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  • Public defence: 2018-05-31 13:00 Betula, umeå
    Faraz, Mahmood
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Investigations of Leucine-rich repeats and immunoglobulin-like domain-proteins 1 and 2 (LRIG1 and LRIG2) and their genes in cancer2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The mammalian leucine-rich repeats and immunoglobulin-like domains (LRIG) gene family consists of three different members, LRIG1, LRIG2, and LRIG3. These genes are expressed in all human and mouse tissues analyzed to date. All LRIG proteins share similar and evolutionary conserved structural domains including a leucine-rich repeat domain, three immunoglobulin-like domains, a transmembrane domain, and a cytosolic tail. Since the discovery of this family, around 20 years ago, various research groups have shown the importance of this family in cancer biology and prognosis. The aim of this thesis was to further investigate the role of LRIG1 and LRIG2 in cancer.

    To investigate the roles of LRIG1 and LRIG2 in physiology and gliomagenesis, we generated Lrig1- and Lrig2-deficient mice and induced platelet-derived growth factor B (PDGFB)-driven gliomagenesis. We studied the effects of Lrig2 ablation on mouse development and survival and investigated if the ablation of Lrig1 or Lrig2 affects the incidence or malignancy of induced gliomas. We also investigated if Lrig2 ablation affects Pdgfr signaling in mouse embryonic fibroblasts (MEFs). Additionally, we analyzed the effects of ectopic LRIG1 expression in human primary glioblastoma cell lines TB101 and TB107, in vivo and in vitro. We reported no macroscopic anatomical defect but reduced growth and increased spontaneous mortality rate in Lrig2-deficient mice. However, the Lrig2-deficient mice were protected against the induced gliomagenesis. Lrig2-deficient MEFs showed faster kinetics of induction of immediate-early genes in response to PDGFB stimulation, whereas the phosphorylations of Pdgfra, Pdgfrb, Erk1/2, and Akt1 appeared unaltered. Lrig1-heterozygote mice showed a higher incidence of high-grade tumors (grade IV) compared to wildtype mice, demonstrating a haploinsufficient function of Lrig1. LRIG1 overexpression suppressed TB107 cell invasion in vivo and in vitro, which was partially mediated through the suppression of the MET receptor tyrosine kinase.

    To identify LRIG1-interacting proteins, we used the yeast-two hybrid system and data-mined the Bio-Plex network of high throughput protein-protein interaction database. To study the function of interactors, we used a triple co-transfection system to overexpress LRIG1 and PDGFRA and downregulate endogenous levels of interactors by short hairpin RNAs (shRNAs), simultaneously. This analysis demonstrated that CNPY3, CNPY4, GAL3ST1, GML, HLA-DRA, LRIG2, LRIG3, LRRC40, PON2, RAB4A, and ZBTB16 were important for the PDGFRA-downregulating function of LRIG1.

    To investigate the clinical significance of LRIG1 copy number alterations (CNAs) in breast cancer, we used droplet digital PCR (ddPCR) to analyze 423 breast cancer tumors. We found that LRIG1 CNAs were significantly different in steroid-receptor-positive vs steroid-receptor-negative tumors and in ERBB2-amplified vs ERBB2-non-amplified tumors. In the whole cohort, patients with LRIG1 loss or gain had a worse metastasis-free survival than patients with normal LRIG1 copy numbers, however, among the early-stage breast cancer subgroup, this difference was not significant. 

    In summary, Lrig1 behaved like a haploinsufficient tumor suppressor gene in malignant glioma, whereas Lrig2 appeared to promote malignant glioma. Our functional analysis of LRIG1 interactome uncovered several unanticipated and novel proteins that might be important for the regulation of receptor tyrosine kinases by LRIG1. LRIG1 CNAs predicted metastasis-free survival time in breast cancer. Hopefully, our findings might lead to a better understanding of the regulation of growth factor signaling and its importance in cancer biology and prognosis.

     

  • Public defence: 2018-06-01 09:00 Major Groove, NUS byggnad 6L, Umeå
    Karlsson, Jessica
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Endocannabinoid metabolism: the impact of inflammatory factors and pharmacological inhibitors2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The endocannabinoid (eCB) system is an endogenous signaling system consisting of ligands (referred to as endocannabinoids, eCBs), receptors and metabolic enzymes. The eCB system is involved in homeostatic control of a variety of biological functions such as neuronal signaling, mood, appetite and pathological conditions such as pain, inflammation and tumour progression. The main eCBs N- arachidonoylethanolamine (AEA, anandamide) and 2-arachidonoylglycerol (2-AG) are synthesised upon stimuli when and where their action is demanded. The signaling is brief and the eCBs are quickly degraded. The enzyme primarily responsible for eCB degradation is fatty acid amide hydrolase (FAAH) for AEA and monoacylglycerol lipase (MAGL) for 2-AG. In addition, both substances are substrates for cyclooxygenase-2 (COX-2). COX-2 is upregulated in inflammation, pain and in several tumours including prostate cancers, but it is not known whether COX-2 contribute significantly to eCB metabolism under these conditions.

    Increasing endogenous levels of eCBs by inhibiting their degradation is exploited as a future therapy for pain conditions. One suggested therapeutic strategy is dual inhibition of enzymes FAAH and COX-2 to raise AEA levels. Paper I and II of this thesis investigates FAAH and COX inhibitory effects of: the major metabolites and enantiomers of derivatives (flu-AM1 and ibu-AM5) of the current clinically used NSAIDs ibuprofen and flurbiprofen. The metabolites 3 ́hydroxyibuprofen and 4 ́hydroxyflurbiprofen retained the FAAH and COX- inhibitory effects seen by the parent compounds although at lower potencies. Both enantiomers of flu-AM1 were equally potent as FAAH inhibitors and displayed a useful substrate selective COX-2 inhibition profile, favoring eCBs as substrates rather than arachidonic acid.

    Paper III explores the impact of COX-2 and the effect of (R)-flu-AM1 upon AEA levels and degradation in mouse leukemic macrophage RAW264.7 cells. Despite the high inhibitory potency in enzyme assays, neither (R)-flu-AM1 nor the combination of a FAAH inhibitor with flurbiprofen increased AEA levels in the intact cells to any great extent. This suggests that the eCB turnover in these cells is rather slow. Further, in paper IV, induction of COX-2 did not unmask an ability of this enzyme to “gate” the uptake of AEA analogous to that seen with FAAH.

