umu.sePublications
Change search
Refine search result
1234567 51 - 100 of 662
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 51.
    Billing, Ola
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kao, Gautam
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Mitochondrial function is required for secretion of DAF-28/insulin in C. elegans.2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 1, p. e14507-Article in journal (Refereed)
    Abstract [en]

    While insulin signaling has been extensively studied in Caenorhabditis elegans in the context of ageing and stress response, less is known about the factors underlying the secretion of insulin ligands upstream of the insulin receptor. Activation of the receptor governs the decision whether to progress through the reproductive lifecycle or to arrest growth and enter hibernation. We find that animals with reduced levels of the mitochondrial outer membrane translocase homologue TOMM-40 arrest growth as larvae and have decreased insulin signaling strength. TOMM-40 acts as a mitochondrial translocase in C. elegans and in its absence animals fail to import a mitochondrial protein reporter across the mitochondrial membrane(s). Inactivation of TOMM-40 evokes the mitochondrial unfolded protein response and causes a collapse of the proton gradient across the inner mitochondrial membrane. Consequently these broadly dysfunctional mitochondria render an inability to couple food abundance to secretion of DAF-28/insulin. The secretion defect is not general in nature since two other neuropeptides, ANF::GFP and INS-22::VENUS, are secreted normally. RNAi against two other putative members of the TOMM complex give similar phenotypes, implying that DAF-28 secretion is sensitive to mitochondrial dysfunction in general. We conclude that mitochondrial function is required for C. elegans to secrete DAF-28/insulin when food is abundant. This modulation of secretion likely represents an additional level of control over DAF-28/insulin function.

  • 52.
    Billing, Ola
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Natarajan, Balasubramanian
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Mohammed, Ateequrrahman
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Kao, Gautam
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    A directed RNAi screen based on larval growth arrest reveals new modifiers of C. elegans insulin signaling2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4, p. e34507-Article in journal (Refereed)
    Abstract [en]

    Genes regulating Caenorhabditis elegans insulin/IGF signaling (IIS) have largely been identified on the basis of their involvement in dauer development or longevity. A third IIS phenotype is the first larval stage (L1) diapause, which is also influenced by asna-1, a regulator of DAF-28/insulin secretion. We reasoned that new regulators of IIS strength might be identified in screens based on the L1 diapause and the asna-1 phenotype. Eighty-six genes were selected for analysis by virtue of their predicted interaction with ASNA-1 and screened for asna-1-like larval arrest. ykt-6, mrps-2, mrps-10 and mrpl-43 were identified as genes which, when inactivated, caused larval arrest without any associated feeding defects. Several tests indicated that IIS strength was weaker and that insulin secretion was defective in these animals. This study highlights the role of the Golgi network and the mitochondria in insulin secretion and provides a new list of genes that modulate IIS in C. elegans.

  • 53.
    Bitar, Aziz
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    De, Rituparna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Melgar, Silvia
    Aung, Kyaw Min
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Rahman, Arman
    Qadri, Firdausi
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Shirin, Tahmina
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Induction of immunomodulatory miR-146a and miR-155 in small intestinal epithelium of Vibrio cholerae infected patients at acute stage of cholera2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 3, article id 0173817Article in journal (Refereed)
    Abstract [en]

    The potential immunomodulatory role of microRNAs in small intestine of patients with acute watery diarrhea caused by Vibrio cholerae O1 or enterotoxigenic Escherichia coli (ETEC) infection was investigated. Duodenal biopsies were obtained from study-participants at the acute (day 2) and convalescent (day 21) stages of disease, and from healthy individuals. Levels of miR-146a, miR-155 and miR-375 and target gene (IRAK1, TRAF6, CARD10) and 11 cytokine mRNAs were determined by qRT-PCR. The cellular source of microRNAs in biopsies was analyzed by in situ hybridization. The ability of V. cholerae bacteria and their secreted products to cause changes in microRNA- and mRNA levels in polarized tight monolayers of intestinal epithelial cells was investigated. miR-146a and miR-155 were expressed at significantly elevated levels at acute stage of V. cholerae infection and declined to normal at convalescent stage (P<0.009 versus controls; P = 0.03 versus convalescent stage, pairwise). Both microRNAs were mainly expressed in the epithelium. Only marginal down-regulation of target genes IRAK1 and CARD10 was seen and a weak cytokine-profile was identified in the acute infected mucosa. No elevation of microRNA levels was seen in ETEC infection. Challenge of tight monolayers with the wild type V. cholerae O1 strain C6706 and clinical isolates from two study-participants, caused significant increase in miR-155 and miR-146a by the strain C6706 (P<0.01). One clinical isolate caused reduction in IRAK1 levels (P<0.05) and none of the strains induced inflammatory cytokines. In contrast, secreted factors from these strains caused markedly increased levels of IL-8, IL-1β, and CARD10 (P<0.001), without inducing microRNA expression. Thus, miR-146a and miR-155 are expressed in the duodenal epithelium at the acute stage of cholera. The inducer is probably the V. cholerae bacterium. By inducing microRNAs the bacterium can limit the innate immune response of the host, including inflammation evoked by its own secreted factors, thereby decreasing the risk of being eliminated.

  • 54. Bjerg, Anders
    et al.
    Ekerljung, Linda
    Eriksson, Jonas
    Olafsdóttir, Inga Sif
    Middelveld, Roelinde
    Franklin, Karl A.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Forsberg, Bertil
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Larsson, Kjell
    Lötvall, Jan
    Torén, Kjell
    Dahlén, Sven-Erik
    Lundbäck, Bo
    Janson, Christer
    Higher risk of wheeze in female than male smokers: results from the Swedish GA(2)LEN study2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, article id e54137Article in journal (Refereed)
    Abstract [en]

    Background: Women who smoke have higher risk of lung function impairment, COPD and lung cancer than smoking men. An influence of sex hormones has been demonstrated, but the mechanisms are unclear and the associations often subject to confounding. This was a study of wheeze in relation to smoking and sex with adjustment for important confounders.

    Methods: In 2008 the Global Allergy and Asthma European Network (GA2LEN) questionnaire was mailed to 45.000 Swedes (age 16–75 years), and 26.851 (60%) participated. “Any wheeze”: any wheeze during the last 12 months. “Asthmatic wheeze”: wheeze with breathlessness apart from colds.

    Results: Any wheeze and asthmatic wheeze was reported by 17.3% and 7.1% of women, vs. 15.8% and 6.1% of men (both p<0.001). Although smoking prevalence was similar in both sexes, men had greater cumulative exposure, 16.2 pack-years vs. 12.8 in women (p<0.001). Most other exposures and characteristics associated with wheeze were significantly overrepresented in men. Adjusted for these potential confounders and pack-years, current smoking was a stronger risk factor for any wheeze in women aged <53 years, adjusted odds ratio (aOR) 1.85 (1.56–2.19) vs. 1.60 (1.30–1.96) in men. Cumulative smoke exposure and current smoking each interacted significantly with female sex, aOR 1.02 per pack-year (p<0.01) and aOR 1.28 (p = 0.04) respectively. Female compared to male current smokers also had greater risk of asthmatic wheeze, aOR 1.53 vs. 1.03, interaction aOR 1.52 (p = 0.02). These interactions were not seen in age ≥53 years.

    Discussion: In addition to the increased risk of COPD and lung cancer female, compared to male, smokers are at greater risk of significant wheezing symptoms in younger age. This became clearer after adjustment for important confounders including cumulative smoke exposure. Estrogen has previously been shown to increase the bioactivation of several compounds in tobacco smoke, which may enhance smoke-induced airway inflammation in fertile women.

  • 55.
    Bjerg, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Ekerljung, Linda
    Middelveld, Roelinde
    Dahlén, Sven-Erik
    Forsberg, Bertil
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Franklin, Karl
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Larsson, Kjell
    Lötvall, Jan
    Ólafsdóttir, Inga Sif
    Torén, Kjell
    Lundbäck, Bo
    Janson, Christer
    Increased prevalence of symptoms of rhinitis but not of asthma between 1990 and 2008 in Swedish adults: comparisons of the ECRHS and GA2LEN surveys2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 2, p. e16082-Article in journal (Refereed)
    Abstract [en]

    Background

    The increase in asthma prevalence until 1990 has been well described. Thereafter, time trends are poorly known, due to the low number of high quality studies. The preferred method for studying time trends in prevalence is repeated surveys of similar populations. This study aimed to compare the prevalence of asthma symptoms and their major determinants, rhinitis and smoking, in Swedish young adults in 1990 and 2008.

    Methods

    In 1990 the European Community Respiratory Health Survey (ECRHS) studied respiratory symptoms, asthma, rhinitis and smoking in a population-based sample (86% participation) in Sweden. In 2008 the same symptom questions were included in the Global Allergy and Asthma European Network (GA2LEN) survey (60% participation). Smoking questions were however differently worded. The regions (Gothenburg, Uppsala, Umeå) and age interval (20–44 years) surveyed both in 1990 (n = 8,982) and 2008 (n = 9,156) were analysed.

    Results

    The prevalence of any wheeze last 12 months decreased from 20% to 16% (p<0.001), and the prevalence of “asthma-related symptoms” was unchanged at 7%. However, either having asthma attacks or using asthma medications increased from 6% to 8% (p<0.001), and their major risk factor, rhinitis, increased from 22% to 31%. Past and present smoking decreased.

    Conclusion

    From 1990 to 2008 the prevalence of obstructive airway symptoms common in asthma did not increase in Swedish young adults. This supports the few available international findings suggesting the previous upward trend in asthma has recently reached a plateau. The fact that wheeze did not increase despite the significant increment in rhinitis, may at least in part be due to the decrease in smoking.

  • 56. Bjorck, Lena
    et al.
    Rosengren, Annika
    Winkvist, Anna
    Capewell, Simon
    Adiels, Martin
    Bandosz, Piotr
    Critchley, Julia
    Boman, Kurt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Guzman-Castillo, Maria
    O'Flaherty, Martin
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Changes in Dietary Fat Intake and Projections for Coronary Heart Disease Mortality in Sweden: A Simulation Study2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 8, article id e0160474Article in journal (Refereed)
    Abstract [en]

    Objective In Sweden, previous favourable trends in blood cholesterol levels have recently levelled off or even increased in some age groups since 2003, potentially reflecting changing fashions and attitudes towards dietary saturated fatty acids (SFA). We aimed to examine the potential effect of different SFA intake on future coronary heart disease (CHD) mortality in 2025. Methods We compared the effect on future CHD mortality of two different scenarios for fat intake a) daily SFA intake decreasing to 10 energy percent (E%), and b) daily SFA intake rising to 20 E %. We assumed that there would be moderate improvements in smoking (5%), salt intake (1g/day) and physical inactivity (5% decrease) to continue recent, positive trends. Results In the baseline scenario which assumed that recent mortality declines continue, approximately 5,975 CHD deaths might occur in year 2025. Anticipated improvements in smoking, dietary salt intake and physical activity, would result in some 380 (-6.4%) fewer deaths (235 in men and 145 in women). In combination with a mean SFA daily intake of 10 E%, a total of 810 (-14%) fewer deaths would occur in 2025 (535 in men and 275 in women). If the overall consumption of SFA rose to 20 E%, the expected mortality decline would be wiped out and approximately 20 (0.3%) additional deaths might occur. Conclusion CHD mortality may increase as a result of unfavourable trends in diets rich in saturated fats resulting in increases in blood cholesterol levels. These could cancel out the favourable trends in salt intake, smoking and physical activity.

