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E-cadherin and Choline Kinase: two challenging drug discovery targets
Get PDFThe data presented in this thesis was generated using molecular biology, protein chemistry and X-ray
crystallography techniques. However, while the methodologies employed are essentially the same,
the research work presented here refers to two different proteins, which are part of different research
projects in the laboratory. For this reason, the content of this thesis is divided in two independent
parts, each provided with an introduction and a general overview of the research topic and state-ofthe-
art, a materials and methods section discussing the techniques used and the protocols followed,
and a section where the results are presented and discussed in detail.
The first half of the thesis deals with the structural characterization of the complex between human
E-cadherin and three different small molecule potential inhibitors identified via a fragment-based
drug discovery (FBDD) screening campaign that was conducted using a library of commercially
available small fluorinated chemical fragments. For this screening phase, we used 19F-NMR as
readout. The NMR experiments were done by our collaborator Dr. Marina Veronesi at the D3
PharmaChemistry division of the Italian Institute of Technology (IIT) in Genova (Italy). Functional
cell adhesion assays to validate the inhibitory effects of the fragments thus identified were carried out
in collaboration with Prof. Frédéric André at the University of Marseille (France).
The second half of the thesis describes the structural characterization of Plasmodium falciparum
Choline Kinase (PfChoK), an important pharmaceutical target in the fight against malaria, as well as
the biochemical characterization of a library of potential inhibitors of PfChoK. These inhibitors were
synthetized in the group of Prof. Luisa Carlota López-Cara at the Department of Pharmaceutical and
Organic Chemistry of the University of Granada (Spain) in the framework of an ongoing
collaboration between the two groups
ESIX materials: insertion chemistry from a wide perspective
Get PDFThis thesis aim is the synthesis, characterization and ESIX proprieties studies of Prussian Blue analogues (or Metal Hexacyanometallates, MHCMs). They are distinguished by the generic formula AxMy[B(CN)6].mH2O where, x, y, and m indicate stoichiometric coefficients, M and B are transition metals and A an alkaline metal cation. Prussian Blue (PB) analogues materials exhibit excellent physicochemical characteristics as ionic sieve. Moreover, their face-centered cubic crystal structure and the possibility to change the transition metal leads them to be an extremely versatile compound, in terms of synthesis and applications.
Properties and structures of these synthetized compounds, are investigated by using a multi-technique approach including X-ray Powder Diffraction (XRD), Scanning Electron Microscopy (SEM), Infrared Spectroscopy (IR) and electrochemical measurements. They were obtained both via electrochemical and chemical synthesis on the basis of the application field.
The main topic is related to the MHCFs release/uptake capabilities, specifically associated to structural changing.
Furthermore, their environmental sustainability and their wide field of application from sensing to batteries, allow to define them as innovative materials suitable for new analytical technologies.
Finally, the synthesis and characterization of green rust thin film is deepened, highlighting the electrochemical behavior of Akaganèite, which has a key role in the corrosion progress. Thus, understanding the electrochemical reaction involved in the corrosion processes, is useful for the diagnosis and prevention of artefacts. Also, VIMP technique allows to compare the controlled- electrodeposited green rust electrochemical behaviour with the real sample one
Automotive Antennas for V2X Communications
Get PDFThe main topic of this thesis is about the design and prototyping of automotive antennas that allows Vehicle to Everything (V2X) communications, that is the communication between the vehicle and all what else is relevant. In particular 5G will be an enabling technology for these communications.
Vehicular connectivity is a mandatory feature in nowadays car. Typical applications are that one related to the infotainment, i.e. radio or mobile telephone, or security ones, i.e. radars. The antennas that support this type of communications can be divided in two frequency range: the sub-6GHz range and the millimeter wave (mmW) range. Also the 5G standard can be divided in this two frequency ranges. In this work different automotive antennas solutions are presented for both the frequency bands.
