| 1. |
- Andersson, Helena M., et al.
(författare)
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Activated protein C cofactor function of protein S: a critical role for Asp95 in the EGF1-like domain
- 2010
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 115:23, s. 4878-4885
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Tidskriftsartikel (refereegranskat)abstract
- Protein S has an established role in the protein C anticoagulant pathway, where it enhances the factor Va (FVa) and factor VIIIa (FVIIIa) inactivating property of activated protein C (APC). Despite its physiological role and clinical importance, the molecular basis of its action is not fully understood. To clarify the mechanism of the protein S interaction with APC, we have constructed and expressed a library of composite or point variants of human protein S, with residue substitutions introduced into the Gla, thrombin-sensitive region (TSR), epidermal growth factor 1 (EGF1), and EGF2 domains. Cofactor activity for APC was evaluated by calibrated automated thrombography (CAT) using protein S-deficient plasma. Of 27 variants tested initially, only one, protein S D95A (within the EGF1 domain), was largely devoid of functional APC cofactor activity. Protein S D95A was, however, gamma-carboxylated and bound phospholipids with an apparent dissociation constant (Kd(app)) similar to that of wildtype (WT) protein S. In a purified assay using FVa R506Q/R679Q, purified protein S D95A was shown to have greatly reduced ability to enhance APC-induced cleavage of FVa Arg306. It is concluded that residue Asp95 within EGF1 is critical forAPC cofactor function of protein S and could define a principal functional interaction site for APC. (Blood. 2010;115(23):4878-4885)
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| 2. |
- Christoffersen, Christina, et al.
(författare)
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The plasma concentration of HDL-associated apoM is influenced by LDL receptor-mediated clearance of apoB-containing particles
- 2012
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Ingår i: Journal of Lipid Research. - 1539-7262. ; 53:10, s. 2198-2204
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Tidskriftsartikel (refereegranskat)abstract
- ApoM is mainly associated with HDL. Nevertheless, we have consistently observed positive correlations of apoM with plasma LDL cholesterol in humans. Moreover, LDL receptor deficiency is associated with increased plasma apoM in mice. Here, we tested the idea that plasma apoM concentrations are affected by the rate of LDL receptor-mediated clearance of apoB-containing particles. We measured apoM in humans each carrying one of three different LDL receptor mutations (n = 9) or the apoB3500 mutation (n = 12). These carriers had increased plasma apoM (1.34 +/- 0.13 mu M, P = 0.003, and 1.23 +/- 0.10 mu M, P = 0.02, respectively) as compared with noncarriers (0.93 +/- 0.04 mu M). When we injected human apoM-containing HDL into Wt (n = 6) or LDL receptor-deficient mice (n = 6), the removal of HDL-associated human apoM was delayed in the LDL receptor-deficient mice. After 2 h, 54 +/- 5% versus 90 +/- 8% (P < 0.005) of the initial amounts of human apoM remained in the plasma of Wt and LDL receptor-deficient mice, respectively. Finally, we compared the turnover of radio-iodinated LDL and plasma apoM concentrations in 45 normocholesterolemic humans. There was a negative correlation between plasma apoM and the fractional catabolic rate of LDL (r = -0.38, P = 0.009). These data suggest that the plasma clearance of apoM, despite apoM primarily being associated with HDL, is influenced by LDL receptor-mediated clearance of apoB-containing particles.-Christoffersen, C., M. Benn, P. M. Christensen, P. L. S. M. Gordts, A. J. M. Roebroek, R. Frikke-Schmidt, A. Tybjaerg-Hansen, B. Dahlback, and L. B. Nielsen. The plasma concentration of HDL-associated apoM is influenced by LDL receptor-mediated clearance of apoB-containing particles. J. Lipid Res. 2012. 53: 2198-2204.
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| 3. |
- Christoffersen, Christina, et al.
(författare)
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Opposing Effects of Apolipoprotein M on Catabolism of Apolipoprotein B-Containing Lipoproteins and Atherosclerosis.
- 2010
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Ingår i: Circulation Research. - 1524-4571. ; 106:10, s. 1624-1634
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Plasma apolipoprotein (apo)M is mainly associated with high-density lipoprotein (HDL). HDL-bound apoM is antiatherogenic in vitro. However, plasma apoM is not associated with coronary heart disease in humans, perhaps because of a positive correlation with plasma low-density lipoprotein (LDL). Objective: We explored putative links between apoM and very-low-density (VLDL)/LDL metabolism and the antiatherogenic potential of apoM in vivo. Methods and Results: Plasma apoM was increased approximately 2.1 and approximately 1.5 fold in mice lacking LDL receptors (Ldlr(-/-)) and expressing dysfunctional LDL receptor-related protein 1 (Lrp1(n2/n2)), respectively, but was unaffected in apoE-deficient (ApoE(-/-)) mice. Thus, pathways controlling catabolism of VLDL and LDL affect plasma apoM. Overexpression ( approximately 10-fold) of human apoM increased (50% to 70%) and apoM deficiency decreased ( approximately 25%) plasma VLDL/LDL cholesterol in Ldlr(-/-) mice, whereas apoM did not affect plasma VLDL/LDL in mice with intact LDL receptors. Moreover, plasma clearance of apoM-enriched VLDL/LDL was slower than that of control VLDL/LDL in mice lacking functional LDL receptors and LRP1, suggesting that apoM impairs the catabolism of VLDL/LDL that occurs independently of the LDL receptor and LRP1. ApoM overexpression decreased atherosclerosis in ApoE(-/-) (60%) and cholate/cholesterol-fed wild-type mice (70%). However, in Ldlr(-/-) mice the antiatherogenic effect of apoM was attenuated by its VLDL/LDL-raising effect. Conclusion: The data suggest that defect LDL receptor function leads to increased plasma apoM concentrations, which in turn, impairs the removal of VLDL/LDL from plasma. This mechanism opposes the otherwise antiatherogenic effect of apoM.
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| 4. |
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| 5. |
- Lanke, E., et al.
(författare)
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Co-segregation of the PROS1 locus and protein S deficiency in families having no detectable mutations in PROS1
- 2004
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Ingår i: Journal of Thrombosis and Haemostasis. - : Wiley-Blackwell. - 1538-7933 .- 1538-7836. ; 2:11, s. 1918-1923
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Tidskriftsartikel (refereegranskat)abstract
- Inherited deficiency of protein S constitutes an important risk factor of venous thrombosis. Many reports have demonstrated that causative mutations in the protein S gene are found only in approximately 50% of the cases with protein S deficiency. It is uncertain whether the protein S gene is causative in all cases of protein S deficiency or if other genes are involved in cases where no mutation is identified. The aim of the current study was to determine whether haplotypes of the protein S gene cosegregate with the disease phenotype in cases where no mutations have been found. Eight protein S-deficient families comprising 115 individuals where previous DNA sequencing had failed to detect any causative mutations were analyzed using four microsatellite markers in the protein S gene region. Co-segregation between microsatellite haplotypes and protein S deficiency was found in seven of the investigated families, one family being uninformative. This suggests that the causative genetic defects are located in or close to the protein S gene in a majority of such cases where no mutations have been found.
