1,720,983 research outputs found
Exploring alternative antiviral strategies: a complementary study of SARS-CoV-2 spike glycoprotein through computational studies and surface plasmon analysis.
Full text linkLe infezioni virali rimangono una seria sfida per la salute, come è stato evidenziato drammaticamente dalla recente pandemia di COVID-19 causata dal virus SARS-CoV-2, rendendo impellente la disponibilità di misure antivirali efficaci. Dato il ruolo centrale della proteina spike nel processo di infezione, essa è stata facilmente identificata come principale bersaglio per lo sviluppo di nuovi trattamenti per il SARS-CoV-2. Nel mio progetto di dottorato, con lo scopo di valutare strategie antivirali basate su meccanismi di azione a livello molecolare, ho adottato un approccio combinato caratterizzato da studi computazionali (modellazione molecolare) e analisi sperimentali dell’interazione macromolecolare (surface plasmon resonance, SPR). La combinazione di queste due tecniche offre preziose informazioni sulla struttura, il comportamento e le interazioni delle strutture coinvolte nell'infezione da SARS-CoV-2, fornendo una solida base per la progettazione di trattamenti terapeutici innovativi. Nella prima fase del progetto, ho effettuato simulazioni computazionali per valutare l'impatto di diverse mutazioni sulla struttura della proteina spike, ottenendo una conoscenza più approfondita della complessa relazione tra la sua struttura e funzione. Con queste informazioni a disposizione, ho avviato una seconda fase dedicata all’analisi computazionale e alla valutazione sperimentale di diverse strategie antivirali volte a inibire l'ingresso del virus SARS-CoV-2 nelle cellule ospiti. In questo contesto, ho contribuito a uno studio che ha portato all’identificazione delle basi molecolari sottostanti all’inattivazione di SARS-CoV-2 mediante esposizione a luce UV-C. I risultati ottenuti tramite studi computazionali e l’analisi SPR hanno rivelato che la luce UV-C provoca la rottura di un ponte disolfuro specifico all'interno della proteina spike, producendo effetti allosterici sul dominio RBD, riducendo così la sua affinità di legame al recettore ACE2 presente sulle cellule ospiti. A loro volta, questi risultati hanno indicato il ponte disolfuro identificato come un promettente bersaglio farmacologico per inattivare la proteina spike. A questo scopo, è stata applicato un approccio di drug repositioning per selezionare composti in grado di replicare gli effetti della luce UV-C ma con scopo terapeutico. Questo obbiettivo è stato raggiunto con successo con l'identificazione di una molecola attualmente in fase di convalida sperimentale. Per affrontare la necessità di sviluppare strategie antivirali in grado di combattere un'ampia gamma di virus sono state esaminate due categorie di molecole in grado di interferire con la capacità conservata dei virus di interagire con gli heparan sulfate proteoglycans (HSPGs) presenti sulla superficie delle cellule ospiti. Le molecole studiate includono i polisaccaridi analoghi all'eparina, noti come K5, e i dendrimeri. I risultati ottenuti sono promettenti e sicuramente meritano ulteriori sviluppi.
In fine, ho trascorso sei mesi nel laboratorio del Professor Vendruscolo presso il Dipartimento di Chimica dell'Università di Cambridge per apprendere un avanzato metodo computazionale noto come "Metadynamic Electron Microscopy Metainference" (MEMMI). Questo metodo è essenziale per condurre un'analisi dettagliata della dinamica delle proteine, una caratteristica fondamentale per identificare nuovi farmaci e per comprenderne con sempre maggiore precisione i meccanismi d'azione. Questa conoscenza ottenuta potrà essere sfruttata per approfondire la ricerca di agenti antivirali contro SARS-CoV-2.Viral infections remain a serious health challenge, as dramatically exposed by the recent COVID-19 pandemic caused by the SARS-CoV-2 virus that has made mandatory the availability of effective antiviral measures. Given the central role of the spike protein in the process of infection, it has been soon taken in consideration as main target for the development of new SARS-CoV-2 treatments. To pursue a comprehensive and molecularly informed antiviral strategy in my PhD project I’ve adopted a combined approach consisting in computational studies (molecular modelling) and experimental macromolecular binding analysis (surface plasmon resonance, SPR). The exploitation of these two techniques offers valuable insights into the structure, behaviour and interactions of spike and host structures involved in SARS-CoV-2 infection, providing a solid foundation for the design of innovative therapeutic interventions.
In a first phase, I’ve performed computational simulations to assess the impact of various mutations on the structure of spike as to provide a deeper knowledge of the intricate structure/function relationship of the spike protein and to identify key spike domains whose targeting would possibly bring to its inhibition/inactivation. With this information at hand, I’ve started a second phase devoted to the computational design and experimental evaluation of different antiviral strategies aimed at inhibiting the entry of the SARS-CoV-2 virus into host cells.
In this frame, I’ve contributed to a study that has shed a light on the molecular bases of SARS-CoV-2 inactivation by means of UV-C light irradiation: coincident computational predictions and SPR analysis results revealed that UV-C light causes the disruption of a specific disulfide bridge within the spike protein, reducing its binding to its ACE2 receptor present on host cells.
In turn, these results pointed to the identified disulfide bridge as a promising pharmacological target to inactivate spike protein. To this aim, a drug repositioning approach was applied to select compounds capable of replicating the effects of UV-C with therapeutic potential, a task that was successfully completed with the identification of a candidate molecule that is currently under experimental validation.
Also, two other types of compounds, namely heparin-like K5 polysaccharides and dendrimers have been evaluated for their capacity to interfere with the interaction of SARS-CoV2 or herpes simplex virus host cell heparan sulfate proteoglycans (HSPGs), that is crucial for the infection process of different virus species and is highly conserved among the various SARS-CoV2 variants. These studies yielded promising results that surely deserve further development.
Comprehensively these studies confirmed the importance of computational studies at speeding up the drug discovery process for COVID-19. With this in mind, I’ve spent six month at Professor Vendruscolo's laboratory in the Department of Chemistry at the University of Cambridge to work with an important advanced computational technique, namely the Metadynamic Electron Microscopy Metainference (MEMMI) that is crucial for a detailed analysis of protein dynamics that is in turn required for the identification of new drugs and the characterization of their mechanisms of action with increasing precision, with the intention to exploit it in the identification of spike inhibitors to be developed in COVID-19 drugs
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
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
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