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Sökning: WFRF:(Persson Anders) > Umeå universitet > (2005-2009)

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1.
  • Olofsson, Anders, et al. (författare)
  • Amide solvent protection analysis demonstrates that amyloid-beta(1-40) and amyloid-beta(1-42) form different fibrillar structures under identical conditions.
  • 2007
  • Ingår i: Biochem J. - 1470-8728. ; 404:1, s. 63-70
  • Tidskriftsartikel (refereegranskat)abstract
    • AD (Alzheimer's disease) is a neurodegenerative disorder characterized by self-assembly and amyloid formation of the 39–43 residue long Ab (amyloid-b)-peptide. The most abundant species, Ab(1–40) and Ab(1–42), are both present within senile plaques, but Ab(1–42) peptides are considerably more prone to self-aggregation and are also essential for the development of AD. To understand the molecular and pathological mechanisms behind AD, a detailed knowledge of the amyloid structures of Ab-peptides is vital. In the present study we have used quenched hydrogen/deuterium-exchange NMR experiments to probe the structure of Ab(1–40) fibrils. The fibrils were prepared and analysed identically as in our previous study on Ab(1–42) fibrils, allowing a direct comparison of the two fibrillar structures. The solvent protection pattern of Ab(1–40) fibrils revealed two well-protected regions, consistent with a structural arrangement of two b-strands connected with a bend. This protection pattern partly resembles the pattern found in Ab(1–42) fibrils, but the Ab(1–40) fibrils display a significantly increased protection for the N-terminal residues Phe4–His14, suggesting that additional secondary structure is formed in this region. In contrast, the C-terminal residues Gly37–Val40 show a reduced protection that suggests a loss of secondary structure in this region and an altered filament assembly. The differences between the present study and other similar investigations suggest that subtle variations in fibril-preparation conditions may significantly affect the fibrillar architecture.
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2.
  • Olofsson, Anders, et al. (författare)
  • Quenched hydrogen/deuterium exchange NMR characterization of amyloid-β peptide aggregates formed in the presence of Cu2+ or Zn2
  • 2009
  • Ingår i: The FEBS Journal. - : Wiley InterScience. - 1742-464X .- 1742-4658. ; 276:15, s. 4051-4060
  • Tidskriftsartikel (refereegranskat)abstract
    • Alzheimer's disease, a neurodegenerative disorder causing synaptic impairment and neuronal cell death, is strongly correlated with aggregation of the amyloid-β peptide (Aβ). Divalent metal ions such as Cu2+ and Zn2+ are known to significantly affect the rate of aggregation and morphology of Aβ assemblies in vitro and are also found at elevated levels within cerebral plaques in vivo. The present investigation characterized the architecture of the aggregated forms of Aβ(1–40) and Aβ(1–42) in the presence or absence of either Cu2+ or Zn2+ using quenched hydrogen/deuterium exchange combined with solution NMR spectroscopy. The NMR analyses provide a quantitative and residue-specific structural characterization of metal-induced Aβ aggregates, showing that both the peptide sequence and the type of metal ion exert an impact on the final architecture. Common features among the metal-complexed peptide aggregates are two solvent-protected regions with an intervening minimum centered at Asn27, and a solvent-accessible N-terminal region, Asp1–Lys16. Our results suggest that Aβ in complex with either Cu2+ or Zn2+ can attain an aggregation-prone β-strand–turn–β-strand motif, similar to the motif found in fibrils, but where the metal binding to the N-terminal region guides the peptide into an assembly distinctly different from the fibril form.
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3.
  • Björk, Glenn, et al. (författare)
  • A conserved modified wobble nucleoside (mcm5s2U) in lysyl-tRNA is required for viability in yeast.
  • 2007
  • Ingår i: RNA. - : Cold Spring Harbor Laboratory. - 1355-8382 .- 1469-9001. ; 13:8, s. 1245-55
  • Tidskriftsartikel (refereegranskat)abstract
    • Transfer RNAs specific for Gln, Lys, and Glu from all organisms (except Mycoplasma) and organelles have a 2-thiouridine derivative (xm(5)s(2)U) as wobble nucleoside. These tRNAs read the A- and G-ending codons in the split codon boxes His/Gln, Asn/Lys, and Asp/Glu. In eukaryotic cytoplasmic tRNAs the conserved constituent (xm(5)-) in position 5 of uridine is 5-methoxycarbonylmethyl (mcm(5)). A protein (Tuc1p) from yeast resembling the bacterial protein TtcA, which is required for the synthesis of 2-thiocytidine in position 32 of the tRNA, was shown instead to be required for the synthesis of 2-thiouridine in the wobble position (position 34). Apparently, an ancient member of the TtcA family has evolved to thiolate U34 in tRNAs of organisms from the domains Eukarya and Archaea. Deletion of the TUC1 gene together with a deletion of the ELP3 gene, which results in the lack of the mcm(5) side chain, removes all modifications from the wobble uridine derivatives of the cytoplasmic tRNAs specific for Gln, Lys, and Glu, and is lethal to the cell. Since excess of the unmodified form of these three tRNAs rescued the double mutant elp3 tuc1, the primary function of mcm(5)s(2)U34 seems to be to improve the efficiency to read the cognate codons rather than to prevent mis-sense errors. Surprisingly, overexpression of the mcm(5)s(2)U-lacking tRNA(Lys) alone was sufficient to restore viability of the double mutant.
