Rag2-/-;gammac-/- immunodeficient mice, a new preclinical model to study antitumor approaches

Animal models have been relevant to study the molecular mechanisms of cancer and to develop new antitumor agents. Anyway, the huge divergence in mouse and human evolution made difficult the translation of the gained achievements in preclinical mouse based studies. The generation of clinically relevant murine models requires their humanization both concerning the creation of transgenic models and the generation of humanized mice in which to engraft a functional human immune system, and reproduce the physiological effects and molecular mechanisms of growth and metastasization of human tumors. In particular, the availability of genotypically stable immunodepressed mice able to accept tumor injection and allow human tumor growth and metastasization would be important to develop anti-tumor and anti-metastatic strategies. Recently, Rag2-/-;gammac-/- mice, double knockout for genes involved in lymphocyte differentiation, had been developed (CIEA, Central Institute for Experimental Animals, Kawasaki, Japan). Studies of human sarcoma metastasization in Rag2-/-; gammac-/- mice (lacking B, T and NK functionality) revealed their high metastatic efficiency and allowed the expression of human metastatic phenotypes not detectable in the conventionally used nude murine model. In vitro analysis to investigate the molecular mechanisms involved in the specific pattern of human sarcomas metastasization revealed the importance of liver-produced growth and motility factors, in particular the insulin-like growth factors (IGFs). The involvement of this growth factor was then demonstrated in vivo through inhibition of IGF signalling pathway. Due to the high growth and metastatic propensity of tumor cells, Rag2-/-;gammac-/- mice were used as model to investigate the metastatic behavior of rhabdomyosarcoma cells engineered to improve the differentiation. It has been recently shown that this immunodeficient model can be reconstituted with a human immune system through the injection of human cord blood progenitor cells. The work illustrated in this thesis revealed that the injection of different human progenitor cells (CD34+ or CD133+) showed peculiar engraftment and differentiation abilities. Experiments of cell vaccination were performed to investigate the functionality of the engrafted human immune system and the induction of specific human immune responses. Results from such experiments will allow to collect informations about human immune responses activated during cell vaccination and to define the best reconstitution and experimental conditions to create a humanized model in which to study, in a preclinical setting, immunological antitumor strategies.

A New Prediction Model for Slope Stability Analysis

The instability of river bank can result in considerable human and land losses. The Po river is the most important in Italy, characterized by main banks of significant and constantly increasing height. This study presents multilayer perceptron of artificial neural network (ANN) to construct prediction models for the stability analysis of river banks along the Po River, under various river and groundwater boundary conditions. For this aim, a number of networks of threshold logic unit are tested using different combinations of the input parameters. Factor of safety (FS), as an index of slope stability, is formulated in terms of several influencing geometrical and geotechnical parameters. In order to obtain a comprehensive geotechnical database, several cone penetration tests from the study site have been interpreted. The proposed models are developed upon stability analyses using finite element code over different representative sections of river embankments. For the validity verification, the ANN models are employed to predict the FS values of a part of the database beyond the calibration data domain. The results indicate that the proposed ANN models are effective tools for evaluating the slope stability. The ANN models notably outperform the derived multiple linear regression models.

The United Nations 'quasi-prosecutorial' investigative mechanisms: assessing a new institutional model in the international criminal justice landscape

This work aims to provide a theoretical examination of three recently created bodies of the United Nations mandated to investigate the alleged international crimes committed in Syria (IIIM), Iraq (UNITAD) and Myanmar (IIMM). Established as a compromise solution in the paralysis of international criminal jurisdictions, these essentially overlapping entities have been depicted as a ‘new generation’ of UN investigative mechanisms. While non-judicial in nature, they depart indeed from traditional commissions of inquiry in several respects due to their increased criminal or ‘quasi-prosecutorial’ character. After clarifying their legal basis and different mandating authorities, a comparative institutional analysis is thus carried out in order to ascertain whether these ‘mechanisms’ can be said to effectively represent a new institutional model. Through an in-depth assessment of their mandates, the thesis is also intended to outline both the strengths and the criticalities of these organs. Given their aim to facilitate criminal proceedings by sharing information and case files, it is suggested that more attention shall be paid to the position of the person under investigation. To this end, some proposals are made in order to enhance the mechanisms’ frameworks, especially from the angle of procedural safeguards. As a third aspect, the cooperation with judicial authorities is explored, in order to shed light on the actors involved, the relevant legal instruments and the possible obstacles, in particular from a human rights perspective. Ultimately, drawing from the detected issues, the thesis seeks to identify some lessons learned which could be taken into account in case of creation of new ad hoc investigative mechanisms or of a permanent institution of this kind.

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.

Estimation of Quasi-Rational DSGE Models

Small-scale dynamic stochastic general equilibrium have been treated as the benchmark of much of the monetary policy literature, given their ability to explain the impact of monetary policy on output, inflation and financial markets. One cause of the empirical failure of New Keynesian models is partially due to the Rational Expectations (RE) paradigm, which entails a tight structure on the dynamics of the system. Under this hypothesis, the agents are assumed to know the data genereting process. In this paper, we propose the econometric analysis of New Keynesian DSGE models under an alternative expectations generating paradigm, which can be regarded as an intermediate position between rational expectations and learning, nameley an adapted version of the "Quasi-Rational" Expectatations (QRE) hypothesis. Given the agents' statistical model, we build a pseudo-structural form from the baseline system of Euler equations, imposing that the length of the reduced form is the same as in the `best' statistical model.

