| 41. |
- Gkouskos, Dimitrios, 1983, et al.
(författare)
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Exploring User Experience in the Wild: Facets of the Modern Car
- 2015
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Ingår i: Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics). - Cham : Springer International Publishing. - 1611-3349 .- 0302-9743. - 9783319208893 - 9783319208886 ; 9188, s. 450-461
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Konferensbidrag (refereegranskat)abstract
- Experiential approaches to technology create opportunities for facilitating a wider range of in-car user experiences, however holistic knowledge regarding experiences that car users find enjoyable is lacking. We present the experience themes of the car as a caretaker, the car as a space for relatedness, the car as a space for stimulation, and the car as a space for transition, collected through a holistic study of 16 drivers, using contextual interviews, reflexive photography and the UX curve method. The use of the themes is exemplified through a design example. The experience themes can help designers empathize with users and create design solutions that can support positive in-car experiences, while the methodology used, serves as an example of how user’s experiences with technology can be studied.
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| 42. |
- Golden, Gregory J, et al.
(författare)
-
Endothelial Heparan Sulfate Mediates Hepatic Neutrophil Trafficking and Injury during Staphylococcus aureus Sepsis
- 2021
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Ingår i: mBio. - 2161-2129. ; 12:5
-
Tidskriftsartikel (refereegranskat)abstract
- Hepatic failure is an important risk factor for poor outcome in septic patients. Using a chemical tagging workflow and high-resolution mass spectrometry, we demonstrate that rapid proteome remodeling of the vascular surfaces precedes hepatic damage in a murine model of Staphylococcus aureus sepsis. These early changes include vascular deposition of neutrophil-derived proteins, shedding of vascular receptors, and altered levels of heparin/heparan sulfate-binding factors. Modification of endothelial heparan sulfate, a major component of the vascular glycocalyx, diminishes neutrophil trafficking to the liver and reduces hepatic coagulopathy and organ damage during the systemic inflammatory response to infection. Modifying endothelial heparan sulfate likewise reduces neutrophil trafficking in sterile hepatic injury, reflecting a more general role of heparan sulfate contribution to the modulation of leukocyte behavior during inflammation. IMPORTANCE Vascular glycocalyx remodeling is critical to sepsis pathology, but the glycocalyx components that contribute to this process remain poorly characterized. This article shows that during Staphylococcus aureus sepsis, the liver vascular glycocalyx undergoes dramatic changes in protein composition associated with neutrophilic activity and heparin/heparan sulfate binding, all before organ damage is detectable by standard circulating liver damage markers or histology. Targeted manipulation of endothelial heparan sulfate modulates S. aureus sepsis-induced hepatotoxicity by controlling the magnitude of neutrophilic infiltration into the liver in both nonsterile and sterile injury. These data identify an important vascular glycocalyx component that impacts hepatic failure during nonsterile and sterile injury.
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| 43. |
- Gorski, Mathias, et al.
(författare)
-
1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function.
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10(-8) previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.
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| 44. |
- Gusarova, Viktoria, et al.
(författare)
-
Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes
- 2018
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9, s. 1-11
-
Tidskriftsartikel (refereegranskat)abstract
- Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 × 10-10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49-0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D.
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| 45. |
- Heard-Costa, Nancy L, et al.
(författare)
-
NRXN3 is a novel locus for waist circumference : a genome-wide association study from the CHARGE Consortium
- 2009
-
Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 5:6, s. e1000539-
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Tidskriftsartikel (refereegranskat)abstract
- Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4×10−7)]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3×10−8 for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4×10−6, 0.024 z-score units (0.10 kg/m2) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07–1.19; p = 3.2×10−5 per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.
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| 46. |
- Hedenfalk, Ingrid, et al.
