Application of evolutionary algorithms and the boundary element method in the optimization of noise barrier profiles

[EN]This Ph.D. thesis presents a general, robust methodology that may cover any type of 2D acoustic optimization problem. A procedure involving the coupling of Boundary Elements (BE) and Evolutionary Algorithms is proposed for systematic geometric modifications of road barriers that lead to designs with ever-increasing screening performance. Numerical simulations involving single- and multi-objective optimizations of noise barriers of varied nature are included in this document. results disclosed justify the implementation of this methodology by leading to optimal solutions of previously defined topologies that, in general, greatly outperform the acoustic efficiency of classical, widely used barrier designs normally erected near roads.

Genetic variability and structuring of deep Corallium rubrum (Linnaeus, 1758) populations

ABSTRACT Given the decline of shallow-water red coral populations resulting from over-exploitation and mass mortality events, deeper populations below 50 metres depth (mesophotic populations) are currently the most harvested; unfortunately, very little is known about their biology and ecology. The persistence of these populations is tightly linked to their adult density, reproductive success, larval dispersal and recruitment. Moreover, for their conservation, it is paramount understand processes such as connectivity within and among populations. Here, for the first time, genetic variability and structuring of Corallium rubrum populations collected in the Tyrrhenian Sea ranging from 58 to 118 metres were analyzed using ten microsatellite loci and two mitochondrial markers (mtMSH and MtC). The aims of the work were 1) to examine patterns of genetic diversity within each geographic area (Elba, Ischia and Praiano) and 2) to define population structuring at different spatial scales (from tens of metres to hundreds of kilometres). Based on microsatellite data set, significant deviations from Hardy-Weinberg equilibrium due to elevated heterozygote deficiencies were detected in all samples, probably related to the presence of null alleles and/or inbreeding, as was previously observed in shallow-water populations. Moreover, significant levels of genetic differentiation were observed at all spatial scale, suggesting a recent isolation of populations. Biological factors which act at small spatial scale and/or abiotic factors at larger scale (e.g. summer gyres or absence of suitable substrata for settlement) could determine this genetic isolation. Using mitochondrial markers, significant differences were found only at wider scale (between Tuscany and Campania regions). These results could be related to the different mutation rate of the molecular makers or to the occurrence of some historical links within regions. A significant isolation by distance pattern was then observed using both data sets, confirming the restricted larval dispersal capability of the species. Therefore, the hypothesis that deeper populations may act as a source of larvae helping recovery of threatened shallow-water populations is not proved. Conservation strategies have to take into account these results, and management plans of deep and currently harvested populations have to be defined at a regional or sub regional level, similarly to shallow-water populations. Nevertheless, further investigations should be needed to understand better the genetic structuring of this species in the mesophotic zone, e.g. extending studies to other Mediterranean deep-water populations.

Algorithms and Models For Combinatorial Optimization Problems

In this thesis we present some combinatorial optimization problems, suggest models and algorithms for their effective solution. For each problem,we give its description, followed by a short literature review, provide methods to solve it and, finally, present computational results and comparisons with previous works to show the effectiveness of the proposed approaches. The considered problems are: the Generalized Traveling Salesman Problem (GTSP), the Bin Packing Problem with Conflicts(BPPC) and the Fair Layout Problem (FLOP).

New path integral simulation algorithms and their application to creep in the quantum sine-Gordon chain

