64 research outputs found
UvA-DARE (Digital Academic Repository) HUMU 780 A Single Ser259Arg Mutation in the Gene for Lipoprotein Lipase Causes Chylomicronemia in Moroccans of Berber Ancestry
No full textA single Ser 259Arg mutation in the gene for lipoprotein lipase causes chylomicronemia in Moroccans of Berber ancestry Foubert, L.; Bruin, T.; de Gennes, J.L.; Ehrenborg, E.; Furioli, J.; Kastelein, J.J.P.; Benlian, P.; Hayden, M.R. Published in: Human Mutation Link to publication Citation for published version (APA): Foubert, L., Bruin, T., de Gennes, J. L., Ehrenborg, E., Furioli, J., Kastelein, J. J. P., ... Hayden, M. R. (1997). A single Ser 259Arg mutation in the gene for lipoprotein lipase causes chylomicronemia in Moroccans of Berber ancestry. Human Mutation, 10, 179-185. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible
Regulation of Skeletal Muscle Physiology and Metabolism by Peroxisome Proliferator-Activated Receptor δ
No full textAn ex vivo RT-qPCR-based assay for human peripheral leukocyte responsiveness to glucocorticoids in surgically induced inflammation
No full textTruls Gråberg,1 Lovisa Strömmer,1 Erik Hedman,2 Mehmet Uzunel,3 Ewa Ehrenborg,4 Ann-Charlotte Wikström5 1Division of Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, 2Department of Clinical Pharmacology, Karolinska University Hospital, 3Division of Therapeutic Immunology, Department of Laboratory Medicine, 4Atherosclerosis Research Unit, Department of Medicine, Solna, 5Unit of Translational Immunology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden Introduction: An assay to determine glucocorticoid (GC) responsiveness in humans could be used to monitor GC non-responsiveness in states of GC insufficiency and could provide a tool to adapt GC treatment to individual patients. We propose an ex vivo assay to test GC responsiveness in peripheral leukocytes. The assay was evaluated in a human experimental model of surgery-induced inflammation. Patients and methods: Changes in expression of the GC-regulated genes GILZ, IL1R2, FKBP5, and HLA-DR and glucocorticoid receptor alpha (GRα) were determined by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) in peripheral leukocytes from surgical patients and healthy blood donors (total n=60) in response to low (1 nM) and high (1 µM) dexamethasone (DEX). The final selection of a suitable endogenous control gene was based on the studies of stability during DEX treatment and inflammation. Correlations between pre- and postoperative GC-induced gene expression, the postoperative systemic inflammatory and metabolic response (CRP, IL-6, white blood cell count, cytokines, resistin, free fatty acids, glucose, insulin, and adiponectin), and the clinical outcome were analyzed. The length of stay in the intensive care unit (ICU-LOS), the length of stay in the hospital, and postoperative complications were used to measure clinical outcome. Results: When the blood donors were compared to the patients, there were no significant differences in the regulation of the genes in response to DEX, except for GRα. Preoperative, but not postoperative, gene regulation of GILZ and GRα was negatively correlated to ICU-LOS (P<0.05 and P<0.01, respectively). Preoperative GILZ and FKBP5 gene regulation was negatively correlated to postoperative systemic TNFα and MIP-1α levels. Conclusion: We suggest that this assay could be used to determine GC responsiveness. An alteration in preoperative GC responsiveness may be related to a patient's ability to recover from surgically induced inflammatory stress. Keywords: glucocorticoid responsiveness, gene regulation, clinical outcome, GILZ, GRα, cytokine
CXCL16 and CD137 in atherosclerosis [Elektronisk resurs]
No full textAtherosclerosis is a progressive inflammatory disease that is characterized by the accumulation of lipids, infiltrated cells and fibrous elements in large arteries. This thesis focuses on the molecular mechanisms behind foam cell formation and inflammation, two central processes in the development of atherosclerosis. More specific, we studied the effects of proinflammatory cytokines on CXCL16 expression and its role as scavenger receptor on macrophages and smooth muscle cells in atherogenesis. CXCL16 is defined as a chemokine and a scavenger receptor, regulating adhesion and chemoattraction of CXCR6 expressing cells and uptake of oxLDL. We show that the expression of CXCL16 and its receptor CXCR6 are more pronounced in human atherosclerotic lesions compared with non-atherosclerotic vessels. Increased expression of CXCL16 was also seen in atherosclerotic aortas of apoE-/- mice compared