    Paper IV and V focus upon the role of the eCB system in prostate cancer. The eCB system is altered in cancer and is linked to the progression and prognosis of prostate cancer. How and whereby this change occurs is unknown. This thesis explores the impact of the inflammatory factors TNFα, IL-6 and lactic acid induced low pH upon the mRNA levels of eCB related enzymes and the functional impact upon AEA degradation in human DU145 and rat AT-1 prostate cancer cells. TNFα treatment of DU145 and IL-6 and lactic acid induced low pH exposure of AT-1 changed the mRNA levels of 2-AG related enzymes leaving AEA rather unaffected other than for a substantial induction of COX-2 mRNA in DU145 cells. Thus, AEA homeostasis was not shifted in prostate cancer cell lines exposed to inflammatory factors. The results suggest that COX-2 does not gate the uptake of AEA and is a minor contributor to AEA degradation in intact cells. 

  • Public defence: 2018-06-01 09:00 Sal 933, målpunkt B, 9 tr, Norrlands Universitetssjukhus, Umeå
    Granlund, Lena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Vitamin D deficiency in Northern Sweden: a cross-sectional study of an immigrant population at latitude 63° N, including an open partially randomized, controlled trial studying the effect of supplementation with different doses of cholecalciferol2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Vitamin D is a prohormone that plays a key role in the calcium and phosphate balance and has physiological functions throughout the entire body. Vitamin D is supplied by exposure to ultraviolet light or by food. The prevalence of vitamin D deficiency in immigrants in Northern Sweden was unknown. There was no consensus on how to define or treat vitamin D deficiency and no pure preparations of cholecalciferol available in Sweden.

    Aims: To study the prevalence and determinants of vitamin D deficiency in immigrants of African and Middle Eastern origin, to examine associations between vitamin D status and muscle strength, anxiety, depression and quality of life, and to determine the effect of supplementation with cholecalciferol on 25-hydroxyvitamin D3 [25(OH)D] and vitamin D status.

    Methods: 1. A cross-sectional, population-based study. Immigrants ages 25-65 from Africa and the Middle East (n=1306) living in Umeå, Sweden, were invited to participate. A total of 111 men and 106 women (16.5%) participated. 25(OH)D was measured by LC-MsMs. Anthropometry, medical, socioeconomic and lifestyle data was registered. Examinations: lower limb muscle strength, grip strength, HAD, health-related quality of life (QoL) 2. An open, partially randomized, controlled trial including immigrants from Africa or the Middle East, 192 subjects screened, 160 included and 147 completed the study. Intervention: cholecalciferol 12±2 weeks, 4 parallel groups; Group 1: 25(OH)D <25nmol/L: 10000 IU/d, Groups 2a and 2b: 25(OH)D 25-49 nmol/L: 2000 IU/d or 2000 IU/w, Group 3: 25(OH)D 50-74 nmol/L: 2000 IU/d.

    Results: Twelve percent of the immigrants showed a vitamin D deficiency (25(OH)D ˂25 nmol/L) and 73 % showed 25(OH)D ˂50 nmol/L. Vitamin D deficiency was twice as common in African immigrants as in the Middle Eastern group. Vitamin D deficiency was associated with intake of fatty fish less than once a week, absence of travel abroad and use of long-sleeved clothing in summer. Lower limb muscle strength was associated with 25(OH)D levels and weaker grip strength was associated with vitamin D deficiency. Vitamin D deficiency was not associated with anxiety, depression or QoL in the total immigrant population. In Middle Eastern women, in whom prevalence of anxiety was higher, anxiety was associated with 25(OH)D ≤49 nmol/L. Oral cholecalciferol was effective in increasing 25(OH)D. At study end, 100% in Group 1, 89% in Group 2a, 55% in Group 2b and 96% in Group 3 reached adequate vitamin D status (25(OH)D ˃50 nmol/L). In Group 1; 62 % reached 25(OH)D ≥125 nmol/L.

    Conclusions: Vitamin D deficiency and insufficiency was common in the immigrant group and no difference was shown between men and women. A diet including a high intake of fatty fish was most important in avoiding vitamin D deficiency. Vitamin D status was associated with muscle strength in all immigrants. Vitamin D deficiency was not associated with anxiety, depression or QoL in the immigrants. In female immigrants from the Middle East, anxiety was associated with 25(OH)D levels ≤49 nmol/L. Supplementation with cholecalciferol 2000 IU/day for three months was safe in healthy individuals with initial 25(OH)D 25-49 nmol/L, but monitoring is warranted since 11 % did not attain sufficient vitamin D status. The dose 10 000 IU/day in patients with initial 25(OH)D <25 nmol/L was unnecessarily high.

    The full text will be freely available from 2018-12-01 00:51
  • Public defence: 2018-06-01 10:00 Hörsal F, Humanisthuset, Umeå
    Junkka, Johan
    Umeå University, Faculty of Arts, Department of historical, philosophical and religious studies. Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Shared practices: social networks and fertility decline during the Swedish demographic transition, 1850-19502018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis studies how social interactions influenced the fertility decline during the Swedish demographic transition between 1850 and 1950. This, to gain insights into how and why norms and values affected married couples' birth control practices, and how this shaped the fertility decline. Social interaction effects are studied in two different networks, voluntary associations and spatial communities using regression-based methods, in four research papers. The relationship between social interactions and fertility, in turn, is studied at different levels of society, on a macro-, meso- and micro-level. The results show that married couples reproductive practices were affected by social interactions during the whole study period. Members of unions, free churches and temperance associations had, in general, lower fertility than others. Additionally, couples living near a union or a free-church was also more inclined to limit their fertility. Finally, the results show significant spatial autocorrelations in fertility of neighbours and couples in adjacent neighbourhoods. These results suggest that increased use of birth control was diffused within social networks through social interaction mechanisms and collective action. However, the most substantial effects are seen during the fertility transition. This was a time of large-scale societal changes, which made the perceived net benefits of childbearing more uncertain. The results of this thesis indicate that couples drew upon the experiences of others to make more informed decisions. Over time, these new shared practices were formed into social norms, connecting ideas of respectability with family limitation, diffused within social networks.

