We describe a model of neutral DNA evolution that allows substitution rates at a site to depend on the two flanking nucleotides (''context''), the branch of the phylogenetic tree, and position within the sequence and implement it by using a flexible and computationally efficient Bayesian Markov chain Monte Carlo approach. We then apply this approach to characterize phylogenetic variation in context-dependent substitution patterns in a 1.7-megabase genomic region in 19 mammalian species. In contrast to other substitution types, CpG transition substitutions have accumulated in a relatively clock-like fashion. More broadly, our results support the notion that context-dependent DNA replication errors, cytosine deamination, and biased gene conversion are major sources of naturally occurring mutations whose relative contributions have varied in mammalian evolution as a result of changes in generation times, effective population sizes, and recombination rates. Despite their fundamental role in evolution and genetic disease, relatively little is known about the causes of naturally occurring mutations in mammalian genomes. Even basic questions, such as the relative proportions attributable to replication errors or to chemical or radiation damage, remain unresolved. Neutrally evolving genomic DNA in principle provides a faithful record of the mutations occurring within it, and through its analysis, an increasingly complex picture of the characteristics of the mutation process is emerging. Studies of pseudogenes have found that transition substitutions occur at higher rates than transversions and that substitutions from S (G or C) to W (A or T) nucleotides generally occur at a higher rate than those from W to S (1, 2). The nucleotides that flank a site have a large (Ϸ50-fold) effect on substitution rate (3, 4); the most dramatic instance is CpG dinucleotide ''hotspots'' (5), where the elevated rate reflects deamination of methyl cytosine, but there are significant (and as yet not understood) effects of other flanking nucleotides as well. Such ''context effects'' are also detected in studies of single-nucleotide polymorphisms (6) and disease-causing mutations (7).With the availability of large genomic datasets, more subtle trends are being uncovered. Comparison of human and mouse genomic sequences have revealed that substitution rates vary by position on a large scale (8). Recombination rate is correlated both with overall substitution rate (9) and with the ratio of W3S to S3W rates (10), the latter correlation probably reflecting biased gene conversion (11-13). There is an asymmetry in the substitution process within transcribed regions, with higher rates of purine than of pyrimidine transitions on the nontranscribed strand (14); this is hypothesized to result from an asymmetry in DNA polymerase errors that is uncovered by transcriptioncoupled repair.Analysis of evolutionarily diverse, multispecies datasets, such as those being developed by the NISC Comparative Sequencing Program (15), provides increasing opportunity to ga...

Imidazoquinolines have potent direct activity against bladder cancer cells by decreasing cell viability and inducing apoptosis and cytokine production. In addition, in vivo data suggest antitumor effects in an orthotopic bladder cancer mouse model. Therefore, imidazoquinolines may have therapeutic potential as a synthetic intravesical agent against bladder cancer.