A path integral simulation algorithm which includes a higher-order Trotter approximation (HOA)is analyzed and compared to an approach which includes the correct quantum mechanical pair interaction (effective Propagator (EPr)). It is found that the HOA algorithmconverges to the quantum limit with increasing Trotter number P as P^{-4}, while the EPr algorithm converges as P^{-2}.The convergence rate of the HOA algorithm is analyzed for various physical systemssuch as a harmonic chain,a particle in a double-well potential, gaseous argon, gaseous helium and crystalline argon. A new expression for the estimator for the pair correlation function in the HOA algorithm is derived. A new path integral algorithm, the hybrid algorithm, is developed.It combines an exact treatment of the quadratic part of the Hamiltonian and thehigher-order Trotter expansion techniques.For the discrete quantum sine-Gordon chain (DQSGC), it is shown that this algorithm works more efficiently than all other improved path integral algorithms discussed in this work. The new simulation techniques developed in this work allow the analysis of theDQSGC and disordered model systems in the highly quantum mechanical regime using path integral molecular dynamics (PIMD)and adiabatic centroid path integral molecular dynamics (ACPIMD).The ground state phonon dispersion relation is calculated for the DQSGC by the ACPIMD method.It is found that the excitation gap at zero wave vector is reduced by quantum fluctuations. Two different phases exist: One phase with a finite excitation gap at zero wave vector, and a gapless phase where the excitation gap vanishes.The reaction of the DQSGC to an external driving force is analyzed at T=0.In the gapless phase the system creeps if a small force is applied, and in the phase with a gap the system is pinned. At a critical force, the systems undergo a depinning transition in both phases and flow is induced. The analysis of the DQSGC is extended to models with disordered substrate potentials. Three different cases are analyzed: Disordered substrate potentials with roughness exponent H=0, H=1/2,and a model with disordered bond length. For all models, the ground state phonon dispersion relation is calculated.

Influence of genetic variants and post transcriptional factors on imatinib transporters as determinants of the pharmacological response

Introduction – Although imatinib (IM) is a recognized gold standard in chronic myeloid leukemia (CML) therapy, resistance has emerged in a significant proportion of patients. Aim – The aim of this study was: (1) to investigate the role of genetic variants in genes encoding for IM transporters, as candidate of IM responsiveness and (2) to test the influence of miRNAs on IM response, focusing on efflux transporters. Methods – As a first step, a panel of polymorphisms (SNPs) was genotyped in a subgroup population of 189 patients enrolled in the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial. The association with cytogenetic response and molecular response (MR) was assessed for each SNP. As a second step, an in vitro IM-resistant model (K-562 CML cell line) was established. miRNAs profiles were analyzed using Taqman arrays and in silico search was performed for miRNAs deregulated after IM treatment. mRNA and protein expression were quantified using TaqMan realtime PCR and Western blotting, respectively. Results – (1) Among Caucasian patients, ABCB1 rs60023214 significantly correlated with complete MR (P = 0.005). Concerning SNPs combination in IM uptake transporters, the associations with treatment outcomes were statistically significant for both major and complete MR (P = 0.005 and P = 0.01, respectively). (2) ABCB1 protein was not expressed under any conditions of treatment, differently from ABCG2. Two deregulated miRNAs, namely miR-212 and miR-328, were identified to be inversely correlated with ABCG2 (r2= 0.57; p=0.03 and r2=0.47; p=0.06, respectively). Experiments of loss and gain of function confirmed the functional influence of these miRNAs on ABCG2. Conclusion – The multiple candidate gene approach identified single and combination of SNPs that can be proposed as predictor of IM response. The in vitro study suggested that IM resistance could be mediated by miRNA-dependent mechanism. Further studies are needed to validate these preliminary findings.

Genetic structure and connectivity between populations of two common Mediterranean sessile invertebrates

Population genetic and phylogeography of two common mediterranean species were studied in 10 localities located on the coasts of Toscana, Puglia and Calabria. The aim of the study was to verify the extent of genetic breaks, in areas recognized as boundaries between Mediterranean biogeographic sectors. From about 100 sequences obtained from the mitochondrial Cytochrome Oxidase subunit I (COI) gene of Halocynthia papillosa and Hexaplex trunculus genetic diversity, genetic structure at small and large distances and demographic history of both specieswere analyzed. No evidences of genetic breaks were found for the two species in Toscana and Puglia. The genetic structure of H. trunculus evidences the extent of a barrier to gene flow localized in Calabria, which could be represented by the Siculo-Tunisian Strait and the Strait of Messina. The observed patterns showed similar level of gene flow at small distances in both species, although the two species have different larval ecology. These results suggest that other factors, such as currents, local dynamics and seasonal temperatures, influence the connectivity along the Italian peninsula. The geographic distribution of the haplotypes shows that H. papillosacould represent a single genetic pool in expansion, whereas H. trunculus has two distinct genetic pools in expansion. The demographic pattern of the two species suggests that Pleistocene sea level oscillations, in particular of the LGM, may have played a key role in shaping genetic structure of the two species. This knowledge provides basic information, useful for the definition of management plans, or for the design of a network of marine protected areas along the Italian peninsula.

