Localizzazione della topoisomerasi IB sui telomeri di S. cerevisiae e ruolo della sua attività catalitica sulle modificazioni istoniche

Il superavvolgimento del DNA nelle cellule, regolato dalle DNA Topoisomerasi, influenza molti processi biologici, quali la trascrizione, la replicazione, la ricombinazione ed il rimodellamento della cromatina. La DNA Topoisomerasi IB eucariotica, (Top1), è un enzima efficiente nella rimozione dei superavvolgimenti del DNA in vitro e la sua principale funzione cellulare è la rimozione dei superavvolgimenti positivi e negativi generati durante la trascrizione e la replicazione. Risultati recenti hanno fornito evidenze sperimentali del coinvolgimento di Top1 in meccanismi multipli di regolazione dell’espressione genica eucariotica, in particolare nella fase di inizio e maturazione dei trascritti. Tuttavia, le funzioni di Top1 non sono ancora state stabilite a livello globale. Pertanto, nella presente tesi di dottorato abbiamo risposto a questa domanda con l’analisi dei profili di trascrizione genica globale e con studi di immunoprecipitazione della cromatina (ChIP) in cellule di S. cerevisiae. Circa il 9% dei geni sono influenzati da Top1, e l’analisi dei profili di espressione mostra che Top1 wt aumenta l’utilizzo del glucosio e dei pathway per la produzione di energia, con specifica diminuzione della trascrizione dei geni telomerici e subtelomerici. Abbiamo inoltre dimostrato che Top1 wt, ma non il suo mutante inattivo, aumenta la velocità di crescita cellulare nelle cellule di lievito studiate. Le analisi di ChIP mostrano che, in confronto all’assenza dell’enzima, Top1 wt diminuisce l’acetilazione dell’istone H4, compresa quella specifica della lisina 16, nel telomero destro del cromosoma XIV mentre la mutazione che inattiva l’enzima aumenta in maniera marcata l’acetilazione dell’istone H4 e la di-metilazione della lisina 4 dell’istone H3. Top1 wt incrementa anche il reclutamento di Sir3 nelle regioni di confine della cromatina silenziata dello stesso telomero. Studi di immunoprecipitazione indicano che l’enzima interagisce direttamente con la struttura della cromatina telomerica poichè entrambe le proteine, quella wt e quella inattiva, sono localizzate sulle ripetizioni telomeriche dei cromosomi di lievito. Questi risultati dimostrano che Top1, una proteina non essenziale in lievito, ottimizza i livelli globali dei trascritti per una crescita più efficiente di cellule in fase esponenziale. Indagando il meccanismo che è alla base della specifica repressione dei geni telomerici, abbiamo dimostrato che Top1 favorisce delle modifiche posttraduzionali degli istoni che indicano una struttura della cromatina repressa nelle regioni telomeriche.

Il futuro delle Alpi sui sentieri della sostenibilità. Qualità ambientale e sviluppo economico nelle regioni alpine

Il tema dello sviluppo sostenibile, e i numerosi ambiti di ricerca e di applicazione a esso connessi, è oramai coralmente accettato dalla comunità scientifica, intellettuale e politica internazionale. Tuttavia, una certa tendenza a una sua iper-utilizzazione può comportare svuotamento di significati e perdita di valore. Obiettivo della presente ricerca, dunque, è quello di ripensare il concetto della sostenibilità tenuto conto delle trasformazioni strutturali che hanno interessato le regioni alpine tra il XIX e il XX secolo e sulla base di esperienze realizzate, in atto o in potenza che ben ne evidenzino le possibili applicazioni a livello regionale e locale. A tal fine, nel corso della trattazione si propone un’analisi delle buone pratiche incontrate lungo il cammino compiuto sui sentieri della sostenibilità.

