Welfare provision in Sweden and the dominant position of the Sap

There have been almost fifty years since Harry Eckstein' s classic monograph, A Theory of Stable Democracy (Princeton, 1961), where he sketched out the basic tenets of the “congruence theory”, which was to become one of the most important and innovative contributions to understanding democratic rule. His next work, Division and Cohesion in Democracy, (Princeton University Press: 1966) is designed to serve as a plausibility probe for this 'theory' (ftn.) and is a case study of a Northern democratic system, Norway. What is more, this line of his work best exemplifies the contribution Eckstein brought to the methodology of comparative politics through his seminal article, “ “Case Study and Theory in Political Science” ” (in Greenstein and Polsby, eds., Handbook of Political Science, 1975), on the importance of the case study as an approach to empirical theory. This article demonstrates the special utility of “crucial case studies” in testing theory, thereby undermining the accepted wisdom in comparative research that the larger the number of cases the better. Although not along the same lines, but shifting the case study unit of research, I intend to take up here the challenge and build upon an equally unique political system, the Swedish one. Bearing in mind the peculiarities of the Swedish political system, my unit of analysis is going to be further restricted to the Swedish Social Democratic Party, the Svenska Arbetare Partiet. However, my research stays within the methodological framework of the case study theory inasmuch as it focuses on a single political system and party. The Swedish SAP endurance in government office and its electoral success throughout half a century (ftn. As of the 1991 election, there were about 56 years - more than half century - of interrupted social democratic "reign" in Sweden.) are undeniably a performance no other Social Democrat party has yet achieved in democratic conditions. Therefore, it is legitimate to inquire about the exceptionality of this unique political power combination. Which were the different components of this dominance power position, which made possible for SAP's governmental office stamina? I will argue here that it was the end-product of a combination of multifarious factors such as a key position in the party system, strong party leadership and organization, a carefully designed strategy regarding class politics and welfare policy. My research is divided into three main parts, the historical incursion, the 'welfare' part and the 'environment' part. The first part is a historical account of the main political events and issues, which are relevant for my case study. Chapter 2 is devoted to the historical events unfolding in the 1920-1960 period: the Saltsjoebaden Agreement, the series of workers' strikes in the 1920s and SAP's inception. It exposes SAP's ascent to power in the mid 1930s and the party's ensuing strategies for winning and keeping political office, that is its economic program and key economic goals. The following chapter - chapter 3 - explores the next period, i.e. the period from 1960s to 1990s and covers the party's troubled political times, its peak and the beginnings of the decline. The 1960s are relevant for SAP's planning of a long term economic strategy - the Rehn Meidner model, a new way of macroeconomic steering, based on the Keynesian model, but adapted to the new economic realities of welfare capitalist societies. The second and third parts of this study develop several hypotheses related to SAP's 'dominant position' (endurance in politics and in office) and test them afterwards. Mainly, the twin issues of economics and environment are raised and their political relevance for the party analyzed. On one hand, globalization and its spillover effects over the Swedish welfare system are important causal factors in explaining the transformative social-economic challenges the party had to put up with. On the other hand, Europeanization and environmental change influenced to a great deal SAP's foreign policy choices and its domestic electoral strategies. The implications of globalization on the Swedish welfare system will make the subject of two chapters - chapters four and five, respectively, whereupon the Europeanization consequences will be treated at length in the third part of this work - chapters six and seven, respectively. Apparently, at first sight, the link between foreign policy and electoral strategy is difficult to prove and uncanny, in the least. However, in the SAP's case there is a bulk of literature and public opinion statistical data able to show that governmental domestic policy and party politics are in a tight dependence to foreign policy decisions and sovereignty issues. Again, these country characteristics and peculiar causal relationships are outlined in the first chapters and explained in the second and third parts. The sixth chapter explores the presupposed relationship between Europeanization and environmental policy, on one hand, and SAP's environmental policy formulation and simultaneous agenda-setting at the international level, on the other hand. This chapter describes Swedish leadership in environmental policy formulation on two simultaneous fronts and across two different time spans. The last chapter, chapter eight - while trying to develop a conclusion, explores the alternative theories plausible in explaining the outlined hypotheses and points out the reasons why these theories do not fit as valid alternative explanation to my systemic corporatism thesis as the main causal factor determining SAP's 'dominant position'. Among the alternative theories, I would consider Traedgaardh L. and Bo Rothstein's historical exceptionalism thesis and the public opinion thesis, which alone are not able to explain the half century social democratic endurance in government in the Swedish case.

