spectroscopic and electrochemical techniques have been used to understand key steps during their synthesis, and to gain further information on the conjugative properties of their π-systems. A mechanism is proposed for the formation of the butadiyne-substituted and diacetylenic phosphaalkenes and it is shown that the phosphorus heteroatom is an intrinsic part of the π-conjugated system. The incorporation of the phosphorus heteroatom leads to decreased HOMO-LUMO gaps compared to all-carbon based reference compounds.

In the second part of the thesis, acetylenic phosphaalkenes are utilized for the preparation of phosphaalkene-substituted phospholes. A first step towards the exploration of the difference in reactivity of the σ², λ³ phosphaalkene-P and the σ³, λ³phosphole-P is presented as the oxidation of the compounds by sulfur proceeds selectively at the σ³, λ³–P. Spectroscopic and electrochemical investigations show that the phosphaalkene is an integral part of the compounds’ π-systems, and induces a HOMO-LUMO gap decrease compared to reference compounds that lack the P=C substituent.

The third part of this thesis presents an exploratory study concerning the suitability of metathesis reactions for the assembly of alkene-bridged phosphaalkenes.

"A Feminist Libertarian Aesthetic" : Angela Carter and Surrealism

Anna Watz — Tue, 15 May 2012 14:14:30 +0200

This study examines the intersection of surrealism and feminism in the writing of Angela Carter. Tracing the full extent to which Carter’s writing was influenced by surrealist aesthetics and politics, it reveals the way in which her growing discontent with the movement’s gender politics gave critical content to her own feminist poetics. Surrealism, as a direct influence on her writing and as an integral part of her feminism, is shown to have remained a crucial element in Carter’s literary project as a whole. This study also extends critical feminist debates on surrealism more broadly in order to explore both the limits and the possibilities for feminism in reclaiming the representation of women and female desire.

As a first step, chapter 1 elucidates the central presence in surrealism of the figure of woman and outlines key feminist responses to this figure. Carter’s early influence by, and subsequent critique of, surrealism is then situated in the context of this debate. Chapter 2 shows how – at the beginning of her literary career – Carter adopted a surrealist iconography of violence in order to produce both estrangement and shock, the effect of which is double-edged. While her writing at this stage aimed to challenge prescribed notions of femininity, it simultaneously uncritically made use of – and perpetuated – arguably misogynist surrealist imagery of gendered violence. Chapter 3 traces the subsequent shift in Carter’s writing towards a more overt use of surrealist iconography, at the same time as she began to formulate a more distinctly feminist critique of surrealist representations of women. Chapter 4 argues that Carter’s ensuing translation of Xavière Gauthier’s path-breaking study Surréalisme et sexualité is to be considered as a major reference point in Carter’s feminism. Furthermore, it argues that Gauthier’s study should be read as a companion piece to Carter’s polemic The Sadeian Woman. Lastly, chapter 5 investigates Carter’s fictional response to both Gauthier’s text and surrealism, and suggests that this response – both a critique and a celebration of surrealism – constitutes a renewal of surrealism itself.

Twisting and Gluing : On Topological Field Theories, Sigma Models and Vertex Algebras

Johan Källén — Wed, 16 May 2012 08:40:09 +0200

This thesis consists of two parts, which can be read separately. In the first part we study aspects of topological field theories. We show how to topologically twist three-dimensional N=2 supersymmetric Chern-Simons theory using a contact structure on the underlying manifold. This gives us a formulation of Chern-Simons theory together with a set of auxiliary fields and an odd symmetry. For Seifert manifolds, we show how to use this odd symmetry to localize the path integral of Chern-Simons theory. The formulation of three-dimensional Chern-Simons theory using a contact structure admits natural generalizations to higher dimensions. We introduce and study these theories. The focus is on the five-dimensional theory, which can be understood as a topologically twisted version of N=1 supersymmetric Yang-Mills theory. When formulated on contact manifolds that are circle fibrations over a symplectic manifold, it localizes to contact instantons. For the theory on the five-sphere, we show that the perturbative part of the partition function is given by a matrix model.

