| 1. |
- Ayesa, Susana, et al.
(author)
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Solid-phase parallel synthesis and SAR of 4-amidofuran-3-one inhibitors of cathepsin S : Effect of sulfonamides P3 substituents on potency and selectivity.
- 2009
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In: Bioorganic & Medicinal Chemistry. - : Elsevier. - 0968-0896 .- 1464-3391. ; 17:3, s. 1307-1324
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Journal article (peer-reviewed)abstract
- Highly potent and selective 4-amidofuran-3-one inhibitors of cathepsin S are described. The synthesis and structure–activity relationship of a series of inhibitors with a sulfonamide moiety in the P3 position is presented. Several members of the series show sub-nanomolar inhibition of the target enzyme as well as an excellent selectivity profile and good cellular potency. Molecular modeling of the most interesting inhibitors describes interactions in the extended S3 pocket and explains the observed selectivity towards cathepsin K.
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| 2. |
- Carlsson, Josefine, et al.
(author)
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Health risks from exposure to chemicals in clothing - non-regulated halogenated aromatic compounds
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Other publication (other academic/artistic)abstract
- The objective of the present study was to investigate some commonly detected halogenated textile pollutants for their hazardous properties and bioavailability. Release into artificial sweat and skin absorption in vitro were examined as well as mutagenic effects by Ames test, and skin-sensitizing properties from a peptide reactivity assay combined with a cell test.All investigated compounds were shown to migrate from the textile into sweat and be absorbed by skin, although to a different extent. The experimental values for migration were found to be up to 390 times higher compared to literature values. Two of the studied compounds, 2,5-dinitrochlorobenzene and 3,5-dinitrobromobenzene, both exhibited mutagenic effects in the Ames test, while both 2,5-dinitrochlorobenzene and 2,6-dichlorobenzene-1,4-diamine showed strong skin sensitization potencies, thus being classified as substances of UN GHS subcategory 1A.Risks for the induction of skin allergy and other non-carcinogenic effects from dermal exposure to the individual compounds were found low, even when considering clothing with the highest reported levels. However, the complex mixtures of chemicals often present in garments may still constitute a health risk, especially when considering the many hours of daily exposure. The toxicity of other frequently occurring chemicals as well as the chemical “cocktail” in textiles should be further investigated.
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| 3. |
- Demoulin, Jean-Baptiste, et al.
(author)
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Platelet-derived growth factor stimulates membrane lipid synthesis through activation of phosphatidylinositol 3-kinase and sterol regulatory element-binding proteins
- 2004
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In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 279:34, s. 35392-35402
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Journal article (peer-reviewed)abstract
- We analyzed the transcriptional program elicited by stimulation of normal human fibroblasts with platelet-derived growth factor (PDGF) using cDNA microarrays. 103 significantly regulated transcripts that had not been previously linked to PDGF signaling were identified. Among them, a cluster of genes involved in fatty acid and cholesterol biosynthesis, including stearoyl-CoA desaturase (SCD), fatty acid synthase, and hydroxymethylglutaryl-CoA synthase (HMGCS), was up-regulated by PDGF after 24 h of treatment, and their expression correlated with increased membrane lipid production. These genes are known to be controlled by sterol regulatory element-binding proteins (SREBP). PDGF increased the amount of mature SREBP-1 and regulated the promoters of SCD and HMGCS in an SREBP-dependent manner. In line with these results, blocking SREBP processing by addition of 25-hydroxycholesterol blunted the effects of PDGF on lipogenic enzymes. SREBP activation was dependent on the phosphatidylinositol 3-kinase (PI3K) pathway, as judged from the effects of the inhibitor LY294002 and mutation of the PDGFbeta receptor tyrosines that bind the PI3K adaptor subunit p85. Fibroblast growth factors (FGF-2 and FGF-4) and other growth factors mimicked the effects of PDGF on NIH3T3 and human fibroblasts. In conclusion, our results suggest that growth factors induce membrane lipid synthesis via the activation SREBP and PI3K.
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| 4. |
- Eidevåg, Tobias, 1987, et al.
