Pattern-based segmentation of digital documents: model and implementation

This thesis proposes a new document model, according to which any document can be segmented in some independent components and transformed in a pattern-based projection, that only uses a very small set of objects and composition rules. The point is that such a normalized document expresses the same fundamental information of the original one, in a simple, clear and unambiguous way. The central part of my work consists of discussing that model, investigating how a digital document can be segmented, and how a segmented version can be used to implement advanced tools of conversion. I present seven patterns which are versatile enough to capture the most relevant documents’ structures, and whose minimality and rigour make that implementation possible. The abstract model is then instantiated into an actual markup language, called IML. IML is a general and extensible language, which basically adopts an XHTML syntax, able to capture a posteriori the only content of a digital document. It is compared with other languages and proposals, in order to clarify its role and objectives. Finally, I present some systems built upon these ideas. These applications are evaluated in terms of users’ advantages, workflow improvements and impact over the overall quality of the output. In particular, they cover heterogeneous content management processes: from web editing to collaboration (IsaWiki and WikiFactory), from e-learning (IsaLearning) to professional printing (IsaPress).

The assessment of change in rural landscape and the analysis of the driving forces. Proposal of a spatial model for the rural built environment

The presented study carried out an analysis on rural landscape changes. In particular the study focuses on the understanding of driving forces acting on the rural built environment using a statistical spatial model implemented through GIS techniques. It is well known that the study of landscape changes is essential for a conscious decision making in land planning. From a bibliography review results a general lack of studies dealing with the modeling of rural built environment and hence a theoretical modelling approach for such purpose is needed. The advancement in technology and modernity in building construction and agriculture have gradually changed the rural built environment. In addition, the phenomenon of urbanization of a determined the construction of new volumes that occurred beside abandoned or derelict rural buildings. Consequently there are two types of transformation dynamics affecting mainly the rural built environment that can be observed: the conversion of rural buildings and the increasing of building numbers. It is the specific aim of the presented study to propose a methodology for the development of a spatial model that allows the identification of driving forces that acted on the behaviours of the building allocation. In fact one of the most concerning dynamic nowadays is related to an irrational expansion of buildings sprawl across landscape. The proposed methodology is composed by some conceptual steps that cover different aspects related to the development of a spatial model: the selection of a response variable that better describe the phenomenon under study, the identification of possible driving forces, the sampling methodology concerning the collection of data, the most suitable algorithm to be adopted in relation to statistical theory and method used, the calibration process and evaluation of the model. A different combination of factors in various parts of the territory generated favourable or less favourable conditions for the building allocation and the existence of buildings represents the evidence of such optimum. Conversely the absence of buildings expresses a combination of agents which is not suitable for building allocation. Presence or absence of buildings can be adopted as indicators of such driving conditions, since they represent the expression of the action of driving forces in the land suitability sorting process. The existence of correlation between site selection and hypothetical driving forces, evaluated by means of modeling techniques, provides an evidence of which driving forces are involved in the allocation dynamic and an insight on their level of influence into the process. GIS software by means of spatial analysis tools allows to associate the concept of presence and absence with point futures generating a point process. Presence or absence of buildings at some site locations represent the expression of these driving factors interaction. In case of presences, points represent locations of real existing buildings, conversely absences represent locations were buildings are not existent and so they are generated by a stochastic mechanism. Possible driving forces are selected and the existence of a causal relationship with building allocations is assessed through a spatial model. The adoption of empirical statistical models provides a mechanism for the explanatory variable analysis and for the identification of key driving variables behind the site selection process for new building allocation. The model developed by following the methodology is applied to a case study to test the validity of the methodology. In particular the study area for the testing of the methodology is represented by the New District of Imola characterized by a prevailing agricultural production vocation and were transformation dynamic intensively occurred. The development of the model involved the identification of predictive variables (related to geomorphologic, socio-economic, structural and infrastructural systems of landscape) capable of representing the driving forces responsible for landscape changes.. The calibration of the model is carried out referring to spatial data regarding the periurban and rural area of the study area within the 1975-2005 time period by means of Generalised linear model. The resulting output from the model fit is continuous grid surface where cells assume values ranged from 0 to 1 of probability of building occurrences along the rural and periurban area of the study area. Hence the response variable assesses the changes in the rural built environment occurred in such time interval and is correlated to the selected explanatory variables by means of a generalized linear model using logistic regression. Comparing the probability map obtained from the model to the actual rural building distribution in 2005, the interpretation capability of the model can be evaluated. The proposed model can be also applied to the interpretation of trends which occurred in other study areas, and also referring to different time intervals, depending on the availability of data. The use of suitable data in terms of time, information, and spatial resolution and the costs related to data acquisition, pre-processing, and survey are among the most critical aspects of model implementation. Future in-depth studies can focus on using the proposed model to predict short/medium-range future scenarios for the rural built environment distribution in the study area. In order to predict future scenarios it is necessary to assume that the driving forces do not change and that their levels of influence within the model are not far from those assessed for the time interval used for the calibration.

