| 1. |
- Folkersen, Lasse, et al.
(författare)
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Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease
- 2017
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Ingår i: PLOS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 13:4
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Tidskriftsartikel (refereegranskat)abstract
- Recent advances in highly multiplexed immunoassays have allowed systematic large-scale measurement of hundreds of plasma proteins in large cohort studies. In combination with genotyping, such studies offer the prospect to 1) identify mechanisms involved with regulation of protein expression in plasma, and 2) determine whether the plasma proteins are likely to be causally implicated in disease. We report here the results of genome-wide association (GWA) studies of 83 proteins considered relevant to cardiovascular disease (CVD), measured in 3,394 individuals with multiple CVD risk factors. We identified 79 genome-wide significant (p<5e-8) association signals, 55 of which replicated at P<0.0007 in separate validation studies (n = 2,639 individuals). Using automated text mining, manual curation, and network-based methods incorporating information on expression quantitative trait loci (eQTL), we propose plausible causal mechanisms for 25 trans-acting loci, including a potential post-translational regulation of stem cell factor by matrix metalloproteinase 9 and receptor-ligand pairs such as RANK-RANK ligand. Using public GWA study data, we further evaluate all 79 loci for their causal effect on coronary artery disease, and highlight several potentially causal associations. Overall, a majority of the plasma proteins studied showed evidence of regulation at the genetic level. Our results enable future studies of the causal architecture of human disease, which in turn should aid discovery of new drug targets.
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| 2. |
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| 3. |
- Backman, Helena, et al.
(författare)
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Lung function trajectories and associated mortality among adults with and without airway obstruction
- 2023
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - : American Thoracic Society. - 1073-449X .- 1535-4970. ; 208:10, s. 1063-1074
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Spirometry is essential for diagnosis and assessment of prognosis in COPD.Objectives: To identify FEV1 trajectories and their determinants, based on annual spirometry measurements among individuals with and without airway obstruction. Furthermore, to assess mortality in relation to trajectories.Methods: In 2002-04, individuals with airway obstruction (AO) (FEV1/VC<0.70, n=993) and age- and sex-matched non-obstructive (NO) referents were recruited from population-based cohorts. Annual spirometries until 2014 were utilized in joint-survival Latent Class Mixed Models to identify lung function trajectories. Mortality data were collected during 15 years of follow-up.Results: Three trajectories were identified among the AO-cases and two among the NO referents. Trajectory membership was driven by baseline FEV1%predicted (%pred) in both groups and additionaly, pack-years in AO and current smoking in NO. Longitudinal FEV1%pred level depended on baseline FEV1%pred, pack-years and obesity. The trajectories were distributed: 79.6% T1AO FEV1-high with normal decline, 12.8% T2AO FEV1-high with rapid decline, and 7.7% T3AO FEV1-low with normal decline (mean 27, 72 and 26 mL/year) among AO-individuals, and 96.7% T1NO FEV1-high with normal decline and 3.3% T2NO FEV1-high with rapid decline (mean 34 and 173 mL/year) among referents. Hazard for death was increased for T2AO (HR1.56) and T3AO (HR3.45) vs. T1AO, and for T2NO (HR2.99) vs. T1NO.Conclusions: Three different FEV1 trajectories were identified among those with airway obstruction and two among the referents, with different outcomes in terms of FEV1-decline and mortality. The FEV1 trajectories among airway obstructive and the relationship between low FVC and trajectory outcome are of particular clinical interest.
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| 4. |
- Björk, Göran, 1956, et al.
(författare)
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Flow of Canadian Basin Deep Water in the Western Eurasian Basin of the Arctic Ocean
- 2010
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Ingår i: Deep Sea Research. - : Elsevier BV. - 0967-0637 .- 1879-0119. ; 57:4, s. 577-586
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Tidskriftsartikel (refereegranskat)abstract
- The LOMROG 2007 expedition targeted the previously unexplored southern part of the Lomonosov Ridge north of Greenland together with a section from the Morris Jesup Rise to Gakkel Ridge. The oceanographic data shows that Canadian Basin Deep Water (CBDW) passes the Lomonosov Ridge in the area of the Intra Basin close to the North Pole and then continues along the ridge towards Greenland and further along its northernmost continental slope. The CBDW is clearly evident as a salinity maximum and oxygen minimum at a depth of about 2000 m. The cross slope sections at the Amundsen Basin side of the Lomonosov Ridge and further south at the Morris Jesup Rise show a sharp frontal structure higher up in the water column between Makarov Basin water and Amundsen Basin water. The frontal structure continues upward into the Atlantic Water up to a depth of about 300 m. The observed water mass division at levels well above the ridge crest indicates a strong topographic steering of the flow and that different water masses tend to pass the ridge guided by ridge-crossing isobaths at local topographic heights and depressions. A rough scaling analysis shows that the extremely steep and sharply turning bathymetry of the Morris Jesup Rise may force the boundary current to separate and generate deep eddies.
