Dynamic regulation of quaternary organization of the M1 muscarinic receptor by subtype-selective antagonist drugs

Although rhodopsin-like G protein-coupled receptors can exist as both monomers and non-covalently associated dimers/oligomers, the steady-state proportion of each form and whether this is regulated by receptor ligands is unknown. Herein we address these topics for the M1 muscarinic acetylcholine receptor, a key molecular target for novel cognition enhancers, by employing Spatial Intensity Distribution Analysis. This method can measure fluorescent particle concentration and assess oligomerization states of proteins within defined regions of living cells. Imaging and analysis of the basolateral surface of cells expressing some 50 molecules.microm-2 of the human muscarinic M1 receptor identified an ~75/25 mixture of receptor monomers and dimers/oligomers. Both sustained and shorter-term treatment with the selective M1 antagonist pirenzepine resulted in a large shift in the distribution of receptor species to favor the dimeric/oligomeric state. Although sustained treatment with pirenzepine also resulted in marked upregulation of the receptor, simple mass-action effects were not the basis for ligand-induced stabilization of receptor dimers/oligomers. The related antagonist telenzepine also produced stabilization and enrichment of the M1 receptor dimer population but the receptor subtype non-selective antagonists atropine and N-methylscopolamine did not. In contrast, neither pirenzepine nor telenzepine altered the quaternary organization of the related M3 muscarinic receptor. These data provide unique insights into the selective capacity of receptor ligands to promote and/or stabilize receptor dimers/oligomers and demonstrate that the dynamics of ligand regulation of the quaternary organization of G protein-coupled receptors is markedly more complex than previously appreciated. This may have major implications for receptor function and behavior

The effects of parasitism and body length on positioning within wild fish shoals

The influence of body length and parasitism on the positioning behaviour of individuals in wild fish shoals was investigated by a novel means of capturing entire shoals of the banded killifish (Fundulus diaphanus, Lesueur) using a grid-net that maintained the two-dimensional positions of individuals within shoals. Fish in the front section of a shoal were larger than those in the rear. Individuals parasitized by the digenean trematode (Crassiphiala bulboglossa, Haitsma) showed a tendency to occupy the front of shoals. Parasitized fish were also found more in peripheral positions than central ones in a significant number of shoals. Shoal geometry was affected by the overall parasite prevalence of shoal members; shoals with high parasite prevalence displayed increasingly phallanx-like shoal formations, whereas shoals with low prevalence were more elliptical. There was no relationship between body length and parasite abundance or prevalence in the fish population which suggests body length and parasite status are independent predictors of positioning behaviour. Solitary individuals found outside shoals were both more likely to be parasitized and had higher parasite abundance than individuals engaged in shoaling. Differences in the shoaling behaviour of parasitized and unparasitized fish are discussed in the context of the adaptive manipulation hypothesis

Electrostatic Patch Effect in Cylindrical Geometry. I. Potential and Energy between Slightly Non-Coaxial Cylinders

We study the effect of any uneven voltage distribution on two close cylindrical conductors with parallel axes that are slightly shifted in the radial and by any length in the axial direction. The investigation is especially motivated by certain precision measurements, such as the Satellite Test of the Equivalence Principle (STEP). By energy conservation, the force can be found as the energy gradient in the vector of the shift, which requires determining potential distribution and energy in the gap. The boundary value problem for the potential is solved, and energy is thus found to the second order in the small transverse shift, and to lowest order in the gap to cylinder radius ratio. The energy consists of three parts: the usual capacitor part due to the uniform potential difference, the one coming from the interaction between the voltage patches and the uniform voltage difference, and the energy of patch interaction, entirely independent of the uniform voltage. Patch effect forces and torques in the cylindrical configuration are derived and analyzed in the next two parts of this work.Comment: 26 pages, 1 Figure. Submitted to Classical and Quantum Gravit

The Effect of the Environment on alpha-Al_2O_3 (0001) Surface Structures

We report that calculating the Gibbs free energy of the alpha-Al_2O_3 (0001) surfaces in equilibrium with a realistic environment containing both oxygen and hydrogen species is essential for obtaining theoretical predictions consistent with experimental observations. Using density-functional theory we find that even under conditions of high oxygen partial pressure, the metal terminated surface is surprisingly stable. An oxygen terminated alpha-Al_2O_3 (0001) surface becomes stable only if hydrogen is present on the surface. In addition, including hydrogen on the surface resolves discrepancies between previous theoretical work and experimental results with respect to the magnitude and direction of surface relaxations.Comment: 4 pages including 2 figures. Submitted to Phys. Rev. Lett. Related publications can be found at http://www.fhi-berlin.mpg.de/th/paper.htm