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| 6. |
- Lutgens, E., et al.
(författare)
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Genetic loss of Gas6 induces plaque stability in experimental atherosclerosis
- 2008
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 216:1, s. 55-63
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Tidskriftsartikel (refereegranskat)abstract
- The growth arrest-specific gene 6 (Gas6) plays a role in pro-atherogenic processes such as endothelial and leukocyte activation, smooth muscle cell migration and thrombosis, but its role in atherosclerosis remains uninvestigated. Here, we report that Gas6 is expressed in all stages of human and mouse atherosclerosis, in plaque endothelial cells, smooth muscle cells and macrophages. Gas6 expression is most abundant in lesions containing high amounts of macrophages, ie thin fibrous cap atheroma and ruptured plaque. Genetic loss of Gas6 does not affect the number and size of initial and advanced plaques in ApoE(-/-) mice, but alters its plaque composition. Compared to Gas6(+/+): ApoE(-/-) mice, initial and advanced plaques of Gas6(-/-): ApoE(-/-) mice contained more smooth muscle cells and more collagen and developed smaller lipid cores, while the expression of TGFbeta was increased. In addition, fewer macrophages were found in advanced plaques of Gas6(-/-): ApoE(-/-) mice. Hence, loss of Gas6 promotes the formation of more stable atherosclerotic lesions by increasing plaque fibrosis and by attenuating plaque inflammation. These findings identify a role for Gas6 in plaque composition and stability.
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| 7. |
- Malm, Johan, et al.
(författare)
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Developments in biobanking workflow standardization providing sample integrity and stability
- 2013
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Ingår i: Journal of Proteomics. - : Elsevier BV. - 1874-3919 .- 1876-7737. ; 95:SI, s. 38-45
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Tidskriftsartikel (refereegranskat)abstract
- Recommendations and outlines for standardization in biobanking processes are presented by a research team with long-term experience in clinical studies. These processes have important bearing on the use of samples in developing assays. These measurements are useful to document states of health and disease that are beneficial for academic research, commercial healthcare, drug development industry and government regulating agencies. There is a need for increasing awareness within proteomic and genomic communities regarding the basic concepts of collecting, storing and utilizing clinical samples. Quality control and sample suitability for analysis need to be documented and validated to ensure data integrity and establish contexts for interpretation of results. Standardized methods in proteomics and genomics are required to be practiced throughout the community allowing datasets to be comparable and shared for analysis. For example, sample processing of thousands of clinical samples, performed in 384 high-density sample tube systems in a fully automated workflow, preserves sample content and is presented showing validation criteria. Large studies will be accompanied by biological and molecular information with corresponding clinical records from patients and healthy donors. These developments position biobanks of human patient samples as an increasingly recognized major asset in disease research, future drug development and within patient care. Biological significance: The current manuscript is of major relevance to the proteomic and genomic fields, as it outlines the standardization aspects of biobanking and the requirements that are needed to run future clinical studies that will benefit the patients where OMICS science will play a major role. A global view of the field is given where best practice and conventional acceptances are presented along with ongoing large-scale biobanking projects. The authors represent broadly stakeholders that cover the academic, pharma, biotech and healthcare fields with extensive experience and deliveries. This contribution will be a milestone paper to the proteomic and genomic scientists to present data in the future that will have impact to the life science area.This article is part of a Special Issue entitled: Standardization and Quality Control in Proteomics.
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| 8. |
- Massih, Ali R, et al.
(författare)
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Effect of beta-to-alpha phase transition rate on corrosion behaviour of Zircaloy
- 2006
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Ingår i: Corrosion Science. - : Elsevier. - 0010-938X .- 1879-0496. ; 48:5, s. 1154-1181
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Tidskriftsartikel (refereegranskat)abstract
- The effect of β → α phase transition rate employed at the late stages of the fabrication process of Zircaloy-2 cladding tubes on the in-reactor corrosion behaviour is investigated. A cladding tube manufactured with a slower quenching exhibits a superior uniform corrosion resistance in boiling water reactors than the tube manufactured with a faster quenching. Scanning and transmission electron microscopy observations show that the slow β quench material has larger second phase particles and smaller particle number densities than the fast β quench material. It is argued that the larger SPPs with the lower number density survive the neutron irradiation field longer than the smaller ones. We have related the effective β quenching rate to the mean lamella grain size width, formed upon β quenching.
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| 9. |
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| 10. |
- Maurissen, Lisbeth F A, et al.
(författare)
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Re-evaluation of the role of the protein S-C4b binding protein complex in activated protein C-catalyzed factor Va-inactivation
- 2008
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 111:6, s. 3034-3041
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Tidskriftsartikel (refereegranskat)abstract
- Protein S expresses cofactor activity for activated protein C (APC) by enhancing the APC-catalyzed proteolysis at R-306 in factor Va. It is generally accepted that only free protein S is active and that complex formation with C4b-binding protein (C4BP) inhibits the APC-cofactor activity of protein S. However, the present study shows that protein S-C4BP expresses APC-cofactor activity and stimulates APC-catalyzed proteolysis at R-306 more than 10-fold, but instead inhibits proteolysis at R-506 by APC 3- to 4-fold. Free protein S stimulates APC-catalyzed cleavage at R-306 approximately 20-fold and has no effect on cleavage at R-506. The resulting net effect of protein S-C4BP complex formation on APC-catalyzed factor Va inactivation is a 6- to 8-fold reduction in factor Va inactivation when compared with free protein S, which is not explained by inhibition of APC-cofactor activity of protein S at R306, but by generation of a specific inhibitor for APC-catalyzed proteolysis at R-506 of factor Va. These results are of interest for carriers of the factor V-Leiden mutation (R(506)Q), as protein S-C4BP effectively enhances APC-catalyzed factor Va (R-306) inactivation in plasma containing factor V-Leiden.
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| 11. |
- Ooi, Esther M. M., et al.
