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Sökning: WFRF:(Scheele C)

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  • Davegardh, C., et al. (författare)
  • VPS39-deficiency observed in type 2 diabetes impairs muscle stem cell differentiation via altered autophagy and epigenetics
  • 2021
  • Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 12:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Insulin resistance and lower muscle quality (strength divided by mass) are hallmarks of type 2 diabetes (T2D). Here, we explore whether alterations in muscle stem cells (myoblasts) from individuals with T2D contribute to these phenotypes. We identify VPS39 as an important regulator of myoblast differentiation and muscle glucose uptake, and VPS39 is downregulated in myoblasts and myotubes from individuals with T2D. We discover a pathway connecting VPS39-deficiency in human myoblasts to impaired autophagy, abnormal epigenetic reprogramming, dysregulation of myogenic regulators, and perturbed differentiation. VPS39 knockdown in human myoblasts has profound effects on autophagic flux, insulin signaling, epigenetic enzymes, DNA methylation and expression of myogenic regulators, and gene sets related to the cell cycle, muscle structure and apoptosis. These data mimic what is observed in myoblasts from individuals with T2D. Furthermore, the muscle of Vps39(+/-) mice display reduced glucose uptake and altered expression of genes regulating autophagy, epigenetic programming, and myogenesis. Overall, VPS39-deficiency contributes to impaired muscle differentiation and reduced glucose uptake. VPS39 thereby offers a therapeutic target for T2D. Insulin resistance and lower muscle strength in relation to mass are hallmarks of type 2 diabetes. Here, the authors report alterations in muscle stem cells from individuals with type 2 diabetes that may contribute to these phenotypes through VPS39 mediated effects on autophagy and epigenetics.
  • Nilsson, E., et al. (författare)
  • Altered DNA Methylation and Differential Expression of Genes Influencing Metabolism and Inflammation in Adipose Tissue From Subjects With Type 2 Diabetes
  • 2014
  • Ingår i: Diabetes. - : American Diabetes Association Inc.. - 0012-1797 .- 1939-327X. ; 63:9, s. 2962-2976
  • Tidskriftsartikel (refereegranskat)abstract
    • Genetics, epigenetics, and environment may together affect the susceptibility for type 2 diabetes (T2D). Our aim was to dissect molecular mechanisms underlying T2D using genome-wide expression and DNA methylation data in adipose tissue from monozygotic twin pairs discordant for T2D and independent case-control cohorts. In adipose tissue from diabetic twins, we found decreased expression of genes involved in oxidative phosphorylation; carbohydrate, amino acid, and lipid metabolism; and increased expression of genes involved in inflammation and glycan degradation. The most differentially expressed genes included ELOVL6, GYS2, FADS1, SPP1 (OPN), CCL18, and IL1RN. We replicated these results in adipose tissue from an independent case-control cohort. Several candidate genes for obesity and T2D (e.g., IRS1 and VEGFA) were differentially expressed in discordant twins. We found a heritable contribution to the genome-wide DNA methylation variability in twins. Differences in methylation between monozygotic twin pairs discordant for T2D were subsequently modest. However, 15,627 sites, representing 7,046 genes including PPARG, KCNQ1, TCF7L2, and IRS1, showed differential DNA methylation in adipose tissue from unrelated subjects with T2D compared with control subjects. A total of 1,410 of these sites also showed differential DNA methylation in the twins discordant for T2D. For the differentially methylated sites, the heritability estimate was 0.28. We also identified copy number variants (CNVs) in monozygotic twin pairs discordant for T2D. Taken together, subjects with T2D exhibit multiple transcriptional and epigenetic changes in adipose tissue relevant to the development of the disease.
