1,720,987 research outputs found
In silico identification of small molecules engaging the TNFR2-TNF-α interaction: a novel approach for targeting demyelinating diseases
No full textTumor necrosis factor alpha (TNF-) is a potent cytokine secreted by macrophages,. It is involved in immune and pro-inflammatory responses,, but under certain conditions it can also promote cellular proliferation and differentiation. TNF- exists in two isoforms, both arranged homotrimeric complexes: a a soluble form one,(solTNF), involved inthat participates to pathological mechanisms of demyelinating and neurodegenerative diseases preferably via TNF receptor 1 (TNFR1), and a transmembrane one form(tmTNF), which can mediate neurorepair and remyelination. TmTNF represents the constitutive and not processed form, while solTNF derives from the cleavage of the tmTNF extracellular domain by TNF- converting enzyme (TACE). Both isoforms interact with their receptors, TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2), in their homotrimeric form through the receptor soluble domain. As previously described in literature, tmTNF preferably acts via TNFR2 signalling, while solTNF via TNFR1. Because Due to theof the protective role of TNFR2tmTNF in demyelinating central nervous systemdiseases (CNS), aim of this study is to identify , through an in silico approach, a set of small molecules which could act as ligandsselective TNFR2 ligands, able to selectively enhanceing TNFR2::tmTNF- engagement for and thus promoting its reparative effects.
To achieve this goal, To achieve this goal, we firstwe first characterized in silico TNFR2 structure, underlying the differences with TNFR1. In particular, wWe found thate analyzed, in specific topological regions, the the interaction surface of both receptors, that are it is composed of four topological regions. We focused on regions three and four, which seem to be the most dissimilar regions between the two receptors and are characterized by opposite electrostatic potential surfaces,. Actually, in TNFR1 region three, the electrostatic potential surface is positively charged while in region four is negatively charged; conversely, in TNFR2, region three is negatively charged while region four is positively charged . These findings suggesting that the ability of the two TNF- isoforms to selectively engage either TNFR1 or TNFR2 could may partially depend on these electrostatic differences.
To find molecules able to selectively recognize and engage TNFR2::TNF-complex, On this basis, wwe tested a large library of commercially available drug-like compounds against this complex, through performed aan in silico virtual high-throughput screening (HTS). Wanalysis against the TNFR2::TNF-complex, testing a large library of commercially available drug-like compounds specifically designed to influence protein::protein interactions (Asinex PPI database), to find molecules able to selectively recognize and engage this receptor. Among the approx. 11,000 tested molecules, we identified 20 compounds that in silico were able to bindinteract with high affinity with TNFR2::TNF- complex in the TNF- binding site but without affecting TNFR2::TNF- interaction.
Then, to evaluate if these compounds were actually able to foster the TNFR2 engagement by TNF-, for each TNFR2::TNF-::ligand complex, we computed the difference between the G binding free energy value of the TNFR2::TNF- complex alone, and the G binding free energy of the complex in association with each investigated small moleculesligands (G), showing that. Results showed that aall the 20 compounds seem to enhance the affinity of TNF- for TNFR2., since the interaction energy of the complex in association with each single ligand is more negative than that of the complex alone.
Finally, since these compounds should exhibit their activity in the central nervous system (CNS), to assess whether they could be efficiently delivered to the brain, their ability to target CNS was predicted in silico by computing three significant pharmacokinetic descriptors. Five out of the 20 selected compounds were characterized by a potential CNS activity., according to predicted in silico parameters such as of CNS, QPlogBB and QPPMDCK.
To date, all the available approaches targeting the TNFR1/2::TNF- axis for promoting TNFR2 neuroprotection are based on the use of biotechnological moleculesdrugs. On this basis,
Globally, our promising preliminary data suggest that it may be possible topave the way for the development of a new therapeutic strategy for demyelinating diseases that is based on TNFR2 engagement by small molecules with drug-like properties to promote its reparative effects
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
In silico investigations of N-glycosylation role in modulating IgG1 conformational behavior and Fc effector functions
Get PDFCurrently, monoclonal antibodies (mAbs) are the most used biopharmaceuticals for human therapy. One of the key aspects in their development is the control of effector functions mediated by the interaction between fragment crystallizable (Fc) and Fcγ receptors, that is a secondary mechanism of action of biotherapeutics. N-glycosylation at Fc portion can regulate these mechanisms and many experimental evidences suggest that modifications of glycosydic chains can affect the antibody binding to FcγRIIIa, consequently impacting the immune response. In this work, we try to elucidate via in silico procedures the structural role exhibited by glycans, particularly fucose, that can potentially affect the receptor recognition. By using adalimumab, a marketed IgG1, as general template, after rebuilding its three-dimensional (3D) structure through homology modeling approaches, we carried out molecular dynamics simulations of three species: aglycosylated, afucosylated and fucosylated antibody, alone and in complex with FcγRIIIa. Trajectory analyses showed different dynamical behaviors among antibodies, highlighting that sugars can influence the overall 3D structure of the molecule and the orientation of Fragment antigen binding (Fab) domains. Moreover, oppositely to what happens in the fucosylated complex, in absence of fucose Fab arms can participate to the receptor recognition and many antibody residues considered critical for the complex formation by mutagenesis studies were found to interact with FcγRIIIa. Our study suggests a putative structural mechanism by which the fucose introduces conformational constraints in the whole antibody and not only in the Fc domain, preventing a conformation suitable for the interaction with the receptor. As secondary evidence, we observed a high flexibility of the antibodies that is translated in an asymmetric behavior of Fab portions shown by all the simulated biopolymers, suggesting a new molecular aspect that may be deeply investigated. In conclusion, these findings can help understand the contribution of sugars on the structural architecture of mAbs, paving the way to novel strategies of pharmaceutical development
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
- …
