3,145 research outputs found
Specific molecular modelling and dynamics to study the structure/function relationship in clonogenic HIV-1 p17 protein variants: preliminary set up of a computational drug repositioning pipeline
No full textNel mio progetto di ricerca ho studiato le varianti della proteina di matrice p17 di HIV-1 (vp17s), caratterizzate da inserzioni di amminoacidi nella regione C-terminale della proteina virale. A differenza della p17 wild-type (refp17), queste varianti mostrano una forte capacità di promuovere la crescita delle cellule B e sono prevalentemente riscontrate nei pazienti affetti da linfoma rispetto ai pazienti HIV-1 positivi senza linfoma, suggerendo un loro ruolo chiave nella linfomagenesi nei pazienti HIV-1+. Attraverso l’analisi genomica, abbiamo identificato hot spots di mutazione nel gene Gag, concentrandoci in particolare sulla porzione della matrice (MA), che sembrano originarsi da un arresto della trascrittasi inversa (RT) durante la replicazione virale. Questo fenomeno è probabilmente guidato da sequenze palindromiche e ripetitive, oltre a un elevato contenuto di adenina, creando instabilità genomica che favorisce eventi di ricombinazione e la generazione di vp17s.
Il progetto ha incluso anche un approccio sperimentale per validare le analisi bioinformatiche: i miei colleghi hanno misurato la frequenza degli eventi di ricombinazione associati agli hot spots mutazionali identificati. I risultati hanno confermato un ampio spettro di eventi di ricombinazione che si verificano in queste regioni instabili, contribuendo alla generazione di vp17s con attività clonogenica.
Per approfondire i meccanismi molecolari alla base del potenziale clonogenico delle vp17s, ho condotto studi computazionali, come le simulazioni di dinamica molecolare (MDs). Le MDs hanno rivelato che le vp17s subiscono cambiamenti conformazionali significativi, alterando notevolmente la loro struttura secondaria ed il network di legami idrogeno. In particolare, i residui idrofobici Trp16 e Tyr29 si dissociano dal loro nucleo idrofobico, cruciale per la stabilità di refp17. Questo distacco espone epitopi funzionali, in grado ipoteticamente di attivare vie di segnalazione proliferativa nelle cellule B. Mutazioni sito-specifiche di Trp16 e Tyr29 in refp17 hanno prodotto una proteina con attività clonogenica, confermando l'importanza di questi residui nella regolazione della crescita cellulare. Inoltre, ho esplorato approcci di riposizionamento farmacologico per identificare farmaci esistenti in grado di contrastare le vp17s e inibire la loro attività clonogenica.
Le MDs e gli studi di docking hanno identificato alcune molecole che potrebbero interagire con specifici residui delle vp17, suggerendo nuovi potenziali trattamenti per prevenire lo sviluppo di linfomi nei pazienti HIV-1+.
Infine, ho trascorso sei mesi nel laboratorio di Pietro Liò presso il Computer Laboratory dell'Università di Cambridge, focalizzandomi sull'integrazione dei metodi di simulazione di dinamica molecolare con metodologie di intelligenza artificiale e sviluppando strategie di validazione robuste per i modelli generativi. Le conoscenze acquisite da questa esperienza saranno applicate per approfondire i miei futuri studi su target terapeutici sia virali che non virali.
In conclusione, il mio lavoro ha contribuito a chiarire i meccanismi molecolari alla base dell’evoluzione e della funzione delle vp17s, identificando vulnerabilità strutturali che potrebbero essere sfruttate per lo sviluppo di nuove strategie terapeutiche. Questo studio non solo avanza la comprensione delle vp17s nella patogenesi dell'HIV, ma apre anche nuove prospettive per interventi farmacologici mirati a prevenire i linfomi associati.In my research project, I studied HIV-1 matrix protein p17 variants (vp17s), characterized by insertions of amino acid at the COOH-terminal region of the viral protein. Unlike the wild-type p17 (refp17), these variants show potent B-cell growth and clonogenic activity and are prevalently found in lymphoma patients than in HIV-1 infected patients without lymphoma, suggesting their key role in lymphomagenesis in HIV-1+ patients. Through genomic analysis, we identified mutation hotspots in Gag, focusing particularly to the matrix (MA) portion, which likely arise from reverse transcriptase (RT) stalling during viral replication. These appear to be driven by palindromic and repetitive sequences, as well as a high adenine content, creating genomic instability that favors recombination events and the generation of vp17s. The project also included an experimental approach to validate these computational observations: my colleagues measured the frequency of recombination events associated with the identified mutational hotspots. The results confirmed a broad range of recombination events occurring in these unstable regions, contributing to the generation of vp17s with oncogenic activity.
