Development of advanced analytical methodologies for Alzheimer’s disease drug discovery

Advanced analytical methodologies were developed to characterize new potential active MTDLs on isolated targets involved in the first stages of Alzheimer’s disease (AD). In addition, the methods investigated drug-protein bindings and evaluated protein-protein interactions involved in the neurodegeneration. A high-throughput luminescent assay allowed the study of the first in class GSK-3β/ HDAC dual inhibitors towards the enzyme GSK-3β. The method was able to identify an innovative disease-modifying agent with an activity in the micromolar range both on GSK-3β, HDAC1 and HDAC6. Then, the same assay reliably and quickly selected true positive hit compounds among natural Amaryllidaceae alkaloids tested against GSK-3β. Hence, given the central role of the amyloid pathway in the multifactorial nature of AD, a multi-methodological approach based on mass spectrometry (MS), circular dichroism spectroscopy (CD) and ThT assay was applied to characterize the potential interaction of CO releasing molecules (CORMs) with Aβ1-42 peptide. The comprehensive method provided reliable information on the different steps of the fibrillation process and regarding CORMs mechanism of action. Therefore, the optimal CORM-3/Aβ1−42 ratio in terms of inhibitory effect was identified by mass spectrometry. CD analysis confirmed the stabilizing effect of CORM-3 on the Aβ1−42 peptide soluble form and the ThT Fluorescent Analysis ensured that the entire fibrillation process was delayed. Then the amyloid aggregation process was studied in view of a possible correlation with AD lipid brain alterations. Therefore, SH-SY5Y cells were treated with increasing concentration of Aß1-42 at different times and the samples were analysed by a RP-UHPLC system coupled with a high-resolution quadrupole TOF mass spectrometer in comprehensive data-independent SWATH acquisition mode. Each lipid class profiling in SH-SY5Y cells treated with Aß1-42 was compared to the one obtained from the untreated. The approach underlined some peculiar lipid alterations, suitable as biomarkers, that might be correlated to Aß1-42 different aggregation species.

Inequality of income and poverty persistence in the Municipality of Bologna: a cross-sectional and longitudinal analysis through administrative data

This work is part of a project promoted by Emilia-Romagna that aims at encouraging research activities in order to support the innovation strategies of the regional economic system through the exploitation of new data sources. To gain this scope, a database containing administrative data is provided by the Municipality of Bologna. This is achieved by linking data from the Register Office of the Municipality and fiscal data coming from the tax returns submitted to the Revenue Agency and released by the Ministry of Economy and Finance for the period 2002-2017. The main purpose of the project is the analysis of the medium term financial and distributional trends of income of the citizens residing in the Municipality of Bologna. Exploiting this innovative source of data allow us to analyse the dynamics of income at municipal level, overcoming the lack of information in official survey-based statistic. We investigate these trends by building inequality indicators and by examining the persistence of in-work poverty. Our results represent an important informative element to improve the effectiveness and equity of welfare policies at the local level, and to guide the distribution of economic and social support and urban redevelopment interventions in different areas of the Municipality.

Rising China and Internet governance: Multistakeholderism, fragmentation and the Liberal Order in the age of digital sovereignty

In its open and private-based dimension, the Internet is the epitome of the Liberal International Order in its global spatial dimension. Therefore, normative questions arise from the emergence of powerful non-liberal actors such as China in Internet governance. In particular, China has supported a UN-based multilateral Internet governance model based on state sovereignty aimed at replacing the existing ICANN-based multistakeholder model. While persistent, this debate has become less dualistic through time. However, fear of Internet fragmentation has increased as the US-China technological competition grew harsher. This thesis inquires “(To what extent) are Chinese stakeholders reshaping the rules of Global Internet Governance?”. This is further unpacked in three smaller questions: (i) (To what extent) are Chinese stakeholders contributing to increased state influence in multistakeholder fora?; (ii) (how) is China contributing to Internet fragmentation?; and (iii) what are the main drivers of Chinese stakeholders’ stances? To answer these questions, Chinese stakeholders’ actions are observed in the making and management of critical Internet resources at the IETF and ICANN respectively, and in mobile connectivity standard-making at 3GPP. Through the lens of norm entrepreneurship in regime complexes, this thesis interprets changes and persistence in the Internet governance normative order and Chinese attitudes towards it. Three research methods are employed: network analysis, semi-structured expert interviews, and thematic document analysis. While China has enhanced state intervention in several technological fields, fostering debates on digital sovereignty, this research finds that the Chinese government does not exert full control on its domestic private actors and concludes that Chinese stakeholders have increasingly adapted to multistakeholder Internet governance as they grew influential within it. To enhance control over Internet-based activities, the Chinese government resorted to regulatory and technical control domestically rather than establishing a splinternet. This is due to Chinese stakeholders’ interest in retaining the network benefits of global interconnectivity.