For the sub-6GHz range two different antennas are presented: a tin sheet 5G-sub6 radiating element and a complete 5G-GNSS-V2X shark fin module. For the mmW frequency band, an automotive PCB planar solution is presented. Since these frequencies are a novelty for the automotive market, satellite communications (SatCom) field has been considered. In SatCom applications mmW solutions are a well-established technology. Thus, also mmW antennas solutions for SatCom applications are here presented
Geometric optimization of complex thermal-fluid dynamic system by means of constructal design
Get PDFIn this work the Constructal Theory is exposed in its generality, trying to approach it through examples mostly of a physical-engineering nature. Constructal Theory proposes to see living bodies as elements subject to constraints, which are built with a goal, an objective, which is to obtain maximum efficiency. Constructal Theory is characterized by Constructal Law, which states that if a system has the freedom to morph it develops over time a flow architecture that provides easier access to the currents that pass through it. The Constructal Law is as general as the First and Second Laws of Thermodynamics, but it has a very different purpose which makes it unique and complementary to those laws. While the First Law points to the conservation of energy, both the Constructal Law and the Second Law point to change, that is, to a direction in time. Contrary to the Second Law, the Constructal Law applies to systems that are out of balance, that is, to systems that evolve over time. While the second law deals with state variables, the Constructal Law combines flows and design. The thesis continues with the application of the Constructal Theory for a cardiac bypass shape optimization. Through the Constructal Theory the constraints under which the system is free to morph are defined and, through the classical engineering optimization processes (numerical simulations and optimization algorithms) the optimum conditions are defined, i.e., those conditions that guarantee the minimum resistance to the passage of the fluid. The characterization of the blood flow was an important step in the study of this system, as the heartbeat induces a pulsed regime inside the veins. Therefore, the simulations conducted in transient regime consider the deformed velocity profile according to the conditions dictated by the pressure gradient established by the heartbeat
Biomaterials for osteoarticular applications: role of functionalization
Get PDFThis work was focused on the development of functionalized materials with potential applications for the substitution/repair of damaged tissues. The materials utilized as substrates were calcium orthophosphates, namely hydroxyapatite, β-tricalcium phosphate, monetite and brushite, and gelatin films. This choice was based on a biomimetic strategy: the inorganic component of the hard tissues of vertebrates is a basic calcium phosphate similar to synthetic hydroxyapatite, and gelatin is a degradation product of the main proteic component of the human body, collagen.
Functionalization of calcium phosphates was performed through ionic substitution, adsorption of metallic nanoparticles, organic molecules, amino and polyamino acids.
The results indicated that the possibility of ionic substitution depends both on the type of calcium phosphate and of the foreign ion. Strontium substitutes for calcium up to 100at% in the structure of monetite an up to about 80at% in β-tricalcium phosphate, whereas the replacement is limited to 38at% in brushite. The maximum incorporation of zinc into β-tricalcium phosphate is much lower.
Hydroxyapatites were utilized as supports for Pt nanoparticles and β-lactams. The amount of adsorbed β-lactam can reach values greater than 20wt% and depends both on the type of molecule and on the polarity of the loading solution. Adsorption of Pt nanoparticles provided materials with very good anti-oxidant properties. Both Pt nanoparticles and β-lactams displayed a controlled release over time.
The interaction of aspartic acid and polyaspartic acid with brushite revealed that both molecules inhibit crystallization. However, the specific interaction of polyaspartic acid causes its adsorption up to 2.3wt%, whereas aspartic acid is not adsorbed at all. Both molecules inhibit brushite hydrolysis.
Finally the properties of gelatin films were modified using two polyphenols, quercetin and curcumin, which are known for their good anti-inflammatory, anti-oxidant and anti-cancer activities.
The results indicate that the functionalizing agents provide new materials with enhanced beneficial characteristics
Ochratoxin A, metals, insecticides and phytoextracts: evaluation of the effects and residual aspects in poultry and in foods intended for human.
Get PDFLa presente tesi di Dottorato di Ricerca descrive le attività di ricerca riguardanti diversi ambiti della sicurezza alimentare, della farmacologia e tossicologia veterinaria. Sono presentati i dati relativi alla ricerca di ocratossina A (OTA) in campioni di bile, rene e fegato di polli, salami artigianali e diversi tipi di formaggio; le concentrazioni di diversi metalli pesanti in uova di galline rurali e 5 tipologie di uova industriali; i dati preliminari ottenuti dalle analisi dei primi campioni di uova e penne provenienti da allevamenti amatoriali di pollame, analizzati per la ricerca del fipronil e metaboliti. Sempre per fipronil, e la molecola foxim, sono presentati dati inerenti a studi di potenziale farmaco-resistenza di popolazioni naturali di Dermanyssus gallinae, e dell’attività insetticida di alcuni fitocomposti a base di tannini. Riguardo all’uso di fitoestratti, sono presentati i dati preliminari ottenuti nei primi mesi di una prova sperimentale in galline di razza Livornese allevata con metodo free-range, finalizzata allo studio della attività anti-infiammatoria e immuno-stimolante, nonché alla valutazione