  • Timmons, James A., et al. (författare)
  • Using molecular classification to predict gains in maximal aerobic capacity following endurance exercise training in humans
  • 2010
  • Ingår i: Journal of applied physiology. - 8750-7587 .- 1522-1601. ; 108:6, s. 1487-1496
  • Tidskriftsartikel (refereegranskat)abstract
    • Timmons JA, Knudsen S, Rankinen T, Koch LG, Sarzynski M, Jensen T, Keller P, Scheele C, Vollaard NB, Nielsen S, Akerstrom T, MacDougald OA, Jansson E, Greenhaff PL, Tarnopolsky MA, van Loon LJ, Pedersen BK, Sundberg CJ, Wahlestedt C, Britton SL, Bouchard C. Using molecular classification to predict gains in maximal aerobic capacity following endurance exercise training in humans. J Appl Physiol 108: 1487-1496, 2010. First published February 4, 2010; doi:10.1152/japplphysiol.01295.2009.-A low maximal oxygen consumption ((V) over dotO(2max)) is a strong risk factor for premature mortality. Supervised endurance exercise training increases (V) over dotO(2max) with a very wide range of effectiveness in humans. Discovering the DNA variants that contribute to this heterogeneity typically requires substantial sample sizes. In the present study, we first use RNA expression profiling to produce a molecular classifier that predicts (V) over dotO(2max) training response. We then hypothesized that the classifier genes would harbor DNA variants that contributed to the heterogeneous (V) over dotO(2max) response. Two independent preintervention RNA expression data sets were generated (n = 41 gene chips) from subjects that underwent supervised endurance training: one identified and the second blindly validated an RNA expression signature that predicted change in (V) over dotO(2max) (""predictor"" genes). The HERITAGE Family Study (n = 473) was used for genotyping. We discovered a 29-RNA signature that predicted (V) over dotO(2max) training response on a continuous scale; these genes contained similar to 6 new single-nucleotide polymorphisms associated with gains in (V) over dotO(2max) in the HERITAGE Family Study. Three of four novel candidate genes from the HERITAGE Family Study were confirmed as RNA predictor genes (i.e., ""reciprocal"" RNA validation of a quantitative trait locus genotype), enhancing the performance of the 29-RNA-based predictor. Notably, RNA abundance for the predictor genes was unchanged by exercise training, supporting the idea that expression was preset by genetic variation. Regression analysis yielded a model where 11 single-nucleotide polymorphisms explained 23% of the variance in gains in (V) over dotO(2max), corresponding to similar to 50% of the estimated genetic variance for (V) over dotO(2max). In conclusion, combining RNA profiling with single-gene DNA marker association analysis yields a strongly validated molecular predictor with meaningful explanatory power. (V) over dotO(2max) responses to endurance training can be predicted by measuring a similar to 30-gene RNA expression signature in muscle prior to training. The general approach taken could accelerate the discovery of genetic biomarkers, sufficiently discrete for diagnostic purposes, for a range of physiological and pharmacological phenotypes in humans.
  • Bigert, Carolina, et al. (författare)
  • Myocardial infarction among professional drivers.
  • 2003
  • Ingår i: Epidemiology. - 1044-3983 .- 1531-5487. ; 14:3, s. 333-9
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Professional drivers are at an increased risk of myocardial infarction but the underlying causes for this increased risk are uncertain. METHODS: We identified all first events of myocardial infarction among men age 45-70 years in Stockholm County for 1992 and 1993. We selected controls randomly from the population. Response rates of 72% and 71% resulted in 1067 cases and 1482 controls, respectively. We obtained exposure information from questionnaires. We calculated odds ratios (ORs), with and without adjustment for socioeconomic status, tobacco smoking, alcohol drinking, physical inactivity at leisure time, overweight status, diabetes and hypertension. RESULTS: The crude OR among bus drivers was 2.14 (95% confidence interval = 1.34-3.41), among taxi drivers 1.88 (1.19-2.98) and among truck drivers 1.66 (1.22-2.26). Adjustment for potential confounders gave lower ORs: 1.49 (0.90-2.45), 1.34 (0.82-2.19) and 1.10 (0.79-1.53), respectively. Additional adjustment for job strain lowered the ORs only slightly. An exposure-response pattern (by duration of work) was found for bus and taxi drivers. CONCLUSIONS: The high risk among bus and taxi drivers was partly explained by unfavorable life-style factors and social factors. The work environment may contribute to their increased risk. Among truck drivers, individual risk factors seemed to explain most of the elevated risk.
  • Olofsson, Henrik, 1972, et al. (författare)
  • Odin water mapping in the Orion KL region
  • 2003
  • Ingår i: Astronomy and Astrophysics. - 0004-6361 .- 1432-0746. ; 402:3, s. L47-L54
  • Tidskriftsartikel (refereegranskat)abstract
    • New results from water mapping observations of the Orion KL region using the submm/mm wave satellite Odin (2.1′ beam size at 557 GHz), are presented. The ortho-H2O JK(+)K(-) = l1.0 → l0.1 ground state transition was observed in a 7′ × 7′ rectangular grid with a spacing of 1′, while the same line of H218O was measured in two positions, Orion KL itself and 2′ south of Orion KL. In the main water species, the KL molecular outflow is largely resolved from the ambient cloud and it is found to have an extension of 60″-110″. The H2O outflow profile exhibits a rather striking absorption-like asymmetry at the line centre. Self-absorption in the near (or "blue") part of the outflow (and possibly in foreground quiescent halo gas) is tentatively suggested to play a role here. We argue that the dominant part of the KL H218O outflow emission emanates from the compact (size ∼15″) low-velocity flow and here estimate an H2O abundance of circa 10-5 compared to all H2 in the flow - an order of magnitude below earlier estimates of the H2O abundance in the shocked gas of the high-velocity flow. The narrow ambient cloud lines show weak velocity trends, both in the N-S and E-W directions. H218O is detected for the first time in the southern position at a level of ∼0.15 K and we here estimate an H2O abundance of (1-8) × 10-8.
