I Comuni incarnano idealmente delle piazze in cui il dibattito politico può svilupparsi in assenza di particolari filtri ed intermediazioni, con un rapporto diretto tra cittadini ed istituzioni. Essi costituiscono uno snodo di centrale importanza nell'esercizio della sovranità popolare e, al contempo, sono terreno fertile per la sperimentazione di modelli di partecipazione democratica. Prendendo come punto di vista l'esperienza dei Comuni italiani, si è scelto di focalizzare l'attenzione su uno degli strumenti “istituzionali” – nonché uno tra i più tradizionali – di partecipazione popolare, ovvero il referendum, nelle diverse forme ed accezioni che rientrano nel campo semantico di tale espressione. Questa è generalmente impiegata per indicare tutte quelle votazioni popolari non elettive su questioni politicamente rilevanti, formulate attraverso un quesito con due o più risposte alternative tra loro. L'analisi della disciplina legislativa degli istituti di partecipazione negli enti locali e lo studio delle disposizioni statutarie e regolamentari previste dai singoli Comuni, nonché le informazioni raccolte da alcuni casi di studio, rappresentano, in questo contesto, l'occasione per indagare le caratteristiche peculiari dell'istituto referendario, la sua effettività ed il suo impatto sulla forma di governo. In particolare, si è verificata positivamente la compatibilità del referendum, classificato dalla prevalente dottrina come istituto di democrazia diretta, con le forme attuali di democrazia rappresentativa. Si è tentato, altresì, un accostamento ai concetti di democrazia partecipativa e deliberativa, evidenziando come manchi del tutto, nel procedimento referendario (che pure è dotato di massima inclusività) un momento di confronto “deliberativo”. Il raffronto tra le esperienze riscontrate nei diversi Comuni ha consentito, inoltre, di ricercare le cause di alcuni aspetti critici (scarsa affluenza, mancata trasformazione del voto in decisioni politiche, aumento del conflitto) e, al contempo, di individuarne possibili soluzioni, tracciate sulla scorta delle migliori pratiche rilevate. / Municipalities ideally embody the places where political debate can be developed without particular filters and intermediation, in a direct relationship between citizens and institutions. They represent the hub of the exercise of popular sovereignty and, at the same time, a fertile ground where models of democratic participation can be tested. Taking as point of view the experience of Italian Municipalities, it has been decided to focus the attention on one of the institutional instruments of popular participation, which is at the same time one of the most traditional: the referendum, in all its several forms and meanings, included initiative. This expression is generally used to indicate all those not elective popular votes on relevant political issues, formulated through a question having two or more alternative answers. The analysis of the legislative framework of participatory institutions and the study of single municipalities regulations, as well as the information collected by choosing case studies, represent, in this context, an opportunity to investigate the referendum features, its effectiveness and its impact on the form of government. Specifically, it has been observed in a positive way the compatibility of the referendum, which is classified by the prevailing doctrine as an institution of direct democracy, with the current forms of representative democracy. It has also been tried to compare the institution of referendum with the concepts of participatory and deliberative democracy highlighting the complete lack of a deliberative process in the referendum proceedings (although they are characterized by a total inclusiveness). The comparison between the different experiences of several municipalities has also made possible to examine the causes of some critical aspects (e.g. low turnout, failure to transform the vote in political decisions, increase of the conflict) and, at the same time, to identify possible solutions on the basis of the best practices studied.

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The subject of this doctoral dissertation concerns the definition of a new methodology for the morphological and morphometric study of fossilized human teeth, and therefore strives to provide a contribution to the reconstruction of human evolutionary history that proposes to extend to the different species of hominid fossils. Standardized investigative methodologies are lacking both regarding the orientation of teeth subject to study and in the analysis that can be carried out on these teeth once they are oriented. The opportunity to standardize a primary analysis methodology is furnished by the study of certain early Neanderthal and preneanderthal molars recovered in two caves in southern Italy [Grotta Taddeo (Taddeo Cave) and Grotta del Poggio (Poggio Cave), near Marina di Camerata, Campania]. To these we can add other molars of Neanderthal and modern man of the upper Paleolithic era, specifically scanned in the paleoanthropology laboratory of the University of Arkansas (Fayetteville, Arkansas, USA), in order to increase the paleoanthropological sample data and thereby make the final results of the analyses more significant. The new analysis methodology is rendered as follows: 1. Standardization of an orientation system for primary molars (superior and inferior), starting from a scan of a sample of 30 molars belonging to modern man (15 M1 inferior and 15 M1 superior), the definition of landmarks, the comparison of various systems and the choice of a system of orientation for each of the two dental typologies. 2. The definition of an analysis procedure that considers only the first 4 millimeters of the dental crown starting from the collar: 5 sections parallel to the plane according to which the tooth has been oriented are carried out, spaced 1 millimeter between them. The intention is to determine a method that allows for the differentiation of fossilized species even in the presence of worn teeth. 3. Results and Conclusions. The new approach to the study of teeth provides a considerable quantity of information that can better be evaluated by increasing the fossil sample data. It has been demonstrated to be a valid tool in evolutionary classification that has allowed (us) to differentiate the Neanderthal sample from that of modern man. In a particular sense the molars of Grotta Taddeo, which up until this point it has not been possible to determine with exactness their species of origin, through the present research they are classified as Neanderthal.

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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.