Indagine sull’influenza di differenti sistemi d’allevamento sui connotati nutrizionali, tecnologici, sensoriali e di freschezza dell’orata (Sparus aurata) allevata in Italia

On account of the commercial importance of gilthead sea bream (Sparus aurata) in Italy the aim of the present study is the evaluation of the quality of nutritional, technological, sensory and freshness aspects. Sea bream production is growing in the Mediterranean and the evaluation of its quality concerns both producers and consumers alike. The culture system greatly influences final product quality. In Italy most of sea bream culture is carried out in cages but there is also a production in land based facilities and in lagoons. In this study external appeareance differentiations are pronounced. Different results were found for nutritional aspects, for fatty acids and for mineral content. Some differences in the freshness indices are also found. Furthermore, organoleptic differences have been described between culture system.

Doxorubicina coniugata alla albumina umana lattosaminata: azione antineoplastica sui carcinomi epatocellulari indotti nel ratto dalla dietilnitrosammina

The experiments described in the thesis for my PhD were addressed to the study of the anticancer activity of a conjugate of doxorubicin (DOXO) with lactosaminated human albumin (L-HSA) on hepatocellular carcinomas (HCCs) induced in rats by diethylnitrosamine. L-HSA is a neoglycoprotein exposing galactosyl residues. The conjugate was prepared to improve the chemo therapeutic index of DOXO in the treatment of the well differentiated (WD) HCCs whose cells mantain the receptor for galactosyl terminating glycoproteins and consequently can actively internalize L-HSA. In my first experiments I found that L-HSA coupled DOXO produced concentrations of DOXO higher than those raised by an equal dose of free drug, not only in WD HCCs, but also in the poorly differentiated forms (PD) of these tumors which do no express the receptor for galactosyl terminating glycoproteins. Subsequently I provided evidence that penetration of L-HSA-DOXO in PD HCCs was due to a non-specific adsorption mediated by the DOXO residues of the conjugate which interact with the cell surface mainly because at physiological pH they are positively charged and bind to anionic phospholipids of the cell membrane. In subsequent experiments, by ultrasound technique, I studied the action of free and L-HSA coupled DOXO on the growth of rat HCCs. I found that L-HSA coupled DOXO hindered the development of new neoplastic nodules and inhibited the growth of the established tumors. In contrast, the free drug neither inhibited the development of HCCs nor prevented the growth of the established tumors. Moreover, the free drug produced a severe loss of weight of rats, a sign of severe toxicity, which was not caused by the conjugate. In conclusion assuming that the results obtained in rats can be applied to patients, the results of my thesis suggest that the conjugate by increasing the efficacy and tolerability of DOXO could improve the value of this drug in the treatment of human HCCs.

Studio di fenomeni d'instabilità gravitativa sui fondali marini, con particolare riferimento all'isola di Stromboli