(författare)
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Association of apolipoprotein M with high-density lipoprotein kinetics in overweight-obese men
- 2010
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Ingår i: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 210:1, s. 326-330
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of this study was to investigate associations between plasma apoM concentration and HDL apoA-I and apoA-II kinetics in 60 overweight-obese, insulin resistant men. Methods: Plasma apoM concentration was determined using a sandwich ELISA with two monoclonal antibodies (CV < 5%). The kinetics of HDL apoA-I and apoA-II were measured using intravenous administration of D-3-leucine, gas chromatography-mass spectrometry and multi-compartmental modeling. Results: Plasma apoM was inversely associated with body mass index and positively associated with plasma total cholesterol, LDL cholesterol and HDL cholesterol (p < 0.05). There were no associations between plasma apoM and plasma triglyceride, NEFA, insulin, glucose, HOMA score or adiponectin concentrations. Plasma apoM was positively associated with both apoA-I and apoA-II concentrations (r = 0.406, p < 0.01 and r = 0.510, p < 0.01, respectively) and negatively associated with HDL apoA-I and apoA-II fractional catabolic rate (FCR) (r = -0.291, p = 0.03 and r = -0.291, p = 0.026, respectively). No significant associations were observed between plasma apoM and HDL apoA-I and apoA-II production rate. In multivariate regression models, both plasma apoM and triglycerides were significant, independent predictors of HDL apoA-I FCR (adjusted R-2 = 16%, p < 0.01) and HDL apoA-II FCR (adjusted R-2 = 14%, p < 0.01). Conclusion: ApoM may be a significant, independent predictor of HDL apoA-I and apoA-II catabolism in overweight-obese, insulin resistant men. Crown Copyright (C) 2009 Published by Elsevier Ireland Ltd. All rights reserved.
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| 12. |
- Reglinska-Matveyev, Natalia, et al.
(författare)
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TFPI cofactor function of protein S: essential role of the protein S SHBG-like domain
- 2014
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 123:25, s. 3979-3987
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Tidskriftsartikel (refereegranskat)abstract
- Protein S is a cofactor for tissue factor pathway inhibitor (TFPI), accelerating the inhibition of activated factor X (FXa). TFPI Kunitz domain 3 residue Glu226 is essential for enhancement of TFPI by protein S. To investigate the complementary functional interaction site on protein S, we screened 44 protein S point, composite or domain swap variants spanning the whole protein S molecule for their TFPI cofactor function using a thrombin generation assay. Of these variants, two protein S/growth arrest-specific 6 chimeras, with either the whole sex hormone-binding globulin (SHBG)-like domain (Val243-Ser635; chimera III) or the SHBG laminin G-type 1 subunit (Ser283-Val459; chimera I), respectively, substituted by the corresponding domain in growth arrest-specific 6, were unable to enhance TFPI. The importance of the protein S SHBG-like domain (and its laminin G-type 1 subunit) for binding and enhancement of TFPI was confirmed in FXa inhibition assays and using surface plasmon resonance. In addition, protein S bound to C4b binding protein showed greatly reduced enhancement of TFPI-mediated inhibition of FXa compared with free protein S. We show that binding of TFPI to the protein S SHBG-like domain enables TFPI to interact optimally with FXa on a phospholipid membrane.
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| 13. |
- Serra, J, et al.
(författare)
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Multicentre evaluation of IL Test (TM) Free PS: A fully automated assay to quantify Free Protein S
- 2002
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 88:6, s. 975-983
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Tidskriftsartikel (refereegranskat)abstract
- Deficiency of the anticoagulant vitamin K-dependent protein S (PS) is associated with increased risk of venous thrombosis. In human plasma, PS circulates in two forms: as free protein (free PS) and PS bound to C4b-binding protein (C4BP), a regulator of the complement system. Assays for free PS have higher sensitivity and specificity for protein S deficiency than assays for total protein S. We have extensively evaluated the analytical performance of a novel assay for free PS, the IL Test(TM) Free Protein S, which takes advantage of the affinity of C4BP for free PS, and compared its performance to existing methods. IL Test(TM) Free Protein S is a rapid, fully automated turbidimetric assay consisting of two reagents: a C4BP coated latex and an anti-PS monoclonal antibody coated latex. The test range, precision and linearity were adequate and the assay tolerated high concentrations of interfering substances of clinical significance. The reference range agreed with previously published studies. The analysis of 903 patient samples belonging to 20 different clinical. categories with the new assay yielded free PS results that agreed well with those obtained using the assays established in the participating laboratories. The study demonstrated the IL Test(TM) Free Protein S to be rapid, reliable and easy to perform.
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| 14. |
- Vincent, Lisa M., et al.
(författare)
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Coagulation factor V-A2440G causes east Texas bleeding disorder via TFPI alpha
- 2013
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 123:9, s. 3777-3787
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Tidskriftsartikel (refereegranskat)abstract
- The autosomal dominantly inherited east Texas bleeding disorder is linked to an A2440G variant in exon 13 of the F5 gene. Affected individuals have normal levels of coagulation factor V (FV) activity, but demonstrate inhibition of global coagulation tests. We demonstrated that the A2440G mutation causes upregulation of an alternatively spliced F5 transcript that results in an in-frame deletion of 702 amino acids of the large activation fragment, the B domain. The approximately 250-kDa FV isoform (FV-short), which can be fully activated by thrombin, is present in all A2440G carriers' plasma (n = 16). FV-short inhibits coagulation through an indirect mechanism by forming a complex with tissue factor pathway inhibitor-alpha (TFPI alpha), resulting in an approximately 10-fold increase in plasma TFPI alpha, suggesting that the TFPI alpha:FV-short complexes are retained in circulation. The TFPI alpha:FV-short complexes efficiently inhibit thrombin generation of both intrinsic and extrinsic coagulation pathways. These data demonstrate that the east Texas bleeding disorder-associated F5(A2440G) leads to the formation of the TFPI alpha:FV-short complex, which inhibits activation and propagation of coagulation.
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| 15. |
- Astermark, J., et al.
(författare)
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Symposium in memory of Professor Inga Marie Nilsson
- 2001
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Ingår i: Haemophilia. - : Wiley. - 1351-8216. ; 7:4, s. 401-410
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Konferensbidrag (refereegranskat)abstract
- Professor Inga Marie Nilsson (1923-99) was a pioneer in the field of bleeding and thrombo-embolic disorders and made several major scientific contributions during her career. To honour her memory, colleagues from all over the world were invited to cover several aspects of haemostasis by giving state-of-the-art lectures at an international symposium in Malmö on September 22-23, 2000, chaired by Professors Lou Aledort and Erik Berntorp. Colleagues of Professor Nilsson in Malmö gave a short introduction to each topic. A short review of the meeting will be presented.
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| 16. |
- Balogh, Istvan, et al.
(författare)
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Analysis of Gas6 in Human Platelets and Plasma.