Work and Family: a complex interplay. An Italian application of the DISC Model on health care workers

The present thesis investigates the issue of work-family conflict and facilitation in a sanitarian contest, using the DISC Model (De Jonge and Dormann, 2003, 2006). The general aim has been declined in two empirical studies reported in this dissertation chapters. Chapter 1 reporting the psychometric properties of the Demand-Induced Strain Compensation Questionnaire. Although the empirical evidence on the DISC Model has received a fair amount of attention in literature both for the theoretical principles and for the instrument developed to display them (DISQ; De Jonge, Dormann, Van Vegchel, Von Nordheim, Dollard, Cotton and Van den Tooren, 2007) there are no studies based solely on psychometric investigation of the instrument. In addition, no previous studies have ever used the DISC as a model or measurement instrument in an Italian context. Thus the first chapter of the present dissertation was based on psychometric investigation of the DISQ. Chapter 2 reporting a longitudinal study contribution. The purpose was to examine, using the DISC model, the relationship between emotional job characteristics, work-family interface and emotional exhaustion among a health care population. We started testing the Triple Match Principle of the DISC Model using solely the emotional dimension of the strain-stress process (i.e. emotional demands, emotional resources and emotional exhaustion). Then we investigated the mediator role played by w-f conflict and w-f facilitation in relation to emotional job characteristics and emotional exhaustion. Finally we compared the mediator model across workers involved in chronic illness home demands and workers who are not involved. Finally, a general conclusion, integrated and discussed the main findings of the studies reported in this dissertation.

Classical limit of the Nelson model

Since the development of quantum mechanics it has been natural to analyze the connection between classical and quantum mechanical descriptions of physical systems. In particular one should expect that in some sense when quantum mechanical effects becomes negligible the system will behave like it is dictated by classical mechanics. One famous relation between classical and quantum theory is due to Ehrenfest. This result was later developed and put on firm mathematical foundations by Hepp. He proved that matrix elements of bounded functions of quantum observables between suitable coherents states (that depend on Planck's constant h) converge to classical values evolving according to the expected classical equations when h goes to zero. His results were later generalized by Ginibre and Velo to bosonic systems with infinite degrees of freedom and scattering theory. In this thesis we study the classical limit of Nelson model, that describes non relativistic particles, whose evolution is dictated by Schrödinger equation, interacting with a scalar relativistic field, whose evolution is dictated by Klein-Gordon equation, by means of a Yukawa-type potential. The classical limit is a mean field and weak coupling limit. We proved that the transition amplitude of a creation or annihilation operator, between suitable coherent states, converges in the classical limit to the solution of the system of differential equations that describes the classical evolution of the theory. The quantum evolution operator converges to the evolution operator of fluctuations around the classical solution. Transition amplitudes of normal ordered products of creation and annihilation operators between coherent states converge to suitable products of the classical solutions. Transition amplitudes of normal ordered products of creation and annihilation operators between fixed particle states converge to an average of products of classical solutions, corresponding to different initial conditions.

Improvement of photon transport model by including coupled photon-electron transport and kernel refinement