Metaheuristics for Search Problems in Genomics - New Algorithms and Applications

In this thesis we made the first steps towards the systematic application of a methodology for automatically building formal models of complex biological systems. Such a methodology could be useful also to design artificial systems possessing desirable properties such as robustness and evolvability. The approach we follow in this thesis is to manipulate formal models by means of adaptive search methods called metaheuristics. In the first part of the thesis we develop state-of-the-art hybrid metaheuristic algorithms to tackle two important problems in genomics, namely, the Haplotype Inference by parsimony and the Founder Sequence Reconstruction Problem. We compare our algorithms with other effective techniques in the literature, we show strength and limitations of our approaches to various problem formulations and, finally, we propose further enhancements that could possibly improve the performance of our algorithms and widen their applicability. In the second part, we concentrate on Boolean network (BN) models of gene regulatory networks (GRNs). We detail our automatic design methodology and apply it to four use cases which correspond to different design criteria and address some limitations of GRN modeling by BNs. Finally, we tackle the Density Classification Problem with the aim of showing the learning capabilities of BNs. Experimental evaluation of this methodology shows its efficacy in producing network that meet our design criteria. Our results, coherently to what has been found in other works, also suggest that networks manipulated by a search process exhibit a mixture of characteristics typical of different dynamical regimes.

Genetic engineering and preclinical evaluation of oncolytic herpes simplex viruses retargeted to cancer-specific receptors

Oncolytic virotherapy exploits the ability of viruses to infect and kill cells. It is suitable as treatment for tumors that are not accessible by surgery and/or respond poorly to the current therapeutic approach. HSV is a promising oncolytic agent. It has a large genome size able to accommodate large transgenes and some attenuated oncolytic HSVs (oHSV) are already in clinical trials phase I and II. The aim of this thesis was the generation of HSV-1 retargeted to tumor-specific receptors and detargeted from HSV natural receptors, HVEM and Nectin-1. The retargeting was achieved by inserting a specific single chain antibody (scFv) for the tumor receptor selected inside the HSV glycoprotein gD. In this research three tumor receptors were considered: epidermal growth factor receptor 2 (HER2) overexpressed in 25-30% of breast and ovarian cancers and gliomas, prostate specific membrane antigen (PSMA) expressed in prostate carcinomas and in neovascolature of solid tumors; and epidermal growth factor receptor variant III (EGFRvIII). In vivo studies on HER2 retargeted viruses R-LM113 and R-LM249 have demonstrated their high safety profile. For R-LM249 the antitumor efficacy has been highlighted by target-specific inhibition of the growth of human tumors in models of HER2-positive breast and ovarian cancer in nude mice. In a murine model of HER2-positive glioma in nude mice, R-LM113 was able to significantly increase the survival time of treated mice compared to control. Up to now, PSMA and EGFRvIII viruses (R-LM593 and R-LM613) are only characterized in vitro, confirming the specific retargeting to selected targets. This strategy has proved to be generally applicable to a broad spectrum of receptors for which a single chain antibody is available.

