1,721,014 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
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A dose-sensitive OGT-TET3 complex is necessary for normal Xist RNA distribution and function
Full text linkFemale (XX) mouse embryonic stem cells (mESCs) differ from their male (XY) counterparts because they have lower levels of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). This difference in DNA modifications is a result of having two X chromosomes (Xs), both of which are active at this developmental stage. To test whether OGT is one of the X-linked proteins that regulate 5mC and 5hmC in mESCs, we manipulated OGT dose in XX and XY mESCs. We found that OGT abundance controls cytosine modifications, implicating OGT targets in 5mC and 5hmC regulation. Our quantitative comparison of the O-GlcNAcylated proteome in XX and XY mESCs revealed that O-GlcNAc modified TET3 peptides were more abundant in XX mESCs, which reflected an increase in TET3 amount in these cells. In addition to differing in abundance, TET3 and OGT distribution were also different in XX and XY mESCs. In XX cells, TET3 and OGT were enriched in the nucleus, while they were predominantly cytoplasmic in XY cells. TET3 and OGT occur in different high molecular weight complexes in XX and XY mESCs. When OGT is expressed from one X in XX mESCs, OGT and TET3 are predominantly cytoplasmic and 5mC/5hmC levels increase, indicating that OGT is one X-linked regulator of DNA cytosine modifications. To directly query whether TET3 is necessary for the female-specific 5mC and 5hmC in mESCs we generated homozygous TET3 mutant XX mESCs. In these cells, 5mC and 5hmC levels were decreased relative to wildtype XX mESCs, without dramatic gene expression changes. To investigate the developmental significance of TET3, examined the effects of this mutation on the ability of cells to undergo X chromosome inactivation (XCI) an epigenetic change that occurs when mESCs are differentiated into the next developmental stage, epiblast-like (mEpiL) cells. The establishment of XCI is characterized by the up-regulation of a non-coding RNA, Xist RNA, which remains in the nucleus and ‘coats’ the X concomitant with silencing. In TET3 mutant XX mEpiLCs Xist RNA exhibits abnormal distribution and silencing defects. These results link the activity of a dose-sensitive complex containing X and autosomal proteins to regulation of cytosine DNA modifications and XCI
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
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Investigating the OGT-TET interaction in vitro and in mouse embryonic stem cells
Full text linkProper spatial and temporal control of gene expression is necessary for cellular survival and proper function. Addition of a methyl group to the 5’ carbon of cytosine in DNA (5mC) is a major mechanism used to modulate gene expression. The Ten-Eleven Translocation (TET) family of enzymes iteratively oxidize 5mC to 5-hydroxymethylcytosine (5hmC), 5- formylcytosine (5fC), and 5-carboxylcytosine (5caC). These modifications function both as stable epigenetic marks and transient intermediates in the demethylation of DNA. Improper placement of these epigenetic marks often causes death or disease. Among the proteins that interact with TET enzymes is O-linked N-acetylglucosamine (O-GlcNAc) Transferase (OGT). OGT is the sole enzyme responsible for attaching a GlcNAc sugar to serine, threonine, and cysteine residues of over 1,000 nuclear, cytoplasmic, and mitochondrial proteins. OGT has been termed a “nutrient sensor” because its activity requires the sugar donor UDP-GlcNAc, whose abundance is dependent upon the levels of various cellular metabolites. Thus the reversible O-GlcNAc modification dynamically regulates the functions of OGT’s targets in response to nutrient status. OGT stably interacts with and modifies TET proteins and its genome-wide distribution overlaps significantly with TETs. However, the significance of the OGT-TET interactions are poorly understood. In this work, we explore the consequences of the OGT-TET interactions in vitro and in mouse embryonic stem cells (mESCs). We show that OGT directly binds and modifies TET1 in vitro, and the O-GlcNAc modification enhances TET1 activity. We identify a point mutation in TET1 that disrupts its interaction with OGT and use this to interrogate the effects on TET activity, gene expression, and epigenetic patterning of disrupting the OGT-TET1 interaction in mESCs. To assess the importance of the OGT-TET interaction for OGT function, we use quantitative SILAC mass spectrometry to examine proteome-wide changes in O-GlcNAcylation in mESCs when Tets are deleted. We also identify sites of O-GlcNAcylation on TET1 and TET2, further analyze the interactions between OGT and all three TETs, and examine the effect of O-GlcNAcylation on TET2 and TET3 activity in vitro. Our results link metabolism and epigenetic control, which may be relevant to the developmental and disease processes regulated by these two enzymes
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Investigation into the Role of Zn72D and Belle in the Regulation of Drosophila Dosage Compensation
Full text linkThe Male Specific Lethal (MSL) complex of proteins is enriched on the single X chromosome in male Drosophila melanogaster, resulting in a twofold enrichment of gene expression from the X chromosome in order to equalize expression with females, which have two X chromosomes. In Chapter I, we show that the zinc finger protein Zn72D is required for proper splicing of the maleless (mle) transcript, which encodes one of the proteins in the MSL complex. In addition, we found that Zn72D colocalizes with elongating RNA Polymerase, suggesting it has a broader role in regulating gene expression outside of its role in dosage compensation. In Chapter II, we identify proteins that interact with Zn72D and find it interacts with several proteins involved in RNA metabolism. Co-knockdown of Zn72D and one of the proteins that interacts with Zn72D, the DEAD box helicase Belle, resulted in partial restoration of mle splicing and 70% restoration of MLE protein levels, suggesting that Zn72D and Belle regulate translation of MLE. These results implicate Zn72D as a protein that links mRNA splicing to localization and translation
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Dissecting the mechanism of HP1 mediated chromatin compaction
