Semi-synthetic bile acids as novel drug candidate in liver diseases: physico-chemical characterization and HPLC-ES-MS/MS methods for their quali-quantitative analysis in different experimental animal models

The physico-chemical characterization, structure-pharmacokinetic and metabolism studies of new semi synthetic analogues of natural bile acids (BAs) drug candidates have been performed. Recent studies discovered a role of BAs as agonists of FXR and TGR5 receptor, thus opening new therapeutic target for the treatment of liver diseases or metabolic disorders. Up to twenty new semisynthetic analogues have been synthesized and studied in order to find promising novel drugs candidates. In order to define the BAs structure-activity relationship, their main physico-chemical properties (solubility, detergency, lipophilicity and affinity with serum albumin) have been measured with validated analytical methodologies. Their metabolism and biodistribution has been studied in “bile fistula rat”, model where each BA is acutely administered through duodenal and femoral infusion and bile collected at different time interval allowing to define the relationship between structure and intestinal absorption and hepatic uptake ,metabolism and systemic spill-over. One of the studied analogues, 6α-ethyl-3α7α-dihydroxy-5β-cholanic acid, analogue of CDCA (INT 747, Obeticholic Acid (OCA)), recently under approval for the treatment of cholestatic liver diseases, requires additional studies to ensure its safety and lack of toxicity when administered to patients with a strong liver impairment. For this purpose, CCl4 inhalation to rat causing hepatic decompensation (cirrhosis) animal model has been developed and used to define the difference of OCA biodistribution in respect to control animals trying to define whether peripheral tissues might be also exposed as a result of toxic plasma levels of OCA, evaluating also the endogenous BAs biodistribution. An accurate and sensitive HPLC-ES-MS/MS method is developed to identify and quantify all BAs in biological matrices (bile, plasma, urine, liver, kidney, intestinal content and tissue) for which a sample pretreatment have been optimized.

Development of quantitative methods for sustainability assessment in process industry

The increasing aversion to technological risks of the society requires the development of inherently safer and environmentally friendlier processes, besides assuring the economic competitiveness of the industrial activities. The different forms of impact (e.g. environmental, economic and societal) are frequently characterized by conflicting reduction strategies and must be holistically taken into account in order to identify the optimal solutions in process design. Though the literature reports an extensive discussion of strategies and specific principles, quantitative assessment tools are required to identify the marginal improvements in alternative design options, to allow the trade-off among contradictory aspects and to prevent the “risk shift”. In the present work a set of integrated quantitative tools for design assessment (i.e. design support system) was developed. The tools were specifically dedicated to the implementation of sustainability and inherent safety in process and plant design activities, with respect to chemical and industrial processes in which substances dangerous for humans and environment are used or stored. The tools were mainly devoted to the application in the stages of “conceptual” and “basic design”, when the project is still open to changes (due to the large number of degrees of freedom) which may comprise of strategies to improve sustainability and inherent safety. The set of developed tools includes different phases of the design activities, all through the lifecycle of a project (inventories, process flow diagrams, preliminary plant lay-out plans). The development of such tools gives a substantial contribution to fill the present gap in the availability of sound supports for implementing safety and sustainability in early phases of process design. The proposed decision support system was based on the development of a set of leading key performance indicators (KPIs), which ensure the assessment of economic, societal and environmental impacts of a process (i.e. sustainability profile). The KPIs were based on impact models (also complex), but are easy and swift in the practical application. Their full evaluation is possible also starting from the limited data available during early process design. Innovative reference criteria were developed to compare and aggregate the KPIs on the basis of the actual sitespecific impact burden and the sustainability policy. Particular attention was devoted to the development of reliable criteria and tools for the assessment of inherent safety in different stages of the project lifecycle. The assessment follows an innovative approach in the analysis of inherent safety, based on both the calculation of the expected consequences of potential accidents and the evaluation of the hazards related to equipment. The methodology overrides several problems present in the previous methods proposed for quantitative inherent safety assessment (use of arbitrary indexes, subjective judgement, build-in assumptions, etc.). A specific procedure was defined for the assessment of the hazards related to the formations of undesired substances in chemical systems undergoing “out of control” conditions. In the assessment of layout plans, “ad hoc” tools were developed to account for the hazard of domino escalations and the safety economics. The effectiveness and value of the tools were demonstrated by the application to a large number of case studies concerning different kinds of design activities (choice of materials, design of the process, of the plant, of the layout) and different types of processes/plants (chemical industry, storage facilities, waste disposal). An experimental survey (analysis of the thermal stability of isomers of nitrobenzaldehyde) provided the input data necessary to demonstrate the method for inherent safety assessment of materials.

