1,720,963 research outputs found
The Q336H MAPT mutation linked to Pick's disease leads to increased binding of tau to the microtubule network via altered conformational and phosphorylation effects
Get PDFTauopathies are neurodegenerative disorders characterized by Tau aggregation. Genetic studies on familial cases allowed for the discovery of mutations in the MAPT gene that increase Tau propensity to detach from microtubules and to form insoluble cytoplasmic Tau aggregates. Recently, the rare mutation Q336H has been identified to be associated with Pick's disease (PiD) and biochemical analyses demonstrated its ability to increase the microtubules (MTs) polymerization, thus revealing an opposite character compared to other Tau mutations studied so far. Here we investigated the biophysical and molecular properties of Tau(Q336H) in living cells by the employment of the conformational Tau biosensor CST. We found that this mutation alters Tau conformation on microtubules, stabilizes its binding to tubulin, and is associated with a paradoxical lower level of Tau phosphorylation. Moreover, we found that this mutation impacts the cytoskeletal complexity by increasing the tubulin filament length and the number of branches. However, despite these apparently non-pathological traits, we observed the formation of intracellular inclusions confirming that Q336H leads to aggregation. Our results suggest that the Tau aggregation process might be triggered by molecular mechanisms other than Tau destabilization or post-translational modifications which are likely to be detrimental to neuronal function in vivo
LEDGF/p75 controls 3D-localization of HIV-1 provirus in the nuclear compartment of infected cells
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A new intramolecular biosensor reveals Tau conformational changes in pathological conditions
No full textThe onset of Tau misfolding during early pathogenesis remains unidentified due to both the intrinsic disordered structure of the protein and the lack of suitable molecular tools.
In order to overcome this limitation we are developing a set of engineered biosensors based on FRET.
The wild type Tau biosensor, by virtue of its peculiar features, modulates its biophysical state in response to structural modifications occurring at early stages of neurodegeneration and it allows to monitor the conformational changes of Tau by FRET and the processing and mobility of cleaved fragments by FRAP.
We monitored the conformation dynamics of tau-microtubules interplay and demonstrated that tau assumes a loop-conformation only when it is bound to microtubules.
The disruption of tau-microtubules interaction and consequently the loss of tau loop-conformation detects one of the first events of tau misfolding occurring in neurodegeneration.
Remarkably, by time lapse experiments we observed the rapid formation of tau aggregates similar to pathological aggregates in Alzheimer and tauopathies.
Tau biosensors with mutations on residues involved in tau pathology have been subjected to this analysis in order to determine the contribution of each mutation.
Recently several studies demonstrated that misfolded Tau species are able to propagate into the brain inducing the sprouting of the disease.
In order to develop a sensitive tool to study the ability of infectious Tau species to propagate and to induce the misfolding into normal cells we set up a seeding activity assay by engineering a reporter cell line expressing the Tau biosensor.
We demonstrated that the biosensor is a powerful readout in detecting the uptake of misfolded infectious tau species and their effect on endogenous Tau.
In conclusion the tau biosensor is a suitable and sensitive tool to detect by imaging Tau conformational changes occurring during neurodegeneration, Tau aggregation and processing at early stages of pathology
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Get PDFWe 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
Tau Modulates VGluT1 Expression
Get PDFTau displacement from microtubules is the first step in the onset of tauopathies and is followed by toxic protein aggregation. However, other non-canonical functions of Tau might have a role in these pathologies. Here, we demonstrate that a small amount of Tau localizes in the nuclear compartment and accumulates in both the soluble and chromatin-bound fractions. We show that favoring Tau nuclear translocation and accumulation, by Tau overexpression or detachment from MTs, increases the expression of VGluT1, a disease-relevant gene directly involved in glutamatergic synaptic transmission. Remarkably, the P301L mutation, related to frontotemporal dementia FTDP-17, impairs this mechanism leading to a loss of function. Altogether, our results provide the demonstration of a direct physiological role of Tau on gene expression. Alterations of this mechanism may be at the basis of the onset of neurodegeneration
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe 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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