Record-breaking ozone loss in the Arctic winter 2010/2011: comparison with 1996/1997

We present a detailed discussion of the chemical and dynamical processes in the Arctic winters 1996/1997 and 2010/2011 with high resolution chemical transport model (CTM) simulations and space-based observations. In the Arctic winter 2010/2011, the lower stratospheric minimum temperatures were below 195 K for a record period of time, from December to mid-April, and a strong and stable vortex was present during that period. Simulations with the Mimosa-Chim CTM show that the chemical ozone loss started in early January and progressed slowly to 1 ppmv (parts per million by volume) by late February. The loss intensified by early March and reached a record maximum of ~2.4 ppmv in the late March–early April period over a broad altitude range of 450–550 K. This coincides with elevated ozone loss rates of 2–4 ppbv sh^(−1) (parts per billion by volume/sunlit hour) and a contribution of about 30–55% and 30–35% from the ClO-ClO and ClO-BrO cycles, respectively, in late February and March. In addition, a contribution of 30–50% from the HO_x cycle is also estimated in April. We also estimate a loss of about 0.7–1.2 ppmv contributed (75%) by the NO_x cycle at 550–700 K. The ozone loss estimated in the partial column range of 350–550 K exhibits a record value of ~148 DU (Dobson Unit). This is the largest ozone loss ever estimated in the Arctic and is consistent with the remarkable chlorine activation and strong denitrification (40–50%) during the winter, as the modeled ClO shows ~1.8 ppbv in early January and ~1 ppbv in March at 450–550 K. These model results are in excellent agreement with those found from the Aura Microwave Limb Sounder observations. Our analyses also show that the ozone loss in 2010/2011 is close to that found in some Antarctic winters, for the first time in the observed history. Though the winter 1996/1997 was also very cold in March–April, the temperatures were higher in December–February, and, therefore, chlorine activation was moderate and ozone loss was average with about 1.2 ppmv at 475–550 K or 42 DU at 350–550 K, as diagnosed from the model simulations and measurements

Therapeutic and educational objectives in robot assisted play for children with autism

“This material is presented to ensure timely dissemination of scholarly and technical work. Copyright and all rights therein are retained by authors or by other copyright holders. All persons copying this information are expected to adhere to the terms and constraints invoked by each author's copyright. In most cases, these works may not be reposted without the explicit permission of the copyright holder." “Copyright IEEE. Personal use of this material is permitted. However, permission to reprint/republish this material for advertising or promotional purposes or for creating new collective works for resale or redistribution to servers or lists, or to reuse any copyrighted component of this work in other works must be obtained from the IEEE.” DOI: 10.1109/ROMAN.2009.5326251This article is a methodological paper that describes the therapeutic and educational objectives that were identified during the design process of a robot aimed at robot assisted play. The work described in this paper is part of the IROMEC project (Interactive Robotic Social Mediators as Companions) that recognizes the important role of play in child development and targets children who are prevented from or inhibited in playing. The project investigates the role of an interactive, autonomous robotic toy in therapy and education for children with special needs. This paper specifically addresses the therapeutic and educational objectives related to children with autism. In recent years, robots have already been used to teach basic social interaction skills to children with autism. The added value of the IROMEC robot is that play scenarios have been developed taking children's specific strengths and needs into consideration and covering a wide range of objectives in children's development areas (sensory, communicational and interaction, motor, cognitive and social and emotional). The paper describes children's developmental areas and illustrates how different experiences and interactions with the IROMEC robot are designed to target objectives in these areas.Final Published versio

Effects of study design and allocation on participant behaviour-ESDA: study protocol for a randomized controlled trial

