The benefits of a functional exercise circuit for older adults

The physical benefits of a functional exercise circuit are not well known in an elderly population. The purpose of this study was to evaluate the effect of a functional exercise circuit on mobility and perceived health in the elderly. Subjects were 119 men and women (aged 74 [+/-4.2] years) who received pre- and posttests of mobility (e.g., sit to stand, get up and go, timed walk), flexibility (sit and reach), and balance (standing reach) and who completed the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). A supervised functional exercise circuit that included 10 different upper- and lower-body exercises performed under time constraints was performed 3 times per week for 12 consecutive weeks. Paired t-tests showed significant differences at posttest for the get up and go (p < 0.001), standing reach (p < 0.001), sit and reach (p < 0.001), and selected items from the SF-36, including physical functioning (p < 0.001), pain (p = 0.001), vitality (p = 0.001), and number of doctor visits (p < 0.001). A functional exercise circuit such as the one employed in this study may offer promise as an effective means of promoting mobility and perceived health in older adults.     

Discovery and characterization of orthosteric and allosteric muscarinic M2 acetylcholine receptor ligands by affinity selection-mass spectrometry

Screening assays using target-based affinity selection coupled with high-sensitivity detection technologies to identify small-molecule hits from chemical libraries can provide a useful discovery approach that complements traditional assay systems. Affinity selection-mass spectrometry (AS-MS) is one such methodology that holds promise for providing selective and sensitive high-throughput screening platforms. Although AS-MS screening platforms have been used to discover small-molecule ligands of proteins from many target families, they have not yet been used routinely to screen integral membrane proteins. The authors present a proof-of-concept study using size exclusion chromatography coupled to AS-MS to perform a primary screen for small-molecule ligands of the purified muscarinic M2 acetylcholine receptor, a G-protein-coupled receptor. AS-MS is used to characterize the binding mechanisms of 2 newly discovered ligands. NGD-3350 is a novel M2-specific orthosteric antagonist of M2 function. NGD-3366 is an allosteric ligand with binding properties similar to the allosteric antagonist W-84, which decreases the dissociation rate of N-methyl-scopolamine from the M2 receptor. Binding properties of the ligands discerned from AS-MS assays agree with those from in vitro biochemical assays. The authors conclude that when used with appropriate small-molecule libraries, AS-MS may provide a useful high-throughput assay system for the discovery and characterization of all classes of integral membrane protein ligands, including allosteric modulators.     

Selective effects of isomeric cis and trans fatty acids on fatty acyl delta 9 and delta 6 desaturation by human skin fibroblasts

Human skin fibroblasts incorporate and actively desaturate long-chain fatty acids. Growth of these cells in lipid-free medium can be used to enhance delta 9 and delta 6 desaturation of [14C]stearate and [14C]linoleate, respectively. Medium supplementation with cis fatty acids inhibits delta 9 desaturation; effectiveness as inhibitors is linoleate (9c,12c-18:2) greater than oleate (9c-18:1) greater than vaccenate (11c-18:1). Linoelaidate (9t,12t-18:2), trans-vaccenate (11t-18:1) and saturated fatty acids are without effect; elaidate (9t-18:1) appears stimulatory. By contrast, the trans fatty acids elaidate and linoelaidate are potent inhibitors of delta 6 desaturation; inhibition by trans-vaccenate is 50% of that of elaidate. Desaturation of [14C]linoleate is only slightly inhibited by oleate, cis-vaccenate, or (6c,9c,12c)-linolenate. The relative effectiveness of isomeric cis- and trans-octadecenoic acids as inhibitors of delta 9 and delta 6 desaturation in intact human cells is different from that found in microsomal studies. The cell culture system can thus be important in evaluating physiological effects of isomeric fatty acids on cellular metabolic processes.