Plutarch's chemistry of stones and metals: conceptions and explanations. With an appendix on the TheSu XML annotation scheme

This dissertation presents a systematic and analytic overview of most of the information related to stones, minerals, and stone masonry which is found in the corpus of Plutarch of Chaeronea, combined with most of the information on metals and metalworking which is connected to the former. This survey is intended as a first step in the reconstruction of the full landscape of ‘chemical’ ideas occurring in Plutarch’s writings; accordingly, the exposition of the relevant passages, the assessment of their possible interpretations, the discussion on their implications, and their contextualization in the ancient traditions have been conducted with a special interest in the ‘mineralogical’ and ‘metallurgic’ themes developed in the frame of natural philosophy and meteorology. Although in this perspective physical etiology could have come to acquire central prominence, non-etiological information on Plutarch’s ideas on the nature and behaviour of stones and metals has been treated as equally relevant to reach a fuller understanding of how Plutarch conceptualized and visualized them in general, in- and outside the frame of philosophical explanation. Such extensive outline of Plutarch’s ideas on stones and metals is a prerequisite for an accurate inquiry into his use of the two in analogies, metaphors, and symbols: to predispose this kind of research was another aim of the present survey, and this aim has contributed to shape it; moreover, a special attention has been paid to the analysis of analogical and figurative speaking due to the nature itself of a large part of Plutarch’s references to stones and metals, which are either metaphorical, presented in close association with metaphors, or framed in analogies. Much of the information used for the present overview has been extracted —always with supporting argumentation— from the implications of such metaphors and analogies.

Solutions for the conservation and restoration of cement-based materials in XX Century architectural heritage

Among the most representative materials of XX Century architectural heritage, this dissertation focuses on the cement-based ones, investigating some different fields where they were exploited. Primarily, concerning the surface preservation of cement-based materials used with aesthetic intent, new self-cleaning treatments based on titania nanoparticles embedded in inorganic matrices were tested. In order to consider the role of porosity, the treatments were applied to different kinds of materials (cement-based mortar, marble and concrete) and several analyses were conducted to investigate the morphology of the coatings, their photocatalytic effectiveness, their durability and the interaction between the coating and the substrate material. The outcomes showed that several parameters influence the treatment’s performances, in particular, the presence and nature of the matrix, the concentration and dispersion of nanoparticles and, in some cases, the amount of substrate material which interacts with the coatings. Secondly, this dissertation deals with the historic “Terranova” render, a colored dry-mix mortar largely widespread in Europe in the first half of XX Century, whose formulation is still basically unknown. Some original samples of supposedly Terranova renders were subjected to several characterization analyses and the results were compared to those of the original “Terranova” render of the Engineering Faculty in Bologna. Despite the recurrence of some features, defining a common formulation seemed to be challenging. Finally, the repair and conservation of structural reinforced concrete in heritage buildings were investigated, adopting the former “Casa del Fascio” in Predappio (FC, Italy) as case study. Three different materials and solutions were tested on a slab of the building, making its repair only from the intrados. Then several analyses were conducted both on site and in laboratory. Aside from the specific features characterizing every product, the results highlighted that the application method played a fundamental role in the effectiveness of the retrofit strategies.

Effect of pulsed electromagnetic fields (pemfs) on muscle activity, tissue oxygenation and vo2 during exercise.

