Synthesis and surface modification of semiconductor nanocrystals

The last decade has witnessed an exponential growth of activities in the field of nanoscience and nanotechnology worldwide, driven both by the excitement of understanding new science and by the potential hope for applications and economic impacts. The largest activity in this field up to date has been in the synthesis and characterization of new materials consisting of particles with dimensions in the order of a few nanometers, so-called nanocrystalline materials. [1-8] Semiconductor nanomaterials such as III/V or II/VI compound semiconductors exhibit strong quantum confinement behavior in the size range from 1 to 10 nm. Therefore, preparation of high quality semiconductor nanocrystals has been a challenge for synthetic chemists, leading to the recent rapid progress in delivering a wide variety of semiconducting nanomaterials. Semiconductor nanocrystals, also called quantum dots, possess physical properties distinctly different from those of the bulk material. Typically, in the size range from 1 to 10 nm, when the particle size is changed, the band gap between the valence and the conduction band will change, too. In a simple approximation a particle in a box model has been used to describe the phenomenon[9]: at nanoscale dimensions the degenerate energy states of a semiconductor separate into discrete states and the system behaves like one big molecule. The size-dependent transformation of the energy levels of the particles is called “quantum size-effect”. Quantum confinement of both the electron and hole in all three dimensions leads to an increase in the effective bandgap of the material with decreasing crystallite size. Consequently, both the optical absorption and emission of semiconductor nanaocrystals shift to the blue (higher energies) as the size of the particles gets smaller. This color tuning is well documented for CdSe nanocrystals whose absorption and emission covers almost the whole visible spectral range. As particle sizes become smaller the ratio of surface atoms to those in the interior increases, which has a strong impact on particle properties, too. Prominent examples are the low melting point [8] and size/shape dependent pressure resistance [10] of semiconductor nanocrystals. Given the size dependence of particle properties, chemists and material scientists now have the unique opportunity to change the electronic and chemical properties of a material by simply controlling the particle size. In particular, CdSe nanocrystals have been widely investigated. Mainly due to their size-dependent optoelectronic properties [11, 12] and flexible chemical processibility [13], they have played a distinguished role for a number of seminal studies [11, 12, 14, 15]. Potential technical applications have been discussed, too. [8, 16-27] Improvement of the optoelectronic properties of semiconductor nanocrystals is still a prominent research topic. One of the most important approaches is fabricating composite type-I core-shell structures which exhibit improved properties, making them attractive from both a fundamental and a practical point of view. Overcoating of nanocrystallites with higher band gap inorganic materials has been shown to increase the photoluminescence quantum yields by eliminating surface nonradiative recombination sites. [28] Particles passivated with inorganic shells are more robust than nanocrystals covered by organic ligands only and have greater tolerance to processing conditions necessary for incorporation into solid state structures or for other applications. Some examples of core-shell nanocrystals reported earlier include CdS on CdSe [29], CdSe on CdS, [30], ZnS on CdS, [31] ZnS on CdSe[28, 32], ZnSe on CdSe [33] and CdS/HgS/CdS [34]. The characterization and preparation of a new core-shell structure, CdSe nanocrystals overcoated by different shells (CdS, ZnS), is presented in chapter 4. Type-I core-shell structures as mentioned above greatly improve the photoluminescence quantum yield and chemical and photochemical stability of nanocrystals. The emission wavelengths of type-I core/shell nanocrystals typically only shows a small red-shift when compared to the plain core nanocrystals. [30, 31, 35] In contrast to type-I core-shell nanocrystals, only few studies have been conducted on colloidal type-II core/shell structures [36-38] which are characterized by a staggered alignment of conduction and valence bands giving rise to a broad tunability of absorption and emission wavelengths, as was shown for CdTe/CdSe core-shell nanocrystals. [36] The emission of type-II core/shell nanocrystals mainly originates from the radiative recombination of electron-hole pairs across the core-shell interface leading to a long photoluminescence lifetime. Type-II core/shell nanocrystals are promising with respect to photoconduction or photovoltaic applications as has been discussed in the literature.[39] Novel type-II core-shell structures with ZnTe cores are reported in chapter 5. The recent progress in the shape control of semiconductor nanocrystals opens new fields of applications. For instance, rod shaped CdSe nanocrystals can enhance the photo-electro conversion efficiency of photovoltaic cells, [40, 41] and also allow for polarized emission in light emitting diodes. [42, 43] Shape control of anisotropic nanocrystals can be achieved by the use of surfactants, [44, 45] regular or inverse micelles as regulating agents, [46, 47] electrochemical processes, [48] template-assisted [49, 50] and solution-liquid-solution (SLS) growth mechnism. [51-53] Recently, formation of various CdSe nanocrystal shapes has been reported by the groups of Alivisatos [54] and Peng, [55] respectively. Furthermore, it has been reported by the group of Prasad [56] that noble metal nanoparticles can induce anisotropic growth of CdSe nanocrystals at lower temperatures than typically used in other methods for preparing anisotropic CdSe structures. Although several approaches for anisotropic crystal growth have been reported by now, developing new synthetic methods for the shape control of colloidal semiconductor nanocrystals remains an important goal. Accordingly, we have attempted to utilize a crystal phase control approach for the controllable synthesis of colloidal ZnE/CdSe (E = S, Se, Te) heterostructures in a variety of morphologies. The complex heterostructures obtained are presented in chapter 6. The unique optical properties of nanocrystals make them appealing as in vivo and in vitro fluorophores in a variety of biological and chemical investigations, in which traditional fluorescence labels based on organic molecules fall short of providing long-term stability and simultaneous detection of multiple emission colours [References]. The ability to prepare water soluble nanocrystals with high stability and quantum yield has led to promising applications in cellular labeling, [57, 58] deep-tissue imaging, [59, 60] and assay labeling [61, 62]. Furthermore, appropriately solubilized nanocrystals have been used as donors in fluorescence resonance energy transfer (FRET) couples. [63-65] Despite recent progress, much work still needs to be done to achieve reproducible and robust surface functionalization and develop flexible (bio-) conjugation techniques. Based on multi-shell CdSe nanocrystals, several new solubilization and ligand exchange protocols have been developed which are presented in chapter 7. The organization of this thesis is as follows: A short overview describing synthesis and properties of CdSe nanocrystals is given in chapter 2. Chapter 3 is the experimental part providing some background information about the optical and analytical methods used in this thesis. The following chapters report the results of this work: synthesis and characterization of type-I multi-shell and type-II core/shell nanocrystals are described in chapter 4 and chapter 5, respectively. In chapter 6, a high–yield synthesis of various CdSe architectures by crystal phase control is reported. Experiments about surface modification of nanocrystals are described in chapter 7. At last, a short summary of the results is given in chapter 8.