The first part of this work deals with the inverse problem solution in the X-ray spectroscopy field. An original strategy to solve the inverse problem by using the maximum entropy principle is illustrated. It is built the code UMESTRAT, to apply the described strategy in a semiautomatic way. The application of UMESTRAT is shown with a computational example. The second part of this work deals with the improvement of the X-ray Boltzmann model, by studying two radiative interactions neglected in the current photon models. Firstly it is studied the characteristic line emission due to Compton ionization. It is developed a strategy that allows the evaluation of this contribution for the shells K, L and M of all elements with Z from 11 to 92. It is evaluated the single shell Compton/photoelectric ratio as a function of the primary photon energy. It is derived the energy values at which the Compton interaction becomes the prevailing process to produce ionization for the considered shells. Finally it is introduced a new kernel for the XRF from Compton ionization. In a second place it is characterized the bremsstrahlung radiative contribution due the secondary electrons. The bremsstrahlung radiation is characterized in terms of space, angle and energy, for all elements whit Z=1-92 in the energy range 1–150 keV by using the Monte Carlo code PENELOPE. It is demonstrated that bremsstrahlung radiative contribution can be well approximated with an isotropic point photon source. It is created a data library comprising the energetic distributions of bremsstrahlung. It is developed a new bremsstrahlung kernel which allows the introduction of this contribution in the modified Boltzmann equation. An example of application to the simulation of a synchrotron experiment is shown.

Development and characterisation of a neurogenic model of brain cancer

Primary glioblastoma (GB), the most common and aggressive adult brain tumour, is refractory to conventional therapies and characterised by poor prognosis. GB displays striking cellular heterogeneity, with a sub-population, called Glioblastoma Stem Cells (GSCs), intrinsically resistant to therapy, hence the high rate of recurrence. Alterations of the tumour suppressor gene PTEN are prevalent in primary GBM, resulting in the inhibition of the polarity protein Lgl1 due to aPKC hyperactivation. Dysregulation of this molecular axis is one of the mechanisms involved in GSC maintenance. After demonstrating that the PTEN/aPKC/Lgl axis is conserved in Drosophila, I deregulated it in different cells populations of the nervous system in order to individuate the cells at the root of neurogenic brain cancers. This analysis identified the type II neuroblasts (NBs) as the most sensitive to alterations of this molecular axis. Type II NBs are a sub-population of Drosophila stem cells displaying a lineage similar to that of the mammalian neural stem cells. Following aPKC activation in these stem cells, I obtained an adult brain cancer model in Drosophila that summarises many phenotypic traits of human brain tumours. Fly tumours are indeed characterised by accumulation of highly proliferative immature cells and keep growing in the adult leading the affected animals to premature death. With the aim to understand the role of cell polarity disruption in this tumorigenic process I carried out a molecular characterisation and transcriptome analysis of brain cancers from our fly model. In summary, the model I built and partially characterised in this thesis work may help deepen our knowledge on human brain cancers by investigating many different aspects of this complicate disease.

A conceptualisation of a governance model for biobanks in the digital society

Biobanks are key infrastructures in data-driven biomedical research. The counterpoint of this optimistic vision is the reality of biobank governance, which must address various ethical, legal and social issues, especially in terms of open consent, privacy and secondary uses which, if not sufficiently resolved, may undermine participants’ and society’s trust in biobanking. The effect of the digital paradigm on biomedical research has only accentuated these issues by adding new pressure for the data protection of biobank participants against the risks of covert discrimination, abuse of power against individuals and groups, and critical commercial uses. Moreover, the traditional research-ethics framework has been unable to keep pace with the transformative developments of the digital era, and has proven inadequate in protecting biobank participants and providing guidance for ethical practices. To this must be added the challenge of an increased tendency towards exploitation and the commercialisation of personal data in the field of biomedical research, which may undermine the altruistic and solidaristic values associated with biobank participation and risk losing alignment with societal interests in biobanking. My research critically analyses, from a bioethical perspective, the challenges and the goals of biobank governance in data-driven biomedical research in order to understand the conditions for the implementation of a governance model that can foster biomedical research and innovation, while ensuring adequate protection for biobank participants and an alignment of biobank procedures and policies with society’s interests and expectations. The main outcome is a conceptualisation of a socially-oriented and participatory model of biobanks by proposing a new ethical framework that relies on the principles of transparency, data protection and participation to tackle the key challenges of biobanks in the digital age and that is well-suited to foster these goals.

