| 31. |
- Hicks, Andrew A., et al.
(författare)
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Genetic determinants of circulating sphingolipid concentrations in European populations
- 2009
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 5:10, s. e1000672-
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Tidskriftsartikel (refereegranskat)abstract
- Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingolipid metabolism are being associated with complex disease phenotypes. Direct experimental evidence supports a role of specific sphingolipid species in several common complex chronic disease processes including atherosclerotic plaque formation, myocardial infarction (MI), cardiomyopathy, pancreatic β-cell failure, insulin resistance, and type 2 diabetes mellitus. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, yet little is known about the major genetic variants that influence their circulating levels in the general population. We performed a genome-wide association study (GWAS) between 318,237 single-nucleotide polymorphisms (SNPs) and levels of circulating sphingomyelin (SM), dihydrosphingomyelin (Dih-SM), ceramide (Cer), and glucosylceramide (GluCer) single lipid species (33 traits); and 43 matched metabolite ratios measured in 4,400 subjects from five diverse European populations. Associated variants (32) in five genomic regions were identified with genome-wide significant corrected p-values ranging down to 9.08×10−66. The strongest associations were observed in or near 7 genes functionally involved in ceramide biosynthesis and trafficking: SPTLC3, LASS4, SGPP1, ATP10D, and FADS1–3. Variants in 3 loci (ATP10D, FADS3, and SPTLC3) associate with MI in a series of three German MI studies. An additional 70 variants across 23 candidate genes involved in sphingolipid-metabolizing pathways also demonstrate association (p = 10−4 or less). Circulating concentrations of several key components in sphingolipid metabolism are thus under strong genetic control, and variants in these loci can be tested for a role in the development of common cardiovascular, metabolic, neurological, and psychiatric diseases.
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| 32. |
- 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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| 33. |
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| 34. |
- Macovez, R., et al.
(författare)
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Electronic surface reconstruction and correlation in the fcc and dimer phases of RbC60
- 2007
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Ingår i: Physical Review B. Condensed Matter and Materials Physics. - 1098-0121 .- 1550-235X. ; 75:19, s. 195424-
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Tidskriftsartikel (refereegranskat)abstract
- A combined photoemission and x-ray absorption study of a RbC60 crystalline film is presented. We find evidence for an electronic charge reconstruction of the film surface in both the fcc and the dimer phases of RbC60. We confirm the previous conclusion on less crystalline films that the dimer phase is insulating. Several observations, such as the presence of molecular features in the photoemission spectra, indicate that at least partial electron localization occurs in the high-temperature fcc phase. In the fcc phase, the surface consists in a half-charge C60(111) plane and appears weakly metallic, as found for the bulk. In the dimer phase, the charge reconstruction simply implies the presence of neutral C60 in the surface layer. The identification of neutral molecules in the surface layer drastically improves the agreement between calculations of the electronic density of states and photoelectron spectra in both phases.
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| 35. |
- Meisl, Christina J., et al.
(författare)
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Nomograms including the UBC (R) Rapid test to detect primary bladder cancer based on a multicentre dataset
- 2022
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Ingår i: BJU International. - : John Wiley & Sons. - 1464-4096 .- 1464-410X. ; 130:6, s. 754-763
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To evaluate the clinical utility of the urinary bladder cancer antigen test UBC (R) Rapid for the diagnosis of bladder cancer (BC) and to develop and validate nomograms to identify patients at high risk of primary BC. Patients and Methods Data from 1787 patients from 13 participating centres, who were tested between 2012 and 2020, including 763 patients with BC, were analysed. Urine samples were analysed with the UBC (R) Rapid test. The nomograms were developed using data from 320 patients and externally validated using data from 274 patients. The diagnostic accuracy of the UBC (R) Rapid test was evaluated using receiver-operating characteristic curve analysis. Brier scores and calibration curves were chosen for the validation. Biopsy-proven BC was predicted using multivariate logistic regression. Results The sensitivity, specificity, and area under the curve for the UBC (R) Rapid test were 46.4%, 75.5% and 0.61 (95% confidence interval [CI] 0.58-0.64) for low-grade (LG) BC, and 70.5%, 75.5% and 0.73 (95% CI 0.70-0.76) for high-grade (HG) BC, respectively. Age, UBC (R) Rapid test results, smoking status and haematuria were identified as independent predictors of primary BC. After external validation, nomograms based on these predictors resulted in areas under the curve of 0.79 (95% CI 0.72-0.87) and 0.95 (95% CI: 0.92-0.98) for predicting LG-BC and HG-BC, respectively, showing excellent calibration associated with a higher net benefit than the UBC (R) Rapid test alone for low and medium risk levels in decision curve analysis. The R Shiny app allows the results to be explored interactively and can be accessed at www.blucab-index. net. Conclusion The UBC (R) Rapid test alone has limited clinical utility for predicting the presence of BC. However, its combined use with BC risk factors including age, smoking status and haematuria provides a fast, highly accurate and non-invasive tool for screening patients for primary LG-BC and especially primary HG-BC.
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| 36. |
- Reiter, W., et al.
(författare)
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Validation of regulated protein phosphorylation events in yeast by quantitative mass spectrometry analysis of purified proteins
- 2012
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Ingår i: Proteomics. - : Wiley. - 1615-9853. ; 12:19-20, s. 3030-3043
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Tidskriftsartikel (refereegranskat)abstract
- Global phosphoproteomic studies based on MS have generated qualitative and quantitative data describing protein phosphorylation events in various biological systems. Since high-throughput data for protein modifications are inherently incomplete, we developed a strategy to extend and validate such primary datasets. We selected interesting protein candidates from a global screen in yeast and employed a modified histidine biotin tag that allows tandem affinity purifications of our targets under denaturing conditions. Products in question can be digested directly from affinity resins and phosphopeptides can be further enriched via TiO2 before MS analysis. Our robust protocol can be amended for SILAC as well as iTRAQ quantifications or label-free approaches based on selective reaction monitoring, allowing completion of the phosphorylation pattern in a first step, followed by a detailed analysis of the phosphorylation kinetics. We exemplify the value of such a strategy by an in-depth analysis of Pan1, a highly phosphorylated factor involved in early steps of endocytosis. The study of Pan1 under osmotic stress conditions in different mutant backgrounds allowed us to differentiate between mitogen-activated protein kinase Hog1 driven and Hog1 independent stress responses.
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| 37. |
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