with aortas of non-atherosclerotic, age-matched C57BL/6 mice. In vitro, IFN gamma induced CXCL16 expression in primary human monocytes and smooth muscle cells which resulted in an increased uptake of oxLDL. Treatment of mice with IFN gamma also induced CXCL16 expression in atherosclerotic lesions. Thus, we have demonstrated a role for IFN gamma in foam cell formation through upregulation of CXCL16. The expression of CXCR6 was defined to the same regions as for CXCL16 in the lesion, indicating the presence of cells able to respond to CXCL16. Consequently, CXCL16 could serve as a molecular link between lipid metabolism and immune activity in atherosclerotic lesion. CD137 belongs to the TNF family and mediates several important processes in inflammation. CD137 is involved in the activation of T cells, NK cells, B cells and monocytes and regulate cytokine production, proliferation and apoptosis in these cells. A limited number of studies have demonstrated CD137 expression on smooth muscle cells and endothelial cells. Our results show that CD137 mRNA is higher expressed in human atherosclerotic lesions compared with unaffected vessels. We found that endothelial cells express CD137 in atherosclerotic lesions and that cultured endothelial cells and smooth muscle cells express CD137 and CD137 ligand in vitro. CD137 was regulated differentially by proinflammatory cytokines (i.e. IFN gamma, TNF alpha, IL-1 beta) and bacterial lipopolysaccharide depending on cell type. Furthermore, we investigated the effects of CD137 signalling, demonstrating that binding of the CD137 ligand to its receptor increases proliferation and migration of smooth muscle cells. In summary, this thesis has focused on the expression, regulation and role of CXCL16 and CD137, two genes that have not been described earlier in the concept of atherosclerosis. The findings demonstrate some of the molecular mechanisms involved in vascular inflammation and may increase our knowledge about the development of atherosclerosis.</p
The Poincaré-extended ab-index
No full textMotivated by a conjecture concerning Igusa local zeta functions for intersection posets of hyperplane arrangements, we introduce and study the Poincaré-extended ab-index, which generalizes both the ab-index and the Poincaré polynomial. For posets admitting R-labelings, we give a combinatorial description of the coefficients of the extended ab-index, proving their nonnegativity. In the case of intersection posets of hyperplane arrangements, we prove the above conjecture of the second author and Voll as well as another conjecture of the second author and Kühne. We also define the pullback ab-index generalizing the cd-index of face posets for oriented matroids. Our results recover, generalize and unify results from Billera-Ehrenborg-Readdy, Bergeron-Mykytiuk-Sottile-van Willigenburg, Saliola-Thomas, and Ehrenborg. This connection allows us to translate our results into the language of quasisymmetric functions, and-in the special case of symmetric functions-make a conjecture about Schur positivity. A proof of this conjecture now appears an appendix by Ricky Ini Liu.v5: incorporated referee feedback, version to appear in JLMS; v4: Added an appendix from Ricky Ini Liu with a proof of Conjecture 3.
The Poincaré-extended -index
No full textMotivated by a conjecture concerning Igusa local zeta functions for intersection posets of hyperplane arrangements, we introduce and study the Poincaré-extended -index, which generalizes both the -index and the Poincaré polynomial. For posets admitting -labelings, we give a combinatorial description of the coefficients of the extended -index, proving their nonnegativity. In the case of intersection posets of hyperplane arrangements, we prove the above conjecture of the second author and Voll as well as another conjecture of the second author and Kühne. We also define the pullback -index, generalizing the -index of face posets for oriented matroids. Our results recover, generalize, and unify results from Billera–Ehrenborg–Readdy, Bergeron–Mykytiuk–Sottile–van Willigenburg, Saliola– Thomas, and Ehrenborg. This connection allows us to translate our results into the language of quasisymmetric functions, and — in the special case of symmetric functions — pose a conjecture about Schur positivity. This conjecture was strengthened and proved by Ricky Liu, and the proof appears as an appendix.This work is supported by DFG Heisenberg grant STU 563/{4-6}-1 “Noncrossing phenomena in Algebra and Geometry” (Galen Dorpalen-Barry, Christian Stump) and by DFG-GRK 2297 “Mathematical Complexity Reduction” (Joshua Maglione).
