Key Obs SAS

Orléans, France

Key Obs SAS

Orléans, France
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Grant
Agency: European Commission | Branch: FP7 | Program: CP | Phase: SPA-2007-1.1-01 | Award Amount: 40.31M | Year: 2009

SAFER aims at implementing preoperational versions of the Emergency Response Core Service. SAFER will reinforce European capacity to respond to emergency situations: fires, floods, earthquakes, volcanic eruptions, landslides, humanitarian crisis. The main goal is the upgrade of the core service and the validation of its performance with 2 priorities: First priority is the short term improvement of response when crisis occurs, with the rapid mapping capacity after disastrous events, including the relevant preparatory services (reference maps). For validation purposes, the project will deliver as from 2008 services at full scale for real events or during specific exercises. The main performance criterion is the response time. RTD work addresses technical, operational and organisational issues. The content of this first action is consistent with the definition of the preparatory action recently decided. The second priority is the extension to core service components before and after the crisis. It targets the longer term service evolution, through the provision of thematic products, to be added in the portfolio of services. The main performance criterion is the added-value of products with risk-specific information. In SAFER, thematic products will cover mainly the meteorological and geophysical risks. SAFER includes also some transverse RDT actions, with the objective to increase added-value of the overall service chain. Users involvement is a key driver and a specific task addresses the federation of the key users, both for interventions in Europe and outside Europe. The emphasis put on quality assurance and validation methodology is reflected in the work plan. The consortium is built around a core team of European service providers, already involved in the former or ongoing projects, in the frame of FP6 or ESA programmes. A wide network of scientific partners and service providers will extend the European dimension, in particular in the new member states.


De la Torre R.,IMIM Hospital del Mar Research Institute | De la Torre R.,CIBER ISCIII | De la Torre R.,University Pompeu Fabra | De Sola S.,IMIM Hospital del Mar Research Institute | And 24 more authors.
Molecular Nutrition and Food Research | Year: 2014

Scope: Trisomy for human chromosome 21 results in Down syndrome (DS), which is among the most complex genetic perturbations leading to intellectual disability. Accumulating data suggest that overexpression of the dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), is a critical pathogenic mechanisms in the intellectual deficit. Methods and results: Here we show that the green tea flavonol epigallocatechin-gallate (EGCG), a DYRK1A inhibitor, rescues the cognitive deficits of both segmental trisomy 16 (Ts65Dn) and transgenic mice overexpressing Dyrk1A in a trisomic or disomic genetic background, respectively. It also significantly reverses cognitive deficits in a pilot study in DS individuals with effects on memory recognition, working memory and quality of life. We used the mouse models to ensure that EGCG was able to reduce DYRK1A kinase activity in the hippocampus and found that it also induced significant changes in plasma homocysteine levels, which were correlated with Dyrk1A expression levels. Thus, we could use plasma homocysteine levels as an efficacy biomarker in our human study. Conclusion: We conclude that EGCG is a promising therapeutic tool for cognitive enhancement in DS, and its efficacy may depend of Dyrk1A inhibition. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


PubMed | Key Obs S.A., University Claude Bernard Lyon 1, University of Strasbourg, Mount Sinai School of Medicine and 3 more.
Type: Journal Article | Journal: PLoS genetics | Year: 2015

The trisomy of human chromosome 21 (Hsa21), which causes Down syndrome (DS), is the most common viable human aneuploidy. In contrast to trisomy, the complete monosomy (M21) of Hsa21 is lethal, and only partial monosomy or mosaic monosomy of Hsa21 is seen. Both conditions lead to variable physiological abnormalities with constant intellectual disability, locomotor deficits, and altered muscle tone. To search for dosage-sensitive genes involved in DS and M21 phenotypes, we created two new mouse models: the Ts3Yah carrying a tandem duplication and the Ms3Yah carrying a deletion of the Hspa13-App interval syntenic with 21q11.2-q21.3. Here we report that the trisomy and the monosomy of this region alter locomotion, muscle strength, mass, and energetic balance. The expression profiling of skeletal muscles revealed global changes in the regulation of genes implicated in energetic metabolism, mitochondrial activity, and biogenesis. These genes are downregulated in Ts3Yah mice and upregulated in Ms3Yah mice. The shift in skeletal muscle metabolism correlates with a change in mitochondrial proliferation without an alteration in the respiratory function. However, the reactive oxygen species (ROS) production from mitochondrial complex I decreased in Ms3Yah mice, while the membrane permeability of Ts3Yah mitochondria slightly increased. Thus, we demonstrated how the Hspa13-App interval controls metabolic and mitochondrial phenotypes in muscles certainly as a consequence of change in dose of Gabpa, Nrip1, and Atp5j. Our results indicate that the copy number variation in the Hspa13-App region has a peripheral impact on locomotor activity by altering muscle function.


PubMed | University Pompeu Fabra, University of Strasbourg, Key Obs SAS, University of Paris Descartes and 3 more.
Type: | Journal: Neurobiology of disease | Year: 2014

PCP4/PEP19 is a modulator of Ca(2+)-CaM signaling. In the brain, it is expressed in a very specific pattern in postmitotic neurons. In particular, Pcp4 is highly expressed in the Purkinje cell, the sole output neuron of the cerebellum. PCP4, located on human chromosome 21, is present in three copies in individuals with Down syndrome (DS). In a previous study using a transgenic mouse model (TgPCP4) to evaluate the consequences of 3 copies of this gene, we found that PCP4 overexpression induces precocious neuronal differentiation during mouse embryogenesis. Here, we report combined analyses of the cerebellum at postnatal stages (P14 and adult) in which we identified age-related molecular, electrophysiological, and behavioral alterations in the TgPCP4 mouse. While Pcp4 overexpression at P14 induces an earlier neuronal maturation, at adult stage it induces increase in cerebellar CaMK2alpha and in cerebellar LTD, as well as learning impairments. We therefore propose that PCP4 contributes significantly to the development of Down syndrome phenotypes through molecular and functional changes.