Therapeutic microbiology: characterization of Bifidobacterium strains for the treatment of enteric disorders in newborns.

Several studies support the use of probiotics for the treatment of minor gastrointestinal problems in infants. Positive effects on newborn colics have been evidenced after administration of Lactobacillus strains, whereas no studies have been reported regarding the use of bifidobacteria for this purpose. This work was therefore aimed at the characterization of Bifidobacterium strains capable of inhibiting the growth of pathogens typical of the infant gastro-intestinal tract and of coliforms isolated from colic newborns. Among the 46 Bifidobacterium strains considered, 16 showed high antimicrobial activity against potential pathogens; these strains were further characterized from a taxonomic point of view, for the presence and transferability of antibiotic resistances, for citotoxic effects and adhesion to non tumorigenic gut epithelium cell lines. Moreover, their ability to stimulate gut health by increasing the metabolic activity and the immune response of epithelial cells was also studied. The examination of all these features allowed to identify 3 B. breve strains and a B. longum subsp. longum strain as potential probiotics for the treatments of enteric disorders in newborns such as infantile colics. The formulation of a synbiotic product with an appropriate prebiotic fiber capable of supporting the growth of the selected Bifidobacterium strains was also considered in this study. In this respect the ability of the 4 selected Bifidobacterium strains to use as the sole carbon source and energy source different polisaccharide fibers was investigated The last phase of the work has been dedicated to the evaluation of the gut microbial diversity in newborns whose mothers has been subjected to antibiotic therapy a few hours before the delivery because of a Streptococcus type B infection. These newborns can represent a possible target for the probiotic strains selected in this work.

