Neurotensin Receptor Allosterism Revealed in Complex with a Biased Allosteric Modulator

The NTSR1 neurotensin receptor (NTSR1) is a G protein-coupled receptor (GPCR) found in the brain and peripheral tissues with neurotensin (NTS) being its endogenous peptide ligand. In the brain, NTS modulates dopamine neuronal activity, induces opioid-independent analgesia, and regulates food intake. Recent studies indicate that biasing NTSR1 toward β-arrestin signaling can attenuate the actions of psychostimulants and other drugs of abuse. Here, we provide the cryoEM structures of NTSR1 ternary complexes with heterotrimeric Gq and GoA with and without the brain-penetrant small-molecule SBI-553. In functional studies, we discovered that SBI-553 displays complex allosteric actions exemplified by negative allosteric modulation for G proteins that are Gα subunit selective and positive allosteric modulation and agonism for β-arrestin translocation at NTSR1. Detailed structural analysis of the allosteric binding site illuminated the structural determinants for biased allosteric modulation of SBI-553 on NTSR1

Gebrauchtoelanalyse und Motorenbewertung des M 100-Flottentests Abschlussbericht. Projektlaufzeit: 1980-1984

TIB: RN 4117 (260-13) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Personality, Leisure Experiences and Happiness

extraversion, neuroticism, leisure involvement, leisure satisfaction, SWB,

The motivational effects of cross-linguistic awareness : developing third language pedagogies to address the negative impact of the L2 on the L3 self-concept

Learning a third language (TL) brings with it particular pedagogical demands. In the pedagogy of TL learning now emerging, the development of students' metalinguistic and crosslinguistic awareness is of central importance. In particular, emphasis is placed on the benefits of cross-referencing with supporter languages. While comparisons with supporter languages have been shown to facilitate L3 production, recent research suggests that cross-referencing with the L2 may be detrimental to motivation. In the current study, 21 students learning L2 English and L3 German or Spanish were interviewed about comparisons involving L3 and L2 self-concepts. Results revealed that nearly all of the students were aware of making such comparisons. A number, however, had developed strategies to counteract the potentially detrimental effect that comparisons with the L2-speaking/using self-concept can have on L3 motivation. It is argued here that in emerging pedagogies of L3 learning proper account needs to be taken of cognitive and affective individual difference factors. In particular, as a means of offsetting the negative impact that a high-status supporter language can have on the learner's L3 self-concept, students should be made aware of the problem and helped to develop and make use of counteracting strategies