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- Alfredsson, Jessica, 1975-
(författare)
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Molecular Studies of Mast Cell Migration and Apoptosis : Two Ways of Regulating Mast Cell Numbers at Sites of Inflammation
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Upon activation mast cells release numerous proinflammatory mediators. With this feature, mast cells play an important role in host defense against pathogens, and are involved in tissue remodeling and wound healing. However, in cases of excessive inflammation the effects of mast cells are detrimental. This is observed in allergy, asthma, rheumatoid arthritis, atherosclerosis, certain types of heart failure, and in several other chronic destructive inflammations. Mast cell numbers are typically increased at inflammatory sites. There they act both directly, as effector cells, and in a regulatory manner, secreting agents that recruit and activate other immune cells.The studies presented here investigated mechanisms regulating mast cell numbers at sites of inflammation, focusing on cell migration and regulation of survival/apoptosis. We report that SCF-induced mast cell migration requires p38 MAP kinase activity. Moreover, we found that SCF-mediated mast cell survival is regulated through downregulation of the proapoptotic Bcl-2 family member Bim, as well as through phoshorylation of Bim. SCF seems to control Bim protein levels via FOXO transcription factors, and to induce phosphorylation of Bim via the Mek/Erk and the PI3-kinase/Akt signaling pathways. Furthermore, mast cell death triggered by deprivation of SCF and/or IL-3 involves the Bim protein, as demonstrated using bim-/- mast cells. Additional studies revealed that IgE-receptor activation, which occurs in allergy, promotes both prosurvival and proapoptotic signaling events. This includes upregulation of Bim and the prosurvival Bcl-XL and A1, as well as phosphorylation of Akt, FOXO factors, GSK-3β, IκB-α, Bad, and Bim. The simultaneous stimulation of prosurvival and proapoptotic signaling events could be a way to fine-tune the fate of mast cells after IgE-receptor activation and degranulation.The new insights about mechanisms involved in mast cell migration and regulation of survival/apoptosis might prove useful for future efforts to design new drugs to be used for mast cell-associated diseases.
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- Andersson, Urban, 1965, et al.
(författare)
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Projektet Forskningsdata inom humaniora och konstnärliga vetenskaper – open access? : slutrapport
- 2011
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Projektet syftar till att öka tillgängligheten av forskningsdata inom humaniora och konstnärliga vetenskaper. Efter en inledande kartläggning av vilka forskningsdata som finns vid våra respektive lärosäten kommer vi att försöka besvara nedanstående frågeställningar: Var och hur ska forskningsdata lagras? Vilka delar kan publiceras som open access? Hur bör koppling ske mellan öppna arkiv och Svensk Nationell datatjänst? Hur bör koppling ske mellan publikation och tillhörande forskningsdata?
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- Edstorp, Jessica, et al.
(författare)
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Incidence of lada and type 2 diabetes in relation to tobacco use and genetic susceptibility to type 2 diabetes and related traits : Findings from a swedish case-control study and the norwegian hunt study
- 2023
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 46:5, s. 1028-1036
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE Smoking and Swedish smokeless tobacco (snus) are associated with latent autoimmune diabetes in adults (LADA) and type 2 diabetes (T2D). Our aim was to investigate whether genetic susceptibility to T2D, insulin resistance (IR), and insulin secretion (IS) aggravate these associations. RESEARCH DESIGN AND METHODS We used data from two population-based Scandinavian studies with case subjects with LADA (n = 839) and T2D (n = 5,771), matched control subjects (n = 3,068), and 1,696,503 person-years at risk. Pooled, multivariate relative risks (RR) with 95% CI were estimated for smoking/genetic risk scores (T2D-GRS, IS-GRS, and IR-GRS), and ORs for snus or tobacco/GRS (case-control data). We estimated additive (proportion attributable to interaction [AP]) and multiplicative interaction between tobacco use and GRS. RESULTS The RR of LADA was elevated in high IR-GRS heavy smokers (‡15 pack-years; RR 2.01 [CI 1.30, 3.10]) and tobacco users (‡15 box/pack-years; RR 2.59 [CI 1.54, 4.35]) compared with low IR-GRS individuals without heavy use, with evidence of additive (AP 0.67 [CI 0.46, 0.89]; AP 0.52 [CI 0.21, 0.83]) and multiplicative (P = 0.003; P = 0.034) interaction. In heavy users, there was additive interaction between T2D-GRS and smoking, snus, and total tobacco use. The excess risk conferred by tobacco use did not differ across GRS categories in T2D. CONCLUSIONS Tobacco use may confer a higher risk of LADA in individuals with genetic susceptibility to T2D and insulin resistance, whereas genetic susceptibility does not seem to influence the increased T2D incidence associated with tobacco use.