Comparative Analysis of Alternative Hybrid Systems for Automotive Applications

The main objective of this work was to investigate the impact of different hybridization concepts and levels of hybridization on fuel economy of a standard road vehicle where both conventional and non-conventional hybrid architectures are treated exactly in the same way from the point of view of overall energy flow optimization. Hybrid component models were developed and presented in detail as well as the simulations results mainly for NEDC cycle. The analysis was performed on four different parallel hybrid powertrain concepts: Hybrid Electric Vehicle (HEV), High Speed Flywheel Hybrid Vehicle (HSF-HV), Hydraulic Hybrid Vehicle (HHV) and Pneumatic Hybrid Vehicle (PHV). In order to perform equitable analysis of different hybrid systems, comparison was performed also on the basis of the same usable system energy storage capacity (i.e. 625kJ for HEV, HSF and the HHV) but in the case of pneumatic hybrid systems maximal storage capacity was limited by the size of the systems in order to comply with the packaging requirements of the vehicle. The simulations were performed within the IAV Gmbh - VeLoDyn software simulator based on Matlab / Simulink software package. Advanced cycle independent control strategy (ECMS) was implemented into the hybrid supervisory control unit in order to solve power management problem for all hybrid powertrain solutions. In order to maintain State of Charge within desired boundaries during different cycles and to facilitate easy implementation and recalibration of the control strategy for very different hybrid systems, Charge Sustaining Algorithm was added into the ECMS framework. Also, a Variable Shift Pattern VSP-ECMS algorithm was proposed as an extension of ECMS capabilities so as to include gear selection into the determination of minimal (energy) cost function of the hybrid system. Further, cycle-based energetic analysis was performed in all the simulated cases, and the results have been reported in the corresponding chapters.

Feeding behaviour of the Corydoradinae

The evolution of a sub-family of south-american freshwater catfishes has created a great diversification of its representants into a huge number of species, usually members of characteristic mimicry communities. After the work of Alexandrou (Alexandrou, 2011) on the phylogeny of the group that discovered the existence of more deep divisions, from the taxonomic point of view, of the sub-family, even from the ecological point of view, I tried to reconfirm these statements from the ethological point of view, settling watching and recording sessions and an experiment that could show their interactions on the environment by observing their substrate mixing action.

'A Distortion in the mirror of being': verso un modello liquido di personaggio. Da Nabokov alle sperimentazioni contemporanee in ambito slavo

La tesi mira a ridefinire lo statuto del personaggio nell’ambito del self-conscious novel postmoderno, alla luce delle più recenti tendenze narratologiche, con particolare riferimento all’unnatural narratology. Per poter presentare un modello scientificamente valido si è fatto ricorso alla comparazione della produzione letteraria di due macro-aree: quella britannica e quella slava (Russia - Unione Sovietica - e Polonia). Come figura di mediazione tra queste due culture si pone senza dubbio Vladimir V. Nabokov, cardine e personalità di spicco della ricerca. Tra le analisi testuali proposte sono stati presi in considerazione i seguenti autori: Julian Barnes, Vladimir Nabokov, Daniil Charms, Konstantin Vaginov, Andrej Bitov, Saša Sokolov, Bruno Schulz e Tadeusz Kantor.

