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  • 101. Farkas, Sanja A.
    et al.
    Befekadu, Rahel
    Hahn-Stroemberg, Victoria
    Nilsson, Torbjörn K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    DNA methylation and expression of the folate transporter genes in colorectal cancer2015In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 36, no 7, p. 5581-5590Article in journal (Refereed)
    Abstract [en]

    Folate has a central role in the cell metabolism. This study aims to explore the DNA methylation pattern of the folate transporter genes FOLR1, PCFT, and RFC1 as well as the corresponding protein expressions in colorectal cancer (CRC) tissue and adjacent non-cancerous mucosa (ANCM). Our results showed statistically significant differences in the DNA-methylated fraction of all three genes at several gene regions; we identified three differentially methylated CpG sites in the FOLR1 gene, five CpG sites in the PCFT gene, and six CpG sites in the RFC1 gene. There was a pronounced expression of the FR alpha and RFC proteins in both the CRC and ANCM tissues, though the expression was attenuated in cancer compared to the paired ANCM tissues. The PCFT protein was undetectable or expressed at a very low level in both tissue types. Higher methylated fractions of the CpG sites 3-5 in the RFC1 gene were associated with a lower protein expression, suggestive of epigenetic regulation by DNA methylation of the RFC1 gene in the colorectal cancer. Our results did not show any association between the RFC and FR alpha protein expression and tumor stage, TNM classification, or tumor location. In conclusion, this is the first study to simultaneously evaluate both DNA methylation and protein expression of all three folate transporter genes, FOLR1, PCFT, and RFC1, in colorectal cancer. The results encourage further investigation into the possible prognostic implications of folate transporter expression and DNA methylation.

  • 102. Fleury, Christophe
    et al.
    Su, Yu-Ching
    Hallstroem, Teresia
    Sandblad, Linda
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Zipfel, Peter F.
    Riesbeck, Kristian
    Identification of a Haemophilus influenzae Factor H-Binding Lipoprotein Involved in Serum Resistance2014In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 192, no 12, p. 5913-5923Article in journal (Refereed)
    Abstract [en]

    Haemophilus influenzae is a Gram-negative human pathogen that resides in the upper respiratory tract. Encapsulated H. influenzae type b (Hib) and type f (Hif) are the most common serotypes associated with invasive disease. H. influenzae displays various strategies to circumvent the host innate immune response, including the bactericidal effect of the complement system. In this study, we identified an H. influenzae lipoprotein having the ability to bind factor H (FH), the major regulator of the alternative pathway of complement activation. This protein, named protein H (PH), was surface exposed and was found in all clinical Hib and Hif isolates tested. Deletion of the gene encoding for PH (lph) in Hib and Hif significantly reduced the interaction between bacteria and FH. When Hib and Hif PH variants were separately expressed in nontypeable ( unencapsulated) H. influenzae, which did not bind FH, an increased FH affinity was observed. We recombinantly expressed the two PH variants in Escherichia coli, and despite sharing only 56% identical amino acids, both FH-binding Haemophilus proteins similarly interacted with the complement regulator FH short consensus repeats 7 and 18-20. Importantly, Hib and Hif resistance against the bactericidal effect of human serum was significantly reduced when bacterial mutants devoid of PH were tested. In conclusion, we have characterized a hitherto unknown bacterial protein that is crucial for mediating an interaction between the human pathogen H. influenzae and FH. This novel interaction is important for H. influenzae resistance against complement activation and will consequently promote bacterial pathogenesis.

  • 103. Fogh, Isabella
    et al.
    Ratti, Antonia
    Gellera, Cinzia
    Lin, Kuang
    Tiloca, Cinzia
    Moskvina, Valentina
    Corrado, Lucia
    Soraru, Gianni
    Cereda, Cristina
    Corti, Stefania
    Gentilini, Davide
    Calini, Daniela
    Castellotti, Barbara
    Mazzini, Letizia
    Querin, Giorgia
    Gagliardi, Stella
    Del Bo, Roberto
    Conforti, Francesca L.
    Siciliano, Gabriele
    Inghilleri, Maurizio
    Sacca, Francesco
    Bongioanni, Paolo
    Penco, Silvana
    Corbo, Massimo
    Sorbi, Sandro
    Filosto, Massimiliano
    Ferlini, Alessandra
    Di Blasio, Anna M.
    Signorini, Stefano
    Shatunov, Aleksey
    Jones, Ashley
    Shaw, Pamela J.
    Morrison, Karen E.
    Farmer, Anne E.
    Van Damme, Philip
    Robberecht, Wim
    Chi, Adriano
    Traynor, Bryan J.
    Sendtner, Michael
    Melki, Judith
    Meininger, Vincent
    Hardiman, Orla
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Leigh, Nigel P.
    Glass, Jonathan D.
    Overste, Daniel
    Diekstra, Frank P.
    Veldink, Jan H.
    van Es, Michael A.
    Shaw, Christopher E.
    Weale, Michael E.
    Lewis, Cathryn M.
    Williams, Julie
    Brown, Robert H.
    Landers, John E.
    Ticozzi, Nicola
    Ceroni, Mauro
    Pegoraro, Elena
    Comi, Giacomo P.
    DAlfonso, Sandra
    van den Berg, Leonard H.
    Taroni, Franco
    Al-Chalabi, Ammar
    Powell, John
    Silani, Vincenzo
    A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis2014In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 23, no 8, p. 2220-2231Article in journal (Refereed)
    Abstract [en]

    Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (90) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P 1.11 10(8); OR 0.82) that was validated when combined with genotype data from a replication cohort (P 8.62 10(9); OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P 7.69 10(9); OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as 12 using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.

  • 104.
    Forsberg, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jonsson, P Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Bergemalm, Daniel
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Graffmo, Karin S
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jacobsson, Johan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Rosquist, Roland
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Novel antibodies reveal inclusions containing non-native SOD1 in sporadic ALS patients2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 7, p. e11552-Article in journal (Refereed)
    Abstract [en]

    Mutations in CuZn-superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS) and are found in 6% of ALS patients. Non-native and aggregation-prone forms of mutant SOD1s are thought to trigger the disease. Two sets of novel antibodies, raised in rabbits and chicken, against peptides spaced along the human SOD1 sequence, were by enzyme-linked immunosorbent assay and an immunocapture method shown to be specific for denatured SOD1. These were used to examine SOD1 in spinal cords of ALS patients lacking mutations in the enzyme. Small granular SOD1-immunoreactive inclusions were found in spinal motoneurons of all 37 sporadic and familial ALS patients studied, but only sparsely in 3 of 28 neurodegenerative and 2 of 19 non-neurological control patients. The granular inclusions were by confocal microscopy found to partly colocalize with markers for lysosomes but not with inclusions containing TAR DNA binding protein-43, ubiquitin or markers for endoplasmic reticulum, autophagosomes or mitochondria. Granular inclusions were also found in carriers of SOD1 mutations and in spinobulbar muscular atrophy (SBMA) patients and they were the major type of inclusion detected in ALS patients homozygous for the wild type-like D90A mutation. The findings suggest that SOD1 may be involved in ALS pathogenesis in patients lacking mutations in the enzyme.

  • 105.
    Forsgren, Nina
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    Lamont, Richard J
    Persson, Karina
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    Two intramolecular isopeptide bonds are identified in the crystal structure of the Streptococcus gordonii SspB c-terminal domain2010In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 397, no 3, p. 740-751Article in journal (Refereed)
    Abstract [en]

    Streptococcus gordonii is a primary colonizer and is involved in the formation of dental plaque. This bacterium expresses several surface proteins. One of them is the adhesin SspB, which is a member of the Antigen I/II family of proteins. SspB is a large multi-domain protein that has interactions with surface molecules on other bacteria and on host cells, and is thus a key factor in the formation of biofilms. Here, we report the crystal structure of a truncated form of the SspB C-terminal domain, solved by single-wavelength anomalous dispersion to 1.5Å resolution. The structure represents the first of a C-terminal domain from a streptococcal Antigen I/II protein and is comprised of two structurally related β-sandwich domains, C2 and C3, both with a Ca2+ bound in equivalent positions. In each of the domains, a covalent isopeptide bond is observed between a lysine and an asparagine, a feature that is believed to be a common stabilization mechanism in Gram-positive surface proteins. S. gordonii biofilms contain attachment sites for the periodontal pathogen Porphyromonas gingivalis and the SspB C-terminal domain has been shown to have one such recognition motif, the SspB adherence region. The motif protrudes from the protein, and serves as a handle for attachment. The structure suggests several additional putative binding surfaces, and other binding clefts may be created when the fulllength protein is folded.

  • 106.
    Forshell, Linus Plym
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Li, Yongmei
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Plym Forshell, Tacha Zi
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Rudelius, Martina
    Department of Pathology, Technical University of Munich, Munich, Germany.
    Nilsson, Lisa
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Keller, Ulrich
    Department of Medicine, Technical University of Munich, Munich, Germany.
    Nilsson, Jonas
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    The direct Myc target Pim3 cooperates with other Pim kinases in supporting viability of Myc-induced B-cell lymphomas2011In: Oncotarget, ISSN 1949-2553, Vol. 2, no 6, p. 448-460Article in journal (Refereed)
    Abstract [en]

    The Pim kinases are weak oncogenes. However, when co-expressed with a strong oncogene, such as c-Myc, Pim kinases potentiate the oncogenic effect resulting in an acceleration of tumorigenesis. In this study we show that the least studied Pim kinase, Pim-3, is encoded by a gene directly regulated by c-Myc via binding to one of the conserved E-boxes within the Pim3 gene. Accordingly, lymphomas arising in Myc-transgenic mice and Burkitt lymphoma cell lines exhibit elevated levels of Pim-3. Interestingly, inhibition of Pim kinases by a novel pan-Pim kinase inhibitor, Pimi, in Myc-induced lymphoma results in cell death that appears independent of caspases. The data indicate that Pim kinase inhibition could be a viable treatment strategy in certain human lymphomas that rely on Pim-3 kinase expression.

