Trying to understand the complex interactions that substrates and inhibitors have with the efflux transporter P-glycoprotein has been the subject of various publications. In this work, we have confined our study to substrates by picking a diverse set of 129 compounds based on the efflux ratios from Caco-2 permeability measurements. These compounds were then evaluated for P-glycoprotein inhibition using a calcein-AM assay. The subsequent data was used in a 3D-QSAR analysis using GRIND pharmacophore-based and physicochemical descriptors. Pharmacophore-based descriptors produced a much more robust model than the one obtained from physicochemical-based descriptors. This supports the process proposed by Seelig and co-workers previously published whereby the substrate enters the membrane as the first step and is then recognized by P-glycoprotein in a second step. The strong correlation, highlighted by PLS statistical analysis, between pharmacophoric descriptors and inhibition values suggests that substrate interaction, with perhaps the mouth of the protein or another binding site, plays a key role in the efflux process, yielding a model in which diffusion across the membrane is less important than substrate-protein interaction. One pharmacophore emerged from the analysis of the model. We pose that the recognition elements, at least determined by the molecules used in this study, are two hydrophobic groups 16.5 A apart and two hydrogen-bond-acceptor groups 11.5 A apart and that the dimensions of the molecule also plays a role in its recognition as a substrate.

A new instrument capable of recording the load-extension behavior of a yarn in cyclic testing is described. The instrument is constructed in such a fashion that it is possible to vary both the humidity and the temperature of the air in which the yarn is tested. Frequency and amplitude are also variable over a limited range.It is shown that the range of fatigue lifetimes of yarns in cycling conforms to the Weibull distribution, which is based on the theory of extreme values. Experimental evidence indicates that increased "plasticization" brought about by heat and/or water tends to increase the fatigue life of fibers.The failure of twisted yarns in fatigue testing is different than that observed in untwisted structures This fact points out the difficulty in extrapolating the results presented here to actual tire cord failures.-

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A procedure giving reproducible data has been devised for the preparation, exposure, and testing of yarns in fabric form for resistance to actinic degradation. Effects of season, test location, and sample presentation have been considered. It has been shown that ultraviolet radiation is a more useful index of exposure than total incident radiation. It is suggested that the cyclical seasonal variation of ozone in the upper atmosphere is responsible for the observed seasonal variations in ultraviolet radiation. It is also suggested that the difference in degradation rate noted between South Florida and Arizona are primarily a function of the observed large difference in relative humidity between those sites. Preliminary accelerated tests in Xenon and Sunshine Carbon Arc Weatherometers are shown to correlate with direct-to-weather tests based on an ultraviolet radiation index.

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The only improvement seen in increasing the molecular orientation of PBI fiber over that exhibited by presently defined target property material is the improvement seen in the strength and stiffness of the material at high strain rates. This improvement, however, cannot be extrapolated to a good impact performance. No advantage of fiber crystallization was detected in the properties measured in this evaluation conducted in accordance with the current state of the art of testing of high temperature fibers. However, as the testing of high temperature performance fibers becomes more sophisticated, advantages of crystallization undetectable in this investigation may appear. Should this occur, it would then be advisable to explore the crystallization of PBI further in an attempt to induce a higher degree of crystallinity than accomplished in this work while maintaining adequate tensile properties.