Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

The proteasome is the central component of the main cellular protein degradation pathway. During the past four decades, the critical function of the proteasome in numerous physiological processes has been revealed, and proteasome activity has been linked to various human diseases. The proteasome prevents the accumulation of misfolded proteins, controls the cell cycle, and regulates the immune response, to name a few important roles for this macromolecular “machine.” As a therapeutic target, proteasome inhibitors have been approved for the treatment of multiple myeloma and mantle cell lymphoma. However, inability to sufficiently inhibit proteasome activity at tolerated doses has hampered efforts to expand the scope of proteasome inhibitor-based therapies. With emerging new modalities in myeloma, it might seem challenging to develop additional proteasome-based therapies. However, the constant development of new applications for proteasome inhibitors and deeper insights into the intricacies of protein homeostasis suggest that proteasome inhibitors might have novel therapeutic applications. Herein, we summarize the latest advances in proteasome inhibitor development and discuss the future of proteasome inhibitors and other proteasome-based therapies in combating human diseases

Proteasome Inhibitors: Harnessing Proteostasis to Combat Disease

The proteasome is the central component of the main cellular protein degradation pathway. During the past four decades, the critical function of the proteasome in numerous physiological processes has been revealed, and proteasome activity has been linked to various human diseases. The proteasome prevents the accumulation of misfolded proteins, controls the cell cycle, and regulates the immune response, to name a few important roles for this macromolecular “machine.” As a therapeutic target, proteasome inhibitors have been approved for the treatment of multiple myeloma and mantle cell lymphoma. However, inability to sufficiently inhibit proteasome activity at tolerated doses has hampered efforts to expand the scope of proteasome inhibitor-based therapies. With emerging new modalities in myeloma, it might seem challenging to develop additional proteasome-based therapies. However, the constant development of new applications for proteasome inhibitors and deeper insights into the intricacies of protein homeostasis suggest that proteasome inhibitors might have novel therapeutic applications. Herein, we summarize the latest advances in proteasome inhibitor development and discuss the future of proteasome inhibitors and other proteasome-based therapies in combating human diseases

Pressure-induced hole doping of the Hg-based cuprate superconductors

We investigate the electronic structure and the hole content in the copper-oxygen planes of Hg based high Tc cuprates for one to four CuO2 layers and hydrostatic pressures up to 15 GPa. We find that with the pressure-induced additional number of holes of the order of 0.05e the density of states at the Fermi level changes approximately by a factor of 2. At the same time the saddle point is moved to the Fermi level accompanied by an enhanced k_z dispersion. This finding explains the pressure behavior of Tc and leads to the conclusion that the applicability of the van Hove scenario is restricted. By comparison with experiment, we estimate the coupling constant to be of the order of 1, ruling out the weak coupling limit.Comment: 4 pages, 4 figure

Analysis of Diffusion of Ras2 in Saccharomyces cerevisiae Using Fluorescence Recovery after Photobleaching

Binding, lateral diffusion and exchange are fundamental dynamic processes involved in protein association with cellular membranes. In this study, we developed numerical simulations of lateral diffusion and exchange of fluorophores in membranes with arbitrary bleach geometry and exchange of the membrane localized fluorophore with the cytosol during Fluorescence Recovery after Photobleaching (FRAP) experiments. The model simulations were used to design FRAP experiments with varying bleach region sizes on plasma-membrane localized wild type GFP-Ras2 with a dual lipid anchor and mutant GFP-Ras2C318S with a single lipid anchor in live yeast cells to investigate diffusional mobility and the presence of any exchange processes operating in the time scale of our experiments. Model parameters estimated using data from FRAP experiments with a 1 micron x 1 micron bleach region-of-interest (ROI) and a 0.5 micron x 0.5 micron bleach ROI showed that GFP-Ras2, single or dual lipid modified, diffuses as single species with no evidence of exchange with a cytoplasmic pool. This is the first report of Ras2 mobility in yeast plasma membrane. The methods developed in this study are generally applicable for studying diffusion and exchange of membrane associated fluorophores using FRAP on commercial confocal laser scanning microscopes.Comment: Accepted for publication in Physical Biology (2010). 28 pages, 7 figures, 3 table

Identification and analysis of the bacterial endosymbiont specialized for production of the chemotherapeutic natural product ET‐743

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/115956/1/emi12908.pd

The ACS Virgo Cluster Survey IV: Data Reduction Procedures for Surface Brightness Fluctuation Measurements with the Advanced Camera for Surveys

The Advanced Camera for Surveys (ACS) Virgo Cluster Survey is a large program to image 100 early-type Virgo galaxies using the F475W and F850LP bandpasses of the Wide Field Channel of the ACS instrument on the Hubble Space Telescope (HST). The scientific goals of this survey include an exploration of the three-dimensional structure of the Virgo Cluster and a critical examination of the usefulness of the globular cluster luminosity function as a distance indicator. Both of these issues require accurate distances for the full sample of 100 program galaxies. In this paper, we describe our data reduction procedures and examine the feasibility of accurate distance measurements using the method of surface brightness fluctuations (SBF) applied to the ACS Virgo Cluster Survey F850LP imaging. The ACS exhibits significant geometrical distortions due to its off-axis location in the HST focal plane; correcting for these distortions by resampling the pixel values onto an undistorted frame results in pixel correlations that depend on the nature of the interpolation kernel used for the resampling. This poses a major challenge for the SBF technique, which normally assumes a flat power spectrum for the noise. We investigate a number of different interpolation kernels and show through an analysis of simulated galaxy images having realistic noise properties that it is possible, depending on the kernel, to measure SBF distances using distortion-corrected ACS images without introducing significant additional error from the resampling. We conclude by showing examples of real image power spectra from our survey.Comment: ApJS, in press, complete version of the paper at the link: http://www.physics.rutgers.edu/~pcote/acs/publications.htm

Change in hematologic indices over time in pediatric inflammatory bowel disease treated with azathioprin

Azathioprine leads to changes in mean corpuscular volume (MCV) and white blood cell (WBC) indices reflecting efficacy or toxicity. Understanding the interactions between bone marrow stem cells and azathioprine could highlight abnormal response patterns as forerunners for hematologic malignancies. This study gives a statistical description of factors influencing the relationship between MCV and WBC in children with inflammatory bowel disease treated with azathioprine. We found that leukopenia preceded macrocytosis. Macrocytosis is therefore not a good predictor of leukopenia. Further studies will be necessary to determine the subgroup of patients at increased risk of malignancies based on bone marrow response. © 2010 Soman et al., publisher and licensee Adis Data Information BV