1,720,957 research outputs found
PICCOLE MOLECOLE BIOATTIVE DA SCREENING VIRTUALE DI LIBRERIE CHIMICHE PER IL TARGETING DEI MITOCONDRI NELLE MALATTIE RARE
No full textLa disfunzione mitocondriale assume un ruolo centrale nella fisiopatologia di numerosi disturbi metabolici rari, spesso derivanti da mutazioni in geni nucleari o mitocondriali che codificano proteine mitocondriali essenziali. Queste patologie, frequentemente classificate come malattie orfane, necessitano di nuove e significative sfide nella ricerca e nello sviluppo terapeutico. Negli ultimi tre decenni, strategie come il “drug repurposing” e la modulazione mirata di proteine mitocondriali sono emerse come possibili approcci terapeutici. Tra le varie analisi effettuate, la ricerca sulla Carnitina O-Acetiltransferasi (CRAT) ha permesso lo sviluppo di una pipeline volta a identificare nuovi modulatori selettivi per le varianti di CRAT.
CRAT, enzima cruciale nel metabolismo mitocondriale, è implicato nella patologia della sindrome di Leigh quando sono presenti specifiche varianti. Il nostro approccio ha integrato analisi di docking in silico e screening virtuale di librerie chimiche per predire piccole molecole ad alta affinità per CRAT, seguite da validazione in vitro. Questa metodologia ha permesso di individuare specifiche piccole molecole modulatrici in grado di agire selettivamente contro la proteina mutata e patogenica CRAT p.Tyr110Cys, dimostrando la sinergia tra previsioni computazionali e successiva validazione sperimentale.
Il caso di CRAT sottolinea la necessità di studiare le relazioni struttura-funzione nelle proteine mitocondriali, evidenziando che la localizzazione e l'impatto specifico delle mutazioni devono essere attentamente valutati prima di procedere con lo sviluppo di farmaci o con l'uso di terapie antiossidanti sinergiche. La localizzazione delle mutazioni può dare indicazioni sull’efficacia dei trattamenti somministrati, incluse terapie antiossidanti o basate su cofattori, oppure evidenziare eventuali effetti collaterali e non desiderati. Capire con precisione il ruolo dei siti mutati permette una maggiore ottimizzazione degli interventi terapeutici e una predizione dei risultati a seguito del trattamento.
I nostri risultati evidenziano anche il ruolo più ampio che assumono le proteine mitocondriali come bersagli farmacologici, in condizioni caratterizzate da stress ossidativo, omeostasi energetica non funzionante, e disfunzione mitocondriale, tra cui sindrome metabolica, malattie legate all'invecchiamento e malattie cardiovascolari. L’avanzamento nella metodologia sia in silico che in vitro per indagare e modulare le funzioni mitocondriali apre nuove e promettenti strade per il trattamento di patologie correlate ad una corretta funzionalità mitocondriale.Mitochondrial dysfunction is central to the pathophysiology of numerous rare metabolic disorders, often stemming from mutations in nuclear or mitochondrial genes that encode essential mitochondrial proteins. These disorders, frequently categorized as orphan diseases, face significant research and therapeutic development challenges. Over the past three decades, strategies such as drug repurposing and targeted modulation of mitochondrial proteins have emerged as viable therapeutic pathways. Among the various performed analyses, research on Carnitine O-Acetyltransferase (CRAT) has enabled the development of a pipeline aimed at identifying new selective modulators for CRAT variants.
CRAT, a critical enzyme in mitochondrial metabolism, is implicated in the pathology of Leigh syndrome when specific variants are present. Our approach integrated in silico docking analyses and virtual screening of chemical libraries to predict high-affinity small molecules for CRAT, followed by in vitro validation. This methodology uncovered selective small-molecule modulators effective against the pathogenic CRAT variant p.Tyr110Cys, demonstrating the synergy between computational predictions and experimental verification.
The case of CRAT underscores the necessity of studying structure-function relationships in mitochondrial proteins, emphasizing that the localization and specific impact of mutations must be thoroughly assessed before advancing drug development or employing synergistic antioxidant therapies. The localization of mutations can influence whether administered treatments, including antioxidants or cofactor-based strategies, achieve their intended efficacy or pose risks due to unintended interactions. Such precision in understanding mutation sites helps optimize therapeutic interventions and predict treatment outcomes.
Our findings also highlight the broader relevance of mitochondrial proteins as pharmacological targets for conditions marked by oxidative stress, disrupted energy homeostasis, and mitochondrial dysfunction, such as metabolic syndrome, age-related disorders, and cardiovascular diseases. Advancing in silico and in vitro techniques to probe and modulate mitochondrial functions offers promising new avenues for treating pathologies reliant on mitochondrial health
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
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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