PEMF are a medical and non-invasive therapy successfully used for clinical treatments of bone disease, due to the piezoelectric effect that improve bone mass and density, by the stimulation of osteoblastogenesis, with modulation of calcium storages and mineral metabolism. PEMF enhance tissue oxygenation, microcirculation and angiogenesis, in rats and cells erythrocytes, in cells-free assay. Such responses could be caused by a modulation of nitric oxide signal and interaction between PEMF and Ca2+/NO/cGMP/PKG signal. PEMF improve blood flow velocity of smallest vein without changing their diameter. PEMF therapy helpful in patients with diabetes, due to increased microcirculation trough enhance capillary blood velocity and diameter. We investigated the influence of stimulation on muscular activity, tissue oxygenation and pulmonary VO2, during exercise, on different intensity, as heavy or moderate, different subjects, as a athlete or sedentary, and different sport activity, as a cycling or weightlifting. In athletes, we observed a tendency for a greater change and a faster kinetic of HHb concentration. PEMF increased the velocity and the quantity of muscle O2 available, leading to accelerate the HHb kinetics. Stimulation induced a bulk muscle O2 availability and a greater muscle O2 extraction, leading to a reduced time delay of the HHb slow component. Stimulation increased the amplitude of muscle activity under different conditions, likely caused by the effect of PEMF on contraction mechanism of muscular fibers, by the change of membrane permeability and Ca2+ channel conduction. In athletes, we observed an increase of overall activity during warm-up. In sedentary people, stimulation increased the magnitude of muscle activity during moderate constant-load exercise and warm-up. In athletes and weightlifters, stimulation caused an increase of blood lactate concentration during exercise, confirming a possible influence of stimulation on muscle activity and on glycolytic metabolism of type-II muscular fibers.

Transitional Justice as a Post-Revolution Constitutional Arrangement: A Law and Economics Approach

This dissertation addresses the timely questions of transitional justice (TJ) in the aftermath of revolutions against autocratic regimes, dealing with TJ as a constitutional arrangement through the lenses of constitutional economics. After an introductory chapter, chapter 2 deals with why nations rarely adopt meaningful TJ processes in the first place, it then explains the limitations of civil society as the arbiter, facilitator, and enforcer of TJ policies. Chapter 3 tackles the question of which mechanisms to choose? It uses the UN Guidelines on TJ that sets five principal TJ mechanisms. It provides a cost-benefit analysis (CBA) of each mechanism and suggests policy implications accordingly. The CBA inspires chapter 4 analysis, suggesting a tradeoff between restrictive fair trial standards under constitutional laws and justice considerations. The tradeoff explains the suggested efficiency of the balanced TJ approaches that combine trials and amnesties. This approach is used for the case study analysis of TJ in Tunisia after the 2011 revolution in chapter 5. The chapter presents the first index of TJ mechanisms in Tunisia through novel data collected by the author. It shows an ultimate TJ design that ended with a modest harvest in the application. The lack of cooperation between the Tunisian parties, added to the absence of transparency in many TJ measures, threatens any possible positive outcomes of the partial TJ process. It is also alarming regarding constitutional compliance in a system that – until recently - was considered the only democracy in the Arab region. Chapter 6 is a summary

Equità di genere e pratiche trasformative in educazione fisica

A partire da un paradigma ecologico ad indirizzo critico, seguendo il filone degli studi femministi, le finalità della ricerca sono state: smascherare le forme di oppressione di genere nei contesti educativi (finalità trasformativa) e produrre un sapere utile alla pratica (finalità emancipativa). Data la complessità del contesto educativo scolastico e dell’argomento stesso che interseca vari domini di sapere, è stato adottato un approccio metodologico di metodo misto (mixed method) per poter dapprima costruire una configurazione del fenomeno oggetto d’interesse attraverso strumenti quantitativi e poi approfondirlo attraverso l’impiego di tecniche qualitative. Gli strumenti utilizzati sono stati: il questionario, l’intervista strutturata, le osservazioni, le biografie professionali, i focus-group. In sintesi, le evidenze emerse in letteratura ed empiriche mettono in luce la presenza di stereotipi di genere nelle lezioni di EF, sotto forma di pratiche inconsapevoli che gli insegnanti riproducono a seguito di un habitus socializzato in forma binaria secondo i due sessi e gerarchizzato. La dipendenza dell’EF dal mondo sportivo, dove gli stereotipi di genere sono presenti per ragioni storico-culturali e dal quale gli insegnanti attingono spesso parte del loro sapere professionale, li rende partecipi inconsapevoli del sistema di rinforzo degli stereotipi stessi, attraverso le pratiche che vanno sotto il nome di curricolo nascosto. Il termine nascosto sottolinea l’inconsapevolezza di tali pratiche, appunto nascoste alla coscienza e si deduce che la possibilità di svelarle necessita di una formazione specifica per gli insegnanti, una formazione che attinga ai processi riflessivi.

