Text entry workstation for visual impaired : a public service project

Issued as Subject report, and Final report, Project no. K-10-80

Geographies of marketization: Studying markets in postneoliberal times

This paper is as an invitation to rethink social studies of economization and geographies of marketization at a time when the heydays of neoliberal marketization seem to be over. After briefly summarizing the thrust of the economization/marketization approach, we make two suggestions to develop the perspective further. The first is to make use of economic geography’s heterodox tradition and contribute to the ongoing “provincialization” of the neoclassical market. Second, theorizing actually existing market arrangements as necessarily involving struggles between competing logics and rationalities, we open social studies of economization and geographies of marketization for questions of social inequality, marginalization and exclusion

Dopamine D3 receptor ligands—Recent advances in the control of subtype selectivity and intrinsic activity

AbstractVarious pharmacological studies have implicated the dopamine D3 receptor as an interesting therapeutic target in the treatment of different neurological disorders. Because of these putative therapeutic applications, D3 receptor ligands with diverse intrinsic activities have been an active field of research in recent years. Separation of purely D3-mediated drug effects from effects produced by interactions with similar biogenic amine receptors allows to verify the therapeutic impact of D3 receptors and to reduce possible side-effects caused by “promiscuous” receptor interactions. The requirement to gain control of receptor selectivity and in particular subtype selectivity has been a challenging task in rational drug discovery for quite a few years. In this review, recently developed structural classes of D3 ligands are discussed, which cover a broad spectrum of intrinsic activities and show interesting selectivities

Champtoceaux – La Colinière, enceinte urbaine

Le bourg de Champtoceaux, situé sur la rive gauche de la Loire entre Ancenis et Nantes, domine directement le fleuve depuis un éperon barré, situé entre 50 et 70 m d’altitude. Cette topographie favorable lui permet de jouer à l’époque médiévale un rôle majeur sur les marches de l’Anjou et de la Bretagne, aux confins du Poitou. Les sources écrites, littéraires et iconographiques soulignent cette importance. Plus encore, les vestiges monumentaux subsistant aujourd’hui témoignent de la richesse ..

Elektrochemische Abscheidung von Zinkoxid-Schichten unter dem Einfluss von strukturdirigierenden Additiven für die Anwendung in farbstoffsensibilisierten Solarzellen

[no abstract

Embracing the Diversity of Halogen Bonding Motifs in Fragment-Based Drug Discovery—Construction of a Diversity-Optimized Halogen-Enriched Fragment Library

Halogen bonds have recently gained attention in life sciences and drug discovery. However, it can be difficult to harness their full potential, when newly introducing them into an established hit or lead structure by molecular design. A possible solution to overcome this problem is the use of halogen-enriched fragment libraries (HEFLibs), which consist of chemical probes that provide the opportunity to identify halogen bonds as one of the main features of the binding mode. Initially, we have suggested the HEFLibs concept when constructing a focused library for finding p53 mutant stabilizers. Herein, we broaden and extent this concept aiming for a general HEFLib comprising a huge diversity of binding motifs and, thus, increasing the applicability to various targets. Using the construction principle of feature trees, we represent each halogenated fragment by treating all simple to complex substituents as modifiers of the central (hetero)arylhalide. This approach allows us to focus on the proximal binding interface around the halogen bond and, thus, its integration into a network of interactions based on the fragment's binding motif. As a first illustrative example, we generated a library of 198 fragments that unifies a two-fold strategy: Besides achieving a diversity-optimized basis of the library, we have extended this “core” by structurally similar “satellite compounds” that exhibit quite different halogen bonding interfaces. Tuning effects, i.e., increasing the magnitude of the σ-hole, can have an essential influence on the strength of the halogen bond. We were able to implement this key feature into the diversity selection, based on the rapid and efficient prediction of the highest positive electrostatic potential on the electron isodensity surface, representing the σ-hole, by VmaxPred

Exploiting transient protein states for the design of small-molecule stabilizers of mutant p53

The destabilizing p53 cancer mutation Y220C creates an extended crevice on the surface of the protein that can be targeted by small-molecule stabilizers. Here, we identify different classes of small molecules that bind to this crevice and determine their binding modes by X-ray crystallography. These structures reveal two major conformational states of the pocket and a cryptic, transiently open hydrophobic subpocket that is modulated by Cys220. In one instance, specifically targeting this transient protein state by a pyrrole moiety resulted in a 40-fold increase in binding affinity. Molecular dynamics simulations showed that both open and closed states of this subsite were populated at comparable frequencies along the trajectories. Our data extend the framework for the design of high-affinity Y220C mutant binders for use in personalized anticancer therapy and, more generally, highlight the importance of implementing protein dynamics and hydration patterns in the drug-discovery process