Statistical properties of Radio Halos and the re-acceleration model

Galaxy clusters occupy a special position in the cosmic hierarchy as they are the largest bound structures in the Universe. There is now general agreement on a hierarchical picture for the formation of cosmic structures, in which galaxy clusters are supposed to form by accretion of matter and merging between smaller units. During merger events, shocks are driven by the gravity of the dark matter in the diffuse barionic component, which is heated up to the observed temperature. Radio and hard-X ray observations have discovered non-thermal components mixed with the thermal Intra Cluster Medium (ICM) and this is of great importance as it calls for a “revision” of the physics of the ICM. The bulk of present information comes from the radio observations which discovered an increasing number of Mpcsized emissions from the ICM, Radio Halos (at the cluster center) and Radio Relics (at the cluster periphery). These sources are due to synchrotron emission from ultra relativistic electrons diffusing through µG turbulent magnetic fields. Radio Halos are the most spectacular evidence of non-thermal components in the ICM and understanding the origin and evolution of these sources represents one of the most challenging goal of the theory of the ICM. Cluster mergers are the most energetic events in the Universe and a fraction of the energy dissipated during these mergers could be channelled into the amplification of the magnetic fields and into the acceleration of high energy particles via shocks and turbulence driven by these mergers. Present observations of Radio Halos (and possibly of hard X-rays) can be best interpreted in terms of the reacceleration scenario in which MHD turbulence injected during these cluster mergers re-accelerates high energy particles in the ICM. The physics involved in this scenario is very complex and model details are difficult to test, however this model clearly predicts some simple properties of Radio Halos (and resulting IC emission in the hard X-ray band) which are almost independent of the details of the adopted physics. In particular in the re-acceleration scenario MHD turbulence is injected and dissipated during cluster mergers and thus Radio Halos (and also the resulting hard X-ray IC emission) should be transient phenomena (with a typical lifetime <» 1 Gyr) associated with dynamically disturbed clusters. The physics of the re-acceleration scenario should produce an unavoidable cut-off in the spectrum of the re-accelerated electrons, which is due to the balance between turbulent acceleration and radiative losses. The energy at which this cut-off occurs, and thus the maximum frequency at which synchrotron radiation is produced, depends essentially on the efficiency of the acceleration mechanism so that observations at high frequencies are expected to catch only the most efficient phenomena while, in principle, low frequency radio surveys may found these phenomena much common in the Universe. These basic properties should leave an important imprint in the statistical properties of Radio Halos (and of non-thermal phenomena in general) which, however, have not been addressed yet by present modellings. The main focus of this PhD thesis is to calculate, for the first time, the expected statistics of Radio Halos in the context of the re-acceleration scenario. In particular, we shall address the following main questions: • Is it possible to model “self-consistently” the evolution of these sources together with that of the parent clusters? • How the occurrence of Radio Halos is expected to change with cluster mass and to evolve with redshift? How the efficiency to catch Radio Halos in galaxy clusters changes with the observing radio frequency? • How many Radio Halos are expected to form in the Universe? At which redshift is expected the bulk of these sources? • Is it possible to reproduce in the re-acceleration scenario the observed occurrence and number of Radio Halos in the Universe and the observed correlations between thermal and non-thermal properties of galaxy clusters? • Is it possible to constrain the magnetic field intensity and profile in galaxy clusters and the energetic of turbulence in the ICM from the comparison between model expectations and observations? Several astrophysical ingredients are necessary to model the evolution and statistical properties of Radio Halos in the context of re-acceleration model and to address the points given above. For these reason we deserve some space in this PhD thesis to review the important aspects of the physics of the ICM which are of interest to catch our goals. In Chapt. 1 we discuss the physics of galaxy clusters, and in particular, the clusters formation process; in Chapt. 2 we review the main observational properties of non-thermal components in the ICM; and in Chapt. 3 we focus on the physics of magnetic field and of particle acceleration in galaxy clusters. As a relevant application, the theory of Alfv´enic particle acceleration is applied in Chapt. 