PubMed · 15895056
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M S Duggal, M E J Curzon, R Balmer, J Roberts. 2005-05-14. Potential toxicity.. https://doi.org/10.1038/sj.bdj.4812338
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G-proteins cycle between an inactive GDP-bound state and an active GTP-bound state, serving as molecular switches that coordinate cellular signaling. We recently used phage display to identify a series of peptides that bind G alpha subunits in a nucleotide-dependent manner [Johnston, C. A., Willard, F. S., Jezyk, M. R., Fredericks, Z., Bodor, E. T., Jones, M. B., Blaesius, R., Watts, V. J., Harden, T. K., Sondek, J., Ramer, J. K., and Siderovski, D. P. (2005) Structure 13, 1069-1080]. Here we describe the structural features and functions of KB-1753, a peptide that binds selectively to GDP x AlF4(-)- and GTPgammaS-bound states of G alpha(i) subunits. KB-1753 blocks interaction of G alpha(transducin) with its effector, cGMP phosphodiesterase, and inhibits transducin-mediated activation of cGMP degradation. Additionally, KB-1753 interferes with RGS protein binding and resultant GAP activity. A fluorescent KB-1753 variant was found to act as a sensor for activated G alpha in vitro. The crystal structure of KB-1753 bound to G alpha(i1) x GDP x AlF4(-) reveals binding to a conserved hydrophobic groove between switch II and alpha3 helices and, along with supporting biochemical data and previous structural analyses, supports the notion that this is the site of effector interactions for G alpha(i) subunits.
PURPOSE: To quantify the effects of the ratio of indomethacin to Neusilin US2 and the processing humidity on the amorphization kinetics, stability and nature of the interaction. MATERIALS AND METHODS: A porcelain jar mill with zirconia balls was used to affect conversion of the physical mixtures (48 g) of indomethacin and Neusilin US2 (in the ratios 1:1 to 1:5) to amorphous states at room temperature (25 degrees C) employing either 0% RH or 75% RH. The percent crystallinity in the samples was determined from ATR-FTIR scans chemometrically. The physical stability of these co-ground amorphous powders was evaluated at 40 degrees C/75% RH and 40 degrees C/0% RH. RESULTS: The lower the ratio of indomethacin to Neusilin US2, the faster is the amorphization during co-grinding. Higher humidity facilitates amorphization with a more pronounced effect at the lower ratio of indomethacin to Neusilin US2. There is further amorphization of some of the partially amorphized samples on storage at 40 degrees C/75% RH for 3 months. Hydrogen bonding and surface interaction between metal ions of Neusilin US2 and indomethacin can explain changes in the FTIR spectra. CONCLUSIONS: The processing humidity and the ratio of indomethacin to Neusilin US2 are important factors to be considered to affect amorphization during ball milling. Amorphous indomethacin can be stabilized by co-grinding with Neusilin US2.
Recent advances in physical models of skeletal dosimetry utilize high-resolution 3-dimensional microscopic computed tomography images of trabecular spongiosa. These images are coupled to radiation transport codes to assess energy deposition within active bone marrow and trabecular endosteum. These transport codes rely primarily on the segmentation of the spongiosa images into bone and marrow voxels. Image thresholding has been the segmentation of choice for bone sample images because of its extreme simplicity. However, the ability of the segmentation to reproduce the physical boundary between bone and marrow depends on the selection of the threshold value. Statistical models, as well as visual inspection of the image, have been employed extensively to determine the correct threshold. Both techniques are affected by partial volume effect and can provide unexpected results if performed without care. In this study, we propose a new technique to threshold trabecular spongiosa images based on visual inspection of the image gradient magnitude. We first show that the gradient magnitude of the image reaches a maximum along a surface that remains almost independent of partial volume effect and that is a good representation of the physical boundary between bone and marrow. A computer program was then developed to allow a user to compare the position of the iso-surface produced by a threshold with the gradient magnitude. The threshold that produces the iso-surface that best coincides with the maximum gradient is chosen. The technique was finally tested with a set of images of a true bone sample with different resolutions, as well as with three images of a cube of Duocell aluminium foam of known mass and density. Both tests demonstrate the ability of the gradient magnitude technique to retrieve sample volumes or media volume fractions with 1% accuracy at 30 microm voxel size.