  • Public defence: 2018-06-01 10:00 Carl Kempe salen (KBE 303), KBC-huset, Umeå
    Strandberg, Anna
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
    Fuel conversion and ash formation interactions: a thermochemical study on lignocellulosic biomass2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Biomass is considered to be CO2 neutral, and to be able to reduce the dependency on fossil fuels the need for expanded and sustainable biomass feedstock is increasing. Ash-related problems are some of the most important aspects of this increasing use of new biomass assortments in thermal energy conversion systems. An improved basic understanding of fuel conversion, ash formation, ash transformation and ash interactions with the converting fuel is therefore important.

    In the present thesis, the main objective was to provide new knowledge on thermochemical fuel conversion, specifically on how ash formation interacts with fuel conversion for lignocellulosic biomasses. The main methods used were experimental characterization of decomposition behavior and analysis of morphology and elemental composition of samples, using different appliances, analytical methods and fuels. Multivariate data analysis was successfully used on thermogravimetric data for prediction of compositional data and fuel properties.

    New, detailed explanations of structural changes in char morphology and ash properties during conversion were provided including descriptions of the influences of ash formation on fuel conversion rates under different conditions. The influences were found different depending on both particle size and ash composition. One implication of these findings is that for fuels with low temperature melting ash, the diffusion barrier formed causes difficulties for typical thermogravimetric experiments aiming at determination of reactivity in the kinetically controlled regime. This is recommended to carefully consider for future studies. On a single pellet level, char encapsulation was not found to dominate and limit gas transport and conversion for any of the fuels tested. In practical applications, however, the situation may be different with thick ash layers accumulating on a fuel bed surface. Another important finding was the extensive formation of cracks and internal cavities during combustion of pellets, providing new insights in the fundamentals of fuel conversion.

    Clean woody fuels, rich in calcium, formed a porous ash layer with no sign of limiting char conversion rates. The phase chemical transformations involving carbonate and oxide formation from poplar pellets was studied in detail. For grassy fuels, on the other hand, low melting point silicates are expected to form. The physical properties of K-Ca-silicates from silicon rich straw fuels were also characterized, providing new insights on ash formation on micrometer scale resolution; at high temperature, the silicate melt formed bubbles on the surface that partially covered the char, while for lower temperature a more rigid net structure was formed.

  • Public defence: 2018-06-01 13:00 Sal B, 9 tr., byggnad 1D, målpunkt T, Umeå
    Pettersson, Mattias
    Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry.
    On titanium release from dental implants and the inflammatory response2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In dentistry, dental implants have become a standard treatment for single tooth loss and partial and total edentulism since their introduction by P-I Brånemark in the 1960s. Long-term follow-up studies have shown that dental implantation is a predictable treatment, with an overall implant survival over ninety-five percent. Mucositis and peri-implantitis are types of inflammation in the peri-implant soft tissue, and the latter occurs with the simultaneous loss of supporting bone. The pathogenesis of mucositis and peri-implantitis is considered a microbial infection in the peri-implant tissue that causes bone loss induced by inflammation. Immune and resident cells are activated by bacterial products and toxins, which induce the release of a cascade of proinflammatory cytokines and chemokines that can activate osteoclasts and cause further bone resorption. Noninfection-induced inflammatory reactions caused by wear particles from an orthopedic implant leading to loss of the prosthesis is a well-known condition in orthopedics. This immune response induced by metal particles has been shown to act by the assembly of a protein complex, i.e., an inflammasome, in macrophages, leading to the release of proinflammatory cytokines, e.g., interleukin 1 beta (IL-1β). Whether metal particles from a dental implant are associated in the pathogenesis of peri-implantitis has not yet been investigated thoroughly. Although titanium dioxide (TiO2) nanoparticles are known to induce a proinflammatory response, the relation between titanium (Ti) and peri-implantitis is not known.

    The overall aim of this thesis was to gain knowledge of the proinflammatory capacity of Ti and its potential association with the pathogenesis of peri-implantitis. The null hypothesis in this thesis is that Ti has no proinflammatory effect.

    To investigate the proinflammatory capacity of Ti, we exposed macrophages derived from a human cell line and monocytes isolated from human blood to Ti. We identified the activation and release of the proinflammatory cytokine IL-1β after the exposure of human macrophages to Ti ions, indicating activation of the inflammasome complex. A five-fold increase in the release of IL-β was found when cells were primed with bacterial products, e.g., Escherichia coli lipopolysaccharide (E. coli LPS) prior to exposure to Ti in culture medium. The proinflammatory effect of Ti was shown to be mediated by metal-protein aggregates formed in the medium and phagocytosed by macrophages. 

    The exposure of macrophages to E. coli LPS mediates the production of intracellular pro-IL-1β, and a second stimulus is needed to cleave the proform of the cytokine, resulting in active IL-1β. Caspase-1, an intracellular protein, is activated through the assembly of the inflammasome complex and is needed for the activation of pro-IL-1β into its active form. Our findings indicate that the Ti-induced activation and release of IL-1β is mediated through the inflammasome complex, as the effect was reduced in the presence of a caspase-1 inhibitor. Peri-implantitis and periodontitis soft tissue samples were investigated chemically and microscopically, and a high content of Ti could be identified in the peri-implantitis tissue samples. The Ti particles identified in the peri-implantitis soft tissue might aggravate the inflammatory response and jeopardize the peri-implant treatment outcome. Transmission electron microscopy (TEM) was used to visualize the formed Ti-protein aggregates, and we discovered that the morphology of the aggregates differed in the presence of cobalt (Co). By microscopy, we could show the uptake of Ti-protein aggregates into macrophage phagolysosomes and that the location of these aggregates differed when Co was present. The origin of the Ti particles found in peri-implantitis soft tissue is unknown, but we could show that Ti is abraded from the implant during insertion into the bone. This abrasion of Ti from the implant surface into the bone is more prominent from an implant with a rough surface than with a smooth surface. 

    We can conclude that Ti can act as a secondary stimulus to macrophages and activate the release of active IL-1β via inflammasome complex assembly. Additionally, Ti forms metal-protein aggregates with a proinflammatory effect that can be inhibited by the presence of Co. Peri-implantitis soft tissue samples contained high concentrations of Ti and metal fragments. Lastly, Ti particles are abraded from the implant during insertion into the bone in amounts that could be proinflammatory. The proinflammatory effect induced by Ti can act in synergy with infection-induced inflammation and cause an imbalance in the host response, leading to the progression of peri-implantitis. The null hypothesis could be rejected.

