1,721,015 research outputs found
Decreased mTOR Signaling Via p70S6K/eIF4B Is Associated with Loss of the Excitatory Postsynaptic Marker PSD-95 in Autism
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A modern diagnostic dilemma: pelvic malignancy versus actinomycosis. A case report with preventive, diagnostic and therapeutic strategies
No full textIn vitro modeling of dendritic atrophy in Rett syndrome: determinants for phenotypic drug screening in neurodevelopmental disorders
Full text linkDendritic atrophy, defined as the reduction in complexity of the neuronal arborization, is a hallmark of several neurodevelopmental disorders, including Rett Syndrome (RTT). RTT, affecting 1:10,000 girls worldwide, is mainly caused by mutations in the MECP2 gene and has no cure. We describe here an in vitro model of dendritic atrophy in Mecp2−/y mouse hippocampal primary cultures, suitable for phenotypic drug-screening. Using High-Content Imaging techniques, we systematically investigated the impact of culturing determinants on several parameters such as neuronal survival, total dendritic length, dendritic endpoints, soma size, cell clusterization, spontaneous activity. Determinants included cell-seeding density, glass or polystyrene substrates, coating with poly-Ornithine with/without Matrigel and miniaturization from 24 to 96-half surface multiwell plates. We show that in all plate-sizes at densities below 320 cells/mm2, morphological parameters remained constant while spontaneous network activity decreased according to the cell-density. Mecp2−/y neurons cultured at 160 cells/mm2 density in 96 multiwell plates, displayed significant dendritic atrophy and showed a marked increase in dendritic length following treatment with Brain-derived neurotrophic factor (BDNF) or Mirtazapine. In conclusion, we have established a phenotypic assay suitable for fast screening of hundreds of compounds, which may be extended to other neurodevelopmental diseases with dendritic atrophy
Signaling pathways controlling activity-dependent local translation of BDNF and their localization in dendritic arbors
Full text linkBrain-derived neurotrophic factor (BDNF) is encoded by multiple mRNA variants whose differential subcellular distribution constitutes a "spatial code" for local translation of BDNF and selective morphological remodeling of dendrites. Here, we investigated where BDNF translation takes place and what are the signaling pathways involved. Cultured hippocampal neurons, treated with KCl showed increased BDNF in the soma, proximal and distal dendrites even in quaternary branches. Activity-dependent increase of BDNF is abolished by cycloheximide, suggesting local translation, and requires activation of glutamate and Trk receptors. Our data show that BDNF translation is regulated by multiple signaling cascades including RAS/Erk and mTOR pathways, CaMKII/CPEB1, Aurora-A/CPEB1 and Src/ZBP1 pathways. Aurora-A, CPEB1, ZBP1, eiF4E, S6 are present throughout the dendritic arbor. Neuronal activity increases Aurora-A, CPEB1, ZBP1 levels in distal dendrites while eiF4E, S6 are unaffected. BDNF-6, the main dendritic BDNF transcript, is translated in the same subcellular domains and in response to the same pathways as total BDNF. In conclusion, we identified the signaling cascades controlling BDNF translation and we describe how their localization is modulated in response to electrical activity
BDNF mRNA splice variants display activity-dependent targeting to distinct hippocampal laminae
No full textBrain-derived neurotrophic factor (BDNF) may exert contrasting effects depending on its different subcellular sites of action (soma, dendrites, axons). These contrasting effects may explain contradictory findings, for example that BDNF may favour or oppose epileptogenesis. We determined the distribution of five BDNF splice variants in the soma and dendrites of rat hippocampal principal neurons, after application of stimuli that prompt BDNF mRNA accumulation in dendrites (epileptogenic seizures). Under basal conditions, no BDNF mRNA splice variant was detectable in dendrites, while specific splice variants were found in dendrites in response to epileptogenic seizures. Three h after pilocarpine administration, exon VI and exon II splice variants were found in dendrites, while exons I and IV transcripts displayed a strictly somatic localization. Three h after kainate administration, only exon VI was found in dendrites. These data suggest that the regulated expression of different splice variants may provide a code to ensure the delivery of BDNF to precise destinations in the cell soma or along the dendrites
Substrate Dissipation Energy Regulates Cell Adhesion and Spreading
Full text linkRecent evidence has led to the hypothesis that dissipation of energy through the viscoelastic extracellular matrix (ECM) can play a cardinal role in directing cell-fate decisions, but whether and how it correlates with specific cell response is at present unclear. Here, viscoelastic and plastic 2D chitosan-based substrates endowed with different dissipative energies are developed and cell behavior studied in terms of adhesion and spreading. While keeping constant stress relaxation and systematically decoupling overall stiffness from linear elongation, an energy dissipation term (J mol−1) is introduced, that is the molar energy required to deviate from linear stress–strain regime and enter into plastic region. Strikingly, an inverse relationship is unveiled between substrate dissipation energy and cell response, with high adhesion/high spreading and low adhesion/no spreading detected for substrates at low and high dissipation energy, respectively. It is concluded that cells decide how to react depending on the effective energy they can earmark for their functions
Uterine malformations and pregnancy losses: is cervical cerclage effective?
No full textFor many years, we and others have reported the efficacy of cervical cerclage in the prevention of miscarriage in patients with uterine malformations. In this paper the experience of 275 cases collected between 1978 and 1998 is reported. Our data indicate that cervical cerclage is effective in preventing miscarriages, prevalently in those pregnancies bearing uterine malformations with simultaneous cervical incompetence
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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