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- Lindahl, Lina, 1984, et al.
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THE INFLUENCE OF MEMBRANE COMPOSTION ON ACETIC ACID PERMEABILITY AND POTENTIALLY ACETIC ACID TOLERANCE
- 2014
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In: ISSY31: 31st International Specialised Symposium on Yeast.
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Other publication (other academic/artistic)abstract
- Compounds entering the cell do so either by passive diffusion over the plasma membrane or through transporters in the membrane. The specific lipid composition of the plasma membrane influences both the passive diffusion rate but also the activity of membrane proteins. Acetic acid, a major hurdle in fermentation processes using lignocellulosic material, is believed to pass through the membrane in its protonated from mainly by passive diffusion [1]. Sterols and sphingolipids are lipid classes thought to contribute to membrane rigidity. Sterols are often found to be involved in stress resistance [2, 3] and in our previous work sphingolipids were pointed at as an important constituent of the plasma membrane of the yeast Zygosaccharomyces bailii, known to be very tolerant to acetic acid, suggesting a possible link between acetic acid tolerance and sphingolipid relative abundance in the membrane [4]. Here we will provide supporting evidence of the importance of sphingolipids and sterols in acetic acid membrane permeability. We have combined biochemistry techniques with in silico membrane modeling to answer the question how membrane engineering can be used to decrease acetic acid membrane permeability. [1] Verduyn et al. Yeast (1992) 501-517. [2] Alexandre et al. FEMS Microbiology Letters (1994) 124:17-22. [3] Liu et al. Journal of Applied Microbiology (2013) 114:482-491. [4] Lindberg et al. PlosONE (2003) 8(9): e73936.
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- Skoglund, Karin, et al.
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In vivo CYP3A activity and pharmacokinetics of imatinib in relation to therapeutic outcome in chronic myeloid leukemia patients
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Other publication (other academic/artistic)abstract
- Introduction: The hepatic enzymes CYP3A4 and CYP3A5 metabolize the tyrosine kinase inhibitor imatinib into a large number of metabolites including the pharmacologically active N-desmethyl imatinib (CGP74588). Because the metabolic activity of CYP3A varies considerably between individuals and a previous pilot study suggested an inverse association between in vivo CYP3A metabolic activity and therapeutic outcome of imatinib, the primary aim of this study was to investigate the influence of CYP3A metabolic activity on the outcome of imatinib therapy in chronic myeloid leukemia patients.Methods: Fifty-five patients were included and CYP3A activity was estimated in vivo using quinine as a probe drug. Imatinib and CGP74588 trough concentrations in the plasma were determined at steady state in 34 patients. Cytogenetic and molecular responses after 12 months of first-line imatinib were retrospectively collected from patients’ medical records.Results: Patients with optimal response to imatinib (complete cytogenetic response (CCgR) or molecular response of BCR-ABL <1%) did not have different levels of CYP3A activity compared to non-optimal responders. Similar results were found when analyzing the molecular response and CCgR separately. Neither the imatinib trough concentration nor the CGP74588/imatinib ratio were significantly associated with CYP3A activity.Conclusion: CYP3A enzyme activity, as measured by quinine metabolic ratio, does not correlate with the plasma concentrations of imatinib or CGP74588 and is not predictive of imatinib therapeutic outcome. These results indicate that even though imatinib is metabolized by CYP3A enzymes, this activity is not the ratelimiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes such as plasma protein binding or transport protein activity to look for the major contributor to patient variability in imatinib plasma concentration.
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- Toijer, Elin, et al.
(author)
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Ab initio investigation of effects of solute segregation onintergranular fracture in nickel: Importance of fracture path andstructural modification
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Other publication (other academic/artistic)abstract
- In the present work, the impact of chromium and silicon impurities on thegrain boundary strength of nickel has been investigated by means of densityfunctional theory (DFT) modelling. The excess-energy approach has beenused to model the impact of the solutes, and a quantitative comparison of their corresponding impact in combination with the impact of phosphorus, self-interstitial Ni is here presented. The results of main importance are inreference to the Cr: It is shown that the common assumption that interstitial Cr segregates to the center of a GB gives decisively erroneous resultsregarding the impact of the solute in this context. The solute will instead remain at the GB surface, and consequently self interstitial Ni will migrateto the GB center. This configuration will give an important weakening tothe structure, in clear contrast to previous studies were Cr has been shown to promote strengthening of the same structure. However, the results in the current work further show that this weakening is in fact not due to the presence of Cr, but to the enrichment of self-interstitial atoms in the GB center.
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