1,720,978 research outputs found
The Selective Sphingosine-1-Phosphate Receptor 1 (S1P1) Modulator Ponesimod Enhances Murine Oligodendrocyte Precursor Cell (OPC) Differentiation and Retains OPC Migration
No full textMethods: Reversible, blue light (BL) stimulated, optogenetic A1 protein expression plasmids, containing wild-type A1, tagged with both the optogene Cryptochrome 2 and mCherry, were trans-fected into HEK293T cells and a differentiated neuronal cell line and used to examine the effects of RNA oligo treatment on protein dynamics and downstream cellular pathway functions in real-time. Using this in vitro optogenetic paradigm of A1 dysfunction, we gathered evidence on how RNA oligo treatment affects A1 self-association clustering and downstream neuronal morphology and viability. Results: Imitating an acute environmental cell stress using a BL stimulus followed by a steady period of recovery, our data show that RNA oligo treatment significantly decreased the kinetics of cytoplasmic A1 cluster formation [half-maximal formation time (minutes): Oligo=100; no treatment (NT)=62] and significantly decreased the number of cells with A1 clustering (percent cells w/ A1 clusters: Oligo=33%; NT=50%). We found that RNA oligo treatment stabilized the structure of A1 upon binding (avg. protein denaturation temp.: Oligo=62°C; NT=61°C), and significantly increased the quantity of A1 clusters (avg. clusters/cell: Oligo=19 ; NT=5) and decreased their size (avg. cluster size (µm2): Oligo=0.31; NT=0.95). Finally, we show that neuron morphology and viability were perturbed with A1 cluster formation. Conclusions: Using an in vitro optogenetic approach, this study presents evidence that A1 clustering negatively affects neuronal morphology, and that RNA oligo treatment attenuates MS-associated A1 dysfunction, indicating that A1 protein dys-function perturbation may affect NDG in MS. Background: Sphingosine-1-phosphate receptor (S1PR) modu-lators are clinically applied to target relapse remitting multiple sclerosis (MS) and the early phase of progressive MS when inflammation still prevails. S1P1 receptor modulation (functional antagonism) is known to prevent lymphocytes egression from lymph nodes, hence hampering neuroinflammation in MS. Recent findings suggest a potential additional role for S1P1 receptor modulation in neuroprotection and remyelination. Objectives: As the Giα-coupled S1P1 is the most prominently expressed S1P receptor in oligodendrocyte precursor cells (OPCs), we hypothesized that functional antagonism by the S1P1-monoselective modulator ponesimod induces OPC differentiation. Methods: Primary mouse OPCs were harvested via the shake-off method and treated in vitro with the S1P1-selective modulator ponesimod (3nM-3000nM), the S1P5-selective modulator A971432 (3nM-3000nM) or a phosphorylated form of the non-selective modulator fingolimod (3000nM). Migration wa
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
PDE4D inhibition to improve peripheral myelination, Schwann cell differentiation and motor function in Charcot-Marie-Tooth disease type 1A
No full textCharcot-Marie-Tooth disease type 1A (CMT1A) is an inherited neuropathy of the peripheral nervous system. Symptoms include distal muscle weakness and atrophy, as well as sensory loss. Currently, no therapies for CMT1A are available. CMT1A is characterized by Schwann cell (SC) dedifferentiation and demyelination. The differentiation of SCs to the myelinating phenotype and the subsequent myelination process are positively regulated by cAMP. Therefore, we hypothesized that elevating intracellular cAMP levels by inhibiting PDE4D, a main cAMP-hydrolyzing enzyme in SCs, can stimulate SC differentiation, myelination and subsequent functional repair in the C3-PMP22 mouse model. Primary SCs were treated with 3 different inhibitors and their differentiation was investigated by assessing gene expression of several SC differentiation markers by qPCR, as well as the protein levels of several markers using immunocytochemistry. These experiments were inconclusive. Secondly, the therapeutic potential of PDE4D inhibitor GEBR-32a was evaluated in vivo. Mice were injected with 0.3 mg/kg GEBR-32a twice per day for 7 weeks, and motor function was assessed using several behavioral assays. We found that GEBR-32a treatment significantly improves motor function in C3-PMP22 mice. Furthermore, electrophysiological recordings showed a significant increase in nerve conduction speed. In conclusion, these findings indicate a promising therapeutic potential of PDE4D inhibition in CMT1A, although the exact molecular mechanisms need to be evaluated in vitro
PDE4D inhibition to improve peripheral myelination, Schwann cell differentiation and motor function in Charcot-Marie-Tooth disease type 1A