4 where we report the most important results from calculations we have done in the framework of the re-acceleration scenario. In this Chapter we show that a fraction of the energy of fluid turbulence driven in the ICM by the cluster mergers can be channelled into the injection of Alfv´en waves at small scales and that these waves can efficiently re-accelerate particles and trigger Radio Halos and hard X-ray emission. The main part of this PhD work, the calculation of the statistical properties of Radio Halos and non-thermal phenomena as expected in the context of the re-acceleration model and their comparison with observations, is presented in Chapts.5, 6, 7 and 8. In Chapt.5 we present a first approach to semi-analytical calculations of statistical properties of giant Radio Halos. The main goal of this Chapter is to model cluster formation, the injection of turbulence in the ICM and the resulting particle acceleration process. We adopt the semi–analytic extended Press & Schechter (PS) theory to follow the formation of a large synthetic population of galaxy clusters and assume that during a merger a fraction of the PdV work done by the infalling subclusters in passing through the most massive one is injected in the form of magnetosonic waves. Then the processes of stochastic acceleration of the relativistic electrons by these waves and the properties of the ensuing synchrotron (Radio Halos) and inverse Compton (IC, hard X-ray) emission of merging clusters are computed under the assumption of a constant rms average magnetic field strength in emitting volume. The main finding of these calculations is that giant Radio Halos are naturally expected only in the more massive clusters, and that the expected fraction of clusters with Radio Halos is consistent with the observed one. In Chapt. 6 we extend the previous calculations by including a scaling of the magnetic field strength with cluster mass. The inclusion of this scaling allows us to derive the expected correlations between the synchrotron radio power of Radio Halos and the X-ray properties (T, LX) and mass of the hosting clusters. For the first time, we show that these correlations, calculated in the context of the re-acceleration model, are consistent with the observed ones for typical µG strengths of the average B intensity in massive clusters. The calculations presented in this Chapter allow us to derive the evolution of the probability to form Radio Halos as a function of the cluster mass and redshift. The most relevant finding presented in this Chapter is that the luminosity functions of giant Radio Halos at 1.4 GHz are expected to peak around a radio power » 1024 W/Hz and to flatten (or cut-off) at lower radio powers because of the decrease of the electron re-acceleration efficiency in smaller galaxy clusters. In Chapt. 6 we also derive the expected number counts of Radio Halos and compare them with available observations: we claim that » 100 Radio Halos in the Universe can be observed at 1.4 GHz with deep surveys, while more than 1000 Radio Halos are expected to be discovered in the next future by LOFAR at 150 MHz. This is the first (and so far unique) model expectation for the number counts of Radio Halos at lower frequency and allows to design future radio surveys. Based on the results of Chapt. 6, in Chapt.7 we present a work in progress on a “revision” of the occurrence of Radio Halos. We combine past results from the NVSS radio survey (z » 0.05 − 0.2) with our ongoing GMRT Radio Halos Pointed Observations of 50 X-ray luminous galaxy clusters (at z » 0.2−0.4) and discuss the possibility to test our model expectations with the number counts of Radio Halos at z » 0.05 − 0.4. The most relevant limitation in the calculations presented in Chapt. 5 and 6 is the assumption of an “averaged” size of Radio Halos independently of their radio luminosity and of the mass of the parent clusters. This assumption cannot be released in the context of the PS formalism used to describe the formation process of clusters, while a more detailed analysis of the physics of cluster mergers and of the injection process of turbulence in the ICM would require an approach based on numerical (possible MHD) simulations of a very large volume of the Universe which is however well beyond the aim of this PhD thesis. On the other hand, in Chapt.8 we report our discovery of novel correlations between the size (RH) of Radio Halos and their radio power and between RH and the cluster mass within the Radio Halo region, MH. In particular this last “geometrical” MH − RH correlation allows us to “observationally” overcome the limitation of the “average” size of Radio Halos. Thus in this Chapter, by making use of this “geometrical” correlation and of a simplified form of the re-acceleration model based on the results of Chapt. 5 and 6 we are able to discuss expected correlations between the synchrotron power and the thermal cluster quantities relative to the radio emitting region. This is a new powerful tool of investigation and we show that all the observed correlations (PR − RH, PR − MH, PR − T, PR − LX, . . . ) now become well understood in the context of the re-acceleration model. In addition, we find that observationally the size of Radio Halos scales non-linearly with the virial radius of the parent cluster, and this immediately means that the fraction of the cluster volume which is radio emitting increases with cluster mass and thus that the non-thermal component in clusters is not self-similar.

