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  • Public defence: 2016-10-06 10:00 KB3A9, Umeå
    Norén Lindbäck, Louise
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Norén Lindbäck, Louise
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Coordination of two different genomes in response to light and stress2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    About 1.5 billion years ago, a photosynthetic bacteria was engulfed by a eukaryotic cell which initiated a symbiotic relationship and the evolution of the chloroplast as we know it today. The chloroplast has retained its own genome encoding for a number of proteins required for the function of the chloroplast. However, during the evolution most genes were transferred to the nucleus and the chloroplast is thus dependent on the nucleus to provide the majority of proteins necessary for its function. The distribution of genes encoding plastid proteins between two different cellular compartments requires a tight communication in order to coordinate gene expression during different growth conditions. The focus of my PhD studies has been to elucidate signalling pathways between the chloroplast and nucleus that enables the coordination of these two genomes in response to light and stress. The results in this thesis demonstrate that chloroplast retrograde signals triggered by changes in tetrapyrrole levels are important both in response to day-night cycles and during the response to stress. We identified a cytosolic regulatory complex and a novel mechanism that could explain how the tetrapyrrole-mediated signal can be transduced from the plastid to the nucleus and regulate nuclear gene expression in response to changes in the environment. My work further demonstrates that the tetrapyrrole-triggered plastid signalling pathway integrates with the circadian clock in order to fine-tune nuclear gene expression during photoperiodic conditions. These findings provide novel insight into how clock components and plastid signals converge in order to obtain the proper output. I have also examined the regulation of nuclear gene expression in response to redox and early-light signals by identifying transcription factors responding to these signals. My work demonstrates a novel mechanism by which redox-regulation of specific transcription factors directly links cellular redox status to gene regulation. The identified transcription factors were further shown to regulate nuclear genes encoding plastid proteins and they are of particular importance for anterograde control during the early light response and establishment of photomorphogenic growth.

  • Public defence: 2016-10-07 09:00 Sal 135, Allmänmedicin NUS, Umeå
    Randell, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Randell, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Adolescent boys’ health: managing emotions, masculinities and  subjective social status2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The health of adolescent boys is complex and surprisingly little is known about how adolescent boys perceive, conceptualise and experience their health. Thus, the overall aim of this thesis was to explore adolescent boys’ perceptions and experiences of health, emotions, masculinity and subjective social status (SSS).

    This thesis consists of a qualitative, a quantitative and a mixed methods study. The qualitative study aimed to explore how adolescent boys understand the concept of health and what they find important for its achievement. Furthermore, the adolescent boys’ views of masculinity, emotion management and their potential effects on wellbeing were explored. For this purpose, individual interviews were conducted with 33 adolescent boys aged 16-17 years. The quantitative study aimed to investigate the associations between pride, shame and health in adolescence. Data were collected through a cross-sectional postal survey with 705 adolescents. The purpose of the mixed methods study was to investigate associations between SSS in school, socioeconomic status (SES) and self-rated health (SRH), and to explore the concept of SSS in school. Cross-sectional data were combined with interview data in which the meaning of SSS was further explored. Individual interviews with 35 adolescents aged 17-18 years were conducted.

    In the qualitative study, data were analysed using Grounded Theory. In the quantitative study, statistical analyses (e.g., chi-square test and uni- and multivariable logistic regression analyses) were performed. In the mixed method study, a combination of statistical analyses and thematic network analysis was applied.

    The results showed that there was a complexity in how the adolescent boys viewed, experienced, dealt with and valued health. On a conceptual level, they perceived health as holistic but when dealing with difficult emotions, they were prone to separate the body from the mind. Thus, the adolescent boys experienced a difference between health as a concept and health as an experience (paper I). Concerning emotional orientation in masculinity, two main categories of masculine conceptions were identified: a gender-normative masculinity and a non-gender-normative masculinity (paper II). Gender-normative masculinity comprised two seemingly opposite emotional masculinity orientations, one towards toughness and the other towards sensitivity, both of which were highly influenced by contextual and situational group norms and demands, despite that their expressions are in contrast to each other. Non-gender-normative masculinity included an orientation towards sincerity, emphasising the personal values of the boys. Emotions were expressed more independently of peer group norms. The findings suggest that different masculinities and the expression of emotions are intricately intertwined and that managing emotions is vital for wellbeing. The present findings also showed that both shame and pride were significantly associated with SRH, and furthermore, that there seems to be a protective effect of experiencing pride for health (paper III). The results also demonstrated that SSS is strongly related to SRH, and high SRH is related to high SSS, and further that the positioning was done in a gendered space (paper IV).

    Results from all studies suggest that the emotional and relational aspects, as well as perceived SSS, were strongly related to SRH. Positive emotions, trustful relationships and having a sense of belonging were important factors for health and pride was an important emotion protecting health. Physical health, on the other hand, had a more subordinated value, but the body was experienced as an important tool to achieve health. Even though health was mainly perceived in a holistic manner by the boys, there were boys who were prone to dichotomise the health experience into a mind-body dualism when having to deal with difficult emotions.

    In conclusion, this thesis demonstrates that young, masculine health is largely experienced through emotions and relationships between individuals and their contexts affected by gendered practices. Health is to feel and function well in mind and body and to have trusting relationships. The results support theories on health as a social construction of interconnected processes. Having confidence in self-esteem, access to trustful relationships and the courage to resist traditional masculine norms while still reinforcing and maintaining social status are all conducive to good health. Researchers as well as professionals need to consider the complexity of adolescent boys’ health in which norms, values, relationships and gender form its social determinants. Those working with young boys should encourage them to integrate physical, social and emotional aspects of health into an interconnected and holistic experience.

  • Public defence: 2016-10-07 09:00 E04, byggnad 6A, Umeå
    Vonderstein, Kirstin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Vonderstein, Kirstin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Viperin vs. tick-borne encephalitis virus: mechanism of a potent antiviral protein2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Tick-borne encephalitis virus (TBEV) is a very important virus medically, causing mild or severe encephalitis often with long-lasting sequelae. Treatment of tick-borne encephalitis is limited to supportive care, and antiviral drugs are much needed.

    The type-I interferon (IFN) system is the first line of host defense against many viruses. Infected cells secrete type-I IFN to alert neighboring cells. These cells in turn upregulate the expression of antiviral proteins to protect themselves from the virus.

    In this work, we found that the interferon-induced host protein viperin (virus-inhibitory protein, endoplasmic reticulum-associated, interferon-inducible) has a pronounced antiviral effect against TBEV.

     

    Viperin is an evolutionarily conserved protein with three domains: the N-terminus, the radical S-adenosyl methionine (SAM) domain, and the C-terminus. Viperin shows antiviral activity against a broad spectrum of different viruses. However, its mode of action appears to be virus-specific.

