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  • Public defence: 2018-01-19 09:00 E04, Umeå
    Gylling, Björn
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Biomarkers of one-carbon metabolism in colorectal cancer risk2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    One-carbon metabolism, a network of enzymatic reactions involving the transfer of methyl groups, depends on B-vitamins as cofactors, folate as a methyl group carrier, and amino acids, betaine, and choline as methyl group donors. One-carbon metabolism influences many processes in cancer initiation and development such as DNA synthesis, genome stability, and histone and epigenetic methylation. To study markers of one-carbon metabolism and inflammation in relation to colorectal cancer (CRC) risk, we used prediagnostic plasma samples from over 600 case participants and 1200 matched control participants in the population-based Northern Sweden Health and Disease Study cohort.

    This thesis studies CRC risk with respect to the following metabolites measured in pre-diagnostic plasma samples: 1) folate, vitamin B12, and homocysteine; 2) components of one-carbon metabolism (choline, betaine, dimethylglycine, sarcosine, and methionine); and 3) three markers of different aspects of vitamin B6 status. In addition, this thesis examines three homocysteine ratios as determinants of total B-vitamin status and their relation to CRC risk.

    In two previous studies, we observed an association between low plasma concentrations of folate and a lower CRC risk, but we found no significant association between plasma concentrations of homocysteine and vitamin B12 with CRC risk. We have replicated these results in a study with a larger sample size and found that low folate can inhibit the growth of established pre-cancerous lesions.

    Using the full study cohort of over 1800 participants, we found inverse associations between plasma concentrations of the methionine cycle metabolites betaine and methionine and CRC risk. This risk was especially low for participants with the combination of low folate and high methionine versus the combination of low folate and low methionine. Well-functioning methionine cycle lowers risk, while impaired DNA synthesis partly explains the previous results for folate.

    We used the full study cohort to study associations between CRC risk and the most common marker of vitamin B6 status, pyridoxal' 5-phosphate (PLP), and two metabolite ratios, PAr (4-pyridoxic acid/(PLP + pyridoxal)) estimating vitamin B6 related inflammatory processes and the functional vitamin B6 marker 3-hydroxykynurenine to xanthurenic acid (HK:XA). Increased vitamin B6-related inflammation and vitamin B6 deficiency increase CRC risk. Inflammation was not observed to initiate tumorigenesis.

    Total B-vitamin status can be estimated by three different recently introduced homocysteine ratios. We used the full study cohort to relate the ratios as determinants of the total B-vitamin score in case and control participants and estimated the CRC risk for each marker. Sufficient B-vitamin status as estimated with homocysteine ratios was associated with a lower CRC risk.

    These studies provide a deeper biochemical knowledge of the complexities inherent in the relationship between one-carbon metabolism and colorectal tumorigenesis. 

  • Public defence: 2018-01-19 09:00 MA 121, MIT-huset, Umeå
    Torshage, Axel
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Non-selfadjoint operator functions2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Spectral properties of linear operators and operator functions can be used to analyze models in nature. When dispersion and damping are taken into account, the dependence of the spectral parameter is in general non-linear and the operators are not selfadjoint.

    In this thesis non-selfadjoint operator functions are studied and several methods for obtaining properties of unbounded non-selfadjoint operator functions are presented. Equivalence is used to characterize operator functions since two equivalent operators share many significant characteristics such as the spectrum and closeness. Methods of linearization and other types of equivalences are presented for a class of unbounded operator matrix functions.

    To study properties of the spectrum for non-selfadjoint operator functions, the numerical range is a powerful tool. The thesis introduces an optimal enclosure of the numerical range of a class of unbounded operator functions. The new enclosure can be computed explicitly, and it is investigated in detail. Many properties of the numerical range such as the number of components can be deduced from the enclosure. Furthermore, it is utilized to prove the existence of an infinite number of eigenvalues accumulating to specific points in the complex plane. Among the results are proofs of accumulation of eigenvalues to the singularities of a class of unbounded rational operator functions. The enclosure of the numerical range is also used to find optimal and computable estimates of the norm of resolvent and a corresponding enclosure of the ε-pseudospectrum. 

  • Public defence: 2018-01-19 09:00 A5_R0, Umeå
    Kurhade, Chaitanya
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Interplay between tick-borne encephalitis virus and the host innate immunity2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Flaviviruses are important emerging and re-emerging arthropod-borne pathogens that cause significant morbidity and mortality in humans. It consists of globally distributed human pathogens such as tick-borne encephalitis virus (TBEV), West Nile virus (WNV), Japanese encephalitis virus (JEV), yellow fever virus (YFV), dengue virus (DENV), and Zika virus (ZIKV). Depending on type, flaviviruses can cause a variety of symptoms ranging from haemorrhage to neurological disorders.