Open access funding provided by IReL.peer-reviewe
Genetic association studies of symptoms, comorbidity and outcome in bipolar disorder and schizophrenia
No full textSchizophrenia and bipolar disorder are complex brain disorders. Research has focused on applying brain research to understand the etiology, as well as clinical research to improve treatment, prognosis and progression. Schizophrenia and bipolar disorder are not lethal in and of themselves, but suicide and the presence of associated physical illnesses are of great concern, since these are the major causes of shortened life in afflicted individuals. In particular, the prevalence of type 2 diabetes and cardiovascular disease are twice as great in schizophrenia and bipolar disorder. By shifting the focus to underlying, sometimes comorbid causes, it is possible to increase knowledge of morbidity and mortality in cardiovascular disease, and thus improve the prognosis and progression for individuals with schizophrenia and bipolar disorder. Another interesting strategy for better understanding such complex disorders is to limit examination to symptoms in order to distinguish the genetics of the symptoms from the disorder itself. Genetic association studies are often used to investigate complex disease. The aim of this thesis was to investigate genetic associations between gene variants and metabolic risk factors in schizophrenia and bipolar disorder patients. An additional aim was to investigate known psychiatric risk genes in the dopamine system and their association to cognitive function.In Study I, D-amino acid oxidase activator gene (DAOA) and catechol-O-methyltransferase gene (COMT) were analyzed for allelic association to cognitive dysfunction in bipolar disorder patients. In Studies II-V, common metabolic risk gene variants were analyzed for allelic association to metabolic risk factors in schizophrenia and bipolar disorder patients, and to disorders per se. In Study VI, metabolic risk variants were analyzed for possible association to high-sensitive troponin T levels, which is a sensitive biomarker of cardiovascular damage in patients with acute coronary syndrome.In study I, single nucleotide polymorphisms in D-amino acid oxidase activator gene (DAOA) and catechol-O-methyltransferase gene (COMT) were associated to cognitive dysfunction in bipolar disorder patients. Data also suggest interaction between these genes. In studies II-V, single nucleotide polymorphisms in common metabolic risk genes: insulin-like growth factor II mRNA binding protein 2 (IGF2BP2), neurogenic locus notch homolog 2 (NOTCH2), thyroid adenoma associated (THADA), wolfram syndrome 1 (WFS1), purinergic receptor P2X, ligand-gated ion channel, 7 (P2RX7), and melatonin receptor 1B (MTNR1B) were associated with increased fasting plasma glucose in schizophrenia. Peroxisome proliferatoractivated receptor delta gene (PPARD) was associated with schizophrenia independent of glucose levels. Single nucleotide polymorphisms in common metabolic risk genes: calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2), melanoma inhibitory activity family, member 3 (MIA3), purinergic receptor P2X, ligand-gated ion channel, 7 gene (P2RX7), muscle RAS oncogene homolog gene (MRAS), SMAD family member 3 gene (SMAD3), peroxisome proliferator-activated receptor delta gene (PPARD), melatonin receptor 1B gene (MTNR1B), neurogenic locus notch homolog 2 gene (NOTCH2), HNF1 homeobox B gene (HNF1B) were associated with increased waist circumference in schizophrenia patients. Peroxisome proliferator-activated receptor delta gene (PPARD), melatonin receptor 1B gene (MTNR1B), neurogenic locus notch homolog 2 gene (NOTCH2), and homeobox B gene (HNF1B) were associated with schizophrenia irrespective of waist circumference. A genetic overlap between schizophrenia and bipolar disorder was identified through an association between melatonin receptor 1B gene (MTNR1B) and increased fasting plasma glucose also in bipolar disorder patients. Neurogenic locus notch homolog 2 gene (NOTCH2) was associated to bipolar disorder per se. In study VI, melatonin receptor 1B gene (MTNR1B) and neurogenic locus notch homolog 2 gene (NOTCH2) were associated with high-sensitive troponin T levels in schizophrenia women.Our genetic