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Coming dissertations at Uppsala university

Please note that the date and time given on these pages is the time of electronic publication, and not the date of the public defense. To find the time and venue of the public defense, please follow the link to DiVA of the thesis in question.
  • Molecular studies of endocrine tumors : Insights from genetics and epigenetics

    Author: Samuel Backman
    Publication date: 2020-11-19 10:25

    Endocrine tumors may be benign or malignant and may occur in any of the hormone producing tissues. They share several biological characteristics, including a low mutation-burden, and may co-occur in several hereditary tumor syndromes. The aim of this thesis was to identify genetic and epigenetic aberrations in endocrine tumors.

    In paper I we performed a comprehensive DNA methylation analysis of 39 pheochromocytomas/paragangliomas as well as 4 normal adrenal medullae on the HumanMethylation27 BeadChip array. We validated two previously described clusters based on DNA methylation with distinct genetic associations.

    In Paper II we performed a transcriptomic analysis of 15 aldosterone producing adenomas. CTNNB1-mutated tumors were found to form a distinct subgroup based on gene expression and to share gene expression similarities with non-aldosterone producing adrenocortical tumors with CTNNB1 mutations, including overexpression of AFF3 and ISM1.

    In paper III we used whole genome sequencing to identify germline genetic variants in 14 patients with Multiple Endocrine Neoplasia type 1 previously found to be wildtype for the MEN1 gene on routine clinical testing. Three patients were found to carry previously undetected MEN1 mutations. Two patients were confirmed to have phenocopies caused by variants affecting CASR or CDC73. In total 9/14 patients were not found to have a disease-causing germline variant, suggesting that the syndrome may in some cases be due to chance co-occurrence of several sporadic tumors.

    In paper IV RNA-Seq and whole genome sequencing of a cohort of SI-NETs selected on the basis of unusually short or long survival was performed in order to identify disease causing genes and potential prognostic factors. We confirmed known genetic aberrations and found rare variants in known cancer driver genes. Based on gene expression two clusters that differ in prognosis were detected. Moreover, through integration of copy number variation data and gene expression, we identied novel potential disease causing genes.

  • Insights into the Effects of Type 2 Diabetes on Bone Health

    Author: Adam Mitchell
    Publication date: 2020-11-19 09:22

    Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of hip fracture, despite a stable or even greater bone mineral density (BMD). Bone area is linked to hip fracture risk independent of BMD and smaller bone area has been reported in T2DM subjects at the radius and tibia, but information at the hip is lacking. The Mediterranean diet is associated with a lower risk of hip fracture yet the mechanisms are unclear. The diet’s effect on T2DM status may be a possible mechanism. This thesis aims to discern the effects fasting glucose levels and T2DM have on bone.

    In paper I, clinical cut offs of fasting glucose used to define T2DM, were used to explore the association with BMD, bone area and bone turnover markers in the Swedish mammography cohort clinical (SMCC) and the Uppsala longitudinal study of adult men (ULSAM). T2DM was associated with greater BMD yet lower bone area at the total hip when compared to those without T2DM. T2DM was also associated with lower levels of bone turnover markers.

    In paper II, a Mendelian randomisation (MR) study was used to assess the potential causal effects of genetically predicted fasting glucose concentrations on bone area and BMD in partici-pants from SMCC, the prospective investigation in the vasculature of Uppsala seniors (PIVUS) and ULSAM. Results suggest an increase in genetically predicted fasting glucose concentrations may be a causal risk factor for lower bone area and possibly greater BMD.

    In paper III, the association between T2DM status and change in bone area and BMD over 8 years, was analysed in the SMCC, PIVUS and ULSAM. Those with incident T2DM had a lesser expansion in bone area at the total hip compared to those without T2DM.

    In paper IV, causal inference mediation analyses were used to estimate the direct effect of Mediterranean diet on the risk of hip fracture and the possible mediating effects of T2DM and BMI in the Swedish mammography cohort (SMC) and the cohort of Swedish men (COSM). Results showed a direct effect of the Mediterranean diet on the risk of hip fracture but ruled out the effects of T2DM and BMI as major mediators.

    In summary, T2DM and fasting glucose were associated with lower bone area at the hip. This may provide important mechanistic evidence as to why those with T2DM have a greater risk of hip fracture. We cannot rule out mediation or counteracting effects but there is an effect of Medi-terranean diet on hip fracture that does not go through T2DM and BMI.