- 2005
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - 1524-4636. ; 25:6, s. 1280-1286
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Tidskriftsartikel (refereegranskat)abstract
- Objective - Gas6 is a member of the vitamin K-dependent protein family. Gas6- deficient mice were found to be resistant to thrombosis because of defective platelet function. Mouse Gas6 was demonstrated to be present in platelets and found to be involved in platelet aggregation. The aim of this study was to investigate the presence of Gas6 in human platelets and plasma and determine its role in platelet function. Methods and Results - The presence of Gas6 in human platelets and plasma was analyzed using sensitive immunologic methods. Mass spectrometry and ELISA were used to identify and quantify Gas6 in plasma. Gas6 was demonstrated to be present in human plasma, at a concentration determined to be 13 to 23 ng/mL (0.16 to 0.28 nM). Furthermore, plasma Gas6 levels were found to be lower in patients administered with warfarin. However, Gas6 was undetectable in human platelets. Conclusions - This is the first report to identify and quantify Gas6 in human plasma. However, Gas6 protein was not detected in human platelets, suggesting that any potential platelet-specific function could be because of Gas6 from the circulation. These findings open up new directions regarding the role of Gas6 in normal and pathophysiological situations such as inflammation, autoimmune disease, thrombosis and arteriosclerosis.
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| 17. |
- Blom, Anna M., et al.
(författare)
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A novel interaction between type IV pili of Neisseria gonorrhoeae and the human complement regulator C4B-binding protein
- 2001
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 166:11, s. 6764-6770
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Tidskriftsartikel (refereegranskat)abstract
- C4b-binding protein (C4BP) is an important plasma inhibitor of the classical pathway of complement activation. Several bacterial pathogens bind C4BP, which may contribute to their virulence. In the present report we demonstrate that isolated type IV pili from Neisseria gonorrhoeae bind human C4BP in a dose-dependent and saturable manner. C4BP consists of seven identical alpha-chains and one beta-chain linked together with disulfide bridges. We found that pili bind to the alpha-chain of C4BP, which is composed of eight homologous complement control protein (CCP) domains. From the results of an inhibition assay with C4b and a competition assay in which we tested mutants of C4BP lacking individual CCPs, we concluded that the binding area for pili is localized to CCP1 and CCP2 of the alpha-chain. The binding between pili and C4BP was abolished at 0.25 M NaCl, implying that it is based mostly on ionic interactions, similarly to what have been observed for C4b-C4BP binding. Furthermore, the N-terminal part of PilC, a structural component of pili, appeared to be responsible for binding of C4BP. Membrane cofactor protein, previously shown to be a receptor for pathogenic N. gonorrhoeae on the surface of epithelial cells, competed with C4BP for binding to pili only at high concentrations, suggesting that different parts of pili are involved in these two interactions. Accordingly, high concentrations of C4BP were required to inhibit binding of N. gonorrhoeae to Chang conjunctiva cells, and no inhibition of binding was observed with cervical epithelial cells.
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| 18. |
- Brinkman, Herm Jan M., et al.
(författare)
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Pleiotropic anticoagulant functions of protein S, consequences for the clinical laboratory. Communication from the SSC of the ISTH
- 2021
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 19:1, s. 281-286
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Tidskriftsartikel (refereegranskat)abstract
- Hereditary deficiencies of protein S (PS) increase the risk of thrombosis. However, assessing the plasma levels of PS is complicated by its manifold physiological interactions, while the large inter-individual variability makes it problematic to establish reliable cut-off values. PS has multiple physiological functions, with only two appearing to have significant anticoagulant properties: the activated protein C (APC) and tissue factor pathway inhibitor alpha (TFPIα) cofactor activities. Current clinical laboratory investigations for deficiency in PS function rely only on the APC-dependent activity. This communication presents an argument for reclassifying the qualitative PS deficiencies to differentiate the two major anticoagulant functions of PS. Reliable assays are necessary for accurate evaluation of PS function when making a specific diagnosis of PS deficiency based on the anticoagulant phenotype alone. This report emphasizes the pleiotropic anticoagulant functions of PS and presents evidence-based recommendations for their implementation in the clinical laboratory.
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| 19. |
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| 20. |
- Dahlbäck, Björn, et al.
(författare)
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Assignment of gene for coagulation factor V to chromosome 1 in man and to chromosome 13 in rat
- 1988
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Ingår i: Somatic Cell and Molecular Genetics. - 0740-7750. ; 14:5, s. 14-509
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Tidskriftsartikel (refereegranskat)abstract
- Two different factor V cDNA fragments were used as hydridization probes in the chromosomal assignment of the human and rat factor V genes. A 1.6-kb EcoRI fragment was used as a hybridization probe to analyze a panel of human-rodent somatic cell hybrids. Cosegregation of factor V specific DNA restriction fragments with human chromosome 1 was observed. In addition, a panel of rat-mouse somatic cell hybrids was analyzed with another human factor V cDNA probe to localize the gene for rat coagulation factor V. In the rat, the gene for coagulation factor V was found to be located in chromosome 13. This is the first gene in the rat to be localized to chromosome 13.
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| 21. |
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| 22. |
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| 23. |
- Dahlbäck, Robin, 1985, et al.
(författare)
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A Tunable 240–290 GHz Waveguide Enclosed 2-D Grid HBV Frequency Tripler
- 2016
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Ingår i: IEEE Transactions on Terahertz Science and Technology. - 2156-342X .- 2156-3446. ; 6:3, s. 503-509
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents a high-power 240–290 GHz waveguide enclosed two-dimensional (2-D) grid heterostructure barrier varactor (HBV) frequency multiplier. A 35 mW of output power is produced at 247 GHz with an input power of 900 mW. The operational bandwidth is tunable within a 50 GHz span by the use of an input tuner able to adjust the input matching of the 2-D grid HBV frequency multiplier. Tuning is achieved by moving a suspended dielectric slab in the input waveguide.
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| 24. |
- Dahlbäck, Robin, 1985, et al.
(författare)
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A Waveguide Embedded 250 GHz Frequency-Tripler 2D Array
- 2014
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Ingår i: Micro-and Millimetre Wave Technology and Techniques Workshop 2014, 25-27 November 2014.
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Konferensbidrag (refereegranskat)abstract
- This work reports on a 248 GHz HBV (Heterostructure Barrier Varactors)-varactor quasi-optical multiplier array with a maximum output power of 18 mW and a corresponding conversion efficiency of 2 %. The module utilizes a mechanically compact and simple shim system, combining the large array power handling capability with the convenience of waveguide interfaced circuits. At the same time this approach offers excellent power and frequency scalability. The multiplier is based on a 12 by 6 element, 72 in total, planar 2D HBV varactor array. The diodes are fabricated on a three barrier InGaAs/InAlAs material system on InP as carrier substrate. Easch diode consist of two 20um^2 serially connected mesas, yielding a total of six barrier per diode. The HBV diodes are coupled to a uniform dipole array through which the power is coupled in and out. One HBV diode and the corresponding dipole make up a square unit cell with a side of 211 um. The chip measures 2,54 x 1,27 mm^2, fitting inside a standard WR10 waveguide. The complete module consists of three parts, the 2D HBV array, a combined output filter and output matching slab and an input matching slab. A rhombic aperture frequency selective surface is used as the uutput bandpass filter and the quartz filter substrate also serves as a matching slab for the output tone. On the input a piece of InP substrate is used to match the incoming pump signal to the diodes. The components are mounted inside two WR-10 waveguide shims, providing an easy assembly and a modular system. The current version of the multiplier module produces 18 mW at 248 GHz but a significant increase in output power and efficiency is expected with a new output matching network and more pump power. Recent measurement results will be presented together with a detailed discussion regarding the design, pointing out advantages and challenges compared to more traditional approaches to frequency multiplier design in the frequency range. Future improvements and challenges will also be covered.