Analysis of optimal control problems for the incompressible MHD equations and implementation in a finite element multiphysics code

This thesis deals with the study of optimal control problems for the incompressible Magnetohydrodynamics (MHD) equations. Particular attention to these problems arises from several applications in science and engineering, such as fission nuclear reactors with liquid metal coolant and aluminum casting in metallurgy. In such applications it is of great interest to achieve the control on the fluid state variables through the action of the magnetic Lorentz force. In this thesis we investigate a class of boundary optimal control problems, in which the flow is controlled through the boundary conditions of the magnetic field. Due to their complexity, these problems present various challenges in the definition of an adequate solution approach, both from a theoretical and from a computational point of view. In this thesis we propose a new boundary control approach, based on lifting functions of the boundary conditions, which yields both theoretical and numerical advantages. With the introduction of lifting functions, boundary control problems can be formulated as extended distributed problems. We consider a systematic mathematical formulation of these problems in terms of the minimization of a cost functional constrained by the MHD equations. The existence of a solution to the flow equations and to the optimal control problem are shown. The Lagrange multiplier technique is used to derive an optimality system from which candidate solutions for the control problem can be obtained. In order to achieve the numerical solution of this system, a finite element approximation is considered for the discretization together with an appropriate gradient-type algorithm. A finite element object-oriented library has been developed to obtain a parallel and multigrid computational implementation of the optimality system based on a multiphysics approach. Numerical results of two- and three-dimensional computations show that a possible minimum for the control problem can be computed in a robust and accurate manner.

An Analysis of Living Conditions in Rural Villages in China. A New Geography of the Country.

Analysts, politicians and international players from all over the world look at China as one of the most powerful countries on the international scenario, and as a country whose economic development can significantly impact on the economies of the rest of the world. However many aspects of this country have still to be investigated. First the still fundamental role played by Chinese rural areas for the general development of the country from a political, economic and social point of view. In particular, the way in which the rural areas have influenced the social stability of the whole country has been widely discussed due to their strict relationship with the urban areas where most people from the countryside emigrate searching for a job and a better life. In recent years many studies have mostly focused on the urbanization phenomenon with little interest in the living conditions in rural areas and in the deep changes which have occurred in some, mainly agricultural provinces. An analysis of the level of infrastructure is one of the main aspects which highlights the principal differences in terms of living conditions between rural and urban areas. In this thesis, I first carried out the analysis through the multivariate statistics approach (Principal Component Analysis and Cluster Analysis) in order to define the new map of rural areas based on the analysis of living conditions. In the second part I elaborated an index (Living Conditions Index) through the Fuzzy Expert/Inference System. Finally I compared this index (LCI) to the results obtained from the cluster analysis drawing geographic maps. The data source is the second national agricultural census of China carried out in 2006. In particular, I analysed the data refer to villages but aggregated at province level.

Multidimensional Measures of Firm Competitiveness: a Model-Based Approach

The concept of competitiveness, for a long time considered as strictly connected to economic and financial performances, evolved, above all in recent years, toward new, wider interpretations disclosing its multidimensional nature. The shift to a multidimensional view of the phenomenon has excited an intense debate involving theoretical reflections on the features characterizing it, as well as methodological considerations on its assessment and measurement. The present research has a twofold objective: going in depth with the study of tangible and intangible aspect characterizing multidimensional competitive phenomena by assuming a micro-level point of view, and measuring competitiveness through a model-based approach. Specifically, we propose a non-parametric approach to Structural Equation Models techniques for the computation of multidimensional composite measures. Structural Equation Models tools will be used for the development of the empirical application on the italian case: a model based micro-level competitiveness indicator for the measurement of the phenomenon on a large sample of Italian small and medium enterprises will be constructed.

Statistical Physics and Modeling of Human Mobility

In this thesis, we extend some ideas of statistical physics to describe the properties of human mobility. By using a database containing GPS measures of individual paths (position, velocity and covered space at a spatial scale of 2 Km or a time scale of 30 sec), which includes the 2% of the private vehicles in Italy, we succeed in determining some statistical empirical laws pointing out "universal" characteristics of human mobility. Developing simple stochastic models suggesting possible explanations of the empirical observations, we are able to indicate what are the key quantities and cognitive features that are ruling individuals' mobility. To understand the features of individual dynamics, we have studied different aspects of urban mobility from a physical point of view. We discuss the implications of the Benford's law emerging from the distribution of times elapsed between successive trips. We observe how the daily travel-time budget is related with many aspects of the urban environment, and describe how the daily mobility budget is then spent. We link the scaling properties of individual mobility networks to the inhomogeneous average durations of the activities that are performed, and those of the networks describing people's common use of space with the fractional dimension of the urban territory. We study entropy measures of individual mobility patterns, showing that they carry almost the same information of the related mobility networks, but are also influenced by a hierarchy among the activities performed. We discover that Wardrop's principles are violated as drivers have only incomplete information on traffic state and therefore rely on knowledge on the average travel-times. We propose an assimilation model to solve the intrinsic scattering of GPS data on the street network, permitting the real-time reconstruction of traffic state at a urban scale.