Hybrid constraint programming and metaheuristic methods for large scale optimization problems

This work presents hybrid Constraint Programming (CP) and metaheuristic methods for the solution of Large Scale Optimization Problems; it aims at integrating concepts and mechanisms from the metaheuristic methods to a CP-based tree search environment in order to exploit the advantages of both approaches. The modeling and solution of large scale combinatorial optimization problem is a topic which has arisen the interest of many researcherers in the Operations Research field; combinatorial optimization problems are widely spread in everyday life and the need of solving difficult problems is more and more urgent. Metaheuristic techniques have been developed in the last decades to effectively handle the approximate solution of combinatorial optimization problems; we will examine metaheuristics in detail, focusing on the common aspects of different techniques. Each metaheuristic approach possesses its own peculiarities in designing and guiding the solution process; our work aims at recognizing components which can be extracted from metaheuristic methods and re-used in different contexts. In particular we focus on the possibility of porting metaheuristic elements to constraint programming based environments, as constraint programming is able to deal with feasibility issues of optimization problems in a very effective manner. Moreover, CP offers a general paradigm which allows to easily model any type of problem and solve it with a problem-independent framework, differently from local search and metaheuristic methods which are highly problem specific. In this work we describe the implementation of the Local Branching framework, originally developed for Mixed Integer Programming, in a CP-based environment. Constraint programming specific features are used to ease the search process, still mantaining an absolute generality of the approach. We also propose a search strategy called Sliced Neighborhood Search, SNS, that iteratively explores slices of large neighborhoods of an incumbent solution by performing CP-based tree search and encloses concepts from metaheuristic techniques. SNS can be used as a stand alone search strategy, but it can alternatively be embedded in existing strategies as intensification and diversification mechanism. In particular we show its integration within the CP-based local branching. We provide an extensive experimental evaluation of the proposed approaches on instances of the Asymmetric Traveling Salesman Problem and of the Asymmetric Traveling Salesman Problem with Time Windows. The proposed approaches achieve good results on practical size problem, thus demonstrating the benefit of integrating metaheuristic concepts in CP-based frameworks.

Comparison between analytical and numerical methods for the assessment of masonry arch bridges: Case study of Clemente Bridge on Savio river

This research has focused on the study of the behavior and of the collapse of masonry arch bridges. The latest decades have seen an increasing interest in this structural type, that is still present and in use, despite the passage of time and the variation of the transport means. Several strategies have been developed during the time to simulate the response of this type of structures, although even today there is no generally accepted standard one for assessment of masonry arch bridges. The aim of this thesis is to compare the principal analytical and numerical methods existing in literature on case studies, trying to highlight values and weaknesses. The methods taken in exam are mainly three: i) the Thrust Line Analysis Method; ii) the Mechanism Method; iii) the Finite Element Methods. The Thrust Line Analysis Method and the Mechanism Method are analytical methods and derived from two of the fundamental theorems of the Plastic Analysis, while the Finite Element Method is a numerical method, that uses different strategies of discretization to analyze the structure. Every method is applied to the case study through computer-based representations, that allow a friendly-use application of the principles explained. A particular closed-form approach based on an elasto-plastic material model and developed by some Belgian researchers is also studied. To compare the three methods, two different case study have been analyzed: i) a generic masonry arch bridge with a single span; ii) a real masonry arch bridge, the Clemente Bridge, built on Savio River in Cesena. In the analyses performed, all the models are two-dimensional in order to have results comparable between the different methods taken in exam. The different methods have been compared with each other in terms of collapse load and of hinge positions.

