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- Westerberg, Per-Anton, et al.
(författare)
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Variation in the klotho gene is not associated with mortality risk among elderly men in MR OS Sweden
- 2012
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 50:Suppl 1, s. S103-S104
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Polymorphisms in the Klotho (Kl) gene, which is central for vitamin D regulation by fibroblast growth factor 23 (FGF23), have been associated with longevity, coronary disease and stroke. The CC genotype of the single nucleotide polymorphism (SNP) rs577912 in the Kl-gene is associated with decreased Kl expression, as well as increased mortality in end stage renal disease. We examined if SNP in the Kl-gene was associated with mortality in the community derived cohort of 70 to 80 year old males of MrOS Sweden (N = 3014).High throughput genotyping of the KLOTHO SNPs was achieved by use of SequenomR MassEXTEND/Mass/ARRAY technology. 2738 subjects had a valid result for rs577912: CC 73.1% and CA + AA 26.9%. There were no differences in the serum levels of FGF23, phosphate, parathyroid hormone or renal function between genotypes CC and CA + AA. During a follow-up of a median of 4.5 years there were 337 deaths, 253 (12.6%) in the CC group and 84 (11.4%) in the CA + AA group. With log rank analysis there were no differences in mortality between the genotypes for all cause mortality (P = 0.39) or cardiovascular mortality (P = 0.60). None of the other SNPs in the Kl gene was associated with mortality in this cohort either.Conclusion:There is no association between the SNP rs577912 in the Kl-gene and mortality among elderly men.
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- Westerberg, C Möller, et al.
(författare)
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Proteasome inhibition upregulates Bim and induces caspase-3-dependent apoptosis in human mast cells expressing the Kit D816V mutation
- 2012
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Ingår i: Cell Death and Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 3, s. e417-
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Tidskriftsartikel (refereegranskat)abstract
- The majority of patients with systemic mastocytosis exhibit a D816V mutation in the activating loop of the Kit receptor expressed on mast cells. The Kit ligand regulates mast cell survival by transcriptional repression of the proapoptotic BH3-only protein Bim and by promoting Bim phosphorylation that makes it vulnerable for proteasomal-dependent degradation. We investigated here whether prevention of Bim degradation by a proteasomal inhibitor, MG132, would induce apoptosis in mast cells with the D816V mutation. Human umbilical cord blood-derived mast cells (CBMCs) with wild-type (wt) Kit and two different subclones of the human mast cell line-1 (HMC-1) were used for the study: HMC-1.1 with the V560G mutation in the juxtamembrane domain and HMC-1.2 carrying the V560G mutation together with the D816V mutation. MG132 at 1 μM induced apoptosis in all cell types, an effect accompanied by increased BH3-only proapoptotic protein Bim. The raise of Bim was accompanied by caspase-3 activation, and a caspase-3 inhibitor reduced MG132-induced apoptosis. Further, MG132 caused a reduction of activated Erk, a negative regulator of Bim expression, and thus Bim upregulation. We conclude that decreased phosphorylation and increased levels of Bim overcome the prosurvival effect of the D816V mutation and that the results warrant further investigations of the clinical effects of proteasomal inhibition in systemic mastocytosis.
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- Westerberg, Ida, et al.
(författare)
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Calibration of hydrological models using flow-duration curves
- 2011
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Ingår i: Hydrology and Earth System Sciences. - : Copernicus GmbH. - 1027-5606 .- 1607-7938. ; 15:7, s. 2205-2227
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Tidskriftsartikel (refereegranskat)abstract
- The degree of belief we have in predictions from hydrologic models will normally depend on how well they can reproduce observations. Calibrations with traditional performance measures, such as the Nash-Sutcliffe model efficiency, are challenged by problems including: (1) uncertain discharge data, (2) variable sensitivity of different performance measures to different flow magnitudes, (3) influence of unknown input/output errors and (4) inability to evaluate model performance when observation time periods for discharge and model input data do not overlap. This paper explores a calibration method using flow-duration curves (FDCs) to address these problems. The method focuses on reproducing the observed discharge frequency distribution rather than the exact hydrograph. It consists of applying limits of acceptability for selected evaluation points (EPs) on the observed uncertain FDC in the extended GLUE approach. Two ways of selecting the EPs were tested - based on equal intervals of discharge and of volume of water. The method was tested and compared to a calibration using the traditional model efficiency for the daily four-parameter WAS-MOD model in the Paso La Ceiba catchment in Honduras and for Dynamic TOPMODEL evaluated at an hourly time scale for the Brue catchment in Great Britain. The volume method of selecting EPs gave the best results in both catchments with better calibrated slow flow, recession and evaporation than the other criteria. Observed and simulated time series of uncertain discharges agreed better for this method both in calibration and prediction in both catchments. An advantage with the method is that the rejection criterion is based on an estimation of the uncertainty in discharge data and that the EPs of the FDC can be chosen to reflect the aims of the modelling application, e. g. using more/less EPs at high/low flows. While the method appears less sensitive to epistemic input/output errors than previous use of limits of acceptability applied directly to the time series of discharge, it still requires a reasonable representation of the distribution of inputs. Additional constraints might therefore be required in catchments subject to snow and where peak-flow timing at sub-daily time scales is of high importance. The results suggest that the calibration method can be useful when observation time periods for discharge and model input data do not overlap. The method could also be suitable for calibration to regional FDCs while taking uncertainties in the hydrological model and data into account.
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- Westerberg, LS, et al.
(författare)
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Activating WASP mutations associated with X-linked neutropenia result in enhanced actin polymerization, altered cytoskeletal responses, and genomic instability in lymphocytes
- 2010
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 207:6, s. 1145-1152
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Tidskriftsartikel (refereegranskat)abstract
- X-linked neutropenia (XLN) is caused by activating mutations in the Wiskott-Aldrich syndrome protein (WASP) that result in aberrant autoinhibition. Although patients with XLN appear to have only defects in myeloid lineages, we hypothesized that activating mutations of WASP are likely to affect the immune system more broadly. We generated mouse models to assess the role of activating WASP mutations associated with XLN (XLN-WASP) in lymphocytes. XLN-WASP is expressed stably in B and T cells and induces a marked increase in polymerized actin. XLN-WASP–expressing B and T cells migrate toward chemokines but fail to adhere normally. In marked contrast to WASP-deficient cells, XLN-WASP–expressing T cells proliferate normally in response to cell-surface receptor activation. However, XLN-WASP–expressing B cells fail to proliferate and secrete lower amounts of antibodies. Moreover, XLN-WASP expression in lymphocytes results in modestly increased apoptosis associated with increased genomic instability. These data indicate that there are unique requirements for the presence and activation status of WASP in B and T cells and that WASP-activating mutations interfere with lymphocyte cell survival and genomic stability.
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