(författare)
-
Molecular classification of familial non-BRCA1/BRCA2 breast cancer
- 2003
-
Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 100:5, s. 2532-2537
-
Tidskriftsartikel (refereegranskat)abstract
- In the decade since their discovery, the two major breast cancer susceptibility genes BRCA1 and BRCA2, have been shown conclusively to be involved in a significant fraction of families segregating breast and ovarian cancer. However, it has become equally clear that a large proportion of families segregating breast cancer alone are not caused by mutations in BRCA1 or BRCA2. Unfortunately, despite intensive effort, the identification of additional breast cancer predisposition genes has so far been unsuccessful, presumably because of genetic heterogeneity, low penetrance, or recessive/polygenic mechanisms. These non-BRCA1/2 breast cancer families (termed BRCAx families) comprise a histopathologically heterogeneous group, further supporting their origin from multiple genetic events. Accordingly, the identification of a method to successfully subdivide BRCAx families into recognizable groups could be of considerable value to further genetic analysis. We have previously shown that global gene expression analysis can identify unique and distinct expression profiles in breast tumors from BRCA1 and BRCA2 mutation carriers. Here we show that gene expression profiling can discover novel classes among BRCAx tumors, and differentiate them from BRCA1 and BRCA2 tumors. Moreover, microarray-based comparative genomic hybridization (CGH) to cDNA arrays revealed specific somatic genetic alterations within the BRCAx subgroups. These findings illustrate that, when gene expression-based classifications are used, BRCAx families can be grouped into homogeneous subsets, thereby potentially increasing the power of conventional genetic analysis.
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| 47. |
- Herrera-Marschitz, M, et al.
(författare)
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On the origin of extracellular glutamate levels monitored in the basal ganglia of the rat by in vivo microdialysis
- 1996
-
Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 66:4, s. 1726-1735
-
Tidskriftsartikel (refereegranskat)abstract
- Several putative neurotransmitters and metabolites were monitored simultaneously in the extracellular space of neostriatum, substantia nigra, and cortex and in subcutaneous tissue of the rat by in vivo microdialysis. Glutamate (Glu) and aspartate (Asp) were at submicromolar and gamma-aminobutyric acid (GABA) was at nanomolar concentrations in all brain regions. The highest concentration of dopamine (DA) was in the neostriatum. Dynorphin B (Dyn B) was in the picomolar range in all brain regions. Although no GABA, DA, or Dyn B could be detected in subcutaneous tissue, Glu and Asp levels were 5 and approximately 5 and approximately 0.4 microM, respectively. Lactate and pyruvate concentrations were approximately 200 and approximately 10 microM in all regions. The following criteria were applied to ascertain the neuronal origin of substances quantified by microdialysis: sensitivity to (a) K+ depolarization, (b) Na+ channel blockade, (c) removal of extracellular Ca2+, and (d) depletion of presynaptic vesicles by local administration of alpha-latrotoxin. DA, Dyn B, and GABA largely satisfied all these criteria. In contrast, Glu and Asp levels were not greatly affected by K+ depolarization and were increased by perfusing with tetrodotoxin or with Ca2+-free medium, arguing against a neuronal origin. However, Glu and Asp, as well as DA and GABA, levels were decreased under both basal and K+-depolarizing conditions by alpha-latrotoxin. Because the effect of K+ depolarization on Glu and Asp could be masked by reuptake into nerve terminals and glial cells, the reuptake blocker dihydrokainic acid (DHKA) or L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) was included in the microdialysis perfusion medium. The effect of K+ depolarization on Glu and Asp levels was increased by DHKA, but GABA levels were also affected. In contrast, PDC increased only Glu levels. It is concluded that there is pool of releasable Glu and Asp in the rat brain. However, extracellular levels of amino acids monitored by in vivo microdialysis reflect the balance between neuronal release and reuptake into surrounding nerve terminals and glial elements.
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| 48. |
- Justice, Anne E., et al.
(författare)
-
Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution
- 2019
-
Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 452-469
-
Tidskriftsartikel (refereegranskat)abstract
- Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF >= 5%) and nine low-frequency or rare (MAF < 5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
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| 49. |
- Kaminski, Thomas, et al.