    Virus infection is detected by host pattern recognition receptors (PRRs), and through downstream signalling it leads to the production of interferons (IFNs). These IFNs then act in an autocrine or paracrine manner on the cells to induce various IFN-stimulated genes (ISGs), which have antiviral roles. However, the amount of IFN produced depends on the nature of the PRRs used by host cells to detect a particular virus. Although there are many PRRs present in the host cells, their relative contribution in different cell types and against a specific virus may vary. In the first study, we determined the importance of IPS-1 signalling in immunity and pathogenicity of tick-borne flaviviruses. This is an adaptor protein for cytoplasmic RIG-I-like receptors. Using IPS-1-deficient mice, we showed its importance against TBEV and Langat virus (LGTV) infection (the LGTV model virus belongs to the TBEV serogroup). Absence of IPS-1 leads to uncontrolled virus replication in the central nervous system (CNS), but it has only a minor role in shaping the humoral immune response at the periphery. LGTV-infected IPS-1-deficient mice showed apoptosis, activation of microglia and astrocytes, an elevated proinflammatory response, and recruitment of immune cells to the CNS. Interestingly, we also found that IFN-b upregulation after viral infection was dependent on IPS-1 in the olfactory bulb of the brain.  Thus, our results suggest that local immune microenvironment of distinct brain regions is critical for determination of virus permissiveness.

    Interferons can upregulate several ISGs. Viperin is one such ISG that has a broad-spectrum antiviral action against many viruses. However, the importance of cell type and the significance of viperin in controlling many flavivirus infections in vivo is not known. Using viperin-deficient mice, we found that viperin was necessary for restriction of LGTV replication in the olfactory bulb and cerebrum, but not in the cerebellum. This finding was also confirmed with primary neurons derived from these brain regions. Furthermore, we could also show the particular importance of viperin in cortical neurons against TBEV, WNV, and ZIKV infection. The results suggested that a single ISG can shape the susceptibility and immune response to a flavivirus in different regions of the brain.

    Although viperin is such an important ISG against flaviviruses, the exact molecular mechanism of action is not known. To understand the mechanism, we performed co-immunoprecipitation screening to identify TBEV proteins that could interact with viperin. While viperin interacted with the prM, E, NS2A, NS2B, and NS3 proteins of TBEV, its interaction with NS3 led to its degradation through the proteosomal pathway. Furthermore, viperin could reduce the stability of other viperin-binding TBEV proteins in an NS3-dependent manner. We screened for viperin activity regarding interaction with NS3 proteins of other flaviviruses. Viperin interacted with NS3 of JEV, ZIKV, and YFV, but selectively degraded NS3 proteins of TBEV and ZIKV, and this activity correlated with its antiviral activity against these viruses.

    The last study was based on in vivo characterization of the newly isolated MucAr HB 171/11 strain of TBEV which caused unusual gastrointestinal and constitutional symptoms. This strain was compared with another strain, Torö-2003, of the same European subtype of TBEV but isolated from the different focus. Here we found unique differences in their neuroinvasiveness and neurovirulence, and in the immune response to these two strains.

    In summary, my work shed some light on the interplay between tick-borne flavivirus and the innate immune system. I have shown two examples of CNS region-specific differences in innate immune response regarding both in IFN induction pathways and antiviral effectors. Furthermore, we have investigated the in vivo pathogenesis of a strain of TBEV that caused unusual gastrointestinal and constitutional symptoms.

  • Public defence: 2018-01-26 13:00 Hörsal D, Unod T9, 9 tr., Umeå
    Brunström, Mattias
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Effect of antihypertensive treatment at different blood pressure levels2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background

    High blood pressure is associated with an increased risk of cardiovascular disease and premature death. The shape of association between blood pressure and the risk of cardiovascular events is debated. Some researchers suggest that the association is linear or log-linear, whereas others suggest it is J-shaped. Randomized controlled trials of antihypertensive treatment have been successful in hypertension, but ambiguous in the high normal blood pressure range. Previous systematic reviews have not found any interaction between baseline systolic blood pressure and treatment effect, with beneficial effects at systolic blood pressure levels well below what is currently recommended. These reviews, however, use a method to standardize treatment effects and study weights according to within-trial blood pressure differences that may introduce bias.