  • 57.
    Björklund, Emmelie
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Blomqvist, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Joel, Hedlin
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Persson, Emma
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Fowler, Christopher
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Involvement of Fatty Acid Amide Hydrolase and Fatty Acid Binding Protein 5 in the Uptake of Anandamide by Cell Lines with Different Levels of Fatty Acid Amide Hydrolase Expression: A Pharmacological Study2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, p. e103479-Article in journal (Refereed)
    Abstract [en]

    Background:

    The endocannabinoid ligand anandamide (AEA) is removed from the extracellular space by a process ofcellular uptake followed by metabolism. In many cells, such as the RBL-2H3 cell line, inhibition of FAAH activity reduces theobserved uptake, indicating that the enzyme regulates uptake by controlling the intra- : extracellular AEA concentrationgradient. However, in other FAAH-expressing cells, no such effect is seen. It is not clear, however, whether these differencesare methodological in nature or due to properties of the cells themselves. In consequence, we have reinvestigated the roleof FAAH in gating the uptake of AEA.Methodology/Principal Findings: The effects of FAAH inhibition upon AEA uptake were investigated in four cell lines: AT1rat prostate cancer, RBL-2H3 rat basophilic leukaemia, rat C6 glioma and mouse P19 embryonic carcinoma cells. SemiquantitativePCR for the cells and for a rat brain lysate confirmed the expression of FAAH. No obvious expression of atranscript with the expected molecular weight of FLAT was seen. FAAH expression differed between cells, but all four couldaccumulate AEA in a manner inhibitable by the selective FAAH inhibitor URB597. However, there was a difference in thesensitivities seen in the reduction of uptake for a given degree of FAAH inhibition produced by a reversible FAAH inhibitor,with C6 cells being more sensitive than RBL-2H3 cells, despite rather similar expression levels and activities of FAAH. Thefour cell lines all expressed FABP5, and AEA uptake was reduced in the presence of the FABP5 inhibitor SB-FI-26, suggestingthat the different sensitivities to FAAH inhibition for C6 and RBL2H3 cells is not due to differences at the level of FABP-5.Conclusions/Significance: When assayed using the same methodology, different FAAH-expressing cells display differentsensitivities of uptake to FAAH inhibition.

  • 58.
    Björklund, Emmelie
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Increased expression of cannabinoid CB(1) receptors in achilles tendinosis2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 9, p. e24731-Article in journal (Refereed)
    Abstract [en]

    Background: The endogenous cannabinoid system is involved in the control of pain. However, little is known as to the integrity of the cannabinoid system in human pain syndromes. Here we investigate the expression of the cannabinoid receptor 1 (CB(1)) in human Achilles tendons from healthy volunteers and from patients with Achilles tendinosis.

    Methodology: Cannabinoid CB(1) receptor immunoreactivity (CB(1)IR) was evaluated in formalin-fixed biopsies from individuals suffering from painful Achilles tendinosis in comparison with healthy human Achilles tendons.

    Principal Findings: CB(1)IR was seen as a granular pattern in the tenocytes. CB(1)IR was also observed in the blood vessel wall and in the perineurium of the nerve. Quantification of the immunoreactivity in tenocytes showed an increase of CB(1) receptor expression in tendinosis tissue compared to control tissue.

    Conclusion: Expression of cannabinoid receptor 1 is increased in human Achilles tendinosis suggesting that the cannabinoid system may be dysregulated in this disorder.

  • 59.
    Björklund, Emmelie
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Larsson, Therese N. L.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Jacobsson, Stig O. P.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Ketoconazole Inhibits the Cellular Uptake of Anandamide via Inhibition of FAAH at Pharmacologically Relevant Concentrations2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 1, p. e87542-Article in journal (Refereed)
    Abstract [en]

    Background: The antifungal compound ketoconazole has, in addition to its ability to interfere with fungal ergosterol synthesis, effects upon other enzymes including human CYP3A4, CYP17, lipoxygenase and thromboxane synthetase. In the present study, we have investigated whether ketoconazole affects the cellular uptake and hydrolysis of the endogenous cannabinoid receptor ligand anandamide (AEA). Methodology/Principal Findings: The effects of ketoconazole upon endocannabinoid uptake were investigated using HepG2, CaCo2, PC-3 and C6 cell lines. Fatty acid amide hydrolase (FAAH) activity was measured in HepG2 cell lysates and in intact C6 cells. Ketoconazole inhibited the uptake of AEA by HepG2 cells and CaCo2 cells with IC50 values of 17 and 18 mu M, respectively. In contrast, it had modest effects upon AEA uptake in PC-3 cells, which have a low expression of FAAH. In cell-free HepG2 lysates, ketoconazole inhibited FAAH activity with an IC50 value (for the inhibitable component) of 34 mu M. Conclusions/Significance: The present study indicates that ketoconazole can inhibit the cellular uptake of AEA at pharmacologically relevant concentrations, primarily due to its effects upon FAAH. Ketoconazole may be useful as a template for the design of dual-action FAAH/CYP17 inhibitors as a novel strategy for the treatment of prostate cancer.

  • 60.
    Blanco-Rivero, Amaya
    et al.
    Madrid, Spain.
    Shutova, Tatiana
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    José Román, María
    Madrid, Spain.
    Villarejo, Arsenio
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Department of Biology, Universidad Autónoma de Madrid, Madrid, Spain.
    Martinez, Flor
    Madrid, Spain.
    Phosphorylation Controls the Localization and Activation of the Lumenal Carbonic Anhydrase in Chlamydomonas reinhardtii2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 11, article id e49063Article in journal (Refereed)
    Abstract [en]

    Background: Cah3 is the only carbonic anhydrase (CA) isoform located in the thylakoid lumen of Chlamydomonas reinhardtii. Previous studies demonstrated its association with the donor side of the photosystem II (PSII) where it is required for the optimal function of the water oxidizing complex. However this enzyme has also been frequently proposed to perform a critical function in inorganic carbon acquisition and CO2 fixation and all mutants lacking Cah3 exhibit very poor growth after transfer to low CO2 conditions. Results/Conclusions: In the present work we demonstrate that after transfer to low CO2, Cah3 is phosphorylated and that phosphorylation is correlated to changes in its localization and its increase in activity. When C. reinhardtii wild-type cells were acclimated to limiting CO2 conditions, the Cah3 activity increased about 5-6 fold. Under these conditions, there were no detectable changes in the level of the Cah3 polypeptide. The increase in activity was specifically inhibited in the presence of Staurosporine, a protein kinase inhibitor, suggesting that the Cah3 protein was post-translationally regulated via phosphorylation. Immunoprecipitation and in vitro dephosphorylation experiments confirm this hypothesis. In vivo phosphorylation analysis of thylakoid polypeptides indicates that there was a 3-fold increase in the phosphorylation signal of the Cah3 polypeptide within the first two hours after transfer to low CO2 conditions. The increase in the phosphorylation signal was correlated with changes in the intracellular localization of the Cah3 protein. Under high CO2 conditions, the Cah3 protein was only associated with the donor side of PSII in the stroma thylakoids. In contrast, in cells grown at limiting CO2 the protein was partly concentrated in the thylakoids crossing the pyrenoid, which did not contain PSII and were surrounded by Rubisco molecules. Significance: This is the first report of a CA being post-translationally regulated and describing phosphorylation events in the thylakoid lumen.

  • 61.
    Blennow, Kristina
    et al.
    Sveriges lantbruksuniversitet.
    Persson, Johannes
    Lunds Universitet.
    Persson, Erik
    Sveriges lantbruksuniversitet.
    Hanewinkel, Mark
    University of Freiburg.
    Forest Owners' Response to Climate Change: University Education Trumps Value Profile2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 5, article id e0155137Article in journal (Refereed)
    Abstract [en]

    Do forest owners' levels of education or value profiles explain their responses to climatechange? The cultural cognition thesis (CCT) has cast serious doubt on the familiar andoften criticized "knowledge deficit" model, which says that laypeople are less concernedabout climate change because they lack scientific knowledge. Advocates of CCT maintainthat citizens with the highest degrees of scientific literacy and numeracy are not the mostconcerned about climate change. Rather, this is the group in which cultural polarization isgreatest, and thus individuals with more limited scientific literacy and numeracy are moreconcerned about climate change under certain circumstances than those with higher scientificliteracy and numeracy. The CCT predicts that cultural and other values will trump thepositive effects of education on some forest owners' attitudes to climate change. Here,using survey data collected in 2010 from 766 private forest owners in Sweden and Germany,we provide the first evidence that perceptions of climate change risk are uncorrelatedwith, or sometimes positively correlated with, education level and can be explained withoutreference to cultural or other values. We conclude that the recent claim that advanced scientificliteracy and numeracy polarizes perceptions of climate change risk is unsupported bythe forest owner data. In neither of the two countries was university education found toreduce the perception of risk from climate change. Indeed in most cases university educationincreased the perception of risk. Even more importantly, the effect of university educationwas not dependent on the individuals' value profile.

  • 62.
    Bodén, Stina
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wennberg, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Shivappa, Nitin
    Hébert, James R
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Nilsson, Lena Maria
    Umeå University, Arctic Research Centre at Umeå University. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    The inflammatory potential of diet in determining cancer risk: a prospective investigation of two dietary pattern scores2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 4, article id e0214551Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Inflammation-related mechanisms may contribute to the link between diet and cancer. We sought to investigate the inflammatory impact of diet on cancer risk using the Dietary inflammatory index (DII) and an adapted Mediterranean diet score (MDS).

    METHODS: This population-based, prospective cohort study used self-reported dietary data from the Västerbotten Intervention Programme, including 100,881 participants, of whom 35,393 had repeated measures. Associations between dietary patterns and cancer risk were evaluated using Cox proportional hazards regression. We also used restricted cubic splines to test for potential non-linear associations.

    RESULTS: A total of 9,250 incident cancer cases were diagnosed during a median follow-up of 15 years. The two dietary patterns were moderately correlated to each other and had similar associations with cancer risk, predominantly lung cancer in men (DII per tertile decrease: Hazard ratio (HR) 0.81 (0.66-0.99), MDS per tertile increase: HR 0.86 (0.72-1.03)), and gastric cancer in men (DII: 0.73 (0.53-0.99), MDS: 0.73 (0.56-0.96)). Associations were, in general, found to be linear. We found no longitudinal association between 10-year change in diet and cancer risk.

    CONCLUSION: We confirm small, but consistent and statistically significant associations between a more anti-inflammatory or healthier diet and reduced risk of cancer, including a lower risk of lung and gastric cancer in men. The dietary indexes produced similar associations with respect to the risk of cancer.

  • 63. Boettcher, Johanna
    et al.
    Leek, Linda
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Matson, Lisa
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Holmes, Emily A.
    Browning, Michael
    MacLeod, Colin
    Andersson, Gerhard
    Carlbring, Per
    Internet-Based Attention Bias Modification for Social Anxiety: A Randomised Controlled Comparison of Training towards Negative and Training Towards Positive Cues2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, p. e71760-Article in journal (Refereed)
    Abstract [en]

    Biases in attention processes are thought to play a crucial role in the aetiology and maintenance of Social Anxiety Disorder (SAD). The goal of the present study was to examine the efficacy of a programme intended to train attention towards positive cues and a programme intended to train attention towards negative cues. In a randomised, controlled, double-blind design, the impact of these two training conditions on both selective attention and social anxiety were compared to that of a control training condition. A modified dot probe task was used, and delivered via the internet. A total of 129 individuals, diagnosed with SAD, were randomly assigned to one of these three conditions and took part in a 14-day programme with daily training/control sessions. Participants in all three groups did not on average display an attentional bias prior to the training. Critically, results on change in attention bias implied that significantly differential change in selective attention to threat was not detected in the three conditions. However, symptoms of social anxiety reduced significantly from pre- to follow-up-assessment in all three conditions (d(within) = 0.63-1.24), with the procedure intended to train attention towards threat cues producing, relative to the control condition, a significantly greater reduction of social fears. There were no significant differences in social anxiety outcome between the training condition intended to induce attentional bias towards positive cues and the control condition. To our knowledge, this is the first RCT where a condition intended to induce attention bias to negative cues yielded greater emotional benefits than a control condition. Intriguingly, changes in symptoms are unlikely to be by the mechanism of change in attention processes since there was no change detected in bias per se. Implications of this finding for future research on attention bias modification in social anxiety are discussed. Trial Registration: ClinicalTrials.gov NCT01463137

  • 64.
    Bohlin, Ludvig
    et al.
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Rosvall, Martin
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Stock Portfolio Structure of Individual Investors Infers Future Trading Behavior2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, p. e103006-Article in journal (Refereed)
    Abstract [en]

    Although the understanding of and motivation behind individual trading behavior is an important puzzle in finance, little is known about the connection between an investor's portfolio structure and her trading behavior in practice. In this paper, we investigate the relation between what stocks investors hold, and what stocks they buy, and show that investors with similar portfolio structures to a great extent trade in a similar way. With data from the central register of shareholdings in Sweden, we model the market in a similarity network, by considering investors as nodes, connected with links representing portfolio similarity. From the network, we find investor groups that not only identify different investment strategies, but also represent individual investors trading in a similar way. These findings suggest that the stock portfolios of investors hold meaningful information, which could be used to earn a better understanding of stock market dynamics.

