Relationship between rooting behaviour and foraging in growing pigs

The objective of the present study was to investigate the relationship between rooting behaviour and foraging in growing pigs. In study 1, forty-eight 11-week-old pigs were housed in eight groups of six with access to a rooting substrate in the form of spent mushroom compost. In half of the groups the rooting substrate contained food rewards, and in the other half of the groups it did not. All pigs had ad libitum access to feed. In study 2, one hundred and ninety-two 11-week-old pigs were housed in thirty-two groups of six, all with access to spent mushroom compost, and eight groups were each fed to 70, 80, 90 or 100% appetite. Treatments were applied over a two-week period in both studies. The number of pigs involved in active rooting (rooting in substrate while standing), inactive rooting (rooting in substrate while sitting or lying) or non-rooting activity (standing in substrate area and involved in any activity except rooting) was recorded by scan sampling. These behaviours tended to reach a peak in the morning and again in the afternoon. Inactive rooting was not significantly affected by treatments in study I or study 2. Food rewards in the rooting substrate led to a significant reduction in active rooting behaviour and in non-rooting activity during peak periods of the day (P

Discovery of novel Agonists and antagonists of the free fatty acid receptor 1 (FFAR1) using virtual screening

The G-protein-coupled receptor free fatty acid receptor 1 (FFAR1), previously named GPR40, is a possible novel target for the treatment of type 2 diabetes. In an attempt to identify new ligands for this receptor, we performed virtual screening (VS) based on two-dimensional (2D) similarity, three-dimensional (3D) pharmacophore searches, and docking studies by using the structure of known agonists and our model of the ligand binding site, which was validated by mutagenesis. VS of a database of 2.6 million compounds followed by extraction of structural neighbors of functionally confirmed hits resulted in identification of 15 compounds active at FFAR1 either as full agonists, partial agonists, or pure antagonists. Site-directed mutagenesis and docking studies revealed different patterns of ligand-receptor interactions and provided important information on the role of specific amino acids in binding and activation of FFAR1.

Discovery and Evaluation of BMS-708163, a Potent, Selective and Orally Bioavailable gamma-Secretase Inhibitor

During the course of our research efforts to develop a potent and selective gamma-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-beta precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of gamma-secretase (A beta 40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced A beta 40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs.