1,720,962 research outputs found
Ruolo delle alterazioni mitocondriali nel processo di morte cellulare in patologie neurodegenerative
Get PDFI processi di morte cellulare sono caratterizzati da profondi cambiamenti morfologico-funzionali delle diverse componenti cellulari. In queste condizioni i mitocondri vanno incontro ad una serie di evidenti alterazioni, tra le quali la perdita del potenziale di membrana mitocondriale (MMP) (Reed and Kroemer, 2000) può rappresentare sia un evento precoce dei processi di apoptosi sia un segnale associato all’autofagocitosi degli organelli stessi (Rodriguez-Enriquez et al., 2004).
Nel nostro gruppo è stato osservato che cellule di neuroblastoma umano (TGA) iper-esprimenti la Ttransglutaminasi di tipo 2 (TG2), presentavano alterazioni sia nell’ultrastuttura sia nella fisiologia dei mitocondri (Piacentini et al., 2002), tra cui una iperpolarizzazione costitutiva della membrana interna. Benché l’espressione della TG2 venga indotta durante i processi di morte cellulare per apoptosi, il ruolo di questo enzima nella cascata di eventi che inducono la cellula a morire, non è stata ancora completamente chiarito. Lo scopo di parte di questa tesi di dottorato è stato quello di verificare, a livello molecolare, quali fossero le modificazioni TG2-dipendenti dei mitocondri e le eventuali interazioni con proteine implicate nella regolazione della via mitocondriale dell’apoptosi.
L’analisi della sequenza primaria della TG2 ha portato all’identificazione di una regione con un’elevata omologia col dominio BH3 delle proteine della famiglia di Bcl-2, le quali controllano l’omeostasi mitocondriale e mediano il rilascio dei fattori pro- ed anti-apoptotici dai mitocondri. Il ruolo biologico di questo dominio della TG2 è stato studiato mediante l’utilizzo di peptidi in grado di penetrare la cellula e mimare l’azione del dominio stesso. Questa strategia ha rivelato come la TG2 sia in grado di interagire con Bax a livello mitocondriale e mediante questa interazione provocare la fuoriuscita del citocromo c dagli organelli. La prima parte dei risultati presentati in questa tesi, analizzano l’azione della TG2 e suggeriscono che essa possa essere un nuovo tipo di proteina “BH3-only” e le modalità della sua interazione e/o attivazione di Bax, la collocano esattamente tra le così dette “Bid-like proteins”. Queste proteine, tramite il loro dominio BH3, sono in grado di attivare in modo diretto Bax e sono potenzialmente in grado di regolare la funzionalità si altri membri della famiglia di Bcl-2.
Contestualmente, il nostro gruppo si è occupato dello studio del possibile coinvolgimento della TG2 come modulatore della morte cellulare nella corea di Huntington (HD), una patologia caratterizzata da notevoli disfunzioni mitocondriali. Malgrado l’iper-espressione della TG2 induca alterazioni mitocondriali e stress ossidativo favorendo la morte cellulare (Piacentini et al., 2002), l’incrocio di topi transgenici (HD) R6/1 con i topi knock out per la TG2, evidenzia una riduzione della morte cellulare, un significativo miglioramento della motilità degli animali ed una prolungata sopravvivenza (Mastroberardino et al., 2002). Questo effetto è comunque indipendente dalla capacità dell’attività transamidasica della TG2 a formare le caratteristiche inclusioni intranucleari osservate nella patologia (Bailey and Johnson, 2005). Nella corea di Huntington, la degenerazione cellulare sembra dipendere dall’acquisizione di funzione tossica da parte dell’huntingtina mutata e la perdita di funzione protettiva da parte della proteina normale. Entrambi questi eventi portano a numerose alterazioni cellulari, che coinvolgono anche i mitocondri. Tali alterazioni possono indurre morte cellulare, che può manifestarsi sia come apoptosi sia come autofagia.
