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

Systemic analysis of production scenarios for bioethanol produced from ligno-cellulosic biomass [abstract]

Defining alternatives for non-renewable energy sources constitutes a priority to the development of our societies. One of these alternatives is biofuels production starting from energy crops, agricultural wastes, forest products or wastes. In this context, a "second generation" biofuels production, aiming at utilizing the whole plant, including ligno-cellulosic (hemicelluloses, cellulose, lignin) fractions (Ogier et al., 1999) that are not used for human food, would allow the reduction of the drawbacks of bioethanol production (Schoeling, 2007). However, numerous technical, economical, ethical and environmental questions are still pending. One of the aims of the BioEtha2 project, directed by the Walloon Agricultural Research Centre, is to define the position of bioethanol produced from ligno-cellulosic biomass among the different renewable energy alternatives that could be developed in Wallonia towards 2020. With this aim, and in order to answer the numerous questions in this field, the project aims at using tools and methods coming from the concept of "forecasting scenarios" (Sebillotte, 2002; Slegten et al., 2007; For-learn, 2008). This concept, based on a contemporary reality, aims to explore different possible scenarios for the future development of alternative sources of energy production. The principle is to evaluate, explore, possible futures of the studied problematic, through the establishment of possible evolution trajectories. We contribute to this prospective through a systemic approach (Vanloqueren, 2007) that allows lightening the existing interactions within the system "ligno-cellulosic biomass chain" without isolating it from its environment. We explain and sketch the two contexts needed to identify primary stakes. The global context includes inter-dependant and auto-regulating fields such as society, politics, technology and economy. These four fields influence each part of the "chain" with specific tools. However, the interest and possible action fields lay within the intermediary context representing the "resources" such as agriculture, forestry, "driving" elements such as mobility, mediation elements such as territories and environment and concurrent elements such as non-cellulosic biomass, the energy mix and the non-energy valorization

An Incremental Learning Method to Support the Annotation of Workflows with Data-to-Data Relations

Workflow formalisations are often focused on the representation of a process with the primary objective to support execution. However, there are scenarios where what needs to be represented is the effect of the process on the data artefacts involved, for example when reasoning over the corresponding data policies. This can be achieved by annotating the workflow with the semantic relations that occur between these data artefacts. However, manually producing such annotations is difficult and time consuming. In this paper we introduce a method based on recommendations to support users in this task. Our approach is centred on an incremental rule association mining technique that allows to compensate the cold start problem due to the lack of a training set of annotated workflows. We discuss the implementation of a tool relying on this approach and how its application on an existing repository of workflows effectively enable the generation of such annotations

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

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

Ozone and temperature trends

An update of the extensive reviews of the state of knowledge of measured ozone trends published in the Report of the International Ozone Trends Panel is presented. The update contains a review of progress since these reports, including reviewing of the ozone records, in most cases through March 1991. Also included are some new, unpublished reanalyses of these records including a complete reevaluation of 29 stations located in the former Soviet Union. The major new advance in knowledge of the measured ozone trend is the existence of independently calibrated satellite data records from the Total Ozone Mapping Spectrometer (TOMS) and Stratospheric Aerosol and Gas Experiment (SAG) instruments. These confirm many of the findings, originally derived from the Dobson record, concerning northern mid-latitude changes in ozone. We now have results from several instruments, whereas the previously reported changes were dependent on the calibration of a single instrument. This update will compare the ozone records from many different instruments to determine whether or not they provide a consistent picture of the ozone change that has occurred in the atmosphere. The update also briefly considers the problem of stratospheric temperature change. As in previous reports, this problem received significantly less attention, and the report is not nearly as complete. This area needs more attention in the future

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