  • 65. Bohman, Tony
    et al.
    Tegern, Matthias
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation. Department of Neurobiology, Care Sciences and Society, Division of Physiotherapy, Karolinska Institutet, Stockholm, Sweden.
    Halvarsson, Alexandra
    Broman, Lisbet
    Larsson, Helena
    Concurrent validity of an isokinetic lift test used for admission to the Swedish Armed Forces2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 11, article id e0207054Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to assess the concurrent validity of the IsoKai isokinetic lift test peak force (IsoKai(Peak))1 in comparison to a submaximal 5-1ORM deadlift test (5-10RM(DL)), and to develop an equation for converting the IsoKai(Peak) in Newton (N) to an estimated 1 RM (1 RMest) deadlift load in kilograms (kg). The participants included 28 males and 16 female employees in the Swedish Armed Forces (20-59 years). Each participant conducted the IsoKai lift test, followed by the 5-1ORM(DL) test at one occasion. The Pearson's correlation coefficient, with a 95% confidence interval was calculated to evaluate the validity between the IsoKai(peak) and the 1 RMest deadlift load derived from the 5-10RM(DL) test. Univariate and multivariable linear regressions were used to derive the equation for calculating the 1 RMest deadlift load based on the IsoKai(Peak)- The IsoKai(p)(eak) showed good- to-excellent correlation with the 1 RMest deadlift weight with a correlation coefficient of 0.84 (0.72-0.91) for the total sample, and 0.65 (0.37-0.83) and 0.81 (0.53-0.93) in males and females, respectively. The final equation, 1 RMest deadlift weight (kg) = -51.63 + (0.08 x IsoKai(Peak))1+ (2.28 x BMI), explained 72% (adjusted R-2 = 0.72) of the total variance in the 1 RMest, and had a standard error of the estimate (SEE) of 16.57 kg. In conclusion, the IsoKai isokinetic lift test could be considered a highly valid measure of maximal dynamic muscular strength in comparison to the 5-10RM(DL). The equation can be used to convert the IsoKai lift test (N) results to an 1 RMest deadlift load (kg), but with consideration of the relative large SEE.

  • 66. Bohman, Tony
    et al.
    Tegern, Matthias
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation. Department of Neurobiology, Care Sciences and Society, Division of Physiotherapy, Karolinska Institutet, Stockholm, Sweden.
    Halvarsson, Alexandra
    Broman, Lisbet
    Larsson, Helena
    Reliability and agreement of the IsoKai isokinetic lift test - A test used for admission to the Swedish Armed Forces2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 12, article id e0209419Article in journal (Refereed)
    Abstract [en]

    This study was performed to evaluate the reliability and agreement of the IsoKai isokinetic lift test as it is currently administered in admission to the Swedish Armed Forces. The study included an intrarater (n = 534) and interrater reliability sample (n = 137), of Swedish male conscripts who performed the test on two test occasions about two hours apart. Two-to-four lifts were performed at each occasion, and the highest mean (IsoKai(MF)) and peak force (IsoKai(PF)) produced (N) were used for evaluation. All intraclass coefficients showed excellent reliability. The interrater analyses resulted in intraclass coefficients of 0.942 (95% CI; 0.920-0.959) and 0.858 (95% CI; 0.806-0.896) for the IsoKai(MF) and IsoKai(PF), respectively, while the corresponding coefficients for the intrarater analyses were 0.935 (95% CI; 0.923-0.946) and 0.865 (95% CI; 0.842-0.886). Agreement, the capability of a test to detect changes, was assessed by the standard error of measurement (SEM/SEM%) and the smallest real difference (SRD/SRD%). These estimate indicated that it is possible to achieve measurements relevant to use in real practice with the IsoKai isokinetic lift test. Bland and Altman analyses revealed no systematic errors in either sample. Based on these findings, the IsoKai isokinetic lift test is suggested to be a highly reliable test for maximal dynamic muscular strength. The test could be of use in selection procedures in order to accurately evaluate maximal dynamic muscular strength, and for evaluating longitudinal changes in strength.

  • 67. Boldinova, Elizaveta O.
    et al.
    Stojkovic, Gorazd
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Khairullin, Rafil
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Kazan Volga Reg Fed Univ, Russia.
    Wanrooij, Sjoerd
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Makarova, Alena V.
    Optimization of the expression, purification and polymerase activity reaction conditions of recombinant human PrimPol2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 9, article id e0184489Article in journal (Refereed)
    Abstract [en]

    Human PrimPol is a DNA primase/polymerase involved in DNA damage tolerance and prevents nuclear genome instability. PrimPol is also localized to the mitochondria, but its precise function in mitochondrial DNA maintenance has remained elusive. PrimPol works both as a translesion (TLS) polymerase and as the primase that restarts DNA replication after a lesion. However, the observed biochemical activities of PrimPol vary considerably between studies as a result of different reaction conditions used. To reveal the effects of reaction composition on PrimPol DNA polymerase activity, we tested the polymerase activity in the presence of various buffer agents, salt concentrations, pH values and metal cofactors. Additionally, the enzyme stability was analyzed under various conditions. We demonstrate that the reaction buffer with pH 6-6.5, low salt concentrations and 3 mM Mg2+ or 0.3-3 mM Mn2+ cofactor ions supports the highest DNA polymerase activity of human PrimPol in vitro. The DNA polymerase activity of PrimPol was found to be stable after multiple freeze-thaw cycles and prolonged protein incubation on ice. However, rapid heat-inactivation of the enzyme was observed at 37 degrees C. We also for the first time describe the purification of human PrimPol from a human cell line and compare the benefits of this approach to the expression in Escherichia coli and in Saccharomyces cerevisiae cells. Our results show that active PrimPol can be purified from E. coli and human suspension cell line in high quantities and that the activity of the purified enzyme is similar in both expression systems. Conversely, the yield of full-length protein expressed in S. cerevisiae was considerably lower and this system is therefore not recommended for expression of full-length recombinant human PrimPol.

  • 68. Bonnedahl, Jonas
    et al.
    Drobni, Mirva
    Gauthier-Clerc, Michel
    Hernandez, Jorge
    Granholm, Susanne
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Kayser, Yves
    Melhus, Asa
    Kahlmeter, Gunnar
    Waldenström, Jonas
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Olsen, Björn
    Uppsala universitet.
    Dissemination of Escherichia coli with CTX-M type ESBL between humans and yellow-legged gulls in the south of France2009In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 6, p. e5958-Article in journal (Refereed)
    Abstract [en]

    Extended Spectrum beta-Lactamase (ESBL) producing Enterobacteriaceae started to appear in the 1980s, and have since emerged as some of the most significant hospital-acquired infections with Escherichia coli and Klebsiella being main players. More than 100 different ESBL types have been described, the most widespread being the CTX-M beta-lactamase enzymes (bla(CTX-M) genes). This study focuses on the zoonotic dissemination of ESBL bacteria, mainly CTX-M type, in the southern coastal region of France. We found that the level of general antibiotic resistance in single randomly selected E. coli isolates from wild Yellow-legged Gulls in France was high. Nearly half the isolates (47.1%) carried resistance to one or more antibiotics (in a panel of six antibiotics), and resistance to tetracycline, ampicillin and streptomycin was most widespread. In an ESBL selective screen, 9.4% of the gulls carried ESBL producing bacteria and notably, 6% of the gulls carried bacteria harboring CTX-M-1 group of ESBL enzymes, a recently introduced and yet the most common clinical CTX-M group in France. Multi locus sequence type and phylogenetic group designations were established for the ESBL isolates, revealing that birds and humans share E. coli populations. Several ESBL producing E. coli isolated from birds were identical to or clustered with isolates with human origin. Hence, wild birds pick up E. coli of human origin, and with human resistance traits, and may accordingly also act as an environmental reservoir and melting pot of bacterial resistance with a potential to re-infect human populations.

  • 69. Borena, Wegene
    et al.
    Edlinger, Michael
    Bjørge, Tone
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lindkvist, Björn
    Nagel, Gabriele
    Engeland, Anders
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Institute of Preventive Medicine, Copenhagen University Hospital, Copenhagen, Denmark.
    Strohmaier, Susanne
    Manjer, Jonas
    Selmer, Randi
    Tretli, Steinar
    Concin, Hans
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ulmer, Hanno
    A prospective study on metabolic risk factors and gallbladder cancer in the metabolic syndrome and cancer (Me-Can) collaborative study2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 2, p. e89368-Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate the association between metabolic risk factors (individually and in combination) and risk of gallbladder cancer (GBC). Methods: The metabolic syndrome and cancer project (Me-Can) includes cohorts from Norway, Austria, and Sweden with data on 578,700 men and women. We used Cox proportional hazard regression models to calculate relative risks of GBC by body mass index (BMI), blood pressure, and plasma levels of glucose, cholesterol, and triglycerides as continuous standardised variables and their standardised sum of metabolic syndrome (MetS) z-score. The risk estimates were corrected for random error in measurements. Results: During an average follow-up of 12.0 years (SD = 7.8), 184 primary gallbladder cancers were diagnosed. Relative risk of gallbladder cancer per unit increment of z-score adjusted for age, smoking status and BMI (except for BMI itself) and stratified by birth year, sex and sub-cohorts, was for BMI 1.31 (95% confidence interval 1.11, 1.57) and blood glucose 1.76 (1.10, 2.85). Further analysis showed that the effect of BMI on GBC risk is larger among women in the premenopausal age group (1.84 (1.23, 2.78)) compared to those in the postmenopausal age group (1.29 (0.93, 1.79)). For the other metabolic factors no significant association was found (mid blood pressure 0.96 (0.71, 1.31), cholesterol 0.84 (0.66, 1.06) and serum triglycerides 1.16 (0.82, 1.64)). The relative risk per one unit increment of the MetS z-score was 1.37 (1.07, 1.73). Conclusion: This study showed that increasing BMI and impaired glucose metabolism pose a possible risk for gallbladder cancer. Beyond the individual factors, the results also showed that the metabolic syndrome as an entity presents a risk constellation for the occurrence of gallbladder cancer.

  • 70.
    Borssen, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Lars
    Karrman, Kristina
    Abrahamsson, Jonas
    Behrendtz, Mikael
    Heldrup, Jesper
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Promoter DNA methylation pattern identifies prognostic subgroups in childhood T-cell acute lymphoblastic leukemia2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 6, p. e65373-Article in journal (Refereed)
    Abstract [en]

    Background: Treatment of pediatric T-cell acute lymphoblastic leukemia (T-ALL) has improved, but there is a considerable fraction of patients experiencing a poor outcome. There is a need for better prognostic markers and aberrant DNA methylation is a candidate in other malignancies, but its potential prognostic significance in T-ALL is hitherto undecided.

    Design and Methods: Genome wide promoter DNA methylation analysis was performed in pediatric T-ALL samples (n = 43) using arrays covering >27000 CpG sites. Clinical outcome was evaluated in relation to methylation status and compared with a contemporary T-ALL group not tested for methylation (n = 32).

