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  • 301.
    Karlsson, Jessica
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Fowler, Christopher
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Inhibition of Endocannabinoid Metabolism by the Metabolites of Ibuprofen and Flurbiprofen2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, p. e103589-Article in journal (Refereed)
    Abstract [en]

    Background: In addition to their effects upon prostaglandin synthesis, the non-steroidal anti-inflammatory drugs ibuprofen and flurbiprofen inhibit the metabolism of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) by cyclooxygenase-2 (COX-2) and fatty acid amide hydrolase (FAAH), respectively. Here, we investigated whether these effects upon endocannabinoid metabolism are shared by the main metabolites of ibuprofen and flurbiprofen. Methodology/Principal Findings:COX activities were measured via changes in oxygen consumption due to oxygenation of arachidonic acid (for COX-1) and arachidonic acid and 2-AG (for COX-2). FAAH activity was quantified by measuring hydrolysis of tritium labelled AEA in rat brain homogenates. The ability of ibuprofen and flurbiprofen to inhibit COX-2-catalysed oxygenation of 2-AG at lower concentrations than the oxygenation of arachidonic acid was seen with 4'-hydroxyflurbiprofen and possibly also 3'-hydroxyibuprofen, albeit at lower potencies than the parent compounds. All ibuprofen and flurbiprofen metabolites retained the ability to inhibit FAAH in a pH-dependent manner, although the potency was lower than seen with the parent compounds. Conclusions/Significance: It is concluded that the primary metabolites of ibuprofen and flurbiprofen retain some of the properties of the parent compound with respect to inhibition of endocannabinoid metabolism. However, these effects are unlikely to contribute to the actions of the parent compounds in vivo.

  • 302.
    Karlsson, Jessica
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Gouveia-Figueira, Sandra
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Swedish Univ Agr Sci, Umea, Sweden.
    Alhouayek, Mireille
    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.
    Effects of tumour necrosis factor alpha upon the metabolism of the endocannabinoid anandamide in prostate cancer cells2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 9, article id e0185011Article in journal (Refereed)
    Abstract [en]

    Tumour necrosis factor a (TNF alpha) is involved in the pathogenesis of prostate cancer, a disease where disturbances in the endocannabinoid system are seen. In the present study we have investigated whether treatment of DU145 human prostate cancer cells affects anandamide (AEA) catabolic pathways. Additionally, we have investigated whether cyclooxygenase- 2 (COX-2) can regulate the uptake of AEA into cells. Levels of AEA synthetic and catabolic enzymes were determined by qPCR. AEA uptake and hydrolysis in DU145 and RAW264.7 macrophage cells were assayed using AEA labeled in the arachidonic and ethanolamine portions of the molecule, respectively. Levels of AEA, related N-acylethanolamines (NAEs), prostaglandins (PG) and PG-ethanolamines (PG-EA) in DU145 cells and medium were quantitated by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis. TNF alpha treatment of DU145 cells increased mRNA levels of PTSG2 (gene of COX-2) and decreased the mRNA of the AEA synthetic enzyme N-acylphosphatidylethanolamine selective phospholipase D. mRNA levels of the AEA hydrolytic enzymes fatty acid amide hydrolase (FAAH) and N-acylethanolamine-hydrolyzing acid amidase were not changed. AEA uptake in both DU145 and RAW264.7 cells was inhibited by FAAH inhibition, but not by COX-2 inhibition, even in RAW264.7 cells where the expression of this enzyme had greatly been induced by lipopolysaccharide + interferon. treatment. AEA and related NAEs were detected in DU145 cells, but PGs and PGE(2)-EA were only detected when the cells had been preincubated with 100 nM AEA. The data demonstrate that in DU145 cells, TNFa treatment changes the relative expression of the enzymes involved in the hydrolytic and oxygenation catabolic pathways for AEA. In RAW264.7 cells, COX-2, in contrast to FAAH, does not regulate the cellular accumulation of AEA. Further studies are necessary to determine the extent to which inflammatory mediators are involved in the abnormal endocannabinoid signalling system in prostate cancer.

  • 303.
    Karlsson, Jessica
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Morgillo, Carmine M.
    Deplano, Alessandro
    Smaldone, Giovanni
    Pedone, Emilia
    Javier Luque, F.
    Svensson, Mona
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Novellino, Ettore
    Congiu, Cenzo
    Onnis, Valentina
    Catalanotti, Bruno
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Interaction of the N-(3-Methylpyridin-2-yl) amide Derivatives of Flurbiprofen and Ibuprofen with FAAH: Enantiomeric Selectivity and Binding Mode2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 11, article id e0142711Article in journal (Refereed)
    Abstract [en]

    Background Combined fatty acid amide hydrolase (FAAH) and cyclooxygenase (COX) inhibition is a promising approach for pain-relief. The Flu-AM1 and Ibu-AM5 derivatives of flurbiprofen and ibuprofen retain similar COX-inhibitory properties and are more potent inhibitors of FAAH than the parent compounds. However, little is known as to the nature of their interaction with FAAH, or to the importance of their chirality. This has been explored here. Methodology/Principal Findings FAAH inhibitory activity was measured in rat brain homogenates and in lysates expressing either wild-type or FAAH(T488A)-mutated enzyme. Molecular modelling was undertaken using both docking and molecular dynamics. The (R)-and (S)-enantiomers of Flu-AM1 inhibited rat FAAH with similar potencies (IC50 values of 0.74 and 0.99 mu M, respectively), whereas the (S)-enantiomer of Ibu-AM5 (IC50 0.59 mu M) was more potent than the (R)-enantiomer (IC50 5.7 mu M). Multiple inhibition experiments indicated that both (R)-Flu-AM1 and (S)-Ibu-AM5 inhibited FAAH in a manner mutually exclusive to carprofen. Computational studies indicated that the binding site for the Flu-AM1 and Ibu-AM5 enantiomers was located between the acyl chain binding channel and the membrane access channel, in a site overlapping the carprofen binding site, and showed a binding mode in line with that proposed for carprofen and other non-covalent ligands. The potency of (R)-Flu-AM1 was lower towards lysates expressing FAAH mutated at the proposed carprofen binding area than in lysates expressing wild-type FAAH. Conclusions/Significance The study provides kinetic and structural evidence that the enantiomers of Flu-AM1 and Ibu-AM5 bind in the substrate channel of FAAH. This information will be useful in aiding the design of novel dual-action FAAH: COX inhibitors.

  • 304.
    Karlsson, Terese
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Persson, Emma
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Tumor Cell-Derived Exosomes from the Prostate Cancer Cell Line TRAMP-C1 Impair Osteoclast Formation and Differentiation2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 11, article id e0166284Article in journal (Refereed)
    Abstract [en]

    Skeletal metastatic disease is a deleterious consequence of dissemination of tumor cells from numerous primary sites, such as prostate, lung and breast. Skeletal metastases are still incurable, resulting in development of clinical complications and decreased survival for cancer patients with metastatic disease. During the last decade, tumor cell-derived microvesicles have been identified and suggested to be involved in cancer disease progression. Whether cancer exosomes are involved in tumor and bone cell interactions in the metastatic site is still, however, a rather unexplored field. Here we show that exosomes isolated from the murine prostate cancer cell line TRAMP-C1 dramatically decrease fusion and differentiation of monocytic osteoclast precursors to mature, multinucleated osteoclasts. The presence of tumor cell-derived exosomes also clearly decreased the expression of established markers for osteoclast fusion and differentiation, including DC-STAMP, TRAP, cathepsin K, and MMP-9. In contrast, exosomes derived from murine fibroblastic cells did not affect osteoclast formation. Our findings suggest that exosomes released from tumor cells in the tumor-bone interface are involved in pathological regulation of bone cell formation in the metastatic site. This further strengthens the role of tumor cell-derived microvesicles in cancer progression and disease aggressiveness.

  • 305.
    Karlsson-Lindahl, Linda
    et al.
    University of Gothenburg.
    Schmidt, Linnea
    University of Gothenburg.
    Haage, David
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Hansson, Caroline
    University of Gothenburg.
    Taube, Magdalena
    University of Gothenburg.
    Egeciouglu, Emil
    University of Gothenburg.
    Tan, Ying-xia
    University of Uppsala.
    Admyre, Therese
    AstraZeneca, R&D Mölndal.
    Jansson, John-Olov
    University of Gothenburg.
    Vlodavsky, Israel
    Cancer and Vascular Biology Research Center, the Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
    Li, Jin-Ping
    University of Uppsala.
    Lindahl, Ulf
    University of Uppsala.
    Dickson, Suzanne L.
    University of Gothenburg.
    Heparanase Affects Food Intake and Regulates Energy Balance in Mice2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 3, p. e34313-Article in journal (Refereed)
    Abstract [en]

    Mutation of the melanocortin-receptor 4 (MC4R) is the most frequent cause of severe obesity in humans. Binding of agouti-related peptide (AgRP) to MC4R involves the co-receptor syndecan-3, a heparan sulfate proteoglycan. The proteoglycan can be structurally modified by the enzyme heparanase. Here we tested the hypothesis that heparanase plays a role in food intake behaviour and energy balance regulation by analysing body weight, body composition and food intake in genetically modified mice that either lack or overexpress heparanase. We also assessed food intake and body weight following acute central intracerebroventricular administration of heparanase; such treatment reduced food intake in wildtype mice, an effect that was abolished in mice lacking MC4R. By contrast, heparanase knockout mice on a high-fat diet showed increased food intake and maturity-onset obesity, with up to a 40% increase in body fat. Mice overexpressing heparanase displayed essentially the opposite phenotypes, with a reduced fat mass. These results implicate heparanase in energy balance control via the central melanocortin system. Our data indicate that heparanase acts as a negative modulator of AgRP signaling at MC4R, through cleavage of heparan sulfate chains presumably linked to syndecan-3.

  • 306.
    Kassem, Ali
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Lindholm, Catharina
    Lerner, Ulf H.
    Umeå University, Faculty of Medicine, Department of Odontology. Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition at Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Toll-Like Receptor 2 Stimulation of Osteoblasts Mediates Staphylococcus Aureus Induced Bone Resorption and Osteoclastogenesis through Enhanced RANKL2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 6, article id e0156708Article in journal (Refereed)
    Abstract [en]

    Severe Staphylococcus aureus (S. aureus) infections pose an immense threat to population health and constitute a great burden for the health care worldwide. Inter alia, S. aureus septic arthritis is a disease with high mortality and morbidity caused by destruction of the infected joints and systemic bone loss, osteoporosis. Toll-Like receptors (TLRs) are innate immune cell receptors recognizing a variety of microbial molecules and structures. S. aureus recognition via TLR2 initiates a signaling cascade resulting in production of various cytokines, but the mechanisms by which S. aureus causes rapid and excessive bone loss are still unclear. We, therefore, investigated how S. aureus regulates periosteal/endosteal osteoclast formation and bone resorption. S. aureus stimulation of neonatal mouse parietal bone induced ex vivo bone resorption and osteoclastic gene expression. This effect was associated with increased mRNA and protein expression of receptor activator of NF-kappa B ligand (RANKL) without significant change in osteoprotegerin (OPG) expression. Bone resorption induced by S. aureus was abolished by OPG. S. aureus increased the expression of osteoclastogenic cytokines and prostaglandins in the parietal bones but the stimulatory effect of S. aureus on bone resorption and Tnfsf11 mRNA expression was independent of these cytokines and prostaglandins. Stimulation of isolated periosteal osteoblasts with S. aureus also resulted in increased expression of Tnfsf11 mRNA, an effect lost in osteoblasts from Tlr2 knockout mice. S. aureus stimulated osteoclastogenesis in isolated periosteal cells without affecting RANKL-stimulated resorption. In contrast, S. aureus inhibited RANKL-induced osteoclast formation in bone marrow macrophages. These data show that S. aureus enhances bone resorption and periosteal osteoclast formation by increasing osteoblast RANKL production through TLR2. Our study indicates the importance of using different in vitro approaches for studies of how S. aureus regulates osteoclastogenesis to obtain better understanding of the complex mechanisms of S. aureus induced bone destruction in vivo.

