Calcium Ions Promote Formation of Amyloid β-Peptide (1–40) Oligomers Causally Implicated in Neuronal Toxicity of Alzheimer's Disease

Amyloid β-peptide (Aβ) is directly linked to Alzheimer's disease (AD). In its monomeric form, Aβ aggregates to produce fibrils and a range of oligomers, the latter being the most neurotoxic. Dysregulation of Ca2+ homeostasis in aging brains and in neurodegenerative disorders plays a crucial role in numerous processes and contributes to cell dysfunction and death. Here we postulated that calcium may enable or accelerate the aggregation of Aβ. We compared the aggregation pattern of Aβ(1–40) and that of Aβ(1–40)E22G, an amyloid peptide carrying the Arctic mutation that causes early onset of the disease. We found that in the presence of Ca2+, Aβ(1–40) preferentially formed oligomers similar to those formed by Aβ(1–40)E22G with or without added Ca2+, whereas in the absence of added Ca2+ the Aβ(1–40) aggregated to form fibrils. Morphological similarities of the oligomers were confirmed by contact mode atomic force microscopy imaging. The distribution of oligomeric and fibrillar species in different samples was detected by gel electrophoresis and Western blot analysis, the results of which were further supported by thioflavin T fluorescence experiments. In the samples without Ca2+, Fourier transform infrared spectroscopy revealed conversion of oligomers from an anti-parallel β-sheet to the parallel β-sheet conformation characteristic of fibrils. Overall, these results led us to conclude that calcium ions stimulate the formation of oligomers of Aβ(1–40), that have been implicated in the pathogenesis of AD

Physiopathologie et génétique de l’épilepsie : données récentes

Des stratégies nouvelles sont nécessaires pour le traitement de l’épilepsie, du point de vue de l’efficacité, de la sécurité et de la prévention. La recherche d’anti-épileptiques innovants est basée sur le choix de cibles biologiques appropriées, parmi lesquelles les plus pertinentes semblent être les canaux chlore et potassium. L’analyse transcriptomique/protéomique est également susceptible de révéler des gènes ou des protéines impliquées dans la maladie, notamment par la comparaison entre biopsies de tissu cérébral sain et épileptique. Des modèles génétiques animaux permettent d’analyser des épilepsies dont l’étiologie est unique. Enfin certaines cibles peuvent être découvertes fortuitement à l’occasion de programmes de recherche portant sur d’autres domaines, notamment sur les cytokines pro-inflammatoires

Effects of riluzole on the evolution of focal cerebral ischemia: a magnetic resonance imaging study

The aim of this study was to investigate the effects of riluzole on the lesion induced by a permanent middle cerebral artery occlusion (MCAO) in rats. Riluzole at 4 or 8 mg/kg i.v. significantly reduced the cortical ischemic brain damage. With the most effective dose of 8 mg/kg, the time evolution of the lesion was assessed by T2-weighted magnetic resonance imaging (MRI) repeated on the same animals after MCAO. MRI obtained at 24, 48, and 72 hours after MCAO showed a progressive increase of the ischemic lesion, except in the cortex of the riluzole-treated rats (8 mg/kg i.v.). Furthermore, there was no difference between lesion volumes as measured by MRI or by histology. This study indicates that MRI may be a valuable method to quantify in vivo the neuroprotective profile of a drug

Multidrug efflux pumps and their role in antibiotic and antiseptic resistance: a pharmacodynamic perspective

International audienceIntroduction: Worrying levels of bacterial resistance have been reported worldwide involving the failure of many available antibiotic treatments. Multidrug resistance (MDR) in Gram-negative bacteria is often ascribed to the presence of multiple and different resistance mechanisms in the same strain. RND efflux pumps play a major role and are an attractive target to discover new antibacterial drugs.Areas covered: This review discusses the prevalence of efflux pumps, their overexpression in clinical scenarios, their polyselectivity, their effect on the intracellular concentrations of various antibiotics associated with the alteration of the membrane permeability and their involvement in pathogenicity are discussed.Expert opinion: Efflux pumps are new targets for the development of adjuvant in antibiotic treatments by of efflux pump inhibition. They may allow us to rejuvenate old antibiotics acting on their concentration inside the bacteria and thus potentiating their activity while blocking the release of virulence factors. It is a pharmacodynamic challenge to finalize new combined therapy. ARTICLE HISTOR

