Rapid synthesis of triazine inhibitors of inosine monophosphate dehydrogenase

A series of novel triazine-based small molecule inhibitors (IV) of inosine monophosphate dehydrogenase was prepared. The synthesis and the structure-activity relationships (SAR) derived from in vitro studies are described.     

Mechanisms of motor protein reversal

Members of the kinesin superfamily of microtubule-based motors and the myosin superfamily of actin-based motors that move 'backwards' have been identified. As the core catalytic domains of myosins and kinesins are similar in structure, this raises the intriguing questions of how direction reversal is accomplished and whether kinesins and myosins share mechanisms for switching their motors into reverse.     

Isolation of humic acid from the brown algaPilayella littoralis

A standard humic acid extraction procedure has been used to isolate dark brown organic residues from samples of the macroscopic marine brown algaPilayella littoralis. The residues are insoluble in water, but soluble at high pH, and are similar in elemental composition, ash content, UV-visible, IR, PMR and X-Ray fluorescence spectra, X-Ray diffractograms and scanning electron micrographs to residues of a humic acid isolated from municipal compost. These results indicate thatPilayella produces humic acids.Author for correspondence     

Selective inhibition of prostaglandin biosynthesis by gold salts and phenylbutazone

Gold salts and phenylbutazone selectively inhibit the synthesis of PGF_2α and PGE₂ respectively. Lowered production of one prostaglandin species is accompanied by an increased production of the other. Selective inhibition by these drugs was observed in the presence of adrenaline, reduced glutathione and copper sulphate under conditions when most anti-inflammatory compounds inhibited PGE₂ and PGF_2α syntheses equally. It is postulated that selective inhibitors may have a different mode of action and beneficial effects may be related to the endogenous ratio of PGE to PGF required for normal function.     

The evolution and ecology of multiple antipredator defences

Prey seldom rely on a single type of antipredator defence, often using multiple defences to avoid predation. In many cases, selection in different contexts may favour the evolution of multiple defences in a prey. However, a prey may use multiple defences to protect itself during a single predator encounter. Such “defence portfolios” that defend prey against a single instance of predation are distributed across and within successive stages of the predation sequence (encounter, detection, identification, approach (attack), subjugation and consumption). We contend that at present, our understanding of defence portfolio evolution is incomplete, and seen from the fragmentary perspective of specific sensory systems (e.g., visual) or specific types of defences (especially aposematism). In this review, we aim to build a comprehensive framework for conceptualizing the evolution of multiple prey defences, beginning with hypotheses for the evolution of multiple defences in general, and defence portfolios in particular. We then examine idealized models of resource trade-offs and functional interactions between traits, along with evidence supporting them. We find that defence portfolios are constrained by resource allocation to other aspects of life history, as well as functional incompatibilities between different defences. We also find that selection is likely to favour combinations of defences that have synergistic effects on predator behaviour and prey survival. Next, we examine specific aspects of prey ecology, genetics and development, and predator cognition that modify the predictions of current hypotheses or introduce competing hypotheses. We outline schema for gathering data on the distribution of prey defences across species and geography, determining how multiple defences are produced, and testing the proximate mechanisms by which multiple prey defences impact predator behaviour. Adopting these approaches will strengthen our understanding of multiple defensive strategies.     

Structure-activity relationships of anthranilamide-based factor Xa inhibitors containing piperidinone and pyridinone P4 moieties

Introduction of the phenyl piperidinone and phenyl pyridinone P4 moieties in the anthranilamide scaffold led to potent, selective, and orally bioavailable inhibitors of factor Xa. Anthranilamide 28 displayed comparable efficacy to apixaban in the rabbit arteriovenous-shunt (AV) thrombosis model.     

Characterization of the interaction between calpactin I and fodrin (non-erythroid spectrin)

Calpactin I, a calcium-binding protein associated with the membrane cytoskeleton, has been reported to bind to a calcium-dependent manner to fodrin, to certain phospholipids, and to F-actin. We have investigated the interaction between calpactin I and fodrin. Using a gel filtration assay, we observed one or more calpactin I molecules were bound calcium-dependently only at high concentrations of calpactin (greater than 1 microM), indicating that the interaction is of only moderate affinity. At higher concentrations of calpactin I, the calpactin coprecipitated with fodrin in a calcium-dependent manner. The molar ratio of calpactin to fodrin tetramer in the precipitate was greater than 25:1, indicating that the calpactin binds to a large number of sites. Moreover, the monomeric form of calpactin I (p36), which did not induce precipitation of fodrin, showed no evidence of saturation in its binding to fodrin even when more than 30 mol of p36 were bound per mole of fodrin tetramer. Several proteins other than fodrin, including clathrin, alpha-actinin, and neurofilament-H, also interacted calcium-dependently with calpactin I in the gel filtration assay. These results demonstrate that the interaction between calpactin and fodrin is not of high affinity, is not readily saturated, and is not specific for fodrin. Our results suggest that calpactin's interaction with fodrin is a particular example of a calcium-dependent, but promiscuous, binding of calpactin to proteins.     

Oxalate uptake by everted sacs of rat colon. Regional differences and the effects of pH and ricinoleic acid

Hyperoxaluria is a complication of disorders associated with steatorrhea. The colon is the presumed site of enhanced oxalate absorption in patients with steatorrhea. We performed studies of colonic mucosal oxalate uptake in everted sacs of rat colon to determine the kinetics of colonic oxalate transport and to evaluate the effect of both pH and ricinoleic acid, a hydroxy fatty acid, on colonic oxalate uptake. Our study demonstrated that oxalate is transported throughout the colon by passive diffusion. Tissue uptake increased linearly with increasing oxalate concentrations and was unaffected by metabolic inhibitors, oxygen deprivation, or temperature changes. There were pH-dependent regional differences of oxalate uptake both in the presence and absence of ricinoleic acid. In the absence of ricinoleic acid, the highest oxalate uptake occurred at the lower pH values (5.4 and 6.4). In the presence of ricinoleic acid oxalate uptake was enhanced at the higher pH values (7.4 and 8.4); a finding most likely related to decreased solubility of ricinoleic acid at pH 5.4 and 6.4. Intraluminal pH is an important determinant of colonic oxalate uptake in the presence and absence of ricinoleic acid.