  • 307.
    Kauppi, Anna M.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Edin, Alicia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Ziegler, Ingrid
    Mölling, Paula
    Sjöstedt, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Gylfe, Åsa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Strålin, Kristoffer
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Metabolites in Blood for Prediction of Bacteremic Sepsis in the Emergency Room2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 1, article id e0147670Article in journal (Refereed)
    Abstract [en]

    A metabolomics approach for prediction of bacteremic sepsis in patients in the emergency room (ER) was investigated. In a prospective study, whole blood samples from 65 patients with bacteremic sepsis and 49 ER controls were compared. The blood samples were analyzed using gas chromatography coupled to time-of-flight mass spectrometry. Multivariate and logistic regression modeling using metabolites identified by chromatography or using conventional laboratory parameters and clinical scores of infection were employed. A predictive model of bacteremic sepsis with 107 metabolites was developed and validated. The number of metabolites was reduced stepwise until identifying a set of 6 predictive metabolites. A 6-metabolite predictive logistic regression model showed a sensitivity of 0.91(95% CI 0.69-0.99) and a specificity 0.84 (95% CI 0.58-0.94) with an AUC of 0.93 (95% CI 0.89-1.01). Myristic acid was the single most predictive metabolite, with a sensitivity of 1.00 (95% CI 0.85-1.00) and specificity of 0.95 (95% CI 0.74-0.99), and performed better than various combinations of conventional laboratory and clinical parameters. We found that a metabolomics approach for analysis of acute blood samples was useful for identification of patients with bacteremic sepsis. Metabolomics should be further evaluated as a new tool for infection diagnostics.

  • 308.
    Keefover-Ring, Ken
    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). Department of Entomology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
    Ahnlund, Maria
    Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå Plant Science Centre, Umeå, Sweden.
    Abreu, Ilka Nacif
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå Plant Science Centre, Umeå, Sweden.
    Jansson, Stefan
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Moritz, Thomas
    Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå Plant Science Centre, Umeå, Sweden.
    Albrectsen, Benedicte Riber
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Department of Plant and Environmental Sciences, University of Copenhagen, Frederiksberg, Denmark.
    No evidence of geographical structure of salicinoid chemotypes within Populus tremula2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 10, p. e107189-Article in journal (Refereed)
    Abstract [en]

    Salicinoids are well-known defense compounds in salicaceous trees and careful screening at the population level is warranted to fully understand their diversity and function. European aspen, Populus tremula, is a foundation species in Eurasia and highly polymorphic in Sweden. We exhaustively surveyed 102 replicated genotypes from the Swedish Aspen collection (SwAsp) for foliar salicinoids using UHPLC-ESI-TOF/MS and identified nine novel compounds, bringing the total to 19 for this species. Salicinoid structure followed a modular architecture of a salicin skeleton with added side groups, alone or in combination. Two main moieties, 2'-cinnamoyl and 2'-acetyl, grouped the SwAsp population into four distinct chemotypes, and the relative allocation of salicinoids was remarkably constant between different environments, implying a highly channeled biosynthesis of these compounds. Slightly more than half of the SwAsp genotypes belonged to the cinnamoyl chemotype. A fraction synthesized the acetyl moiety alone (similar to 7%) or in combination with cinnamoyl (similar to 2%), and close to forty percent lacked either of the two characteristic moieties, and thus resemble P. tremuloides in their salicinoid profile. The two most abundant chemotypes were evenly distributed throughout Sweden, unlike geographical patterns reported for SwAsp phenology traits, plant defense genes, and herbivore community associations. Here we present the salicinoid characterization of the SwAsp collection as a resource for future studies of aspen chemical ecology, salicinoid biosynthesis, and genetics.

  • 309. Kelly, Rachel S.
    et al.
    Lundh, Thomas
    Porta, Miquel
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Palli, Domenico
    Johansson, Ann-Sofie
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Botsivali, Maria
    Vineis, Paolo
    Vermeulen, Roel
    Kyrtopoulos, Soterios A.
    Chadeau-Hyam, Marc
    Blood erythrocyte concentrations of cadmium and lead and the risk of B-cell non-Hodgkin's lymphoma and multiple myeloma: a nested case-control study2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 11, p. Article Number: UNSP e81892-Article in journal (Refereed)
    Abstract [en]

    Background: Cadmium (Cd) and lead (Pb) are hypothesised to be risk factors for non-Hodgkin's lymphoma (NHL), a group of haematological malignancies with a suspected environmental aetiology. Within the EnviroGenoMarkers study we utilised pre-diagnostic erythrocyte concentrations of Cd and Pb to determine whether exposure was associated with risk of B-cell NHL and multiple myeloma. Methods: 194 incident cases of B-cell NHL and 76 cases of multiple myeloma diagnosed between 1990 and 2006 were identified from two existing cohorts; EPIC-Italy and the Northern Sweden Health and Disease Study. Cases were matched to healthy controls by centre, age, gender and date of blood collection. Cd and Pb were measured in blood samples provided at recruitment using inductively coupled plasma-mass spectrometry. Logistic regression was applied to assess the association with risk. Analyses were stratified by cohort and gender and by subtype where possible. Results: There was little evidence of an increased risk of B-cell NHL or multiple myeloma with exposure to Cd (B-cell NHL: OR 1.09 95%CI 0.61, 1.93, MM: OR 1.16 95% CI: 0.40, 3.40) or Pb (B-cell NHL: 0.93 95% CI 0.43, 2.02, multiple myeloma: OR 1.63 95% CI 0.45, 5.94) in the total population when comparing the highest to the lowest quartile of exposure. However, gender and cohort specific differences in results were observed. In females the risk of B-cell NHL was more than doubled in those with a body burden of Cd >1 mu g/L (OR 2.20 95% CI; 1.04, 4.65). Conclusions: This nested case-control study does not support a consistent positive association between Cd or Pb and NHL, but there is some indication of a gender specific effect suggesting further research is warranted.

  • 310. Kersulyte, Dangeruta
    et al.
    Kalia, Awdhesh
    Gilman, Robert H
    Mendez, Melissa
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Herrera, Phabiola
    Cabrera, Lilia
    Velapatiño, Billie
    Balqui, Jacqueline
    Paredes Puente de la Vega, Freddy
    Rodriguez Ulloa, Carlos A
    Cok, Jaime
    Hooper, Catherine C
    Dailide, Giedrius
    Tamma, Sravya
    Berg, Douglas E
    Helicobacter pylori from Peruvian amerindians: traces of human migrations in strains from remote Amazon, and genome sequence of an Amerind strain2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 11, p. e15076-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The gastric pathogen Helicobacter pylori is extraordinary in its genetic diversity, the differences between strains from well-separated human populations, and the range of diseases that infection promotes.

    PRINCIPAL FINDINGS: Housekeeping gene sequences from H. pylori from residents of an Amerindian village in the Peruvian Amazon, Shimaa, were related to, but not intermingled with, those from Asia. This suggests descent of Shimaa strains from H. pylori that had infected the people who migrated from Asia into The Americas some 15,000+ years ago. In contrast, European type sequences predominated in strains from Amerindian Lima shantytown residents, but with some 12% Amerindian or East Asian-like admixture, which indicates displacement of ancestral purely Amerindian strains by those of hybrid or European ancestry. The genome of one Shimaa village strain, Shi470, was sequenced completely. Its SNP pattern was more Asian- than European-like genome-wide, indicating a purely Amerind ancestry. Among its unusual features were two cagA virulence genes, each distinct from those known from elsewhere; and a novel allele of gene hp0519, whose encoded protein is postulated to interact with host tissue. More generally, however, the Shi470 genome is similar in gene content and organization to those of strains from industrialized countries.

    CONCLUSIONS: Our data indicate that Shimaa village H. pylori descend from Asian strains brought to The Americas many millennia ago; and that Amerind strains are less fit than, and were substantially displaced by, hybrid or European strains in less isolated communities. Genome comparisons of H. pylori from Amerindian and other communities should help elucidate evolutionary forces that have shaped pathogen populations in The Americas and worldwide.

  • 311.
    Keskin, Isil
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Forsgren, Elin
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Lange, Dale J.
    Weber, Markus
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Synofzik, Matthis
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Effects of Cellular Pathway Disturbances on Misfolded Superoxide Dismutase-1 in Fibroblasts Derived from ALS Patients2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 2, article id e0150133Article in journal (Refereed)
    Abstract [en]

    Mutations in superoxide dismutase-1 (SOD1) are a common known cause of amyotrophic lateral sclerosis (ALS). The neurotoxicity of mutant SOD1s is most likely caused by misfolded molecular species, but disease pathogenesis is still not understood. Proposed mechanisms include impaired mitochondrial function, induction of endoplasmic reticulum stress, reduction in the activities of the proteasome and autophagy, and the formation of neurotoxic aggregates. Here we examined whether perturbations in these cellular pathways in turn influence levels of misfolded SOD1 species, potentially amplifying neurotoxicity. For the study we used fibroblasts, which express SOD1 at physiological levels under regulation of the native promoter. The cells were derived from ALS patients expressing 9 different SOD1 mutants of widely variable molecular characteristics, as well as from patients carrying the GGGGCC-repeat-expansion in C9orf72 and from non-disease controls. A specific ELISA was used to quantify soluble, misfolded SOD1, and aggregated SOD1 was analysed by western blotting. Misfolded SOD1 was detected in all lines. Levels were found to be much lower in non-disease control and the non-SOD1 C9orf72 ALS lines. This enabled us to validate patient fibroblasts for use in subsequent perturbation studies. Mitochondrial inhibition, endoplasmic reticulum stress or autophagy inhibition did not affect soluble misfolded SOD1 and in most cases, detergent-resistant SOD1 aggregates were not detected. However, proteasome inhibition led to uniformly large increases in misfolded SOD1 levels in all cell lines and an increase in SOD1 aggregation in some. Thus the ubiquitin-proteasome pathway is a principal determinant of misfolded SOD1 levels in cells derived both from patients and controls and a decline in activity with aging could be one of the factors behind the mid-to late-life onset of inherited ALS.

  • 312. Khademi, Mohsen
    et al.
    Dring, Ann M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Gilthorpe, Jonathan D.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Wuolikainen, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Al Nimer, Faiez
    Harris, Robert A.
    Andersson, Magnus
    Brundin, Lou
    Piehl, Fredrik
    Olsson, Tomas
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Intense Inflammation and Nerve Damage in Early Multiple Sclerosis Subsides at Older Age: A Reflection by Cerebrospinal Fluid Biomarkers2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 5, p. e63172-Article in journal (Refereed)
    Abstract [en]

    Inflammatory mediators have crucial roles in leukocyte recruitment and subsequent central nervous system (CNS) neuroinflammation. The extent of neuronal injury and axonal loss are associated with the degree of CNS inflammation and determine physical disability in multiple sclerosis (MS). The aim of this study was to explore possible associations between a panel of selected cerebrospinal fluid biomarkers and robust clinical and demographic parameters in a large cohort of patients with MS and controls (n = 1066) using data-driven multivariate analysis. Levels of matrix metalloproteinase 9 (MMP9), chemokine (C-X-C motif) ligand 13 (CXCL13), osteopontin (OPN) and neurofilament-light chain (NFL) were measured by ELISA in 548 subjects comprising different MS subtypes (relapsing-remitting, secondary progressive and primary progressive), clinically isolated syndrome and persons with other neurological diseases with or without signs of inflammation/infection. Principal component analyses and orthogonal partial least squares methods were used for unsupervised and supervised interrogation of the data. Models were validated using data from a further 518 subjects in which one or more of the four selected markers were measured. There was a significant association between increased patient age and lower levels of CXCL13, MMP9 and NFL. CXCL13 levels correlated well with MMP9 in the younger age groups, but less so in older patients, and after approximately 54 years of age the levels of CXCL13 and MMP9 were consistently low. CXCL13 and MMP9 levels also correlated well with both NFL and OPN in younger patients. We demonstrate a strong effect of age on both inflammatory and neurodegenerative biomarkers in a large cohort of MS patients. The findings support an early use of adequate immunomodulatory disease modifying drugs, especially in younger patients, and may provide a biological explanation for the relative inefficacy of such treatments in older patients at later disease stages.

  • 313. Khalil, Hussein
    et al.
    Olsson, Gert
    Ecke, Frauke
    Evander, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Hjertqvist, Marika
    Magnusson, Magnus
    Löfvenius, Mikaell Ottosson
    Hörnfeldt, Birger
    The importance of bank vole density and rainy winters in predicting nephropathia epidemica incidence in Northern Sweden.2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, article id e111663Article in journal (Refereed)
    Abstract [en]

    Pathogenic hantaviruses (family Bunyaviridae, genus Hantavirus) are rodent-borne viruses causing hemorrhagic fever with renal syndrome (HFRS) in Eurasia. In Europe, there are more than 10,000 yearly cases of nephropathia epidemica (NE), a mild form of HFRS caused by Puumala virus (PUUV). The common and widely distributed bank vole (Myodes glareolus) is the host of PUUV. In this study, we aim to explain and predict NE incidence in boreal Sweden using bank vole densities. We tested whether the number of rainy days in winter contributed to variation in NE incidence. We forecast NE incidence in July 2013-June 2014 using projected autumn vole density, and then considering two climatic scenarios: 1) rain-free winter and 2) winter with many rainy days. Autumn vole density was a strong explanatory variable of NE incidence in boreal Sweden in 1990-2012 (R2 = 79%, p<0.001). Adding the number of rainy winter days improved the model (R2 = 84%, p<0.05). We report for the first time that risk of NE is higher in winters with many rainy days. Rain on snow and ground icing may block vole access to subnivean space. Seeking refuge from adverse conditions and shelter from predators, voles may infest buildings, increasing infection risk. In a rainy winter scenario, we predicted 812 NE cases in boreal Sweden, triple the number of cases predicted in a rain-free winter in 2013/2014. Our model enables identification of high risk years when preparedness in the public health sector is crucial, as a rainy winter would accentuate risk.

  • 314.
    Khan, Ghazanfar Ali
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Berglund, Björn
    Khan, Kashif Maqbool
    Lindgren, Per-Eric
    Fick, Jerker
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Occurrence and abundance of antibiotics and resistance genes in rivers, canal and near drug formulation facilities: a study in Pakistan2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 6, p. e62712-Article in journal (Refereed)
    Abstract [en]

    Antibiotic resistance (AR) is a global phenomenon that has severe epidemiological ramifications world-wide. It has been suggested that antibiotics that have been discharged into the natural aquatic environments after usage or manufacture can promote the occurrence of antibiotic resistance genes (ARG). These environmental ARGs could serve as a reservoir and be horizontally transferred to human-associated bacteria and thus contribute to AR proliferation. The aim of this study was to investigate the anthropogenic load of antibiotics in Northern Pakistan and study the occurrence of ARGs in selected samples from this region. 19 sampling sites were selected; including six rivers, one dam, one canal, one sewage drain and four drug formulation facilities. Our results show that five of the rivers have antibiotic levels comparable to surface water measurements in unpolluted sites in Europe and the US. However, high levels of antibiotics could be detected in the downstream river in close vicinity of the 10 million city Lahore, 1100, 1700 and 2700 ng L-1 for oxytetracycline, trimethoprim, and sulfamethoxazole respectively. Highest detected levels were at one of the drug formulation facilities, with the measured levels of 1100, 4100, 6200, 7300, 8000, 27000, 28000 and 49000 ng L 21 of erythromycin, lincomycin, ciprofloxacin, ofloxacin, levofloxacin, oxytetracycline, trimethoprim and sulfamethoxazole respectively. ARGs were also detected at the sites and the highest levels of ARGs detected, sulI and dfrA1, were directly associated with the antibiotics detected at the highest concentrations, sulfamethoxazole and trimethoprim. Highest levels of both antibiotics and ARGs were seen at a drug formulation facility, within an industrial estate with a low number of local residents and no hospitals in the vicinity, which indicates that the levels of ARGs at this site were associated with the environmental levels of antibiotics

  • 315. Khmelinskii, Anton
    et al.
    Meurer, Matthias
    Duishoev, Nurlanbek
    Delhomme, Nicolas
    Knop, Michael
    Seamless gene tagging by endonuclease-driven homologous recombination.2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 8Article in journal (Refereed)
    Abstract [en]

    Gene tagging facilitates systematic genomic and proteomic analyses but chromosomal tagging typically disrupts gene regulatory sequences. Here we describe a seamless gene tagging approach that preserves endogenous gene regulation and is potentially applicable in any species with efficient DNA double-strand break repair by homologous recombination. We implement seamless tagging in Saccharomyces cerevisiae and demonstrate its application for protein tagging while preserving simultaneously upstream and downstream gene regulatory elements. Seamless tagging is compatible with high-throughput strain construction using synthetic genetic arrays (SGA), enables functional analysis of transcription antisense to open reading frames and should facilitate systematic and minimally-invasive analysis of gene functions.

  • 316.
    Khoshnood, Behzad
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Dacklin, Ingrid
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Grabbe, Caroline
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    A proteomics approach to identify targets of the ubiquitin-like molecule Urm1 in Drosophila melanogaster2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 9, article id e0185611Article in journal (Refereed)
    Abstract [en]

    By covalently conjugating to target proteins, ubiquitin-like modifiers (UBLs) act as important regulators of target protein localization and activity, thereby playing a critical role in the orchestration of cellular biology. The most ancient and one of the least studied UBLs is Urm1, a dual-function protein that in parallel to performing similar functions as its prokaryotic ancestors in tRNA modification, also has adopted the capacity to conjugate to cellular proteins analogous to ubiquitin and other UBL modifiers. In order to increase the understanding of Urm1 and its role in multicellular organisms, we have used affinity purification followed by mass spectrometry to identify putative targets of Urm1 conjugation (urmylation) at three developmental stages of the Drosophila melanogaster lifecycle. Altogether we have recovered 79 Urm1-interacting proteins in Drosophila, which include the already established Urm1 binding partners Prx5 and Uba4, together with 77 candidate urmylation targets that are completely novel in the fly. Among these, the majority was exclusively identified during either embryogenesis, larval stages or in adult flies. We further present biochemical evidence that four of these proteins are covalently conjugated by Urm1, whereas the fifth verified Urm1-binding protein appears to interact with Urm1 via non-covalent means. Besides recapitulating the previously established roles of Urm1 in tRNA modification and during oxidative stress, functional clustering of the newly identified Urm1-associated proteins further positions Urm1 in protein networks that control other types of cellular stress, such as immunological threats and DNA damage. In addition, the functional characteristics of several of the candidate targets strongly match the phenotypes displayed by Urm1(n123) null animals, including embryonic lethality, reduced fertility and shortened lifespan. In conclusion, this identification of candidate targets of urmylation significantly increases the knowledge of Urm1 and presents an excellent starting point for unravelling the role of Urm1 in the context of a complex living organism.

  • 317.
    Kieselbach, Thomas
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Zijnge, Vincent
    Granström, Elisabeth
    Umeå University, Faculty of Medicine, Department of Odontology.
    Oscarsson, Jan
    Umeå University, Faculty of Medicine, Department of Odontology.
    Proteomics of Aggregatibacter actinomycetemcomitans Outer Membrane Vesicles2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 9, article id e0138591Article in journal (Refereed)
    Abstract [en]

    Aggregatibacter actinomycetemcomitans is an oral and systemic pathogen associated with aggressive forms of periodontitis and with endocarditis. Outer membrane vesicles (OMVs) released by this species have been demonstrated to deliver effector proteins such as cytolethal distending toxin (CDT) and leukotoxin (LtxA) into human host cells and to act as triggers of innate immunity upon carriage of NOD1- and NOD2-active pathogen-associated molecular patterns (PAMPs). To improve our understanding of the pathogenicity-associated functions that A. actinomycetemcomitans exports via OMVs, we studied the proteome of density gradient-purified OMVs from a rough-colony type clinical isolate, strain 173 (serotype e) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). This analysis yielded the identification of 151 proteins, which were found in at least three out of four independent experiments. Data are available via ProteomeXchange with identifier PXD002509. Through this study, we not only confirmed the vesicle-associated release of LtxA, and the presence of proteins, which are known to act as immunoreactive antigens in the human host, but we also identified numerous additional putative virulence-related proteins in the A. actinomycetemcomitans OMV proteome. The known and putative functions of these proteins include immune evasion, drug targeting, and iron/nutrient acquisition. In summary, our findings are consistent with an OMV-associated proteome that exhibits several offensive and defensive functions, and they provide a comprehensive basis to further disclose roles of A. actinomycetemcomitans OMVs in periodontal and systemic disease.

  • 318.
    Kindgren, Peter
    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).
    Dubreuil, Carole
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Strand, Åsa
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    The Recovery of Plastid Function Is Required for Optimal Response to Low Temperatures in Arabidopsis2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 9, article id e0138010Article in journal (Refereed)
    Abstract [en]

    Cold acclimation is an essential response in higher plants to survive freezing temperatures. Here, we report that two independent mutant alleles of the H-subunit of Mg-chelatase, CHLH, gun5-1 and cch in Arabidopsis are sensitive to low temperatures. Plants were grown in photoperiodic conditions and exposed to low temperatures for short-and long-term periods. Tetrapyrrole biosynthesis was initially significantly inhibited in response to low temperature but recovered in wild type (Col-0), although the tetrapyrrole levels were lower in cold compared to control conditions. The gun5-1 and cch alleles showed an inability to recover chlorophyll biosynthesis in addition to a significant decrease in freezing tolerance. We found that the impaired plastid function in the CHLH mutant plants resulted in compromised de novo protein synthesis at low temperatures. The expression of the transcription factors CBF1-3 was super-induced in gun5-1 and cch mutant alleles but expression levels of their target genes, COR15a, COR47 and COR78 were similar or even lower compared to Col-0. In addition, the protein levels of COR15a were lower in gun5-1 and cch and a general defect in protein synthesis could be seen in the gun5-1 mutant following a 35S labelling experiment performed at low temperature. Taken together, our results demonstrate the importance of a functional chloroplast for the cold acclimation process and further suggest that impaired plastid function could result in inhibition of protein synthesis at low temperature.

