Synthese et activite pharmacologique d'inhibiteurs de la capture du GABA, derives de l'acide nipecotique et de la guvacine

SIGLECNRS T Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Non-linear Label Ranking for Large-scale Prediction of Long-Term User Interests

We consider the problem of personalization of online services from the viewpoint of ad targeting, where we seek to find the best ad categories to be shown to each user, resulting in improved user experience and increased advertisers ’ revenue. We propose to address this problem as a task of ranking the ad categories depending on a user’s preference, and introduce a novel label ranking approach capable of efficiently learning non-linear, highly accurate models in large-scale settings. Ex-periments on real-world advertising data set with more than 3.2 million users show that the proposed algorithm outper-forms the existing solutions in terms of both rank loss and top-K retrieval performance, strongly suggesting the benefit of using the proposed model on large-scale ranking problems

Common mechanisms of inhibition for the Na(+)/glucose (hSGLT1) and Na(+)/Cl(−)/GABA (hGAT1) cotransporters

1. Electrophysiological methods were used to investigate the interaction of inhibitors with the human Na(+)/glucose (hSGLT1) and Na(+)/Cl(−)/GABA (hGAT1) cotransporters. Inhibitor constants were estimated from both inhibition of substrate-dependent current and inhibitor-induced changes in cotransporter conformation. 2. The competitive, non-transported inhibitors are substrate derivatives with inhibition constants from 200 nM (phlorizin) to 17 mM (esculin) for hSGLT1, and 300 nM (SKF89976A) to 10 mM (baclofen) for hGAT1. At least for hSGLT1, values determined using either method were proportional over 5-orders of magnitude. 3. Correlation of inhibition to structure of the inhibitors resulted in a pharmacophore for glycoside binding to hSGLT1: the aglycone is coplanar with the pyranose ring, and binds to a hydrophobic/aromatic surface of at least 7×12Å. Important hydrogen bond interactions occur at five positions bordering this surface. 4. In both hSGLT1 and hGAT1 the data suggests that there is a large, hydrophobic inhibitor binding site ∼8Å from the substrate binding site. This suggests an architectural similarity between hSGLT1 and hGAT1. There is also structural similarity between non-competitive and competitive inhibitors, e.g., phloretin is the aglycone of phlorizin (hSGLT1) and nortriptyline resembles SKF89976A without nipecotic acid (hGAT1). 5. Our studies establish that measurement of the effect of inhibitors on presteady state currents is a valid non-radioactive method for the determination of inhibitor binding constants. Furthermore, analysis of the presteady state currents provide novel insights into partial reactions of the transport cycle and mode of action of the inhibitors