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| 25. |
- Dahlbäck, Robin, 1985, et al.
(författare)
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A waveguide embedded 250 GHz quasi-optical frequency-tripler array
- 2014
-
Ingår i: 44th European Microwave Conference, EuMC 2014 - Held as Part of the 17th European Microwave Week, EuMW 2014; Fiera di RomaRome; Italy; 6 October 2014 through 9 October 2014. - 9782874870354 ; , s. 802-805
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Konferensbidrag (refereegranskat)abstract
- A waveguide embedded 250 GHz HBV-varactor quasi-optical multiplier array is presented. The module utilizes a mechanically compact and simple shim system, combining the large array power handling capability with the convenience of waveguide interfaced circuits. At the same time this approach offers excellent power and frequency scalability. The current tripler prototype produces a non saturated output power of 8 mW at 248 GHz during initial measurements at medium pump power.
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| 26. |
- Ferreira, Silvia A., et al.
(författare)
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Biocompatibility of mannan nanogel-safe interaction with plasma proteins
- 2012
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Ingår i: Biochimica et Biophysica Acta. General Subjects. - : Elsevier BV. - 0304-4165. ; 1820:7, s. 1043-1051
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Tidskriftsartikel (refereegranskat)abstract
- Background: Self-assembled mannan nanogels are designed to provide a therapeutic or vaccine delivery platform based on the bioactive properties of mannan to target mannose receptor expressed on the surface of antigen-presenting cells, combined with the performance of nanogels as carriers of biologically active agents. Methods: Proteins in the corona around mannan nanogel formed in human plasma were identified by mass spectrometry after size exclusion chromatography or centrifugation followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Structural changes and time dependent binding of human apolipoprotein A-I (apoA-I) and human serum albumin (HSA) to mannan nanogel were studied using intrinsic tryptophan fluorescence and circular dichroism spectroscopy. The mannan nanogel effect on blood coagulation and fibrillation of Alzheimer's disease-associated amyloid beta peptide and hemodialysis-associated amyloidosis beta 2 microglobulin was evaluated using thrombin generation assay or thioflavin T fluorescence assay, respectively. Results: The protein corona around mannan nanogel is formed through a slow process, is quite specific comprising apolipoproteins B-100, A-I and E and HSA, evolves over time, and the equilibrium is reached after hours to days. Structural changes and time dependent binding of apoA-I and HSA to mannan nanogel are minor. The mannan nanogel does not affect blood coagulation and retards the fibril formation. Conclusions: Mannan nanogel has a high biosafety and biocompatibility, which is mandatory for nanomaterials to be used in biomedical applications. General Significance: Our research provides a molecular approach to evaluate the safety aspects of nanomaterials, which is of general concern in society and science. (C) 2012 Elsevier B.V. All rights reserved.
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| 27. |
- Forsgren, P, et al.
(författare)
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Intrapulmonary deposition of aerosolized Evans blue dye and liposomes in an experimental porcine model of early ARDS.
- 1990
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Ingår i: Upsala Journal of Medical Sciences. - 0300-9734 .- 2000-1967. ; 95:2, s. 117-36
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Tidskriftsartikel (refereegranskat)abstract
- In early ARDS (Adult Respiratory Distress Syndrome) and other inflammatory pulmonary disorders the lung might benefit from a high local deposition of an active drug, in order to optimize the local concentration without systemic side effects. In this methodological study we used pigs under controlled ventilation. The study was carried out in two steps. In the first part Evans blue dye in NaCl was delivered in aerosolized form. In the second part a dry powder containing FITC (fluorescein-isothiocyanate)-labelled-liposomes in NaCl was delivered in the same way. We evaluated whether there was an even, central, peripheral and/or alveolar deposition, whether the procedure was reproducible, and whether there was an interaction with alveolar macrophages. Sixteen animals under chlormethiazole anaesthesia and intermittent positive pressure ventilation (IPPV) were included in the study. Four animals were sacrificed after nebulization and baseline measurements. Five animals served as controls and received saline i.v. Six animals received endotoxin i.v. (18 micrograms.kg-1.h-1). One animal underwent broncho-alveolar lavage 15 min and 2 h after liposome administration. At the end of each experiment the lungs were inflated with air, excised and dried in a microwave oven. The left lung of each animal was sliced in a reproducible manner and lung-pieces from different regions were analyzed. The Evans blue dye or the phospholipid fraction of the lungs (containing liposomes), was extracted and analyzed spectrofluorometrically. This study shows that it is possible, under reproducible conditions, to administer aerosolized Evans blue dye and liposomes and to achieve a deposition in the terminal airways and/or alveolar spaces. The broncho-alveolar lavage demonstrated an interaction of liposomes with alveolar macrophages. The results imply that liposomes carrying active drugs and administered by inhalation may be used for local pulmonary treatment in early ARDS and other related inflammatory pulmonary diseases.
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| 28. |
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| 29. |
- Garcia de Frutos, Pablo, et al.
(författare)
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Differential regulation of α and β chains of C4b-binding protein during acute-phase response resulting in stable plasma levels of free anticoagulant protein S
- 1994
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Ingår i: Blood. - 1528-0020. ; 84:3, s. 815-822
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Tidskriftsartikel (refereegranskat)abstract
- Regulation of C4b-binding protein (C4BP) isoforms during acute phase and its relationship to the plasma concentration of free protein S was elucidated. An assay for β chain containing C4BP (C4BPβ+) was developed and the concentrations of total C4BP, C4BPβ+, total, free, and bound protein S were measured in patients with acute-phase response. Even though total C4BP was increased to 162% (mean value) of controls, the corresponding value of C4BPβ+ was only 122%. In the acute-phase group, total protein S was increased to the same extent as C4BPβ+ (mean value of 124%), whereas free protein S was not decreased. In controls, total and bound protein S correlated with total C4BP and C4BPβ+. However, in the acute-phase group, the correlation between bound protein S and total C4BP was lost, although the correlation between C4BPβ+ and protein S remained. The present results suggest stable levels of free protein S during acute phase to be the result of differential regulation of C4BP α- and β-chain expression, and the concentration of free protein S to be the resulting molar excess of protein S over C4BPβ+. This mechanism ensures functional levels of free anticoagulant protein S despite high levels of C4BP.
