1,720,961 research outputs found
Deciphering the Role of METTL3-Dependent m6A-epitranscriptome in Glioma Stem-like Cells
No full textThe major roadblocks in treatment for GBM are resistance to therapy and recurrence
of GBM cells. Regardless of various treatment strategies, the average survival of GBM
patients is poor and incidence of recurrence remains high. The presence of GSCs, a dynamic
cellular system within GBM contributes to chemo/radio resistance and recurrence. The
plasticity of GSCs is supported by reversible biological processes including DNA
methylation, histone modifications and RNA modifications. m6A is a reversible mRNA
methylation which regulates various steps of RNA processing. In this thesis, we attempted to
elucidate the METTL3- mediated m6A as a molecular mechanism behind the dynamic nature
of GSCs. It comprises of two parts:
Part 1- The landscape of METTL3-dependent m6A-epitranscriptome in GSCs and the
functional orchestration of m6A targets
Part 2- Essential role of METTL3 mediated m6A modification in glioma stem-like cells
maintenance and radioresistance
In first part, we demonstrate levels of m6A modified RNAs and METTL3 are
maintained high in GSCs and they are attenuated during serum induced differentiation. Other
members involved in m6A modification are either down regulated or unregulated in GSCs
which confirms the dependency of GSCs in METTL3 for creating m6A marks. In addition,
previous reports provide support that solely METTL3 carry catalytic domain for SAMbinding.
Based on these facts, we elucidate the METTL3-dependent global m6A modification
in GSCs and the impact of METTL3 targets in coordinating various functions. By
comprehensive analysis of m6A-RIP seq and whole transcriptome post METTL3 silencing in
GSCs, we identified the direct and indirect targets for METTL3-mediated m6A modification.
The genes which preserve stem cell properties and aid in tumorigenesis were predominantly
inhibited by METTL3 silencing in GSCs suggesting a universal oncogenic role of METTL3
in GBM. Large subset of genes was down regulated after METTL3 silencing suggesting a
global destabilization of transcripts. The enrichment of m6A peaks near stop codon and
3’UTR indicates functional importance of METTL3 in RNA stabilization and translation
termination. In addition to protein coding genes, METTL3 fine-tunes the expression of non coding RNAs which includes lncRNAs, anti-sense RNAs etc. Interestingly, we identified m6A peaks which encompass miRNA target sites and we hypothesize that m6A modification
may scrutinize the binding affinity of miRNAs. We further determined the inter-play between chromatin remodeling with m6A epitranscriptome. Genes which carry active chromatin marks and transcription factor binding are further stabilized by METLT3-
dependent m6A modification. The altered secondary/tertiary structure induced by m6A may act as loading site for various RBPs and achieve various RNA processing functions. Our analysis deduced RBPs HuR and QKI preferentially bind to m6A marked RNAs and helps in enhancing the expression of m6A modified targets. Together, this study provides a panoramic
view on global m6A modification mediated by METTL3 in GSCs.
In second part, we examined the crucial role of METTL3 in glioma stem cell
physiology. Inhibition of METTL3 hinder the neurosphere formation and stem cell properties
of GSCs. Anti-METTL3 RIP studies combined with m6A RIP-seq results identified SOX2 as
a key m6A mediator of METTL3 and the m6A marks created by METTL3 sustains SOX2
transcript stability. The exogenous over expression of 3’UTR-less SOX2 significantly
alleviated the inhibition of neurosphere formation observed in METTL3 silenced GSCs.
METTL3 interaction and m6A modification in vivo required intact three METTL3/m6A sites
present in the SOX2- 3’UTR. Further, we found that HuR recruitment to m6A modified RNA
is essential for SOX2 mRNA stabilization by METTL3 and at global level HuR-RNA
interaction prefers the m6A modified transcripts. METTL3 silenced GSCs showed enhanced
sensitivity to γ-irradiation due to reduced DNA repair. Exogenous overexpression of 3’UTRless
SOX2 in METTL3 silenced GSCs rescues efficiency of DNA repair and specifically
homologous recombination repair. It also resulted in the significant rescue of neurosphere
formation from METTL3 silencing induced radiosensitivity. GBM tumors have elevated
METTL3 transcripts and silencing METTL3 in GSCs inhibited tumor growth and prolonged
mice survival. METTL3 transcript levels predicted poor survival in GBMs which are
enriched for GSC-specific signature. Thus our study reports the importance of m6A
modification in GSCs and uncovers METTL3 as a potential molecular target in GBM
therap
mRNA Traffic Control Reviewed: N6-Methyladenosine (m(6)A) Takes the Driver's Seat
No full textMessenger RNA is a flexible tool box that plays a key role in the dynamic regulation of gene expression. RNA modifications variegate the message conveyed by the mRNA. Similar to DNA and histone modifications, mRNA modifications are reversible and play a key role in the regulation of molecular events. Our understanding about the landscape of RNA modifications is still rudimentary in contrast to DNA and histone modifications. The major obstacle has been the lack of sensitive detection methods since they are non-editing events. However, with the advent of next-generation sequencing techniques, RNA modifications are being identified precisely at single nucleotide resolution. In recent years, methylation at the N6 position of adenine (m(6)A) has gained the attention of RNA biologists. The m(6)A modification has a set of writers (methylases), erasers (demethylases), and readers. Here, we provide a summary of interesting facts, conflicting findings, and recent advances in the technical and functional aspects of the m(6)A epitranscriptome
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
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
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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