| 1. |
- Ekoff, Maria, et al.
(författare)
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The BH3-only protein Puma plays an essential role in cytokine deprivation-induced apoptosis of mast cells
- 2007
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 110:9, s. 3209-3217
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Tidskriftsartikel (refereegranskat)abstract
- Mast cells play critical roles in the regulation of inflammation. One characteristic feature of mast cells is their relatively long lifespan in vivo. Members of the Bcl-2 protein family are regulators of cell survival and apoptosis, where the BH3-only proteins are critical proapoptotic proteins. In this study we investigated the role of the BH3-only proteins Noxa, Bad, Bim, Bmf, Bid, and Puma in apoptosis of mucosal-like mast cells (MLMCs) and connective tissue-like mast cells (CTLMCs). We demonstrate that Puma is critical for the induction of mast-cell death following cytokine deprivation and treatment with the DNA-damaging agent etoposide in MLMCs and CTLMCs. Using p53-/- mast cells, we found that cytokine deprivation-induced apoptosis, in contrast to that elicited by etoposide, is p53-independent. Interestingly, mast cells deficient in FOXO3a, previously proposed as a transcription factor for Puma induction in response to growth factor deprivation, were markedly resistant to cytokine withdrawal compared with wildtype cells. Moreover, overexpression of phosphorylation-deficient, constitutively active FOXO3a caused an up-regulation of Puma. In conclusion, our data demonstrate a pivotal role for Puma in the regulation of cytokine deprivation-induced mast-cell apoptosis and suggest a plausible role for Puma in the regulation of mast cell numbers in vivo. © 2007 by The American Society of Hematology.
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| 2. |
- Höglund, Andreas, 1980-, et al.
(författare)
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Myc sensitizes p53-deficient cancer cells to the DNA-damaging effects of the DNA methyltransferase inhibitor decitabine
- 2009
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Ingår i: Blood. - : The American Society of Hematology. - 0006-4971 .- 1528-0020. ; 113:18, s. 4281-4288
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Tidskriftsartikel (refereegranskat)abstract
- Decitabine (also referred to as 5-aza-2'-deoxycytidine) is a drug that has recently been approved by the Food and Drug Administration (FDA) for the treatment of myelodysplastic syndrome (MDS). The mechanism of action is believed to be the blocking of DNA methylation and thereby reactivating silenced genes involved in harnessing MDS. When analyzing reactivation of genes involved in Burkitt lymphoma (BL), we discovered that decitabine also sensitizes tumor cells by inducing DNA damage. This sensitization is grossly augmented by the MYC oncogene, which is overexpressed in BL, and occurs in cells lacking a functional p53 tumor suppressor pathway. In p53-deficient BL cells and p53(-/-) mouse embryo fibroblasts, Myc overrides a transient G2-block exerted by decitabine via activation of Chk1. This triggers aneuploidy and cell death that correlates with, but can occur in the absence of, Epstein-Barr virus (EBV) reactivation, caspase activation, and/or expression of the BH3-only protein Puma. In vivo modeling of Myc-induced lymphoma suggests that decitabine constitutes a potential new drug against lymphoma that would selectively sensitize tumor cells but spare normal tissue.
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| 3. |
- Mathsson, Linda, et al.
(författare)
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Cryoglobulin-induced cytokine production via FcgammaRIIa: inverse effects of complement blockade on the production of TNF-alpha and IL-10. Implications for the growth of malignant B-cell clones.
- 2005
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Ingår i: British Journal of Haematology. ; 129:6, s. 830-838
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Tidskriftsartikel (refereegranskat)abstract
- Monoclonal antibodies produced by patients with lymphoproliferative diseases sometimes appear as cryoglobulins (CG), immunoglobulins (Ig) that reversibly agglutinate and form immune complexes (IC) when cooled below normal body temperature or through variation in pH and ionic strength. In accordance with our findings of IC-induced cytokine production from peripheral blood mononuclear cells (PBMC) in systemic lupus erythematosus, we investigated whether CG can also induce cytokine production. One IgG and one IgM type I CG from two patients with multiple myeloma and Waldenstrom's macroglobulinaemia were individually purified and added to PBMC cultures. In separate experiments temperature and ionic strength were varied, or FcgammaRIIa, FcgammaRIII and complement activation were blocked; supernatant cytokine levels were then determined by enzyme-linked immunosorbent assay. CG-induced cytokine production from monocytes varied with precipitation induced by changes in temperature and ionic strength and was mediated via FcRIIa- and complement-dependent mechanisms. Complement blockade resulted in increased IgG CG-induced interleukin (IL)-10 production that was inversely correlated with decreased production of tumour necrosis factor-alpha. CG-induced IL-10 might be a growth factor for malignant B-lymphocytes in CG-associated lymphoproliferative diseases with constant complement consumption. Knowledge of mechanisms underlying CG-induced cytokine production can be useful for designing treatments for type I CG-associated pathology in lymphoproliferative diseases.