The EU’s foreign policy towards the Western Balkans during the Juncker Commission. The cases of Bosnia Herzegovina and Serbia.

In February 2018, four years after the President of the Commission Jean Claude Juncker explicitly deprioritised the enlargement dossier, the European Commission relaunched the enlargement strategy to the region of the Western Balkans. This occurred despite the persistent polarisation around the topic among the EU Member States and the still-present struggles, when not outright regression, of some of the countries in pursuing the demanded reforms. This thesis carries out a multilevel foreign policy analysis of EU foreign policy toward the region of the Western Balkans during the period of the Juncker Commission, through the cases of Bosnia Herzegovina and Serbia. Drawing from Actorness theory (Bretherton and Vogler 2006), combined with perspectives from new institutional leadership (Smeets and Beach 2020), and new intergovernmentalism (Moravcsik 2018; Bickerton et al. 2015), this study seeks to explain the relaunch of enlargement by examining three dimensions: the international context and the role of non-EU actors such as China, Russia, and Turkey; the EU context, through the interaction of the significant EU Member States and Institutions; finally, the local context, through the analysis of the changes in the local perception of the EU and the considered non-EU actors. This study posits two interconnected points: first, that the changes in the international context, specifically the increased presence of non-EU actors such as China, Russia, and Turkey in the region, acted as triggering factors for the relaunch of the strategy. In addition, it argues that this relaunch was successful due to the peculiar combination of Germany’s interests and leadership within the Council, coupled with the Commission’s priorities.

A double chance to investigate populist influence: The Five Star Movement.

In the last decade, new kinds of European populist parties and movements characterized by a left wing, right wing or “eclectic” attitude have succeeded in entering in governments where they could exert a direct populist influence on their coalition partners or, conversely, become victims themselves of the influence of the institutional background. Such a scenario brought this research to formulate two questions: (i) “To what extent did populist parties succeed in influencing their government coalition partners, leading them to adopt populist rhetoric and change their policy positions?” and (ii) “Have populist parties been able to retain their populist “outside mainstream politics” identity, or have they been assimilated to mainstream parties?”. As a case study this project chose the Italian Five Star Movement. Since 2018 this eclectic populist actor has experienced three different governments first with the radical right wing populist League (2018-2019) and then with the mainstream center left Democratic Party (2019-2021). In addition to this, currently the Five Star Movement is a coalition partner of the ongoing Draghi’s government. Theoretically based on the ideological definition of populism (Mudde, 2004), on a new “revised” model of the inclusionary - exclusionary framework to classify populist parties and on a novel definition of “populist influence”,this research made use of both quantitative (bidimensional and text analysis) and qualitative methods (semi-structured interviews) and mainly focuses on the years 2017- 2020.The importance of this study is threefold. First it contributes to the study of populist influence in government in relation to the ideological attachment of the political actors involved. Second, it contributes to understand if populists in power necessarily need to tone down their anti-system character in order to survive. Third, this study introduces conceptual and methodological novelties within the study of populism and populist influence in government.

