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- Labberton, L, et al.
(författare)
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Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection
- 2016
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7, s. 12616-
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Tidskriftsartikel (refereegranskat)abstract
- Polyphosphate is an inorganic procoagulant polymer. Here we develop specific inhibitors of polyphosphate and show that this strategy confers thromboprotection in a factor XII-dependent manner. Recombinant Escherichia coli exopolyphosphatase (PPX) specifically degrades polyphosphate, while a PPX variant lacking domains 1 and 2 (PPX_Δ12) binds to the polymer without degrading it. Both PPX and PPX_Δ12 interfere with polyphosphate- but not tissue factor- or nucleic acid-driven thrombin formation. Targeting polyphosphate abolishes procoagulant platelet activity in a factor XII-dependent manner, reduces fibrin accumulation and impedes thrombus formation in blood under flow. PPX and PPX_Δ12 infusions in wild-type mice interfere with arterial thrombosis and protect animals from activated platelet-induced venous thromboembolism without increasing bleeding from injury sites. In contrast, targeting polyphosphate does not provide additional protection from thrombosis in factor XII-deficient animals. Our data provide a proof-of-concept approach for combating thrombotic diseases without increased bleeding risk, indicating that polyphosphate drives thrombosis via factor XII.
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- Chaillou, Thomas, 1985-, et al.
(författare)
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NDUFA4L2 : Connecting metabolic signals and mitochondrial function in cardiac and skeletal muscle
- 2016
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Ingår i: Free Radical Biology & Medicine. - : Elsevier. - 0891-5849 .- 1873-4596. ; 100:Suppl., s. S186-S186
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Tidskriftsartikel (refereegranskat)abstract
- The nuclear-encoded mitochondrial protein NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like 2 (NDUFA4L2) was recently identified. NDUFAe4L2 is shown to be induced by hypoxia via HIF1α and is thought to inhibit production of mitochondrial reactive oxygen species in fibroblasts exposed to hypoxia. Here the aim was to characterize the role of NDUFA4L2 in the mitochondria-rich tissues skeletal and cardiac muscle. We show hypoxia induced NDUFA4L2 expression in isolated muscle fibers and in cardiomyocytes with full activation after ~3-6 h in hypoxia. The half-maximal O2 level for NDUFA4L2 expression (~4.6 % of ambient O2) suggests sensitivity to changes in O2 tension that occur under physiological conditions (e.g. exercise, moderate ischemia). We identified that the NDUFA4L2 gene promoter has binding sites for transcription factors other than HIF-1α; repetitive sites for PPARα,γ and one for Nrf2. NDUFA4L2 overexpression resulted in functional effects on skeletal and cardiac muscle; e.g. it alters cellular Ca2+ signaling and the expression of Ca2+ handling genes. Further, NDUFA4L2 overexpression reduces muscle mass (~20%), leading to a decreased force production in skeletal muscle. The NDUFA4L2-induced loss of muscle mass was associated with increases in mRNA levels of e.g. MurF1, Mul1, caspase-3 and Bax. Additionally, femoral artery ligation (FAL) induced NDUFA4L2 expression, which correlates with the decreased force production eight days post-FAL in skeletal muscle. Moreover, NDUFA4L2 upregulates antioxidant gene expression and silencing NDUFA4L2 makes cardiac cells less tolerant to hypoxia/re-oxygenation. Our results suggest that NDUFA4L2 expression affects vital functions in muscle cells and at least part of this effect is mediated by a link between NDUFA4L2 and nuclear gene expression. Thus, NDUFA4L2 might act as an integrator of the nutritional, environmental and functional status in muscle cells.
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- Fredlund, E., et al.
(författare)
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Metabolite profiles of the biocontrol yeast Pichia anomala J121 grown under oxygen limitation
- 2004
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Ingår i: Applied Microbiology and Biotechnology. - : Springer. - 0175-7598 .- 1432-0614. ; 64:3, s. 403-409
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Tidskriftsartikel (refereegranskat)abstract
- The biocontrol yeast Pichia anomala J121 prevents mould growth during the storage of moist grain under low oxygen/high carbon dioxide conditions. Growth and metabolite formation of P. anomala was analyzed under two conditions of oxygen limitation: (a) initial aerobic conditions with restricted oxygen access during the growth period and (b) initial microaerobic conditions followed by anaerobiosis. Major intra- and extracellular metabolites were analyzed by high-resolution magic-angle spinning (HR-MAS) NMR and HPLC, respectively. HR-MAS NMR allows the analysis of major soluble compounds inside intact cells, without the need for an extraction step. Biomass production was higher in treatment (a), whereas the specific ethanol production rate during growth on glucose was similar in both treatments. This implies that oxygen availability affected the respiration and not the fermentation of the yeast. Following glucose depletion, ethanol was oxidized to acetate in treatment (a), but continued to be produced in (b). Arabitol accumulated in the culture substrate of both treatments, whereas glycerol only accumulated in treatment (b). Trehalose, arabitol, and glycerol accumulated inside the cells in both treatments. The levels of these metabolites were generally significantly higher in treatment (b) than in (a), indicating their importance for P. anomala during severe oxygen limitation/anaerobic conditions.
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- Harding, SG, et al.
(författare)
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Water transport during the drying of cardboard studied by NMR imaging and diffusion techniques
- 2001
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Ingår i: Chemical Engineering Science. - 0009-2509. ; 56:18, s. 5269-5281
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Tidskriftsartikel (refereegranskat)abstract
- An understanding of the distribution of water in wood pulp during drying is of fundamental importance to the paper industry. In this study nuclear magnetic resonance (NMR) imaging is used to measure quantitative water profiles during the drying of liquid packaging board with initial water ratio (water: dry mass) of approximately 1.5. The drying was carried out in situ within the magnet, under a range of air temperatures (20-60 degreesC), flow rates (135-400 1 h(-1)) and humidity conditions. One dimensional (1D) slice selective profiles were acquired along the thickness direction of the cardboard with a spatial resolution of 15 mum pixel(-1) at regular time points during the drying process. To give further insight into the distribution of water within the cellulose fibre matrix pulsed gradient spin echo (PGSE) diffusion measurements were acquired on samples equilibrated to water ratios between 0.2 and 2.0. The water profiles show that the initial water concentration varies between the three layers in the composite cardboard. At faster drying conditions the initial water loss is predominantly from the two outer layers, while with slower drying conditions the water loss is more homogeneous throughout all layers. The diffusion coefficient of the fibre water was found to decrease significantly with water content and was slower across the cardboard thickness (thus across the fibres) than parallel to the cardboard surface. (C) 2001 Elsevier Science Ltd. All rights reserved.
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