  • 107.
    Forslund, Anna-Lena
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Forsberg, Åke
    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 Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Kuoppa, Kerstin
    FOI Swedish Defence Research Agency, Division of CBRN Defence and Security.
    Meibom, Karin L.
    Université Paris Descartes, Faculté de Médecine Necker-Enfants Malades; INSERM, U570, Unit of Pathogenesis of Systemic Infections.
    Alkhuder, Khaled
    Université Paris Descartes, Faculté de Médecine Necker-Enfants Malades; INSERM, U570, Unit of Pathogenesis of Systemic Infections.
    Dubail, Iharilalao
    Université Paris Descartes, Faculté de Médecine Necker-Enfants Malades; INSERM, U570, Unit of Pathogenesis of Systemic Infections.
    Dupuis, Marion
    Université Paris Descartes, Faculté de Médecine Necker-Enfants Malades; INSERM, U570, Unit of Pathogenesis of Systemic Infections.
    Charbit, Alain
    Université Paris Descartes, Faculté de Médecine Necker-Enfants Malades; INSERM, U570, Unit of Pathogenesis of Systemic Infections.
    Hfq, a novel pleiotropic regulator of virulence-associated genes in Francisella tularensis2009In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 77, no 5, p. 1866-80Article in journal (Refereed)
    Abstract [en]

    Francisella tularensis is a highly infectious pathogen that infects animals and humans, causing tularemia. The ability to replicate within macrophages is central for virulence and relies on expression of genes located in the Francisella pathogenicity island (FPI), as well as expression of other genes. Regulation of FPI-encoded virulence gene expression in F. tularensis involves at least four regulatory proteins and is not fully understood. Here we studied the RNA-binding protein Hfq in F. tularensis and particularly the role that it plays as a global regulator of gene expression in stress tolerance and pathogenesis. We demonstrate that Hfq promotes resistance to several cellular stresses (including osmotic and membrane stresses). Furthermore, we show that Hfq is important for the ability of the F. tularensis vaccine strain LVS to induce disease and persist in organs of infected mice. We also demonstrate that Hfq is important for stress tolerance and full virulence in a virulent clinical isolate of F. tularensis, FSC200. Finally, microarray analyses revealed that Hfq regulates expression of numerous genes, including genes located in the FPI. Strikingly, Hfq negatively regulates only one of two divergently expressed putative operons in the FPI, in contrast to the other known regulators, which regulate the entire FPI. Hfq thus appears to be a new pleiotropic regulator of virulence in F. tularensis, acting mostly as a repressor, in contrast to the other regulators identified so far. Moreover, the results obtained suggest a novel regulatory mechanism for a subset of FPI genes.

  • 108.
    Fowler, Christopher J.
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thors, Lina
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Chung, Sui Chu
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Tumour epithelial expression levels of endocannabinoid markers modulate the value of endoglin-positive vascular density as a prognostic marker in prostate cancer2013In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, ISSN 1388-1981, E-ISSN 1879-2618, Vol. 1831, no 10, p. 1579-1587Article in journal (Refereed)
    Abstract [en]

    Fatty acid amide hydrolase (FAAH) is responsible for the hydrolysis of the endogenous cannabinoid (CB) receptor ligand anandamide. Here we have investigated whether the expression levels of FAAH and CB1 receptors influence the prognostic value of markers of angiogenesis in prostate cancer. Data from a cohort of 419 patients who were diagnosed with prostate cancer at transurethral resection for lower urinary tract symptoms, of whom approximately 2/3 had been followed by expectancy, were used. Scores for the angiogenesis markers endoglin and von Willebrand factor (vWf), the endocannabinoid markers fatty acid amide hydrolase (FAAH) and cannabinoid CB1 receptors and the cell proliferation marker Ki-67 were available in the database. For the cases followed by expectancy, the prognostic value of endoglin was dependent upon the tumour epithelial FAAH immunoreactivity (FAAH-IR) and CB1IR scores, and the non-malignant epithelial FAAH-IR scores, but not the non-malignant CB1IR scores or the tumour blood vessel FAAH-IR scores. This dependency upon the tumour epithelial FAAH-IR or CB1IR scores was less apparent for vWf, and was not seen for Ki-67. Using an endoglin cut-off value of 10 positively stained vessels per core and a median split of tumour FAAH-IR, four groups could be generated, with 15 year of disease-specific survival (%) of 68 +/- 7 (low endoglin, low FAAH), 45 +/- 11 (high endoglin, low FAAH), 77 +/- 6 (low endoglin, high FAAH) and 21 +/- 10 (high endoglin, high FAAH). Thus, the cases with high endoglin and high FAAH scores have the poorest rate of disease-specific survival. At diagnosis, the number of cases with tumour stages 1a-1b relative to stages 2-4 was sensitive to the endoglin score in a manner dependent upon the tumour FAAH-IR. It is concluded that the prognostic value of endoglin as a marker of neovascularisation in prostate cancer can be influenced by the expression level of markers of the endocannabinoid system. This article is part of a Special Issue entitled Lipid Metabolism in Cancer.

  • 109. Franke, Lude
    et al.
    el Bannoudi, Hanane
    Jansen, Diahann T. S. L.
    Kok, Klaas
    Trynka, Gosia
    Diogo, Dorothee
    Swertz, Morris
    Fransen, Karin
    Knevel, Rachel
    Gutierrez-Achury, Javier
    Ärlestig, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Greenberg, Jeffrey D.
    Kremer, Joel
    Pappas, Dimitrios A.
    Kanterakis, Alexandros
    Weersma, Rinse K.
    van der Helm-van Mil, Annette H. M.
    Guryev, Viktor
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Gregersen, Peter K.
    Plenge, Robert M.
    Wijmenga, Cisca
    Huizinga, Tom W-J
    Ioan-Facsinay, Andreea
    Toes, Rene E. M.
    Zhernakova, Alexandra
    Association analysis of copy numbers of FC-gamma receptor genes for rheumatoid arthritis and other immune-mediated phenotypes2016In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 24, no 2, p. 263-270Article in journal (Refereed)
    Abstract [en]

    Segmental duplications (SDs) comprise about 5% of the human genome and are enriched for immune genes. SD loci often show copy numbers variations (CNV), which are difficult to tag with genotyping methods. CNV in the Fc gamma receptor region (FCGR) has been suggested to be associated with rheumatic diseases. The objective of this study was to delineate association of FCGR-CNV with rheumatoid arthritis (RA), coeliac disease and Inflammatory bowel disease incidence. We developed a method to accurately quantify CNV in SD loci based on the intensity values from the Immunochip platform and applied it to the FCGR locus. We determined the method's validity using three independent assays: segregation analysis in families, arrayCGH, and whole genome sequencing. Our data showed the presence of two separate CNVs in the FCGR locus. The first region encodes FCGR2A, FCGR3A and part of FCGR2C gene, the second encodes another part of FCGR2C, FCGR3B and FCGR2B. Analysis of CNV status in 4578 individuals with RA and 5457 controls indicated association of duplications in the FCGR3B gene in antibody-negative RA (P = 0.002, OR = 1.43). Deletion in FCGR3B was associated with increased risk of antibody-positive RA, consistently with previous reports (P = 0.023, OR = 1.23). A clear genotype-phenotype relationship was observed: CNV polymorphisms of the FCGR3A gene correlated to CD16A expression (encoded by FCGR3A) on CD8 T-cells. In conclusion, our method allows determining the CNV status of the FCGR locus, we identified association of CNV in FCGR3B to RA and showed a functional relationship between CNV in the FCGR3A gene and CD16A expression.

  • 110. Fransson, Eleonor I
    et al.
    Stadin, Magdalena
    Nordin, Maria
    Umeå University, Faculty of Social Sciences, Department of Psychology. Stress Research Institute, Stockholm University, Stockholm, Sweden.
    Malm, Dan
    Knutsson, Anders
    Alfredsson, Lars
    Westerholm, Peter J M
    The Association between Job Strain and Atrial Fibrillation: Results from the Swedish WOLF Study2015In: BioMed Research International, ISSN 2314-6133, E-ISSN 2314-6141, article id 371905Article in journal (Refereed)
    Abstract [en]

    Introduction: Atrial fibrillation (AF) is a common heart rhythmdisorder. Several life-style factors have been identified as risk factors for AF, but less is known about the impact of work-related stress. This study aims to evaluate the association between work-related stress, defined as job strain, and risk of AF. Methods: Data from the Swedish WOLF study was used, comprising 10,121 working men and women. Job strain was measured by the demand-control model. Information on incident AF was derived from national registers. Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between job strain and AF risk. Results: In total, 253 incident AF cases were identified during a total follow-up time of 132,387 person-years. Job strain was associated with AF risk in a time-dependent manner, with stronger association after 10.7 years of follow-up (HR 1.93, 95% CI 1.10-3.36 after 10.7 years, versus HR 1.11, 95% CI 0.67-1.83 before 10.7 years). The results pointed towards a dose-response relationship when taking accumulated exposure to job strain over time into account. Conclusion: This study provides support to the hypothesis that work-related stress defined as job strain is linked to an increased risk of AF.

  • 111.
    Ganai, Rais A.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Howard Hughes Medical Institute, Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, USA.
    Zhang, Xiao-Ping
    Heyer, Wolf-Dietrich
    Johansson, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Strand displacement synthesis by yeast DNA polymerase epsilon2016In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 44, no 17, p. 8229-8240Article in journal (Refereed)
    Abstract [en]

    DNA polymerase epsilon (Pol epsilon) is a replicative DNA polymerase with an associated 3'aEuro"5' exonuclease activity. Here, we explored the capacity of Pol epsilon to perform strand displacement synthesis, a process that influences many DNA transactions in vivo. We found that Pol epsilon is unable to carry out extended strand displacement synthesis unless its 3'aEuro"5' exonuclease activity is removed. However, the wild-type Pol epsilon holoenzyme efficiently displaced one nucleotide when encountering double-stranded DNA after filling a gap or nicked DNA. A flap, mimicking a D-loop or a hairpin structure, on the 5' end of the blocking primer inhibited Pol epsilon from synthesizing DNA up to the fork junction. This inhibition was observed for Pol epsilon but not with Pol delta, RB69 gp43 or Pol eta. Neither was Pol epsilon able to extend a D-loop in reconstitution experiments. Finally, we show that the observed strand displacement synthesis by exonuclease-deficient Pol epsilon is distributive. Our results suggest that Pol epsilon is unable to extend the invading strand in D-loops during homologous recombination or to add more than two nucleotides during long-patch base excision repair. Our results support the hypothesis that Pol epsilon participates in short-patch base excision repair and ribonucleotide excision repair.

  • 112. Gangabadage, Chinthaka Saneth
    et al.
    Zdunek, Janusz
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Tessari, Marco
    Nilsson, Solveig
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Olivecrona, Gunilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Wijmenga, Sybren Sipke
    Structure and dynamics of human apolipoprotein CIII2008In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 283, no 25, p. 17416-17427Article in journal (Refereed)
    Abstract [en]

    Human apolipoprotein CIII (apoCIII) is a surface component of chylomicrons, very low density lipoproteins, and high density lipoproteins. ApoCIII inhibits lipoprotein lipase as well as binding of lipoproteins to cell surface heparan sulfate proteoglycans and receptors. High levels of apoCIII are often correlated with elevated levels of blood lipids (hypertriglyceridemia). Here, we report the three-dimensional NMR structure and dynamics of human apo-CIII in complex with SDS micelles, mimicking its natural lipid-bound state. Thanks to residual dipolar coupling data, the first detailed view is obtained of the structure and dynamics of an intact apolipoprotein in its lipid-bound state. ApoCIII wraps around the micelle surface as a necklace of six approximately 10-residue amphipathic helices, which are curved and connected via semiflexible hinges. Three positively charged (Lys) residues line the polar faces of helices 1 and 2. Interestingly, their three-dimensional conformation is similar to that of the low density lipoprotein receptor binding motifs of apoE/B and the receptor-associated protein. At the C-terminal side of apoCIII, an array of negatively charged residues lines the polar faces of helices 4 and 5 and the adjacent flexible loop. Sequence comparison shows that this asymmetric charge distribution along the solvent-exposed face of apoCIII as well as other structural features are conserved among mammals. This structure provides a template for exploration of molecular mechanisms by which human apoCIII inhibits lipoprotein lipase and receptor binding.