  • 319. Kirchhoff, Tomas
    et al.
    Gaudet, Mia M
    Antoniou, Antonis C
    McGuffog, Lesley
    Humphreys, Manjeet K
    Dunning, Alison M
    Bojesen, Stig E
    Nordestgaard, Børge G
    Flyger, Henrik
    Kang, Daehee
    Yoo, Keun-Young
    Noh, Dong-Young
    Ahn, Sei-Hyun
    Dork, Thilo
    Schürmann, Peter
    Karstens, Johann H
    Hillemanns, Peter
    Couch, Fergus J
    Olson, Janet
    Vachon, Celine
    Wang, Xianshu
    Cox, Angela
    Brock, Ian
    Elliott, Graeme
    Reed, Malcolm W R
    Burwinkel, Barbara
    Meindl, Alfons
    Brauch, Hiltrud
    Hamann, Ute
    Ko, Yon-Dschun
    Broeks, Annegien
    Schmidt, Marjanka K
    Van 't Veer, Laura J
    Braaf, Linde M
    Johnson, Nichola
    Fletcher, Olivia
    Gibson, Lorna
    Peto, Julian
    Turnbull, Clare
    Seal, Sheila
    Renwick, Anthony
    Rahman, Nazneen
    Wu, Pei-Ei
    Yu, Jyh-Cherng
    Hsiung, Chia-Ni
    Shen, Chen-Yang
    Southey, Melissa C
    Hopper, John L
    Hammet, Fleur
    Van Dorpe, Thijs
    Dieudonne, Anne-Sophie
    Hatse, Sigrid
    Lambrechts, Diether
    Andrulis, Irene L
    Bogdanova, Natalia
    Antonenkova, Natalia
    Rogov, Juri I
    Prokofieva, Daria
    Bermisheva, Marina
    Khusnutdinova, Elza
    van Asperen, Christi J
    Tollenaar, Robert A E M
    Hooning, Maartje J
    Devilee, Peter
    Margolin, Sara
    Lindblom, Annika
    Milne, Roger L
    Arias, José Ignacio
    Zamora, M Pilar
    Benítez, Javier
    Severi, Gianluca
    Baglietto, Laura
    Giles, Graham G
    Spurdle, Amanda B
    Beesley, Jonathan
    Chen, Xiaoqing
    Holland, Helene
    Healey, Sue
    Wang-Gohrke, Shan
    Chang-Claude, Jenny
    Mannermaa, Arto
    Kosma, Veli-Matti
    Kauppinen, Jaana
    Kataja, Vesa
    Agnarsson, Bjarni A
    Caligo, Maria A
    Godwin, Andrew K
    Nevanlinna, Heli
    Heikkinen, Tuomas
    Fredericksen, Zachary
    Lindor, Noralane
    Nathanson, Katherine L
    Domchek, Susan M
    Loman, Niklas
    Karlsson, Per
    Stenmark Askmalm, Marie
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    von Wachenfeldt, Anna
    Hogervorst, Frans B L
    Verheus, Martijn
    Rookus, Matti A
    Seynaeve, Caroline
    Oldenburg, Rogier A
    Ligtenberg, Marjolijn J
    Ausems, Margreet G E M
    Aalfs, Cora M
    Gille, Hans J P
    Wijnen, Juul T
    Gómez García, Encarna B
    Peock, Susan
    Cook, Margaret
    Oliver, Clare T
    Frost, Debra
    Luccarini, Craig
    Pichert, Gabriella
    Davidson, Rosemarie
    Chu, Carol
    Eccles, Diana
    Ong, Kai-Ren
    Cook, Jackie
    Douglas, Fiona
    Hodgson, Shirley
    Evans, D Gareth
    Eeles, Rosalind
    Gold, Bert
    Pharoah, Paul D P
    Offit, Kenneth
    Chenevix-Trench, Georgia
    Easton, Douglas F
    Breast cancer risk and 6q22.33: combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/22012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 6, article id e35706Article in journal (Refereed)
    Abstract [en]

    Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.

  • 320. Klein, Alison P.
    et al.
    Lindström, Sara
    Mendelsohn, Julie B.
    Steplowski, Emily
    Arslan, Alan A.
    Bueno-de-Mesquita, H. Bas
    Fuchs, Charles S.
    Gallinger, Steven
    Gross, Myron
    Helzlsouer, Kathy
    Holly, Elizabeth A.
    Jacobs, Eric J.
    Lacroix, Andrea
    Li, Donghui
    Mandelson, Margaret T.
    Olson, Sara H.
    Petersen, Gloria M.
    Risch, Harvey A.
    Stolzenberg-Solomon, Rachael Z.
    Zheng, Wei
    Amundadottir, Laufey
    Albanes, Demetrius
    Allen, Naomi E.
    Bamlet, William R.
    Boutron-Ruault, Marie-Christine
    Buring, Julie E.
    Bracci, Paige M.
    Canzian, Federico
    Clipp, Sandra
    Cotterchio, Michelle
    Duell, Eric J.
    Elena, Joanne
    Gaziano, J. Michael
    Giovannucci, Edward L.
    Goggins, Michael
    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.
    Hassan, Manal
    Hutchinson, Amy
    Hunter, David J.
    Kooperberg, Charles
    Kurtz, Robert C.
    Liu, Simin
    Overvad, Kim
    Palli, Domenico
    Patel, Alpa V.
    Rabe, Kari G.
    Shu, Xiao-Ou
    Slimani, Nadia
    Tobias, Geoffrey S.
    Trichopoulos, Dimitrios
    Van Den Eeden, Stephen K.
    Vineis, Paolo
    Virtamo, Jarmo
    Wactawski-Wende, Jean
    Wolpin, Brian M.
    Yu, Herbert
    Yu, Kai
    Zeleniuch-Jacquotte, Anne
    Chanock, Stephen J.
    Hoover, Robert N.
    Hartge, Patricia
    Kraft, Peter
    An absolute risk model to identify individuals at elevated risk for pancreatic cancer in the general population.2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, article id e72311Article in journal (Refereed)
    Abstract [en]

    PURPOSE: We developed an absolute risk model to identify individuals in the general population at elevated risk of pancreatic cancer.

    PATIENTS AND METHODS: Using data on 3,349 cases and 3,654 controls from the PanScan Consortium, we developed a relative risk model for men and women of European ancestry based on non-genetic and genetic risk factors for pancreatic cancer. We estimated absolute risks based on these relative risks and population incidence rates.

    RESULTS: Our risk model included current smoking (multivariable adjusted odds ratio (OR) and 95% confidence interval: 2.20 [1.84-2.62]), heavy alcohol use (>3 drinks/day) (OR: 1.45 [1.19-1.76]), obesity (body mass index >30 kg/m(2)) (OR: 1.26 [1.09-1.45]), diabetes >3 years (nested case-control OR: 1.57 [1.13-2.18], case-control OR: 1.80 [1.40-2.32]), family history of pancreatic cancer (OR: 1.60 [1.20-2.12]), non-O ABO genotype (AO vs. OO genotype) (OR: 1.23 [1.10-1.37]) to (BB vs. OO genotype) (OR 1.58 [0.97-2.59]), rs3790844(chr1q32.1) (OR: 1.29 [1.19-1.40]), rs401681(5p15.33) (OR: 1.18 [1.10-1.26]) and rs9543325(13q22.1) (OR: 1.27 [1.18-1.36]). The areas under the ROC curve for risk models including only non-genetic factors, only genetic factors, and both non-genetic and genetic factors were 58%, 57% and 61%, respectively. We estimate that fewer than 3/1,000 U.S. non-Hispanic whites have more than a 5% predicted lifetime absolute risk.

    CONCLUSION: Although absolute risk modeling using established risk factors may help to identify a group of individuals at higher than average risk of pancreatic cancer, the immediate clinical utility of our model is limited. However, a risk model can increase awareness of the various risk factors for pancreatic cancer, including modifiable behaviors.

  • 321.
    Klinth, Jeanna E.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Physics. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Castelain, Mickael
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Axner, Ove
    Umeå University, Faculty of Science and Technology, Department of Physics.
    The Influence of pH on the Specific Adhesion of P Piliated Escherichia coli2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 6, p. e38548-Article in journal (Refereed)
    Abstract [en]

    Adhesion to host tissues is an initiating step in a majority of bacterial infections. In the case of Gram-negative bacteria this adhesion is often mediated by a specific interaction between an adhesin, positioned at the distal end of bacterial pili, and its receptor on the surface of the host tissue. Furthermore, the rod of the pilus, and particularly its biomechanical properties, is believed to be crucial for the ability of bacteria to withstand external forces caused by, for example, (in the case of urinary tract infections) urinary rinsing flows by redistributing the force to several pili. In this work, the adhesion properties of P-piliated E. coli and their dependence of pH have been investigated in a broad pH range by both the surface plasmon resonance technique and force measuring optical tweezers. We demonstrate that P piliated bacteria have an adhesion ability throughout the entire physiologically relevant pH range (pH 4.5 - 8). We also show that pH has a higher impact on the binding rate than on the binding stability or the biomechanical properties of pili; the binding rate was found to have a maximum around pH 5 while the binding stability was found to have a broader distribution over pH and be significant over the entire physiologically relevant pH range. Force measurements on a single organelle level show that the biomechanical properties of P pili are not significantly affected by pH.

  • 322. Kristen, Arnt V.
    et al.
    Maurer, Mathew S.
    Rapezzi, Claudio
    Mundayat, Rajiv
    Suhr, Ole B.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Damy, Thibaud
    Impact of genotype and phenotype on cardiac biomarkers in patients with transthyretin amyloidosis - Report from the Transthyretin Amyloidosis Outcome Survey (THAOS)2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 4, article id e0173086Article in journal (Refereed)
    Abstract [en]

    Aim: Cardiac troponins and natriuretic peptides are established for risk stratification in light-chain amyloidosis. Data on cardiac biomarkers in transthyretin amyloidosis (ATTR) are lacking.

    Methods and results: Patients (n = 1617) with any of the following cardiac biomarkers, BNP (n = 1079), NT-proBNP (n = 550), troponin T (n = 274), and troponin I (n = 108), available at baseline in the Transthyretin Amyloidosis Outcomes Survey (THAOS) were analyzed for differences between genotypes and phenotypes and their association with survival. Median level of BNP was 68.0 pg/mL (IQR 30.5–194.9), NT-proBNP 337.9 pg/mL (IQR 73.0–2584.0), troponin T 0.03 μg/L (IQR 0.01–0.05), and troponin I 0.08 μg/L (IQR 0.04–0.13). NT-proBNP and BNP were higher in wild-type than mutant-type ATTR, troponin T and I did not differ, respectively. Non-Val30Met patients had higher BNP, NT-proBNP and troponin T levels than Val30Met patients, but not troponin I. Late-onset Val30Met was associated with higher levels of troponin I and troponin T compared with early-onset. 115 patients died during a median follow-up of 1.2 years. Mortality increased with increasing quartiles (BNP/NT-proBNP Q1 = 1.7%, Q2 = 5.2%, Q3 = 21.7%, Q4 = 71.3%; troponin T/I Q1 = 6.5%, Q2 = 14.5%, Q3 = 33.9%, Q4 = 45.2%). Three-year overall-survival estimates for BNP/NT-proBNP and troponin T/I quartiles differed significantly (p<0.001). Stepwise risk stratification was achieved by combining NT-proBNP/BNP and troponin T/I. From Cox proportional hazards model, age, modified body mass index, mutation (Val30Met vs. Non-Val30Met) and BNP/NT-proBNP (Q1–Q3 pooled vs. Q4) were identified as independent predictors of survival in patients with mutant-type ATTR.

    Conclusions: In this ATTR patient cohort, cardiac biomarkers were abnormal in a substantial percentage of patients irrespective of genotype. Along with age, mBMI, and mutation (Val30Met vs. Non-Val30Met), cardiac biomarkers were associated with surrogates of disease severity with BNP/NT-proBNP identified as an independent predictor of survival in ATTR.

  • 323. Kristiansson, Erik
    et al.
    Fick, Jerker
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Janzon, Anders
    Grabic, Roman
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Rutgersson, Carolin
    Weijdegård, Birgitta
    Söderström, Hanna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Larsson, D G Joakim
    Pyrosequencing of antibiotic-contaminated river sediments reveals high levels of resistance and gene transfer elements2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 2, p. e17038-Article in journal (Refereed)
    Abstract [en]

    The high and sometimes inappropriate use of antibiotics has accelerated the development of antibiotic resistance, creating a major challenge for the sustainable treatment of infections world-wide. Bacterial communities often respond to antibiotic selection pressure by acquiring resistance genes, i.e. mobile genetic elements that can be shared horizontally between species. Environmental microbial communities maintain diverse collections of resistance genes, which can be mobilized into pathogenic bacteria. Recently, exceptional environmental releases of antibiotics have been documented, but the effects on the promotion of resistance genes and the potential for horizontal gene transfer have yet received limited attention. In this study, we have used culture-independent shotgun metagenomics to investigate microbial communities in river sediments exposed to waste water from the production of antibiotics in India. Our analysis identified very high levels of several classes of resistance genes as well as elements for horizontal gene transfer, including integrons, transposons and plasmids. In addition, two abundant previously uncharacterized resistance plasmids were identified. The results suggest that antibiotic contamination plays a role in the promotion of resistance genes and their mobilization from environmental microbes to other species and eventually to human pathogens. The entire life-cycle of antibiotic substances, both before, under and after usage, should therefore be considered to fully evaluate their role in the promotion of resistance.