Essays in Macroeconomics

The dissertation consists of four papers that aim at providing new contributions in the field of macroeconomics, monetary policy and financial stability. The first paper proposes a new Dynamic Stochastic General Equilibrium (DSGE) model with credit frictions and a banking sector to study the pro-cyclicality of credit and the role of different prudential regulatory frameworks in affecting business cycle fluctuations and in restoring macroeconomic and financial stability. The second paper develops a simple DSGE model capable of evaluating the effects of large purchases of treasuries by central banks. This theoretical framework is employed to evaluate the impact on yields and the macroeconomy of large purchases of medium- and long-term government bonds recently implemented in the US and UK. The third paper studies the effects of ECB communications about unconventional monetary policy operations on the perceived sovereign risk of Italy over the last five years. The empirical results are derived from both an event-study analysis and a GARCH model, which uses Italian long-term bond futures to disentangle expected from unexpected policy actions. The fourth paper proposes a DSGE model with an endogenous term structure of interest rates, which is able to replicate the stylized facts regarding the yield curve and the term premium in the US over the period 1987:3-2011:3, without compromising its ability to match macro dynamics.

Essays in Macroecometrics: methodological aspects and empirical applications

In the first chapter, I develop a panel no-cointegration test which extends Pesaran, Shin and Smith (2001)'s bounds test to the panel framework by considering the individual regressions in a Seemingly Unrelated Regression (SUR) system. This allows to take into account unobserved common factors that contemporaneously affect all the units of the panel and provides, at the same time, unit-specific test statistics. Moreover, the approach is particularly suited when the number of individuals of the panel is small relatively to the number of time series observations. I develop the algorithm to implement the test and I use Monte Carlo simulation to analyze the properties of the test. The small sample properties of the test are remarkable, compared to its single equation counterpart. I illustrate the use of the test through a test of Purchasing Power Parity in a panel of EU15 countries. In the second chapter of my PhD thesis, I verify the Expectation Hypothesis of the Term Structure in the repurchasing agreements (repo) market with a new testing approach. I consider an "inexact" formulation of the EHTS, which models a time-varying component in the risk premia and I treat the interest rates as a non-stationary cointegrated system. The effect of the heteroskedasticity is controlled by means of testing procedures (bootstrap and heteroskedasticity correction) which are robust to variance and covariance shifts over time. I fi#nd that the long-run implications of EHTS are verified. A rolling window analysis clarifies that the EHTS is only rejected in periods of turbulence of #financial markets. The third chapter introduces the Stata command "bootrank" which implements the bootstrap likelihood ratio rank test algorithm developed by Cavaliere et al. (2012). The command is illustrated through an empirical application on the term structure of interest rates in the US.

Topics in climate change risk

In this Thesis, we analyze how climate risk impacts economic players and its consequences on the financial markets. Essentially, literature unravels two main channels through which climate change poses risks to the status quo, namely physical and transitional risk, that we cover in three works. Firstly, the call for a global shift to a net-zero economy implicitly devalues assets that contribute to global warming that regulators are forcing to dismiss. On the other hand, abnormal changes in the temperatures as well as weather-related events challenge the environmental equilibrium and could directly affect operations as well as profitability. We start the analysis with the physical component, by presenting a statistical measure that generally represents shocks to the distribution of temperature anomalies. We oppose this statistic to classical physical measures and assess that it is the driver of the electricity consumption, in the weather derivatives market, and in the cross-section of equity returns. We find two transmission channels, namely investor attention, and firm operations. We then analyze the transition risk component, by associating a regulatory horizon characterization to fixed income valuation. We disentangle a risk driver for corporate bond overperformance that is tight to change in credit riskiness. After controlling a statistical learning algorithm to forecast excess returns, we include carbon emission metrics without clear evidence. Finally, we analyze the effects of change in carbon emission on a regulated market such as the EU ETS by selecting utility sector corporate bond and, after controlling for the possible risk factor, we document how a firm’s carbon profile differently affects the term structure of credit riskiness.