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| 5. |
- Edstorp, Jessica, et al.
(författare)
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Smoking, use of smokeless tobacco, HLA genotypes and incidence of latent autoimmune diabetes in adults
- 2023
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 66, s. 70-81
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypotheses: Smoking and use of smokeless tobacco (snus) are associated with an increased risk of type 2 diabetes. We investigated whether smoking and snus use increase the risk of latent autoimmune diabetes in adults (LADA) and elucidated potential interaction with HLA high-risk genotypes. Methods: Analyses were based on Swedish case–control data (collected 2010–2019) with incident cases of LADA (n=593) and type 2 diabetes (n=2038), and 3036 controls, and Norwegian prospective data (collected 1984–2019) with incident cases of LADA (n=245) and type 2 diabetes (n=3726) during 1,696,503 person-years of follow-up. Pooled RRs with 95% CIs were estimated for smoking, and ORs for snus use (case–control data only). The interaction was assessed by attributable proportion (AP) due to interaction. A two-sample Mendelian randomisation (MR) study on smoking and LADA/type 2 diabetes was conducted based on summary statistics from genome-wide association studies. Results: Smoking (RRpooled 1.30 [95% CI 1.06, 1.59] for current vs never) and snus use (OR 1.97 [95% CI 1.20, 3.24] for ≥15 box-years vs never use) were associated with an increased risk of LADA. Corresponding estimates for type 2 diabetes were 1.38 (95% CI 1.28, 1.49) and 1.92 (95% CI 1.27, 2.90), respectively. There was interaction between smoking and HLA high-risk genotypes (AP 0.27 [95% CI 0.01, 0.53]) in relation to LADA. The positive association between smoking and LADA/type 2 diabetes was confirmed by the MR study. Conclusions/interpretation: Our findings suggest that tobacco use increases the risk of LADA and that smoking acts synergistically with genetic susceptibility in the promotion of LADA. Data availability: Analysis codes are shared through GitHub (https://github.com/jeseds/Smoking-use-of-smokeless-tobacco-HLA-genotypes-and-incidence-of-LADA). Graphical abstract: [Figure not available: see fulltext.]
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| 9. |
- Möller, Christine, et al.
(författare)
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Stem cell factor promotes mast cell survival via inactivation of FOXO3a-mediated transcriptional induction and MEK-regulated phosphorylation of the proapoptotic protein Bim
- 2005
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 106:4, s. 1330-1336
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Tidskriftsartikel (refereegranskat)abstract
- Mast cells are found in tissues throughout the body where they play important roles in the regulation of inflammatory responses. One characteristic feature of mast cells is their longevity. Although it is well established that mast cell survival is dependent on stem cell factor (SCF), it has not been described how this process is regulated. Herein, we report that SCF promotes mast cell survival through inactivation of the Forkhead transcription factor FOXO3a (forkhead box, class O3A) and down-regulation and phosphorylation of its target Bim (Bcl-2 [B-cell lymphoma-2] interacting modulator of cell death), a Bcl-2 homology 3 (BH3)-only proapoptotic protein. SCF induced a rapid and transient phosphorylation of Akt (protein kinase B) and FOXO3a. SCF treatment prevented up-regulation of Bim protein expression and led to increased Bim phosphorylation. Bim phosphorylation was inhibited by PD98059 and LY294002 treatment, suggesting the involvement of mitogen-activated protein kinase kinase/mitogen-activated protein kinase (MEKJMAPK) and phosphatidylinositol 3 (PI3)-kinase pathways in this process. Overexpression of phosphorylation-deficient FOXO3a caused an up-regulation of Bim and induced mast cell apoptosis even in the presence of SCF. Mast cell apoptosis induced by the phosphorylation-deficient FOXO3a was attenuated in bim(-/-) mast cells. Because apoptosis is abnormally reduced in bim(-/-) mast cells, these data provide evidence that Akt-mediated inhibition of FOXO3a and its transcription target Bim provides an important mechanism by which SCF acts to prevent apoptosis in mast cells.
