Area-specific temporal control of corticospinal motor neuron differentiation by COUP-TFI

Transcription factors with gradients of expression in neocortical progenitors give rise to distinct motor and sensory cortical areas by controlling the area-specific differentiation of distinct neuronal subtypes. However, the molecular mechanisms underlying this area-restricted control are still unclear. Here, we show that COUP-TFI controls the timing of birth and specification of corticospinal motor neurons (CSMN) in somatosensory cortex via repression of a CSMN differentiation program. Loss of COUP-TFI function causes an area-specific premature generation of neurons with cardinal features of CSMN, which project to subcerebral structures, including the spinal cord. Concurrently, genuine CSMN differentiate imprecisely and do not project beyond the pons, together resulting in impaired skilled motor function in adult mice with cortical COUP-TFI loss-of-function. Our findings indicate that COUP-TFI exerts critical areal and temporal control over the precise differentiation of CSMN during corticogenesis, thereby enabling the area-specific functional features of motor and sensory areas to arise.Stem Cell and Regenerative Biolog

Alpha-synuclein targets GluN2A NMDA receptor subunit causing striatal synaptic dysfunction and visuospatial memory alteration

Parkinson's disease is a progressive neurodegenerative disorder characterized by altered striatal dopaminergic signalling that leads to motor and cognitive deficits. Parkinson's disease is also characterized by abnormal presence of soluble toxic forms of \u3b1-synuclein that, when clustered into Lewy bodies, represents one of the pathological hallmarks of the disease. However, \u3b1-synuclein oligomers might also directly affect synaptic transmission and plasticity in Parkinson's disease models. Accordingly, by combining electrophysiological, optogenetic, immunofluorescence, molecular and behavioural analyses, here we report that \u3b1-synuclein reduces N-methyl-d-aspartate (NMDA) receptor-mediated synaptic currents and impairs corticostriatal long-term potentiation of striatal spiny projection neurons, of both direct (D1-positive) and indirect (putative D2-positive) pathways. Intrastriatal injections of \u3b1-synuclein produce deficits in visuospatial learning associated with reduced function of GluN2A NMDA receptor subunit indicating that this protein selectively targets this subunit both in vitro and ex vivo. Interestingly, this effect is observed in spiny projection neurons activated by optical stimulation of either cortical or thalamic glutamatergic afferents. We also found that treatment of striatal slices with antibodies targeting \u3b1-synuclein prevents the \u3b1-synuclein-induced loss of long-term potentiation and the reduced synaptic localization of GluN2A NMDA receptor subunit suggesting that this strategy might counteract synaptic dysfunction occurring in Parkinson's disease

Precipitation products from the hydrology SAF

Abstract. The EUMETSAT Satellite Application Facility on Support to Operational Hydrology and Water Management (H-SAF) was established by the EUMETSAT Council on 3 July 2005, starting activity on 1 September 2005. The Italian Meteorological Service serves as Leading Entity on behalf of twelve European member countries. H-SAF products include precipitation, soil moisture and snow parameters. Some products are based only on satellite observations, while other products are based on the assimilation of satellite measurements/products into numerical models. In addition to product development and generation, H-SAF includes a product validation program and a hydrological validation program that are coordinated, respectively, by the Italian Department of Civil Protection and by the Polish Institute of Meteorology and Water Management. The National Center of Aeronautical Meteorology and Climatology (CNMCA) of the Italian Air Force is responsible for operational product generation and dissemination. In this paper we describe the H-SAF precipitation algorithms and products, which have been developed by the Italian Institute of Atmospheric Sciences and Climate (in collaboration with the international community) and by CNMCA during the Development Phase (DP, 2005–2010) and the first Continuous Development and Operations Phase (CDOP-1, 2010–2012). The precipitation products are based on passive microwave measurements obtained from radiometers onboard different sun-synchronous low-Earth-orbiting satellites (especially, the SSM/I and SSMIS radiometers onboard DMSP satellites and the AMSU-A + AMSU-B/MHS radiometer suites onboard EPS-MetOp and NOAA-POES satellites), as well as on combined infrared/passive microwave measurements in which the passive microwave precipitation estimates are used in conjunction with SEVIRI images from the geostationary MSG satellite. Moreover, the H-SAF product generation and dissemination chain and independent product validation activities are described. Also, the H-SAF program and its associated activities that currently are being carried out or are planned to be performed within the second CDOP phase (CDOP-2, 2012–2017) are presented in some detail. Insofar as CDOP-2 is concerned, it is emphasized that all algorithms and processing schemes will be improved and enhanced so as to extend them to satellites that will be operational within this decade – particularly the geostationary Meteosat Third Generation satellites and the low-Earth-orbiting Core Observatory of the international Global Precipitation Measurement mission. Finally, the role of H-SAF within the international science and operations community is explained.</p

