Implementazione di un modulatore sigma-delta digitale per la sintesi di segnali pwm ad alta fedelta.

La modulazione a durata d'impulso (PWM) è utilizzata soprattutto perchè permette di ottenere alta efficenza energetica. In ambito accademico è stato proposto un modulatore PWM che sfrutta la tecnica di noise shaping, Sigma Delta, per avere elevata fedeltà. Il lavoro di questa tesi è stato l'implementazione su FPGA del modulatore Sigma DeltaDigitale utilizzato: quarto ordine, con quantizzatore a 4 bit e SNR in banda di 60 dB. Il dimensionamento è stato fatto determinando l'effetto che la lunghezza delle parole dei segnali ha sul rumore prodotto dal sistema. Questo studio è stato svolto con analisi euristiche ed algoritmi di ricerca implementati in ambiente MATLAB. Lo studio fatto è di carattere generale ed estendibile a generiche architetture Sigma Delta.

A universal delta model

This thesis presents a universal model of documents and deltas. This model formalize what it means to find differences between documents and to shows a single shared formalization that can be used by any algorithm to describe the differences found between any kind of comparable documents. The main scientific contribution of this thesis is a universal delta model that can be used to represent the changes found by an algorithm. The main part of this model are the formal definition of changes (the pieces of information that records that something has changed), operations (the definitions of the kind of change that happened) and deltas (coherent summaries of what has changed between two documents). The fundamental mechanism tha makes the universal delta model a very expressive tool is the use of encapsulation relations between changes. In the universal delta model, changes are not always simple records of what has changed, they can also be combined into more complex changes that reflects the detection of more meaningful modifications. In addition to the main entities (i.e., changes, operations and deltas), the model describes and defines also documents and the concept of equivalence between documents. As a corollary to the model, there is also an extensible catalog of possible operations that algorithms can detect, used to create a common library of operations, and an UML serialization of the model, useful as a reference when implementing APIs that deal with deltas. The universal delta model presented in this thesis acts as the formal groundwork upon which algorithm can be based and libraries can be implemented. It removes the need to recreate a new delta model and terminology whenever a new algorithm is devised. It also alleviates the problems that toolmakers have when adapting their software to new diff algorithms.

Synthesis of new bioactive β-lactam compounds

New biologically active β-lactams were designed and synthesized, developing novel antibiotics and enzymatic inhibitors directed toward specific targets. Within a work directed to the synthesis of mimetics for RGD (Arg-Gly-Asp) sequence able to interact with αvβ3 and α5β1-type integrins, new activators were developed and their Structure-Activity Relationships (SAR) analysis deepened, enhancing their activity range towards the α4β1 isoform. Moreover, to synthesize novel compounds active both against bacterial infections and pulmonary conditions of cystic fibrosis patients, new β-lactam candidates were studied. Among the abundant library of β-lactams prepared, mainly with antioxidant and antibacterial double activities, it was identified a single lead to be pharmacologically tested in vivo. Its synthesis was optimized up to the gram-scale, and pretreatment method and HPLC-MS/MS analytical protocol for sub-nanomolar quantifications were developed. Furthermore, replacement of acetoxy group in 4-acetoxy-azetidinone derivatives was studied with different nucleophiles and in aqueous media. A phosphate group was introduced and the reactivity exploited using different hydroxyapatites, obtaining biomaterials with multiple biological activities. Following the same kind of reactivity, a small series of molecules with a β-lactam and retinoic hybrid structure was synthesized as epigenetic regulators. Interacting with HDACs, two compounds were respectively identified as an inhibitor of cell proliferation and a differentiating agent on steam cells. Additionally, in collaboration with Professor L. De Cola at ISIS, University of Strasbourg, some new photochemically active β-lactam Pt (II) complexes were designed and synthesized to be used as bioprobes or theranostics. Finally, it was set up and optimized the preparation of new chiral proline-derived α-aminonitriles through an enantioselective Strecker reaction, and it was developed a chemo-enzymatic oxidative method for converting alcohols to aldehydes or acid in a selective manner, and amines to relative aldehydes, amides or imines. Moreover, enzymes and other green chemistry methodologies were used to prepare Active Pharmaceutical Ingredients (APIs).

