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Evaluation of the PI3K/Akt/mTOR pathway in Multiple Sclerosis
No full textBackground
The PI3K/AKT/mTOR pathway is an intracellular signaling pathway that regulates cell activation. proliferation, metabolism and apoptosis. Increasing body of data suggests that alterations in the PI3K/AKT/mTOR pathway may result in an enhanced susceptibility to autoimmunity. Aim of our work was to evaluate the involvement of the mTOR pathway in the pathogenesis of autoimmune diseases, with particular focus on Multiple Sclerosis (MS). Multiple sclerosis (MS) is one of the most common chronic inflammatory diseases of the central nervous system leading to demyelination and neurodegeneration. Drugs targeting the PI3K/AKT/mTOR pathway are currently under extensive investigation for their possible use as cancer chemotherapics and as immunosuppressive agents, but no clinical trial has been so far approved for the evaluation of their efficacy in the context of immunological disorders.
Methods
In the current study, we have firstly evaluated in silico the involvement of the mTOR network on the generation and progression of MS, making use of currently available whole-genome transcriptomic data. Also, the involvement of the mTOR network on oligondendrocyte function was studied, in order to ascertain whether treatment with drugs targeting the PI3K/Akt/mTOR pathway may be useful to promote the remyelination process, so to reverse disability in MS patients.
Then, the data generated in silico were subjected to an ex-vivo evaluation. To this aims the involvement of mTOR was validated on a well-known animal model of MS and in vitro on Th17 cells.
Results
Our data indicate that there is a significant involvement of the mTOR network in the ethiopathogenesis of MS and that Rapamycin treatment may represent a useful therapeutic approach in the clinical setting. Ex vivo analysis showed that treatment of MOG-specific T cells from EAE affected mice with the mTOR inhibitor, Rapamycin, and the dual PI3K/mTOR inhibitor, BEZ-235, was able to significantly reduce antigen-specific proliferation. In addition, we show that Rapamycin treatment of murine T cell stimulated under Th17 conditions, was able to significantly inhibit the expression of some of the genes previously identified in the in silico analysis. On the other hand, our data showed that a significant involvement of the mTOR network could be observed only in the early phases of oligodendrocyte maturation, but not in the maturation process of adult oligodendrocytes and in the process of remyelination following demyelinating injury.
Conclusions
Overall, our study suggest that targeting the PI3K/mTOR pathway, although it may not be a useful therapeutic approach to promote remyelination in MS patients, it can be exploited to exert immunomodulation, preventing/delaying relapses, and to treat MS patients in order to slow down the progression of disability
Numerical Methods for All Mach Number flows for Gas Dynamics
No full textAn original numerical method to solve the all-Mach number flow for the Euler equations of gas dynamics on staggered grid is presented in this thesis. The system is discretized to second order in space on staggered grid, in a fashion similar to the Nessyahu-Tadmor central scheme for 1D model and Jang-Tadmor central scheme for 2D model, thus simplifying the flux computation. This approach turns out to be extremely simple, since it requires no equation splitting. We consider the isentropic case and the general case. For simplicity we assume a gamma-law gas in both cases.
Both approaches are based on IMEX strategy, in which some term is treated explicitly, while other terms are treated implicitly, thus avoiding the classical CFL restriction due to acoustic waves.
- In Isentropic Euler Case: The core if the implicit term contains a non-linear elliptic equation for the pressure, which has to be treated by a fully implicit technique. Because of the non-linearity, it is necessary to adopt an iterative method to compute the pressure. In our numerical experiments Newton's method worked with few iterations.
- General Euler Case: In this case the implicit term is treated in a semi-implicit fashion, thus avoiding the use of Newton's iterations.
In both cases the schemes are implemented to second order accuracy in time. Suitably well-prepared initial conditions are considered, which depend on the Mach number. In one space dimension we obtain the same profiles found in the literature for the isentropic case and for the general Euler system for all Mach numbers.
In particular, the schemes have been shown to be AP, in the sense that they become a consistent discretizzation of the incompressible Euler equation as the Mach number approaches zero. Numerical evidence of such AP property is provided on a two dimensional test case.
The last chapter deals with the piston problem in Lagrangian coordinates treated by a semi-implicit scheme. The implicit treatment of the boundary conditions is originally developed in the thesis. It is shown that for very low Mach number the scheme is able to recover the adiabatic solution with very large CFL numbers. For moderate Mach numbers, or in presence of an initial acoustic wave, loss of accuracy is observerd if the CFL is too large. This drawback can be cured by using a suitable time step control, which will be subject of future investigation.