    We therefore concentrated on determining the antiviral mechanism of viperin against TBEV. The specific questions addressed in this thesis are: (1) which steps of the TBEV infectious cycle are targeted by viperin?, (2) which domains of viperin are responsible for its antiviral activity?, and (3) which interaction partners does viperin need in order to have an antiviral effect against TBEV?

    First, we investigated which step(s) of the TBEV life cycle viperin targets by using several assays to examine the effects of viperin on virus binding, entry, genome replication, assembly, and release.

    We found that viperin inhibited the replication of positive-sense genomic RNA and also targeted particle release, selectively enhancing the release of membrane-associated capsid particles.

    For inhibition of genome replication, viperin was dependent on the host cellular protein CIAO1 (cytosolic iron-sulfur assembly component 1). CIAO1 interacted with the C-terminus of viperin and was necessary for the maturation and stability of viperin, and also for loading of an iron-sulfur cluster onto the SAM domain. The SAM domain required this iron-sulfur cluster to perform its function as a radical SAM enzyme, which was required for the inhibition of TBEV genome replication. In addition to the SAM domain and the C-terminus, viperin needed its N-terminus in order to be fully antivirally active during late replication, since the N-terminus directed viperin to the endoplasmic reticulum, where genome replication takes place.

    Furthermore, viperin targeted GBF1 (Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1), a host protein known to be involved in the secretory pathway. Interaction between the N-terminus of viperin and GBF1 appeared to induce an enhance release of capsid particles independently of the later steps of the classical secretory pathway. The enhanced secretion of capsid particles by viperin occurred at the expense of whole, infectious virions and is therefore a completely novel antiviral mechanism.

     

    In summary, this work identified viperin as a very strong inhibitor of TBEV, and its antiviral mechanism was characterized in detail. Viperin was found to target multiple steps in the TBEV infectious cycle by both inhibiting viral RNA replication and inducing secretion of capsid particles. These findings provide new insights into the interplay between TBEV and viperin, and offer new approaches to our understanding of the molecular and cellular mechanisms of TBEV infection, which may contribute to the development of a treatment for TBEV.

    The full text will be freely available from 2017-10-07 23:31
  • Public defence: 2016-10-07 10:00 KB3B1, Umeå
    Zhang, Jin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Zhang, Jin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    In silico Identification of Thyroid Disrupting Chemicals: among industrial chemicals and household dust contaminants2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Thyroid disruptions by xenobiotics have been associated with a broad spectrum of severe adverse human health effects, such as impaired brain development and metabolic syndrome. Ingestion of indoor dust and contact with industrial chemicals are two significant human exposure routes of thyroid hormone disrupting chemicals (THDCs), raising serious concerns for human health. However, it is a laborious and costly process to identify THDCs using conventional experimental methods, due to the number of chemicals in commerce and the varieties of potential disruption mechanisms.

    In this thesis, we are aimed at in silico identification of novel THDCs targeting transthyretin (TTR) and thyroid hormone receptor (THR) among dust contaminants and commonly used industrial chemicals. In vitro assays were used to validate the in silico prediction results. Co-crystallization and molecular dynamics (MD) simulations were applied to reveal binding modes of THDCs at the studied biological targets and to explain their intermolecular recognition.

    The main findings presented in this thesis are:

    1. Over 144 environmental pollutants have been confirmed as TTR-binders in vitro and these cover a wide range of environmental pollutants and show distinct chemical profiles including a large group of halogenated aromatic compounds and a second group of per- and polyfluoroalkyl substances. (Paper I)

    2. In total 485 organic contaminants have been reported to be detected in household dust. The developed QSAR classification model predicted 7.6% of these dust contaminants and 53.1% of their metabolites as potential TTR-binders, which emphasizes the importance of metabolic bioactivation. After in vitro validation, four novel TTR binders with IC50 ≤ 10 µM were identified, i.e. perfluoroheptanesulfonic acid, 2,4,2',4'-tetrahydroxybenzophenone (BP2), 2,4,5-trichlorophenoxyacetic acid, and 3,5,6-trichloro-2-pyridinol. (Paper II)

    3. The development of a robust structure-based virtual screening (VS) protocol resulted in the prediction of 31 dust contaminants as potential binders to THRβ1 including musk compounds, PFASs, and bisphenol A derivatives. The in vitro experiments confirmed four compounds as weak binders to THRβ1, i.e. 2,4,5-trichlorophenoxyacetic acid, bisphenol A (3-chloro-2-hydroxypropyl) (2,3-dihydroxypropyl) ether, 2,4,2',4'-tetrahydroxybenzophenone, and 2,4-dichlorophenoxyacetic acid. (Paper III)

    4. We revealed the binding conformations of perfluorooctanesulfonic acid, perfluorooctanoic acid, and BP2 in the thyroxine binding sites (TBSs) of TTR by co-crystallizing TTR with the three compounds. A VS protocol was developed based on the TTR complex structures that predicted 192 industrial chemicals as potential binders to TTR. Seven novel TTR binders were confirmed by in vitro experiments including clonixin, 2,6-dinitro-p-cresol (DNPC), triclopyr, fluroxypyr, bisphenol S, picloram, and mesotrione. We further co-crystallized TTR with PBS, clonixin, DNPC, and triclopyr, and their complex structures showed that the compounds bind in the TBSs as proposed by the VS protocol.

    In summary, 13 indoor dust contaminants and industrial chemicals were identified as THDCs using a combination of in silico and in vitro approaches. To the best of our knowledge, none of these compounds has previously been reported to bind to TTR or THR. The identifications of these THDCs improve our understanding on the structure-activity relationships of THDCs. The crystal structures of TTR-THDC complexes and the information on THDC-Target intermolecular interactions provide a better understanding on the mechanism-of-actions behind thyroid disruption. The dataset compiled and in silico methods developed serve as a basis for identification of more diverse THDCs in the future and a tool for guiding de novo design of safer replacements.

  • Public defence: 2016-10-07 10:00 BT102, Umeå
    Björk, Stefan
    Umeå University, Faculty of Social Sciences, Department of Psychology. Umeå University, Faculty of Social Sciences, Umeå Centre for Gender Studies (UCGS).
    Björk, Stefan
    Umeå University, Faculty of Social Sciences, Department of Psychology. Umeå University, Faculty of Social Sciences, Umeå Centre for Gender Studies (UCGS).
    Män möter mödravård: om betydelsen av "vi" i mötet med mödrahälsovård, förlossningsvård och BB-vård2016Doctoral thesis, monograph (Other academic)
    Abstract [en]

    In contemporary Sweden it is a matter of course that prospective fathers should be involved in pregnancy, childbirth and care of the newborn. Most fathers are present at the visits to the antenatal clinic, including the ultrasound examination; they participate in parental education classes; and they are present at the birth of their child. Yet many fathers express dissatisfaction with prenatal care, delivery care and postnatal care: they frequently feel excluded, invisible and irrelevant. This study is an attempt to better understand those experiences of exclusion, invisibility and irrelevancy.

    The study is based on interviews with ten Swedish fathers. Their narratives about their encounter with prenatal, delivery and postnatal care were analysed with a phenomenological--hermeneutic narrative approach. Special attention was paid to the way the major characters were positioned in the father's narratives.

    The results can be summarised in three points: (1) The strong focus in health care on the physical aspects of pregnancy and childbirth may make it difficult for prospective and new fathers to find a meaningful position in the encounter with prenatal, delivery and postnatal care. (2) The narratives of the interviewed fathers can be roughly divided into "we"-narratives where the father found an untroubled position and "I"-narratives where he didn't. I take this to mean that the fathers sought a "we"-position where pregnancy and childbirth could become a joint concern for the mother and the father. (3) The difficulty of finding an untroubled position in the encounter with prenatal, delivery and postnatal care is first and foremost a consequence of the fact that the prospective/new father is not pregnant, not of the fact that he is a man. It is whether the body is pregnant or not that matters, not the sex category to which the body belongs. The desired "we"-position can therefore be characterised as gender irrelevant.

    One conclusion is that for prenatal, delivery, and postnatal care to truly involve the expectant mother's partner in pregnancy, childbirth and care of the newborn, they need to seriously consider the question of how they can help the prospective mother's partner to find a position that better includes him/her in this encounter. One possibility is the "we"-position that this study emphasizes. This is a position in which pregnancy, childbirth and care of the newborn is a joint concern for both parents. Making way for a "we"-position also means widening the time perspective from the here-and-now of pregnancy, beyond the approaching childbirth to what comes next: parenthood -- no matter who was pregnant.

  • Public defence: 2016-10-07 13:00 s205, Umeå
    Abrahamsson, Jan
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Business Administration.
    Abrahamsson, Jan
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Business Administration.
    Beyond Going Global: Essays on business development of International New Ventures past early internationalization2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The notion of International New Ventures, or INVs, emerged in academia in the early-to-mid 1990s and generally refers to entrepreneurial firms that tend to internationalize very early in their life-cycle, and whose expansion into foreign markets occurs much more quickly than predicted by earlier theories of the incremental internationalization process. Previous literature proposes effective networking with market partners and, more recently, internationally viable business model among key distinguishing features of INVs that allow for such early and rapid entry into international markets. Nevertheless, little is yet known regarding how these younger firms develop over time and how they could sustain international growth. With the purpose of filling this gap, this doctoral dissertation scrutinizes business models and business model innovation of INVs beyond their early internationalization, with a particular emphasis on INVs’ external relationships configurations.

     

    The dissertation consists of four self-contained essays that represent a methodological mixture of qualitative and quantitative approaches and incorporate longitudinal case studies, surveys and register-based data encompassing nine years of Swedish INVs’ development. The findings highlight the importance of the business model as an initial market entry tool, and of business model innovation as a potential growth vehicle over time. Findings also display that INVs work with a broader range of external partners compared to other firms for innovative purposes, and that INVs have different business model innovation patterns compared to other types of internationalized firms. Moreover, INVs focus more heavily on value capture innovations in their business models as they mature and seek to obtain a more centralized position in their industry ecosystem by re-configuring the parameters of existing external relationships or developing new ones.

     

    Overall, this dissertation contributes to the international entrepreneurship and business model literature by explicating how maturing INVs need to operate under different business model configurations as compared to emerging INVs, as the original business model might lack scalability after a certain point in time. Furthermore, the dissertation suggests how INVs can pursue a dynamic business model approach and utilize dynamic capabilities to design business models that put the focal firm more in control of the surrounding ecosystem, and reduce constraints that can limit the value capturing potential and thus the growth and development of INVs.

  • Public defence: 2016-10-10 10:00 N450, Umeå
    von Sydow, Lotta
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    von Sydow, Lotta
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Characterization of auxiliary membrane proteins in the chloroplast of Arabidopsis thaliana2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In nature, sessile plants have to adapt to their environment and to the never ending changes they are exposed to. They do so mainly by proteomic and metabolomic changes. In all cells, there are complex networks of auxiliary proteins that are responsible for quality control of all the cell's proteins. The auxiliary proteins are divided into chaperones and proteases, and these are further separated into different groups. Chaperones help other proteins in terms of stability and folding. In order for a protein to achieve its function, the three-dimensional structure has to be precise. A protease is a helper protein that is able to break peptide bonds in a process termed proteolysis. Chaperones and proteases can work independently, but sometimes the chaperone unfolds the substrate of the protease to ensure full degradation of the protein. In some cases, the chaperone and the protease functions are combined in one protein.

    All proteins studied within this thesis are localized in the chloroplast, the organelle that originated from cyanobacteria, in which plants and algae convert the energy from sunlight into carbohydrates in the process called photosynthesis. Molecular oxygen is released as a by-product, and carbon dioxide is consumed. Photosystem II (PSII), one of the major protein complexes involved in photosynthesis, consists of more than 30 protein subunits, where around half of them are termed low molecular weight (LMW) proteins with a molecular size less than 10 kDa. In this thesis, data identifying one PSII LMW protein, PsbY, as a chaperone for the PSII subcomplex Cytochrome b559 are presented. In the absence of PsbY, Arabidopsis plants were more sensitive to photoinhibition, and the protective circular electron transport around PSII is completely blocked.

    Data on members of the Filamentation temperature sensitive protein H (FtsH) protease family are also discussed, with a focus on FtsH11 and FtsHi1-i5. Members of the FtsH protease family carry a protease domain and a chaperone domain. Our data show that FtsH11 has an influence on the structure and function of chloroplasts of Arabidopsis plants grown under continuous light along with protein import into the same. FtsHi1-5 are five members with mutations within the proteolytic motif, most probably rendering them proteolytically inactive, hence they are referred to as ''inactive FtsH proteases''. Knock-out plants of the inactive members are embryo lethal, and knock-down plants grow slower than wild type, probably because of an affected level of plastid proteins at the translational level.

  • Public defence: 2016-10-11 09:00 hörsal E04, Umeå
    Yang, Hairu
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Yang, Hairu
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Drosophila skeletal muscles regulate the cellular immune response against wasp infection2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Drosophila melanogaster is widely used as a model organism to study the innate immune system because it lacks an adaptive immune response that could mask its innate immune response. The innate immune response of Drosophila primarily consists of humoral and cellular immune responses. The humoral immune response ismediated by antimicrobial peptides, and is induced by bacterial and fungal infections. The cellular immune response is mediated by blood cells (hemocytes), and is induced by bacterial and wasp infection. While the humoral immune response of Drosophila has been studied extensively, the cellular immune response is less well understood.

