Biological Evaluation and X‐ray Co‐crystal Structures of Cyclohexylpyrrolidine Ligands for Trypanothione Reductase,an Enzyme from the Redox Metabolism of Trypanosoma

The tropical diseases human African trypanosomiasis, Chagas disease, and the various forms of leishmaniasis are caused by parasites of the family of trypanosomatids. These protozoa possess a unique redox metabolism based on trypanothione and trypanothione reductase (TR), making TR a promising drug target. We report the optimization of properties and potency of cyclohexylpyrrolidine inhibitors of TR by structure‐based design. The best inhibitors were freely soluble and showed competitive inhibition constants (K_i) against Trypanosoma (T.) brucei TR and T. cruzi TR and in vitro activities (half‐maximal inhibitory concentration, IC₅₀) against these parasites in the low micromolar range, with high selectivity against human glutathione reductase. X‐ray co‐crystal structures confirmed the binding of the ligands to the hydrophobic wall of the “mepacrine binding site” with the new, solubility‐providing vectors oriented toward the surface of the large active site.     

VLSI implementation of a CDMA blind adaptiveinterference-mitigating detector

This paper presents the design and the main performance results of a single-ASIC implementation of the recently proposed extended complex-valued blind anchored interference-mitigating detector (EC-BAID) for code division multiple access (CDMA) transmission. Such a detector, which exhibits a remarkable robustness to multiple access interference, operates in blind mode, i.e., it only requires knowledge of the timing of the wanted user's signature code, and it is therefore very well-suited for integration into handheld single-user terminal demodulators. The implementation of the interference-mitigating detector is based on a patented optimized architecture which leads, in 0.25-μm CMOS technology, to a roughly 25 Kgate plus 23-Kbit RAM single-chip ASIC supporting chip rates up to 4 Mchip/s with a maximum internal clock frequency of 32.768 MHz. The main design drivers are thoroughly discussed, and the relevant performance results are compared to the theoretical behavior. A possible extension to multirate CDMA systems adopting orthogonal variable spreading factor (OVSF) sequences is also addressed     

A methodology to determine the elastic properties of anisotropic rocks from a single uniaxial compression test

This paper introduces a new methodology to measure the elastic constants of transversely isotropic rocks from a single uniaxial compression test. We first give the mathematical proof that a uniaxial compression test provides only four independent strain equations. As a result, the exact determination of all five independent elastic constants from only one test is not possible. An approximate determination of the Young's moduli and the Poisson's ratios is however practical and efficient when adding the Saint–Venant relation as the fifth equation. Explicit formulae are then developed to calculate both secant and tangent definitions of the five elastic constants from a minimum of four strain measurements. The results of this new methodology applied on three granitic samples demonstrate a significant stress-induced nonlinear behavior, where the tangent moduli increase by a factor of three to four when the rock is loaded up to 20 MPa. The static elastic constants obtained from the uniaxial compression test are also found to be significantly smaller than the dynamic ones obtained from the ultrasonic measurements.     

A performance comparison of orthogonal code divisionmultiple-access techniques for mobile satellite communications

In recent years, code division multiple-access (CDMA) techniques have received a great deal of attention for mobile terrestrial/satellite communication systems. Primarily considered for the noteworthy features of low power flux density emission and robustness to interference and multipath, CDMA is known to bear reduced bandwidth and power efficiency when compared to traditional TDMA and FDMA due to the intrinsic cochannel self-noise. Early attempts to increase the capacity of CDMA-based systems for commercial applications relied on voice activation and frequency reuse. More recently, practical solutions to implement (synchronous) orthogonal CDMA signaling are being developed independently in Europe and in the USA. This paper is focused on the comparative performance analysis of those two orthogonal CDMA schemes in the operating renditions of a mobile satellite communications system. In particular, the two CDMA systems are compared in the presence of that and frequency-selective multipath fading and a typical satellite transponder nonlinearity. Most numerical results are derived through a time-domain system simulation that confirms and integrates the theoretical findings     

Binding to Large Enzyme Pockets: Small‐Molecule Inhibitors of Trypanothione Reductase

The causative agents of the parasitic disease human African trypanosomiasis belong to the family of trypanosomatids. These parasitic protozoa exhibit a unique thiol redox metabolism that is based on the flavoenzyme trypanothione reductase (TR). TR was identified as a potential drug target and features a large active site that allows a multitude of possible ligand orientations, which renders rational structure‐based inhibitor design highly challenging. Herein we describe the synthesis, binding properties, and kinetic analysis of a new series of small‐molecule inhibitors of TR. The conjunction of biological activities, mutation studies, and virtual ligand docking simulations led to the prediction of a binding mode that was confirmed by crystal structure analysis. The crystal structures revealed that the ligands bind to the hydrophobic wall of the so‐called “mepacrine binding site”. The binding conformation and potency of the inhibitors varied for TR from Trypanosoma brucei and T. cruzi.     

Cellular and karyotypic characterization of two doxorubicin resistant cell lines isolated from the same parental human leukemia cell line

Separate mechanisms underlying the multidrug resistant (MDR) phenotype were identified in 2 independent approaches to select tumour cells resistant to low concentrations of doxorubicin (Dox) from the sensitive T cell leukemia cell line CCRF-CEM. The CEM/A7 cell line was selected at an initial concentration of 0.005 microgram/ml of Dox and maintained at 0.07 microgram/ml. In contrast, the CEM/A5 line was selected using an initial concentration of 0.01 microgram/ml and maintained in Dox at a concentration of 0.05 microgram/ml. P-glycoprotein expression was demonstrated in the CEM/A7 line but not the CEM/A5 line. Amplification of the mdrI gene was not observed in the CEM/A7 cell line. Both cell lines showed cross-resistance to a number of structurally unrelated cytotoxic drugs including anthracyclines and etoposide (VP-16), although only the CEM/A7 line was cross resistant to Vinca alkaloids. Immunoblots of total cell lysates of the CEM/A5 line have revealed almost undetectable levels of topoisomerase II alpha and beta in this line. Cytogenetic analyses of both lines revealed numerous karyotypic abnormalities which were present in the parental cell line as well as both resistant cell lines. The CEM/A7 line also demonstrated a duplication of part of the long arm of chromosome 7 which included the region containing the mdrI gene, a finding not seen in the parental or CEM/A5 line. CEM/A5, however, demonstrated an abnormality of chromosome 7, outside the region of the mdrI gene, and it also contained a deletion of the short arm of chromosome 2. Abnormalities in this latter region of genome have been associated with non-P-glycoprotein-mediated MDR.