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4.
  • Fridberg, Marie, et al. (författare)
  • Protein expression and cellular localization in two prognostic subgroups of diffuse large B-cell lymphoma : higher expression of ZAP70 and PKC-beta II in the non-germinal center group and poor survival in patients deficient in nuclear PTEN
  • 2007
  • Ingår i: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 48:11, s. 2221-2232
  • Tidskriftsartikel (refereegranskat)abstract
    • Patients diagnosed with diffuse large B-cell lymphoma (DLBCL) show varying responses to conventional therapy, and this might be contributed to the differentiation stage of the tumor B-cells. The aim of the current study was to evaluate a panel of kinases (ZAP70, PKC-β I and II and phosphorylated PKB/Akt) and phosphatases (PTEN, SHP1 and SHP2) known to be frequently deregulated in lymphoid malignancies. De novo DLBCL cases were divided into two subgroups, the germinal center (GC) group (14/28) and the non-germinal center (non-GC) or activated B-cell (ABC) group (14/28). ZAP70 and PKC-β II were expressed in a significantly higher percentage of tumor cells in the clinically more aggressive non-GC group compared with the prognostically favourable GC group. Also, the subcellular localization of PKC-β I and II differed in DLBCL cells, with the PKC-β I isoform being expressed in both the cytoplasm and nucleus, while PKC-β II was found exclusively in the cytoplasm. Loss of nuclear PTEN correlated with poor survival in cases from both subgroups. In addition, five cell lines of DLBCL origin were analyzed for protein expression and for mRNA levels of PTEN and SHP1. For the first time, we show that ZAP70 is expressed in a higher percentage of tumor cells in the aggressive non-GC subgroup of DLBCL and that PKC-β I and II are differently distributed in the two prognostic subgroups of de novo DLBCL.
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6.
  • Goldin, Stephen, 1948- (författare)
  • Living in the present with the past : mental health of Bosnian refugee children in Sweden
  • 2008
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • The negative impact of war on child mental health has been repeatedly documented. Still, the majority of children exposed to ethnic and political violence show no signs of clinical disorder. In Western countries of exile, these findings have prompted a variety of attempts to evaluate refugee children, in the hope of identifying and offering support to those children “at risk”. This study critically examines one such attempt. The aims are fourfold: 1. to describe the range and pattern of child trauma-stress exposure and mental health reactions as captured on clinician semi-structured interview; 2. to critically compare clinician assessment with independent parent, child and teacher reports; 3. to identify factors of potential risk or protective import for child mental health; 4. to draw clinical implications: from whom and by what means can children at risk be reasonably identified? The target of our study was the entire population of Bosnian-Serbian-Croatian speaking child refugee families assigned to Umeå and surrounding municipalities during 1994-95. Fifty families, containing 90 children aged one month to 20 years, were included in the study. Assessment occurred in two phases. First, a semi-structured interview was conducted that inquired broadly as to the child’s family background, trauma-stress exposure, emotional-behavioral problems, patterns of family functioning, and future hopes. Second, standardized self-report questionnaires were administered, separately to parent and child, to provide alternative appraisal of the child’s war exposure, mental health symptoms, coping strategies, and social network. Teacher evaluation of child cognitive-social functioning as well as emotional-behavioral problems was also obtained. Clinician semi-structured interview revealed the child’s pre-war period as preponderantly good, and provided richly detailed narratives of child exposure during war and resettlement that clustered into a limited number of type-stories. Independent parent assessment captured the same broad strokes of child war exposure; but both approaches – fixed questionnaire and semi-structured interview – showed specific areas of blindness. Teenage self-report offered a disparate but equally rich account of war exposure, while that of primary school child was significantly less detailed. Nearly half of the study children (48%) were identified on clinician interview with one or more mental health problem “demanding further attention”. Depressiveness was the single most prevalent symptom (31%), followed by posttraumatic reactions (23%) and anxiety-regressiveness (15%). Independent symptom appraisal by parent and primary school child was largely concordant with that of clinician, while teenagers made similar assessment as to who was in distress, but defined the nature of that distress differently. Teacher report stood apart, identifying fewer inward emotional problems and asserting the cognitive-social competence of the vast majority of study children. Trauma-stress exposure during both war and resettlement presented as an unequivocal risk to mental health, but accounted for only part of outcome variance. Additional factors of strong import related broadly to “living in the present”. Parent impairment of daily routines, child dissatisfaction with school and an ongoing quarrelsome relationship presented as risk factors. Protection was associated with parent maintenance of a warm family climate and of concrete physical-emotional caring, child social ties to physically present others, including teacher; and above all, a family sense of hope for the future. Results support the general robustness of our semi-structured approach. Exploring the child’s present well-being in narrative relation to past and future, our assessment captured and gave meaning to the complexity of child exposure and behavior. At the same time, independent parent and child appraisals provided an additional richness to the retelling and evaluation of child experience. Particularly the apartness of teacher report underscores the need to incorporate an outside-world vantage point in the process of risk assessment.