    In this work, I investigated the communication between different signaling pathways and tissues in Drosophila during infection by the parasitic wasp Leptopilina boulardi. I find that JAK/STAT signaling is strongly activated by wasp infection, in both hemocytes and (unexpectedly) larval skeletal muscles. This activation is mediated by the cytokines Upd2 and Upd3, which are secreted from circulating hemocytes. Deletion of upd2 or/and upd3 weakens the wasp-induced activation of JAK/STAT signaling in skeletal muscles and the cellular immune response to wasp infection, leading to reduced encapsulation of wasp eggs and a decrease in the number of circulating lamelloyctes. The suppression of JAK/STAT signaling also significantly weakens the cellular immune response in skeletal muscles, but not in fat bodies and hemocytes. However, the activation of this signaling in skeletal muscles has no obvious effect on the cellular immune response. Together, these results suggest that rather than being uninvolved bystanders, Drosophila skeletal musclesactively participate in cellular immune responses against wasp infection.

    To answer how Drosophila larval muscles participate cellular immune response, I min-screened the effects of several immune related signaling pathways in the muscles and the fat body on the cellular immune response. Interestingly, the cellular immune response was only significantly compromised by the suppression ofinsulin signaling in skeletal muscles, in a way that was veryreminiscent of the phenotypes induced by suppressing JAK/STAT signaling in muscles. While wasp infection activates JAK/STAT signaling in muscles, it has the opposite effect on insulin signaling. In addition, I find that insulin signaling in skeletal muscles can positively regulate JAK/STAT signaling. On the other hand, suppression of JAK/STAT signaling in muscles reduces insulin signaling locally in muscles and systemically in the fat body. Suppression of either insulin or JAK/STAT signaling in muscles leads to reductions in glycogen storage in muscles, the trehalose concentration in the hemolymph, and the frequency of feeding behavior. All these results indicate that JAK/STAT and insulin signaling in Drosophila skeletal muscles regulate cellular immune responses via their effects on carbohydrate metabolism. Our findings shed new light on the interactions between diabetes, metabolism, the immune system, and tissue communication.

  • Public defence: 2016-10-11 10:00 KB3B1 (Stora Hörsalen), Umeå
    Erik, Edlund
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Erik, Edlund
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Regulatory Control of Autumn Senescence in Populus tremula2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Autumn senescence is a visually spectacular phenomenon in which trees prepare for the oncoming winter. The mechanism for regulation of autumn senescence in trees has been very hard to pinpoint. In this thesis the main focus is to investigate how autumn senescence is regulated in aspens (Populus tremula).

    Previous work has established that autumn senescence in aspens is under daylight control, in this thesis the metabolic status and the effect on autumn senescence was investigated. The metabolic status was altered by girdling which leads to accumulation of photosynthates in the canopy. This resulted in an earlier onset of senescence but also the speed of senescence was changed. At the onset of senescence the girdled trees also accumulated or retained anthocyanins.

    The nitrogen status of aspens during autumn senescence was also investigated, we found that high doses of fertilization could significantly delay the onset of senescence. The effects of various nitrogen forms was investigated by delivering organic and inorganic nitrogen through a precision fertilization delivery system that could inject solutes directly into the xylem of the mature aspens. The study showed that addition of nitrate delayed senescence, addition of arginine did not have any effect on the autumn senescence in aspens, and furthermore the nitrate altered the trees leaf metabolism that was more profound in high dosages of supplied nitrate. 

    Cytokinins are plant hormones believed to delay or block senescence, studies have suggested that the decrease of cytokinins and/or cytokinin signalling may precede senescence in some plants. To investigate how cytokinin regulates autumn senescence in aspens we profiled 34 cytokinin types in a free growing mature aspen. The study begun before autumn senescence was initiated and ended with the shedding of the leaves, and spanned three consecutive years. The study showed that the individual cytokinin profiles varied significantly between the years, this despite that senescence was initiated at the same time each year. Senescence was furthermore not connected to the depletion of either active or total cytokinins levels. The gene pattern of genes known to be associated with cytokinin was also studied, but no gene expression pattern that the profile generated could explain the onset of senescence. These results suggest that the depletion of cytokinins is unlikely to explain the tightly regulated onset of autumn leaf senescence in aspen.

  • Public defence: 2016-10-13 09:00 N200, Umeå
    Tükenmez, Hasan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Tükenmez, Hasan
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Influence of wobble uridine modifications on eukaryotic translation2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Elongator is a conserved six subunit protein (Elp1p-Elp6p) complex that is required for the formation of ncm5 and mcm5 side chains at wobble uridines in transfer RNAs (tRNAs). Moreover, loss-of-function mutations in any gene encoding an Elongator subunit results in translational defects and a multitude of phenotypic effects. This thesis is based on investigations of effects of wobble uridine modifications on translation.

    In Saccharomyces cerevisiae, ncm5U34-, mcm5U34- and mcm5s2U34- modified wobble nucleosides in tRNAs are important for proper codonanticodon interactions. My colleagues and I (hereafter we) showed that mcm5 and s2 groups at wobble uridine in tRNAs are vital for maintaining the reading frame during translation, as absence of these modifications increases the frequency of +1 frameshifting. We also showed that +1 frameshifting events at lysine AAA codons in Elongator mutants are due to slow entry of the hypomodified tRNA Lyss2UUU to the ribosomal A-site.

    Ixr1p is a protein that plays a key role in increasing production of deoxynucleotides (dNTPs) in responses to DNA damage, via induction of Ribonucleotide reductase 1 (Rnr1p), in S. cerevisiae. We showed that expression of Ixr1p is reduced in elp3Δ mutants due to a post-transcriptional defect, which results in lower levels of Rnr1p in responses to DNA damage. Collectively, these results suggest that high sensitivity of Elongator mutants to DNA damaging agents might be partially due to reductions in Ixr1p expression and hence Rnr1p levels.

    Elongator mutant phenotypes are linked to several cellular processes. To probe the mechanisms involved we investigated the metabolic perturbations associated with absence of a functional ELP3 gene in S. cerevisiae. We found that its absence results in widespread metabolic perturbations under both optimal (30°C) and semi-permissive (34°C) growth conditions. We also found that changes in levels of certain metabolites (but not others) were ameliorated by elevated levels of hypomodified tRNAs, suggesting that amelioration of perturbations of these metabolites might be sufficient for suppression of the Elongator mutant phenotypes.