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| 5. |
- Boström, Martina, et al.
(författare)
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A role for endothelial cells in radiation-induced inflammation
- 2018
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Ingår i: International Journal of Radiation Biology. - : Informa UK Limited. - 0955-3002 .- 1362-3095. ; 94:3, s. 259-271
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To unravel the role of the vasculature in radiation-induced brain tissue damage.Materials and methods: Postnatal day 14 mice received a single dose of 10Gy cranial irradiation and were sacrificed 6h, 24h or 7 days post-irradiation. Endothelial cells were isolated from the hippocampus and cerebellum using fluorescence-activated cell sorting, followed by cell cycle analysis and gene expression profiling.Results: Flow cytometric analysis revealed that irradiation increased the percentage of endothelial cells, relative to the whole cell population in both the hippocampus and the cerebellum. This change in cell distribution indicates that other cell types are more susceptible to irradiation-induced cell death, compared to endothelial cells. This was supported by data showing that genes involved in endothelial cell-specific apoptosis (e.g. Smpd1) were not induced at any time point investigated but that genes involved in cell-cycle arrest (e.g. Cdkn1a) were upregulated at all investigated time points, indicating endothelial cell repair. Inflammation-related genes, on the other hand, were strongly induced, such as Ccl2, Ccl11 and Il6.Conclusions: We conclude that endothelial cells are relatively resistant to ionizing radiation but that they play an active, hitherto unknown, role in the inflammatory response after irradiation. In the current study, this was shown in both the hippocampus, where neurogenesis and extensive cell death after irradiation occurs, and in the cerebellum, where neurogenesis no longer occurs at this developmental age.
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| 6. |
- Eriksson, Anders, 1975, et al.
(författare)
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Direct Transmission Detection of Tunable Mechanical Resonance in an Individual Carbon Nanofiber Relay
- 2008
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Ingår i: Nano Letters. - : American Chemical Society (ACS). - 1530-6984 .- 1530-6992. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- A direct on-chip transmission measurement of the resonance frequency of an individual singly clamped carbon nanofiber relay is reported. The experimental results are in good agreement with a small signal model and show the expected tuning of the resonance frequency with changing bias voltage.
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| 7. |
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| 8. |
- Lagou, Vasiliki, et al.
(författare)
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Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
- 2021
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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| 10. |
- Lipcsey, Miklós, 1975-
(författare)
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Pathophysiological, Inflammatory and Haemostatic Responses to Various Endotoxaemic Patterns : An Experimental Study in the Pig
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Septic shock is frequently seen in intensive care units and is associated with significant mortality. Endotoxin – a major mediator of the pathophysiologic responses – is released during lysis of Gram-negative bacteria. These responses can be mimicked in the endotoxaemic pig. This thesis focuses on the following topics: the inflammatory and pathophysiological responses to various endotoxin doses and infusion patterns; covariations between endotoxin induced inflammatory and pathophysiological responses; whether the biological effects of endotoxin can be modulated by clopidogrel and whether tobramycin or ceftazidime reduce plasma cytokine levels. Endotoxin induced linear log-log cytokine and F2-isoprostane responses. Leukocyte and platelet responses, pulmonary compliance, circulatory variables as well as indicators of plasma leakage and hypoperfusion exhibited log-linear responses to the endotoxin dose. Biological responses to endotoxaemia such as inflammation, hypotension, hypoperfusion and organ dysfunction were more expressed when the organism was exposed to endotoxin at a higher rate. These results may facilitate the possibility to choose relevant endotoxin administration, when experiments are set up in order to evaluate certain responses to endotoxaemia. Correlation studies between cytokines, leukocytes, platelets and the endotoxin dose were in agreement with the well-known ability of endotoxin to induce cytokine expression and to activate both primary haemostasis and leukocytes. Free radical mediated lipid peroxidation and COX-mediated inflammation correlated to cytokine expression and organ dysfunction in endotoxaemic shock. Endotoxaemic pigs pretreated with clopidogrel, exhibited a trend towards less expressed deterioration of renal function, although blocking of ADP-induced primary haemostasis is not a key mediator of endotoxin induced deterioration of renal function. Tobramycin did not neutralise the biological effects of endotoxin or the plasma levels of endotoxin, suggesting that these antibiotics do not bind to endotoxin. Reduction in IL-6 was greater in pigs treated with ceftazidime and tobramycin as compared with those given saline, indicating a possible anti-inflammatory effect of both antibiotics.
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