Lysosomotropic Properties of Weakly Basic Anticancer Agents Promote Cancer Cell Selectivity In Vitro

A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author’s publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.Drug distribution in cells is a fundamentally important, yet often overlooked, variable in drug efficacy. Many weakly basic anticancer agents accumulate extensively in the acidic lysosomes of normal cells through ion trapping. Lysosomal trapping reduces the activity of anticancer drugs, since anticancer drug targets are often localized in the cell cytosol or nucleus. Some cancer cells have defective acidification of lysosomes, which causes a redistribution of trapped drugs from the lysosomes to the cytosol. We have previously established that such differences in drug localization between normal and cancer cells can contribute to the apparent selectivity of weakly basic drugs to cancer cells in vitro. In this work, we tested whether this intracellular distribution-based drug selectivity could be optimized based on the acid dissociation constant (pKa) of the drug, which is one of the determinants of lysosomal sequestration capacity. We synthesized seven weakly basic structural analogs of the Hsp90 inhibitor geldanamycin (GDA) with pKa values ranging from 5 to 12. The selectivity of each analog was expressed by taking ratios of anti-proliferative IC50 values of the inhibitors in normal fibroblasts to the IC50 values in human leukemic HL-60 cells. Similar selectivity assessments were performed in a pair of cancer cell lines that differed in lysosomal pH as a result of siRNA-mediated alteration of vacuolar proton ATPase subunit expression. Optimal selectivity was observed for analogs with pKa values near 8. Similar trends were observed with commercial anticancer agents with varying weakly basic pKa values. These evaluations advance our understanding of how weakly basic properties can be optimized to achieve maximum anticancer drug selectivity towards cancer cells with defective lysosomal acidification in vitro. Additional in vivo studies are needed to examine the utility of this approach for enhancing selectivity

Rheological Chaos in a Scalar Shear-Thickening Model

We study a simple scalar constitutive equation for a shear-thickening material at zero Reynolds number, in which the shear stress \sigma is driven at a constant shear rate \dot\gamma and relaxes by two parallel decay processes: a nonlinear decay at a nonmonotonic rate R(\sigma_1) and a linear decay at rate \lambda\sigma_2. Here \sigma_{1,2}(t) = \tau_{1,2}^{-1}\int_0^t\sigma(t')\exp[-(t-t')/\tau_{1,2}] {\rm d}t' are two retarded stresses. For suitable parameters, the steady state flow curve is monotonic but unstable; this arises when \tau_2>\tau_1 and 0>R'(\sigma)>-\lambda so that monotonicity is restored only through the strongly retarded term (which might model a slow evolution of material structure under stress). Within the unstable region we find a period-doubling sequence leading to chaos. Instability, but not chaos, persists even for the case \tau_1\to 0. A similar generic mechanism might also arise in shear thinning systems and in some banded flows.Comment: Reference added; typos corrected. To appear in PRE Rap. Com

Implementation of kriging methods in mobile GIS to estimate damage to buildings in crisis scenarios

In the paper an example for the application of kriging methods to estimate damage to buildings in crisis scenarios is introduced. Furthermore, the Java implementations for Ordinary and Universal Kriging on mobile GIS are presented. As variogram models an exponential, a Gaussian and a spherical variogram are tested in detail. Different test constellations are introduced with various information densities. As test data set, public data from the analysis of the 2010 Haiti earthquake by satellite images are pre-processed and visualized in a Geographic Information System. As buildings, topography and other external influences cannot be seen as being constant for the whole area under investigation, semi variograms are calculated by consulting neighboured classified buildings using the so called moving window method. The evaluation of the methods shows that the underlying variogram model is the determining factor for the quality of the interpolation rather than the choice of the kriging method or increasing the information density of a random sample. The implementation is completely realized with the programming language Java. Thereafter, the implemented software component is integrated into GeoTech Mobile, a mobile GIS Android application based on the processing of standardized spatial data representations defined by the Open Geospatial Consortium (OGC). As a result the implemented methods can be used on mobile devices, i.e. they may be transferred to other application fields. That is why we finally point out further research with new applications in the Dubai region

GRAVITY: getting to the event horizon of Sgr A*

We present the second-generation VLTI instrument GRAVITY, which currently is in the preliminary design phase. GRAVITY is specifically designed to observe highly relativistic motions of matter close to the event horizon of Sgr A*, the massive black hole at center of the Milky Way. We have identified the key design features needed to achieve this goal and present the resulting instrument concept. It includes an integrated optics, 4-telescope, dual feed beam combiner operated in a cryogenic vessel; near infrared wavefront sensing adaptive optics; fringe tracking on secondary sources within the field of view of the VLTI and a novel metrology concept. Simulations show that the planned design matches the scientific needs; in particular that 10 microarcsecond astrometry is feasible for a source with a magnitude of K=15 like Sgr A*, given the availability of suitable phase reference sources.Comment: 13 pages, 11 figures, to appear in the conference proceedings of SPIE Astronomical Instrumentation, 23-28 June 2008, Marseille, Franc

An Intermetallic CaFe6Ge6 Approach to Unprecedented Ca Fe O Electrocatalyst for Efficient Alkaline Oxygen Evolution Reaction

