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.     

Simplified body-surface electrocardiographic maps with depolarization magnitude and direction

A new technique is presented for extracting the magnitude and direction of ventricular depolarization at the body surface from surface electrocardiographic (ECG) map data. Bipolar electrocardiograms were obtained from 36 sites on the chest surface in five normal subjects. The direction and magnitude of depolarization as seen from the chest surface were calculated for 18 body-surface areas centred between electrode positions V1 and V6. Each area was bounded by three electrodes with an electrode spacing of 5 cm. A major depolarization component could be calculated for all triangular areas, with 48% of areas having a smaller second component. The area with the greatest magnitude in each subject had a depolarization vector pointing downwards and to the left, with an average angle to the horizontal of 55 degrees. This was consistent with an average angle of 51 degrees obtained from the subjects' 12-lead electrocardiograms. There was more variability in vector angle between adjacent areas on the right-hand side. At the V5/V6 areas, close to the cardiac apex, the vector component had an upwards orientation in all subjects, opposing the overall downward component of ventricular depolarization. The technique was able to determine local depolarization directions which were in agreement with the normal cardiac vector derived from standard electrocardiography. Reversal of the vector direction close to the cardiac apex and the collision of depolarization components from different directions could be detected. This simple form of body-surface mapping can reduce the essential features of depolarization to a single map, and provide information not directly available from a 12-lead electrocardiogram.     

Fast Subsumption Checks Using Anti-Links

The concept of anti-link is defined (an anti-link consists of two occurrences of the same literal in a formula), and useful equivalence-preserving operations based on anti-links are introduced. These operations eliminate a potentially large number of subsumed paths in a negation normal form formula. Those anti-links that directly indicate the presence of subsumed paths are characterized. The operations have linear time complexity in the size of that part of the formula containing the anti-link.The problem of removing all subsumed paths in an NNF formula is shown to be NP-hard, even though such formulas may be small relative to the size of their path sets. The general problem of determining whether there exists a pair of subsumed paths associated with an arbitrary anti-link is shown to be NP-complete. Additional techniques that generalize the concept of pure literals are introduced and are also shown to eliminate redundant subsumption checks. The effectiveness of these techniques is examined with respect to some benchmark examples from the literature.     

Capillary electrophoresis of supercoiled and linear DNA in dilute hydroxyethyl cellulose solution

Capillary electrophoresis in dilute hydroxyethyl cellulose is shown to separate supercoiled DNA in the size range 2000-16,000 base pairs. The plasmids migrate more slowly than linear ds-DNA of the same sizes. Plasmid bandwidths are larger than observed for ds-DNA, allowing identification of the type of DNA by bandwidth. The differing dependence of mobility on chain length can be explained by assuming that a plasmid migrates as an elastic rod, while ds-DNA migrates as a wormlike chain.     

Influence of the gas—liquid separator design on hydrodynamic and mass transfer performance of split-channel airlift reactors

Three geometric configurations of gas–liquid separators were used in split-channel airlift reactors (0·1 m³ liquid volume; riser-to-downcomer cross-sectional area ratio = 0·7; aspect ratio = 3.6) to test the effect of geometry on hydrodynamic performance and oxygen transfer behaviour. For otherwise fixed conditions, the design of gas–liquid separators affected the induced liquid circulation rate, the depth of penetration of the bubble layer in the downcomer, the gas holdup in the downcomer, the mixing time and the overall volumetric gas–liquid oxygen transfer coefficient. The gas holdup in the riser was only marginally affected by the design of the separator. The impact of the various separator designs on hydrodynamic behaviour could be explained as emanating from a combination of the gas–liquid separating ability of the design and its hydraulic resistance.