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| 30. |
- Gustafsson, Anna, et al.
(författare)
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Gas6-Axl signaling in presence of Sunitinib is enhanced, diversified and sustained in renal tumor cells, resulting in tumor-progressive advantages
- 2017
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827. ; 355:1, s. 47-56
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Tidskriftsartikel (refereegranskat)abstract
- Clear Cell Renal Cell Carcinoma (CCRCC) is a lethal cancer with bad prognosis due to development of chemoresistance and recurrence of more aggressive tumors. Investigation of Gas6-mediated Axl signaling in CCRCC and endothelial cells reveals a Sunitinib resistant Gas6-Axl signaling that is sustained and enhanced and specifically triggers downstream AKT and PRAS40 activation in an intensified manner. Gas6-induced Axl signaling in presence of Sunitinib is also diversified displaying onset of Axl-dependent EGFR and METR activation and activation of classical MAPK pathways. Gas6+Sunitinib-adapted CCRCC cells present increased viability and decreased apoptosis and enhanced production of the multi-tumorigenic Osteopontin (OPN) and of one of its activator matrix metalloproteinase-7. Axl activity is necessary for CCRCC cell sphere formation and the ability of the cells to attach after non-adhesive growth. In addition, Gas6+Sunitinib-adapted CCRCC cells displayed enhanced migration and sphere formation, both mechanisms being Axl and OPN dependent. Altogether, this suggests that Sunitinib while targeting endothelial cells and tumor angiogenesis, simultaneously provides protumorigenic effects due to a constitutively, intensified and divergent Gas6-Axl system. Implications: Gas6-mediated Axl signaling, which is enhanced and diversified in the presence of Sunitinib possibly contributes to acquired chemoresistance, recurrence of aggressive disease and metastasis of CCRCC tumors. Therefore, combinatorial Axl-targeted therapy might be beneficial for CCRCC patients intended for Sunitinib treatment.
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| 31. |
- Hillarp, A, et al.
(författare)
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Protein S binding in relation to the subunit composition of human C4b-binding protein
- 1989
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Ingår i: FEBS Letters. - : Wiley. - 0014-5793. ; 259:1, s. 6-53
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Tidskriftsartikel (refereegranskat)abstract
- The human regulatory complement component C4b-binding protein (C4BP) circulates in plasma either as a free protein or in a bimolecular complex with the vitamin K-dependent protein S. The major form of C4BP is composed of 7 identical, disulfide-linked 70 kDa subunits (alpha-chains), the arrangement of which gives the C4BP molecule a spider-like appearance. Recently, we identified a unique 45 kDa subunit (beta-chain) in C4BP. We have now isolated a subpopulation of C4BP, which does not bind protein S. This C4BP species, which had a molecular weight slightly lower than that of the predominant form, was found to lack the beta-chain. Another lower molecular weight form of C4BP was also purified. It contained the beta-chain and was efficient in binding protein S. Its subunit composition was judged to comprise six alpha-chains and one beta-chain. These results indicate C4BP in plasma to be heterogeneous at a molecular level vis-a-vis subunit composition and/or protein S binding ability and provide support for the concept that the beta-chain of C4BP contains the single protein S binding site.
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| 32. |
- Johansson, Anna M., et al.
(författare)
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Large deletions of the PROS1 gene in a large fraction of mutation-negative patients with protein S deficiency
- 2005
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 94:5, s. 951-957
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Tidskriftsartikel (refereegranskat)abstract
- Protein S deficiency is an autosomal dominant disorder that results from mutations in the PROS1 gene. Conventional mutation detection techniques fail to detect a pathogenic PROS1 mutation in approximately 50% of cases. The present study investigates whether large deletions of PROS1 are found in families where mutations in the PROS1 gene have not been found despite sequencing. For this purpose,a dense set of SNP and microsatellite markers were used in segregation analysis to identify deletions. Large deletions were identified by this technique in three out of eight investigated families (38%). The deletions encompassed at least 35 kb, 437 kb and 449 kb respectively. The deletions were confirmed by quantitative PCR. Haplotype analysis showed that the three large deletions and the five other disease haplotypes were all different. All of the eight disease haplotypes co-segregated with protein S deficiency, but each of the five non-deletion haplotypes were present also in normal individuals. In conclusion: Large deletions of PROS1 are relatively common in protein S deficiency patients and screening for large deletions in PROS1 mutation-negative individuals are therefore warranted.
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| 33. |
- Kober, Alexandra Carmen, et al.
(författare)
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Implications of cerebrovascular ATP-binding cassette transporter G1 (ABCG1) and apolipoprotein M in cholesterol transport at the blood-brain barrier
- 2017
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Ingår i: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. - : Elsevier BV. - 1388-1981. ; 1862:6, s. 573-588
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Tidskriftsartikel (refereegranskat)abstract
- Impaired cholesterol/lipoprotein metabolism is linked to neurodegenerative diseases such as Alzheimer's disease (AD). Cerebral cholesterol homeostasis is maintained by the highly efficient blood-brain barrier (BBB) and flux of the oxysterols 24(S)-hydroxycholesterol and 27-hydroxycholesterol, potent liver-X-receptor (LXR) activators. HDL and their apolipoproteins are crucial for cerebral lipid transfer, and loss of ATP binding cassette transporters (ABC)G1 and G4 results in toxic accumulation of oxysterols in the brain. The HDL-associated apolipoprotein (apo)M is positively correlated with pre-β HDL formation in plasma; its presence and function in the brain was thus far unknown. Using an in vitro model of the BBB, we examined expression, regulation, and functions of ABCG1, ABCG4, and apoM in primary porcine brain capillary endothelial cells (pBCEC). RT Q-PCR analyses and immunoblotting revealed that in addition to ABCA1 and scavenger receptor, class B, type I (SR-BI), pBCEC express high levels of ABCG1, which was up-regulated by LXR activation. Immunofluorescent staining, site-specific biotinylation and immunoprecipitation revealed that ABCG1 is localized both to early and late endosomes and on apical and basolateral plasma membranes. Using siRNA interference to silence ABCG1 (by 50%) reduced HDL-mediated [3H]-cholesterol efflux (by 50%) but did not reduce [3H]-24(S)-hydroxycholesterol efflux. In addition to apoA-I, pBCEC express and secrete apoM mainly to the basolateral (brain) compartment. HDL enhanced expression and secretion of apoM by pBCEC, apoM-enriched HDL promoted cellular cholesterol efflux more efficiently than apoM-free HDL, while apoM-silencing diminished cellular cholesterol release. We suggest that ABCG1 and apoM are centrally involved in regulation of cholesterol metabolism/turnover at the BBB.