  • Public defence: 2018-06-01 13:00 KB.E3.01 (Lilla hörsalen), Kemiskt Biologiskt Centrum (KBC), Umeå
    Dingeldein, Artur
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bax and oxidized phospholipids - a deadly complex: Apoptotic protein-lipid assemblies studied by MAS NMR spectroscopy2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Mitochondria are renowned for their vital role as cellular powerhouses because they provide ATP via cellular respiration. Additionally, these organelles also play an important role in other physiological processes, such as apoptosis. Apoptosis, or regulated cell death, is an important mechanism that regulates, for example, tissue homeostasis and embryonic development. Malfunctioning apoptosis can cause severe diseases such as various types of cancer and neurodegenerative diseases. The significance of mitochondria for apoptosis is that mitochondria host a variety of apoptogenic factors, such as cytochrome c. The release of these factors after the formation of an apoptotic pore can be regarded as a point of no return in the onset of apoptosis as these factors trigger the activation of caspases and consequently nuclear fragmentation.

    The mitochondrial outer membrane (MOM) is essential for deciding the cell’s fate, since the MOM provides an interaction surface for the pro- and anti-apoptotic proteins of the Bcl-2 protein family. Further, oxidized phospholipids (OxPls) within the MOM that are generated under oxidative stress conditions (a potent pro-apoptotic stimulus) can directly affect the equilibrium between pro- and anti-apoptotic proteins at the MOM surface, hence influencing the formation of apoptotic pores.

    To characterize the impact of different OxPls on membrane dynamics and organization, several MOM-mimicking systems were studied by solid-state magic angle spinning nuclear magnetic resonance spectroscopy (MAS NMR). These main experiments were accompanied by fluorescence spectroscopy and differential scanning calorimetry (DSC) studies to investigate the impact of OxPls and their interactions with the pro-apoptotic Bax protein at both the macroscopic and molecular levels. By combining several orthogonal methods, we were able to obtain a detailed description of the changes in MOM-mimicking vesicles induced by several types of OxPls. Moreover, we demonstrated how these changes impact the interaction between liposomes and the pro-apoptotic Bax protein.

    By using DSC, we were able to determine not only the macroscopic effect of two OxPls – PazePC and PoxnoPC – but also a concentration threshold. Both OxPls disrupted the membrane order such that the melting behavior of the MOM-mimicking vesicles became less cooperative. A decrease in cooperativity was detectable for OxPl concentrations of up to 5 mol%, after which the cooperativity remained constant. The addition of Bax resulted in an observable ordering effect, as some of the membrane disorder was negated by Bax and the melting process became more cooperative again. The ordering effect of Bax was subsequently confirmed by 31P MAS NMR experiments and cross polarization (CP) buildup curves. Analysis of the buildup curves revealed that at the molecular level, Bax enabled more efficient CP transfer, which indicated rigidification of the membranes after Bax insertion. Furthermore, the 31P NMR experiments provided the first molecular evidence of the importance of cardiolipin as a membrane contact site for Bax.

    Despite having similar disordering effects when studied with DSC, PoxnoPC and PazePC exhibited opposing effects on the pore formation ability of Bax. In studies with fluorescent dye-based leakage assays, Bax was able to form long-lived, stable pores in PazePC-containing giant unilamellar vesicles (GUVs). However, the observed leakage mechanism in PoxnoPC-containing GUVs could no longer be explained by an all-or-none leakage mechanism due to the brevity of the formed pores, leading to partially leaked vesicles, indicating a graded leakage mechanism instead.

    To investigate the possible reasons for the different leakage activities and to obtain mechanistic insights, we conducted 13C MAS NMR experiments. These experiments enabled us to pinpoint specific carbon sites in the different MOM-mimicking systems and to study their dynamic profile as a function of temperature. Though the OxPl-containing multilamellar vesicles (MLVs), compared with non-oxidized systems, also showed drastic dynamic changes, the molecular differences between PazePC- and PoxnoPC-containing vesicles were not significant enough to constitute a structural reason for the opposing leakage activities.

    In addition to investigating membrane dynamics, we were able to establish a novel strategy for producing cytotoxic Bax protein. This novel expression and purification strategy increased the obtained yields by an order of magnitude. By deploying a double fusion approach, we were able to inhibit both termini of the protein from exhibiting their disruptive, yield-diminishing interactions with the host cell membranes.

    In conclusion, over the course of this thesis we were able to develop fast, yet powerful tools to investigate the dynamic changes of MOM-mimicking vesicles under the influence of OxPls and pro-apoptotic Bax. In the future, these tools could be used to characterize the underlying protein-lipid interactions that are responsible for the opposing leakage activities. Due to the development of a novel Bax production strategy, future research could shift to protein-focused studies with the primary goal of determining the structure of the apoptotic Bax pore.

  • Public defence: 2018-06-01 13:15 MA121, Umeå
    Larsson, Joel
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    On random satisfiability and optimization problems2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In Paper I, we study the following optimization problem: in the complete bipartite graph where edges are given i.i.d. weights of pseudo-dimension q>0, find a perfect matching with minimal total weight. The generalized Mézard-Parisi conjecture states that the limit of this minimum exists and is given by the solution to a certain functional equation. This conjecture has been confirmed for q=1 and for q>1. We prove it for the last remaining case 0<q<1.

    In Paper II, we study generalizations of the coupon collector problem. Versions of this problem shows up naturally in various context and has been studied since the 18th century. Our focus is on using existing methods in greater generality in a unified way, so that others can avoid ad-hoc solutions.

    Papers III & IV concerns the satisfiability of random Boolean formulas. The classic model is to pick a k-CNF with m clauses on n variables uniformly at random from all such formulas. As the ratio m/n increases, the formulas undergo a sharp transition from satisfiable (w.h.p.) to unsatisfiable (w.h.p.). The critical ratio for which this occurs is called the satisfiability threshold.

    We study two variations where the signs of variables in clauses are not chosen uniformly. In paper III, variables are biased towards occuring pure rather than negated. In paper IV, there are two types of clauses, with variables in them biased in opposite directions. We relate the thresholds of these models to the threshold of the classical model.

  • Public defence: 2018-06-05 13:00 Astrid Fagraeus hörsal A103, byggnad 6E, Umeå Universitet, Umeå
    Bitar, Aziz
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Vibrio cholerae modulates the immune defense of human gut mucosa2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The key function of innate immunity is to sense danger signals and initiate effective responses as a defense mechanism against pathogens. Simultaneously, effector responses must be regulated to avoid excessive inflammation with resulting tissue damage. microRNAs (miRNAs), are small endogenous molecules, that has recently gained attention as important regulatory elements in the human inflammation cascade. The control over host miRNA expression may represent a previously uncharacterized molecular strategy exploited by pathogens to mitigate innate host cell responses.