della sicurezza della integrazione nella dieta di Boswellia serrata e Salix alba. Sono stati condotti anche studi traslazionali con altri settori scientifici, relativamente la prevalenza sierologica e microbiologica per Salmonella enterica var. enteritidis e var. thiphymurium in allevamenti ornamentali e da auto-consumo di pollame, e di prevalenza e caratterizzazione di potenziali varianti virali e batteriche (incluse zoonosiche) di alcune malattie infettive del pollame ornamentale. In specie avicole ornamentali è riportato anche uno studio di campo sul trattamento off-label con Fenbendazolo e Flubendazolo in infestazioni massive da Cyathostoma bronchialis in oche esotiche ornamentali. A seguito di una collaborazione con l’Università di Firenze, sono presentati anche i risultati ottenuti da uno studio su modelli murini, dell’azione e funzionamento dei recettori Beta3, espressi nelle neoplasie più frequenti che si verificano nelle donne in gravidanza.This PhD thesis describes the research activities concerning food-safety, veterinary pharmacology and toxicology areas. Data relating to the detection of ochratoxin A (OTA) in samples of bile, kidney and liver of self-consumption backyard chickens, artisanal salami and different types of cheese are presented; the concentrations of different heavy metals in backyard hen eggs and 5 types of industrial eggs; the preliminary data obtained from the analysis of the first samples of eggs and feathers from backyard poultry farms, analysed for the presence for fipronil and metabolites. Again for fipronil, and the molecule foxim, data concerning the potential drug-resistance studies of natural populations of Dermanyssus gallinae mites, and the insecticidal activity of some phytocompounds based on tannins are presented. Regarding the use of phytoextracts, are also presented the preliminary data obtained in the first months of an experimental trial in Leghorn hens reared with the free-range method, focused at the studying the anti-inflammatory and immuno-stimulating activity, as well as the evaluation of safety of the integration in the diet of Boswellia serrata and Salix alba. Translational studies were conducted in other scientific areas, relating to the serological and microbiological prevalence for Salmonella enterica var. enteritidis and var. thiphymurium in ornamental and self-consumption poultry farms, and prevalence and characterization of potential viral and bacterial (including zoonotic) variants of some infectious diseases of ornamental poultry. In ornamental poultry species a field study is also reported on off-label treatment with Fenbendazole and Flubendazole in massive infection of Cyathostoma bronchialis in exotic ornamental geese. Following a collaboration with the University of Florence, the results obtained from a study on murine models, of the action and functioning of Beta3 receptors, expressed in the most frequent neoplasms that occur in pregnant women, are also presented
Non-covalent interactions in weakly bound molecular complexes: a high-resolution rotational spectroscopy study
Get PDFMy research interests during my doctoral years have been focused on high resolution rotational studies of molecules and weakly bound molecular complexes. Information on the molecular structure, internal motions and intermolecular interactions that can be obtained by applying suitable theoretical models to the analysis of these unusually complex spectra allows the determination and understanding of the driving forces involved in formation of the molecular complex. In this way, many types of non-covalent interactions have been characterized, from pure van der Waals interactions in complexes of rare gases to moderate-strength and weak hydrogen bonds (HBs) and to the most recent halogen bonds, pnicogen4 or chalcogen bonds.
In this thesis, we first introduce the theory of rotational spectroscopy, including that of the asymmetrical rotor, the effects of centrifugal distortion, nuclear quadrupole coupling effects end those of internal motions In the second part, we introduce the experimental apparatuses that were used and related theoretical knowledge. In the third part, chloropentafluorobenzene (C6F5Cl) and bromopentafluorobenzene (C6F5Br) are chosen as case studies to investigate the effect of perfluorination on the molecular structure and electronic properties.In the fourth and fifth parts, we discuss the 1:1 complexes of acrolein-methanol and acrolein-ethanol. In chapter six to eight I report the results on the microwave detection and analysis of the 1:1 complexes of dimethyl sulfoxide (DMSO) with water, methanol and ethanol, respectively, in the gas phase
Quasars at the dawn of cosmic time
Get PDFQuasars beyond redshift z ~ 6 (age of the Universe 6 quasars are therefore ideal laboratories to characterize the physical properties of the interstellar medium in extreme conditions, and they provide an insight of the interplay between star formation and black hole accretion in massive galaxies emerging from cosmic dawn. The redshift z ~ 6 range is of particular interest because it coincides with the last phase transition of the Universe -- from neutral to mostly ionized. Hence, z > 6 quasars can be used as beacons to shed new light on the properties of intergalactic medium at the end of the Epoch of Reionization. Models and numerical simulations of massive black hole formation at early epochs predict that z>6 quasars reside at the extreme peak of the large-scale density structure such that they can be used to pinpoint the first galaxy overdensities. [abridged
Three-dimensional ultrasound technique in the diagnosis of levator ani muscle avulsion after vaginal birth
Get PDFObiettivi: Valutare la concordanza tra l'ecografia tomografica (TUI), considerata il gold standard, e l'OmniView-VCI nella diagnosi di avulsione del muscolo elevatore dell'ano (LAM) e nella misurazione della distanza elevatore-uretra (LUG: levator urethral gap).