Ri-costruire per ri-generare. Un modello per le periferie urbane

In Italia, quasi il 90% delle abitazioni esistenti sono state edificate prima degli anni Settanta del Novecento, se consideriamo la tipologia costruttiva, le normative per la sicurezza strutturale in ambito sismico e il comportamento energetico, ne deriva che la maggior parte non risponde agli standard vigenti. A questo si aggiunge la consapevolezza che il patrimonio residenziale costruito in quel periodo, e che occupa le prime periferie delle città, non si presta per sua natura costitutiva ad essere oggetto di interventi di riqualificazione che siano giustificabili in termini di costi-benefici dal punto di vista economico e per ottimizzazione ingegneristica. È opportuno ripensare piani e programmi di rinnovamento non circoscritti alle categorie di risanamento, efficientamento, manutenzione, adeguamento, ma che siano in grado di assumere in positivo il tema della sostituzione secondo il paradigma del ri-costruire per ri-generare per sviluppare strategie a medio-lungo termine per soddisfare un quadro esigenziale-prestazionale coerente con la legislazione europea, in termini di sicurezza, efficienza e impatto ambientale, e promuovere la pianificazione e lo sviluppo sostenibile delle città. L’edilizia circolare è qui intesa come un’attività finalizzata alla costruzione e gestione degli edifici all’interno di un ecosistema economico basato sulla circolarità dei processi. L’obiettivo della ricerca è duplice: (i) metodologico, rivolto alla formalizzazione di un modello innovativo d’intervento associato ai principi della circolarità e basato sulla conoscenza approfondita del patrimonio esistente; e (ii) progettuale, prevede la progettazione di un prototipo di unità abitativa e l’applicazione del modello ad un caso di studio, che viene assunto come applicazione sperimentale ad un contesto reale e momento conclusivo del processo. La definizione di una matrice valutativa consente di formulare indicazioni operative nella fase precedente l’intervento per rendere espliciti, attraverso un indice sintetico di supporto decisionale, i criteri su cui fondare le scelte tra le due macro-categorie di intervento (demolizione con ricostruzione o rinnovo).

A Unified Model for XVA, including Interest Rates and Rating

We start in Chapter 2 to investigate linear matrix-valued SDEs and the Itô-stochastic Magnus expansion. The Itô-stochastic Magnus expansion provides an efficient numerical scheme to solve matrix-valued SDEs. We show convergence of the expansion up to a stopping time τ and provide an asymptotic estimate of the cumulative distribution function of τ. Moreover, we show how to apply it to solve SPDEs with one and two spatial dimensions by combining it with the method of lines with high accuracy. We will see that the Magnus expansion allows us to use GPU techniques leading to major performance improvements compared to a standard Euler-Maruyama scheme. In Chapter 3, we study a short-rate model in a Cox-Ingersoll-Ross (CIR) framework for negative interest rates. We define the short rate as the difference of two independent CIR processes and add a deterministic shift to guarantee a perfect fit to the market term structure. We show how to use the Gram-Charlier expansion to efficiently calibrate the model to the market swaption surface and price Bermudan swaptions with good accuracy. We are taking two different perspectives for rating transition modelling. In Section 4.4, we study inhomogeneous continuous-time Markov chains (ICTMC) as a candidate for a rating model with deterministic rating transitions. We extend this model by taking a Lie group perspective in Section 4.5, to allow for stochastic rating transitions. In both cases, we will compare the most popular choices for a change of measure technique and show how to efficiently calibrate both models to the available historical rating data and market default probabilities. At the very end, we apply the techniques shown in this thesis to minimize the collateral-inclusive Credit/ Debit Valuation Adjustments under the constraint of small collateral postings by using a collateral account dependent on rating trigger.