    Methods

    We performed two systematic reviews to assess the effect of antihypertensive treatment on cardiovascular disease and mortality at different blood pressure levels. The first review was limited to people with diabetes mellitus. The second review included all patient categories except those with heart failure and acute myocardial infarction. Both reviews were designed with guidance from Cochrane Collaborations Handbook for Systematic Reviews of Interventions, and are reported according to PRISMA guidelines. We included randomized controlled trials assessing any antihypertensive agent against placebo or any blood pressure targets against each other. Results were combined in random-effects meta-analyses, stratified by baseline systolic blood pressure. Non-stratified analyses were performed for coronary heart disease trials and post-stroke trials. Interaction between blood pressure level and treatment effect was assessed with Cochran’s Q in the first review, and multivariable-adjusted metaregression in the second review.

    The third paper builds on data from the second paper, and assesses the effect of standardization according to within-trial blood pressure differences on the results of meta-analyses. We performed non-standardized analyses, analyses with standardized treatment effects, and analyses with standardized treatment effects and standard errors. We compared treatment effect measures and heterogeneity across different methods of standardization. We also compared treatment effect estimates between fixed-effects and random-effects meta-analyses within each method of standardization. Lastly, we assessed the association between number of events and study weights, using linear regression.

    Results

    Forty-nine trials assessed the effect of antihypertensive treatment in people with diabetes mellitus. Treatment effect on cardiovascular mortality and myocardial infarction decreased with lower baseline systolic blood pressure. Treatment reduced the risk of death and cardiovascular disease if baseline systolic blood pressure was 140 mm Hg or higher. If baseline systolic blood pressure was below 140 mm Hg, however, treatment increased the risk of cardiovascular death by 15 % (0-32 %).

    Fifty-one trials assessed the effect of antihypertensive treatment in primary prevention. Treatment effect on cardiovascular mortality, major cardiovascular events, and heart failure decreased with lower baseline systolic blood pressure. If baseline systolic blood pressure was 160 mm Hg or higher treatment reduced the risk of major cardiovascular events by 22 % (95 % confidence interval 13-30 %). If systolic blood pressure was 140-159 mm Hg treatment reduced the risk by 12 % (4-20 %), whereas if systolic blood pressure was below 140 mm Hg, treatment effect was neutral (4 % increase to 10 % reduction). All-cause mortality was reduced if systolic blood pressure was 140 mm Hg or higher, with neutral effect at lower levels.

    Twelve trials compared antihypertensive treatment against placebo in people with coronary heart disease. Mean baseline systolic blood pressure was 138 mm Hg. Treatment reduced the risk of major cardiovascular events by 10 % (3-16 %), whereas the effect on mortality was neutral (7 % increase to 11 % reduction).

    Standardization of treatment effects resulted in more extreme effect estimates for individual trials. This caused increased between-study heterogeneity, and different results with fixed- and random-effects model. Standardization of standard errors shifted weights from trials with many events to trials with large blood pressure differences. This caused biased overall effect estimates. Standardization of standard errors also resulted in wider confidence intervals, masking the previously increased heterogeneity. This reduced the possibility to find different treatment effects at different blood pressure levels.

    Conclusion The effect of antihypertensive treatment depends on blood pressure level before treatment. Treatment reduces the risk of death and cardiovascular disease if baseline systolic blood pressure is 140 mm Hg or higher. Below this level, treatment is potentially harmful in people with diabetes, has neutral effect in primary prevention, but might offer additional protection in people with coronary heart disease. Standardization should generally be avoided in meta-analyses of antihypertensive treatment. Previous meta-analyses using standardized methods should be interpreted with caution.

  • Public defence: 2018-01-26 13:00 hörsal E04, byggnad 6E, Norrlands Universitetsjukhus., Umeå
    Khoshnood, Behzad
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Function and targets of the Urm1/Uba4 conjugation machinery in Drosophila melanogaster2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Posttranslational modification (PTM) of proteins is essential to maintain homeostasis and viability in all eukaryotic cells. Hence, besides the sequence and 3D folding of a polypeptide, modification by multiple types of PTMs, ranging from small molecular groups to entire protein modules, adds another layer of complexity to protein function and regulation. The ubiquitin-like modifiers (UBLs) are such a group of evolutionary conserved protein modifiers, which by covalently conjugating to target proteins can modulate the subcellular localization and activity of their targets. One example of such a UBL, is the Ubiquitin related modifier 1 (Urm1). Since its discovery in 2000, Urm1 has been depicted as a dual function protein, which besides acting as a PTM, in addition functions as a sulfur carrier during the thio-modification of a specific group of tRNAs. Due to this dual capacity, Urm1 is considered as the evolutionary ancestor of the entire UBL family. At present, it is well established that Urm1, with help of its dedicated E1 enzyme Uba4/MOCS3, conjugates to multiple target proteins (urmylation) and that Urm1 thus plays important roles in viability and the response against oxidative stress.

