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- de Rojas, I., et al.
(författare)
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).
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- Kato, S, et al.
(författare)
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Telomere Attrition and Elongation after Chronic Dialysis Initiation in Patients with End-Stage Renal Disease
- 2016
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Ingår i: Blood purification. - : S. Karger AG. - 1421-9735 .- 0253-5068. ; 41:1-3, s. 25-33
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Aims:</i></b> To analyze changes in telomere length (TL) after dialysis initiation. <b><i>Methods:</i></b> In 59 Japanese incident dialysis patients, associations between TL in peripheral blood leukocytes, inflammatory biomarkers and nutritional status at baseline and changes in TL during 1 year of dialysis, were investigated. <b><i>Results:</i></b> Whereas relative TL decreased by 8.6% (median 14.4%), TL elongation occurred in 16 patients (27%). Change in TL (ΔTL), defined as TL at 1 year minus TL at baseline, was associated with baseline TL (ρ = -0.70, p < 0.0001) and leukocyte count (ρ = 0.26, p = 0.044). In a logistic regression model, baseline TL (p < 0.0001) and leukocyte count (p = 0.047) were associated with ΔTL. <b><i>Conclusions:</i></b> TL shortening was observed in most incident dialysis patients. In 16 of the 59 patients, TL elongation occurred, possibly reflecting a more robust biological aging in patients whose naïve leukocytes may have undergone less proliferation to replace lost leukocytes.
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- Craven, H, et al.
(författare)
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Socioeconomic position links circulatory microbiota differences with biological age
- 2021
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1, s. 12629-
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Tidskriftsartikel (refereegranskat)abstract
- Imbalanced nutrition is associated with accelerated ageing, possibly mediated by microbiota. An analysis of the circulatory microbiota obtained from the leukocytes of participants in the MRC Twenty-07 general population cohort was performed. We now report that in this cohort, the most biologically aged exhibit a significantly higher abundance of circulatory pathogenic bacteria, including Neisseria, Rothia and Porphyromonas, while those less biologically aged possess more circulatory salutogenic (defined as being supportive of human health and wellbeing) bacteria, including Lactobacillus, Lachnospiraceae UCG-004 and Kocuria. The presence of these salutogenic bactreria is consistent with a capacity to metabolise and produce Nrf2 agonists. We also demonstrate that associated one carbon metabolism, notably betaine levels, did not vary with chronological age, but displayed a difference with socioeconomic position (SEP). Those at lower SEP possessed significantly lower betaine levels indicative of a poorer diet and poorer health span and consistent with reduced global DNA methylation levels in this group. Our data suggest a clear route to improving age related health and resilience based on dietary modulation of the microbiota.
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- Krishnamurthy, S, et al.
(författare)
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Soft-x-ray spectroscopic investigation of ferromagnetic Co-doped ZnO
- 2006
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Ingår i: Journal of Applied Physics. - : AIP Publishing. - 0021-8979 .- 1089-7550. ; 99:8
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Tidskriftsartikel (refereegranskat)abstract
- The electronic properties of cobalt-doped ZnO were investigated through site-selective and element-sensitive x-ray-absorption spectroscopy in the vicinity of the Co L-2,L-3 edge, the oxygen K edge, and at the Zn L-3 edge. The spectroscopic measurements of the ferromagnetic cobalt-doped ZnO films appear to have additional components in the O K edge x-ray-absorption spectrum not observed in the undoped films. The observed features may derive from both hybridization with unoccupied Co 3d states and also from lattice defects such as oxygen vacancies. Only minor changes in the Zn L-3 edge spectra were observed. These observations are consistent with a polaron percolation model in which the ferromagnetic coupling is mediated by shallow donor electrons trapped in oxygen vacancies and couples the Co atoms substituted on Zn sites in the hexagonal wurtzite ZnO structure.
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- Escott-Price, Valentina, et al.
(författare)
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Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. e94661-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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- Jones, Lesley, et al.
(författare)
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Convergent genetic and expression data implicate immunity in Alzheimer's disease
- 2015
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:6, s. 658-671
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Tidskriftsartikel (refereegranskat)abstract
- Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
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| 15. |
- Jung, M. J., et al.