findings regarding D-amino acid oxidase activator gene (DAOA) and catecholO-methyltransferase gene (COMT) are in line with the dopamine hypothesis of cognitive function. Single nucleotide polymorphisms that increase metabolic risk in the general population are associated with elevated plasma glucose and increased waist circumference among schizophrenia and bipolar disorder patients, as well as with schizophrenia and bipolar disorder per se. The melatonin receptor 1B gene (MTNR1B) –dependent vulnerability for elevated fasting plasma glucose levels is evident in both schizophrenia and bipolar disorder. Neurogenic locus notch homolog 2 gene (NOTCH2) is associated to both to schizophrenia and bipolar disorder type 1 per se. These findings may reflect increased metabolic genetic vulnerability in schizophrenia and bipolar disorder patients, as well as common genetics between type 2 diabetes mellitus and these psychiatric disorders. In addition, in women with schizophrenia, there is a possible metabolic genetic component affecting high-sensitive troponin T levels, a biomarker for cardiovascular damage in individuals with acute coronary syndrome (chest pain).List of scientific papersI. Dzana Sudic Hukic, Louise Frisén, Lena Backlund, Catharina Lavebratt, Mikael Landén, Lil Träskman-Bendz, Gunnar Edman, Martin Schalling, Urban Ösby. Cognitive manic symptoms in bipolar disorder associated with polymorphisms in the DAOA and COMT genes. PLos One 2013 Jul 5;8(7):e67450. https://doi.org/10.1371/journal.pone.0067450 II. Dzana Sudic Hukic, Eric Olsson, Agneta Hildnig, Claes-Göran Östensson, Harvest F Gu, Ewa Ehrenborg, David Erlinge, Gunnar Edman, Martin Schalling, Catharina Lavebratt, and Urban Ösby. Genes associated with increased fasting glucose in patients with schizophrenia spectrum disorders. J. Diabetes Metabolism 2015, 6(3):1000512. https://doi.org/10.4172/2155-6156.1000512III. Dzana Sudic Hukic, Catharina Lavebratt, Louise Frisén, Lena Backlund, Agneta Hilding, Claes-Göran Östenson, David Erlinge, Ewa Ehrenborg, Martin Schalling, Urban Ösby. Melatonin receptor 1B gene associated with increased fasting glucose in bipolar disorder. Psychiatric Genetics 2016, 00:000–000. https://doi.org/10.1097/YPG.0000000000000131 IV. Dzana Sudic Hukic, Urban Ösby, Eric Olsson, Agneta Hilding, Claes-Göran Östensson, Harvest F Gu, Ewa Ehrenborg, Gunnar Edman, Martin Schalling, Catharina Lavebratt, Louise Frisén. Genetic variants of increased waist circumference in psychosis. [Manuscript]V. Dzana Sudic Hukic, Catharina Lavebratt, Louise Frisén, Lena Backlund, Agneta Hilding, Harvest F Gu, Claes-Göran Östensson, David Erlinge, Ewa Ehrenborg, Martin Schalling, Urban Ösby. NOTCH2 associated with bipolar disorder. [Manuscript]VI. Dzana Sudic Hukic, Catharina Lavebratt, Eric Olsson, Claes-Göran Östensson, Sven V. Eriksson, David Erlinge, Martin Schalling, Urban Ösby.Troponin T levels associated with genetic variants in NOTCH2 and MTNR1B in women with schizophrenia. [Manuscript]</p
Alternative splicing of human peroxisome proliferator-activated receptor delta (PPARdelta):effects on translation efficiency and trans-activation ability
No full textMicroRNA 486-3P as a stability marker in acute coronary syndrome
No full textEasily accessible biomarkers are needed to diagnose cardiovascular disease precisely-particularly, to distinguish between disease subtypes that are encountered in clinical practice. Per the hypothesis that plasma miRNA is valuable for this purpose, we performed complete transcriptional profiling of an miRNA discovery-set in 14 samples: three patients with ST-elevated acute myocardial infarction (STEMI) at baseline and after three months of follow-up, four with stable ischaemic heart disease (stable-IHD) and four healthy age-matched volunteers. Our aim was to determine whether we could distinguish patients with unstable plaques from stable patients following a STEMI event. After analysing miRNA profiles, we conducted a validation study comparing three-month STEMI (n=40) with stable-IHD (n=35), which confirmed that miR-486-3P differentiates patients with three-month STEMI from those with stable-IHD (P=0.019)
European Lipoprotein Club:Report of the 35th ELC Annual Conference (Tutzing, 10th-13th September 2012)
No full text- …
