Evaluation of selected chemotypes in coupled cellular and molecular target-based screens identifies novel HIV-1 zinc finger inhibitors

Conservation of the Cys-Xaa2-Cys-Xaa4-His-Xaa4-Cys retroviral zinc finger sequences and their absolute requirement in both the early and late phases of retroviral replication make these chemically reactive structures prime antiviral targets. We recently reported that select 2,2'-dithiobisbenzamides (DIBAs) chemically modify the zinc finger Cys residues, resulting in release of zinc from the fingers and inhibition of HIV replication. In the current study we surveyed 21 categories of disulfide-based compounds from the chemical repository of the National Cancer Institute for their capacity to act as retroviral zinc finger inhibitors. Aromatic disulfides that exerted anti-HIV activity tended to cluster in the substituted aminobenzene, benzoate, and benzenesulfonamide disulfide subclasses. Only one thiuram derivative exerted moderate anti-HIV activity, while a number of nonaromatic thiosulfones and miscellaneous disulfide congeners were moderately antiviral. Two compounds (NSC 20625 and NSC 4493) demonstrated anti-cultures. The two compounds chemically modified the p7NC zinc fingers in two separate in vitro assays, and interatomic surface molecular modeling docked the compounds efficiently but differentially into the zinc finger domains. The combined efforts of rational drug selection, cell-based screening, and molecular target-based screening led to the identification of zinc finger inhibitors that can now be optimized by medicinal chemistry for the development of biopharmaceutically useful anti-HIV agents.     

Preparation of high-T c oxide films via flaming solvent spray

Thick films of the high-temperature superconductors YBa₂Cu₃O_7?x and Bi_1.7Pb_0.3Sr₂Ca₂Cu₃O₁₀ have been prepared by spraying an ignited ethanol, ethylene glycol, or liquid ammonia solution of stoichiometric amounts of the metal nitrates (or acetates) onto polycrystalline MgO. The flaming spray is mechanically forced to traverse a region directly in front of the substrates. This new method is simple and inexpensive, and eliminates the problem of substrate cooling encountered in normal spray pyrolysis methods. Since decomposition of the solvent and metal salts occurs before deposition, the resulting films are relatively free of craters and nonuniformities common with spray methods. The method can be adapted to coat large areas and irregular or nonplanar shapes (i.e., cylinders), which could have useful magnetic shielding properties. The films were characterized by XRD and show single-phase material with preferredc-axis orientation. For YBa₂Cu₃O_7?x , resistance vs. temperature measurements show aT _c onset at 90 K and aT _c 0 at 76 K. Silver nitrate has been added to some of the solutions in an attempt to improve contact among individual grains.     

Exact and approximate methods for determining the thermal parameters of the forging process

Numerical simulation of the forged body plastic flow is a very important and indispensable technique in the mechanical forming. The correct simulation of changing the shape of a hot blank requires the use of very accurately determined physical parameters. There is thus a pressing need to create and supplement a database containing the exact physical parameters of forged materials. The following paper shows the results of development of methods to determine two thermal parameters of a solid body: the average value of the total emissivity and the average coefficient of heat transfer by convection. The methods of determining thermal parameters, described below, are considerably simpler than traditional ones, and they do not require the use of complicated equipment. The exact method is based only on processing of experimental data. In the approximate method, both the experimental data and theoretical values of thermal parameters available in the literature are used.

The developed methods were applied to determine thermal parameters of test bodies of SAE 1045 steel and ABNT 6061 aluminum alloy.     

Polymorphism and divergence at a Drosophila pseudogene locus

The larval cuticle protein (Lcp) cluster in Drosophila melanogaster contains four functional genes and a closely related pseudogene. A 630-bp fragment including the larval cuticle pseudogene locus (Lcp psi) was nucleotide sequenced in 10 strains of D. melanogaster and a 458-bp Lcp psi fragment from D. simulans was also sequenced. We used these data to test the hypotheses that the rates of synonymous and nonsynonymous substitution are equal, that the absolute levels of variation are higher than in functional genes, and that intraspecific polymorphism is correlated with interspecific divergence. As predicted, synonymous and nonsynonymous substitution rates were equivalent, and overall nucleotide divergence between D. melanogaster and D. simulans (Jukes-Cantor distance = 0.149 +/- 0.150) was extremely high. However, within-species DNA sequence comparisons at Lcp psi revealed lower levels of polymorphism (theta = 0.001 +/- 0.001) than at many functional loci in D. melanogaster. Using the HUDSON, KREITMAN, and AGUADE (HKA) test, we show that the level of polymorphism in Lcp psi within D. melanogaster is lower than expected given the amount of divergence between D. melanogaster and D. simulans when the pseudogene data are compared to the Adh 5' flanking region. Because the Lcp psi lies in a region of relatively infrequent recombination, we suggest that the low level of within-species polymorphism is the result of background selection.     