Current work is also related on the development of higher order accurate schemes for 1D and 2D problems
Synthesis and biological evaluation of pirrolidine, oxazolidin-2-imine and mercaptoketones derivates as HCV, HIV and HDAC inhibitors
No full textThe main objective of this thesis was the synthesis of modified azanucleosides potential ihibitors of non-structural proteins of HCV virus ((NS) NS3/4A, NS4B, NS5A and NS5B). Moreover the research project included the synthesis of pyrimidine-1,3-oxazolidin-2-arylimino hybrids as HIV ihibitors and the synthesis of mercaptoketone deriatives as antitumor agents potential HDAC's inhibitor
Surface plasmon resonamce imaging biosensors for the detection of pathognes and toxins in food
No full textThe detection of pathogens and toxins in food represents an essential requirement for food quality control. Standard methods for pathogen detection rely on laborious and time-consuming growth of pathogens in different culture media followed by biochemical or serological identification. Such methods often operate with poor sensitivity and selectivity. In recent years, efforts have been made to provide rapid, reliable and sensitive detection platforms for foodborne pathogens detection. The demand for more rapid, sensitive and accurate methods has been push forward by the implementation of the Hazard Analysis and Critical Control Points (HACCP) protocols. In this context, biosensing platforms provide promising alternatives for the detection of pathogens and toxins with good selectivity and sensitivity. In particular, optical biosensors based on Surface Plasmon Resonance Imaging (SPRI) are attractive because they allow the sensitive detection of analytes from food matrices in real-time. SPRI can assays crude samples without purification and can exploits antibodies or single-stranded DNA (ssDNA) probes for the specific detection of pathogens and toxins with high sensitivity.
My research activity has been aimed at developing SPRI biosensors able to detect pathogens and toxins in food matrices in a rapid, specific and sensitive way. In this perspective, specific oligonucleotide sequences and antibodies have been used for the detection of DNA and bacterial toxins, respectively. SPRI biosensor sensitivity benefited of the use of properly functionalized gold nanoparticles (AuNPs). The combination of the SPRI sensing apparatus with microfluidics devices reduces the amount of sample needed for the analysis and provides an efficient environment for the detection
Dynamics of Classical Systems in the Operator Algebra of Quantum Mechanics
No full textThe use of the formalism and the operatorial techniques typical of quantum mechanics proved in recent years to be an effective approach for the description of even macroscopic systems characterized by complex interactions in several contexts with interesting applications both in the bioecological and in the socioeconomic area.
The operatorial approach, based on raising and lowering operators, especially using the number representation, provides useful tools for modeling collective dynamics of spatially distributed physical systems in a completely general and precise way. Quantum-like models (not necessarily related to the microscopic approach) offer an interesting mathematical insight into phenomena and processes even at macroscopic scales in several situations in which some quantities changing discontinuously are well described in terms of the integer eigenvalues of certain self-adjoint operators useful for a complete description of the system under consideration (the so-called observables of the system itself).
Moreover, according to the innovative approach called rule-induced dynamics, the derivation of the dynamics in the operator algebra of quantum mechanics from a time-independent Hamiltonian operator may be enriched by means of the repeated application of specific ''rules'' including in the dynamics meaningful effects occurring during the time evolution of the system and, therefore, producing an adjustment of the model itself as a consequence of its evolution. This method is of great interest to describe systems for which a nontrivial and sufficiently regular asymptotic behavior is expected.