Customer Evolution in Sales Channel Migration

This research has been triggered by an emergent trend in customer behavior: customers have rapidly expanded their channel experiences and preferences beyond traditional channels (such as stores) and they expect the company with which they do business to have a presence on all these channels. This evidence has produced an increasing interest in multichannel customer behavior and it has motivated several researchers to study the customers’ channel choices dynamics in multichannel environment. We study how the consumer decision process for channel choice and response to marketing communications evolves for a cohort of new customers. We assume a newly acquired customer’s decisions are described by a “trial” model, but the customer’s choice process evolves to a “post-trial” model as the customer learns his or her preferences and becomes familiar with the firm’s marketing efforts. The trial and post-trial decision processes are each described by different multinomial logit choice models, and the evolution from the trial to post-trial model is determined by a customer-level geometric distribution that captures the time it takes for the customer to make the transition. We utilize data for a major retailer who sells in three channels – retail store, the Internet, and via catalog. The model is estimated using Bayesian methods that allow for cross-customer heterogeneity. This allows us to have distinct parameters estimates for a trial and an after trial stages and to estimate the quickness of this transit at the individual level. The results show for example that the customer decision process indeed does evolve over time. Customers differ in the duration of the trial period and marketing has a different impact on channel choice in the trial and post-trial stages. Furthermore, we show that some people switch channel decision processes while others don’t and we found that several factors have an impact on the probability to switch decision process. Insights from this study can help managers tailor their marketing communication strategy as customers gain channel choice experience. Managers may also have insights on the timing of the direct marketing communications. They can predict the duration of the trial phase at individual level detecting the customers with a quick, long or even absent trial phase. They can even predict if the customer will change or not his decision process over time, and they can influence the switching process using specific marketing tools

Essays on European economic and monetary integration

This thesis focuses on two aspects of European economic integration: exchange rate stabilization between non-euro Countries and the Euro Area, and real and nominal convergence of Central and Eastern European Countries. Each Chapter covers these aspects from both a theoretical and empirical perspective. Chapter 1 investigates whether the introduction of the euro was accompanied by a shift in the de facto exchange rate policy of European countries outside the euro area, using methods recently developed by the literature to detect "Fear of Floating" episodes. I find that European Inflation Targeters have tried to stabilize the euro exchange rate, after its introduction; fixed exchange rate arrangements, instead, apart from official policy changes, remained stable. Finally, the euro seems to have gained a relevant role as a reference currency even outside Europe. Chapter 2 proposes an approach to estimate Central Bank preferences starting from the Central Bank's optimization problem within a small open economy, using Sweden as a case study, to find whether stabilization of the exchange rate played a role in the Monetary Policy rule of the Riksbank. The results show that it did not influence interest rate setting; exchange rate stabilization probably occurred as a result of increased economic integration and business cycle convergence. Chapter 3 studies the interactions between wages in the public sector, the traded private sector and the closed sector in ten EU Transition Countries. The theoretical literature on wage spillovers suggests that the traded sector should be the leader in wage setting, with non-traded sectors wages adjusting. We show that large heterogeneity across countries is present, and sheltered and public sector wages are often leaders in wage determination. This result is relevant from a policy perspective since wage spillovers, leading to costs growing faster than productivity, may affect the international cost competitiveness of the traded sector.

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.

Non Invasive Tools for Early Detection of Autism Spectrum Disorders

Autism Spectrum Disorders (ASDs) describe a set of neurodevelopmental disorders. ASD represents a significant public health problem. Currently, ASDs are not diagnosed before the 2nd year of life but an early identification of ASDs would be crucial as interventions are much more effective than specific therapies starting in later childhood. To this aim, cheap an contact-less automatic approaches recently aroused great clinical interest. Among them, the cry and the movements of the newborn, both involving the central nervous system, are proposed as possible indicators of neurological disorders. This PhD work is a first step towards solving this challenging problem. An integrated system is presented enabling the recording of audio (crying) and video (movements) data of the newborn, their automatic analysis with innovative techniques for the extraction of clinically relevant parameters and their classification with data mining techniques. New robust algorithms were developed for the selection of the voiced parts of the cry signal, the estimation of acoustic parameters based on the wavelet transform and the analysis of the infant’s general movements (GMs) through a new body model for segmentation and 2D reconstruction. In addition to a thorough literature review this thesis presents the state of the art on these topics that shows that no studies exist concerning normative ranges for newborn infant cry in the first 6 months of life nor the correlation between cry and movements. Through the new automatic methods a population of control infants (“low-risk”, LR) was compared to a group of “high-risk” (HR) infants, i.e. siblings of children already diagnosed with ASD. A subset of LR infants clinically diagnosed as newborns with Typical Development (TD) and one affected by ASD were compared. The results show that the selected acoustic parameters allow good differentiation between the two groups. This result provides new perspectives both diagnostic and therapeutic.

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.