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| 10. |
- Ollas, Patrik, et al.
(författare)
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Evaluating the role of solar photovoltaic and battery storage in supporting electric aviation and vehicle infrastructure at Visby Airport
- 2023
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Ingår i: Applied Energy. - : Elsevier. - 0306-2619 .- 1872-9118. ; 352
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Tidskriftsartikel (refereegranskat)abstract
- Following the societal electrification trend, airports face an inevitable transition of increased electric demand,driven by electric vehicles (EVs) and the potential rise of electric aviation (EA). For aviation, short-haul flightsare first in line for fuel exchange to electrified transportation. This work studies the airport of Visby, Sweden and the effect on the electrical power system from EA and EV charging. It uses the measured airport loaddemand from one year’s operation and simulated EA and EV charging profiles. Solar photovoltaic (PV) and electrical battery energy storage systems (BESS) are modelled to analyse the potential techno-economical gains.The BESS charge and discharge control are modelled in four ways, including a novel multi-objective (MO) dispatch to combine self-consumption (SC) enhancement and peak power shaving. Each model scenario iscompared for peak power shaving ability, SC rate and pay-back-period (PBP). The BESS controls are alsoevaluated for annual degradation and associated cost. The results show that the novel MO dispatch performswell for peak shaving and SC, effectively reducing the BESS’s idle periods. The MO dispatch also results in the battery controls’ lowest PBP (6.9 years) using the nominal economic parameters. Furthermore, a sensitivityanalysis for the PBP shows that the peak power tariff significantly influences the PBP for BESS investment.
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| 12. |
- Ullerås, Erik, et al.
(författare)
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NFAT but not NF-kappaB is critical for transcriptional induction of the prosurvival gene A1 after IgE receptor activation in mast cells.
- 2008
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 111:6, s. 3081-9
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Tidskriftsartikel (refereegranskat)abstract
- FcepsilonRI-activation-induced survival of mast cells is dependent on the expression and function of the prosurvival protein A1. The expression of A1 in lymphocytes and monocytes has previously been described to be transcriptionally regulated by NF-kappaB. Here we demonstrate that the expression of A1 in mast cells is not dependent on NF-kappaB but that NFAT plays a crucial role. FcepsilonRI-induced A1 expression was not affected in mast cells overexpressing an IkappaB-alpha super-repressor or cells lacking NF-kappaB subunits RelA, c-Rel, or c-Rel plus NF-kappaB1 p50. In contrast, inhibition of calcineurin and NFAT by cyclosporin A abrogated the expression of A1 in mast cells on FcepsilonRI-activation but had no effect on lipopolysaccharide-induced expression of A1 in J774A.1 monocytic cells. Cyclosporin A also inhibited luciferase expression in an A1 promoter reporter assay. A putative NFAT binding site in the A1 promoter showed inducible protein binding after FcepsilonRI crosslinking or treatment with ionomycin as detected in a band shift assay or chromatin immunoprecipitation. The binding protein was identified as NFAT1. Finally, mast cells expressing constitutively active NFAT1 exhibit increased expression of A1 after FcepsilonRI-stimulation. These results indicate that, in FcepsilonRI stimulated mast cells, A1 is transcriptionally regulated by NFAT1 but not by NF-kappaB.
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| 13. |
- Watson, Hunna J., et al.
(författare)
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Common Genetic Variation and Age of Onset of Anorexia Nervosa
- 2022
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Ingår i: BIOLOGICAL PSYCHIATRY: GLOBAL OPEN SCIENCE. - : Elsevier BV. - 2667-1743. ; 2:4, s. 368-378
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Genetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche.METHODS: A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (,13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses.RESULTS: Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism-h2) were 0.01-0.04 for age of onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early-and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early -onset AN.CONCLUSIONS: Our results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction.
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