The original contributions of this thesis, besides the construction and the numerical investigation of operatorial models to describe complex systems of interest in many areas (mathematics, physics, ecology, social sciences), are concerned with the introduction and exploitation of the so called (H, rho)-induced dynamics. The combined action of the Hamiltonian and of some rules allowed to take into account in the model relevant effects that can not be described by a time independent self-adjoint Hamiltonian. This strategy, which provides a powerful strategy to simulate the effect of using a time-dependent Hamiltonian, revealed capable of greatly enriching the dynamics of the considered models still with simple quadratic Hamiltonians without additional computational costs
Caratteri stratigrafici, strutturali e geomorfologici della piattaforma continentale siciliana: esempi dal Tirreno meridionale e dal Canale di Sicilia
No full textThe Pelagian Archipelago is located in a complex and wide geodynamic system characterized by the occurrence of two independent tectonic processes acting simultaneously: convergence along the Apennine-Maghrebian accretionary wedge and late Miocene-early Pliocene rifting in the Sicily Channel. Through high resolution seismic profiles acquired around the Lampedusa Island offshore, the reconstruction of an updated structural setting of this area and its regional correlation has been performed. The late Miocene-early Pliocene rifting affects directly the structural evolution of the Lampedusa plateau, with the development of a graben and half-graben setting in most of the offshore area, widely filled with the syn-rift deposits. In the northern sector, the activity of the normal faults associated with the rifting is active up to the early Pliocene, whereas it is quiescent since late Miocene in southern sector. This current fabric of the Lampedusa plateau derives by its involvement in regional extensional regime, lying in a dextral-transtensive zone and marked by pull-apart basins. In particular, two systems of the normal faults in the Lampedusa offshore have been recognized. The Master Extensional Faults oriented WNW-ESE represent the main structural alignment of the Lampedusa offshore and reflect the extensional trending of the Sicily Channel. The Second order of Extensional Faults, oriented NNW-SSE, bounds smaller pull-apart basins and are probably associated with the main dextral-transtensive regional regime. From the comparison with some preexisting models, an update stratigraphic-structural model is proposed also to the southeastern continental shelf between the Gela-Catania foredeep and the Hyblean foreland offshore, along the Marina di Ragusa offshore. The seismo-stratigraphic interpretation shows a NE-SW extensional faults system that involves only the late Miocene formations, probably connected to history of the Scicli Line. Furthermore, the late Miocene extensional tectonic activity involves widely affects the offshore portions of the Hyblean foreland and its ramp, but it does not show evidences that this activity has involved the Plio-Pleistocene succession. The deposition of the Gessoso-Solfifera Formation has been widely recognized in the Hyblean foreland ramp, demonstrating that the evaporitic deposition does not is a peculiarity only of the deposits within the semi-isolated and marginal sub-basins or of the thrust top mini-basins of the Appennine-Maghrebides belt, but extends also in areas where the extensional tectonic have been dominant. Through Multibeam bathymetric data, an update characterization of the geomorphological setting of the north-east Sicily continental shelf, between Milazzo Promontory and the area offshore from the Saponara River, is provided. Furthermore, through high-resolution CHIRP seismic profiles interpretation, a reconstruction of the evolution of the last eustatic sea level cycle is performed. The lowstand succession, corresponding with the foreset of the prograding clinoforms of the continental margin deposits, determines the accommodation space for the depositional processes that occur during the rise of the sea level. In fact, the evolution of the transgressive and highstand wedges is strongly influenced by the geometry of the underlying lowstand succession. The transgressive wedge is developed in the 80-100 m bathymetric range and consists of the relict geomorphic elements that represent past landscape. These elements tracked the variations in coastline position during the last sea-level rise, formed during an interval of relatively reduced rate of sealevel rise. Furthermore, a reconstruction of the geomorphological evolution of the past coastal systems during the last transgressive stage is provided. The highstand wedge consists of the Corriolo, Muto, Niceto, Cocuzzaro and Rometta delta deposits that widely develop on the offshore portions of the inner continental shelf
Polymer strategies for water purification based on photocatalysis and molecular imprinting
No full textNanomaterials show a better performance in environmental remediation than other conventional techniques because of their high surface area and their associated high reactivity. Nanostructured photocatalysts, especially TiO2, are widely studied for the treatment of contaminated water. They can indeed degrade organic pollutants and biological substances. In the first part of this thesis, the fundamentals of heterogeneous photocatalysis are described, with particular attention to the most important recent progresses in the field of nanostructured TiO2 for water treatment. The strategies used to improve its efficiency and to enhance its photocatalytic performance in the visible region are also illustrated. However, although the nanoscale catalysts show considerable improvement in terms of their physical and chemical properties, their size remains the main problem in a large-scale process because of the need of a post-treatment recovery, necessary to avoid their impact on the environment. For this reason, immobilization of photocatalysts on different substrates has been drawing a significant attention. Considering the various substrates, polymers seem to be very promising. Aim of this dissertation is to propose polymer nanocomposites for water treatment as potential alternative to the traditional methods. This thesis describes the synthesis, the characterization, and the photocatalytic and antibacterial properties under UV light of the PMMA/TiO2 nanocomposites. It reports also the combination of these nanocomposites with carbon nanotubes to increase their photocatalytic efficiency and the functionalization of the TiO2 surface with a porphyrin, in order to obtain active systems under visible light. In the last part, the use of molecularly imprinted polymers for wastewater treatment is discussed, showing preliminary results and future perspectives for the selective removal of emerging contaminants from water
Decentralization and health performance in Italy: theoretical and empirical issues
No full textThree chapters constitute the main structure of this contribution. The first chapter investigates the relationship between fiscal decentralization and regional health outcomes, as measured by infant mortality rates, in Italy. The paper employs a panel of all Italian regions over a period of 17 years (from 1996 to 2012), applying a linear Fixed-Effect model. Two different quantitative measures of fiscal decentralization are used, which capture the degree of regional decision-making autonomy in the allocation of tax revenues and the extent of regional transfer dependency from the central government (i.e vertical fiscal imbalance). Methodologically, to account for the temporal dynamics of the decentralization impact, the robustness of the findings is checked, among others, with respect to the use of an Error Correction Model, which allows to disentangle short and long run effects. The analysis also deals with the issue of heterogeneous distributional geographical responses by modelling the asymmetric impact of decentralization on infant mortality rates according to the level of regional wealth.