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7.
  • Håkansson, Katarina, et al. (författare)
  • Torrefaction and Gasification of Hydrolysis Residue
  • 2008
  • Ingår i: 16th European Biomass Conference and Exhibition: Proceedings.
  • Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
    • When producing ethanol from lignocellulosic material using hydrolysis combined with fermentation, a large amount of residue consisting of mainly lignin is generated. A significant amount of energy is retained in this residue which may be utilised as a measure for the process to become economically viable. One possibility is as fuel in a gasification process for synthesis gas production, improving the fuel yield and the overall plant efficiency. Furthermore, the pre-treatment method torrefaction has been shown to significantly improve biomass fuel characteristics such as energy density, moisture content, feeding and hydrophobic properties, as well as significantly facilitate particle size reduction. Therefore, the process chain from hydrolysis residue to synthesis gas was investigated and demonstrated in the present work through bench-scale experiments in a batch torrefaction reactor and a bubbling fluidised bed gasifier. The results from the torrefaction work confirmed the improved fuel characteristics and the effects of process variables were evaluated by factorial designed experiments. The torrefaction residence time was identified as the most influential variable. The results from reactivity tests and gasification experiments indicate that hydrolysis residue and corresponding torrefied residue are suitable for synthesis gas production, with some improved feedstock handling characteristics for the latter.
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8.
  • Lindhagen-Persson, Malin, et al. (författare)
  • Formation of cytotoxic transthyretin is not dependent on inter-molecular disulphide bridges commonly found within the amyloid form
  • 2008
  • Ingår i: Amyloid. - : Informa UK Limited. - 1350-6129 .- 1744-2818. ; 15:4, s. 240-245
  • Tidskriftsartikel (refereegranskat)abstract
    • Familial amyloidotic polyneuropathy (FAP) is linked to destabilising point mutations in the human plasma protein transthyretin (TTR). Consistent with similar amyloid disorders, low molecular weight TTR oligomers have been shown to exert the major cytotoxic effect. The amyloid structure of TTR contains non-native inter-molecular disulphide linkages via the cysteine at position 10 (Cys10). Moreover, substitution of Cys10 in a mouse model for TTR-amyloidosis abolishes TTR deposits, indicating an important role of Cys10 in FAP pathogenesis. However, the role of disulphide bridges in TTR cytotoxicity has not been elucidated. By probing Cys10Ser TTR variants to the human neuroblastoma SH-SY5Y cell line, we have addressed this question, and our results clearly show that formation of an inter-molecular disulphide bridge is not a pre-requisite for TTR cytotoxicity. This finding suggests that prevention of inter-molecular TTR disulphide bridges as a therapeutic intervention will not impair the cytotoxic potential of TTR.
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10.
  • Ohlson, Nina, et al. (författare)
  • Castration rapidly decreases local insulin-like growth factor-1 levels and inhibits its effects in the ventral prostate in mice.
  • 2006
  • Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 66:16, s. 1687-1697
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The mechanisms by which castration induces prostate involution are largely unknown. METHODS: Early responses to castration in mouse ventral prostate (VP) were explored by quantitative microscopy, cDNA array expression, quantitative RT-PCR, and Western blot analysis. As several changes occurred in the insulin-like growth factor (IGF) system this was studied in more detail. Laser micro-dissection was used to localize sites of IGF-1 and IGF-1 receptor (IGF-R1) production. IGF-1 protein levels and IGF-R1 mediated signaling via insulin regulated substrate 1 and 2 (IRS-1 and 2) were examined. IGF-1 was injected into the VP in intact, and castrated mice and effects studied 1 day later. RESULTS: IGF-1 and IGF binding protein 2 (IGFBP-2) mRNA were rapidly reduced whereas IGFBP-3 and IGF-R1 mRNA were increased after castration. IGF-1 was principally produced in the stromal compartment, while IGF-R1 was produced in both epithelial and stromal cells. IGF-1 and IRS-1 protein levels were decreased 1 and 3 days after castration, respectively, while IRS-2 was unchanged. Inactivating phosphorylation of IRS-1 at serine 307 was increased 1 day after castration, and activating phosphorylation at tyrosine 612 was decreased 2 days later. These changes were accompanied by decreased cell proliferation and increased cell death in the glandular and vascular compartment. Local injection of IGF-1 increased vascular density and epithelial cell proliferation in intact mice, but had no effect in castrated animals. CONCLUSION: Decreased IGF-1 levels and action may mediate some of the key features of castration-induced prostate involution.
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