1,720,979 research outputs found
The Role of the Prion Protein in Neurodegenerative Disorders
Full text linkThe cellular prion protein (PrPC) is a cell surface glycoprotein predominantly expressed in the central nervous system. A modification of the mainly α-helical PrPC into an isoform enriched in β-strands generates the prion, the infectious particle at the basis of fatal prion diseases. In spite of PrPC’s intimate involvement in prion propagation, its physiological function remains enigmatic. Past observations have supported the possibility that PrPC regulates Ca2+ homeostasis, a notion that has been recently reinforced by the demonstration that PrPC controls Ca2+ fluxes in domains close to the neuronal plasma membrane, and interacts physically with a ionotropic glutamate receptor, thus protecting from glutamate excitotoxicity. Recently, however, it has been proposed that PrPC serves as a high-affinity receptor for soluble amyloid-β (Aβ) oligomers implicated in Alzheimer’s disease (AD), and this interaction could thus be crucial for AD-related synaptic dysfunctions.
In light of this background, using genetically-encoded Ca2+ probes targeting different cell domains of cerebellar granule neurons expressing, or not, PrPC, this work focused on whether PrPC regulates local Ca2+ fluxes arising from the activation of storeoperated Ca2+ entry (SOCE), and/or of glutamate receptors. We found that, with respect to PrPC-expressing neurons, the absence of PrPC caused alterations of several local Ca2+ fluxes, indicating that PrPC could act as a key component of the system(s) controlling neuronal Ca2+ homeostasis. As to the molecular mechanism enabling PrPC to exert such control, the results showed the implication of Fyn tyrosine kinase and of the Ca2+-induced-Ca2+-release from the ryanodine receptor.
The study has also analyzed whether soluble Aβ oligomers could affect the PrPC-dependent regulation of Ca2+ homeostasis. Obtained results have shown that the acute treatment of neurons with Aβ oligomers abrogates the control of PrPC over Fyn and SOCE, and alters mitochondrial Ca2+ uptake after stimulation of ionotropic glutamate receptors. This data thus suggests a PrPC-dependent mechanism for Aβ-induced neuronal Ca2+ dyshomeostasis
Mutations in PMCA2 and hereditary deafness: a molecular analysis of the pump defect.
No full textThe inner ear converts sound waves into hearing signals through the mechanoelectrical transduction (MET) process. Deflection of the stereocilia bundle of hair cells causes the opening of channels that allow the entry of endolymph K(+) and Ca(2+). Ca(2+) that enters is crucial to the hearing process and is exported to the endolymph by the plasma membrane Ca(2+) pump (isoform PMCA2w/a): disturbances of the balance between Ca(2+) penetration and ejection, e.g. by pump mutations, generate deafness. Hearing loss caused by PMCA defects is frequently exacerbated by mutations in cadherin 23, a single pass stereociliar Ca(2+) binding protein that forms the tip links which permit the deflection of the stereocilia bundle and thus the opening of the MET channels. The PMCA2w/a pump ejects Ca(2+) to the endolymph even in the absence of the natural activator calmodulin. This satisfies the special Ca(2+) homeostasis requirements of the stereocilia/endolymph system. Here we have analyzed a mice and a human previously described pump mutant. The human mutant only exacerbated the deafness produced by a cadherin 23 mutation. The murine mutant overexpressed in model cells displayed an evident defect both in the basal activity of the pump and in the long range ejection of Ca(2+), the human mutant instead failed to impair the Ca(2+) ejection by the pump
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
Orai channel pharmacological manipulation reduces metabolic flexibility in cardiac fibroblasts