Applicability of Process Mining Techniques in Business Environments

This thesis analyses problems related to the applicability, in business environments, of Process Mining tools and techniques. The first contribution is a presentation of the state of the art of Process Mining and a characterization of companies, in terms of their "process awareness". The work continues identifying circumstance where problems can emerge: data preparation; actual mining; and results interpretation. Other problems are the configuration of parameters by not-expert users and computational complexity. We concentrate on two possible scenarios: "batch" and "on-line" Process Mining. Concerning the batch Process Mining, we first investigated the data preparation problem and we proposed a solution for the identification of the "case-ids" whenever this field is not explicitly indicated. After that, we concentrated on problems at mining time and we propose the generalization of a well-known control-flow discovery algorithm in order to exploit non instantaneous events. The usage of interval-based recording leads to an important improvement of performance. Later on, we report our work on the parameters configuration for not-expert users. We present two approaches to select the "best" parameters configuration: one is completely autonomous; the other requires human interaction to navigate a hierarchy of candidate models. Concerning the data interpretation and results evaluation, we propose two metrics: a model-to-model and a model-to-log. Finally, we present an automatic approach for the extension of a control-flow model with social information, in order to simplify the analysis of these perspectives. The second part of this thesis deals with control-flow discovery algorithms in on-line settings. We propose a formal definition of the problem, and two baseline approaches. The actual mining algorithms proposed are two: the first is the adaptation, to the control-flow discovery problem, of a frequency counting algorithm; the second constitutes a framework of models which can be used for different kinds of streams (stationary versus evolving).

Models and Algorihtm for the Optimization of Real-World Routing and Logistics Problems

Logistics involves planning, managing, and organizing the flows of goods from the point of origin to the point of destination in order to meet some requirements. Logistics and transportation aspects are very important and represent a relevant costs for producing and shipping companies, but also for public administration and private citizens. The optimization of resources and the improvement in the organization of operations is crucial for all branches of logistics, from the operation management to the transportation. As we will have the chance to see in this work, optimization techniques, models, and algorithms represent important methods to solve the always new and more complex problems arising in different segments of logistics. Many operation management and transportation problems are related to the optimization class of problems called Vehicle Routing Problems (VRPs). In this work, we consider several real-world deterministic and stochastic problems that are included in the wide class of the VRPs, and we solve them by means of exact and heuristic methods. We treat three classes of real-world routing and logistics problems. We deal with one of the most important tactical problems that arises in the managing of the bike sharing systems, that is the Bike sharing Rebalancing Problem (BRP). We propose models and algorithms for real-world earthwork optimization problems. We describe the 3DP process and we highlight several optimization issues in 3DP. Among those, we define the problem related to the tool path definition in the 3DP process, the 3D Routing Problem (3DRP), which is a generalization of the arc routing problem. We present an ILP model and several heuristic algorithms to solve the 3DRP.

Development of a patient-specific model for stroke risk assessment in atrial fibrillation patients

Atrial fibrillation is associated with a five-fold increase in the risk of cerebrovascular events,being responsible of 15-18% of all strokes.The morphological and functional remodelling of the left atrium caused by atrial fibrillation favours blood stasis and, consequently, stroke risk. In this context, several clinical studies suggest that stroke risk stratification could be improved by using haemodynamic information on the left atrium (LA) and the left atrial appendage (LAA). The goal of this study was to develop a personalized computational fluid-dynamics (CFD) model of the left atrium which could clarify the haemodynamic implications of atrial fibrillation on a patient specific basis. The developed CFD model was first applied to better understand the role of LAA in stroke risk. Infact, the interplay of the LAA geometric parameters such as LAA length, tortuosity, surface area and volume with the fluid-dynamics parameters and the effects of the LAA closure have not been investigated. Results demonstrated the capabilities of the CFD model to reproduce the real physiological behaviour of the blood flow dynamics inside the LA and the LAA. Finally, we determined that the fluid-dynamics parameters enhanced in this research project could be used as new quantitative indexes to describe the different types of AF and open new scenarios for the patient-specific stroke risk stratification.

Reduced-order modelling, circuit-level design and SOI fabrication of microelectromechanical resonators

