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  • Coutard, B, et al. (författare)
  • The VIZIER project : preparedness against pathogenic RNA viruses
  • 2008
  • Ingår i: Antiviral Research. - 0166-3542 .- 1872-9096. ; 78:1, s. 37-46
  • Tidskriftsartikel (refereegranskat)abstract
    • Life-threatening RNA viruses emerge regularly, and often in an unpredictable manner. Yet, the very few drugs available against known RNA viruses have sometimes required decades of research for development. Can we generate preparedness for outbreaks of the, as yet, unknown viruses? The VIZIER (VIral enZymes InvolvEd in Replication) (http://www.vizier-europe.org/) project has been set-up to develop the scientific foundations for countering this challenge to society. VIZIER studies the most conserved viral enzymes (that of the replication machinery, or replicases) that constitute attractive targets for drug-design. The aim of VIZIER is to determine as many replicase crystal structures as possible from a carefully selected list of viruses in order to comprehensively cover the diversity of the RNA virus universe, and generate critical knowledge that could be efficiently utilized to jump-start research on any emerging RNA virus. VIZIER is a multidisciplinary project involving (i) bioinformatics to define functional domains, (ii) viral genomics to increase the number of characterized viral genomes and prepare defined targets, (iii) proteomics to express, purify, and characterize targets, (iv) structural biology to solve their crystal structures, and (v) pre-lead discovery to propose active scaffolds of antiviral molecules.
  • Jansen, Willemijn J, et al. (författare)
  • Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia.
  • 2018
  • Ingår i: JAMA psychiatry. - 2168-6238. ; 75:1, s. 84-95
  • Tidskriftsartikel (refereegranskat)abstract
    • IMPORTANCE Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials. OBJECTIVE To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017. MAIN OUTCOMES AND MEASURES Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype. RESULTS Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4%[95%CI, 0%-7%] at 72 years and 21% [95%CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3%[95%CI, -1%to 6%], P = .16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16%[95%CI, 12%-20%], P < .001) and low MMSE (mean difference, 14%[95%CI, 12%-17%], P < .001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years. CONCLUSIONS AND RELEVANCE Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.
  • Jansen, Willemijn J, et al. (författare)
  • Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis.
  • 2015
  • Ingår i: JAMA. - 1538-3598. ; 313:19, s. 1924-38
  • Tidskriftsartikel (refereegranskat)abstract
    • Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies.
  • Tedner, S. G., et al. (författare)
  • Maternal sensitization during pregnancy
  • 2018
  • Ingår i: Allergy. European Journal of Allergy and Clinical Immunology. - WILEY. - 0105-4538 .- 1398-9995. ; 73:Suppl. 105, s. 694-694
  • Tidskriftsartikel (övrigt vetenskapligt)
  • Assarsson, Maria, et al. (författare)
  • Restoring proper radical generation by azide binding to the iron site of the E238A mutant R2 protein of ribonucleotide reductase from Escherichia coli.
  • 2001
  • Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 276:29, s. 26852-26859
  • Tidskriftsartikel (refereegranskat)abstract
    • The enzyme activity of Escherichia coli ribonucleotide reductase requires the presence of a stable tyrosyl free radical and diiron center in its smaller R2 component. The iron/radical site is formed in a reconstitution reaction between ferrous iron and molecular oxygen in the protein. The reaction is known to proceed via a paramagnetic intermediate X, formally a Fe(III)-Fe(IV) state. We have used 9.6 GHz and 285 GHz EPR to investigate intermediates in the reconstitution reaction in the iron ligand mutant R2 E238A with or without azide, formate, or acetate present. Paramagnetic intermediates, i.e. a long-living X-like intermediate and a transient tyrosyl radical, were observed only with azide and under none of the other conditions. A crystal structure of the mutant protein R2 E238A/Y122F with a diferrous iron site complexed with azide was determined. Azide was found to be a bridging ligand and the absent Glu-238 ligand was compensated for by azide and an extra coordination from Glu-204. A general scheme for the reconstitution reaction is presented based on EPR and structure results. This indicates that tyrosyl radical generation requires a specific ligand coordination with 4-coordinate Fe1 and 6-coordinate Fe2 after oxygen binding to the diferrous site.
  • Bos, Isabelle, et al. (författare)
  • The frequency and influence of dementia risk factors in prodromal Alzheimer's disease
  • 2017
  • Ingår i: Neurobiology of Aging. - Elsevier. - 0197-4580. ; 56, s. 33-40
  • Tidskriftsartikel (refereegranskat)abstract
    • We investigated whether dementia risk factors were associated with prodromal Alzheimer's disease (AD) according to the International Working Group-2 and National Institute of Aging-Alzheimer's Association criteria, and with cognitive decline. A total of 1394 subjects with mild cognitive impairment from 14 different studies were classified according to these research criteria, based on cognitive performance and biomarkers. We compared the frequency of 10 risk factors between the subgroups, and used Cox-regression to examine the effect of risk factors on cognitive decline. Depression, obesity, and hypercholesterolemia occurred more often in individuals with low-AD-likelihood, compared with those with a high-AD-likelihood. Only alcohol use increased the risk of cognitive decline, regardless of AD pathology. These results suggest that traditional risk factors for AD are not associated with prodromal AD or with progression to dementia, among subjects with mild cognitive impairment. Future studies should validate these findings and determine whether risk factors might be of influence at an earlier stage (i.e., preclinical) of AD.
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