Synthesis and evaluation of alkoxy-phenylamides and alkoxy-phenylimidazoles as potent sphingosine-1-phosphate receptor subtype-1 agonists

In the design of potent and selective sphingosine-1-phosphate receptor agonists, we were able to identify two series of molecules based on phenylamide and phenylimidazole analogs of FTY-720. Several designed molecules in these scaffolds have demonstrated selectivity for S1P receptor subtype 1 versus 3 and excellent in vivo activity in mouse. Two molecules PPI-4621 (4b) and PPI-4691 (10a), demonstrated dose responsive lymphopenia, when administered orally.     

Starvation tolerance, development time and egg production of Calanoides carinatus in the Southern Benguela Current

The intermittent nature of phytoplankton blooms in the extremesouth of the Benguela Current may be an important factor limitingthe zooplankton population. Calanoides carinatus, a dominantzooplankton species, was studied in the laboratory to measureits tolerance to starvation, development time and rate of eggproduction. The species was found to have a large food reservein the form of a lipid sac which gives it a high tolerance tostarvation. Starvation tolerance depends on age, temperatureand feeding during development but once mature, feeding doesnot increase the tolerance. Development time depends on temperatureand feeding and is of the order of 25 days at average temperaturesin the area (13–15C). Egg production is rapid (–70eggs per female per day) when food is abundant and ceases immediatelyfood is removed. Overall the species shows considerable toleranceof a patchy food regime but nevertheless is probably controlledto some degree by the intermittent food supply, especially duringthe juvenile stages.     

Biological destruction of coral reefs

The major agents of biological destruction of coral reefs can be divided into grazers, etchers and borers. Each of these groups is reviewed on a world wide basis, together with the mechanisms by which they destroy the coral substrate. Rates of bioerosion attributed to major agents of grazers, etchers and borers are given, together with limitations of some of the measurements. Recent work is highlighting the variability in rates of bioerosion both over time and space. Factors which may be responsible for this variability are discussed. Bioerosion is a major factor influencing reef morphology and the ways in which this is achieved is discussed in some detail. Although the review concentrates mainly on present day reefs, some attempt is made to consider the impact of bioerosion on older reefs.     

Dynamic Localization of Tat Protein Transport Machinery Components in Streptomyces coelicolor

The Tat pathway transports folded proteins across the bacterial cytoplasmic membrane and is a major route of protein export in the Streptomyces genus of bacteria. In this study, we have examined the localization of Tat components in the model organism Streptomyces coelicolor by constructing enhanced green fluorescent protein (eGFP) and mCherry fusions with the TatA, TatB, and TatC proteins. All three components colocalized dynamically in the vegetative hyphae, with foci of each tagged protein being prominent at the tips of emerging germ tubes and of the vegetative hyphae, suggesting that this may be a primary site of Tat secretion. Time-lapse imaging revealed that localization of the Tat components was highly dynamic during tip growth and again demonstrated a strong preference for apical sites in growing hyphae. During aerial hypha formation, TatA-eGFP and TatB-eGFP fusions relocalized to prespore compartments, indicating repositioning of Tat components during the Streptomyces life cycle.     

Monoclonal anti-β1-adrenergic receptor antibodies activate G protein signaling in the absence of β-arrestin recruitment

Thermostabilized G protein-coupled receptors used as antigens for in vivo immunization have resulted in the generation of functional agonistic anti-β₁-adrenergic (β₁AR) receptor monoclonal antibodies (mAbs). The focus of this study was to examine the pharmacology of these antibodies to evaluate their mechanistic activity at β₁AR. Immunization with the β₁AR stabilized receptor yielded five stable hybridoma clones, four of which expressed functional IgG, as determined in cell-based assays used to evaluate cAMP stimulation. The antibodies bind diverse epitopes associated with low nanomolar agonist activity at β₁AR, and they appeared to show some degree of biased signaling as they were inactive in an assay measuring signaling through β-arrestin. In vitro characterization also verified different antibody-receptor interactions reflecting the different epitopes on the extracellular surface of β₁AR to which the mAbs bind. The anti-β₁AR mAbs only demonstrated agonist activity when in dimeric antibody format, but not as the monomeric Fab format, suggesting that agonist activation may be mediated through promoting receptor dimerization. Finally, we have also shown that at least one of these antibodies exhibits in vivo functional activity at a therapeutically-relevant dose producing an increase in heart rate consistent with β₁AR agonism.