1,721,009 research outputs found
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
Investigating the role of dynamic histone modification in the mechanism of action of lysine deacetylase inhibitor (KDACi)
Full text linkMethylation and acetylation of histones are tightly connected to the control of gene expression. Changes in patterns of methylation and acetylation of histones are associated with changes in gene expression during growth and development. It has become widely accepted that misregulation of histone modifications, including histone methylation and acetylation, can play a critical role in cancer cells. Consequently, inhibitors targeting histone-modifying enzymes, such as lysine deacetylase inhibitors (KDACis), have shown therapeutic potential against a number of different types of cancer. Multiple hydroxamate-based KDACis have been approved for clinical use. However, the exact mechanism of action of these compounds remains uncertain as do the mechanisms of resistance that are either intrinsic or acquired on KDACi treatment.
Hydroxamate-based KDACis such as Trichostatin A (TSA) induces rapid initial acetylation of histone 3 (H3) proteins which are already modified by tri-methylation on lysine 4 (H3K4me3) while acetylation of bulk histones happens later. In this thesis, I reveal the role of dynamic acetylation in the mechanism of action of hydroxamates using the eukaryotic social amoeba Dictyostelium discoideum as a model. Loss of H3K4me3 in strains with mutations in the gene encoding the methylating enzyme or the histone molecules themselves confers resistance to KDACi-induced inhibition of development and slows the accumulation of histone acetylation. Furthermore, the dynamic rapid acetylation of H3K4me3 requires the Dictyostelium orthologue of Sgf29 which recognizes the H3K4me3 mark via its tandem Tudor domain. Disruption of the gene encoding Sgf29 abolished rapid dynamic acetylation of H3K4me3 and led to developmental resistance to TSA.
However, loss of rapid acetylation of H3K4me3 did not provide resistance to growth inhibition caused by TSA. Aiming to identify genes involved in the process, a genome-wide screen was performed using a newly established technology REMI-seq (REMI-seq.org). This allows parallel phenotyping of thousands of insertional mutants in a population to identify strains with growth advantage under TSA treatment. The screen identified genes encoding proteins such as ABC transporters, transcription factors and protein kinases and a number were demonstrated to be resistant to TSA during growth as single clones but not resistant during development. The results of this thesis provide a previously unidentified role of dynamic acetylation of H3K4me3 in the mode of action of hydroxamates and prove that REMI-seq is a powerful tool in Dictyostelium to identify resistance-related genes when studying drug mechanisms
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
Characterisation of a novel mouse model of mitochondrial disease – a hypomorphic Wars2 ENU-induced allele
Full text linkMitochondrial aminoacyl-tRNA synthetases (mtRS) are vital for mitochondrial translation. mtRSs catalyse the aminoacylation of mitochondrial tRNA with their cognate amino acid. Mutations in mtRS genes are associated with distinct clinical pathologies in humans. Studying mtRS mutations in model organisms is difficult because mtRS knock-out alleles are haplosufficient and cause embryonic lethality in their homozygous state. In this study, we phenotypically and mechanistically characterised a hypomorphic, ENU-induced Wars2 allele (Wars2-V117L) in mouse with the aim to determine the cause of the tissue-specific penetrance of mtRS mutant alleles. The Wars2-V117L allele caused tissue-specific pathology in mice. Wars2V117L/V117L mice developed hypertrophic cardiomyopathy, sensorineural hearing loss, reduced adiposity, increased glucose tolerance and systemic changes in metabolism. Furthermore, we showed that the Wars2V117L/V117L allele causes abnormal adipose tissue pathology as shown by 'browning' of WAT depots and lipid accumulation in BAT in Wars2V117L/V117Lmice. The Wars2V117L/V117L allele disrupts Wars2 mRNA splicing, resulting in reduced full-length Wars2 (Wars2-FL) mRNA in Wars2V117L/V117L tissues and cells. Reduced Wars2-FL mRNA caused tissue-specific reductions in mt-TrpRS protein and mitochondrial OXPHOS deficiencies in Wars2V117L/V117L mice in vivo. OXPHOS deficiencies lead to activation of the Integrated Stress Response (ISR) in Wars2V117L/V117L heart and liver. Activation of the ISR in Wars2V117L/V117L heart caused up-regulation of Fgf21 mRNA and increased plasma FGF21, leading to systemic changes in metabolism. Finally, we showed that up-regulation of Pgc1a and mitochondrial biogenesis prevented inhibition of mitochondrial translation in Wars2V117L/V117L skeletal muscle and mouse embryonic fibroblasts. Overall, we have characterised the first mouse model of mitochondrial disease caused by a global, hypomorphic, mutation in an mtRS gene. We showed that the tissue-specific pathology observed in Wars2V117L/V117L mice was due to activation of tissue-specific stress response mechanisms that either lead to disease pathology, such as activation of the ISR in the heart, or protection against inhibition of mitochondrial translation, such as up-regulation of Pgc1a in iWAT and MEFs. This study provides some evidence that up-regulation of mitochondrial biogenesis could be utilised as a therapeutic strategy to treat human patients with mtRS mutations in the future