This thesis deals with two important research aspects concerning radio frequency (RF) microresonators and switches. First, a new approach for compact modeling and simulation of these devices is presented. Then, a combined process flow for their simultaneous fabrication on a SOI substrate is proposed. Compact models for microresonators and switches are extracted by applying mathematical model order reduction (MOR) to the devices finite element (FE) description in ANSYS c° . The behaviour of these devices includes forms of nonlinearities. However, an approximation in the creation of the FE model is introduced, which enables the use of linear model order reduction. Microresonators are modeled with the introduction of transducer elements, which allow for direct coupling of the electrical and mechanical domain. The coupled system element matrices are linearized around an operating point and reduced. The resulting macromodel is valid for small signal analysis around the bias point, such as harmonic pre-stressed analysis. This is extremely useful for characterizing the frequency response of resonators. Compact modelling of switches preserves the nonlinearity of the device behaviour. Nonlinear reduced order models are obtained by reducing the number of nonlinearities in the system and handling them as input to the system. In this way, the system can be reduced using linear MOR techniques and nonlinearities are introduced directly in the reduced order model. The reduction of the number of system nonlinearities implies the approximation of all distributed forces in the model with lumped forces. Both for microresonators and switches, a procedure for matrices extraction has been developed so that reduced order models include the effects of electrical and mechanical pre-stress. The extraction process is fast and can be done automatically from ANSYS binary files. The method has been applied for the simulation of several devices both at devices and circuit level. Simulation results have been compared with full model simulations, and, when available, experimental data. Reduced order models have proven to conserve the accuracy of finite element method and to give a good description of the overall device behaviour, despite the introduced approximations. In addition, simulation is very fast, both at device and circuit level. A combined process-flow for the integrated fabrication of microresonators and switches has been defined. For this purpose, two processes that are optimized for the independent fabrication of these devices are merged. The major advantage of this process is the possibility to create on-chip circuit blocks that include both microresonators and switches. An application is, for example, aswitched filter bank for wireless transceiver. The process for microresonators fabrication is characterized by the use of silicon on insulator (SOI) wafers and on a deep reactive ion etching (DRIE) step for the creation of the vibrating structures in single-crystal silicon and the use of a sacrificial oxide layer for the definition of resonator to electrode distance. The fabrication of switches is characterized by the use of two different conductive layers for the definition of the actuation electrodes and by the use of a photoresist as a sacrificial layer for the creation of the suspended structure. Both processes have a gold electroplating step, for the creation of the resonators electrodes, transmission lines and suspended structures. The combined process flow is designed such that it conserves the basic properties of the original processes. Neither the performance of the resonators nor the performance of the switches results affected by the simultaneous fabrication. Moreover, common fabrication steps are shared, which allows for cheaper and faster fabrication.

Each one teaches one: characterizing active forms of proteins by single molecule force spectroscopy

This Ph.D. candidate thesis collects the research work I conducted under the supervision of Prof.Bruno Samor´ı in 2005,2006 and 2007. Some parts of this work included in the Part III have been begun by myself during my undergraduate thesis in the same laboratory and then completed during the initial part of my Ph.D. thesis: the whole results have been included for the sake of understanding and completeness. During my graduate studies I worked on two very different protein systems. The theorical trait d’union between these studies, at the biological level, is the acknowledgement that protein biophysical and structural studies must, in many cases, take into account the dynamical states of protein conformational equilibria and of local physico-chemical conditions where the system studied actually performs its function. This is introducted in the introductory part in Chapter 2. Two different examples of this are presented: the structural significance deriving from the action of mechanical forces in vivo (Chapter 3) and the complexity of conformational equilibria in intrinsically unstructured proteins and amyloid formation (Chapter 4). My experimental work investigated both these examples by using in both cases the single molecule force spectroscopy technique (described in Chapter 5 and Chapter 6). The work conducted on angiostatin focused on the characterization of the relationships between the mechanochemical properties and the mechanism of action of the angiostatin protein, and most importantly their intertwining with the further layer of complexity due to disulfide redox equilibria (Part III). These studies were accompanied concurrently by the elaboration of a theorical model for a novel signalling pathway that may be relevant in the extracellular space, detailed in Chapter 7.2. The work conducted on -synuclein (Part IV) instead brought a whole new twist to the single molecule force spectroscopy methodology, applying it as a structural technique to elucidate the conformational equilibria present in intrinsically unstructured proteins. These equilibria are of utmost interest from a biophysical point of view, but most importantly because of their direct relationship with amyloid aggregation and, consequently, the aetiology of relevant pathologies like Parkinson’s disease. The work characterized, for the first time, conformational equilibria in an intrinsically unstructured protein at the single molecule level and, again for the first time, identified a monomeric folded conformation that is correlated with conditions leading to -synuclein and, ultimately, Parkinson’s disease. Also, during the research work, I found myself in the need of a generalpurpose data analysis application for single molecule force spectroscopy data analysis that could solve some common logistic and data analysis problems that are common in this technique. I developed an application that addresses some of these problems, herein presented (Part V), and that aims to be publicly released soon.