In the second part of the thesis, we study supersymmetric sigma models in the Hamiltonian formalism, both in a classical and in a quantum mechanical setup. We argue that the so called Chiral de Rham complex, which is a sheaf of vertex algebras, is a natural framework to understand quantum aspects of supersymmetric sigma models in the Hamiltonian formalism. We show how a class of currents which generate symmetry algebras for the classical sigma model can be defined within the Chiral de Rham complex framework, and for a six-dimensional Calabi-Yau manifold we calculate the equal-time commutators between the currents and show that they generate the Odake algebra.

Making Accounting Matter : A Study of the Constitutive Practices of Accounting Framers

Charlotta Bay — Wed, 16 May 2012 13:11:36 +0200

The idea of accounting as a constitutive means, making people think and act in particular ways, is well established in the social strand of accounting literature. In professional organisations, for example, accounting is claimed to be critical to processes of turning people into rational and responsible economic actors. However, this thesis refocuses the empirical attention away from the organisation and into the private sphere of people’s everyday financial lives. As this is a field partly inhabited by people who for various reasons are believed to have difficulty in making sense of financial accounts, a dilemma arises regarding how to influence people’s way of managing their own finances by means of accounting information. How this dilemma is assumed to be resolved in order to make accounting matter is the query of this thesis.

Through a study of four cases, the thesis investigates the practices of public authorities, a television makeover show, and a pension insurance company – here referred to as accounting framers – whose task it is to construct accounting in such a way so as to make it come across as important, relevant and useful to various groups of the general public. By examining how people’s accounting interpretations are elaborated in order to make them responsive to financial accounts, the thesis contributes to problematising the constitutive role of accounting and the conditions believed to enable it to turn people into financially responsible actors.

Molecular Evolution of the Vertebrate Genome

Kiwoong Nam — Tue, 15 May 2012 15:00:05 +0200

In this thesis, I studied molecular evolution of the vertebrate genome, focusing on sex chromosomes, protein coding genes, and genome size variation. The evolutionary history of avian sex chromosomes was analyzed by comparing substitution rate among 12 gametologous gene pairs on the Z and W chromosomes. Divergence estimates were distributed into three discrete clusters, evolutionary strata, implying stepwise cessations of recombination. Stratum 3 and stratum 2 are located the intervals 1-11Mb and 16-53Mb on the chicken Z chromosome, respectively. Stratum 1 was located in the middle of stratum 2, suggesting a chromosomal inversion. Using a molecular clock, the estimated times for cessation of recombination between Z and W are 132–150 (stratum 1), 71–99 (stratum 2), and 47–57 (stratum 3) million years ago.

Higher divergence rate in the Z chromosome than in autosomes (faster-Z) can be explained by positive selections on recessive alleles in hemizygous females, or by stronger genetic drift due to the smaller effective population size of the Z chromosomes. I found there was no difference in the intensity of the faster-Z effect among male-biased, female-biased, and unbiased genes, as might have been expected under a selection model. This result therefore supports the hypothesis that faster-Z is predominantly due to genetic drift.

Next, I analyzed molecular evolution of protein-coding genes in birds. In the comparison of zebra finch, chicken and non-avian outgroups, I found that neutral substitution rate was highest in zebra finch, intermediate in chicken, and lowest in ancestral birds. This difference seems attributable to differences in generation time, ancestral birds being most long-lived. Several functional categories were overrepresented among positively selected genes in avian lineages, such as transporter activity and calcium ion binding. I also found that many genes involved with cognitive processes including vocal learning were positively selected in zebra finch. I also found evidence for Hill-Robertson interference acting against the removal of slightly deleterious mutations at linked loci.

Finally, I studied the impact of recombination on genome size variation. I found that highly recombining regions have a more condensed genome structure, including shorter lengths of intron, intergenic spacer, transposable elements and higher gene density. In chicken and zebra finch I found that recombination rate was positively correlated with deletion bias, estimated by sequence comparisons between individual transposable elements (LINEs) and the corresponding master sequences. These observations indicate that the more compact genome structure in highly recombining region is due to a higher rate of sequence loss. Higher deletion bias in autosomes than in sex chromosomes supports this idea. I also found that sequence loss due to the deletion bias can explain nearly 20% of genome size reduction after the split of birds from other reptiles. In human, the recombination rate was positively correlated with the deletion bias estimated from polymorphic indels. These results support the hypothesis that the recombination drives genome contraction via the mutation process.