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MITOCHONDRIAL PERMEABILITY TRANSITION PORE (mPTP) OPENING INHIBITORS AS POTENTIAL DRUGS FOR THE TREATMENT OF ISCHEMIA REPERFUSION INJURY (IRI): DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF DIFFERENT CLASSES OF SMALL MOLECULES.
No full textMitochondrion is the intracellular organelle, which produces ATP through oxidative phosphorylation
(OXPHOS). Its homeostasis is strictly controlled and permeability modification of its membranes is correlated
with events both in cellular and systemic levels.
ATP synthase is the latter enzyme involved in the OXPHOS: it makes use of electrochemical energy to power
the synthesis of ATP. It is constituted by two subunits, FO and F1.
Significant for this project is the c-ring, which is part of the FO subunit and through which protons flows and
ATP synthesis (or hydrolysis) is promoted. It appears to be involved in the formation and regulation of mPTP,
a pore in the inner mitochondrial membrane (IMM). Its opening makes the IMM not more selectively
permeable, causing collapse of the mitochondrial membrane potential, ATP depletion, OMM rupture,
activation of apoptotic cascade. So, it is believed that mPT is a central event implicated in a wide range of
pathologies, including ischemia reperfusion injury (IRI).
The aim of this project was to synthesize compounds which are inhibitors of mitochondrial permeability
transition pore opening.
Initially, we developed small urea derivatives with three different but similar functionalities (urea, thiourea
and carbamates scaffold), starting from the fact that DCU is able to bind the c-ring and to inhibit calciuminduced
mPTP opening. This study has allowed us to understand how H-bond acceptor or donor moieties can
affect the interaction with the target and the activity of the molecules.
The other classes of derivatives take inspiration from natural compound Oligomycin A, that is known to
interact with the c-ring of the ATP synthase and block the proton flow.
We synthesized various different substituted monospiranic compounds. The main core of the natural
reference compound has been slightly modified, making it more stable upon metabolic inactivation,
obtaining an 1,3,8-triazaspiro[4.5]decan-4-one core. The syntheses were associated with computational
studies, thanks to which it was possible to predict the interactions of the molecules with the aminoacidic
residues of the c-ring. Thanks to an HTVS, we also hypothesized structures with a potentially high binding
affinity to the c-ring. By combining the knowledge previously obtained with these new insights, several
molecules were obtained, all of which have the same core and to which gradual and rational modifications
were made.
Moreover, inspired again by the spiranic structure of Oligomycin A, we designed dispiranic derivatives with
both piperidine and pyrrolidine scaffolds, functionalized with elements useful for interaction (aromatic
element, carbonyl group, five-atoms cycle, nitrogen as H-bonds acceptors), but with increased rigidity and
steric size. We also studied the scale up of the reaction, that challenged us a lot, but gave us important
information about the mechanistic dynamics of product formation.
The final part of the project concerned biological evaluations. The tests were conducted in two different
laboratories to test the mPTP opening inhibitory potential of the molecules both in a cardiac and in a renal
model. A selection of compounds was tested on AC16 cells in the labs of professor Paolo Pinton (dept. of
Medical Sciences, University of Ferrara) with the cobalt-calcein assay. Other studies were conducted in the
labs of Professor Alessandro Arcovito (sect. of Applied Biochemistry, Università cattolica del Sacro Cuore -
Rome), testing another selection of compounds with tests on RPTEC cells. We also examined the biological
profile of the most interesting compounds and their properties as cardioprotective agents preventing cells
from apoptosis, both in vitro and ex vivo, specifically in a model of cardiac IRI.
Future perspectives will be focused on proceeding with the testing in vivo, on pig’s heart subjected to
ischemia and then perfusedIl mitocondrio è un organello che produce ATP attraverso la fosforilazione ossidativa. La sua omeostasi è strettamente controllata e la modifica della permeabilità delle sue membrane è correlata a eventi sia a livello cellulare che sistemico.