Grant
Agency: European Commission | Branch: FP7 | Program: CSA-SA | Phase: SPA.2009.3.2.01 | Award Amount: 1.34M | Year: 2010

To enable and enhance the ability of African states to use satellite Earth Observation for the management of natural and man-made humanitarian emergencies. To develop a network of EU, African organisations and African users, in order to build economic, technical and commercial capacity within African states, along the priority lines being identified in consultation with the African Union under the GMES and Africa initiative.


Regnier V.,University Paris Diderot | Regnier V.,French National Center for Scientific Research | Billard J.-M.,University of Paris Descartes | Gupta S.,Fox Chase Cancer Center | And 13 more authors.
PLoS ONE | Year: 2012

Background: The cystathionine β-synthase (CBS) gene, located on human chromosome 21q22.3, is a good candidate for playing a role in the Down Syndrome (DS) cognitive profile: it is overexpressed in the brain of individuals with DS, and it encodes a key enzyme of sulfur-containing amino acid (SAA) metabolism, a pathway important for several brain physiological processes. Methodology/Principal Findings: Here, we have studied the neural consequences of CBS overexpression in a transgenic mouse line (60.4P102D1) expressing the human CBS gene under the control of its endogenous regulatory regions. These mice displayed a ~2-fold increase in total CBS proteins in different brain areas and a ~1.3-fold increase in CBS activity in the cerebellum and the hippocampus. No major disturbance of SAA metabolism was observed, and the transgenic mice showed normal behavior in the rotarod and passive avoidance tests. However, we found that hippocampal synaptic plasticity is facilitated in the 60.4P102D1 line. Conclusion/Significance: We demonstrate that CBS overexpression has functional consequences on hippocampal neuronal networks. These results shed new light on the function of the CBS gene, and raise the interesting possibility that CBS overexpression might have an advantageous effect on some cognitive functions in DS. © 2012 Régnier et al.


Trovero F.,Key Obs SAS | David S.,Key Obs SAS | Bernard P.,Greenpharma SAS | Puech A.,Groupe Hospitalier Pitie Salpetriere | And 4 more authors.
PLoS ONE | Year: 2016

Alcohol-dependence is a chronic disease with a dramatic and expensive social impact. Previous studies have indicated that the blockade of two monoaminergic receptors, a1b-adrenergic and 5-HT2A, could inhibit the development of behavioral sensitization to drugs of abuse, a hallmark of drug-seeking and drug-taking behaviors in rodents. Here, in order to develop a potential therapeutic treatment of alcohol dependence in humans, we have blocked these two monoaminergic receptors by a combination of antagonists already approved by Health Agencies. We show that the association of ifenprodil (1 mg/kg) and cyproheptadine (1 mg/kg) (a1-adrenergic and 5-HT2 receptor antagonists marketed as Vadilex ® and Periactine ® in France, respectively) blocks behavioral sensitization to amphetamine in C57Bl6 mice and to alcohol in DBA2 mice. Moreover, this combination of antagonists inhibits alcohol intake in mice habituated to alcohol (10% v/v) and reverses their alcohol preference. Finally, in order to verify that the effect of ifenprodil was not due to its anti-NMDA receptors property, we have shown that a combination of prazosin (0.5 mg/kg, an a1b-adrenergic antagonist, Mini-Press ® in France) and cyproheptadine (1 mg/kg) could also reverse alcohol preference. Altogether these findings strongly suggest that combined prazosin and cyproheptadine could be efficient as a therapy to treat alcoholism in humans. Finally, because a1b-adrenergic and 5-HT2A receptors blockade also inhibits behavioral sensitization to psychostimulants, opioids and tobacco, it cannot be excluded that this combination will exhibit some efficacy in the treatment of addiction to other abused drugs. © 2016 Trovero et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


PubMed | Greenpharma SAS, groupe hospitalier Pitie Salpetriere, University Pierre and Marie Curie and Key Obs SAS
Type: Journal Article | Journal: PloS one | Year: 2016

Alcohol-dependence is a chronic disease with a dramatic and expensive social impact. Previous studies have indicated that the blockade of two monoaminergic receptors, 1b-adrenergic and 5-HT2A, could inhibit the development of behavioral sensitization to drugs of abuse, a hallmark of drug-seeking and drug-taking behaviors in rodents. Here, in order to develop a potential therapeutic treatment of alcohol dependence in humans, we have blocked these two monoaminergic receptors by a combination of antagonists already approved by Health Agencies. We show that the association of ifenprodil (1 mg/kg) and cyproheptadine (1 mg/kg) (1-adrenergic and 5-HT2 receptor antagonists marketed as Vadilex and Periactine in France, respectively) blocks behavioral sensitization to amphetamine in C57Bl6 mice and to alcohol in DBA2 mice. Moreover, this combination of antagonists inhibits alcohol intake in mice habituated to alcohol (10% v/v) and reverses their alcohol preference. Finally, in order to verify that the effect of ifenprodil was not due to its anti-NMDA receptors property, we have shown that a combination of prazosin (0.5 mg/kg, an 1b-adrenergic antagonist, Mini-Press in France) and cyproheptadine (1 mg/kg) could also reverse alcohol preference. Altogether these findings strongly suggest that combined prazosin and cyproheptadine could be efficient as a therapy to treat alcoholism in humans. Finally, because 1b-adrenergic and 5-HT2A receptors blockade also inhibits behavioral sensitization to psychostimulants, opioids and tobacco, it cannot be excluded that this combination will exhibit some efficacy in the treatment of addiction to other abused drugs.

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