Array Analysis of Seismo-Volcanic Activity with Distributed Acoustic Sensing

International audienceContinuous seismic monitoring of volcanoes is challenging due to harsh environments and associated hazards. However, the investigation of volcanic phenomena is essential for eruption forecasting. In seismo-volcanic applications, Distributed Acoustic Sensing (DAS) offers new possibilities for long-duration surveys. We analyse DAS strain rate signals generated by volcanic explosions and tremor at Stromboli volcano (Italy) recorded along 1 km of dedicated fibre-optic cable. We validate DAS recordings with co-located nodal seismometers. Converting node measurements to strain rate, we observe a perfect match in phase between DAS and node waveforms. However, DAS amplitudes appear to be around 2.7 times smaller than those of node records, which we explain as due to the inefficient ground-to-fibre strain transfer in the loose cable. We invert time delays between strain rate waveforms and confirm that the DAS enables us to retrieve a dominant and persistent seismic source in the proximity of active craters. This stable source location is confirmed by node array analyses. Despite an observed high noise level of strain rate signals outside a range of 2-15 Hz, our results demonstrate the potential of this new technology in monitoring volcanic areas

A machine-learning approach for automatic classification of volcanic seismicity at La Soufrière Volcano, Guadeloupe

International audienceThe classification of seismo-volcanic signals is performed manually at La Soufrière Volcano, which is time consuming and can be biased by subjectivity of the operator. We propose here a machine-learning-based model for classification of these signals, to handle large datasets and provide objective and reproducible results. To describe the properties of the signals, we used 104 statistical, entropy, and shape descriptor features computed from the time waveform, the spectrum, and the cepstrum. First, we trained a random forest classifier with a dataset provided by the Observatoire Volcanologique et Sismologique de Guadeloupe that consisted of 845 labeled events that were recorded from 2013 to 2018: 542 volcano-tectonic (VT); 217 Nested; and 86 long period (LP). We obtained an overalll accuracy of 72%. We determined that the VT class includes a variety of signals that cover the VT, Nested and LP classes. After visual inspection of the waveforms and spectral characteristics of the data set, we introduced two new classes: Hybrid and Tornillo. A new random forest classifier was trained with this new information, and we obtained a much better overall accuracy of 82%. The model is very good for recognition of all event classes, except Hybrid events (67% accuracy, 70% precision). Hybrid events are often considered to be a mix of VT and LP events. This can be explained by the nature of this class and the physical processes that include both fracturing and resonating components with different modal frequencies. By analyzing the feature weights and by training a model with the most important features, we show that a subset of the 14 best features is sufficient to obtain a performance that is close to that of the model with the whole feature set. However, these best features are different from the 13 best features obtained for another volcano in Peru, with only one feature common to both sets of best features. Therefore, the model is not universal and it must be trained for each volcano, or it is too specific to the one station used here

Evaluation de l'interet du macaque rhesus comme modele de l'hypoxie chez l'homme

Available at INIST (FR), Document Supply Service, under shelf-number : RP 12138 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueSIGLEFRFranc

RPR 119990, a Novel ␣-Amino-3-hydroxy-5-methyl-4- isoxazolepropionic Acid Antagonist: Synthesis, Pharmacological Properties, and Activity in an Animal Model of Amyotrophic Lateral Sclerosis

ABSTRACT ␣-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonists are of potential interest for the treatment of certain acute and chronic neurodegenerative diseases, including amyotrophic lateral sclerosis. Here, we describe the synthesis and pharmacological properties of 9-carboxymethyl-4-oxo-5H,10H-imidaz