1,721,241 research outputs found
Modulation of Ca2+ refilling mediated by ORAI-1, STIM1 and NCX as a new therapeutical strategy in neurodegeneration
No full textPhysiological Ca2+ signals are essential for cell function and survival. On the other hand, perturbations of intracellular Ca2+ homeostasis can enhance mechanisms leading to cell death. In respect to the Ca2+-induced cytotoxicity in neuronal and non-neuronal cells of CNS, “source specificity hypothesis” reasons that it occurs not simply as a function of increased Ca2+ levels, but is instead linked to the route of Ca2+ entry (1). Accordingly, calcium-mediated degeneration, in general, may occur through different mechanisms implying the dysregulation of both specific plasma membrane and intracellular proteins as well as several Ca2+-dependent signaling pathways. In these conditions, some elements become unable to correctly transduce vital signals from the plasma membrane to the intracellular compartments. The identification of specific targets involved in this route may re-equilibrate cell status thus interfering with the neurodegenerative process and inducing a certain Ca2+ remodeling process. Moreover, impaired Ca2+ homeostasis is now considered an important feature of dysfunctional motor neurons in ALS. Accordingly, the stimulation of Akt/ERK1/2 signaling pathway via a rapid intracellular Ca2+ increase is able to prevent endoplasmic reticulum (ER) stress in Guam type of ALS (2). Interestingly, under these conditions, Ca2+ ions partially flow from the extracellular space and partially derive from ER (2), likely through the Ca2+ release induced by Ca2+-mobilizing second messengers (i.e. IP3 and/or the NAD+-derived second messengers cADPR or NAADP)(3). Moreover, a part the important role played by plasma membrane proteins in regulating Ca2+ homeostasis at neuronal level, also Ca2+-storing organelles play an important role in buffering intracellular calcium ions. When dysfunctional, Ca2+ stores may trigger death pathways. Among these organelle, nuclear envelope (NE) is now considered an emerging Ca2+-storing organelle whose dysfunction can enhance cell death process. In this view, it has been postulated that the leakiness of nuclear pore complex, mediated by calcium overload, may trigger neuronal demise through the alteration of nucleo-cytoplasmic transport thus determining cell condemned to death (4). In this symposium, the speakers will bring new elements to the discussion on “the source specificity hypothesis” related to the Ca2+-mediated degeneration in neurodegenerative disorders including ALS, Stroke, Alzheimer’s disease as well as in PNS diseases associated to demyelination. Interestingly, an interrelationship of metabolic syndromes and neurodegenerative diseases has been postulated. Also in this respect, they will discuss about some newly identified targets involved in Ca2+ homeostasis control at both plasma membrane and intracellular level within the complex neuronal architecture
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
Pharmacological inhibition of lysosomal two-pore channel 2 (TPC2) confers neuroprotection in stroke via autophagy regulation
No full textLysosomal function and organellar Ca2+ homeostasis become dysfunctional in Stroke causing disturbances in autophagy, the major process for the degradation of abnormal protein aggregates and dysfunctional organelles. However, the role of autophagy in Stroke is controversial since excessive or prolonged autophagy activation exacerbates ischemic brain injury. Of note, glutamate evokes NAADP-dependent Ca2+ release via lysosomal TPC2 channels thus controlling basal autophagy. Considering the massive release of excitotoxins in Stroke, autophagic flux becomes uncontrolled with abnormal formation of autophagosomes causing, in turn, disruption of excitotoxins clearance and neurodegeneration. Here, a fine regulation of autophagy via a proper pharmacological modulation of lysosomal TPC2 channel has been tested in preclinical Stroke models. Primary cortical neurons were subjected to oxygen and glucose deprivation+reoxygenation to reproduce in vitro brain ischemia. Focal brain ischemia was induced in rats by transient middle cerebral artery occlusion (tMCAO). Under these conditions, TPC2 protein expression as well as autophagy and endoplasmic reticulum (ER) stress markers were studied by Western blotting, while TPC2 localization and activity were measured by immunocytochemistry and single-cell video-imaging, respectively. TPC2 protein expression and immunosignal were highly modulated in primary cortical neurons exposed to extreme hypoxic conditions causing dysfunction in organellar Ca2+ homeostasis, ER stress and autophagy-induced cell death. TPC2 knocking down and pharmacological inhibition by Ned-19 during hypoxia induced neuroprotection. The effect of Ned-19 was reversed by the permeable form of TPC2 endogenous agonist, NAADP-AM. Of note, Ned-19 prevented ER stress, as measured by GRP78 (78 kDa glucose-regulated protein) protein reduction and caspase 9 downregulation. In this way Ned-19 restored organellar Ca2+ level. Interestingly, Ned-19 reduced the infarct volume and neurological deficits in rats subjected to tMCAO and prevented hypoxia-induced cell death by blocking autophagic flux. Collectively, the pharmacological inhibition of TPC2 lysosomal channel by Ned-19 protects from focal ischemia by hampering a hyperfunctional autophag
New perspectives for selective NCX activators in neurodegenerative diseases
No full textThe Na+/Ca2+ exchanger plays a relevant role in several neurological disorders, thus the pharmacological modulation of its isoforms might represent a promising strategy to ameliorate the course of some neurological pathologies including stroke, neonatal hypoxia, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer Disease (AD), and spinal muscular atrophy (SMA). This review will summarize heterocyclic, peptidergic, genetic and epigenetic compounds activating or inhibiting the expression/activity of each NCX isoform. In addition, we will focus our attention on the development of new strategies aimed to ameliorate the pathophysiological conditions in which NCX isoform changes are found
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
- …
