1,720,967 research outputs found
Validation of novel inhibitors of mexxy-oprm and nora efflux pumps to counteract the antibiotic resilience of p. aeruginosa and s. aureus
Full text linkIl costante aumento del fenomeno dell’ antibiotico resistenza è attualmente uno dei più preoccupanti problemi di salute pubblica e rischia di costituire una vera emergenza nel prossimo futuro. A complicare ulteriormente il quadro, le forme batteriche antibiotico tolleranti e persistenti sono in grado di sopravvivere a elevate dosi di antibiotico senza tuttavia portare specifici determinanti di resistenza. Si tratta di forme transienti, capaci di sopravvivere in condizioni sfavorevoli grazie a modifiche temporanee dell’espressione genica. Tra tutti i meccanismi di resistenza agli antibiotici, le pompe di efflusso sono tra i più comuni nei patogeni sia Gram-positivi che Gram-negativi; tali complessi proteici sono in grado di espellere molecole tossiche, compresi gli antibiotici, evitando quindi un loro accumulo all’interno del citoplasma. Inoltre, recenti studi hanno dimostrato un importante coinvolgimento delle pompe di efflusso anche in altri processi fisiologici batterici come la comunicazione intercellulare, la formazione di biofilm, la regolazione della virulenza e la formazione di cellule persistenti. Un sempre maggior interesse si sta concentrando sull’uso di Inibitori delle Pompe di Efflusso (EPIs) in combinazione con antimicrobici già in uso, come strategia per contrastare le infezioni resistenti agli antibiotici; ad oggi tuttavia nessuna di queste molecole è attualmente utilizzata in clinica a causa della intrinseca elevata tossicità. Questo progetto di dottorato ha avuto come obiettivo la validazione di nuovi inibitori delle pompe di efflusso MexXY-OprM di Pseudomonas aeruginosa e NorA di Staphylococcus aureus, due tra i patogeni più resilienti al trattamento antibiotico. L’alcaloide naturale berberina legandosi alla pompa di efflusso MexXY-OprM, principale responsabile dell’efflusso degli aminoglicosidi, si è rivelato in grado di potenziare (di 2-3 log) l’attività battericida della tobramicina e di ridurre sia la resistenza (di almeno 4 volte) che la persistenza (di 10-1000 volte) al farmaco in 23 ceppi sia di laboratorio che clinici alla concentrazione di 80 μg/ml, senza mostrare alcun effetto sul ceppo di laboratorio K1525 (ΔmexY) e senza mostrare attività emolitica alle concentrazioni usate. Tre composti (3a, 3b e 37a) basati su un nucleo chinolinico sono stati caratterizzati per la loro capacità di inibire l’efflusso della ciprofloxacina tramite NorA in S. aureus dimostrando una capacità di inibizione > 60%. Questi composti si sono rivelati inoltre sinergici con la ciprofloxacina, riducendone la MIC di almeno 4-volte nei confronti del ceppo SA1199B (over-esprimente norA) già a basse concentrazioni (6.25 e 3.13 μg/ml). Le concentrazioni sinergiche di questi composti non hanno mostrato né attività emolitica né attività citotossica nei confronti delle linee cellulari THP-1 e A549. In conclusione, in questo lavoro sono stati identificati nuovi EPIs in grado di contrastare la resilienza agli antibiotici sia in P. aeruginosa che S. aureus: queste molecole, risultate promettenti per la loro attività sinergica in combinazione con gli antibiotici e la loro mancanza di tossicità, possono costituire un ottimo punto di partenza per lo sviluppo di molecole ottimizzate in termini di affinità con le loro strutture bersaglio e di sinergia con l’antibiotico nella prospettiva di un loro utilizzo nella pratica clinica contro infezioni difficili da trattare sostenute da ceppi MDR/XDR/PDR di P. aeruginosa e S. aureus.The increase of the antibiotic resistance is one of the most alarming health care problems and tends to become a threatening emergency in the next future. Tolerant and persistent bacterial cells largely contribute to this alarming scenario, since, thanks to a transient modification of genes expression, they can tolerate heavy antibiotic pressure without the need to acquire resistance genetic determinants. Efflux pumps (EP) are main antibiotic resistance mechanisms in both Gram-negatives and Gram-positives by extruding from the cell different toxic compounds, including antibiotics. Moreover, recent findings unraveled their role in different bacterial functions as inter-cellular communication, biofilm development, virulence and persistence. The use of efflux pump inhibitors (EPIs) in combination with known antibiotics seems a promising strategy to counteract multidrug-resistant (MDR) infections. This PhD project aimed to validate novel EPIs against MexXY-OprM and NorA of respectively Pseudomonas aeruginosa and Staphylococcus aureus, two of the most difficult to treat nosocomial pathogens. The results showed that the natural alkaloid berberine can bind to the MexY inner channel of the aminoglycoside-extruding pump MexXY-OprM lowering, at the concentration of 80 μg/ml, both tobramycin MIC (at least four-folds) and persisters amount (between 10 and 1000 times) of 23 lab and clinical P. aeruginosa strains, without affecting the mexY deleted strain K1525; moreover, killing curves assays highlighted an up to 3 log enhanced bacterial killing of tobramycin in association with berberine, which did not show any hemolytic activity at the active concentrations. Three quinoline-based compounds (3a, 3b and 37a) were selected and characterized as S. aureus NorA EPIs, according to their ability to reduce (>60%) the efflux of ethidium bromide; their synergistic (four-fold MIC reduction) activity at very low concentrations (6.25 and 3.13 μg/ml) with ciprofloxacin was demonstrated against the norA-overexpressing strain SA199B. All active quinoline derivatives showed no toxic effects at the synergistic concentrations by hemolysis and human cell (THP-1 and A549) toxicity tests. In conclusion, novel efflux pump inhibitors were identified, able to rescue tobramycin and ciprofloxacin susceptibility of both P. aeruginosa and S aureus; these new molecules could represent i) promising adjuvants to be used in drugs associations and ii) new lead structures to be further optimized to find new strategies to counteract difficult to treat bacterial infections
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
- …