    A mutation in the IKBKAP (hELP1) gene results in lower levels of the full-length hELP1 protein, which causes a neurodegenerative disease in humans called familial dysautonomia (FD). We showed that the levels of mcm5s2U-modified wobble nucleoside in tRNAs are lower in both brain tissues and fibroblast cell lines derived from FD patients than in corresponding materials derived from healthy individuals. This suggests that FD may result from inefficient translation due to partial loss of mcm5s2U-modified nucleosides in tRNAs.

  • Public defence: 2016-10-14 10:00 Hörsal 1031, Norra Beteendevetarhuset, Umeå
    Bergman, Bengt
    Umeå University, Faculty of Social Sciences, Department of Education.
    Bergman, Bengt
    Umeå University, Faculty of Social Sciences, Department of Education.
    Poliser som utbildar poliser: Reflexivitet, meningsskapande och professionell utveckling2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This compilation thesis concerns how an educator task in Swedish police education context can be understood as individual and collective meaning making and professional development. The main actors in this thesis are police teachers, police supervisors and field training officers (FTOs), and they have a mutual task in educating new police officers and hence preparing for a complex occupation. However, due to varied educating preparations these three groups of police educators seem to perform their task with different prerequisites in a constantly revised and developed Swedish police education. During the last twenty years research and literature regarding occupational and professional education concern, among other issues, professional development and professionalization, frequently from a learner orientated and lifelong learning perspective. Hence, as ideas of transferring occupational knowledge from person to person increasingly appears to be regarded as obsolete, internship education through supervising pedagogies seems to have evolved during the last decades. The rarely investigated intra-professional educators (e.g., police officers educating new police officers) have an important role in this kind of learning process, especially due to socialisation phenomena frequently described in worldwide research regarding the police occupation. The conceptions of Swedish intra-professional police educators are investigated through an exploratory and qualitative design using mainly focus-group interviews and with a reflexive approach and hermeneutic analyse models. Viewed through a theoretical framework based on meaning making, reflexivity and thought styles/thought collectives, the findings disclose that the Swedish police educators clearly share similar views on pedagogies although they have disparate preparations before the task. Their conceptions reveal how the police educating task works as an incentive for increased insights in the police task, as well as in the educating task. These findings are also conceptualized as a collective process in interacting with police students and police probationers, with reflexivity as a main tool for meaning making, especially in the educating task. In conclusion this thesis argues how the conceptions of the Swedish police educators can vitalize the discussion about how police educators better can be prepared, especially through courses with reflexive pedagogies. The conclusion also emphasizes on how the positive, reflexive and creative intentions within the intra-professional police educators can be used as a role model and as an incentive in developing the Swedish police force, and that these ideas can be applied on other occupations and professions.

  • Public defence: 2016-10-14 14:00 Lilla Hörsalen (KB3A9), KBC-huset, Umeå
    Holmgren, Marie
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Holmgren, Marie
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Trametes versicolor as biodegrader and biocatalyst when using lignocellulose for ethanol production2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Energy consumption has increased rapidly during the last century due to population growth and greater industrialization. Lignocellulosic-based biofuels are being developed as alternatives to fossil fuels. For many years the question of how 5-carbon sugars in biomass are utilized in nature has been a vexed one. A patent by Sellstedt and Holmgren (2005) showed increased ethanol production, compared with fermentation using only Saccharomyces cerevisiae, through the use of a fungal mix from a degraded wood sample found in a forest.

    The aim of the work presented in this thesis was to find a fungus that naturally utilizes 5-carbon sugars and metabolizes these sugars to ethanol; elucidate the capacity of this fungus to utilize 5-carbon and 6-carbon sugars simultaneously; assess the ability of the fungus to metabolize the inhibitors produced when lignocellulose is used; and find out whether this fungus could be used for biological pretreatment of lignocellulose to replace industrially produced enzymes.

    The results showed that the fungal mix grew well on glucose, xylose, hemicellulose and cellulose. In addition, we were able to identify the fungi present, by using PCR-amplification and sequencing of DNA, as Chalara parvispora, Xylaria sp and Trametes hirsutaTrametes versicolor. In a reconstitution study, the fungi so identified were shown to produce an amount of ethanol equal to that of the fungal mix. We were also able to show that C. parvispora could produce ethanol from xylose.

    T. versicolor could be grown in culture, under hypoxic conditions, with various mixtures of hexoses and xylose and with xylose alone. After 354 h of culture we found very strong correlations between ethanol fermentation (alcohol dehydrogenase activity and ethanol production), sugar consumption and xylose catabolism (xylose reductase, xylitol dehydrogenase and xylulokinase activities) in the cultures. In a medium containing a 1:1 glucose/xylose ratio, the efficiency of fermentation of total sugars into ethanol was 80 %.

    A variety of inhibitors are formed during pretreatment procedures; they include, for example, phenolics, levulinic acid, HMF and furfural. These inhibitors were used in this study in order to reveal their effects on the growth of cells as well as on sugar utilization, enzyme activities and ethanol production by the white-rot fungus T. versicolor. The inhibitors had a positive effect on fresh weight, the largest increase being observed with the inhibitor furfural. T. versicolor metabolized all the inhibitors during 15 days of experimentation.

    It is known that fungi can degrade cellulose, hemicellulose and lignin through a series of enzymatic reactions. Is it possible to eliminate chemical pretreatment and instead use a biological pretreatment? If T. versicolor could serve as both a biodegrader and a biocatalyst it would lead to reductions in the costs of ethanol production and lower costs for pretreatments for other renewable fuels too. Experiments with different pretreatments applied to Salix viminalis and Populus tremula were conducted with and without fungi, as well as with enzymes, to evaluate whether T. versicolor was suitable as a biodegrader. The results showed that T. versicolor was able to degrade lignocellulose to glucose, and thus is suitable as a biodegrader and in addition has xylanase and beta-glucosidase enzymes that are related to similar enzymes in other fungi.

  • Public defence: 2016-10-21 09:00 Föreläsningssalen ÖNH, by 1B plan 3, Umeå
    Loizou, Christos
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Loizou, Christos
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Human papillomavirus in recurrent respiratory papillomatosis, tonsillar and mobile tongue cancer2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis focuses on the effects of the human papillomavirus (HPV) in tonsillar cancer, mobile tongue cancer, and recurrent respiratory papillomatosis (RRP). The purpose was to characterize patients with RRP in northern Sweden in order to identify more care-intensive RRP patients and to describe the voice and quality of life aspects that follow RRP. Further aims were to confirm the expected increase of HPV-positive tonsillar cancer cases in northern Sweden, and to study the correlation between HPV, its surrogate marker p16 and HPV receptor syndecan-1 in both tonsillar cancer and mobile tongue cancer.