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| 4. |
- Nilsson, K. Peter R., et al.
(författare)
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Imaging distinct conformational states of amyloid-beta fibrils in Alzheimer's disease using novel luminescent probes
- 2007
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Ingår i: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 2:8, s. 553-560
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Tidskriftsartikel (refereegranskat)abstract
- Using luminescent conjugated polyelectrolyte probes (LCPs), we demonstrate the possibility to distinguish amyloid-β 1–42 peptide (Aβ1–42) fibril conformations, by analyzing in vitro generated amyloid fibrils of Aβ1–42 formed under quiescent and agitated conditions. LCPs were then shown to resolve such conformational heterogeneity of amyloid deposits in vivo. A diversity of amyloid deposits depending upon morphology and anatomic location was illustrated with LCPs in frozen ex vivo brain sections from a transgenic mouse model (tg-APP swe) of Alzheimer’s disease. Comparative LCP fluorescence showed that compact-core plaques of amyloid β precursor protein transgenic mice were composed of rigid dense amyloid. A more abundant form of amyloid plaque displayed morphology of a compact center with a protruding diffuse exterior. Surprisingly, the compact center of these plaques showed disordered conformations of the fibrils, and the exterior was composed of rigid amyloid protruding from the disordered center. This type of plaque appears to grow from more loosely assembled regions toward solidified amyloid tentacles. This work demonstrates how application of LCPs can prove helpful to monitor aggregate structure of in vivo formed amyloid deposits such as architecture, maturity, and origin.
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| 5. |
- Nilsson, Peter, et al.
(författare)
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Imaging distinct conformational states of amyloid-β fibrils in Alzheimer's disease using novel luminescent probes
- 2007
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Ingår i: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 2:8, s. 553-560
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Tidskriftsartikel (refereegranskat)abstract
- Using luminescent conjugated polyelectrolyte probes (LCPs), we demonstrate the possibility to distinguish amyloid-β 1-42 peptide (Aβ1-42) fibril conformations, by analyzing in vitro generated amyloid fibrils of Aβ1-42 formed under quiescent and agitated conditions. LCPs were then shown to resolve such conformational heterogeneity of amyloid deposits in vivo. A diversity of amyloid deposits depending upon morphology and anatomic location was illustrated with LCPs in frozen ex vivo brain sections from a transgenic mouse model (tg-APPswe) of Alzheimer's disease. Comparative LCP fluorescence showed that compact-core plaques of amyloid β precursor protein transgenic mice were composed of rigid dense amyloid. A more abundant form of amyloid plaque displayed morphology of a compact center with a protruding diffuse exterior. Surprisingly, the compact center of these plaques showed disordered conformations of the fibrils, and the exterior was composed of rigid amyloid protruding from the disordered center. This type of plaque appears to grow from more loosely assembled regions toward solidified amyloid tentacles. This work demonstrates how application of LCPs can prove helpful to monitor aggregate structure of in vivo formed amyloid deposits such as architecture, maturity, and origin.
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| 6. |
- Nord, Andreas, et al.
(författare)
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Patterns and dynamics of rest-phase hypothermia in wild and captive blue tits during winter.
- 2009
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Ingår i: Journal of Comparative Physiology B. - : Springer Science and Business Media LLC. - 0174-1578 .- 1432-136X. ; 179, s. 737-745
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated biotic and abiotic predictors of rest-phase hypothermia in wintering blue tits (Cyanistes caeruleus) and also assessed how food availability influences nightly thermoregulation. On any given night, captive blue tits (with unrestricted access to food) remained largely homeothermic, whereas free-ranging birds decreased their body temperature (T (b)) by about 5 degrees C. This was not an effect of increased stress in the aviary as we found no difference in circulating corticosterone between groups. Nocturnal T (b) in free-ranging birds varied with ambient temperature, date and time. Conversely, T (b) in captive birds could not be explained by climatic or temporal factors, but differed slightly between the sexes. We argue that the degree of hypothermia is controlled predominantly by birds' ability to obtain sufficient energy reserves during the day. However, environmental factors became increasingly important for thermoregulation when resources were limited. Moreover, as birds did not enter hypothermia in captivity when food was abundant, we suggest that this strategy has associated costs and hence is avoided whenever resource levels permit.
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| 7. |
- Puschmann, Andreas, et al.
(författare)
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A Swedish family with de novo alpha-synuclein A53T mutation: Evidence for early cortical dysfunction.
