1,720,992 research outputs found
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
Establishment of DNA methylation patterns during mouse development
Get PDFMethylation is the only known modification of DNA and in animals it mainly
occurs at cytosines in a CpG context. The pattern of DNA methylation varies among
organisms; some invertebrates are totally devoid of it, while others have densely
methylated regions embedded in an otherwise unmethylated genome. The genome of
mammals on the other hand, is very rich in DNA methylation with the exception of
regions with high CpG frequency, known as CpG islands, that are often found devoid
of methylation. Little is known about the factors that determine the genome-wide
pattern of DNA methylation. Moreover, although there appears to be a specific
developmental program for the establishment of methylation in specific genomic
regions, the molecular events that lead to methylation establishment remain
unknown. The establishment of methylation in the regulatory region of the murine
Oct4 gene as well as the occurrence and establishment of methylation in mouse CpG
islands are investigated in this study.
The promoter of Oct4, which encodes an important developmental regulator,
is known to gain methylation as the gene becomes silenced during early
development. An in vitro model of murine early development has been used to
recapitulate the events that lead to the gene’s silencing. In accordance to other
reports, detailed methylation analysis of the gene’s entire upstream region and
expression analysis showed that DNA methylation establishment follows the gene’s
downregulation. Moreover, establishment of methylation at the Oct4 locus seems to
start from the gene’s proximal enhancer and then spread towards the distal enhancer
and the promoter. Although the initial establishment of methylation in the distal enhancer was not impaired in G9a -/- cells, methylation in these cells was unable to
spread and accumulate. These findings demonstrate that the promoter of the gene is
not the primary target for methylation as previously assumed and give rise to two
possible mechanisms for DNA methylation establishment at this gene; one
possibility is that methylation is actively targeted to the proximal enhancer, while the
other is that the promoter and the distal enhancer are resistant to methylation,
perhaps because of transcription factors bound to them. Moreover, the finding that
G9a is not necessary for DNA methylation establishment but appears to have a role
in methylation spreading, together with observations on the kinetics of the
downregulation and the timing of methylation establishment, allowed the formation
of a possible model for the role of DNA methylation in this gene’s downregulation.
According to this model, DNA methylation acts to accelerate the gene’s
downregulation ensuring its coordinated repression in the developing organism.
For the study of methylation in CpG islands, first a novel algorithm was
applied for the identification of CpG islands in the mouse genome. Approximately
21,000 CpG islands were identified in the mouse genome, half of which localised at
the 5’ of genes, while the majority of the remaining was equally distributed in
intragenic and intergenic regions. Only a very small proportion of the CpG islands
localised at the 3’ of genes. When the gene ontology terms related with the CpG
island-associated genes where interrogated, two main gene functions emerged as
being preferentially associated with CpG islands, development and cell maintenance.
Then, an affinity purification method, together with microarray hybridisation was
applied for the identification of methylated CpG islands from mouse brain.
Approximately 18% of all CpG islands were methylated in brain, with the big
majority localised at 5’ and intragenic regions. When the gene ontology of the
methylated CpG island-associated genes was analysed, developmental but not
housekeeping genes were overrepresented in the methylated fraction. In order to
further investigate the relationship of CpG islands with developmental genes, the
same methodology was applied for the identification of CpG islands that become
methylated after the in vitro induction of differentiation of ES cells. Although this
approach failed to produce genome-wide data, it enforced the idea of a
developmental program for CpG island methylation
Global analysis of the methyl-CpG binding protein MeCP2
Get PDFMeCP2 was initially identified as an abundant protein in the brain, with an affinity for
methylated DNA in vitro. Interestingly, both deficiency and excess of the protein leads to
severe neurological problems, such as Rett syndrome, which is the result of mutations in the
MECP2 gene. Subsequent transfection experiments showed that MeCP2 can recruit corepressor
complexes and inhibit gene expression in vivo. MeCP2 was therefore thought to
repress specific gene targets and the aetiology of Rett syndrome was proposed to result from
aberrant gene expression in the MeCP2-deficient brain. Although gene expression is
perturbed in the Mecp2-null mouse brain, few specific targets have been verified and
alternative hypotheses for MeCP2 function have been put forward. Previous binding studies
have also failed to clearly identify MeCP2 targets. To shed light on these matters, a novel
technique was generated to isolate neuronal and glial nuclei and established that the amount
of MeCP2 is unexpectedly high in neurons, with an abundance approaching that of the
histone octamer. Chromatin immunoprecipitation experiments on mature mouse brain
showed widespread binding of MeCP2, consistent with its high abundance, tracking the
methyl-CpG density of the genome. MeCP2 deficiency results in global changes in neuronal
chromatin structure, including elevated histone acetylation and a doubling of histone H1.