Effect of training systems and pruning methods on fruit quality in apple

The introduction of dwarfed rootstocks in apple crop has led to a new concept of intensive planting systems with the aim of producing early high yield and with returns of the initial high investment. Although yield is an important aspect to the grower, the consumer has become demanding regards fruit quality and is generally attracted by appearance. To fulfil the consumer’s expectations the grower may need to choose a proper training system along with an ideal pruning technique, which ensure a good light distribution in different parts of the canopy and a marketable fruit quality in terms of size and skin colour. Although these aspects are important, these fruits might not reach the proper ripening stage within the canopy because they are often heterogeneous. To describe the variability present in a tree, a software (PlantToon®), was used to recreate the tree architecture in 3D in the two training systems. The ripening stage of each of the fruits was determined using a non-destructive device (DA-Meter), thus allowing to estimate the fruit ripening variability. This study deals with some of the main parameters that can influence fruit quality and ripening stage within the canopy and orchard management techniques that can ameliorate a ripening fruit homogeneity. Significant differences in fruit quality were found within the canopies due to their position, flowering time and bud wood age. Bi-axis appeared to be suitable for high density planting, even though the fruit quality traits resulted often similar to those obtained with a Slender Spindle, suggesting similar fruit light availability within the canopies. Crop load confirmed to be an important factor that influenced fruit quality as much as the interesting innovative pruning method “Click”, in intensive planting systems.

Numerical and Analytical Methods for Laser-Plasma Acceleration Physics

Theories and numerical modeling are fundamental tools for understanding, optimizing and designing present and future laser-plasma accelerators (LPAs). Laser evolution and plasma wave excitation in a LPA driven by a weakly relativistically intense, short-pulse laser propagating in a preformed parabolic plasma channel, is studied analytically in 3D including the effects of pulse steepening and energy depletion. At higher laser intensities, the process of electron self-injection in the nonlinear bubble wake regime is studied by means of fully self-consistent Particle-in-Cell simulations. Considering a non-evolving laser driver propagating with a prescribed velocity, the geometrical properties of the non-evolving bubble wake are studied. For a range of parameters of interest for laser plasma acceleration, The dependence of the threshold for self-injection in the non-evolving wake on laser intensity and wake velocity is characterized. Due to the nonlinear and complex nature of the Physics involved, computationally challenging numerical simulations are required to model laser-plasma accelerators operating at relativistic laser intensities. The numerical and computational optimizations, that combined in the codes INF&RNO and INF&RNO/quasi-static give the possibility to accurately model multi-GeV laser wakefield acceleration stages with present supercomputing architectures, are discussed. The PIC code jasmine, capable of efficiently running laser-plasma simulations on Graphics Processing Units (GPUs) clusters, is presented. GPUs deliver exceptional performance to PIC codes, but the core algorithms had to be redesigned for satisfying the constraints imposed by the intrinsic parallelism of the architecture. The simulation campaigns, run with the code jasmine for modeling the recent LPA experiments with the INFN-FLAME and CNR-ILIL laser systems, are also presented.

Creazione e sviluppo di corpora multimediali. Nuove metodologie di ricerca nella traduzione audiovisiva