  • Gentrifiktionen : Zur literarischen Verarbeitung der Gentrifizierung in deutschsprachigen Berlin-Romanen nach 2000

    Author: Hanna Henryson
    Publication date: 2020-11-13 13:35

    Since the fall of the Berlin Wall, gentrification has restructured the urban fabric of the German capital profoundly. Although gentrification is one of the most widespread and controversial urban processes in many parts of the world today, literary discourses on gentrification remain under-studied.

    This study investigates literary representations of gentrification in Berlin after 2000. Gentrification is here understood as a gradual transformation of a low-status city district into an (upper) middle-class area, resulting in a degree of indirect or direct displacement of the established lower-status population. The competition between social groups and individual actors to obtain power over urban space is therefore an inherent feature of gentrification.

    The aim of this study is to connect existing sociological research on gentrification with literary analysis of character perspectives on the process. The theoretical framework is therefore derived from narratology as well as sociology, especially Pierre Bourdieu’s research on social inequality. Representations of characters and their (re-)actions when confronted with typical aspects of gentrification such as (the threat of) displacement from their homes are at the center of this interdisciplinary approach.

    The analysis is built around the novels Kress by Aljoscha Brell (2015), Teil der Lösung by Ulrich Peltzer (2007), Der amerikanische Investor by Jan Peter Bremer (2011) and Walpurgistag by Annett Gröschner (2011). Their (main) characters correspond to different actors and stakeholders in the gentrification process: the so-called ‘pioneers’, the potential gentrifiers, the ‘financifiers’ and long-time residents (in some cases recently displaced). This selection of texts enables a discussion of a multitude of perspectives on the possibilities and difficulties facing different gentrification actors.

    One major finding of the analysis is the over-representation of a narrative perspective that belongs to a West German, middle-class creative worker with small financial means but substantial cultural capital. In contrast, perspectives of East Germans, members of the working class or migrants are marginalized. The character constellations of the analyzed gentrification narratives are thus partly standardized and tend to attribute certain roles to the same sets of actors. In a final chapter, these results are also found to apply to many other literary representations of gentrification in Berlin.

  • Engineered temporary networks : Effects of control and temporality on inter-organizational interaction

    Author: Carl Kronlid
    Publication date: 2020-11-12 14:24

    The world is facing a growing threat of antibiotic resistance. The development of new antibiotics is of utmost importance; otherwise, we go back to the pre-antibiotic era where common infections become life-threatening. Despite this need for new antibiotics, a market failure is hampering its development. To mitigate this market failure, policy makers have initiated inter-organizational R&D projects for antibiotic development. These projects involve different actors, are intentionally created, and have clearly defined objectives, as well as duration, for developing new antibiotics. These initiatives can be seen as engineered temporary networks. Engineered temporary networks need to be managed in order to avoid the risk of not reaching the network objectives. Managing these networks is a matter of formally controlling the interaction among the organizations involved in the networks, making sure that the network proceeds toward its objectives. 

    The aim of this thesis is to understand the effects of formal control mechanisms used to engineer a temporary network on inter-organizational interaction, with a special focus on temporality. The thesis uses a case study of ENABLE, an engineered temporary network initiated by the EU to develop a specific set of antibiotics. The formal control mechanisms are identified, including the use of temporality as a formal control mechanism. The effects of the control mechanisms are analyzed on the dyadic and network levels, for example, in terms of e.g., heterogeneity, interdependence, and co-evolution, on the activity, resource, and actor layers in line with the Industrial Marketing and Purchasing (IMP) perspective. The formal control mechanisms are grouped into five categories (mobilization, coordination, cooperation, performance, and temporality), highlighting key aspects of engineered temporary networks to be controlled. The thesis also identifies differences between emergent networks and engineered temporary networks in how interaction is structured and develops over time. In contrast to emergent networks where inter-organizational interaction occurs freely and has agency in organizing and structuring the network, it is formal control that organizes and structures engineered temporary networks, while the agency of interaction is limited. The thesis contributes to the literature on industrial networks and network management, explicitly highlighting the use of formal control and its effects on inter-organizational interaction.