(författare)
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The Influence of Orthopedic Surgery on Circulating Metabolite Levels, and Their Associations with the Incidence of Postoperative Delirium
- 2022
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Ingår i: Metabolites. - : MDPI AG. - 2218-1989. ; 12:7
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Tidskriftsartikel (refereegranskat)abstract
- The mechanisms underlying the occurrence of postoperative delirium development are unclear and measurement of plasma metabolites may improve understanding of its causes. Participants (n = 54) matched for age and gender were sampled from an observational cohort study investigating postoperative delirium. Participants were >= 65 years without a diagnosis of dementia and presented for primary elective hip or knee arthroplasty. Plasma samples collected pre- and postoperatively were grouped as either control (n = 26, aged: 75.8 +/- 5.2) or delirium (n = 28, aged: 76.2 +/- 5.7). Widespread changes in plasma metabolite levels occurred following surgery. The only metabolites significantly differing between corresponding control and delirium samples were ornithine and spermine. In delirium cases, ornithine was 17.6% higher preoperatively, and spermine was 12.0% higher postoperatively. Changes were not associated with various perioperative factors. In binary logistic regression modeling, these two metabolites did not confer a significantly increased risk of delirium. These findings support the hypothesis that disturbed polyamine metabolism is an underlying factor in delirium that warrants further investigation.
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- Pan, X. B., et al.
(författare)
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Cerebrospinal Fluid Spermidine, Glutamine and Putrescine Predict Postoperative Delirium Following Elective Orthopaedic Surgery
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Delirium is a marker of brain vulnerability, associated with increasing age, pre-existing cognitive impairment and, recently, cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease. This nested case-control study used a targeted quantitative metabolomic methodology to profile the preoperative CSF of patients (n = 54) who developed delirium following arthroplasty (n = 28) and those who did not (n = 26). The aim was to identify novel preoperative markers of delirium, and to assess potential correlations with clinical data. Participants without a diagnosis of dementia (>= 65 years) undergoing elective primary hip or knee arthroplasty were postoperatively assessed for delirium once-daily for three days. Groups were compared using multivariate, univariate and receiving operator characteristic (ROC) methods. Multivariate modelling using Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) of metabolomic data readily distinguished between delirium and control groups (R2 <= 0.56; Q2 <= 0.10). Three metabolites (spermidine, putrescine and glutamine) significantly differed between groups (P < 0.05; FDR < 0.07), and performed well as CSF biomarkers (ROC > 0.75). The biomarker performance of the two polyamines (spermidine/putrescine) was enhanced by ratio with CSF A beta 42 (ROC > 0.8), and spermidine significantly correlated with A beta 42 (pearson r = -0.32; P = 0.018). These findings suggest that spermidine and putrescine levels could be useful markers of postoperative delirium risk, particularly when combined with A beta 42, and this requires further investigation.
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| 20. |
- Simonov, K. A., et al.
(författare)
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Synthesis of armchair graphene nanoribbons from the 10,10′-dibromo-9,9′-bianthracene molecules on Ag(111) : The role of organometallic intermediates
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- We investigate the bottom-up growth of N = 7 armchair graphene nanoribbons (7-AGNRs) from the 10,10′-dibromo-9,9′-bianthracene (DBBA) molecules on Ag(111) with the focus on the role of the organometallic (OM) intermediates. It is demonstrated that DBBA molecules on Ag(111) are partially debrominated at room temperature and lose all bromine atoms at elevated temperatures. Similar to DBBA on Cu(111), debrominated molecules form OM chains on Ag(111). Nevertheless, in contrast with the Cu(111) substrate, formation of polyanthracene chains from OM intermediates via an Ullmann-type reaction is feasible on Ag(111). Cleavage of C-Ag bonds occurs before the thermal threshold for the surface-catalyzed activation of C-H bonds on Ag(111) is reached, while on Cu(111) activation of C-H bonds occurs in parallel with the cleavage of the stronger C-Cu bonds. Consequently, while OM intermediates obstruct the Ullmann reaction between DBBA molecules on the Cu(111) substrate, they are required for the formation of polyanthracene chains on Ag(111). If the Ullmann-type reaction on Ag(111) is inhibited, heating of the OM chains produces nanographenes instead. Heating of the polyanthracene chains produces 7-AGNRs, while heating of nanographenes causes the formation of the disordered structures with the possible admixture of short GNRs.
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