Evaluation of JNJ-54717793 a Novel Brain Penetrant Selective Orexin 1 Receptor Antagonist in Two Rat Models of Panic Attack Provocation

Orexin neurons originating in the perifornical and lateral hypothalamic area are highly reactive to anxiogenic stimuli and have strong projections to anxiety and panic-associated circuitry. Recent studies support a role for the orexin system and in particular the orexin 1 receptor (OX1R) in coordinating an integrative stress response. However, no selective OX1R antagonist has been systematically tested in two preclinical models of using panicogenic stimuli that induce panic attack in the majority of people with panic disorder, namely an acute hypercapnia-panic provocation model and a model involving chronic inhibition of GABA synthesis in the perifornical hypothalamic area followed by intravenous sodium lactate infusion. Here we report on a novel brain penetrant, selective and high affinity OX1R antagonist JNJ-54717793 (1S,2R,4R)-7-([(3-fluoro-2-pyrimidin-2-ylphenyl)carbonyl]-N-[5-(trifluoromethyl)pyrazin-2-yl]-7-azabicyclo[2.2.1]heptan-2-amine). JNJ-54717793 is a high affinity/potent OX1R antagonist and has an excellent selectivity profile including 50 fold versus the OX2R. Ex vivo receptor binding studies demonstrated that after oral administration JNJ-54717793 crossed the blood brain barrier and occupied OX1Rs in the rat brain. While JNJ-54717793 had minimal effect on spontaneous sleep in rats and in wild-type mice, its administration in OX2R knockout mice, selectively promoted rapid eye movement sleep, demonstrating target engagement and specific OX1R blockade. JNJ-54717793 attenuated CO2 and sodium lactate induced panic-like behaviors and cardiovascular responses without altering baseline locomotor or autonomic activity. These data confirm that selective OX1R antagonism may represent a novel approach of treating anxiety disorders, with no apparent sedative effects

Humeral retroversion and its relationship to glenohumeral rotation in the shoulder of college baseball players

We point out that resonant phonon modes with quasiconfined behavior may arise in semiconductor superlattices in the continuum frequency range, i.e., where both constituents have allowed bulk frequencies with real wave vector. With reference to the cases of Si/Ge and InAs/GaSb (001) superlattices, we show that such modes appear close to the edge of overlapping optical frequencies, with displacement patterns and Raman strengths comparable to those of true confined modes. However their degree of confinement and their actual number and frequency location are found to be more sensitive to the adjacent layer and to the details of the interfaces. Their study can therefore yield additional structural information on the interface region with respect to the study of true confined modes

Public COAPI Toolkit of Open Access Policy Resources

The Coalition of Open Access Policy Institutions (COAPI, https://sparcopen.org/coapi ) is committed to sharing information and resources to assist in the development and implementation of institutional Open Access (OA) policies. The COAPI Toolkit includes a diverse collection of resources that COAPI members have developed in the course of their OA policy initiatives. These resources are openly accessible and published here under Creative Commons Attribution 4.0 licenses, unless otherwise noted on the resources themselves