The role of ECL2 in CGRP receptor activation: a combined modelling and experimental approach

The calcitonin gene-related peptide (CGRP) receptor is a complex of a calcitonin receptor-like receptor (CLR), which is a family B G-protein-coupled receptor (GPCR) and receptor activity modifying protein 1. The role of the second extracellular loop (ECL2) of CLR in binding CGRP and coupling to Gs was investigated using a combination of mutagenesis and modelling. An alanine scan of residues 271–294 of CLR showed that the ability of CGRP to produce cAMP was impaired by point mutations at 13 residues; most of these also impaired the response to adrenomedullin (AM). These data were used to select probable ECL2-modelled conformations that are involved in agonist binding, allowing the identification of the likely contacts between the peptide and receptor. The implications of the most likely structures for receptor activation are discussed.</jats:p

Brane-World Gravity

The observable universe could be a 1+3-surface (the "brane") embedded in a 1+3+\textit{d}-dimensional spacetime (the "bulk"), with Standard Model particles and fields trapped on the brane while gravity is free to access the bulk. At least one of the \textit{d} extra spatial dimensions could be very large relative to the Planck scale, which lowers the fundamental gravity scale, possibly even down to the electroweak ($\sim$ TeV) level. This revolutionary picture arises in the framework of recent developments in M theory. The 1+10-dimensional M theory encompasses the known 1+9-dimensional superstring theories, and is widely considered to be a promising potential route to quantum gravity. At low energies, gravity is localized at the brane and general relativity is recovered, but at high energies gravity "leaks" into the bulk, behaving in a truly higher-dimensional way. This introduces significant changes to gravitational dynamics and perturbations, with interesting and potentially testable implications for high-energy astrophysics, black holes, and cosmology. Brane-world models offer a phenomenological way to test some of the novel predictions and corrections to general relativity that are implied by M theory. This review analyzes the geometry, dynamics and perturbations of simple brane-world models for cosmology and astrophysics, mainly focusing on warped 5-dimensional brane-worlds based on the Randall--Sundrum models. We also cover the simplest brane-world models in which 4-dimensional gravity on the brane is modified at \emph{low} energies -- the 5-dimensional Dvali--Gabadadze--Porrati models. Then we discuss co-dimension two branes in 6-dimensional models.Comment: A major update of Living Reviews in Relativity 7:7 (2004) "Brane-World Gravity", 119 pages, 28 figures, the update contains new material on RS perturbations, including full numerical solutions of gravitational waves and scalar perturbations, on DGP models, and also on 6D models. A published version in Living Reviews in Relativit

Recall of a live and personally experienced eyewitness event by adults with autism spectrum disorder

The aim of the present study was to (a) extend previous eyewitness research in autism spectrum disorder (ASD) using a live and personally experienced event; (b) examine whether witnesses with ASD demonstrate a facilitative effect in memory for self- over other-performed actions; (c) explore source monitoring abilities by witnesses with ASD in discriminating who performed which actions within the event. Eighteen high-functioning adults with ASD and 18 age- and IQ-matched typical counterparts participated in a live first aid scenario in which they and the experimenter each performed a number of actions. Participants were subsequently interviewed for their memory of the event using a standard interview procedure with free recall followed by questioning. The ASD group recalled just as many correct details as the comparison group from the event overall, however they made more errors. This was the case across both free recall and questioning phases. Both groups showed a self-enactment effect across both interview phases, recalling more actions that they had performed themselves than actions that the experimenter had performed. However, the ASD group were more likely than their typical comparisons to confuse the source of self-performed actions in free recall, but not in questioning, which may indicate executive functioning difficulties with unsupported test procedures. Findings are discussed in terms of their theoretical and practical implications

Remyelination after chronic spinal cord injury is associated with proliferation of endogenous adult progenitor cells after systemic administration of guanosine

Axonal demyelination is a consistent pathological sequel to chronic brain and spinal cord injuries and disorders that slows or disrupts impulse conduction, causing further functional loss. Since oligodendroglial progenitors are present in the demyelinated areas, failure of remyelination may be due to lack of sufficient proliferation and differentiation of oligodendroglial progenitors. Guanosine stimulates proliferation and differentiation of many types of cells in vitro and exerts neuroprotective effects in the central nervous system (CNS). Five weeks after chronic traumatic spinal cord injury (SCI), when there is no ongoing recovery of function, intraperitoneal administration of guanosine daily for 2 weeks enhanced functional improvement correlated with the increase in myelination in the injured cord. Emphasis was placed on analysis of oligodendrocytes and NG2-positive (NG2+) cells, an endogenous cell population that may be involved in oligodendrocyte replacement. There was an increase in cell proliferation (measured by bromodeoxyuridine staining) that was attributable to an intensification in progenitor cells (NG2+ cells) associated with an increase in mature oligodendrocytes (determined by Rip+ staining). The numbers of astroglia increased at all test times after administration of guanosine whereas microglia only increased in the later stages (14 days). Injected guanosine and its breakdown product guanine accumulated in the spinal cords; there was more guanine than guanosine detected. We conclude that functional improvement and remyelination after systemic administration of guanosine is due to the effect of guanosine/guanine on the proliferation of adult progenitor cells and their maturation into myelin-forming cells. This raises the possibility that administration of guanosine may be useful in the treatment of spinal cord injury or demyelinating diseases such as multiple sclerosis where quiescent oligodendroglial progenitors exist in demyelinated plaques

Reality Monitoring and Metamemory in Adults with Autism Spectrum Conditions.

Studies of reality monitoring (RM) often implicate medial prefrontal cortex (mPFC) in distinguishing internal and external information, a region linked to autism-related deficits in social and self-referential information processing, executive function, and memory. This study used two RM conditions (self-other; perceived-imagined) to investigate RM and metamemory in adults with autism. The autism group showed a deficit in RM, which did not differ across source conditions, and both groups exhibited a self-encoding benefit on recognition and source memory. Metamemory for perceived-imagined information, but not for self-other information, was significantly lower in the autism group. Therefore, reality monitoring and metamemory, sensitive to mPFC function, appear impaired in autism, highlighting a difficulty in remembering and monitoring internal and external details of past events.This research was supported by a James S. McDonnell Scholar Award to J.S.S., and an Economic and Social Research Council Award to R.A.C