(author)
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Angle of repose of snow: An experimental study on cohesive properties
- 2022
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In: Cold Regions Science and Technology. - : Elsevier BV. - 0165-232X .- 1872-7441. ; 194
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Journal article (peer-reviewed)abstract
- The angle of repose is a measure reflecting the internal friction and cohesion properties of a granular material. In this paper, we present an experimental setup and measurements for the angle of repose of snow for seven different snow samples over a large range of temperatures. The results show that the angle of repose is dependent on the fall height, the temperature, and the grain size of the snow. These variables are quantified, and their interdependencies are separately studied. With increased snow temperature, the angle of repose increases, and this can be explained by the presence of a liquid layer on ice that can be thermodynamically stable at temperatures below the melting point of water. With decreasing grain size the angle of repose also increases which is expected since the cohesive energy decreases more slowly than the grain mass. For increasing fall height, the snow grains generally accelerate to larger collisional velocities, yielding a smaller angle of repose. In general, the dimensionless cohesion number was found to largely reflect the dependencies of the variables and is therefore useful for understanding what affects the angle of repose. The results demonstrate that the drag force and collision dynamics of ice grains are important for understanding how snow accumulates on a surface, for example if one desires predicting snow accretion by simulating a dispersed cloud of snow. © 2021
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| 5. |
- Eidevåg, Tobias, 1987, et al.
(author)
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Snow Contamination of Simplified Automotive Bluff Bodies: A Comparison between Wind Tunnel Experiments and Numerical Modeling
- 2022
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In: SAE Technical Paper Series. - 400 Commonwealth Drive, Warrendale, PA, United States : SAE International. - 2641-9637 .- 0148-7191 .- 2688-3627.
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Conference paper (peer-reviewed)abstract
- We describe experiments and numerical modeling of snow surface contamination on two simplified automotive bluff bodies: The Ahmed body and a wedge. The purpose was twofold: 1) To obtain well defined experimental results of snow contamination on simple geometries; 2) To propose a numerical modeling approach for snow contamination. The experiments were performed in a climatic wind tunnel using a snow cannon at −15 °C and the results show that the snow accumulation depends on the aerodynamics of the studied bluff bodies. Snow accumulates on surfaces in proximity to the aerodynamic wakes of the bodies and characteristic snow patterns are obtained on side surfaces. The numerical modeling approach consisted of an aerodynamic setup coupled with Lagrangian particle tracking. Particles were determined to adhere or rebound depending on an adhesion model combined with a resuspension criterion. The adhesion model was based on adhesive-elastic contact theory and the resuspension criterion is derived from the balance between the aerodynamic forces acting on a particle and the critical force for onset of resuspension. The results show that the numerical method can predict certain characteristic snow patterns obtained from the experiments and we also highlight deviations obtained between experimental and simulation results. The simulation results show that the snow accumulation patterns on a bluff body will depend on the smallest ice particles in a snow sample which implies that samples with larger ice particle (for example natural snow) could produce different snow patterns than the fine machine-made snow used in this study.
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| 6. |
- Ekman, Simon, et al.
(author)
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SHP-2 is involved in heterodimer specific loss of phosphorylation of Tyr771 in the PDGF β-receptor
- 2002
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In: Oncogene. - : Nature Publishing Group. - 0950-9232 .- 1476-5594. ; 21:12, s. 1870-1875
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Journal article (peer-reviewed)abstract
- We have previously shown that the binding site for GTPase activating protein of Ras (RasGAP) in the PDGF beta-receptor, Tyr771, is phosphorylated to a much lower extent in the heterodimeric configuration of PDGF alpha- and beta-receptors, compared to the PDGF beta-receptor homodimer. The decreased recruitment of the RasGAP to the receptor leads to prolonged activation of the Ras/MAP kinase pathway, which could explain the increase in mitogenicity seen upon induction of heterodimers. The molecular mechanism underlying these differences was investigated. We could show that the loss of phosphorylation of Tyr771 was dependent on presence of intact binding sites for the protein tyrosine phosphatase SHP-2 on the PDGF beta-receptor. Thus, in PDGF receptor mutants in which binding of SHP-2 was lost, a higher degree of phosphorylation of Tyr771 was seen, while other phosphorylation sites in the receptor remained virtually unaffected. Thus, SHP-2 appears to play an important role in modulating phosphorylation of Y771, thereby controlling RasGAP recruitment and Ras/MAP kinase signaling in the heterodimeric configuration of the PDGF receptors.
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| 7. |
- Kallin, Anders, et al.
