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Caratterizzazione molecolare e funzionale di nuove mutazioni nelle encefalomiopatie mitocondriali
Get PDFLe encefalomiopatie mitocondriali rappresentano un gruppo di malattie estremamente eterogeneo ed in continua crescita sia per il sempre maggiore numero di fenotipi clinici descritti che per le conoscenze delle basi molecolari che le sottendono. Esse sono, collettivamente, il risultato di una diminuita capacità da parte dei mitocondri di soddisfare le richieste energetiche della cellula, a causa per lo più della ridotta attività enzimatica della catena respiratoria e la conseguente compromessa produzione di ATP intracellulare.
In questo studio sono state indagate le conseguenze patogenetiche delle quattro mutazioni più frequentemente associate alla NARP/MILS - T8993G (L156R), T9176G (L217R), T8993C (L156P) e T9176C (L217P) - nel gene mitocondriale ATPasi 6, che codifica per una subunità del complesso V. La F1F0-ATP sintetasi (complesso V) è un enzima ubiquitario, presente nelle membrane dei batteri, dei cloroplasti e nella membrana interna dei mitocondri dove sintetizza ATP, l' ultimo step della fosforilazione ossidativa (Garcia, 2002). L' enzima è costituito da due subcomplessi F0 e F1. L' attività catalitica dell' enzima è localizzata nella porzione F1, che è estrinseca alla membrana ed utilizza il gradiente protonico per convertire ADP in ATP e viceversa; la subunità F0 si trova nella membrana mitocondriale interna e permette il flusso di protoni dallo spazio intermembrana alla matrice. Valutando la capacità duplicativa delle cellule in terreno standard, abbiamo potuto osservare che i fibroblasti di pazienti con la mutazione T->G, crescono con maggiore difficoltà rispetto a quelli con la mutazione T->C ed ai fibroblasti di controllo. Questa condizione si aggrava ulteriormente quando le cellule vengono sottoposte a stress, come la sostituzione del glucosio con il galattosio, un metabolita che entrando nella glicolisi più a valle, fornisce un numero minore di molecole di ATP e mette in evidenza i danni a carico della catena respiratoria. L' attività del complesso V, in termini di sintesi ed idrolisi, della catena respiratoria è stata valutata sui mitocondri ottenuti sia dai fibroblasti omoplasmici per le quattro mutazioni, che da cloni a diversa percentuale di mutazione. Tali indagini, effettuate mediante metodiche di tipo spettrofotometrico, hanno confermato la gravità delle mutazioni T->G rispetto alle varianti alleliche in entrambi i tipi cellulari. Lâ utilizzo inoltre di cloni a diversa percentuale di mutazione, ha consentito di determinare la soglia del fenotipo patologico per le mutazioni T->G.
Inoltre abbiamo studiato lâ effetto dell' oligomicina e della sonicazione sull' attività dell' ATPasi nelle cellule primarie e nei cloni. I nostri risultati suggeriscono che le linee primarie con la mutazione L156R esibiscono una porzione F1 debolmente legata alla membrana poiché l' attività idrolitica non è pienamente sensibile alla oligomicina e poiché a 20â di sonicazione l' ATPasi diventa insensibile all'inibitore, probabilmente per il dovuto rilascio della porzione F1 dalla membrana.Mitocondrial ATP synthase consists of two functional domains, F1 and F0. F1 protudes in to the matrix, is hydrophilic, and contains five subunits (3α,3β,γ,δ,ε) and inibibitor protein. F0 is hydrophobic, is embedded in the mitochondrial inner membrane, and contains subunits a, b, c, d, e, f, g, F6, OSCP and A6L. F1 is connected to F0 by a stalk that contains the subunits OSCP, F6, b, d. Subunits 6 and A6L are encoded by the mitochondrial genome whereas all of the other subunits are encoded by nuclear genes. ATP synthase deficiency can therefore be due to mutations of either nuclear or mitochondrial genes.
Mutations in the ATPase 6 gene, characterized by a profound defect of the activity of the enzyme, are recognized as a cause of maternally-inherited LS. Leighâ s syndrome (LS) is a neurodegenerative disorder of infancy characterized by developmental delay, psychomotor regression, seizures, and symptons of brainstem dysfunction. In addition, biochemical defects in complex I, complex IV and PDHC underlie most of the LS patients.
In order to know the different pathogenic mechanism leading to diverse clinical severity, of the mutations in the ATPase 6 gene, we compared cellular ATP production, cell growth and entity of cellular response upon use of metabolic stressors in primary cell cultures obtained from patients harboring either the T8993G, or T8993C, or T9176G, or T9176C and in cybrids clones obtained after fusion of each primary cell lines with Ï 0 cells.
Arginine (â â Râ â ) mutations were associated with a much more severe phenotype than Proline ( P ) mutations, in terms of both biochemical activity and growth capacity. Also, a threshold effect in both R mutations appeared at 50% mutation load. Different mechanisms seemed to emerge for the two R mutations: the F1 seemed loosely bound to the membrane in the L156R mutant, whereas the L217R mutant induced low activity of complex V, possibly the result of a reduced rate of proton flow through the A6 channel
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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