    Results: Based on CpG island methylator phenotype (CIMP), T-ALL samples were subgrouped as CIMP+ (high methylation) and CIMP- (low methylation). CIMP- T-ALL patients had significantly worse overall and event free survival (p = 0.02 and p = 0.001, respectively) compared to CIMP+ cases. CIMP status was an independent factor for survival in multivariate analysis including age, gender and white blood cell count. Analysis of differently methylated genes in the CIMP subgroups showed an overrepresentation of transcription factors, ligands and polycomb target genes.

    Conclusions: We identified global promoter methylation profiling as being of relevance for subgrouping and prognostication of pediatric T-ALL.

  • 71.
    Bortes, Cristian
    et al.
    Umeå University, Faculty of Social Sciences, Department of Social Work.
    Strandh, Mattias
    Umeå University, Faculty of Social Sciences, Department of Social Work. Centre for Research on Child and Adolescent Mental Health, Karlstad University, Karlstad, Sweden.
    Nilsson, Karina
    Umeå University, Faculty of Social Sciences, Department of Sociology.
    Health problems during childhood and school achievement: Exploring associations between hospitalization exposures, gender, timing, and compulsory school grades2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 12, p. 1-14, article id e0208116Article in journal (Refereed)
    Abstract [en]

    AIMS:

    To investigate while accounting for health at birth 1) associations between health problems during childhood, measured as hospitalizations, and school achievement in the final year of compulsory school, measured as overall grade points and eligibility for upper secondary education, 2) if and how gender moderates the association between health problems and school achievement, 3) if and how the timing of a health problem during childhood is associated with later school achievement.

    METHODS:

    Analyzes were performed on a population-based cohort (n = 115 196) born in 1990 in Sweden (51.3% boys, 48.7% girls) using data from several national registries. Multiple linear regression and logistic regression were used to analyze associations between study variables.

    RESULTS:

    Overall grade points and eligibility for continuation to upper secondary school were lower for individuals exposed to hospitalizations. Only the association between hospitalizations and overall grade points was moderated by gender and only for ages 13-16 years. Exposure close to actual grading had worst outcomes.

    CONCLUSIONS:

    Health problems, measured through hospitalizations, was significantly associated with lower school achievements among Swedish children. Girls exposed to health problems requiring hospitalizations had relatively poorer school achievements as compared to boys. Health problems requiring hospitalization during junior high school had the greatest negative association with final achievement at compulsory school.

  • 72.
    Bosson, Jenny A
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Stenfors, Nikolai
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Helleday, Ragnberth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Kelly, Frank J.
    Behndig, Annelie F.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Mudway, Ian S.
    Peripheral blood neutrophilia as a biomarker of ozone-induced pulmonary inflammation2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, article id e81816Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Ozone concentrations are predicted to increase over the next 50 years due to global warming and the increased release of precursor chemicals. It is therefore urgent that good, reliable biomarkers are available to quantify the toxicity of this pollutant gas at the population level. Such a biomarker would need to be easily performed, reproducible, economically viable, and reflective of ongoing pathological processes occurring within the lung.

    METHODOLOGY: We examined whether blood neutrophilia occurred following a controlled ozone challenge and addressed whether this could serve as a biomarker for ozone-induced airway inflammation. Three separate groups of healthy subjects were exposed to ozone (0.2 ppm, 2h) and filtered air (FA) on two separate occasions. Peripheral blood samples were collected and bronchoscopy with biopsy sampling and lavages was performed at 1.5h post exposures in group 1 (n=13), at 6h in group 2 (n=15) and at 18h in group 3 (n=15). Total and differential cell counts were assessed in blood, bronchial tissue and airway lavages.

    RESULTS: In peripheral blood, we observed fewer neutrophils 1.5h after ozone compared with the parallel air exposure (-1.1±1.0x10(9) cells/L, p<0.01), at 6h neutrophil numbers were increased compared to FA (+1.2±1.3x10(9) cells/L, p<0.01), and at 18h this response had fully attenuated. Ozone induced a peak in neutrophil numbers at 6h post exposure in all compartments examined, with a positive correlation between the response in blood and bronchial biopsies.

    CONCLUSIONS: These data demonstrate a systemic neutrophilia in healthy subjects following an acute ozone exposure, which mirrors the inflammatory response in the lung mucosa and lumen. This relationship suggests that blood neutrophilia could be used as a relatively simple functional biomarker for the effect of ozone on the lung.

  • 73. Boström, Elisabeth A.
    et al.
    Kindstedt, Elin
    Umeå University, Faculty of Medicine, Department of Odontology.
    Sulniute, Rima
    Umeå University, Faculty of Medicine, Department of Odontology.
    Palmqvist, Py
    Umeå University, Faculty of Medicine, Department of Odontology.
    Majster, Mirjam
    Holm, Cecilia Koskinen
    Umeå University, Faculty of Medicine, Department of Odontology.
    Zwicker, Stephanie
    Clark, Reuben
    Önell, Sebastian
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Lerner, Ulf H.
    Umeå University, Faculty of Medicine, Department of Odontology. Univ Gothenburg, Sahlgrenska Acad, Ctr Bone & Arthrit Res, Gothenburg, Sweden.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Increased Eotaxin and MCP-1 Levels in Serum from Individuals with Periodontitis and in Human Gingival Fibroblasts Exposed to Pro-Inflammatory Cytokines2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 8, article id e0134608Article in journal (Refereed)
    Abstract [en]

    Periodontitis is a chronic inflammatory disease of tooth supporting tissues resulting in periodontal tissue destruction, which may ultimately lead to tooth loss. The disease is characterized by continuous leukocyte infiltration, likely mediated by local chemokine production but the pathogenic mechanisms are not fully elucidated. There are no reliable serologic biomarkers for the diagnosis of periodontitis, which is today based solely on the degree of local tissue destruction, and there is no available biological treatment tool. Prompted by the increasing interest in periodontitis and systemic inflammatory mediators we mapped serum cytokine and chemokine levels from periodontitis subjects and healthy controls. We used multivariate partial least squares (PLS) modeling and identified monocyte chemoattractant protein-1 (MCP-1) and eotaxin as clearly associated with periodontitis along with C-reactive protein (CRP), years of smoking and age, whereas the number of remaining teeth was associated with being healthy. Moreover, body mass index correlated significantly with serum MCP-1 and CRP, but not with eotaxin. We detected higher MCP-1 protein levels in inflamed gingival connective tissue compared to healthy but the eotaxin levels were undetectable. Primary human gingival fibroblasts displayed strongly increased expression of MCP-1 and eotaxin mRNA and protein when challenged with tumor necrosis factor-alpha (TNF-alpha and interleukin-1 beta (IL-1 beta), key mediators of periodontal inflammation. We also demonstrated that the upregulated chemokine expression was dependent on the NF-kappa B pathway. In summary, we identify higher levels of CRP, eotaxin and MCP-1 in serum of periodontitis patients. This, together with our finding that both CRP and MCP-1 correlates with BMI points towards an increased systemic inflammatory load in patients with periodontitis and high BMI. Targeting eotaxin and MCP-1 in periodontitis may result in reduced leukocyte infiltration and inflammation in periodontitis and maybe prevent tooth loss.

  • 74. Boström, Elisabeth A.
    et al.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    The Newly Discovered Cytokine IL-34 Is Expressed in Gingival Fibroblasts, Shows Enhanced Expression by Pro-Inflammatory Cytokines, and Stimulates Osteoclast Differentiation2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. e81665-Article in journal (Refereed)
    Abstract [en]

    Background: Interleukin-34 (IL-34) is a recently discovered cytokine functionally overlapping macrophage colony stimulating factor (M-CSF), a mediator of inflammation and osteoclastogenesis in bone-degenerative diseases such as rheumatoid arthritis. The objective of this study was to assess the expression of IL-34 in human gingival fibroblasts and investigate if the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and Interleukin-1B (IL-1 beta) modulate its expression, and moreover if IL-34 could contribute to recruitment of bone-resorbing osteoclasts. Methods: IL-34 expression was evaluated in gingival fibroblasts by real time PCR following stimulation by TNF-alpha, IL-1 beta, and treatment with inhibitors of intracellular pathways. The formation of osteoclasts was evaluated by tartrate-resistant acid phosphatase (TRAP) staining of bone marrow macrophages treated with IL-34 or M-CSF in addition to receptor activator of nuclear factor kappa-B ligand (RANKL). Results: IL-34 was expressed in gingival fibroblasts. The expression was enhanced by TNF-alpha and IL-1 beta, regulated by the transcription factor nuclear factor kappa B (NF-kappa B) and activation of c-Jun N-terminal kinase (JNK). Further, IL-34 supports RANKL-induced osteoclastogensis of bone marrow macrophages, independently of M-CSF. Summary: In conclusion, this study shows for the first time IL-34 expression in human gingival fibroblasts, stimulated by TNF-alpha and IL-1 beta, key mediators of periodontal inflammation. Furthermore, IL-34 can be substituted for M-CSF in RANKL-induced osteoclastogenesis. IL-34 may contribute to inflammation and osteoclastogenesis in bone-degenerative diseases such as periodontitis.

  • 75. Braem, Marieke G. M.
    et al.
    Onland-Moret, N. Charlotte
    Schouten, Leo J.
    Kruitwagen, Roy F. P. M.
    Lukanova, Annekatrin
    Allen, Naomi E.
    Wark, Petra A.
    Tjonneland, Anne
    Hansen, Louise
    Brauner, Christina Marie
    Overvad, Kim
    Clavel-Chapelon, Francoise
    Chabbert-Buffet, Nathalie
    Teucher, Birgit
    Floegel, Anna
    Boeing, Heiner
    Trichopoulou, Antonia
    Adarakis, George
    Plada, Maria
    Rinaldi, Sabina
    Fedirko, Veronika
    Romieu, Isabelle
    Pala, Valeria
    Galasso, Rocco
    Sacerdote, Carlotta
    Palli, Domenico
    Tumino, Rosario
    Bueno-de-Mesquita, H. Bas
    Gram, Inger Torhild
    Gavrilyuk, Oxana
    Lund, Eiliv
    Sanchez, Maria-Jose
    Bonet, Catalina
    Chirlaque, Maria-Dolores
    Larranaga, Nerea
    Barricarte Gurrea, Aurelio
    Quiros, Jose R.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Ohlson, Nina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jirstrom, Karin
    Butt, Salma
    Tsilidis, Konstantinos K.
    Khaw, Kay-Tee
    Wareham, Nick
    Riboli, Elio
    Kaaks, Rudolf
    Peeters, Petra H. M.
    Multiple Miscarriages Are Associated with the Risk of Ovarian Cancer: Results from the European Prospective Investigation into Cancer and Nutrition2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, p. e37141-Article in journal (Refereed)
    Abstract [en]

    While the risk of ovarian cancer clearly reduces with each full-term pregnancy, the effect of incomplete pregnancies is unclear. We investigated whether incomplete pregnancies (miscarriages and induced abortions) are associated with risk of epithelial ovarian cancer. This observational study was carried out in female participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). A total of 274,442 women were followed from 1992 until 2010. The baseline questionnaire elicited information on miscarriages and induced abortions, reproductive history, and lifestyle-related factors. During a median follow-up of 11.5 years, 1,035 women were diagnosed with incident epithelial ovarian cancer. Despite the lack of an overall association (ever vs. never), risk of ovarian cancer was higher among women with multiple incomplete pregnancies (HR >= 4vs.0: 1.74, 95% CI: 1.20-2.70; number of cases in this category: n = 23). This association was particularly evident for multiple miscarriages (HR >= 4vs.0: 1.99, 95% CI: 1.06-3.73; number of cases in this category: n = 10), with no significant association for multiple induced abortions (HR >= 4vs.0: 1.46, 95% CI: 0.68-3.14; number of cases in this category: n = 7). Our findings suggest that multiple miscarriages are associated with an increased risk of epithelial ovarian cancer, possibly through a shared cluster of etiological factors or a common underlying pathology. These findings should be interpreted with caution as this is the first study to show this association and given the small number of cases in the highest exposure categories.