To further investigate the molecular mechanisms underlying the clonogenic potential of vp17s, I performed computational studies, such as molecular dynamics (MDs). MDs revealed that vp17s undergo dramatic conformational changes, significantly altering their secondary structure and hydrogen bond networks. Notably, the hydrophobic residues Trp16 and Tyr29 detach from their hydrophobic core, which is crucial for refp17 stability. This detachment exposes functional epitopes, capable of activating proliferative signaling pathways in B cells. Site-specific mutations of Trp16 and Tyr29 in refp17 resulted in a protein with clonogenic activity, confirming the importance of these residues in regulating cell growth. Moreover, I explored drug repositioning approaches to identify existing drugs capable of counteracting vp17s and inhibiting their B-cell clonogenic activity.
Molecular dynamics simulations (MDs) and docking studies revealed that certain molecules could target specific residues of vp17s, suggesting new potential treatments to prevent lymphoma development in HIV-1+ patients.
Finally, I spent six months in Pietro Liò’s laboratory at the Computer Laboratory of the University of Cambridge, focusing my studies on integrating molecular dynamics simulation methods with artificial intelligence methodologies and developing robust validation strategies for generative models. The knowledge gained from this experience will be applied to further deepen my future studies on both viral and non-viral therapeutic targets.
In conclusion, my work contributed to elucidating the molecular mechanisms behind vp17 evolution and function, identifying structural vulnerabilities that could be exploited for the development of new therapeutic strategies. This study not only advances the understanding of vp17s in HIV pathogenesis but also opens new avenues for targeted pharmacological interventions to prevent HIV-associated lymphomas
A imagem de Alessandro Baricco no Brasil
No full textDissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Comunicação e Expressão, Programa de Pós-Graduação em Estudos da Tradução, Florianópolis, 2013.Com a intenção de delinear o modo pelo qual o escritor italiano Alessandro Baricco se inseriu no sistema literário brasileiro e os caminhos percorridos pelos seus livros traduzidos, esta dissertação dá voz às experiências tradutórias de seus tradutores. A inserção de Bariccono Brasil tem seu início em 1997, através de uma proposição da Profa. Dra. Roberta Barni à editora Iluminuras da tradução de Oceano Mare. A partir daí, outras sete obras foram publicadas no Brasil, sendo três delas traduzidas por Roberta Barni e as outras quatro por quatro tradutores diferentes. De um lado, considera-se o tradutor como figura principal namediação entre culturas, e, de outro, se analisa a realidade desta figuradentro do sistema literário, sua invisibilidade, seus limites e o exercíciode sua profissão. A pesquisa conta, ainda, com críticas e resenhas referentes ao autor italiano publicadas em jornais consagrados no Brasil, considerando estas como parte constituinte da imagem de Baricco refletida em território nacional. Abstract : Intending to delineate the way the Italian writer Alessandro Baricco has been inserted in the Brazilian literary system and the paths his translated books have followed, this thesis gives voice to the translating experiences of his translators. Baricco's insertion in Brazil began in 1997, through a personal project of Dr. Roberta Barni, with her translation of Oceano Mare. Since then, seven other of his works have been published in Brazil, three of which were translated by Roberta Barni and the other four by four different translators. On the one hand,the translator is considered as the main figure in mediation betweencultures and, on the other, this figure's reality is analyzed within theliterary system: its invisibility, its limits and its professional practice. Criticisms and reviews of this Italian author published in well established Brazilian newspapers are also considered, with the understanding that they are part of Baricco's image reflected here
La maturità di Alessandro Fei del Barbiere, in bilico tra Maniera e Riforma