(author)
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Gab1 contributes to cytoskeletal reorganization and chemotaxis in response to platelet-derived growth factor
- 2004
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In: Journal of Biological Chemistry. - : The American Society for Biochemistry and Molecular Biology, Inc.. - 0021-9258 .- 1083-351X. ; 279:17, s. 17897-17904
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Journal article (peer-reviewed)abstract
- Gab1 is a scaffolding/docking protein that has been suggested to play a role in signal transduction downstream of certain plasma membrane receptors, including platelet-derived growth factor (PDGF) receptors. We found that PDGF induced a rapid Gab1 phosphorylation, which depended on the recruitment of Grb2, indicating that Grb2 acts as a bridge between Gab1 and the PDGF beta-receptor. PDGF also enhanced the binding of Gab1 to the phosphatase SHP-2, but not to p85. To further study the role of Gab1 in PDGF signaling, we transfected porcine aortic endothelial cells with a doxycycline-inducible Gab1 construct. Increased Gab1 expression enhanced the recruitment and activation of SHP-2, as well as the phosphorylation of the mitogen-activated protein kinases Erk and p38 by PDGF. Gab1 expression also enhanced the formation of lamellipodia and cellular protrusions. In Gab1-deficient mouse embryonic fibroblasts, the same phenotype was induced by restoring the expression of wild-type Gab1, but not a mutant Gab1 that was unable to associate with SHP-2. These effects of PDGF on the actin cytoskeleton were not altered by the inhibition of p38 or Erk, but could be blocked by a dominant-negative form of Rac (Asn(17)). Finally, Gab1-deficient fibroblasts showed a decreased chemotactic response toward gradients of PDGF as compared with wild-type cells. In conclusion, Gab1 plays a selective role in the regulation of the mitogen-activated protein kinases Erk and p38 downstream of the PDGF beta-receptor, and contributes to cytoskeletal reorganization and chemotaxis in response to PDGF.
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| 8. |
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| 9. |
- Kallin, Anders, et al.
(author)
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SREBP-1 regulates the expression of heme oxygenase 1 and the phosphatidylinositol-3 kinase regulatory subunit p55 gamma
- 2007
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In: Journal of Lipid Research. - 0022-2275 .- 1539-7262. ; 48:7, s. 1628-1636
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Journal article (peer-reviewed)abstract
- Sterol-regulatory element binding proteins (SREBPs) control the expression of genes involved in fatty acid and cholesterol biosynthesis. Using microarrays, we observed that mature SREBP-1 also induced the expression of genes unrelated to lipid metabolism, such as heme oxygenase 1 (HMOX1), plasma glutathione peroxidase, the phosphatidylinositol-3 kinase regulatory subunit p55 gamma, synaptic vesicle glycoprotein 2A, and COTE1. The expression of these genes was repressed upon addition of sterols, which block endogenous SREBP cleavage, and was induced by the statin drug mevinolin. Stimulation of fibroblasts with platelet-derived growth factor, which activates SREBP-1, had a similar effect. Fasted mice that were refed with a high-carbohydrate diet presented an increased expression of HMOX1 and p55 gamma in the liver. Overall, the transcriptional signature of SREBP-1 in fibroblasts stimulated by growth factors was very similar to that described in liver cells. We analyzed the HMOX1 promoter and found one SREBP binding site of the E-box type, which was required for regulation by SREBP-1a and SREBP-1c but was insensitive to SREBP-2. In conclusion, our data suggest that SREBP-1 regulates the expression of stress response and signaling genes, which could contribute to the metabolic response to insulin and growth factors in various tissues.
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| 10. |
- Kerzeli, Iliana K., et al.
(author)
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MALT1 inhibition suppresses antigen-specific T cell responses
- 2024
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In: Cellular Immunology. - : Elsevier. - 0008-8749 .- 1090-2163. ; 397
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Journal article (peer-reviewed)abstract
- The aim of this study was to assess the potential use of a selective small molecule MALT1 inhibitor in solid tumor treatment as an immunotherapy targeting regulatory T-cells (Tregs). In vitro, MALT1 inhibition suppressed the proteolytic cleavage of the MALT1-substrate HOIL1 and blocked IL-2 secretion in Jurkat cells. It selectively suppressed the proliferation of PBMC-derived Tregs, with no effect on conventional CD4+ T-cells. In vivo, however, no evident anti-tumor effect was achieved by MALT1 inhibition monotherapy or in combination with anti-CTLA4 in the MB49 cancer model. Despite decreased Treg-frequencies in lymph nodes of tumor-bearing animals, intratumoral Treg depletion was not observed. We also showed that MALT1-inhibition caused a reduction of antigen-specific CD8+ T-cells in an adoptive T-cell transfer model. Thus, selective targeting of Tregs would be required to improve the immunotherapeutic effect of MALT1-inhibition. Also, various dosing schedules and combination therapy strategies should be carefully designed and evaluated further.
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