  • 76. Bravo, Verónica
    et al.
    Puhar, Andrea
    Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, Paris, France; INSERM, Paris, France.
    Sansonetti, Philippe
    Parsot, Claude
    Toro, Cecilia S
    Distinct mutations led to inactivation of type 1 fimbriae expression in Shigella spp2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, article id e0121785Article in journal (Refereed)
    Abstract [en]

    Shigella spp. are responsible for bacillary dysentery in humans. The acquisition or the modification of the virulence plasmid encoding factors promoting entry of bacteria into and dissemination within epithelial cells was a critical step in the evolution of these bacteria from their Escherichia coli ancestor(s). Incorporation of genomic islands (GI) and gene inactivation also shaped interactions between these pathogens and their human host. Sequence analysis of the GI inserted next to the leuX tRNA gene in S. boydii, S. dysenteriae, S. flexneri, S. sonnei and enteroinvasive E. coli (EIEC) suggests that this region initially carried the fec, yjhATS and fim gene clusters. The fim cluster encoding type I fimbriae is systematically inactivated in both reference strains and clinical isolates and distinct mutations are responsible for this inactivation in at least three phylogenetic groups. To investigate consequences of the presence of fimbriae on the outcome of the interaction of Shigella with host cells, we used a S. flexneri strain harboring a plasmid encoding the E. coli fim operon. Production of fimbriae by this recombinant strain increased the ability of bacteria to adhere to and enter into epithelial cells and had no effect on their ability to disseminate from cell to cell. The observations that production of type I fimbriae increases invasion of epithelial cells and that independent mutations abolish fimbriae production in Shigella suggest that these mutations correspond to pathoadaptive events.

  • 77.
    Brenner, Philip
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Alexanderson, Kristina
    Division of Insurance Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden .
    Björkenstam, Charlotte
    Division of Insurance Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden .
    Hillert, Jan
    Division of Neuro, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Jokinen, Jussi
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Mittendorfer-Rutz, Ellenor
    Division of Insurance Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Tinghög, Petter
    Division of Insurance Medicine, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Psychiatric diagnoses, medication and risk for disability pension in multiple sclerosis patients: a population-based register study2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 8, p. e104165-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Psychiatric comorbidity is common among multiple sclerosis (MS) patients. The majority of MS patients of working ages are on disability pension. The aims of this study were to chart the prevalences of psychiatric diagnoses and medications among MS patients of working ages, and to investigate their association with the risk for future disability pension.

    METHODS: This nationwide, population-based prospective cohort study includes 10,750 MS patients and 5,553,141 non-MS individuals who in 2005 were aged 17-64 years. Psychiatric diagnoses and medications were identified using nationwide registers. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated adjusting for socio-demographics. Furthermore, a survival analysis with five-year follow-up was performed among the 4,571 MS patients not on disability pension in 2005, with psychiatric diagnoses and medication as risk factors, and disability pension as the outcome.

    RESULTS: Among MS patients, 35% had been prescribed psychiatric medication compared to 10% of non-MS individuals, adjusted OR 3.72 (95% CI 3.57 to 3.88). Ten percent of MS patients had received a psychiatric diagnosis, compared to 5.7% of non-MS individuals, OR 1.82 (95% CI 1.71 to 1.94). Serotonin reuptake inhibitors (SSRIs), were the most commonly prescribed drugs (17%) among MS patients, while depression (4.8%) was the most common psychiatric diagnosis. In the survival analysis, MS patients with any psychiatric diagnosis had a hazard ratio (HR) of 1.83 (95% CI 1.53 to 2.18) for disability pension compared to other MS patients. MS patients with any psychiatric drug prescription had a HR for disability pension of 2.09 (95% CI 1.84 to 2.33).

    CONCLUSION: Psychiatric diagnoses and medications are common among MS patients and adversely affect risk for disability pension. This highlights the importance of correct diagnosis and management of psychiatric comorbidity, in a clinical as well as in a societal perspective.

  • 78.
    Brohlin, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikova, Liudmila
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Novikov, Lev
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Aging effect on neurotrophic activity of human mesenchymal stem cells2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 9, p. e45052-Article in journal (Refereed)
    Abstract [en]

    Clinical efficacy of stem cells for nerve repair is likely to be influenced by issues including donor age and in vitro expansion time. We isolated human mesenchymal stem cells (MSC) from bone marrow of young (16–18 years) and old (67–75 years) donors and analyzed their capacity to differentiate and promote neurite outgrowth from dorsal root ganglia (DRG) neurons. Treatment of MSC with growth factors (forskolin, basic fibroblast growth factor, platelet derived growth factor-AA and glial growth factor-2) induced protein expression of the glial cell marker S100 in cultures from young but not old donors. MSC expressed various neurotrophic factor mRNA transcripts. Growth factor treatment enhanced the levels of BDNF and VEGF transcripts with corresponding increases in protein release in both donor cell groups. MSC in co-culture with DRG neurons significantly enhanced total neurite length which, in the case of young but not old donors, was further potentiated by treatment of the MSC with the growth factors. Stem cells from young donors maintained their proliferation rate over a time course of 9 weeks whereas those from the old donors showed increased population doubling times. MSC from young donors, differentiated with growth factors after long-term culture, maintained their ability to enhance neurite outgrowth of DRG. Therefore, MSC isolated from young donors are likely to be a favourable cell source for nerve repair.

  • 79.
    Brännström, Kristoffer
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lindhagen-Persson, Malin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Gharibyan, Anna L.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Iakovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Vestling, Monika
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sellin, Mikael E.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Morozova-Roche, Ludmilla
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    A Generic Method for Design of Oligomer-Specific Antibodies2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 3, p. e90857-Article in journal (Refereed)
    Abstract [en]

    Antibodies that preferentially and specifically target pathological oligomeric protein and peptide assemblies, as opposed to their monomeric and amyloid counterparts, provide therapeutic and diagnostic opportunities for protein misfolding diseases. Unfortunately, the molecular properties associated with oligomer-specific antibodies are not well understood, and this limits targeted design and development. We present here a generic method that enables the design and optimisation of oligomer-specific antibodies. The method takes a two-step approach where discrimination between oligomers and fibrils is first accomplished through identification of cryptic epitopes exclusively buried within the structure of the fibrillar form. The second step discriminates between monomers and oligomers based on differences in avidity. We show here that a simple divalent mode of interaction, as within e. g. the IgG isotype, can increase the binding strength of the antibody up to 1500 times compared to its monovalent counterpart. We expose how the ability to bind oligomers is affected by the monovalent affinity and the turnover rate of the binding and, importantly, also how oligomer specificity is only valid within a specific concentration range. We provide an example of the method by creating and characterising a spectrum of different monoclonal antibodies against both the A beta peptide and alpha-synuclein that are associated with Alzheimer's and Parkinson's diseases, respectively. The approach is however generic, does not require identification of oligomer-specific architectures, and is, in essence, applicable to all polypeptides that form oligomeric and fibrillar assemblies.

  • 80.
    Brännström, Kristoffer
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Öhman, Anders
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Aβ peptide fibrillar architectures controlled by conformational constraints of the monomer2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 9, p. e25157-Article in journal (Refereed)
    Abstract [en]

    Anomalous self-assembly of the Aβ peptide into fibrillar amyloid deposits is strongly correlated with the development of Alzheimer's disease. Aβ fibril extension follows a template guided "dock and lock" mechanism where polymerisation is catalysed by the fibrillar ends. Using surface plasmon resonance (SPR) and quenched hydrogen-deuterium exchange NMR (H/D-exchange NMR), we have analysed the fibrillar structure and polymerisation properties of both the highly aggregation prone Aβ1-40 Glu22Gly (Aβ(40Arc)) and wild type Aβ1-40 (Aβ(40WT)). The solvent protection patterns from H/D exchange experiments suggest very similar structures of the fibrillar forms. However, through cross-seeding experiments monitored by SPR, we found that the monomeric form of Aβ(40WT) is significantly impaired to acquire the fibrillar architecture of Aβ(40Arc). A detailed characterisation demonstrated that Aβ(40WT) has a restricted ability to dock and isomerise with high binding affinity onto Aβ(40Arc) fibrils. These results have general implications for the process of fibril assembly, where the rate of polymerisation, and consequently the architecture of the formed fibrils, is restricted by conformational constraints of the monomers. Interestingly, we also found that the kinetic rate of fibril formation rather than the thermodynamically lowest energy state determines the overall fibrillar structure.

  • 81.
    Bröms, Jeanette E.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Meyer, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lavander, Moa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Larsson, Pär
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    DotU and VgrG, core components of type VI secretion systems, are essential for Francisella LVS pathogenicity2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4, article id e34639Article in journal (Refereed)
    Abstract [en]

    The Gram-negative bacterium Francisella tularensis causes tularemia, a disease which requires bacterial escape from phagosomes of infected macrophages. Once in the cytosol, the bacterium rapidly multiplies, inhibits activation of the inflammasome and ultimately causes death of the host cell. Of importance for these processes is a 33-kb gene cluster, the Francisella pathogenicity island (FPI), which is believed to encode a type VI secretion system (T6SS). In this study, we analyzed the role of the FPI-encoded proteins VgrG and DotU, which are conserved components of type VI secretion (T6S) clusters. We demonstrate that in F. tularensis LVS, VgrG was shown to form multimers, consistent with its suggested role as a trimeric membrane puncturing device in T6SSs, while the inner membrane protein DotU was shown to stabilize PdpB/IcmF, another T6SS core component. Upon infection of J774 cells, both Delta vgrG and Delta dotU mutants did not escape from phagosomes, and subsequently, did not multiply or cause cytopathogenicity. They also showed impaired activation of the inflammasome and marked attenuation in the mouse model. Moreover, all of the DotU-dependent functions investigated here required the presence of three residues that are essentially conserved among all DotU homologues. Thus, in agreement with a core function in T6S clusters, VgrG and DotU play key roles for modulation of the intracellular host response as well as for the virulence of F. tularensis.

  • 82.
    Bröms, Jeanette E.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Meyer, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Sun, Kun
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lavander, Moa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Unique substrates secreted by the type VI secretion system of Francisella tularensis during intramacrophage infection2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 11, article id e50473Article in journal (Refereed)
    Abstract [en]

    Gram-negative bacteria have evolved sophisticated secretion machineries specialized for the secretion of macromolecules important for their life cycles. The Type VI secretion system (T6SS) is the most widely spread bacterial secretion machinery and is encoded by large, variable gene clusters, often found to be essential for virulence. The latter is true for the atypical T6SS encoded by the Francisella pathogenicity island (FPI) of the highly pathogenic, intracellular bacterium Francisella tularensis. We here undertook a comprehensive analysis of the intramacrophage secretion of the 17 FPI proteins of the live vaccine strain, LVS, of F. tularensis. All were expressed as fusions to the TEM beta-lactamase and cleavage of the fluorescent substrate CCF2-AM, a direct consequence of the delivery of the proteins into the macrophage cytosol, was followed over time. The FPI proteins IglE, IglC, VgrG, IglI, PdpE, PdpA, IglJ and IglF were all secreted, which was dependent on the core components DotU, VgrG, and IglC, as well as IglG. In contrast, the method was not directly applicable on F. novicida U112, since it showed very intense native beta-lactamase secretion due to FTN_1072. Its role was proven by ectopic expression in trans in LVS. We did not observe secretion of any of the LVS substrates VgrG, IglJ, IglF or IglI, when tested in a FTN_1072 deficient strain of F. novicida, whereas IglE, IglC, PdpA and even more so PdpE were all secreted. This suggests that there may be fundamental differences in the T6S mechanism among the Francisella subspecies. The findings further corroborate the unusual nature of the T6SS of F. tularensis since almost all of the identified substrates are unique to the species.

  • 83.
    Buren, Stefan
    et al.
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Ortega-Villasante, Cristina
    Ötvös, Krisztina
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Samuelsson, Göran
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Bako, Laszlo
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Villarejo, Arsenio
    Use of the foot-and-mouth disease virus 2A peptide co-expression system to study intracellular protein trafficking in arabidopsis2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12, p. e51973-Article in journal (Refereed)
    Abstract [en]

    Background: A tool for stoichiometric co-expression of effector and target proteins to study intracellular protein trafficking processes has been provided by the so called 2A peptide technology. In this system, the 16-20 amino acid 2A peptide from RNA viruses allows synthesis of multiple gene products from single transcripts. However, so far the use of the 2A technology in plant systems has been limited.