A projection into the ideas and technologies of "non-place" and "space of flow" in urban context

The meaning of a place has been commonly assigned to the quality of having root (rootedness) or sense of belonging to that setting. While on the contrary, people are nowadays more concerned with the possibilities of free moving and networks of communication. So, the meaning, as well as the materiality of architecture has been dramatically altered with these forces. It is therefore of significance to explore and redefine the sense and the trend of architecture at the age of flow. In this dissertation, initially, we review the gradually changing concept of "place-non-place" and its underlying technological basis. Then we portray the transformation of meaning of architecture as influenced by media and information technology and advanced methods of mobility, in the dawn of 21st century. Against such backdrop, there is a need to sort and analyze architectural practices in response to the triplet of place-non-place and space of flow, which we plan to achieve conclusively. We also trace the concept of flow in the process of formation and transformation of old cities. As a brilliant case study, we look at Persian Bazaar from a socio-architectural point of view. In other word, based on Robert Putnam's theory of social capital, we link social context of the Bazaar with architectural configuration of cities. That is how we believe "cities as flow" are not necessarily a new paradigm.

Shear behaviour of reinforced cconcrete slab under concentrated load: an investigation through non-linear and sequentially linear analysis

English: The assessment of safety in existing bridges and viaducts led the Ministry of Public Works of the Netherlands to finance a specific campaing aimed at the study of the response of the elements of these infrastructures. Therefore, this activity is focused on the investigation of the behaviour of reinforced concrete slabs under concentrated loads, adopting finite element modeling and comparison with experimental results. These elements are characterized by shear behaviour and crisi, whose modeling is, from a computational point of view, a hard challeng, due to the brittle behavior combined with three-dimensional effects. The numerical modeling of the failure is studied through Sequentially Linear Analysis (SLA), an alternative Finite Element method, with respect to traditional incremental and iterative approaches. The comparison between the two different numerical techniques represents one of the first works and comparisons in a three-dimensional environment. It's carried out adopting one of the experimental test executed on reinforced concrete slabs as well. The advantage of the SLA is to avoid the well known problems of convergence of typical non-linear analysis, by directly specifying a damage increment, in terms of reduction of stiffness and resistance in particular finite element, instead of load or displacement increasing on the whole structure . For the first time, particular attention has been paid to specific aspects of the slabs, like an accurate constraints modeling and sensitivity of the solution with respect to the mesh density. This detailed analysis with respect to the main parameters proofed a strong influence of the tensile fracture energy, mesh density and chosen model on the solution in terms of force-displacement diagram, distribution of the crack patterns and shear failure mode. The SLA showed a great potential, but it requires a further developments for what regards two aspects of modeling: load conditions (constant and proportional loads) and softening behaviour of brittle materials (like concrete) in the three-dimensional field, in order to widen its horizons in these new contexts of study.