(författare)
-
Assessing the constraint of atmospheric CO2 and NO2 measurements from space on city-scale fossil fuel CO2 emissions in a data assimilation system
- 2022
-
Ingår i: Frontiers in Remote Sensing. - : Frontiers Media SA. - 2673-6187. ; 3
-
Tidskriftsartikel (refereegranskat)abstract
- The European Copernicus programme plans to install a constellation of multiple polar orbiting satellites (Copernicus Anthropogenic CO2 Monitoring Mission, CO2M mission) for observing atmospheric CO2 content with the aim to estimate fossil fuel CO2 emissions. We explore the impact of potential CO2M observations of column-averaged CO2 (XCO2), nitrogen dioxide (NO2), and aerosols in a 200 × 200 km2 domain around Berlin. For the quantification of anticipated XCO2 random and systematic errors we developed and applied new error parameterisation formulae based on artificial neural networks. For the interpretation of these data, we further established a CCFFDAS modelling chain from parameters of emission models to XCO2 and NO2 observations to simulate the 24 h periods preceeding simulated CO2M overpasses over the study area. For one overpass in winter and one in summer, we present a number of assessments of observation impact in terms of the posterior uncertainty in fossil fuel emissions on scales ranging from 2 to 200 km. This means the assessments include temporal and spatial scales typically not covered by inventories. The assessments differentiate the fossil fuel CO2 emissions into two sectors, an energy generation sector (power plants) and the complement, which we call “other sector.” We find that combined measurements of XCO2 and aerosols provide a powerful constraint on emissions from larger power plants; the uncertainty in fossil fuel emissions from the largest three power plants in the domain was reduced by 60%–90% after assimilating the observations. Likewise, these measurements achieve an uncertainty reduction for the other sector that increases when aggregated to larger spatial scales. When aggregated over Berlin the uncertainty reduction for the other sector varies between 28% and 48%. Our assessments show a considerable contribution of aerosol observations onboard CO2M to the constraint of the XCO2 measurements on emissions from all power plants and for the other sector on all spatial scales. NO2 measurements onboard CO2M provide a powerful additional constraint on the emissions from power plants and from the other sector. We further apply a Jacobian representation of the CCFFDAS modelling chain to decompose a simulated CO2 column in terms of spatial emission impact. This analysis reveals the complex structure of the footprint of an observed CO2 column, which indicates the limits of simple mass balances approaches for interpretation of such observations.
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| 50. |
- Kaminski, Thomas, et al.
(författare)
-
Assessing the Impact of Atmospheric CO2 and NO2 Measurements From Space on Estimating City-Scale Fossil Fuel CO2 Emissions in a Data Assimilation System
- 2022
-
Ingår i: Frontiers in Remote Sensing. - : Frontiers Media SA. - 2673-6187. ; 3
-
Tidskriftsartikel (refereegranskat)abstract
- The European Copernicus programme plans to install a constellation of multiple polar orbiting satellites (Copernicus Anthropogenic CO2 Monitoring Mission, CO2M mission) for observing atmospheric CO2 content with the aim to estimate fossil fuel CO2 emissions. We explore the impact of potential CO2M observations of column-averaged CO2 (XCO2), nitrogen dioxide (NO2), and aerosols in a 200 × 200 km2 domain around Berlin. For the quantification of anticipated XCO2 random and systematic errors we developed and applied new error parameterisation formulae based on artificial neural networks. For the interpretation of these data, we further established a CCFFDAS modelling chain from parameters of emission models to XCO2 and NO2 observations to simulate the 24 h periods preceeding simulated CO2M overpasses over the study area. For one overpass in winter and one in summer, we present a number of assessments of observation impact in terms of the posterior uncertainty in fossil fuel emissions on scales ranging from 2 to 200 km. This means the assessments include temporal and spatial scales typically not covered by inventories. The assessments differentiate the fossil fuel CO2 emissions into two sectors, an energy generation sector (power plants) and the complement, which we call “other sector.” We find that combined measurements of XCO2 and aerosols provide a powerful constraint on emissions from larger power plants; the uncertainty in fossil fuel emissions from the largest three power plants in the domain was reduced by 60%–90% after assimilating the observations. Likewise, these measurements achieve an uncertainty reduction for the other sector that increases when aggregated to larger spatial scales. When aggregated over Berlin the uncertainty reduction for the other sector varies between 28% and 48%. Our assessments show a considerable contribution of aerosol observations onboard CO2M to the constraint of the XCO2 measurements on emissions from all power plants and for the other sector on all spatial scales. NO2 measurements onboard CO2M provide a powerful additional constraint on the emissions from power plants and from the other sector. We further apply a Jacobian representation of the CCFFDAS modelling chain to decompose a simulated CO2 column in terms of spatial emission impact. This analysis reveals the complex structure of the footprint of an observed CO2 column, which indicates the limits of simple mass balances approaches for interpretation of such observations.
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