Metodi: Abbiamo acquisito volumi dinamici 4D con ecografie transperineali da 114 donne. Ogni set di dati è stato analizzato sulla massima contrazione del pavimento pelvico mediante tecniche TUI e OmniView-VCI per verificare l’eventuale presenza di avulsione del LAM. Inoltre, abbiamo misurato il LUG utilizzando sia la TUI che l’OmniView-VCI, due volte da un operatore e una volta da un altro per valutare la riproducibilità intraoperatore e interoperatore. La riproducibilità e la concordanza tra i metodi sono state studiate mediante il coefficiente di correlazione interclasse (ICC) e il coefficiente kappa di Cohen.
Risultati: Nella diagnosi di avulsione dell'elevatore dell'ano, le due tecniche hanno mostrato una buona concordanza (κ di Cohen = 0,691, intervallo di confidenza al 95% [CI], 0,522-0,860; P < .001); abbiamo anche riportato una buona concordanza intraosservatore e interosservatore (κ di Cohen = 0,738, IC 95%, 0,597-0.879; P < .001 e di Cohen = 0.864, IC 95%, 0,750-0,978; P < .001, rispettivamente). Le misurazioni del LUG con la tecnica OmniView-VCI hanno mostrato un'elevata riproducibilità intraosservatore (ICC 0.895; 95% CI, 0.866-0.918) e interosservatore (ICC 0.821; 95% CI, 0.774-0.858). È stata dimostrata un'elevata concordanza tra i due metodi (ICC 0,813; 95% CI, 0,764-0,853). L'area sotto la curva ROC per la misurazione del LUG nel predire l'avulsione era 0,931 (0,868-0,994, 95% CI; P <0,001) con 24 mm, cut-off che mostra la migliore sensibilità (82%) e specificità (97%).
Conclusioni: OmniView-VCI è una tecnica affidabile per la misurazione del LUG e per la diagnosi dell'avulsione dell'elevatore dell’ano.Aims: To evaluate the intermethod agreement between the tomographic ultrasound imaging (TUI), considered as the gold standard, and the OmniView-VCI in the diagnosis of levator ani muscle (LAM) avulsion and in the measurement of levator-urethral gap (LUG).
Methods: We acquired dynamic 4D transperineal ultrasound volumes from 114 women. Each data set was analyzed on maximal pelvic floor contraction by TUI and OmniView-VCI techniques to check for LAM avulsion. Moreover, we measured LUG using both TUI and OmniView-VCI, twice by an operator and once by another to assess intraobserver and interobserver reproducibility. Reproducibility and intermethod agreement were studied by means of intraclass correlation coefficient (ICC) and Cohen's kappa coefficient.
Results: In the diagnosis of ani levator avulsion, the two techniques showed a good agreement (Cohen's κ = 0.691, 95% confidence interval [CI], 0.522-0.860; P < .001); we also reported a good intraobserver and interobserver agreement (Cohen's κ = 0.738, 95% CI, 0.597-0.879; P < .001, and Cohen's κ = 0.864, 95% CI, 0.750-0.978; P < .001, respectively). LUG measurements by OmniView-VCI technique showed high intraobserver (ICC 0.895; 95% CI, 0.866-0.918) and interobserver (ICC 0.821; 95% CI, 0.774-0.858) reproducibility. High intermethod agreement was demonstrated between the two methods (ICC 0.813; 95% CI, 0.764-0.853). The area under the receiver-operating characteristic curve of LUG in predicting avulsion was 0.931 (0.868-0.994, 95% CI; P < .001) with 24 mm showing the best sensitivity (82%) and specificity (97%).
Conclusions: OmniView-VCI is a reliable method for LUG measurement and for levator avulsion diagnosis
Climate variability in an Earth system Model of Intermediate Complexity: from interannual to centennial timescales
Get PDFThis thesis explores the climate mean state and climate variability repro- duced by atmosphere-ocean coupled configurations of the Planet Simulator (PlaSim), an Earth-system Model of Intermediate Complexity (EMIC). In particular, the sensitivity to variations in oceanic parameters is explored in three atmosphere-ocean coupled configurations: using a simple mixed-layer (ML) ocean at two horizontal resolutions (T21 - 600 km and T42 - 300 km) or a more complex dynamical ocean, the Large Scale Geostrophic (LSG) ocean, at T21 atmospheric horizontal resolution. Sensitivity experiments allow to identify a reference oceanic diffusion coefficient in the ML ocean and a vertical oceanic diffusion profile in LSG, which ensure a simulated climate in good agreement with the present climate. For each model configuration, the Equilibrium Climate Sensitivity (ECS) is estimated from simulations with an increased CO2 concentration compared to pre-industrial simulations. The resulting ECS values are higher than values estimated in other EMICs or models of the Coupled Intercomparison Project Phase 5 (CMIP5) and Phase 6 (CMIP6), especially in the PlaSim-ML configurations. The climate variability of the model is then explored on different timescales, from the centennial to the interannual one