Technology acquisition through licensing. Implications for firm strategy

Nowadays licensing practices have increased in importance and relevance driving the widespread diffusion of markets for technologies. Firms are shifting from a tactical to a strategic attitude towards licensing, addressing both business and corporate level objectives. The Open Innovation Paradigm has been embraced. Firms rely more and more on collaboration and external sourcing of knowledge. This new model of innovation requires firms to leverage on external technologies to unlock the potential of firms’ internal innovative efforts. In this context, firms’ competitive advantage depends both on their ability to recognize available opportunities inside and outside their boundaries and on their readiness to exploit them in order to fuel their innovation process dynamically. Licensing is one of the ways available to firm to ripe the advantages associated to an open attitude in technology strategy. From the licensee’s point view this implies challenging the so-called not-invented-here syndrome, affecting the more traditional firms that emphasize the myth of internal research and development supremacy. This also entails understanding the so-called cognitive constraints affecting the perfect functioning of markets for technologies that are associated to the costs for the assimilation, integration and exploitation of external knowledge by recipient firms. My thesis aimed at shedding light on new interesting issues associated to in-licensing activities that have been neglected by the literature on licensing and markets for technologies. The reason for this gap is associated to the “perspective bias” affecting the works within this stream of research. With very few notable exceptions, they have been generally concerned with the investigation of the so-called licensing dilemma of the licensor – whether to license out or to internally exploit the in-house developed technologies, while neglecting the licensee’s perspective. In my opinion, this has left rooms for improving the understanding of the determinants and conditions affecting licensing-in practices. From the licensee’s viewpoint, the licensing strategy deals with the search, integration, assimilation, exploitation of external technologies. As such it lies at the very hearth of firm’s technology strategy. Improving our understanding of this strategy is thus required to assess the full implications of in-licensing decisions as they shape firms’ innovation patterns and technological capabilities evolution. It also allow for understanding the so-called cognitive constraints associated to the not-invented-here syndrome. In recognition of that, the aim of my work is to contribute to the theoretical and empirical literature explaining the determinants of the licensee’s behavior, by providing a comprehensive theoretical framework as well as ad-hoc conceptual tools to understand and overcome frictions and to ease the achievement of satisfactory technology transfer agreements in the marketplace. Aiming at this, I investigate licensing-in in three different fashions developed in three research papers. In the first work, I investigate the links between licensing and the patterns of firms’ technological search diversification according to the framework of references of the Search literature, Resource-based Theory and the theory of general purpose technologies. In the second paper - that continues where the first one left off – I analyze the new concept of learning-bylicensing, in terms of development of new knowledge inside the licensee firms (e.g. new patents) some years after the acquisition of the license, according to the Dynamic Capabilities perspective. Finally, in the third study, Ideal with the determinants of the remuneration structure of patent licenses (form and amount), and in particular on the role of the upfront fee from the licensee’s perspective. Aiming at this, I combine the insights of two theoretical approaches: agency and real options theory.

Fluid-structure interaction by a coupled lattice Boltzmann-finite element approach

In this thesis, a strategy to model the behavior of fluids and their interaction with deformable bodies is proposed. The fluid domain is modeled by using the lattice Boltzmann method, thus analyzing the fluid dynamics by a mesoscopic point of view. It has been proved that the solution provided by this method is equivalent to solve the Navier-Stokes equations for an incompressible flow with a second-order accuracy. Slender elastic structures idealized through beam finite elements are used. Large displacements are accounted for by using the corotational formulation. Structural dynamics is computed by using the Time Discontinuous Galerkin method. Therefore, two different solution procedures are used, one for the fluid domain and the other for the structural part, respectively. These two solvers need to communicate and to transfer each other several information, i.e. stresses, velocities, displacements. In order to guarantee a continuous, effective, and mutual exchange of information, a coupling strategy, consisting of three different algorithms, has been developed and numerically tested. In particular, the effectiveness of the three algorithms is shown in terms of interface energy artificially produced by the approximate fulfilling of compatibility and equilibrium conditions at the fluid-structure interface. The proposed coupled approach is used in order to solve different fluid-structure interaction problems, i.e. cantilever beams immersed in a viscous fluid, the impact of the hull of the ship on the marine free-surface, blood flow in a deformable vessels, and even flapping wings simulating the take-off of a butterfly. The good results achieved in each application highlight the effectiveness of the proposed methodology and of the C++ developed software to successfully approach several two-dimensional fluid-structure interaction problems.

