Highlightsand CB2-AM12033 are determined d Structural evidence of G protein selectivity by CB1 and CB2 is identified d MD simulations reveal the distinct binding behavior of HU308 in CB2 and CB1 d Cholesterol molecule as an endogenous allosteric modulator of CB1 is uncovered

The glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR) are members of the secretin-like class B family of G-protein-coupled receptors (GPCRs) and have opposing physiological roles in insulin release and glucose homeostasis. The treatment of type 2 diabetes requires positive modulation of GLP-1R to inhibit glucagon secretion and stimulate insulin secretion in a glucose-dependent manner. Here we report crystal structures of the human GLP-1R transmembrane domain in complex with two different negative allosteric modulators, PF-06372222 and NNC0640, at 2.7 and 3.0 Å resolution, respectively. The structures reveal a common binding pocket for negative allosteric modulators, present in both GLP-1R and GCGR and located outside helices V-VII near the intracellular half of the receptor. The receptor is in an inactive conformation with compounds that restrict movement of the intracellular tip of helix VI, a movement that is generally associated with activation mechanisms in class A GPCRs. Molecular modelling and mutagenesis studies indicate that agonist positive allosteric modulators target the same general region, but in a distinct sub-pocket at the interface between helices V and VI, which may facilitate the formation of an intracellular binding site that enhances G-protein coupling.

As telecommunication technologies have become more widely available and affordable, opportunities for psychologists to engage in telebehavioral health (TBH) have expanded greatly. A national sample of 164 professional psychologists completed a 28-item survey focusing on (a) current and anticipated use of telecommunication technologies in delivering TBH services, (b) types of telecommunication modalities currently used in clinical practice, (c) ethical and legal/regulatory concerns related to delivery of TBH services, and (d) educational and training needs for TBH practice. Associations between demographic factors (i.e., age, gender, practice setting, practice region, and years since completion of highest academic degree) and responses on survey items were examined. In descending order, the technologies most commonly used by psychologists were: landline telephone, mobile telephone, e-mail, and videoconferencing. A lower proportion of psychologists working in public settings used landline telephones, mobile telephones, or e-mail to deliver TBH than that of psychologists engaged in independent practice. In regard to respondents' age, the proportion of psychologists delivering TBH collapsed across technologies was substantially higher among respondents 37 years of age or older compared with that of 36-year-olds or younger. Respondents also noted several ethical/legal barriers in providing TBH services, particularly managing emergencies, licensure requirements, and uncertainties about security, as well as confidentiality, Health Insurance Portability and Account Act (HIPAA) compliance, and malpractice insurance coverage. Overall, a substantial discrepancy was noted between psychologists' positive appraisals of ROBERT L. GLUECKAUF received his MS and PhD in clinical psychology from Florida State University. He is Professor in the Department of Behavioral Sciences & Social Medicine at the Florida State University College of Medicine and research director of the Tallahassee Memorial HealthCare Memory Disorder Clinic. His research interests lie in the development and evaluation of telehealth-based interventions for individuals with chronic health conditions and their family care partners, outcomes measurement, and spirituality and health. MARLENE M. MAHEU received her MA and PhD in clinical psychology from the California School of Professional Psychology-San Diego. She is founder and executive director of the Telebehavioral Health Institute, Inc. Her areas of professional interest include telebehavioral health professional training and consultation on legal and ethical best practices for telehealth and various technologies. KENNETH P. DRUDE received his PhD in counseling psychology from the University of Illinois. He currently serves on the Ohio Board of Psychology and has an outpatient practice in the Dayton, Ohio area. His areas of professional interest include telebehavioral training, practice, policy, and standards.

Purpose To assess the neuroprotective effect of virally-mediated over-expression of ciliary derived neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) in experimental rat glaucoma. Methods Laser-induced glaucoma was produced in one eye of 224 Wistar rats after injection of adeno-associated viral vectors (type 2) containing either CNTF, BDNF or both, using saline injected eyes and uninjected glaucoma eyes as controls. IOP was measured with the TonoLab and semi-automated optic nerve axon counts were performed by masked observers. IOP exposure over time was adjusted in multivariate regression analysis to calculate the effect of CNTF and BDNF. Results By multivariate regression, CNTF had a significant protective effect, with 15% less RGC axon death (p < 0.01). Both combined CNTF—BDNF and BDNF over-expression alone had no statistically significant improvement in RGC axon survival. By Western blot, there was a quantitative increase in CNTF and BDNF expression in retinas exposed to single viral vectors carrying each gene, but no increase with sequential injection of both vectors. Conclusion These data confirm that CNTF can exert a protective effect in experimental glaucoma. The reason for a lack of observed effect with the BDNF overexpression groups is unclear, but may be a function of the level of neurotrophin expression achieved.

Slow‐binding inhibitors with long residence time on the target often display superior efficacy in vivo. Rationally designing inhibitors with low off‐target rates is restricted by a limited understanding of the structural basis of slow‐binding inhibition kinetics in enzyme–drug interactions. 4‐Hydroxyphenylpyruvate dioxygenase (HPPD) is an important target for drug and herbicide development. Although the time‐dependent behavior of HPPD inhibitors has been studied for decades, its structural basis and mechanism remain unclear. Herein, we report a detailed experimental and computational study that explores structures for illustrating the slow‐binding inhibition kinetics of HPPD. We observed the conformational change of Phe428 at the C‐terminal α‐helix in the inhibitor‐bound structures and further identified that the inhibition kinetics of drugs are related to steric hindrance of Phe428. These detailed structural and mechanistic insights illustrate that steric hindrance is highly associated with the time‐dependent behavior of HPPD inhibitors. These findings may enable rational design of new potent HPPD‐targeted drugs or herbicides with longer target residence time and improved properties. Database Structure data are available in the PDB under the accession numbers (released), (released), and (released).