No full textCharcot-Marie-Tooth disease type 1A (CMT1A) is an inherited neuropathy of the peripheral nervous system. Symptoms include distal muscle weakness and atrophy, as well as sensory loss. Currently, no therapies for CMT1A are available. CMT1A is characterized by Schwann cell (SC) dedifferentiation and demyelination. The differentiation of SCs to the myelinating phenotype and the subsequent myelination process are positively regulated by cAMP. Therefore, we hypothesized that elevating intracellular cAMP levels by inhibiting PDE4D, a main cAMP-hydrolyzing enzyme in SCs, can stimulate SC differentiation, myelination and subsequent functional repair in the C3-PMP22 mouse model. Primary SCs were treated with 3 different inhibitors and their differentiation was investigated by assessing gene expression of several SC differentiation markers by qPCR, as well as the protein levels of several markers using immunocytochemistry. These experiments were inconclusive. Secondly, the therapeutic potential of PDE4D inhibitor GEBR-32a was evaluated in vivo. Mice were injected with 0.3 mg/kg GEBR-32a twice per day for 7 weeks, and motor function was assessed using several behavioral assays. We found that GEBR-32a treatment significantly improves motor function in C3-PMP22 mice. Furthermore, electrophysiological recordings showed a significant increase in nerve conduction speed. In conclusion, these findings indicate a promising therapeutic potential of PDE4D inhibition in CMT1A, although the exact molecular mechanisms need to be evaluated in vitro
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Activation of glycine receptors decreases pacemaking activity in midbrain dopamine neurons independent of the alpha 2 subunit
No full textDopamine is a neurotransmitter of the brain and tight modulation of its release is essential for a proper brain function. Dysfunction of dopamine signaling is associated with various diseases, such as Parkinson's disease and psychosis. The activity of dopamine releasing neurons is modulated in the midbrain and elucidating these modulatory mechanisms is essential for unveiling the etiology of these diseases and development of new treatment strategies.
The neurotransmitter glycine plays a major role in the modulation of dopamine neuron activity, yet it is unclear which subunits are involved. To address this gap, we first confirmed the inhibitory effect of glycine on basal dopamine neuron firing in the substantia nigra pars compacta (SNc) within the midbrain. Next, since preliminary data from our lab indicate a significant role for the alpha 2 subunit of the glycine receptor (GlyR'2) in dopaminergic signaling, we checked the presence of the subunit on dopamine neurons and repeated the firing experiments in GlyR'2 knock-out littermates to determine its functional role.
Our findings clearly demonstrate the involvement of glycine receptors in modulation of dopamine neuron activity, but modulation was independent of GlyR'2s at baseline activity and activity in presence of synaptic glycine concentrations. However, it is conceivable that high-affinity GlyR'2s are involved in the modulation at lower, tonic glycine concentrations and/or in phasic activity
Activation of glycine receptors decreases pacemaking activity in midbrain dopamine neurons independent of the alpha 2 subunit
No full textDopamine is a neurotransmitter of the brain and tight modulation of its release is essential for a proper brain function. Dysfunction of dopamine signaling is associated with various diseases, such as Parkinson's disease and psychosis. The activity of dopamine releasing neurons is modulated in the midbrain and elucidating these modulatory mechanisms is essential for unveiling the etiology of these diseases and development of new treatment strategies.
The neurotransmitter glycine plays a major role in the modulation of dopamine neuron activity, yet it is unclear which subunits are involved. To address this gap, we first confirmed the inhibitory effect of glycine on basal dopamine neuron firing in the substantia nigra pars compacta (SNc) within the midbrain. Next, since preliminary data from our lab indicate a significant role for the alpha 2 subunit of the glycine receptor (GlyR'2) in dopaminergic signaling, we checked the presence of the subunit on dopamine neurons and repeated the firing experiments in GlyR'2 knock-out littermates to determine its functional role.
Our findings clearly demonstrate the involvement of glycine receptors in modulation of dopamine neuron activity, but modulation was independent of GlyR'2s at baseline activity and activity in presence of synaptic glycine concentrations. However, it is conceivable that high-affinity GlyR'2s are involved in the modulation at lower, tonic glycine concentrations and/or in phasic activity
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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