Sintesi di PNA a libertà conformazionale ridotta

The present work started a research project aimed at the synthesis of conformationally “locked” PNA (Peptide Nucleic Acids) monomers. Compared to classic aeg-PNA, this structural modification would result in an improvement in the pairing properties with natural nucleic acids, due to entropic variations in the process. Specifically, an attempt was made to build a PNA monomer around a β-lactam ring. That ring could be imagined as obtained by linking the methylene groups in α position of both the nucleobase and the carboxyl function. These structural properties would imply pre-organization of the final oligomer, improving the pairing process in biological systems. The first step of this work was the investigation of the Staudinger reaction for the ciclization of the lactam ring, and in particular the activation method of the carboxylic group of the nucleobase derivatives. Use of triazine chloride led to the synthesis of the adenine-based β-lactam-PNA. Attempts to synthesize the same monomer based on cytosine, guanine and thymine were unsuccessful, so alternative methods for carboxylic group activation were investigated. Conversion of carboxylic acids to acyl chlorides led to a partial result: despite the method worked well with analogues of the final reactants, it didn’t worked with substrates needed for lactam based PNAs. Search for a valid activation process continued involving carbonyl diimidazole, Mukayama reagent, and LDA (with methylester derivative of nucelobase) without good results. Last, it was investigated a different synthetic approach by first synthesizing a proper backbone with a chlorine in the β- lactam ring. This chlorine ring should undergo substitution by a nucleobase anion to give the desired PNA monomer. Unluckily also this synthetic route didn’t lead to the desired monomers.

High mobility rates during the period of the "Celtic migrations"? - 87 Sr, 86 Sr and delta 18 O evidence from Early La Tène Europe

Although the period of the historic “Celtic migrations” is archaeologically extensively studied, the long-lasting question whether mass migration or increased individual mobility caused the expansion of the La Tène culture throughout continental Europe persist. Strontium (Sr) and in part oxygen (O) isotope analysis of human remains from the early La Tène cemeteries of Nebringen (Germany), Münsingen-Rain (Switzerland), Monte Bibele (Italy) and the Czech cemeteries of Radovesice I, Radovesice II and Kutná Hora was, therefore, carried out to investigate the importance of residential changes during this time period. These isotope analyses showed that most analysed individuals either came from the area they were buried in or from the surrounding area of the cemetery. An exception was formed by the Czech cemeteries, where almost a quarter of the studied individuals appeared non-local. Together with Nebringen, these cemeteries also had the most varied Sr isotope ratios, which suggest highly mobile communities in which individuals regularly changed their residency. The isotopic ratios of the cemeteries of Münsingen-Rain and Monte Bibele appeared far less varied. In part, these differences might be explained by the community structures of these cemeteries. Morphological kinship analysis in Münsingen-Rain demonstrated biological relatedness among most of the analysed individuals. These related individuals also shared similar isotope signatures, which suggest an origin from the surrounding Aar Valley. In the vicinity of the cemetery of Monte Bibele, an associated settlement site was discovered. The deceased presumably not only shared this settlement, but also cultivated the same land plots. Dispersed settlement structures were suggested for Nebringen, Radovesice and Kutná Hora, as these agriculturally favourable landscapes were densely populated during prehistoric times. Connected to these community structures are the prevailing geological conditions in these areas. Both Münsingen-Rain and Monte Bibele are located in a region where homogeneous geological conditions prevail, whereas the landscapes of Nebringen, Radovesice and Kutná Hora are characterised by complex heterogeneous geological conditions. As the majority of individuals in Nebringen and the Czech cemeteries correspond to the expected isotope values for the studied areas, regularly changing land plots might have contributed to the observed variation. Although mass migration as depicted by the historical sources was not observed individual mobility of a small part of these studied communities certainly played a role. Males appeared, thereby, to have slightly more often a non-local birthplace or moved during childhood. Male mobility was, however, not always associated with burial as a warrior. Females, on the other hand, originated more often from the region. Patrilocal residential patterns, with the exception of the Czech cemeteries, were nevertheless not observed. Objects and ideas also seem to have been exchanged freely, as there are no indications that individuals with particular grave goods came from specific areas. It rather appears that the individuals buried with them were either local or had different places of origin. This can be explained by the fact that the exact origin of grave goods is difficult to establish and the occurrence of similar 87Sr/86Sr values in different areas. This study provided important new insights on the period of the “Celtic migrations” and the way of life of these prehistoric people.