    Methodology/Principal Findings: The aim of this work was to assess the suitability of the 2A peptide technology to study the effects exerted by dominant mutant forms of three small GTPase proteins, RABD2a, SAR1, and ARF1 on intracellular protein trafficking in plant cells. Special emphasis was given to CAH1 protein from Arabidopsis, which is trafficking to the chloroplast via a poorly characterized endoplasmic reticulum-to-Golgi pathway. Dominant negative mutants for these GTPases were co-expressed with fluorescent marker proteins as polyproteins separated by a 20 residue self-cleaving 2A peptide. Cleavage efficiency analysis of the generated polyproteins showed that functionality of the 2A peptide was influenced by several factors. This enabled us to design constructs with greatly increased cleavage efficiency compared to previous studies. The dominant negative GTPase variants resulting from cleavage of these 2A peptide constructs were found to be stable and active, and were successfully used to study the inhibitory effect on trafficking of the N-glycosylated CAH1 protein through the endomembrane system.

    Conclusions/Significance: We demonstrate that the 2A peptide is a suitable tool when studying plant intracellular protein trafficking and that transient protoplast and in planta expression of mutant forms of SAR1 and RABD2a disrupts CAH1 trafficking. Similarly, expression of dominant ARF1 mutants also caused inhibition of CAH1 trafficking to a different extent. These results indicate that early trafficking of the plastid glycoprotein CAH1 depends on canonical vesicular transport mechanisms operating between the endoplasmic reticulum and Golgi apparatus.

  • 84. Burger, Koert NJ
    et al.
    Beulens, Joline WJ
    van der Schouw, Yvonne T
    Sluijs, Ivonne
    Spijkerman, Annemieke MW
    Sluik, Diewertje
    Boeing, Heiner
    Kaaks, Rudolf
    Teucher, Birgit
    Dethlefsen, Claus
    Overvad, Kim
    Tjonneland, Anne
    Kyro, Cecilie
    Barricarte, Aurelio
    Bendinelli, Benedetta
    Krogh, Vittorio
    Tumino, Rosario
    Sacerdote, Carlotta
    Mattiello, Amalia
    Nilsson, Peter M
    Orho-Melander, Marju
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Maria Huerta, Jose
    Crowe, Francesca
    Allen, Naomi
    Noethlings, Ute
    Dietary fiber, carbohydrate quality and quantity, and mortality risk of individuals with diabetes mellitus2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 8, p. e43127-Article in journal (Refereed)
    Abstract [en]

    Background: Dietary fiber, carbohydrate quality and quantity are associated with mortality risk in the general population. Whether this is also the case among diabetes patients is unknown.Objective: To assess the associations of dietary fiber, glycemic load, glycemic index, carbohydrate, sugar, and starch intake with mortality risk in individuals with diabetes. Methods: This study was a prospective cohort study among 6,192 individuals with confirmed diabetes mellitus (mean age of 57.4 years, and median diabetes duration of 4.4 years at baseline) from the European Prospective Investigation into Cancer and Nutrition (EPIC). Dietary intake was assessed at baseline (1992-2000) with validated dietary questionnaires. Cox proportional hazards analysis was performed to estimate hazard ratios (HRs) for all-cause and cardiovascular mortality, while adjusting for CVD-related, diabetes-related, and nutritional factors. Results: During a median follow-up of 9.2 y, 791 deaths were recorded, 306 due to CVD. Dietary fiber was inversely associated with all-cause mortality risk (adjusted HR per SD increase, 0.83 [95% CI, 0.75-0.91]) and CVD mortality risk (0.76[0.64-0.89]). No significant associations were observed for glycemic load, glycemic index, carbohydrate, sugar, or starch. Glycemic load (1.42[1.07-1.88]), carbohydrate (1.67[1.18-2.37]) and sugar intake (1.53[1.12-2.09]) were associated with an increased total mortality risk among normal weight individuals (BMI <= 25 kg/m(2); 22% of study population) but not among overweight individuals (P interaction <= 0.04). These associations became stronger after exclusion of energy misreporters. Conclusions: High fiber intake was associated with a decreased mortality risk. High glycemic load, carbohydrate and sugar intake were associated with an increased mortality risk in normal weight individuals with diabetes.

  • 85. Burkhardt, Christian
    et al.
    Neuwirth, Christoph
    Sommacal, Andreas
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Weber, Markus
    Is survival improved by the use of NIV and PEG in amyotrophic lateral sclerosis (ALS)?: A post-mortem study of 80 ALS patients2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 5, article id e0177555Article in journal (Refereed)
    Abstract [en]

    Background: Non-invasive ventilation (NIV) and percutaneous gastrostomy (PEG) are guideline-recommended interventions for symptom management in amyotrophic lateral sclerosis (ALS). Their effect on survival is controversial and the impact on causes of death is unknown.

    Objective: To investigate the effect of NIV and PEG on survival and causes of death in ALS patients.

    Methods: Eighty deceased ALS patients underwent a complete post mortem analysis for causes of death between 2003 and 2015. Forty-two of these patients consented for genetic testing. Effects of NIV and PEG on survival and causes of death were analyzed in a multivariable Cox proportional hazard regression.

    Results: Six patients, who requested assisted suicide causing drug-induced hypoxia, were excluded from final analysis. Respiratory failure was the main cause of death in 72 out of 74 patients. Fifteen out of 74 died of aspiration pneumonia 23/74 of bronchopneumonia and 8/74 of a combination of aspiration pneumonia and bronchopneumonia. Twenty died of hypoxia without concomitant infection, and six patients had pulmonary embolism alone or in combination with pneumonia. NIV (p = 0.01) and PEG (p<0.01) had a significant impact on survival. In patients using NIV bronchopneumonia was significantly more frequent (p <0.04) compared to non-NIV patients. This effect was even more pronounced in limb onset patients (p<0.002). Patients with C9orf72 hexanucleotide repeat expansions showed faster disease progression and shorter survival (p = 0.01).

    Conclusion: The use of NIV and PEG prolongs survival in ALS. This study supports current AAN and EFNS guidelines which recommend NIV and PEG as a treatment option in ALS. The risk of bronchopneumonia as cause of death may be increased by NIV.

  • 86.
    Burén, Stefan
    et al.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Ortega-Villasante, Cristina
    Blanco-Rivero, Amaya
    Martínez-Bernardini, Andrea
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Shutova, Tatiana
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Shevela, Dmitriy
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Messinger, Johannes
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Bako, Laszlo
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Villarejo, Arsenio
    Samuelsson, Göran
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Importance of post-translational modifications for functionality of a chloroplast-localized carbonic anhydrase (CAH1) in Arabidopsis thaliana2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 6, p. e21021-Article in journal (Refereed)
    Abstract [en]

    Background

    The Arabidopsis CAH1 alpha-type carbonic anhydrase is one of the few plant proteins known to be targeted to the chloroplast through the secretory pathway. CAH1 is post-translationally modified at several residues by the attachment of N-glycans, resulting in a mature protein harbouring complex-type glycans. The reason of why trafficking through this non-canonical pathway is beneficial for certain chloroplast resident proteins is not yet known. Therefore, to elucidate the significance of glycosylation in trafficking and the effect of glycosylation on the stability and function of the protein, epitope-labelled wild type and mutated versions of CAH1 were expressed in plant cells.

    Methodology/Principal Findings

    Transient expression of mutant CAH1 with disrupted glycosylation sites showed that the protein harbours four, or in certain cases five, N-glycans. While the wild type protein trafficked through the secretory pathway to the chloroplast, the non-glycosylated protein formed aggregates and associated with the ER chaperone BiP, indicating that glycosylation of CAH1 facilitates folding and ER-export. Using cysteine mutants we also assessed the role of disulphide bridge formation in the folding and stability of CAH1. We found that a disulphide bridge between cysteines at positions 27 and 191 in the mature protein was required for correct folding of the protein. Using a mass spectrometric approach we were able to measure the enzymatic activity of CAH1 protein. Under circumstances where protein N-glycosylation is blocked in vivo, the activity of CAH1 is completely inhibited.

    Conclusions/Significance

    We show for the first time the importance of post-translational modifications such as N-glycosylation and intramolecular disulphide bridge formation in folding and trafficking of a protein from the secretory pathway to the chloroplast in higher plants. Requirements for these post-translational modifications for a fully functional native protein explain the need for an alternative route to the chloroplast.

  • 87.
    Byass, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Ivarsson, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    The global burden of childhood coeliac disease: a neglected component of diarrhoeal mortality?2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 7, p. e22774-Article in journal (Refereed)
    Abstract [en]

    Objectives Coeliac disease has emerged as an increasingly recognised public health problem over the last half-century, and is now coming to be seen as a global phenomenon, despite a profound lack of globally representative epidemiological data. Since children with coeliac disease commonly present with chronic diarrhoea and malnutrition, diagnosis is often overlooked, particularly in poorer settings where children often fail to thrive and water-borne infectious diarrhoeas are common. This is the first attempt to make global estimates of the burden of coeliac disease in childhood.

    Methods We built a relatively crude model of childhood coeliac disease, incorporating estimates of population prevalence, probability of non-diagnosis, and likelihood of mortality among the undiagnosed across all countries from 1970 to 2010, based around the few available data. All our assumptions are stated in the paper and the model is available as a supplementary file.

    Findings Our model suggests that in 2010 there were around 2.2 million children under 5 years of age living with coeliac disease. Among these children there could be 42,000 deaths related to coeliac disease annually. In 2008, deaths related to coeliac disease probably accounted for approximately 4% of all childhood diarrhoeal mortality.

    Conclusions Although coeliac disease may only account for a small proportion of diarrhoeal mortality, these deaths are not preventable by applying normal diarrhoea treatment guidelines, which may even involve gluten-based food supplements. As other causes of diarrhoeal mortality decline, coeliac disease will become a proportionately increasing problem unless consideration is given to trying gluten-free diets for children with chronic diarrhoea and malnutrition.

  • 88.
    Byass, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Sankoh, Osman
    Tollman, Stephen M
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Högberg, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Wall, Stig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Lessons from history for designing and validating epidemiological surveillance in uncounted populations2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 8, p. e22897-Article in journal (Refereed)
    Abstract [en]

    Background

    Due to scanty individual health data in low- and middle-income countries (LMICs), health planners often use imperfect data sources. Frequent national-level data are considered essential, even if their depth and quality are questionable. However, quality in-depth data from local sentinel populations may be better than scanty national data, if such local data can be considered as nationally representative. The difficulty is the lack of any theoretical or empirical basis for demonstrating that local data are representative where data on the wider population are unavailable. Thus these issues can only be explored empirically in a complete individual dataset at national and local levels, relating to a LMIC population profile.

    Methods and Findings

    Swedish national data for 1925 were used, characterised by relatively high mortality, a low proportion of older people and substantial mortality due to infectious causes. Demographic and socioeconomic characteristics of Sweden then and LMICs now are very similar. Rates of livebirths, stillbirths, infant and cause-specific mortality were calculated at national and county levels. Results for six million people in 24 counties showed that most counties had overall mortality rates within 10% of the national level. Other rates by county were mostly within 20% of national levels. Maternal mortality represented too rare an event to give stable results at the county level.

    Conclusions

    After excluding obviously outlying counties (capital city, island, remote areas), any one of the remaining 80% closely reflected the national situation in terms of key demographic and mortality parameters, each county representing approximately 5% of the national population. We conclude that this scenario would probably translate directly to about 40 LMICs with populations under 10 million, and to individual states or provinces within about 40 larger LMICs. Unsubstantiated claims that local sub-national population data are “unrepresentative” or “only local” should not therefore predominate over likely representativity.