  • 113. Gasperov, Nina Milutin
    et al.
    Farkas, Sanja A.
    Nilsson, Torbjörn K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Grce, Magdalena
    Epigenetic activation of immune genes in cervical cancer2014In: Immunology Letters, ISSN 0165-2478, E-ISSN 1879-0542, Vol. 162, no 2, p. 256-257Article in journal (Refereed)
    Abstract [en]

    Immune system provides us protection from infectious pathogens and tumors formation during lifetime. Cervical cancer (CC), and its cause, human papillomavirus (HPV) are both challenges for the immune system. We present here evidence of epigenetic activation of immune system genes in CC. Illumina Infinium Human Methylation 450 K BeadChip identified genes, which were all significantly hypomethylated in CC tissue versus normal tissue. The GeneMANIA computer program identified a tight network between those genes. The most strongly correlated genes based on their function are immune effectors' process (AIM2, BST2, BTN3A3, and IL12RB1) and response to virus related genes (AIM2, BST2, and IL12RB1). Thus, activation of those genes through demethylation is probably triggered by HPV oncogenes. In conclusion, the immune system of women who do not develop CC is probably activated earlier through DNA demethylation.

  • 114. Gavriljuk, Konstantin
    et al.
    Schartner, Jonas
    Seidel, Hans
    Dickhut, Clarissa
    Zahedi, Rene P.
    Hedberg, Christian
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Kötting, Carsten
    Gerwert, Klaus
    Unraveling the Phosphocholination Mechanism of the Legionella pneumophila Enzyme AnkX2016In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 55, no 31, p. 4375-4385Article in journal (Refereed)
    Abstract [en]

    The intracellular pathogen Legionella pneumophila infects lung macrophages and injects numerous effector proteins into the host cell to establish a vacuole for proliferation. The necessary interference with vesicular trafficking of the host is achieved by modulation of the function of Rab GTPases. The effector protein AnkX chemically modifies Rab1b and Rab35 by covalent phosphocholination of serine or threonine residues using CDP-choline as a donor. So far, the phosphoryl transfer mechanism and the relevance of observed autophosphocholination of AnkX remained disputable. We designed tailored caged compounds to make this type of enzymatic reaction accessible for time-resolved Fourier transform infrared difference spectroscopy. By combining spectroscopic and biochemical methods, we determined that full length AnkX is autophosphocholinated at Ser521, Thr620, and Thr943. However, autophosphocholination loses specificity for these sites in shortened constructs and does not appear to be relevant for the catalysis of the phosphoryl transfer. In contrast, transient phosphocholination of His229 in the conserved catalytic motif might exist as a short-lived reaction intermediate. Upon substrate binding, His229 is deprotonated and locked in this state, being rendered capable of a nucleophilic attack on the pyrophosphate moiety of the substrate. The proton that originated from His229 is transferred to a nearby carboxylic acid residue. Thus, our combined findings support a ping-pong mechanism involving phosphocholination of His229 and subsequent transfer of phosphocholine to the Rab GTPase. Our approach can be extended to the investigation of further nucleotidyl transfer reactions, which are currently of reemerging interest in regulatory pathways of host–pathogen interactions.

  • 115. Georgiou, Melanie
    et al.
    Golding, Jon P.
    Loughlin, Alison J.
    Kingham, Paul J.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Phillips, James B.
    Engineered neural tissue with aligned, differentiated adipose-derived stem cells promotes peripheral nerve regeneration across a critical sized defect in rat sciatic nerve2015In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 37, p. 242-251Article in journal (Refereed)
    Abstract [en]

    Adipose-derived stem cells were isolated from rats and differentiated to a Schwann cell-like phenotype in vitro. The differentiated cells (dADSCs) underwent self-alignment in a tethered type-1 collagen gel, followed by stabilisation to generate engineered neural tissue (EngNT-dADSC). The pro-regenerative phenotype of dADSCs was enhanced by this process, and the columns of aligned dADSCs in the aligned collagen matrix supported and guided neurite extension in vitro. EngNT-dADSC sheets were rolled to form peripheral nerve repair constructs that were implanted within NeuraWrap conduits to bridge a 15 mm gap in rat sciatic nerve. After 8 weeks regeneration was assessed using immunofluorescence imaging and transmission electron microscopy and compared to empty conduit and nerve graft controls. The proportion of axons detected in the distal stump was 3.5 fold greater in constructs containing EngNT-dADSC than empty tube controls. Our novel combination of technologies that can organise autologous therapeutic cells-within an artificial tissue construct provides a promising new cellular biomaterial for peripheral nerve repair. 

  • 116.
    Gharibyan, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Zamotin, Vladimir
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Yanamandra, Kiran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Moskaleva, Olesya S
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Margulis, BA
    Kostanyan, IA
    Morozova-Roche, Ludmilla
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lysozyme amyloid oligomers and fibrils induce cellular death via different apoptotic/necrotic pathways2007In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 365, no 5, p. 1337-1349Article in journal (Refereed)
    Abstract [en]

    Among the newly discovered amyloid properties, its cytotoxicity plays a key role. Lysozyme is a ubiquitous protein involved in systemic amyloidoses in vivo and forming amyloid under destabilising conditions in vitro. We characterized both oligomers and fibrils of hen lysozyme by atomic force microscopy and demonstrated their dose (5–50 μM) and time-dependent (6–48 h) effect on neuroblastoma SH-SY5Y cell viability. We revealed that fibrils induce a decrease of cell viability after 6 h due to membrane damage shown by inhibition of WST-1 reduction, early lactate dehydrogenase release, and propidium iodide intake; by contrast, oligomers activate caspases after 6 h but cause the cell viability to decline only after 48 h, as shown by fluorescent-labelled annexin V binding to externalized phosphatidylserine, propidium iodide DNA staining, lactate dehydrogenase release, and by typical apoptotic shrinking of cells. We conclude that oligomers induce apoptosis-like cell death, while the fibrils lead to necrosis-like death. As polymorphism is a common property of an amyloid, we demonstrated that it is not a single uniform species but rather a continuum of cross-β-sheet-containing amyloids that are cytotoxic. An abundance of lysozyme highlights a universal feature of this phenomenon, indicating that amyloid toxicity should be assessed in all clinical applications involving proteinaceous materials.

  • 117. Gillman, Anna
    et al.
    Muradrasoli, Shaman
    Mardnas, Andreas
    Söderstrom, Hanna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Fedorova, Ganna
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Faculty of Fisheries and Protection of Waters, South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Vodnany, University of South Bohemia in Ceske Budejovice, Czech Republic.
    Lowenthal, Max
    Wille, Michelle
    Daggfeldt, Annika
    Jarhult, Josef D.
    Oseltamivir Resistance in Influenza A(H6N2) Caused by an R292K Substitution in Neuraminidase Is Not Maintained in Mallards without Drug Pressure2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 9, article id e0139415Article in journal (Refereed)
    Abstract [en]

    Background Wild waterfowl is the natural reservoir of influenza A virus (IAV); hosted viruses are very variable and provide a source for genetic segments which can reassort with poultry or mammalian adapted IAVs to generate novel species crossing viruses. Additionally, wild waterfowl act as a reservoir for highly pathogenic IAVs. Exposure of wild birds to the antiviral drug oseltamivir may occur in the environment as its active metabolite can be released from sewage treatment plants to river water. Resistance to oseltamivir, or to other neuraminidase inhibitors (NAIs), in IAVs of wild waterfowl has not been extensively studied. Aim and Methods In a previous in vivo Mallard experiment, an influenza A(H6N2) virus developed oseltamivir resistance by the R292K substitution in the neuraminidase (NA), when the birds were exposed to oseltamivir. In this study we tested if the resistance could be maintained in Mallards without drug exposure. Three variants of resistant H6N2/R292K virus were each propagated during 17 days in five successive pairs of naive Mallards, while oseltamivir exposure was decreased and removed. Daily fecal samples were analyzed for viral presence, genotype and phenotype. Results and Conclusion Within three days without drug exposure no resistant viruses could be detected by NA sequencing, which was confirmed by functional NAI sensitivity testing. We conclude that this resistant N2 virus could not compete in fitness with wild type subpopulations without oseltamivir drug pressure, and thus has no potential to circulate among wild birds. The results of this study contrast to previous observations of drug induced resistance in an avian H1N1 virus, which was maintained also without drug exposure in Mallards. Experimental observations on persistence of NAI resistance in avian IAVs resemble NAI resistance seen in human IAVs, in which resistant N2 subtypes do not circulate, while N1 subtypes with permissive mutations can circulate without drug pressure. We speculate that the phylogenetic group N1 NAs may easier compensate for NAI resistance than group N2 NAs, though further studies are needed to confirm such conclusions.

  • 118. Gillman, Anna
    et al.
    Muradrasoli, Shaman
    Söderström, Hanna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Holmberg, Fredrik
    Latorre-Margalef, Neus
    Tolf, Conny
    Waldenström, Jonas
    Gunnarsson, Gunnar
    Olsen, Björn
    Jarhult, Josef D.
    Oseltamivir-Resistant Influenza A (H1N1) Virus Strain with an H274Y Mutation in Neuraminidase Persists without Drug Pressure in Infected Mallards2015In: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336, Vol. 81, no 7, p. 2378-2383Article in journal (Refereed)
    Abstract [en]

    Influenza A virus (IAV) has its natural reservoir in wild waterfowl, and emerging human IAVs often contain gene segments from avian viruses. The active drug metabolite of oseltamivir (oseltamivir carboxylate [OC]), stockpiled as Tamiflu for influenza pandemic preparedness, is not removed by conventional sewage treatment and has been detected in river water. There, it may exert evolutionary pressure on avian IAV in waterfowl, resulting in the development of resistant viral variants. A resistant avian IAV can circulate among wild birds only if resistance does not restrict viral fitness and if the resistant virus can persist without continuous drug pressure. In this in vivo mallard (Anas platyrhynchos) study, we tested whether an OC-resistant avian IAV (H1N1) strain with an H274Y mutation in the neuraminidase (NA-H274Y) could retain resistance while drug pressure was gradually removed. Successively infected mallards were exposed to decreasing levels of OC, and fecal samples were analyzed for the neuraminidase sequence and phenotypic resistance. No reversion to wild-type virus was observed during the experiment, which included 17 days of viral transmission among 10 ducks exposed to OC concentrations below resistance induction levels. We conclude that resistance in avian IAV that is induced by exposure of the natural host to OC can persist in the absence of the drug. Thus, there is a risk that human-pathogenic IAVs that evolve from IAVs circulating among wild birds may contain resistance mutations. An oseltamivir-resistant pandemic IAV would pose a substantial public health threat. Therefore, our observations underscore the need for prudent oseltamivir use, upgraded sewage treatment, and surveillance for resistant IAVs in wild birds.