New computational biology tools for the systematic analysis of the structure and expression of human genes

From the late 1980s, the automation of sequencing techniques and the computer spread gave rise to a flourishing number of new molecular structures and sequences and to proliferation of new databases in which to store them. Here are presented three computational approaches able to analyse the massive amount of publicly avalilable data in order to answer to important biological questions. The first strategy studies the incorrect assignment of the first AUG codon in a messenger RNA (mRNA), due to the incomplete determination of its 5' end sequence. An extension of the mRNA 5' coding region was identified in 477 in human loci, out of all human known mRNAs analysed, using an automated expressed sequence tag (EST)-based approach. Proof-of-concept confirmation was obtained by in vitro cloning and sequencing for GNB2L1, QARS and TDP2 and the consequences for the functional studies are discussed. The second approach analyses the codon bias, the phenomenon in which distinct synonymous codons are used with different frequencies, and, following integration with a gene expression profile, estimates the total number of codons present across all the expressed mRNAs (named here "codonome value") in a given biological condition. Systematic analyses across different pathological and normal human tissues and multiple species shows a surprisingly tight correlation between the codon bias and the codonome bias. The third approach is useful to studies the expression of human autism spectrum disorder (ASD) implicated genes. ASD implicated genes sharing microRNA response elements (MREs) for the same microRNA are co-expressed in brain samples from healthy and ASD affected individuals. The different expression of a recently identified long non coding RNA which have four MREs for the same microRNA could disrupt the equilibrium in this network, but further analyses and experiments are needed.

Multilevel Domain Decomposition Algorithms for Monolithic Fluid-Structure Interaction Problems with Application to Haemodynamics

Finite element techniques for solving the problem of fluid-structure interaction of an elastic solid material in a laminar incompressible viscous flow are described. The mathematical problem consists of the Navier-Stokes equations in the Arbitrary Lagrangian-Eulerian formulation coupled with a non-linear structure model, considering the problem as one continuum. The coupling between the structure and the fluid is enforced inside a monolithic framework which computes simultaneously for the fluid and the structure unknowns within a unique solver. We used the well-known Crouzeix-Raviart finite element pair for discretization in space and the method of lines for discretization in time. A stability result using the Backward-Euler time-stepping scheme for both fluid and solid part and the finite element method for the space discretization has been proved. The resulting linear system has been solved by multilevel domain decomposition techniques. Our strategy is to solve several local subproblems over subdomain patches using the Schur-complement or GMRES smoother within a multigrid iterative solver. For validation and evaluation of the accuracy of the proposed methodology, we present corresponding results for a set of two FSI benchmark configurations which describe the self-induced elastic deformation of a beam attached to a cylinder in a laminar channel flow, allowing stationary as well as periodically oscillating deformations, and for a benchmark proposed by COMSOL multiphysics where a narrow vertical structure attached to the bottom wall of a channel bends under the force due to both viscous drag and pressure. Then, as an example of fluid-structure interaction in biomedical problems, we considered the academic numerical test which consists in simulating the pressure wave propagation through a straight compliant vessel. All the tests show the applicability and the numerical efficiency of our approach to both two-dimensional and three-dimensional problems.

Next-Generation Sequencing-Based Mutations Scanning Strategy of the BCR-ABL Kinase Domain in Patients with PhiladelPhia-Chromosome Positive Leukemias Treated with Tyrosine Kinase Inhibitors

