1,720,969 research outputs found
Disulfide-containing High Mobility Group Box-1 promotes N-methyl-D-aspartate receptor function and excitotoxicity by activating Toll-Like Receptor 4-dependent signaling in hippocampal neurons.
No full textAims: Using primary cultures of mouse hippocampal neurons, we studied the molecular and functional interactionsbetween high mobility group box-1 (HMGB1) and the N-methyl-d-aspartate receptor (NMDAR), twoproteins playing a key role in neuronal hyperexcitability. By measuring NMDA-induced calcium (Ca2+) increasein neuronal somata and neurotoxicity as functional read-out parameters, we explored the role of the redox stateof HMGB1, the receptor involved, and the molecular signaling underlying its interactions with postsynapticNMDAR. We also investigated whether HMGB1 redox state affects its proconvulsive effects in mice. Results:Nonoxidizable HMGB1 with a triple cysteine-to-serine replacement (3S-HMGB1) was ineffective on NMDAresponse. Conversely, the disulfide-containing form of HMGB1 dose dependently enhanced NMDA-inducedCa2+ increase in neuronal cell bodies. This effect was prevented by BoxA, a competitive HMGB1 antagonist, andby Rhodobacter sphaeroides lipopolysaccharide (LPS-RS), a toll-like receptor 4 (TLR4) selective antagonist, andit was abrogated in neurons lacking TLR4 while persisting in the absence of receptor for advanced glycation endproducts (RAGE). TLR4 and NMDAR subunit 1 (NR1) and 2B (NR2B) were colocalized in neurons. DisulfideHMGB1 effect on NMDA-induced Ca2+ influx was prevented by 3-O-methylsphingomyelin (3-O-MS) and 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo [3,4-d] pyrimidine, (PP2) selective inhibitors of neutral sphingomyelinaseand Src-family Tyr kinases, respectively. Disulfide HMGB1, but not 3S-HMGB1, increased Tyr1472phosphorylation of the NR2B subunit of the NMDAR, which is known to increase Ca2+ channel permeability.Similarly, disulfide HMGB1 increased NMDA-induced neuronal cell death in vitro and enhanced kainate-inducedseizures in vivo. Innovation and Conclusion: We describe a novel molecular neuronal pathway activatedby HMGB1 that could be targeted in vivo to prevent neurodegeneration and seizures mediated by excessiveNMDARs stimulation
Inflammation and reactive oxygen species in status epilepticus: Biomarkers and implications for therapy.
No full textreclinical studies in immature and adult rodents and clinical observations show that neuroinflammation and oxidative stress are rapid onset phenomena occurring in the brain during status epilepticus and persisting thereafter. Notably, both neuroinflammation and oxidative stress contribute to the acute and long-term sequelae of status epilepticus thus representing potential druggable targets. Antiinflammatory drugs that interfere with the IL-1β pathway, such as anakinra, can control benzodiazepine-refractory status epilepticus in animals, and there is recent proof-of-concept evidence for therapeutic effects in children with Febrile infection related epilepsy syndrome (FIRES). Inhibitors of monoacylglycerol lipase and P2X7 receptor antagonists are also promising antiinflammatory drug candidates for rapidly aborting de novo status epilepticus and provide neuroprotection. Antiinflammatory and antioxidant drugs administered to rodents during status epilepticus and transiently thereafter, prevent long-term sequelae such as cognitive deficits and seizure progression in animals developing epilepsy. Some drugs are already in medical use and are well-tolerated, therefore, they may be considered for treating status epilepticus and its neurological consequences. Finally, markers of neuroinflammation and oxidative stress are measureable in peripheral blood and by neuroimaging, which offers an opportunity for developing prognostic and predictive mechanistic biomarkers in people exposed to status epilepticus. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures
Inflammation and reactive oxygen species as disease modifiers in epilepsy.
No full textNeuroinflammation and reactive oxygen and nitrogen species are rapidly induced in the brain after acute cerebral injuries that are associated with an enhanced risk for epilepsy in humans and related animal models. These phenomena reinforce each others and persist during epileptogenesis as well as during chronic spontaneous seizures. Anti-inflammatory and anti-oxidant drugs transiently administered either before, or shortly after the clinical onset of symptomatic epilepsy, similarly block the progression of spontaneous seizures, and may delay their onset. Moreover, neuroprotection and rescue of cognitive deficits are also observed in the treated animals. Therefore, although these treatments do not prevent epilepsy development, they offer clinically relevant disease-modification effects. These therapeutic effects are mediated by targeting molecular signaling pathways such as the IL-1β-IL-1 receptor type 1 and TLR4, P2X7 receptors, the transcriptional anti-oxidant factor Nrf2, while the therapeutic impact of COX-2 inhibition for reducing spontaneous seizures remains controversial. Some anti-inflammatory and anti-oxidant drugs that are endowed of disease modification effects in preclinical models are already in medical use and have a safety profile, therefore, they provide potential re-purposed treatments for improving the disease course and for reducing seizure burden. Markers of neuroinflammation and oxidative stress can be measured in blood or by neuroimaging, therefore they represent testable prognostic and predictive biomarkers for selecting the patient's population at high risk for developing epilepsy therefore eligible for novel treatment
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
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
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
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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