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21.
22.
Cyril Rauch Stuart W. Paine Peter Littlewood 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
Failure of treatment in over 90% of patients with metastatic cancer is due to acquired MDR. P-glycoprotein (Pgp) remains the archetypal drug membrane transporter expressed in many MDR cancer cells. Albeit the ATPase activity of Pgp is triggered by the presence of drug in the membrane, it is commonly assumed that when two drug molecules meet the same Pgp the protein cannot handle them efficiently due to steric effects and as a result the ATPase activity drops. However it is also possible that drug accumulating in the lipid-phase may affect the membrane in such a way that it imposes the mechanical closure of transporters by opposing the force mediated by ATP consumption. In this context, long range interactions between drug and membrane proteins could exist.Methods
Recent data concerning Pgp structure have allowed us to formalize this hypothesis and we present a physico-mathematical model that is not based on predictive QSAR or other empirical methods applied to experimental data.Results
Long range mechanical interactions between Pgp and drugs are predicted to occur at an external concentration of drug ~ 10–100 μM as previously determined experimentally at which concentration ~ 50% of transporters should be rendered inactive.Conclusion
Distance interaction(s) between Pgp and drugs exist explaining an ill-defined effect concerning the ability of any drug to inhibit Pgp once a threshold concentration in the membrane has been reached.General significance
Potential application of the theory in the field of pharmacology concentrating on the notion of molecular promiscuity and toxicity in drug discovery prediction is discussed. 相似文献23.
24.
Christine Rauch Michael Trieb Fajar R. Wibowo Bernd Wellenzohn Erwin Mayer Klaus R. Liedl 《Journal of biomolecular structure & dynamics》2013,31(6):695-706
Abstract CpG methylation determines a variety of biological functions of DNA. The methylation signal is interpreted by proteins containing a methyl-CpG binding domain (MBDs). Based on the NMR structure of MBD1 complexed with methylated DNA we analysed the recognition mode by means of molecular dynamics simulations. As the protein is monomeric and recognizes a symmetrically methylated CpG step, the recognition mode is an asymmetric one. We find that the two methyl groups do not contribute equally to the binding energy. One methyl group is associated with the major part of the binding energy and the other one nearly does not contribute at all. The contribution of the two cytosine methyl groups to binding energy is calculated to be ?3.6 kcal/mol. This implies a contribution of greater than two orders of magnitude to the binding constant. The conserved amino acid Asp32 is known to be essential for DNA binding by MBD1, but so far no direct contact with DNA has been observed. We detected a direct DNA base contact to Asp32. This could be the main reason for the importance of this amino acid. MBD contacts DNA exclusively in the major groove, the minor groove is reserved for histone contacts. We found a deformation of the minor groove shape due to complexation by MBD1, which indicates an information transfer between the major and the minor groove. 相似文献
25.
Qiaomei Fu Alissa Mittnik Philip L.F. Johnson Kirsten Bos Martina Lari Ruth Bollongino Chengkai Sun Liane Giemsch Ralf Schmitz Joachim Burger Anna Maria Ronchitelli Fabio Martini Renata G. Cremonesi Jiří Svoboda Peter Bauer David Caramelli Sergi Castellano David Reich Johannes Krause 《Current biology : CB》2013,23(7):553-559
26.
Viral vectors have a wide variety of applications ranging from fundamental studies of viruses to therapeutics. Recombinant viral vectors are usually constructed using methods of reverse genetics to obtain the genetic material of the viral vector. The physicochemical properties of DNA and RNA make them unable to access cells by themselves, and they require assistance to achieve intracellular delivery. Non-viral delivery vectors can be used for this purpose if they enable efficient intracellular delivery without interfering with the viral life cycle. In this report, we utilize Semliki Forest virus (genus alphavirus) based RNA and DNA vectors to study the transfection efficiency of the non-viral cell-penetrating peptide-based delivery vector PepFect6 in comparison with that of the cationic liposome-based Lipofectamine 2000, and assess their impact on viral replication. The optimal conditions for transfection were determined for both reagents. These results demonstrate, for the first time, the ability of PepFect6 to transport large (13-19 kbp) constructs across the cell membrane. Curiously, DNA molecules delivered using the PepFect6 reagent were found to be transported to the cell nucleus approximately 1.5 hours later than DNA molecules delivered using the Lipofectamine 2000 reagent. Finally, although both PepFect6 and Lipofectamine 2000 reagents can be used for alphavirus research, PepFect6 is preferred because it does not induce changes in the normal cellular phenotype and it does not affect the normal replication-infection cycle of viruses in previously transfected cells. 相似文献
27.
