| 1. |
- Ayesa, Susana, et al.
(författare)
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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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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier. - 0968-0896 .- 1464-3391. ; 17:3, s. 1307-1324
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Tidskriftsartikel (refereegranskat)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.
(författare)
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Health risks from exposure to chemicals in clothing - non-regulated halogenated aromatic compounds
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Annan publikation (övrigt vetenskapligt/konstnärligt)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.
(författare)
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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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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 279:34, s. 35392-35402
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Tidskriftsartikel (refereegranskat)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.
(författare)
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Angle of repose of snow: An experimental study on cohesive properties
- 2022
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Ingår i: Cold Regions Science and Technology. - : Elsevier BV. - 0165-232X .- 1872-7441. ; 194
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Tidskriftsartikel (refereegranskat)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.
(författare)
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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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Ingår i: SAE Technical Paper Series. - 400 Commonwealth Drive, Warrendale, PA, United States : SAE International. - 2641-9637 .- 0148-7191 .- 2688-3627.
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Konferensbidrag (refereegranskat)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.
(författare)
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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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Ingår i: Oncogene. - : Nature Publishing Group. - 0950-9232 .- 1476-5594. ; 21:12, s. 1870-1875
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Tidskriftsartikel (refereegranskat)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.
(författare)
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Gab1 contributes to cytoskeletal reorganization and chemotaxis in response to platelet-derived growth factor
- 2004
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Ingår i: 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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Tidskriftsartikel (refereegranskat)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.
(författare)
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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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Ingår i: Journal of Lipid Research. - 0022-2275 .- 1539-7262. ; 48:7, s. 1628-1636
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Tidskriftsartikel (refereegranskat)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.
(författare)
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MALT1 inhibition suppresses antigen-specific T cell responses
- 2024
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Ingår i: Cellular Immunology. - : Elsevier. - 0008-8749 .- 1090-2163. ; 397
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Tidskriftsartikel (refereegranskat)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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| 11. |
- Kerzeli, Iliana Kyriaki, et al.
(författare)
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MALT1 inhibition suppresses T-cell dependent immune surveillance
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- MALT1 supports the development of natural regulatory T cells (Tregs), while protease-dead MALT1 (MALT1-PD) mice develop autoimmunity and an intrinsic capacity to reject syngeneic tumor transplantation. Herein, a small molecule inhibitor targeting MALT1 was developed and evaluated for potential use in Treg inhibition as part of a cancer immunotherapy strategy.In vitro, MALT1 inhibitor treatment inhibited the proteolytic cleavage of the MALT1 substrate HOIL1 in Jurkat cells and blocked IL-2 secretion by immune cells. Moreover, orally administrated MV088428 inhibited anti-CD3 induced IL-2 release in vivo. In vitro MALT1 inhibition selectively suppressed the proliferation of PBMC derived CD25+ FoxP3+ CD4+ T cells, while no direct effect was noted on the proliferation and viability of CD25- CD4+ T cells. In vivo, no evident anti-tumor effect as a monotherapy in the MB49 bladder cancer model was achieved and despite selective decrease of Treg frequencies in lymph nodes of tumor bearing animals, intratumoral Treg depletion was not observed. No synergistic anti-tumor effects were noted when MALT1 inhibitor was combined with anti-PD1 therapy, and concomitant treatment with MALT1 inhibitor abrogated the efficacy of anti-CTLA4 therapy. MALT1 inhibition had no impact on the frequencies of viable NK, lymphocyte and myeloid cells or on proliferation of conventional CD4 and CD8 T cells. However, there was a significant decrease of antigen-specific T cells in vivo upon adoptive T cell transfer and peptide vaccination. Thus, while MALT1 inhibition substantially reduced Treg populations in lymph nodes, but less so in tumors, off-target effects on antigen-experienced T cells along with the lack of impact on tumor Tregs likely abolish the compound’s efficacy. The off-target effect on antigen-experienced T cells could present implications for the use of MALT1 inhibitors for cancer indications where tumor control is likely to be mediated via T cell driven immune surveillance. Thus, dosing length and combination therapy strategies should be carefully designed and evaluated further.