  • 119. Ginley, Brandon G
    et al.
    Emmons, Tiffany
    Lutnick, Brendon
    Urban, Constantin F
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Segal, Brahm H
    Sarder, Pinaki
    Computational detection and quantification of human and mouse neutrophil extracellular traps in flow cytometry and confocal microscopy2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, no 1, article id 17755Article in journal (Refereed)
    Abstract [en]

    Neutrophil extracellular traps (NETs) are extracellular defense mechanisms used by neutrophils, where chromatin is expelled together with histones and granular/cytoplasmic proteins. They have become an immunology hotspot, implicated in infections, but also in a diverse array of diseases such as systemic lupus erythematosus, diabetes, and cancer. However, the precise assessment of in vivo relevance in different disease settings has been hampered by limited tools to quantify occurrence of extracellular traps in experimental models and human samples. To expedite progress towards improved quantitative tools, we have developed computational pipelines to identify extracellular traps from an in vitro human samples visualized using the ImageStream® platform (Millipore Sigma, Darmstadt, Germany), and confocal images of an in vivo mouse disease model of aspergillus fumigatus pneumonia. Our two in vitro methods, tested on n = 363/n =145 images respectively, achieved holdout sensitivity/specificity 0.98/0.93 and 1/0.92. Our unsupervised method for thin lung tissue sections in murine fungal pneumonia achieved sensitivity/specificity 0.99/0.98 in n = 14 images. Our supervised method for thin lung tissue classified NETs with sensitivity/specificity 0.86/0.90. We expect that our approach will be of value for researchers, and have application in infectious and inflammatory diseases.

  • 120. Gold, Judith E.
    et al.
    Hallman, David M.
    Hellström, Fredrik
    Björklund, Martin
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy. Centre for Musculoskeletal Research, Department of Occupational and Public Health Sciences, University of Gävle, Gävle, Sweden.
    Crenshaw, Albert G.
    Djupsjobacka, Mats
    Heiden, Marina
    Mathiassen, Svend Erik
    Piligian, George
    Barbe, Mary F.
    Systematic review of biochemical biomarkers for neck and upper-extremity musculoskeletal disorders2016In: Scandinavian Journal of Work, Environment and Health, ISSN 0355-3140, E-ISSN 1795-990X, Vol. 42, no 2, p. 103-124Article, review/survey (Refereed)
    Abstract [en]

    Objective This study systematically summarizes biochemical biomarker research in non-traumatic musculoskeletal disorders (MSD). Two research questions guided the review: (i) Are there biochemical markers associated with neck and upper-extremity MSD? and (ii) Are there biochemical markers associated with the severity of neck and upper-extremity MSD?

    Methods A literature search was conducted in PubMed and SCOPUS, and 87 studies met primary inclusion criteria. Following a quality screen, data were extracted from 44 articles of sufficient quality.

    Results Most of the 87 studies were cross-sectional and utilized convenience samples of patients as both cases and controls. A response rate was explicitly stated in only 11 (13%) studies. Less than half of the studies controlled for potential confounding through restriction or in the analysis. Most sufficient-quality studies were conducted in older populations (mean age in one or more analysis group >50 years). In sufficient-quality articles, 82% demonstrated at least one statistically significant association between the MSD and biomarker(s) studied. Evidence suggested that: (i) the collagen-repair marker TIMP-1 is decreased in fibroproliferative disorders, (ii) 5-HT (serotonin) is increased in trapezius myalgia, and (iii) triglycerides are increased in a variety of MSD. Only 5 studies showed an association between a biochemical marker and MSD severity.

    Conclusion While some MSD biomarkers were identified, limitations in the articles examined included possible selection bias, confounding, spectrum effect (potentially heterogeneous biomarker associations in populations according to symptom severity or duration), and insufficient attention to comorbid conditions. A list of recommendations for future studies is provided.

  • 121.
    Goldsteins, Gundars
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Andersson, Karin
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Dacklin, Ingrid
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Edvinsson, Åsa
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Sandgren, Ola
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Thylén, Christina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lundgren, Erik
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Characterisation of two highly amyloidogenic mutants of transthyretin1997In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 36, no 18, p. 5346-5352Article in journal (Refereed)
    Abstract [en]

    The plasma protein transthyretin (TTR) has the potential to form amyloid under certain conditions. More than 50 different point mutations have been associated with amyloid formation that occurs only in adults. It is not known what structural changes are introduced into the structure of this otherwise stable molecule that results in its aggregation into insoluble amyloid fibrils. On the basis of calculations of the frequency of known mutations over the polypeptide, we have constructed two mutants in the D-strand of the polypeptide. These molecules, containing either a deletion or a substitution at amino acid positions 53−55, were unstable and spontaneously formed aggregates upon storage in TBS (pH 7.6). The precipitates were shown to be amyloid by staining with thioflavin T and Congo Red. Their ultrastructure was very similar to that of amyloid fibrils deposited in the vitreous body of patients with familial amyloidotic polyneuropathy type 1 with an amino acid replacement in position 30 (TTRmet30). Like amyloid isolated from the vitreous body of the eye, the amyloid precipitates generated from the TTR mutants exposed a trypsin cleavage site between amino acid residues 48 and 49, while plasma TTRmet30 isolated from amyloidosis patients as well as wild-type TTR only showed minor trypsin sensitivity. Our data indicate that the mutants we have constructed are similar to amyloid precursors or may share structural properties with intermediates on a pathway leading to amyloid deposits of plasma TTR.

  • 122.
    Goldsteins, Gundars
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Persson, Håkan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Andersson, Karin
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Dacklin, Ingrid
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Edvinsson, Åsa
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Saraiva, Maria João
    Lundgren, Erik
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Exposure of cryptic epitopes on transthyretin only in amyloid and in amyloidogenic mutants1999In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 96, no 6, p. 3108-3113Article in journal (Refereed)
    Abstract [en]

    The structural requirements for generation of amyloid from the plasma protein transthyretin (TTR) are not known, although it is assumed that TTR is partly misfolded in amyloid. In a search for structural determinants important for amyloid formation, we generated a TTR mutant with high potential to form amyloid. We demonstrated that the mutant represents an intermediate in a series of conformational changes leading to amyloid. Two monoclonal antibodies were generated against this mutant; each displayed affinity to ex vivo TTR and TTR mutants with amyloidogenic folding but not to wild-type TTR or mutants exhibiting the wild-type fold. Two cryptic epitopes were mapped to a domain of TTR, where most mutations associated with amyloidosis occur and which we propose is displaced at the initial phase of amyloid formation, opening up new surfaces necessary for autoaggregation of TTR monomers. The results provide direct biochemical evidence for structural changes in an amyloidogenic intermediate of TTR.

  • 123. Goris, An
    et al.
    van Setten, Jessica
    Diekstra, Frank
    Ripke, Stephan
    Patsopoulos, Nikolaos A.
    Sawcer, Stephen J.
    van Es, Michael
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Melki, Judith
    Meininger, Vincent
    Hardiman, Orla
    Landers, John E.
    Brown, Robert H., Jr.
    Shatunov, Aleksey
    Leigh, Nigel
    Al-Chalabi, Ammar
    Shaw, Christopher E.
    Traynor, Bryan J.
    Chio, Adriano
    Restagno, Gabriella
    Mora, Gabriele
    Ophoff, Roel A.
    Oksenberg, Jorge R.
    Van Damme, Philip
    Compston, Alastair
    Robberecht, Wim
    Dubois, Benedicte
    van den Berg, Leonard H.
    De Jager, Philip L.
    Veldink, Jan H.
    de Bakker, Paul I. W.
    No evidence for shared genetic basis of common variants in multiple sclerosis and amyotrophic lateral sclerosis2014In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 23, no 7, p. 1916-1922Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies have been successful in identifying common variants that influence the susceptibility to complex diseases. From these studies, it has emerged that there is substantial overlap in susceptibility loci between diseases. In line with those findings, we hypothesized that shared genetic pathways may exist between multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). While both diseases may have inflammatory and neurodegenerative features, epidemiological studies have indicated an increased co-occurrence within individuals and families. To this purpose, we combined genome-wide data from 4088 MS patients, 3762 ALS patients and 12 030 healthy control individuals in whom 5 440 446 single-nucleotide polymorphisms (SNPs) were successfully genotyped or imputed. We tested these SNPs for the excess association shared between MS and ALS and also explored whether polygenic models of SNPs below genome-wide significance could explain some of the observed trait variance between diseases. Genome-wide association meta-analysis of SNPs as well as polygenic analyses fails to provide evidence in favor of an overlap in genetic susceptibility between MS and ALS. Hence, our findings do not support a shared genetic background of common risk variants in MS and ALS.

  • 124.
    Gorzsás, András
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, Ingegärd
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Pettersson, Lage
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Speciation in Aqueous Vanadate – Ligand and Peroxovanadate – Ligand systems2009In: Journal of Inorganic Biochemistry, ISSN 0162-0134, E-ISSN 1873-3344, Vol. 103, no 4, p. 517-526Article in journal (Refereed)
    Abstract [en]

    In the present focused review, the speciation studies of aqueous vanadate-ligand (L) and peroxovanadate-L systems are addressed. The paper focuses solely on the systems studied at our department in the context of potential insulin-enhancing effects, including the following ligands: imidazole, alanylhistidine, alanylserine, lactate, picolinate, citrate, phosphate, maltol, and uridine. We summarise the results of detailed and thorough potentiometric (glass electrode) and 51V NMR (Bruker AMX-500 MHz) spectroscopic studies, performed at 25 °C in 0.150 M Na(Cl), a medium representing human blood. The importance of experimental conditions is discussed and illustrated. A detailed overview of our methodology, based on combining potentiometric and 51V integral and chemical shift data by means of the computer program LAKE, is also given. We list the important steps of equilibrium analysis and the kinds of information available from different sets of NMR spectra. The ligand picolinate is chosen to exemplify our working method, but conclusions are drawn from all systems, reviewing trends and common features. An overview of all systems is given in two tables, including e.g. types and number of species formed. Previously unpublished modelling results at physiological conditions are also shown for all peroxovanadate-ligand systems.

