1,720,969 research outputs found
Ca2+ related mechanisms of cellular dysfunction in neurodegeneration
No full textCalcium is a pleiotropic intracellular messenger regulating mitochondrial bioenergetics and proteostasis, both altered in Alzheimer’s disease (AD). In my PhD project I have studied the cause-effect relationships between calcium dishonesties and cellular dysfunction in astrocytes.
In this context I investigated the discrepancy, described in AD astrocytes, between deficient mitochondrial calcium uptake and increased ER-mitochondria interaction, which in principle should promote ER-mitochondrial calcium transfer. To solve this issue, I investigated the correlation between ER-mitochondria distances and efficiency of calcium transfer: I designed a palette of ER-mitochondria linkers, discovering that ER-mitochondria calcium transfer is strongly inhibited at 10nm distances, and is strongly potentiated at 20nm, explaining why increased ER-mitochondria interaction at 8-10nm, in AD astrocytes, results in reduced mitochondrial calcium uptake.
Another aspect of my PhD thesis is the investigation of Calcineurin (CaN) role in both physiology of astrocytes and AD related astrocytes dysfunction. In astrocytes, eIF2α-mediated protein synthesis and proteasomal degradation are under CaN control. While, in and AD mice model, deletion of astroglial CaN displayed a protective effect, reducing memory impairment, aβ plaques deposition and tau hyper-phosphorylation. These results indicate that CaN, under pathological conditions can drive pathology progression.
I demonstrated that ER-mitochondria interaction and calcineurin represents promising therapeutic targets to mitigate AD related astroglial pathophysiology, given the importance of astrocytes for brain functions further studies are warranted to elucidate mechanisms of these dysfunctions
Calcineurin Signalling in Astrocytes: From Pathology to Physiology and Control of Neuronal Functions
No full textCalcineurin (CaN), a Ca2+/calmodulin-activated serine/threonine phosphatase, acts as a Ca2+-sensitive switch regulating cellular functions through protein dephosphorylation and activation of gene transcription. In astrocytes, the principal homeostatic cells in the CNS, over-activation of CaN is known to drive pathological transcriptional remodelling, associated with neuroinflammation in diseases such as Alzheimer's disease, epilepsy and brain trauma. Recent reports suggest that, in physiological conditions, the activity of CaN in astrocytes is transcription-independent and is required for maintenance of basal protein synthesis rate and activation of astrocytic Na+/K+ pump thereby contributing to neuronal functions such as neuronal excitability and memory formation. In this contribution we overview the role of Ca2+ and CaN signalling in astroglial pathophysiology focusing on the emerging physiological role of CaN in astrocytes. We propose a model for the context-dependent switch of CaN activity from the post-transcriptional regulation of cell proteostasis in healthy astrocytes to the CaN-dependent transcriptional activation in neuroinflammation-associated diseases
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
Rescue of protein dyshomeostasis in hippocampal astrocytes from an Alzheimer’s disease mouse model by stabilizing ER-mitochondrial interactions at a 20 nm distance
Full text linkBackground: Alzheimer’s disease (AD) is the major age-related form of dementia in which dysfunctional ubiquitin-proteasome system (UPS) and autophagy represent primary mechanisms leading to accumulation of misfolded proteins, dysfunction of astroglial cells, neuroinflammation and neurodegeneration. Alterations of the endoplasmic reticulum (ER)-mitochondria contact sites (MERCS), specifically the shortening of the distance between the organelles, was proposed as a key mechanism of cell dysfunction in AD. However, its link to the impairment of the proteolytic system in AD remains unexplored. Methods: We used, as a model, hippocampal astrocytes from 3xTg-AD mice expressing either control plasmid or synthetic linkers stabilizing ER-mitochondrial interaction at 10 nm (10 nm-EML) or at 20 nm (20 nm-EML). Alternatively, astrocytes were treated with mitochondrial Ca2+ uptake inhibitor benzethonium chloride or activator amorolfine. We used Western blot to assess protein expression and specific enzymatic activity tests for the analysis of proteasomal, autophagic and lysosomal activities. Single cell fluorescent Ca2+ imaging, using 4mtD3cpv probe targeted to the mitochondrial matrix, was used to assess mitochondrial Ca2+ uptake. Results: Stabilization of MERCS at 20 nm (20 nm-MERCS), which promotes mitochondrial Ca2+ uptake, rescued protein ubiquitination, UPS composition and activity. Immunoproteasome components β2i and β5i, upregulated in AD astrocytes, and INFγ, a master-regulator of UPS remodelling in inflammatory conditions, were also rescued. Autophagic markers beclin 1, LC3II and p62, and lysosome-related marker cathepsin B, all upregulated in AD astrocytes, were significantly reduced, while autophagic flux was rescued, by stabilizing 20 nm-MERCS. Furthermore, stabilization of 20 nm-MERCS fully rescued previously reported deficit of mitochondrial Ca2+ uptake. Strikingly, application of a mitochondrial Ca2+ uptake positive modulator, amorolfine, partially rescued pathological remodelling of UPS and autophagy, suggesting that both mitochondrial Ca2+-related and Ca2+-unrelated mechanisms play a role in the beneficial effect of 20 nm-MERCS stabilization on protein dyshomeostasis. Conclusions: Our results suggest that disruption of ER-mitochondrial interaction is a key factor for AD-related dysregulation of protein degradation and provide a proof that stabilization of MERCS at a defined distance and/or pharmacological rescue of mitochondrial Ca2+ uptake represent valuable strategies for the development of future anti-AD therapy
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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