  • Function and morbidity of the esophagus and respiratory system in the growing child with esophageal atresia

    Author: Felipe Donoso
    Publication date: 2020-11-12 13:08

    Background: Esophageal atresia (EA) is a congenital malformation that consists of various degrees of discontinuity of the esophagus and affects about 1:3000 live births. EA is usually corrected at birth with survival rates over 90%, which has shifted the focus towards improvement of associated morbidity and health-related quality of life.

    The aims of this thesis were to investigate how morbidity in the esophagus and respiratory system in children with EA relates with diagnostic and function tests included in the follow-up programme after EA repair and evaluate the efficacy of the recommended proton pump inhibitor (PPI) prophylaxis.

    Methods: The study population consists of 169 children treated for EA in the Department of Pediatric Surgery at University Children’s Hospital, Uppsala between 1994 and 2018. The patients participated in the multidisciplinary follow-up programme that was established in 2011 for patients with EA. The thesis is based on four observational studies that investigated the outcome of the patients and generalisability of the results; risk factors for anastomotic strictures and the efficacy of PPI-treatment regimen in reducing its incidence; pulmonary function and risk factors for pulmonary function impairment; and association between ambulatory 24h pH test, endoscopic findings of esophagitis and hiatal hernia, symptoms of gastroesophageal reflux (GER), and histopathological esophagitis. The studies were approved by the Regional Committee for Medical Research Ethics.

    Results: The demographics and outcome of our study population are comparable with centres of higher caseload, showing low mortality rate but significant morbidity, especially considering anastomotic strictures and patients with long gap EA. Long gap EA, higher birth weight, and anastomotic tension were independent risk factors of anastomotic stricture formation. Prophylactic PPI-treatment did not reduce anastomotic strictures compared with symptomatic PPI-treatment. Respiratory morbidity and obstruction of the airways were common in children and adolescents after EA repair. The risk for pulmonary function impairment increased with lower birth weight and older age at follow-up. Neither ambulatory 24h pH-metry, clinical symptoms of GER nor endoscopic esophagitis were reliable tools to identify histopathological esophagitis in children and adolescents after EA repair and cannot replace esophageal biopsies.

    Conclusion: The poor correlation between clinical symptoms and morbidity of the esophagus and respiratory system justifies the need of clinical follow-up programmes in patients with EA. A general recommendation to stop prophylactic PPI-treatment after EA repair cannot be supported, however, sufficient evidence is available to support randomised controlled studies.

  • Care for the New-Born : Breastfeeding and Skin-to-Skin Contact

    Author: Paola Oras
    Publication date: 2020-11-12 09:29

    Breastfeeding is associated with improved health in mothers and children and human milk is especially beneficial for preterm infants. The vast majority of pregnant women in Sweden intend to breastfeed, but breastfeeding rates are suboptimal, with even lower rates for preterm infants.

    The overall aim of this thesis was to describe breastfeeding patterns of preterm and term infants and to evaluate an intervention based on the Ten steps to successful breastfeeding on breastfeeding outcomes.

    In Paper I, mothers of preterm infants reported large variations in breastfeeding frequencies and patterns. The median breastfeeding frequencies from birth to six months ranged from 10–14 times per 24 hours with the majority practicing on demand breastfeeding.

    In Paper II the median daily duration of skin-to-skin contact in preterm infants during the hospital stay was associated with earlier breastfeeding attainment. Infants commenced full breastfeeding at a median postmenstrual age of 35+0 weeks (range 32+1 to 37+5). Breastfeeding duration was shorter than national statistics.

    Paper III describes the development and implementation of a breastfeeding support program for term and preterm infants using Intervention Mapping. The method was time-consuming, but allowed for a solid theoretical base, high involvement of stakeholders and was sufficiently comprehensive.

    Paper IV included term infants at age two months and their mothers and consisted of a baseline group and intervention group. Mothers reported large variations in breastfeeding frequencies and patterns. Mothers in the intervention group breastfed more frequently, in median 14 times compared to 11 times in the baseline group, and they also practiced on demand breastfeeding to a larger extent. Mothers with exclusive breastfeeding reported higher self -efficacy.

