Linking the population pharmacokinetics of tenofovir and its metabolites with its cellular uptake and metabolism.

Empirical pharmacokinetic models are used to explain the pharmacokinetics of the antiviral drug tenofovir (TFV) and its metabolite TFV diphosphate (TFV-DP) in peripheral blood mononuclear cells. These empirical models lack the ability to explain differences between the disposition of TFV-DP in HIV-infected patients vs. healthy individuals. Such differences may lie in the mechanisms of TFV transport and phosphorylation. Therefore, we developed an exploratory model based on mechanistic mass transport principles and enzyme kinetics to examine the uptake and phosphorylation kinetics of TFV. TFV-DP median Cmax from the model was 38.5 fmol/10(6) cells, which is bracketed by two reported healthy volunteer studies (38 and 51 fmol/10(6) cells). The model presented provides a foundation for exploration of TFV uptake and phosphorylation kinetics for various routes of TFV administration and can be updated as more is known on actual mechanisms of cellular transport of TFV.

The complete genome sequence of the Streptomyces temperate phage straight phiC31: evolutionary relationships to other viruses.

The completed genome sequence of the temperate Streptomyces phage straight phiC31 is reported. straight phiC31 contains genes that are related by sequence similarities to several other dsDNA phages infecting many diverse bacterial hosts, including Escherichia, Arthrobacter, Mycobacterium, Rhodobacter, Staphylococcus, Bacillus, Streptococcus, Lactobacillus and Lactococcus. These observations provide further evidence that dsDNA phages from diverse bacterial hosts are related and have had access to a common genetic pool. Analysis of the late genes was particularly informative. The sequences of the head assembly proteins (portal, head protease and major capsid) were conserved between straight phiC31, coliphage HK97, staphylococcal phage straight phiPVL, two Rhodobacter capsulatus prophages and two Mycobacterium tuberculosis prophages. These phages and prophages (where non-defective) from evolutionarily diverse hosts are, therefore, likely to share a common head assembly mechanism i.e. that of HK97. The organisation of the tail genes in straight phiC31 is highly reminiscent of tail regions from other phage genomes. The unusual organisation of the putative lysis genes in straight phiC31 is discussed, and speculations are made as to the roles of some inessential early gene products. Similarities between certain phage gene products and eukaryotic dsDNA virus proteins were noted, in particular, the primase/helicases and the terminases (large subunits). Furthermore, the complete sequence clarifies the overall transcription map of the phage during lytic growth and the positions of elements involved in the maintenance of lysogeny.

Evolutionary relationships among diverse bacteriophages and prophages: all the world's a phage.

We report DNA and predicted protein sequence similarities, implying homology, among genes of double-stranded DNA (dsDNA) bacteriophages and prophages spanning a broad phylogenetic range of host bacteria. The sequence matches reported here establish genetic connections, not always direct, among the lambdoid phages of Escherichia coli, phage phiC31 of Streptomyces, phages of Mycobacterium, a previously unrecognized cryptic prophage, phiflu, in the Haemophilus influenzae genome, and two small prophage-like elements, phiRv1 and phiRv2, in the genome of Mycobacterium tuberculosis. The results imply that these phage genes, and very possibly all of the dsDNA tailed phages, share common ancestry. We propose a model for the genetic structure and dynamics of the global phage population in which all dsDNA phage genomes are mosaics with access, by horizontal exchange, to a large common genetic pool but in which access to the gene pool is not uniform for all phage.

Off-day scheduling with hierarchical worker categories.

A work force includes workers of m types. The worker categories are ordered, with type-1 workers the most highly qualified, type-2 the next, and so on. If the need arises, a type-k worker is able to substitute for a worker of any type j greater than k (k = 1, ..., m - 1). For 7-day-a-week operation, daily requirements are for at least Dk workers of type-k or better, of which at least dk must be precisely type-k. Formulas are given to find the smallest number and most economical mix of workers, assuming that each worker must have 2 off-days per week and a given fraction of weekends off. Algorithms are presented which generate a feasible schedule, and provide work stretches between 2 and 5 days, and consecutive weekdays off when on duty for 2 weekends in a row, without additional staff.