The validation service of the hydrological SAF geostationary and polar satellite precipitation products

Abstract. The development phase (DP) of the EUMETSAT Satellite Application Facility for Support to Operational Hydrology and Water Management (H-SAF) led to the design and implementation of several precipitation products, after 5 yr (2005–2010) of activity. Presently, five precipitation estimation algorithms based on data from passive microwave and infrared sensors, on board geostationary and sun-synchronous platforms, function in operational mode at the H-SAF hosting institute to provide near real-time precipitation products at different spatial and temporal resolutions. In order to evaluate the precipitation product accuracy, a validation activity has been established since the beginning of the project. A Precipitation Product Validation Group (PPVG) works in parallel with the development of the estimation algorithms with two aims: to provide the algorithm developers with indications to refine algorithms and products, and to evaluate the error structure to be associated with the operational products. In this paper, the framework of the PPVG is presented: (a) the characteristics of the ground reference data available to H-SAF (i.e. radar and rain gauge networks), (b) the agreed upon validation strategy settled among the eight European countries participating in the PPVG, and (c) the steps of the validation procedures. The quality of the reference data is discussed, and the efforts for its improvement are outlined, with special emphasis on the definition of a ground radar quality map and on the implementation of a suitable rain gauge interpolation algorithm. The work done during the H-SAF development phase has led the PPVG to converge into a common validation procedure among the members, taking advantage of the experience acquired by each one of them in the validation of H-SAF products. The methodology is presented here, indicating the main steps of the validation procedure (ground data quality control, spatial interpolation, up-scaling of radar data vs. satellite grid, statistical score evaluation, case study analysis). Finally, an overview of the results is presented, focusing on the monthly statistical indicators, referred to the satellite product performances over different seasons and areas

Worsening of Cardiomyopathy Using Deflazacort in an Animal Model Rescued by Gene Therapy

We have previously demonstrated that gene therapy can rescue the phenotype and extend lifespan in the delta-sarcoglycan deficient cardiomyopathic hamster. In patients with similar genetic defects, steroids have been largely used to slow down disease progression. Aim of our study was to evaluate the combined effects of steroid treatment and gene therapy on cardiac function. We injected the human delta-sarcoglycan cDNA by adeno-associated virus (AAV) 2/8 by a single intraperitoneal injection into BIO14.6 Syrian hamsters at ten days of age to rescue the phenotype. We then treated the hamsters with deflazacort. Treatment was administered to half of the hamsters that had received the AAV and the other hamsters without AAV, as well as to normal hamsters. Both horizontal and vertical activities were greatly enhanced by deflazacort in all groups. As in previous experiments, the AAV treatment alone was able to preserve the ejection fraction (70±7% EF). However, the EF value declined (52±14%) with a combination of AAV and deflazacort. This was similar with all the other groups of affected animals. We confirm that gene therapy improves cardiac function in the BIO14.6 hamsters. Our results suggest that deflazacort is ineffective and may also have a negative impact on the cardiomyopathy rescue, possibly by boosting motor activity. This is unexpected and may have significance in terms of the lifestyle recommendations for patients