  • Väremo, Leif, et al. (författare)
  • Proteome- and Transcriptome-Driven Reconstruction of the Human Myocyte Metabolic Network and Its Use for Identification of Markers for Diabetes
  • 2015
  • Ingår i: Cell reports. - 2211-1247 .- 2211-1247. ; 11:6, s. 921-933
  • Tidskriftsartikel (refereegranskat)abstract
    • Skeletal myocytes are metabolically active and susceptible to insulin resistance and are thus implicated in type 2 diabetes (T2D). This complex disease involves systemic metabolic changes, and their elucidation at the systems level requires genome-wide data and biological networks. Genome-scale metabolic models (GEMs) provide a network context for the integration of high-throughput data. We generated myocyte-specific RNA-sequencing data and investigated their correlation with proteome data. These data were then used to reconstruct a comprehensive myocyte GEM. Next, we performed a meta-analysis of six studies comparing muscle transcription in T2D versus healthy subjects. Transcriptional changes were mapped on the myocyte GEM, revealing extensive transcriptional regulation in T2D, particularly around pyruvate oxidation, branched-chain amino acid catabolism, and tetrahydrofolate metabolism, connected through the downregulated dihydrolipoamide dehydrogenase. Strikingly, the gene signature underlying this metabolic regulation successfully classifies the disease state of individual samples, suggesting that regulation of these pathways is a ubiquitous feature of myocytes in response to T2D.
  • Gustavsson, P, et al. (författare)
  • A population-based case-referent study of myocardial infarction and occupational exposure to motor exhaust, other combustion products, organic solvents, lead, and dynamite. Stockholm Heart Epidemiology Program (SHEEP) Study Group.
  • 2001
  • Ingår i: Epidemiology. - 1044-3983 .- 1531-5487. ; 12:2, s. 222-8
  • Tidskriftsartikel (refereegranskat)abstract
    • This case-referent study investigated the risk of myocardial infarction from occupational exposure to motor exhaust, other combustion products, organic solvents, lead, and dynamite. We identified first-time, nonfatal myocardial infarctions among men and women 45-70 years of age in Stockholm County from 1992 through 1994. We selected referent subjects from the population to match the demographic characteristics of the cases. A lifetime history of occupations was obtained by questionnaire. The response rate was 81% for the cases and 74% for the referents, with 1,335 cases and 1,658 referents included in the study. An occupational hygienist assessed occupational exposures, coding the intensity and probability of exposure for each subject. We adjusted relative risk estimates for tobacco smoking, alcohol drinking, hypertension, diabetes mellitus, overweight, and physical inactivity at leisure time. The relative risk of myocardial infarction was 2.11 (95% confidence interval = 1.23-3.60) among those who were highly exposed and 1.42 (95% confidence interval = 1.05-1.92) among those who were intermediately exposed to combustion products from organic material. We observed an exposure-response pattern, in terms of both maximum exposure intensity and cumulative dose. Exposure to dynamite and organic solvents was possibly associated with an increased risk. The other exposures were not consistently associated with myocardial infarction.
  • Hjalmarson, Å., et al. (författare)
  • Highlights from the first year of Odin observations
  • 2003
  • Ingår i: Astronomy and Astrophysics. - 0004-6361 .- 1432-0746. ; 402, s. L39-L46
  • Tidskriftsartikel (refereegranskat)abstract
    • Key Odin operational and instrumental features and highlights from our sub-millimetre and millimetre wave observations of H2O, H218O, NH3, 15NH3 and O2 are presented, with some insights into accompanying Odin Letters in this A&A issue. We focus on new results where Odin's high angular resolution, high frequency resolution, large spectrometer bandwidths, high sensitivity or/and frequency tuning capability are crucial: H2O mapping of the Orion KL, W3, DR21, S140 regions, and four comets; H2O observations of Galactic Centre sources, of shock enhanced H2O towards the SNR IC443, and of the candidate infall source IRAS 16293-2422; H218O detections in Orion KL and in comet Ikeya-Zhang; sub-mm detections of NH3 in Orion KL (outflow, ambient cloud and bar) and ρ Oph, and very recently, of 15NH3 in~Orion KL. Simultaneous sensitive searches for the 119 GHz line of O2 have resulted in very low abundance limits, which are difficult to accomodate in chemical models. We also demonstrate, by means of a quantitative comparison of Orion KL H2O results, that the Odin and SWAS observational data sets are very consistently calibrated. Odin is a Swedish-led satellite project funded jointly by the Swedish National Space Board (SNSB), the Canadian Space Agency (CSA), the National Technology Agency of Finland (Tekes), and the Centre National d'études Spatiales (CNES, France). The Swedish Space Corporation (SSC) has been the prime industrial contractor, and is also responsible for the satellite operation from its Odin Mission Control Centre at SSC in Solna and its Odin Control Centre at ESRANGE near Kiruna in northern Sweden. See also the SNSB Odin web page: http://www.snsb.se/eng_odin_intro.shtml
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