In the last decade the interest for submarine instability grew up, driven by the increasing exploitation of natural resources (primary hydrocarbons), the emplacement of bottom-lying structures (cables and pipelines) and by the development of coastal areas, whose infrastructures increasingly protrude to the sea. The great interest for this topic promoted a number of international projects such as: STEAM (Sediment Transport on European Atlantic Margins, 93-96), ENAM II (European North Atlantic Margin, 96-99), GITEC (Genesis and Impact of Tsunamis on the European Coast 92-95), STRATAFORM (STRATA FORmation on Margins, 95-01), Seabed Slope Process in Deep Water Continental Margin (Northwest Gulf of Mexico, 96-04), COSTA (Continental slope Stability, 00-05), EUROMARGINS (Slope Stability on Europe’s Passive Continental Margin), SPACOMA (04-07), EUROSTRATAFORM (European Margin Strata Formation), NGI's internal project SIP-8 (Offshore Geohazards), IGCP-511: Submarine Mass Movements and Their Consequences (05-09) and projects indirectly related to instability processes, such as TRANSFER (Tsunami Risk ANd Strategies For the European region, 06-09) or NEAREST (integrated observations from NEAR shore sourcES of Tsunamis: towards an early warning system, 06-09). In Italy, apart from a national project realized within the activities of the National Group of Volcanology during the framework 2000-2003 “Conoscenza delle parti sommerse dei vulcani italiani e valutazione del potenziale rischio vulcanico”, the study of submarine mass-movement has been underestimated until the occurrence of the landslide-tsunami events that affected Stromboli on December 30, 2002. This event made the Italian Institutions and the scientific community more aware of the hazard related to submarine landslides, mainly in light of the growing anthropization of coastal sectors, that increases the vulnerability of these areas to the consequences of such processes. In this regard, two important national projects have been recently funded in order to study coastal instabilities (PRIN 24, 06-08) and to map the main submarine hazard features on continental shelves and upper slopes around the most part of Italian coast (MaGIC Project). The study realized in this Thesis is addressed to the understanding of these processes, with particular reference to Stromboli submerged flanks. These latter represent a natural laboratory in this regard, as several kind of instability phenomena are present on the submerged flanks, affecting about 90% of the entire submerged areal and often (strongly) influencing the morphological evolution of subaerial slopes, as witnessed by the event occurred on 30 December 2002. Furthermore, each phenomenon is characterized by different pre-failure, failure and post-failure mechanisms, ranging from rock-falls, to turbidity currents up to catastrophic sector collapses. The Thesis is divided into three introductive chapters, regarding a brief review of submarine instability phenomena and related hazard (cap. 1), a “bird’s-eye” view on methodologies and available dataset (cap. 2) and a short introduction on the evolution and the morpho-structural setting of the Stromboli edifice (cap. 3). This latter seems to play a major role in the development of largescale sector collapses at Stromboli, as they occurred perpendicular to the orientation of the main volcanic rift axis (oriented in NE-SW direction). The characterization of these events and their relationships with successive erosive-depositional processes represents the main focus of cap.4 (Offshore evidence of large-scale lateral collapses on the eastern flank of Stromboli, Italy, due to structurally-controlled, bilateral flank instability) and cap. 5 (Lateral collapses and active sedimentary processes on the North-western flank of Stromboli Volcano), represented by articles accepted for publication on international papers (Marine Geology). Moreover, these studies highlight the hazard related to these catastrophic events; several calamities (with more than 40000 casualties only in the last two century) have been, in fact, the direct or indirect result of landslides affecting volcanic flanks, as observed at Oshima-Oshima (1741) and Unzen Volcano (1792) in Japan (Satake&Kato, 2001; Brantley&Scott, 1993), Krakatau (1883) in Indonesia (Self&Rampino, 1981), Ritter Island (1888), Sissano in Papua New Guinea (Ward& Day, 2003; Johnson, 1987; Tappin et al., 2001) and Mt St. Augustine (1883) in Alaska (Beget& Kienle, 1992). Flank landslide are also recognized as the most important and efficient mass-wasting process on volcanoes, contributing to the development of the edifices by widening their base and to the growth of a volcaniclastic apron at the foot of a volcano; a number of small and medium-scale erosive processes are also responsible for the carving of Stromboli submarine flanks and the transport of debris towards the deeper areas. The characterization of features associated to these processes is the main focus of cap. 6; it is also important to highlight that some small-scale events are able to create damage to coastal areas, as also witnessed by recent events of Gioia Tauro 1978, Nizza, 1979 and Stromboli 2002. The hazard potential related to these phenomena is, in fact, very high, as they commonly occur at higher frequency with respect to large-scale collapses, therefore being more significant in terms of human timescales. In the last chapter (cap. 7), a brief review and discussion of instability processes identified on Stromboli submerged flanks is presented; they are also compared with respect to analogous processes recognized in other submerged areas in order to shed lights on the main factors involved in their development. Finally, some applications of multibeam data to assess the hazard related to these phenomena are also discussed.