  • 324.
    Kumar, Keshav
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Espaillat, Akbar
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Cava, Felipe
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    PG-metrics: a chemometric-based approach for classifying bacterial peptidoglycan data sets and uncovering their subjacent chemical variability2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 10, article id e0186197Article in journal (Refereed)
    Abstract [en]

    Bacteria cells are protected from osmotic and environmental stresses by an exoskeleton-like polymeric structure called peptidoglycan ( PG) or murein sacculus. This structure is fundamental for bacteria's viability and thus, the mechanisms underlying cell wall assembly and how it is modulated serve as targets for many of our most successful antibiotics. Therefore, it is now more important than ever to understand the genetics and structural chemistry of the bacterial cell walls in order to find new and effective methods of blocking it for the treatment of disease. In the last decades, liquid chromatography and mass spectrometry have been demonstrated to provide the required resolution and sensitivity to characterize the fine chemical structure of PG. However, the large volume of data sets that can be produced by these instruments today are difficult to handle without a proper data analysis work-flow. Here, we present PG-metrics, a chemometric based pipeline that allows fast and easy classification of bacteria according to their muropeptide chromatographic profiles and identification of the subjacent PG chemical variability between e.g. bacterial species, growth conditions and, mutant libraries. The pipeline is successfully validated here using PG samples from different bacterial species and mutants in cell wall proteins. The obtained results clearly demonstrated that PG-metrics pipeline is a valuable bioanalytical tool that can lead us to cell wall classification and biomarker discovery.

  • 325.
    Kunz, Sabine
    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).
    Pesquet, Edouard
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Kleczkowski, Leszek A.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Functional Dissection of Sugar Signals Affecting Gene Expression in Arabidopsis thaliana2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 6, p. e100312-Article in journal (Refereed)
    Abstract [en]

    Background: Sugars modulate expression of hundreds of genes in plants. Previous studies on sugar signaling, using intact plants or plant tissues, were hampered by tissue heterogeneity, uneven sugar transport and/or inter-conversions of the applied sugars. This, in turn, could obscure the identity of a specific sugar that acts as a signal affecting expression of given gene in a given tissue or cell-type. Methodology/Principal Findings: To bypass those biases, we have developed a novel biological system, based on stem-cell-like Arabidopsis suspension culture. The cells were grown in a hormone-free medium and were sustained on xylose as the only carbon source. Using functional genomics we have identified 290 sugar responsive genes, responding rapidly (within 1 h) and specifically to low concentration (1 mM) of glucose, fructose and/or sucrose. For selected genes, the true nature of the signaling sugar molecules and sites of sugar perception were further clarified using non-metabolizable sugar analogues. Using both transgenic and wild-type A. thaliana seedlings, it was shown that the expression of selected sugar-responsive genes was not restricted to a specific tissue or cell type and responded to photoperiod-related changes in sugar availability. This suggested that sugar-responsiveness of genes identified in the cell culture system was not biased toward heterotrophic background and resembled that in whole plants. Conclusions: Altogether, our research strategy, using a combination of cell culture and whole plants, has provided an unequivocal evidence for the identity of sugar-responsive genes and the identity of the sugar signaling molecules, independently from their inter-conversions or use for energy metabolism.

  • 326. Källberg, Eva
    et al.
    Vogl, Thomas
    Liberg, David
    Olsson, Anders
    Björk, Per
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Roth, Johannes
    Ivars, Fredrik
    Leanderson, Tomas
    S100A9 Interaction with TLR4 Promotes Tumor Growth2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 3, p. e34207-Article in journal (Refereed)
    Abstract [en]

    By breeding TRAMP mice with S100A9 knock-out (S100A9(-/-)) animals and scoring the appearance of palpable tumors we observed a delayed tumor growth in animals devoid of S100A9 expression. CD11b(+) S100A9 expressing cells were not observed in normal prostate tissue from control C57BL/6 mice but were readily detected in TRAMP prostate tumors. Also, S100A9 expression was observed in association with CD68(+) macrophages in biopsies from human prostate tumors. Delayed growth of TRAMP tumors was also observed in mice lacking the S100A9 ligand TLR4. In the EL-4 lymphoma model tumor growth inhibition was observed in S100A9(-/-) and TLR4(-/-), but not in RAGE(-/-) animals lacking an alternative S100A9 receptor. When expression of immune-regulating genes was analyzed using RT-PCR the only common change observed in mice lacking S100A9 and TLR4 was a down-regulation of TGF beta expression in splenic CD11b(+) cells. Lastly, treatment of mice with a small molecule (ABR-215050) that inhibits S100A9 binding to TLR4 inhibited EL4 tumor growth. Thus, S100A9 and TLR4 appear to be involved in promoting tumor growth in two different tumor models and pharmacological inhibition of S100A9-TLR4 interactions is a novel and promising target for anti-tumor therapies.

  • 327.
    Landfors, Mattias
    et al.
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Philip, Philge
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Rydén, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Stenberg, Per
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Normalization of high dimensional genomics data where the distribution of the altered variables is skewed2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 11, p. e27942-Article in journal (Refereed)
    Abstract [en]

    Genome-wide analysis of gene expression or protein binding patterns using different array or sequencing based technologies is now routinely performed to compare different populations, such as treatment and reference groups. It is often necessary to normalize the data obtained to remove technical variation introduced in the course of conducting experimental work, but standard normalization techniques are not capable of eliminating technical bias in cases where the distribution of the truly altered variables is skewed, i.e. when a large fraction of the variables are either positively or negatively affected by the treatment. However, several experiments are likely to generate such skewed distributions, including ChIP-chip experiments for the study of chromatin, gene expression experiments for the study of apoptosis, and SNP-studies of copy number variation in normal and tumour tissues. A preliminary study using spike-in array data established that the capacity of an experiment to identify altered variables and generate unbiased estimates of the fold change decreases as the fraction of altered variables and the skewness increases. We propose the following work-flow for analyzing high-dimensional experiments with regions of altered variables: (1) Pre-process raw data using one of the standard normalization techniques. (2) Investigate if the distribution of the altered variables is skewed. (3) If the distribution is not believed to be skewed, no additional normalization is needed. Otherwise, re-normalize the data using a novel HMM-assisted normalization procedure. (4) Perform downstream analysis. Here, ChIP-chip data and simulated data were used to evaluate the performance of the work-flow. It was found that skewed distributions can be detected by using the novel DSE-test (Detection of Skewed Experiments). Furthermore, applying the HMM-assisted normalization to experiments where the distribution of the truly altered variables is skewed results in considerably higher sensitivity and lower bias than can be attained using standard and invariant normalization methods.

  • 328. Laricchiuta, Daniela
    et al.
    Rojo, Maria Luisa
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Rodriguez-Gaztelumendi, Antonio
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Ferlazzo, Fabio
    Petrosini, Laura
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    CB1 Receptor Autoradiographic Characterization of the Individual Differences in Approach and Avoidance Motivation2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e42111-Article in journal (Refereed)
    Abstract [en]

    Typically, approach behaviour is displayed in the context of moving towards a desired goal, while avoidance behaviour is displayed in the context of moving away from threatening or novel stimuli. In the current research, we detected three sub-populations of C57BL/6J mice that spontaneously responded with avoiding, balancing or approaching behaviours in the presence of the same conflicting stimuli. While the balancing animals reacted with balanced responses between approach and avoidance, the avoiding or approaching animals exhibited inhibitory or advance responses towards one of the conflicting inputs, respectively. Individual differences in approach and avoidance motivation might be modulated by the normal variance in the level of functioning of different systems, such as endocannabinoid system (ECS). The present research was aimed at analysing the ECS involvement on approach and avoidance behavioural processes. To this aim, in the three selected sub-populations of mice that exhibited avoiding or balancing or approaching responses in an approach/avoidance Y-maze we analysed density and functionality of CB1 receptors as well as enzyme fatty acid amide hydrolase activity in different brain regions, including the networks functionally responsible for emotional and motivational control. The main finding of the present study demonstrates that in both approaching and avoiding animals higher CB1 receptor density in the amygdaloidal centro-medial nuclei and in the hypothalamic ventro-medial nucleus was found when compared with the CB1 receptor density exhibited by the balancing animals. The characterization of the individual differences to respond in a motivationally based manner is relevant to clarify how the individual differences in ECS activity are associated with differences in motivational and affective functioning.

  • 329.
    Larson, Keith W.
    et al.
    Department of Biology, Centre for Animal Movement Research, Lund University, Lund, Sweden.
    Liedvogel, Miriam
    Addison, BriAnne
    Kleven, Oddmund
    Laskemoen, Terje
    Lifjeld, Jan T.
    Lundberg, Max
    Åkesson, Susanne
    Bensch, Staffan
    Allelic Variation in a Willow Warbler Genomic Region Is Associated with Climate Clines2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 5, article id e95252Article in journal (Refereed)
    Abstract [en]

    Local adaptation is an important process contributing to population differentiation which can occur in continuous or isolated populations connected by various amounts of gene flow. The willow warbler (Phylloscopus trochilus) is one of the most common songbirds in Fennoscandia. It has a continuous breeding distribution where it is found in all forested habitats from sea level to the tree line and therefore constitutes an ideal species for the study of locally adapted genes associated with environmental gradients. Previous studies in this species identified a genetic marker (AFLP-WW1) that showed a steep north-south cline in central Sweden with one allele associated with coastal lowland habitats and the other with mountainous habitats. It was further demonstrated that this marker is embedded in a highly differentiated chromosome region that spans several megabases. In the present study, we sampled 2,355 individuals at 128 sites across all of Fennoscandia to study the geographic and climatic variables associated with the allele frequency distributions of WW1. Our results demonstrate that 1) allele frequency patterns significantly differ between mountain and lowland populations, 2) these allele differences coincide with extreme temperature conditions and the short growing season in the mountains, and milder conditions in coastal areas, and 3) the northern-allele or "altitude variant" of WW1 occurs in willow warblers that occupy mountainous habitat regardless of subspecies. Finally these results suggest that climate may exert selection on the genomic region associated with these alleles and would allow us to develop testable predictions for the distribution of the genetic marker based on climate change scenarios.

  • 330.
    Larsson, Christer
    et al.
    Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
    Luna, Brian
    Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
    Ammerman, Nicole C
    Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
    Maiga, Mamoudou
    Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
    Agarwal, Nisheeth
    Vaccine and Infectious Disease Research Center Translational Health Science and Technology Institute, Gurgaon (Haryana), India.
    Bishai, William R
    Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
    Gene expression of Mycobacterium tuberculosis putative transcription factors whiB1-7 in redox environments2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e37516-Article in journal (Refereed)
    Abstract [en]

    The seven WhiB proteins of Mycobacterium tuberculosis (M.tb) are widely believed to be redox-sensing transcription factors due to their binding of iron-sulfur clusters and similarities to DNA binding proteins. Here, we explored the nature of this hypothesized relationship. We exposed M.tb to physiologic conditions such as gradual hypoxia, nitric oxide (NO), cyclic AMP and in vivo conditions, and measured transcription of the whiB genes. We found whiB3 to be induced both by hypoxia and NO, whiB7 to be induced in macrophage-like cells, and whiB4 to be induced in mouse lung. Cyclic AMP induced whiB1,-2, -4, -6 and -7. Our data indicate that the M.tb whiB genes are induced independently by various stimuli which may add versatility to their suggested redox-sensing properties.