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| 12. |
- Kruljac-Letunic, Anamarija, et al.
(författare)
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The tyrosine kinase Pyk2 regulates Arf1 activity by phosphorylation and inhibition of the Arf-GTPase-activating protein ASAP1.
- 2003
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Ingår i: J Biol Chem. - 0021-9258. ; 278:32, s. 29560-70
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Tidskriftsartikel (refereegranskat)abstract
- Proline-rich tyrosine kinase 2 (Pyk2), a non-receptor tyrosine kinase structurally related to focal adhesion kinase, has been implicated in the regulation of mitogen-activated protein kinase cascades and ion channels, the induction of apoptosis, and in the modulation of the cytoskeleton. In order to understand how Pyk2 signaling mediates these diverse cellular functions, we performed a yeast two-hybrid screening using the C-terminal part of Pyk2 that contains potential protein-protein interaction sites as bait. A prominent binder of Pyk2 identified by this method was the Arf-GTPase-activating protein ASAP1. Pyk2-ASAP1 interaction was confirmed in pull-down as well as in co-immunoprecipitation experiments, and contact sites were mapped to the proline-rich regions of Pyk2 and the SH3 domain of ASAP1. Pyk2 directly phosphorylates ASAP1 on tyrosine residues in vitro and increases ASAP1 tyrosine phosphorylation when co-expressed in HEK293T cells. Phosphorylation of tyrosine 308 and 782 affects the phosphoinositide binding profile of ASAP1, and fluorimetric Arf-GTPase assays with purified proteins revealed an inhibition of ASAP1 GTPase-activating protein activity by Pyk2-mediated tyrosine phosphorylation. We therefore provide evidence for a functional interaction between Pyk2 and ASAP1 and a regulation of ASAP1 and hence Arf1 activity by Pyk2-mediated tyrosine phosphorylation.
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| 13. |
- Rönnstrand, Lars, et al.
(författare)
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SHP-2 binds to Tyr763 and Tyr1009 in the PDGF β-receptor and mediates PDGF-induced activation of the Ras/MAP kinase pathway and chemotaxis
- 1999
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Ingår i: Oncogene. - : Stockton Press. - 0950-9232. ; 18:25, s. 3696-3702
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Tidskriftsartikel (refereegranskat)abstract
- Activation of the beta-receptor for platelet-derived growth factor (PDGF) by its ligand leads to autophosphorylation on a number of tyrosine residues. Here we show that Tyr763 in the kinase insert region is a novel autophosphorylation site, which after phosphorylation binds the protein tyrosine phosphatase SHP-2. SHP-2 has also previously been shown to bind to phosphorylated Tyr1009 in the PDGF beta-receptor. Porcine aortic endothelial (PAE) cells transfected with a PDGF beta-receptor in which Tyr763 and Tyr1009 were mutated to phenylalanine residues failed to associate with SHP-2 after ligand stimulation. Moreover, PDGF-BB-induced Ras GTP-loading and Erk2 activation were severely compromised in the receptor mutant. Whereas the mitogenic response to PDGF-BB remained at the same level as in cells expressing wild-type PDGF beta-receptor, chemotaxis induced by PDGF-BB was significantly decreased in the case of the Y763F/Y1009F mutant cells, suggesting an important role for SHP-2 in chemotactic signaling.
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| 14. |
- Åkerlund, Thomas, et al.
(författare)
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Stable IgG-antibody levels in patients with mild SARS-CoV-2 infection
- 2021
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Ingår i: Medrxiv. - : Cold Spring Harbor Laboratory.
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Tidskriftsartikel (refereegranskat)abstract
- More knowledge regarding persistence of antibody response to SARS-CoV-2 infections in the general population with mild symptoms is needed. We measured and compared levels of SARS CoV-2 spike- and nucleocapsid-specific IgG-antibodies in serum samples from 145 laboratory confirmed COVID-19 cases and 324 non-cases. The IgG-antibody levels against the spike protein in cases were stable over the time-period studied (14 to 256 days), while antibody levels against the nucleocapsid protein decreased over time
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