Studio morfo-batimetrico dei canali distributori del delta del Po di Pila

In questa tesi sono state analizzate, a partire da dati batimetrici ad alta risoluzione ottenuti tramite tecnologia multibeam, le morfologie caratteristiche dei tre canali tributari del Delta del Po di Pila: Busa di Dritta, Busa di Tramontana, Busa di Scirocco. Lo studio è stato effettuato col software Global Mapper, che ha permesso la mappatura e l’analisi morfometrica dei principali elementi morfologici osservati, ovvero aree depresse, zone con presenza di forme di fondo, zone a fondo piano e depositi da instabilità gravitativa sulle sponde dei canali. La loro distribuzione nei vari tratti dei canali è stata messa in relazione alle caratteristiche morfologiche e idrauliche del tratto fluviale e ai processi erosivi e deposizionali che interessano i tre canali ad intensità variabile, nell’ambito dell’evoluzione molto recente di questa porzione del delta. I risultati di questo studio indicano come l’utilizzo in ambito fluviale delle più recenti tecniche di acquisizione dei dati batimetrici multibeam possa costituire la base per un dettagliato studio delle morfologie fluviali e delle dinamiche ad esse associate.

Synthesis and functionalization of a lactam-pyrazole molecular scaffold as a promising anticancer compound

The importance of pyrazole and lactam-based molecules in medical and pharmaceutical fields is underlined by the multitude of active ingredients on trade, such as Sildenafil or Apixaban, by Pfizer. In this work, a synthesis of an organic molecule with promising anticancer activity has been developed. This molecular scaffold is characterized by a δ-lactam-fused pyrazolic core, with a well-known biological activity and amenable of further functionalization. The synthetic strategy adopted for the obtainment of the core was based on a 1,3-dipolar cycloaddition of a nitrilimine with an α,β-unsaturated δ-lactam. Secondly, in order to give the final compound an elevated pharmacological activity, a functionalization with a double “side chain”, namely molecular fragment able to improve the interaction with particular biological receptors, was achieved. The target compound was thus obtained, with a highly convergent synthesis, and will be tested for antiproliferative activities towards different cellular lines.

Alternative derivative expansion in Functional RG and application

We give a brief review of the Functional Renormalization method in quantum field theory, which is intrinsically non perturbative, in terms of both the Polchinski equation for the Wilsonian action and the Wetterich equation for the generator of the proper verteces. For the latter case we show a simple application for a theory with one real scalar field within the LPA and LPA' approximations. For the first case, instead, we give a covariant "Hamiltonian" version of the Polchinski equation which consists in doing a Legendre transform of the flow for the corresponding effective Lagrangian replacing arbitrary high order derivative of fields with momenta fields. This approach is suitable for studying new truncations in the derivative expansion. We apply this formulation for a theory with one real scalar field and, as a novel result, derive the flow equations for a theory with N real scalar fields with the O(N) internal symmetry. Within this new approach we analyze numerically the scaling solutions for N=1 in d=3 (critical Ising model), at the leading order in the derivative expansion with an infinite number of couplings, encoded in two functions V(phi) and Z(phi), obtaining an estimate for the quantum anomalous dimension with a 10% accuracy (confronting with Monte Carlo results).

