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Tumour suppressor role of Serine hydroxymethyltransferase in Drosophila melanogaster
No full textSerine hydroxymethyltransferase (SHMT) works in the one carbon
(1C) pathway to regulate essential cellular processes such as
nucleotide synthesis and epigenetic maintenance. SHMT catalyses
the reversible interconversion of serine and tetrahydrofolate (THF)
to glycine and 5,10-methyleneTHF (meTHF). The one carbon
units produced in this reaction are used by thymidylate synthase
enzyme (TS) to produce Thymidylate (dTMP) an essential
precursor of DNA. Therefore, it is expected that a depletion of
SHMT could reduce the biosynthesis of dTMP, thus increasing the
genome instability. To test this hypothesis, we depleted SHMT in
Drosophila melanogaster, using the RNA interference strategy,
which reduced the catalytic activity of SHMT of about 40%.
We showed that SHMT depletion resulted in chromosome damage
that was also produced by RNAi-mediated TS silencing.
Interestingly, dTMP supplementation reduced the chromosome
aberrations suggesting the SHMT depletion impacts on genome
integrity by impairing the folate cycle.
More interestingly, we found that the administration of pyridoxal
5’-phosphate (PLP), the enzymatic cofactor of SHMT was able to
rescue the chromosome damage. In contrast, the administration of
the PLP antagonist 4-deoxypyridoxine (4DP) exacerbated the CAB
phenotype, thus unveiling a gene-nutrient relationship between
SHMT and vitamin B6 which impacts on genome stability.
Several studies associated the overexpression of SHMT2 and, at
lesser extent SHMT1, to cancer indicating that this activity takes
part to metabolic reprograming by supplying cancer cells with
molecular building blocks essential for their rapid growth. On the
other hand, only a few studies have focused on the consequence of
reduced SHMT levels in cancer.
Dottorato di ricerca in Genetica e Biologia Molecolare
Pag. 9
In this thesis we exploited the RasV12DlgRNAi Drosophila cancer
model to test whether the RNAi-induced silencing of SHMT could
increase the malignancy of tumours induced by the expression of
the RasV12 oncogene combined to silencing of Disc large (Dlg)
polarity gene in larval eye discs. From this analysis it emerged that
SHMT depletion exacerbates cancer phenotype of RasV12DlgRNAi
tumours and causes genome instability by synergizing with the
tumour background. CABs induced by SHMT silencing were
rescued by dTMP supplementation that likewise rescued the
malignant phenotype of RasV12DlgRNAi larvae, thus linking genome
instability to tumours. Moreover, we provided evidence that the
levels of PLP can modulate the tumour phenotypes as well as the
genome instability resulting from SHMT silencing, thus suggesting
that the gene-nutrient interaction between SHMT and vitamin B6 is
able to impact on cancer through the genome damage.
We found that SHMT depletion in RasV12DlgRNAi cells promotes
the formation reactive oxygen species (ROS) due to the
overexpression of the NAPDH oxidase enzyme, suggesting that
ROS may contribute to CABs which, in turn, might be responsible
for promoting tumour phenotypes in the RasV12DlgRNAi cells
depleted of SHMT.
Taken together, our studies highlighted a clear tumour suppressor
role of SHMT that acts as a safeguard against the genome damage
and also showed, for the first time, how the interplay between
SHMT activity and the vitamin B6 availability can modulate the
cancer risk by impacting on genome integrity
Vitamin B6 deficiency promotes loss of heterozygosity (LOH) at the Drosophila warts (wts) locus
Get PDFThe active form of vitamin B6, pyridoxal 5′-phosphate (PLP), is a cofactor for more than
200 enzymes involved in many metabolic pathways. Moreover, PLP has antioxidant properties and
quenches the reactive oxygen species (ROS). Accordingly, PLP deficiency causes chromosome
aberrations in Drosophila, yeast, and human cells. In this work, we investigated whether PLP
depletion can also cause loss of heterozygosity (LOH) of the tumor suppressor warts (wts) in
Drosophila. LOH is usually initiated by DNA breakage in heterozygous cells for a tumor suppressor
mutation and can contribute to oncogenesis inducing the loss of the wild-type allele. LOH at the wts
locus results in epithelial wts homozygous tumors easily detectable on adult fly cuticle. Here, we
found that PLP depletion, induced by two PLP inhibitors, promotes LOH of wts locus producing
significant frequencies of wts tumors (∼7% vs. 2.3%). In addition, we identified the mitotic
recombination as a possible mechanism through which PLP deficiency induces LOH. Moreover,
LOH of wts locus, induced by PLP inhibitors, was rescued by PLP supplementation. These data
further confirm the role of PLP in genome integrity maintenance and indicate that vitamin B6
deficiency may impact on cancer also by promoting LOH
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
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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