Il conflitto fra trasparenza sui mercati finanziari ed esigenza di riservatezza della società

The thesis main topic is the conflict between disclosure in financial markets and the need for confidentiality of the firm. After a recognition of the major dynamics of information production and dissemination in the stock market, the analysis moves to the interactions between the information that a firm is tipically interested in keeping confidential, such as trade secrets or the data usually covered by patent protection, and the countervailing demand for disclosure arising from finacial markets. The analysis demonstrates that despite the seeming divergence between informational contents tipically disclosed to investors and information usually covered by intellectual property protection, the overlapping areas are nonetheless wide and the conflict between transparency in financial markets and the firm’s need for confidentiality arises frequently and sistematically. Indeed, the company’s disclosure policy is based on a continuous trade-off between the costs and the benefits related to the public dissemination of information. Such costs are mainly represented by the competitive harm caused by competitors’ access to sensitive data, while the benefits mainly refer to the lower cost of capital that the firm obtains as a consequence of more disclosure. Secrecy shields the value of costly produced information against third parties’ free riding and constitutes therefore a means to protect the firm’s incentives toward the production of new information and especially toward technological and business innovation. Excessively demanding standards of transparency in financial markets might hinder such set of incentives and thus jeopardize the dynamics of innovation production. Within Italian securities regulation, there are two sets of rules mostly relevant with respect to such an issue: the first one is the rule that mandates issuers to promptly disclose all price-sensitive information to the market on an ongoing basis; the second one is the duty to disclose in the prospectus all the information “necessary to enable investors to make an informed assessment” of the issuers’ financial and economic perspectives. Both rules impose high disclosure standards and have potentially unlimited scope. Yet, they have safe harbours aimed at protecting the issuer need for confidentiality. Despite the structural incompatibility between public dissemination of information and the firm’s need to keep certain data confidential, there are certain ways to convey information to the market while preserving at the same time the firm’s need for confidentality. Such means are insider trading and selective disclosure: both are based on mechanics whereby the process of price reaction to the new information takes place without any corresponding activity of public release of data. Therefore, they offer a solution to the conflict between disclosure and the need for confidentiality that enhances market efficiency and preserves at the same time the private set of incentives toward innovation.

I fattori alla base dell'instabilità dei prezzi agricoli sui mercati internazionali

Fra il 2006 e il 2008, molte commodity hanno fatto registrare rapidi e intensi aumenti di prezzo sui mercati internazionali. Fra queste, anche alcuni prodotti agricoli alla base dell’alimentazione umana. Il presente lavoro concentra l’attenzione su alcune commodity - frumento, riso, mais e semi di soia - riportando le loro quotazioni mensili a partire dal 2002, quindi con un largo anticipo rispetto al manifestarsi del fenomeno. L’obiettivo principale del lavoro è offrire una valida interpretazione dell’instabilità de prezzo di questi prodotti, individuando i fattori che sono alla base della volatilità e sottolineandone le implicazioni economiche e politiche a livello globale. La metodologia usata è duplice e composta da un’attenta analisi descrittiva dei fattori che hanno agito sulla domanda e sull’offerta dei prodotti in questione e un’analisi quantitativa, facendo ricorso alle tecniche statistiche proprie delle serie storiche.

Gli effetti degli episodi di disoccupazione sulla durata della ricerca di lavoro. Uno studio sui dati del panel europeo

Nel corso degli ultimi venti anni si è assistito ad un incremento generalizzato della disoccupazione in Europa in particolare di quella giovanile: nel 1997 in molti paesi europei il tasso di disoccupazione della classe 15-24 anni è doppio rispetto a quello degli adulti. Questo lavoro si propone di dare una descrizione realistica del fenomeno della disoccupazione giovanile in Italia come risultante dalle prime 4 waves dell’indagine European Household Community Panel indagando la probabilità di transizione dallo stato di disoccupazione a quello di occupazione. Nell’ambito di un’impostazione legata alla teoria dei processi stocastici e dei dati di durata si indagheranno gli effetti che episodi di disoccupazione precedenti possono avere sulla probabilità di trovare un lavoro, in particolare, nell’ambito di processi stocastici più generali si rilascerà l’ipotesi di semi-markovianità del processo per considerare l’effetto di una funzione della storia passata del processo sulla transizione attuale al lavoro. La stima della funzione di rischio a vari intervalli di durata si dimostra più appropriata quando si tiene conto della storia passata del processo, in particolare, si verifica l’ipotesi che la possibilità di avere successo nella ricerca di un lavoro è negativamente influenzata dall’aver avuto in passato molte transizioni disoccupazione-occupazione-disoccupazione.