On the development of novel cocaine-analogues for in vivo imaging of the dopamine transporter status

The present thesis is concerned with the development of novel cocaine-derived dopamine transporter ligands for the non-invasive exploration of the striatal and extra-striatal dopamine transporter (DAT) in living systems. The presynaptic dopamine transporter acquires an important function within the mediation of dopaminergic signal transduction. Its availability can serve as a measure for the overall integrity of the dopaminergic system. The DAT is upregulated in early Parkinson’s disease (PD), resulting in an increased availability of DAT-binding sites in the striatal DAT domains. Thereby, DAT imaging has become an important routine diagnostic tool for the early diagnosis of PD in patients, as well as for the differentiation of PD from symptomatically similar medical conditions. Furthermore, the dopaminergic system is involved in a variety of psychiatric diseases. In this regard, DAT-selective imaging agents may provide detailed insights into the scientific understanding of the biochemical background of both, the progress as well as the origins of the symptoms. DAT-imaging may also contribute to the determination of the dopaminergic therapeutic response for a given medication and thereby contribute to more convenient conditions for the patient. From an imaging point of view, the former demands a high availability of the radioactive probe to facilitate broad application of the modality, whereas the latter profits from short-lived probes, suitable for multi-injection studies. Therefore, labelling with longer-lived 18F-fluoride and in particular the generator nuclide 68Ga is worthwhile for clinical routine imaging. In contrast, the introduction of a 11C-label is a prerequisite for detailed scientific studies of neuronal interactions. The development of suitable DAT-ligands for medical imaging has often been complicated by the mixed binding profile of many compounds that that interact with the DAT. Other drawbacks have included high non-specific binding, extensive metabolism and slow accumulation in the DAT-rich brain areas. However, some recent examples have partially overcome the mentioned complications. Based on the structural speciality of these leads, novel ligand structures were designed and successfully synthesised in the present work. A structure activity relationship (SAR) study was conducted wherein the new structural modifications were examined for their influence on DAT-affinity and selectivity. Two of the compounds showed improvements in in vitro affinity for the DAT as well as selectivity versus the serotonin transporter (SERT) and norepinephrine transporter (NET). The main effort was focussed on the high-affinity candidate PR04.MZ, which was subsequently labelled with 18F and 11C in high yield. An initial pharmacological characterisation of PR04.MZ in rodents revealed highly specific binding to the target brain structures. As a result of low non-specific binding, the DAT-rich striatal area was clearly visualised by autoradiography and µPET. Furthermore, the radioactivity uptake into the DAT-rich brain regions was rapid and indicated fast binding equilibrium. No radioactive metabolite was found in the rat brain. [18F]PR04.MZ and [11C]PR04.MZ were compared in the primate brain and the plasma metabolism was studied. It was found that the ligands specifically visualise the DAT in high and low density in the primate brain. The activity uptake was rapid and quantitative evaluation by Logan graphical analysis and simplified reference tissue model was possible after a scanning time of 30 min. These results further reflect the good characteristics of PR04.MZ as a selective ligand of the neuronal DAT. To pursue 68Ga-labelling of the DAT, initial synthetic studies were performed as part of the present thesis. Thereby, a concept for the convenient preparation of novel bifunctional chelators (BFCs) was developed. Furthermore, the suitability of novel 1,4,7-triazacyclononane based N3S3-type BFCs for biomolecule-chelator conjugates of sufficient lipophilicity for the penetration of the blood-brain-barrier was elucidated.

Reactivity of activated electrophiles and nucleophiles: labile intermediates and properties of the reaction products

The main topic of my Ph.D. thesis is the study of nucleophilic and electrophilic aromatic substitution reaction, in particular from a mechanistic point of view. The research was mainly focused on the reactivity of superactivated aromatic systems. In spite of their high reactivity (hence the high reaction’s rate), we were able to identify and in some case to isolate -complexes until now only hypothesized. For example, interesting results comes from the study of the protonation of the supernucleophiles tris(dialkylamino)benzenes. However, the best result obtained in this field was the isolation and structural characterization of the first stables zwitterionic Wheland-Meisenheimer complexes by using 2,4-dipyrrolidine-1,3-thiazole as supernucleophile and 4,6-dinitrobenzofuroxan or 4,6-dinitrotetrazolepyridine as superelectrophile. These reactions were also studied by means of computational chemistry, which allowed us to better investigate on the energetic and properties of the reactions and reactants studied. We also discovered, in some case fortuitously, some relevant properties and application of the compounds we synthesized, such as fluorescence in solid state and nanoparticles, or textile dyeing. We decided to investigate all these findings also by collaborating with other research groups. During a period in the “Laboratoire de Structure et Réactivité des Systèmes Moléculaires Complexes-SRSMC, Université de Lorraine et CNRS, France, I carried out computational studies on new iron complexes for the use as dyes in Dye Sensitized Solar Cells (DSSC). Furthermore, thanks to this new expertise, I was involved in a collaboration for the study of the ligands’ interaction in biological systems. A collaboration with University of Urbino allowed us to investigate on the reactivity of 1,2-diaza-1,3-dienes toward nucleophiles such as amino and phosphine derivatives, which led to the synthesis of new products some of which are 6 or 7 member heterocycles containing both phosphorus and nitrogen atoms.