Background: What study participants think about the nature of a study has been hypothesised to affect subsequent behaviour and to potentially bias study findings. In this trial we examine the impact of awareness of study design and allocation on participant drinking behaviour. Methods/Design: A three-arm parallel group randomised controlled trial design will be used. All recruitment, screening, randomisation, and follow-up will be conducted on-line among university students. Participants who indicate a hazardous level of alcohol consumption will be randomly assigned to one of three groups. Group A will be informed their drinking will be assessed at baseline and again in one month (as in a cohort study design). Group B will be told the study is an intervention trial and they are in the control group. Group C will be told the study is an intervention trial and they are in the intervention group. All will receive exactly the same brief educational material to read. After one month, alcohol intake for the past 4 weeks will be assessed. Discussion: The experimental manipulations address subtle and previously unexplored ways in which participant behaviour may be unwittingly influenced by standard practice in trials. Given the necessity of relying on self-reported outcome, it will not be possible to distinguish true behaviour change from reporting artefact. This does not matter in the present study, as any effects of awareness of study design or allocation involve bias that is not well understood. There has been little research on awareness effects, and our outcomes will provide an indication of the possible value of further studies of this type and inform hypothesis generation

Theories of behaviour change synthesised into a set of theoretical groupings: Introducing a thematic series on the Theoretical Domains Framework

Behaviour change is key to increasing the uptake of evidence into healthcare practice. Designing behaviour-change interventions first requires problem analysis, ideally informed by theory. Yet the large number of partly overlapping theories of behaviour makes it difficult to select the most appropriate theory. The need for an overarching theoretical framework of behaviour change was addressed in research in which 128 explanatory constructs from 33 theories of behaviour were identified and grouped. The resulting Theoretical Domains Framework (TDF) appears to be a helpful basis for investigating implementation problems. Research groups in several countries have conducted TDF-based studies. It seems timely to bring together the experience of these teams in a thematic series to demonstrate further applications and to report key developments. This overview article describes the TDF, provides a brief critique of the framework, and introduces this thematic series. In a brief review to assess the extent of TDF-based research, we identified 133 papers that cite the framework. Of these, 17 used the TDF as the basis for empirical studies to explore health professionals’ behaviour. The identified papers provide evidence of the impact of the TDF on implementation research. Two major strengths of the framework are its theoretical coverage and its capacity to elicit beliefs that could signify key mediators of behaviour change. The TDF provides a useful conceptual basis for assessing implementation problems, designing interventions to enhance healthcare practice, and understanding behaviour-change processes. We discuss limitations and research challenges and introduce papers in this series

Coherence of long-term stratospheric ozone vertical distribution time series used for the study of ozone recovery at a northern mid-latitude station

The coherence of stratospheric ozone time series retrieved from various observational records is investigated at Haute-Provence Observatory (OHP–43.93° N, 5.71° E). The analysis is accomplished through the intercomparison of collocated ozone measurements of Light Detection and Ranging (lidar) with Solar Backscatter UltraViolet(/2) (SBUV(/2)), Stratospheric Aerosol and Gas Experiment II (SAGE~II), Halogen Occultation Experiment (HALOE), Microwave Limb Sounder (MLS) on Upper Atmosphere Research Satellite (UARS) and Aura and Global Ozone Monitoring by Occultation of Stars (GOMOS) satellite observations as well as with in situ ozonesondes and ground-based Umkehr measurements performed at OHP. A detailed statistical study of the relative differences of ozone observations over the whole stratosphere is performed to detect any specific drift in the data. On average, all instruments show their best agreement with lidar at 20–40 km, where deviations are within ±5 %. Discrepancies are somewhat higher below 20 and above 40 km. The agreement with SAGE II data is remarkable since average differences are within ±1 % at 17–41 km. In contrast, Umkehr data underestimate systematically the lidar measurements in the whole stratosphere with a near zero bias at 16–8 hPa (~30 km). Drifts are estimated using simple linear regression for the data sets analysed in this study, from the monthly averaged difference time series. The derived values are less than ±0.5 % yr<sup>−1</sup> in the 20–40 km altitude range and most drifts are not significant at the 2<i>σ</i> level. We also discuss the possibilities of extending the SAGE II and HALOE data with the GOMOS and Aura MLS data in consideration with relative offsets and drifts since the combination of such data sets are likely to be used for the study of stratospheric ozone recovery in the future

Systematic stratospheric observations on the Antarctic continent at Dumont d'Urville

Results of different routine measurements performed in Dumont d'Urville (66 deg S, 140 deg E) since 1988 are presented. They include the seasonal variation of total ozone and NO2 as measured by a SAOZ UV-Visible spectrometer, Polar Stratospheric Cloud observations by a backscatter lidar and more recently, vertical ozone profiles by ECC sondes and ozone and aerosols stratospheric profiles by a DIAL lidar. The particular results of 1991 in relation with the volcanic events of Mount Pinatubo and Mount Hudson, and the position of the polar vortex over Dumont d'Urville are discussed