    This thesis provides a better understanding of breastfeeding patterns in preterm and term infants and it demonstrates that breastfeeding frequencies and on demand breastfeeding can be influenced with improved breastfeeding support. For preterm infants, breastfeeding attainment is facilitated by skin-to-skin-contact and they have the capability to breastfeed at a low postmenstrual age. This thesis also demonstrates a possible link between breastfeeding patterns and mothers’ ability to interpret infant cues. Intervention Mapping is a useful tool in the development of breastfeeding support programs.

  • Craniofacial malformations and psychiatric disorders from a neurodevelopmental perspective

    Author: Karin K. Tillman
    Publication date: 2020-11-12 09:09

    Orofacial clefts (OFC) and craniosynostosis (CS) are the two most common craniofacial malformations. Of note, craniofacial abnormalities share some overlapping risk factors with psychiatric disorders. Thus, this thesis aimed to study psychiatric and educational outcomes in this group.

    In study I and III we examined psychiatric outcomes among children with nonsyndromic OFC stratified on cleft lip (CL), cleft lip and palate (CLP), cleft palate only (CPO), unilateral and bilateral CL and CLP. In study II we studied associations between nonsyndromic CS (NSCS) and psychiatric disorders. Study IV assessed national standardised tests in Swedish and mathematics, school grades and university degrees in children with CL, CLP and CPO. Children with craniofacial malformations were identified through the Swedish National Patient Register and compared to a cohort from the general population that was matched for month and year of birth, sex and county of birth. In addition, children with craniofacial malformations were compared to their unaffected siblings.

    Individuals with OFC presented risk increases for intellectual disability, language disorders, psychosis, autism spectrum disorder, attention-deficit/hyperactivity disorder and behavioural disorders in childhood. CPO showed the most robust associations, followed in descending order by CLP and CL. Nonaffected siblings had a lower risk of psychiatric disorders. Females generally had higher risks for psychiatric comorbidity (Study I).

    Children with bilateral clefts had higher risk increases for psychiatric disorders compared to children with unilateral clefts. We also found that females with bilateral CLP showed higher risks for intellectual disability and neurodevelopmental disorders compared to males with bilateral CLP (Study III).

    Risk increases for any psychiatric disorder including intellectual disability, language disorders, other neurodevelopmental disorders and other psychiatric disorders, were seen in individuals with NSCS. In the crude analyses full siblings with NSCS, as compared to nonaffected siblings, were more likely to be diagnosed with any psychiatric disorder, intellectual disability, language disorders and other neurodevelopmental disorders. The higher risk for any psychiatric disorder and intellectual disability remained after adjusting for confounders. Females displayed borderline higher risk increases than males (Study II).

    Finally, children with OFC had lower school performance almost throughout the educational years, especially in mathematics. Lower academic achievement was most evident in children with OFC without a concurrent psychiatric disorder. In the ninth school year and upper secondary school female academic outcomes were more negatively affected than male academic outcomes (Study IV).

    In summary, craniofacial malformations were associated with increased risks for multiple psychiatric disorders and lower academic achievement.

  • Understanding Neural Machine Translation : An investigation into linguistic phenomena and attention mechanisms

    Author: Gongbo Tang
    Publication date: 2020-11-11 13:01

    In this thesis, I explore neural machine translation (NMT) models via targeted investigation of various linguistic phenomena and thorough exploration of the internal structure of NMT models, in particular the attention mechanism. With respect to linguistic phenomena, I explore the ability of NMT models to translate ambiguous words, to learn long-range dependencies, to learn morphology, and to translate negation—linguistic phenomena that have been challenging for the older paradigm of statistical machine translation. I find that morphological inflection and negation are better modeled in encoder hidden states, while the senses of ambiguous words are better learned in decoder hidden states. Hidden states from lower layers are better at capturing aspects of form, such as morphological inflections and negation cues, while hidden states from higher layers are better at capturing semantic and relational aspects, such as word senses, negation events, and negation scope. I conclude that NMT models learn linguistic knowledge in a bottom-up manner. In the final part of the thesis, I interpret attention mechanisms in encoder-free models and character-level models. I show that attending to word embeddings directly does not make attention mechanisms more alignment-like but instead demonstrates that the attention mechanism is adaptable and more important for NMT than encoders. In character-level models, all characters attract equal attention except the final separators. Overall, the ability of NMT models to deal with the studied linguistic phenomena gets stronger with the evolution of architectures. NMT models perform well in translating frequent ambiguous words and learning long-range dependencies, but still suffer from morphological errors and the under-translation of negation. Attention mechanisms are crucial and adaptable, and there is no uniform behavior in different settings.

