1,721,009 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
Investigation of HMA derivatives as small molecule inhibitors of viroporins
No full textSeasonal and pandemic viral infections continue to pose severe challenges to human health. Antivirals that can effectually complement current vaccination strategies are vital in the battle against drug-resistant pandemic viral strains. Many viruses express small, predominantly hydrophobic and multi-functional proteins that can assemble into oligomeric ion channels capable of passing ions, called viroporins. These small proteins have historically been effective antiviral targets for drugs like amantadine that effectively inhibit the wild-type M2 ion channel of Influenza A. However, drug resistance has rendered adamantane-based antivirals ineffective against circulating strains of influenza A. Similarly, various studies have reported that hexamethylene amiloride (HMA), a previously used diuretic, is also capable of inhibiting the ion channel activity of influenza A M2 and SARS-CoV-1 and 2 Envelope (E) proteins.
This dissertation elaborates on the functional properties of a panel of in-house designed and synthesized HMA derivatives and evaluates the activity of these amiloride-derived compounds against known viroporins of influenza A and SARS-CoV-2 through an iterative approach, employing synthetic organic chemistry, electrophysiological measurements and computational techniques and quantification of anti-viral activity through in vitro viral assays.
Through studying the structure activity relationship of this chemical class, we report compounds that effectively inhibit the wild-type and adamantane-resistant forms of influenza A M2 ion channel. We found that tert-butyl 4'-(carbamimidoylcarbamoyl)-2',3-dinitro-[1,1'-biphenyl]-4-carboxylate exhibits dual inhibitory effect against both adamantane-sensitive as well as S31N mutant influenza A M2. This compound has an inhibitory effect against the replication of influenza viruses encoding wild-type M2 and M2(S31N) in vitro.
Furthermore, by utilizing in silico techniques such as molecular modelling, docking simulations, molecular dynamics, and steered molecular dynamic, we report that these HMA derivatives are able to bind and effectively block the lumen of SARS-CoV-2 E protein with higher affinity as compared to HMA. Whilst, more work is still needed to utilize these HMA derivatives as therapeutic options, the findings presented in this thesis highlight the potential of amiloride-derived compounds as antivirals against drug-resistant strains of influenza A and important drug leads for the design and further development of inhibitors of SARS-CoV-2 E protein.Medicine, Faculty ofAnesthesiology, Pharmacology and Therapeutics, Department ofGraduat
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
A structure determination of the xKCNQ1-R2/CaM ion channel using cryo-EM
No full textBackground: Mutations of the KCNQ1 cardiac ion channel are known causes of arrhythmia disorders, including LQT-interval syndrome. This unique channel deviates from the conventional mechanism driving voltage-gated ion channel opening, as channel conductance is observed in mutants holding the VSD in both the expected fully-activated conformation and an elusive intermediate orientation. The objective of this study was to utilize a mutant known to produce currents characteristic of this intermediate-open state, E1R/R2E, to recapitulate the structure of the channel in this conformation.
Methodology: Extensive troubleshooting was done to isolate protein of adequate yield and purity. Avenues for optimization included cell culture technique, choice of detergent and membrane isolation. Successfully isolated protein was vitrified, screened and finally assayed for data collection. Movies were then put through a cryoSPARC processing pathway with a model built using Coot from a KCNQ1 wild-type starting model. Phenix was used for final refinements.
Results: A 3.66 Å data set was successfully determined using cryo-EM, with the 3D model showing a closed pore and VSD distinct from wild-type. Though the resolution in the VSD is adequate for main chain conformation, it is not adequate to confidently make assertions about residue interactions. Interestingly, it does not appear that the expected salt-bridge interaction believed to stabilize the intermediate state in this mutant is possible, given the model. Major observation included a slight downward movement of the S4 and significant movement of the S1 and S2 helices in the VSD.
Conclusion: This model is the first-ever high-resolution structural model of the KCNQ1-R2/CaM and therefore fills an important knowledge gap about the intermediate state.Medicine, Faculty ofGraduat
Multiple effects of KCNQ1 activators on the delayed cardiac rectifier potassium channel molecular complex
No full textThe cardiac delayed rectifier potassium current, IKs, formed by the co-assembly of KCNQ1 and KCNE1 subunits, plays a critical role in cardiac repolarization, acting as a reserve to adapt to higher heart rates and compensating when other repolarization currents are impaired, thereby preventing arrhythmias. Loss of function mutations in these subunits impair cardiac repolarization and are associated with inherited long QT syndrome, increasing the risk of developing a polymorphic ventricular tachycardia known as Torsades de Pointes, which can result in syncope and sudden death. Therapeutic interventions targeting the IKs channel directly to reverse the malignant effects of long QT syndrome hold significant potential but have historically been challenging due to the previously unknown binding sites for IKs activators.
In this thesis, I delved into the binding mechanisms of two well-known IKs activators, mefenamic acid and 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS), and successfully elucidated their binding sites using electrophysiological and structural biology techniques. These activators potentiate the IKs current by inducing and stabilizing a conformational change in an otherwise hidden binding pocket within the S1/KCNE1/pore complex, slowing channel deactivation.
Furthermore, I uncovered a dual mechanism of action for mefenamic acid on the IKs channel. At high concentrations (300 µM), mefenamic acid inhibits wild-type IKs current amplitude while preserving the delay in channel deactivation. Moreover, KCNE1 and KCNQ1 mutations in the previously elucidated binding pocket unmasked the inhibitory actions at lower drug concentrations. I propose that a lower affinity, secondary binding site near the primary binding site is responsible for inhibition, and specific mutations reveal the site.
Finally, I demonstrated the graded stoichiometric effects of mefenamic acid on the wild-type IKs channel complex. The K41C mutation in KCNE1, which disrupts the primary binding site, abolishes the effects of mefenamic acid. My findings further quantified this graded loss of effect, showing that the response to mefenamic acid diminishes as the proportion of K41C-mutated subunits increases.
Using mefenamic acid as an archetype for designing therapeutically useful IKs agonists, results from this thesis provide critical insights into the molecular mechanisms of IKs modulation and offers future directions for developing targeted therapies.Medicine, Faculty ofMedicine, Department ofGraduat
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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