    A total of 27 consecutive patients with RRP were evaluated at 3 months postoperatively using the voice handicap index (VHI) and SF-36 questionnaires to assess the impact on life and voice in a RRP population. The values were compared to normative data. This report was further extended by examining consecutive data from 21 new patients in order to characterize RRP patients in northern Sweden. In order to study HPV DNA in tonsillar (n= 65) and mobile tongue cancer (n=109), HPV DNA was extracted from paraffin-embedded biopsies and detected by polymerase chain reaction using general primers Gp5+/6+ and CpI/IIG. Expression of HPV surrogate marker p16 and the HPV receptor syndecan-1 was analysed by immunohistochemistry.

    Patients that underwent more than one RRP surgery per year were younger than those treated less frequently and they had significantly impaired voice quality as compared to normal subjects. Females, patients with frequent surgical treatment sessions, and patients with the high-risk HPV subtypes scored significantly lower in several domains of the quality of life assessment as compared with normal subjects. Forty-eight RRP patients had a median age of 44.5 years; 71% were men and 29% females, preferentially infected with HPV6. Patients with high surgical treatment frequency/year showed more widespread RRP in the larynx compared to the patients treated less frequently.

    A total of 214 tonsillar cancer cases were identified. The vast majority were men. They had a median age of 58 years at diagnosis and expressed HPV as well as p16. The incidence of tonsillar cancer revealed a 2,7-fold increase in men between the years 1990 and 2013. The study demonstrates a strong association between p16 and HPV infection in tonsillar malignancies. These findings are in contrast to the mobile tongue cancer cases, where no evidence of HPV DNA could be detected although one-third showed p16 staining. This demonstrated a poor correlation between HPV and p16 in mobile tongue cancer. There was no difference in the expression of the primary HPV receptor, syndecan-1, between tonsillar and mobile tongue cancer.

    In conclusion, the frequency of RRP operations, age at onset, gender and subtype of the HPV may be used as factors to predict voice disability. RRP patients with high surgical treatment frequency were significantly younger and had a more widespread laryngeal disease compared to the low-frequency treated group. This study confirms the existence of a clinical RRP group, not primarily related to HPV subtype, but to a more care-intensive RRP population. Our findings identify a 2,7-fold increase in the incidence of tonsillar cancer, HPV and p16 in men between 1990-2013. We can use p16 to detect HPV in tonsillar cancer but not in tongue cancer.

    The introduction of vaccination against HPV may have a role in the prevention of specific HPV-subtype positive head and neck malignancies and recurrent respiratory papillomatosis since the current vaccine protects against HPV6, 11, 16, 18, 31, 33, 45, 52 and 58. Males will definitely benefit indirectly from vaccination of females, though males will still remain at risk of cancers associated with HPV. This highlights the need for sex-neutral vaccination strategy. Our intention is that this thesis will provide scientific data to support a gender-neutral vaccination and to develop simple tools to detect HPV in tonsillar cancer.

  • Public defence: 2016-10-21 09:00 Betula, Umeå
    Kien, Vu Duy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Kien, Vu Duy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Inequalities in non-communicable diseases in urban Hanoi, Vietnam: health care utilization, expenditure and responsiveness of commune health stations2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Non-communicable diseases (NCDs) are the leading causes of morbidity and mortality among adults in Vietnam. Little is known about the magnitude of socioeconomic inequalities in NCDs and other NCD-related factors in urban areas, in particular among the poor living in slum areas. Understanding these disparities are essential in contributing to the knowledge, needed to reduce inequalities and close the related health gaps burdening the disadvantaged populations in urban areas. 

    Objective: To examine the burden and health system responsiveness to NCDs in Hanoi, Vietnam and investigate the role of socioeconomic inequalities in their prevalence, subsequent healthcare utilization and related impoverishment due to health expenditures. 

    Methods: A cross-sectional study was conducted among 3,736 individuals aged 15 years and over who lived in 1211 randomly selected households in 2013 in urban Hanoi, Vietnam. The study collected information on household’s characteristics, household expenditures, and household member information. A qualitative approach was implemented to explore the responsiveness of commune health stations to the increasing burden of NCDs in urban Hanoi. In-depth interview approach was conducted among health staff involved in NCD tasks at four commune health stations in urban Hanoi. Furthermore, NCD managers at relevance district, provincial and national levels were interviewed. 

    Results: The prevalence of self-reported NCDs was significantly higher among individuals in non-slum areas (11.6%) than those in slum areas (7.9%). However, the prevalence of self-reported NCDs concentrated among the poor in both slum and non-slum areas. In slum areas, the poor needed more health care services, but the rich consumed more health care services. Among households with at least one household member reporting diagnosis of NCDs, the proportion of household facing catastrophic health expenditure and impoverishment were the greater in slum areas than in non-slum areas. Poor households in slum areas were more likely to face catastrophic health expenditure and impoverishment. The poor in non-slum areas were also more likely to face impoverishment if their household members experienced NCDs. Health system responses to NCDs at commune health stations in urban Hanoi were weak, characterized by the lack of health information, inadequate human resources, poor financing, inadequate quality and quantity of services, lack of essential medicines. The commune health stations were not prepared to respond to the rising prevalence of NCDs in urban Hanoi. 

    Conclusion: This thesis shows the existence of socioeconomic inequalities in the prevalence of self-reported NCDs in both non-slum and slum areas in urban Hanoi. NCDs associated with the inequalities in health care utilization, catastrophic health expenditure and impoverishment, particular in slum areas. Appropriate interventions should focus more on specific population groups to reduce the socioeconomic inequalities in the NCD prevalence and health care utilization related to NCDs to prevent catastrophic health expenditure and impoverishment among the households of NCD patients.  The functions of commune health stations in the urban setting should be strengthened through the development of NCDs service packages covered by the health insurance.

  • Public defence: 2016-10-21 09:30 Hörsal E, Humanisthuset, Umeå
    Lindmark, Anita
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Lindmark, Anita
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Statistical methods for register based studies with applications to stroke2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis adds to the area of register based research, with a particular focus on health care quality and (in)equality. Contributions are made to the areas of hospital performance benchmarking, mediation analysis, and regression when the outcome variable is limited, with applications related to Riksstroke (the Swedish stroke register).

    An important part of quality assurance is to identify, follow up, and understand the mechanisms of inequalities in outcome and/or care between different population groups. The first paper of the thesis uses Riksstroke data to investigate socioeconomic differences in survival during different time periods after stroke. The second paper focuses on differences in performance between hospitals, illustrating the diagnostic properties of a method for benchmarking hospital performance and highlighting the importance of balancing clinical relevance and the statistical evidence level used.

    Understanding the mechanisms behind observed differences is a complicated but important issue. In mediation analysis the goal is to investigate the causal mechanisms behind an effect by decomposing it into direct and indirect components. Estimation of direct and indirect effects relies on untestable assumptions and a mediation analysis should be accompanied by an analysis of how sensitive the results are to violations of these assumptions. The third paper proposes a sensitivity analysis method for mediation analysis based on binary probit regression. This is then applied to a mediation study based on Riksstroke data.