    Vibrio cholerae is a Gram-negative bacterium that colonizes the human small intestine and causes life-threatening secretory diarrhea, essentially mediated by cholera toxin (CT). It is considered a non-invasive pathogen and does not cause clinical inflammation. Still, cholera is associated with inflammatory changes of the small intestine. Furthermore, CT-negative strains of V. cholerae cause gastroenteritis and are associated with extra-intestinal manifestations, suggesting that other virulence factors than CT are also involved in the pathogenesis.

    The innate immune response to V. cholerae is poorly investigated and the potential role of miRNA in cholera had not been studied before. Therefore, this thesis explores the role of intestinal epithelial cells in response to V. cholerae infection with a focus on regulatory miRNA as a potential contributor to the pathogenesis. The in vivo material was small intestinal biopsies from patients suffering from V. cholerae infection. As an in vitro model for V. cholerae attack on intestinal epithelium, we used tight monolayers of T84 cells infected with V. cholerae and their released factors. We analyzed changes in levels of cytokines, immunomodulatory microRNA and their target genes.

    We showed that miRNA-146a and miRNA-155 reached significantly elevated levels in the intestinal mucosa at acute stages of disease in V. cholerae infected patients and declined to normal levels at the convalescent stage. Low-grade inflammation was identified at the acute stage of V. cholerae infection, which correlated with elevated levels of regulatory miRNA. Furthermore, outer membrane vesicles (OMVs) released by the bacteria were shown to induce miR-146a and live bacteria induced miR-155 in intestinal epithelial cells. In addition, OMVs decreased epithelial permeability and caused mRNA suppression of pro-inflammatory cytokines, including immune cell attractant IL-8 and CLL20, and the inflammasome markers IL-1b and IL-18. These results propose that V. cholerae regulates the host expression of miRNA during infection and may set the threshold for activation of the intestinal epithelium.

    Moreover, we showed that V. cholerae also harbors inflammatory-inducing capabilities, by secreting a pore-forming toxin, Vibrio cholerae cytolysin (VCC). By using genetically modified strains as well as soluble protein challenge experiments, VCC was found solely responsible for the increased epithelial permeability and induction of several pro-inflammatory cytokines in intestinal epithelial cells. In contrast to OMVs, VCC displayed strong upregulation of the pro-inflammatory cytokines IL-8, TNF-a, CCL20 and IL-1b and IRAK2, a key signaling molecule in the IL-1 inflammasome pathway. This suggest that VCC is an important virulence factor in the V. cholerae pathogenesis, particularly in CT-negative strains. Furthermore, we showed that the bacterium could control the inflammatory actions of VCC by secreting the PrtV protease, which degraded VCC and consequently abolished inflammation.  

    In summary, we showed that V. cholerae harbors immunomodulating capabilities, both at the gene level, through induction of host regulatory miRNA, and at the protein level, through secretion of VCC and PrtV. These strategies may be relevant for V. cholerae to promote survival in the gut and cause successful infections in the human host.

  • Public defence: 2018-06-07 09:00 Vårdvetarhusets aula, Umeå
    Ann, Jacobsson
    Umeå University, Faculty of Medicine, Department of Nursing.
    Exploring firefighters' health and wellbeing2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: This thesis supports the assumption that firefighters’ health and mental well-being is important, in order to cope with the stress that the profession implies. As health is an essential part of everyday life, it seems substantially to understand how an almost exclusively male workforce of firefighters construct their discourse in relation to health and well-being. The overall purpose of this thesis is to explore health and ill-health among firefighters in relation to their work environment, including coping strategies, critical incidents and ‘ordinary’ day-to-day work at the fire and rescue service station.

    Methods: In Study I, 180 firefighters (16 women, 164 men) answered an open-ended question. Qualitative content analysis was used based on free text answers and focused on critical incidents. Study II, was based on a cross-sectional survey measuring burnout, psychosocial work environment and coping strategies. Participants were randomly selected and the final sample consisted of 476 firefighters (58 women, 418 men) and analyzed with multiple linear regression. In Study III and Study IV, a total of 28 fire-fighters (4 women and 24 men) participated in the study. Regarding Study IV a strategic sample of policy documents was also included. For Study III and IV, the research questions was dealt with applying critical discourse analysis on the focus group discussions (FGD) and individual interviews. In Study IV the analysed material also included policy documents.

    Results: Findings from Study I were presented in four categories; ‘overwhelming critical situations’, ‘risks of delay, ‘risk of failure’ and ‘risks to oneself’. Women in Study I described their experiences in a more distanced account, while men described their experiences more vividly. Results from Study II showed overall low mean values in the burnout scales of emotional exhaustion (EE) and depersonalization (DP) among both women and men. Only 2 % of women and 1% of men scored high levels of EE, and only 2% of women and 3% of men scored high level of DP. A multiple linear regression showed that high demand and lack of social support contributed significantly to predicting EE among men. The coping strategies among firefighters influence the level of EE and DP, and these strategies were different between women and men. In Study III six dominant themes were identified. A strong sense of the firefighter community was articulated as health promoting. The physical exercise at work and the balance between emergency and station work were also two recurrent theme supporting firefighters’ health. Another health-promoting theme concerns clarity of roles among firefighters. Peer support and tolerance in the work group was another common theme, alongside with expressions of the firefighter as hero or helper. Themes described as hindrances to health and well-being in firefighters’ discourse were; diversity, preventive work and education. All hindrance themes were articulated as important struggles in the firefighter discourse against changes in work. In Study IV, we have identified two sides in the struggles, on the one hand we have the ‘insiders’, a majority of male firefighters working in the fire and rescue services representing a collective defending its autonomy and traditions. On the other hand we have the ‘outsiders’, represented by the government, the Swedish Civil Contingencies Agency, (MSB), municipalities, politicians at different levels and academic researchers.