Based on the low cost and relatively high catalytic activity, considerable efforts have been devoted towards developing redox active transition metal TM oxygen electrocatalysts for the alkaline oxygen evolution reaction OER while the role of redox inactive alkaline earth metals has often been neglected in OER. Herein, for the first time, we developed a novel ternary intermetallic CaFe6Ge6 precatalyst, whose surface rapidly transforms into a porous ultrathin Ca amp; 8722;Fe amp; 8722;O heteroshell structure during alkaline OER through the oxidative leaching of surficial Ge. Benefiting from synergistic effects, this highly efficient OER active material with distinct Ca amp; 8722;Fe amp; 8722;O layers has a large electrochemical surface area and more exposed active Fe sites than a Ca free FeOx phase. Also, the presence of Ca in Ca amp; 8722;Fe amp; 8722;O is responsible for the enhanced transport and activation of hydroxyls and related OER reaction intermediate as unequivocally illustrated by a combination of quasi in situ Raman spectroscopy and various ex situ method

Black Hole Mass Estimates Based on CIV are Consistent with Those Based on the Balmer Lines

Using a sample of high-redshift lensed quasars from the CASTLES project with observed-frame ultraviolet or optical and near-infrared spectra, we have searched for possible biases between supermassive black hole (BH) mass estimates based on the CIV, Halpha and Hbeta broad emission lines. Our sample is based upon that of Greene, Peng & Ludwig, expanded with new near-IR spectroscopic observations, consistently analyzed high S/N optical spectra, and consistent continuum luminosity estimates at 5100A. We find that BH mass estimates based on the FWHM of CIV show a systematic offset with respect to those obtained from the line dispersion, sigma_l, of the same emission line, but not with those obtained from the FWHM of Halpha and Hbeta. The magnitude of the offset depends on the treatment of the HeII and FeII emission blended with CIV, but there is little scatter for any fixed measurement prescription. While we otherwise find no systematic offsets between CIV and Balmer line mass estimates, we do find that the residuals between them are strongly correlated with the ratio of the UV and optical continuum luminosities. Removing this dependency reduces the scatter between the UV- and optical-based BH mass estimates by a factor of approximately 2, from roughly 0.35 to 0.18 dex. The dispersion is smallest when comparing the CIV sigma_l mass estimate, after removing the offset from the FWHM estimates, and either Balmer line mass estimate. The correlation with the continuum slope is likely due to a combination of reddening, host contamination and object-dependent SED shapes. When we add additional heterogeneous measurements from the literature, the results are unchanged.Comment: Accepted for publication in The Astrophysical Journal. 37 text pages + 8 tables + 23 figures. Updated with comments by the referee and with a expanded discussion on literature data including new observation

An overview of the mid-infrared spectro-interferometer MATISSE: science, concept, and current status

MATISSE is the second-generation mid-infrared spectrograph and imager for the Very Large Telescope Interferometer (VLTI) at Paranal. This new interferometric instrument will allow significant advances by opening new avenues in various fundamental research fields: studying the planet-forming region of disks around young stellar objects, understanding the surface structures and mass loss phenomena affecting evolved stars, and probing the environments of black holes in active galactic nuclei. As a first breakthrough, MATISSE will enlarge the spectral domain of current optical interferometers by offering the L and M bands in addition to the N band. This will open a wide wavelength domain, ranging from 2.8 to 13 um, exploring angular scales as small as 3 mas (L band) / 10 mas (N band). As a second breakthrough, MATISSE will allow mid-infrared imaging - closure-phase aperture-synthesis imaging - with up to four Unit Telescopes (UT) or Auxiliary Telescopes (AT) of the VLTI. Moreover, MATISSE will offer a spectral resolution range from R ~ 30 to R ~ 5000. Here, we present one of the main science objectives, the study of protoplanetary disks, that has driven the instrument design and motivated several VLTI upgrades (GRA4MAT and NAOMI). We introduce the physical concept of MATISSE including a description of the signal on the detectors and an evaluation of the expected performances. We also discuss the current status of the MATISSE instrument, which is entering its testing phase, and the foreseen schedule for the next two years that will lead to the first light at Paranal.Comment: SPIE Astronomical Telescopes and Instrumentation conference, June 2016, 11 pages, 6 Figure

Methodological considerations on tract-based spatial statistics (TBSS)

Having gained a tremendous amount of popularity since its introduction in 2006, tract-based spatial statistics (TBSS) can now be considered as the standard approach for voxel-based analysis (VBA) of diffusion tensor imaging (DTI) data. Aiming to improve the sensitivity, objectivity, and interpretability of multi-subject DTI studies, TBSS includes a skeletonization step that alleviates residual image misalignment and obviates the need for data smoothing. Although TBSS represents an elegant and user-friendly framework that tackles numerous concerns existing in conventional VBA methods, it has limitations of its own, some of which have already been detailed in recent literature. In this work, we present general methodological considerations on TBSS and report on pitfalls that have not been described previously. In particular, we have identified specific assumptions of TBSS that may not be satisfied under typical conditions. Moreover, we demonstrate that the existence of such violations can severely affect the reliability of TBSS results. With TBSS being used increasingly, it is of paramount importance to acquaint TBSS users with these concerns, such that a well-informed decision can be made as to whether and how to pursue a TBSS analysis. Finally, in addition to raising awareness by providing our new insights, we provide constructive suggestions that could improve the validity and increase the impact of TBSS drastically