  • 125.
    Gouveia-Figueira, Sandra
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Martens, Dries S.
    Nawrot, Tim S.
    Nording, Malin L.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Department of Entomology and Nematology, University of California, Davis, CA, USA.
    Cord blood eicosanoid signatures and newborn gestational age2017In: Prostaglandins & other lipid mediators, ISSN 1098-8823, E-ISSN 2212-196X, Vol. 133, p. 123-127Article in journal (Refereed)
    Abstract [en]

    Beyond prostaglandins, the function of eicosanoids and other oxylipins in pregnancy and labor is poorly understood. In contrast to earlier work focusing on preterm infants, we investigated how oxylipin levels in newborns (measured in cord blood) vary during the last weeks of pregnancy in 190 mother-newborns (≥37 weeks of gestation) of the ENVIRONAGE birth cohort, Belgium. We found increased levels of PGE2 (p = 0.003), PGF (p = 0.042), 8,9-DHET (p = 0.037), 11-HETE (p = 0.034), and 15-HETrE (p = 0.008) associated with full term pregnancy compared to early term labor. Furthermore, late vs early term was associated with increased levels of PGE2 (p = 0.012) and TXB2 (p = 0.033), while late vs full term was associated with decreased levels of 14,15-DHET (p = 0.029), 11,12-DHET (p = 0.033), and 5-HETE (p = 0.045). To summarize, nine eicosanoids, derived via three enzymatic pathways, were significantly associated with gestational age. Eight of these were derived from arachidonic acid, and one from dihomo-γ-linolenic acid.

  • 126. Groenning, Minna
    et al.
    Campos, Raul I
    Hirschberg, Daniel
    IFM – Department of Chemistry, Linköping University, Linköping, Sweden.
    Hammarström, Per
    Vestergaard, Bente
    Considerably Unfolded Transthyretin Monomers Preceed and Exchange with Dynamically Structured Amyloid Protofibrils2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 11443Article in journal (Refereed)
    Abstract [en]

    Despite numerous studies, a detailed description of the transthyretin (TTR) self-assembly mechanism and fibril structure in TTR amyloidoses remains unresolved. Here, using a combination of primarily small -angle X-ray scattering (SAXS) and hydrogen exchange mass spectrometry (HXMS) analysis, we describe an unexpectedly dynamic TTR protofibril structure which exchanges protomers with highly unfolded monomers in solution. The protofibrils only grow to an approximate final size of 2,900 kDa and a length of 70 nm and a comparative HXMS analysis of native and aggregated samples revealed a much higher average solvent exposure of TTR upon fibrillation. With SAXS, we reveal the continuous presence of a considerably unfolded TTR monomer throughout the fibrillation process, and show that a considerable fraction of the fibrillating protein remains in solution even at a late maturation state. Together, these data reveal that the fibrillar state interchanges with the solution state. Accordingly, we suggest that TTR fibrillation proceeds via addition of considerably unfolded monomers, and the continuous presence of amyloidogenic structures near the protofibril surface offers a plausible explanation for secondary nucleation. We argue that the presence of such dynamic structural equilibria must impact future therapeutic development strategies.

  • 127. Gruden, Marina A.
    et al.
    Davidova, Tatiana V.
    Yanamandra, Kiran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kucheryanu, Valery G.
    Morozova-Roche, Ludmilla A.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sherstnev, Vladimir V.
    Sewell, Robert D. E.
    Nasal inoculation with a-synuclein aggregates evokes rigidity, locomotor deficits and immunity to such misfolded species as well as dopamine2013In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 243, p. 205-212Article in journal (Refereed)
    Abstract [en]

    Animal models of Parkinson's disease (PD) have been widely used to investigate the pathogenesis of this neurodegenerative disorder which is typically associated with the specific and largely disordered protein alpha-synuclein (alpha-syn). In the current study, the nasal vector was used to deliver alpha-syn aggregates to the brain. Both alpha-syn oligomers and its fibrils were firstly characterized using atomic force microscopy and the thioflavin T binding assay. The toxic oligomers alone (0.48 mg/kg) or their 50:50 combination with fibrils (in a total dose of 0.48 mg/kg) were then given intranasally for ten days in mice and PD-mimetic symptoms as well as humoral immunity to these species and dopamine (DA) were evaluated simultaneously. Open-field behavioral deficits indicated by rigidity and reduced locomotor activity were induced by the dual administration of alpha-syn oligomers plus fibrils but not the oligomers by themselves under the 10-day dosing regimen. In contrast, using ELISA, high levels of serum autoantibodies to alpha-syn monomeric, oligomeric and fibrillar conformers as well as DA were observed in both treatment groups reflecting immune system activation and this substantiates previous clinical studies in Parkinson's disease patients. Thus, nasal administration of alpha-syn amyloidogenic species may be a potential experimental PD model which results not only in motor deficits but also incitement of humoral protection to mimic the disease. Such a paradigm may be exploitable in the quest for potential therapeutic strategies and further studies are warranted.

  • 128. Grönholm, Juha
    et al.
    Kaustio, Meri
    Myllymäki, Henna
    Kallio, Jenni
    Saarikettu, Juha
    Kronhamn, Jesper
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Valanne, Susanna
    Silvennoinen, Olli
    Rämet, Mika
    Not4 enhances JAK/STAT pathway-dependent gene expression in Drosophila and in human cells2012In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, no 3, p. 1239-1250Article in journal (Refereed)
    Abstract [en]

    The JAK/STAT pathway is essential for organogenesis, innate immunity, and stress responses in Drosophila melanogaster. The JAK/STAT pathway and its associated regulators have been highly conserved in evolution from flies to humans. We have used a genome-wide RNAi screen in Drosophila S2 cells to identify regulators of the JAK/STAT pathway, and here we report the characterization of Not4 as a positive regulator of the JAK/STAT pathway. Overexpression of Not4 enhanced Stat92E-mediated gene responses in vitro and in vivo in Drosophila. Specifically, Not4 increased Stat92E-mediated reporter gene activation in S2 cells; and in flies, Not4 overexpression resulted in an 8-fold increase in Turandot M (TotM) and in a 4-fold increase in Turandot A (TotA) stress gene activation when compared to wild-type flies. Drosophila Not4 is structurally related to human CNOT4, which was found to regulate interferon-gamma- and interleukin-4-induced STAT-mediated gene responses in human HeLa cells. Not4 was found to coimmunoprecipitate with Stat92E but not to affect tyrosine phosphorylation of Stat92E in Drosophila cells. However, Not4 is required for binding of Stat92E to its DNA recognition sequence in the TotM gene promoter. In summary, Not4/CNOT4 is a novel positive regulator of the JAK/STAT pathway in Drosophila and in humans.

  • 129. Guan, J.
    et al.
    Tucker, E. R.
    Wan, H.
    Chand, D.
    Danielson, L. S.
    Ruuth, Kristina
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    El Wakil, A.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Witek, B.
    Jamin, Y.
    Umapathy, G.
    Robinson, S. P.
    Johnson, T. W.
    Smeal, T.
    Martinsson, T.
    Chesler, L.
    Palmer, R. H.
    Hallberg, B.
    The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN2016In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 9, no 9, p. 941-952Article in journal (Refereed)
    Abstract [en]

    The first-in-class inhibitor of ALK, c-MET and ROS1, crizotinib (Xalkori), has shown remarkable clinical efficacy in treatment of ALK-positive non-small cell lung cancer. However, in neuroblastoma, activating mutations in the ALK kinase domain are typically refractory to crizotinib treatment, highlighting the need for more potent inhibitors. The next-generation ALK inhibitor PF-06463922 is predicted to exhibit increased affinity for ALK mutants prevalent in neuroblastoma. We examined PF-06463922 activity in ALK-driven neuroblastoma models in vitro and in vivo. In vitro kinase assays and cell-based experiments examining ALK mutations of increasing potency show that PF-06463922 is an effective inhibitor of ALK with greater activity towards ALK neuroblastoma mutants. In contrast to crizotinib, single agent administration of PF-06463922 caused dramatic tumor inhibition in both subcutaneous and orthotopic xenografts as well as a mouse model of high-risk neuroblastoma driven by Th-ALK(F1174L)/MYCN. Taken together, our results suggest PF-06463922 is a potent inhibitor of crizotinib-resistant ALK mutations, and highlights an important new treatment option for neuroblastoma patients.

  • 130.
    Gudey, Shyam Kumar
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sundar, Reshma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Mu, Yabing
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wallenius, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zang, Guangxiang
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Heldin, Carl-Henrik
    Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University.
    Landström, Marene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University.
    TRAF6 stimulates the tumor-promoting effects of TGF beta type I receptor through polyubiquitination and activation of Presenilin 12014In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 7, no 307, article id ra2Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor-beta (TGF beta) can be both a tumor promoter and suppressor, although the mechanisms behind the protumorigenic switch remain to be fully elucidated. The TGF beta type I receptor (T beta RI) is proteolytically cleaved in the ectodomain region. Cleavage requires the combined activities of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and TNF-alpha-converting enzyme (TACE). The cleavage event occurs selectively in cancer cells and generates an intracellular domain (ICD) of T beta RI, which enters the nucleus to mediate gene transcription. Presenilin 1 (PS1), a gamma-secretase catalytic core component, mediates intramembrane proteolysis of transmembrane receptors, such as Notch. We showed that TGF beta increased both the abundance and activity of PS1. TRAF6 recruited PS1 to the T beta RI complex and promoted lysine-63-linked polyubiquitination of PS1, which activated PS1. Furthermore, PS1 cleaved T beta RI in the transmembrane domain between valine-129 and isoleucine-130, and ICD generation was inhibited when these residues were mutated to alanine. We also showed that, after entering the nucleus, T beta RI-ICD bound to the promoter and increased the transcription of the gene encoding T beta RI. The TRAF6- and PS1-induced intramembrane proteolysis of T beta RI promoted TGF beta-induced invasion of various cancer cells in vitro. Furthermore, when a mouse xenograft model of prostate cancer was treated with the gamma-secretase inhibitor DBZ {(2S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b, d]azepin-7-yl)-propionamide}, generation of T beta RI-ICD was prevented, transcription of the gene encoding the proinvasive transcription factor Snail1 was reduced, and tumor growth was inhibited. These results suggest that gamma-secretase inhibitors may be useful for treating aggressive prostate cancer.

  • 131. Guo, Xiang
    et al.
    Cavka, Adnan
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Industrial Graduate School.
    Jönsson, Leif J
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hong, Feng
    Comparison of methods for detoxification of spruce hydrolysate for bacterial cellulose production2013In: Microbial Cell Factories, ISSN 1475-2859, E-ISSN 1475-2859, Vol. 12, article id 93Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Bacterial cellulose (BC) is a nanostructured material with unique properties and wide applicability. In order to decrease the production cost of bacterial cellulose, lignocellulose-based media have considerable potential as alternative cost-effective feedstocks. However, pretreatment and enzymatic hydrolysis of lignocellulose to sugars also generate fermentation inhibitors. Detoxification of lignocellulosic hydrolysates is needed to achieve efficient production of BC. In this investigation, different methods for detoxification of spruce hydrolysate prior to production of BC were compared with respect to effects on potential inhibitors and fermentable sugars, sugar consumption, BC yield, and cell viability. The objectives were to identify efficient detoxification methods and to achieve a better understanding of the role played by different inhibitors in lignocellulosic hydrolysates.