    Data registration is not always complete and sometimes data on a variable are unavailable above or below some value. This is referred to as censoring or truncation, depending on the extent to which data are missing. The final two papers of the thesis are concerned with the estimation of linear regression models for limited outcome variables. The fourth paper presents a software implementation of three semi-parametric estimators of truncated linear regression models. The fifth paper extends the sensitivity analysis method proposed in the third paper to continuous outcomes and mediators, and situations where the outcome is truncated or censored.

  • Public defence: 2016-10-21 10:00 MA 121, MIT-huset, Umeå
    Dyrvold, Anneli
    Umeå University, Faculty of Science and Technology, Umeå Mathematics Education Research Centre (UMERC). Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Dyrvold, Anneli
    Umeå University, Faculty of Science and Technology, Umeå Mathematics Education Research Centre (UMERC). Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Difficult to read or difficult to solve?: the role of natural language and other semiotic resources in mathematics tasks2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    When students solve mathematics tasks, the tasks are commonly given as written text, usually consisting of natural language, mathematical notation and different types of images. This is one reason why reading and interpreting such texts are important parts of being mathematically proficient, at least within the school context. The ability utilized when dealing with aspects of mathematical text is denoted in this thesis as a mathematical reading ability; this ability is useful when reading mathematical language, for example, in task text. There is, however, a lack of knowledge of what characterizes this mathematical language, what students need to learn regarding the mathematical language, and exactly which mathematical language that tests should preferably assess. Therefore, the purpose of this thesis is to contribute to the knowledge of aspects of difficulty related to textual features in mathematics tasks. In particular, one aim is to distinguish between a difficulty that has to do with a mathematical ability and another that has not. Different types of text analyses are utilized to capture textural features that might be demanding for the students when reading and solving mathematics tasks. Aspects regarding vocabulary are investigated both in a literature review and in a study where corpora are used to analyse word commonness. Other textual analyses focus on textual features that concern mathematical notation and images, besides natural language. Statistical methods are used to analyse potential relations between the textual features of interest and both task difficulty and task demand on reading ability. The results from the research review are sparse regarding difficult vocabulary, since few of the reviewed studies analyses word aspects separately. Several of the analysed textual features are related to aspects of difficulty. The results show that tasks with more words that are uncommon both in a mathematical context and in an everyday context, may favour students with good reading ability rather than students with good mathematical ability. Another textual feature that is likely to be demanding for students, is if the task texts contains many meaning relations, for example, when several words refer to the same or similar object. These results have implications for the school practice both regarding textual features that are important from an educational perspective and regarding the construction of tests. The research does also contribute to an understanding of what characterizes a mathematical language.

  • Public defence: 2016-10-21 10:00 N 320 (Naturvetarhuset, Umeå universitet), Umeå
    Rantala, Anna
    Umeå University, Faculty of Social Sciences, Department of applied educational science.
    Rantala, Anna
    Umeå University, Faculty of Social Sciences, Department of applied educational science.
    - Snälla du! Kan du sätta dig?: om vägledning i förskolan2016Doctoral thesis, monograph (Other academic)
    Abstract [en]

    The aim of the thesis is to deepen understanding of how socialization is performed in preschool. The empirical material upon which the results are based comprises video observations in which everyday situations were documented at two Swedish preschools. The analysis draws from Foucauldian theories of power.

    Swedish preschools have their own curriculum (National Agency for Education, 2010) in which the tasks of the preschool are formulated. As they are presented, these tasks may be perceived as complex. This offers wide scope for interpretation, where the task of socializing children is veiled under words with positive connotations, such as democracy, solidarity, empathy, consideration and respect. The vague expression of this task of socializating children lends importance to the study of how socialization is performed in the preschool.

    In this thesis, results of a thematic analysis of the normative utterances of educators are presented. The results uncover activities in everyday situations where children are guided in various ways and in which power, discipline and normalization are common elements. A picture emerges from the analysis of how attempts are made to communicate norms about how people should behave in a democratic society, even as the guidance provided varies both between genders and among individual children.

    The thesis contributes to deeper understanding of how socialization is performed in preschool by visualizing guidance in various situations, which makes it possible to analyse both how this guidance is delivered and the direction in which the children are guided. 

  • Public defence: 2016-10-21 13:00 Aulan, Sundsvall
    Björck, Fredrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Björck, Fredrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Warfarin treatment quality in stroke prevention2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background

    Ischemic stroke is a serious condition often associated to presence of atrial fibrillation (AF). Use of anticoagulants for AF patients greatly reduces the risk of stroke. Warfarin is the most commonly used anticoagulant in Sweden. The aim of this thesis was to study the impact of warfarin treatment quality in Swedish stroke prevention.

    Methods

    Study I, II and IV were relatively large multicentre, retrospective, cohort studies based on Swedish registries, especially AuriculA, a quality register for AF and anticoagulation. Background data as well as bleeding and thromboembolic complications were retrieved from the National Patient Register. The Cause of Death Register was used in study II and IV. The Swedish Prescribed Drug Register was used in study IV, for data on concomitant acetylsalicylic acid (ASA) use. Study period was January 1, 2006, to December 31, 2011. Study III enrolled all warfarin treated AF patients in Sundsvall, registered in AuriculA on January 1, 2010. This smaller cohort was followed until discontinuation or study-stop December 31, 2013. All used data were collected from each patient’s medical record.

    Results

    The annual risk of major bleedings and thromboembolic events for warfarin treated patients, including all different indications for warfarin, was relatively low (2.24% and 2.66%), with incidence of intracranial bleeding of 0.37% per treatment year. The overall mean time in therapeutic range (TTR) was 76.5%. Patients started on warfarin due to AF had a mean TTR of 68.6%, with an annual risk of major bleeding and thromboembolic events of 2.23% and 2.95%, and with 0.44% annual risk of intracranial bleeding. No significant differences in overall complications were found when comparing treatment monitored in anticoagulation clinics (ACC) with treatment monitored in primary health care centers (PHCC). There were significantly increased risk of both overall major bleedings and thromboembolic events for those warfarin treated AF patients receiving additional ASA treatment, having individual TTR (iTTR) below 70%, or having high international normalized ratio (INR) variability. AF patients with low INR variability had generally lower complication rates, compared with patients with high INR variability. There were however no alteration on cumulative incidence of complications due to INR variability, for AF patients with iTTR ≥70%. The overall proportion of persistence to warfarin treatment for stroke patients with AF was found to be 0.69 after 2 years treatment and 0.47 after 5 years. Stroke patients with diagnosed dementia at baseline were more than two-times likely of discontinuing warfarin than others. Excessive alcohol use, chronic obstructive pulmonary disease, cancer and chronic heart failure were baseline diagnoses each associated with over 20% increased risk of treatment discontinuation. Lower persistence to treatment was linked to increasing start-age and CHA2DS2-VASc scores. As documented reasons for warfarin treatment discontinuation in AF patients, we found regained sinus rhythm as the most common addressed cause (31.2%), followed by problematic monitoring and bleedings. We estimated that only half (49.5%) of the treatment discontinuations were clinically well motivated.

