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

Refactorings of Design Defects using Relational Concept Analysis

Software engineers often need to identify and correct design defects, ıe} recurring design problems that hinder development and maintenance\ud by making programs harder to comprehend and--or evolve. While detection\ud of design defects is an actively researched area, their correction---mainly\ud a manual and time-consuming activity --- is yet to be extensively\ud investigated for automation. In this paper, we propose an automated\ud approach for suggesting defect-correcting refactorings using relational\ud concept analysis (RCA). The added value of RCA consists in exploiting\ud the links between formal objects which abound in a software re-engineering\ud context. We validated our approach on instances of the <span class='textit'></span>Blob\ud design defect taken from four different open-source programs

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

Effect of heuristics on serendipity in path-based storytelling with linked data

Path-based storytelling with Linked Data on the Web provides users the ability to discover concepts in an entertaining and educational way. Given a query context, many state-of-the-art pathfinding approaches aim at telling a story that coincides with the user's expectations by investigating paths over Linked Data on the Web. By taking into account serendipity in storytelling, we aim at improving and tailoring existing approaches towards better fitting user expectations so that users are able to discover interesting knowledge without feeling unsure or even lost in the story facts. To this end, we propose to optimize the link estimation between - and the selection of facts in a story by increasing the consistency and relevancy of links between facts through additional domain delineation and refinement steps. In order to address multiple aspects of serendipity, we propose and investigate combinations of weights and heuristics in paths forming the essential building blocks for each story. Our experimental findings with stories based on DBpedia indicate the improvements when applying the optimized algorithm

Variations in sea surface roughness induced by the 2004 Sumatra-Andaman tsunami

Observations of tsunamis away from shore are critically important for improving early warning systems and understanding of tsunami generation and propagation. Tsunamis are difficult to detect and measure in the open ocean because the wave amplitude there is much smaller than it is close to shore. Currently, tsunami observations in deep water rely on measurements of variations in the sea surface height or bottom pressure. Here we demonstrate that there exists a different observable, specifically, ocean surface roughness, which can be used to reveal tsunamis away from shore. The first detailed measurements of the tsunami effect on sea surface height and radar backscattering strength in the open ocean were obtained from satellite altimeters during passage of the 2004 Sumatra-Andaman tsunami. Through statistical analyses of satellite altimeter observations, we show that the Sumatra-Andaman tsunami effected distinct, detectable changes in sea surface roughness. The magnitude and spatial structure of the observed variations in radar backscattering strength are consistent with hydrodynamic models predicting variations in the near-surface wind across the tsunami wave front. Tsunami-induced changes in sea surface roughness can be potentially used for early tsunami detection by orbiting microwave radars and radiometers, which have broad surface coverage across the satellite ground track

Influence of topography on tide propagation and amplification in semi-enclosed basins

An idealized model for tide propagation and amplification in semi-enclosed rectangular basins is presented, accounting for depth differences by a combination of longitudinal and lateral topographic steps. The basin geometry is formed by several adjacent compartments of identical width, each having either a uniform depth or two depths separated by a transverse topographic step. The problem is forced by an incoming Kelvin wave at the open end, while allowing waves to radiate outward. The solution in each compartment is written as the superposition of (semi)-analytical wave solutions in an infinite channel, individually satisfying the depth-averaged linear shallow water equations on the f plane, including bottom friction. A collocation technique is employed to satisfy continuity of elevation and flux across the longitudinal topographic steps between the compartments. The model results show that the tidal wave in shallow parts displays slower propagation, enhanced dissipation and amplified amplitudes. This reveals a resonance mechanism, occurring when\ud the length of the shallow end is roughly an odd multiple of the quarter Kelvin wavelength. Alternatively, for sufficiently wide basins, also Poincaré waves may become resonant. A transverse step implies different wavelengths of the incoming and reflected Kelvin wave, leading to increased amplitudes in shallow regions and a shift of amphidromic points in the direction of the deeper part. Including the shallow parts near the basin’s closed end (thus capturing the Kelvin resonance mechanism) is essential to reproduce semi-diurnal and diurnal\ud tide observations in the Gulf of California, the Adriatic Sea and the Persian Gulf

Gully Formation at the Haughton Impact Structure (Arctic Canada) Through the Melting of Snow and Ground Ice, with Implications for Gully Formation on Mars

The formation of gullies on Mars has been the topic of active debate and scientific study since their first discovery by Malin and Edgett in 2000. Several mechanisms have been proposed to account for gully formation on Mars, from dry mass movement processes, release of water or brine from subsurface aquifers, and the melting of near-surface ground ice or snowpacks. In their global documentation of martian gullies, report that gullies are confined to ~2783S and ~2872N latitudes and span all longitudes. Gullies on Mars have been documented on impact crater walls and central uplifts, isolated massifs, and on canyon walls, with crater walls being the most common situation. In order to better understand gully formation on Mars, we have been conducting field studies in the Canadian High Arctic over the past several summers, most recently in summer 2018 and 2019 under the auspices of the Canadian Space Agency-funded Icy Mars Analogue Program. It is notable that the majority of previous studies in the Arctic and Antarctica, including our recent work on Devon Island, have focused on gullies formed on slopes generated by regular endogenic geological processes and in regular bedrock. How-ever, as noted above, meteorite impact craters are the most dominant setting for gullies on Mars. Impact craters provide an environment with diverse lithologies including impact-generated and impact-modified rocks and slope angle, and thus greatly variable hill slope processes could occur within a localized area. Here, we investigate the formation of gullies within the Haughton impact structure and compare them to gullies formed in unimpacted target rock in the nearby Thomas Lee Inle

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

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

Do self-reported intentions predict clinicians behaviour: a systematic review.

Background: Implementation research is the scientific study of methods to promote the systematic uptake of clinical research findings into routine clinical practice. Several interventions have been shown to be effective in changing health care professionals' behaviour, but heterogeneity within interventions, targeted behaviours, and study settings make generalisation difficult. Therefore, it is necessary to identify the 'active ingredients' in professional behaviour change strategies. Theories of human behaviour that feature an individual's "intention" to do something as the most immediate predictor of their behaviour have proved to be useful in non-clinical populations. As clinical practice is a form of human behaviour such theories may offer a basis for developing a scientific rationale for the choice of intervention to use in the implementation of new practice. The aim of this review was to explore the relationship between intention and behaviour in clinicians and how this compares to the intention-behaviour relationship in studies of non-clinicians. Methods: We searched: PsycINFO, MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, Science/Social science citation index, Current contents (social & behavioural med/clinical med), ISI conference proceedings, and Index to Theses. The reference lists of all included papers were checked manually. Studies were eligible for inclusion if they had: examined a clinical behaviour within a clinical context, included measures of both intention and behaviour, measured behaviour after intention, and explored this relationship quantitatively. All titles and abstracts retrieved by electronic searching were screened independently by two reviewers, with disagreements resolved by discussion. Discussion: Ten studies were found that examined the relationship between intention and clinical behaviours in 1623 health professionals. The proportion of variance in behaviour explained by intention was of a similar magnitude to that found in the literature relating to non-health professionals. This was more consistently the case for studies in which intention-behaviour correspondence was good and behaviour was self-reported. Though firm conclusions are limited by a smaller literature, our findings are consistent with that of the non-health professional literature. This review, viewed in the context of the larger populations of studies, provides encouragement for the contention that there is a predictable relationship between the intentions of a health professional and their subsequent behaviour. However, there remain significant methodological challenges