The mutant brain also shows elevated transcription of repetitive elements, which are
distributed throughout the mouse genome. Based on this data, we propose that MeCP2 binds
genome wide and suppresses spurious transcription through binding in a DNA methylation
dependent manner
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
Role of CpG island methylation and MBD2 in immune cell gene regulation
Get PDFThe phenomenon of cell type-specific DNA methylation has received much attention
in recent years and a number of DNA methylation differences have been described
between cells of the immune system. Of particular interest when studying DNA
methylation are CpG islands (CGIs) which are distinct from the rest of the genome
due to their elevated CpG content, generally unmethylated state and promoter
association. In the instances when they become methylated this is associated with
gene repression although it is unclear the extent to which differential methylation
corresponds to differential gene expression. I have used an immune system model to
assess the role of CGI methylation and the role of the methylation reader MBD2 in
regulation of gene expression.
A relatively small number of DNA methylation differences were seen between
immune cell types with the most developmentally related cells showing the fewest
methylation differences. Interestingly, the vast majority of CGI-associated cellspecific
methylation occurred at intragenic CGIs located, not at transcription start
sites, but in the gene body. Increased intragenic CGI methylation tended to associate
with gene repression, although the precise reason for this remains unclear. Most
differentially methylated CGIs were depleted for the active chromatin mark
H3K4me3 regardless of their methylation state but some of these were associated
with the silencing mark H3K27me3 when unmethylated. These findings suggest that
intragenic CGIs are a distinct class of genomic element particularly susceptible to
cell type-specific methylation. I also looked at the effect of removing the methyl-
CpG binding domain protein MBD2 from immune system cells. Immune cells from
Mbd2-/- mice showed a number of previously uncharacterised phenotypes as well as
a number of differences in gene expression compared to wild-type animals. Most of
these genes increased their expression in the absence of MBD2 consistent with
MBD2’s role as a transcriptional repressor and Mbd2-/- Th1 cells showed increases
in histone H3 acetylation compared to wild-type Th1 cells. This work provides an
insight into the role played by cell-specific CGI methylation and MBD2 in regulating
gene expression
Quantitative modelling predicts the impact of DNA methylation on RNA polymerase II traffic
Get PDFPatterns of gene expression are primarily determined by proteins that locally enhance or repress transcription. While many transcription factors target a restricted number of genes, others appear to modulate transcription levels globally. An example is MeCP2, an abundant methylated-DNA binding protein that is mutated in the neurological disorder Rett Syndrome. Despite much research, the molecular mechanism by which MeCP2 regulates gene expression is not fully resolved. Here we integrate quantitative, multidimensionalexperimental analysis and mathematical modelling to indicate that MeCP2 is a novel type of global transcriptional regulator whose binding to DNA creates "slow sites" in gene bodies. We hypothesise that waves of slowed-down RNA polymerase II formed behind these sites travel backward and indirectly affect initiation, reminiscent of defect-induced shock waves in non-equilibrium physics transport models. This mechanism differs from conventional gene regulation mechanisms, which often involve direct modulation of transcription initiation. Our findings point to a genome-wide function of DNA methylation that may account for the reversibility of Rett syndrome in mice. Moreover, our combined theoretical and experimental approach provides a general method for understanding how global gene expression patterns are choreographed
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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