    The aim of this thesis has been to, for the first time, investigate the role of Urm1 and Uba4 in a multicellular organism, utilising a multidisciplinary approach that integrates Drosophila genetics with classical biochemical assays and proteomics. In Paper I, we first characterized the Drosophila orthologues of Urm1 (CG33276) and Uba4 (CG13090), verified that they interact physically as well as genetically, and that they together can induce urmylation in the fly. By subsequently generating an Urm1 null Drosophila mutant (Urm1n123), we established that Urm1 is essential for viability and that flies lacking Urm1 are resistant to oxidative stress. Providing a molecular explanation for this phenotype, we demonstrated an involvement of Urm1 in the regulation of JNK signaling, including the transcription of the cytoprotective genes Jafrac1 and gstD1. Besides the resistance to oxidative stress, we have moreover (Manuscript IV) made an in-depth investigation of another phenotype displayed by Urm1n123 mutants, an overgrowth of third instar larval neuromuscular junctions (NMJs), a phenotype which is shared also with mutants lacking Uba4 (Uba4n29).

    To increase the understanding of Urm1 in the fly, we next employed a proteomics-based approach to identify candidate Urm1 target proteins (Paper II). Using this strategy, we identified 79 Urm1-interacting proteins during three different stages of fly development. Of these, six was biochemically confirmed to interact covalently with Urm1, whereas one was found to be associated with Urm1 by non-covalent means. In Manuscript III, we additionally identified the virally encoded oncogene Tax as a target of Urm1, both in Drosophila tissues and mammalian cell lines. In this study, we established a strong correlation between Tax urmylation and subcellular localization, and that Urm1 promoted a cytoplasmic accumulation and enhanced signalling activity of Tax, with implications for a potential role of Urm1 in Tax-induced oncogenesis.

    Taken together, this thesis provides a basic understanding of the potential roles and targets of Urm1 in a multicellular organism. The four studies included cover different aspects of Urm1 function and clearly points towards a highly dynamic role of protein urmylation in fly development, as well as in adult life.

  • Public defence: 2018-02-02 09:00 Hörsal D, Umeå
    Liu-Helmersson, Jing
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Climate Change, Dengue and Aedes Mosquitoes: Past Trends and Future Scenarios2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background Climate change, global travel and trade have facilitated the spread of Aedes mosquitoes and have consequently enabled the diseases they transmit (dengue fever, Chikungunya, Zika and yellow fever) to emerge and re-emerge in uninfected areas. Large dengue outbreaks occurred in Athens in 1927 and in Portuguese island, Madeira in 2012, but there are almost no recent reports of Aedes aegypti, the principal vector, in Europe. A dengue outbreak needs four conditions: sufficient susceptible humans, abundant Aedes vector, dengue virus introduction, and conducive climate. Can Aedes aegypti establish themselves again in Europe in the near future if they are introduced? How do the current and future climate affect dengue transmission globally, and regionally as in Europe? This thesis tries to answer these questions.

    Methods Two process-based mathematical models were developed in this thesis. Model 1 describes a vector’s ability to transmit dengue – vectorial capacity – based on temperature and diurnal temperature range (DTR). Model 2 describes vector population dynamics based on the lifecycle of Aedes aegypti. From this model, vector abundance was estimated using both climate as a single driver, and climate together with human population and GDP as multiple drivers; vector population growth rate was derived as a threshold condition to estimate the vector’s invasion to a new place.

    Results Using vectorial capacity, we estimate dengue epidemic potential globally for Aedes aegypti and in Europe for Aedes aegypti and Aedes albopictus. We show that mean temperature and DTR are both important in modelling dengue transmission, especially in a temperate climate zone like Europe. Currently, South Europe is over the threshold for dengue epidemics if sufficient dengue vectors are present. Aedes aegypti is on the borderline of invasion into the southern tip of Europe. However, by end of this century, the invasion of Aedes aegypti may reach as far north as the middle of Europe under the business-as-usual climate scenario. Or it may be restricted to the south Europe from the middle of the century if the low carbon emission – Paris Agreement – is implemented to limit global warming to below 2°C.

    Conclusion Climate change will increase the area and time window for Aedes aegypti’s invasion and consequently the dengue epidemic potential globally, and in Europe in particular. Successfully achieving the Paris Agreement would considerably change the future risk scenario of a highly competent vector – Aedes aegypti’s – invasion into Europe. Therefore, the risk of transmission of dengue and other infectious diseases to the mainland of Europe depends largely on human efforts to mitigate climate change.