  • 331. Larsson, Helena
    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.
    Monnier, Andreas
    Skoglund, Jörgen
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation.
    Helander, Charlotte
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation.
    Persson, Emelie
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Malm, Christer
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine.
    Broman, Lisbet
    Aasa, Ulrika
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation. Department of Neurobiology, Care Sciences and Society, Division of Physiotherapy, Karolinska Institutet.
    Content Validity Index and Intra- and Inter-Rater Reliability of a New Muscle Strength/Endurance Test Battery for Swedish Soldiers2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, article id e0132185Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to examine the content validity of commonly used muscle performance tests in military personnel and to investigate the reliability of a proposed test battery. For the content validity investigation, thirty selected tests were those described in the literature and/or commonly used in the Nordic and North Atlantic Treaty Organization (NATO) countries. Nine selected experts rated, on a four-point Likert scale, the relevance of these tests in relation to five different work tasks: lifting, carrying equipment on the body or in the hands, climbing, and digging. Thereafter, a content validity index (CVI) was calculated for each work task. The result showed excellent CVI (>= 0.78) for sixteen tests, which comprised of one or more of the military work tasks. Three of the tests; the functional lower-limb loading test (the Ranger test), dead-lift with kettlebells, and back extension, showed excellent content validity for four of the work tasks. For the development of a new muscle strength/endurance test battery, these three tests were further supplemented with two other tests, namely, the chins and side-bridge test. The inter-rater reliability was high (intraclass correlation coefficient, ICC2,1 0.99) for all five tests. The intra-rater reliability was good to high (ICC3,1 0.82-0.96) with an acceptable standard error of mean (SEM), except for the side-bridge test (SEM%>15). Thus, the final suggested test battery for a valid and reliable evaluation of soldiers' muscle performance comprised the following four tests; the Ranger test, dead-lift with kettlebells, chins, and back extension test. The criterion-related validity of the test battery should be further evaluated for soldiers exposed to varying physical workload.

  • 332.
    Larsson, Miriam
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Uvell, Hanna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sandström, Jenny
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Rydén, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Selth, Luke A.
    Mechanisms of Transcription Laboratory, Clare Hall Laboratories, Cancer Research UK London Research Institute.
    Björklund, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Functional Studies of the Yeast Med5, Med15 and Med16 Mediator Tail Subunits2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 8, p. e73137-Article in journal (Refereed)
    Abstract [en]

    The yeast Mediator complex can be divided into three modules, designated Head, Middle and Tail. Tail comprises the Med2, Med3, Med5, Med15 and Med16 protein subunits, which are all encoded by genes that are individually non-essential for viability. In cells lacking Med16, Tail is displaced from Head and Middle. However, inactivation of MED5/MED15 and MED15/MED16 are synthetically lethal, indicating that Tail performs essential functions as a separate complex even when it is not bound to Middle and Head. We have used the N-Degron method to create temperature-sensitive (ts) mutants in the Mediator tail subunits Med5, Med15 and Med16 to study the immediate effects on global gene expression when each subunit is individually inactivated, and when Med5/15 or Med15/16 are inactivated together. We identify 25 genes in each double mutant that show a significant change in expression when compared to the corresponding single mutants and to the wild type strain. Importantly, 13 of the 25 identified genes are common for both double mutants. We also find that all strains in which MED15 is inactivated show down-regulation of genes that have been identified as targets for the Ace2 transcriptional activator protein, which is important for progression through the G1 phase of the cell cycle. Supporting this observation, we demonstrate that loss of Med15 leads to a G1 arrest phenotype. Collectively, these findings provide insight into the function of the Mediator Tail module.

  • 333. Lassale, Camille
    et al.
    Gunter, Marc J.
    Romaguera, Dora
    Peelen, Linda M.
    Van der Schouw, Yvonne T.
    Beulens, Joline W. J.
    Freisling, Heinz
    Muller, David C.
    Ferrari, Pietro
    Huybrechts, Inge
    Fagherazzi, Guy
    Boutron-Ruault, Marie-Christine
    Affret, Aurelie
    Overvad, Kim
    Dahm, Christina C.
    Olsen, Anja
    Roswall, Nina
    Tsilidis, Konstantinos K.
    Katzke, Verena A.
    Kuehn, Tilman
    Buijsse, Brian
    Quiros, Jose-Ramon
    Sanchez-Cantalejo, Emilio
    Etxezarreta, Nerea
    Maria Huerta, Jose
    Barricarte, Aurelio
    Bonet, Catalina
    Khaw, Kay-Tee
    Key, Timothy J.
    Trichopoulou, Antonia
    Bamia, Christina
    Lagiou, Pagona
    Palli, Domenico
    Agnoli, Claudia
    Tumino, Rosario
    Fasanelli, Francesca
    Panico, Salvatore
    Bueno-de-Mesquita, H. Bas
    Boer, Jolanda M. A.
    Sonestedt, Emily
    Nilsson, Lena Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Weiderpass, Elisabete
    Skeie, Guri
    Lund, Eiliv
    Moons, Karel G. M.
    Riboli, Elio
    Tzoulaki, Ioanna
    Diet Quality Scores and Prediction of All-Cause, Cardiovascular and Cancer Mortality in a Pan-European Cohort Study2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 7, article id e0159025Article in journal (Refereed)
    Abstract [en]

    Scores of overall diet quality have received increasing attention in relation to disease aetiology; however, their value in risk prediction has been little examined. The objective was to assess and compare the association and predictive performance of 10 diet quality scores on 10-year risk of all-cause, CVD and cancer mortality in 451,256 healthy participants to the European Prospective Investigation into Cancer and Nutrition, followed-up for a median of 12.8y. All dietary scores studied showed significant inverse associations with all outcomes. The range of HRs (95% CI) in the top vs. lowest quartile of dietary scores in a composite model including non-invasive factors (age, sex, smoking, body mass index, education, physical activity and study centre) was 0.75 (0.72-0.79) to 0.88 (0.84-0.92) for all-cause, 0.76 (0.69-0.83) to 0.84 (0.76-0.92) for CVD and 0.78 (0.73-0.83) to 0.91 (0.85-0.97) for cancer mortality. Models with dietary scores alone showed low discrimination, but composite models also including age, sex and other non-invasive factors showed good discrimination and calibration, which varied little between different diet scores examined. Mean C-statistic of full models was 0.73, 0.80 and 0.71 for all-cause, CVD and cancer mortality. Dietary scores have poor predictive performance for 10-year mortality risk when used in isolation but display good predictive ability in combination with other non-invasive common risk factors.

  • 334. Lavebratt, Catharina
    et al.
    Sjöholm, Louise K
    Soronen, Pia
    Paunio, Tiina
    Vawter, Marquis P
    Bunney, William E
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Forsell, Yvonne
    Wu, Joseph C
    Kelsoe, John R
    Partonen, Timo
    Schalling, Martin
    CRY2 is associated with depression2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 2, article id e9407Article in journal (Refereed)
    Abstract [en]

    Background: Abnormalities in the circadian clockwork often characterize patients with major depressive and bipolar disorders. Circadian clock genes are targets of interest in these patients. CRY2 is a circadian gene that participates in regulation of the evening oscillator. This is of interest in mood disorders where a lack of switch from evening to morning oscillators has been postulated.

    Principal Findings: We observed a marked diurnal variation in human CRY2 mRNA levels from peripheral blood mononuclear cells and a significant up-regulation (P = 0.020) following one-night total sleep deprivation, a known antidepressant. In depressed bipolar patients, levels of CRY2 mRNA were decreased (P = 0.029) and a complete lack of increase was observed following sleep deprivation. To investigate a possible genetic contribution, we undertook SNP genotyping of the CRY2 gene in two independent population-based samples from Sweden (118 cases and 1011 controls) and Finland (86 cases and 1096 controls). The CRY2 gene was significantly associated with winter depression in both samples (haplotype analysis in Swedish and Finnish samples: OR = 1.8, P = 0.0059 and OR = 1.8, P = 0.00044, respectively).

    Conclusions: We propose that a CRY2 locus is associated with vulnerability for depression, and that mechanisms of action involve dysregulation of CRY2 expression.

  • 335.
    Lee, Joanne E.
    et al.
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Neumann, Manuela
    Duro, Daniel Iglesias
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Schmid, Markus
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Max Planck Institute for Developmental Biology, Department of Molecular Biology, Tu ¨bingen, Germany; Beijing Advanced Innovation Centre for Tree Breeding by Molecular Design, Beijing Forestry University, Beijing, People's Republic of China.
    CRISPR-based tools for targeted transcriptional and epigenetic regulation in plants2019In: PLoS ONE, E-ISSN 1932-6203, Vol. 14, no 9, article id e0222778Article in journal (Refereed)
    Abstract [en]

    Programmable gene regulators that can modulate the activity of selected targets in trans are a useful tool for probing and manipulating gene function. CRISPR technology provides a convenient method for gene targeting that can also be adapted for multiplexing and other modifications to enable strong regulation by a range of different effectors. We generated a vector toolbox for CRISPR/dCas9-based targeted gene regulation in plants, modified with the previously described MS2 system to amplify the strength of regulation, and using Golden Gate-based cloning to enable rapid vector assembly with a high degree of flexibility in the choice of promoters, effectors and targets. We tested the system using the floral regulator FLOWERING LOCUS T (FT) as a target and a range of different effector domains including the transcriptional activator VP64, the H3K27 acetyltransferase p300 and the H3K9 methyltransferase KRYPTONITE. When transformed into Arabidopsis thaliana, several of the constructs caused altered flowering time phenotypes that were associated with changes in FT expression and/or epigenetic status, thus demonstrating the effectiveness of the system. The MS2-CRISPR/dCas9 system can be used to modulate transcriptional activity and epigenetic status of specific target genes in plants, and provides a versatile tool that can easily be used with different targets and types of regulation for a range of applications.

  • 336.
    Lee, Sungmin
    et al.
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Ramenzoni, Veronica
    University of Virginia.
    Holme, Petter
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Emergence of collective memories2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 9, p. e12522-Article in journal (Refereed)
    Abstract [en]

    Background We understand the dynamics of the world around us as by associating pairs of events, where one event has some influence on the other. These pairs of events can be aggregated into a web of memories representing our understanding of an episode of history. The events and the associations between them need not be directly experienced—they can also be acquired by communication. In this paper we take a network approach to study the dynamics of memories of history.

    Methodology/Principal Findings First we investigate the network structure of a data set consisting of reported events by several individuals and how associations connect them. We focus our measurement on degree distributions, degree correlations, cycles (which represent inconsistencies as they would break the time ordering) and community structure. We proceed to model effects of communication using an agent-based model. We investigate the conditions for the memory webs of different individuals to converge to collective memories, how groups where the individuals have similar memories (but different from other groups) can form.

    Conclusions/Significance Our work outlines how the cognitive representation of memories and social structure can co-evolve as a contagious process. We generate some testable hypotheses including that the number of groups is limited as a function of the total population size.

