L-770,644: a potent and selective human beta3 adrenergic receptor agonist with improved oral bioavailability.

L-770,644 (9c) is a potent and selective agonist of the human beta3 adrenergic receptor (EC50 = 13 nM). It shows good oral bioavailability in both dogs and rats (%F = 27), and is a full agonist for glycerolemia in the rhesus monkey (ED50 = 0.21 mg/kg). Based on its desirable in vitro and in vivo properties, L-770,644 was chosen for further preclinical evaluation.     

3-Amino-1,5-benzodiazepinones: potent, state-dependent sodium channel blockers with anti-epileptic activity

A series of 3-amino-1,5-benzodiazepinones were synthesized and evaluated as potential sodium channel blockers in a functional, membrane potential-based assay. One member of this series displayed subnanomolar, state-dependent sodium channel block, and was orally efficacious in a mouse model of epilepsy.     

Pyridopyrimidine based cannabinoid-1 receptor inverse agonists: Synthesis and biological evaluation

The synthesis, SAR and binding affinities are described for cannabinoid-1 receptor (CB1R) specific inverse agonists based on pyridopyrimidine and heterotricyclic scaffolds. Food intake and pharmacokinetic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R.     

Curvature in models of the photosynthesis‐irradiance response

An equation for the rate of photosynthesis as a function of irradiance introduced by T. T. Bannister included an empirical parameter b to account for observed variations in curvature between the initial slope and the maximum rate of photosynthesis. Yet researchers have generally favored equations with fixed curvature, possibly because b was viewed as having no physiological meaning. We developed an analytic photosynthesis‐irradiance equation relating variations in curvature to changes in the degree of connectivity between photosystems, and also considered a recently published alternative, based on changes in the size of the plastoquinone pool. When fitted to a set of 185 observed photosynthesis‐irradiance curves, it was found that the Bannister equation provided the best fit more frequently compared to either of the analytic equations. While Bannister's curvature parameter engendered negligible improvement in the statistical fit to the study data, we argued that the parameter is nevertheless quite useful because it allows for consistent estimates of initial slope and saturation irradiance for observations exhibiting a range of curvatures, which would otherwise have to be fitted to different fixed‐curvature equations. Using theoretical models, we also found that intra‐ and intercellular self‐shading can result in biased estimates of both curvature and the saturation irradiance parameter. We concluded that Bannister's is the best currently available equation accounting for variations in curvature precisely because it does not assign inappropriate physiological meaning to its curvature parameter, and we proposed that b should be thought of as the expression of the integration of all factors impacting curvature.     

Platelet-activating factor stimulates phosphatidylinositol turnover in human platelets.

Platelet-activating factor stimulates phosphatidylinositol turnover in human platelets as indicated by [32P]phosphatidate accumulation in platelets pre-labelled with [32P]Pi, and by [3H]phosphatidate accumulation and [3H]phosphatidylinositol loss in platelets pre-labelled with [3H]arachidonate. These effects of platelet-activating factor are direct and are independent of the production and/or release of endogenous platelet agonists such as ADP, 5-hydroxytryptamine and thromboxane A2.     

PHOTOSYNTHESIS AND REGULATION OF RUBISCO ACTIVITY IN NET PHYTOPLANKTON FROM DELAWARE BAY1

Net phytoplankton (> 20 μm) comprised 51 ± 9% of the total chlorophyll (Chl) in a Skeletonema costatum– dominated spring bloom in Delaware Bay. The net phytoplankton had low C:N and high protein: carbohydrate ratios, indicating that their growth was nutrient-replete. Their photosynthetic responses were characterized by low specific absorption, low light-limited and light-saturated rates of photosynthesis, and high quantum yields, indicative of acclimation to low irradiance and internal self-shading. High fucoxanthin: Chi ratios also indicated low light acclimation, but high photoprotective xanthophyll: Chi ratios suggested a high capacity for photoprotective energy dissipation. Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) could be activated and deactivated in response to changes in irradiance and was fully activated at the surface of the water column and fully deactivated in aphotic deep water. Maximum Rubisco activity was correlated with Rubisco content and bulk protein content of the phytoplankton and with light-saturated rates of photosynthesis measured in short (< 20-min) incubations. Long (60-min) incubations caused a decrease in the light-saturated rate of photosynthesis, possibly because of feedback limitation. While feedback limitation is unlikely to occur in the water column, it should be considered when estimating productivity in well-mixed waters from fixed light-depth incubations.     

Utility of the white gene in estimating phylogenetic relationships among mosquitoes (Diptera: Culicidae)

The utility of a nuclear protein-coding gene for reconstructing phylogenetic relationships within the family Culicidae was explored. Relationships among 13 species representing three subfamilies and nine genera of Culicidae were analyzed using a 762-bp fragment of coding sequence from the eye color gene, white. Outgroups for the study were two species from the sister group Chaoboridae. Sequences were determined from clone PCR products amplified from genomic DNA, and aligned following conceptual intron splicing and amino acid translation. Third codon positions were characterized by high levels of divergence and biased nucleotide composition, the intensity and direction of which varied among taxa. Equal weighting of all characters resulted in parsimony and neighboring-joining trees at odds with the generally accepted phylogenetic hypothesis based on morphology and rDNA sequences. The application of differential weighting schemes recovered the traditional hypothesis, in which the subfamily Anophelinae formed the basal clade. The subfamily Toxorhynchitinae occupied an intermediate position, and was a sister group to the subfamily Culicinae. Within Culicinae, the genera Sabethes and Tripteroides formed an ancestral clade, while the Culex-Deinocerites and Aedes- Haemagogus clades occupied increasingly derived positions in the molecular phylogeny. An intron present in the Culicinae- Toxorhynchitinae lineage and one outgroup taxon was absent in the basal Anophelinae lineage and the second outgroup taxon, suggesting that intron insertions or deletions may not always be reliable systematic characters.