  • Public defence: 2018-02-02 09:00 Forum Hörsal M, Campus Skellefteå., Skellefteå
    Norberg, Catharina
    Umeå University, Faculty of Medicine, Department of Nursing.
    Understanding spirituality and religiosity among very old people: measurements and experiences2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Spirituality is a multifaceted concept. In this thesis, spirituality is understood as an overarching term and a core of a person´s being. Religiosity is seen as one of many expressions of spirituality. Very old people are a vulnerable population, with an increased risk to be exposed to negative life events. Spirituality is suggested to have an impact on the possibility to adapt to life circumstances and manage age-related challenges.

    Aim: The overall aim of this thesis was to assess psychometric properties of instruments and to gain understanding about associations and experiences in relation to spirituality and religiosity among very old people.

    Method: The thesis has been conducted in the population based Umeå 85+/GERDA study. Half of those aged 85, all 90 year old, and all aged 95 and older in Umeå, Västerbotten, northern Sweden and in Ostrobothnia in Western Finland were invited to participate (cf. Näsman et al, 2017). Questionnaires used to measure religiosity versus spirituality were the Religious Orientations Scale (SROS) and the Self-Transcendence Scale (STS). None of these has previously been validated among very old people in a Swedish context. Factors associated and correlating with STS score are presented. How very old people express and perceive spirituality is also studied. 

    Result: The participants in study I scored high on both subscales, indicating that they were religious in both an intrinsic and extrinsic manner. The SROS ability to distinguish between intrinsic and extrinsic items was tested. The cluster analysis revealed three clusters interpreted as intrinsic, extrinsic-personal, and extrinsic-social religious orientation, with no cross-loadings. The revised version of STS, (study II) with 10 items, had satisfactory psycho­metric properties (α .83). A factor analysis resulted in a two-factor solution (α .78 & .73). Test-retest reliability and concurrent criterion validity were supported. In study III STS showed a positive association with psychological well-being, self-rated health, having someone to talk with, and being able to go outdoors indepen­dently. A negative association was found between STS and diagnosis of depression, dementia disease, osteoporosis, living in a geriatric care institution, and feeling lonely. An accumulation of negative life events was associated with a larger decline of STS score over five years. Findings in study IV showed that spirituality was perceived as a connectedness to God, and other people. Telling about spiritual experiences was described as un­common in conversation due to the private nature of the subject area and because of a fear of being considered as dubious. The findings also showed that experiences of spirituality were connected to a view of life where participants were transcending life’s circumstances, and experiencing mysteries.

    Conclusion: The results propose that the Swedish version of SROS and STS, aimed to measure religious orientation versus self-transcendence have satisfactory psychometric properties and are feasible to use among very old people. Furthermore, self-transcendence was positively and significantly, associated and correlated, to a number of factors known to enhance well-being. Spirituality was understood as including religiosity, a belief in God, connectedness to other people and conviction about a spiritual reality. The very old expressed a desire to share personal beliefs and experiences of spirituality, but they found it difficult due to a fear of not being taken serious. Hence spiritual needs can be unnoticed within the health care context, health care professionals need knowledge in order to recognize expressions of spirituality, and skills to support patients in a need of spiritual care. 

     

    The full text will be freely available from 2019-02-02 00:00
  • Public defence: 2018-02-02 10:00 Hörsal E, Humanisthuset, Umeå
    Pennlert, Julia
    Umeå University, Faculty of Arts, Department of culture and media studies.
    Poesi pågår: en studie av Poeter.se 2003-20162018Doctoral thesis, monograph (Other academic)
    Abstract [en]

    This dissertation presents a study of Poeter.se, a Swedish web community for reading and writing poetry. The aim is to examine and analyze how a literary community online works, how the writers present themselves as authors and how conventions connected to poetry migrate into or are negotiated in the digital environment. The vast amount of material published on the website during the time-period 2003-2016 (2 million comments and about 860 000 poems) makes it imperative to raise questions about methodology and the dissertation highlights how a researcher dealing with digital material can combine methods. 

    The study is divided into six chapters in which I use different theoretical frameworks, such as the concept of digital paratexts, theories and discussions about the function of the author in a digital media landscape, and media-specific theories about how reading and writing can be approached when they occur online. The central research questions are: What characterizes the connection between genre-specific traits in poetry and the digital platform on which they are published? What kind of relations can be seen between the participants and their publication patterns, and the website? How do the members present their writing and their participation at the site?