    RESULTS: In a first series of experiments, the detoxification methods investigated included treatments with activated charcoal, alkali [sodium hydroxide, calcium hydroxide (overliming), and ammonium hydroxide], anion and cation ion-exchange resins, and reducing agents (sodium sulfite and sodium dithionite). A second series of detoxification experiments included enzymatic treatments (laccase and peroxidase). The potential inhibitors studied included aliphatic acids, furan aldehydes, and phenolic compounds. The best effects in the first series of detoxification experiments were achieved with activated charcoal and anion exchanger. After detoxification with activated charcoal the BC yield was 8.2 g/L, while, it was 7.5 g/L in a reference medium without inhibitors. Treatments with anion exchanger at pH 10 and pH 5.5 gave a BC yield of 7.9 g/L and 6.3 g/L, respectively. The first series of experiments suggested that there was a relationship between the BC yield and phenolic inhibitors. Therefore, the second series of detoxification experiments focused on treatments with phenol-oxidizing enzymes. The BC yield in the laccase-detoxified hydrolysate reached 5.0-5.5 g/L after 14 days cultivation, which demonstrated the important inhibitory role played by phenolic compounds.

    CONCLUSIONS: The investigation shows that detoxification methods that efficiently remove phenolics benefit bacterial growth and BC production. Negative effects of salts could not be excluded and the osmotolerance of Gluconacetobacter xylinus needs to be further investigated in the future. Combinations of detoxification methods that efficiently decrease the concentration of inhibitors remain as an interesting option.

  • 132.
    Gupta, Arun
    et al.
    Umeå University.
    Reinartz, Ines
    Spilotros, Alessandro
    Jonna, Venkateswara R.
    Umeå University.
    Hofer, Anders
    Umeå University.
    Svergun, Dmitri I.
    Schug, Alexander
    Wolf-Watz, Magnus
    Umeå University.
    Global Disordering in Stereo-Specific Protein Association2017In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 112, no 3, p. 33A-33AArticle in journal (Refereed)
  • 133.
    Gustafsson, Tomas N.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Osman, Harer
    Werngren, Jim
    Hoffner, Sven
    Engman, Lars
    Holmgren, Arne
    Ebselen and analogs as inhibitors of Bacillus anthracis thioredoxin reductase and bactericidal antibacterials targeting Bacillus species, Staphylococcus aureus and Mycobacterium tuberculosis2016In: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1860, no 6, p. 1265-1271Article in journal (Refereed)
    Abstract [en]

    Background: Bacillus anthracis is the causative agent of anthrax, a disease associated with a very high mortality rate in its invasive forms. Methods: We studied a number of ebselen analogs as inhibitors of B. anthracis thioredoxin reductase and their antibacterial activity on Bacillus subtilis, Staphylococcus aureus, Bacillus cereus and Mycobacterium tuberculosis. Results: The most potent compounds in the series gave IC50 values down to 70 nM for the pure enzyme and minimal inhibitory concentrations (MICs) down to 0.4 mu M (0.12 mu g/ml) for B. subtilis,1.5 mu M (0.64 mu g/ml) for S. aureus, 2 mu M (0.86 mu g/ml) for B. cereus and 10 mu g/ml for M. tuberculosis. Minimal bactericidal concentrations (MBCs) were found at 1-1.5 times the MIC, indicating a general, class-dependent, bactericidal mode of action. The combined bacteriological and enzymological data were used to construct a preliminary structure-activity-relationship for the benzoisoselenazol class of compounds. When S. aureus and B. subtilis were exposed to ebselen, we were unable to isolate resistant mutants on both solid and in liquid medium suggesting a high resistance barrier. Conclusions: These results suggest that ebselen and analogs thereof could be developed into a novel antibiotic class, useful for the treatment of infections caused by B. anthracis, S. aureus, M. tuberculosis and other clinically important bacteria. Furthermore, the high barrier against resistance development is encouraging for further drug development. General significance: We have characterized the thioredoxin system from B. anthracis as a novel drug target and ebselen and analogs thereof as a potential new class of antibiotics targeting several important human pathogens.

  • 134.
    Gustavsson, Sandra
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Granåsen, Gabriel
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Grönlund, Christer
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Wiklund, Urban
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Henein, Michael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Can echocardiography and ECG discriminate hereditary transthyretin V30M amyloidosis from hypertrophic cardiomyopathy?2015In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 22, no 3, p. 163-170Article in journal (Refereed)
    Abstract [en]

    Objective: Hereditary transthyretin (ATTR) amyloidosis with increased left ventricular wall thickness could easily be misdiagnosed by echocardiography as hypertrophic cardiomyopathy (HCM). Our aim was to create a diagnostic tool based on echocardiography and ECG that could optimise identification of ATTR amyloidosis. Methods: Data were analysed from 33 patients with biopsy proven ATTR amyloidosis and 30 patients with diagnosed HCM. Conventional features from ECG were acquired as well as two dimensional and Doppler echocardiography, speckle tracking derived strain and tissue characterisation analysis. Classification trees were used to select the most important variables for differentiation between ATTR amyloidosis and HCM. Results: The best classification was obtained using both ECG and echocardiographic features, where a QRS voltage >30 mm was diagnostic for HCM, whereas in patients with QRS voltage <30 mm, an interventricular septal/posterior wall thickness ratio (IVSt/PWt) >1.6 was consistent with HCM and a ratio <1.6 supported the diagnosis of ATTR amyloidosis. This classification presented both high sensitivity (0.939) and specificity (0.833). Conclusion: Our study proposes an easily interpretable classification method for the differentiation between HCM and increased left ventricular myocardial thickness due to ATTR amyloidosis. Our combined echocardiographic and ECG model could increase the ability to identify ATTR cardiac amyloidosis in clinical practice.

  • 135.
    Hadrévi, Jenny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine. Högskolan i Gävle, Centrum för belastningsskadeforskning.
    New Aspects on Chronic Trapezius Myalgia: Contribution of Metabolomics and Proteomics2014In: Journal of Musculoskeletal Pain, ISSN 1058-2452, E-ISSN 1540-7012, Vol. 22, no 4, p. 382-388Article, review/survey (Refereed)
    Abstract [en]

    Several hypotheses regarding the underlying mechanisms and the maintenance behind chronic work-related musculoskeletal disorders have been presented. Chronic low load work and psychosocial stress is believed to be the underlying causes to these pain conditions. The recent application of comprehensive screening methods: omnics methods; to this field of research could contribute to current knowledge regarding the pathophysiology of these disorders. The pathophysiological mechanisms behind chronic trapezius myalgia are discussed in the context of new findings obtained with proteomic and metabolomic methods. Proteins and metabolites which differ in abundance between healthy muscle and muscle suffering from chronic trapezius myalgia are presented. Primarily, the pathways and effects of the proteins and metabolites found in three recently published papers are discussed. Proteomics and metabolomics are efficient screening methods enabling the presentation of potential biomarkers and pathophysiological mechanisms explaining the pathophysiology of chronic work-related trapezius myalgia. The previous findings detecting systematic differences of proteins and metabolites when comparing chronic myalgic muscle to healthy muscle, indicating a higher glycogen metabolism, increased muscle turnover and increased neuronal signalling in the myalgic muscle, are discussed in this review.

  • 136. Haglund, Kaisa
    et al.
    Nezis, Ioannis P
    Lemus, Dafne
    Grabbe, Caroline
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Wesche, Jörgen
    Liestol, Knut
    Dikic, Ivan
    Palmer, Ruth
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Stenmark, Harald
    Cindr interacts with anillin to control cytokinesis in Drosophila melanogaster2010In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 20, no 10, p. 944-950Article in journal (Refereed)
    Abstract [en]

    Cytokinesis, the final step of cell division, conventionally proceeds to cell separation by abscission, or complete cytokinesis [1, 2], but may in certain tissues be incomplete, yielding daughter cells that are interconnected in syncytia by stable intercellular bridges [3]. The mechanisms that determine complete versus incomplete cytokinesis are not known. Here we report a novel in vivo role of the Drosophila CD2AP/CIN85 ortholog Cindr in both complete and incomplete cytokinesis. We also show evidence for the presence of persistent intercellular bridges in the major larval imaginal disc epithelia. During conventional division of both cultured and embryonic cells, Cindr localizes to cleavage furrows, intercellular bridges, and midbodies. Moreover, in cells undergoing incomplete cytokinesis in the female germline and the somatic ovarian follicle cell and larval imaginal disc epithelia, Cindr localizes to arrested cleavage furrows and stable intercellular bridges, respectively. In these structures, Cindr colocalizes with the essential cytokinesis regulator Anillin. We show that Cindr interacts with Anillin and that depletion of either Cindr or Anillin gives rise to binucleate cells and fewer intercellular bridges in vivo. We propose that Cindr and Anillin cooperate to promote intercellular bridge stability during incomplete cytokinesis in Drosophila melanogaster.

  • 137.
    Hallberg, Magnus
    Umeå University, Faculty of Medicine, Medical Biochemistry and Biophsyics.
    Studies of Functional Interactions within Yeast Mediator and a Proposed Novel Mechanism for Regulation of Gene Expression2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The yeast Mediator complex is required for transcriptional regulation both in vivo and in vitro and the identification of similar complexes from metazoans indicates that its function is conserved through evolution. Mediator subunit composition and structure is well characterized both by biochemical, genetic and biophysical methods. In contrast, little is known about the mechanisms by which Mediator operates and how the complex is regulated. The aim of my thesis was to elucidate how Mediator functions at the molecular level and to investigate functional interactions within Mediator.

    It is possible to recruit RNA polymerase II to a target promoter and thus to activate transcription by fusing Mediator subunits to a DNA binding domain. In order to investigate functional interactions within Mediator, we made such fusion proteins where different Mediator subunits were fused to the DNA binding domain of lexA. The expression of a reporter gene containing binding sites for lexA was subsequently measured in both a wild type strain and in strains where genes encoding specific Mediator subunits had been disrupted. We found that lexA-Med2 and lexA-Gal11 are strong activators that function independently of all Mediator subunits tested. On the other hand, lexA-Srb10 is a weak activator that depends on Srb8 and Srb11 and lexA-Med1 and lexA-Srb7 are both cryptic activators that become active in the absence of Srb8, Srb10, Srb11, or Sin4. Both lexA-Med1 and lexA-Srb7 proteins showed a stable association with the Mediator subunits Med4 and Med8 in wild type cells and in all deletion strains tested, indicating that they were functionally incorporated into the Mediator complex. We also showed that both Med4 and Med8 exist in two forms that differed in electrophoretic mobility and that these forms differed in their ability to associate with Mediator immuno-purified from the LEXA-SRB7 and LEXA-MED1 strains. Dephosphorylation assays of purified Mediator indicated that the two mobility forms of Med4 corresponded to the phosphorylated and unphosphorylated forms of the Med4 protein respectively.

