1,720,957 research outputs found
Role of cellular prion protein in central nervous system myelination
Full text linkThe cellular form of the prion protein (PrPC) has been widely investigated since its alternative folded isoform is the causative agent of prion disorders. PrPC is highly expressed in the nervous system, where it is involved in many physiological processes such as the maintenance of peripheral nervous system (PNS) myelination. A similar role in the central nervous system (CNS) is still controversial, since PrPC absence affects proliferation and maturation of oligodendrocyte precursor cells without affecting myelination. On the other hand, PrPC is involved in metal homeostasis and modulates oxidative stress, two processes influencing myelin formation and maintenance. In light of these considerations, we took advantage of wild-type (WT, Prnp+/+) and PrPC knock-out (KO, Prnp0/0) mice to investigate PrPC role in CNS myelination. Myelin composition was examined in mouse brains at different developmental stages, from early postnatal days to aging, through cholesterol content measurement and through myelin protein and gene expression evaluation. Furthermore, peripheral myelin status was also investigated in the sciatic nerve (SN) in order to have a comparative analysis between the CNS and PNS myelin. Finally, an ex vivo model based on organotypic hippocampal cultures (OHC) was established to better investigate PrPC role in CNS myelin.
Concerning the PNS, most of our results are consistent with the PNS myelin degeneration observed in literature. Accordingly, results show a 50% decrease in SN cholesterol content, a strong reduction of myelin genes transcription and an altered expression level of some myelin proteins during Prnp0/0 mouse aging. Moreover, some changes in the early postnatal period were also detected. Focusing on the CNS, a small reduction in cholesterol content was observed at postnatal day 1 and in aging brains of Prnp0/0 mice, suggesting an alteration in CNS myelin status. Differently from PNS, CNS myelin proteins are slightly upregulated in Prnp0/0 brains during the whole life. In particular, in Prnp0/0 brains a higher amount of myelin proteolipid protein, myelin basic protein, myelin oligodendrocyte glycoprotein and the glycosylated form of myelin associated glycoprotein was detected. This myelin protein upregulation correlates with a higher gene expression in Prnp0/0 mouse brains. To better investigate PrPC role in CNS myelination, an ex vivo model based on OHC was established. In accordance with in vivo experiments, after 28 days in vitro the amount of myelin proteins and myelin gene expression is higher in Prnp0/0 than in Prnp+/+ OHC. Furthermore, the copper chelator cuprizone (CZ) was administered to OHC to investigate its effect in PrPC presence or absence. CZ treatment did not trigger the expected myelin degeneration. Differently it induced an increase in myelin protein percentage particularly in Prnp+/+ OHC, while the effect on Prnp0/0 OHC was milder. Thus, different response of Prnp+/+ and Prnp0/0 OHC to CZ exposure denotes a distinct CNS susceptibility to this kind of stimulus in the presence or absence of PrPC.
Altogether, these results support the hypothesis that PrPC is involved in CNS myelination, although in a different manner compared to the PNS. In fact, the differences observed in CNS lipid composition, protein expression and gene transcription are less pronounced compared to PNS, but are extended for the whole lifetime. Since electron microscopy on CNS myelinated regions did not show gross morphological changes between Prnp+/+ and Prnp0/0 mice, it is possible that myelin protein overexpression could be the result of a compensatory mechanism to prevent functional abnormalities. Furthermore, since PrPC plays neuroprotective roles, it is possible that it could protect myelin under stress conditions
In Absence of the Cellular Prion Protein, Alterations in Copper Metabolism and Copper-Dependent Oxidase Activity Affect Iron Distribution
Full text linkEssential elements as copper and iron modulate a wide range of physiological functions. Their metabolism is strictly regulated by cellular pathways, since dysregulation of metal homeostasis is responsible for many detrimental effects. Neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and prion diseases are characterized by alterations of metal ions. These neurodegenerative maladies involve proteins that bind metals and mediate their metabolism through not well-defined mechanisms. Prion protein, for instance, interacts with divalent cations via multiple metal-binding sites and it modulates several metal-dependent physiological functions, such as S-nitrosylation of NMDA receptors. In this work we focused on the effect of prion protein absence on copper and iron metabolism during development and adulthood. In particular, we investigated copper and iron functional values in serum and several organs such as liver, spleen, total brain and isolated hippocampus. Our results show that iron content is diminished in prion protein-null mouse serum, while it accumulates in liver and spleen. Our data suggest that these alterations can be due to impairments in copper-dependent cerulopalsmin activity which is known to affect iron mobilization. In prion protein-null mouse total brain and hippocampus, metal ion content shows a fluctuating trend, suggesting the presence of homeostatic compensatory mechanisms. However, copper and iron functional values are likely altered also in these two organs, as indicated by the modulation of metal-binding protein expression levels. Altogether, these results reveal that the absence of the cellular prion protein impairs copper metabolism and copper-dependent oxidase activity, with ensuing alteration of iron mobilization from cellular storage compartments
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
Prion protein and copper cooperatively protect neurons by modulating NMDA receptor through S-nitrosylation
Full text linkAIMS:
Several neurodegenerative disorders show alterations in glutamatergic synapses and increased susceptibility to excitotoxicity. Mounting evidence suggests a central role for the cellular prion protein (PrP(C)) in neuroprotection. Therefore, the loss of PrP(C) function occurring in prion disorders may contribute to the disease progression and neurodegeneration. Indeed, PrP(C) modulates N-methyl-d-aspartate receptors (NMDAR), thus preventing cell death. In this study, we show that PrP(C) and copper cooperatively inhibit NMDAR through S-nitrosylation, a post-translational modification resulting from the chemical reaction of nitric oxide (NO) with cysteines.
RESULTS:
Comparing wild-type Prnp (Prnp(+/+)) and PrP(C) knockout (Prnp(0/0)) mouse hippocampi, we found that GluN1 and GluN2A S-nitrosylation decrease in Prnp(0/0). Using organotypic hippocampal cultures, we found that copper chelation decreases NMDAR S-nitrosylation in Prnp(+/+) but not in Prnp(0/0). This suggests that PrP(C) requires copper to support the chemical reaction between NO and thiols. We explored PrP(C)-Cu neuroprotective role by evaluating neuron susceptibility to excitotoxicity in Prnp(+/+) and Prnp(0/0) cultures. We found that (i) PrP(C)-Cu modulates GluN2A-containing NMDAR, those inhibited by S-nitrosylation; (ii) PrP(C) and copper are interdependent to protect neurons from insults; (iii) neuronal NO synthase inhibition affects susceptibility in wild-type but not in Prnp(0/0), while (iv) the addition of a NO donor enhances Prnp(0/0) neurons survival.
INNOVATION AND CONCLUSIONS:
Our results show that PrP(C) and copper support NMDAR S-nitrosylation and cooperatively exert neuroprotection. In addition to NMDAR, PrP(C) may also favor the S-nitrosylation of other proteins. Therefore, this mechanism may be investigated in the context of the different cellular processes in which PrP(C) is involved
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
Prions Strongly Reduce NMDA Receptor S-Nitrosylation Levels at Pre-symptomatic and Terminal Stages of Prion Diseases
No full textPrion diseases are fatal neurodegenerative disorders characterized by the cellular prion protein (PrPC) conversion into a misfolded and infectious isoform termed prion or PrPSc. The neuropathological mechanism underlying prion toxicity is still unclear, and the debate on prion protein gain- or loss-of-function is still open. PrPC participates to a plethora of physiological mechanisms. For instance, PrPC and copper cooperatively modulate N-methyl-D-aspartate receptor (NMDAR) activity by mediating S-nitrosylation, an inhibitory post-translational modification, hence protecting neurons from excitotoxicity. Here, NMDAR S-nitrosylation levels were biochemically investigated at pre- and post-symptomatic stages of mice intracerebrally inoculated with RML, 139A, and ME7 prion strains. Neuropathological aspects of prion disease were studied by histological analysis and proteinase K digestion. We report that hippocampal NMDAR S-nitrosylation is greatly reduced in all three prion strain infections in both pre-symptomatic and terminal stages of mouse disease. Indeed, we show that NMDAR S-nitrosylation dysregulation affecting prion-inoculated animals precedes the appearance of clinical signs of disease and visible neuropathological changes, such as PrPSc accumulation and deposition. The pre-symptomatic reduction of NMDAR S-nitrosylation in prion-infected mice may be a possible cause of neuronal death in prion pathology, and it might contribute to the pathology progression opening new therapeutic strategies against prion disorders
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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