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| 34. |
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| 35. |
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| 36. |
- Massih, Ali R, et al.
(författare)
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The effect of beta quenching in final dimension on the irradiation growth of tubes and channels
- 2005
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Ingår i: Journal of ASTM International. - 1546-962X. ; :2
-
Tidskriftsartikel (refereegranskat)abstract
- The effect of β-quenching performed in the final size of Zircaloy-4 guide tubes and Zircaloy-2 sheets during fabrication process on the products' mechanical properties, crystallographic texture, microstructure, and corrosion behavior has been investigated and presented in this paper. Moreover, the impact of this processing on the irradiation growth of pressurized water reactor Zircaloy-4 guide tubes in a test reactor and Zircaloy-2 fuel channels in boiling water reactors has been evaluated. The results indicate that the irradiation growth rates of the final dimension β-quenched (FDBQ) products are substantially lower than those fabricated by conventional (Standard) techniques. BWR channels irradiated up to a fast neutron fluence of about 9 × 1025 m−2 maintain this low growth behavior. Corrosion properties of FDBQ products have been made similar to that of the Standard material by performing an α-annealing step after the β-quenching. The annealing temperature and annealing time have been optimized in order to obtain good corrosion resistance. In-reactor data on Zircaloy-2 channels irradiated to a fuel assembly exposure of about 50 MWd/kgU indicate similar corrosion performance for the FDBQ and Standard materials. Finally, the in-reactor data on Zircaloy-2 channels show that bowing of the FDBQ and Standard channels is comparable up to a fast neutron fluence of about 7 × 1025 m−2.
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| 37. |
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| 38. |
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| 39. |
- Oslakovic, Cecilia, et al.
(författare)
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The role of phospholipid transfer protein in lipoprotein-mediated neutralization of the procoagulant effect of anionic liposomes.
- 2010
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 8, s. 766-772
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Tidskriftsartikel (refereegranskat)abstract
- Summary Background: Serum has the ability to neutralize the procoagulant properties of anionic liposomes, with transfer of phospholipids (PLs) to both high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles. Phospholipid transfer protein (PLTP) mediates transfer of PLs between HDL and other lipoproteins and conversion of HDL into larger and smaller particles. Objectives: To examine the role of PLTP in the neutralization of procoagulant liposomes. Methods: Procoagulant liposomes were incubated with different lipoproteins in the presence or absence of PLTP, and then tested for their ability to stimulate thrombin formation. Results and Conclusions: In the absence of added PLTP, the lipoprotein-enriched fraction, total HDL, HDL(3) and very high-density lipoprotein (VHDL) were all able to neutralize the procoagulant properties of the liposomes. In these samples, endogenous PLTP was present, as judged by western blotting. In contrast, no PLTP was present in LDL, HDL(2) and lipoprotein-deficient serum, all of which displayed no ability to neutralize the procoagulant liposomes. The phospholipid (PL) transfer activity was dependent on both enzyme (PLTP) and PL acceptor (lipoproteins). After treatment of the VHDL fraction with antiserum against PLTP, the neutralization of procoagulant activity was reduced, but could be regained by the addition of active PLTP. The neutralizing activity was dependent on a catalytically active form of PLTP, and addition of a low activity form of PLTP had no effect. In conclusion, PLTP was found to mediate transfer of anionic PLs to HDL and LDL, thereby neutralizing the effect of procoagulant liposomes resulting in a reduction of procoagulant activity.
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| 40. |
- Plymoth, A., et al.
(författare)
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Human bronchoalveolar lavage: biofluid analysis with special emphasis on sample preparation
- 2003
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Ingår i: Proteomics. ; 3:6
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Tidskriftsartikel (refereegranskat)abstract
- Respiratory diseases are an important health problem throughout the world. Whether caused by industrial pollutants, infections, smoking, cancer or metabolic diseases, damage to the lungs and airways often lead to morbidity or death. Bronchoalveolar lavage (BAL) obtained by fiber-optic bronchoscopy is a biofluid mirroring the expression of normally secreted pulmonary proteins and the products of activated cells and destructive processes. The characterization of the proteome within this compartment provides an opportunity to establish temporal and prognostic indicators of airway disease. The objective of this study was to develop methods of analysis of BAL samples, which achieved the highest level of annotation of the expression map of this proteome. We have optimized the process of sample preparation after investigating a variety of techniques including dialysis, ultramembrane filtration, precipitation and gel filtration. We have further studied methods to remove albumin from BAL in order to unmask proteins hidden on two-dimensional gels. In a pilot application of the method, BAL protein profiles obtained from healthy nonsmokers and smokers at risk for developing chronic obstructive pulmonary disease showed distinct differences.
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| 41. |
- Plymoth, Amelie, et al.
(författare)
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Rapid proteome analysis of bronchoalveolar lavage samples of lifelong smokers and never-smokers by micro-scale liquid chromatography and mass spectrometry
- 2006
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Ingår i: Clin Chem.. - : Oxford University Press (OUP). ; 52:4, s. 671-679
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The aim of this study was to determine whether relative qualitative and quantitative differences in protein expression could be related to smoke exposure or smoke-induced airway inflammation. We therefore explored and characterized the protein components found in bronchoalveolar lavage (BAL) fluid sampled from either lifelong smokers or never-smokers. METHODS: BAL fluid samples obtained by bronchoscopy from 60-year-old healthy never-smokers (n = 18) and asymptomatic smokers (n = 30) were analyzed in either pooled or individual form. Initial global proteomic analysis used shotgun digestion approaches on unfractionated BAL fluid samples (after minimal sample preparation) and separation of peptides by gradient (90-min) liquid chromatography (LC) coupled with on-line linear ion trap quadropole mass spectrometry (LTQ MS) for identification and analysis. RESULTS: LTQ MS identified 481 high- to low-abundance proteins. Relative differences in patterns of BAL fluid proteins in smokers compared with never-smokers were observed in pooled and individual samples as well as by 2-dimensional gel analysis. Gene ontology categorization of all annotated proteins showed a wide spectrum of molecular functions and biological processes. CONCLUSIONS: The described method provides comprehensive qualitative proteomic analysis of BAL fluid protein expression from never-smokers and from smokers at risk of developing chronic obstructive pulmonary disease. Many of the proteins identified had not been detected in previous studies of BAL fluid; thus, the use of LC-tandem MS with LTQ may provide new information regarding potentially important patterns of protein expression associated with lifelong smoking.
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| 42. |
- Prochazka, M, et al.
