1,720,969 research outputs found
Transcriptional activity of mouse major satellite repeat sequences
No full textMajor satellite repeats (MSR) are noncoding repetitive DNA sequences in the mouse genome and a major component of constitutive heterochromatin. Although found within heterochromatin, MSR sequences are transcriptionally competent under stress conditions, during the cell cycle, and early embryonic development. MSR transcripts have been shown to aid in the formation of pericentric heterochromatin. Dysregulation of MSR transcription disrupts genome stability and induces apoptosis and cell death. These data suggest that regulated MSR transcription protects genome stability. However, how MSR transcription is regulated has remained elusive. To address this, first, we tested the response of MSR sequences to topoisomerase inhibitors; second, we probed for intrinsic promoter activity among MSR consensus sequences, MSR variants, and satellite DNA (satDNA) using a luciferase reporter-based assay; third, we tested RNA quality control factors if they are involved in MSR RNA processing. We observed that MSR derepressed upon topoisomerase inhibition. This indicates that topological changes could facilitate MSR transcription. When we probed for intrinsic promoter activity among MSR consensus, we observed modest promoter activity with MSR variants (GE1041MSR308r and GE283MSRr) and no significant promoter activity with the MSR consensus or satDNA sequences. We identified INTS11 as a novel regulator that attenuates the MSR transcript level. Taken together, MSR sequences possess only modest intrinsic promoter activity, nonetheless, alterations in chromatin topology derepress MSR and endoribonuclease INTS11 are involved in the attenuation of MSR transcripts
The role of PBRM1 in clear cell renal cell carcinoma
No full textClear cell renal cell carcinoma (ccRCC) is the 14th most common cancer type worldwide, accounting for 2 % of cancer-related deaths. Despite the recent advances in therapy with the combination of checkpoint inhibitors with tyrosine kinase inhibitors, the prognosis for patients with advanced ccRCC remains poor in many cases. Besides almost universal loss of VHL, PBRM1 is mutated in approximately 40 % of ccRCC tumours. However, the contribution of loss of PBRM1 to tumour formation and metastatic spread is poorly understood. Moreover, there is no tailored therapy for PBRM1-mutant ccRCC.Thus, to identify compounds preferentially targeting PBRM1-mutant cancer cells, a compound screening using Sellekchem Bioactive Compound library of approximately 2,700 compounds was performed on human ccRCC cell lines. This did not identify compounds preferentially targeting PBRM1-mutant cells over their isogenic PBRM1-competent counterparts.Using an established autochthonous mouse model of ccRCC, it was shown that additional deletion of Pbrm1 accelerates tumour formation in male, but not in female mice, suggesting a potentially sex-specific role in tumour formation. Single-cell RNA-sequencing of tumour-infiltrating immune cells indicated altered frequencies of immune cell types attributable to deletion of Pbrm1. Moreover, there were indications of altered immune cell behaviour and reduced tumour cell killing capacities, which will be further followed up on.In a xenograft model of metastatic ccRCC, knock out of PBRM1 moderately increased metastatic spread. Metastatic subclones were isolated from mouse lungs and characterised in vitro. RNA-sequencing of parental cell lines and metastatic subclones suggested a context-dependent role of PBRM1, rather than a distinct set of target genes, in line with the cell line-specific effects and discrepancies between in vivo and in vitro data published. Moreover, it identified a transcriptional signature of genes controlled by PBRM1 and upregulated in metastatic, PBRM1-mutant subclones. Taken together, these findings rather argue for metastasis by other means than for general increase of metastasis upon loss of PBRM1.In the metastatic subclones of 786-O, there were striking discrepancies between the relative mRNA and protein levels of the gene signature identified. General alterations in the transcription or translation machinery and differences in mRNA stability attributable to loss of PBRM1 could be ruled out. To identify the mechanism underlying the discrepancies between mRNA and protein levels and to define whether this mechanism contributes to increased metastatic spread and/or might represent an approach to target metastatic PBRM1-mutant ccRCC, further investigations will be required
greenPipes: an integrated data analysis pipeline for greenCUT&RUN and CUT&RUN genome-localization datasets
No full textMotivationTo study gene regulation through transcription factors and chromatin modifiers, a variety of genome-wide techniques are used. Recently, CUT&RUN-based technologies have become popular, but a pipeline for the comprehensive analysis of CUT&RUN datasets is currently lacking. Here, we present the “greenPipes” package, which includes fine-tuned parameters specifically for bioinformatic analyses of greenCUT&RUN and CUT&RUN datasets. greenPipes provides additional functionalities for data analysis and data integration with other -omics technologies, which are either not available in other pipelines developed for CUT&RUN datasets or scattered in the literature as individual packages
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
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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