  • Computational Ecotoxicology

    Author: Sergio Manzetti
    Publication date: 2020-11-09 13:09

    Human society has progressed by polluting ecosystems since the early industrial revolution. Thus, large amounts of harmful chemical compounds have been dispersed in soils, seas, groundwaters and wildlife habitats, leading to a persistent toxicological load on the environment. Pollution is a threat to biodiversity, to the health of ecosystems, and to all living organisms. Advances in environmental sciences are needed so that pollutants can be distinguished from harmless compounds. New methods could ease the enormous task of sorting out hazardous chemicals and also facilitate the study of existing problems in toxicology, which are often hampered by insufficient data. In our research, we apply several methods in computational chemistry to predict the interactions of various toxins, carcinogens, nanoparticles and xenobiotics with proteins, DNA, and cell membranes. Methods such as molecular dynamics simulations, docking, partition coefficient- and quantum chemistry-calculations are at the core of these studies, each having its role in facilitating the enormous task of transforming in vitro toxicology to in silico toxicology. We perform detailed studies of a few compounds and receptors as well as larger, more inclusive groups of compounds. We also outline approaches for drawing computational conclusions about the molecular behavior of various potential environmental toxins by modeling their interactions with DNA and proteins, and we use partition coefficients to describe their ability to permeate the cell membrane. Methods for studying the purification of pollutants from essential sources, such as water, are proposed. We also investigate the emerging problem of nanoparticle pollution and propose computational approaches to model the formation of nanoparticles from combustion emissions and the interactions of such particles with atmospheric components.

  • Theoretical Investigations of Two-Dimensional Materials : Studies on Electronic, Magnetic, Mechanical, and Thermal Properties

    Author: Xin Chen
    Publication date: 2020-11-09 07:50

    Two-dimensional (2D) materials have been paid enormous attention since the first realization of graphene in 2004, in connection to high-speed flexible electronics, 2D magnetism, optoelectronics, and so on. Apart from graphene, many new 2D materials with special properties have been predicted and synthesized. For the understanding of several interesting phenomena and prediction of new 2D materials, materials-specific density functional theory (DFT) plays a very important role.

    In this thesis, based on first-principles calculations, structural, magnetic, electronic, mechanical, and thermal transport properties of two kinds of 2D systems are investigated.

    The first kind of 2D materials is based on the synthesized material or the predicted structure with ultralow energy. These materials were functionalized by adsorbing transition metal atoms or oxygen atoms, which makes a significant difference in the properties. A part of the thesis covers the study of the self-assembly process of 3d transition metal hexamers on graphene with different defects. Interestingly, it is found that the easy axis of magnetization can be tuned between in-plane and out-of-plane directions in the presence of an external electric field. The second subsection is the oxygen functionalized form of 2D honeycomb and zigzag dumbbell silicene. Interestingly, both the structures are Dirac semimetal.

    The other kind of 2D materials discussed in this thesis are new materials which were never reported before. Starting from a global structure search, we predicted several structures with ultrahigh stability and novel properties. One work is about a new allotrope of graphene, namely PAI-graphene. It is a new structural motif, which is energetically very close to graphene with interesting properties. PAI-graphene is a semimetal with distorted Dirac cones. By applying tensile strain, three different topological phases can be achieved. The second subsection is the work about new 2D structural forms of A2B (A=Cu, Ag, Au, and B=S, Se). Our obtained square-A2B (s-A2B) structures are energetically more favored than all the reported 2D structures for A2B. s-A2B structures are direct bandgap semiconductors with high carrier mobilities. All the s-A2B structures have unusually low lattice thermal conductivities. Moreover, s-A2B monolayers have ultra-low Young’s moduli and in-plane negative Poisson’s ratios. The third work is about the phase transition in s-A2B monolayers. We proposed two new s-A2B structure, s(I)- and s(II)-Au2Te. S(I)-Au2Te is an auxetic direct-gap semiconductor, while s(II)-Au2Te is a topological insulator. By applying strain or using thermal means, we can achieve a structural phase transition between the two phases.