Genetic characterisation and global comparison of ancient Mediterranean Great White Sharks population (Carcharodon carcharias, L.1758)

This study poses as its objective the genetic characterization of the ancient population of the Great White shark, Carcharodon carcharias, L.1758, present in the Mediterranean Sea. Using historical evidence, for the most part buccal arches but also whole, stuffed examples from various national museums, research institutes and private collections, a dataset of 18 examples coming from the Mediterranean Sea has been created, in order to increase the informations regarding this species in the Mediterranean. The importance of the Mediterranean provenance derives from the fact that a genetic characterization of this species' population does not exist, and this creates gaps in the knowledge of this species in the Mediterranean. The genetic characterization of the individuals will initially take place by the extraction of the ancient DNA and the analysis of the variations in the sequence markers of the mitochondrial DNA. This approach has allowed the genetic comparison between ancient populations of the Mediterranean and contemporary populations of the same geographical area. In addition, the genetic characterization of the population of white sharks of the Mediterranean, has allowed a genetic comparison with populations from global "hot spots", using published sequences in online databases (NCBI, GenBank). Analyzing the variability of the dataset, both in terms space and time, I assessed the evolutionary relationships of the Mediterranean population of Great Whites with the global populations (Australia/New Zealand, South Africa, Pacific USA, West Atlantic), and the temporal trend of the Mediterranean population variability. This method based on the sequencing of two portions of mitochondrial DNA genes, markers showed us how the population of Great White Sharks in the Mediterranean, is genetically more similar to the populations of the Australia Pacific ocean, American Pacific Ocean, rather than the population of South Africa, and showing also how the population of South Africa is abnormally distant from all other clusters. Interestingly, these results are inconsistent with the results from tagging of this species. In addition, there is evidence of differences between the ancient population of the Mediterranean with the modern one. This differentiation between the ancient and modern population of white shark can be the result of events impacting on this species occurred over the last two centuries.

Genetic variability and differentiation in the Mediterranean endemic starry ray Raja asterias (Delaroche, 1809)

The present study deal with the population structure and connectivity of the Mediterranean endemic starry ray Raja asterias (Delaroche, 1809) in the Western and Eastern Mediterranean basin. A panel of eight microsatellite loci which cross-amplify in Rajidae (El Nagar, 2010) was used to assess population connectivity and structure. Those aims were investigated by analyzing the genetic variation of 9 population sample for a total of 185 individuals collected during past scientific surveys (MEDITS, GRUND), commercial trawling and also directly at fish markets. The purpose of this thesis is to estimate the genetic divergence occurring between the Mediterranean populations and, in particular, to assess the presence of any barrier (geographic, hydrogeological and biological) to gene flow for this species. Different statistical approaches were performed to reach this aim evaluating both the genetic diversity (nucleotide diversity, allelic richness, observed and expected heterozygosity and Hardy-Weinberg equilibrium test) and the population differentiation patterns (pairwise Fst estimated and population structure analysis). The results obtained from the analysis of the microsatellite dataset suggest a geographic and genetic separation between the starry ray populations of the Mediterranean basin into three or four distinct groups: Western and Eastern Mediterranean basins and Sicilian coast always clustering as an independent group and Algeria which could be or not considered another separate group. The data were discussed from both an evolutionary and a conservation point of view and in relation to previous results obtained by the analysis of mitochondrial marker. A comparison with other Mediterranean demersal skate species was performed in order to better contextualise our results. Finally, our results could offer useful information to protect vulnerable species as R. asterias and developing effective conservation plans in the Mediterranean.