No full textThis article studies the mature career of the Florentine painter Alessandro Fei del Barbiere (1537-1592), beginning with the rediscovery of the 'Ascension' altarpiece formerly in the Albizi Chapel in the destroyed church of San Pier Maggiore, Florence. Studying this painting and others recorded in 1584 by the biographer Raffaello Borghini, such as the two altarpieces for Santa Maria delle Grazie and the Madonna dell'Umiltà in Pistoia, the author reconstructs a body of works showing how in the 1580s Fei gradually went beyond the archaic style of his apprenticeship - he had been trained by Ridolfo del Ghirlandaio and Pierfrancesco Foschi, but was also marked by the Maniera of Vasari - evolving towards naturalism in both mimesis and pictorial handling. In Florence, his development partly parallels that of Santi di Tito and his circle, but Fei was also influenced by a probable sojourn during the early part of that decade in Rome, where he could have been inspired by Girolamo Muziano and the painters working for Pope Gregory XIII. Among other proposals, the author suggests that the artist was responsible for decorating the chancel of Fiesole Cathedral (c. 1584-1589), which consisted of an altarpiece, only rarely discussed by scholars, and a cycle of frescoes hitherto attributed to Nicodemo Ferrucci
Oltre la Ferrara moderna: passeggiata nel Novecento ferrarese - Beyond Modern Ferrara: a walk through the Twentieth Century
No full textFerrara is renowned for its Renaissance heritage, characterized by art and architecture that marked an extended period of splendor. Historiography frequently emphasizes this era, overlooking a significant cultural ferment in the first half of the twentieth century. Architects such as Ciro Contini, Carlo Savonuzzi, and Giorgio Gandini contributed to reshaping Ferrara, attempting to craft a new identity for the city. This guided walk aims to showcase some of the city center’s most iconic buildings, ranging from the Liberty villas designed by Contini to the modernist structures by Gandini and Savonuzzi
Tra socialdemocrazie e Perestrojka. Le relazioni internazionali del Pci attraverso le carte di Alessandro Natta
No full textThis essay reconstructs the foreign policy of the Italian Communist Party during the four
years of Alessandro Natta’s secretariat (1984-1988) through largely original archival documentation,
from the Alessandro Natta Fonds of the Historical Archive of the Chamber of
Deputies. Natta’s papers are also cross-referenced with those kept in the PCI Archive at the
Gramsci Foundation. The author analyses the relationship that the PCI establishes with
Gorbachev’s Perestroika, Deng’s China, and European social democracies during the last
years of the Cold War
Volta Alessandro
No full textThe New Dictionary of Scientific Biography (extension and updating of the Dictionary of Scientific Biography) is one of the most substantial reference works in the field of the history of science. An up-to-date overview on Alessandro Volta's science with new perspectives offered by the author. Information and critical analysis is also provided on the main secondary literature produced on this main protagonist of enlightenment science after the 1976 entry "Volta Alessandro" in the Dictionary of Scientific Biography
"Muy señor nuestro Alessandro Varaldo". La ricognizione del mondo spagnolo e portoghese per riscoprire un autore italiano di successo ma dimenticato
No full textWho is Alessandro Varaldo (1876-1953)? This first analysis about what was said, adapted and translated of Varaldo’s work in the Iberian Peninsula and South America, maybe the only areas outside Italy where some traces of Italian author can be found, is a chance to go along his literary paths that overtook two temporal barriers (1900 and 1950), although it has not overtaken the oblivion’s threshold.Questa è una prima ricognizione di ciò che è stato detto, adattato e tradotto di Alessandro Varaldo (1876-1953) nella Penisola iberica e in Sud America, che si sospetta siano gli unici territori stranieri dove si riesca a ritracciare qualcosa dell’autore italiano, ed è un’occasione per ripercorrerne la traiettoria letteraria che ha superato due transenne temporali come il 1900 e il 1950 ma non quella della dimenticanza
Lean six sigma in a call centre : a case study
No full textThis paper, a case study, aims to illustrate the application of lean six sigma in a call centre of a service industry corporation. The study draws on process information and primary data from a real project. The study describes improvements in the operation of the call centre attributable to lean six sigma: increase in first-call resolution ratio, reduction in operator turnover and streamlining of processes. The introduction of lean six sigma into the call centre daily operations' management may have organizational benefits. Although lean six sigma has been extremely successful in the last two decades in the manufacturing sector, its applicability to the service sector has been a controversial topic. This study illustrates its application to a fast-growing area of the service sector, assisting companies in identifying areas of development for their call centres
- …