- 2009
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Ingår i: Parkinsonism & Related Disorders. - : Elsevier BV. - 1873-5126 .- 1353-8020. ; 15, s. 627-632
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Tidskriftsartikel (refereegranskat)abstract
- A de novo alpha-synuclein A53T (p.Ala53 Th; c.209G > A) mutation has been identified in a Swedish family with autosomal dominant Parkinson's disease (PD). Two affected individuals had early-onset (before 31 and 40 years), severe levodopa-responsive PD with prominent dysphasia, dysarthria, and cognitive decline. Longitudinal clinical follow-up, EEG, SPECT and CSF biomarker examinations suggested an underlying encephalopathy with cortical involvement. The mutated allele (c.209A) was present within a haplotype different from that shared among mutation carriers in the Italian (Contursi) and the Greek-American Family H kindreds. One unaffected family member carried the mutation haplotype without the c.209A mutation, strongly suggesting its de novo occurrence within this family. Furthermore, a novel mutation c.488G > A (p.Arg163His; R163H) in the presenilin-2 (PSEN2) gene was detected, but was not associated with disease state.
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| 8. |
- Agebro, Markus, et al.
(författare)
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Driver preferences of steering gear ratio and steering wheel effort : A driving simulator study
- 2006
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Ingår i: Proceedings of the FISITA World Automotive Congress, Yokohama, Japan 2006..
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Konferensbidrag (refereegranskat)abstract
- When driving an automobile, the driver has to correct the course as a result of road curvature and external disturbances. In order to make the vehicle both controllable and comfortable to drive, it is important that the steering system is designed with different drivers in mind. In this work, driver preferences of steering system characteristics is investigated by comparing standard steering wheel settings with unconventional steering gear ratio and steering wheel effort. The investigation is made using 18 test subjects in a moving base driving simulator. The evaluation includes two scenarios. In the first scenario the driver is overtaking a bus at 110 km/h when meeting traffic in the opposite lane. In the second scenario the driver is doing a manoeuvre by following a cone track at 55 km/h. To investigate if there are differences in preference of drivers with varying experience of driving, the drivers are chosen to either be low or high mileage drivers. People that drive less than 5,000 km/year are considered to be low mileage drivers, and people that drive more than 25,000 km/year are considered to be high mileage drivers. The results show that original settings of a typical passenger car, which served as reference, prove to display favourable characteristics compared to the unconventional settings investigated. However, there might be settings within the investigated intervals that can be considered superior. A distinct trend in the results is that increasing effort will lead to increased perceived stability, independent of ratio. High mileage drivers find the setting with low ratio and reference effort to possess better qualities than the reference when evaluating the attributes steering wheel force and response and only slightly less favourable properties than the reference when evaluating the attribute stability. High mileage drivers display a more distinct opinion and a higher sensitivity when evaluating the attributes. Despite the differing setup of the scenarios, many similarities can be observed when studying the results. Even though there are similarities in the results both between the scenarios and the categories of drivers, a study of the individual test subjects´ preferences reveal that several drivers prefer other settings than the reference for the investigated scenarios. Therefore, it is clear that the driver-vehicle system would benefit from tailoring the steering characteristics to the situation and driver.
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| 9. |
- Aidas, Kestutis, et al.
(författare)
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On the performance of quantum chemical methods to predict solvatochromic effects: The case of acrolein in aqueous solution.
- 2008
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Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 128:19, s. 1-194503
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Tidskriftsartikel (refereegranskat)abstract
- The performance of the Hartree-Fock method and the three density functionals B3LYP, PBE0, and CAM-B3LYP is compared to results based on the coupled cluster singles and doubles model in predictions of the solvatochromic effects on the vertical n-->pi(*) and pi-->pi(*) electronic excitation energies of acrolein. All electronic structure methods employed the same solvent model, which is based on the combined quantum mechanics/molecular mechanics approach together with a dynamical averaging scheme. In addition to the predicted solvatochromic effects, we have also performed spectroscopic UV measurements of acrolein in vapor phase and aqueous solution. The gas-to-aqueous solution shift of the n-->pi(*) excitation energy is well reproduced by using all density functional methods considered. However, the B3LYP and PBE0 functionals completely fail to describe the pi-->pi(*) electronic transition in solution, whereas the recent CAM-B3LYP functional performs well also in this case. The pi-->pi(*) excitation energy of acrolein in water solution is found to be very dependent on intermolecular induction and nonelectrostatic interactions. The computed excitation energies of acrolein in vacuum and solution compare well to experimental data.
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| 10. |
- Ask, Urban, 1956, et al.
(författare)
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IT Governance in the light of Paradox - A Social System Theory Perspective
- 2006
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Ingår i: The 40th Hawaii International Conference on System Sciences, 2007.
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Konferensbidrag (refereegranskat)abstract
- This paper uses Niclas Luhmann's concepts of paradox and deparadoxization as a starting point for looking at IT governance within large, Swedish organizations. All in all a total of 25 organizations within both the public and private sector have been investigated through interviews with the companies Chief Information Officers. The results are presented in relation to a number of areas within the study that could be identified as dichotomies, or areas where the respondents had to deal with conflicting logics. The results are discussed in general terms in relation to IT governance practice as well as the potential value of applying Luhmann's theory of social systems to the study of IT governance
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