Comparison of possible covariates for use in a random regression model for analyses of test day yields

Random regression models have been proposed for the genetic evaluation of dairy cattle using test day records. Random regression models contain linear functions of fixed and random coefficients and a set of covariates to describe the shapes of lactation curves for groups of cows and for individual cows. Previous work has used a linear function of five covariates to describe lactation shape. This study compared the function of five covariates with a function of only three covariates in three random regression models. Comparisons of estimates of components of variances and covariances, as well as comparisons of EBV and their prediction errors for milk yield, were made among models. Small practical differences existed between models in all respects. The model using regressions with five covariates had a slight advantage for comparison of prediction error variances of daily yields.     

Preparation of high-Tc oxide films via flaming solvent spray

Thick films of the high-temperature superconductors YBa₂Cu₃O_7–x and Bi_1.7Pb_0.3Sr₂Ca₂Cu₃O₁₀ have been prepared by spraying an ignited ethanol, ethylene glycol, or liquid ammonia solution of stoichiometric amounts of the metal nitrates (or acetates) onto polycrystalline MgO. The flaming spray is mechanically forced to traverse a region directly in front of the substrates. This new method is simple and inexpensive, and eliminates the problem of substrate cooling encountered in normal spray pyrolysis methods. Since decomposition of the solvent and metal salts occurs before deposition, the resulting films are relatively free of craters and nonuniformities common with spray methods. The method can be adapted to coat large areas and irregular or nonplanar shapes (i.e., cylinders), which could have useful magnetic shielding properties. The films were characterized by XRD and show single-phase material with preferredc-axis orientation. For YBa₂Cu₃O_7–x , resistance vs. temperature measurements show aT _c onset at 90 K and aT _c 0 at 76 K. Silver nitrate has been added to some of the solutions in an attempt to improve contact among individual grains.     

Multifocal motor neuropathies with conduction blocks. 39 cases

Clinical, biological and electrophysiological features from a cohort of 39 multifocal motor neuropathies with conduction blocks (NMM with CB) have been studied. There were 29 males and 10 females with an average of 47.3. At the first evaluation, the mean duration of the symptoms was of 8 years with extremes between 1 and 28. Pain and paresthesias were present in respectively 10 and 18 p. 100 of the patients. Fasciculations and cramps were observed in more than 2/3 of the cases. Three patients had tremor at rest. Upper limb muscular weakness was the predominant initial symptom (84.6 p. 100). The weakness always affected distal and unilateral muscles. Radial and cubital nerve distribution are mainly affected and in half of the cases an unilateral motor deficit in the lower limb was associated. Muscle atrophy was frequent (74 p. 100) and rapidly developed in the first 2 years. Reflexes were decreased or absent in 64 p. 100. In 78 p. 100 of cases, biological study showed normal serum immunoelectrophoresis and CSF. IgM anti-GM1 antibodies were found in 24/36 patients. Very high titres were found in 5 cases. All patients had CB in upper limbs. The preferential localizations of the CB were equally at the median and ulnar nerves. Only 7 patients had CB localized to the lower limbs. In many cases, marked reduction of the motor amplitude prevented the detection of CB, marked reduction of the motor amplitude prevented the detection of CB. Moderate fibrillation potentials were found in 28 p. 100 of patients. Giant muscular unit potentials were frequent (21/39). F-waves in nerve with CB were always abnormal with marked increased latencies. Late responses sometimes seemed to be repeater F-waves. Axon reflexes were detected in 5 cases. The late responses abnormalities could precede the block. Clinical, biological and electrophysiological described arguments could may distinguish NMM with CB from motor neuron disease and relate them to the group of chronic demyelinating neuropathies.     

A performance analysis of transposition-table-driven workscheduling in distributed search

This paper discusses a new work-scheduling algorithm for parallel search of single-agent state spaces, called transposition-table-driven work scheduling, that places the transposition table at the heart of the parallel work scheduling. The scheme results in less synchronization overhead, less processor idle time, and less redundant search effort. Measurements on a 128-processor parallel machine show that the scheme achieves close-to-linear speedups; for large problems the speedups are even superlinear due to better memory usage. On the same machine, the algorithm is 1.6 to 12.9 times faster than traditional work-stealing-based schemes     

Elastic light-scattering measurements of single biological cells in an optical trap

We have developed an instrument for determination of the angular light scattering of beads and biological cells. The instrument uses radiation pressure for levitation of particles inside a cuvette. The setup consists of two 780-nm diode lasers in a vertical double-beam trapping configuration. In the horizontal direction a weakly focused 633-nm probe beam is used to illuminate the trapped particle. One can detect scattered light over the range of from - 150 to 150 deg with an angular resolution of 0.9 deg using an avalanche photodiode. With this setup light scattering from polystyrene beads was measured, and the obtained scattering patterns were compared with theoretical scattering patterns from Lorenz-Mie theory. The results show that the setup is stable, gives reproducible patterns, and qualitatively agrees with the calculations. Trapping of biological cells is more difficult than trapping of beads, because smaller forces result from smaller refractive indices. We present an angular scattering pattern measured from a human lymphocyte measured from 20 to 60 deg.