Permutation classes, sorting algorithms, and lattice paths

A permutation is said to avoid a pattern if it does not contain any subsequence which is order-isomorphic to it. Donald Knuth, in the first volume of his celebrated book "The art of Computer Programming", observed that the permutations that can be computed (or, equivalently, sorted) by some particular data structures can be characterized in terms of pattern avoidance. In more recent years, the topic was reopened several times, while often in terms of sortable permutations rather than computable ones. The idea to sort permutations by using one of Knuth’s devices suggests to look for a deterministic procedure that decides, in linear time, if there exists a sequence of operations which is able to convert a given permutation into the identical one. In this thesis we show that, for the stack and the restricted deques, there exists an unique way to implement such a procedure. Moreover, we use these sorting procedures to create new sorting algorithms, and we prove some unexpected commutation properties between these procedures and the base step of bubblesort. We also show that the permutations that can be sorted by a combination of the base steps of bubblesort and its dual can be expressed, once again, in terms of pattern avoidance. In the final chapter we give an alternative proof of some enumerative results, in particular for the classes of permutations that can be sorted by the two restricted deques. It is well-known that the permutations that can be sorted through a restricted deque are counted by the Schrӧder numbers. In the thesis, we show how the deterministic sorting procedures yield a bijection between sortable permutations and Schrӧder paths.

Brain-Computer Interfaces for augmented communication: Asynchronous and adaptive algorithms and evaluation with end users

This thesis aimed at addressing some of the issues that, at the state of the art, avoid the P300-based brain computer interface (BCI) systems to move from research laboratories to end users’ home. An innovative asynchronous classifier has been defined and validated. It relies on the introduction of a set of thresholds in the classifier, and such thresholds have been assessed considering the distributions of score values relating to target, non-target stimuli and epochs of voluntary no-control. With the asynchronous classifier, a P300-based BCI system can adapt its speed to the current state of the user and can automatically suspend the control when the user diverts his attention from the stimulation interface. Since EEG signals are non-stationary and show inherent variability, in order to make long-term use of BCI possible, it is important to track changes in ongoing EEG activity and to adapt BCI model parameters accordingly. To this aim, the asynchronous classifier has been subsequently improved by introducing a self-calibration algorithm for the continuous and unsupervised recalibration of the subjective control parameters. Finally an index for the online monitoring of the EEG quality has been defined and validated in order to detect potential problems and system failures. This thesis ends with the description of a translational work involving end users (people with amyotrophic lateral sclerosis-ALS). Focusing on the concepts of the user centered design approach, the phases relating to the design, the development and the validation of an innovative assistive device have been described. The proposed assistive technology (AT) has been specifically designed to meet the needs of people with ALS during the different phases of the disease (i.e. the degree of motor abilities impairment). Indeed, the AT can be accessed with several input devices either conventional (mouse, touchscreen) or alterative (switches, headtracker) up to a P300-based BCI.

Towards the 3D attenuation imaging of active volcanoes: methods and tests on real and simulated data

The purpose of my PhD thesis has been to face the issue of retrieving a three dimensional attenuation model in volcanic areas. To this purpose, I first elaborated a robust strategy for the analysis of seismic data. This was done by performing several synthetic tests to assess the applicability of spectral ratio method to our purposes. The results of the tests allowed us to conclude that: 1) spectral ratio method gives reliable differential attenuation (dt*) measurements in smooth velocity models; 2) short signal time window has to be chosen to perform spectral analysis; 3) the frequency range over which to compute spectral ratios greatly affects dt* measurements. Furthermore, a refined approach for the application of spectral ratio method has been developed and tested. Through this procedure, the effects caused by heterogeneities of propagation medium on the seismic signals may be removed. The tested data analysis technique was applied to the real active seismic SERAPIS database. It provided a dataset of dt* measurements which was used to obtain a three dimensional attenuation model of the shallowest part of Campi Flegrei caldera. Then, a linearized, iterative, damped attenuation tomography technique has been tested and applied to the selected dataset. The tomography, with a resolution of 0.5 km in the horizontal directions and 0.25 km in the vertical direction, allowed to image important features in the off-shore part of Campi Flegrei caldera. High QP bodies are immersed in a high attenuation body (Qp=30). The latter is well correlated with low Vp and high Vp/Vs values and it is interpreted as a saturated marine and volcanic sediments layer. High Qp anomalies, instead, are interpreted as the effects either of cooled lava bodies or of a CO2 reservoir. A pseudo-circular high Qp anomaly was detected and interpreted as the buried rim of NYT caldera.