    Conclusion: Firefighters described critical incidents at work as overwhelming situations, along with negative experiences of organizational and practical tasks. Despite these experiences firefighters were reported as healthy according to EE and DP (Study I and II). Results of Study II also showed a relationship between psychosocial work environment and burnout among men, but not among women. The coping strategies among firefighters influence the level of burnout, and these strategies differ between women and men. The well-being in firefighters’ discourse, at least partly, is gained from a strong sense of belonging to a homosocial group characterized by closeness to each other and peers who take care of each other. The firefighters in our studies articulate this community-sense, and describe the importance of the similarity, rather than diversity (Studies III and IV). Findings from our studies regarding health and well-being, add knowledge to the current explanations relating to firefighters’ resistance to change.

  • Public defence: 2018-06-08 09:00 N320, Naturvetarhuset, Umeå
    Lindfors, Maria
    Umeå University, Faculty of Science and Technology, Department of Science and Mathematics Education.
    "Kunskap är vad du vet, och vet du inte kan du alltid googla!": elevers epistemic beliefs i naturvetenskaplig undervisningskontext2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    One important goal of science education is to help students develop an adequate understanding of what science is and how it is done. An understanding of science includes epistemic beliefs, that is, individuals’ beliefs about the nature of knowledge, how knowledge is constructed, and how knowledge can be justified. The epistemic beliefs are hypothesized to exist on a continuum ranging from naïve to sophisticated. Students’ epistemic beliefs and their epistemic cognition have been shown to influence various facets of learning. The overarching purpose of this thesis is to contribute to our knowledge and understanding of the role played by epistemic beliefs within the context of science education. The thesis intended to answer the following three general questions within a scientific context: 1) What prerequisites for drawing conclusions about epistemic beliefs are given based on the choice of questionnaire as a measurement method, including its design and content? 2) What is the relation between students’ epistemic beliefs and other phenomena that are important in learning situations? 3) What is the relation between students’ epistemic beliefs and their epistemic practices?

    The studies used both quantitative and qualitative methods to examine students’ epistemic beliefs and epistemic practices. Data sources included questionnaires, video and screen observations, and semi-structured interviews. Participants in the studies were students in Grade 5-11 in Sweden and Germany. A series of four papers address the purpose of the thesis and respond to the three general questions. The first paper investigate relations between students’ epistemic beliefs and perceived classroom characteristics and whether differences could be found between the two countries. The second paper investigate the relative importance of epistemic beliefs dimensions for predicting achievement goals in Grade 5 through 11, in both a cross-sectional and a longitudinal study. The third paper explore the relationships between students’ scientific epistemic beliefs, their problemsolving process, and the quality of solutions produced by students. Finally, the fourth paper describe students’ epistemic practices of problem solving in science and their sense making in the moment, to deepen the understanding of the process of the students’ epistemic cognition. In relation to the first question, results indicate that the chosen measurement method for epistemic beliefs generates certain prerequisites for how epistemic beliefs can be understood and characterized. This in turn may have consequences when epistemic beliefs are studied in relation to, for example, other phenomena and epistemic practices. With regard to the second question, findings show that there are many relationships between epistemic beliefs and other phenomena, but also that they are in many cases context and/or situation dependent. Regarding the third question, the results point out that the relationship between students’ epistemic beliefs and their epistemic practices should be understood by how the students show, through words and actions, that they understand what the situation requires. Thus, there is no universal relationship between sophisticated epistemic beliefs and successful epistemic practices. It can be concluded that students’ epistemic beliefs do not exist in a vacuum without interacting with other phenomena, but that they depend on the surrounding context or situation in different ways. More studies that take into account different types of situations are required. This would in turn most likely also contribute to a better understanding of how students’ epistemic beliefs, epistemic cognition, and epistemic practices develop in relation to the surrounding teaching context.

  • Public defence: 2018-06-08 09:00 Aulan, Vårdvetarhuset, Umeå
    Molin, Jenny
    Umeå University, Faculty of Medicine, Department of Nursing.
    Time Together: a nursing intervention targeting everyday life in psychiatric inpatient care : patient and staff perspectives2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Patient and staff descriptions of everyday life in psychiatric inpatient care are consistent, revealing a challenging environment with over-reliance on medication and, power imbalances. Patients and staff ask for the opportunity to develop relationships; however, the literature on nursing interventions targeting these issues is sparse. This thesis comprises four studies with a twofold overall aim. The first part constructs a theoretical understanding of everyday life processes in psychiatric inpatient care, and the second part evaluates a nursing intervention in psychiatric inpatient care.

    Methods: Studies I and II used a grounded theory design with individual interviews (I, II), dyadic interviews (II) and focus group discussions (II). Study III used mixed methods, a single system experimental design with questionnaires and a qualitative process evalu­ation with logs and participant observations. Study IV used a qualitative design with individual semi structured interviews. The participants were 16 patients with experiences of psychiatric inpatient care (I), 36 staff members who worked in psychiatric inpatient care (II), 80 patients and 50 staff members in the evaluated wards (III) and 11 patients who had taken part in the nursing intervention Time Together (IV). In studies I and II the analysis followed grounded theory. In study III data were subjected to visual analysis, per­centage of non-overlapping data and qualitative content analysis, also used in study IV.

    Results: Patients in psychiatric inpatient care experienced everyday life as being influenced by interactions between patients and staff, the environment and the content of care. The quality of interactions was what tied these components together. Having trustful interactions could compensate for an otherwise poor environment and a confusing care content, while adapting to absence of, or obstructive interactions contributed to experiences of the environment as stigmatizing and the care content as confusing (I). Staff had ideals regarding everyday life on the wards but obstacles hindered them from putting their ideals into practice. To cope with this, they appeared to shift their focus from the patient’s best to their own survival. This resignation made it even more difficult for them to work in a way that aligned with their ideals (II). The theoretical understanding that was constructed from study I and II revealed that what patients described as absent or obstructive interactions, or passivity, were mirrored by staff descriptions of obstacles in their everyday life on the wards. Furthermore, what patients described as trustful inter­actions and satisfying activities were mirrored by staff descriptions of having the patients’ best interest at heart. This is interpreted as when staff is able to focus on the patients’ best interests, improvements in the everyday life in psychiatric inpatient care are possible.

    The nursing intervention called Time Together was feasible to introduce in psychiatric inpatient care. The intervention was enabled by shared responsibility, a friendly approach and a predictable structure, whilst it was hindered by a distant approach and unpredictable structure. Measurements showed no effect on the quality of interactions between patients and staff, but questionable effects on perceived stress and stress of conscience among staff, as well as on staff satisfaction with interactions with patients (III). Patients described their experiences of taking part in the intervention as being seen as a human among other humans, that it contributed to hope for recovery but also, that feelings of distance to staff were fostered when Time Together sessions were not offered (IV).

