New Synthetic Polyamines as Multi-Target-Directed Ligands for the Treatment of Alzheimer's Disease and Cancer: Design, Synthesis and Biological Evaluation

Alzheimer's disease (AD) and cancer represent two of the main causes of death worldwide. They are complex multifactorial diseases and several biochemical targets have been recognized to play a fundamental role in their development. Basing on their complex nature, a promising therapeutical approach could be represented by the so-called "Multi-Target-Directed Ligand" approach. This new strategy is based on the assumption that a single molecule could hit several targets responsible for the onset and/or progression of the pathology. In particular in AD, most currently prescribed drugs aim to increase the level of acetylcholine in the brain by inhibiting the enzyme acetylcholinesterase (AChE). However, clinical experience shows that AChE inhibition is a palliative treatment, and the simple modulation of a single target does not address AD aetiology. Research into newer and more potent anti-AD agents is thus focused on compounds whose properties go beyond AChE inhibition (such as inhibition of the enzyme β-secretase and inhibition of the aggregation of beta-amyloid). Therefore, the MTDL strategy seems a more appropriate approach for addressing the complexity of AD and may provide new drugs for tackling its multifactorial nature. In this thesis, it is described the design of new MTDLs able to tackle the multifactorial nature of AD. Such new MTDLs designed are less flexible analogues of Caproctamine, one of the first MTDL owing biological properties useful for the AD treatment. These new compounds are able to inhibit the enzymes AChE, beta-secretase and to inhibit both AChE-induced and self-induced beta-amyloid aggregation. In particular, the most potent compound of the series is able to inhibit AChE in subnanomolar range, to inhibit β-secretase in micromolar concentration and to inhibit both AChE-induced and self-induced beta-amyloid aggregation in micromolar concentration. Cancer, as AD, is a very complex pathology and many different therapeutical approaches are currently use for the treatment of such pathology. However, due to its multifactorial nature the MTDL approach could be, in principle, apply also to this pathology. Aim of this thesis has been the development of new molecules owing different structural motifs able to simultaneously interact with some of the multitude of targets responsible for the pathology. The designed compounds displayed cytotoxic activity in different cancer cell lines. In particular, the most potent compounds of the series have been further evaluated and they were able to bind DNA resulting 100-fold more potent than the reference compound Mitonafide. Furthermore, these compounds were able to trigger apoptosis through caspases activation and to inhibit PIN1 (preliminary result). This last protein is a very promising target because it is overexpressed in many human cancers, it functions as critical catalyst for multiple oncogenic pathways and in several cancer cell lines depletion of PIN1 determines arrest of mitosis followed by apoptosis induction. In conclusion, this study may represent a promising starting pint for the development of new MTDLs hopefully useful for cancer and AD treatment.

The school environment as a teacher. The role of space and place in enhancing ecological literacy and social competence development in children and young people

Can space and place foster child development, and in particular social competence and ecological literacy? If yes, how can space and place do that? This study shows that the answer to the first question is positive and then tries to explain the way space and place can make a difference. The thesis begins with the review of literature from different disciplines – child development and child psychology, education, environmental psychology, architecture and landscape architecture. Some bridges among such disciplines are created and in some cases the ideas from the different areas of research merge: thus, this is an interdisciplinary study. The interdisciplinary knowledge from these disciplines is translated into a range of design suggestions that can foster the development of social competence and ecological literacy. Using scientific knowledge from different disciplines is a way of introducing forms of evidence into the development of design criteria. However, the definition of design criteria also has to pass through the study of a series of school buildings and un-built projects: case studies can give a positive contribution to the criteria because examples and good practices can help “translating” the theoretical knowledge into design ideas and illustrations. To do that, the different case studies have to be assessed in relation to the various themes that emerged in the literature review. Finally, research by design can be used to help define the illustrated design criteria: based on all the background knowledge that has been built, the role of the architect is to provide a series of different design solutions that can give answers to the different “questions” emerged in the literature review.

Produzione automatizzata per nastratura di componenti strutturali in materiale composito

Questa dissertazione tratterà l’argomento dello studio di metodi di progettazione e processi tecnologici innovativi per l’industrializzazione in medio-grande serie di componenti strutturali in materiale composito. L’interesse della ricerca verso questo ambito è suscitato dai notevoli vantaggi che l’utilizzo di materiali dall’alto rapporto prestazioni meccaniche/peso danno nella ricerca di elevate prestazioni in applicazioni sportive e diminuzione dei consumi ed emissioni inquinanti in mezzi di trasporto di grande serie. Lo studio di componenti in materiale composito è caratterizzato dalla peculiarità di non poter disgiungere la progettazione della geometria della parte da quella del materiale e del processo, ed in questo senso nella figura del progettista si vanno a riassumere sinergicamente competenze riguardanti i tre ambiti. Lo scopo di questo lavoro è la proposizione di una metodologia di progettazione e produzione di componenti strutturali che permetta l’utilizzazione ottimale della natura fibrosa del materiale composito sia dal punto di vista del trasferimento dei carichi tra diversi componenti, sia dal punto di vista del processo di laminazione che avviene per nastratura automatizzata. Lo studio è volto a mostrare in quali termini tale tecnologia sia potenzialmente in grado di superare i vincoli di forma ed i limiti di efficienza meccanica delle giunzioni tra le parti e di garantire maggiore produttività e costi inferiori rispetti ai diversi metodi di produzione che rappresentano oggi lo stato dell’arte dell’industrializzazione in medio-grande serie. Particolare attenzione verrà posta sull’utilizzo della tecnologia oggetto di studio per la produzione di telai automobilistici.