No full textCardiac fibroblasts (CFs) play a crucial role in regulating normal heart function and are also involved in the pathological remodeling of the heart that occurs due to hypertension, myocardial infarction, and heart failure. Metabolic changes in fibroblasts are key drivers in the progression of these diseases. Calcium (Ca2 + ) signaling and Ca2 + ion channels control many functions of fibroblasts. Orai Ca2 + channels are abundantly expressed in fibroblasts; however, their exact role is not yet fully understood. This study examined the role of Orai Ca2 + channels in maintaining Ca2 + homeostasis within organelles and in energy production in CFs. We found that chronic inhibition of Orai activity altered the expression levels of major metabolic enzymes, affecting the overall cell metabolism. Orai channels are required to refill the endoplasmic reticulum (ER) store. Acute Orai channel activity inhibition reduced Ca2 + content in the ER and mitochondria and was associated with the impaired ability to use glucose as a primary energy source. These results have significant implications for understanding the role of Orai-dependent Ca2 + entry in maintaining organellar Ca2 + homeostasis and cellular metabolic flexibility, sparking further research in this area
The role of the prion protein in neurodegenerative disorders
No full textThe cellular prion protein (PrPC) is a cell surface glycoprotein mainly expressed in the central nervous system. A β sheet-reach conformer of PrPC generates the prion, the infectious particle causing prion diseases. The physiological role of PrPC remains enigmatic although it has been suggested that it could serve in cell survival, signal transduction, copper metabolism (Linden et al., 2008) and Ca2+ homeostasis (Lazzari et al., 2011). Recently it has been demonstrated that PrPC is a high-affinity receptor for amyloid-β (Aβ) fragments of the amyloid precursor protein implicated in Alzheimer’s disease (AD), and that PrPC-Aβ interactions could be crucial for AD-related impairment of synaptic plasticity (Lauren et al., 2009). In the present study, utilizing the Ca2+ probe aequorin targeted to different neuronal compartments we have measured Ca2+ fluxes in the plasma membrane, cytosol and the mitochondrial matrix of cerebellar granule neurons (CGN) derived from PrP-knockout (PrP-KO) mice and, as controls, from Tg46 mice in which normal PrPC levels were rescued over a PrP-KO genotype mice. We found that, compared to controls, PrP-KO neurons have significant increased Ca2+ transients in all the above domains after activating both store-operated Ca2+ channels (SOCC), glutamate and/or NMDA receptors (R) and that Aβ affects neuronal local Ca2+ fluxes in a PrPC-dependent way. Because of the involvement of p59Fyn and p42/p44 ERK (ERK 1/2) in regulating SOCC and the NMDA-R (Pozo-Guisado et al., 2010, Nakazawa et al., 2001), we then explored the possibility that PrPC modulates SOCC and the NMDA-R through p59Fyn and ERK 1/2 signaling pathways. We found that PrP-KO CGN had higher levels of active p59Fyn before activating both SOCC and NMDA-R and increased phosphorylated ERK1/2 only under the conditions that preceded NMDA-R activation. The difference of phosphorylated 59Fyn observed in untreated neurons before stimulating SOCC was abrogated by the presence of Aβ (1-42) fragments. These preliminary results indicate that p59Fyn and ERK 1/2 participate in the PrPC-dependent modulation of Ca2+ movements via SOCC and NMDA-R, and that PrPC-Aβ interactions increase SOCC-mediated Ca2+ transients by abolishing the PrPC-dependent downregulation of the p59Fyn pathway
Hair cells, plasma membrane Ca2+ ATPase and deafness
No full textHearing relies on the ability of the inner ear to convert sound waves into electrical signals. The main actors in this process are hair cells. Their stereocilia contain a number of specific proteins and a scaffold of actin molecules. They are organized in bundles by tip-link filaments composed of cadherin 23 and protocadherin 15. The bundle is deflected by sound waves leading to the opening of mechano-transduction channels and to the influx of K(+) and Ca(2+) into the stereocilia. Cadherin 23 and the plasma membrane calcium ATPase isoform 2 (PMCA2) are defective in human and murine cases of deafness. While the involvement of cadherin 23 in deafness/hearing could be expected due to its structural role in the tip-links, that of PMCA2 has been discovered only recently. This review will summarize the structural and functional characteristics of hair cells, focusing on the proteins whose mutations may lead to a deafness phenotype
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
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