Molecular modelling of mammalian CYP2B isoforms and their interaction with substrates, inhibitors and redox partners

1. The construction of three-dimensional models of CYP2B isozymes from rat (CYP2B1), rabbit (CYP2B4) and man (CYP2B6), based on a multiple sequence alignment with CYP102, a unique eukaryotic-like bacterial P450 (in terms of possessing an NADPH-dependent FAD- and FMN-containing oxidoreductase redox partner) of known crystal structure, is reported. 2. The enzyme models described are shown to be consistent with experimental evidence from site-directed mutagenesis studies, antibody recognition sites and amino acid residues identified as being associated with redox partner interactions, together with the location of a key serine residue (Ser-128) likely to be involved in protein kinaseA-mediated phosphorylation. 3. A substantial number of known substrates and inhibitors of CYP2B isozymes are shown to fit the putative active sites of the enzyme models in agreement with their reported position of metabolism or mode of inhibition respectively. In particular, there is complementarity between the characteristic non-planar geometries of CYP2B substrates and key groups in the enzymes' active sites. 4. Molecular modelling of CYP2B isozymes appears to rationalize a number of the reported findings from quantitative structure-activity relationship investigations on series of CYP2B substrates and inhibitors.     

Structural studies of TiN/ZrN multilayer coating deposited by physical vapour deposition

Multilayer coatings have been produced using unbalanced magnetron physical vapour deposition in which discrete layers of TiN and ZrN were co-deposited. It has been shown that the multilayers exhibited two-fold periodicity having values of 13 and 2.8 nm. This periodicity, measured both by cross-sectional transmission electron microscopy and low-angle X-ray diffraction, has been precisely related to the process parameters used. Analysis has shown that a third, previously unreported, phase existed within the coating having a lattice parameter comparable to that of TiN and a well-defined orientation relationship with the primary phases. The existence of this phase has been explained in terms of variations in the stoichometry of the coating due to non-uniform metal to nitrogen deposition rates within the chamber. Textural studies revealed that preferred orientation existed in the coating; the degree of which was greater in the ZrN layers than the TiN layers.     

A study of self poisoning with oral salbutamol--laboratory and clinical features

A review of 35 patients > 60 years of age with odontoid fractures showed that a type II injury (Anderson and D'Alonso) was the most common fracture pattern (82% of cases). On the basis of mechanism of injury and sex incidence, we deduced that osteopenia is a contributory factor in the occurrence of odontoid fractures. A fall in a domestic setting was the cause in 53%. The peg was posteriorly displaced in 88% of type II fractures, and primary union occurred in 23%. The incidence of concomitant spinal cord injury with type II fractures was higher in older patients than it was in those < 60 years of age. The outcome for these patients was largely determined by their neurological status at presentation. Myelopathy as a late complication of nonunion was not observed in nine patients with an average follow-up of 21 months. The data suggest that vigorous attempts to secure both primary union and a sound arthrodesis for non-union are questionable in the elderly except in unusual circumstances.     

Spherical-wave source-scattering matrix analysis of coupled antennas; A general system two-port solution

Expressions are given for the coupling between two antennas in terms of each antenna's spherical-wave source-scattering matrix. A comparison with the "classical" scattering matrix representation is given in sufficient detail to permit conversion back and forth between the source-scattering matrix and the classical scattering matrix. Expressions for the transmission formulas, showing two different expressions corresponding to reversing the direction of propagation are given. However, if both antennas are reciprocal with equal characteristic waveguide impedances, then the two-port scattering matrix is a symmetric matrix.     

A model for bilayer membrane electroporation based on resultant electromechanical stress

Reconsideration of the effect of an electrical field applied across a phospholipid bilayer membrane shows that, in addition to a compressive stress normal to the membrane plane, transverse traction stresses are generated in the lateral plane of the membrane. In the fields usually employed for electroporation these transverse stresses are likely to be sufficient to reduce the membrane tension considerably, causing electroporation and rupture. This mode of field-induced change in the membrane provides a natural model for the various forms of electroporation.     

Nuclear-chemical synthesis of tritium-labeled phenyl-substituted picoline derivatives

Ion-molecule reactions of free phenyl cations with six-membered nitrogen-containing heterocyclic compounds: α-, β-, and γ-picolines, were studied. Phenyl cations were generated by tritium β-decay in double-labeled benzene. The mechanism of competing reactions of electrophilic addition to the nitrogen heteroatom in the ring and electrophilic substitution of the C-H bond in the pyridine ring was examined. The effect of methyl substituent in the pyridine molecule on the reaction pathway was evaluated. A one-step procedure for nuclear-chemical synthesis of tritium-labeled N-phenylpicolinium salts and phenyl-substituted picolines was developed.