(författare)
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Factor V Leiden in pregnancies complicated by placental abruption
- 2003
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Ingår i: BJOG: An International Journal of Obstetrics & Gynaecology. - 1471-0528. ; 110:5, s. 462-466
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Tidskriftsartikel (refereegranskat)abstract
- Objective Recent studies suggest an increased prevalence of obstetric complications in female carriers of hereditary or acquired thrombophilias. The aim of the study was to determine if carriership of the factor V (FV) Leiden mutation (activated protein C [APC] resistance) is higher in women who have had of placental abruption during pregnancy. Design A retrospective case-control study. Setting University Hospital MAS, Malmo, Sweden. Methods A comparison of 102 women with placental abruption with 2371 prospectively collected controls. Carriership of FV Leiden was determined and the women were interviewed. Main outcome measures Proportion of FV Leiden carriership, first degree heritage of thrombosis and previous placental abruption in cases and controls. Results Carriage of FV Leiden was found in 15.7% of women who have had placental abruption as compared with 10.8% of controls (P = 0.12, odds ratio [OR] = 1.5, 95% confidence interval [CI] = 0.9-2.7). Around 20% of women with placental abruption reported first degree heritage for venous thrombosis, as compared with 6.7% of controls (P less than or equal to 0.001). Conclusions FV Leiden carriership was not significantly different in women with placental abruption. However, there was an increased prevalence of first degree heritage for venous thrombosis in women with placental abruption, indicating a higher prevalence of thrombophilia among women with placental abruption.
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| 43. |
- Rezende, SM, et al.
(författare)
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Genetic and phenotypic variability between families with hereditary protein S deficiency
- 2002
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 87:2, s. 258-265
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Tidskriftsartikel (refereegranskat)abstract
- While many mutations thought to result in protein S (PS) deficiency are known. there have been few attempts to relate genotype expression with plasma phenotype. We have investigated the nature and consequence of PS gene (PROS 1) mutations in 17 PS-deficient families who presented with mixed type I and type III phenotypes. Seven different mutations were found in nine families: delG-34 (STOP codon at -24), Val-24Glu, Arg49Cys. Asn217Ser, Gly295Val, +5 G to A intron j and His623Pro. PS wild type (PSWT) and the five missense mutants were transiently expressed in COS-1 cells. All mutants expressed lower (p<0.05) PS antigen compared to PSWT (100%). The mutants Val-24Glu, Gly295Val and His623Pro expressed very low/undetectable PS levels. The Mutant Asn217Ser produced around 30% of PSWT, while the mutant Arg49Cys had the highest PS levels (around 50%). Metabolic labelling and pulse-chase experiments showed that all of the mutants had impaired secretion, but this was of variable severity. Also, enhanced intracellular degradation of unsecreted material was found for all mutants. There was a strong correspondence between plasma free PS levels in carriers of the mutations. secreted PS from transfected COS-1 cells and labelled PS from 24 h conditioned medium in pulse-chase experiment. We conclude that the magnitude of secretion defect depends on the nature of the PROS1 mutation and influences the level of free PS in plasma. It is likely that the severity of the secretion defect will determine the risk for venous thrombosis.
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| 44. |
- Somajo, Sofia, et al.
(författare)
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Amino acid residues in the laminin G domains of protein S involved in tissue factor pathway inhibitor interaction.
- 2015
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 113:5, s. 976-987
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Tidskriftsartikel (refereegranskat)abstract
- Protein S functions as a cofactor for tissue factor pathway inhibitor (TFPI) and activated protein C (APC). The sex hormone binding globulin (SHBG)-like region of protein S, consisting of two laminin G-like domains (LG1 and LG2), contains the binding site for C4b-binding protein (C4BP) and TFPI. Furthermore, the LG-domains are essential for the TFPI-cofactor function and for expression of full APC-cofactor function. The aim of the current study was to localise functionally important interaction sites in the protein S LG-domains using amino acid substitutions. Four protein S variants were created in which clusters of surface-exposed amino acid residues within the LG-domains were substituted. All variants bound normally to C4BP and were fully functional as cofactors for APC in plasma and in pure component assays. Two variants, SHBG2 (E612A, I614A, F265A, V393A, H453A), involving residues from both LG-domains, and SHBG3 (K317A, I330A, V336A, D365A) where residues in LG1 were substituted, showed 50-60 % reduction in enhancement of TFPI in FXa inhibition assays. For SHBG3 the decreased TFPI cofactor function was confirmed in plasma based thrombin generation assays. Both SHBG variants bound to TFPI with decreased affinity in surface plasmon resonance experiments. The TFPI Kunitz 3 domain is known to contain the interaction site for protein S. Using in silico analysis and protein docking exercises, preliminary models of the protein S SHBG/TFPI Kunitz domain 3 complex were created. Based on a combination of experimental and in silico data we propose a binding site for TFPI on protein S, involving both LG-domains.
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| 45. |
- Varkey, Emma, et al.
(författare)
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Physical activity, self-efficacy and quality of life in patients with chronic pain, assessed during and 1 year after physiotherapy rehabilitation - a prospective follow-up study
- 2022
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Ingår i: Disability and Rehabilitation. - : Informa UK Limited. - 0963-8288 .- 1464-5165. ; 44:22, s. 6730-6737
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Tidskriftsartikel (refereegranskat)abstract
- Purpose The aim of this prospective cohort study was to evaluate the level of physical activity, self-efficacy and health-related quality of life in patients with chronic pain, at baseline and one year after physiotherapy rehabilitation at a specialist pain clinic. Materials and methods All patients who underwent rehabilitation at the physiotherapy unit at the Pain Centre at Sahlgrenska University Hospital/ostra in Gothenburg during a nine-month period were asked to participate in the study. The participants were evaluated regarding self-efficacy, health-related quality of life (HRQoL) and physical activity during physiotherapy treatment and one year later. Physical activity was measured both subjectively (self-reported physical activity) and objectively (accelerometer). Results Out of 42 patients who participated in the baseline evaluation, 28 (19 women and nine men) were included in the one-year follow-up. The patients had increased levels of vigorous physical activity at one-year follow-up, without deterioration of pain. There were no significant changes regarding self-efficacy and HRQoL. Levels of physical activity and perceived physical function may be associated to levels of physical activity 1 year after rehabilitation. Conclusion Patients with chronic pain can increase their level of vigorous physical activity after a period of rehabilitation without deterioration of pain.IMPLICATIONS FOR REHABILIATION Physical activity is an important part of rehabilitation for chronic pain patients, but many patients expect more pain after exercise, which they fear may affect performance and maintenance of physical activity. Patients with chronic pain at a specialist clinic increased their level of vigorous physical activity one year after physiotherapist led rehabilitation without deterioration of pain. Levels of physical activity and perceived physical function during rehabilitation may predict levels of physical activity 1 year after rehabilitation. Physiotherapist led rehabilitation seems to be beneficial for long-term improved physical activity in patients with chronic pain
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