Selective delta-opioid receptor ligands: potential PET ligands based on naltrindole

Two series of delta-selective ligands related to the prototypic delta-antagonist naltrindole have been prepared and evaluated in opioid binding assays with the aim of developing new PET ligands for the delta-opioid receptor. One compound (5d) had significantly higher selectivity than naltrindole, but with substantially reduced binding affinity. For those compounds retaining similar affinity to naltrindole, those having ethyl and fluoroethyl substituents afforded the highest levels of selectivity. However, none of the compounds combined the high level of affinity and selectivity ideally suited to the development of an imaging agent.     

Mathematical consequences of the genealogical species concept

A genealogical species is defined as a basal group of organisms whose members are all more closely related to each other than they are to any organisms outside the group ("exclusivity"), and which contains no exclusive group within it. In practice, a pair of species is so defined when phylogenies of alleles from a sample of loci shows them to be reciprocally monophyletic at all or some specified fraction of the loci. We investigate the length of time it takes to attain this status when an ancestral population divides into two descendant populations of equal size with no gene exchange, and when genetic drift and mutation are the only evolutionary forces operating. The number of loci used has a substantial effect on the probability of observing reciprocal monophyly at different times after population separation, with very long times needed to observe complete reciprocal monophyly for a large number of loci. In contrast, the number of alleles sampled per locus has a relatively small effect on the probability of reciprocal monophyly. Because a single mitochondrial or chloroplast locus becomes reciprocally monophyletic much faster than does a single nuclear locus, it is not advisable to use mitochondrial and chloroplast DNA to recognize genealogical species for long periods after population divergence. Using a weaker criterion of assigning genealogical species status when more than 50% of sampled nuclear loci show reciprocal monophyly, genealogical species status depends much less on the number of sampled loci, and is attained at roughly 4-7 N generations after populations are isolated, where N is the historically effective population size of each descendant. If genealogical species status is defined as more than 95% of sampled nuclear loci showing reciprocal monophyly, this status is attained after roughly 9-12 N generations.     

Membrane association and kinase-like motifs of the RamC protein of Streptomyces coelicolor

The protein RamC is required for the production of the spore-forming cells called aerial hyphae by the filamentous bacterium Streptomyces coelicolor. We showed that RamC, which contains several weakly predicted membrane-spanning sequences, is located exclusively in the S. coelicolor membrane. By constructing site-directed mutants in the cloned ramC gene and complementing a ramC null mutant, we showed that protein kinase-like sequence motifs in the amino-terminal half of the protein are required for function in vivo. These data suggest that RamC is a membrane-associated receptor kinase.     

Persistent Chlamydiae and chronic arthritis

Urogenital infection with Chlamydia trachomatis can lead to development of an acute inflammatory arthritis, and this acute disease becomes chronic in some individuals. Research indicates that the organism is present in synovial tissue of patients with chronic disease in a persistent, rather than an actively growing, form. Importantly, metabolic and other characteristics of persistent Chlamydia differ from those of actively growing bacteria. Other studies suggest that Chlamydia pneumoniae can be found in a persistent state in the synovium and that it too may be involved in joint pathogenesis. These and other observations suggest a more complex role for the Chlamydiae in joint disease than previously recognized. This realization should engender a realignment of thinking among clinicians and researchers concerning both mechanisms of chlamydial pathogenesis in the synovium and design of new treatments for the disease.     

Generating samples under a Wright-Fisher neutral model of genetic variation

A Monte Carlo computer program is available to generate samples drawn from a population evolving according to a Wright-Fisher neutral model. The program assumes an infinite-sites model of mutation, and allows recombination, gene conversion, symmetric migration among subpopulations, and a variety of demographic histories. The samples produced can be used to investigate the sampling properties of any sample statistic under these neutral models.