Towards a standard typology of endogenous landslide seismic sources

The objective of this work is to propose a standard classification of seismic signals generated by gravitational processes and detected at close distances (1 Hz) where most of the seismic energy is recorded at the 1 km sensor to source distances. Several signal properties (duration, spectral content and spectrogram shape) are used to describe the sources. We observe that similar gravitational processes generate similar signals at different slopes. Three main classes can be differentiated mainly from the length of the signals, the number of peaks and the duration of the autocorrelation. The classes are the “slopequake” class, which corresponds to sources potentially occurring within the landslide body; the “rockfall” class, which corresponds to signals generated by rock block impacts; and the “granular flow” class, which corresponds to signals generated by wet or dry debris/rock flows. Subclasses are further proposed to differentiate specific signal properties (frequency content, resonance, precursory signal). The signal properties of each class and subclass are described and several signals of the same class recorded at different slopes are presented. Their potential origins are discussed. The typology aims to serve as a standard for further comparisons of the endogenous microseismicity recorded on landslides.Peer ReviewedPostprint (published version

Homodimerization of the Death-Associated Protein Kinase Catalytic Domain: Development of a New Small Molecule Fluorescent Reporter

Agence Nationale de Recherche (ANR); Centre National de la Recherche Scientifique (CNRS); University of StrasbourgBackground: Death-Associated Protein Kinase (DAPK) is a member of the Ca(2+)/calmodulin regulated serine/threonine protein kinases. Its biological function has been associated with induced cell death, and in vivo use of selective small molecule inhibitors of DAPK catalytic activity has demonstrated that it is a potential therapeutic target for treatment of brain injuries and neurodegenerative diseases. Methodology/Principal Findings: In the in vitro study presented here, we describe the homodimerization of DAPK catalytic domain and the crucial role played by its basic loop structure that is part of the molecular fingerprint of death protein kinases. Nanoelectrospray ionization mass spectrometry of DAPK catalytic domain and a basic loop mutant DAPK protein performed under a variety of conditions was used to detect the monomer-dimer interchange. A chemical biological approach was used to find a fluorescent probe that allowed us to follow the oligomerization state of the protein in solution. Conclusions/Significance: The use of this combined biophysical and chemical biology approach facilitated the elucidation of a monomer-dimer equilibrium in which the basic loop plays a key role, as well as an apparent allosteric conformational change reported by the fluorescent probe that is independent of the basic loop structure

Diastereoselective Synthesis of Novel Aza-diketopiperazines via a Domino Cyclohydrocarbonylation/Addition Process

Herein, we report an unprecedented, short and diastereo-selective synthesis of newly reported aza-diketopiperazine (aza-DKP) scaffolds starting from amino acids. The strategy is based on a Rh(I)-catalyzed hydroformylative cyclohydrocarbonylation of allyl-substituted aza-DKP, followed by a diastereoselective functionalization of the platform. This methodology allows the synthesis of novel bicyclic and tricyclic aza-DKP scaffolds incorporating six- or seven-membered rings, with potential applications in medicinal chemistry

A step-economical multicomponent synthesis of 3D-shaped aza-diketopiperazines and their drug-like chemical space analysis

A rapid and atom economical multicomponent synthesis of complex aza-diketopiperazines (aza-DKPs) driven by Rh(I)-catalyzed hydroformylation of alkenylsemicarbazides is described. Combined with catalytic amounts of acid and the presence of nucleophilic species, this unprecedented multicomponent reaction (MCR) enabled the formation of six bonds and a controlled stereocenter from simple substrates. The efficacy of the strategy was demonstrated with a series of various allyl-substituted semicarbazides and nucleophiles leading to the preparation of 3D-shaped bicyclic aza-DKPs. Moreover, an analysis of their 3D molecular descriptors and “drug-likeness” properties highlights not only their originality in the chemical space of aza-heterocycles but also their great potential for medicinal chemistry

Limitations in a frataxin knockdown cell model for Friedreich ataxia in a high-throughput drug screen

<p>Abstract</p> <p>Background</p> <p>Pharmacological high-throughput screening (HTS) represents a powerful strategy for drug discovery in genetic diseases, particularly when the full spectrum of pathological dysfunctions remains unclear, such as in Friedreich ataxia (FRDA). FRDA, the most common recessive ataxia, results from a generalized deficiency of mitochondrial and cytosolic iron-sulfur cluster (ISC) proteins activity, due to a partial loss of frataxin function, a mitochondrial protein proposed to function as an iron-chaperone for ISC biosynthesis. In the absence of measurable catalytic function for frataxin, a cell-based assay is required for HTS assay.</p> <p>Methods</p> <p>Using a targeted ribozyme strategy in murine fibroblasts, we have developed a cellular model with strongly reduced levels of frataxin. We have used this model to screen the Prestwick Chemical Library, a collection of one thousand off-patent drugs, for potential molecules for FRDA.</p> <p>Results</p> <p>The frataxin deficient cell lines exhibit a proliferation defect, associated with an ISC enzyme deficit. Using the growth defect as end-point criteria, we screened the Prestwick Chemical Library. However no molecule presented a significant and reproducible effect on the proliferation rate of frataxin deficient cells. Moreover over numerous passages, the antisense ribozyme fibroblast cell lines revealed an increase in frataxin residual level associated with the normalization of ISC enzyme activities. However, the ribozyme cell lines and FRDA patient cells presented an increase in Mthfd2 transcript, a mitochondrial enzyme that was previously shown to be upregulated at very early stages of the pathogenesis in the cardiac mouse model.</p> <p>Conclusion</p> <p>Although no active hit has been identified, the present study demonstrates the feasibility of using a cell-based approach to HTS for FRDA. Furthermore, it highlights the difficulty in the development of a stable frataxin-deficient cell model, an essential condition for productive HTS in the future.</p

Approches moléculaires et thérapeutiques des interactions entre l’ocytocine et son récepteur

L’ocytocine est une neurohormone connue à l’origine pour son rôle dans les contractions de l’utérus au moment de l’accouchement et les contractions des glandes mammaires pour permettre l’éjection du lait lors de la tétée. Depuis les 25 dernières années, de multiples autres effets centraux et périphériques ont été identifiés, notamment dans les processus d’attachement entre parents et enfant, entre adultes et entre un individu et son groupe social. Nous avons abordé au cours de cette période la question fondamentale de l’architecture structurale et fonctionnelle du complexe formé par l’ocytocine et son récepteur et l’application de ce savoir à la conception de candidats médicaments. Ceci a conduit à la découverte du premier agoniste non peptidique de l’ocytocine, le LIT-001, restaurant l’interaction sociale dans un modèle animal d’autisme

Chimiokines et santé (développement d'une prodrogue antiinflammatoire)

STRASBOURG ILLKIRCH-Pharmacie (672182101) / SudocSudocFranceF

Essai d' identification du ligand du récepteur C5L2 par synthèse de protéines recombinantes

STRASBOURG ILLKIRCH-Pharmacie (672182101) / SudocSudocFranceF

Découverte et optimisation structurale d'effecteurs allostériques pour les récepteurs couplés aux protéines G et synthèse de dérivés marqués pour l'étude de paramètres cinétiques et topologiques

STRASBOURG ILLKIRCH-Pharmacie (672182101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

L'aripiprazole (Abilify) (un antipsychotique original ?)

STRASBOURG ILLKIRCH-Pharmacie (672182101) / SudocSudocFranceF