The second chapter addresses the issue of convergence. Here the main research questions are whether health outcomes in Italy converge/diverge over time and, more importantly, whether decentralization has played a somewhat role in the convergence/divergence process. Using a pooled dataset with the same time span as the previous one, the conventional measures of sigma- and beta- (both absolute and conditional) convergence are estimated for two different regional health outcomes (i.e. infant mortality rate and life expectancy at birth). Again, two measures of decentralization are employed in order to catch both the degree of fiscal regional decision-making autonomy (i.e. the same indicator as in chapter 1) and the political decentralization dynamics (i.e. a dummy variable taking the value of 1 after the introduction of the 2001 constitutional reform). From a methodological point of view, the real novelty of the analysis is to take spatial dependence and neighbourhood effects among the regions into consideration. Modelling the impact of decentralization through an interaction term, the speed of convergence is found to be significantly affected by the level of decentralization.
The third and last chapter deals with the issue of the effects of decentralization from a different but related viewpoint. Compared to the previous chapters, it examines descriptively the administrative aspects of decentralization by a lower (micro) level perspective, looking at the managerial autonomy of local healthcare structures. The emphasis is here on the role of intrinsic and extrinsic motivations in enhancing accountability and improving the performance of healthcare system, in general, and the quality of hospital care, in particular. Though the focus is not specifically on the Italian system, the analysis is particularly relevant for this country, where regional governments, in charge of the responsibilities for the financing and the delivery of healthcare, act through a network of Local Health Authorities i.e. public entities with their own budgets and management, which directly run small public hospitals -, public hospital trusts with full managerial autonomy and accredited for-profit private providers. The understanding research hypothesis here is that the way in which the financial incentive schemes for providers are designed and structured is likely to affect their effectiveness in pursuing the expected results (e.g. improved efficiency and quality of healthcare service delivery). However, the same incentive is expected to work differently according to the provider s degree of decision-making autonomy and its utility function
Stampa democratica Catania 1860-1876
No full textIl candidato ha ultimato la propria indagine sulla stampa democratica a Catania pervenendo ad una interessante ricostruzione dell assetto e dell attività dello schieramento democratico nella città etnea nel periodo postunitario 1860 1876.
Nella sua ricerca, Luca Platania,ha fatto riferimento a vaste e qualificate fonti presenti nell Archivio di Stato di Catania, alle quali ha affiancato lo spoglio di pamphlet e periodici conservati presso le Biblioteche Riunite Civica e Ursino Recupero e presso la Biblioteca Regionale Universitaria Caruso .
Lo stesso candidato sottolinea un primato della città etnea: una simile produzione di stampa democratica non è ravvisabile, nel medesimo arco temporale, in tutta la Sicilia Orientale, nemmeno in città di forte tradizione democratica come Messina e Siracusa.
La tesi di Platania dimostra come la Sicilia acquisisce, con l Unità d Italia, la possibilità per le sue intellighenzie e la sua tradizione culturale di un confronto pubblico più ampio di quello concesso dal ricco ma angusto dibattito accademico delle sue università.I giornali studiati in questa tesi presentano importanti interventi sui temi dell ammodernamento dell amministrazione, delle infrastrutture, dell economia siciliana e dell incivilimento del suo popolo minuto, afflitto dall analfabetismo.
Si dimostra qui come la stampa democratica contribuisca al dibattito politico attraverso la divulgazione culturale, scegliendo temi e modalità che possono raggiungere il popolo. Forte dell esperienza del 1848 e dell influsso del giornalismo mazziniano, che in Italia dagli anni Trenta batteva insistentemente sul tema dell istruzione popolare e in particolare di quella degli operai, i periodici catanesi oggetto del lavoro di studio della tesi, intervengono sulle questioni in dibattito al Comune come l ammodernamento del porto, l istituzione delle scuole elementari, persino la gestione della nettezza urbana ed il decoro pubblico e dibattendo la divulgazione storica e i diritti delle donne, l abolizione della pena di morte ed il suffragio universale. Il tuttoè venato da un persistente laicismo che sfocia talvolta in un netto anticlericalismo.
