Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor

The κ-opioid receptor (KOP) mediates the actions of opioids with hallucinogenic, dysphoric, and analgesic activities. The design of KOP analgesics devoid of hallucinatory and dysphoric effects has been hindered by an incomplete structural and mechanistic understanding of KOP agonist actions. Here, we provide a crystal structure of human KOP in complex with the potent epoxymorphinan opioid agonist MP1104 and an active-state-stabilizing nanobody. Comparisons between inactive- and active-state opioid receptor structures reveal substantial conformational changes in the binding pocket and intracellular and extracellular regions. Extensive structural analysis and experimental validation illuminate key residues that propagate larger-scale structural rearrangements and transducer binding that, collectively, elucidate the structural determinants of KOP pharmacology, function, and biased signaling. These molecular insights promise to accelerate the structure-guided design of safer and more effective κ-opioid receptor therapeutics. A crystal structure of the active κ-opioid receptor provides a guide for the development of safe and effective new analgesics. © 2017 Elsevier Inc

TRANSIENT LOADING OF THIN-WALLED CYLINDERS. Interim Technical Report

The effect of internal static loading and internal transient loading on the deformation of thin-walled tube specimens was studied for both the elastic and plastic regions. The specimens employed were six inch sections of type 304, seamless, stainless steel tubing having a nominal O.D. and wall thickness of 3/4 inch and 0.020 inch, respectively. The transient forces were obtained from detonations of stoichiometric hydrogen-oxygen mixtures contained in a shocktype detonation tube. Each specimen was postfixed to the detonation tube and then acted as an extension of the tube. The detonation wave travelled through the system and exerted on the specimen walls a strain from either a single incident wave pressure or from an incident plus reflected wave pressure combination, depending upon the apparatus used to cap the downstream end of the specimen. Strains in the elastic region were measured with bonded electric resistance strain gages, while strains in the post-yield region were measured with a micrometer. The static loading forces were obtained from high pressure oil fed from a hydraulic pump into the specimen. The Young's Modulus of Elasticity for transient loading was 1.22 times greater than for static loading. Similarly, the 0.2 percent offset yield strength for the incident detonation wave transient loading case and for the incident plus refiected detonation wave transient loading case were 1.41 and 1.50, respectively, times the static yield strength. The results of this investigation indicated that as the time of force application decreased, the ability of type 304 stainless steel to resist deformation increased. In other words, the specimen exhibited a much higher value of toughness, elastic resilience and hyper-elastic resilience when loaded by a transient force than when loaded statically. (auth

Ocular, Neurologic and Systemic Findings of the Cases with Optic Nerve Hypoplasia

AIM: To describe the associated ocular, neurologic, and systemic findings in a population of children with optic nerve hypoplasia (ONH) and to evaluate the relationship between ocular signs and neurologic findings. METHOD: A retrospective chart review of 53 patients with the diagnosis of ONH seen between December 1998 and September 2012 was performed. All neurodevelopmental anomalies, neuroradiologic findings, endocrinologic and systemic findings were recorded. Poor vision was defined as the visual acuity poorer than logMAR 1.0 or inadequate central steady maintained fixation. RESULTS: Thirty (56.6%) of the 53 children with ONH were boys. Mean age at presentation was 56.2±46.8 months (range; 3 months to 18 years). Poor vision defined for the purpose of this study was found in 47.2% of 53 patients. Thirty-three (62.3%) children had nystagmus. Thirty-four (64.2%) children had strabismus. Thirteen (38.2%) of those with strabismus had esotropia, 20 (58.8%) had exotropia. The total number of the children with neurodevelopmental deficit was 22 (41.5%) in our study. CONCLUSION: The vision of young children with ONH should be monitored at least annually, and any refractive errors should be treated. Neuroimaging of the brain and endocrinologic evaluation is necessary in all cases with ONH

Joint Procrustes Analysis for Simultaneous Nonsingular Transformation of Component Score and Loading Matrices

joint Procrustes analysis, component analysis, nonsingular transformation, singular value decomposition,