    Conclusion: By implementing Time Together in psychiatric inpatient care, staff is allowed access to a nursing intervention that can meet patients’ needs for high-quality interactions in everyday life and that may have potential to decrease perceived stress and stress of conscience among staff and increase their satisfaction with interactions with patients. By using joint activities as bridging actions, this intervention could lead to the development of nurse-patient relationships built on reciprocity and engagement, something that is emphasised in recovery-oriented mental health nursing.

  • Public defence: 2018-06-08 10:00 Lilla hörsalen, KB.E3.01, Umeå
    Chrobok, Daria
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    To “leaf” or not to “leaf”: Understanding the metabolic adjustments associated with leaf senescence2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The adequate execution of the final developmental stage of a leaf, leaf senescence, is crucial to the long-term survival of the plant. During senescence cellular structures like membranes, proteins, lipids and macromolecules are degraded and released nutrients are relocated to developing parts of the plant, such as young leaves, stems, flowers, siliques and ultimately seeds that are dependent on this nutrient remobilization. The first visible sign of senescence is the yellowing of leaves indicating the degradation of chlorophyll and the dismantling of chloroplasts. As a consequence, senescing leaves cannot perform photosynthesis anymore and the delivery of energy from the chloroplast is compromised. As chloroplasts lose their function, the course of the senescence program requires a stable alternative energy sources that support nutrient remobilization while simultaneously ensuring a basic metabolism.

    To study leaf senescence I used the model plant Arabidopsis thaliana and applied different experimental approaches: Developmental Leaf Senescence (DLS), individual darkened leaves (IDL), completely darkened plants (DP) and a stay-green mutant which displays a delayed senescence phenotype during IDL. Using a combination of physiological, microscopic, transcriptomic and metabolomic analyses similarities and differences between these experimental setups were investigated with focus on the functions of mitochondria during leaf senescence.

    The catabolism of amino acids and the subsequent release of glutamate into the mitochondrial matrix seem to play an important role for nitrogen remobilization during DLS and IDL. Glutamate is then transported to the cytoplasm and transformed into glutamine, which can serve as long distance nitrogen export metabolite in the plant. Furthermore, senescing leaves in IDL are not only source tissues for nutrient remobilization in the plant, but we also detected labelled carbon in the darkened leaves, indicating a communication between the IDL and leaves in light. In contrary to the senescence inducing systems of DLS and IDL, in DP and the stay-green mutant investigated here, senescence is not induced by dark treatment. In both experimental setups we measured an accumulation of amino acids in the darkened leaves, in particular those with high N content. This could make reduced carbon available as alternative energy source during darkness. In this thesis we observed that mitochondria play an important role in nutrient reallocation processes during leaf senescence. The overall energy status of senescing tissues depends on mitochondria and especially amino acid metabolism seems to have a vital role during the senescence processes both for energy supply and nutrient reallocation.

  • Public defence: 2018-06-08 10:15 S213H, Umeå
    Nilsson Blom, Marcus
    Umeå University, Faculty of Social Sciences, Department of Social Work.
    Opioidberoende: en studie om beroendevården och det sociala sammanhangets betydelse2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Opioid dependence is highly associated with health problems relating to physical health (infectious diseases) as well as mental health (depression, anxiety, antisocial behavior). In addition, research has found an association between use of opioids and increased risk of premature death as a consequence of overdose or other circumstances, such as suicide. Furthermore, opioid dependent individuals experience a high level of social exclusion and problems with relationships, housing, income and livelihood. Overall, there is a connection between opioid dependence and physical, psychological and social vulnerability as well as premature death.

    The importance of social cohesion has rarely been the focus in research on opioid dependence. Therefore, there is a need to further explore whether differences in outcomes (medication assisted treatment, mortality and co-morbidity) in addition to individual characteristics, can be derived from social aspects of the opioid dependent individual’s life.

    The overall aim of the dissertation is to examine individual and social factors among individuals who are dependent on opioids and how they are associated with outcomes relating to: a) medication assisted treatment; and b) mortality and co-morbidity.

    This dissertation is based on data from four different registers. The first and second sub-studies use ASI data. The third uses DOK data from the National Board of Institutions (SiS) and the Death Registry (National Board of Health and Welfare). The fourth study is based on both DOKdata and data from the national patient registry (National Board of Health and Welfare).

    Overall, this dissertation confirms the understanding of opioid dependence as associated with a high level of vulnerability. This dissertation shows that opioid dependence is characterized by extensive care efforts, low levels of employment, and a high level of mental health and comorbidity.

    This dissertation shows that the characteristics related to the social network (parenting, work and education) are of significance for being in treatment, but also remaining in care (medication assisted treatment), which in turn promotes the individual's health and long-term health development. In that, this dissertation shows that for individuals dependent on opioids, there is an association between being part of a social network and favorable health development.

  • Public defence: 2018-06-08 13:00 Sal N420, Umeå
    Bohlin, Ludvig
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Toward higher-order network models2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Complex systems play an essential role in our daily lives. These systems consist of many connected components that interact with each other. Consider, for example, society with billions of collaborating individuals, the stock market with numerous buyers and sellers that trade equities, or communication infrastructures with billions of phones, computers and satellites.

    The key to understanding complex systems is to understand the interaction patterns between their components - their networks. To create the network, we need data from the system and a model that organizes the given data in a network representation. Today's increasing availability of data and improved computational capacity for analyzing networks have created great opportunities for the network approach to further prosper. However, increasingly rich data also gives rise to new challenges that question the effectiveness of the conventional approach to modeling data as a network. In this thesis, we explore those challenges and provide methods for simplifying and highlighting important interaction patterns in network models that make use of richer data.

    Using data from real-world complex systems, we first show that conventional network modeling can provide valuable insights about the function of the underlying system. To explore the impact of using richer data in the network representation, we then expand the analysis for higher-order models of networks and show why we need to go beyond conventional models when there is data that allows us to do so. In addition, we also present a new framework for higher-order network modeling and analysis. We find that network models that capture richer data can provide more accurate representations of many real-world complex systems.