I nuovi operatori del mondo sportivo e la tutela della salute nella dimensione dei moderni servizi di welfare

Lo studio mira ad individuare i passaggi salienti dell’evoluzione dello sport inteso come strumento di salute e benessere preventivo, per rinvenire le manifestazioni di questo concetto, con l’obiettivo precipuo di fare emergere l’ossatura legislativa in evoluzione su cui impostare la transizione del sistema delle attività motorie. Partendo dallo studio del dato normativo e giurisprudenziale e con un’ampia analisi dottrinale sullo sfondo, lo studio descrive l’evoluzione legislativa sul tema poggiandosi su considerazioni e risultati di indagini sociologiche e farmacologiche. La creazione della Società Sport e Salute S.p.a. e di un Dipartimento per lo sport ha permesso un’azione diretta al sostegno delle organizzazioni sportive di base e mirata alla promozione di piani per l’implementazione dei corretti stili di vita. Il d.lgs. 38/2021 contiene una serie di norme volte alla valorizzazione dell’importanza anche territoriale degli enti sportivi, che possono favorire questi e i loro partners privati nell’affidamento degli impianti. La nuova figura professionale del chinesiologo rappresenta lo strumento centrale per il rilancio degli enti sportivi, in quanto capace di organizzare nuovi servizi paralleli allo sport e fondamentali in ottica educativa preventiva. L’accresciuta rilevanza del concetto di work-life balance spinge le imprese alla creazione di nuove politiche di welfare per i lavoratori attraverso investimenti per la riqualificazione dell’impiantistica, in modo da favorire gli enti che li gestiscono collaborando per offrire maggiori servizi anche al territorio. Il legislatore ha creato uno strato normativo volto a permettere un’azione diretta dello Stato nella promozione dello sport sociale e volto all’implementazione dei corretti stili di vita. È ora possibile teorizzare un modello di ente che offra una nuova tipologia di servizi da erogare all’interno di moderni impianti, riqualificati grazie al supporto di imprese che vedono le associazioni sportive come presidi per la salute dei lavoratori, favorendo il benessere collettivo oltre che la propria immagine.

Multi-Principal Agency and the Compliance with Professional Guidelines in Health Systems: Economic and Regulatory Perspectives

Amid the trend of rising health expenditure in developed economies, changing the healthcare delivery models is an important point of action for service regulators to contain this trend. Such a change is mostly induced by either financial incentives or regulatory tools issued by the regulators and targeting service providers and patients. This creates a tripartite interaction between service regulators, professionals, and patients that manifests a multi-principal agent relationship, in which professionals are agents to two principals: regulators and patients. This thesis is concerned with such a multi-principal agent relationship in healthcare and attempts to investigate the determinants of the (non-)compliance to regulatory tools in light of this tripartite relationship. In addition, the thesis provides insights into the different institutional, economic, and regulatory settings, which govern the multi-principal agent relationship in healthcare in different countries. Furthermore, the thesis provides and empirically tests a conceptual framework of the possible determinants of (non-)compliance by physicians to regulatory tools issued by the regulator. The main findings of the thesis are first, in a multi-principal agent setting, the utilization of financial incentives to align the objectives of professionals and the regulator is important but not the only solution. This finding is based on the heterogeneity in the financial incentives provided to professionals in different health markets, which does not provide a one-size-fits-all model of financial incentives to influence clinical decisions. Second, soft law tools as clinical practice guidelines (CPGs) are important tools to mitigate the problems of the multi-principal agent setting in health markets as they reduce information asymmetries while preserving the autonomy of professionals. Third, CPGs are complex and heterogeneous and so are the determinants of (non-)compliance to them. Fourth, CPGs work but under conditions. Factors such as intra-professional competition between service providers or practitioners might lead to non-compliance to CPGs – if CPGs are likely to reduce the professional’s utility. Finally, different degrees of soft law mandate have different effects on providers’ compliance. Generally, the stronger the mandate, the stronger the compliance, however, even with a strong mandate, drivers such as intra-professional competition and co-management of patients by different professionals affected the (non-)compliance.

