1,721,084 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
Epithelial cell intrinsic and extrinsic effects of WNT disruption in colorectal tumorigenesis
No full textDespite cancer initiation being attributed to specific pools of epithelial
stem cells, tumorigenic transformation is a complex process that entails
the co-evolution of the epithelial and stromal compartments. Here, I studied how the stem cell composition of a given malignancy shapes the interactions established between tissue compartments in Colorectal Cancer
(CRC).
For many years, Lgr5+ Crypt Base Columnar (CBC) cells have been acknowledged as the cell of origin of CRC. However, alternative pools of
intestinal progenitors, the Regenerative Stem Cells (RSC), have been described in settings of regenerations. In this piece of work, I analysed the
contribution of these pools of stem cells to colorectal neoplasia. Using
a RNA sequencing-based analytics pipeline, a range of mouse and human pre-malignant lesions and cancers could be classified based on their
Stem Cell composition. This revealed that lesions with different molecular
characteristics preferentially select for the expansion of specific progenitors. Furthermore, I narrowed down the molecular drive that may be
conferring CBC and RSC characteristics. Finally, I demonstrated that
these populations are not static, but tumours can change their stem cell
composition to adapt to therapeutic selective pressure.
Using genetic models of colorectal disease, I investigated how alterations
in epithelial-stromal interactions can drive colorectal transformation. In
the Vil1-Grem1 mouse, epithelial upregulation of GREM1 was enough
to cause the activation of fibroblast populations and modulate the production of niche factors within the intestinal stroma. This enabled the
formation of polyps which presented pools of progenitors in ectopic locations. Importantly, these alterations could be reversed by a Gremlin-1
blocking antibody.
Despite WNT-driven immune evasion being an acknowledged phenomena in CRC, the molecular mechanisms by which it operates are yet notcompletely understood. Here I used a range of models of WNT-driven intestinal transformation to investigate this phenomena. I found that WNT
activation comes with the downregulation of pyroptosis, an immunogenic
form of cell death. Furthermore, treatment of the Lgr5-Rspo3 mouse
with a WNT inhibitor was enough to drive re-infiltration of polyps by
T lymphocytes, which came together with upregulation of the pyroptosis
effector Gsdmc4. However, in APCMin animals, lymphocytic infiltration
after Lgr5+ cell ablation did not correlate with an increase in pyroptosis,
suggesting that mouse models with different molecular drives/progenitor
composition may possess alternative immune evasion mechanisms.
Overall, in this piece of work, I present a tool to infer the Stem Cell admixture within colorectal lesions, which could be used to inform clinical
practice and to facilitate CRC research in the future. Moreover, I provided evidence for mechanisms by which epithelial cell-intrinsic characteristics can alter the fibroblasts and immune compartment within colorectal
polyps
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
Organoid models to characterise colonic stem cell plasticity
No full textCellular plasticity is the capability of cells to alter their phenotype in response to cues in the surrounding milieu, a vital property in several biological processes. The colon is a prime example of the importance of cellular plasticity in homeostasis as its epithelial lining is extremely dynamic, with cells constantly selecting between proliferation, differentiation, migration and apoptosis, depending on the needs of the tissue. While plasticity plays an important role in healthy tissues, genetic alterations and microenvironmental influences can also generate aberrant cellular plasticity which can mediate numerous diseases, including colorectal cancer. In colorectal cancer, the dysregulation of cellular plasticity causes phenotypic heterogeneity within the tumour, which is known to drive resistance to therapy. Consequently, despite progress in drug development in the past decades, curative treatment for this highly heterogeneous and metastatic disease remains difficult, with a significant proportion of cancer-related mortality worldwide attributable to colorectal cancer.
Understanding of the cellular plasticity mediating treatment resistance in colorectal cancer is a key step towards improving patient outcomes. In this study, in order to elucidate how genetic alterations and microenvironmental influences affected the cellular plasticity exhibited by colonic stem cells, a library of colon organoids (colonoids) harbouring driver gene mutations common in colorectal cancer were generated. Study of cellular plasticity was achieved by analysing this colonoid library with a novel, high-throughput, and unbiased organoid phenotyping platform, termed Shape, Appearance and Motion (SAM), which identified instantaneous mutant colonoid states and generated phenotype trajectories to compare mutant trait development over time. SAM analyses revealed that colorectal cancer-associated driver mutations significantly alter the cellular plasticity of colonoids and generate distinct genotype-phenotype profiles unique to each driver mutation. Notably, Apc mutant colonoids demonstrated a phenotypic dynamic that was particularly distinct from colonoids carrying all other driver mutations assessed, adopting a unique two-dimensional eccentric appearance.
To understand the molecular basis for the differences seen in cellular plasticity between the various mutant colonoids, phenotypic findings were integrated with single-cell RNA-sequencing. The distinct spatiotemporal dynamics exhibited by Apc mutant colonoids were found to be associated with a unique gene expression profile characterised by elevated Yap signalling and the acquisition of a regenerative stem cell and foetal gene signature. Furthermore, Apc mutant colonoids had decreased expression of tight junction proteins and increased expression of Yap-dependent extracellular matrix remodelling proteins. Together these findings suggest that Apc mutant colonoids are engaged in a Yap-mediated regenerative response, a process normally observed in the repairing intestinal epithelium. By combining these data with microscopic observation of developing Apc mutant colonoids, a mechanistic model for the unique Apc mutant colonoid phenotype is developed, whereby the two-dimensional eccentric appearance activates Yap-mediated mechanotransduction pathways and pushes the colonoids towards the regenerative stem cell molecular phenotype. Accordingly, the usual basal stem cell molecular phenotype imposed by the Apc mutation is overwritten by microenvironmentally influenced plasticity, which is able to induce a phenotypic shift towards a regenerative stem cell state regardless of the normal basal stem cell molecular phenotype associated with this mutation.
To extend this phenotypic study of mutant colonoids to model the subclonal dynamics and intratumoral heterogeneity driving tumour evolution and drug resistance in colorectal cancer, co-culture of mutant colonoids was employed. Findings suggested that mutant colonoids exhibit cooperative interactions in co-culture which significantly alter their individual phenotypes and increase their capacity for growth. scRNA-seq analysis on these co-cultured mutant colonoids showed that, while most mutant genotypes showed considerable transcriptomic changes during co-culture, Apc mutant colonoids were less susceptible to modifications of their transcriptomic profile in response to the presence of other mutant genotypes.
Finally, to advance the co-culture approach towards highly defined structures that more closely represent the clonal architecture of the tumour milieu, a novel organoid co-culture protocol which provides spatial control and patterning of mutant colonoids and facilitates the incorporation of cells usually present in the tumour microenvironment was developed. The mixed colonoid model represents an exciting tool for future research to further understand the direct subclonal interactions, intratumoural heterogeneity, and cellular plasticity present in colorectal cancer tumours and clarify the influence that the tumour microenvironment has on tumour evolution. In summary, the findings and methods developed in this work using a driver mutation colonoid library provide further insight into how driver mutations co-opt cellular plasticity to drive colorectal cancer
Control of intestinal progenitor cell fate by the microenvironment
No full textThe conventional model of intestinal epithelial architecture describes a unidirectional tissue organisational hierarchy with stem cells situated at the crypt base and daughter cells proliferating and terminally differentiating as they progress along the vertical (crypt-luminal) axis. In this model, the fate of a cell that has left the
niche is determined and its lifespan limited. I look at evidence to suggest that stem cell control and daughter cell fate determination is not solely an intrinsic, cell autonomous property but is heavily influenced by the microenvironment. Selective pressures that disrupt the homeostatic balance, such as intestinal inflammation or
morphogen dysregulation, can cause committed progenitor cells and even some differentiated cells to regain stem cell properties. Disruption of cell fate determination can lead to somatic mutation and neoplastic transformation of cells situated outside the crypt base stem cell niche. The Wnt, BMP and Hedgehog pathways are explored in terms of epithelial and mesenchymal compartmentalisation and cross-talk, both in homeostasis and inflammation. Interactions between BMP and Hedgehog pathways are studied in vivo and in vitro. The BMP antagonist GREM1
is discussed, and the effect of a compartmental switch in its expression in humans (Hereditary Mixed Polyposis Syndrome) and in mouse models. This leads to ectopic crypts with supposed stem cell activity, and evidence for stem cell activity is interrogated using lineage tracing models and organoid cultures. The functionality
of Sox9, a marker of ectopic crypts, is explored. An epithelial Sox9 knockout model is studied in terms of its effect on ectopic crypt formation. The role of Sox9 in intestinal restitution is also examined by using a chemical colitis model and a biopsy wounding model.</p
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
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