The role of sphingosine-1-phosphate lyase (SPL) in the brain : Studies in brain-targeted SPL-deficient mice

The bioactive lipid sphingosine 1-phosphate (S1P) is a degradation product of sphingolipids that are particularly abundant in neurons. It was shown previously that neuronal S1P accumulation is toxic leading to ER-stress and an increase in intracellular calcium. To clarify the neuronal function of S1P, a brain-specific knockout mouse model was generated, in which S1P-lyase (SPL), the enzyme responsible for irreversible S1P cleavage was inactivated (SPLfl/fl/Nes mice). SPL cleaves S1P into ethanolamine phosphate, which is directed towards the synthesis of phosphatidylethanolamine (PE) that is an anchor to autophagosomes for LC3-I. In the brains of SPLfl/fl/Nes mic significantly reduced PE levels were detected. Accordingly, autophagy alterations involving decreased conversion of LC3-I to LC3-II and increased beclin-1 and p62 levels were apparent. Alterations were also noticed in downstream events of the autophagic-lysosomal pathway like increased levels of lysosomal markers and aggregate prone proteins such as amyloid precursor protein, α-synuclein and tau protein. Genetic and pharmacological inhibition of SPL in cultured neurons promoted these alterations while addition of PE was sufficient to restore LC3-I to LC3-II conversion, and control levels of p62, APP and α-synuclein. Rapamycin, which is an agonist of autophagy by inhibition of mTOR kinase, had no effect on autophagy in neuronal cultures from SPLfl/fl/Nes mice suggesting that the impaired autophagy seen in SPLfl/fl/Nes mice is mTOR independent. Electron and immunofluorescence microscopy showed accumulation of unclosed phagophore-like structures, reduction of autophagolysosomes and altered distribution of LC3 in SPLfl/fl/Nes brains. Experiments using mRFP-EGFP-LC3 provided further support for blockage of the autophagic flux at initiation stages upon SPL deficiency due to PE paucity. Developmental ablation of SPL in the brain (SPLfl/fl/Nes) caused marked accumulation of S1P and sphingosine. These changes in lipid composition lead to morphological, molecular and behavioral abnormalities. We observed altered presynaptic architecture including a significant decrease in number and density of synaptic vesicles (Mitroi et al. in press), and decreased expression of several presynaptic proteins in hippocampal neurons from SPLfl/fl/Nes mice. At the molecular level, accumulation of S1P induced a calcium mediated activation of the ubiquitin-proteasome system (UPS) which resulted in a decreased expression of the deubiquitinating enzyme USP14 and several presynaptic proteins. Upon inhibition of proteasomal activity, expression of USP14 and of preysnaptic proteins were restored. In addition, these mice displayed cognitive deficits. These findings identify S1P metabolism as a novel player in modulating synaptic architecture, and emphasize a formerly overlooked direct role of SPL in neuronal autophagy

Equal Opportunities and Treatment and the Real Training Needs of Adult Learners - A Case Study

AbstractAdult training in the field of equal opportunity and treatment is the main way of raising awareness, informing and promoting measures to prevent and fight discrimination in Romania. Contrary to many andragogical principles according to which adults learn if by learning they can solve specific personal problems, these training courses are generally designed starting from the global analysis of problems and needs of trainees. The case study referred to in this article was conducted as a result of a training initiative on equal opportunity and treatment for employees in the public administration (50 adult trainees, Timis County, Romania), which resulted in the identification of specific training needs for employees and local community members. To this end, we made a comparison between our initial training objectives and those redesigned based on the feedback from the participants. The conclusion of this contrastive approach was that, to have the desired impact, the goals and objectives of adult education courses must meet the real needs of the participants

Structural results on convexity relative to cost functions

Mass transportation problems appear in various areas of mathematics, their solutions involving cost convex potentials. Fenchel duality also represents an important concept for a wide variety of optimization problems, both from the theoretical and the computational viewpoints. We drew a parallel to the classical theory of convex functions by investigating the cost convexity and its connections with the usual convexity. We give a generalization of Jensen's inequality for cost convex functions.Comment: 10 page

Intelligent control interfaces developed on versatile portable intelligent platform in order to improving autonomous navigation robots performances

The paper presents Intelligent Control Interfaces (ICIs) for real-time control for terrestrial mobile robots or unmanned aerial robots in order to improve the navigation performances. Intelligent control interfaces using advanced control strategies adapted to robot environment are presented, implemented through IT & C techniques with fast processing and real-time communications in order to develop a versatile, intelligent and portable VIPRO Platform with behavior of e-learning platform, which allows achievement inter-academic research networks and building new intelligent vectors robots. Implementation of ICIs laws in the intelligent real time control interfaces depends on the particular circumstances of the characteristics model used and the exact definition of optimization problem. The results led to the development of the ICI interfaces through image analysis using Images Operation Sampling & Quantization (IOSQ)

Neutral sphingomyelinase mediates the co-morbidity trias of alcohol abuse, major depression and bone defects

