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Sahdeo S.,Hoffmann-La Roche | Sahdeo S.,University of California at Davis | Wallace T.,Hoffmann-La Roche | Wallace T.,SRI International | And 14 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2014

Both preclinical evidence and clinical evidence suggest that α7 nicotinic acetylcholine receptor activation (α7nAChR) improves cognitive function, the decline of which is associated with conditions such as Alzheimer's disease and schizophrenia. Moreover, allosteric modulation of α7nAChR is an emerging therapeutic strategy in an attempt to avoid the rapid desensitization properties associated with the α7nAChR after orthosteric activation. We used a calcium assay to screen for positive allosteric modulators (PAMs) of α7nAChR and report on the pharmacologic characterization of the novel compound RO5126946 (5-chloro-N-[(1S,3R)-2,2-dimethyl-3-(4-sulfamoyl- phenyl)-cyclopropyl]-2-methoxy-benzamide), which allosterically modulates α7nAChR activity. RO5126946 increased acetylcholine-evoked peak current and delayed current decay but did not affect the recovery of α7nAChRs from desensitization. In addition, RO5126946's effects were absent when nicotine-evoked currents were completely blocked by coapplication of the α7nAChR-selective antagonist methyl-lycaconitine. RO5126946 enhanced α7nAChR synaptic transmission and positively modulated GABAergic responses. The absence of RO5126946 effects at human α4β2nAChR and 5-hydroxytryptamine 3 receptors, among others, indicated selectivity for α7nAChRs. In vivo, RO5126946 is orally bioavailable and brain-penetrant and improves associative learning in a scopolamine-induced deficit model of fear conditioning in rats. In addition, procognitive effects of RO5126946 were investigated in the presence of nicotine to address potential pharmacologic interactions on behavior. RO5126946 potentiated nicotine's effects on fear memory when both compounds were administered at subthreshold doses and did not interfere with procognitive effects observed when both compounds were administered at effective doses. Overall, RO5126946 is a novel α7nAChR PAM with cognitive-enhancing properties. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Gilardoni M.,Polytechnic of Milan | Reguzzoni M.,Polytechnic of Milan | Sampietro D.,GReD
International Association of Geodesy Symposia | Year: 2014

National geoids of neighbouring countries usually do not fit to each other along the borders. This problem is mainly due to inconsistencies between the national reference frames used to estimate local geoids: it is well known that a change in the height datum and in the reference ellipsoid causes systematic effects in terms of geoid undulation. Therefore, before merging national geoids, these effects should be estimated and removed. The availability of a global geoid coming from satellite data, such as one of the GOCE models or a GOCE-GRACE combined model, can be of great importance to solve this problem. In fact, these models are not affected by local biases since they do not make use of any ground gravity data and they are referred to a global geocentric ellipsoid. In the present work a merging strategy based on two steps is proposed. Firstly, the bias and the systematic effect due to an ellipsoidal centre variation are estimated for each national geoid by exploiting GOCE data; particular attention is dedicated to the covariancemodelling of all involved quantities. Secondly, these straightened geoids are “sewn” to each other by applying a standard collocation procedure along the borders. In this way the final result is an unbiased geoid, joining in a optimal way the national models. The merging strategy is here applied to create a new geoid model for Spain, Portugal, France, Italy, Switzerland and part of the Mediterranean Sea. © Springer International Publishing Switzerland 2014.

Frankenberg S.,GReD | Gerbe F.,GReD | Bessonnard S.,GReD | Belville C.,GReD | And 3 more authors.
Developmental Cell | Year: 2011

During preimplantation mouse development, the inner cell mass (ICM) differentiates into two cell lineages-the epiblast and the primitive endoderm (PrE)-whose precursors are identifiable by reciprocal expression of Nanog and Gata6, respectively. PrE formation depends on Nanog by a non-cell-autonomous mechanism. To decipher early cell- and non-cell-autonomous effects, we performed a mosaic knockdown of Nanog and found that this is sufficient to induce a PrE fate cell autonomously. Strikingly, in Nanog null embryos, Gata6 expression is maintained, showing that initiation of the PrE program is Nanog independent. Treatment of Nanog null embryos with pharmacological inhibitors revealed that RTK dependency of Gata6 expression is initially direct but later indirect via Nanog repression. Moreover, we found that subsequent expression of Sox17 and Gata4-later markers of the PrE-depends on the presence of Fgf4 produced by Nanog-expressing cells. Thus, our results reveal three distinct phases in the PrE differentiation program. © 2011 Elsevier Inc.

Figeac N.,GReD | Jagla T.,GReD | Aradhya R.,GReD | Da Ponte J.P.,GReD | Jagla K.,GReD
Fly | Year: 2011

During development, transient stem cells play critical roles in the formation of specific tissues. Adult Muscle Precursors (AMPs) are at the origin of all adult Drosophila muscles and as we report here represent a novel population of muscle-committed transient stem cells. Similar to vertebrate muscle stem cells, AMPs keep Notch signaling active and express Enhancer of split m6 (E(spl) m6) gene, a read-out of Notch pathway. To get insights into AMP cell specification we performed a gain-of-function screen and found that the rhomboidtriggered Epidermal Growth Factor (EGF) signaling pathway controls both the specification and the subsequent maintenance of AMPs. Our findings are supported by the identification of EGFsecreting cells in the lateral domain and the EGF-dependent regulatory modules that drive expression of the ladybird gene in lateral AMPs. Interestingly, by targeting GFP to the AMP cell membranes we also demonstrated that AMPs send long cellular processes and form a network of interconnected cells. As revealed by laser ablation experiments, the main role of AMP cell connections is to maintain their correct spatial positioning. © 2010 Landes Bioscience.

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