348 research outputs found

    Altered striatal endocannabinoid signaling in a transgenic mouse model of spinocerebellar ataxia type-3

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    Spinocerebellar ataxia type-3 (SCA-3) is the most prevalent autosomal dominant inherited ataxia. We recently found that the endocannabinoid system is altered in the post-mortem cerebellum of SCA-3 patients, and similar results were also found in the cerebellar and brainstem nuclei of a SCA-3 transgenic mouse model. Given that the neuropathology of SCA-3 is not restricted to these two brain regions but rather, it is also evident in other structures (e.g., the basal ganglia), we studied the possible changes to endocannabinoid signaling in the striatum of these transgenic mice. SCA-3 mutant mice suffer defects in motor coordination, balance and they have an abnormal gait, reflecting a cerebellar/brainstem neuropathology. However, they also show dystonia-like behavior (limb clasping) that may be related to the malfunction/deterioration of specific neurons in the striatum. Indeed, we found a loss of striatal projecting neurons in SCA-3 mutant mice, accompanied by a reduction in glial glutamate transporters that could potentially aggravate excitotoxic damage. In terms of endocannabinoid signaling, no changes in CB2 receptors were evident, yet an important reduction in CB1 receptors was detected by qPCR and immunostaining. The reduction in CB1 receptors was presumed to occur in striatal afferent and efferent neurons, also potentially aggravating excitotoxicity. We also measured the endocannabinoid lipids in the striatum and despite a marked increase in the FAAH enzyme in this area, no overall changes in these lipids were found. Collectively, these studies confirm that the striatal endocannabinoid system is altered in SCA-3 mutant mice, adding to the equivalent changes found in other strongly affected CNS structures in this type of ataxia (i.e.: the cerebellum and brainstem). These data open the way to search for drugs that might correct these changes.Funding: This study has been supported: (i) by MICINN (SAF2009-11847 and SAF2015-68580-C2-1-R), CIBERNED (CB06/05/0089) and ‚ÄúFundaci√≥n Eugenio Rodr√≠guez Pascual‚ÄĚ, to JFR; (ii) by the Research and Education Component of the Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin, to CJH; and (iii) by Funda√ß√£o para a Ci√™ncia e Tecnologia through the project POCI-01-0145-FEDER-016818 (PTDC/NEU-NMC/3648/2014) and co-financed by the Portuguese North Regional Operational Program (ON.2 ‚Äď O Novo Norte) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER), to PM. Carmen Rodr√≠guez-Cueto was a predoctoral fellow supported by FPI Program-Ministry of Science. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.info:eu-repo/semantics/publishedVersio

    Test beam performance of a CBC3-based mini-module for the Phase-2 CMS Outer Tracker before and after neutron irradiation

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    The Large Hadron Collider (LHC) at CERN will undergo major upgrades to increase the instantaneous luminosity up to 5‚Äď7.5√ó1034^{34} cm‚ąí2^{-2}s‚ąí1^{-1}. This High Luminosity upgrade of the LHC (HL-LHC) will deliver a total of 3000‚Äď4000 fb-1 of proton-proton collisions at a center-of-mass energy of 13‚Äď14 TeV. To cope with these challenging environmental conditions, the strip tracker of the CMS experiment will be upgraded using modules with two closely-spaced silicon sensors to provide information to include tracking in the Level-1 trigger selection. This paper describes the performance, in a test beam experiment, of the first prototype module based on the final version of the CMS Binary Chip front-end ASIC before and after the module was irradiated with neutrons. Results demonstrate that the prototype module satisfies the requirements, providing efficient tracking information, after being irradiated with a total fluence comparable to the one expected through the lifetime of the experiment

    Beam test performance of a prototype module with Short Strip ASICs for the CMS HL-LHC tracker upgrade

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    The Short Strip ASIC (SSA) is one of the four front-end chips designed for the upgrade of the CMS Outer Tracker for the High Luminosity LHC. Together with the Macro-Pixel ASIC (MPA) it will instrument modules containing a strip and a macro-pixel sensor stacked on top of each other. The SSA provides both full readout of the strip hit information when triggered, and, together with the MPA, correlated clusters called stubs from the two sensors for use by the CMS Level-1 (L1) trigger system. Results from the first prototype module consisting of a sensor and two SSA chips are presented. The prototype module has been characterized at the Fermilab Test Beam Facility using a 120 GeV proton beam

    Search for high-mass exclusive ő≥ő≥ ‚Üí WW and ő≥ő≥ ‚Üí ZZ production in proton-proton collisions at s \sqrt{s} = 13 TeV