In chronic myeloid leukemia and Philadelphia-positive acute lymphoblastic leukemia patients resistant to tyrosine kinase inhibitors (TKIs), BCR-ABL kinase domain mutation status is an essential component of the therapeutic decision algorithm. The recent development of Ultra-Deep Sequencing approach (UDS) has opened the way to a more accurate characterization of the mutant clones surviving TKIs conjugating assay sensitivity and throughput. We decided to set-up and validated an UDS-based for BCR-ABL KD mutation screening in order to i) resolve qualitatively and quantitatively the complexity and the clonal structure of mutated populations surviving TKIs, ii) study the dynamic of expansion of mutated clones in relation to TKIs therapy, iii) assess whether UDS may allow more sensitive detection of emerging clones, harboring critical 2GTKIs-resistant mutations predicting for an impending relapse, earlier than SS. UDS was performed on a Roche GS Junior instrument, according to an amplicon sequencing design and protocol set up and validated in the framework of the IRON-II (Interlaboratory Robustness of Next-Generation Sequencing) International consortium.Samples from CML and Ph+ ALL patients who had developed resistance to one or multiple TKIs and collected at regular time-points during treatment were selected for this study. Our results indicate the technical feasibility, accuracy and robustness of our UDS-based BCR-ABL KD mutation screening approach. UDS was found to provide a more accurate picture of BCR-ABL KD mutation status, both in terms of presence/absence of mutations and in terms of clonal complexity and showed that BCR-ABL KD mutations detected by SS are only the “tip of iceberg”. In addition UDS may reliably pick 2GTKIs-resistant mutations earlier than SS in a significantly greater proportion of patients.The enhanced sensitivity as well as the possibility to identify low level mutations point the UDS-based approach as an ideal alternative to conventional sequencing for BCR-ABL KD mutation screening in TKIs-resistant Ph+ leukemia patients

Cannabinoid system combined to classic targets for a new MTDL strategy: design and synthesis of natural inspired molecules for Alzheimer's disease

In this thesis is described the design and synthesis of potential agents for the treatment of the multifactorial Alzheimer’s disease (AD). Our multi-target approach was to consider cannabinoid system involved in AD, together with classic targets. In the first project, designed modifications were performed on lead molecule in order to increase potency and obtain balanced activities on fatty acid amide hydrolase and cholinesterases. A small library of compounds was synthesized and biological results showed increased inhibitory activity (nanomolar range) related to selected target. The second project was focused on the benzofuran framework, a privileged structure being a common moiety found in many biologically active natural products and therapeutics. Hybrid molecules were designed and synthesized, focusing on the inhibition of cholinesterases, Aβ aggregation, FAAH and on the interaction with CB receptors. Preliminary results showed that several compounds are potent CB ligands, in particular the high affinity for CB2 receptors, could open new opportunities to modulate neuroinflammation. The third and the fourth project were carried out at the IMS, Aberdeen, under the supervision of Prof. Matteo Zanda. The role of the cannabinoid system in the brain is still largely unexplored and the relationship between the CB1 receptors functional modification, density and distribution and the onset of a pathological state is not well understood. For this reasons, Rimonabant analogues suitable as radioligands were synthesized. The latter, through PET, could provide reliable measurements of density and distribution of CB1 receptors in the brain. In the fifth project, in collaboration with CHyM of York, the goal was to develop arginine analogues that are target specific due to their exclusively location into NOS enzymes and could work as MRI contrasting agents. Synthesized analogues could be suitable substrate for the transfer of polarization by p-H2 molecules through SABRE technique transforming MRI a more sensitive and faster technique.

Influence of plant structure, cultural pratices and environmental conditions on the development of the bacterial canker of kiwifruits

Italy has a preeminent rank in kiwifruit industry, being the first exporter and the second largest producer after China. However, in the last years kiwifruit yields and the total cultivated area considerably decreased, due to the pandemic spread of the bacterial canker caused by Pseudomonas syringae pv. actinidiae (Psa). Several climatic conditions and cultural practices affect the development of the bacterial canker. This research work focused on the impact of agricultural practices and microclimate conditions on the incidence and epidemiology of Psa in the orchard. Therefore, the effect of fertilization, irrigation, use of bio-regulators, rootstock, training system and pruning were examined. The effect of different tunnel systems was analyzed as well, to study the plant-pathogen interaction. Considering the importance of insects as vectors in other pathosystems, the role of Metcalfa pruinosa in the spread of the bacterial canker was investigated in controlled conditions. In addition, quality and storage properties of fruits from infected plants were assessed. The study of all these aspects of the agronomic practices is useful to define a strategy to limit the bacterial diffusion in the orchard. Overall, excess nitrogen fertilization, water stress, stagnant water supplies, pruning before summer and the high number of Metcalfa pruinosa increased the Psa incidence. In contrast, tunnel covers may be useful for the control of the disease, with special attention to the kind of material.