  • Public defence: 2018-06-08 13:00 MA121, Umeå
    Bayisa, Fekadu Lemessa
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Statistical methods in medical image estimation and sparse signal recovery2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis presents work on methods for the estimation of computed tomography (CT) images from magnetic resonance (MR) images for a number of diagnostic and therapeutic workflows. The study also demonstrates sparse signal recovery method, which is an intermediate method for magnetic resonance image reconstruction. The thesis consists of four articles. The first three articles are concerned with developing statistical methods for the estimation of CT images from MR images. We formulated spatial and non-spatial models for CT image estimation from MR images, where the spatial models include hidden Markov model (HMM) and hidden Markov random field model (HMRF) while the non-spatial models incorporate Gaussian mixture model (GMM) and skewed-Gaussian mixture model (SGMM). The statistical models are estimated via a maximum likelihood approach using the EM-algorithm in GMM and SGMM, the EM gradient algorithm in HMRF and the Baum–Welch algorithm in HMM. We have also examined CT image estimation using GMM and supervised statistical learning methods. The performance of the models is evaluated using cross-validation on real data. Comparing CT image estimation performance of the models, we have observed that GMM combined with supervised statistical learning method has the best performance, especially on bone tissues. The fourth article deals with a sparse modeling in signal recovery. Using spike and slab priors on the signal, we formulated a sparse signal recovery problem and developed an adaptive algorithm for sparse signal recovery. The developed algorithm has better performance than the recent iterative convex refinement (ICR) algorithm. The methods introduced in this work are contributions to the lattice process and signal processing literature. The results are an input for the research on replacing CT images by synthetic or pseudo-CT images, and for an efficient way of recovering sparse signal.

  • Public defence: 2018-06-08 13:00 Karl Kempe Salen, Umeå
    Pourbozorgi Langroudi, Parham
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Insights into the roles of the essential Pfh1 DNA helicase in the nuclear and mitochondrial genomes2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Eukaryotic cells have two sets of genomes, the nuclear and mitochondrial, and both need to be accurately maintained. Also, the rate of transcription must be precisely regulated in these genomes. However, there are many natural barriers that dysregulate these processes. The aim of this thesis was to enhance our understanding of the Schizosaccharomyces pombe, Pif1 family helicase, Pfh1, and its roles in the nuclear and mitochondrial genomes. The S. pombe genome contains 446 predicted Gquadruplex (G4) structures. By circular dichroism and Thioflavin-T assay we demonstrated that sequences from the ribosomal DNA (rDNA) and telomeres form G4 structures in vitro. The recombinant nuclear isoform of Pfh1 bound and unwound these G4 structures. Also, by chromatin immunoprecipitation combined with quantitative PCR (ChIP-qPCR), we showed that Pfh1 binds these sequences in vivo. This work provides evidence that G4 structure formation in the rDNA and telomere regions is biologically important and that unwinding of G4 structures is a conserved property of Pif1 family helicases. Using ChIP-seq we found that Pfh1 binds to natural fork barriers, such as highly transcribed genes, and nucleosome depleted regions, and that replication through these sites were dependent on Pfh1. By immunoaffinity precipitation combined with mass spectrometry, Pfh1 interacted with several replisome components, as well as DNA repair proteins, and mitochondrial proteins. Furthermore, Pfh1 moved with similar kinetics as the leading strand polymerase. These findings suggest that Pfh1 is needed at natural fork barriers to promote fork progression, and that it is not just recruited to its target sites but moves with the replisome. Based on these findings, we anticipated that lack of Pfh1 would affect expression of highly transcribed genes. By performing genome-wide transcriptome analysis of S. pombe in the absence of Pfh1, we showed that highly transcribed genes are downregulated more often than other genes. Furthermore, combining absence of Pfh1 together with Topoisomerase 1 (Top1), resulted in slower cell growth, reduced DNA synthesis rate compared to single mutants, and upregulation of genes associated with DNA repair and apoptosis. These data suggest that, cells lacking both Pfh1 and Top1 have severe problem in maintaining their genomes. By ChIP-qPCR analysis we showed that Pfh1 and Top1 directly bind to mitochondrial DNA. In addition, these cells upregulated many metabolic pathways and lost about 80% of their mtDNA. These data suggest that both Pfh1 and Top1 are required for maintenance of mtDNA. This is the first evidence showing that Top1 is present in S. pombe mitochondria. In conclusion, Pfh1 directly binds mitochondrial DNA, and natural fork barriers in the nuclear DNA, such as G4 structures. In the nucleus, Pfh1 is part of the replisome. Cells lacking Pfh1 and Top1 grow slower, rapidly lose their mitochondrial DNA, have slower nuclear DNA synthesis, and induce apoptotic pathways. Finally, this thesis emphasizes the importance of both Pfh1 and Top1 in maintaining the nuclear and mitochondrial genomes.

  • Public defence: 2018-06-11 10:15 Hörsal E, Umeå
    Larsson, Magnus
    Umeå University, Faculty of Social Sciences, Department of Sociology.
    National environmental evaluation systems: guiding towards sustainability?2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Dealing with environmental threats is one of the largest, if not the largest, challenge contemporary societies face. One way to better deal with this challenge would be to produce knowledge that can be used to improve environmental work and environmental policy and thus ultimately contribute to sustainable development. National environmental evaluations, which this thesis explores, could potentially fill this function because they are supposed to generate applicable and useful knowledge for improving environmental policy and practice for a sustainable transition. However, what different environmental actors view as useful knowledge varies, and needs to be empirically investigated. Against this background, the aim of this thesis is to investigate whether, and how, national environmental evaluation systems contribute to key actors’ environmental work and sustainable development. The thesis explores two national environmental evaluation systems in Sweden.

    Method: A mixed methods approach is applied that combines three methods. Firstly, a narrative synthesis is developed and applied to compile a list of sustainable development effects from national environmental evaluations. Secondly, a critical program theory is used to investigate the evaluation system’s underlying logic and to assess the likelihood of it achieving its intended effects. Thirdly, a directed content analysis is used to explore the usability and use of environmental evaluations and evaluation systems. The methods are applied to various documents, interviews with key actors, and observations at two environmental seminars.

    Results: The results show that, to contribute to sustainable development in the context of evaluation systems and network governance, environmental evaluations need to be of sufficient quality and meet different stakeholders’ knowledge needs. However, only some evaluations meet this demand. The main value of national environmental evaluations and evaluation systems is that they reinforce the national objectives, provide a recurrent report on achievement of objectives, and push actors to take responsibility to improve their environmental work.