    Some of the data presented in this study as well as previous genetic and biochemical data obtained in our lab suggested a functional link between the Med1, Med2, Srb10 and Srb11 proteins. We extended these findings by showing that the Srb10 kinase phosphorylates the Med2 protein at residue serine 208, both in vitro and in vivo. We also showed that a point mutation of the single phosphorylation site to an alanine or to an aspartic acid residue altered the gene expression of a specific set of genes. Taken together, these data indicate that posttranslational modification of Mediator subunits is a so far uncharacterized mechanism for regulation of gene expression.

    In order to study the function of the Srb7 subunit of Mediator, we isolated a temperature sensitive strain where the amino acids 2 to 8 of srb7 were deleted. The Mediator subunits Nut2 and Med7 were isolated as high copy suppressor of srb7-∆(2-8) and we were also able to show that Srb7 interacted with Nut2 and Med7 both in a 2-hybrid system and in co-immuno precipitation experiments using recombinantly expressed proteins. Interestingly, a deletion of amino acids 2 to 8 of Srb7 abolishes its interaction with both Med7 and Nut2 in vitro. Med4 also interacted with Srb7 in the 2-hybrid system and surprisingly, the first eight amino acids of Srb7 were shown to be sufficient for this interaction.

  • 138. Hamark, Christoffer
    et al.
    Berntsson, Ronnie Per-Arne
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Department of Biochemistry and Biophysics, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden.
    Masuyer, Geoffrey
    Henriksson, Linda M.
    Gustafsson, Robert
    Stenmark, Pal
    Widmalm, Goran
    Glycans Confer Specificity to the Recognition of Ganglioside Receptors by Botulinum Neurotoxin A2017In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 139, no 1, p. 218-230Article in journal (Refereed)
    Abstract [en]

    The highly poisonous botulinum neurotoxins, produced by the bacterium Clostridium botulinum, act on their hosts by a high-affinity association to two receptors on neuronal cell surfaces as the first step of invasion. The glycan motifs of gangliosides serve as initial coreceptors for these protein complexes, whereby a membrane protein receptor is bound. Herein we set out to characterize the carbohydrate minimal binding epitope of the botulinum neurotoxin serotype A. By means of ligand-based NMR spectroscopy, X-ray crystallography, computer simulations, and isothermal titration calorimetry, a screening of ganglioside analogues together with a detailed characterization of various carbohydrate ligand complexes with the toxin were accomplished. We show that the representation of the glycan epitope to the protein affects the details of binding. Notably, both branches of the oligosaccharide GD la can associate to botulinum neurotoxin serotype A when expressed as individual trisaccharides. It is, however, the terminal branch of GD1a as well as this trisaccharide motif alone, corresponding to the sialyl-Thomsen-Friedenreich antigen, that represents the active ligand epitope, and these compounds bind to the neurotoxin with a high degree of predisposition but with low affinities. This finding does not correlate with the oligosaccharide moieties having a strong contribution to the total affinity, which was expected to be the case. We here propose that the glycan part of the ganglioside receptors mainly provides abundance and specificity, whereas the interaction with the membrane itself and protein receptor brings about the strong total binding of the toxin to the neuronal membrane.

  • 139. Hansen, Lori M.
    et al.
    Gideonsson, Pär
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Canfield, Don R.
    Borén, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Solnick, Jay V.
    Dynamic Expression of the BabA Adhesin and Its BabB Paralog during Helicobacter pylori Infection in Rhesus Macaques2017In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 85, no 6, article id e00094Article in journal (Refereed)
    Abstract [en]

    Most Helicobacter pylori strains express the BabA adhesin, which binds to ABO/Leb blood group antigens on gastric mucin and epithelial cells and is found more commonly in strains that cause peptic ulcers or gastric cancer, rather than asymptomatic infection. We and others have previously reported that in mice, gerbils, and rhesus macaques, expression of babA is lost, either by phase variation or by gene conversion, in which the babB paralog recombines into the babA locus. The functional significance of loss of babA expression is unknown. Here we report that in rhesus monkeys, there is independent selective pressure for loss of babA and for overexpression of BabB, which confers a fitness advantage. Surprisingly, loss of babA by phase variation or gene conversion is not dependent on the capacity of BabA protein to bind Leb, which suggests that it may have other, unrecognized functions. These findings have implications for the role of outer membrane protein diversity in persistent H. pylori infection.

  • 140.
    Harandi, Vahid M.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    A Muscle Perspective on the Pathophysiology of Amyotrophic Lateral Sclerosis: Differences between extraocular and limb muscles2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Amyotrophic lateral sclerosis (ALS) is a late-onset progressive neurodegenerative disorder. ALS has been traditionally believed to be primarily a motor neuron disease. However, accumulating data indicate that loss of contact between the axons and the muscle fibres occurs early; long before the death of motor neurons and that muscle fibres may initiate motor neuron degeneration. Thus, the view of ALS is changing focus from motor neurons alone to also include the muscle fibres and the neuromuscular junctions (NMJs). While skeletal muscles are affected in ALS, oculomotor disturbances are not dominant features of this disease and extraocular muscles (EOMs) are far less affected than limb muscles. Why oculomotor neurons and EOMs are capable to be more resistant in the pathogenetic process of ALS is still unknown.

    The overall goal of this thesis is to explore the pathophysiology of ALS from a muscle perspective and in particular study the expression and distribution of key neurotrophic factors (NTFs) and Wnt proteins in EOMs and limb muscles from ALS donors and from SOD1G93A transgenic mice. Comparisons were made with age-matched controls to distinguish between changes related to ALS and to ageing.

    Results: Brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4) were present in EOMs and limb muscles at both mRNA and protein levels in control mice. The mRNA levels of BDNF, NT-3 and NT-4 were significantly lower in EOMs than in limb muscles of early and/or late control mice, indicating an intrinsic difference in NTFs expression between EOMs and limb muscles. qRT-PCR analysis showed significantly upregulated mRNA levels of NT-3 and GDNF in EOMs but significantly downregulated mRNA levels of NT-4 in limb muscles from SOD1G93A transgenic mice at early stage. The NTFs were detected immunohistochemically in NMJs, nerve axons and muscle fibres. The expression of BDNF, GDNF and NT-4 on NMJs of limb muscles, but not of EOMs, was significantly decreased in terminal stage ALS animals as compared to the limb muscles of the age-matched controls. In contrast, NTFs expression in intramuscular nerve axons did not present significant changes in either muscle group of early or late ALS mice. NTFs, especially BDNF and NT-4 were upregulated in some small-sized muscle fibres in limb muscles of late stage ALS mice. All the four Wnt isoforms, Wnt1, Wnt3a, Wnt5a and Wnt7a were detected in most axon profiles in all human EOMs with ALS, whereas significantly fewer axon profiles were positive in the human limb muscles except for Wnt5a. Similar differential patterns were found in myofibres, except for Wnt7a, where its expression was elevated within sarcolemma of limb muscle fibres. β-catenin, a marker of the canonical Wnt pathway was activated in a subset of myofibres in the EOMs and limb muscle in all ALS patients. In the SOD1G93A mouse, all four Wnt isoforms were significantly decreased in the NMJs at the terminal stage compared to age matched controls.

    Conclusions: There were clear differences in NTF and Wnt expression patterns between EOM and limb muscle, suggesting that they may play a role in the distinct susceptibility of these two muscle groups to ALS. In particular, the early upregulation of GDNF and NT-3 in the EOMs might play a role in the preservation of the EOMs in ALS. Further studies are needed to determine whether these proteins and the pathways they control may be have a future potential as protecting agents for other muscles.

  • 141.
    Hauryliuk, Vasili
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Institute of Technology, University of Tartu, Nooruse 1, Tartu 50411, Estonia.
    Atkinson, Gemma C.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Institute of Technology, University of Tartu, Nooruse 1, Tartu 50411, Estonia.
    Murakami, Katsuhiko S.
    Department of Biochemistry and Molecular Biology, Center for RNA Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
    Tenson, Tanel
    Institute of Technology, University of Tartu, Nooruse 1, Tartu 50411, Estonia.
    Gerdes, Kenn
    Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark.
    Recent functional insights into the role of (p)ppGpp in bacterial physiology2015In: Nature Reviews Microbiology, ISSN 1740-1526, E-ISSN 1740-1534, Vol. 13, no 5, p. 298-309Article, review/survey (Refereed)
    Abstract [en]

    The alarmones guanosine tetraphosphate and guanosine pentaphosphate (collectively referred to as (p) ppGpp) are involved in regulating growth and several different stress responses in bacteria. In recent years, substantial progress has been made in our understanding of the molecular mechanisms of (p) ppGpp metabolism and (p) ppGpp-mediated regulation. In this Review, we summarize these recent insights, with a focus on the molecular mechanisms governing the activity of the RelA/SpoT homologue (RSH) proteins, which are key players that regulate the cellular levels of (p) ppGpp. We also discuss the structural basis of transcriptional regulation by (p) ppGpp and the role of (p) ppGpp in GTP metabolism and in the emergence of bacterial persisters.

  • 142.
    Hauser, Jannek
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Grundström, Christine
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Kumar, Ramesh
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Grundström, Thomas
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Signal regulated localisation of a mutagenic protein complex at the Igh locus2015In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 282, p. 13-13Article in journal (Other academic)
    Abstract [en]

    Our system to produce antibodies is critical for our survival against numerous infections, but it causes also many tumors. B-lymphocytes can modify their immunoglobulin (Ig) genes to generate specific antibodies with a new isotype and enhanced affinity against an antigen. Activation-induced cytidine deaminase (AID) is the key mutagenic enzyme that initiates these processes by deaminating cytosine to uracil. How somatic hypermutation (SH) and class switch recombination (CSR) are targeted is key to understanding the defect DNA integrity in lymphomas and also in other tumors where inflammatory signals aberrantly induces AID. The trans-acting factors mediating specific targeting of AID and thereby SH and CSR have remained elusive. Here we show that mutant E2A with defect inhibition by the Ca2+sensor protein calmodulin results in reduced B cell receptor- (BCR-), IL4-plus CD40 ligand-stimulated CSR to IgE and instead aberrant CSR. AID is shown to be together with the transcription factors E2A, PAX5 and IRF4 in a complex on key sequences of the Igh locus in activated mouse splenic B cells. Calmodulin shows proximity with each of them after BCR stimulation. Direct protein-protein interactions enable formation of the complexes. BCR signaling reduces binding of the proteins to some of the target sites on the Igh locus, and calmodulin resistance of E2A blocks reduction of binding to these target sites and increases binding to other target sites. Thus, E2A, AID, PAX5 and IRF4 are components of a CSR and SH complex that is redistributed on the IgH gene by BCR signaling through calmodulin binding.