L'ATP sintasi è l'ultimo enzima coinvolto nell'OXPHOS: sfrutta l'energia elettrochimica per alimentare la
sintesi di ATP. È costituito da due subunità, FO e F1. Significativo per questo progetto è il c-ring, che fa parte della subunità FO: è un canale attraverso cui i protoni passano e viene promossa la sintesi (o idrolisi) di ATP. Questo sembra essere coinvolto
nella formazione e nella regolazione dell’mPTP, un poro nella membrana mitocondriale interna. La
sua apertura rende l'IMM non più selettivamente permeabile, causando il collasso del potenziale di
membrana mitocondriale, la deplezione di ATP, la rottura dell'OMM e l'attivazione della cascata apoptotica. Si ritiene quindi che la mPT sia un evento centrale implicato in un'ampia gamma di patologie, tra cui il danno da ischemia da riperfusione (IRI).
Lo scopo di questo progetto è stato quello di sintetizzare composti inibitori dell'apertura del poro di
transizione di permeabilità mitocondriale. Inizialmente, abbiamo sviluppato piccoli derivati dell'urea con tre funzionalità diverse ma simili (uree, tiouree e carbammati), partendo dal fatto che DCU è in grado di legare il c-ring e di inibire l'apertura della
mPTP indotta dal calcio. Questo studio ci ha permesso di capire come accettori o donatori di legami H
possano influenzare l'interazione con il bersaglio e anche l'attività delle molecole. Le altre classi di derivati si ispirano al composto naturale Oligomicina A, noto per interagire con l'anello c dell'ATP sintasi e bloccare il flusso di protoni.
Abbiamo sintetizzato composti monospiranici diversamente sostituiti. Il nucleo principale del composto naturale di riferimento è stato leggermente modificato, rendendolo più stabile all'inattivazione metabolica, ottenendo un nucleo 1,3,8-triazaspiro[4.5]decan-4-one. Le sintesi sono state associate a studi computazionali, grazie ai quali è stato possibile prevedere le interazioni delle molecole con i residui
aminoacidici del c-ring. Grazie a un HTVS, abbiamo anche ipotizzato strutture con un'affinità di legame potenzialmente elevata con l'anello c. Combinando le conoscenze ottenute in precedenza con queste nuove, sono state ottenute diverse molecole, tutte con lo stesso nucleo, al quale sono state apportate modifiche graduali e razionali.
Inoltre, sempre ispirandoci alla struttura spiranica dell'Oligomicina A, abbiamo progettato derivati dispiranici con scaffold sia piperidinico che pirrolidinico, funzionalizzati con elementi utili all'interazione (elementi aromatici, gruppo carbonilico, ciclo a cinque atomi, azoto come accettore di legami H), ma con maggiore rigidità e dimensione sterica. Abbiamo anche studiato lo scale up della reazione, che ci ha fornito importanti informazioni sulla dinamica della formazione dei prodotti.
La parte finale del progetto ha riguardato le valutazioni biologiche. I test sono stati condotti in due diversi laboratori per verificare il potenziale inibitorio dell'apertura della mPTP delle molecole sia in un modello cardiaco sia in uno renale. Una selezione di composti è stata testata su AC16 nei laboratori del professorPinton (Dip di Scienze Mediche dell'Università di Ferrara) con il saggio della cobaltocalceina. Altri studi sono stati condotti nei laboratori del professor Arcovito (dip di Biochimica applicata, Università cattolica del Sacro Cuore - Roma), testando un'altra selezione di composti con il Mito stress test su RPTEC. Abbiamo inoltre esaminato il profilo biologico dei composti più interessanti e le loro proprietà come agenti cardioprotettivi che prevengono l'apoptosi delle cellule, sia in vitro che ex vivo, in particolare in un modello di IRI cardiaco. Prospettive future sono incentrate su studi in vivo
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
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