La seconda parte di questa tesi riguarda lo studio dell’effetto delle alterazioni mitocondriali che si riscontrano in linfociti derivati da pazienti affetti da HD. I linfoblasti presentano alcune delle caratteristiche osservate nei neuroni HD, d'altra parte, non essendo interessati dal processo degenerativo, permettono sia un'analisi diretta degli effetti dell'htt mutata rispetto a quella wild-type sia l’effetto della mutazione in etero- ed omo-zigosi. Infatti, recenti evidenze, hanno evidenziato una più rapida progressione della malattia nei pazienti omozigoti (Squitieri et al., 2003) probabilmente imputabile alla presenza in doppia dose della proteina mutata ed alla totale mancanza del ruolo protettivo svolto dall'htt normale.
Nella seconda parte di questa tesi sono state analizzate le diverse vie di morte cellulare e le alterazioni mitocondriali attraverso uno studio comparativo tra eterozigoti e omozigoti. In entrambi i casi si osservano evidenti e significative alterazioni morfologico-funzionali dei mitocondri che correlano con il genotipo delle linee cellulari.Apoptosis and autophagy are cell death pathways characterised by great modification of the cell structure, among which morphological and functional alterations of mitochondria. The loss of mitochondrial membrane potential (MMP) (Reed and Kroemer, 2000) could be considered both an early event towards apoptosis or a signal associated with autophagy of the organelles (Rodriguez-Enriquez et al., 2004).
We previously observed that TG2 (Transglutaminase 2) over-expressing cells showed mitochondria that were greatly modified with respect to both their ultrastructure and physiology (Piacentini et al., 2002), with a constitutive hyperpolarization of the inner membrane. Even if TG2 expression is increased during apoptosis, the exact role of the enzyme in the cascade of events leading to cell death remain to be clarified. The first part of this thesis investigated, at a molecular level, the extension of TG2- mitochondrial modification as well as the possible interaction between TG2 and the proteins involved in the regulation of the mitochondrial pathway of apoptosis.
The analysis of the TG2 primary sequence lead to the identification of a region with high homology with the BH3 domain of Bcl-2 family, to which belongs pro- and anti-apoptotic proteins. The biological role of the TG2 domain has been studied by means of cell-permeable peptides, mimicking the domain sequence. This kind of approach allow us to characterise the effect of TG2 at mitochondrial level, where it interacts with Bax and causes cytochrome c release. The obtained results suggest that TG2 might be a new kind of BH3-only protein and its modality of interaction and/or activation of Bax, place it in the so called “Bid-like” proteins. These proteins, by means of their BH3 domain, are direct activators of Bax and potentially able to regulate others Bcl-2 family members.
At the same time our group had been studying the possible involvement of TG2 as a cell death modulator in Huntington’s disease (HD). In fact, it is known that over-expression of TG2 leads to cell death in human neuronal cells by inducing mitochondrial alterations and oxidative stress (Piacentini et al., 2002), but also by crossing HD R6/1 transgenic mice with TG2 knockout mice, a marked reduction in cell death is observed in R6/1, TG2 null when compared withR6/1 transgenic mice. The reduction in cell death is paralleled by a significant improvement in motor performances of R6/1, TG2 null versus R6/1 mice and extended survival (Mastroberardino et al., 2002). However this is independent from TG2 capability to make intranuclear inclusions by its cross-linking activity (Bailey and Johnson, 2005). The degenerative process of Huntington disease, relies both on the acquisition of toxic function by mutated huntingtin (htt) as well as on the loss of protection exerted by the wild type protein. Both these events lead to a lot of cellular alterations, which involve also mitochondria and they lead to cell death by apoptosis and/or autophagy. The second part of this thesis deal with the study of mitochondrial alterations observed in lymphocyte derived from HD patients. Lymphoblasts display some characteristics observed in HD neurons, otherwise, as they are not involved in neurodegenerative process, they allow a direct analysis of mutated htt effects in respect to the wild-type one as well as the effect of the mutation in hetero- and homo-zygosis. Recent evidences suggested that, the faster progression of the disease observed in homozygous patients, might be due to the presence in double dose of the mutated protein, coupled to the complete loss of the wild type one’s protective role (Squitieri et al., 2003).
The second part of this thesis analyzes the different cell death pathways and the mitochondrial alterations in HD cell lines, through comparative study between heterozygous and homozygous patients. The results obtained show that in both cases we can observe plain and remarkable morfologial-functional alterations of mitochondria that correlates with the genotype of the patient
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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