  • 143. Heckl, Dirk
    et al.
    Charpentier, Emmanuelle
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Regulation in Infection Biology, Helmholtz Centre for Infection Research, Germany ; Department of Regulation in Infection Biology, Hannover Medical School, Hannover, Germany.
    Toward whole-transcriptome editing with CRISPR-Cas92015In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 58, no 4, p. 560-562Article in journal (Other academic)
    Abstract [en]

    Targeted regulation of gene expression holds huge promise for biomedical research. In a series of recent publications (Gilbert et al., 2014; Konermann et al., 2015; Zalatan et al., 2015), sophisticated, multiplex-compatible transcriptional activator systems based on the CRISPR-Cas9 technology and genome-scale libraries advance the field toward whole-transcriptome control.

  • 144.
    Hedberg, Maria E.
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Israelsson, Anne
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Moore, Edward R. B.
    Svensson-Stadler, Liselott
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Pietz, Grzegorz
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hammarstrom, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Prevotella jejuni sp nov., isolated from the small intestine of a child with coeliac disease2013In: International Journal of Systematic and Evolutionary Microbiology, ISSN 1466-5026, E-ISSN 1466-5034, Vol. 63, no 11, p. 4218-4223Article in journal (Refereed)
    Abstract [en]

    Five obligately anaerobic, Gram-stain-negative, saccharolytic and proteolytic, non-spore-forming bacilli (strains CD3 :27, CD3 :28(T), CD3 :33, CD3 :32 and CD3 :34) are described. All five strains were isolated from the small intestine of a female child with coeliac disease. Cells of the five strains were short rods or coccoid cells with longer filamentous forms seen sporadically. The organisms produced acetic acid and succinic acid as major metabolic end products. Phylogenetic analysis based on comparative 16S rRNA gene sequence analysis revealed close relationships between CD3 : 27, CD3 :28(T) and CD3 :33, between CD3 :32 and Prevotella histicola CCUG 55407(T), and between CD3 :34 and Prevotella melaninogenica CCUG 4944B(T). Strains CD3 : 27, CD3 :28(T) and CD3 :33 were clearly different from all recognized species within the genus Prevotella and related most closely to but distinct from P. melaninogenica. Based on 16S rRNA, RNA polymerase) beta-subunit (rpoB) and 60 kDa chaperonin protein subunit (cpn60) gene sequencing, and phenotypic, chemical and biochemical properties, strains CD3 :27, CD3 :28(T) and CD3 :33 are considered to represent a novel species within the genus Prevotella, for which the name Prevotella jejuni sp. nov. is proposed. Strain CD3 : 28(T) (=CCUG 60371(T)=DSM 26989(T)) is the type strain of the proposed novel species. All five strains were able to form homologous aggregates, in which tube-like structures were connecting individual bacteria cells. The five strains were able to bind to human intestinal carcinoma cell lines at 37 degrees C.

  • 145.
    Helferich, Anika M.
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Brockmann, Sarah J.
    Reinders, Jörg
    Deshpande, Dhruva
    Holzmann, Karlheinz
    Brenner, David
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience. Department of Neurology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
    Petri, Susanne
    Thal, Dietmar R.
    Michaelis, Jens
    Otto, Markus
    Just, Steffen
    Ludolph, Albert C.
    Danzer, Karin M.
    Freischmidt, Axel
    Weishaupt, Jochen H.
    Dysregulation of a novel miR-1825/TBCB/TUBA4A pathway in sporadic and familial ALS2018In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 75, no 23, p. 4301-4319Article in journal (Refereed)
    Abstract [en]

    Genetic and functional studies suggest diverse pathways being affected in the neurodegenerative disease amyotrophic lateral sclerosis (ALS), while knowledge about converging disease mechanisms is rare. We detected a downregulation of microRNA-1825 in CNS and extra-CNS system organs of both sporadic (sALS) and familial ALS (fALS) patients. Combined transcriptomic and proteomic analysis revealed that reduced levels of microRNA-1825 caused a translational upregulation of tubulin-folding cofactor b (TBCB). Moreover, we found that excess TBCB led to depolymerization and degradation of tubulin alpha-4A (TUBA4A), which is encoded by a known ALS gene. Importantly, the increase in TBCB and reduction of TUBA4A protein was confirmed in brain cortex tissue of fALS and sALS patients, and led to motor axon defects in an in vivo model. Our discovery of a microRNA-1825/TBCB/TUBA4A pathway reveals a putative pathogenic cascade in both fALS and sALS extending the relevance of TUBA4A to a large proportion of ALS cases.

  • 146.
    Henein, Michael Y.
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Response: Atrial impairment in transthyretin cardiac amyloidosis: an early marker of cardiac involvement and a prognostic factor2018In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 25, no 2, p. 136-136Article in journal (Refereed)
  • 147. Hernández-Torres, Gloria
    et al.
    Cipriano, Mariateresa
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Hedén, Erika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Björklund, Emmelie
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Canales, Ángeles
    Zian, Debora
    Feliú, Ana
    Mecha, Miriam
    Guaza, Carmen
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Ortega-Gutiérrez, Silvia
    López-Rodríguez, María L.
    A reversible and selective inhibitor of monoacylglycerol lipase ameliorates multiple sclerosis2014In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 53, no 50, p. 13765-13770Article in journal (Refereed)
    Abstract [en]

    Monoacylglycerol lipase (MAGL) is the enzyme responsible for the inactivation of the endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL inhibitors show analgesic and tissue-protecting effects in several disease models. However, the few efficient and selective MAGL inhibitors described to date block the enzyme irreversibly, and this can lead to pharmacological tolerance. Hence, additional classes of MAGL inhibitors are needed to validate this enzyme as a therapeutic target. Here we report a potent, selective, and reversible MAGL inhibitor (IC50=0.18M) which is active in vivo and ameliorates the clinical progression of a multiple sclerosis (MS) mouse model without inducing undesirable CB1-mediated side effects. These results support the interest in MAGL as a target for the treatment of MS.

  • 148. Herrera, Phabiola M
    et al.
    Mendez, Melissa
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Velapatiño, Billie
    Santivañez, Livia
    Balqui, Jacqueline
    Finger, S Alison
    Sherman, Jonathan
    Zimic, Mirko
    Cabrera, Lilia
    Watanabe, Jose
    Rodríguez, Carlos
    Gilman, Robert H
    Berg, Douglas E
    DNA-level diversity and relatedness of Helicobacter pylori strains in shantytown families in Peru and transmission in a developing-country setting.2008In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 46, no 12, p. 3912-3918Article in journal (Refereed)
    Abstract [en]

    The efficiency of transmission of a pathogen within families compared with that between unrelated persons can affect both the strategies needed to control or eradicate infection and how the pathogen evolves. In industrialized countries, most cases of transmission of the gastric pathogen Helicobacter pylori seems to be from mother to child. An alternative model, potentially applicable among the very poor in developing countries, where infection is more common and the sanitary infrastructure is often deficient, invokes frequent transmission among unrelated persons, often via environmental sources. In the present study, we compared the genotypes of H. pylori from members of shantytown households in Peru to better understand the transmission of H. pylori in developing-country settings. H. pylori cultures and/or DNAs were obtained with informed consent by the string test (a minimally invasive alternative to endoscopy) from at least one child and one parent from each of 62 families. The random amplified polymorphic DNA fingerprints of 57 of 81 (70%) child-mother strain pairs did not match, nor did the diagnostic gene sequences (>1% DNA sequence difference), independent of the child's age (range, 1 to 39 years). Most strains from siblings or other paired family members were also unrelated. These results suggest that H. pylori infections are often community acquired in the society studied. Transmission between unrelated persons should facilitate the formation of novel recombinant genotypes by interstrain DNA transfer and selection for genotypes that are well suited for individual hosts. It also implies that the effective prevention of H. pylori infection and associated gastroduodenal disease will require anti-H. pylori measures to be applied communitywide.

  • 149. Hille, Frank
    et al.
    Charpentier, Emmanuelle
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Regulation in Infection Biology, Max Planck Institute for Infection Biology, Berlin 10117, Germany.
    CRISPR-Cas: biology, mechanisms and relevance2016In: Philosophical Transactions of the Royal Society of London. Biological Sciences, ISSN 0962-8436, E-ISSN 1471-2970, Vol. 371, no 1707, article id 20150496Article, review/survey (Refereed)
    Abstract [en]

    Prokaryotes have evolved several defence mechanisms to protect themselves from viral predators. Clustered regularly interspaced short palindromic repeats (CRISPR) and their associated proteins (Cas) display a prokaryotic adaptive immune system that memorizes previous infections by integrating short sequences of invading genomes-termed spacers-into the CRISPR locus. The spacers interspaced with repeats are expressed as small guide CRISPR RNAs (crRNAs) that are employed by Cas proteins to target invaders sequence-specifically upon a reoccurring infection. The ability of the minimal CRISPR-Cas9 system to target DNA sequences using programmable RNAs has opened new avenues in genome editing in a broad range of cells and organisms with high potential in therapeutical applications. While numerous scientific studies have shed light on the biochemical processes behind CRISPR-Cas systems, several aspects of the immunity steps, however, still lack sufficient understanding. This review summarizes major discoveries in the CRISPR-Cas field, discusses the role of CRISPR-Cas in prokaryotic immunity and other physiological properties, and describes applications of the system as a DNA editing technology and antimicrobial agent. This article is part of the themed issue 'The new bacteriology'.

  • 150. Hillmann, Steffi
    et al.
    Wiedmann, Silke
    Fraser, Alec
    Baeza, Juan
    Rudd, Anthony
    Norrving, Bo
    Asplund, Kjell
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Niewada, Maciej
    Dennis, Martin
    Hermanek, Peter
    Wolfe, Charles D A
    Heuschmann, Peter U
    Temporal Changes in the Quality of Acute Stroke Care in Five National Audits across Europe2015In: BioMed Research International, ISSN 2314-6133, E-ISSN 2314-6141, article id 432497Article in journal (Refereed)
    Abstract [en]

    Background: Data on potential variations in delivery of appropriate stroke care over time are scarce. We investigated temporal changes in the quality of acute hospital stroke care across five national audits in Europe over a period of six years. Methods: Data were derived from national stroke audits in Germany, Poland, Scotland, Sweden, and England/Wales/Northern Ireland participating within the European Implementation Score (EIS) collaboration. Temporal changes in predefined quality indicators with comparable information between the audits were investigated. Multivariable logistic regression analyses were performed to estimate adherence to quality indicators over time. Results: Between 2004 and 2009, individual data from 542,112 patients treated in 538 centers participating continuously over the study period were included. In most audits, the proportions of patients who were treated on a SU, were screened for dysphagia, and received thrombolytic treatment increased over time and ranged from 2-fold to almost 4-fold increase in patients receiving thrombolytic therapy in 2009 compared to 2004. Conclusions: A general trend towards a better quality of stroke care defined by standardized quality indicators was observed over time. The association between introducing a specific measure and higher adherence over time might indicate that monitoring of stroke care performance contributes to improving quality of care.

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