1,721,073 research outputs found
Rescuing defective CFTR applying a drug repositioning strategy based on computational studies, surface plasmon resonance and cell-based assays
No full textCystic Fibrosis (CF) is caused by mutations (mainly F508del) of the
cystic fibrosis transmembrane conductance regulator (CFTR). Current
CF therapies are aimed at symptoms alleviation, calling for new
drugs to rescue CFTR function.
Hypothesis and objectives
Drug repositioning is aimed at finding new applications for already
marketed drugs, reducing cost and duration and the likelihood of
unforeseen adverse events. In this project we have integrated drug
repositioning with computational studies, surface plasmon resonance
(SPR) [1] and well-tried cellular models [2] to identify new CF drugs
and to comprehend their mechanism of action.
Methods and results
We have prepared a new structural homology model of intact human
F508del-CFTR embedded in a phospholipid bilayer and a SPR biosensor
containing the same protein in a cell membrane-mimicking lipid
film.
These tools, along with appropriate cell-based assays, have been
firstly used to analyze a mixed library of well-known and new compounds
that allowed the validation of the system and the identification
of a promising molecule endowed with a F508del-binding and
rescuing capacity that is higher than those of drugs already in use.
With the computational model we have then performed a virtual
drug repositioning on a library of 846 drugs, identifying 10 drugs
that were reduced to 4 on the basis of toxicity profile and patient
compliance. These drugs will be now subjected to experimental analysis
by cell-based and SPR assays for their effective capacity to bind
F508del-CFTR and rescue its activity. Also, we will proceed to the virtual
repositioning of a library of natural compounds.
Spin-off for research & clinical purposes
The novel computational models and biosensors will widen the study
of CF drugs and made available to other research groups in the field
of CF.
References
1. Rusnati M, Sala D, Orro A, Bugatti A, Trombetti G, Cichero E, Urbinati C,
Di Somma M, Millo E, Galietta LJV, Milanesi L, Fossa P, D'Ursi P. Speeding
Up the Identification of Cystic Fibrosis Transmembrane Conductance
Regulator-Targeted Drugs: An Approach Based on Bioinformatics Strategies
and Surface Plasmon Resonance. Molecules. 2018 Jan 8;23(1). pii:
E120. doi: 10.3390/molecules23010120.
2. Tomati V, Pesce E, Caci E, Sondo E, Scudieri P, Marini M, Amato F,
Castaldo G, Ravazzolo R, Galietta LJV, Pedemonte N. High-throughput
screening identifies FAU protein as a regulator of mutant cystic fibrosis
transmembrane conductance regulator channel. J Biol Chem. 2018 Jan
26;293(4):1203-1217. doi: 10.1074/jbc.M117.816595. Epub 2017 Nov 20.
Acknowledgment FFC#11/2018 funded by FFC and supported by Delegazione
FFC di Torin
α(V)β3 integrin mediates the cell-adhesive capacity and biological activity of basic fibroblast growth factor (FGF-2) in cultured endothelial cells
No full textFibroblast growth factor-2 (FGF-2) immobilized on non-tissue culture plastic promotes adhesion and spreading of bovine and human endothelial cells that are inhibited by anti-FGF-2 antibody. Heat-inactivated FGF-2 retains its cell-adhesive activity despite its incapacity to bind to tyrosine-kinase FGF receptors or to cell-surface heparan sulfate proteoglycans. Recombinant glutathione-S-transferase-FGF-2 chimeras and synthetic FGF-2 fragments identify two cell-adhesive domains in FGF-2 corresponding to amino acid sequences 38-61 and 82-101. Both regions are distinct from the FGF-receptor- binding domain of FGF-2 and contain a DGR sequence that is the inverse of the RGD cell-recognition sequence. Calcium deprivation, RGD-containing eptapeptides, soluble vitronectin (VN), but not fibronectin (FN), inhibit cell adhesion to FGF-2. Conversely, soluble FGF-2 prevents cell adhesion to VN but not FN, thus implicating VN receptor in the cell-adhesive activity of FGF-2. Accordingly, monoclonal and polyclonal anti-α(v)β3 antibodies prevent cell adhesion to FGF-2. Also, purified human α(v)β3 binds to immobilized FGF-2 in a cation-dependent manner, and this interaction is competed by soluble VN but not by soluble FN. Finally, anti-α(v)β3 monoclonal and polyclonal antibodies specifically inhibit mitogenesis and urokinase-type plasminogen activator (uPA) up-regulation induced by free FGF- 2 in endothelial cells adherent to tissue culture plastic. These data demonstrate that FGF-2 interacts with α(v)β3 integrin and that this interaction mediates the capacity of the angiogenic growth factor to induce cell adhesion, mitogenesis, and uPA up-regulation in endothelial cells
The discovery of basic fibroblast growth factor/fibroblast growth factor-2 and its role in haematological malignancies
No full text
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
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