Mental disorders are highly comorbid and occur together with physical diseases, which are often considered to arise from separate pathogenic pathways. We observed in alcohol-dependent patients increased serum activity of neutral sphingomyelinase. A genetic association analysis in 456,693 volunteers found associations of haplotypes of SMPD3 coding for NSM-2 (NSM) with alcohol consumption, but also with affective state, and bone mineralisation. Functional analysis in mice showed that NSM controls alcohol consumption, affective behaviour, and their interaction by regulating hippocampal volume, cortical connectivity, and monoaminergic responses. Furthermore, NSM controlled bone–brain communication by enhancing osteocalcin signalling, which can independently supress alcohol consumption and reduce depressive behaviour. Altogether, we identified a single gene source for multiple pathways originating in the brain and bone, which interlink disorders of a mental–physical co-morbidity trias of alcohol abuse—depression/anxiety—bone disorder. Targeting NSM and osteocalcin signalling may, thus, provide a new systems approach in the treatment of a mental–physical co-morbidity trias

Use of efavirenz for the treatment of lipid storage diseases

The present invention relates to the use of efavirenz for manufacturing a medicament for the treatment of lipid storagediseases such as Niemann-Pick diseases. By activating CYP46, which promotes cholesterol eliminati n in neurons among other lipids, o efavirenz is capable of normalizing the levels of these lipids and neuronal fnnction. Efavirenz can also be used in combination with another active principie considered effective for the treatment of these diseases, to enhance the therapeutic effectsPeer reviewedConsejo Superior de Investigaciones Científicas (España)A1 Solicitud de patente con informe sobre el estado de la técnic

Uso de efavirenz para el tratamiento de enfermedades de almacenamiento lipídico

La presente invención se refiere al uso de efavirenz para fabricar un medicamento para el tratamiento de enfermedades de almacenamiento lipídico tales como enfermedades de Niemann-Pick . Mediante la activación de CYP46, que estimula la eliminación de colesterol en las neuronas , entre otros lípidos ,efavirenz es capaz de normalizar los niveles de estos lípidos y la función neuronal. Efavirenz también se puede usar en combinación con otro principio activo considerado eficaz para el tratamiento de estas enfermedades, para mejorar los efectos terapéuticosPeer reviewedConsejo Superior de Investigaciones Científicas (España)A1 Solicitud de patente con informe sobre el estado de la técnic

Intelligent Control Interfaces Using Extenics Multidimensional Theory Applied on VIPRO Platforms for Developing the IT INDUSTRY 4.0 Concept

The paper presents new concepts and approaches to achieving intelligent control interfaces for solving contradictory problems using Extenics multidimensional theory applied on VIPRO Versatile Intelligent Portable Platforms. VIPRO platform enables developing the IT Industry 4.0 concept through the design, testing and experimentation of new intelligent control interfaces on a classical mechatronic control system without the need to modify its hardware structure, and, from optimal decisions and information fusion between the intelligent control interfaces, resulting in a high degree of versatility and portability to a global communications network. The Cyber-Physical Systems as like a VIPRO Platform’s component, developed through advanced intelligent control interfaces integrate the dynamics of the physical processes with those of the software and networking, providing a powerful environment for modeling, design, and analysis techniques for an integrated whole IT Industry. The portability characteristics results allow test and improve the motion performance of the mechatronic system, and furthermore implement the intelligent control and decision interfaces on their own control system, applying Industry 4.0 components: cognitive computing including intelligence and signal processing, cyber-physical systems, internet of things and cloud computing, exemplified on an Extenics multidimensional control intelligent interfaces

Single-nucleus transcriptome analysis reveals disease- and regeneration-associated endothelial cells in white matter vascular dementia.

BackgroundVascular dementia (VaD) is the accumulation of vascular lesions in the subcortical white matter of the brain. These lesions progress and there is no direct medical therapy.AimsTo determine the specific cellular responses in VaD so as to provide molecular targets for therapeutic development.Materials and methodsSingle-nucleus transcriptome analysis was performed in human periventricular white matter (PVWM) samples of VaD and normal control (NC) subjects.ResultsDifferential analysis shows that cell type-specific transcriptomic changes in VaD are associated with the disruption of specific biological processes, including angiogenesis, immune activation, axonal injury and myelination. Each cell type in the neurovascular unit within white matter has a specific alteration in gene expression in VaD. In a central cell type for this disease, subcluster analysis of endothelial cells (EC) indicates that VaD contains a disease-associated EC subcluster that expresses genes associated with programmed cell death and a response to protein folding. Two other subpopulations of EC in VaD express molecular systems associated with regenerative processes in angiogenesis, and in axonal sprouting and oligodendrocyte progenitor cell maturation.ConclusionThis comprehensive molecular profiling of brain samples from patients with VaD reveals previously unknown molecular changes in cells of the neurovascular niche, and an attempt at regeneration in injured white matter