  • 89.
    Byrnes, Andrea
    et al.
    Dept Genetics and dept Biostatistics, University of North Carolina.
    Jacks, Andreas
    Dept Medical Epidemiology and Biostatistics, Karolinska Institutet.
    Dahlman-Wright, Karin
    Dept Biosciences and Nutrition, Karolinska Institutet.
    Evengård, Birgitta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Wright, Fred A
    Dept Biostatistics, University of North Carolina.
    Pedersen, Nancy L
    Dept Medical Epidemiology and Biostatistis, Karolinska Institutet.
    Sullivan, Patrick F
    Dept Genetics, Univ of North Carolina, Dept Medical Epid and Biostat, Karol Institutet.
    Gene expression in peripheral blood leukocytes in monozygotic twins discordant for chronic fatigue: no evidence of a biomarker2009In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 6, p. e5805-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Chronic fatiguing illness remains a poorly understood syndrome of unknown pathogenesis. We attempted to identify biomarkers for chronic fatiguing illness using microarrays to query the transcriptome in peripheral blood leukocytes.

    METHODS: Cases were 44 individuals who were clinically evaluated and found to meet standard international criteria for chronic fatigue syndrome or idiopathic chronic fatigue, and controls were their monozygotic co-twins who were clinically evaluated and never had even one month of impairing fatigue. Biological sampling conditions were standardized and RNA stabilizing media were used. These methodological features provide rigorous control for bias resulting from case-control mismatched ancestry and experimental error. Individual gene expression profiles were assessed using Affymetrix Human Genome U133 Plus 2.0 arrays.

    FINDINGS: There were no significant differences in gene expression for any transcript.

    CONCLUSIONS: Contrary to our expectations, we were unable to identify a biomarker for chronic fatiguing illness in the transcriptome of peripheral blood leukocytes suggesting that positive findings in prior studies may have resulted from experimental bias.

  • 90. Byström, Jonas
    et al.
    Thomson, Scott J.
    Johansson, Jörgen
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Edin, Matthew L.
    Zeldin, Darryl C.
    Gilroy, Derek W.
    Smith, Andrew M.
    Bishop-Bailey, David
    Inducible CYP2J2 and its product 11,12-EET promotes bacterial phagocytosis: a role for CYP2J2 deficiency in the pathogenesis of Crohn's disease?2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, article id e75107Article in journal (Refereed)
    Abstract [en]

    The epoxygenase CYP2J2 has an emerging role in inflammation and vascular biology. The role of CYP2J2 in phagocytosis is not known and its regulation in human inflammatory diseases is poorly understood. Here we investigated the role of CYP2J2 in bacterial phagocytosis and its expression in monocytes from healthy controls and Crohns disease patients. CYP2J2 is anti-inflammatory in human peripheral blood monocytes. Bacterial LPS induced CYP2J2 mRNA and protein. The CYP2J2 arachidonic acid products 11,12-EET and 14,15-EET inhibited LPS induced TNFα release. THP-1 monocytes were transformed into macrophages by 48h incubation with phorbol 12-myristate 13-acetate. Epoxygenase inhibition using a non-selective inhibitor SKF525A or a selective CYP2J2 inhibitor Compound 4, inhibited E. coli particle phagocytosis, which could be specifically reversed by 11,12-EET. Moreover, epoxygenase inhibition reduced the expression of phagocytosis receptors CD11b and CD68. CD11b also mediates L. monocytogenes phagocytosis. Similar, to E. coli bioparticle phagocytosis, epoxygenase inhibition also reduced intracellular levels of L. monocytogenes, which could be reversed by co-incubation with 11,12-EET. Disrupted bacterial clearance is a hallmark of Crohn's disease. Unlike macrophages from control donors, macrophages from Crohn's disease patients showed no induction of CYP2J2 in response to E. coli. These results demonstrate that CYP2J2 mediates bacterial phagocytosis in macrophages, and implicates a defect in the CYP2J2 pathway may regulate bacterial clearance in Crohn's disease.

  • 91.
    Byström, Pär
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Ask, Per
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Andersson, Jens
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Persson, Lennart
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Preference for cannibalism and ontogenetic constraints in competitive ability of piscivorous top predators2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 7, p. e70404-Article in journal (Refereed)
    Abstract [en]

    We experimentally show that the piscivorous top predator Arctic char (Salvelinus alpinus) have higher attack rates on cannibal prey compared to the interspecific prey species ninespine stickleback (Pungitius pungitius), and that sticklebacks are more efficient competitiors for zooplankton resources compared to juvenile char. We also conducted a literature survey that together with our experiments showed that piscivorous top consumers selected cannibal prey over interspecific prey in 9 out of 10 cases. Our literature survey also showed that specialist prey species are competitively superior compared to juvenile piscivorous species within the zooplankton niche. We discuss our results in relation to omnivory in fish communities and we suggest that the observed general preference for cannibal prey over interspecific prey in piscivores and the competitive advantage of prey species over juvenile piscivores may be major mechanisms for coexistence in fish communities.

  • 92. Calbet, Albert
    et al.
    Sazhin, Andrey F.
    Nejstgaard, Jens C.
    Berger, Stella A.
    Tait, Zachary S.
    Olmos, Lorena
    Sousoni, Despoina
    Isari, Stamatina
    Martinez, Rodrigo A.
    Bouquet, Jean-Marie
    Thompson, Eric M.
    Båmstedt, Ulf
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Jakobsen, Hans H.
    Future Climate Scenarios for a Coastal Productive Planktonic Food Web Resulting in Microplankton Phenology Changes and Decreased Trophic Transfer Efficiency2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 4, p. e94388-Article in journal (Refereed)
    Abstract [en]

    We studied the effects of future climate change scenarios on plankton communities of a Norwegian fjord using a mesocosm approach. After the spring bloom, natural plankton were enclosed and treated in duplicates with inorganic nutrients elevated to pre-bloom conditions (N, P, Si; eutrophication), lowering of 0.4 pH units (acidification), and rising 3 degrees C temperature (warming). All nutrient-amended treatments resulted in phytoplankton blooms dominated by chain-forming diatoms, and reached 13-16 mu g chlorophyll (chl) a l(-1). In the control mesocosms, chl a remained below 1 mu g l(-1). Acidification and warming had contrasting effects on the phenology and bloom-dynamics of autotrophic and heterotrophic microplankton. Bacillariophyceae, prymnesiophyceae, cryptophyta, and Protoperidinium spp. peaked earlier at higher temperature and lower pH. Chlorophyta showed lower peak abundances with acidification, but higher peak abundances with increased temperature. The peak magnitude of autotrophic dinophyceae and ciliates was, on the other hand, lowered with combined warming and acidification. Over time, the plankton communities shifted from autotrophic phytoplankton blooms to a more heterotrophic system in all mesocosms, especially in the control unaltered mesocosms. The development of mass balance and proportion of heterotrophic/autotrophic biomass predict a shift towards a more autotrophic community and less-efficient food web transfer when temperature, nutrients and acidification are combined in a future climate-change scenario. We suggest that this result may be related to a lower food quality for microzooplankton under acidification and warming scenarios and to an increase of catabolic processes compared to anabolic ones at higher temperatures.

  • 93. Calounova, Gabriela
    et al.
    Livera, Gabriel
    Zhang, Xiao-Qun
    Liu, Kui
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Gosden, Roger G.
    Welsh, Michael
    The Src Homology 2 Domain-Containing Adapter Protein B (SHB) Regulates Mouse Oocyte Maturation2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 6, article id e11155Article in journal (Refereed)
    Abstract [en]

    SHB (Src homology 2 domain-containing adapter protein B) is involved in receptor tyrosine kinase signaling. Mice deficient in the Shb gene have been found to exhibit a transmission ratio distortion with respect to inheritance of the Shb null allele among offspring and this phenomenon was linked to female gamete production. Consequently, we postulated that Shb plays a role for oocyte biology and thus decided to investigate oocyte formation, meiotic maturation, and early embryo development in relation to absence of the Shb gene. Oogenesis was apparently accelerated judging from the stages of oocyte development on fetal day 18.5 and one week postnatally in Shb(-/-) mice; but in adulthood ovarian follicle maturation was impaired in these mice. Completion of meiosis I (first polar body extrusion) was less synchronized, with a fraction of oocytes showing premature polar body extrusion in the absence of Shb. In vitro fertilization of mature oocytes isolated from Shb +/+, +/- and -/- mice revealed impaired early embryo development in the -/- embryos. Moreover, the absence of Shb enhanced ERK (extracellular-signal regulated kinase) and RSK (ribosomal S6 kinase) signaling in oocytes and these effects were paralleled by an increased ribosomal protein S6 phosphorylation and activation. It is concluded that SHB regulates normal oocyte and follicle development and that perturbation of SHB signaling causes defective meiosis I and early embryo development.

  • 94. Cammaerts, Sophia
    et al.
    Strazisar, Mojca
    Smets, Bart
    Weckhuysen, Sarah
    Nordin, Annelie
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    De Jonghe, Peter
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    De Rijk, Peter
    Del Favero, Jurgen
    Schizophrenia-Associated MIR204 Regulates Noncoding RNAs and Affects Neurotransmitter and Ion Channel Gene Sets2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 12, article id e0144428Article in journal (Refereed)
    Abstract [en]

    As regulators of gene expression, microRNAs (miRNAs) are likely to play an important role in the development of disease. In this study we present a large-scale strategy to identify miRNAs with a role in the regulation of neuronal processes. Thereby we found variant rs7861254 located near the MIR204 gene to be significantly associated with schizophrenia. This variant resulted in reduced expression of miR-204 in neuronal-like SH-SY5Y cells. Analysis of the consequences of the altered miR-204 expression on the transcriptome of these cells uncovered a new mode of action for miR-204, being the regulation of noncoding RNAs (ncRNAs), including several miRNAs, such as MIR296. Furthermore, pathway analysis showed downstream effects of miR-204 on neurotransmitter and ion channel related gene sets, potentially mediated by miRNAs regulated through miR-204.

  • 95. Campa, Daniele
    et al.
    Barrdahl, Myrto
    Tsilidis, Konstantinos K
    Severi, Gianluca
    Diver, W Ryan
    Siddiq, Afshan
    Chanock, Stephen
    Hoover, Robert N
    Ziegler, Regina G
    Berg, Christine D
    Buys, Saundra S
    Haiman, Christopher A
    Henderson, Brian E
    Schumacher, Fredrick R
    Le Marchand, Loic
    Flesch-Janys, Dieter
    Lindstroem, Sara
    Hunter, David J
    Hankinson, Susan E
    Willett, Walter C
    Kraft, Peter
    Cox, David G
    Khaw, Kay-Tee
    Tjonneland, Anne
    Dossus, Laure
    Trichopoulos, Dimitrios
    Panico, Salvatore
    van Gils, Carla H
    Weiderpass, Elisabete
    Barricarte, Aurelio
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Gaudet, Mia M
    Giles, Graham
    Southey, Melissa
    Baglietto, Laura
    Chang-Claude, Jenny
    Kaaks, Rudolf
    Canzian, Federico
    A genome-wide "pleiotropy scan'' does not identify new susceptibility loci for estrogen receptor negative breast cancer2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 2, p. e85955-Article in journal (Refereed)
    Abstract [en]

    Approximately 15-30% of all breast cancer tumors are estrogen receptor negative (ER-). Compared with ER- positive (ER+) disease they have an earlier age at onset and worse prognosis. Despite the vast number of risk variants identified for numerous cancer types, only seven loci have been unambiguously identified for ER- negative breast cancer. With the aim of identifying new susceptibility SNPs for this disease we performed a pleiotropic genome-wide association study (GWAS). We selected 3079 SNPs associated with a human complex trait or disease at genome-wide significance level (P<5x10(-8)) to perform a secondary analysis of an ER- negative GWAS from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3), including 1998 cases and 2305 controls from prospective studies. We then tested the top ten associations (i.e. with the lowest P-values) using three additional populations with a total sample size of 3509 ER+ cases, 2543 ER- cases and 7031 healthy controls. None of the 3079 selected variants in the BPC3 ER- GWAS were significant at the adjusted threshold. 186 variants were associated with ER- breast cancer risk at a conventional threshold of P<0.05, with P-values ranging from 0.049 to 2.3 x 10(-4). None of the variants reached statistical significance in the replication phase. In conclusion, this study did not identify any novel susceptibility loci for ER-breast cancer using a "pleiotropic approach''.