Nataliya Di Donato Ying Y. Jean A. Murat Maga Briana D. Krewson Alison B. Shupp Maria I. Avrutsky Achira Roy Sarah Collins Carissa Olds Rebecca A. Willert Agnieszka M. Czaja Rachel Johnson Jessi A. Stover Steven Gottlieb Deborah Bartholdi Anita Rauch Amy Goldstein Victoria Boyd-Kyle Kimberly A. Aldinger Ghayda M. Mirzaa Anke Nissen Karlla W. Brigatti Erik G. Puffenberger Kathleen J. Millen Kevin A. Strauss William B. Dobyns Carol M. Troy Robert N. Jinks 《American journal of human genetics》2016,99(5):1117-1129
28.
Paratscha Roman Von Der Thannen Magdalena Smutny Roman Lampalzer Thomas Strauss Alfred Rauch Hans Peter 《The International Journal of Life Cycle Assessment》2019,24(11):2035-2053
The International Journal of Life Cycle Assessment - This study emerged from a research project that aimed to develop a Life Cycle Assessment (LCA) model for torrent control structures. This... 相似文献
29.
Objective: A previous study showed that increasing the portion sizes of all foods led to an increase in energy intake that was sustained over 2 days. The objective of the present study was to determine whether participants would compensate for excess energy intake or continue to overeat when portion sizes were increased for 11 days. Research Methods and Procedures: Participants in the study were 23 normal‐weight and overweight participants (10 women and 13 men). All of their foods and caloric beverages were provided during two different periods of 11 consecutive days, which were separated by a 2‐week interval. During one period, standard portions of all items were served; during the other, all portion sizes were increased by 50%. Results: The 50% increase in portion sizes resulted in a mean increase in daily energy intake of 423 ± 27 kcal (p < 0.0001), which did not differ significantly between women and men. This increase was sustained for 11 days and did not decline significantly over time, leading to a mean cumulative increase in intake of 4636 ± 532 kcal. A significant effect of portion size on intake was seen at all meals and in all categories of foods except fruit (as a snack) and vegetables. The effect of portion size on intake was not influenced by the body weight status of participants. Discussion: These results strengthen the evidence suggesting that increased portions contribute to the overconsumption of energy and to excess body weight. 相似文献
30.
Böhme H Rudloff E Schöne F Schumann W Hüther L Flachowsky G 《Archives of animal nutrition》2007,61(4):308-316
The nutritive value of genetically modified myristic acid-rich rapeseed, in which a acyl-thioesterase gene inserted, was studied. Crude nutrients, amino acid and fatty acid profiles as well as mineral and glucosinolate contents were determined and compared with those of the non-transgenic parental cultivar. The concentration of crude nutrients, minerals and amino acids were found to be within the range of natural variance. The myristic and palmitic acid content increased from 0.1 - 11.4% and from 3.6-20%, respectively, at the expense of oleic acid, which decreased from 68.6-42.6% of total fatty acids. The glucosinolate contents increased from 12.4 micromol/g in the parental plant to 19 micromol/g DM in the GM-plant. Full-fat rapeseed of both cultivars was incorporated in pig diets at a level of 15%, and the digestibility and the production efficiency were tested under ad libitum feeding conditions with ten pigs each over the growing finishing period from 32-105 kg BW. The experimental diets did not show significant differences in digestibility and energetic feeding value. However, feed intake and weight gain decreased presumably due to the increasing glucosinolate intake associated with the feeding of transgenic rapeseed. The dietary fatty acids profile influenced the fatty acid profile of body fat. Myristic acid accumulated in back fat and intramuscular fat while the oleic acid content decreased. The increased glucosinolate intake affected the weight of thyroid glands and their iodine concentration. 相似文献