NCX-1000, a nitric oxide-releasing derivative of UDCA, does not decrease portal pressure in patients with cirrhosis: results of a randomized, double-blind, dose-escalating study

NCX-1000 (2(acetyloxy) benzoic acid-3(nitrooxymethyl)phenyl ester) is an nitric oxide (NO)-releasing derivative of ursodeoxycholic acid (UDCA), which showed selective vasodilatory effect on intrahepatic circulation in animal models of cirrhosis. This study was aimed at testing the efficacy and tolerability of this compound in patients with cirrhosis and portal hypertension.

Clinical Outcomes Following Treatment of Non-contained Intrabony Defects with Enamel Matrix Derivative (EMD) or Guided Tissue Regeneration (GTR). A 12-month Randomized Controlled Clinical trial

The purpose of this study is to compare the healing of deep, non-contained intrabony defects (i.e., with a ?80% 1-wall component and a residual 2- to 3-wall component in the most apical part) treated with either an enamel matrix derivative (EMD) or guided tissue regeneration (GTR) after 12 months.

Healing of two and three wall intrabony periodontal defects following treatment with an enamel matrix derivative combined with autogenous bone

BACKGROUND: There are still limited data on the outcomes of regenerative periodontal surgery using a combination of an enamel matrix protein derivative (EMD) and autogenous bone (AB). AIM: To evaluate the healing of deep intrabony defects treated with either a combination EMD+AB or EMD alone. MATERIALS AND METHODS: Forty patients with advanced chronic periodontitis, with one deep intrabony defect, were randomly treated with either EMD+AB (test) or EMD (control). Clinical assessments were performed at baseline and at 1 year after treatment. The primary outcome variable was relative attachment level (RAL). RESULTS: Healing was uneventful in all patients. The test sites showed a reduction in the mean probing pocket depth (PPD) of 5.6 +/- 0.9 mm (p<0.001), a gain in the mean RAL of 4.2 +/- 1.1 mm (p<0.001) and a gain in the mean probing bone level (PBL) of 3.9 +/- 1.0 mm (p<0.001). The control group displayed a mean PPD reduction of 4.6 +/- 0.4 mm (p<0.001), a mean RAL gain of 3.4 +/- 0.8 mm (p<0.001) and a mean PBL gain of 2.8 +/- 0.8 mm (p<0.001). RAL gains of > or =4 mm were measured in 90% of the test defects and in 55% of the controls. PBL gains of > or =4 mm were obtained in 85% of the test defects and in 25% of the control ones. The test treatment resulted in statistically higher PPD reductions, RAL gains and PBL gains compared with the control (p<0.01). CONCLUSIONS: Within their limits, the present results indicate that: (i) at 1 year after surgery, both therapies resulted in statistically significant clinical improvements compared with baseline and (ii) although the combination of EMD+AB resulted in statistically significant higher soft and hard tissue improvements compared with treatment with EMD, the clinical relevance of this finding is unclear.

The quassinoid derivative NBT-272 targets both the AKT and ERK signaling pathways in embryonal tumors

The quassinoid analogue NBT-272 has been reported to inhibit MYC, thus warranting a further effort 7to better understand its preclinical properties in models of embryonal tumors (ET), a family of childhood malignancies sharing relevant biological and genetic features such as deregulated expression of MYC oncogenes. In our study, NBT-272 displayed a strong antiproliferative activity in vitro that resulted from the combination of diverse biological effects, ranging from G(1)/S arrest of the cell cycle to apoptosis and autophagy. The compound prevented the full activation of both eukaryotic translation initiation factor 4E (eIF4E) and its binding protein 4EBP-1, regulating cap-dependent protein translation. Interestingly, all responses induced by NBT-272 in ET could be attributed to interference with 2 main proproliferative signaling pathways, that is, the AKT and the MEK/extracellular signal-regulated kinase pathways. These findings also suggested that the depleting effect of NBT-272 on MYC protein expression occurred via indirect mechanisms, rather than selective inhibition. Finally, the ability of NBT-272 to arrest tumor growth in a xenograft model of neuroblastoma plays a role in the strong antitumor activity of this compound, both in vitro and in vivo, with its potential to target cell-survival pathways that are relevant for the development and progression of ET.