  • 96. Campa, Daniele
    et al.
    Hüsing, Anika
    Stein, Angelika
    Dostal, Lucie
    Boeing, Heiner
    Pischon, Tobias
    Tjønneland, Anne
    Roswall, Nina
    Overvad, Kim
    Ostergaard, Jane Nautrup
    Rodríguez, Laudina
    Sala, Núria
    Sánchez, Maria-José
    Larrañaga, Nerea
    Huerta, José María
    Barricarte, Aurelio
    Khaw, Kay-Tee
    Wareham, Nicholas
    Travis, Ruth C
    Allen, Naomi E
    Lagiou, Pagona
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Palli, Domenico
    Sieri, Sabina
    Tumino, Rosario
    Sacerdote, Carlotta
    van Kranen, Henk
    Bueno-de-Mesquita, H Bas
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Romieu, Isabelle
    Jenab, Mazda
    Cox, David G
    Siddiq, Afshan
    Riboli, Elio
    Canzian, Federico
    Kaaks, Rudolf
    Genetic variability of the mTOR pathway and prostate cancer risk in the European prospective investigation on cancer (EPIC)2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 2, p. e16914-Article in journal (Refereed)
    Abstract [en]

    The mTOR (mammalian target of rapamycin) signal transduction pathway integrates various signals, regulating ribosome biogenesis and protein synthesis as a function of available energy and amino acids, and assuring an appropriate coupling of cellular proliferation with increases in cell size. In addition, recent evidence has pointed to an interplay between the mTOR and p53 pathways. We investigated the genetic variability of 67 key genes in the mTOR pathway and in genes of the p53 pathway which interact with mTOR. We tested the association of 1,084 tagging SNPs with prostate cancer risk in a study of 815 prostate cancer cases and 1,266 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). We chose the SNPs (n = 11) with the strongest association with risk (p<0.01) and sought to replicate their association in an additional series of 838 prostate cancer cases and 943 controls from EPIC. In the joint analysis of first and second phase two SNPs of the PRKCI gene showed an association with risk of prostate cancer (OR(allele) = 0.85, 95% CI 0.78-0.94, p = 1.3×10(-3) for rs546950 and OR(allele) = 0.84, 95% CI 0.76-0.93, p = 5.6×10(-4) for rs4955720). We confirmed this in a meta-analysis using as replication set the data from the second phase of our study jointly with the first phase of the Cancer Genetic Markers of Susceptibility (CGEMS) project. In conclusion, we found an association with prostate cancer risk for two SNPs belonging to PRKCI, a gene which is frequently overexpressed in various neoplasms, including prostate cancer.

  • 97. Carlsson, Johanna
    et al.
    Svennerstam, Henrik
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå Plant Science Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Moritz, Thomas
    Egertsdotter, Ulrika
    Ganeteg, Ulrika
    Nitrogen uptake and assimilation in proliferating embryogenic cultures of Norway spruce-Investigating the specific role of glutamine2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 8, article id e0181785Article in journal (Refereed)
    Abstract [en]

    Somatic embryogenesis is an in vitro system employed for plant propagation and the study of embryo development. Nitrogen is essential for plant growth and development and, hence, the production of healthy embryos during somatic embryogenesis. Glutamine has been shown to increase plant biomass in many in vitro applications, including somatic embryogenesis. However, several aspects of nitrogen nutrition during somatic embryogenesis remain unclear. Therefore, we investigated the uptake and assimilation of nitrogen in Norway spruce pro-embryogenic masses to elucidate some of these aspects. In our study, addition of glutamine had a more positive effect on growth than inorganic nitrogen. The nitrogen uptake appeared to be regulated, with a strong preference for glutamine; 67% of the assimilated nitrogen in the free amino acid pool originated from glutamine-nitrogen. Glutamine addition also relieved the apparently limited metabolism (as evidenced by the low concentration of free amino acids) of pro-embryogenic masses grown on inorganic nitrogen only. The unusually high alanine concentration in the presence of glutamine, suggests that alanine biosynthesis was involved in alleviating these constraints. These findings inspire further studies of nitrogen nutrition during the somatic embryogenesis process; identifying the mechanism(s) that govern glutamine enhancement of pro-embryogenic masses growth is especially important in this regard.

  • 98. Carreras-Torres, Robert
    et al.
    Johansson, Mattias
    Haycock, Philip C.
    Wade, Kaitlin H.
    Relton, Caroline L.
    Martin, Richard M.
    Smith, George Davey
    Albanes, Demetrius
    Aldrich, Melinda C.
    Andrew, Angeline
    Arnold, Susanne M.
    Bickeböller, Heike
    Bojesen, Stig E.
    Brunnström, Hans
    Manjer, Jonas
    Brüske, Irene
    Caporaso, Neil E.
    Chen, Chu
    Christiani, David C.
    Christian, W. Jay
    Doherty, Jennifer A.
    Duell, Eric J.
    Field, John K.
    Davies, Michael P. A.
    Marcus, Michael W.
    Goodman, Gary E.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Haugen, Aage
    Hong, Yun-Chul
    Kiemeney, Lambertus A.
    van der Heijden, Erik H. F. M.
    Kraft, Peter
    Johansson, Mikael B.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lam, Stephen
    Landi, Maria Teresa
    Lazarus, Philip
    Le Marchand, Loïc
    Liu, Geoffrey
    Melander, Olle
    Park, Sungshim L.
    Rennert, Gad
    Risch, Angela
    Haura, Eric B.
    Scelo, Ghislaine
    Zaridze, David
    Mukeriya, Anush
    Savić, Milan
    Lissowska, Jolanta
    Swiatkowska, Beata
    Janout, Vladimir
    Holcatova, Ivana
    Mates, Dana
    Schabath, Matthew B.
    Shen, Hongbing
    Tardon, Adonina
    Teare, Dawn
    Woll, Penella
    Tsao, Ming-Sound
    Wu, Xifeng
    Yuan, Jian-Min
    Hung, Rayjean J.
    Amos, Christopher I.
    McKay, James
    Brennan, Paul
    Obesity, metabolic factors and risk of different histological types of lung cancer: a Mendelian randomization study2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 6, article id e0177875Article in journal (Refereed)
    Abstract [en]

    Background: Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. Methods and findings: We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01-1.43] and for small cell lung cancer (OR [95% CI] = 1.52 [1.15-2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m(2)]), but not for adenocarcinoma (OR [95% CI] = 0.93 [0.79-1.08]) (P-heterogeneity = 4.3x10(-3)). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10(-3)), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95% CI] = 0.90 [0.84-0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95% CI] = 1.63 [1.25-2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results. Conclusions: Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior.

  • 99. Casper, Charlotte
    et al.
    Hascoet, Jean-Michel
    Ertl, Tibor
    Gadzinowski, Janusz S.
    Carnielli, Virgilio
    Rigo, Jacques
    Lapillonne, Alexandre
    Couce, Maria L.
    Vagero, Marten
    Palmgren, Ingrid
    Timdahl, Kristina
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Recombinant Bile Salt-Stimulated Lipase in Preterm Infant Feeding: A Randomized Phase 3 Study2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 5, article id e0156071Article in journal (Refereed)
    Abstract [en]

    Introduction Feeding strategies are critical for healthy growth in preterm infants. Bile salt-stimulated lipase (BSSL), present in human milk, is important for fat digestion and absorption but is inactivated during pasteurization and absent in formula. This study evaluated if recombinant human BSSL (rhBSSL) improves growth in preterm infants when added to formula or pasteurized breast milk. Patients and Methods LAIF (Lipase Added to Infant Feeding) was a randomized, double-blind, placebo-controlled phase 3 study in infants born before 32 weeks of gestation. The primary efficacy variable was growth velocity (g/kg/day) during 4 weeks intervention. Follow-up visits were at 3 and 12 months. The study was performed at 54 centers in 10 European countries. Results In total 415 patients were randomized (rhBSSL n = 207, placebo n = 208), 410 patients were analyzed (rhBSSL n = 206, placebo n = 204) and 365 patients were followed until 12 months. Overall, there was no significantly improved growth velocity during rhBSSL treatment compared to placebo (16.77 vs. 16.56 g/kg/day, estimated difference 0.21 g/kg/day, 95% CI [-0.40; 0.83]), nor were secondary endpoints met. However, in a predefined subgroup, small for gestational age infants, there was a significant effect on growth in favor of rhBSSL during treatment. The incidence of adverse events was higher in the rhBSSL group during treatment. Conclusions Although this study did not meet its primary endpoint, except in a subgroup of infants small for gestational age, and there was an imbalance in short-term safety, these data provide insights in nutrition, growth and development in preterm infants.

  • 100. Chajes, Veronique
    et al.
    Biessy, Carine
    Ferrari, Pietro
    Romieu, Isabelle
    Freisling, Heinz
    Huybrechts, Inge
    Scalbert, Augustin
    de Mesquita, Bas Bueno
    Romaguera, Dora
    Gunter, Marc J.
    Vineis, Paolo
    Hansen, Camilla Plambeck
    Jakobsen, Marianne Uhre
    Clavel-Chapelon, Francoise
    Fagherazzi, Guy
    Boutron-Ruault, Marie-Christine
    Katzke, Verana
    Neamat-Allah, Jasmine
    Boeing, Heiner
    Bachlechner, Ursula
    Trichopoulou, Antonia
    Naska, Androniki
    Orfanos, Philippos
    Pala, Valeria
    Masala, Giovanna
    Mattiello, Amalia
    Skeie, Guri
    Weiderpass, Elisabete
    Agudo, Antonio
    Maria Huerta, Jose
    Ardanaz, Eva
    Jose Sanchez, Maria
    Dorronsoro, Miren
    Ramon Quiros, Jose
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Winkvist, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Sonested, Emily
    Key, Tim
    Khaw, Kay-Tee
    Wareham, Nicolas J.
    Peeters, Petra H. M.
    Slimani, Nadia
    Plasma Elaidic Acid Level as Biomarker of Industrial Trans Fatty Acids and Risk of Weight Change: Report from the EPIC Study2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 2, article id e0118206Article in journal (Refereed)
    Abstract [en]

    Background Few epidemiological studies have examined the association between dietary trans fatty acids and weight gain, and the evidence remains inconsistent. The main objective of the study was to investigate the prospective association between biomarker of industrial trans fatty acids and change in weight within the large study European Prospective Investigation into Cancer and Nutrition ( EPIC) cohort. Methods Baseline plasma fatty acid concentrations were determined in a representative EPIC sample from the 23 participating EPIC centers. A total of 1,945 individuals were followed for a median of 4.9 years to monitor weight change. The association between elaidic acid level and percent change of weight was investigated using a multinomial logistic regression model, adjusted by length of follow- up, age, energy, alcohol, smoking status, physical activity, and region. Results In women, doubling elaidic acid was associated with a decreased risk of weight loss ( odds ratio ( OR) = 0.69, 95% confidence interval ( CI) = 0.55- 0.88, p = 0.002) and a trend was observed with an increased risk of weight gain during the 5- year follow- up ( OR = 1.23, 95% CI = 0.97- 1.56, p = 0.082) ( p- trend<. 0001). In men, a trend was observed for doubling elaidic acid level and risk of weight loss ( OR = 0.82, 95% CI = 0.66- 1.01, p = 0.062) while no significant association was found with risk of weight gain during the 5- year follow- up ( OR = 1.08, 95% CI = 0.88- 1.33, p = 0.454). No association was found for saturated and cismonounsaturated fatty acids. Conclusions These data suggest that a high intake of industrial trans fatty acids may decrease the risk of weight loss, particularly in women. Prevention of obesity should consider limiting the consumption of highly processed foods, the main source of industrially- produced trans fatty acids.

1234567 51 - 100 of 662
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf