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The influence of copper on secretion and biological activity of the gastrointestinal factor TFF1
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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
Studio del ruolo funzionale e caratterizzazione strutturale del cuprocomplesso TFF1-Cu
Full text link2009 - 2010The maintenance of gastrointestinal tissue integrity is physiologically essential in the presence of the persistent harassment of microbial flora and injurious agents. Even though the repair of the gastric epithelium may be modulated by several factors, the epithelial continuity also depends on a family of small peptides called trefoil factors (TFFs). The trefoil factors family comprises the gastric peptides pS2/TFF1, the spasmolytic peptide (SP)/TFF2 and the intestinal trefoil factor (ITF)/TFF3; they are characterized by a three looped domain, the “trefoil domain”, stabilized by three disulphide bridges. TFF1 and TFF3 also have a seventh cysteine that allows the formation of omo- and/or hetero-dimers. On the other hand TFF2 presents only a monomeric form, containing two trefoil domains in the same polypeptide chain. TFFs are small protease-resistant proteins that are abundantly produced by mucus-secreting cells of the gastrointestinal tract onto the mucosal surface. TFFs are essential in the protection of the mucosal epithelia against a wide range of biological threats, thus contributing to the mucosal repair. The signaling events that mediate the cellular responses elicited by TFFs are only partially understood. Moreover there are convincing evidence that TFFs do play an important role in tumorigenesis, even though their specific roles in cancer are still unclear.
TFF1 expression is strongly induced after mucosal injury and it has been proposed that TFF1 functions as a gastric tumor suppressor gene. Several studies confirm that TFF1 expression is frequently lost in gastric cancer because of deletions, mutations or methylation of the TFF1 gene. Infection by Helicobacter pylori, a class 1 carcinogen according to WHO classification, is thought to promote stomach carcinogenesis through induction of aberrant DNA methylation. Samples from infected patients show lower expression of TFF1. Recent studies have also shown that there is a direct relationship between Helicobacter pylori and the dimeric form of the protein. In fact, it was demonstrated that the core oligosaccharide portion of H. pylori lipopolysaccharide (RF-LPS) is able to bind to TFF1.
It also seems that the loss of TFF1 is an important event in shaping the NF-kB-mediated inflammatory response during the progression to gastric tumorigenesis, being TFF1 a negative regulator of NF-kB signalling. It is thus emerging a clear correlation between loss of TFF1, the development of inflammatory disease and the neoplastic process.
Recent analyses made by our research group allowed us to point out the up-regulation of TFF1 gene expression in rats fed on copper deficient diets, and allowed us to find out the unexpected ability of TFF1 to bind copper ions. The presence of a cysteine surrounded by several negatively charged residues in the carboxy-terminus of the protein suggested the presence of a copper-binding site. Afterwards, it was shown that Cys58 and at least three Glu surrounding residues are essential to efficiently bind copper. Moreover, the incubation of the native peptide with copper salts increases the fraction of peptide omodimers produced by inter-molecular oxidation of Cys58 and disulphide bond formation.
The Ph.D. research project was aimed at characterising the structure-function relationship of the TFF1-Cu complex. Briefly, we studied the influence of copper on known TFF1 biological activities and on its gene regulation, then we investigated its involvement in the TFF1 mediated mechanisms of Helicobacter pylori virulence and infection.
A preliminary Real Time PCR quantitative analysis showed that copper deficiency positively modulates tff1 expression in an adenocarcinoma cell line (AGS), thus confirming our previous data obtained in vivo in copper deficient rat intestine.
In order to map possible copper responsive elements in the proximal promoter sequence, we analysed the expression of a reporter gene (Luciferase) driven by deletion constructs of the tff1 gene promoter. AGS cells transfected with the deletion constructs allowed us to identify the upstream 5’ gene sequence -583/-435 as a promoter region sensitive to the changes of copper concentration. In fact, copper chelation treatments with bathocuproine disulfonate (BCS) were able to stimulate an increase of the promoter activity of the corresponding deletion construct. Following the sequence analysis (Transfac software) we focused our attention on a putative SP1 binding site identified in this region, whose binding ability was then confirmed by electrophoretic mobility shift assay (-561/-552).
In agreemente with our in vitro results, it was also observed that copper favours the native TFF1 dimer formation in the culture medium of MCF-7 and HT29-MTX cells (a mucus-secreting clone obtained from the HT29 colon cancer cell line), thus confirming a possible role of the metal in the balance between the monomeric and the dimeric forms
To evaluate the effect of copper-TFF1 interaction on the well known motogenic activity of the protein, we performed wound healing assays on an inducible clone of gastric cancer cells (AGS) able to overexpress the peptide (AGS-AC1). As expected, the overexpression of TFF1 stimulates an appreciable increase of cell migration, and copper chelation (BCS) undo the benefits of the increased peptide level.
Our previous results showed that copper treatments decreased the amount of secreted protein in culture medium. Further experiments demonstrated that induced AGS-AC1 cells are able to store intracellularly higher amount of copper if compared to uninduced AGS-AC1 cells. This evidence suggests that TFF1 levels may also play a role also in the uptake/traffic of copper in this in vitro model.
Finally, we studied the combined influence of TFF1 and copper in Helicobacter pylori infections. Our results demonstrate that Cu-TFF1 complex promotes H. pylori colonization of AGS cells. In fact, AGS-AC1
cells overexpressing TFF1 are more efficiently colonised by H. pylori wild-type (str. P12) if compared to uninduced cells. The presence of copper in a duplicate experiment further increases the colonization, as well as copper chelation by bathocuproine disulfonate (BCS) reduces the observed effect. The same result was obtained with H. pylori str. P12Δ479, an isogenic mutant expressing a truncated LPS core still able to bind to TFF1. On the other hand, H. pylori P12Δ1191, unable to bind TFF1, is not affected by copper levels in the culture medium. Parallel experiments were carried out on mucus secreting HT29-E12 goblet cells, to compare and/or confirm the results obtained in AGS-AC1. The results show that also in HT29-E12 cells the H. pylori colonization follows a similar trend, increasing when incubated in the presence of Cu and decreasing after BCS treatment.
The present work contributed interesting results in the field of the biochemistry of the epithelia, in the wake of the research in progress in our laboratory aimed at studying the biological activities of the newly identified metalloprotein Cu-TFF1, whose properties are still poorly characterized. On the basis of the previous structural pieces of evidence we observed that the protein level and the balance of its oligomeric forms can be affected and regulated by copper ions. In turn, this delicate equilibrium is able to affect the integrity and the rheological properties of the epithelial barrier, thus representing a fine tuner, or an Achille’s heel, through which pathogenic microrganisms and deregulated proliferation of neoplastic cells may take advantage for their invasiveness. The role of copper in the TFFs biochemistry represents a new finding in the puzzling and versatile functions of this interesting peptide family, whose thorough comprehension still reserves many questions and surprises. [edited by author]IX n.s
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