  • 337.
    Lee, Sungmin
    et al.
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Rocha, Luis E C
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Liljeros, Fredrik
    Stockholm University.
    Holme, Petter
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Exploiting Temporal Network Structures of Human Interaction to Effectively Immunize Populations2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, p. e36439-Article in journal (Refereed)
    Abstract [en]

    Decreasing the number of people who must be vaccinated to immunize a community against an infectious disease could both save resources and decrease outbreak sizes. A key to reaching such a lower threshold of immunization is to find and vaccinate people who, through their behavior, are more likely than average to become infected and to spread the disease further. Fortunately, the very behavior that makes these people important to vaccinate can help us to localize them. Earlier studies have shown that one can use previous contacts to find people that are central in static contact networks. However, real contact patterns are not static. In this paper, we investigate if there is additional information in the temporal contact structure for vaccination protocols to exploit. We answer this affirmative by proposing two immunization methods that exploit temporal correlations and showing that these methods outperform a benchmark static-network protocol in four empirical contact datasets under various epidemic scenarios. Both methods rely only on obtainable, local information, and can be implemented in practice. For the datasets directly related to contact patterns of potential disease spreading (of sexually-transmitted and nosocomial infections respectively), the most efficient protocol is to sample people at random and vaccinate their latest contacts. The network datasets are temporal, which enables us to make more realistic evaluations than earlier studies—we use only information about the past for the purpose of vaccination, and about the future to simulate disease outbreaks. Using analytically tractable models, we identify two temporal structures that explain how the protocols earn their efficiency in the empirical data. This paper is a first step towards real vaccination protocols that exploit temporal-network structure—future work is needed both to characterize the structure of real contact sequences and to devise immunization methods that exploit these.

  • 338. Lekander, Ingrid
    et al.
    Willers, Carl
    von Euler, Mia
    Lilja, Mikael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Sunnerhagen, Katharina S
    Pessah-Rasmussen, Hélène
    Borgström, Fredrik
    Relationship between functional disability and costs one and two years post stroke2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 4, article id e0174861Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: Stroke affects mortality, functional ability, quality of life and incurs costs. The primary objective of this study was to estimate the costs of stroke care in Sweden by level of disability and stroke type (ischemic (IS) or hemorrhagic stroke (ICH)).

    METHOD: Resource use during first and second year following a stroke was estimated based on a research database containing linked data from several registries. Costs were estimated for the acute and post-acute management of stroke, including direct (health care consumption and municipal services) and indirect (productivity losses) costs. Resources and costs were estimated per stroke type and functional disability categorised by Modified Rankin Scale (mRS).

    RESULTS: The results indicated that the average costs per patient following a stroke were 350,000SEK/€37,000-480,000SEK/€50,000, dependent on stroke type and whether it was the first or second year post stroke. Large variations were identified between different subgroups of functional disability and stroke type, ranging from annual costs of 100,000SEK/€10,000-1,100,000SEK/€120,000 per patient, with higher costs for patients with ICH compared to IS and increasing costs with more severe functional disability.

    CONCLUSION: Functional outcome is a major determinant on costs of stroke care. The stroke type associated with worse outcome (ICH) was also consistently associated to higher costs. Measures to improve function are not only important to individual patients and their family but may also decrease the societal burden of stroke.

  • 339. Lembrechts, Jonas J.
    et al.
    Milbau, Ann
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Nijs, Ivan
    Alien Roadside Species More Easily Invade Alpine than Lowland Plant Communities in a Subarctic Mountain Ecosystem2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 2, p. e89664-Article in journal (Refereed)
    Abstract [en]

    Effects of roads on plant communities are not well known in cold-climate mountain ecosystems, where road building and development are expected to increase in future decades. Knowledge of the sensitivity of mountain plant communities to disturbance by roads is however important for future conservation purposes. We investigate the effects of roads on species richness and composition, including the plant strategies that are most affected, along three elevational gradients in a subarctic mountain ecosystem. We also examine whether mountain roads promote the introduction and invasion of alien plant species from the lowlands to the alpine zone. Observations of plant community composition were made together with abiotic, biotic and anthropogenic factors in 60 T-shaped transects. Alpine plant communities reacted differently to road disturbances than their lowland counterparts. On high elevations, the roadside species composition was more similar to that of the local natural communities. Less competitive and ruderal species were present at high compared with lower elevation roadsides. While the effects of roads thus seem to be mitigated in the alpine environment for plant species in general, mountain plant communities are more invasible than lowland communities. More precisely, relatively more alien species present in the roadside were found to invade into the surrounding natural community at high compared to low elevations. We conclude that effects of roads and introduction of alien species in lowlands cannot simply be extrapolated to the alpine and subarctic environment.

  • 340. Levi, Laura
    et al.
    Toyooka, Tatsushi
    Patarroyo, Manuel
    Frisan, Teresa
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Bacterial genotoxins promote inside-out integrin β1 activation, formation of focal adhesion complexes and cell spreading2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 4, article id e0124119Article in journal (Refereed)
    Abstract [en]

    Integrins are membrane bound receptors that regulate several cellular processes, such as cell adhesion, migration, survival and proliferation, and may contribute to tumor initiation/progression in cells exposed to genotoxic stress. The extent of integrin activation and its role in cell survival upon intoxication with bacterial genotoxins are still poorly characterized. These toxins induce DNA strand breaks in the target cells and activate the DNA damage response (DDR), coordinated by the Ataxia Telangectasia Mutated (ATM) kinase. In the present study, we demonstrate that induction of DNA damage by two bacterial genotoxins promotes activation of integrin β1, leading to enhanced assembly of focal adhesions and cell spreading on fibronectin, but not on vitronectin. This phenotype is mediated by an ATM-dependent inside-out integrin signaling, and requires the actin cytoskeleton remodeler NET1. The toxin-mediated cell spreading and anchorage-independent survival further relies on ALIX and TSG101, two components of the endosomal sorting complex required for transport (ESCRT), known to regulate integrin intracellular trafficking. These data reveal a novel aspect of the cellular response to bacterial genotoxins, and provide new tools to understand the carcinogenic potential of these effectors in the context of chronic intoxication and infection.

  • 341. Levinsson, Anna
    et al.
    Olin, Anna-Carin
    Modig, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Dahgam, Santosh
    Björck, Lena
    Rosengren, Annika
    Nyberg, Fredrik
    Interaction effects of long-term air pollution exposure and variants in the GSTP1, GSTT1 and GSTCD genes on risk of acute myocardial infarction and hypertension: a case-control study2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 6, p. e99043-Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Experimental and epidemiological studies have reported associations between air pollution exposure, in particular related to vehicle exhaust, and cardiovascular disease. A potential pathophysiological pathway is pollution-induced pulmonary oxidative stress, with secondary systemic inflammation. Genetic polymorphisms in genes implicated in oxidative stress, such as GSTP1, GSTT1 and GSTCD, may contribute to determining individual susceptibility to air pollution as a promoter of coronary vulnerability.

    AIMS: We aimed to investigate effects of long-term traffic-related air pollution exposure, as well as variants in GSTP1, GSTT1 and GSTCD, on risk of acute myocardial infarction (AMI) and hypertension. In addition, we studied whether air pollution effects were modified by the investigated genetic variants.

    METHODS: Genotype data at 7 single nucleotide polymorphisms (SNPs) in the GSTP1 gene, and one in each of the GSTT1 and GSTCD genes, as well as air pollution exposure estimates, were available for 119 AMI cases and 1310 randomly selected population controls. Population control individuals with systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg or on daily antihypertensive medication were defined as hypertensive (n = 468). Individual air pollution exposure levels were modeled as annual means of NO₂ (marker of vehicle exhaust pollutants) using central monitoring data and dispersion models, linking to participants' home addresses.

    RESULTS: Air pollution was significantly associated with risk of AMI: OR 1.78 (95%CI 1.04-3.03) per 10 µg/m³ of long-term NO₂ exposure. Three GSTP1 SNPs were significantly associated with hypertension. The effect of air pollution on risk of AMI varied by genotype strata, although the suggested interaction was not significant. We saw no obvious interaction between genetic variants in the GST genes and air pollution exposure for hypertension.

    CONCLUSION: Air pollution exposure entails an increased risk of AMI, and this risk differed over genotype strata for variants in the GSTP1, GSTT1 and GSTCD genes, albeit not statistically-significantly.

  • 342.
    Li, Xingru
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Wang, Sihan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Sitaram, Raviprakash Tumkur
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Andersson, Charlotta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Li, Ai-Hong
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Single Nucleotide Polymorphisms in the Wilms' Tumour Gene 1 in Clear Cell Renal Cell Carcinoma2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 3, article id e58396Article in journal (Refereed)
    Abstract [en]

    The Wilms' tumour gene 1 (WT1) single nucleotide polymorphism (SNP) rs16754 has recently been described as an independent prognostic factor in acute myeloid leukaemia (AML) patients. It is of great interest to test whether WT1 SNPs can be used as a molecular marker in other cancer types in order to improve risk and treatment stratification. We performed sequencing analysis on all 10 exons of the WT1 gene in a total of 182 patients with clear cell renal cell carcinoma (ccRCC). Six different SNPs were identified, in descending order for minor allele frequency: rs2234582, rs16754, rs1799925, rs5030315, rs2234583, and rs2234581. At least one minor allele for WT1 SNP was identified in 61% of ccRCC patients. In the entire study population, only 6% carried two copies of the minor allele. The genotypes of WT1 SNPs in 78 tumour-free kidney tissue specimens were found to be in 95% concordance with corresponding tumour samples. No correlation was observed between WT1 SNP genotypes and RNA expression level. WT1 SNP genotypes did not associate with clinical and pathological characteristics. We found favourable outcomes associated with the homozygous minor allele for WT1 SNP. However, SNP genotypes did not show to be of prognostic significance when comparing wild-type versus homozygous or heterozygous for the minor allele in the entire cohort. None of the previously reported WT1 mutations in AML was found in the present study. A novel WT1 missense mutation was identified in only one patient. Our data suggest that common WT1 mutations are not involved in ccRCC. Due to too few cases harbouring the homozygous minor allele, the prognostic impact needs to be verified in larger study populations.

  • 343.
    Li, Xuan
    et al.
    Ghent, Belgium.
    Yang, Qian
    Gent, Belgium.
    Dierckens, Kristof
    Ghent, Belgium.
    Milton, Debra L.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Southern Research Institute, Birmingham, Alabama, United States of America.
    Defoirdt, Tom
    Ghent, Belgium.
    RpoS and Indole Signaling Control the Virulence of Vibrio anguillarum towards Gnotobiotic Sea Bass (Dicentrarchus labrax) Larvae2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 10, p. e111801-Article in journal (Refereed)
    Abstract [en]

    Quorum sensing, bacterial cell-to-cell communication with small signal molecules, controls the virulence of many pathogens. In contrast to other vibrios, neither the VanI/VanR acylhomoserine lactone quorum sensing system, nor the three-channel quorum sensing system affects virulence of the economically important aquatic pathogen Vibrio anguillarum. Indole is another molecule that recently gained attention as a putative signal molecule. The data presented in this study indicate that indole signaling and the alternative sigma factor RpoS have a significant impact on the virulence of V. anguillarum. Deletion of rpoS resulted in increased expression of the indole biosynthesis gene tnaA and in increased production of indole. Both rpoS deletion and the addition of exogenous indole (50-100 mu M) resulted in decreased biofilm formation, exopolysaccharide production (a phenotype that is required for pathogenicity) and expression of the exopolysaccharide synthesis gene wbfD. Further, indole inhibitors increased the virulence of the rpoS deletion mutant, suggesting that indole acts downstream of RpoS. Finally, in addition to the phenotypes found to be affected by indole, the rpoS deletion mutant also showed increased motility and decreased sensitivity to oxidative stress.

