1,721,044 research outputs found
Common genetic variance at the SMAD9 colorectal cancer risk locus influences tumour mutational phenotype
Full text linkI set out to investigate whether common germline variance associated with
colorectal cancer (CRC) risk can influence the somatic mutational landscapes of CRC.
Some Mendelian cancer syndromes, such as Lynch syndrome (LS) and MUTYH associated
polyposis, associate with defined mutational landscapes and this association can be
functionally informative. In this thesis I investigated instead the influence of common
risk variants such as those identified by GWAS approaches, the functional impacts of
which are currently imperfectly understood.
I identified 8 CRC risk loci for investigation that also exhibited eQTL effects in normal
colorectal mucosa. Comparisons of tumour mutational loads at each of these showed a
significant relationship with the SMAD9 (rs493248) locus and this locus was selected for
further investigations. These revealed a relative depletion of highly mutated
microsatellite instable (MSI) tumours on the risk allele background. This was verified in
a meta-analysis of 5 independent cohorts (OR=0.73, 95%CI 0.63-0.86, p=1x10-4).
Separate case-control studies for MSI and microsatellite stable (MSS) CRC risk at the
SMAD9 risk locus indicated that the risk allele associated specifically with MSS CRC risk.
A corresponding lower risk was demonstrated for MSI CRC (LS excluded) and suggested
instead a protective association for this subtype. The latter was not significant, however
this comparison lacked statistical power.
I further explored two mechanistic hypotheses for these observations. SMAD9 forms
part of the Transforming Growth Factor Beta (TGFb) signalling pathway, with tumour
suppressive functions in early CRC. I suggested that the eQTL may selectively favour
tumours with or without further mutations of TGFb signalling dependent on SMAD9
expression. The correlation with MSS and MSI CRC would come about since these
tumours tend to regulate this pathway differently. Comparison of mutations in CRC
driver genes demonstrated a correlation of TGFb signalling mutations with the SMAD9
locus but lacked causal support. Subsequent knock-down of SMAD9 in MSI and MSS cell
lines did however not indicate a proliferative advantage for MSS CRC. Secondly, I
suggested a possible alternate role for SMAD9 risk variance in increasing DNA mismatch
repair activity. Comparison of single base substitution signatures showed a depletion of
DNA mismatch repair signatures among MSS tumours from risk allele carriers. This
appeared to support my second hypothesis although results require replication.
In conclusion, I discovered a robust correlation between CRC microsatellite instability
and variance at the SMAD9 CRC risk locus and eQTL. This contributes to our functional
understanding of this locus and the genetic basis of CRC susceptibility
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
Germline variants associated with alternative splicing in colonic mucosa
Full text linkThe heritability of colorectal cancer (CRC) has been estimated between 7.4% and 26% from a range of analyses based on family lineages and genetic similarity. Certain rare, high penetrance variants are well characterized, though these are estimated to account for only ~5% of all CRC cases. The majority of GWASidentified risk SNPs for CRC fall within non-coding regions, and the mechanisms by which the majority of these variants contribute to disease predisposition are yet to be elucidated. However, recent studies have highlighted the contribution of alternative splicing to cancer progression, and have linked variants altering splicing patterns to predisposition to other complex traits.
This study has analysed RNA-seq from 221 samples of colonic mucosa (the precise tissue of origin of CRC) from a Scottish cohort to identify variants associated with quantitative changes in the splicing patterns of genes (sQTLs). All individuals were genotyped from blood samples via SNP-chips, and imputation increased the number of testable variants to 4 million. Transcript expression was quantified with the alignment-free Salmon algorithm. Two separate approaches with complementary methodologies were used to identify sQTLs: the sQTLseekeR package which analyses whole transcripts, and the Leafcutter package which infers changes in intron usage. Between the two, over 15,000 variants were identified as corresponding to changes in the ratio of expression of transcripts or the ratio of intron excision from over 6,800 protein-coding and lncRNA genes. Effect size and expression thresholds were applied to retain only the top 8% most likely functionally relevant sQTLs.
The thresholded sQTLs were found to be enriched in peaks of active chromatin marks, DNase accessible regions and putative regulatory elements, relative to a population of 100,000 non-sQTL SNPs sampled from the same search windows and with the same proportions of minor allele frequencies as the sQTL SNPs.
They were similarly enriched within regions predicted to be active from probabilistic deconvolution of signals from multiple histone marks constructed by the Roadmap Epigenetics Consortium. sQTLs were enriched within linkage blocks containing eQTLs (expression quantitative trait loci) identified from the same cohort, and eQTLs identified from GTEx sigmoid and transverse colon tissues; however the lead SNPs associated with sQTLs and eQTLs were different in 97% of cases, implying a strong degree of independence between the two classes of event. Thresholded sQTL variants identified by the Leafcutter package were found to be significantly enriched within a meta-GWAS for CRC consisting of 20,818 cases and 37,822 controls. Between both packages, sQTLs were found for 9 genes associated with CRC in the NHGRI-EBI GWAS catalog, 4 genes curated in the COSMIC database as relevant to CRC progression, and a further 29 oncogenes or tumour suppressors implicated in any cancer.
Together these observations imply that the alteration of patterns of transcript expression in the colonic mucosa mediated by germline SNPs is one of the genetic mechanisms underpinning predisposition to CRC. The sQTLs identified herein could be further used in colocalisation analyses to fine-map GWAS causal variants, and in transcriptome wide association studies (TWAS) to identify new CRC predisposition loci
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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