    Conclusions

    Quality of Swedish warfarin treatment in initiated stroke prevention is high, with generally low rates of complications and high TTRs, no matter treatment in ACC or PHCC, including high long time persistence to warfarin in secondary stroke prevention. For better outcome in future warfarin stroke prophylactic treatment clinicians should aim for iTTRs above 70%, avoid additional ASA therapy, support fragile patients like those with excessive alcohol use and dementia, and base decisions on treatment discontinuations on solid medical arguments.

  • Public defence: 2016-10-21 13:00 135 X1, Umeå
    Petersson, Kerstin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Petersson, Kerstin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    The Swedish Maternal Health Care Register: Internal Validity, User Perspectives and Register Outcomes; and Experiences by Midwives in Antenatal Care2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background

    Established in 1999, the Swedish Maternal Health Care Register (MHCR), collects data on pregnant women and their offspring. Since 2013, the MHCR has been a part of the Swedish Pregnancy Register (SPR). Data are entered manually into the MHCR by midwives in antenatal care (ANC). ANC is primarily organised within public primary health care in Sweden. Midwives are the primary providers of health care during pregnancy, and they are responsible for providing information about prenatal diagnosis to expecting parents.

    Aims

    This thesis investigated internal validity of MHCR data, and user’s experiences of the MHCR. Prenatal diagnosis was explored in regard to local guidelines and to background characteristics and pregnancy outcomes. Factors affecting the work situation for midwives in ANC, as well as their experiences on informing expecting parents about prenatal diagnosis were investigated.

    Methods

    Study I, II and III were cross-sectional studies. Study I included data from MHCR and medical records on 878 pregnancies during 2011. Study III analysed data from MHCR/SPR, in total 284,789 pregnancies for 2011 to 2013. Study II was a questionnaire study with a quantitative and a qualitative component, including 989 participants. Study IV was a qualitative study applying qualitative content analysis. Fifteen midwives participated in individual, telephone interviews.

    Main findings

    Overall, the degree of coverage of variables was high in the MHCR as well as in the medical records. For 17 of the 27 variables, agreement of data in both data sources reached 95% or more. Possible systematic errors were identified for two variables (Paper I). Midwives valued MHCR generally positively, although manual registration of data into the MHCR was perceived burdensome. Foremost midwives engaged in supervision regularly accessed data on pregnant women at their own ANC clinic (Paper II). Offers on prenatal diagnosis varied considerably between the 21 Swedish counties during 2011 to 2013. Maternal age and educational level demonstrated strong associations with uptake of prenatal diagnosis (Paper III). Midwives in ANC reported their work load as manageable. Clinical guidelines, continuing education, and collaboration in the chain of care of pregnant women, were supportive factors for midwives work situation in antenatal care. Administrative work load was perceived as strenuous and informing expecting parents about prenatal diagnosis was challenging (Paper IV).

    Conclusions

    Data in the MHCR demonstrated sufficient internal validity. MHCR was an underutilised source in operational planning of ANC. Offers and uptake on prenatal diagnosis was unequally distributed in Sweden. Midwives enjoyed their work in ANC. Administrative work was strenuous and informing expecting parents about prenatal diagnosis was challenging. The register can further develop its report systems to be used in a higher extent in evaluation and planning of Swedish maternal health care services. Expecting couples in Sweden should be offered the same opportunities on prenatal diagnosis. Pedagogical tools may facilitate midwives mission to inform expecting parents with varying pre-understanding about prenatal diagnosis

  • Public defence: 2016-10-27 09:00 N220, Umeå
    Karlsborn, Tony
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Karlsborn, Tony
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Physiological consequences of Elongator complex inactivation in Eukaryotes2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Mutations found in genes encoding human Elongator complex subunits have been linked to neurodevelopmental disorders such as familial dysautonomia (FD), rolandic epilepsy and amyotrophic lateral sclerosis. In addition, loss-of-function mutations in genes encoding Elongator complex subunits cause defects in neurodevelopment and reduced neuronal function in both mice and nematodes. The Elongator complex is a conserved protein complex comprising six subunits (Elp1p-Elp6p) found in eukaryotes. The primary function of this complex in yeast is formation of the 5-methoxycarbonylmethyl (mcm5) and 5-carbamoylmethyl (ncm5) side chains found on wobble uridines (U34) in tRNAs. The aim of this thesis is to investigate the physiological consequences of Elongator complex inactivation in humans and in the yeast Saccharomyces cerevisiae.

    Inactivation of the Elongator complex causes widespread defects in a multitude of different cellular processes in S. cerevisiae. Thus, we investigated metabolic alterations resulting from Elongator complex inactivation. We show that deletion of the S. cerevisiae ELP3 gene leads to widespread metabolic alterations. Moreover, all global metabolic alterations observed in the elp3Δ strain are not restored in the presence of elevated levels of hypomodified tRNAs that normally have the modified nucleoside mcm5s2U. Collectively, we show that modified wobble nucleosides in tRNAs are required for metabolic homeostasis.

    Elongator mutants display sensitivity to DNA damage agents, but the underlying mechanism explaining this sensitivity remains elusive. We demonstrate that deletion of the S. cerevisiae ELP3 gene results in post-transcriptional reduction of Ixr1p levels. Further, we show that the reduced Ixr1p levels prevent adequate Rnr1p levels upon treatment with DNA damage agents. These findings suggest that reduced Ixr1p levels could in part explain why Elongator mutants are sensitive to DNA damage agents.

    Depletion of Elongator complex subunits results in loss of wobble uridine modifications in plants, nematodes, mice and yeast. Therefore, we investigated whether patients with the neurodegenerative disease familial dysautonomia (FD), who have lower levels of the ELP1 protein, display reduced amounts of modified wobble uridine nucleosides. We show that tRNA isolated from brain tissue and fibroblast cell lines derived from FD patients have 64–71% of the mcm5s2U nucleoside levels observed in total tRNA from non-FD brain tissue and non-FD fibroblasts. Overall, these results suggest that the cause for the neurodegenerative nature of FD could be translation impairment caused by reduced levels of modified wobble uridine nucleosides in tRNAs. Thus, our results give new insight on the importance of modified wobble uridine nucleosides for neurodevelopment.