La stampa democratica, aggiunge Platania, si distingue per la critica ai metodi repressivi della Destra storica, preparando un terreno favorevole per le prime campagne elettorali in Sicilia. Queste contribuiranno alla svolta delle elezioni del 1874 durante le quali, come è noto, una schiacciante maggioranza di deputati (40 su 48) dell opposizione viene eletta nell isola.
La costruzione del monumento a Giuseppe Mazzini nel Giardino Bellini di Catania nel 1875 appena tre anni dopo la morte del pensatore genovese,indagata dal candidato, può forse considerarsi una delle maggiori espressioni pubbliche di questa protesta: si consideri anche la presenza di un monumento ad un repubblicano in uno spazio pubblico in una città che ancora per molti anni non dedicherà nessun monumento né a Cavour né alla dinastia Savoia.
L arco temporale scelto dal candidato nella sua ricerca, permette quindi di comprendere meglio l importante risultato raggiunto dalla sinistra, anche grazie al potere della stampa in Sicilia: quello dell inizio del governo della Sinistra parlamentare in Italia
L'oro blu. L'inestricabile intreccio tra mercato, protezione ambientale e diritto all acqua
No full textLa tesi di dottorato concerne il diritto dell acqua e s interroga su come il «diritto all acqua», cosi come definito dal diritto internazionale, incida sulla gestione dei servizi idrici e sulla protezione dell ambiente nell ordinamento giuridico dell Unione europea.
La ricerca è articolata su un triplice fronte: in primo luogo, quello delle fonti di diritto internazionale, che definiscono la natura giuridica dell acqua nelle relazioni internazionali (Parte I); in secondo luogo, quello dell accesso all acqua, da verificare attraverso l analisi della disciplina dei servizi che rendono disponibile tale risorsa (Parte II); in terzo luogo, il profilo della tutela dell acqua (Parte III). Tutela e accesso all acqua sono analizzati con specifico riferimento all ordinamento giuridico dell Unione europea.
La Parte I si compone di tre capitoli e persegue un duplice obiettivo: definire i termini della dinamica normativa internazionale che interessa l acqua, rilevandone i profili problematici e conflittuali; verificare in che misura l emersione del diritto all acqua incida sulle obbligazioni internazionali degli Stati nella gestione e distribuzione delle risorse idriche.
Il primo capitolo è dunque dedicato alla fonte più antica di diritto internazionale che concerne l acqua, ossia il diritto internazionale delle acque, che definisce l acqua come «risorsa naturale». Il secondo capitolo, invece, concerne le fonti di diritto internazionale dell economia che possono interessare l acqua intesa come «risorsa economica». Il terzo capitolo, infine, si focalizza sulle disposizioni che stanno segnando l emersione del diritto all acqua inteso come «diritto dell uomo».
La Parte II, anch essa composta di tre capitoli, persegue l obiettivo di verificare in che misura l emersione del diritto all acqua abbia inciso sulla disciplina dei servizi idrici e sulla qualificazione dell acqua come «bene pubblico fondamentale» all interno dell ordinamento giuridico dell Unione europea.
Il quarto capitolo è dunque dedicato all emersione del diritto all acqua all interno dell ordinamento giuridico dell UE e al suo impatto sull organizzazione dei servizi idrici nazionali in termini di servizi d interesse economico generale, strutturati come «servizi universali» gravati dall obbligo di «servizio pubblico». Il quinto capitolo, a sua volta, approfondisce la disciplina di mercato dei servizi idrici, verificando lo specifico regime derogatorio accordato in materia di concorrenza e appalti pubblici. Il sesto capitolo è dedicato alla partecipazione del pubblico e alla dimensione della c.d. accessibilità politica.
La Parte III, dedicata alla tutela dell acqua, è volta infine a verificare in che misura il diritto dell UE concorra, da un lato, a fornire una tutela adeguata delle risorse idriche, e dall altro, a definire i tratti di un unica «comunità di diritto dell acqua» in cui la libertà degli Stati è sempre più limitata.
Il settimo capitolo, quindi, muove dalla formulazione di parametri di qualità ambientali comuni e comunitari , che hanno segnato l emersione del diritto europeo delle acque. L ottavo capitolo, a sua volta, approfondisce le questioni del monitoraggio e del trattamento delle acque, che si presentano come i due principali pilastri della politica europea delle acque. Il nono capitolo, infine, riguarda l approccio integrato all acqua e la pianificazione territoriale