Physical activity and osseointegration: "step forward" to improve the quality of life of a trans-femoral amputee person

Lower limb amputation is an event that inevitably changes the lifestyle of the person with a significant impact on quality of life. The socket-type prosthesis entails that the residual limb is in direct contact with the socket which often implies numerous disadvantages. Osseointegrated prosthesis is a solution that avoids skin problems because not include the presence of the socket. In this type of prosthesis, a stem is surgically inserted inside the medullary canal and connected with the external prosthetic limb. Therefore, this thesis aims to highlight and explore the main strengths and problems of osseointegrated prostheses and to examine the role of physical activity, with attention to functional capacity and bone quality. The objectives of the thesis will be developed through 5 studies: (I) A gait analysis of a 44 years-old male patient who underwent surgery for the implantation of an osseointegrated prosthesis; (II) A systematic review to investigate the state of stump bone quality in patients with limb amputations; (III) A systematic review of the technologies involved in such devices has been carried out to identify the most fruitful ones in improving bone quality; (IV) A systematic review investigating the topic of physical activity and bone turnover biomarkers; (V) A systematic review to investigate the effects of physical activity interventions combined with drug treatments on bone biomarkers in people with osteopenia and osteoporosis. The integrated prosthesis is a good solution for people with lower limb amputation who cannot use their traditional socket-type prosthesis. Although many objectives have already been achieved, there are still many aspects that we can improve. These include the creation of a multidisciplinary path that support patients along their path, with particular attention to the pre-surgery and the post-rehabilitation phase that is still lacking even if of fundamental impact in determining the quality of life.

Il ruolo del corpo nell'educazione alla cittadinanza globale: processi di mobilitazione

La tesi colloca il corpo vissuto al centro dei processi di mobilitazione della cittadinanza globale. Riporta le fasi e i risultati di una Grounded Theory che mira a indagare come si sviluppano e prendono forma i processi di attivazione. I dati sono stati raccolti attraverso interviste a giovani attivisti appartenenti a organizzazioni della società civile impegnate in questioni globali. Da questa analisi emerge un modello che descrive l'emergere dell'attivazione come conseguenza concomitante di diversi processi: l'appartenenza dei soggetti a gruppi eterogenei e le loro esperienze di contatto diretto con l'ingiustizia sociale, entrambi visti come scambi incarnati che consentono la costruzione di nuovi orizzonti di significato; insieme queste co-occorrenze si combinano con un’azione conseguente. L'azione rafforza quindi sia la costruzione del significato sia l'appartenenza al gruppo stesso. Infine, la teoria emergente viene approfondita attraverso la discussione di dati provenienti da alcuni contesti educativi formali (scuole). L'intera ricerca mira a esplorare la transizione dalle teorie dell'educazione globale alla partecipazione attiva, la sua ambizione e il suo possibile contributo vanno verso la valorizzazione dei processi educativi incarnati volti a promuovere la mobilitazione.

Nature in the books of seven metals – Ǧābirian corpus in dialogue with ancient Greek philosophy and Byzantine alchemy –

The Ǧābirian corpus was a receiver of ancient Greek ideas and, at the same time, a source of knowledge for the later Greek-speaking world, in particular for medieval Byzantine alchemy. Both aspects are explored in the dissertation with respect to the notion of nature. After a general introduction to the Corpus and the sciences described in it, particular attention is devoted to a Byzantine anonymous text, The Work of Four Elements, which was probably influenced by the Ǧābirian Books of Seventy. These texts exemplify how, in the theory of the Ǧābirian science, things are constructed from four natures (hot, cold, moist and dry), the balance of which defines what a thing is. By changing the balance of natures, one can transmute any metals into gold that is perfectly proportioned in terms of natures. Ǧābir presents the art of dyeing metals gold in the Books of Seven Metals which, along with chrysopoetic recipes, also include medical recipes and theoretical contents such as the theories of four humours, properties, and talismans. Moreover, Ǧābir postulated a substrate that does not change in itself and continues to exist when natures move in and out of things. Such primary existence is called the fifth nature as an additional principle to the four natures. This key concept for the Ǧābirian theory, which has been underexplored so far, is discussed through the textual and critical analysis of various unedited sources: the Books of Seven Metals and the Book of the Fifth Nature. This study confirms that the fifth nature was probably derived from ancient Greek philosophical concepts such as the Empedoclean particles, the Aristotelian fifth element and the Stoic pneuma. Thus, this research indicates the importance of the Ǧābirian corpus both in the history of alchemy and the history of philosophy.