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Coming dissertations at Uppsala university

  • Multi-Resistance Plasmids : Fitness Costs, Dynamics and Evolution Author: Fredrika Rajer Link: Publication date: 2019-09-05 10:10

    Antibiotic resistance is an escalating problem, not only due to less desirable treatment options and outcome, but also due to the economic burden to health care caused by resistant pathogens. Since the process of developing new antibiotics is slow, we need to carefully consider the usage of the antibiotics still available. Therefore it is of importance to minimize the development and spread of resistant pathogens. To do so, we need a better understanding of the mechanisms and dynamics underlying the evolution of highly resistant bacteria.

    In this thesis I have investigated one of the major drivers of resistance gene dissemination in Gram-negative bacteria, namely multi-resistance plasmids. We show that multi-resistance plasmids display a dynamic behavior in vivo, where genes can be readily acquired and lost again. Additionally, plasmids can be shared amongst different bacteria, especially in environments such as the human gut. Interestingly, some resistance plasmids confer a fitness disadvantage to their host displayed by decreased growth rate in absence of antibiotics. We could elucidate that two resistance genes of the multi-resistance plasmid pUUH239.2 were the cause of the lowered growth rate, namely blaCTX-M-15 and tetR/A. In contrast, other resistance genes on the plasmid were cost-free even when overexpressed and likely enable persistence in the bacterial population even under non-selective conditions. Lastly, we studied how the presence of several β-lactamase genes on a plasmid affects treatment with different combinations of β-lactam/β-lactamase inhibitors. We found that an efficient mechanism for bacteria to overcome high levels of antibiotics was by amplification of plasmid-borne resistance genes. This mechanism works as a stepping-stone for additional mutations giving rise to high-level resistance.

    With this work we provide insight into the mechanisms underlying resistance evolution and dissemination due to multi-resistance plasmids. Plasmids enable fast dissemination of multiple resistance genes and therefore simultaneously disable multiple treatment options. Examining the effects of resistance genes and antibiotics on strains carrying multi-resistance plasmids will enable us to understand what factors assist or inhibit plasmid spread. Hopefully, this will aid us in treatment design to prevent resistance development to effective antibiotics and have implications for resistance surveillance as well as prediction.

  • Olikhetens praktiker : Adlig begravningskultur i Sverige c:a 1630-1680 Author: Alexander Engström Link: Publication date: 2019-09-05 09:17

    This thesis examines how the nobility created status and disparity through funeral culture in 17th century Sweden. There were significant societal changes throughout the century that made it problematic to reach consensus on status. This makes the funeral culture a fitting lens to study noble practices.

    By emphasizing the importance of practice this study moves the perspective from a generally applied view where the subject is considered the master of its surroundings, to one where the subject is dependent on a certain set of material cultures, participants, spaces and sounds in order to create status and difference.

    This study argues that hierarchies like gender, age, noble rank, merit, pedigree and marital status made certain practices available to just some of the nobility. Noble funeral culture was therefore not uniform, meaning that some engaged with prominent funeral practices while some were left with practices that were not dissimilar to those practiced by people lower on the social hierarchy. Men of the higher elite were generally those which received the most spectacular funerals.  Societal changes saw that certain values were changing all across the nobility, where merits for instance rose above noble titles in significance. The increasing need of specific spaces and participants in the funeral culture saw a growing number of urban funerals, particularly in the capital Stockholm. The increasing participants, territorializations and paraphernalia resulted in increasingly articulated social differences, causing discord within the noble community as with the clergy, congregations and urban inhabitants.

    Through a broad and diverse empirical body and a novel theoretical approach around how status was generated, this thesis argues that noble status was not uniform, static nor self-evident, but rather cumulatively created. Practices and the creation of status and disparity were dependent on several mutually corresponding and sometimes shifting hierarchies, as well as a corresponding relationship between materiality, participants, space and sound.

  • Complex disease genetics : Utilising targeted sequencing and homogeneous ancestry Author: Argyri Mathioudaki Link: Publication date: 2019-09-04 15:58

    The complex disease investigations presented in this thesis aimed to provide new information regarding underlying genetics by using targeted sequencing and ethnically homogeneous cohorts. This work moved past current methodologies and addressed data stratification issues, that might have been hindering new findings. The results contribute to a more comprehensive view of the genetics of ankylosing spondylitis (AS) and breast cancer (BC), in Sweden.

    Paper-I presents a sex-stratified analysis of a Swedish AS cohort that incorporated both common and rare variants. Single variant and aggregate tests both showed different signals in AS male and female patients, previously masked. Specifically, the RUNX3 locus in males (univariate test: rs7414934, OR=2.58, p=1.7x10-5) and MICB in females (SKAT: 27 variants, p=1.2x10-6; rs3828903, OR=4.62, p=6.2x10-13) exceeded discovery thresholds. In the functional follow up of these loci, risk alleles appear to regulate the expression of genes in multiple tissues. Also, the results highlight the importance of disease regulation from different haplotypes and loci breakdown proved that Sweden’s genetic architecture might be critical for AS studies.

    Paper-II is a replication study, in our modest-sized Swedish cohort, of AS associations, previously discovered in populations of British origin, Initially, power calculations assessed that the Swedish cohort had the power to replicate only published associated markers with high effect (OR > 7), e.g., HLA-B but the replication analysis revealed three associated loci (ORrange:1.9-2.7). Notably, the multiplicated HLA-B marker (rs4349859) was not in HWE equilibrium. Population structure differences could not explain this replication pattern. However, sequencing resolution revealed fine-scale differences with repositioned association signals in the known loci. Specifically, the identification of two CCHCR1 protective haplotypes (OR: 0.14/0.3) that affect other MHC gene expression through eQTLs, provided the first suggestion of the differential function of known associated loci with cis gene regulation.

    Paper-III provides the first fingerprint of the somatic mutation profile of Swedish BC. The significantly mutated genes were PIK3CA (28%), TP53 (21%) and CDH1 (16%) while histone-modifying genes (e.g., KMT2C and ARID1A: together 28%) exhibited an increased somatic mutation prevalence, not observed previously. Additionally, within the patients that did not receive neoadjuvant treatment, there were distinct age groups with different mutational profiles and differential APOBEC signature driving genes.

    Taken together, these studies emphasize the contribution to the underlying genetics deriving from smaller ethnic populations, when assessed with a shift in methodology to account for biological bias, like sex and age. The results will hopefully assist and guide other genetic studies of human complex disease.