The construction and use of multimedia corpora has been advocated for a while in the literature as one of the expected future application fields of Corpus Linguistics. This research project represents a pioneering experience aimed at applying a data-driven methodology to the study of the field of AVT, similarly to what has been done in the last few decades in the macro-field of Translation Studies. This research was based on the experience of Forlixt 1, the Forlì Corpus of Screen Translation, developed at the University of Bologna’s Department of Interdisciplinary Studies in Translation, Languages and Culture. As a matter of fact, in order to quantify strategies of linguistic transfer of an AV product, we need to take into consideration not only the linguistic aspect of such a product but all the meaning-making resources deployed in the filmic text. Provided that one major benefit of Forlixt 1 is the combination of audiovisual and textual data, this corpus allows the user to access primary data for scientific investigation, and thus no longer rely on pre-processed material such as traditional annotated transcriptions. Based on this rationale, the first chapter of the thesis sets out to illustrate the state of the art of research in the disciplinary fields involved. The primary objective was to underline the main repercussions on multimedia texts resulting from the interaction of a double support, audio and video, and, accordingly, on procedures, means, and methods adopted in their translation. By drawing on previous research in semiotics and film studies, the relevant codes at work in visual and acoustic channels were outlined. Subsequently, we concentrated on the analysis of the verbal component and on the peculiar characteristics of filmic orality as opposed to spontaneous dialogic production. In the second part, an overview of the main AVT modalities was presented (dubbing, voice-over, interlinguistic and intra-linguistic subtitling, audio-description, etc.) in order to define the different technologies, processes and professional qualifications that this umbrella term presently includes. The second chapter focuses diachronically on various theories’ contribution to the application of Corpus Linguistics’ methods and tools to the field of Translation Studies (i.e. Descriptive Translation Studies, Polysystem Theory). In particular, we discussed how the use of corpora can favourably help reduce the gap existing between qualitative and quantitative approaches. Subsequently, we reviewed the tools traditionally employed by Corpus Linguistics in regard to the construction of traditional “written language” corpora, to assess whether and how they can be adapted to meet the needs of multimedia corpora. In particular, we reviewed existing speech and spoken corpora, as well as multimedia corpora specifically designed to investigate Translation. The third chapter reviews Forlixt 1's main developing steps, from a technical (IT design principles, data query functions) and methodological point of view, by laying down extensive scientific foundations for the annotation methods adopted, which presently encompass categories of pragmatic, sociolinguistic, linguacultural and semiotic nature. Finally, we described the main query tools (free search, guided search, advanced search and combined search) and the main intended uses of the database in a pedagogical perspective. The fourth chapter lists specific compilation criteria retained, as well as statistics of the two sub-corpora, by presenting data broken down by language pair (French-Italian and German-Italian) and genre (cinema’s comedies, television’s soapoperas and crime series). Next, we concentrated on the discussion of the results obtained from the analysis of summary tables reporting the frequency of categories applied to the French-Italian sub-corpus. The detailed observation of the distribution of categories identified in the original and dubbed corpus allowed us to empirically confirm some of the theories put forward in the literature and notably concerning the nature of the filmic text, the dubbing process and Italian dubbed language’s features. This was possible by looking into some of the most problematic aspects, like the rendering of socio-linguistic variation. The corpus equally allowed us to consider so far neglected aspects, such as pragmatic, prosodic, kinetic, facial, and semiotic elements, and their combination. At the end of this first exploration, some specific observations concerning possible macrotranslation trends were made for each type of sub-genre considered (cinematic and TV genre). On the grounds of this first quantitative investigation, the fifth chapter intended to further examine data, by applying ad hoc models of analysis. Given the virtually infinite number of combinations of categories adopted, and of the latter with searchable textual units, three possible qualitative and quantitative methods were designed, each of which was to concentrate on a particular translation dimension of the filmic text. The first one was the cultural dimension, which specifically focused on the rendering of selected cultural references and on the investigation of recurrent translation choices and strategies justified on the basis of the occurrence of specific clusters of categories. The second analysis was conducted on the linguistic dimension by exploring the occurrence of phrasal verbs in the Italian dubbed corpus and by ascertaining the influence on the adoption of related translation strategies of possible semiotic traits, such as gestures and facial expressions. Finally, the main aim of the third study was to verify whether, under which circumstances, and through which modality, graphic and iconic elements were translated into Italian from an original corpus of both German and French films. After having reviewed the main translation techniques at work, an exhaustive account of possible causes for their non-translation was equally provided. By way of conclusion, the discussion of results obtained from the distribution of annotation categories on the French-Italian corpus, as well as the application of specific models of analysis allowed us to underline possible advantages and drawbacks related to the adoption of a corpus-based approach to AVT studies. Even though possible updating and improvement were proposed in order to help solve some of the problems identified, it is argued that the added value of Forlixt 1 lies ultimately in having created a valuable instrument, allowing to carry out empirically-sound contrastive studies that may be usefully replicated on different language pairs and several types of multimedia texts. Furthermore, multimedia corpora can also play a crucial role in L2 and translation teaching, two disciplines in which their use still lacks systematic investigation.

'Defending the rights'. An integrated model of collective action for "public water" in Italy

In many communities, supplying water for the people is a huge task and the fact that this essential service can be carried out by the private sector respecting the right to water, is a debated issue. This dissertation investigates the mechanisms through which a 'perceived rights violation' - which represents a specific form of perceived injustice which derives from the violation of absolute moral principles – can promote collective action. Indeed, literature on morality and collective action suggests that even if many people apparently sustain high moral principles (like human rights), only a minority decides to act in order to defend them. Taking advantage of the political situation in Italy, and the recent mobilization for "public water" we hypothesized that, because of its "sacred value", the perceived violation of the right to water facilitates identification with the social movement and activism. Through five studies adopting qualitative and quantitative methods, we confirmed our hypotheses demonstrating that the perceived violation of the right to water can sustain activism and it can influence vote intentions at the referendum for 'public water'. This path to collective action coexists with other 'classical' predictors of collective action, like instrumental factors (personal advantages, efficacy beliefs) and anger. The perceived rights violation can derive both from personal values (i.e. universalism) and external factors (i.e. a mobilization campaign). Furthermore, we demonstrated that it is possible to enhance the perceived violation of the right to water and anger through a specifically designed communication campaign. The final chapter summarizes the main findings and discusses the results, suggesting some innovative line of research for collective action literature.