1,721,025 research outputs found
OI zebrafish models and their use to develop new pharmacological treatments
Get PDFL’osteogenesi imperfetta (OI) è una malattia scheletrica rara caratterizzata da fragilità e deformità ossee. Le forme dominanti sono causate da mutazioni nei geni codificanti le catene del collagene di tipo I, COL1A1 e COL1A2. Le forme recessive sono causate da mutazioni in geni coinvolti nei processi di modificazioni post traduzionali, di secrezione e processamento del collagene di tipo I. Lo scopo del mio lavoro di tesi è stato quello di utilizzare lo zebrafish come modello di malattie scheletriche, grazie ai suoi numerosi vantaggi come la trasparenza degli embrioni, la fertilizzazione esterna e la possibilità di applicare facilmente tecniche di genome editing. Nella prima parte della mia tesi ho contribuito alla caratterizzazione del collagene di tipo I di zebrafish che a differenza di quello umano, costituito da due catene α1 e da una catena α2, ha tre diverse catene: α1, α2 e α3. L’espressione spazio-temporale dei geni codificanti le tre catene è simile sia negli embrioni che nei pesci adulti. Nonostante nella pelle, nelle scaglie e nell’osso adulto ci sia un’uguale quantità di α1(I), α3(I) and α2(I), una stechiometria tessuto specifica e la presenza di modifiche post-traduzionali sono state riportate. Con questo primo lavoro abbiamo dimostrato che lo zebrafish è un buon modello per lo studio delle malattie scheletriche. Nella seconda parte ho caratterizzato il modello di OI dominante Chihuahua che ha una sostituzione G574D nella catena α1 del collagene di tipo I. X-Ray e colorazioni specifiche hanno dimostrato la presenza nel Chihuahua di deformità ossee e fratture. Il collagene di tipo I dello zebrafish Chihuahua corre lentamente rispetto a quello di pesci WT a causa della presenza di over modificazione post traduzionale. Tutte queste sono caratteristiche tipiche dei pazienti affetti da OI. La presenza di un allargamento del reticolo endoplasmatico è stata riscontrata grazie a microscopia elettronica e confocale. Per cercare di ridurre lo stress del reticolo abbiamo deciso di utilizzare due chaperonine chimiche, già in commercio, 4PBA e TUDCA. Dopo trattamento con 4PBA, sia a breve che a lungo termine, è stato evidenziato nei Chihuahua un miglioramento sia a livello scheletrico che di secrezione del collagene. Il progetto principale della mia tesi di dottorato si è incentrato sulla generazione di modelli di OI recessiva utilizzando la metodica CRISPR/Cas 9. I primi due modelli generati sono di OI di tipo VII e VIII, causati da mutazioni in CRTAP e P3H1, componenti del complesso che è coinvolto nelle modifiche post traduzionali della Prolina 986 dell’α1 del collagene di tipo I e di tipo II, della Prolina 707 dell’α2 (I). L’ultimo modello generato è stato quello relativo alla forma XIV di OI, causata da mutazioni in TMEM38B. Questo gene codifica per il canale intracellulare cationico della membrana del reticolo endoplasmatico TRIC-B, legato al rilascio di Ca2+. Alterazioni dell’omeostasi del calcio possono risultare in un’alterata attività di diverse proteine che interagiscono con il collagene, causando la anomala regolazione dei processi di biosintesi e provocando alterazioni nelle modifiche post traduzionali. I modelli di OI di tipo VII e VIII sono stati ampliamente caratterizzati sia da un punto di vista morfologico che biochimico ed entrambi sono risultati essere validi modelli di OI, rispecchiando le comuni caratteristiche dei pazienti. La generazione del modello di OI di tipo XIV è stato generato solo recentemente. Lo scopo ultimo sarà quello di utilizzare le chaperonine chimiche già validate sul modello Chihuahua su queste forme recessive della malattia.Osteogenesis Imperfecta is a heritable disorder characterized by bone deformity, skeletal fragility and short stature. Dominant forms of OI are caused by qualitative or quantitative mutations in the collagen genes COL1A1 and COL1A2. Recessive forms of OI are mainly caused by defects in genes involved in collagen posttranslational modification, folding, collagen production and bone mineralization. Zebrafish imposed itself as a powerful model to study skeletal diseases, but a limit to its use is the poor characterization of collagen type I, the most abundant protein in bone and skin.
In the first part of my PhD thesis I contributed to the characterization of collagen type I in zebrafish. In zebrafish three type I collagen genes exist coding for α1(I), α3(I) and α2(I) chains. During embryonic and larval development the three collagen type I genes showed a similar spatio-temporal expression pattern, indicating their co-regulation and interdependence at these stages. In both embryonic and adult tissues, the presence of the three α(I) chains was demonstrated. Even though in adult bone, skin and scales equal amounts of α1(I), α3(I) and α2(I) chains are present, data reported in this paper suggest a tissue-specific stoichiometry and/or post-translational modification status for collagen type I. The second part of my thesis was focused on the characterization of the zebrafish Chihuahua as good model of dominant OI carrying a G574D substitution in the α1 chain of type I collagen. Chihuahua show of bone deformities, fragility and mineralization delay, typical features of human OI and the peculiar OI collagen type I migration pattern, characterized by delay and broader α bands, was observed in SDS-PAGE. The presence of endoplasmic reticulum enlargement was demonstrated by electron and confocal microscopy analysis. I used this model to test a novel treatment for OI using chemical chaperones 4PBA and TUDCA targeting the cellular stress. After both short and long treatment with 4PBA, an amelioration was observed in mutant fish, both at the level of skeletal architecture and of collagen secretion.
The zebrafish Chihuahua shows deformations and fractures in the ribs, altered mineralization patterns, reduced mineral and collagen maturity, and increased bone porosity.
As major project of my PhD thesis I generated three zebrafish models for the recessive OI forms type VII, caused by mutations in CRTAP, type VIII, caused by mutations in P3H1 and type XIV, caused by mutations in TMEM38B, using the CRISPR/Cas9 system. CRTAP and P3H1 are components of an ER-resident complex, the collagen prolyl-3-hydroxylation complex, involved in the post-translational modifications of proline 986 in α1(I). OI type XIV is caused by defects in TMEM38B, which a trimeric ER-membrane cation channel involved in calcium release. Calcium is important to regulate the activity of several ER proteins involved in collagen metabolism. Alterations in ER Ca2+ homeostasis can alter the expression and activities of multiple collagen interacting proteins and deregulate the process of collagen biosynthesis, leading to abnormal collagen modification. OI type VII and VIII models have been deeply characterized both from a morphological and biochemical point of view and validate as good models of the disease. The generation of the OI type XIV zebrafish has only recently been successfully obtained and the model characterization is still ongoing. These recessive models will be used to attempt the same pharmacological treatment based on chemical chaperones, successfully tested in the Chihuahua model for dominant OI. The possibility to treat both dominant and recessive forms of OI, using the same rationale and the same drug, that is already on the market, paves the way for a plausible future therapy for patients
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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