Innovative Strategies for the Synthesis of Biologically Active Small Molecules

The post genomic era, set the challenge to develop drugs that target an ever-growing list of proteins associated with diseases. However, an increase in the number of drugs approved every year is nowadays still not observed. To overcome this gap, innovative approaches should be applied in drug discovery for target validation, and at the same time organic synthetic chemistry has to find new fruitful strategies to obtain biologically active small molecules not only as therapeutic agents, but also as diagnostic tools to identify possible cellular targets. In this context, in view of the multifactorial mechanistic nature of cancer, new chimeric molecules, which can be either antitumor lead candidates, or valuable chemical tools to study molecular pathways in cancer cells, were developed using a multitarget-directed drug design strategy. According to this approach, the desired hybrid compounds were obtained by combining in a single chemical entity SAHA analogues, targeting histone deacetylases (HDACs), with substituted stilbene or terphenyl derivatives able to block cell cycle, to induce apoptosis and cell differentiation and with Sorafenib derivative, a multikinase inhibitor. The new chimeric derivatives were characterized with respect to their cytotoxic activity and their effects on cell cycle progression on leukemia Bcr-Abl-expressing K562 cell lines, as well as their HDACs inhibition. Preliminary results confirmed that one of the hybrid compounds has the desired chimeric profile. A distinct project was developed in the laboratory of Dr Spring, regarding the synthesis of a diversity-oriented synthesis (DOS) library of macrocyclic peptidomimetics. From a biological point of view, this class of molecules is extremely interesting but underrepresented in drug discovery due to the poor synthetic accessibility. Therefore it represents a valid challenge for DOS to take on. A build/couple/pair (B/C/P) approach provided, in an efficient manner and in few steps, the structural diversity and complexity required for such compounds.

Production of bioactive peptides through sequencial action of Yarrowia lipolytica proteases and chemical glycation

This PhD thesis is aimed at studying the suitability of proteases realised by Yarrowia lipolytica to hydrolyse proteins of different origins available as industrial food by-products. Several strains of Y. lipolytica have been screened for the production of extracellular proteases by zymography. On the basis of the results some strains released only a protease having a MW of 37 kDa, which corresponds to the already reported acidic protease, while other produced prevalently or only a protease with a MW higher than 200 kDa. The proteases have been screened for their "cold attitude" on gelatin, gluten and skim milk. This property can be relevant from a biotechnological point of view in order to save energy consumption during industrial processes. Most of the strains used were endowed with proteolytic activity at 6 °C on all the three proteins. The proteolytic breakdown profiles of the proteins, detected at 27 °C, were different related to the specific strains of Y. lipolytica. The time course of the hydrolysis, tested on gelatin, affected the final bioactivities of the peptide mixtures produced. In particular, an increase in both the antioxidant and antimicrobial activities was detected when the protease of the strain Y. lipolytica 1IIYL4A was used. The final part of this work was focused on the improvement of the peptides bioactivities through a novel process based on the production of glycopeptides. Firstly, the main reaction parameters were optimized in a model system, secondly a more complex system, based on gluten hydrolysates, was taken into consideration to produce glycopeptides. The presence of the sugar moiety reduced the hydrophobicity of the glycopeptides, thus affecting the final antimicrobial activity which was significantly improved. The use of this procedure could be highly effective to modify peptides and can be employed to create innovative functional peptides using a mild temperature process.