Novel dual D3R/GSK-3β modulators: an innovative multitarget strategy for bipolar disorder

Among the psychiatric diseases, bipolar disorder (BD) is the sixth leading cause of disability with a prevalence up to 4 % worldwide. BD is a complex neuropsychiatric condition which alternates episodes of mania with symptoms of depression. Although the neurobiological pathways are not completely clarified, the dopamine (DA) hypothesis, recognized as the leading theory explaining the pathophysiology of the malady, states that the dramatically compromised homeostatic regulation of dopaminergic circuits leads to alternated changes in DA neurotransmission. Modulation of D2 and D3 receptors (D2/3R) through partial agonists represents the first-line therapeutic strategy for psychiatric diseases. Moreover, a deregulation of the enzyme glycogen synthase kinase-3β (GSK-3β) has been reported as peculiar feature of BD. In this scenario, the concomitant modulation of D3R and GSK-3β, by employing multitarget compounds, could offer promises to achieve an effective cure of this illness. In the light of these findings, we rationally envisaged the pharmacophoric model at the basis of the design of several D3R partial agonists, suitable to be exploited for the dual D3R/GSK-3β ligand design. Thus, synthetic efforts were addressed to develop a first set of hybrid molecules able to concurrently modulate the selected targets. For a chemical structure point of view, we employed different spacers to combine a substituted aryl-piperazine moiety, reported in previously discovered D3R modulators, with a pyrazole-based fragment, already identified in GSK-3β inhibitors. A fluorescent and a cellular functional assays were carried out to assess the activity of all synthetized compounds against GSK-3β and on D3R, respectively. Most of the derivatives proved to effectively modulate both GSK-3β and D3R with potencies in the low-µM and low-nM range, respectively. The consistent biological data allowed us to identify some lead candidates worth to be further modified with the aim to optimize their biological profile and to perform a structure-activity relationship (SAR) study.

Design and synthesis of E3 ligase RNF5 inhibitors as innovative strategy to trigger mutant CFTR rescue in Cystic Fibrosis

In Cystic Fibrosis (CF) the deletion of phenylalanine 508 (F508del) in the CFTR anion channel is associated to misfolding and defective gating of the mutant protein. Among the known proteins involved in CFTR processing, one of the most promising drug target is the ubiquitin ligase RNF5, which normally promotes F508del-CFTR degradation. In this context, a small molecule RNF5 inhibitor is expected to chemically mimic a condition of RNF5 silencing, thus preventing mutant CFTR degradation and causing its stabilization and plasma membrane trafficking. Hence, by exploiting a virtual screening (VS) campaign, the hit compound inh-2 was discovered as the first-in-class inhibitor of RNF5. Evaluation of inh-2 efficacy on CFTR rescue showed that it efficiently decreases ubiquitination of mutant CFTR and increases chloride current in human primary bronchial epithelia. Based on the promising biological results obtained with inh-2, this thesis reports the structure-based design of potential RNF5 inhibitors having improved potency and efficacy. The optimization of general synthetic strategies gave access to a library of analogues of the 1,2,4-thiadiazol-5-ylidene inh-2 for SAR investigation. The new analogues were tested for their corrector activity in CFBE41o- cells by using the microfluorimetric HS-YFP assay as a primary screen. Then, the effect of putative RNF5 inhibitors on proliferation, apoptosis and the formation of autophagic vacuoles was evaluated. Some of the new analogs significantly increased the basal level of autophagy, reproducing RNF5 silencing effect in cell. Among them, one compound also displayed a greater rescue of the F508del-CFTR trafficking defect than inh-2. Our preliminary results suggest that the 1,2,4-thiadiazolylidene could be a suitable scaffold for the discovery of potential RNF5 inhibitors able to rescue mutant CFTRs. Biological tests are still ongoing to acquire in-depth knowledge about the mechanism of action and therapeutic relevance of this unprecedented pharmacological strategy.