1,721,029 research outputs found
Role of diffuse low-level heteroplasmy of mitochondrial DNA in Alzheimer’s disease neurodegeneration
No full textAlzheimer’s disease (AD) is the most common form of dementia in the elderly. The vast majority of cases are not linked to a known genetic defect and the molecular mechanisms underlying AD pathogenesis are still elusive. Evidence suggests that mitochondrial dysfunction is a prominent feature of the disease, and that mitochondrial DNA (mtDNA) alterations may represent a possible starting point of the pathophysiological cascade. Although specific mtDNA alterations have been reported in AD patients both in brain and peripheral tissues, such as D-loop mutations, 4977-bp deletion and poly-C tract D310 cytosine insertion, a generalized subtle allelic shift has also been demonstrated. This shift is significant for a few nucleotide positions (nps), but it is also detectable for most nps, although at a lower level. As single allelic substitutions can unlikely be determinant, it is proposed that the combination of all of them could lead to a less efficient oxidative phosphorylation, thus influencing AD development and course
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
A RAD51/BRCA2 small molecule inhibitor enhances the antineoplastic effect of the PARPi talazoparib in pancreatic cancer
No full textIntroduction: PARP inhibitors (PARPi) are drugs showing efficacy in HR-defective cancers. The RAD51/BRCA2 interaction is a key step in HR, which is the main DNA double strand break (DSB) repair pathway. As this mechanism is activated following single strand break (SSB) repair inhibition by PARPi, the simultaneous impairment of HR and PARP should lead to increased antineoplastic power of PARPi. We characterized the mechanism of action of ARN24922 (1), which is a new promising RAD51/BRCA2 inhibitor, developed in house. Furthermore, we evaluated its potential to increase the effect of talazoparib (TLZ, a potent PARPi) on 2D and 3D models of pancreatic cancer (PAC).
Materials and methods: We evaluated the potential of 1 in inhibiting HR activity through the mClover HR assay, which is based on the insertion of a mClover-containing sequence into a Cas9-generated DSB in the LaminA gene; the subsequent DSB repair leads to cell fluorescence. To confirm HR inhibition, we examined RAD51 nuclear foci after the induction of DNA damage by cisplatin (CPL) and RAD51/BRCA2 inhibition by 1. Finally, we studied the antineoplastic effect of the 1-TLZ combination in different PAC cell lines (BxPC-3, HPAC, AsPC-1) and in 3D models of PAC (PT291 and PDM41 organoids), with each of the models being characterized by functional BRCA genes and HR.
Results and discussion: Preliminarily, by applying the mClover HR assay, we found that 1 produced an 80% HR inhibition. Moreover, 30 μM 1 caused a significant reduction of RAD51 nuclear foci in CPL exposed cells. This finding is in agreement with the results obtained in the HR assay, supporting the expected mechanism of action of 1. In 2D PAC cultures, we found that 50 μM 1 significantly increased the anti-proliferative effect of 2 μM TLZ. The cell death mechanism involved in this effect was studied in BxPC-3 cells and was characterized as apoptosis. When 1 was co-administered with TLZ, in 3D PAC models, a significant increase in the antineoplastic activity of TLZ was also observed. In addition, in PT291 organoid, 1 was found to increase the DNA damage signatures caused by TLZ, as shown by immunofluorescence detection of γ-H2AX in cell nuclei.
Conclusions: The obtained data support the idea that the inhibition of RAD51/BRCA2 interaction can extend the use TLZ to HR proficient tumor forms, highlighting a promising anticancer strategy for PAC
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
Contribution of non-reference alleles in mtDNA of Alzheimer’s disease patients.
No full textMany observations suggest that mutations of mitochondrial DNA (mtDNA) could be responsible for the neurodegenerative changes of Alzheimer's disease (AD). Here we examined the signal intensity of the four alleles of each mtDNA nucleotide position (np) in whole blood of AD patients and age-matched controls using MitoChip v2.0 array. Our analysis identified 270 significantly different nps which, with one exception, showed an increased contribution of non-reference alleles in AD patients. Principal component analysis (PCA) and cluster analysis showed that five of these nps could discriminate AD from control subjects with 80% of cases correctly classified. Our data support the hypothesis of mtDNA alterations as an important factor in the etiology of AD
- …