The localization and functional analysis
Full text linkNicotinic acid adenine dinucleotide phosphate (NAADP) is the most recently characterized Ca2+ mobilizing second messenger, joining inositol 1,4,5-trisphosphate (IP3) and cyclic ADP-ribose (cADPR). Previous pharmacological and biochemical studies have suggested that NAADP targets acidic Ca2+ stores rather than the ER, which releases Ca2+ in response to IP3 or cADPR. Although NAADP receptors are proposed to be distinct from those for IP3 and cADPR, the molecular identity of NAADP receptors has remained elusive. This study focuses on establishing whether two-pore channels (TPCs), a family of intracellular Ca2+-release channels, function as NAADP receptors. In this thesis, TPC proteins have been investigated as potential NAADP receptors in the sea urchin, Strongylocentrotus purpuratus, whose genome encodes three potential TPC proteins, namely SpTPC1, SpTPC2 and SpTPC3, and in the social amoeba, Dictyostelium discoideum, which encodes only one TPC2 (DdTPC2). These channels were analyzed in multiple model systems namely the sea urchin egg, human cell lines (HEK cells and HeLa cells), an insect cell line (sf9) and Dictyostelium. Analytical approaches including the generation of anti-TPC antibodies, localization studies, ligand binding assays and Ca2+ release studies were employed. SpTPC1 and SpTPC2 were predominantly localized to the ER and the lysosome, respectively. Endogenous sea urchin protein immunoprecipitated with anti-SpTPC3 antibody showed enhanced NAADP binding. However, no correlation between NAADP binding and expression levels of TPCs in HEK cells or Sf9 cells was detectable. In Dictyostelium, TPC2 was localized to the contractile vacuole and the ER, whereas DdTPC2 localized to the lysosome and Golgi apparatus when expressed in HeLa cells. Protein expression of DdTPC2 is regulated developmentally, reaching a peak in the late stages of development. A tpc2 null strain exhibited abnormal post-aggregative development, consistent with a role for DdTPC2 at later stages of development. No high affinity NAADP binding sites or NAADP-induced Ca2+ release were detected in Dictyostelium membranes isolated either at the early or late development stages in these studies. However, NAADP-induced Ca2+ release from vesicle fractions prepared from vegetatively growing cells was observed. On the other hand, arachidonic acid (AA) induced Ca2+ release from vesicles prepared from growing cells and from cells developed for 4 hours or 20 hours. AA-induced Ca2+ release was altered in tpc2 null cells. In sea urchin egg homogenate, AA also elicited Ca2+ release with an EC50 value of approximately 8 μM. Low concentrations of AA effectively inhibited NAADP-induced Ca2+ release. It was not possible to produce evidence of TPCs being NAADP-sensitive Ca2+ channels in the systems investigated. In Dictyostelium, TPC2 does not appear to be responsible for NAADP-induce Ca2+ release. However, TPC2 may play a role in AA-induced Ca2+ release
Role of histones in DNA double-strand break repair in Dictyostelium
Full text linkCorrect repair of DNA double-strand breaks is crucial for maintenance of genome integrity. Despite data showing the importance of histones variants and histone post-translational modifications in the cellular response to DNA damage, there is still a lack of knowledge concerning the role of histone H3 and its variants as well as histone ADP-ribosylation in such processes. In this work Dictyostelium discoideum was employed as genetically tractable model organism to address the role of histone H3 variants and histone ADP-ribosylation in DNA double-strand break (DSB) repair. Vegetative cells lacking two out of three histone H3 variants – H3b and H3c, were shown not to be sensitive to DNA DSB. No evidence for altered DSB repair was found as phosphorylation of histone H2AX (a marker of DSB) and one of the pathways of DSB repair, non-homologous end joining, were not altered. Altogether, this work demonstrates that H3b and c variants are not required for overall DNA DSB repair in Dictyostelium. Among the core histones histone H2B was discovered to be the major acceptor of ADP-ribosylation by major ADP-ribosyl transferase involved in DSB repair, Adprt1a, in vitro. ADP-ribosylation in vitro was shown to occur on glutamate E18 with E19 being a potential regulator of this modification. Using an epitope-tagged overexpressed H2B, in vivo H2B ADP-ribosylation in response to DSBs was observed in Dictyostelium for the first time. Decreased ADP-ribosylation of epitope-tagged H2B mutated in both E18 and E19 residues was demonstrated. Overall, this work demonstrates the presence of the ADP-ribosylation of H2B in Dictyostelium in response to DSBs and identifies the major site of this modification
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