Full text linkHeterochromatin protein-1 (HP1) maintains condensed, stable heterochromatin domains throughout interphase despite the weak binding and rapid exchange of HP1 within heterochromatin. I utilize two methods, DNA curtains and liquid-liquid phase separation (LLPS) assays, to decode a mechanistic understanding of HP1 behavior and directly test if dynamic HP1 binding can maintain static DNA compaction in vitro. Within droplets, we find HP1α and DNA have distinct material properties: HP1α rapidly exchanges within and between droplets while simultaneously condensing DNA into stable domains within a droplet. Further, we show HP1α compacted DNA puncta are resistant to 40pN of force, over twice that required to stall RNA polymerase. I find the disordered regions of the three human HP1 paralogs - HP1α, HP1β, and HP1γ – dictate their DNA compaction and LLPS phenotypes. The HP1α hinge is necessary and sufficient for these activities, and we determine a network of hinge autoregulation within the Nand C- terminal extensions. I demonstrate dynamic HP1α binding primes droplets for regulation as the addition of HP1β, which exhibits minimal DNA compaction and LLPS behavior, invades and dissolves preformed HP1α droplets. Finally, I utilize chromatin substrates and find HP1 maintains separate domains of unmodified and H3K9me3 chromatin. Together this data describes how a pool of weakly bound HP1 proteins exploits both the collective behavior of proteins and the polymer properties of DNA to produce self-organizing domains that are simultaneously stable and fragile
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Mutational Analysis of Xist and the X-inactivation Center
Full text linkIn placental mammals, dosage compensation of the sex chromosomes isachieved through inactivation of one X chromosome in female cells. This Xchromosome inactivation (XCI) requires tight developmental regulation to ensure all butone X chromosome is silenced.At the center of this process is Xist, a long non-coding RNA. Upon differentiationof a female cell, Xist spreads in cis to coat and silence the inactive X chromosome.While upregulation of Xist, has been shown to be sufficient for X inactivation to occur,no one has thoroughly investigated whether Xist is necessary for the establishment of Xchromosome inactivation. In this thesis I provide evidence that Xist is not required fordosage compensation of the X chromosome during epiblast-like cell differentiation. Thisresult suggests Xist-independent silencing mechanisms for this essential process maybe in place.A 1-2 Mb region of the X chromosome, termed the X-inactivation center (Xic) isnecessary in two copies for XCI to occur, indicating it is necessary for cells to count thenumber of X chromosomes present. I delete one copy of the putative 2 Mb Xic in maleand female mouse embryonic stem cells and present evidence that this deletion is notwell tolerated, suggesting that this region requires finer resolution mapping to identifythe minimal element required for counting.Finally, I finish with a review which elaborates on studies that enlighten ourunderstanding of activators and repressors that control XCI. Our findings challengeexisting dogmas in the field and provide the foundation for future work focused onuncovering the molecular mechanisms behind Xist-independent silencing of the Xchromosome
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The Inactive X Chromosome in Resilience Against Brain Aging and Cognitive Decline
Full text linkSex biology influences vulnerability to brain aging and cognitive decline. Females show advantage in lifespan and cognitive deficits in aging human populations – while males are more vulnerable. Historically, female biology has been largely understudied – specifically it is unknown how sex chromosomes influence resilience to age-related cognitive decline. In mammals, the X chromosome is enriched for neural genes and is a major source of biologic sex difference, in part, because females (XX) show increased expression of select X factors. Both sexes (XX and XY) harbor one active X due to random X chromosome inactivation (XCI) in female cells. However, some genes, such as Kdm6a, transcriptionally escape silencing from the inactive X (Xi) during development – leading to higher transcript levels in females. Escapee gene Kdm6a, encodes a lysine demethylase, best known for interaction with tri-/di-methylated histone 3 lysine 27 (H3K27me3/2). Kdm6a contains additional functional domains and is linked with synaptic plasticity and cognition. Previous studies in our lab found that the second X in females promotes neuronal resilience against Alzheimer’s disease (AD)-related toxicity partially through increased expression of Kdm6a.Here (Chapter 2), we used lentiviral-mediated overexpression of escapee Kdm6a – in a form without its demethylase function – to improve spatial learning and memory, in aging male mice, as measured using the Morris water-maze. Then (Chapter 3), we go onto further highlight the importance of the inactive X chromosome (Xi) by identifying and characterizing the transcriptional signatures of Xi during female brain aging using a mouse assay based on strain-specific detection of differing SNPs crossed with a well-established mouse line that contains an Xist deletion, leading to forced activation of the X chromosome. We found that aging preferentially changes female hippocampal gene expression on the X chromosome – which causes an increase in the transcription of several Xi genes: Plp1, Tspan7, Gpm6b, and Pck1n. Top Xi factor Plp1, encodes the myelin proteolipid protein and has increased expression in aging female hippocampal oligodendrocytes, possibly contributing to enhanced cognition. We used oligodendrocyte-specific adeno-associated virus (AAV)-mediated overexpression to increase Plp1 expression in aged XY and XX brains and tested male and female cognition using behavioral tasks. We found that increasing Plp1 – specifically in oligodendrocytes – improved hippocampal-dependent spatial working memory in both aging males and females, as measured using two-trial Y-maze. Plp1 additionally enhanced spatial learning in aging males, but not females, as tested in the Morris water-maze. These findings highlight a role of the inactive X, via baseline and age-induced transcriptional escape, in countering age-related cognitive decline. Understanding how the inactive X may confer female cognitive advantage, and specifically how it is regulated throughout the lifespan, may lead to novel therapeutic targets for age-related cognitive decline in both sexes
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