  • 344. Libard, Sylwia
    et al.
    Popova, Svetlana N.
    Amini, Rose-Marie
    Karja, Vesa
    Pietilainen, Timo
    Hamalainen, Kirsi M.
    Sundstrom, Christer
    Hesselager, Goran
    Bergqvist, Michael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ekman, Simon
    Zetterling, Maria
    Smits, Anja
    Nilsson, Pelle
    Pfeifer, Susan
    de Stahl, Teresita Diaz
    Enblad, Gunilla
    Ponten, Fredrik
    Alafuzoff, Irina
    Human Cytomegalovirus Tegument Protein pp65 Is Detected in All Intra- and Extra-Axial Brain Tumours Independent of the Tumour Type or Grade2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, p. e108861-Article in journal (Refereed)
    Abstract [en]

    Human cytomegalovirus (HCMV) has been indicated being a significant oncomodulator. Recent reports have suggested that an antiviral treatment alters the outcome of a glioblastoma. We analysed the performance of commercial HCMV-antibodies applying the immunohistochemical (IHC) methods on brain sample obtained from a subject with a verified HCMV infection, on samples obtained from 14 control subjects, and on a tissue microarray block containing cores of various brain tumours. Based on these trials, we selected the best performing antibody and analysed a cohort of 417 extra- and intra-axial brain tumours such as gliomas, medulloblastomas, primary diffuse large B-cell lymphomas, and meningiomas. HCMV protein pp65 immunoreactivity was observed in all types of tumours analysed, and the IHC expression did not depend on the patient's age, gender, tumour type, or grade. The labelling pattern observed in the tumours differed from the labelling pattern observed in the tissue with an active HCMV infection. The HCMV protein was expressed in up to 90% of all the tumours investigated. Our results are in accordance with previous reports regarding the HCMV protein expression in glioblastomas and medulloblastomas. In addition, the HCMV protein expression was seen in primary brain lymphomas, lowgrade gliomas, and in meningiomas. Our results indicate that the HCMV protein pp65 expression is common in intra- and extra-axial brain tumours. Thus, the assessment of the HCMV expression in tumours of various origins and pathologically altered tissue in conditions such as inflammation, infection, and even degeneration should certainly be facilitated.

  • 345.
    Lif Holgerson, Pernilla
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Öhman, Carina
    Umeå University, Faculty of Medicine, Department of Odontology.
    Rönnlund, Agneta
    Umeå University, Faculty of Medicine, Department of Odontology.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Maturation of oral microbiota in children with or without dental caries2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, article id e0128534Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The aim of this longitudinal study was to evaluate the oral microbiota in children from age 3 months to 3 years, and to determine the association of the presence of caries at 3 years of age.

    METHODS AND FINDINGS: Oral biofilms and saliva were sampled from children at 3 months (n = 207) and 3 years (n = 155) of age, and dental caries was scored at 3 years of age. Oral microbiota was assessed by culturing of total lactobacilli and mutans streptococci, PCR detection of Streptococcus mutans and Streptococcus sobrinus, 454 pyrosequencing and HOMIM (Human Oral Microbe Identification Microarray) microarray detection of more then 300 species/ phylotypes. Species richness and taxa diversity significantly increased from 3 months to 3 years. Three bacterial genera, present in all the 3-month-old infants, persisted at 3 years of age, whereas three other genera had disappeared by this age. A large number of new taxa were also observed in the 3-year-olds. The microbiota at 3 months of age, except for lactobacilli, was unrelated to caries development at a later age. In contrast, several taxa in the oral biofilms of the 3-year-olds were linked with the presence or absence of caries. The main species/phylotypes associated with caries in 3-year-olds belonged to the Actinobaculum, Atopobium, Aggregatibacter, and Streptococcus genera, whereas those influencing the absence of caries belonged to the Actinomyces, Bergeyella, Campylobacter, Granulicatella, Kingella, Leptotrichia, and Streptococcus genera.

    CONCLUSIONS: Thus, during the first years of life, species richness and taxa diversity in the mouth increase significantly. Besides the more prevalent colonization of lactobacilli, the composition of the overall microbiota at 3 months of age was unrelated to caries development at a later age. Several taxa within the oral biofilms of the 3-year-olds could be linked to the presence or absence of caries.

  • 346. Lind, Peter A
    et al.
    Andersson, Dan I
    Fitness costs of synonymous mutations in the rpsT gene can be compensated by restoring mRNA base pairing.2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 5Article in journal (Refereed)
    Abstract [en]

    We previously reported that the distribution of fitness effects for non-synonymous and synonymous mutations in Salmonella typhimurium ribosomal proteins S20 and L1 are similar, suggesting that fitness constraints are present at the level of mRNA. Here we explore the hypothesis that synonymous mutations confer their fitness-reducing effect by alterating the secondary structure of the mRNA. To this end, we constructed a set of synonymous substitutions in the rpsT gene, encoding ribosomal protein S20, that are located in predicted paired regions in the mRNA and measured their effect on bacterial fitness. Our results show that for 3/9 cases tested, the reduced fitness conferred by a synonymous mutation could be fully or partly restored by introducing a second synonymous substitution that restore base pairing in a mRNA stem. In addition, random mutations in predicted paired regions had larger fitness effects than those in unpaired regions. Finally, we did not observe any correlation between fitness effects of the synonymous mutations and their rarity. These results suggest that for ribosomal protein S20, the deleterious effects of synonymous mutations are not generally due to codon usage effects, but that mRNA secondary structure is a major fitness constraint.

  • 347.
    Lindberg, Ann-Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Idrottsmedicin. Winternet, Boden, Sweden.
    Oksa, Juha
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Malm, Christer
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Idrottsmedicin. Winternet, Boden, Sweden.
    Multivariate Statistical Assessment of Predictors of Firefighters' Muscular and Aerobic Work Capacity2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, article id e0118945Article in journal (Refereed)
    Abstract [en]

    Physical capacity has previously been deemed important for firefighters physical work capacity, and aerobic fitness, muscular strength, and muscular endurance are the most frequently investigated parameters of importance. Traditionally, bivariate and multivariate linear regression statistics have been used to study relationships between physical capacities and work capacities among firefighters. An alternative way to handle datasets consisting of numerous correlated variables is to use multivariate projection analyses, such as Orthogonal Projection to Latent Structures. The first aim of the present study was to evaluate the prediction and predictive power of field and laboratory tests, respectively, on firefighters' physical work capacity on selected work tasks. Also, to study if valid predictions could be achieved without anthropometric data. The second aim was to externally validate selected models. The third aim was to validate selected models on firefighters' and on civilians'. A total of 38 (26 men and 12 women) + 90 (38 men and 52 women) subjects were included in the models and the external validation, respectively. The best prediction (R-2) and predictive power (Q(2)) of Stairs, Pulling, Demolition, Terrain, and Rescue work capacities included field tests (R-2 = 0.73 to 0.84, Q(2) = 0.68 to 0.82). The best external validation was for Stairs work capacity (R-2 = 0.80) and worst for Demolition work capacity (R-2 = 0.40). In conclusion, field and laboratory tests could equally well predict physical work capacities for fire-fighting work tasks, and models excluding anthropometric data were valid. The predictive power was satisfactory for all included work tasks except Demolition.

  • 348.
    Lindberg, Ann-Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Oksa, Juha
    Physical Work Capacity-team, Finnish Institute of Occupational Health, Oulu, Finland.
    Gavhed, Désirée
    Department of Women’s and Children’s Health, Karolinska Institute.
    Malm, Christer
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Field tests for evaluating the aerobic work capacity of firefighters2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 7, p. e68047-Article in journal (Refereed)
    Abstract [en]

    Working as a firefighter is physically strenuous, and a high level of physical fitness increases a firefighter's ability to cope with the physical stress of their profession. Direct measurements of aerobic capacity, however, are often complicated, time consuming, and expensive. The first aim of the present study was to evaluate the correlations between direct (laboratory) and indirect (field) aerobic capacity tests with common and physically demanding firefighting tasks. The second aim was to give recommendations as to which field tests may be the most useful for evaluating firefighters' aerobic work capacity. A total of 38 subjects (26 men and 12 women) were included. Two aerobic capacity tests, six field tests, and seven firefighting tasks were performed. Lactate threshold and onset of blood lactate accumulation were found to be correlated to the performance of one work task (rs = -0.65 and -0.63, p<0.01, respectively). Absolute (mL·min(-1)) and relative (mL·kg(-1)·min(-1)) maximal aerobic capacity was correlated to all but one of the work tasks (rs = -0.79 to 0.55 and -0.74 to 0.47, p<0.01, respectively). Aerobic capacity is important for firefighters' work performance, and we have concluded that the time to row 500 m, the time to run 3000 m relative to body weight (s·kg(-1)), and the percent of maximal heart rate achieved during treadmill walking are the most valid field tests for evaluating a firefighter's aerobic work capacity.

  • 349.
    Lindberg, Ann-Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine. Winternet, Boden.
    Oksa, Juha
    Physical Work Capacity Team, Finnish Institute of Occupational Health, Oulu, Finland.
    Malm, Christer
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Laboratory or field tests for evaluating firefighters' work capacity2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 3, p. e91215-Article in journal (Refereed)
    Abstract [en]

    Muscle strength is important for firefighters work capacity. Laboratory tests used for measurements of muscle strength, however, are complicated, expensive and time consuming. The aims of the present study were to investigate correlations between physical capacity within commonly occurring and physically demanding firefighting work tasks and both laboratory and field tests in full time (N = 8) and part-time (N = 10) male firefighters and civilian men (N = 8) and women (N = 12), and also to give recommendations as to which field tests might be useful for evaluating firefighters' physical work capacity. Laboratory tests of isokinetic maximal (IM) and endurance (IE) muscle power and dynamic balance, field tests including maximal and endurance muscle performance, and simulated firefighting work tasks were performed. Correlations with work capacity were analyzed with Spearman's rank correlation coefficient (rs). The highest significant (p<0.01) correlations with laboratory and field tests were for Cutting: IE trunk extension (rs = 0.72) and maximal hand grip strength (rs = 0.67), for Stairs: IE shoulder flexion (rs = −0.81) and barbell shoulder press (rs = −0.77), for Pulling: IE shoulder extension (rs= −0.82) and bench press (rs = −0.85), for Demolition: IE knee extension (rs = 0.75) and bench press (rs = 0.83), for Rescue: IE shoulder flexion (rs = −0.83) and bench press (rs = −0.82), and for the Terrain work task: IE trunk flexion (rs = −0.58) and upright barbell row (rs = −0.70). In conclusion, field tests may be used instead of laboratory tests. Maximal hand grip strength, bench press, chin ups, dips, upright barbell row, standing broad jump, and barbell shoulder press were strongly correlated (rs≥0.7) with work capacity and are therefore recommended for evaluating firefighters work capacity.

  • 350.
    Lindberg, Josefine
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Norman, Mikael
    Westrup, Bjorn
    Domellöf, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Berglund, Staffan K.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Cardiometabolic risk factors in children born with marginally low birth weight: A longitudinal cohort study up to 7 years-of-age2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 4, article id e0215866Article in journal (Refereed)
    Abstract [en]

    Introduction Low birth weight (LBW, <2500 g) may predict an increased risk of an adverse cardiometabolic profile later in life, but long-term effects in different populations and birth weight strata are still unclear. We explored laboratory markers of cardiometabolic risk in children born with marginally LBW (2000-2500 g). Methods This was a prospective longitudinal cohort study including 285 Swedish marginally LBW children and 95 normal birth weight (NBW, 2501-4500 g) controls. At 3.5 and 7 years of age, blood samples for glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), cholesterol, triglycerides, high-and low density lipoprotein (HDL and LDL), apolipoprotein B (ApoB) and apolipoprotein A1 (ApoA1) were assessed and compared between the groups. Results No significant differences in levels of insulin, HOMA-IR, hs-CRP or blood lipids were observed between marginally LBW and NBW children. At 7 years there was a higher proportion of marginally LBW children with elevated levels of insulin, defined as above the 90th percentile of the control group (21% vs 8.6%, p = 0.038). This association was, however, confounded by maternal ethnicity. In marginally LBW children born small for gestational age (SGA), mean fasting glucose was significantly higher compared to controls (4.7 vs 4.5 mmol/L, p = 0.020). Conclusions There were no significant differences in insulin, insulin resistance, hs-CRP or blood lipids between the marginally LBW children and controls. The subgroup of marginally LBW children born SGA may present early signs of glucose imbalance already at school age.

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