How to increase the safety and efficacy of compounds against neurodegeneration? A multifunctional approach

Successful drug design requires not only the detailed knowledge of the pharmacokinetic and pharmacodynamic profiles of the drug candidate portfolio but also a thorough documentation of the possible toxic effects on humans and the environment. Thus, experimental and computational strategies able to measure or predict specific profiles of designed compounds related to their potential toxicity are highly desired. Moreover, a strategy to avoid toxic effects thus enhancing the potential efficacy of drug candidates is of great interest. To fulfil this aim, the pharmacochemistry research unit at the EPGL has recently developed and improved methodologies that detect the potential human health and environmental hazards of compounds active against neurodegeneration at an early stage. A three-step strategy is presented herein. In particular, i) an alternative index to model the bioconcentration of chemicals in the environment was determined; ii) the antioxidant activity of chemical species against free radicals was evaluated. Moreover, since antioxidants play a key role in both toxicity prevention and neuroprotection, iii) the potential interaction of such compounds with enzymatic targets involved in the neurodegenerative cascade was investigated in silico.     

Stereoselective block of hERG channel by bupivacaine scrutinized at molecular level

In the heart, the hERG voltage-gated potassium channel mediates the I(Kr) current, which is crucial for the duration of cardiac action potential. Undesired block of the channel may prolong the QT interval with increased risk of malignant ventricular arrhythmia called torsades de pointes. Although the molecular determinants of hERG block are intensively studied, stereoselectivity has been poorly investigated. Levo-(S)-bupivacaine was the first drug reported to have higher affinity for hERG than its enantiomer. This study aims at understanding the principles underlying the stereoselectivity of bupivacaine block with the help of molecular modeling. Putative binding modes of levo-(S)- and dextro-(R)-bupivacaine inside an open form model of hERG channel were predicted by docking simulations, allowing a clear depiction of ligand-protein interactions. Estimated binding energies for both enantiomers to wild-type channel are in line with previously published electrophysiology measurements. These results may be considered as a confirmation at the molecular level of bupivacaine stereoselective binding towards hERG. Moreover this information lays the foundations for a structural guideline to filter out potentially cardiotoxic drug candidates in silico.     

Modeling modeling modeling

Model-driven engineering and model-based approaches have permeated all branches of software engineering to the point that it seems that we are using models, as Molière??s Monsieur Jourdain was using prose, without knowing it. At the heart of modeling, there is a relation that we establish to represent something by something else. In this paper we review various definitions of models and relations between them. Then, we define a canonical set of relations that can be used to express various kinds of representation relations and we propose a graphical concrete syntax to represent these relations. We also define a structural definition for this language in the form of a metamodel and a formal interpretation using Prolog. Hence, this paper is a contribution towards a theory of modeling.     

Cultural Heritage Preservation Using Constructive Shape Modeling

Issues of digital preservation of shapes and internal structures of historical cultural objects are discussed. An overview of existing approaches to digital preservation related to shape modeling is presented and corresponding problems are considered. We propose a new digital preservation paradigm based on both constructive modeling reflecting the logical structure of the objects and open standards and procedures. Constructive Solid Geometry (CSG) and Function Representation (FRep) are examined and practically applied as mathematical representations producing compressed yet precise data structures, thus providing inter‐operability between current and future computer platforms crucial to archiving. Examples of CSG reconstruction of historical temples and FRep modeling of traditional lacquer ware are given. We examine the application of fitting of a parameterized FRep model to a cloud of data points as a step towards automation of the modeling process. Virtual venues for public access to cultural heritage objects including real time interactive simulation of cultural heritage sites over the Web are discussed and illustrated.     

Quality assurance during assembly of Wendelstein 7-X

To control all the work and test steps during assembly of Wendelstein 7-X for each major assembly task Quality Assurance and Assembly Plans are used as the central managing instrument. These documents ensure that the order of all steps is carried out as planned and that the envisaged quality will be met. The confirmation of a successful working step often is done by tests and measurement. For each test special instructions were prepared to ensure reproducible and correct results. The tests are either carried out by the certified QA inspectors of the project or by specially qualified internal inspectors. The most important tests and measurements are outlined briefly. All quality deviations are assessed in relation of consequences for later operation.     

Automatic cleaning and segmentation of web images based on colors to build learning databases

This article proposes a method to segment Internet images, that is, a group of images corresponding to a specific object (the query) containing a significant amount of irrelevant images. The segmentation algorithm we propose is a combination of two distinct methods based on color. The first one considers all images to classify pixels into two sets: object pixels and background pixels. The second method segments images individually by trying to find a central object. The final segmentation is obtained by intersecting the results from both. The segmentation results are then used to re-rank images and display a clean set of images illustrating the query. The algorithm is tested on various queries for animals, natural and man-made objects, and results are discussed, showing that the obtained segmentation results are suitable for object learning.     

The evolution of water governance in France from the 1960s: disputes as major drivers for radical changes within a consensual framework

ABSTRACT

This paper provides a synthetic presentation of French water governance and its evolution since the 1960s. Through this French experience, it discusses the Organisation for Economic Co-operation and Development (OECD) water governance cycle showing disputes as the main drivers of change. France has been a pioneer in introducing water river basin management some 50 years ago. It is also noted for its water services management by local authorities, leaving a significant role to private and public companies. But French water governance has not been frozen since the 1960s and continues to change radically within a framework based upon its unique history.